FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Gaddam, S Rizvi, M Nimmagadda, KC Gala, B Nagrani, T Ghavami, F McCord, D Lafferty, J AF Gaddam, Sainath Rizvi, Muniba Nimmagadda, Krishna Chaitanya Gala, Bhavesh Nagrani, Tarun Ghavami, Foad McCord, Donald Lafferty, James TI Proximal atherosclerotic lesion as a cause of very late stent thrombosis SO MEDICAL HYPOTHESES LA English DT Article ID SIROLIMUS-ELUTING STENT; BARE-METAL STENTS; CORONARY-ARTERY; IMPLANTATION AB Very late stent thrombosis is defined as in-stent thrombosis occurring after 1 year of an intra-coronary artery stent placement. Drug eluting stents have lately been criticized for increased reports of very late stent thrombosis. The exact cause of these very late stent thromboses is not clearly understood. Virchow's triad describes the three main factors of thrombus formation to be stasis of blood flow, endothelial injury and hypercoagulability. Based on Virchow's triad, we propose the cause of very late stent thrombosis to be formation of a de novo atherosclerotic lesion in the proximal segment of a stented artery. The de novo atherosclerotic lesion narrows the vessel lumen and causes stasis of blood flow in the distal stent. The de novo lesion can also cause myocardial ischemia creating a prothrombotic environment in the stented region. Stasis of blood flow and prothrombotic environment in the stented region can lead to the formation of very late stent thrombosis. Since atherosclerosis is a dynamic aging process in humans, we propose de novo proximal lesions in the coronary arteries can predispose to very late stent thrombosis. Published by Elsevier Ltd. C1 [Gaddam, Sainath; Rizvi, Muniba] Staten Isl Univ Hosp, Dept Internal Med, Staten Isl, NY 10305 USA. [Gala, Bhavesh; Nagrani, Tarun; Ghavami, Foad; McCord, Donald; Lafferty, James] Staten Isl Univ Hosp, Div Cardiol, Staten Isl, NY 10305 USA. [Nimmagadda, Krishna Chaitanya] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Gaddam, S (reprint author), Staten Isl Univ Hosp, Dept Internal Med, 475 Seaview Ave, Staten Isl, NY 10305 USA. EM gaddamsainath@gmail.com NR 16 TC 3 Z9 3 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0306-9877 J9 MED HYPOTHESES JI Med. Hypotheses PD APR PY 2011 VL 76 IS 4 BP 500 EP 502 DI 10.1016/j.mehy.2010.11.036 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 742FK UT WOS:000288926500012 PM 21185657 ER PT J AU Han, B Xu, XG Chen, GTY AF Han, Bin Xu, X. George Chen, George T. Y. TI Proton radiography and fluoroscopy of lung tumors: A Monte Carlo study using patient-specific 4DCT phantoms SO MEDICAL PHYSICS LA English DT Article ID COMPUTED-TOMOGRAPHY; RANGE VERIFICATION; RADIATION-THERAPY; ANIMAL PATIENT; RECONSTRUCTION; PARAMETERS; EXPERIENCE; PARTICLES; BEAMS AB Purpose: Monte Carlo methods are used to simulate and optimize a time-resolved proton range telescope (TRRT) in localization of intrafractional and interfractional motions of lung tumor and in quantification of proton range variations. Methods: The Monte Carlo N-Particle eXtended (MCNPX) code with a particle tracking feature was employed to evaluate the TRRT performance, especially in visualizing and quantifying proton range variations during respiration. Protons of 230 MeV were tracked one by one as they pass through position detectors, patient 4DCT phantom, and finally scintillator detectors that measured residual ranges. The energy response of the scintillator telescope was investigated. Mass density and elemental composition of tissues were defined for 4DCT data. Results: Proton water equivalent length (WEL) was deduced by a reconstruction algorithm that incorporates linear proton track and lateral spatial discrimination to improve the image quality. 4DCT data for three patients were used to visualize and measure tumor motion and WEL variations. The tumor trajectories extracted from the WEL map were found to be within similar to 1 mm agreement with direct 4DCT measurement. Quantitative WEL variation studies showed that the proton radiograph is a good representation of WEL changes from entrance to distal of the target. Conclusions: MCNPX simulation results showed that TRRT can accurately track the motion of the tumor and detect the WEL variations. Image quality was optimized by choosing proton energy, testing parameters of image reconstruction algorithm, and comparing to ground truth 4DCT. The future study will demonstrate the feasibility of using the time resolved proton radiography as an imaging tool for proton treatments of lung tumors. (C) 2011 American Association of Physicists in Medicine. [DOI: 10.1118/1.3555039] C1 [Han, Bin; Xu, X. George] Rensselaer Polytech Inst, Troy, NY 12180 USA. [Chen, George T. Y.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Xu, XG (reprint author), Rensselaer Polytech Inst, Troy, NY 12180 USA. EM hanbinthu@gmail.com; xug2@rpi.edu OI Han, Bin/0000-0001-8179-5762 FU NIH NCI [CA02139]; Rensselaer Polytechnic Institute FX Dr. G. T. Y. Chen was supported, in part, by NIH NCI Grant No. CA02139 Proton Radiotherapy Research and Mr. B. Han was supported by a Van Auken Fellowship from Rensselaer Polytechnic Institute. Dr. X. G. Xu performed this work during his sabbatical leave at MGH. Dr. F. Sauli provided the detail detector design and experimental data. The authors would like to acknowledge information and technical assistance provided by Dr. S. Mori, Dr. H. Paganetti, Dr. G. Sharp, Dr. B. Bednarz, and Mr. A. Ding and the patient data from IRB approved study at MDAH courtesy of Dr. L. Dong. In addition, the authors would like to thank the reviewers for their helpful comments, which have improved the presentation and quality of this paper. NR 38 TC 7 Z9 8 U1 2 U2 6 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD APR PY 2011 VL 38 IS 4 BP 1903 EP 1911 DI 10.1118/1.3555039 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 745GI UT WOS:000289153500017 PM 21626923 ER PT J AU Fuchs, BB Bishop, LR Kovacs, JA Mylonakis, E AF Fuchs, Beth Burgwyn Bishop, Lisa R. Kovacs, Joseph A. Mylonakis, Eleftherios TI Galleria mellonella are Resistant to Pneumocystis murina Infection SO MYCOPATHOLOGIA LA English DT Article DE Galleria mellonella; Infection model; Pneumocystis murina ID IMMUNE-RESPONSE; CARINII; VIRULENCE; LARVAE; MODEL; MICE; PATHOGENICITY; EXPRESSION AB Studying Pneumocystis has proven to be a challenge from the perspective of propagating a significant amount of the pathogen in a facile manner. The study of several fungal pathogens has been aided by the use of invertebrate model hosts. Our efforts to infect the invertebrate larvae Galleria mellonella with Pneumocystis proved futile since P. murina neither caused disease nor was able to proliferate within G. mellonella. It did, however, show that the pathogen could be rapidly cleared from the host. C1 [Fuchs, Beth Burgwyn; Mylonakis, Eleftherios] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bishop, Lisa R.; Kovacs, Joseph A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Fuchs, BB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Gray Jackson 504,55 Fruit St, Boston, MA 02114 USA. EM hfuchs@partners.org; emylonakis@partners.org FU Intramural NIH HHS [ZIA CL000146-19] NR 18 TC 6 Z9 6 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0301-486X J9 MYCOPATHOLOGIA JI Mycopathologia PD APR PY 2011 VL 171 IS 4 BP 273 EP 277 DI 10.1007/s11046-010-9368-4 PG 5 WC Mycology SC Mycology GA 738TJ UT WOS:000288664900006 PM 20922567 ER PT J AU Schunkert, H Konig, IR Kathiresan, S Reilly, MP Assimes, TL Holm, H Preuss, M Stewart, AFR Barbalic, M Gieger, C Absher, D Aherrahrou, Z Allayee, H Altshuler, D Anand, SS Andersen, K Anderson, JL Ardissino, D Ball, SG Balmforth, AJ Barnes, TA Becker, DM Becker, LC Berger, K Bis, JC Boekholdt, SM Boerwinkle, E Braund, PS Brown, MJ Burnett, MS Buysschaert, I Carlquist, JF Chen, L Cichon, S Codd, V Davies, RW Dedoussis, G Dehghan, A Demissie, S Devaney, JM Diemert, P Do, R Doering, A Eifert, S El Mokhtari, NE Ellis, SG Elosua, R Engert, JC Epstein, SE de Faire, U Fischer, M Folsom, AR Freyer, J Gigante, B Girelli, D Gretarsdottir, S Gudnason, V Gulcher, JR Halperin, E Hammond, N Hazen, SL Hofman, A Horne, BD Illig, T Iribarren, C Jones, GT Jukema, JW Kaiser, MA Kaplan, LM Kastelein, JJP Khaw, KT Knowles, JW Kolovou, G Kong, A Laaksonen, R Lambrechts, D Leander, K Lettre, G Li, MY Lieb, W Loley, C Lotery, AJ Mannucci, PM Maouche, S Martinelli, N McKeown, PP Meisinger, C Meitinger, T Melander, O Merlini, PA Mooser, V Morgan, T Muhleisen, TW Muhlestein, JB Munzel, T Musunuru, K Nahrstaedt, J Nelson, CP Nothen, MM Olivieri, O Patel, RS Patterson, CC Peters, A Peyvandi, F Qu, L Quyyumi, AA Rader, DJ Rallidis, LS Rice, C Rosendaal, FR Rubin, D Salomaa, V Sampietro, ML Sandhu, MS Schadt, E Schafer, A Schillert, A Schreiber, S Schrezenmeir, J Schwartz, SM Siscovick, DS Sivananthan, M Sivapalaratnam, S Smith, A Smith, TB Snoep, JD Soranzo, N Spertus, JA Stark, K Stirrups, K Stoll, M Tang, WHW Tennstedt, S Thorgeirsson, G Thorleifsson, G Tomaszewski, M Uitterlinden, AG van Rij, AM Voight, BF Wareham, NJ Wells, GA Wichmann, HE Wild, PS Willenborg, C Witteman, JCM Wright, BJ Ye, S Zeller, T Ziegler, A Cambien, F Goodall, AH Cupples, LA Quertermous, T Marz, W Hengstenberg, C Blankenberg, S Ouwehand, WH Hall, AS Deloukas, P Thompson, JR Stefansson, K Roberts, R Thorsteinsdottir, U O'Donnell, CJ McPherson, R Erdmann, J Samani, NJ AF Schunkert, Heribert Koenig, Inke R. Kathiresan, Sekar Reilly, Muredach P. Assimes, Themistocles L. Holm, Hilma Preuss, Michael Stewart, Alexandre F. R. Barbalic, Maja Gieger, Christian Absher, Devin Aherrahrou, Zouhair Allayee, Hooman Altshuler, David Anand, Sonia S. Andersen, Karl Anderson, Jeffrey L. Ardissino, Diego Ball, Stephen G. Balmforth, Anthony J. Barnes, Timothy A. Becker, Diane M. Becker, Lewis C. Berger, Klaus Bis, Joshua C. Boekholdt, S. Matthijs Boerwinkle, Eric Braund, Peter S. Brown, Morris J. Burnett, Mary Susan Buysschaert, Ian Carlquist, John F. Chen, Li Cichon, Sven Codd, Veryan Davies, Robert W. Dedoussis, George Dehghan, Abbas Demissie, Serkalem Devaney, Joseph M. Diemert, Patrick Do, Ron Doering, Angela Eifert, Sandra El Mokhtari, Nour Eddine Ellis, Stephen G. Elosua, Roberto Engert, James C. Epstein, Stephen E. de Faire, Ulf Fischer, Marcus Folsom, Aaron R. Freyer, Jennifer Gigante, Bruna Girelli, Domenico Gretarsdottir, Solveig Gudnason, Vilmundur Gulcher, Jeffrey R. Halperin, Eran Hammond, Naomi Hazen, Stanley L. Hofman, Albert Horne, Benjamin D. Illig, Thomas Iribarren, Carlos Jones, Gregory T. Jukema, J. Wouter Kaiser, Michael A. Kaplan, Lee M. Kastelein, John J. P. Khaw, Kay-Tee Knowles, Joshua W. Kolovou, Genovefa Kong, Augustine Laaksonen, Reijo Lambrechts, Diether Leander, Karin Lettre, Guillaume Li, Mingyao Lieb, Wolfgang Loley, Christina Lotery, Andrew J. Mannucci, Pier M. Maouche, Seraya Martinelli, Nicola McKeown, Pascal P. Meisinger, Christa Meitinger, Thomas Melander, Olle Merlini, Pier Angelica Mooser, Vincent Morgan, Thomas Muehleisen, Thomas W. Muhlestein, Joseph B. Muenzel, Thomas Musunuru, Kiran nahrstaedt, Janja Nelson, Christopher P. Noethen, Markus M. Olivieri, Oliviero Patel, Riyaz S. Patterson, Chris C. Peters, Annette Peyvandi, Flora Qu, Liming Quyyumi, Arshed A. Rader, Daniel J. Rallidis, Loukianos S. Rice, Catherine Rosendaal, Frits R. Rubin, Diana Salomaa, Veikko Sampietro, M. Lourdes Sandhu, Manj S. Schadt, Eric Schaefer, Arne Schillert, Arne Schreiber, Stefan Schrezenmeir, Juergen Schwartz, Stephen M. Siscovick, David S. Sivananthan, Mohan Sivapalaratnam, Suthesh Smith, Albert Smith, Tamara B. Snoep, Jaapjan D. Soranzo, Nicole Spertus, John A. Stark, Klaus Stirrups, Kathy Stoll, Monika Tang, W. H. Wilson Tennstedt, Stephanie Thorgeirsson, Gudmundur Thorleifsson, Gudmar Tomaszewski, Maciej Uitterlinden, Andre G. van Rij, Andre M. Voight, Benjamin F. Wareham, Nick J. Wells, George A. Wichmann, H-Erich Wild, Philipp S. Willenborg, Christina Witteman, Jaqueline C. M. Wright, Benjamin J. Ye, Shu Zeller, Tanja Ziegler, Andreas Cambien, Francois Goodall, Alison H. Cupples, L. Adrienne Quertermous, Thomas Maerz, Winfried Hengstenberg, Christian Blankenberg, Stefan Ouwehand, Willem H. Hall, Alistair S. Deloukas, Panos Thompson, John R. Stefansson, Kari Roberts, Robert Thorsteinsdottir, Unnur O'Donnell, Christopher J. McPherson, Ruth Erdmann, Jeanette Samani, Nilesh J. CA CARDIoGRAM Consortium TI Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MYOCARDIAL-INFARCTION; HEART-DISEASE; VARIANTS; DESIGN; RISK; EXPRESSION; GENETICS; ATHEROSCLEROSIS; POLYMORPHISMS AB We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10(-8) and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits. C1 [Schunkert, Heribert; Preuss, Michael; Aherrahrou, Zouhair; Diemert, Patrick; Freyer, Jennifer; Lieb, Wolfgang; Loley, Christina; Maouche, Seraya; nahrstaedt, Janja; Tennstedt, Stephanie; Willenborg, Christina; Erdmann, Jeanette] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Koenig, Inke R.; Preuss, Michael; Loley, Christina; nahrstaedt, Janja; Schillert, Arne; Willenborg, Christina; Ziegler, Andreas] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany. [Kathiresan, Sekar; Musunuru, Kiran] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar; Musunuru, Kiran] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Kathiresan, Sekar; Musunuru, Kiran; Voight, Benjamin F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar; Altshuler, David; Musunuru, Kiran; Voight, Benjamin F.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Reilly, Muredach P.; Rader, Daniel J.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Assimes, Themistocles L.; Knowles, Joshua W.; Quertermous, Thomas] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Holm, Hilma; Gretarsdottir, Solveig; Gulcher, Jeffrey R.; Kong, Augustine; Thorleifsson, Gudmar; Stefansson, Kari; Thorsteinsdottir, Unnur] DeCODE Genet, Reykjavik, Iceland. [Stewart, Alexandre F. R.; Roberts, Robert; McPherson, Ruth] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON, Canada. [Barbalic, Maja; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Gieger, Christian; Doering, Angela; Illig, Thomas; Meisinger, Christa; Peters, Annette; Wichmann, H-Erich] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Absher, Devin] Hudson Alpha Inst, Huntsville, TX USA. [Allayee, Hooman] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Altshuler, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Anand, Sonia S.] McMaster Univ, Hamilton, ON, Canada. [Anand, Sonia S.] Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada. [Andersen, Karl; Thorgeirsson, Gudmundur] Landspitali Univ Hosp, Dept Med, Reykjavik, Iceland. [Andersen, Karl; Gudnason, Vilmundur; Smith, Albert; Thorgeirsson, Gudmundur; Stefansson, Kari; Thorsteinsdottir, Unnur] Univ Iceland, Fac Med, Reykjavik, Iceland. [Anderson, Jeffrey L.; Carlquist, John F.; Horne, Benjamin D.; Muhlestein, Joseph B.] Univ Utah, Div Cardiol, Cardiovasc Dept, Intermt Med Ctr, Salt Lake City, UT 84112 USA. [Ardissino, Diego] Univ Parma, Div Cardiol, Azienda Osped, I-43100 Parma, Italy. [Ball, Stephen G.] Univ Leeds, LIGHT Res Inst, Fac Med & Hlth, Leeds, W Yorkshire, England. [Ball, Stephen G.; Hall, Alistair S.] Univ Leeds, Div Cardiovasc & Neuronal Remodelling, Multidisciplinary Cardiovasc Res Ctr, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England. [Balmforth, Anthony J.; Nelson, Christopher P.] Univ Leeds, Div Cardiovasc & Diabet Res, Multidisciplinary Cardiovasc Res Ctr, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England. [Barnes, Timothy A.; Braund, Peter S.; Codd, Veryan; Kaiser, Michael A.; Tomaszewski, Maciej; Goodall, Alison H.; Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Glenfield Hosp, Leicester, Leics, England. [Becker, Diane M.; Becker, Lewis C.] Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD USA. [Berger, Klaus] Univ Munster, Inst Epidemiol & Social Med, Munster, Germany. [Bis, Joshua C.; Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Cardiovasc Hlth Resarch Unit, Seattle, WA 98195 USA. [Bis, Joshua C.; Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Boekholdt, S. Matthijs; Kastelein, John J. P.; Sivapalaratnam, Suthesh] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Boekholdt, S. Matthijs] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands. [Brown, Morris J.] Univ Cambridge, Clin Pharmacol Unit, Cambridge, England. [Burnett, Mary Susan; Devaney, Joseph M.; Epstein, Stephen E.] Washington Hosp Ctr, Cardiovasc Res Inst, Medstar Hlth Res Inst, Washington, DC 20010 USA. [Buysschaert, Ian] Univ Hosp Gasthuisberg, Dept Cardiol, B-3000 Louvain, Belgium. [Buysschaert, Ian; Lambrechts, Diether] Katholieke Univ Leuven VIB, Vesalius Res Ctr, Louvain, Belgium. [Chen, Li] Univ Ottawa, Inst Heart, Cardiovasc Res Methods Ctr, Ottawa, ON, Canada. [Cichon, Sven; Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany. [Cichon, Sven] Inst Neurosci & Med INM 1, Res Ctr Juelich, Julich, Germany. [Dedoussis, George] Harokopio Univ, Dept Dietetics Nutr, Athens, Greece. [Dehghan, Abbas; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jaqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Demissie, Serkalem; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Demissie, Serkalem; Cupples, L. Adrienne; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Do, Ron; Engert, James C.] McGill Univ, Dept Human Genet, Montreal, PQ, Canada. [Eifert, Sandra; Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [El Mokhtari, Nour Eddine] Kreiskrankenhaus Rendsburg, Innere Med Klin, Rendsburg, Germany. [Ellis, Stephen G.; Tang, W. H. Wilson] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Elosua, Roberto] Ciber Epidemiol & Salud Publ CIBERSP, Cardiovasc Epidemiol & Genet Grp, Inst Municipal Invest Med, Barcelona, Spain. [Engert, James C.] McGill Univ, Dept Med, Montreal, PQ, Canada. [de Faire, Ulf; Gigante, Bruna; Leander, Karin] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden. [de Faire, Ulf; Gigante, Bruna] Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden. [Fischer, Marcus; Stark, Klaus; Hengstenberg, Christian] Klin & Poliklin Innere Med II, Regensburg, Germany. [Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth ARF, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Girelli, Domenico; Martinelli, Nicola; Olivieri, Oliviero] Univ Verona, Dept Med, I-37100 Verona, Italy. [Gudnason, Vilmundur; Smith, Albert] Iceland Heart Assoc, Kopavogur, Iceland. [Halperin, Eran] Tel Aviv Univ, Blavatnik Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Halperin, Eran] Tel Aviv Univ, Dept Mol Microbiol & Biotechnol, IL-69978 Tel Aviv, Israel. [Halperin, Eran] Int Comp Sci Inst, Berkeley, CA 94704 USA. [Hammond, Naomi; Rice, Catherine; Soranzo, Nicole; Stirrups, Kathy; Ouwehand, Willem H.; Deloukas, Panos] Wellcome Trust Sanger Inst, Hinxton, S Cambs, England. [Hazen, Stanley L.] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA. [Iribarren, Carlos] Kaiser Permanente No Calif, Div Res, Oakland, CA USA. [Jones, Gregory T.; van Rij, Andre M.] Univ Otago, Dunedin Sch Med, Dept Surg, Dunedin, New Zealand. [Jukema, J. Wouter] Leiden Univ, Dept Cardiol C5 P, Med Ctr, Leiden, Netherlands. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge, England. [Kolovou, Genovefa] Onassis Cardiac Surg Ctr, Cardiol Dept 1, Athens, Greece. [Laaksonen, Reijo] Tampere Univ Hosp, Sci Ctr, Tampere, Finland. [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Lettre, Guillaume] Univ Montreal, Dept Med, Succursale Ctr Ville, Montreal, PQ H3C 3J7, Canada. [Lotery, Andrew J.] Univ Southampton, Clin Neurosci Div, Sch Med, Southampton, Hants, England. [Lotery, Andrew J.] Southampton Gen Hosp, Southampton Eye Unit, Southampton SO9 4XY, Hants, England. [Mannucci, Pier M.] Osped Maggiore Policlin, Sci Direct, IRCCS, Fdn Ca Granda, Milan, Italy. [McKeown, Pascal P.; Patterson, Chris C.] Queens Univ Belfast, Ctr Publ Hlth, Inst Clin Sci, Belfast, Ireland. [Meitinger, Thomas] Deutsch Forschungszentrum Umwelt & Gesundheit, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Melander, Olle] Lund Univ, Dept Clin Sci Hypertens & Cardiovasc Dis, Scania Univ Hosp, Malmo, Sweden. [Merlini, Pier Angelica] Azienda Osped Niguarda CaGranda, Div Cardiol, Milan, Italy. [Mooser, Vincent] GlaxoSmithKline Inc, Genet Div, King Of Prussia, PA USA. [Mooser, Vincent] GlaxoSmithKline Inc, Drug Discovery, King Of Prussia, PA USA. [Morgan, Thomas] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. [Muenzel, Thomas; Wild, Philipp S.; Zeller, Tanja; Blankenberg, Stefan] Johannes Gutenberg Univ Mainz, Med Klin & Poliklin, Univ Med Mainz, Mainz, Germany. [Patel, Riyaz S.; Quyyumi, Arshed A.] Emory Univ, Sch Med, Atlanta, GA USA. [Patel, Riyaz S.] Cardiff Univ, Cardiff, S Glam, Wales. [Peyvandi, Flora] Univ Milan, Osped Maggiore Policlin, A Bianchi Bonomi Hemophilia & Thrombosis Ctr, Dept Med & Med Specialties,Fdn IRCCS Ca Granda, Milan, Italy. [Peyvandi, Flora] Luigi Villa Fdn, Milan, Italy. [Rader, Daniel J.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Rallidis, Loukianos S.] Univ Athens, Sch Med, Attikon Hosp, Dept Cardiol 2, GR-11527 Athens, Greece. [Rosendaal, Frits R.; Snoep, Jaapjan D.] Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands. [Rosendaal, Frits R.] Leiden Univ, Dept Thrombosis & Haemostasis, Med Ctr, Leiden, Netherlands. [Rosendaal, Frits R.] Leiden Univ, Einthoven Lab Expt Vasc Med, Med Ctr, Leiden, Netherlands. [Rubin, Diana] Univ Klinikum Schleswig Holstein, Med Klin 1, Kiel, Germany. [Salomaa, Veikko] Natl Inst Hlth & Welf, Chron Dis Epidemiol & Prevent Unit, Dept Chron Dis Prevent, Helsinki, Finland. [Sampietro, M. Lourdes] Leiden Univ, Dept Human Genet & Cardiol, Med Ctr, Leiden, Netherlands. [Sandhu, Manj S.] Wellcome Trust Sanger Inst, Genet Epidemiol Grp, Cambridge, England. [Sandhu, Manj S.] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge, England. [Schadt, Eric] Pacific Biosci, Menlo Pk, CA USA. [Schadt, Eric] Sage Bionetworks, Palo Alto, CA USA. [Schaefer, Arne; Schreiber, Stefan] Univ Kiel, Inst Klin Mol Biol, Kiel, Germany. [Schrezenmeir, Juergen] Max Rubner Inst, Inst Physiol & Biochem Nutr, Kiel, Germany. [Schrezenmeir, Juergen] Kiel Innovat & Technol Ctr, Clin Res Ctr Kiel, Kiel, Germany. [Sivananthan, Mohan] Leeds Teaching Hosp Natl Hlth Serv Trust, Cardiol Div, Leeds, W Yorkshire, England. [Smith, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Spertus, John A.] Univ Missouri, Kansas City, MO 64110 USA. [Spertus, John A.] Mid Amer Heart Inst, Kansas City, KS USA. [Stoll, Monika] Univ Munster, Leibniz Inst Arteriosclerosis Res, Munster, Germany. [Tomaszewski, Maciej; Goodall, Alison H.; Samani, Nilesh J.] Glenfield Gen Hosp, Leicester Natl Inst Hlth Res, Biomed Res Unit Cardiovasc Dis, Leicester LE3 9QP, Leics, England. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Voight, Benjamin F.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wareham, Nick J.] Addenbrookes Hosp, MRC, Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Sci Biometry & Epidemiol, Munich, Germany. [Wright, Benjamin J.] Univ Leicester, Dept Cardiovasc Surg, Leicester, Leics, England. [Altshuler, David] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA. [Ye, Shu] Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England. [Cambien, Francois] Univ Paris 06, INSERM, UMRS 937, Fac Med Pierre & Marie Curie, Paris, France. [Maerz, Winfried] Synlab Ctr Lab Diagnost Heidelberg, Heidelberg, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Maerz, Winfried] Univ Heidelberg, Inst Publ Hlth Social & Prevent Med, Med Fac Manneim, Heidelberg, Germany. [Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Ouwehand, Willem H.] NHS Blood Transplant, Cambridge, England. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [McPherson, Ruth] Univ Ottawa, Inst Heart, Atherogen Lab, Ottawa, ON, Canada. RP Schunkert, H (reprint author), Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. EM heribert.schunkert@uk-sh.de; njs@le.ac.uk RI Leander, Karin/C-7261-2017; Erdmann, Jeanette/P-7513-2014; Cichon, Sven/B-9618-2014; Mannucci, Pier/C-3102-2014; Meisinger, Christine/B-5358-2014; Laaksonen, Reijo/D-6323-2014; Boekholdt, Matthijs/G-7562-2014; Peters, Annette/A-6117-2011; Boehm, Bernhard/F-8750-2015; Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; Smith, Albert/K-5150-2015; Martinelli, Nicola/J-5622-2016; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Stark, Klaus/D-3813-2009; Library, Woodruff Health/A-6096-2012; Lieb, Wolfgang/C-1990-2012; Morgan, Tom/C-3478-2012; Stewart, Alexandre/A-5677-2011; Willenborg, Christina/D-2668-2012; Verdrengh, Evelien/H-4571-2012; Gigante, Bruna/I-9252-2012; Deloukas, Panos/B-2922-2013; Tang, Wai Hong/I-1238-2013; Schreiber, Stefan/B-6748-2008; Voight, Benjamin/F-1775-2011; Altshuler, David/A-4476-2009; Cichon, Sven/H-8803-2013 OI Leander, Karin/0000-0002-1404-9222; Cupples, L. Adrienne/0000-0003-0273-7965; Soranzo, Nicole/0000-0003-1095-3852; Stewart, Alexandre/0000-0003-2673-9164; Meisinger, Christa/0000-0002-9026-6544; ELOSUA, ROBERTO/0000-0001-8235-0095; Erdmann, Jeanette/0000-0002-4486-6231; Cichon, Sven/0000-0002-9475-086X; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Martinelli, Nicola/0000-0001-6465-5119; Peyvandi, Flora/0000-0001-7423-9864; Gieger, Christian/0000-0001-6986-9554; Ziegler, Andreas/0000-0002-8386-5397; Nothen, Markus/0000-0002-8770-2464; Jones, Gregory T/0000-0002-6950-4210; Ouwehand, Willem/0000-0002-7744-1790; Dehghan, Abbas/0000-0001-6403-016X; Stark, Klaus/0000-0002-7832-1942; Willenborg, Christina/0000-0001-5217-6882; Deloukas, Panos/0000-0001-9251-070X; Schreiber, Stefan/0000-0003-2254-7771; Altshuler, David/0000-0002-7250-4107; Cichon, Sven/0000-0002-9475-086X FU British Heart Foundation [RG/09/012/28096, PG/08/094/26019]; Medical Research Council [G0401527, G0801566, G1000143, MC_U106179471]; NHLBI NIH HHS [HL087647, N01 HC025195, R01 HL087647, R01HL089650-02] NR 39 TC 734 Z9 742 U1 8 U2 97 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD APR PY 2011 VL 43 IS 4 BP 333 EP U153 DI 10.1038/ng.784 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 741YL UT WOS:000288903700013 PM 21378990 ER PT J AU Chaturvedi, S Greenberg, SM AF Chaturvedi, Seemant Greenberg, Steven M. TI Intracerebral hematoma expansion Making predictions (about the future) SO NEUROLOGY LA English DT Editorial Material ID HEMORRHAGE C1 [Chaturvedi, Seemant] Wayne State Univ, Dept Neurol, Detroit, MI 48201 USA. [Chaturvedi, Seemant] Wayne State Univ, Stroke Program, Detroit, MI 48201 USA. [Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. [Greenberg, Steven M.] Harvard Univ, Sch Med, Boston, MA USA. RP Chaturvedi, S (reprint author), Wayne State Univ, Dept Neurol, 8C-UHC,4201 St Antoine, Detroit, MI 48201 USA. EM SChaturv@med.wayne.edu NR 8 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR PY 2011 VL 76 IS 14 BP 1204 EP 1205 DI 10.1212/WNL.0b013e31821435d0 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 745CV UT WOS:000289142500005 PM 21346224 ER PT J AU Elman, MJ Bressler, NM Qin, HJ Beck, RW Ferris, FL Friedman, SM Glassman, AR Scott, IU Stockdale, CR Sun, JK AF Elman, Michael J. Bressler, Neil M. Qin, Haijing Beck, Roy W. Ferris, Frederick L., III Friedman, Scott M. Glassman, Adam R. Scott, Ingrid U. Stockdale, Cynthia R. Sun, Jennifer K. TI Expanded 2-Year Follow-up of Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema SO OPHTHALMOLOGY LA English DT Article AB Objective: To report expanded 2-year follow-up of a previously reported randomized trial evaluating intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME). Design: Multicenter, randomized clinical trial. Participants: A total of 854 study eyes of 691 participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea. Methods: Continuation of procedures previously reported for the randomized trial. Main Outcome Measures: Best-corrected visual acuity and safety at the 2-year visit. Results: At the 2-year visit, compared with the sham + prompt laser group, the mean change in the visual acuity letter score from baseline was 3.7 letters greater in the ranibizumab + prompt laser group (95% confidence interval adjusted for multiple comparisons [aCI], -0.4 to +7.7), 5.8 letters greater in the ranibizumab + deferred laser group (95% aCI, +1.9 to +9.8), and 1.5 letters worse in the triamcinolone + prompt laser group (95% aCI, -5.5 to +2.4). After the 1- to 2-year visit in the ranibizumab + prompt or deferred laser groups, the median numbers of injections were 2 and 3 (potential maximum of 13), respectively. At the 2-year visit, the percentages of eyes with central subfield thickness >= 250 mu m were 59% in the sham + prompt laser group, 43% in the ranibizumab + prompt laser group, 42% in the ranibizumab + deferred laser group, and 52% in the triamcinolone + prompt laser group. No systemic events attributable to study treatment were apparent. Three eyes in 3 (0.8%) of 375 participants had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Conclusions: The expanded 2-year results reported are similar to results published previously and reinforce the conclusions originally reported: Ranibizumab should be considered for patients with DME and characteristics similar to those of the cohort in this clinical trial, including vision impairment with DME involving the center of the macula. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011;118:609-614 (C) 2011 by the American Academy of Ophthalmology. C1 [Qin, Haijing; Beck, Roy W.; Glassman, Adam R.; Stockdale, Cynthia R.] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. [Elman, Michael J.] PA, Elman Retina Grp, Baltimore, MD USA. [Bressler, Neil M.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA. [Ferris, Frederick L., III] NEI, Bethesda, MD 20892 USA. [Ferris, Frederick L., III] NIH, Bethesda, MD 20892 USA. [Friedman, Scott M.] Florida Retina Consultants, Lakeland, FL USA. [Scott, Ingrid U.] Penn State Univ, Coll Med, Hershey, PA USA. [Sun, Jennifer K.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Qin, HJ (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM drcrstat3@jaeb.org FU National Eye Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; Department of Health and Human Services [EY-14231, EY-14229, EY-18817]; Genentech; Allergan, Inc.; Pfizer; Alcon; Allergan; Office of Research Administration; Bausch Lomb; Carl Zeiss Meditec; EMMES Corporation; Lumenis; Notal Vision; Novartis; QLT; Regeneron; Steba Biotech; Abbott Medical Optics; ForSight Labs; LLC; Genzyme Corporation FX Supported through cooperative agreements from the National Eye Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and Department of Health and Human Services EY-14231, EY-14229, EY-18817; The funding organization (National Institutes of Health) participated in oversight of the conduct of the study and review of the article but not directly in the design or conduct of the study; the collection, management, analysis, or interpretation of the data; or in the preparation of the article. Genentech provided the ranibizumab for the study, and Allergan, Inc., provided the triamcinolone for the study. In addition, Genentech and Allergan, Inc., provided funds to DRCR.net to defray the study's clinical site costs. As described in the DRCR.net Industry Collaboration Guidelines (available at www.drcr.net), the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol. A complete list of all DRCR.net investigator financial disclosures can be found at www.drcr.net. Writing Committee financial disclosures: Michael J. Elman: Genentech (consultant); Scott M. Friedman: Pfizer (financial support); Alcon (financial support); Allergan (financial support); Genentech (financial support); Ingrid U. Scott: Genentech (consultant); Eyetech (consultant); Jennifer K. Sun: Novartis (lecturer); Neil M. Bressler: Grants to investigators at The Johns Hopkins University are negotiated and administered by the institution (e.g., the School of Medicine) that receives the grants, typically through the Office of Research Administration. Individual investigators who participate in the sponsored project(s) are not directly compensated by the sponsor but may receive salary or other support from the institution to support their effort on the projects(s). Dr. Neil Bressler is Principal Investigator of grants at The Johns Hopkins University sponsored by the following entities (not including the National Institutes of Health): Allergan, Bausch & Lomb, Carl Zeiss Meditec, EMMES Corporation, Genentech, Lumenis, Notal Vision, Novartis, QLT, Regeneron, Steba Biotech, Abbott Medical Optics, ForSight Labs, LLC, and Genzyme Corporation. A complete list of all DRCR. net investigator financial disclosures can be found at www.drcr.net. NR 3 TC 202 Z9 209 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD APR PY 2011 VL 118 IS 4 BP 609 EP 614 DI 10.1016/j.ophtha.2010.12.033 PG 6 WC Ophthalmology SC Ophthalmology GA 744DS UT WOS:000289075200002 PM 21459214 ER PT J AU Sen, HN Sangave, AA Goldstein, DA Suhler, EB Cunningham, D Vitale, S Nussenblatt, RB AF Sen, H. Nida Sangave, Amit A. Goldstein, Debra A. Suhler, Eric B. Cunningham, Denise Vitale, Susan Nussenblatt, Robert B. TI A Standardized Grading System for Scleritis SO OPHTHALMOLOGY LA English DT Article ID UVEITIS; INFLAMMATION; AGREEMENT AB Objective: This study evaluated the performance of a standardized grading system for scleritis using standard digital photographs. Design: Cross-sectional interobserver agreement study. Participants: Photo archives from the National Eye Institute. Methods: Three uveitis specialists from 3 different centers graded 79 randomly arranged images of the sclera with various degrees of inflammation. Grading was done using standard screen resolution (1024x768 pixels) on a 0 to 4+ scale in 2 sessions: (1) without using reference photographs and (2) with reference to a set of standard photographs (proposed grading system). The graders were masked to the order of images, and the order of images was randomized. Interobserver agreement in grading the severity of inflammation with and without the use of grading system was evaluated. Main Outcome Measures: Interobserver agreement. Results: The proposed grading system for assessing activity in scleritis demonstrated a good interobserver agreement. Interobserver agreement (pooled kappa) was poor (0.289) without photographic guidance and improved substantially when the "grading system" with standardized photographs was used (kappa = 0.603). Conclusions: This system of standardized images for scleritis grading provides significantly more consistent grading of scleral inflammation in this study and has clear applications in clinical settings and clinical research. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011;118:768-771 (C) 2011 by the American Academy of Ophthalmology. C1 [Sen, H. Nida; Sangave, Amit A.; Cunningham, Denise; Vitale, Susan; Nussenblatt, Robert B.] NEI, NIH, Bethesda, MD 20892 USA. [Goldstein, Debra A.] Univ Illinois, Chicago, IL USA. [Suhler, Eric B.] Oregon Hlth & Sci Univ, Portland, OR USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. RP Sen, HN (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Room 10N112, Bethesda, MD 20892 USA. EM senh@nei.nih.gov FU Celgene; Abbott; Genentech; Novartis; Department of Veterans' Affairs; National Eye Institute FX Dr Eric Suhler receives financial support from Celgene, Abbott, Genentech, Novartis, and the Department of Veterans' Affairs, and institutional support from Research to Prevent Blindness.; Supported by the National Eye Institute Intramural research program support (HNS, RBN, AS, SV). NR 9 TC 13 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD APR PY 2011 VL 118 IS 4 BP 768 EP 771 DI 10.1016/j.ophtha.2010.08.027 PG 4 WC Ophthalmology SC Ophthalmology GA 744DS UT WOS:000289075200025 PM 21093921 ER PT J AU Rosen, BR Napadow, V AF Rosen, Bruce R. Napadow, Vitaly TI Quantitative Markers for Neuropsychiatric Disease: Give It a Rest SO RADIOLOGY LA English DT Editorial Material ID MILD COGNITIVE IMPAIRMENT; FUNCTIONAL CONNECTIVITY; ALZHEIMERS-DISEASE; SENSORY STIMULATION; NETWORKS; CORTEX; MRI C1 [Rosen, Bruce R.; Napadow, Vitaly] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Rosen, BR (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,MNR Ctr 2301, Charlestown, MA 02129 USA. EM bruce@nmr.mgh.harvard.edu FU NCCIH NIH HHS [P01-AT002048, R01 AT004714, P01AT002048, R01-AT004714, P01 AT002048]; NCRR NIH HHS [P41RR014075, P41 RR014075]; NIBIB NIH HHS [R01 EB002066, R01EB002066] NR 19 TC 3 Z9 3 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2011 VL 259 IS 1 BP 17 EP 19 DI 10.1148/radiol.10102253 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 741FM UT WOS:000288848800005 PM 21436093 ER PT J AU Boland, GWL Dwamena, BA Sangwaiya, MJ Goehler, AG Blake, MA Hahn, PF Scott, JA Kalra, MK AF Boland, Giles W. L. Dwamena, Ben A. Sangwaiya, Minal Jagtiani Goehler, Alexander G. Blake, Michael A. Hahn, Peter F. Scott, James A. Kalra, Mannudeep K. TI Characterization of Adrenal Masses by Using FDG PET: A Systematic Review and Meta-Analysis of Diagnostic Test Performance SO RADIOLOGY LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; CONTRAST-ENHANCED CT; F-18-FDG PET/CT; PUBLICATION BIAS; CANCER-PATIENTS; TEST ACCURACY; LUNG-CANCER; IMAGING CHARACTERIZATION; MALIGNANT LESIONS; META-REGRESSION AB Purpose: To perform a systematic review and meta-analysis of published data to determine the diagnostic utility of adrenal fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) for distinguishing benign from malignant adrenal disease. Materials and Methods: Data on FDG PET assessment in MEDLINE and other electronic databases (from inception to November 2009) and in subject matter-specific journals were evaluated and compared with histologic diagnoses and/or established clinical and imaging follow-up results. Methodologic quality was assessed by using Quality Assessment of Diagnostic Accuracy Studies criteria. Bivariate random-effects meta-analytical methods were used to estimate summary and subgroup-specific sensitivity, specificity, and receiver operating characteristic curves and to investigate the effects of study design characteristics and imaging procedure elements on diagnostic accuracy. Results: A total of 1391 lesions (824 benign, 567 malignant) in 1217 patients from 21 eligible studies were evaluated. Qualitative (visual) analysis of 841 lesions (in 14 reports) and quantitative analyses based on standardized uptake values (SUVs) for 824 lesions (in 13 reports) and standardized uptake ratios (SURs) for 562 lesions (in eight reports) were performed. Resultant data were highly heterogeneous, with a model-based inconsistency index of 88% (95% confidence interval [CI]: 79%, 98%). Mean sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio values for differentiating between benign and malignant adrenal disease were 0.97 (95% CI: 0.93, 0.98), 0.91 (95% CI: 0.87, 0.94), 11.1 (95% CI: 7.5, 16.3), 0.04 (95% CI: 0.02, 0.08), and 294 (95% CI: 107, 805), respectively, with no significant differences in accuracy among the visual, SUV, and SUR analyses. Conclusion: Meta-analysis of combination PET-computed tomography (CT) reports revealed that FDG PET was highly sensitive and specific for differentiating malignant from benign adrenal disease. Diagnostic accuracy was not influenced by the type of imaging device (PET vs PET/CT), but specificity was dependent on the clinical status (cancer vs no cancer). (C) RSNA, 2011 C1 [Boland, Giles W. L.; Sangwaiya, Minal Jagtiani; Goehler, Alexander G.; Blake, Michael A.; Hahn, Peter F.; Scott, James A.; Kalra, Mannudeep K.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Dwamena, Ben A.] Univ Michigan, Sch Med, Dept Radiol, Ann Arbor, MI USA. [Dwamena, Ben A.] VA Ann Arbor Healthcare Syst, Nucl Med Serv, Ann Arbor, MI USA. RP Boland, GWL (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,White Bldg 270C, Boston, MA 02114 USA. EM gboland@partners.org FU GE Healthcare FX G.W.L.B. No potential conflicts of interest to disclose. B. A. D. No potential conflicts of interest to disclose. M.J.S. No potential conflicts of interest to disclose. A. G. G. No potential conflicts of interest to disclose. M. A. B. No potential conflicts of interest to disclose. P. F. H. No potential conflicts of interest to disclose. J.A.S. No potential conflicts of interest to disclose. M. K. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: is a member of the board of GE Healthcare; is a paid consultant for GE Healthcare; received a grant or grants are pending from GE Healthcare; received payment from GE Healthcare for the development of educational presentations. Other relationships: none to disclose. NR 66 TC 75 Z9 79 U1 1 U2 6 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD APR PY 2011 VL 259 IS 1 BP 117 EP 126 DI 10.1148/radiol.11100569 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 741FM UT WOS:000288848800016 PM 21330566 ER PT J AU Flaherty, KT AF Flaherty, Keith T. TI Taking Aim at MELANOMA SO SCIENTIST LA English DT Article ID METASTATIC MELANOMA; PHASE-I/II; INHIBITION; RESISTANCE; TRIAL C1 Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Flaherty, KT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 400 MARKET ST, STE 1250, PHILADELPHIA, PA 19106 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD APR PY 2011 VL 25 IS 4 BP 32 EP 37 DI 10.3410/M3-8 PG 6 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 739SL UT WOS:000288738200016 ER PT J AU Halassa, MM AF Halassa, Michael M. TI Thalamocortical dynamics of sleep: Roles of purinergic neuromodulation SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE Sleep; Thalamocortical circuitry; Oscillations; Memory; Astrocytes; ATP; Adenosine ID SLOW-WAVE SLEEP; ADENOSINE A(1) RECEPTOR; IN-VIVO; HOMEOSTATIC REGULATION; PROLONGED WAKEFULNESS; HIPPOCAMPAL RIPPLES; NETWORK ACTIVATION; GENETIC-VARIATION; MEMBRANE-FUSION; BARREL CORTEX AB Thalamocortical dynamics, the millisecond to second changes in activity of thalamocortical circuits, are central to perception, action and cognition. Generated by local circuitry and sculpted by neuromodulatory systems, these dynamics reflect the expression of vigilance states. In sleep, thalamocortical dynamics are thought to mediate "offline" functions including memory consolidation and synaptic scaling. Here, I discuss thalamocortical sleep dynamics and their modulation by the ascending arousal system and locally released neurochemicals. I focus on modulation of these dynamics by electrically silent astrocytes, highlighting the role of purinergic signaling in this glial form of communication. Astrocytes modulate cortical slow oscillations, sleep behavior, and sleep-dependent cognitive function. The discovery that astrocytes can modulate sleep dynamics and sleep-related behaviors suggests a new way of thinking about the brain, in which integrated circuits of neurons and glia control information processing and behavioral output. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Halassa, Michael M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Halassa, Michael M.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Halassa, MM (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St,WACC 805, Boston, MA 02114 USA. EM mhalassa@partners.org FU NINDS NIH HHS [F31 NS059091, F31 NS059091-01] NR 101 TC 14 Z9 14 U1 1 U2 9 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD APR PY 2011 VL 22 IS 2 BP 245 EP 251 DI 10.1016/j.semcdb.2011.02.008 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 744CP UT WOS:000289071500017 PM 21329763 ER PT J AU Narla, A Vlachos, A Nathan, DG AF Narla, Anupama Vlachos, Adrianna Nathan, David G. TI Diamond Blackfan Anemia Treatment: Past, Present, and Future SO SEMINARS IN HEMATOLOGY LA English DT Article ID RED-CELL APLASIA; ERYTHROID HYPOPLASTIC ANEMIA; TREACHER-COLLINS-SYNDROME; MYELODYSPLASTIC SYNDROME; CYCLOSPORINE THERAPY; GENE-TRANSFER; PROTEIN; PROLIFERATION; DIFFERENTIATION; ERYTHROPOIESIS AB Despite significant improvements in our understanding of the pathophysiology of Diamond Blackfan anemia (DBA), there have been few advances in therapy. The cornerstones of treatment remain corticosteroids, chronic red blood cell transfusions, and hematopoietic stem cell transplantation, each of which is fraught with complications. In this article, we will review the history of therapies that have been offered to patients with DBA, summarize the current standard of care, including management of side effects, and discuss novel therapeutics that are being developed in the context of the research into the roles of ribosomal haplo-insufficiency and p53 activation in Diamond Blackfan anemia. Semin Hematol 48:117-123. (C) Published by Elsevier Inc. C1 [Narla, Anupama; Nathan, David G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Narla, Anupama; Nathan, David G.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Narla, Anupama; Nathan, David G.] Childrens Hosp, Boston, MA 02115 USA. [Vlachos, Adrianna] Steven & Alexandra Cohen Childrens Med Ctr New Yo, New Hyde Pk, NY USA. [Vlachos, Adrianna] Hofstra N Shore LIJ Sch Med, New Hyde Pk, NY USA. RP Nathan, DG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,Dana 1644, Boston, MA 02115 USA. EM david_nathan@dfci.harvard.edu FU NHLBI NIH HHS [K08 HL078818, K08 HL078818-05, R01 HL082945] NR 63 TC 10 Z9 11 U1 1 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD APR PY 2011 VL 48 IS 2 BP 117 EP 123 DI 10.1053/j.seminhematol.2011.01.004 PG 7 WC Hematology SC Hematology GA 743SA UT WOS:000289037800007 PM 21435508 ER PT J AU Blay, JY Demetri, GD AF Blay, Jean-Yves Demetri, George D. TI The Evolution of a Revolutionary Class: Extending Benefits of Tyrosine Kinase Inhibitors-Introduction SO SEMINARS IN ONCOLOGY LA English DT Editorial Material C1 [Blay, Jean-Yves] Univ Lyon 1, Ctr Leon Berard, Dept Med, F-69365 Lyon, France. [Demetri, George D.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Blay, JY (reprint author), Univ Lyon 1, Ctr Leon Berard, Dept Med, F-69365 Lyon, France. RI Blay, Jean-Yves/N-3966-2016 OI Blay, Jean-Yves/0000-0001-7190-120X NR 0 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD APR PY 2011 VL 38 IS 2 SU 1 BP S1 EP S2 DI 10.1053/j.seminoncol.2011.01.017 PG 2 WC Oncology SC Oncology GA 743JA UT WOS:000289013400001 PM 21419930 ER PT J AU Demetri, GD AF Demetri, George D. TI Differential Properties of Current Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors SO SEMINARS IN ONCOLOGY LA English DT Review ID CHRONIC MYELOID-LEUKEMIA; GROWTH-FACTOR RECEPTORS; IMATINIB MESYLATE; SELECTIVE INHIBITOR; ACQUIRED-RESISTANCE; BCR-ABL; ANTITUMOR-ACTIVITY; PHASE-II; IN-VITRO; KIT AB During the past decade, tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of gastrointestinal stromal tumors (GIST), providing new treatment options with unprecedented clinical benefit. Recognition of the key role played by the receptor tyrosine kinases KIT and platelet-derived growth factor receptor alpha (PDGFR alpha) in the pathogenesis of GIST led to the development of imatinib, the first TKI for this indication and the current first-line standard of care for unresectable or metastatic GIST. However, the clinical efficacy of imatinib is limited by two concerns: the rare patient-specific intolerance to the drug, and the fact that the majority of patients will eventually develop treatment-refractory disease that is resistant to this selective TKI Although sunitinib has been approved worldwide as second-line therapy for GIST following failure of imatinib, the benefits of sunitinib in treating GIST following imatinib failure are most often more limited than first-line therapy, with emergence of treatment-resistant disease in less than 1 year. Other TKIs studied in clinical trials for GIST include a wide range of different agents, such as sorafenib, dasatinib, pazopanib, regorafenib, masitinib, and nilotinib. Each agent differs in its selectivity for individual tyrosine kinases, conferring each with distinct properties that determine clinical safety and efficacy. No agent has yet reached regulatory approval for management of GIST following the failure of both imatinib and sunitinib. This review highlights relevant differences and similarities in the structures and functions, including kinase selectivity and mechanisms of binding, of the currently approved TKIs and certain others in development for the treatment of advanced GIST. In addition, the ability of some TKIs to inhibit alternative targets with potency similar to or greater than their intended primary target (pleiotropic effects) is also discussed. Semin Oncol 38 (Suppl 1):S10-S19 (c) 2011 Elsevier Inc. All rights reserved. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Demetri, GD (reprint author), Dana Farber Canc Inst, Dana 1212,44 Binney St, Boston, MA 02115 USA. EM gdemetri@partners.org FU Novartis Pharmaceuticals Corporation; Novartis Pharmaceuticals FX Publication of this article was supported by an educational grant from Novartis Pharmaceuticals Corporation.; Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. The author thanks Angelo Russo, PhD, for his medical editorial assistance with the manuscript. Dr Demetri took full responsibility for the final writing and was responsible for fair balance of data and conclusions in the manuscript. NR 45 TC 35 Z9 35 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0093-7754 EI 1532-8708 J9 SEMIN ONCOL JI Semin. Oncol. PD APR PY 2011 VL 38 IS 2 SU 1 BP S10 EP S19 DI 10.1053/j.seminoncol.2011.01.018 PG 10 WC Oncology SC Oncology GA 743JA UT WOS:000289013400003 PM 21419931 ER PT J AU Gokcay, F Arsava, EM Baykaner, T Vangel, M Garg, P Wu, O Singhal, AB Furie, KL Sorensen, AG Ay, H AF Gokcay, Figen Arsava, Ethem Murat Baykaner, Tuna Vangel, Mark Garg, Priya Wu, Ona Singhal, Aneesh B. Furie, Karen L. Sorensen, A. Gregory Ay, Hakan TI Age-Dependent Susceptibility to Infarct Growth in Women SO STROKE LA English DT Article DE cerebral infarct; diffusion-weighted imaging; gender; magnetic resonance imaging; outcome; perfusion-weighted imaging; women & minorities ID SEX-DIFFERENCES; EXPERIMENTAL STROKE; MAGNETIC-RESONANCE; ISCHEMIC-STROKE; ESTROGEN; DIFFUSION; MRI; VOLUME; OUTCOMES; RISK AB Background and Purpose-It is not known if there is a relationship between gender and tissue outcome in human ischemic stroke. We sought to identify whether the proportion of initially ischemic to eventually infarcted tissue was different between men and women with ischemic stroke. Methods-We studied 141 consecutive patients with acute ischemic stroke who had a baseline MRI obtained within 12 hours of symptom onset, a follow-up imaging on Day 4 or later, and diffusion-weighted imaging/mean transmit time mismatch on initial MRI. Lesion growth was calculated as percentage of mismatch tissue that underwent infarction on follow-up (percentage mismatch lost). Multivariable analyses explored the effect of gender and other predictors of tissue outcome on percentage mismatch lost. Results-There was no difference in median percentage mismatch lost between men (19%) and women (11%; P=0.720). There was, however, an interaction between gender and age; median percentage mismatch lost was 7% (0% to 12%) in women and 18% (1% to 35%) in men younger than the population median (71 years, P=0.061). The percentage mismatch lost was not different between men and women >= 71 years old (25% in both groups). The linear regression model revealed gender (P=0.027) and the interaction between age and gender (P=0.023) as independent predictors of percentage mismatch lost. Conclusions-There is an age-by-gender interaction in tissue outcome after ischemic stroke; brain infarcts in women < 70 years grow approximately 50% less than infarcts in their male counterparts. These findings extend the well-known concept that there is a differential age-by-gender effect on stroke incidence, mortality, and functional outcome to the tissue level. (Stroke. 2011;42:947-951.) C1 [Ay, Hakan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Neurol, Charlestown, MA 02129 USA. [Gokcay, Figen; Arsava, Ethem Murat; Baykaner, Tuna; Vangel, Mark; Garg, Priya; Wu, Ona; Sorensen, A. Gregory; Ay, Hakan] Harvard Univ, Sch Med, Dept Radiol, AA Martinos Ctr Biomed Imaging,Massachusetts Gen, Boston, MA 02115 USA. [Singhal, Aneesh B.; Furie, Karen L.; Ay, Hakan] Harvard Univ, Sch Med, Dept Neurol, Stroke Serv,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Ay, H (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Neurol, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM hay@partners.org RI Arsava, Ethem Murat/I-9197-2013 OI Arsava, Ethem Murat/0000-0002-6527-4139 FU National Institutes of Health (NIH) [R01-NS051412, P50-NS051343, R01-NS038477, R01-NS063925, R01-NS059710] FX A.B.S. received National Institutes of Health (NIH) grants R01-NS051412 and P50-NS051343, K.L.F. received NIH grant P50-NS051343, A.G.S. received NIH grants R01-NS038477 and R01-NS063925 (www.biomarkers.org/NewFiles/disclosures.html lists full disclosures), and H. A. received NIH grant R01-NS059710. NR 30 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2011 VL 42 IS 4 BP 947 EP 951 DI 10.1161/STROKEAHA.110.603902 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 741IK UT WOS:000288857200025 PM 21311058 ER PT J AU Wu, O Batista, LM Lima, FO Vangel, MG Furie, KL Greer, DM AF Wu, Ona Batista, Leonardo M. Lima, Fabricio O. Vangel, Mark G. Furie, Karen L. Greer, David M. TI Predicting Clinical Outcome in Comatose Cardiac Arrest Patients Using Early Noncontrast Computed Tomography SO STROKE LA English DT Article DE coma; outcomes; cardiac arrest; CT; prognosis ID WHITE-MATTER; SURVIVORS; RESUSCITATION; HYPOTHERMIA; PROGNOSIS; BRAIN; SCALE; DENSITY; SYSTEM; ATLAS AB Background and Purpose-Early assessment of the likelihood of neurological recovery in comatose cardiac arrest survivors remains challenging. We hypothesize that quantitative noncontrast computed tomography (NCCT) combined with neurological assessments, are predictive of outcome. Methods-We analyzed data sets acquired from comatose cardiac arrest patients who underwent CT within 72 hours of arrest. Images were semiautomatically segmented into anatomic regions. Median Hounsfield units (HU) were measured regionally and in the whole brain (WB). Outcome was based on the 6-month modified Rankin Scale (mRS) score. Logistic regression was used to combine Glasgow Coma Scale (GCS) score measured on Day 3 post arrest (GCS_Day3) with imaging to predict poor outcome (mRS>4). Results-WB HU (P=0.02) and the ratio of HU in the putamen to the posterior limb of the internal capsule (PLIC) (P=0.004) from 175 datasets from 151 patients were univariate predictors of poor outcome. Thirty-three patients underwent hypothermia treatment. Multivariate analysis showed that combining median HU in the putamen (P=0.0006) and PLIC (P=0.007) was predictive of poor outcome. Combining WB HU and GCS_Day3 resulted in 72% [61% to 80%] sensitivity and 100% [73% to 100%] specificity for predicting poor outcome in 86 patients with measurable GCS_Day3. This was an improvement over prognostic performance based on GCS_Day3 <= 8 (98% sensitive but 71% specific). Discussion-Combining density changes on CT with GCS_Day3 may be useful for predicting poor outcome in comatose cardiac arrest patients who are neither rapidly improving nor deteriorating. Improved prognostication with CT compared with neurological assessments can be achieved in patients treated with hypothermia. (Stroke. 2011;42:985-992.) C1 [Wu, Ona; Vangel, Mark G.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Batista, Leonardo M.; Lima, Fabricio O.; Furie, Karen L.; Greer, David M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Vangel, Mark G.] Harvard Univ, Harvard Clin & Translat Sci Ctr, Cambridge, MA 02138 USA. RP Wu, O (reprint author), Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,CNY 2301, Charlestown, MA 02129 USA. EM ona@nmr.mgh.harvard.edu RI Lima, Fabricio/E-6507-2015 OI Lima, Fabricio/0000-0002-0383-4145 FU National Institutes of Health [R01NS59775, P50NS051343, R01NS051412, NCRR [P41RR14075]] FX This research was supported in part by the National Institutes of Health (grants R01NS59775, P50NS051343, R01NS051412, and NCRR [P41RR14075]). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 36 TC 42 Z9 43 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2011 VL 42 IS 4 BP 985 EP 992 DI 10.1161/STROKEAHA.110.594879 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 741IK UT WOS:000288857200031 PM 21330629 ER PT J AU Walvick, RP Bratane, BT Henninger, N Sicard, KM Bouley, J Yu, ZY Lo, E Wang, XY Fisher, M AF Walvick, Ronn P. Bratane, Bernt T. Henninger, Nils Sicard, Kenneth M. Bouley, James Yu, Zhanyang Lo, Eng Wang, Xiaoying Fisher, Marc TI Visualization of Clot Lysis in a Rat Embolic Stroke Model Application to Comparative Lytic Efficacy SO STROKE LA English DT Article DE acute stroke; animal models; ischemia; MRI; thrombolysis ID MAGNETIC-RESONANCE ANGIOGRAPHY; FOCAL CEREBRAL-ISCHEMIA; ANNEXIN-II; PLASMINOGEN; REPERFUSION; DIFFUSION; OCCLUSION; MEDIATOR; THERAPY; SYSTEM AB Background and Purpose-The purpose of this study was to develop a novel MRI method for imaging clot lysis in a rat embolic stroke model and to compare tissue plasminogen activator (tPA)-based clot lysis with and without recombinant Annexin-2 (rA2). Methods-In experiment 1 we used in vitro optimization of clot visualization using multiple MRI contrast agents in concentrations ranging from 5 to 50 mu L in 250 mu L blood. In experiment 2, we used in vivo characterization of the time course of clot lysis using the clot developed in the previous experiment. Diffusion, perfusion, angiography, and T1-weighted MRI for clot imaging were conducted before and during treatment with vehicle (n=6), tPA (n=8), or rA2 plus tPA (n=8) at multiple time points. Brains were removed for ex vivo clot localization. Results-Clots created with 25 mu L Magnevist were the most stable and provided the highest contrast-to-noise ratio. In the vehicle group, clot length as assessed by T1-weighted imaging correlated with histology (r=0.93). Clot length and cerebral blood flow-derived ischemic lesion volume were significantly smaller than vehicle at 15 minutes after treatment initiation in the rA2 plus tPA group, whereas in the tPA group no significant reduction from vehicle was observed until 30 minutes after treatment initiation. The rA2 plus tPA group had a significantly shorter clot length than the tPA group at 60 and 90 minutes after treatment initiation and significantly smaller cerebral blood flow deficit than the tPA group at 90 minutes after treatment initiation. Conclusions-We introduce a novel MRI-based clot imaging method for in vivo monitoring of clot lysis. Lytic efficacy of tPA was enhanced by rA2. (Stroke. 2011; 42: 1110-1115.) C1 [Bratane, Bernt T.; Henninger, Nils; Sicard, Kenneth M.; Bouley, James; Fisher, Marc] Univ Massachusetts Med Sch, Dept Neurol, Worcester, MA USA. [Walvick, Ronn P.] Univ Massachusetts Med Sch, Dept Radiol, Worcester, MA USA. [Yu, Zhanyang; Lo, Eng; Wang, Xiaoying] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroprotect Res Lab,Dept Neurol, Charlestown, MA USA. [Yu, Zhanyang; Lo, Eng; Wang, Xiaoying] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neuroprotect Res Lab,Dept Radiol, Charlestown, MA USA. Harvard Univ, Program Neurosci, Sch Med, Charlestown, MA USA. RP Bratane, BT (reprint author), 303 Belmont St, Worcester, MA 01604 USA. EM Bernt.Bratane@umassmed.edu OI Henninger, Nils/0000-0002-3883-5623 FU NIH FX This study was supported by institutional grants. X. W. was supported by a NIH grant. NR 23 TC 12 Z9 12 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2011 VL 42 IS 4 BP 1110 EP 1115 DI 10.1161/STROKEAHA.110.602102 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 741IK UT WOS:000288857200051 PM 21372305 ER PT J AU Haynes, AB Regenbogen, SE Weiser, TG Lipsitz, SR Dziekan, G Berry, WR Gawande, AA AF Haynes, Alex B. Regenbogen, Scott E. Weiser, Thomas G. Lipsitz, Stuart R. Dziekan, Gerald Berry, William R. Gawande, Atul A. TI Surgical outcome measurement for a global patient population: Validation of the Surgical Apgar Score in 8 countries SO SURGERY LA English DT Article ID SURGERY; HEALTH; CARE AB Background. Surgical care is a vital component. of health care worldwide, yet there is no clinically meaningful measure of operative outcomes that could be applied globally. The Surgical Apgar Score, a simple metric derived from 3 intraoperative parameters, has been shown in U.S. academic medical centers to predict 30-day patient. outcomes after operation, but. has not been validated more broadly. Methods. We collected the components of the Surgical Apgar Score at the time of operation for 5,909 adult patients undergoing noncardiac operative procedures under general anesthesia at 8 hospitals in diverse international settings and evaluated the relationship between patients' scores and the incidence of inpatient postoperative morbidity and mortality, using generalized estimating equations to adjust for clustering within sites. Results. During the first 30 days of postoperative hospitalization, 544 patients (9.2%) experienced >= 1 complications. Compared with patients with the median score of 7-whose complication rate was 9.1%-those with a Surgical Apgar Score <5 (n = 302) had an adjusted complication rate of 32.9% (relative risk [RR], 3.6; 95% CI, 2.9-4.5), whereas those with a score of 10 (n = 238) had a 3.0% adjusted complication. rate (RR, 0.3; 95% CI, 0.1-1.1). The score's c-statistic for prediction of any complication is 0.70; for death. it is 0.77. Conclusion. The Surgical Apgar Score is easily calculated, predictive, and moderately discriminative for major complications among adults undergoing inpatient noncardiac operative procedures. Such. a score could provide objective indication, of relative postoperative, risk for inpatients and provide a potential target for quality improvement efforts, particularly in resource-limited settings. (Surgery 2011;149:519-24.) C1 [Haynes, Alex B.; Regenbogen, Scott E.; Weiser, Thomas G.; Berry, William R.; Gawande, Atul A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Haynes, Alex B.; Regenbogen, Scott E.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Weiser, Thomas G.; Lipsitz, Stuart R.; Berry, William R.; Gawande, Atul A.] Brigham & Womens Hosp, Dept Surg, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Dziekan, Gerald] WHO, Patient Safety Programme, CH-1211 Geneva, Switzerland. RP Gawande, AA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave,Kresge 401, Boston, MA 02115 USA. EM agawande@partners.org RI Haynes, Alex/K-1446-2013; OI Haynes, Alex/0000-0002-5731-329X; Gawande, Atul/0000-0002-1824-9176 FU World Health Organization FX Funded by the World Health Organization. NR 18 TC 38 Z9 39 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD APR PY 2011 VL 149 IS 4 BP 519 EP 524 DI 10.1016/j.surg.2010.10.019 PG 6 WC Surgery SC Surgery GA 743KP UT WOS:000289017500007 PM 21216419 ER PT J AU Dave, BR Sharma, A Kalva, SP Wicky, S AF Dave, Bhavika R. Sharma, Ashish Kalva, Sanjeeva P. Wicky, Stephan TI Nine-Year Single-Center Experience With Transcatheter Arterial Embolization for Hemoptysis: Medium-Term Outcomes SO VASCULAR AND ENDOVASCULAR SURGERY LA English DT Article DE hemoptysis; bronchial arteries; embolization ID LIFE-THREATENING HEMOPTYSIS; SELECTIVE BRONCHIAL ARTERIOGRAPHY; MASSIVE HEMOPTYSIS; CYSTIC-FIBROSIS; MAJOR HEMOPTYSIS; PLATINUM COILS; MANAGEMENT; EMBOLOTHERAPY; IMMEDIATE; DISEASES AB Purpose: To determine the medium-term efficacy of transcatheter arterial embolization (TAE) for hemoptysis. Materials and Methods: A total of 128 TAE were performed from April 1999 to April 2008 in 58 patients (30:28 F:M) with mean age of 49 (range: 16-89). Major causes of hemoptysis included cystic fibrosis/bronchiectasis (24 of 58); lung metastasis (8 of 58); lung cancer (7 of 58); fungal infection (4 of 58). Follow-up was available in 57 of 58 for a median of 1.28 years. Primary and secondary efficacy of TAE for hemoptysis was calculated using Kaplan-Meier estimates. Results: Technical and clinical successes were estimated at 58 (100%) of 58 and 57(98%) of 58, respectively. Recurrent hemoptysis occurred in 40% (23 of 58). In all, 34% (20 of 58) died during follow-up. Kaplan-Meier estimates for primary and secondary efficacy of TAE at 2, 4, 6, and 8 years were 0.82, 0.46, 0.17, and 0.09 (benign disease) and 0.30, 0, 0, and 0 (malignant disease), respectively. Conclusion: TAE is an effective treatment for hemoptysis in both short- and medium-terms, especially in benign lung disease. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Dave, BR (reprint author), Univ Mississippi, Dept Radiol, Med Ctr, Jackson, MS 39216 USA. EM bhavikadave@msn.com NR 45 TC 5 Z9 6 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1538-5744 J9 VASC ENDOVASC SURG JI Vasc. Endovasc. Surg. PD APR PY 2011 VL 45 IS 3 BP 258 EP 268 DI 10.1177/1538574410395036 PG 11 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 740XJ UT WOS:000288827400008 PM 21444351 ER PT J AU Zapawa, LM Hughes, JR Benowitz, NL Rigotti, NA Shiffman, S AF Zapawa, Lisa M. Hughes, John R. Benowitz, Neal L. Rigotti, Nancy A. Shiffman, Saul TI Cautions and warnings on the US OTC label for nicotine replacement: What's a doctor to do? SO ADDICTIVE BEHAVIORS LA English DT Article DE Nicotine replacement therapy; Smoking cessation; Substance use disorder; Tobacco use disorder; Tobacco use cessation ID RANDOMIZED CONTROLLED-TRIAL; SMOKING-CESSATION; TRANSDERMAL NICOTINE; TOBACCO DEPENDENCE; DOUBLE-BLIND; GUM USE; PERSISTENT USE; PATCH THERAPY; QUIT SMOKING; REDUCTION AB Background: FDA-approved labeling for over-the-counter (OTC) nicotine replacement therapy (NRT) limits duration of use to a relatively short period of time (10-12 weeks) and explicitly advises against NRT use while smoking or with additional forms of NRT. Objective: To consider and summarize evidence accumulated since the OTC label was created regarding the safety and efficacy of longer-term and concomitant use to provide recommendations regarding these uses. Method: Literature searches were conducted on Medline, journal websites, and Internet search engines, with findings reviewed by six smoking cessation researchers. Results: Persistent (i.e., long-term) use of NRT does not appear harmful and self-selected persistent use is primarily driven by concerns about relapse to smoking, not addiction. Similarly, continued use of NRT and tobacco during a lapse or relapse and combination NRT treatment do not appear harmful and appear to enhance efficacy. Conclusions: Persistent users of NRT should be counseled to reduce and stop NRT only when they are not concerned about relapsing to smoking. Use of NRT with return to smoking during a lapse or relapse should not be automatically discontinued. Combination NRT therapy should be considered for all smokers, especially those who are unable to quit smoking using a single form of NRT. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Zapawa, Lisa M.; Shiffman, Saul] Pinney Associates Inc, Bethesda Metro Ctr 3, Bethesda, MD 20814 USA. [Hughes, John R.] Univ Vermont, Dept Psychiat, Univ Hlth Ctr, Burlington, VT 05401 USA. [Benowitz, Neal L.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94110 USA. [Benowitz, Neal L.] Univ Calif San Francisco, Dept Psychiat & Biopharmaceut Sci, San Francisco, CA 94110 USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Dept Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Shiffman, Saul] Univ Pittsburgh, Smoking Res Grp, Pittsburgh, PA 15260 USA. RP Zapawa, LM (reprint author), 7864 Secretariat Dr, Saline, MI 48176 USA. EM lzapawa@pinneyassociates.com; john.hughes@uvm.edu; nbenowitz@medsfgh.ucsf.edu; nrigotti@partners.org; shiffman@pinneyassociates.com RI Shiffman, Saul/K-7337-2012 FU National Institute on Drug Abuse (NIDA) [DA000490, DA-11557, DA-17825, DA-02277]; National Heart Lung and Blood (NHLBI) [K24-04440]; National Institute on Health; Pfizer; Abbot Pharmaceuticals; Acrux; Aradigm; American Academy of Addiction Psychiatry; American Psychiatric Association; Begbies Traynor; Cambridge Hospital; Cline; Davis and Mann; Constella Group; Consultants in Behavior Change; Dean Foundation; DLA Piper; EPI-Q European Respiratory Society; Evotec; Exchange Limited; Fagerstrom Consulting; Free and Clear; Glaxo-Smith Kline; Golin Harris;; Healthwise; Insyght; Informed; Invivodata; Johns Hopkins University; Reckner; Maine Medical Center; McGill University Medical School; McNeil Pharmaceuticals; Novartis Pharmaceuticals; Oglivy Health PR; Ottawa Heart Institute; Pfizer Pharmaceuticals; Pinney Associates; Propagate Pharmaceuticals; Reuters; Scientia; Selecta; Temple University of Health Sciences; University of Arkansas; University of California-San Francisco; University of Cantabria; University of Kentucky; University of New Mexico; US National Institutes on Health; Wolters Publishing; Xenova; GSKCH; Nabi Biopharmaceuticals FX Dr. Hughes's work on this paper was supported by National Institute on Drug Abuse (NIDA) Senior Scientist Award DA000490 and NIDA grants DA-11557 and DA-17825. NIDA had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication.; Dr. Benowitz's work in preparing this manuscript was supported in part by NIDA grant DA-02277. NIDA had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication.; Dr. Rigotti's efforts on this manuscript were supported in part by a National Heart Lung and Blood (NHLBI) grant K24-04440. NHLBI had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication.; Dr. Hughes is currently employed by The University of Vermont and Fletcher Allen Health Care. Since 7/1/2007, he has received research grants from the National Institute on Health, Pfizer; the latter two develops and sells smoking cessation medications. During this time, he has accepted honoraria or consulting fees from several non-profit and for-profit organizations and companies that develop, sell or promote smoking cessation products or services or educate/advocate about smoking cessation, including: Abbot Pharmaceuticals; Acrux; Aradigm; American Academy of Addiction Psychiatry; American Psychiatric Association; Begbies Traynor; Cambridge Hospital; Cline, Davis and Mann; Constella Group; Consultants in Behavior Change; Dean Foundation; DLA Piper, EPI-Q European Respiratory Society, Evotec; Exchange Limited; Fagerstrom Consulting; Free and Clear; Glaxo-Smith Kline; Golin Harris; Healthwise; Insyght; Informed; Invivodata; Johns Hopkins University; J L Reckner; Maine Medical Center; McGill University Medical School; McNeil Pharmaceuticals; Novartis Pharmaceuticals; Oglivy Health PR; Ottawa Heart Institute, Pfizer Pharmaceuticals; Pinney Associates; Propagate Pharmaceuticals; Reuters; Scientia; Selecta; Temple University of Health Sciences; University of Arkansas; University of California-San Francisco; University of Cantabria; University of Kentucky; University of New Mexico; US National Institutes on Health; Wolters Publishing; and Xenova.; Dr. Benowitz has served as a paid consultant for several pharmaceutical companies, including GSKCH Pfizer and McNeil, that market and/or are developing nicotine and other medications for smoking cessation. Within the past five years, Dr. Benowitz has received research grant support from GSKCH. His family formerly held stock in Pfizer and Johnson and Johnson. Dr. Benowitz has served as a paid expert witness in litigation against tobacco companies.; In the past three years, Dr. Rigotti's institution has received research grant funding from Pfizer and Nabi Biopharmaceuticals to test marketed or investigational smoking cessation products. She has consulted (without honoraria since 2008) for Pfizer and Free and Clear. NR 59 TC 6 Z9 6 U1 4 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD APR PY 2011 VL 36 IS 4 BP 327 EP 332 DI 10.1016/j.addbeh.2010.12.003 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 734PC UT WOS:000288346700008 PM 21220188 ER PT J AU Melanson, SEF Stevenson, K Kim, H Antin, JH Court, MH Ho, VT Ritz, J Soiffer, RJ Kuo, FC Longtine, JA Jarolim, P AF Melanson, Stacy E. F. Stevenson, Kristen Kim, Haesook Antin, Joseph H. Court, Michael H. Ho, Vincent T. Ritz, Jerome Soiffer, Robert J. Kuo, Frank C. Longtine, Janina A. Jarolim, Petr TI The importance of correct assignment of CYP2B6 genetic variants with respect to cyclophosphamide metabolizer status Response SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter C1 [Melanson, Stacy E. F.; Kuo, Frank C.; Longtine, Janina A.; Jarolim, Petr] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Stevenson, Kristen; Kim, Haesook; Antin, Joseph H.; Ho, Vincent T.; Ritz, Jerome; Soiffer, Robert J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Court, Michael H.] Tufts Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02115 USA. RP Melanson, SEF (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD APR PY 2011 VL 86 IS 4 BP 384 EP 384 DI 10.1002/ajh.21997 PG 1 WC Hematology SC Hematology GA 740JW UT WOS:000288790200015 ER PT J AU Gripp, KW Hopkins, E Sol-Church, K Stabley, DL Axelrad, ME Doyle, D Dobyns, WB Hudson, C Johnson, J Tenconi, R Graham, GE Sousa, AB Heller, R Piccione, M Corsello, G Herman, GE Tartaglia, M Lin, AE AF Gripp, Karen W. Hopkins, Elizabeth Sol-Church, Katia Stabley, Deborah L. Axelrad, Marni E. Doyle, Daniel Dobyns, William B. Hudson, Cindy Johnson, John Tenconi, Romano Graham, Gail E. Sousa, Ana Berta Heller, Raoul Piccione, Maria Corsello, Giovanni Herman, Gail E. Tartaglia, Marco Lin, Angela E. TI Phenotypic Analysis of Individuals With Costello Syndrome due to HRAS p.G13C SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Costello syndrome; genotype-phenotype correlation; loose anagen hair; rasopathy ID LOOSE ANAGEN HAIR; NOONAN-LIKE-SYNDROME; ACTIVATING MUTATIONS; ORIGIN; ABNORMALITIES; DISORDERS; SPECTRUM AB Costello syndrome is characterized by severe failure-to-thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation of the wrist (P<0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below -2 SD) without use of growth hormone (P<0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings. (C) 2011 Wiley-Liss, Inc. C1 [Gripp, Karen W.; Hopkins, Elizabeth] Alfred I DuPont Hosp Children, Div Med Genet, Wilmington, DE 19803 USA. [Sol-Church, Katia; Stabley, Deborah L.] Nemours Childrens Clin, Dept Biomed Res, Wilmington, DE USA. [Axelrad, Marni E.] Texas Childrens Hosp, Baylor Coll Med, Psychol Serv, Sect Psychol,Dept Pediat, Houston, TX 77030 USA. [Doyle, Daniel] Alfred I DuPont Hosp Children, Div Endocrinol, Wilmington, DE 19803 USA. [Dobyns, William B.] Seattle Childrens Res Inst, Seattle, WA USA. [Hudson, Cindy; Johnson, John] Shodair Childrens Hosp, Helena, MT USA. [Tenconi, Romano] Univ Padua, Dept Pediat, Clin Genet Unit, Padua, Italy. [Graham, Gail E.] Childrens Hosp Eastern Ontario, Dept Genet, Ottawa, ON K1H 8L1, Canada. [Sousa, Ana Berta] Hosp Santa Maria, Serv Genet Med, Lisbon, Portugal. [Heller, Raoul] Klinikum Univ Koln, Inst Humangenet, Cologne, Germany. [Piccione, Maria; Corsello, Giovanni] Univ Palermo, Mother & Child Dept, Palermo, Italy. [Herman, Gail E.] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA. [Tartaglia, Marco] Ist Super Sanita, Dept Haematol Oncol & Mol Med, I-00161 Rome, Italy. [Lin, Angela E.] MassGen Hosp Children, Genet Unit, Boston, MA USA. RP Gripp, KW (reprint author), Alfred I DuPont Hosp Children, Div Med Genet, 1600 Rockland Rd, Wilmington, DE 19803 USA. EM kgripp@nemours.org OI Sousa, Ana Berta/0000-0001-5889-2492; Tartaglia, Marco/0000-0001-7736-9672; Dobyns, William/0000-0002-7681-2844 FU Nemours Foundation; NIH [4P20 RR020173-01]; Telethon-Italy [GGP10020]; National Center for Research Resources FX We thank the patients and their families for allowing us to share this information. We thank Dr. Peter Herkenrath from the Children's Hospital at the University of Cologne for sharing clinical data. This report was supported by The Nemours Foundation, funds to KSC from NIH grant number 4P20 RR020173-01 from the National Center for Research Resources, and Telethon-Italy (GGP10020) to MT. NR 26 TC 23 Z9 23 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD APR PY 2011 VL 155A IS 4 BP 706 EP 716 DI 10.1002/ajmg.a.33884 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 740KP UT WOS:000288792700005 PM 21438134 ER PT J AU Lin, AE Singh, KE Strauss, A Nguyen, S Rawson, K Kimonis, VE AF Lin, Angela E. Singh, Kathryn E. Strauss, Arthur Son Nguyen Rawson, Kristyn Kimonis, Virginia E. TI An Additional Patient with Mycophenolate Mofetil Embryopathy: Cardiac and Facial Analyses SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE cardiovascular malformation; congenital heart defect; conotruncal; microtia; mycophenolate mofetil; teratogen ID FETAL MALFORMATIONS; KIDNEY-TRANSPLANTATION; PREGNANCY; EXPOSURE; NEWBORN; EAR; DIAGNOSIS; ANOMALIES AB We describe an infant male of Cambodian background who has typical craniofacial features of mycophenolate mofetil (MMF) embryopathy and a complex congenital heart defect (CHD) (double outlet right ventricle, mitral atresia, pulmonic stenosis, and total anomalous pulmonary venous return). Together with four case reports and the 20 patients included in two recent reviews, we report 24 (19 affected, five normal) patients with this pattern of anomalies. Eight (33%) have a CHD, most commonly, conotruncal or aortic arch defects (6/8, 75%). This would support the hypothesis that disturbance of cranial neural crest migration occurs in exposed infants, and may predict which additional anomalies will be observed in the future. We also attempted to score the severity of the facial anomalies in each MMF patient using a system created by plastic surgeons for patients with hemifacial microsomia. This classification had modest utility in comparing severity and correlating facial to extracranial defects. The findings are viewed with caution because of the preliminary methodology. Finally, since several exposed infants have been reported to be minimally affected, we remind clinicians to be sensitive to the potential mild expression of the effects of this teratogen. This awareness may influence clinical management of apparently normal MMF-exposed individuals. (C) 2011 Wiley-Liss, Inc. C1 [Lin, Angela E.] MassGen Hosp Children, Genet Unit, Boston, MA 02114 USA. [Singh, Kathryn E.; Rawson, Kristyn; Kimonis, Virginia E.] Univ Calif Irvine, Div Genet & Metab, Irvine, CA USA. [Strauss, Arthur; Son Nguyen] Miller Childrens Hosp, Long Beach Mem Med Ctr, Long Beach, CA USA. RP Lin, AE (reprint author), MassGen Hosp Children, Genet Unit, 185 Cambridge St,CPZN 2222, Boston, MA 02114 USA. EM lin.angela@mgh.harvard.edu; vkimonis@uci.edu NR 34 TC 17 Z9 18 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD APR PY 2011 VL 155A IS 4 BP 748 EP 756 DI 10.1002/ajmg.a.33934 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 740KP UT WOS:000288792700012 PM 21594997 ER PT J AU de Gonzalez, AB Kim, KP Knudsen, AB Lansdorp-Vogelaar, I Rutter, CM Smith-Bindman, R Yee, J Kuntz, KM van Ballegooijen, M Zauber, AG Berg, CD AF de Gonzalez, Amy Berrington Kim, Kwang Pyo Knudsen, Amy B. Lansdorp-Vogelaar, Iris Rutter, Carolyn M. Smith-Bindman, Rebecca Yee, Judy Kuntz, Karen M. van Ballegooijen, Marjolein Zauber, Ann G. Berg, Christine D. TI Radiation-Related Cancer Risks From CT Colonography Screening: A Risk-Benefit Analysis SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE colonography; colorectal cancer; CT; CT colonography radiation risk; radiation risk; screening ID COMPUTED TOMOGRAPHIC COLONOGRAPHY; COLORECTAL-CANCER; EXTRACOLONIC FINDINGS; IONIZING-RADIATION; TASK-FORCE; POPULATION; COLONOSCOPY; POLYPS; COST AB OBJECTIVE. The purpose of this study was to estimate the ratio of cancers prevented to induced (benefit-risk ratio) for CT colonography (CTC) screening every 5 years from the age of 50 to 80 years. MATERIALS AND METHODS. Radiation-related cancer risk was estimated using risk projection models based on the National Research Council's Biological Effects of Ionizing Radiation (BEIR) VII Committee's report and screening protocols from the American College of Radiology Imaging Network's National CT Colonography Trial. Uncertainty intervals were estimated using Monte Carlo simulation methods. Comparative modeling with three colorectal cancer microsimulation models was used to estimate the potential reduction in colorectal cancer cases and deaths. RESULTS. The estimated mean effective dose per CTC screening study was 8 mSv for women and 7 mSv for men. The estimated number of radiation-related cancers resulting from CTC screening every 5 years from the age of 50 to 80 years was 150 cases/100,000 individuals screened (95% uncertainty interval, 80-280) for men and women. The estimated number of colorectal cancers prevented by CTC every 5 years from age 50 to 80 ranged across the three microsimulation models from 3580 to 5190 cases/100,000 individuals screened, yielding a benefit-risk ratio that varied from 24: 1 (95% uncertainty interval, 13: 1-45: 1) to 35: 1 (19:1-65:1). The benefit-risk ratio for cancer deaths was even higher than the ratio for cancer cases. Inclusion of radiation-related cancer risks from CT examinations performed to follow up extracolonic findings did not materially alter the results. CONCLUSION. Concerns have been raised about recommending CTC as a routine screening tool because of potential harms including the radiation risks. Based on these models, the benefits from CTC screening every 5 years from the age of 50 to 80 years clearly outweigh the radiation risks. C1 [de Gonzalez, Amy Berrington] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kim, Kwang Pyo] Kyung Hee Univ, Dept Nucl Engn, Yongin, Gyeonggi Do, South Korea. [Knudsen, Amy B.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Lansdorp-Vogelaar, Iris; van Ballegooijen, Marjolein] Univ Med Ctr Rotterdam, Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Rutter, Carolyn M.] Grp Hlth Ctr Hlth Studies, Seattle, WA USA. [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Yee, Judy] Vet Affairs Med Ctr, Dept Radiol, San Francisco, CA 94121 USA. [Kuntz, Karen M.] Univ Minnesota, Div Hlth Policy & Management, Minneapolis, MN USA. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Berg, Christine D.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP de Gonzalez, AB (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM berringtona@mail.nih.gov RI Berg , Christine/K-1047-2014 FU GE Healthcare; NCI [U01 CA-97427, U01-CA-088204, U01-CA-097426, U01-CA-115953] FX J. Yee received a research grant from GE Healthcare.; This research was funded by the NCI Intramural Research Program and by NCI grants (U01 CA-97427, U01-CA-088204, U01-CA-097426, and U01-CA-115953). NR 33 TC 50 Z9 50 U1 2 U2 7 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD APR PY 2011 VL 196 IS 4 BP 816 EP 823 DI 10.2214/AJR.10.4907 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 738OP UT WOS:000288650600038 PM 21427330 ER PT J AU Goehler, A Ollendorf, DA Jaeger, M Ladapo, J Neumann, T Gazelle, GS Pearson, SD AF Goehler, Alexander Ollendorf, Daniel A. Jaeger, Marie Ladapo, Joseph Neumann, Till Gazelle, G. Scott Pearson, Steven D. TI A Simulation Model of Clinical and Economic Outcomes of Cardiac CT Triage of Patients With Acute Chest Pain in the Emergency Department SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE acute chest pain; coronary CT angiography; cost effectiveness; decision analysis; myocardial infarction ID CORONARY-ARTERY-DISEASE; ELEVATION MYOCARDIAL-INFARCTION; 64-SLICE COMPUTED-TOMOGRAPHY; COST-EFFECTIVENESS; MISSED DIAGNOSES; ANGIOGRAPHY; GUIDELINES; ACCURACY; ISCHEMIA; PREVALENCE AB OBJECTIVE. Uncertainty exists as to whether coronary CT angiography (CTA) compared with standard of care (SOC) is more effective and efficient in the triage of low-risk emergency department (ED) patients with acute chest pain. Our objective was to construct a simulation model to estimate clinical and economic outcomes. MATERIALS AND METHODS. We constructed a microsimulation model comparing SOC to coronary CTA-based triage of 1000 55-year-old patients (50% men) with acute chest pain, nonsignificant ECG changes, and initial negative cardiac markers. In SOC, patients were reevaluated with serial cardiac markers after 6-8 hours, followed by either nuclear stress imaging (SPECT) or stress echocardiography. In coronary CTA-based triage, patients were imaged immediately and, depending on the results, discharged, held for SPECT or stress echocardiography, or referred directly to invasive coronary angiography. RESULTS. Compared with SOC, coronary CTA-based triage reduced the number of patients referred for invasive coronary angiography from 406 (SPECT) or 370 (stress echocardiography) to 255 per 1000 and resulted in fewer "missed" cases of acute coronary syndrome overall (5 vs 18). Coronary CTA-based triage also resulted in fewer deaths (4 vs 6). Coronary CTA led to immediate discharge of 706 patients and produced average cost-savings in the ED of $851 (SPECT) or $462 (stress echocardiography) per patient. At 30 days after initial ED triage, coronary CTA-based management produced average savings of $283 (SPECT) and average costs of $292 (stress echocardiography) per patient triaged. CONCLUSION. Our model suggests that coronary CTA-based triage of low-risk patients with acute chest pain in the ED might reduce invasive catheterizations, could improve survival, and may save money. C1 [Goehler, Alexander; Jaeger, Marie; Ladapo, Joseph; Gazelle, G. Scott] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA 02114 USA. [Goehler, Alexander] UMIT Univ Hlth Sci Med Informat & Technol, Dept Publ Hlth Med Decis Making & Hlth Technol As, Hall In Tirol, Austria. [Goehler, Alexander] Univ Duisburg Essen, Alfried Krupp von Bohlen & Halbach Fdn Chair Hlth, Essen, Germany. [Ollendorf, Daniel A.; Pearson, Steven D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Clin & Econ Review, Boston, MA 02114 USA. [Neumann, Till] Univ Essen Gesamthsch, W German Heart Inst, Essen, Germany. [Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Boston, MA 02114 USA. RP Goehler, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, 101 Merrimac St,10th Fl, Boston, MA 02114 USA. EM alex@mgh-ita.org NR 32 TC 6 Z9 6 U1 0 U2 3 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD APR PY 2011 VL 196 IS 4 BP 853 EP 861 DI 10.2214/AJR.10.4962 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 738OP UT WOS:000288650600043 PM 21427336 ER PT J AU Cronin, CG Sharma, A Digumarthy, SR Gilman, MD McLoud, T Muse, VV Shepard, JO AF Cronin, Carmel G. Sharma, Amita Digumarthy, Subba R. Gilman, Mathew D. McLoud, Theresa Muse, Victorine V. Shepard, JoAnne O. TI Percutaneous Lung Biopsy After Pneumonectomy: Factors for Improving Success in the Care of Patients at High Risk SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE lung biopsy; lung cancer; pneumonectomy ID NEEDLE ASPIRATION BIOPSY; CHEST TUBE PLACEMENT; COMPUTED-TOMOGRAPHY; PNEUMOTHORAX RATE; AIR-EMBOLISM; PULMONARY; CANCER; PREVENTION; SURVIVAL; LESIONS AB OBJECTIVE. The purpose of this study was to assess the risks and complications of CT-guided needle biopsy of lung nodules in patients with a single lung after pneumonectomy. MATERIALS AND METHODS. A database search for the records of patients who had undergone lung biopsy over a 9-year period revealed that 1771 patients had done so. Fourteen (0.7%) of these patients (11 men, three women; mean age, 63 years; range, 42.4-79.6 years) had undergone pneumonectomy and been referred for biopsy of the contralateral lung. The images and medical records of these patients were reviewed in detail. RESULTS. Lung biopsy was technically successful in 86% (12/14) of cases. All procedures were fine-needle aspiration, and a core biopsy specimen also was obtained in one case. Fifty percent (6/12) of the procedures were performed with local anesthesia alone and 50% with a combination of local anesthesia and conscious sedation. The pneumothorax rate was 25% (3/12). All pneumothoraces were small and asymptomatic, and none required a chest drain. There were no cases of hemoptysis. No other immediate or delayed complications were encountered. Malignancy was found in 83% (10/12) of cases. In one of the other two cases (8%) the result was false-negative, and in the other, the nodules resolved without chemotherapy and were presumed to be inflammatory. CONCLUSION. Percutaneous lung biopsy performed on the single lung in patients who have undergone pneumonectomy is feasible and successful. Lung biopsy in these circumstances should be performed by an experienced radiologist with thoracic surgical backup. C1 [Cronin, Carmel G.; Sharma, Amita; Digumarthy, Subba R.; Gilman, Mathew D.; McLoud, Theresa; Muse, Victorine V.; Shepard, JoAnne O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Cronin, CG (reprint author), Massachusetts Gen Hosp, Dept Radiol, Founders 202,55 Fruit St, Boston, MA 02114 USA. NR 30 TC 1 Z9 1 U1 0 U2 3 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD APR PY 2011 VL 196 IS 4 BP 929 EP 934 DI 10.2214/AJR.10.4920 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 738OP UT WOS:000288650600054 PM 21427347 ER PT J AU Atalay, MK Prince, EA Pearson, CA Chang, KJ AF Atalay, Michael K. Prince, Ethan A. Pearson, Catherine A. Chang, Kevin J. TI The Prevalence and Clinical Significance of Noncardiac Findings on Cardiac MRI SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE cardiac imaging; incidental findings; MRI ID COMPUTED-TOMOGRAPHY; INCIDENTAL FINDINGS; EXTRACARDIAC FINDINGS; CT; ANGIOGRAPHY; PATHOLOGY AB OBJECTIVE. This study aims to evaluate the prevalence, nature, and clinical significance of noncardiac findings (NCFs) at cardiac MRI. MATERIALS AND METHODS. We retrospectively reviewed 240 consecutive, clinically indicated cardiac MRI examinations conducted over a 21-month period. All noncardiac findings (NCFs) were recorded. Those findings that were included in the report impressions were regarded as clinically important (INCF). Electronic medical records and related imaging studies were then reviewed for all patients having INCFs to determine their actual clinical significance. A finding was significant (SNCF) if it was associated with a new diagnosis, treatment, or intervention. The prevalences of findings in the neck, chest, and abdomen were determined. RESULTS. We found 162 NCFs in 104 studies (43%), of which 94 (58%) were INCFs, and 16 (10%) were SNCFs. There was at least one INCF in 65 studies (27%)-67% of which were new-and at least one SNCF in 13 studies (5%). Compared with younger patients, patients 60 years and older were much more likely to have INCFs (43% vs 17%) and SNCFs (12% vs 1%). Overall, 29% of NCFs were in the abdomen, 70% in the chest, and 1% in the neck. The most common INCFs were pleural effusion (n = 26), air-space disease or atelectasis (n = 13), and adenopathy (n = 9). Five new cases of cancer were diagnosed, including lung (n = 2), lymphoma (n = 2), and thyroid (n = 1). CONCLUSION. NCFs are commonly encountered on cardiac MRI studies, many of which are clinically relevant. Proper recognition of NCFs is critical to the comprehensive management of patients referred for cardiac MRI. C1 [Atalay, Michael K.; Prince, Ethan A.; Chang, Kevin J.] Brown Univ, Rhode Isl Hosp, Warren Alpert Sch Med, Dept Diagnost Imaging, Providence, RI 02903 USA. [Pearson, Catherine A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Atalay, MK (reprint author), Brown Univ, Rhode Isl Hosp, Warren Alpert Sch Med, Dept Diagnost Imaging, 593 Eddy St, Providence, RI 02903 USA. EM atalay_99@yahoo.com OI Chang, Kevin/0000-0001-9441-2740 NR 23 TC 20 Z9 20 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD APR PY 2011 VL 196 IS 4 BP W387 EP W393 DI 10.2214/AJR.09.3302 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 738OP UT WOS:000288650600005 PM 21427301 ER PT J AU Krishnaraj, A AF Krishnaraj, Arun TI Impact of a Voice Recognition System on Radiology Report Turnaround Time: Experience From a Non-English-Speaking South Asian Country Reply SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Letter C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RP Krishnaraj, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. NR 2 TC 0 Z9 0 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD APR PY 2011 VL 196 IS 4 BP W486 EP W486 DI 10.2214/AJR.10.5557 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 738OP UT WOS:000288650600022 ER PT J AU Yuki, K Soriano, SG Shimaoka, M AF Yuki, Koichi Soriano, Sulpicio G. Shimaoka, Motomu TI Sedative Drug Modulates T-Cell and Lymphocyte Function-Associated Antigen-1 Function SO ANESTHESIA AND ANALGESIA LA English DT Article ID HUMAN NEUTROPHIL FUNCTIONS; CONFORMATIONAL REGULATION; CYTOKINE PRODUCTION; INTEGRIN LFA-1; SMALL-MOLECULE; I-DOMAIN; COSTIMULATORY SIGNAL; PROPOFOL; ACTIVATION; INTERLEUKIN-2 AB BACKGROUND: Sedative drugs modify immune cell functions via several mechanisms. However, the effects of sedatives on immune function have been primarily investigated in neutrophils and macrophages, and to the lesser extent lymphocytes. Lymphocyte function-associated antigen-1 (LFA-1) is an adhesion molecule that has a central role in regulating immune function of lymphocytes including interleukin-2 (IL-2) production and lymphocyte proliferation. Previous clinical studies reported that propofol and isoflurane reduced IL-2 level in patients, but midazolam did not. We previously demonstrated that isoflurane inhibited LFA-1 binding to its counter ligand, intercellular adhesion molecule-1 (ICAM-1), which might contribute to the reduction of IL-2 levels. In the current study, we examined the effect of propofol, midazolam, and dexmedetomidine on LFA-1/ICAM-1 binding, and the subsequent biological effects. METHODS: The effect of sedative drugs on T-cell proliferation and IL-2 production was measured by calorimetric assays on human peripheral blood mononuclear cells. Because LFA-1/ICAM-1 binding has an important role in T-cell proliferation and IL-2 production, we measured the effect of sedative drugs on ICAM-1 binding to LFA-1 protein (cell-free assay). This analysis was followed by flow cytometric analysis of LFA-1 expressing T-cell binding to ICAM-1 (cell-based assay). To determine whether the drug/LFA-1 interaction is caused by competitive or allosteric inhibition, we analyzed the sedative drug effect on wild-type and high-affinity LFA-1 and a panel of monoclonal antibodies that bind to different regions of LFA-1. RESULTS: Propofol at 10 to 100 mu M inhibited ICAM-1 binding to LFA-1 in cell-free assays and cell-based assays (P < 0.05). However, dexmedetomidine and midazolam did not affect LFA-1/ICAM-1 binding. Propofol directly inhibits LFA-1 binding to ICAM-1 by binding near the ICAM-1 contact area in a competitive manner. At clinically relevant concentrations, propofol, but not dexmedetomidine or midazolam, inhibited IL-2 production (P < 0.05). Additionally, propofol inhibited lymphocyte proliferation (P < 0.05). CONCLUSIONS: Our study suggests that propofol competitively inhibits LFA-1 binding to ICAM-1 on T-cells and suppresses T-cell proliferation and IL-2 production, whereas dexmedetomidine and midazolam do not significantly influence these immunological assays. (Anesth Analg 2011;112:830-38) C1 [Yuki, Koichi; Soriano, Sulpicio G.; Shimaoka, Motomu] Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Shimaoka, Motomu] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Yuki, Koichi; Soriano, Sulpicio G.; Shimaoka, Motomu] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Shimaoka, Motomu] Immune Dis Inst, Boston, MA USA. RP Yuki, K (reprint author), Childrens Hosp, Dept Anesthesiol Perioperat & Pain Med, 300 Longwood Ave, Boston, MA 02115 USA. EM koichi.yuki@childrens.harvard.edu FU National Institutes of Health [HL048675, CA139444]; Children's Hospital Endowed Chair in Pediatric Neuroanesthesia; CHMC Anesthesia Foundation FX Supported by National Institutes of Health grants HL048675 and CA139444 (MS), Children's Hospital Endowed Chair in Pediatric Neuroanesthesia (SGS), and CHMC Anesthesia Foundation (KY and SGS). NR 53 TC 7 Z9 15 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD APR PY 2011 VL 112 IS 4 BP 830 EP 838 DI 10.1213/ANE.0b013e31820dcabb PG 9 WC Anesthesiology SC Anesthesiology GA 739ET UT WOS:000288697000013 PM 21385989 ER PT J AU Glance, LG Neuman, M Martinez, EA Pauker, KY Dutton, RP AF Glance, Laurent G. Neuman, Mark Martinez, Elizabeth A. Pauker, Kenneth Y. Dutton, Richard P. TI Performance Measurement at a "Tipping Point" SO ANESTHESIA AND ANALGESIA LA English DT Article ID QUALITY IMPROVEMENT PROGRAM; BYPASS GRAFT-SURGERY; NEW-YORK-STATE; CLINICAL-PRACTICE GUIDELINES; SURGICAL CARE IMPROVEMENT; EVIDENCE-BASED MEDICINE; HOSPITAL QUALITY; HEALTH-CARE; OPERATIVE MORTALITY; ADMINISTRATIVE DATA C1 [Glance, Laurent G.] Univ Rochester, Med Ctr, Dept Anesthesiol, Sch Med, Rochester, NY 14642 USA. [Neuman, Mark] Univ Penn, Dept Anesthesiol, Philadelphia, PA 19104 USA. [Martinez, Elizabeth A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesiol Crit Care & Pain Med, Boston, MA USA. [Pauker, Kenneth Y.] Saddleback Mem Med Ctr, Anesthesia Serv Sub Sect, Dept Surg, Laguna Hills, CA USA. [Dutton, Richard P.] Univ Maryland, Dept Anesthesiol, Baltimore, MD 21201 USA. RP Glance, LG (reprint author), Univ Rochester, Med Ctr, Dept Anesthesiol, Sch Med, 601 Elmwood Ave,Box 604, Rochester, NY 14642 USA. EM Laurent_Glance@urmc.rochester.edu FU Agency for Healthcare and Quality Research [RO1 HS 16737, K08 HS 013904]; Department of Anesthesiology at the University of Rochester School of Medicine and Dentistry FX Supported in part by grants from the Agency for Healthcare and Quality Research (RO1 HS 16737 to Dr. Glance, and K08 HS 013904 to Dr. Martinez), and by the Department of Anesthesiology at the University of Rochester School of Medicine and Dentistry. NR 86 TC 11 Z9 11 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD APR PY 2011 VL 112 IS 4 BP 958 EP 966 DI 10.1213/ANE.0b013e31820e778d PG 9 WC Anesthesiology SC Anesthesiology GA 739ET UT WOS:000288697000031 PM 21385976 ER PT J AU Zapol, WM AF Zapol, Warren M. TI Life at the Frontier The Third Annual John W. Severinghaus Lecture on Translational Science SO ANESTHESIOLOGY LA English DT Article ID INHALED NITRIC-OXIDE; ACUTE RESPIRATORY-FAILURE; PERSISTENT PULMONARY-HYPERTENSION; DIVING WEDDELL SEALS; DISTRESS-SYNDROME; GAS-EXCHANGE; NEWBORN; SUPPORT; DISEASE; LAMBS C1 [Zapol, Warren M.] Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. [Zapol, Warren M.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Zapol, WM (reprint author), Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, 55 Fruit St,Thier 503, Boston, MA 02114 USA. EM wzapol@partners.org FU National Institutes of Health (Bethesda, Maryland) FX Received from Harvard Medical School, Cambridge, Massachusetts. Submitted for publication August 27, 2010. Accepted for publication November 5, 2010. The author and his laboratory receive a portion of royalties on patents licensed by Massachusetts General Hospital (Boston) to Linde AG (Munich, Germany) and Ikaria, Inc. (Clinton, New Jersey), on inhaled nitric oxide. Support is also provided from institutional and/or departmental sources as well as National Institutes of Health (Bethesda, Maryland). NR 59 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD APR PY 2011 VL 114 IS 4 BP 771 EP 781 DI 10.1097/ALN.0b013e31820708d7 PG 11 WC Anesthesiology SC Anesthesiology GA 739DT UT WOS:000288694400008 PM 21358318 ER PT J AU Kaur, T Singh, J Huffman, MA Petrzelkova, KJ Taylor, NS Xu, SL Dewhirst, FE Paster, BJ Debruyne, L Vandamme, P Fox, JG AF Kaur, Taranjit Singh, Jatinder Huffman, Michael A. Petrzelkova, Klara J. Taylor, Nancy S. Xu, Shilu Dewhirst, Floyd E. Paster, Bruce J. Debruyne, Lies Vandamme, Peter Fox, James G. TI Campylobacter troglodytis sp. nov., Isolated from Feces of Human-Habituated Wild Chimpanzees (Pan troglodytes schweinfurthii) in Tanzania SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID MAHALE MOUNTAINS; INTESTINAL PARASITES; GENETIC RELATEDNESS; MACACA-NEMESTRINA; NATIONAL-PARK; GREAT APES; IDENTIFICATION; JEJUNI; HELICOBACTER; UPSALIENSIS AB The transmission of simian immunodeficiency and Ebola viruses to humans in recent years has heightened awareness of the public health significance of zoonotic diseases of primate origin, particularly from chimpanzees. In this study, we analyzed 71 fecal samples collected from 2 different wild chimpanzee (Pan troglodytes) populations with different histories in relation to their proximity to humans. Campylobacter spp. were detected by culture in 19/56 (34%) group 1 (human habituated for research and tourism purposes at Mahale Mountains National Park) and 0/15 (0%) group 2 (not human habituated but propagated from an introduced population released from captivity over 30 years ago at Rubondo Island National Park) chimpanzees, respectively. Using 16S rRNA gene sequencing, all isolates were virtually identical (at most a single base difference), and the chimpanzee isolates were most closely related to Campylobacter helveticus and Campylobacter upsaliensis (94.7% and 95.9% similarity, respectively). Whole-cell protein profiling, amplified fragment length polymorphism analysis of genomic DNA, hsp60 sequence analysis, and determination of the mol% G+C content revealed two subgroups among the chimpanzee isolates. DNA-DNA hybridization experiments confirmed that both subgroups represented distinct genomic species. In the absence of differential biochemical characteristics and morphology and identical 16S rRNA gene sequences, we propose to classify all isolates into a single novel nomenspecies, Campylobacter troglodytis, with strain MIT 05-9149 as the type strain; strain MIT 05-9157 is suggested as the reference strain for the second C. troglodytis genomovar. Further studies are required to determine whether the organism is pathogenic to chimpanzees and whether this novel Campylobacter colonizes humans and causes enteric disease. C1 [Taylor, Nancy S.; Xu, Shilu; Fox, James G.] MIT, Div Comparat Med, Cambridge, MA 02139 USA. [Kaur, Taranjit; Singh, Jatinder] Virginia Tech, Virginia Maryland Reg Coll Vet Med, Blacksburg, VA 24061 USA. [Huffman, Michael A.] Kyoto Univ, Primate Res Inst, Aichi, Japan. [Petrzelkova, Klara J.] Acad Sci Czech Republic, Inst Vertebrate Biol, CS-60365 Brno, Czech Republic. [Petrzelkova, Klara J.] Liberec Zoo, Liberec 46001, Czech Republic. [Dewhirst, Floyd E.; Paster, Bruce J.] Forsyth Inst, Boston, MA 02115 USA. [Debruyne, Lies; Vandamme, Peter] Univ Ghent, Dept Biochem & Microbiol, Fac Sci, B-9000 Ghent, Belgium. RP Fox, JG (reprint author), MIT, Div Comparat Med, 77 Massachusetts Ave,Bldg 16-825, Cambridge, MA 02139 USA. EM jgfox@mit.edu RI Vandamme, Peter/B-7967-2009; Petrzelkova, Klara/G-7111-2014; OI Vandamme, Peter/0000-0002-5581-7937 FU [NSF 0238069]; [NIH R01CA067529] FX This work was supported by grants NSF 0238069 (T.J.S.) and NIH R01CA067529 (J.G.F.). NR 59 TC 10 Z9 10 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD APR PY 2011 VL 77 IS 7 BP 2366 EP 2373 DI 10.1128/AEM.01840-09 PG 8 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 741HT UT WOS:000288855500022 PM 21278267 ER PT J AU Nahrendorf, M Keliher, E Marinelli, B Leuschner, F Robbins, CS Gerszten, RE Pittet, MJ Swirski, FK Weissleder, R AF Nahrendorf, Matthias Keliher, Edmund Marinelli, Brett Leuschner, Florian Robbins, Clinton S. Gerszten, Robert E. Pittet, Mikael J. Swirski, Filip K. Weissleder, Ralph TI Detection of Macrophages in Aortic Aneurysms by Nanoparticle Positron Emission Tomography-Computed Tomography SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE aneurysms; imaging agents; macrophages; positron emission tomography; nanoparticle ID FOR-VASCULAR-SURGERY; MYOCARDIAL-INFARCTION; PRACTICE GUIDELINES; SPLENIC RESERVOIR; INFLAMMATION; MONOCYTES; SOCIETY; MICE; WALL; MANAGEMENT AB Objective-Current management of aortic aneurysms (AAs) relies primarily on size criteria to determine whether invasive repair is indicated to preempt rupture. We hypothesized that emerging molecular imaging tools could be used to more sensitively gauge local inflammation. Because macrophages are key effector cells that destabilize the extracellular matrix in the arterial wall, it seemed likely that they would represent suitable imaging targets. We here aimed to develop and validate macrophage-targeted nanoparticles labeled with fluorine-18 ((18)F) for positron emission tomography-computed tomography (PET-CT) detection of inflammation in AAs. Methods and Results-Aneurysms were induced in apolipoprotein E(-/-) mice via systemic administration of angiotensin II. Mice were imaged using PET-CT and a monocyte/ macrophage-targeted nanoparticle. AAs were detected by contrast-enhanced micro-CT and had a mean diameter of 1.85 +/- 0.08 mm, whereas normal aortas measured 1.07 +/- 0.03 (P < 0.05). The in vivo PET signal was significantly higher in aneurysms (standard uptake value, 2.46 +/- 0.48) compared with wild-type aorta (0.82 +/- 0.05, P < 0.05). Validation with scintillation counting, autoradiography, fluorescence, and immunoreactive histology and flow cytometry demonstrated that nanoparticles localized predominantly to monocytes and macrophages within the aneurysmatic wall. Conclusion-PET-CT imaging with (18)F-labeled nanoparticles allows quantitation of macrophage content in a mouse model of AA. (Arterioscler Thromb Vasc Biol. 2011;31:750-757.) C1 [Nahrendorf, Matthias; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Nahrendorf, M (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM mnahrendorf@mgh.harvard.edu; rweissleder@mgh.harvard.edu FU NIH [UO1-HL080731/HHSN268201000044C, R24-CA92782, R01-HL095629, R01-HL096576, R01-HL095612]; American Heart Association Established Investigator Award; Deutsche Herzstiftung e.V FX This work was funded in parts by grants from the NIH Translational Program of Excellence in Nanotechnology Grants UO1-HL080731/HHSN268201000044C, R24-CA92782 (to R.W.), R01-HL095629 and R01-HL096576 (to M.N.), and R01-HL095612 (to F.K.S.); an American Heart Association Established Investigator Award (to R.E.G.); and Deutsche Herzstiftung e.V. (to F.L.). NR 28 TC 72 Z9 72 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD APR PY 2011 VL 31 IS 4 BP 750 EP U67 DI 10.1161/ATVBAHA.110.221499 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 735SP UT WOS:000288437800009 PM 21252070 ER PT J AU Sher, L AF Sher, Leo TI Is it possible to predict suicide? SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY LA English DT Letter C1 [Sher, Leo] James J Peters Vet Adm Med Ctr, New York, NY USA. [Sher, Leo] Mt Sinai Sch Med, New York, NY USA. RP Sher, L (reprint author), James J Peters Vet Adm Med Ctr, New York, NY USA. NR 7 TC 0 Z9 0 U1 1 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0004-8674 J9 AUST NZ J PSYCHIAT JI Aust. N. Z. J. Psych. PD APR PY 2011 VL 45 IS 4 PG 1 WC Psychiatry SC Psychiatry GA 736OK UT WOS:000288503800012 ER PT J AU Lacount, LT Barbieri, R Park, K Kim, J Brown, EN Kuo, B Napadow, V AF Lacount, Lauren T. Barbieri, Riccardo Park, Kyungmo Kim, Jieun Brown, Emery N. Kuo, Braden Napadow, Vitaly TI Static and Dynamic Autonomic Response with Increasing Nausea Perception SO AVIATION SPACE AND ENVIRONMENTAL MEDICINE LA English DT Article DE motion sickness; heart rate variability; skin conductance response; galvanic skin response; vestibular ID HEART-RATE-VARIABILITY; MOTION SICKNESS STIMULATION; SUSCEPTIBILITY; COMPONENTS; CHEMOTHERAPY; DISCOMFORT; MODEL AB LACOUNT LT, BARBIERI R, PARK K, KIM J, BROWN EN, KUO B, NAPADOW V. Static and dynamic autonomic response with increasing nausea perception. Aviat Space Environ Med 2011; 82:424-33. Background: Nausea is a commonly occurring symptom typified by epigastric discomfort with urge to vomit. The relationship between autonomic nervous system (ANS) outflow and increasing nausea perception is not fully understood. Methods: Our study employed a nauseogenic visual stimulus (horizontally translating stripes) while 17 female subjects freely rated transitions in nausea level and autonomic outflow was measured (heart rate, HR; heart rate variability, HRV; skin conductance response, SCR; respiratory rate). We also adopted a recent approach to continuous high-frequency (HF) HRV estimation to evaluate dynamic cardiovagal modulation. Results: HR increased from baseline for all increasing nausea transitions, especially transition to strong nausea (15.0 +/- 11.4 bpm), but decreased (-6.6 +/- 4.6 bpm) once the visual stimulus ceased. SCR also increased for all increasing nausea transitions, especially transition to strong nausea (1.76 +/- 1.68 mu S), but continued to increase (0.52 +/- 0.65 mu S) once visual stimulation ceased. LF/HF HRV increased following transition to moderate (1.54 +/- 2.11 a.u.) and strong (2.57 +/- 3.49 a.u.) nausea, suggesting a sympathetic shift in sympathovagal balance. However, dynamic HF HRV suggested that bursts of cardiovagal modulation precede transitions to higher nausea, perhaps influencing subjects to rate higher levels of nausea. No significant change in respiration rate was found. Conclusions: Our results suggest that increasing nausea perception is associated with both increased sympathetic and decreased parasympathetic ANS modulation. These findings corroborate past ANS studies of nausea, applying perception-linked analyses and dynamic estimation of cardiovagal modulation in response to nausea. C1 [Lacount, Lauren T.; Kim, Jieun; Napadow, Vitaly] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Barbieri, Riccardo; Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Charlestown, MA 02129 USA. [Park, Kyungmo] Kyung Hee Univ, Dept Biomed Engn, Yongin, South Korea. [Kuo, Braden] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastroenterol Unit, Boston, MA USA. RP Napadow, V (reprint author), Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, 149 13th St,2301, Charlestown, MA 02129 USA. EM vitaly@nmr.mgh.harvard.edu OI Barbieri, Riccardo/0000-0001-9381-3833 FU NIH [R01-HL084502, R01-DA015644, DP1-OD003646, K01-AT002166, P01-AT002048, R01-AT004714, F05-AT003770, K23-DK069614]; NCRR [P41RR14075, 1 UL1 RR025758-01]; Mental Illness and Neuroscience Discovery (MIND) Institute; International Foundation of Functional GI Disorders; Institute of Information Technology Advancement, Korea [IITA-2008-(C1090-0801-0002)] FX We would like to thank NIH for funding support (RB: R01-HL084502; EB: R01-DA015644 and DP1-OD003646; VN: K01-AT002166, P01-AT002048, R01-AT004714; KP: F05-AT003770; BK: K23-DK069614), the NCRR (P41RR14075; CRC 1 UL1 RR025758-01), the Mental Illness and Neuroscience Discovery (MIND) Institute, and the International Foundation of Functional GI Disorders. Dr. Park was also supported by the Institute of Information Technology Advancement, Korea IITA-2008-(C1090-0801-0002). We would also like to thank Dr. Mark Vangel for technical assistance on statistical analyses of the data. NR 38 TC 14 Z9 14 U1 2 U2 11 PU AEROSPACE MEDICAL ASSOC PI ALEXANDRIA PA 320 S HENRY ST, ALEXANDRIA, VA 22314-3579 USA SN 0095-6562 EI 1943-4448 J9 AVIAT SPACE ENVIR MD JI Aviat. Space Environ. Med. PD APR PY 2011 VL 82 IS 4 BP 424 EP 433 DI 10.3357/ASEM.2932.2011 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Sport Sciences SC Public, Environmental & Occupational Health; General & Internal Medicine; Sport Sciences GA 740YC UT WOS:000288829300003 PM 21485400 ER PT J AU Taylor, L Zhou, XH AF Taylor, Leslie Zhou, Xiao-Hua TI Methods for clustered encouragement design studies with noncompliance and missing data SO BIOSTATISTICS LA English DT Article DE Causal inference; Clustered encouragement design; Complier average causal effect; Missing data; Multiple imputation; Noncompliance; Nonresponse; Principal stratification ID PRINCIPAL STRATIFICATION APPROACH; BROKEN RANDOMIZED EXPERIMENTS; CHRONIC HEART-FAILURE; TO-TREAT ANALYSIS; CLINICAL-TRIALS; BAYESIAN-INFERENCE; CAUSAL INFERENCE; POTENTIAL OUTCOMES; IGNORABILITY; NONRESPONSE AB Encouragement design studies are particularly useful for estimating the effect of an intervention that cannot itself be randomly administered to some and not to others. They require a randomly selected group receive extra encouragement to undertake the treatment of interest, where the encouragement typically takes the form of additional information or incentives. We consider a "clustered encouragement design" (CED), where the randomization is at the level of the clusters (e.g. physicians), but the compliance with assignment is at the level of the units (e.g. patients) within clusters. Noncompliance and missing data are particular problems in encouragement design studies, where encouragement to take the treatment, rather than the treatment itself, is randomized. The motivating study looks at whether computer-based care suggestions can improve patient outcomes in veterans with chronic heart failure. Since physician adherence has been inadequate, the original study focused on methods to improve physician adherence, although an equally important question is whether physician adherence improves patient outcomes. Here, we reanalyze the data to determine the effect of physician adherence on patient outcomes. We propose causal inference methodology for the effect of a treatment versus a control in a randomized CED study with all-or-none compliance at the unit level. These methods extend the current approaches to account for nonignorable missing data and use an alternative approach to inference using multiple imputation methods, which have been successfully applied to a wide variety of missing data problems and have recently been applied to the potential outcomes framework of causal inference (Taylor and Zhou, 2009b). C1 [Taylor, Leslie; Zhou, Xiao-Hua] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Taylor, Leslie; Zhou, Xiao-Hua] VA Puget Sound Hlth Care Syst, Biostat Unit, Hlth Serv Res & Dev Ctr Excellence, Seattle, WA 98101 USA. RP Zhou, XH (reprint author), Univ Washington, Dept Biostat, Seattle, WA 98195 USA. EM taylorl@u.washington.edu; azhou@u.washington.edu FU VA Puget Sound Health Care System; Dr. Zhou's VA Research Career Scientist Award [RCD 05-196] FX The VA Puget Sound Health Care System and Dr. Zhou's VA Research Career Scientist Award (RCD 05-196). NR 37 TC 1 Z9 1 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 J9 BIOSTATISTICS JI Biostatistics PD APR PY 2011 VL 12 IS 2 BP 313 EP 326 DI 10.1093/biostatistics/kxq065 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 740ND UT WOS:000288800600010 PM 20974677 ER PT J AU Baba, Y Nosho, K Shima, K Hayashi, M Meyerhardt, JA Chan, AT Giovannucci, E Fuchs, CS Ogino, S AF Baba, Yoshifumi Nosho, Katsuhiko Shima, Kaori Hayashi, Marika Meyerhardt, Jeffrey A. Chan, Andrew T. Giovannucci, Edward Fuchs, Charles S. Ogino, Shuji TI Phosphorylated AKT Expression Is Associated With PIK3CA Mutation, Low Stage, and Favorable Outcome in 717 Colorectal Cancers SO CANCER LA English DT Article DE pAKT; PI3K; clinical outcome; personalized medicine; colorectal carcinoma ID ISLAND METHYLATOR PHENOTYPE; FATTY-ACID SYNTHASE; CELL LUNG-CANCER; MICROSATELLITE INSTABILITY; BREAST-CANCER; ACTIVATED AKT; COLON-CANCER; PROGNOSTIC-SIGNIFICANCE; BRAF MUTATION; SURVIVAL AB BACKGROUND: AKT (AKT1, AKT2, and AKT3) was a downstream effector of phosphatidylinositide-3-kinase (PI3K) and played crucial roles in protein synthesis, cellular metabolism, survival, and proliferation. The PI3K/AKT pathway was commonly activated in human cancers and was recognized as a potential target for anticancer therapy. Nonetheless, clinical, molecular, or prognostic features of AKT-activated colon cancer remained uncertain. METHODS: Using a database of 717 colon and rectal cancers in the Nurses' Health Study and the Health Professionals Follow-up Study, Ser473 phosphorylated AKT (p-AKT) expression was detected in 448 (62%) tumors by immunohistochemistry. Cox proportional hazards model was used to compute mortality hazards ratio (HR), adjusting for clinical and tumoral features, including PIK3CA, KRAS, BRAF, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE-1 methylation, TP53 (p53), and FASN (fatty acid synthase). RESULTS: Tumor p-AKT expression was associated with PIK3CA mutation (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.12-2.80; P = .015). p-AKT expression was significantly associated with longer colorectal cancer-specific survival in Kaplan-Meier analysis (log-rank P = .0005), univariate Cox regression (HR, 0.62; 95% CI, 0.47-0.82; P = .0006) and multivariate analysis (adjusted HR, 0.75; 95% CI, 0.56-0.99; P = .048) adjusting for clinical and molecular variables including PIK3CA, MSI, CIMP and LINE-1 hypomethylation. p-AKT expression was inversely associated with high stage (III-IV) (adjusted OR, 0.63; 95% CI, 0.45-0.88, P = .0071). CONCLUSIONS: p-AKT expression in colorectal cancer is associated with low stage and good prognosis. p-AKT may serve as a tissue biomarker to identify patients with superior prognosis and a possible therapeutic target (analogous to estrogen receptor ESR1 in breast cancer). Cancer 2011; 117: 1399-408. (C) 2010 American Cancer Society. C1 [Baba, Yoshifumi; Nosho, Katsuhiko; Shima, Kaori; Hayashi, Marika; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Dept Med Oncol, Boston, MA 02115 USA. [Baba, Yoshifumi; Nosho, Katsuhiko; Shima, Kaori; Hayashi, Marika; Meyerhardt, Jeffrey A.; Giovannucci, Edward; Fuchs, Charles S.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol & Nutr, Boston, MA 02115 USA. [Giovannucci, Edward; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Ogino, S (reprint author), Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Dept Med Oncol, 44 Binney St,Room JF-215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU U.S. National Institute of Health (NIH) [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826, R01 CA151993]; Bennett Family Fund; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; Uehara Memorial Foundation FX Funding: U.S. National Institute of Health (NIH) grants P01 CA87969 (to S. Hankinson), P01 CA55075 (to W. Willett), P50 CA127003 (to C. S. F.), K07 CA122826 (to S.O.), and R01 CA151993 (to S.O.); the Bennett Family Fund; and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. Y.B. was supported by a fellowship grant from the Uehara Memorial Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 52 Z9 55 U1 0 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2011 VL 117 IS 7 BP 1399 EP 1408 DI 10.1002/cncr.25630 PG 10 WC Oncology SC Oncology GA 737IE UT WOS:000288561700009 PM 21425139 ER PT J AU Friese, CR Earle, CC Magazu, LS Brown, JR Neville, BA Hevelone, ND Richardson, LC Abel, GA AF Friese, Christopher R. Earle, Craig C. Magazu, Lysa S. Brown, Jennifer R. Neville, Bridget A. Hevelone, Nathanael D. Richardson, Lisa C. Abel, Gregory A. TI Timeliness and Quality of Diagnostic Care for Medicare Recipients With Chronic Lymphocytic Leukemia SO CANCER LA English DT Article DE chronic lymphocytic leukemia; diagnosis; outcomes; flow cytometry; SEER-Medicare ID FAMILY PHYSICIANS KNOWLEDGE; ACUTE MYOCARDIAL-INFARCTION; BREAST-CANCER; DELAY; MANAGEMENT; SURVIVAL; OLDER; TIME; SEX AB BACKGROUND: Little is known about the patterns of care relating to the diagnosis of chronic lymphocytic leukemia (CLL), including the use of modern diagnostic techniques such as flow cytometry. METHODS: The authors used the SEER-Medicare database to identify subjects diagnosed with CLL from 1992 to 2002 and defined diagnostic delay as present when the number of days between the first claim for a CLL-associated sign or symptom and SEER diagnosis date met or exceeded the median for the sample. The authors then used logistic regression to estimate the likelihood of delay and Cox regression to examine survival. RESULTS: For the 5086 patients analyzed, the median time between sign or symptom and CLL diagnosis was 63 days (interquartile range [IQR] = 0-251). Predictors of delay included age >= 75 (OR 1.45 [1.27-1.65]), female gender (OR 1.22 [1.07-1.39]), urban residence (OR 1.46 [1.19 to 1.79]), >= 1 comorbidities (OR 2.83 [2.45-3.28]) and care in a teaching hospital (OR 1.20 [1.05-1.38]). Delayed diagnosis was not associated with survival (HR 1.11 [0.99-1.25]), but receipt of flow cytometry within thirty days before or after diagnosis was (HR 0.84 [0.76-0.91]). CONCLUSIONS: Sociodemographic characteristics affect diagnostic delay for CLL, although delay does not seem to impact mortality. In contrast, receipt of flow cytometry near the time of diagnosis is associated with improved survival. Cancer 2011; 117: 1470-7. (C) 2010 American Cancer Society. C1 [Abel, Gregory A.] Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Med Oncol, Div Hematol Malignancies, Boston, MA 02115 USA. [Hevelone, Nathanael D.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Richardson, Lisa C.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. [Friese, Christopher R.] Univ Michigan, Sch Nursing, Div Nursing Business & Hlth Syst, Ann Arbor, MI 48109 USA. [Earle, Craig C.] Univ Toronto, Toronto, ON, Canada. [Earle, Craig C.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Magazu, Lysa S.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. RP Abel, GA (reprint author), Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Dept Med Oncol, Div Hematol Malignancies, 44 Binney St,Smith 271, Boston, MA 02115 USA. EM gregory_abel@dfci.harvard.edu RI Friese, Christopher/D-2097-2013; OI Friese, Christopher/0000-0002-2281-2056; Hevelone, Nathanael/0000-0003-4740-2085 FU National Cancer Institute [R25 CA 057711-12]; Division of Cancer Prevention and Control of the Centers for Disease Control and Prevention (CDC) in Atlanta GA [200-2002-00, 575]; National Institute of Health [R00 NR01570] FX This project was supported by grants from the National Cancer Institute (R25 CA 057711-12, Glorian Sorensen), and the Division of Cancer Prevention and Control of the Centers for Disease Control and Prevention (CDC) in Atlanta GA (Grant #200-2002-00,575, Task Order 21, Gregory A. Abel, principal investigator). In addition, Dr. Friese was supported by a grant from the National Institute of Health (R00 NR01570). The findings and conclusions in this report do not necessarily represent the CDC's views. NR 32 TC 12 Z9 12 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD APR 1 PY 2011 VL 117 IS 7 BP 1470 EP 1477 DI 10.1002/cncr.25655 PG 8 WC Oncology SC Oncology GA 737IE UT WOS:000288561700018 PM 21425148 ER PT J AU Tolcher, AW Appleman, LJ Shapiro, GI Mita, AC Cihon, F Mazzu, A Sundaresan, PR AF Tolcher, Anthony W. Appleman, Leonard J. Shapiro, Geoffrey I. Mita, Alain C. Cihon, Frank Mazzu, Arthur Sundaresan, Pavur R. TI A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Cardiovascular adverse event (CAE); Left ventricular ejection fraction (LVEF); Hypertension; QT/QTc interval; Sorafenib; Cardiovascular profile ID RENAL-CELL CARCINOMA; TYROSINE KINASE INHIBITOR; ENDOTHELIAL GROWTH-FACTOR; REFRACTORY SOLID TUMORS; SUNITINIB MALATE; ANTITUMOR-ACTIVITY; CARDIAC TOXICITY; QT PROLONGATION; HEART-FAILURE; HYPERTENSION AB To characterize the cardiovascular profile of sorafenib, a multitargeted kinase inhibitor, in patients with advanced cancer. Fifty-three patients with advanced cancer received oral sorafenib 400 mg bid in continuous 28-day cycles in this open-label study. Left ventricular ejection fraction (LVEF) was evaluated using multigated acquisition scanning at baseline and after 2 and 4 cycles of sorafenib. QT/QTc interval on the electrocardiograph (ECG) was measured in triplicate with a Holter 12-lead ECG at baseline and after 1 cycle of sorafenib. Heart rate (HR) and blood pressure (BP) were obtained in duplicate at baseline and after 1 and 4 cycles of sorafenib. Plasma pharmacokinetic data were obtained for sorafenib and its 3 main metabolites after 1 and 4 cycles of sorafenib. LVEF (SD) mean change from baseline was -0.8 (+/- 8.6) LVEF(%) after 2 cycles (n = 31) and -1.2 (+/- 7.8) LVEF(%) after 4 cycles of sorafenib (n = 24). The QT/QTc mean changes from baseline observed at maximum sorafenib concentrations (t (max)) after 1 cycle (n = 31) were small (QTcB: 4.2 ms; QTcF: 9.0 ms). Mean changes observed after 1 cycle in BP (n = 31) and HR (n = 30) at maximum sorafenib concentrations (t (max)) were moderate (up to 11.7 mm Hg and -6.6 bpm, respectively). No correlation was found between the AUC and C (max) of sorafenib and its main metabolites and any cardiovascular parameters. The effects of sorafenib on changes in QT/QTc interval on the ECG, LVEF, BP, and HR were modest and unlikely to be of clinical significance in the setting of advanced cancer treatment. C1 [Tolcher, Anthony W.] START S Texas Accelerated Res Therapeut, San Antonio, TX 78229 USA. [Appleman, Leonard J.] Univ Pittsburgh, Inst Canc, UPMC Canc Pavil, Pittsburgh, PA 15232 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Dept Med Oncol, Early Drug Dev Ctr, Boston, MA 02115 USA. [Shapiro, Geoffrey I.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Mita, Alain C.] Canc Therapy & Res Ctr S Texas, Inst Drug Dev, San Antonio, TX 78229 USA. [Cihon, Frank] Bayer Healthcare Pharmaceut Inc, Clin Stat, Montville, NJ 07045 USA. [Mazzu, Arthur; Sundaresan, Pavur R.] Bayer Healthcare Pharmaceut Inc, Pharmacodynam, Montville, NJ 07045 USA. RP Tolcher, AW (reprint author), START S Texas Accelerated Res Therapeut, 4319 Med Dr,Suite 205, San Antonio, TX 78229 USA. EM atolcher@start.stoh.com OI Appleman, Leonard/0000-0003-4951-7388 FU Bayer HealthCare Pharmaceuticals-Onyx Pharmaceuticals FX This study was supported by Bayer HealthCare Pharmaceuticals-Onyx Pharmaceuticals. We thank the study participants and their families; study center staff; the clinical data management team at Bayer HealthCare Pharmaceuticals Inc; and Aurora O'Brate, PhD, from Ogilvy Healthworld, who was supported by Bayer HealthCare Pharmaceuticals Inc, to provide editorial support for the preparation of this manuscript. NR 45 TC 29 Z9 29 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 EI 1432-0843 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD APR PY 2011 VL 67 IS 4 BP 751 EP 764 DI 10.1007/s00280-010-1372-3 PG 14 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 740MF UT WOS:000288798100003 PM 20521052 ER PT J AU Shimizu, Y Hamazaki, Y Hattori, M Doi, K Terada, N Kobayashi, T Toda, Y Yamasaki, T Inoue, T Kajita, Y Maeno, A Kamba, T Mikami, Y Kamoto, T Yamada, T Kanno, T Yoshikawa, K Ogawa, O Minato, N Nakamura, E AF Shimizu, Yosuke Hamazaki, Yoko Hattori, Masakazu Doi, Keiko Terada, Naoki Kobayashi, Takashi Toda, Yoshinobu Yamasaki, Toshinari Inoue, Takahiro Kajita, Yoichiro Maeno, Atsushi Kamba, Tomomi Mikami, Yoshiki Kamoto, Toshiyuki Yamada, Tomomi Kanno, Toru Yoshikawa, Kiyotsugu Ogawa, Osamu Minato, Nagahiro Nakamura, Eijiro TI SPA-1 controls the invasion and metastasis of human prostate cancer SO CANCER SCIENCE LA English DT Article ID GTPASE-ACTIVATING PROTEIN; BREAST-CANCER; CELL-ADHESION; RAP1 ACTIVATION; MIGRATION; SURVIVAL; SIGNAL; MECHANISMS; PATHWAY; KINASE AB Recent studies suggest that SIPA1 encoding a Rap GTPase-activating protein SPA-1 is a candidate metastasis efficiency-modifying gene in human breast cancer. In this study, we investigated the expression and function of SPA-1 in human prostate cancer (CaP). Immunohistochemical studies of tumor specimens from CaP patients revealed a positive correlation of SPA-1 expression with disease progression and metastasis. The correlation was recapitulated in human CaP cell lines; LNCaP that rarely showed metastasis in SCID mice expressed an undetectable level of SPA-1, whereas highly metastatic PC3 showed abundant SPA-1 expression. Moreover, SIPA1 transduction in LNCaP caused prominent abdominal lymph node metastasis without affecting primary tumor size, whereas shRNA-mediated SIPA1 knockdown or expression of a dominant-active Rap1 mutant (Rap1V12) in PC3 suppressed metastasis. LNCaP transduced with SPA-1 (LNCaP/SPA-1) showed attenuated adhesion to the precoated extracellular matrices (ECM) including collagens and fibronectin, due to defective ECM-medicated Rap1 activation. In addition, LNCaP/SPA-1 showed a diminished level of nuclear Brd4, which is known to bind SPA-1, resulting in reduced expression of a series of ECM-related genes. These results suggest that SPA-1 plays an important role in controlling metastasis efficiency of human CaP by regulating the expression of and interaction with ECM in the primary sites. (Cancer Sci 2011; 102: 828-836) C1 [Yoshikawa, Kiyotsugu; Nakamura, Eijiro] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yoshikawa, Kiyotsugu; Nakamura, Eijiro] Harvard Univ, Sch Med, Boston, MA USA. [Shimizu, Yosuke; Terada, Naoki; Kobayashi, Takashi; Yamasaki, Toshinari; Inoue, Takahiro; Kajita, Yoichiro; Maeno, Atsushi; Kamba, Tomomi; Kamoto, Toshiyuki; Kanno, Toru; Ogawa, Osamu] Kyoto Univ, Grad Sch Med, Dept Urol, Kyoto, Japan. [Hamazaki, Yoko; Hattori, Masakazu; Doi, Keiko; Minato, Nagahiro] Kyoto Univ, Grad Sch Med, Dept Immunol & Cell Biol, Kyoto, Japan. [Toda, Yoshinobu] Kyoto Univ, Grad Sch Med, Anat Ctr, Kyoto, Japan. [Mikami, Yoshiki] Kyoto Univ, Grad Sch Med, Anat Pathol Lab, Kyoto, Japan. [Yamada, Tomomi] Mie Univ, Grad Sch Med, Tsu, Mie 514, Japan. RP Nakamura, E (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM nakamura_eijiro@dfci.harvard.edu FU Ministry of Education, Culture, Sports, Science and Technology, Japan; Yamaguchi Endocrine Research Association; Organon Urology Academia; Takeda Science Foundation; Japanese Foundation for Prostate Research FX This work was supported by Grant-in-Aid from Ministry of Education, Culture, Sports, Science and Technology, Japan, Yamaguchi Endocrine Research Association, Organon Urology Academia, Takeda Science Foundation and the Japanese Foundation for Prostate Research. NR 35 TC 17 Z9 19 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1347-9032 EI 1349-7006 J9 CANCER SCI JI Cancer Sci. PD APR PY 2011 VL 102 IS 4 BP 828 EP 836 DI 10.1111/j.1349-7006.2011.01876.x PG 9 WC Oncology SC Oncology GA 737DY UT WOS:000288550300023 PM 21251160 ER PT J AU Kalva, SP Marentis, TC Yeddula, K Somarouthu, B Wicky, S Stecker, MS AF Kalva, Sanjeeva P. Marentis, Theodore C. Yeddula, Kalpana Somarouthu, Bhanusupriya Wicky, Stephan Stecker, Michael S. TI Long-Term Safety and Effectiveness of the "OptEase" Vena Cava Filter SO CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID CLINICAL-EXPERIENCE; RETRIEVAL; MULTICENTER; RISK AB To assess the long-term safety and effectiveness of the OptEase inferior vena cava (IVC) filter. In this Institutional Review Board-approved, retrospective study, we reviewed data of 71 patients who received an OptEase filter at our institution from 2002 to 2007. Thirty-nine (55%) patients had symptoms of venous thromboembolism before filter placement. The indications for filter included contraindication to anticoagulation in 31 (44%) patients, prophylaxis against pulmonary embolism (PE) in 29 (41%) patients, and failure of anticoagulation in 11 (15%) patients. Procedure-related complications, such as symptomatic post-filter PE, deep venous thrombosis (DVT), IVC occlusion, and incidental imaging-evident filter-related complications, were recorded. Safety was assessed by the occurrence of filter-related complications during placement and follow-up. Effectiveness was assessed by the occurrence of post-filter PE. Sixty-five (92%) filters were placed under fluoroscopy, and 6 (8%) were placed using intravascular ultrasound guidance. Seventy (99%) filters were placed successfully. Seven (10%) filters were placed in the suprarenal cava. Retrieval was attempted in 14 (20%) patients, and 12 filters were successfully retrieved. Clinical follow-up was available for 20 +/- A 21 months. Symptoms of postfilter PE and DVT occurred in 15% (n = 11) and 10% (n = 7) patients, respectively. None of these patients had computed tomography (CT)-proven PE, and only one had ultrasound-proven new DVT. One patient had symptomatic IVC occlusion. Follow-up abdominal CT in 20 patients showed thrombus in the filter in two of them. There were no instances of filter migration, filter tilt, or caval wall penetration. The OptEase filter appears to have an acceptable long-term safety profile. The filter was effective against PE. C1 [Kalva, Sanjeeva P.; Yeddula, Kalpana; Somarouthu, Bhanusupriya; Wicky, Stephan] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Stecker, Michael S.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Kalva, Sanjeeva P.; Marentis, Theodore C.; Yeddula, Kalpana; Somarouthu, Bhanusupriya; Wicky, Stephan; Stecker, Michael S.] Harvard Univ, Med Sch Boston, Dept Radiol, Boston, MA 02115 USA. RP Kalva, SP (reprint author), Massachusetts Gen Hosp, Dept Radiol, GRB 290,55 Fruit St, Boston, MA 02114 USA. EM skalva@partners.org FU Angiodynamics; Cook Medical; Cordis Endovascular; Rex Medical FX Sanjeeva P. Kalva declares receiving a research grant from Angiodynamics and Cook Medical, consulting fees and honoraria from Cordis Endovascular, and royalties from Amirsys and Elsevier. Stephan Wicky reports receiving a research grant from Angiodynamics and Cook Medical as well as consulting fees and honoraria from Cordis Endovascular. Michael S. Stecker reports receiving a research grant from Rex Medical. Theodore C. Marentis, Kalpana Yeddula, and Bhanusupriya Somarouthu report no conflict of interest. NR 38 TC 14 Z9 16 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0174-1551 J9 CARDIOVASC INTER RAD JI Cardiovasc. Interv. Radiol. PD APR PY 2011 VL 34 IS 2 BP 331 EP 337 DI 10.1007/s00270-010-9969-9 PG 7 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 735VY UT WOS:000288449900015 PM 20820780 ER PT J AU Ballal, SA Gallini, CA Segata, N Huttenhower, C Garrett, WS AF Ballal, Sonia A. Gallini, Carey Ann Segata, Nicola Huttenhower, Curtis Garrett, Wendy S. TI Host and gut microbiota symbiotic factors: lessons from inflammatory bowel disease and successful symbionts SO CELLULAR MICROBIOLOGY LA English DT Review ID GENOME-WIDE ASSOCIATION; CROHNS-DISEASE; INTESTINAL INFLAMMATION; HELICOBACTER-HEPATICUS; IN-VIVO; SUSCEPTIBILITY LOCI; BACTERIAL SYMBIONT; IMMUNE-SYSTEM; GENE ATG16L1; KEY ROLE AB P>Humans are colonized by a diverse collection of microbes, the largest numbers of which reside in the distal gut. The vast majority of humans coexist in a beneficial equilibrium with these microbes. However, disruption of this mutualistic relationship can manifest itself in human diseases such as inflammatory bowel disease. Thus the study of inflammatory bowel disease and its genetics can provide insight into host pathways that mediate host-microbiota symbiosis. Bacteria of the human intestinal ecosystem face numerous challenges imposed by human dietary intake, the mucosal immune system, competition from fellow members of the gut microbiota, transient ingested microbes and invading pathogens. Considering features of human resident gut bacteria provides the opportunity to understand how microbes have achieved their symbiont status. While model symbionts have provided perspective into host-microbial homeostasis, high-throughput approaches are becoming increasingly practical for functionally characterizing the gut microbiota as a community. C1 [Ballal, Sonia A.; Gallini, Carey Ann; Segata, Nicola; Huttenhower, Curtis; Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Ballal, Sonia A.] Childrens Hosp Boston, Boston, MA USA. [Garrett, Wendy S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Garrett, WS (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM wgarrett@hsph.harvard.edu OI Huttenhower, Curtis/0000-0002-1110-0096; Segata, Nicola/0000-0002-1583-5794 FU NCI NIH HHS [R01 CA154426]; NHGRI NIH HHS [R01 HG005969]; NIAID NIH HHS [K08 AI078942] NR 85 TC 12 Z9 13 U1 0 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD APR PY 2011 VL 13 IS 4 BP 508 EP 517 DI 10.1111/j.1462-5822.2011.01572.x PG 10 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 736SM UT WOS:000288514400002 PM 21314883 ER PT J AU Fried, KM Nolan, PE Anthony, M Woosley, RL Freeman, MP AF Fried, Karen M. Nolan, Paul E., Jr. Anthony, Marietta Woosley, Raymond L. Freeman, Marlene P. TI LC-MS Analysis of Sertraline and Its Active Metabolite in Human Serum Using a Silica Column with a Non-Aqueous Polar Mobile Phase SO CHROMATOGRAPHIA LA English DT Article DE Column liquid chromatography-mass spectrometry; NA-HILIC; Serum; Sertraline; Norsertraline ID PERFORMANCE LIQUID-CHROMATOGRAPHY; HYDROPHILIC INTERACTION CHROMATOGRAPHY; SEROTONIN REUPTAKE INHIBITORS; TANDEM MASS-SPECTROMETRY; HUMAN PLASMA; GAS-CHROMATOGRAPHY; N-DESMETHYLSERTRALINE; ANTIDEPRESSANTS; DRUG; PHARMACOKINETICS AB A sensitive liquid chromatography-mass spectrometry method for the simultaneous determination of sertraline (SER) and its major metabolite norsertraline (NOR) from serum was developed and validated in the context of a pharmacokinetic study in pregnant women. The separations were achieved on a silica column with a non-aqueous polar mobile phase consisting of acetonitrile, methanol and ammonium acetate at a flow rate of 0.5 mL min(-1). The concentrations were measured using a single quadruple mass spectroscopic detector supplied with atmospheric pressure ionization electrospray. Sample preparation consisted of a simple liquid-liquid procedure. The detector was set in selective ion mode for each compound of interest, 306 m/z for SER and 275 m/z for NOR. Calibration curves were generated by least square linear regression for concentration of 5-160 ng mL(-1) for SER and from 10 to 320 ng mL(-1) for NOR. The curves for both compounds of interest were linear, with correlation coefficients r (2) a parts per thousand yen 0.999. C1 [Freeman, Marlene P.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Fried, Karen M.] Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA. [Nolan, Paul E., Jr.] Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Tucson, AZ 85721 USA. [Anthony, Marietta; Woosley, Raymond L.] Crit Path Inst, Tucson, AZ USA. RP Freeman, MP (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. EM mfreeman@partners.org FU FDA Office of Women's Health; NIMH FX The authors would like to thank Pfizer Pharmaceutical for its generosity in supplying primary standards for both SER and its metabolite NOR. We are also grateful to the staff at the University of Arizona GCRC, Tucson, AZ for drawing the timed samples and processing all the blood. In addition, we would like to thank Drs. Anne-Francoise Aubry and David K. Lloyd for their invaluable help in editing this manuscript. Foremost, we are indebted to both the FDA Office of Women's Health and NIMH for providing the funding for this project. Finally, we thank Dr. David Bishop for proofreading the manuscript and preparing the final version of the figures. NR 23 TC 5 Z9 5 U1 5 U2 14 PU VIEWEG PI WIESBADEN PA ABRAHAM-LINCOLN-STRABE 46, POSTFACH 15 47, D-65005 WIESBADEN, GERMANY SN 0009-5893 J9 CHROMATOGRAPHIA JI Chromatographia PD APR PY 2011 VL 73 IS 7-8 BP 749 EP 754 DI 10.1007/s10337-011-1919-4 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 740MO UT WOS:000288799100016 ER PT J AU Braun, A Chang, D Mahadevappa, K Gibbons, FK Liu, Y Giovannucci, E Christopher, KB AF Braun, Andrea Chang, Domingo Mahadevappa, Karthik Gibbons, Fiona K. Liu, Yan Giovannucci, Edward Christopher, Kenneth B. TI Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill SO CRITICAL CARE MEDICINE LA English DT Article ID VITAMIN-D DEFICIENCY; PROLONGED CRITICAL ILLNESS; MYOCARDIAL-INFARCTION; UNITED-STATES; ADMINISTRATIVE DATABASES; CARDIOVASCULAR-DISEASE; COMORBIDITY INDEX; OUTCOMES RESEARCH; CLINICAL-DATA; CO-MORBIDITY AB Objective: We hypothesized that deficiency in 25-hydroxyvitamin D before hospital admission would be associated with all-cause mortality in the critically ill. Design: Multicenter observational study of patients treated in medical and surgical intensive care units. Setting: A total of 209 medical and surgical intensive care beds in two teaching hospitals in Boston, MA. Patients: A total of 2399 patients, age >= 18 yrs, in whom 25-hydroxyvitamin D was measured before hospitalization between 1998 and 2009. Interventions: None. Measurements and Main Results: Preadmission 25-hydroxyvitamin D was categorized as deficiency in 25-hydroxyvitamin D (<= 15 ng/mL), insufficiency (16-29 ng/mL), and sufficiency (>= 30 ng/mL). Logistic regression examined death by days 30, 90, and 365 post-intensive care unit admission, in-hospital mortality, and blood culture positivity. Adjusted odds ratios were estimated by multivariable logistic regression models. Preadmission 25-hydroxyvitamin D deficiency is predictive for short-term and long-term mortality. At 30 days following intensive care unit admission, patients with 25-hydroxyvitamin D deficiency have an odds ratio for mortality of 1.69 (95% confidence interval of 1.28-2.23, p <. 0001) relative to patients with 25-hydroxyvitamin D sufficiency. 25-Hydroxyvitamin D deficiency remains a significant predictor of mortality at 30 days following intensive care unit admission following multivariable adjustment (adjusted odds ratio of 1.69, 95% confidence interval of 1.26-2.26, p < .0001). At 30 days following intensive care unit admission, patients with 25-hydroxyvitamin D insufficiency have an odds ratio of 1.32 (95% confidence interval of 1.02-1.72, p = .036) and an adjusted odds ratio of 1.36 (95% confidence interval of 1.03-1.79, p = .029) relative to patients with 25-hydroxyvitamin D sufficiency. Results were similar at 90 and 365 days following intensive care unit admission and for in-hospital mortality. In a subgroup analysis of patients who had blood cultures drawn (n = 1160), 25-hydroxyvitamin D deficiency was associated with increased risk of blood culture positivity. Patients with 25-hydroxyvitamin D insufficiency have an odds ratio for blood culture positivity of 1.64 (95% confidence interval of 1.05-2.55, p = .03) relative to patients with 25-hydroxyvitamin D sufficiency, which remains significant following multivariable adjustment (odds ratio of 1.58, 95% confidence interval of 1.01-2.49, p = .048). Conclusion: Deficiency of 25-hydroxyvitamin D before hospital admission is a significant predictor of short-and long-term all-cause patient mortality and blood culture positivity in a critically ill patient population. (Crit Care Med 2011; 39:671-677) C1 [Braun, Andrea; Chang, Domingo; Mahadevappa, Karthik; Christopher, Kenneth B.] Harvard Univ, Sch Publ Hlth, Div Renal, Brigham & Womens Hosp, Boston, MA 02115 USA. [Gibbons, Fiona K.] Harvard Univ, Sch Publ Hlth, Div Pulm, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Liu, Yan; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Christopher, KB (reprint author), Harvard Univ, Sch Publ Hlth, Div Renal, Brigham & Womens Hosp, 665 Huntington Ave, Boston, MA 02115 USA. EM kbchristopher@partners.org FU National Institutes of Health, Bethesda, MD [5K08AI060881] FX Dr. Christopher is supported, in part, by grant 5K08AI060881 from the National Institutes of Health, Bethesda, MD. The remaining authors have not disclosed any potential conflicts of interest. NR 54 TC 103 Z9 116 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2011 VL 39 IS 4 BP 671 EP 677 DI 10.1097/CCM.0b013e318206ccdf PG 7 WC Critical Care Medicine SC General & Internal Medicine GA 736ZD UT WOS:000288533000009 PM 21242800 ER PT J AU Calfee, CS Ware, LB Glidden, DV Eisner, MD Parsons, PE Thompson, T Matthay, MA AF Calfee, Carolyn S. Ware, Lorraine B. Glidden, David V. Eisner, Mark D. Parsons, Polly E. Thompson, Taylor Matthay, Michael A. CA Natl Heart Blood & Lung Inst Acute TI Use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury SO CRITICAL CARE MEDICINE LA English DT Article DE acute respiratory distress syndrome; biological marker; pulmonary edema; risk prediction; risk reclassification ID RESPIRATORY-DISTRESS-SYNDROME; CLINICAL-OUTCOMES; HOSPITAL MORTALITY; VENTILATION; MARKER; CURVE; DEATH; ICU AB Objective: Multiple single biomarkers have been associated with poor outcomes in acute lung injury; however, no single biomarker has sufficient discriminating power to clearly indicate prognosis. Using both derivation and replication cohorts, we tested novel risk reclassification methods to determine whether measurement of multiple plasma biomarkers at the time of acute lung injury diagnosis would improve mortality prediction in acute lung injury. Design: Analysis of plasma biomarker levels and prospectively collected clinical data from patients enrolled in two randomized controlled trials of ventilator therapy for acute lung injury. Setting: Intensive care units of university hospitals participating in the National Institutes of Health Acute Respiratory Distress Syndrome Network. Patients: Subjects enrolled in a trial of lower tidal volume ventilation (derivation cohort) and subjects enrolled in a trial of higher vs. lower positive end-expiratory pressure (replication cohort). Interventions: None. Measurements and Main Results: The plasma biomarkers were intercellular adhesion molecule-1, von Willebrand factor, interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D. In the derivation cohort (n = 547), adding data on these biomarkers to clinical predictors (Acute Physiology and Chronic Health Evaluation III score) at the time of study enrollment improved the accuracy of risk prediction, as reflected by a net reclassification improvement of 22% (95% confidence interval 13% to 32%; p < .001). In the replication cohort (n = 500), the net reclassification improvement was 17% (95% confidence interval 7% to 26%; p < .001). A reduced set of three biomarkers (interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D) had nearly equivalent prognostic value in both cohorts. Conclusions: When combined with clinical data, plasma biomarkers measured at the onset of acute lung injury can improve the accuracy of risk prediction. Combining three or more biomarkers may be useful for selecting a high-risk acute lung injury population for enrollment in clinical trials of novel therapies. (Crit Care Med 2011; 39:711-717) C1 [Calfee, Carolyn S.; Eisner, Mark D.; Matthay, Michael A.] Univ Calif San Francisco, Pulm & Crit Care Div, Dept Med, San Francisco, CA 94143 USA. [Calfee, Carolyn S.; Eisner, Mark D.; Matthay, Michael A.] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA. [Glidden, David V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Calfee, Carolyn S.; Eisner, Mark D.; Matthay, Michael A.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Ware, Lorraine B.] Vanderbilt Univ, Dept Med, Div Allergy Pulm & Crit Care, Nashville, TN USA. [Parsons, Polly E.] Univ Vermont, Dept Med, Div Pulm & Crit Care Med, Burlington, VT USA. [Thompson, Taylor] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Med Unit, Boston, MA 02114 USA. [Thompson, Taylor] Massachusetts Gen Hosp, Biostat Unit, Boston, MA 02114 USA. RP Calfee, CS (reprint author), Univ Calif San Francisco, Pulm & Crit Care Div, Dept Med, 505 Parnassus Ave,Box 0111, San Francisco, CA 94143 USA. EM carolyn.calfee@ucsf.edu OI Murray, Susan/0000-0003-4387-7673 FU National Heart, Lung, and Blood Institute [N01-HR 46054, 46055, 46056, 46057, 46058, 46059, 46060, 46061, 46062, 46063, 46064, HL 51856, HL081332]; National Heart, Lung, and Blood Institute, Bethesda, MD; Flight Attendant Medical Research Institute, Miami, FL [HL090833]; National Center for Research Resources, a component of the National Institutes of Health, Bethesda, MD [KL2RR024130] FX Supported, in part, by contracts National Heart, Lung, and Blood Institute grant N01-HR 46054, 46055, 46056, 46057, 46058, 46059, 46060, 46061, 46062, 46063, and 46064 with the National Heart, Lung, and Blood Institute, Bethesda, MD. Dr. Calfee was supported by grant HL090833, by the Flight Attendant Medical Research Institute, Miami, FL, and by grant KL2RR024130 from the National Center for Research Resources, a component of the National Institutes of Health, Bethesda, MD. Dr. Matthay was supported by National Heart, Lung, and Blood Institute grant HL 51856. Dr. Ware was supported by grant HL081332. NR 35 TC 48 Z9 53 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0090-3493 EI 1530-0293 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2011 VL 39 IS 4 BP 711 EP 717 DI 10.1097/CCM.0b013e318207ec3c PG 7 WC Critical Care Medicine SC General & Internal Medicine GA 736ZD UT WOS:000288533000015 PM 21283009 ER PT J AU Kacmarek, RM Villar, J AF Kacmarek, Robert M. Villar, Jesus TI When it comes to ventilation, noisy is better than quiet and variability is healthier than constant! SO CRITICAL CARE MEDICINE LA English DT Editorial Material ID PROPORTIONAL ASSIST VENTILATION; MECHANICAL VENTILATION; PRESSURE SUPPORT; LUNG INJURY; BENEFITS; MODEL C1 [Kacmarek, Robert M.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Kacmarek, Robert M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Villar, Jesus] Univ Hosp, Inst Salud Carlos III, CIBER Enfermedades Resp, Las Palmas Gran Canaria, Spain. [Villar, Jesus] Univ Hosp, Res Unit, Las Palmas Gran Canaria, Spain. RP Kacmarek, RM (reprint author), Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. NR 15 TC 4 Z9 4 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2011 VL 39 IS 4 BP 898 EP 899 DI 10.1097/CCM.0b013e31820e6a31 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 736ZD UT WOS:000288533000052 PM 21613844 ER PT J AU Laghi, F AF Laghi, Franco TI Ventilator-induced diaphragmatic dysfunction: Is there a dim light at the end of the tunnel? SO CRITICAL CARE MEDICINE LA English DT Editorial Material ID ANTIOXIDANT SUPPLEMENTATION; FAILURE; HUMANS; DISUSE; MUSCLE; TRIAL C1 [Laghi, Franco] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Laghi, Franco] Loyola Univ, Maywood, IL 60153 USA. RP Laghi, F (reprint author), US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Roosevelt Rd & 5th Ave, Hines, IL 60141 USA. NR 16 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2011 VL 39 IS 4 BP 903 EP 905 DI 10.1097/CCM.0b013e31820a5135 PG 3 WC Critical Care Medicine SC General & Internal Medicine GA 736ZD UT WOS:000288533000055 PM 21613847 ER PT J AU Denton, J Newton, AW Vandeven, AM AF Denton, Jennifer Newton, Alice W. Vandeven, Andrea M. TI Update on child maltreatment: toward refining the evidence base SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE abusive head trauma; child abuse; child maltreatment; child sexual abuse; neglect; shaken baby syndrome ID SEXUALLY-TRANSMITTED INFECTIONS; ABUSIVE HEAD TRAUMA; MUNCHAUSEN-SYNDROME; RISK-FACTORS; HEALTH; VIOLENCE; VICTIMIZATION; DISCIPLINE; PREVENTION; PROTECTION AB Purpose of review This review is designed to aid general pediatricians as they assess cases of possible child maltreatment. The authors have selected salient articles that inform the daily practice of any professional involved in assessing child abuse. Recent findings The incidence of child abuse continues to decline in the United States, although a large number of children still suffer from abuse and neglect, and many are subject to more than one type of maltreatment. Clinicians are encouraged to be vigilant about the subtle indicators of physical abuse, with many authors adding to our understanding about how children present after inflicted abdominal or skeletal trauma. Clinicians are also cautioned to watch for signs of Munchausen syndrome by proxy, which may be elusive and difficult to discern. Summary The field of child abuse pediatrics is still young, with the first board certification in 2009. The volume of research in the field is exploding and there is a greater level of awareness and data collection occurring throughout the world. Pediatric clinicians are encouraged to play a role in preventing abuse and neglect, as well as addressing intimate partner violence, and to maintain vigilance about child maltreatment and its subtle clinical presentations. C1 [Denton, Jennifer; Newton, Alice W.] Childrens Hosp Boston, Child Protect Program, Boston, MA 02115 USA. [Denton, Jennifer; Newton, Alice W.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Newton, Alice W.] Massachusetts Gen Hosp, Child Protect Consultat Program, Boston, MA 02114 USA. [Vandeven, Andrea M.] Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. [Vandeven, Andrea M.] Childrens Mercy Hosp, SCAN Program, Kansas City, MO 64108 USA. RP Newton, AW (reprint author), Childrens Hosp Boston, Child Protect Program, 300 Longwood Ave, Boston, MA 02115 USA. EM alice.newton@childrens.harvard.edu NR 51 TC 2 Z9 2 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD APR PY 2011 VL 23 IS 2 BP 240 EP 248 DI 10.1097/MOP.0b013e3283446010 PG 9 WC Pediatrics SC Pediatrics GA 736LJ UT WOS:000288495900018 PM 21293272 ER PT J AU Liu, Z Segawa, H Aydin, C Reyes, M Erben, RG Weinstein, LS Chen, M Marshansky, V Frohlich, LF Bastepe, M AF Liu, Zun Segawa, Hiroko Aydin, Cumhur Reyes, Monica Erben, Reinhold G. Weinstein, Lee S. Chen, Min Marshansky, Vladimir Froehlich, Leopold F. Bastepe, Murat TI Transgenic Overexpression of the Extra-Large Gs alpha Variant XL alpha s Enhances Gs alpha-Mediated Responses in the Mouse Renal Proximal Tubule in Vivo SO ENDOCRINOLOGY LA English DT Article ID PSEUDOHYPOPARATHYROIDISM-TYPE-IB; ALBRIGHT HEREDITARY OSTEODYSTROPHY; G(S)ALPHA KNOCKOUT MICE; G-PROTEIN; PARATHYROID-HORMONE; CONTROL REGION; TARGETED DISRUPTION; GNAS LOCUS; SUBUNIT; GENE AB XL alpha s, a variant of the stimulatory G protein alpha-subunit (Gs alpha), can mediate receptor-activated cAMP generation and, thus, mimic the actions of Gs alpha in transfected cells. However, it remains unknown whether XL alpha s can act in a similar manner in vivo. We have now generated mice with ectopic transgenic expression of rat XL alpha s in the renal proximal tubule (rptXL alpha s mice), where Gs alpha mediates most actions of PTH. Western blots and quantitative RT-PCR showed that, while Gs alpha and type-1 PTH receptor levels were unaltered, protein kinase A activity and 25-hydroxyvitamin D 1-alpha-hydroxylase (Cyp27b1) mRNAlevels were significantly higher in renal proximal tubules of rptXL alpha s mice than wild-type littermates. Immunohistochemical analysis of kidney sections showed that the sodium- phosphate cotransporter type 2a was modestly reduced in brush border membranes of male rptXL alpha s mice compared to gender-matched controls. Serum calcium, phosphorus, and 1,25 dihydroxyvitamin D were within the normal range, but serum PTH was similar to 30% lower in rptXL alpha s mice than in controls (152 +/- 16 vs. 222 +/- 41 pg/ml; P < 0.05). After crossing the rptXL alpha s mice to mice with ablation of maternal Gnas exon 1 (E1m(-/+)), male offspring carrying both the XL alpha s transgene and maternal Gnas exon 1 ablation (rptXL alpha s/E1m(-/+)) were significantly less hypocalcemic than gender-matched E1m(-/+) littermates. Both E1m(-/+) and rptXL alpha s/E1m(-/+) offspring had higher serum PTH than wild-type littermates, but the degree of secondary hyperparathyroidism tended to be lower in rptXL alpha s/E1m(-/+) mice. Hence, transgenic XL alpha s expression in the proximal tubule enhanced Gs alpha-mediated responses, indicating that XL alpha s can mimic Gs alpha in vivo. (Endocrinology 152: 1222-1233, 2011) C1 [Liu, Zun; Segawa, Hiroko; Aydin, Cumhur; Reyes, Monica; Froehlich, Leopold F.; Bastepe, Murat] Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Marshansky, Vladimir] Massachusetts Gen Hosp, Program Membrane Biol, Ctr Syst Biol, Boston, MA 02114 USA. [Marshansky, Vladimir] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Segawa, Hiroko] Univ Tokushima, Grad Sch, Inst Hlth Biosci, Dept Mol Nutr, Tokushima 7708503, Japan. [Aydin, Cumhur] Gulhane Mil Med Acad, Ctr Dent Sci, Dept Endodont, TR-06018 Ankara, Turkey. [Erben, Reinhold G.] Univ Vet Med, Dept Biomed Sci, A-1210 Vienna, Austria. [Weinstein, Lee S.; Chen, Min] NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Froehlich, Leopold F.] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria. RP Bastepe, M (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Dept Med, 50 Blossom St,Thier 10, Boston, MA 02114 USA. EM bastepe@helix.mgh.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) [R01DK073911]; NIH [DK038452]; Boston Area Diabetes Endocrinology Research Center (BADERC) [DK057521-08]; Gulhane Military Medical Academy, Ankara, Turkey FX This work was supported in part by a research grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (R01DK073911 to M. B). Part of this study was also supported by a NIH Grant DK038452 and by Boston Area Diabetes Endocrinology Research Center (BADERC) Grant DK057521-08 (to V. M.). This work was also partially supported by the Intramural Research Program of NIDDK, NIH. C. A. received a research fellowship award from Gulhane Military Medical Academy, Turkish General Staff, Ankara, Turkey. NR 47 TC 15 Z9 17 U1 0 U2 12 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2011 VL 152 IS 4 BP 1222 EP 1233 DI 10.1210/en.2010-1034 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 739EM UT WOS:000288696300005 PM 21303955 ER PT J AU Barkhoudarian, MT Schwarzschild, MA AF Barkhoudarian, Melita T. Schwarzschild, Michael A. TI Preclinical jockeying on the translational track of adenosine A(2A) receptors SO EXPERIMENTAL NEUROLOGY LA English DT Editorial Material ID MPTP-TREATED MONKEYS; PARKINSONS-DISEASE; ANTAGONIST ISTRADEFYLLINE; MOTOR FLUCTUATIONS; VENTRAL STRIATUM; L-DOPA; CAFFEINE; BRAIN; DYSKINESIA; KW-6002 C1 [Barkhoudarian, Melita T.; Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Schwarzschild, MA (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Room 3002,114 16th St, Boston, MA 02129 USA. EM michaels@helix.mgh.harvard.edu FU NINDS NIH HHS [K24 NS060991, NS054978, R01 NS054978, K24 NS060991-03, R01 NS054978-04S1, NS060991, R01 NS054978-05] NR 47 TC 6 Z9 6 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD APR PY 2011 VL 228 IS 2 BP 160 EP 164 DI 10.1016/j.expneurol.2010.12.022 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 740YI UT WOS:000288829900002 PM 21211537 ER PT J AU Dionne, KR Leser, JS Lorenzen, KA Beckham, JD Tyler, KL AF Dionne, Kalen R. Leser, J. Smith Lorenzen, Kristi A. Beckham, J. David Tyler, Kenneth L. TI A brain slice culture model of viral encephalitis reveals an innate CNS cytokine response profile and the therapeutic potential of caspase inhibition SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Reovirus; Virus; Viral; Apoptosis; Caspase; Encephalitis; Neuron; Ex vivo; Organotypic; Brain slice; Cytokine; IL6; KC; IL8; CXCL10; RANTES; Q-VD-OPh ID CENTRAL-NERVOUS-SYSTEM; HERPES-SIMPLEX-VIRUS; ORGANOTYPIC HIPPOCAMPAL CULTURES; N-TERMINAL KINASE; JAPANESE ENCEPHALITIS; REOVIRUS INFECTION; CELL-DEATH; IN-VITRO; CEREBROSPINAL-FLUID; PARKINSONS-DISEASE AB Viral encephalitis is a significant cause of human morbidity and mortality in large part due to suboptimal diagnosis and treatment. Murine reovirus infection serves as a classic experimental model of viral encephalitis. Infection of neonatal mice with T3 reoviruses results in lethal encephalitis associated with neuronal infection, apoptosis, and CNS tissue injury. We have developed an ex vivo brain slice culture (BSC) system that recapitulates the basic pathological features and kinetics of viral replication seen in vivo. We utilize the BSC model to identify an innate, brain-tissue specific inflammatory cytokine response to reoviral infection, which is characterized by the release of IL6, CXCL10, RANTES, and murine IL8 analog (KC). Additionally, we demonstrate the potential utility of this system as a pharmaceutical screening platform by inhibiting reovirus-induced apoptosis and CNS tissue injury with the pan-caspase inhibitor, Q-VD-OPh. Cultured brain slices not only serve to model events occurring during viral encephalitis, but can also be utilized to investigate aspects of pathogenesis and therapy that are not experimentally accessible in vivo. Published by Elsevier Inc. C1 [Leser, J. Smith; Beckham, J. David; Tyler, Kenneth L.] Univ Colorado Denver, Dept Neurol, Aurora, CO 80045 USA. [Dionne, Kalen R.; Tyler, Kenneth L.] Univ Colorado Denver, Med Scientist Training Program, Aurora, CO 80045 USA. [Dionne, Kalen R.; Tyler, Kenneth L.] Univ Colorado Denver, Neurosci Program, Aurora, CO 80045 USA. [Lorenzen, Kristi A.; Beckham, J. David; Tyler, Kenneth L.] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. [Beckham, J. David; Tyler, Kenneth L.] Univ Colorado Denver, Dept Microbiol, Aurora, CO 80045 USA. [Tyler, Kenneth L.] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. RP Tyler, KL (reprint author), Univ Colorado Denver, Dept Neurol, Res Complex 2,12700 E 19th Ave,B182, Aurora, CO 80045 USA. EM Ken.Tyler@UCDenver.edu OI Tyler, Kenneth/0000-0003-3294-5888 FU VA; Mentored Clinical Science Development award [5K08AI076518, 5K08AI076518-02S1, 5K08AI076518-03S1]; MST Program [T32 GM008497]; National Research Service [F30 NS071630]; [RO1NS050138]; [RO1NS051403] FX This work was supported by RO1NS050138 (K.L.T), RO1NS051403 (K.L.T), and a VA Merit Grant (K.L.T).; J.D.B. was supported by a Mentored Clinical Science Development award (5K08AI076518, 5K08AI076518-02S1, and 5K08AI076518-03S1).; K.R.D. was supported by an institutional MST Program training grant (T32 GM008497) and a National Research Service Award for Predoctoral MD/PhD Fellows (F30 NS071630). NR 60 TC 14 Z9 14 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD APR PY 2011 VL 228 IS 2 BP 222 EP 231 DI 10.1016/j.expneurol.2011.01.006 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 740YI UT WOS:000288829900010 PM 21241693 ER PT J AU Kanwal, F Hoang, T Kramer, JR Asch, SM Goetz, MB Zeringue, A Richardson, P El-Serag, HB AF Kanwal, Fasiha Tuyen Hoang Kramer, Jennifer R. Asch, Steven M. Goetz, Matthew Bidwell Zeringue, Angelique Richardson, Peter El-Serag, Hashem B. TI Increasing Prevalence of HCC and Cirrhosis in Patients With Chronic Hepatitis C Virus Infection SO GASTROENTEROLOGY LA English DT Article DE Liver Cancer; Epidemiology; Virology ID CHRONIC LIVER-DISEASE; HUMAN-IMMUNODEFICIENCY-VIRUS; NON-B-HEPATITIS; UNITED-STATES; HEPATOCELLULAR-CARCINOMA; NATURAL-HISTORY; NON-A; VETERANS; FIBROSIS; PROGRESSION AB BACKGROUND & AIMS: Patients with hepatitis C virus (HCV) infection are at risk for developing costly and morbid complications, although the actual prevalence of these complications is unknown. We examined time trends in the prevalence of cirrhosis and its related complications, such as hepatic decompensation and hepatocellular carcinoma (HCC). METHODS: We calculated the annual prevalence of cirrhosis, decompensated cirrhosis, and HCC in a national sample of veterans diagnosed with HCV between 1996 and 2006. Patients with HCV who had at least one physician visit in a given calendar year were included in the analysis of prevalence for that year. We used direct standardization to adjust the prevalence of cirrhosis and related complications for increasing age of the cohort as well as sex and changes in clinical characteristics. RESULTS: In this cohort, the number of individuals with HCV increased from 17,261 in 1996 to 106,242 in 2006. The prevalence of cirrhosis increased from 9% in 1996 to 18.5% in 2006. The prevalence of patients with decompensated cirrhosis doubled, from 5% in 1996 to 11% in 2006, whereas the prevalence of HCC increased approximately 20-fold (0.07% in 1996 to 1.3% in 2006). After adjustment, the time trend in the prevalence of cirrhosis (and its complications) was lower than the crude trend, although it still increased significantly. CONCLUSIONS: The prevalence of cirrhosis and HCC in HCV-infected patients has increased significantly over the past 10 years. An aging cohort of patients with HCV could partly explain our findings. Clinicians and health care systems should develop strategies to provide timely and effective care to this high-risk population of patients. C1 [Kanwal, Fasiha; Zeringue, Angelique] John Cochran VA Med Ctr, Dept Gastroenterol & Hepatol, St Louis, MO USA. [Kanwal, Fasiha] St Louis Univ, Sch Med, St Louis, MO USA. [Tuyen Hoang; Asch, Steven M.; Goetz, Matthew Bidwell] Greater Los Angeles VA Healthcare Syst, Dept Med & Hlth Serv Res, Los Angeles, CA USA. [Kramer, Jennifer R.; Richardson, Peter; El-Serag, Hashem B.] Michael E DeBakey VA Med Ctr, Houston VA HSR&D Ctr Excellence, Hlth Serv Res & Dev Serv, Houston, TX USA. [Kramer, Jennifer R.; Richardson, Peter; El-Serag, Hashem B.] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Asch, Steven M.; Richardson, Peter; El-Serag, Hashem B.] Baylor Coll Med, Dept Med, Gastroenterol Sect, Houston, TX 77030 USA. [Asch, Steven M.; Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Kanwal, F (reprint author), St Louis VA Med Ctr, 915 N Grand,111-JC-GI, St Louis, MO 63141 USA. EM fasiha.kanwal@va.gov RI Zeringue, Angelique/I-1755-2012; OI Goetz, Matthew/0000-0003-4542-992X FU Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs [IIR-07-111, K24DK078154-03, R01CA125487-03] FX Supported in part by Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs, grant IIR-07-111 (to F. K.) and K24DK078154-03 and R01CA125487-03 (to H.B.E.). NR 35 TC 167 Z9 172 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD APR PY 2011 VL 140 IS 4 BP 1182 EP + DI 10.1053/j.gastro.2010.12.032 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740JV UT WOS:000288789900025 PM 21184757 ER PT J AU Nichols, AC Kneuertz, PJ Deschler, DG Lin, DT Emerick, KS Clark, JR Busse, PW Rocco, JW AF Nichols, Anthony C. Kneuertz, Peter J. Deschler, Daniel G. Lin, Derrick T. Emerick, Kevin S. Clark, John R. Busse, Paul W. Rocco, James W. TI SURGICAL SALVAGE OF THE OROPHARYNX AFTER FAILURE OF ORGAN-SPARING THERAPY SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE surgical salvage; oropharyngeal cancer; radiation; chemoradiation ID SQUAMOUS-CELL CARCINOMA; TRANSORAL ROBOTIC SURGERY; ADVANCED LARYNGEAL-CANCER; RADIATION-THERAPY; ONCOLOGY-GROUP; NECK-CANCER; STAGE-III; HEAD; CHEMORADIATION; PRESERVATION AB Background. The purpose of this study was to evaluate the efficacy of salvage surgery for local recurrences of oropharyngeal squamous cell carcinoma (OPSCC) and identify predictors of survival. Methods. The authors reviewed 264 patients with OPSCC treated with radiation or chemoradiation identified retrospectively. Of the 77 patients that experienced recurrences, 37 had local or local and regional recurrences and were considered for salvage surgery. Results. Of the 37 patients with local or local and regional recurrence, 5 had unresectable disease whereas 3 refused surgery. The remainder underwent salvage surgery with 2-year and 5-year survival rates of 64.5% and 43.4%, respectively. A history of alcohol abuse and positive surgical margins were the only predictors of poorer overall survival (p < .05) after salvage surgery. Conclusion. Surgical salvage of locoregional recurrences can be effective if wide resections are performed so that negative margins can be achieved. (C) 2010 Wiley Periodicals, Inc. Head Neck 33: 516-524, 2011 C1 [Nichols, Anthony C.; Kneuertz, Peter J.; Deschler, Daniel G.; Lin, Derrick T.; Emerick, Kevin S.; Rocco, James W.] Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. [Nichols, Anthony C.] Univ Western Ontario, Dept Otolaryngol Head & Neck Surg, London, ON, Canada. [Clark, John R.] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Busse, Paul W.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Rocco, James W.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Rocco, JW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. EM jrocco@partners.org NR 20 TC 17 Z9 17 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1043-3074 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD APR PY 2011 VL 33 IS 4 BP 516 EP 524 DI 10.1002/hed.21480 PG 9 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 737YT UT WOS:000288607200010 PM 20652974 ER PT J AU Schmittdiel, J Selby, JV Swain, B Daugherty, SL Leong, TK Ho, M Margolis, KL O'Connor, P Magid, DJ Bibbins-Domingo, K AF Schmittdiel, Julie Selby, Joe V. Swain, Bix Daugherty, Stacie L. Leong, Thomas K. Ho, Michael Margolis, Karen L. O'Connor, Patrick Magid, David J. Bibbins-Domingo, Kirsten TI Missed Opportunities in Cardiovascular Disease Prevention? Low Rates of Hypertension Recognition for Women at Medicine and Obstetrics-Gynecology Clinics SO HYPERTENSION LA English DT Article DE hypertension; sex; CVD prevention; primary care; OBGYN ID ACUTE MYOCARDIAL-INFARCTION; AMERICAN-HEART-ASSOCIATION; HIGH BLOOD-PRESSURE; PRIMARY-CARE; HEALTH-CARE; RACIAL-DIFFERENCES; PRACTICE PATTERNS; SEX-DIFFERENCES; SERVICES; GUIDELINES AB Younger women use both internal medicine and obstetrics-gynecology (OBGYN) clinics as primary sources of health care. However, the role of OBGYN clinics in cardiovascular disease prevention is largely unexplored. The objective of this study was to examine rates of hypertension recognition in women <50 years of age who presented with elevated blood pressures in family practice and internal medicine (medicine) OBGYN clinics and to compare these rates across clinic type. The study's population consisted of 34 627 nonpregnant women ages 18 to 49 years with new-onset hypertension (defined as 2 consecutive visits with elevated blood pressures of systolic blood pressure >140 mm Hg or diastolic blood pressure >= 90 mm Hg with no previous hypertension history) from 2002 to 2006. Multivariate logistic regressions predicting the clinical recognition of hypertension (a recorded diagnosis of hypertension and/or an antihypertensive prescription by any provider within 1 year of the second elevated blood pressure) assessed the association between hypertension recognition and the clinic where the second elevated blood pressure was recorded. Analysis showed that hypertension was recognized in <33% of women with new-onset hypertension. Women whose second consecutive elevated blood pressure was recorded in OBGYN clinics were less likely to be recognized as having hypertension within 12 months by any provider compared with women whose second consecutive elevated blood pressure was recorded in a medicine clinic (odds ratio: 0.51 [95% CI: 0.48 to 0.54]). This study suggests that further attention be paid to identifying and treating cardiovascular disease risk factors in women <50 years of age presenting in both medicine and OBGYN clinics and that improved coordination across care settings has the potential to improve cardiovascular disease prevention in young women. (Hypertension. 2011;57:717-722.) C1 [Schmittdiel, Julie; Selby, Joe V.; Swain, Bix; Leong, Thomas K.] Kaiser Permanente No Calif, Div Res, Oakland, CA 94612 USA. [Daugherty, Stacie L.; Ho, Michael] Univ Colorado, Aurora, CO USA. [Margolis, Karen L.; O'Connor, Patrick] HealthPartners, Minneapolis, MN USA. [Bibbins-Domingo, Kirsten] Univ Calif San Francisco, San Francisco Sch Med, San Francisco, CA 94143 USA. [Ho, Michael] Denver Vet Affairs Med Ctr, Denver, CO USA. [Magid, David J.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. RP Schmittdiel, J (reprint author), Kaiser Permanente No Calif, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM Julie.A.Schmittdiel@kp.org FU National Heart, Lung, and Blood Institute [U19 HL91179-01, K08HL103776]; Office of Research in Women's Health Building Interdisciplinary Careers in Women's Health [K12HD052163]; Veterans Affairs Health Services Research and Development Service [05-026-1] FX This study was funded by the National Heart, Lung, and Blood Institute (U19 HL91179-01). The work by J.S. on this study was supported by the Office of Research in Women's Health Building Interdisciplinary Careers in Women's Health K12 Career Development Award (K12HD052163). M. H. is supported by a Veterans Affairs Health Services Research and Development Service Career Development Award (05-026-1). S. L. D. is supported by Award No. K08HL103776 from the National Heart, Lung, and Blood Institute. NR 41 TC 16 Z9 17 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD APR PY 2011 VL 57 IS 4 BP 717 EP 722 DI 10.1161/HYPERTENSIONAHA.110.168195 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 735RL UT WOS:000288434600017 PM 21339475 ER PT J AU Xiao, L Crabb, DM Duffy, LB Paralanov, V Glass, JI Hamilos, DL Waites, KB AF Xiao, Li Crabb, Donna M. Duffy, Lynn B. Paralanov, Vanya Glass, John I. Hamilos, Daniel L. Waites, Ken B. TI Mutations in ribosomal proteins and ribosomal RNA confer macrolide resistance in human Ureaplasma spp. SO INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS LA English DT Article DE Ureaplasma; Macrolide; Resistance; Ribosomal proteins; Ribosomal RNA; Antibiotic ID STREPTOCOCCUS-PNEUMONIAE; CLINICAL STRAINS; ERYTHROMYCIN; GENES; TETRACYCLINE; UREALYTICUM; MECHANISMS; VITRO; TIME AB Genetic mechanisms of macrolide resistance were investigated in six isolates of Ureaplasma spp. with erythromycin minimum inhibitory concentrations (MICs)>= 8 mu g/mL that were derived from 370 cultures obtained over a several year period. Point mutations in domain V of 23S rRNA and/or mutations in ribosomal protein L4 genes are likely to be responsible for this drug resistance. Overall, macrolide resistance was uncommon, in contrast to tetracycline resistance that was documented in 121 unique isolates (33%). (c) 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. C1 [Xiao, Li; Crabb, Donna M.; Duffy, Lynn B.; Waites, Ken B.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Paralanov, Vanya; Glass, John I.] J Craig Venter Inst, Rockville, MD USA. [Hamilos, Daniel L.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Waites, KB (reprint author), Univ Alabama, 619 19th St S,WP 230, Birmingham, AL 35249 USA. EM waiteskb@uab.edu RI Glass, John/A-6572-2015 OI Glass, John/0000-0002-3784-5301 FU National Institute of Allergy and Infectious Diseases (Bethesda, MD) [RO1A1072577, N01-A1-30071] FX This work was supported in part by federal funds under grants RO1A1072577 and contract N01-A1-30071 from the National Institute of Allergy and Infectious Diseases (Bethesda, MD). NR 17 TC 23 Z9 23 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-8579 J9 INT J ANTIMICROB AG JI Int. J. Antimicrob. Agents PD APR PY 2011 VL 37 IS 4 BP 377 EP 379 DI 10.1016/j.ijantimicag.2010.12.012 PG 3 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 736IU UT WOS:000288487700017 PM 21353494 ER PT J AU Chaudhry, S Arena, R Wasserman, K Hansen, JE Lewis, GD Myers, J Belardinelli, R LaBudde, B Menasco, N Boden, WE AF Chaudhry, Sundeep Arena, Ross Wasserman, Karlman Hansen, James E. Lewis, Gregory D. Myers, Jonathan Belardinelli, Romualdo LaBudde, Brian Menasco, Nicholas Boden, William E. TI The utility of cardiopulmonary exercise testing in the assessment of suspected microvascular ischemia SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Letter ID MYOCARDIAL-ISCHEMIA AB Evidence demonstrating the potential value of cardiopulmonary exercise testing (CPET) to accurately detect myocardial ischemia secondary to macro-vascular disease is beginning to emerge. Despite distinct mechanisms mediating ischemia in micro-vascular and macrovascular coronary artery disease (CAD), the net physiologic effect of exercise-induced left ventricular (LV) dysfunction is common to both. The abnormal physiologic response to CPET may, therefore, be similar in patients with macro-and micro-vascular ischemia. The following case report describes the CPET abnormalities in a patient with suspected microvascular CAD and the subsequent improvement in LV function following three weeks of medical therapy with the anti-ischemic drug ranolazine. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Chaudhry, Sundeep; LaBudde, Brian; Menasco, Nicholas] Met Test Inc, Dept Res & Dev, Atlanta, GA USA. [Arena, Ross] Virginia Commonwealth Univ, Dept Internal Med, Richmond, VA USA. [Arena, Ross] Virginia Commonwealth Univ, Dept Phys Therapy, Richmond, VA USA. [Wasserman, Karlman; Hansen, James E.] Univ Calif Los Angeles, Med Ctr, Div Resp & Crit Care Physiol & Med, Los Angeles Biomed Res Inst Harbor, Torrance, CA 90509 USA. [Lewis, Gregory D.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Myers, Jonathan] Stanford Univ, Div Cardiol, VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. [Belardinelli, Romualdo] Lancisi Heart Inst, Ancona, Italy. [Boden, William E.] SUNY Buffalo, Sch Med, Div Cardiovasc Med, Buffalo, NY 14260 USA. [Boden, William E.] SUNY Buffalo, Sch Publ Hlth Buffalo, Div Cardiovasc Med, Buffalo, NY 14260 USA. RP Chaudhry, S (reprint author), 1117 Perimeter Ctr W,Suite W-211, Atlanta, GA 30338 USA. EM schaudhry@mettest.net RI Arena, Ross/A-3141-2008 OI Arena, Ross/0000-0002-6675-1996 FU NHLBI NIH HHS [K23 HL091106-01A1, K23 HL091106] NR 7 TC 9 Z9 10 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD APR PY 2011 VL 148 IS 1 BP E7 EP E9 DI 10.1016/j.ijcard.2009.01.055 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 736JE UT WOS:000288489300003 PM 19233492 ER PT J AU Astrakas, L Blekas, KD Constantinou, C Andronesi, OC Mindrinos, MN Likas, AC Rahme, LG Black, PM Marcus, KJ Tzika, AA AF Astrakas, Loukas Blekas, Konstantinos D. Constantinou, Caterina Andronesi, Ovidiu C. Mindrinos, Michael N. Likas, Aristidis C. Rahme, Laurence G. Black, Peter M. Marcus, Karen J. Tzika, A. Aria TI Combining magnetic resonance spectroscopy and molecular genomics offers better accuracy in brain tumor typing and prediction of survival than either methodology alone SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE brain/central nervous system cancers; tumor biomarkers; ex vivo high-resolution magic angle spinning magnetic resonance spectroscopy; support vector machines; genomics ID GENE-EXPRESSION DATA; SUPPORT VECTOR MACHINES; NERVOUS-SYSTEM CANCERS; RENAL-CELL CARCINOMA; SHORT ECHO TIME; H-1 MR SPECTRA; IN-VIVO; BINDING-PROTEIN; BIOCHEMICAL-CHARACTERIZATION; MYOCARDIAL-INFARCTION AB Recent advents in magnetic resonance spectroscopy (MRS) techniques permit subsequent microarray analysis over the entire human transcriptome in the same tissue biopsies. However, extracting information from such immense quantities of data is limited by difficulties in recognizing and evaluating the relevant patterns of apparent gene expression in the context of the existing knowledge of phenotypes by histopathology. Using a quantitative approach derived from a knowledge base of pathology findings, we present a novel methodology used to process genome-wide transcription and MRS data. This methodology was tested to examine metabolite and genome-wide profiles in MRS and RNA in 55 biopsies from human subjects with brain tumors with similar to 100% certainty. With the guidance of histopathology and clinical outcome, 15 genes with the assistance of 15 MRS metabolites were able to be distinguished by tumor categories and the prediction of survival was better than when either method was used alone. This new method, combining MRS, genomics, statistics and biological content, improves the typing and understanding of the complexity of human brain tumors, and assists in the search for novel tumor biomarkers. It is an important step for novel drug development, it generates testable hypotheses regarding neoplasia and promises to guide human brain tumor therapy provided improved in vivo methods for monitoring response to therapy are developed. C1 [Astrakas, Loukas; Constantinou, Caterina; Andronesi, Ovidiu C.; Tzika, A. Aria] Massachusetts Gen Hosp, Dept Surg, NMR Surg Lab, Boston, MA 02114 USA. [Astrakas, Loukas; Constantinou, Caterina; Andronesi, Ovidiu C.; Rahme, Laurence G.; Tzika, A. Aria] Harvard Univ, Sch Med, Shriners Burn Inst, Boston, MA 02114 USA. [Astrakas, Loukas] Univ Ioannina, Dept Med Phys, GR-45110 Ioannina, Greece. [Blekas, Konstantinos D.; Likas, Aristidis C.] Univ Ioannina, Dept Comp Sci, GR-45110 Ioannina, Greece. [Constantinou, Caterina; Rahme, Laurence G.] Massachusetts Gen Hosp, Dept Surg, Mol Surg Lab, Boston, MA 02114 USA. [Mindrinos, Michael N.] Stanford Univ, Dept Biochem, Sch Med, Stanford, CA 94305 USA. [Andronesi, Ovidiu C.; Tzika, A. Aria] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Boston, MA 02114 USA. [Black, Peter M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Marcus, Karen J.] Harvard Univ, Sch Med, Childrens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. RP Tzika, AA (reprint author), Massachusetts Gen Hosp, Dept Surg, NMR Surg Lab, 51 Blossom St, Boston, MA 02114 USA. EM kmarcus@lroc.harvard.edu; atzika@hms.harvard.edu RI Astrakas, Loukas/F-5918-2011; OI Constantinou, Caterina/0000-0003-3589-0739 FU Departments of Surgery and Radiology at Massachusetts General Hospital; Neurosurgery and Pathology at Brigham; Women's Hospital Boston FX The study was supported in part by discretional funds to A. Aria Tzika. The authors thank the Departments of Surgery and Radiology at Massachusetts General Hospital, as well as Neurosurgery and Pathology at Brigham and Women's Hospital Boston for supporting this study. We thank John Passanese, first year medical student at Harvard Medical for assistance with references cited in Tables. We also thank Drs Ann Power Smith and Kathryn Edmondson of Write Science Right for editorial assistance. NR 147 TC 5 Z9 6 U1 1 U2 3 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD APR PY 2011 VL 38 IS 4 BP 1113 EP 1127 DI 10.3892/ijo.2011.928 PG 15 WC Oncology SC Oncology GA 737PQ UT WOS:000288581100024 PM 21274507 ER PT J AU Kostis, WJ Moreyra, AE Cheng, JQ Dobrzynski, JM Kostis, JB AF Kostis, William J. Moreyra, Abel E. Cheng, Jerry Q. Dobrzynski, Jeanne M. Kostis, John B. TI Continuation of mortality reduction after the end of randomized therapy in clinical trials of lipid-lowering therapy SO JOURNAL OF CLINICAL LIPIDOLOGY LA English DT Article DE Clinical trials; Legacy effect; Lipid-lowering therapy; Mortality; Niacin; Statins ID CORONARY-HEART-DISEASE; AVERAGE CHOLESTEROL CONCENTRATIONS; SCANDINAVIAN SIMVASTATIN SURVIVAL; RENAL-TRANSPLANT RECIPIENTS; PRIMARY-PREVENTION TRIAL; FOLLOW-UP; CARDIAC OUTCOMES; LONG; METAANALYSIS; STATINS AB BACKGROUND: Long-term follow-up of clinical trials with lipid-lowering medications has suggested a continuation of event reduction after study completion. OBJECTIVE: To evaluate the persistence of the benefit of lipid-lowering therapy in decreasing mortality after the end of clinical trials, when all patients were advised to take the same open-label lipid-lowering therapy. METHODS: Through searches of MEDLINE, the Cochrane Library, the Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov until June 2010 we identified randomized clinical trials of lipid-lowering agents with a second report describing results after the end of the trial. RESULTS: Among the 459 trials reviewed, only 8 including 44,255 patients and 8144 deaths qualified for the meta-anlaysis. All-cause and cardiovascular mortality were lower in the active intervention group during the first phase (0.84, 95% confidence interval [Cl] 0.76-0.93; P = .0006 and 0.72, 95% Cl 0.63-0.82, P < .0001, respectively) when 71 +/- 23% of the patients randomized to receive active therapy actually received it compared with 13 +/- 5% of patients who received active therapy although they were randomized to placebo (P = .0001). The lower mortality among those initially randomized to active therapy persisted during the second phase (odds ratio 0.90, 95% Cl 0.84-0.97, P = .0035, and 0.82 95% CI 0.73-0.93, P =.0014), when patients in both randomized groups received active therapy in the same proportions (5 +/- 2% for both groups). Numerous sensitivity analyses support the conclusions of the paper. CONCLUSION: The decrease in mortality with lipid-lowering therapy in clinical trials persists after discontinuation of randomized therapy when patients in the treatment and placebo groups receive active therapy. (C) 2011 National Lipid Association. All rights reserved. C1 [Kostis, William J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Moreyra, Abel E.; Dobrzynski, Jeanne M.; Kostis, John B.] UMDNJ Robert Wood Johnson Med Sch, Dept Med, New Brunswick, NJ USA. [Cheng, Jerry Q.] Columbia Univ, Dept Stat, New York, NY USA. RP Kostis, WJ (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St,GRB-800, Boston, MA 02114 USA. EM wkostis@partners.org NR 33 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-2874 J9 J CLIN LIPIDOL JI J. Clin. Lipidol. PD APR PY 2011 VL 5 IS 2 BP 97 EP 104 DI 10.1016/j.jacl.2011.01.006 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 740ZA UT WOS:000288831700006 PM 21392723 ER PT J AU Trombetta-ESilva, J Yu, H Arias, DN Rossa, C Kirkwood, KL Bradshaw, AD AF Trombetta-eSilva, J. Yu, H. Arias, D. N. Rossa, C., Jr. Kirkwood, K. L. Bradshaw, A. D. TI LPS Induces Greater Bone and PDL Loss in SPARC-null Mice SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE SPARC; periodontal ligament; collagen; BM-40; osteonectin; extracellular matrix; matricellular; periodontal diseases; alveolar bone resorption ID PERIODONTAL-LIGAMENT; EXTRACELLULAR-MATRIX; CYSTEINE SPARC; COLLAGEN; PROTEIN; REGENERATION; FIBROBLASTS; TISSUES; MODEL; RICH AB Individuals with periodontal disease have increased risk of tooth loss, particularly in cases with associated loss of alveolar bone and periodontal ligament (PDL). Current treatments do not predictably regenerate damaged PDL. Collagen I is the primary component of bone and PDL extracellular matrix. SPARC/Osteonectin (SP/ON) is implicated in the regulation of collagen content in healthy PDL. In this study, periodontal disease was induced by injections of lipopolysaccharide (LPS) from Aggregatibacter actinomycetemcomitans in wild-type (WT) and SP/ON-null C57/B16 mice. A 20-mu g quantity of LPS was injected between the first and second molars 3 times a week for 4 weeks, whereas PBS control was injected into the contralateral maxilla. LPS injection resulted in a significant decrease in bone volume fraction in both genotypes; however, significantly greater bone loss was detected in SP/ON-null maxilla. SP/ON-null PDL exhibited more extensive degradation of connective tissue in the gingival tissues. Although total cell numbers in the PDL of SP/ON-null were not different from those in WT, the inflammatory infiltrate was reduced in SP/ON-null PDL. Histology of collagen fibers revealed marked reductions in collagen volume fraction and in thick collagen volume fraction in the PDL of SP/ON-null mice. SP/ON protects collagen content in PDL and in alveolar bone in experimental periodontal disease. C1 [Trombetta-eSilva, J.; Yu, H.; Rossa, C., Jr.; Kirkwood, K. L.; Bradshaw, A. D.] Med Univ S Carolina, Ctr Oral Hlth Res, Charleston, SC 29425 USA. [Bradshaw, A. D.] Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Craniofacial Biol, Charleston, SC 29425 USA. [Trombetta-eSilva, J.; Bradshaw, A. D.] Med Univ S Carolina, Dept Med, Div Cardiol, Charleston, SC 29425 USA. [Arias, D. N.] Erskine Coll, Due West, SC USA. [Bradshaw, A. D.] Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. [Rossa, C., Jr.] Univ Estadual Paulista UNESP, Dept Diag & Surg, Fac Odontol Araraquara, Araraquara, SP, Brazil. RP Bradshaw, AD (reprint author), Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Craniofacial Biol, 114 Doughty St,Rm 223, Charleston, SC 29425 USA. EM bradshad@musc.edu RI Rossa Jr, Carlos/D-8328-2012 OI Rossa Jr, Carlos/0000-0003-1705-5481 FU National Institutes of Health [T32DE017551, R25 HL092611, 2P20RR017696, HL094517, R01DE018290]; Veteran's Administration FX We thank Kylie Martin, Yuhua Zhang, Lauren Card, and Robert Zinna for technical support. This work was supported by the National Institutes of Health [T32DE017551, R25 HL092611, 2P20RR017696, HL094517, R01DE018290] and by a Veteran's Administration Merit Award. NR 31 TC 7 Z9 7 U1 0 U2 2 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 APR PY 2011 VL 90 IS 4 BP 477 EP 482 DI 10.1177/0022034510391800 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 740MK UT WOS:000288798600013 PM 21191126 ER PT J AU Tye, CE Antone, JV Bartlett, JD AF Tye, C. E. Antone, J. V. Bartlett, J. D. TI Fluoride Does Not Inhibit Enamel Protease Activity SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE enamel; fluoride; proteases/proteinases ID HYPOMATURATION AMELOGENESIS-IMPERFECTA; MAXILLARY CENTRAL INCISORS; IN-VITRO; CRITICAL PERIOD; EXPRESSION; MUTATION; MATRIX; TOOTH; FLUOROSIS; LOCALIZATION AB Fluorosed enamel can be porous, mottled, discolored, hypomineralized, and protein-rich if the enamel matrix is not completely removed. Proteolytic processing by matrix metalloproteinase-20 (MMP20) and kallikrein-4 (KLK4) is critical for enamel formation, and homozygous mutation of either protease results in hypomineralized, protein-rich enamel. Herein, we demonstrate that the lysosomal proteinase cathepsin K is expressed in the enamel organ in a developmentally defined manner that suggests a role for cathepsin K in degrading re-absorbed enamel matrix proteins. We therefore asked if fluoride directly inhibits the activity of MMP20, KLK4, dipeptidyl peptidase I (DPPI) (an in vitro activator of KLK4), or cathepsin K. Enzyme kinetics were studied with quenched fluorescent peptides with purified enzyme in the presence of 0-10 mM NaF, and data were fit to Michaelis-Menten curves. Increasing concentrations of known inhibitors showed decreases in enzyme activity. However, concentrations of up to 10 mM NaF had no effect on KLK4, MMP20, DPPI, or cathepsin K activity. Our results show that fluoride does not directly inhibit enamel proteolytic activity. C1 [Bartlett, J. D.] Harvard Univ, Sch Dent Med, Dept Cytokine Biol, Forsyth Inst, Boston, MA 02115 USA. Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. RP Bartlett, JD (reprint author), Harvard Univ, Sch Dent Med, Dept Cytokine Biol, Forsyth Inst, 188 Longwood Ave, Boston, MA 02115 USA. EM jbartlett@forsyth.org FU NIDCR [DE016276, DE016276-04S1, DE018106] FX This investigation was supported by NIDCR grants DE016276, DE016276-04S1, and DE018106 to JDB. NR 34 TC 2 Z9 3 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD APR PY 2011 VL 90 IS 4 BP 489 EP 494 DI 10.1177/0022034510390043 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 740MK UT WOS:000288798600015 PM 21118795 ER PT J AU Powell, WF Barry, KJ Tulum, I Kobayashi, T Harris, SE Bringhurst, FR Pajevic, PD AF Powell, William F., Jr. Barry, Kevin J. Tulum, Irena Kobayashi, Tatsuya Harris, Stephen E. Bringhurst, F. Richard Pajevic, Paola Divieti TI Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID CARBOXYL-TERMINAL REGION; HORMONE-RELATED PEPTIDE; PARATHYROID-HORMONE; TRANSGENIC MICE; BMP ANTAGONIST; IN-VIVO; EXPRESSION; PROTEIN; ALPHA; CELLS AB Parathyroid hormone (PTH) is a major physiologic regulator of calcium, phosphorous, and skeletal homeostasis. Cells of the osteoblastic lineage are key targets of PTH action in bone, and recent evidence suggests that osteocytes might be important in the anabolic effects of PTH. To understand the role of PTH signaling through the PTH/PTHrP receptors (PPR) in osteocytes and to determine the role(s) of these cells in mediating the effects of the hormone, we have generated mice in which PPR expression is specifically ablated in osteocytes. Transgenic mice in which the 10 kb-Dmp1 promoter drives a tamoxifen-inducible Cre-recombinase were mated with animals in which exon 1 of PPR is flanked by lox-P sites. In these animals, osteocyte-selective PPR knockout (Ocy-PPR(cKO) mice) could be induced by administration of tamoxifen. Histological analysis revealed a reduction in trabecular bone and mild osteopenia in Ocy-PPR(cKO) mice. Reduction of trabeculae number and thickness was also detected by micro-computed tomography analysis whereas bone volume fraction (BV/TV%) was unchanged. These findings were associated with an increase in Sost and sclerostin expression. When Ocy-PPR(cKO) mice were subjected to a low-calcium diet to induce secondary hyperparathyroidism, their blood calcium levels were significantly lower than littermate controls. Moreover, PTH was unable to suppress Sost and sclerostin expression in the Ocy-PPR(cKO) animals, suggesting an important role of PTH signaling in osteocytes for proper bone remodeling and calcium homeostasis. Journal of Endocrinology (2011) 209, 21-32 C1 [Powell, William F., Jr.; Barry, Kevin J.; Tulum, Irena; Kobayashi, Tatsuya; Bringhurst, F. Richard; Pajevic, Paola Divieti] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Powell, William F., Jr.; Barry, Kevin J.; Tulum, Irena; Kobayashi, Tatsuya; Bringhurst, F. Richard; Pajevic, Paola Divieti] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Harris, Stephen E.] Univ Texas Hlth Sci Ctr San Antonio, Sch Dent, Dept Periodont, San Antonio, TX 78229 USA. RP Pajevic, PD (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Thier 1101,50 Blossom St, Boston, MA 02114 USA. EM divieti@helix.mgh.harvard.edu FU National Institutes of Health [DK079161, P01AR46798]; MGH-ECOR Interim grant FX This work was supported by the National Institutes of Health grants DK079161 (P D P), P01AR46798 (S E H), and by an MGH-ECOR Interim grant (P D P). NR 40 TC 71 Z9 71 U1 1 U2 6 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD APR PY 2011 VL 209 IS 1 BP 21 EP 32 DI 10.1530/JOE-10-0308 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 737AG UT WOS:000288537500003 PM 21220409 ER PT J AU Jang, JY Shao, RX Lin, WY Weinberg, E Chung, WJ Tsai, WL Zhao, H Goto, K Zhang, LL Mendez-Navarro, J Jilg, N Peng, LF Brockman, MA Chung, RT AF Jang, Jae Young Shao, Run-Xuan Lin, Wenyu Weinberg, Ethan Chung, Woo Jin Tsai, Wei Lun Zhao, Hong Goto, Kaku Zhang, Leiliang Mendez-Navarro, Jorge Jilg, Nikolaus Peng, Lee F. Brockman, Mark A. Chung, Raymond T. TI HIV infection increases HCV-induced hepatocyte apoptosis SO JOURNAL OF HEPATOLOGY LA English DT Article DE HCV-HIV coinfection; Apoptosis; TRAIL receptor ID HEPATITIS-C VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; LIVER FIBROSIS PROGRESSION; TRAIL-INDUCED APOPTOSIS; CELL APOPTOSIS; LIGAND TRAIL; DISEASE; INJURY; IDENTIFICATION; HEPATOTOXICITY AB Background 82 Aims: HCV related liver disease is one of the most important complications in persons with HIV, with accelerated fibrosis progression in coinfected persons compared to those with HCV alone. We hypothesized that HCV-HIV coinfection increases HCV related hepatocyte apoptosis and that HCV and HIV influence TRAIL signaling in hepatocytes. Methods: We analyzed the effect of HIV in JFH1-infected Huh7.5.1 cells. Apoptosis was measured by Caspase-Glo 3/7 assay and Western blotting for cleaved PARP. TRAIL, TRAIL receptor 1 (DR4), and 2 (DR5) mRNA and protein levels were assessed by real-time PCR and Western blot, respectively. We also investigated activation of caspase pathways using caspase inhibitors and assessed expression of Bid and cytochrome C. Results: We found increased caspase 3/7 activity and cleaved PARP in JFH1 HCV-infected Huh7.5.1 cells in the presence of heat-inactivated HIV, compared to Huh7.5.1 cells infected with JFH1 or exposed to heat-inactivated HIV alone. Both DR4 and DR5 mRNA and protein expression were increased in JFH1-infected cells in the presence of inactivated HIV compared to Huh7.5.1 cells infected with JFH1 or exposed to heat-inactivated HIV alone. Pancaspase, caspase-8, and caspase-9 inhibition blocked apoptosis induced by HCV, inactivated HIV, and HCV plus inactivated HIV. A caspase-9 inhibitor blocked apoptosis induced by HCV, HIV, and HCV-HIV comparably to pancaspase and caspase-8 inhibitors. HCV induced the activation of Bid cleavage and cytochrome C release. The addition of HIV substantially augmented this induction. Conclusions: Our findings indicate that hepatocyte apoptosis is increased in the presence of HCV and HIV compared to HCV or HIV alone, and that this increase is mediated by DR4 and DR5 up-regulation. These results provide an additional mechanism for the accelerated liver disease progression observed in HCV-HIV co-infection. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Jang, Jae Young; Shao, Run-Xuan; Lin, Wenyu; Weinberg, Ethan; Chung, Woo Jin; Tsai, Wei Lun; Zhao, Hong; Goto, Kaku; Zhang, Leiliang; Mendez-Navarro, Jorge; Jilg, Nikolaus; Peng, Lee F.; Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. [Jang, Jae Young] Soonchunhyang Univ, Inst Digest Res, Ctr Digest Dis, Dept Internal Med,Coll Med, Seoul, South Korea. [Brockman, Mark A.] Harvard Univ, Div Aids, Cambridge, MA 02138 USA. [Brockman, Mark A.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. RP Chung, RT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Warren 1007, Boston, MA 02114 USA. EM rtchung@partners.org OI Brockman, Mark/0000-0001-6432-1426 FU NIH [AI069939, AI082630, R01 AI069939, U19 AI082630] FX This work was supported in part by NIH grants AI069939 and AI082630 (RTC).; We gratefully acknowledge: Dr. Ralf Bartenschlager, University, Heidelberg, Germany; and Dr. Takaji Wakita, Second Department of Virology, National Institute of Infectious Diseases, Tokyo, Japan (infectious HCV virus JFH1 DNA construct); and Dr. Francis Chisari, Scripps Institute, CA (Huh7.5.1 cells). This work was support by NIH Grants R01 AI069939 and U19 AI082630 (to R.T.C.). NR 44 TC 23 Z9 24 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD APR PY 2011 VL 54 IS 4 BP 612 EP 620 DI 10.1016/j.jhep.2010.07.042 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 740YX UT WOS:000288831400005 PM 21146890 ER PT J AU Duraiswamy, J Ibegbu, CC Masopust, D Miller, JD Araki, K Doho, GH Tata, P Gupta, S Zilliox, MJ Nakaya, HI Pulendran, B Haining, WN Freeman, GJ Ahmed, R AF Duraiswamy, Jaikumar Ibegbu, Chris C. Masopust, David Miller, Joseph D. Araki, Koichi Doho, Gregory H. Tata, Pramila Gupta, Satish Zilliox, Michael J. Nakaya, Helder I. Pulendran, Bali Haining, W. Nicholas Freeman, Gordon J. Ahmed, Rafi TI Phenotype, Function, and Gene Expression Profiles of Programmed Death-1(hi) CD8 T Cells in Healthy Human Adults SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC VIRAL-INFECTION; INTERLEUKIN-7 RECEPTOR-ALPHA; C VIRUS-INFECTION; HUMAN EFFECTOR; UP-REGULATION; PROLIFERATIVE CAPACITY; INHIBITORY RECEPTORS; DISEASE PROGRESSION; HIV-INFECTION; PD-1 PATHWAY AB T cell dysfunction is an important feature of many chronic viral infections. In particular, it was shown that programmed death-1 (PD-1) regulates T cell dysfunction during chronic lymphocytic choriomeningitis virus infection in mice, and PD-1(hi) cells exhibit an intense exhausted gene signature. These findings were extended to human chronic infections such as HIV, hepatitis C virus, and hepatitis B virus. However, it is not known if PD-1(hi) cells of healthy humans have the traits of exhausted cells. In this study, we provide a comprehensive description of phenotype, function, and gene expression profiles of PD-1(hi) versus PD-1(lo) CD8 T cells in the peripheral blood of healthy human adults as follows: 1) the percentage of naive and memory CD8 T cells varied widely in the peripheral blood cells of healthy humans, and PD-1 was expressed by the memory CD8 T cells; 2) PD-1(hi) CD8 T cells in healthy humans did not significantly correlate with the PD-1(hi) exhausted gene signature of HIV-specific human CD8 T cells or chronic lymphocytic choriomeningitis virus-specific CD8 T cells from mice; 3) PD-1 expression did not directly affect the ability of CD8 T cells to secrete cytokines in healthy adults; 4) PD-1 was expressed by the effector memory compared with terminally differentiated effector CD8 T cells; and 5) finally, an interesting inverse relationship between CD45RA and PD-1 expression was observed. In conclusion, our study shows that most PD-1(hi) CD8 T cells in healthy adult humans are effector memory cells rather than exhausted cells. The Journal of Immunology, 2011, 186: 4200-4212. C1 [Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Rollins Res Ctr, Atlanta, GA 30322 USA. [Duraiswamy, Jaikumar; Ibegbu, Chris C.; Masopust, David; Miller, Joseph D.; Araki, Koichi; Zilliox, Michael J.; Ahmed, Rafi] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Doho, Gregory H.] Emory Univ, Emory Biomarker Serv Ctr, Atlanta, GA 30322 USA. [Tata, Pramila; Gupta, Satish] Strand Life Sci, Bangalore 560024, Karnataka, India. [Nakaya, Helder I.; Pulendran, Bali] Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. [Haining, W. Nicholas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Rollins Res Ctr, 1510 Clifton Rd,G211, Atlanta, GA 30322 USA. EM rahmed@emory.edu RI Nakaya, Helder/A-1397-2010 OI Nakaya, Helder/0000-0001-5297-9108 FU National Institutes of Health [P01 AI080192-01]; Grand Challenges in Global Health Initiative [05GCGH0] FX This work was supported by National Institutes of Health Grant P01 AI080192-01 (to R.A.) and Grand Challenges in Global Health Initiative Grant 05GCGH0 (to R.A.). NR 64 TC 68 Z9 69 U1 1 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 1 PY 2011 VL 186 IS 7 BP 4200 EP 4212 DI 10.4049/jimmunol.1001783 PG 13 WC Immunology SC Immunology GA 739WH UT WOS:000288751200045 PM 21383243 ER PT J AU Tai, A Salloum, S Chung, RT AF Tai, A. Salloum, S. Chung, R. T. TI AN ESSENTIAL ROLE FOR A PHOSPHATIDYLINOSITOL 4-KINASE IN HEPATITIS C VIRUS REPLICATION COMPLEX ASSEMBLY SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Meeting Abstract CT Combined Annual Meeting on Midwestern Regional Program CY APR 14-15, 2011 CL Chicago, IL C1 [Tai, A.; Salloum, S.] Univ Michigan, Ann Arbor, MI 48109 USA. [Chung, R. T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 J9 J INVEST MED JI J. Invest. Med. PD APR PY 2011 VL 59 IS 4 BP 723 EP 723 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 738QE UT WOS:000288656200111 ER PT J AU Wilson, RS Krueger, KR Boyle, PA Bennett, DA AF Wilson, Robert S. Krueger, Kristin R. Boyle, Patricia A. Bennett, David A. TI Loss of basic lexical knowledge in old age SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID ADULT READING TEST; ALZHEIMERS-DISEASE; PREMORBID INTELLIGENCE; COGNITIVE FUNCTION; DEMENTIA; DECLINE; NEUROPATHOLOGY; IMPAIRMENT; VALIDATION; ABILITY AB Background Basic lexical skills are hypothesised to be relatively preserved in mild dementia, but clinical studies have reported inconsistent results. Methods More than 400 older Catholic nuns, priests and brothers recruited from groups across the USA completed annual evaluations for up to 15 years, died and underwent brain autopsy. Each clinical evaluation included administration of a 20-item word reading test and a 15-item vocabulary test, which were combined to form a composite measure of word knowledge. In a uniform neuropathological examination, Alzheimer's disease pathology was quantified with a composite index of plaques and tangles, and the presence of gross and microscopic cerebral infarctions and Lewy bodies was recorded. Results The post-mortem level of Alzheimer's disease neuropathology was linearly related to rate of decline in word knowledge. Decline was nearly fourfold faster at a relatively high level of pathology (75th percentile) compared with a relatively low level (25th percentile). Neocortical (but not nigral or limbic) Lewy bodies and gross (but not microscopic) cerebral infarction were also associated with a more rapid decline in word knowledge. Effects for word reading and vocabulary were similar, except that gross cerebral infarction was associated with accelerated decline in vocabulary, but not in word reading. Conclusion Common neuropathological changes associated with late-life dementia impair word knowledge in old age, calling into question the use of word knowledge tests to estimate premorbid cognitive ability. C1 [Wilson, Robert S.; Boyle, Patricia A.; Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Wilson, Robert S.; Bennett, David A.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Wilson, Robert S.; Boyle, Patricia A.] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA. [Krueger, Kristin R.] S Texas Vet Hlth Care Syst, Psychol Serv, San Antonio, TX USA. RP Wilson, RS (reprint author), Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, 600 S Paulina Ave,Suite 1038, Chicago, IL 60612 USA. EM rwilson@rush.edu FU National Institute on Aging [P30AG10161, R01AG15819] FX Support for this project was provided by federal grants from the National Institute on Aging: P30AG10161 and R01AG15819. NR 29 TC 7 Z9 7 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD APR PY 2011 VL 82 IS 4 BP 369 EP 372 DI 10.1136/jnnp.2010.212589 PG 4 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 734ZY UT WOS:000288384100006 PM 20802026 ER PT J AU Duhaine, AC Schwartz, D AF Duhaine, Ann-Christine Schwartz, Daniel TI Monitoring in young patients SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Editorial Material C1 [Duhaine, Ann-Christine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schwartz, Daniel] Surg Monitoring Associates, Springfield, PA USA. RP Duhaine, AC (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 4 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 1933-0707 J9 J NEUROSURG-PEDIATR JI J. Neurosurg.-Pediatr. PD APR PY 2011 VL 7 IS 4 BP 329 EP 329 DI 10.3171/2010.11.PEDS10459 PG 1 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA 739NX UT WOS:000288726000001 PM 21456901 ER PT J AU Reidling, JC Rubin, SA AF Reidling, Jack C. Rubin, Stanley A. TI Promoter analysis of the human ascorbic acid transporters SVCT1 and 2: mechanisms of adaptive regulation in liver epithelial cells SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Ascorbic acid; Nutrient transport; Promoter regulation; SVCT ID VITAMIN-C UPTAKE; THIAMIN UPTAKE; WILD-TYPE; ANTIOXIDANT; EXPRESSION; SLC23A2; HSVCT1 AB Ascorbic acid, the active form of vitamin C, is a vital antioxidant in the human liver, yet the molecular mechanisms involved in the regulation of ascorbic acid transporters [human sodium-dependent vitamin C transporters (hSVCT) 1 and 2] in liver cells are poorly understood. Therefore, we characterized the minimal promoter regions of hSVCT1 and 2 in cultured human liver epithelial cells (HepG2) and examined the effects of ascorbic acid deprivation and supplementation on activity and regulation of the transport systems. Identified minimal promoters required for basal activity were found to include multiple cis regulatory elements, whereas mutational analysis demonstrated that HNF-1 sites in the hSVCT1 promoter and KLF/Sp1 sites in the hSVCT2 promoter were essential for activities. When cultured in ascorbic acid deficient or supplemented media, HepG2 cells demonstrated significant (P<.01) and specific reciprocal changes in [(14)C]-Ascorbic acid uptake, and in hSVCT1 mRNA and protein levels as well as hSVCT1 promoter activity. However, no significant changes in hSVCT2 expression or promoter activity were observed during ascorbic acid deficient or supplemented conditions. We mapped the ascorbic acid responsive region in the hSVCT1 promoter and determined that HNF-1 sites are important for the adaptive regulation response. The results of these studies further characterize the hSVCT1 and 2 promoters establish that ascorbic acid uptake by human liver epithelial cells is adaptively regulated and show that transcriptional mechanisms via HNF-1 in the hSVCT1 promoter may, in part, be involved in this regulation. Published by Elsevier Inc. C1 [Reidling, Jack C.] VA Med Ctr, Long Beach, CA 90822 USA. [Reidling, Jack C.] Univ Calif Irvine, Coll Med, Irvine, CA 92697 USA. [Rubin, Stanley A.] UCLA Sch Med, VA Greater Los Angeles Med Ctr, Dept Med, Los Angeles, CA 90073 USA. RP Reidling, JC (reprint author), VA Med Ctr, Long Beach, CA 90822 USA. EM jreidlin@uci.edu FU National Institutes of Health [DK73032]; Department of Veterans Affairs FX The work was supported by grants from the National Institutes of Health DK73032 and the Department of Veterans Affairs. NR 26 TC 8 Z9 8 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD APR PY 2011 VL 22 IS 4 BP 344 EP 350 DI 10.1016/j.jnutbio.2010.03.001 PG 7 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 740DT UT WOS:000288772500006 PM 20471816 ER PT J AU Gravaghi, C La Perle, KMD Ogrodwski, P Kang, JX Quimby, F Lipkin, M Lamprecht, SA AF Gravaghi, Claudia La Perle, Krista M. D. Ogrodwski, Paul Kang, Jing X. Quimby, Fred Lipkin, Martin Lamprecht, Sergio A. TI Cox-2 expression, PGE(2) and cytokines production are inhibited by endogenously synthesized n-3 PUFAs in inflamed colon of fat-1 mice SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE Cox-2; Fat-1 mice; Colitis; Inflammation ID POLYUNSATURATED FATTY-ACIDS; TRANSGENIC MICE; COLITIS; INFLAMMATION; CANCER; CELLS; PROLIFERATION; PREVENTION; RECEPTORS; APOPTOSIS AB There is great interest in the role of polyunsaturated fatty acids (PUFAs) in promoting (n-6 class) or inhibiting (n-3 class) inflammation. Mammalian cells are devoid of desaturase that converts n-6 to n-3 PUFAs. Consequently, essential n-3 fatty acids must be supplied with the diet. We have studied the effect of endogenously produced n-3 PUFAs on colitis development in fat-1 transgenic mice carrying the Caenorhabditis elegans fat-1 gene encoding n-3 desaturase. Colonic cell lipid profile was measured by capillary gas chromatography in fat-1 and wild-type (WT) littermates fed standard diet supplemented with 10% (w/w) safflower oil rich (76%) in n-6 polyunsaturated linoleic acid (LA). Experimental colitis was induced by administrating 3% dextran sodium sulphate (DSS). Colitis was scored by histopatological analysis. Cyclooxygenase-2 (Cox-2) expression was evaluated by real time polymerase chain reaction. Prostaglandin E-2 (PGE(2)) levels and cytokine production were determined by enzyme and microsphere-based immunoassays, respectively. The n-6/n-3 PUFA ratios in colonic cells of fat-1 mice were markedly lower (9.83 +/- 2.62) compared to WT (54.5 +/- 9.24, P<.001). Results also showed an attenuation of colonic acute and chronic inflammation in fat-1 mice with significant decreases in PGE2 production (P<.01) and Cox-2 expression (P<.01). High levels of colitis-induced proinflammatory cytokines, interleukin (IL)-18, IL-1 alpha, IL-1 beta, IL-6 monocytes chemotactic proteins 1, 2 and 3 (MCP 1,2,3), matrix metalloproteinase 9 and tumor necrosis factor alpha (TNF-alpha) were down-regulated in DSS acutely and chronically treated fat-1 mice. The expression of fat-1 gene in the colon was associated with endogenous n-3 PUFAs production, decreased Cox-2 expression, increased PGE(2) and cytokine production. (C) 2011 Elsevier Inc. All rights reserved. C1 [Gravaghi, Claudia; Ogrodwski, Paul; Lipkin, Martin; Lamprecht, Sergio A.] Cornell Univ, Weill Med Coll, Dept Med, Div Gastroenterol & Hepatol, New York, NY 10065 USA. [La Perle, Krista M. D.] Mem Sloan Kettering Canc Ctr, Lab Comparat Pathol, New York, NY 10021 USA. [Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kang, Jing X.] Harvard Univ, Sch Med, Boston, MA USA. [Quimby, Fred] Rockefeller Univ, Lab Anim Res Ctr, New York, NY 10021 USA. RP Gravaghi, C (reprint author), Cornell Univ, Weill Med Coll, Dept Med, Div Gastroenterol & Hepatol, New York, NY 10065 USA. EM cgravaghi@strang.org RI La Perle, Krista/B-3099-2015 FU AICR [04B036]; NIH FX We thank Dr. Andrew J. Dannenberg and Dr. Kotha Subbaramaiah for careful reading and discussing the manuscript. The work was supported by AICR Grant #04B036 to S.A.L and NIH R25 Postdoctoral Fellowship to C.G. NR 35 TC 39 Z9 40 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD APR PY 2011 VL 22 IS 4 BP 360 EP 365 DI 10.1016/j.jnutbio.2010.03.003 PG 6 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 740DT UT WOS:000288772500008 PM 20655721 ER PT J AU Oshrine, B Lehmann, LE Duncan, CN AF Oshrine, Benjamin Lehmann, Leslie E. Duncan, Christine N. TI Safety and Utility of Liver Biopsy After Pediatric Hematopoietic Stem Cell Transplantation SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE hematopoietic stem cell transplantation; liver biopsy; liver disease; hepatic disease; liver dysfunction ID DYSFUNCTION; CHILDREN AB Liver dysfunction is common after pediatric hematopoietic stem cell transplantation (HSCT) and liver biopsy may be necessary to diagnosis the cause of liver dysfunction and institute therapy. We report our liver biopsy experience in 356 consecutive patients. During the study period, 16 (4.5%) patients underwent 18 biopsies, all after allogeneic HSCT. The median time from HSCT to biopsy was 205.5 days. All patients had transaminase elevation and 67% had hyperbilirubinemia. The most commonly used method of biopsy was the imaging-guided percutaneous approach, performed in 12 of 18 cases. Five biopsies were done transjugularly and 1 was performed during laparotomy. In all the cases a histopathologic diagnosis was made. The most common diagnosis was graft-versus-host disease (GVHD) followed by iron overload. In 12 cases, management was modified based on biopsy results. Complications occurred after 5 biopsies, 4 of which were performed transjugularly. The most common complication was hemorrhage. Two patients required transfer to the intensive care unit for related complications. No complications were observed after percutaneous biopsies. In 2 cases a second procedure was required to manage the complication. We conclude that while liver biopsy yields a high-rate of diagnoses, it is accompanied by high rates of complications, particularly when the transjugular approach is used. C1 [Oshrine, Benjamin] Childrens Hosp, Boston, MA 02115 USA. [Lehmann, Leslie E.; Duncan, Christine N.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Oshrine, B (reprint author), 300 Longwood Ave, Boston, MA 02115 USA. EM benjamin.oshrine@childrens.harvard.edu NR 9 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD APR PY 2011 VL 33 IS 3 BP E92 EP E97 DI 10.1097/MPH.0b013e3182025236 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 739DW UT WOS:000288694700002 PM 21317809 ER PT J AU Mankin, H Trahan, C Hornicek, F AF Mankin, Henry Trahan, Carol Hornicek, Francis TI Pigmented Villonodular Synovitis of Joints SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE PVNS; joints; benign ID GIANT-CELL TUMOR; LOCALIZED NODULAR SYNOVITIS; TENDON SHEATH; ARTHROSCOPIC TREATMENT; KNEE; HIP; TENOSYNOVITIS; DIAGNOSIS; XANTHOMA; ANKLE AB Objectives: The objective of this study is to present two series of cases of pigmented villonodular disease of joints (PVNS) treated at different periods. The 215 cases from our hospital are current (1972-2009) and those 62 from the Jaffe collection from 1920 to 1968. Methods: By use of our computerized tumor data system we were able to define age, gender, site, treatment, complications, and outcome. Examination of the material from the Jaffe collection included all of the above primary data but none on treatment and outcome. Results: The data for the two systems studied were remarkably similar. The average ages were in mid years and the disorder was more frequent in females. The largest numbers of cases for both series were in the knee and foot and less commonly in hip, shoulder, and hand. The treatments were mostly surgical excision with the exception of the hip which required total hip replacement. The results show only a small number of recurrences, no metastatic disease and no deaths. Conclusion: Pigmented villonodular disease of joints is a rare entity, mostly occurring in the knee and foot. The principal treatment is surgical excision which is most often successful in these sites but leads to problems at other locations, especially the hip. J. Surg. Oncol. 2011; 103: 386-389. (C) 2010 Wiley-Liss, Inc. C1 [Mankin, Henry; Hornicek, Francis] Massachusetts Gen Hosp, Dept Orthopaed, Boston, MA 02114 USA. [Mankin, Henry; Trahan, Carol; Hornicek, Francis] Massachusetts Gen Hosp, Dept Res Orthopaed, Boston, MA 02114 USA. RP Mankin, H (reprint author), 1122A Jackson Bldg, Boston, MA 02114 USA. EM hmankin@partners.org NR 43 TC 25 Z9 28 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD APR PY 2011 VL 103 IS 5 BP 386 EP 389 DI 10.1002/jso.21835 PG 4 WC Oncology; Surgery SC Oncology; Surgery GA 737FP UT WOS:000288554800004 PM 21400520 ER PT J AU Johri, AM Witzke, C Solis, J Palacios, IF Inglessis, I Picard, MH Passeri, JJ AF Johri, Amer M. Witzke, Christian Solis, Jorge Palacios, Igor F. Inglessis, Ignacio Picard, Michael H. Passeri, Jonathan J. TI Real-Time Three-Dimensional Transesophageal Echocardiography in Patients with Secundum Atrial Septal Defects: Outcomes following Transcatheter Closure SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Three-dimensional transesophageal echocardiography; Atrial septal defect ID FEASIBILITY; GUIDANCE; DEVICE; FOSSA AB Background: Successful transcatheter closure of atrial septal defects (ASDs) requires the accurate assessment of defect size and morphology. Assessment of ASD anatomy may be difficult by two-dimensional (2D) echocardiography. The aim of this study was to test the hypothesis that real-time three-dimensional (3D) transesophageal echocardiography (TEE) may provide more accurate morphologic assessment of ASDs than multiplane 2D TEE. Methods: Twenty-four patients with ASDs were imaged using 2D and real-time 3D TEE. ASD shape and size were assessed using 3D TEE retrospectively. Maximal ASD dimensions obtained by 3D TEE were compared with unstretched and balloon-stretched dimensions on 2D TEE. Planimetered defect area by 3D TEE was compared with area calculated using the ellipse formula from 2D imaging. Twenty of the 24 patients underwent transcatheter ASD closure. Closure device size was based on findings on 2D TEE. Follow-up was conducted by 2D transthoracic echocardiography. Results: Of the 24 ASDs, 6 (25%) were circular, 10 (42%) were oval, and 8 (33%) were complex in shape. The mean maximal dimension was larger by 3D TEE compared with 2D TEE (1.8 +/- 0.8 vs 1.5 +/- 0.6 cm; P < .05). There was no difference in the mean area measured by either modality, but for complex-shaped defects, area measured by 3D TEE was larger than that by 2D TEE (2.8 +/- 1.3 vs 1.7 +/- 1.4 cm(2); P < .05). Follow-up transthoracic echocardiography was available for 19 of the 20 patients undergoing transcatheter closure. Nine patients had residual right-to-left shunting 1 to 6 months after ASD closure, and the majority of these were complex in shape. In patients with residual shunting, ASD area by 3D TEE was 27% larger than by 2D TEE, whereas in patients without residual shunting, there was significantly less discrepancy between 3D and 2D areas (19%; P = .0027). Conclusions: Three-dimensional TEE can identify ASD shape. Maximal dimensions on 3D TEE were well correlated with balloon-stretched 2D dimensions. Two-dimensional TEE can underestimate the area of complex-shaped ASDs, which may result in residual right-to-left shunting. (J Am Soc Echocardiogr 2011;24:431-7.) C1 [Johri, Amer M.; Witzke, Christian; Solis, Jorge; Palacios, Igor F.; Inglessis, Ignacio; Picard, Michael H.; Passeri, Jonathan J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. RP Passeri, JJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, 55 Fruit St,Yawkey 5E, Boston, MA 02114 USA. EM jpasseri@partners.org OI Picard, Michael/0000-0002-9264-3243 NR 8 TC 18 Z9 24 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD APR PY 2011 VL 24 IS 4 BP 431 EP 437 DI 10.1016/j.echo.2010.12.011 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 740HG UT WOS:000288781700012 PM 21262563 ER PT J AU Tournoux, F Petersen, B Thibault, H Zou, L Raher, MJ Kurtz, B Halpern, EF Chaput, M Chao, W Picard, MH Scherrer-Crosbie, M AF Tournoux, Francois Petersen, Bodil Thibault, Helene Zou, Lin Raher, Michael J. Kurtz, Baptiste Halpern, Elkan F. Chaput, Miguel Chao, Wei Picard, Michael H. Scherrer-Crosbie, Marielle TI Validation of Noninvasive Measurements of Cardiac Output in Mice Using Echocardiography SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Cardiac output; Doppler echocardiography; Flow probe; Mice; Sepsis ID IN-VIVO; CONDUCTANCE CATHETER; VOLUME; PULMONARY; PERFUSION; MOUSE; RATS AB Background: Although multiple echocardiographic methods exist to calculate cardiac output (CO), they have not been validated in mice using a reference method. Methods: Echocardiographic and flow probe measurements of CO were obtained in mice before and after albumin infusion and inferior vena cava occlusions. Echocardiography was also performed before and after endotoxin injection. Cardiac output was calculated using left ventricular volumes obtained from an M-mode or a two-dimensional view, left ventricular stroke volume calculated using the pulmonary flow, or estimated by the measurement of pulmonary velocity time integral (VTI). Results: Close correlations were demonstrated between flow probe-measured CO and all echocardiographic measurements of CO. All echocardiographic-derived CO overestimated the flow probe-measured CO. Two-dimensional image-derived CO was associated with the smallest overestimation of CO. Interobserver variability was lowest for pulmonary VTI-derived CO. Conclusion: In mice, CO calculated from two-dimensional parasternal long-axis images is most accurate when compared with flow probe measurements; however, pulmonary VTI-derived CO is subject to less variability. (J Am Soc Echocardiogr 2011;24:465-70.) C1 [Tournoux, Francois; Thibault, Helene; Kurtz, Baptiste; Chaput, Miguel; Picard, Michael H.; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Petersen, Bodil; Zou, Lin; Raher, Michael J.; Chao, Wei] Massachusetts Gen Hosp, Anesthesia Res Lab, Boston, MA 02114 USA. [Halpern, Elkan F.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Tournoux, Francois] Univ Paris 07, INSERM, Hop Lariboisiere, APHP,Dept Cardiol,U942, Paris, France. RP Scherrer-Crosbie, M (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Blake 254,55 Fruit St, Boston, MA 02114 USA. EM marielle@crosbie.com OI Picard, Michael/0000-0002-9264-3243 FU National Institutes of Health/National Heart, Lung, and Blood Institute [1S10RR0225860-1A1]; Claflin; Federation Francaise de Cardiologie FX Funding: This study was supported by a Shared Equipment Grant (National Institutes of Health/National Heart, Lung, and Blood Institute 1S10RR0225860-1A1, to M. S. C.), the Claflin Award (to M. S. C.), and fellowship grants from the Federation Francaise de Cardiologie (to F.T., H.T., and B.K.). NR 22 TC 24 Z9 24 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD APR PY 2011 VL 24 IS 4 BP 465 EP 470 DI 10.1016/j.echo.2010.12.019 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 740HG UT WOS:000288781700016 PM 21315557 ER PT J AU Teles, FRF Teles, RP Siegelin, Y Paster, B Haffajee, AD Socransky, SS AF Teles, F. R. F. Teles, R. P. Siegelin, Y. Paster, B. Haffajee, A. D. Socransky, S. S. TI RNA-oligonucleotide quantification technique (ROQT) for the enumeration of uncultivated bacterial species in subgingival biofilms SO MOLECULAR ORAL MICROBIOLOGY LA English DT Article DE bacteria; biofilms; oligonucleotide; oral; periodontal; quantification; uncultivated ID POLYMERASE-CHAIN-REACTION; DNA-DNA HYBRIDIZATION; PORPHYROMONAS-GINGIVALIS; TANNERELLA-FORSYTHENSIS; PERIODONTITIS; MICROBIOTA; HEALTHY; PLAQUE; DIVERSITY; MICROORGANISMS AB Approximately 35% of the species present in subgingival biofilms are as yet uncultivated, so their role in periodontal pathogenesis is unknown. The aim of the present study was to develop a high throughput method to quantify a wide range of cultivated and uncultivated taxa in subgingival biofilm samples associated with periodontal disease or health. Oligonucleotides targeting the 16S ribosomal DNA gene were designed, synthesized and labeled with digoxigenin. These probes were hybridized with the total nucleic acids of pure cultures or subgingival biofilm samples. Target species included cultivated taxa associated with periodontal health and disease, as well as uncultivated species, such as TM7 sp. OT 346, Mitsuokella sp. OT 131 and Desulfobulbus sp. OT 041. Sensitivity and specificity of the probes were determined. A Universal probe was used to assess total bacterial load. Sequences complementary to the probes were used as standards for quantification. Chemiluminescent signals were visualized after film exposure or using a CCD camera. In a pilot clinical study, 266 subgingival plaque samples from eight periodontally healthy people and 11 patients with periodontitis were examined. Probes were specific and sensitivity reached 104 cells. Fusobacterium nucleatum ss. polymorphum and Actinomyces gerencseriae were the most abundant cultivated taxa in clinical samples. Among uncultivated/unrecognized species, Mitsuokella sp. OT 131 and Prevotella sp. OT 306 were the most numerous. Porphyromonas gingivalis and Desulfobulbus sp. OT 041 were only detected in patients with periodontitis. Direct hybridization of total nucleic acids using oligonucleotide probes permitted the quantification of multiple cultivated and uncultivated taxa in mixed species biofilm samples. C1 [Teles, F. R. F.; Teles, R. P.; Siegelin, Y.; Haffajee, A. D.; Socransky, S. S.] Forsyth Inst, Dept Periodontol, Cambridge, MA 02142 USA. [Teles, F. R. F.; Teles, R. P.; Paster, B.; Haffajee, A. D.; Socransky, S. S.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Paster, B.] Forsyth Inst, Dept Mol Genet, Cambridge, MA 02142 USA. RP Teles, FRF (reprint author), Forsyth Inst, Dept Periodontol, 245 1st St, Cambridge, MA 02142 USA. EM fteles@forsyth.org FU National Institutes of Dental and Craniofacial Research [T32-DE-07327, DE-12108, DE-14242]; Forsyth Institute/Harvard Medical School FX This work was supported in part by grants T32-DE-07327, DE-12108 and DE-14242 from the National Institutes of Dental and Craniofacial Research. This work was also supported in part by the Eleanor and Miles Shore 50th Anniversary Fellowship Program for Scholars in Medicine (The Forsyth Institute/Harvard Medical School). NR 37 TC 14 Z9 17 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2041-1006 J9 MOL ORAL MICROBIOL JI Mol. Oral Microbiol. PD APR PY 2011 VL 26 IS 2 BP 127 EP 139 DI 10.1111/j.2041-1014.2010.00603.x PG 13 WC Dentistry, Oral Surgery & Medicine; Microbiology SC Dentistry, Oral Surgery & Medicine; Microbiology GA 741DP UT WOS:000288843600004 PM 21375703 ER PT J AU Poelmans, G Buitelaar, JK Pauls, DL Franke, B AF Poelmans, G. Buitelaar, J. K. Pauls, D. L. Franke, B. TI A theoretical molecular network for dyslexia: integrating available genetic findings SO MOLECULAR PSYCHIATRY LA English DT Review DE dyslexia; genetics; neurodevelopment; molecular network; bioinformatics ID QUANTITATIVE-TRAIT LOCUS; END-PRODUCTS RAGE; PROTEIN-ASSOCIATED PROTEIN; FAMILY-BASED ASSOCIATION; LONG-TERM POTENTIATION; FRAGILE-X-SYNDROME; DEVELOPMENTAL DYSLEXIA; READING-DISABILITY; SUSCEPTIBILITY LOCUS; NEURONAL MIGRATION AB Developmental dyslexia is a common specific childhood learning disorder with a strong heritable component. Previous studies using different genetic approaches have identified several genetic loci and candidate genes for dyslexia. In this article, we have integrated the current knowledge on 14 dyslexia candidate genes suggested by cytogenetic findings, linkage and association studies. We found that 10 of the 14 dyslexia candidate genes (ROBO1, KIAA0319, KIAA0319L, S100B, DOCK4, FMR1, DIP2A, GTF2I, DYX1C1 and DCDC2) fit into a theoretical molecular network involved in neuronal migration and neurite outgrowth. Based on this, we also propose three novel dyslexia candidate genes (SLIT2, HMGB1 and VAPA) from known linkage regions, and we discuss the possible involvement of genes emerging from the two reported genome-wide association studies for reading impairment-related phenotypes in the identified network. Molecular Psychiatry (2011) 16, 365-382; doi:10.1038/mp.2010.105; published online 19 October 2010 C1 [Franke, B.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands. [Poelmans, G.; Buitelaar, J. K.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, NL-6500 HB Nijmegen, Netherlands. [Pauls, D. L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Psychiat & Neurodev Genet Uni, Boston, MA USA. [Franke, B.] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Psychiat, NL-6500 HB Nijmegen, Netherlands. RP Franke, B (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, 855,POB 9101, NL-6500 HB Nijmegen, Netherlands. EM b.franke@antrg.umcn.nl RI Franke, Barbara/D-4836-2009; Buitelaar, Jan/E-4584-2012 OI Franke, Barbara/0000-0003-4375-6572; Buitelaar, Jan/0000-0001-8288-7757 FU 'Hersenstichting Nederland' (Brain Foundation of The Netherlands) FX We gratefully acknowledge the families who have made all these studies possible. We are also indebted to the many investigators whose work drives the dyslexia genetics field forward. This work was supported by a research grant from the 'Hersenstichting Nederland' (Brain Foundation of The Netherlands). NR 154 TC 49 Z9 50 U1 5 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD APR PY 2011 VL 16 IS 4 BP 365 EP 382 DI 10.1038/mp.2010.105 PG 18 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 739TK UT WOS:000288740700006 PM 20956978 ER PT J AU Kim, DH Lu, NS Ghaffari, R Kim, YS Lee, SP Xu, LZ Wu, JA Kim, RH Song, JZ Liu, ZJ Viventi, J de Graff, B Elolampi, B Mansour, M Slepian, MJ Hwang, S Moss, JD Won, SM Huang, YG Litt, B Rogers, JA AF Kim, Dae-Hyeong Lu, Nanshu Ghaffari, Roozbeh Kim, Yun-Soung Lee, Stephen P. Xu, Lizhi Wu, Jian Kim, Rak-Hwan Song, Jizhou Liu, Zhuangjian Viventi, Jonathan de Graff, Bassel Elolampi, Brian Mansour, Moussa Slepian, Marvin J. Hwang, Sukwon Moss, Joshua D. Won, Sang-Min Huang, Younggang Litt, Brian Rogers, John A. TI Materials for multifunctional balloon catheters with capabilities in cardiac electrophysiological mapping and ablation therapy SO NATURE MATERIALS LA English DT Article ID PULMONARY VEIN ISOLATION; PAROXYSMAL ATRIAL-FIBRILLATION; OF-THE-ART; RADIOFREQUENCY ABLATION; INTEGRATED-CIRCUITS; ARTIFICIAL SKIN; TACTILE SENSOR; BIOCOMPATIBILITY; HYPERTENSION; SEPTOSTOMY AB Developing advanced surgical tools for minimally invasive procedures represents an activity of central importance to improving human health. A key challenge is in establishing biocompatible interfaces between the classes of semiconductor device and sensor technologies that might be most useful in this context and the soft, curvilinear surfaces of the body. This paper describes a solution based on materials that integrate directly with the thin elastic membranes of otherwise conventional balloon catheters, to provide diverse, multimodal functionality suitable for clinical use. As examples, we present sensors for measuring temperature, flow, tactile, optical and electrophysiological data, together with radiofrequency electrodes for controlled, local ablation of tissue. Use of such 'instrumented' balloon catheters in live animal models illustrates their operation, as well as their specific utility in cardiac ablation therapy. The same concepts can be applied to other substrates of interest, such as surgical gloves. C1 [Kim, Dae-Hyeong; Lu, Nanshu; Kim, Yun-Soung; Xu, Lizhi; Kim, Rak-Hwan; Hwang, Sukwon; Won, Sang-Min; Rogers, John A.] Univ Illinois, Beckman Inst Adv Sci & Technol, Dept Mat Sci & Engn, Urbana, IL 61801 USA. [Kim, Dae-Hyeong; Lu, Nanshu; Kim, Yun-Soung; Xu, Lizhi; Kim, Rak-Hwan; Hwang, Sukwon; Won, Sang-Min; Rogers, John A.] Univ Illinois, Frederick Seitz Mat Res Lab, Urbana, IL 61801 USA. [Ghaffari, Roozbeh; Lee, Stephen P.; de Graff, Bassel; Elolampi, Brian] MC10 Inc, Cambridge, MA 02140 USA. [Wu, Jian; Huang, Younggang] Northwestern Univ, Dept Mech Engn, Evanston, IL 60208 USA. [Wu, Jian; Huang, Younggang] Northwestern Univ, Dept Civil & Environm Engn, Evanston, IL 60208 USA. [Song, Jizhou] Univ Miami, Dept Mech & Aerosp Engn, Coral Gables, FL 33146 USA. [Liu, Zhuangjian] Inst High Performance Comp, Singapore 138632, Singapore. [Viventi, Jonathan; Litt, Brian] Univ Penn, Dept Bioengn, Philadelphia, PA 19104 USA. [Mansour, Moussa] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Slepian, Marvin J.] Univ Arizona, Sarver Heart Ctr, Tucson, AZ 85724 USA. [Moss, Joshua D.] Hosp Univ Penn, Dept Cardiol, Philadelphia, PA 19104 USA. [Litt, Brian] Hosp Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. RP Rogers, JA (reprint author), Univ Illinois, Beckman Inst Adv Sci & Technol, Dept Mat Sci & Engn, Urbana, IL 61801 USA. EM jrogers@uiuc.edu RI Song, Jizhou/B-1935-2008; Kim, Rak-Hwan/A-6155-2012; Rogers, John /L-2798-2016; Wu, Jian/I-3466-2012; Lu, Nanshu/B-1611-2008; Huang, Yonggang/B-6998-2009; Xu, Lizhi/D-8143-2016 OI Lee, Stephen/0000-0002-8521-8652; Xu, Lizhi/0000-0001-6888-0524 FU National Science Foundation [DMI-0328162]; US Department of Energy, Division of Materials Sciences at the University of Illinois at Urbana-Champaign [DE-FG02-07ER46471, DE-FG02-07ER46453]; Beckman Institute; National Security Science and Engineering Faculty FX We thank K. Dowling for help in high-resolution imaging and analysis of devices. We thank B. Dehdashti and members of the Sarver Heart Center for help in preparing the animals for in vivo studies. We thank S. Laferriere and the Massachusetts General Hospital Electrophysiology Laboratory for help with X-ray imaging in animals. This material is based on work supported by the National Science Foundation under grant DMI-0328162 and the US Department of Energy, Division of Materials Sciences, under award DE-FG02-07ER46471, through the Materials Research Laboratory and Center for Microanalysis of Materials (DE-FG02-07ER46453) at the University of Illinois at Urbana-Champaign. N.L. acknowledges support from a Beckman Institute postdoctoral fellowship. J.A.R. acknowledges a National Security Science and Engineering Faculty Fellowship. NR 39 TC 227 Z9 232 U1 17 U2 121 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1476-1122 J9 NAT MATER JI Nat. Mater. PD APR PY 2011 VL 10 IS 4 BP 316 EP 323 DI 10.1038/NMAT2971 PG 8 WC Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Materials Science; Physics GA 739UU UT WOS:000288744700023 PM 21378969 ER PT J AU Stengel, A Goebel, M Tache, Y AF Stengel, A. Goebel, M. Tache, Y. TI Nesfatin-1: a novel inhibitory regulator of food intake and body weight SO OBESITY REVIEWS LA English DT Article DE Food intake; hypothalamus; nesfatin-1; NUCB2; X; A-like cells ID CORTICOTROPIN-RELEASING-FACTOR; MELANOCYTE-STIMULATING HORMONE; SATIETY MOLECULE NESFATIN-1; EDINGER-WESTPHAL NUCLEUS; BLOOD-BRAIN-BARRIER; BINDING-PROTEIN; INSULIN-SECRETION; ARCUATE NUCLEUS; PARAVENTRICULAR NUCLEUS; TRANSCRIPT PEPTIDE AB P>The protein nucleobindin 2 (NUCB2) or NEFA (DNA binding/EF-hand/acidic amino acid rich region) was identified over a decade ago and implicated in intracellular processes. New developments came with the report that post-translational processing of hypothalamic NUCB2 may result in nesfatin-1, nesfatin-2 and nesfatin-3 and convergent studies showing that nesfatin-1 and full length NUCB2 injected in the brain potently inhibit the dark phase food intake in rodents including leptin receptor deficient Zucker rats. Nesfatin-1 also reduces body weight gain, suggesting a role as a new anorexigenic factor and modulator of energy balance. In light of the obesity epidemic and its associated diseases, underlying new mechanisms regulating food intake may be promising targets in the drug treatment of obese patients particularly as the vast majority of them display reduced leptin sensitivity or leptin resistance while nesfatin-1's mechanism of action is leptin independent. Although much progress on the localization of NUCB2/nesfatin-1 in the brain and periphery as well as on the understanding of nesfatin-1's anorexic effect have been achieved during the past three years, several important mechanisms have yet to be unraveled such as the identification of the nesfatin-1 receptor and the regulation of NUCB2 processing and nesfatin-1 release. C1 [Tache, Y.] Univ Calif Los Angeles, Ctr Neurobiol Stress, VA GLA Healthcare Syst, Div Digest Dis, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, CURE Digest Dis Res Ctr, Los Angeles, CA 90073 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Tache, Y (reprint author), Univ Calif Los Angeles, Ctr Neurobiol Stress, VA GLA Healthcare Syst, Div Digest Dis, CURE Bldg 115,Room 117,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM ytache@mednet.ucla.edu FU German Research Foundation [STE 1765/1-1, GO 1718/1-1]; NIHDK [33061]; [DK-41301] FX Supported by: German Research Foundation Grants STE 1765/1-1 (A.S.), GO 1718/1-1 (M.G.), VA Research Career Scientist Award, NIHDK 33061, Center Grant DK-41301 (Animal Core) (Y.T.). NR 61 TC 29 Z9 35 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1467-7881 J9 OBES REV JI Obes. Rev. PD APR PY 2011 VL 12 IS 4 BP 261 EP 271 DI 10.1111/j.1467-789X.2010.00770.x PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 738ZA UT WOS:000288679900004 PM 20546141 ER PT J AU Jena, AB Goldman, DP Joyce, G AF Jena, Anupam B. Goldman, Dana P. Joyce, Geoffrey TI Association Between the Birth of Twins and Parental Divorce SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID NATURAL EXPERIMENT; MULTIPLE BIRTHS; FERTILITY; CHILDREN; WEIGHT; RATES AB OBJECTIVE: Mothers of multiple births face higher rates of postpartum depression, yet evidence on the marital consequences of multiple births is limited. We examined the association between twin births and parental divorce. METHODS: We used the 1980 U.S. Census to identify a large sample of mothers with and without twin births. The goal was to estimate multivariate logistic models of the association between birth of twins and divorce adjusting for race, age at marriage and first birth, and college education. We examined whether the association was affected by maternal education, age and sex composition of twins, and family size. RESULTS: Twins at first birth were associated with greater parental divorce compared with singletons (odds ratio, 1.08; 95% confidence interval, 1.01-1.16; absolute risk 13.7% with twins compared with 12.7%; P=.02). The association was statistically greater among mothers not attending college (14.9% with twins compared with 13.3%; P=.01) compared with those with some college (10.4% with twins compared with 10.5%; P=.34); those with children older than 8 years (15.6% with twins compared with 13.5%; P <.01) compared with younger children (10.6% with twins compared with 10.8%; P=.42); and those with at least one twin girl (13.8% with twins compared with 12.6%; P=.03) compared with twin boys (12.1% with twins compared with 12.5%, P=.38). Mothers with four or more children had a larger association between birth of twins and divorce (15.4% for mothers with twins at fourth birth compared with 11.3% for all other mothers with four or more children; P <.01) compared with mothers with twins at first birth (13.7% for twins at first birth compared with 12.7%; P=.02). CONCLUSION: Health consequences of twin births for children and mothers are well known. Twin births may be associated with longer-term parental divorce. Specific groups, namely mothers not completing college and mothers who already have more children, may be at higher risk. (Obstet Gynecol 2011;117:892-7) DOI: 10.1097/AOG.0b013e3182102adf C1 [Jena, Anupam B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wang Ambulatory Care Ctr,Dept Med, Boston, MA 02114 USA. Univ So Calif, Leonard D Schaeffer Ctr Hlth Policy & Econ, Los Angeles, CA USA. RP Jena, AB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wang Ambulatory Care Ctr,Dept Med, 15 Parkman St, Boston, MA 02114 USA. EM jena.anupam@mgh.harvard.edu FU National Institutes of Health [5 T32 GM07281]; Agency of Healthcare Research and Quality [T32 HS 000046] FX Funding provided by the National Institutes of Health Medical Scientist National Research Award Grant 5 T32 GM07281 and Agency of Healthcare Research and Quality Training Grant T32 HS 000046 (A.B.J.). NR 16 TC 6 Z9 6 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2011 VL 117 IS 4 BP 892 EP 897 DI 10.1097/AOG.0b013e3182102adf PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 738NW UT WOS:000288647500020 PM 21422862 ER PT J AU Shimosegawa, T Chari, ST Frulloni, L Kamisawa, T Kawa, S Mino-Kenudson, M Kim, MH Kloppel, G Lerch, MM Lohr, M Notohara, K Okazaki, K Schneider, A Zhang, LZ AF Shimosegawa, Tooru Chari, Suresh T. Frulloni, Luca Kamisawa, Terumi Kawa, Shigeyuki Mino-Kenudson, Mari Kim, Myung-Hwan Kloeppel, Guenter Lerch, Markus M. Lohr, Matthias Notohara, Kenji Okazaki, Kazuichi Schneider, Alexander Zhang, Lizhi TI International Consensus Diagnostic Criteria for Autoimmune Pancreatitis Guidelines of the International Association of Pancreatology SO PANCREAS LA English DT Article DE autoimmune pancreatitis; international consensus diagnostic criteria; type 1 AIP; type 2 AIP ID FEATURES; SUBTYPES; BIOPSY AB Objectives: To achieve the goal of developing international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP). Methods: An international panel of experts met during the 14th Congress of the International Association of Pancreatology held in Fukuoka, Japan, from July 11 through 13, 2010. The proposed criteria represent a consensus opinion of the working group. Results: Autoimmune pancreatitis was classified into types 1 and 2. The ICDC used 5 cardinal features of AIP, namely, imaging of pancreatic parenchyma and duct, serology, other organ involvement, pancreatic histology, and an optional criterion of response to steroid therapy. Each feature was categorized as level 1 and 2 findings depending on the diagnostic reliability. The diagnosis of type 1 and type 2 AIP can be definitive or probable, and in some cases, the distinction between the subtypes may not be possible (AIP-not otherwise specified). Conclusions: The ICDC for AIP were developed based on the agreement of an international panel of experts in the hope that they will promote worldwide recognition of AIP. The categorization of AIP into types 1 and 2 should be helpful for further clarification of the clinical features, pathogenesis, and natural history of these diseases. C1 [Shimosegawa, Tooru] Tohoku Univ, Div Gastroenterol, Grad Sch Med, Aoba Ku, Sendai, Miyagi 9808574, Japan. [Chari, Suresh T.] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA. [Frulloni, Luca] Univ Verona, Dept Med, I-37100 Verona, Italy. [Kamisawa, Terumi] Tokyo Metropolitan Komagome Hosp, Dept Internal Med, Tokyo, Japan. [Kawa, Shigeyuki] Shinshu Univ, Ctr Hlth Safety & Environm Management, Nagano, Japan. [Mino-Kenudson, Mari] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Kim, Myung-Hwan] Univ Ulsan, Dept Gastroenterol, Coll Med, Asan Med Ctr, Seoul, South Korea. [Kloeppel, Guenter] Tech Univ Munich, Dept Pathol, Munich, Germany. [Lerch, Markus M.] Ernst Moritz Arndt Univ Greifswald, Dept Internal Med A, Greifswald, Germany. [Lohr, Matthias] Karolinska Inst, Dept Surg Gastroenterol, Stockholm, Sweden. [Notohara, Kenji] Kurashiki Cent Hosp, Dept Pathol, Kurashiki, Okayama, Japan. [Okazaki, Kazuichi] Kansai Med Univ, Div Gastroenterol & Hepatol, Osaka, Japan. [Schneider, Alexander] Univ Heidelberg, Dept Med Gastroenterol Hepatol Infect Dis 2, D-6800 Mannheim, Germany. [Zhang, Lizhi] Mayo Clin, Div Anat Pathol, Rochester, MN USA. RP Shimosegawa, T (reprint author), Tohoku Univ, Div Gastroenterol, Grad Sch Med, Aoba Ku, 1-1 Seiryomachi, Sendai, Miyagi 9808574, Japan. RI Lohr, Johannes-Matthias/A-3692-2012; Lerch, Markus M./E-2206-2016; OI Lerch, Markus M./0000-0002-9643-8263; Kloppel, Gunter/0000-0002-6688-086X; Lohr, Matthias/0000-0002-7647-198X; Frulloni, Luca/0000-0001-7417-2655 NR 18 TC 366 Z9 404 U1 4 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD APR PY 2011 VL 40 IS 3 BP 352 EP 358 DI 10.1097/MPA.0b013e3182142fd2 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 736NL UT WOS:000288501300003 PM 21412117 ER PT J AU Chiu, CH Michelow, IC Cronin, J Ringer, SA Ferris, TG Puopolo, KM AF Chiu, Chia-Hua Michelow, Ian C. Cronin, Jonathan Ringer, Steven A. Ferris, Timothy G. Puopolo, Karen M. TI Effectiveness of a Guideline to Reduce Vancomycin Use in the Neonatal Intensive Care Unit SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article; Proceedings Paper CT Annual Meeting of the Pediatric-Academic-Societies CY MAY 02-05, 2009 CL Baltimore, MD SP Pediat Acad Soc DE newborn; neonatal intensive care unit; vancomycin restriction; antibiotic stewardship; infection control ID RESISTANT STAPHYLOCOCCUS-AUREUS; LATE-ONSET SEPSIS; EPIDEMIOLOGY; STEWARDSHIP; ENTEROCOCCI; EXPERIENCE; INFECTION; THERAPY; PROGRAM AB Background: The Centers for Disease Control and Prevention recommend hospitals develop guidelines for the appropriate use of vancomycin as part of comprehensive antimicrobial stewardship. The objective of this study was to evaluate the effectiveness and safety of a guideline to restrict vancomycin use in the neonatal intensive care unit (NICU). Methods: A vancomycin use guideline was introduced in 2 tertiary care NICUs with low incidences of methicillin-resistant Staphylococcus aureus infections. We compared all infants >72 hours of age who were evaluated for late-onset infection before and after implementation of this guideline. Results: Vancomycin start rates were reduced from 6.9 to 4.5 per 1000 patient-days (35% reduction; P = 0.01) at Brigham and Women's Hospital, and from 17 to 6.4 per 1000 patient-days (62% reduction; P < 0.0001) at Massachusetts General Hospital. The number of infants exposed to vancomycin decreased from 5.2 to 3.1 per 1000 patient-days (40% reduction; P = 0.008) at Brigham and Women's Hospital, and 10.8 to 5.5 per 1000 patient-days (49% reduction; P = 0.009) at Massachusetts General Hospital. Causes of infection, duration of bacteremia, and incidence of complications or deaths attributable to late-onset infection did not change significantly at either institution. Conclusions: Implementation of a NICU vancomycin use guideline significantly reduced exposure of newborns to vancomycin without adversely affecting short-term patient safety. Further studies are required to evaluate the long-term effect of vancomycin restriction on NICU patient safety and microbial ecology, particularly among institutions with higher rates of methicillin-resistant Staphylococcus aureus infections. C1 [Ringer, Steven A.; Puopolo, Karen M.] Brigham & Womens Hosp, Dept Newborn Med, Boston, MA 02115 USA. [Chiu, Chia-Hua] Childrens Hosp, Div Newborn Med, Boston, MA 02115 USA. [Michelow, Ian C.] Massachusetts Gen Hosp, Div Pediat Infect Dis, Boston, MA 02114 USA. [Michelow, Ian C.; Cronin, Jonathan; Ringer, Steven A.; Ferris, Timothy G.; Puopolo, Karen M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Cronin, Jonathan] Massachusetts Gen Hosp, Neonatol & Newborn Med Unit, Boston, MA 02114 USA. [Ferris, Timothy G.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Puopolo, KM (reprint author), Brigham & Womens Hosp, Dept Newborn Med, 75 Francis St, Boston, MA 02115 USA. EM kpuopolo@partners.org NR 24 TC 23 Z9 26 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD APR PY 2011 VL 30 IS 4 BP 273 EP 278 DI 10.1097/INF.0b013e3182011d12 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 735SU UT WOS:000288438700004 PM 21085051 ER PT J AU Marshall-Berenz, EC Vujanovic, AA MacPherson, L AF Marshall-Berenz, Erin C. Vujanovic, Anka A. MacPherson, Laura TI Impulsivity and alcohol use coping motives in a trauma-exposed sample: The mediating role of distress tolerance SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE Impulsivity; Alcohol; Coping; Distress tolerance; PTSD ID POSTTRAUMATIC-STRESS-DISORDER; PSYCHOMETRIC PROPERTIES; SCALE; MODELS; VALIDATION; DRINKING; URGENCY AB The present investigation examined the mediating role of distress tolerance in the association between impulsivity and alcohol use coping motives among trauma-exposed individuals. Participants were 86 adults (64.3% women; M(age) = 23.4, SD = 9.3) who met the DSM-IV-TR posttraumatic stress disorder (PTSD) Criterion A for at least one traumatic life event and endorsed alcohol use in the past month. Distress tolerance at least partially mediated the association between impulsivity and alcohol use coping motives, after controlling for the variance explained by PTSD symptom severity and alcohol use problems. Clinical implications and future directions related to this line of inquiry are presented and discussed. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Marshall-Berenz, Erin C.] Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. [Vujanovic, Anka A.] VA Boston Hlth Care Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA 02130 USA. [Vujanovic, Anka A.] Boston Univ, Sch Med, Boston, MA 02130 USA. [MacPherson, Laura] Univ Maryland, College Pk, MD 20742 USA. RP Marshall-Berenz, EC (reprint author), Univ Vermont, Dept Psychol, 2 Colchester Ave,John Dewey Hall, Burlington, VT 05405 USA. EM Erin.Marshall@uvm.edu FU NIMH NIH HHS [F31 MH080453, F31 MH080453-01A1] NR 31 TC 22 Z9 22 U1 3 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD APR PY 2011 VL 50 IS 5 BP 588 EP 592 DI 10.1016/j.paid.2010.11.033 PG 5 WC Psychology, Social SC Psychology GA 728RM UT WOS:000287892200010 PM 21483650 ER PT J AU Yuferov, V Nielsen, DA Levran, O Randesi, M Hamon, S Ho, A Morgello, S Kreek, MJ AF Yuferov, Vadim Nielsen, David A. Levran, Orna Randesi, Matthew Hamon, Sara Ho, Ann Morgello, Susan Kreek, Mary Jeanne TI Tissue-specific DNA methylation of the human prodynorphin gene in post-mortem brain tissues and PBMCs SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE anterior cingulate cortex; bisulfite sequencing; caudate; CpG island; DNA methylation; dynorphin; human post-mortem brain; prodynorphin gene expression ID IMMUNODEFICIENCY-VIRUS TYPE-1; MESSENGER-RNA EXPRESSION; CPG ISLANDS; EPIGENETIC REGULATION; DIFFERENT REGIONS; PDYN EXPRESSION; BINDING FACTOR; BINGE COCAINE; TRANSCRIPTION; DYNORPHIN AB Objective Dynorphins, the endogenous ligands for the kappa opioid receptor, are implicated in neuropsychiatric disorders through modulation of basal and stimuli-induced dopaminergic, glutamatergic, and serotonergic tones. Expression of the prodynorphin gene (PDYN) is critical for rewarding properties of drugs of abuse and stress-induced responses. Epigenetic factors, such as DNA methylation, play an important role in modulation of gene expression. Methods We analyzed DNA methylation patterns of three CpG-rich regions of PDYN, a CpG island, and cluster A in the proximal promoter, and cluster B in coding exon 4, by bisulfite sequencing of DNA from the caudate and anterior cingulate cortex from post-mortem brain of 35 individuals (22 HIV seropositive), and in peripheral blood mononuclear cells from 21 of these individuals. Results We found remarkably similar patterns of methylation across CpG sites in these tissues. However, there were tissue-specific differences in methylation levels (P=0.000001) of the CpG island: higher levels in peripheral blood mononuclear cells (82%) than in the brain tissues, the caudate (62%), and the anterior cingulate cortex (44%). But there was higher PDYN expression in the caudate than in the anterior cingulate cortex. In contrast, cluster A near the transcription start site is hypomethylated. Conclusion This DNA methylation profile of the PDYN gene is typical for primary responsive genes with regulatory elements for both basal and tissue-specific transcription. Our findings provide a rationale for further studies of the role of other epigenetic factors in the regulation of PDYN expression in individuals with psychiatric and neurological disorders. Pharmacogenetics and Genomics 21: 185-196 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Yuferov, Vadim; Nielsen, David A.; Levran, Orna; Randesi, Matthew; Hamon, Sara; Ho, Ann; Kreek, Mary Jeanne] Rockefeller Univ, Lab Biol Addict Dis, New York, NY 10065 USA. [Morgello, Susan] Mt Sinai Med Ctr, New York, NY 10029 USA. [Nielsen, David A.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Nielsen, David A.] Michael E DeBakey Med Ctr, Houston, TX USA. RP Yuferov, V (reprint author), Rockefeller Univ, Lab Biol Addict Dis, Box 171,1230 York Ave, New York, NY 10065 USA. EM yuferov@rockefeller.edu RI Nielsen, David/B-4655-2009 FU NIH-NIDA [P60-DA05130]; NIH-NIMH [R01-MH79880, R24-MH59724, U01MH-083501] FX This study was supported by the NIH-NIDA P60-DA05130 (M.J.K.), the NIH-NIMH R01-MH79880 (M.J.K.), the NIH-NIMH R24-MH59724 and U01MH-083501 (S.M.). NR 60 TC 24 Z9 24 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 EI 1744-6880 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD APR PY 2011 VL 21 IS 4 BP 185 EP 196 DI 10.1097/FPC.0b013e32833eecbc PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 735UH UT WOS:000288444500004 PM 20808262 ER PT J AU Gordon, CR Avery, RK Abouhassan, W Siemionow, M AF Gordon, Chad R. Avery, Robin K. Abouhassan, William Siemionow, Maria TI Cytomegalovirus and Other Infectious Issues Related to Face Transplantation: Specific Considerations, Lessons Learned, and Future Recommendations SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID SOLID-ORGAN TRANSPLANTATION; COMPOSITE TISSUE ALLOTRANSPLANTATION; FACIAL TRANSPLANTATION; CMV INFECTION; VALGANCICLOVIR PROPHYLAXIS; HAND TRANSPLANTATION; PREEMPTIVE THERAPY; RECIPIENTS; DISEASE; ALLOGRAFT AB Background: Composite tissue allotransplantation is fraught with complexities similar to those of solid organ transplantation, including donor-related cytomegalovirus transmission. With this in mind, the authors' objective was to (1) report their team's experience with infections and donor-related cytomegalovirus transmission in relation to face transplantation and (2) review the facial composite tissue allotransplantation literature as it pertains to cytomegalovirus and other various infections. Methods: A MEDLINE literature search and article review was performed in July of 2010 on all published articles specific to face transplantation, cytomegalovirus disease, and all related infections and/or complications. In addition, the authors retrospectively reviewed their own institution's experience with face transplantation. Results: Two of the world's first four face transplant recipients acquired cytomegalovirus viral infection by means of their donated facial organs. Also, the French experience, and our own, has been challenged by cytomegalovints reactivation and graft rejection, therefore necessitating a critical evaluation. The authors have also learned, from their own experience, that facial composite tissue allografts containing mucosa and paranasal sinuses present a distinct challenge with regard to their accompanying flora. Condusions: Although the risk of donor-derived cytomegalovirus is acceptable in life-saving solid organ transplantation, for face transplantation patients, the scenario is different When the authors' team performed the first nearly total face/maxilla transplantation (December of 2008), there was little known regarding the consequences of cytomegalovints-related donor transmission in face transplantation. Therefore, the authors now recommend that all candidates be fully informed as to the risks of cytomegalovirus/infectious transmission and that aggressive viral, bacterial, and fungal prophylaxis be instituted. (Plast. Reconstr. Surg. 127: 1515, 2011.) C1 [Gordon, Chad R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast & Reconstruct Surg,Dept Surg, Boston, MA 02114 USA. Cleveland Clin, Dept Plast Surg, Inst Dermatol & Plast Surg, Cleveland, OH 44106 USA. Cleveland Clin, Dept Infect Dis, Inst Med, Cleveland, OH 44106 USA. RP Gordon, CR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Plast & Reconstruct Surg,Dept Surg, 15 Parkman St,WACC Suite 435, Boston, MA 02114 USA. EM cgordon5@partners.org NR 59 TC 26 Z9 26 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 EI 1529-4242 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD APR PY 2011 VL 127 IS 4 BP 1515 EP 1523 DI 10.1097/PRS.0b013e318208d03c PG 9 WC Surgery SC Surgery GA 741CH UT WOS:000288840200015 PM 21460660 ER PT J AU Abbott, MM Alkire, BC Meara, JG AF Abbott, Megan M. Alkire, Blake C. Meara, John G. TI The Value Proposition: Using a Cost Improvement Map to Improve Value for Patients with Nonsyndromic, Isolated Cleft Palate SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID OROFACIAL CLEFTS; CHILDREN AB Background: As health care costs rise exponentially in the United States, increasing emphasis is being placed on measuring value, which incorporates both quality and costs. Although the concept of continuous quality improvement has taken a firm foothold in health care, techniques for measuring and continuously improving costs at the patient or system level are lacking. Methods: A retrospective, microcosting analysis mapped detailed medical costs over 18 months for 25 patients with nonsyndromic, isolated cleft palate to illustrate the concept of a continuous cost improvement map in a complex, multidisciplinary condition. Results: Care for patients with nonsyndromic, isolated cleft palate was mapped to three timelines based on diagnostic subtype. Patients with Robin sequence requiring early surgical intervention for airway or feeding management (n = 4) had median costs that were triple those of Robin patients managed conservatively (n = 5) ($87,841 versus $27,864, respectively) as compared with patients without Robin sequence (n = 16) ($15,698). Inpatient services accounted for 85 to 95 percent of all costs, which were driven by the operating room, intensive care unit, and inpatient ward. More detailed analysis of each cost driver is reported. Conclusions: The cost improvement map provides a counterpart to the quality improvement map to illustrate how costs may be incorporated into value improvement efforts for complex, multidisciplinary conditions. The transparency and level of detail provided by this methodology are critical for internal improvement efforts and offer valuable insight for health care managers and policy makers, whose decisions should be based on accurate, patient-centered data. (Plast. Reconstr. Surg. 127: 1650, 2011.) C1 [Meara, John G.] Childrens Hosp Boston, Dept Plast & Oral Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Meara, JG (reprint author), Childrens Hosp Boston, Dept Plast & Oral Surg, 300 Longwood Ave,Enders 1, Boston, MA 02115 USA. EM john.meara@childrens.harvard.edu NR 21 TC 4 Z9 4 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD APR PY 2011 VL 127 IS 4 BP 1650 EP 1658 DI 10.1097/PRS.0b013e318208d25e PG 9 WC Surgery SC Surgery GA 741CH UT WOS:000288840200031 PM 21460672 ER PT J AU Scibelli, AC McKinnon, CS Reed, C Burkhart-Kasch, S Li, N Baba, H Wheeler, JM Phillips, TJ AF Scibelli, Angela C. McKinnon, Carrie S. Reed, Cheryl Burkhart-Kasch, Sue Li, Na Baba, Harue Wheeler, Jeanna M. Phillips, Tamara J. TI Selective breeding for magnitude of methamphetamine-induced sensitization alters methamphetamine consumption SO PSYCHOPHARMACOLOGY LA English DT Article DE Reward; Addiction; Stimulation; Locomotor activity; Drinking; Saccharin; Quinine; Potassium chloride; Heritability; Clearance ID RECOMBINANT INBRED MICE; BEHAVIORAL SENSITIZATION; NUCLEUS-ACCUMBENS; EXTRACELLULAR DOPAMINE; LOCOMOTOR RESPONSES; ETHANOL-CONSUMPTION; STIMULANT-DRUGS; ALCOHOL INTAKE; D-AMPHETAMINE; TIME-COURSE AB Genetically determined differences in susceptibility to drug-induced sensitization could be related to risk for drug consumption. Studies were performed to determine whether selective breeding could be used to create lines of mice with different magnitudes of locomotor sensitization to methamphetamine (MA). MA sensitization (MASENS) lines were also examined for genetically correlated responses to MA. Beginning with the F2 cross of C57BL/6J and DBA/2J strains, mice were tested for locomotor sensitization to repeated injections of 1 mg/kg MA and bred based on magnitude of sensitization. Five selected offspring generations were tested. All generations were also tested for MA consumption, and some were tested for dose-dependent locomotor-stimulant responses to MA, consumption of saccharin, quinine, and potassium chloride as a measure of taste sensitivity, and MA clearance after acute and repeated MA. Selective breeding resulted in creation of two lines [MA high sensitization (MAHSENS) and MA low sensitization (MALSENS)] that differed in magnitude of MA-induced sensitization. Initially, greater MA consumption in MAHSENS mice reversed over the course of selection so that MALSENS mice consumed more MA. MAHSENS mice exhibited greater sensitivity to the acute stimulant effects of MA, but there were no significant differences between the lines in MA clearance from blood. Genetic factors influence magnitude of MA-induced locomotor sensitization and some of the genes involved in magnitude of this response also influence MA sensitivity and consumption. Genetic factors leading to greater MA-induced sensitization may serve a protective role against high levels of MA consumption. C1 [Phillips, Tamara J.] Portland VA Med Ctr, Portland, OR 97239 USA. [Scibelli, Angela C.; McKinnon, Carrie S.; Reed, Cheryl; Burkhart-Kasch, Sue; Li, Na; Baba, Harue; Wheeler, Jeanna M.; Phillips, Tamara J.] Oregon Hlth & Sci Univ, Dept Behav Neurosci & Methamphetamine, Abuse Res Ctr, Portland, OR 97201 USA. [Scibelli, Angela C.; McKinnon, Carrie S.; Reed, Cheryl; Burkhart-Kasch, Sue; Li, Na; Baba, Harue; Wheeler, Jeanna M.; Phillips, Tamara J.] Oregon Hlth & Sci Univ, Vet Affairs Med Ctr, Portland, OR 97201 USA. RP Phillips, TJ (reprint author), Portland VA Med Ctr, 3710 SW US Vet Hosp Rd,R&D 32, Portland, OR 97239 USA. EM phillipt@ohsu.edu FU NIDA [P50 DA018165, T32 DA07262]; Department of Veterans Affairs FX This work was supported by grants from NIDA (P50 DA018165 and T32 DA07262) and by the Department of Veterans Affairs. We are grateful to John Belknap for providing statistical software for performance of heritability calculations. All experiments were conducted in compliance with current laws in the United States of America. NR 63 TC 15 Z9 17 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2011 VL 214 IS 4 BP 791 EP 804 DI 10.1007/s00213-010-2086-2 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 739XQ UT WOS:000288755500002 PM 21088960 ER PT J AU Gerstner, ER Sorensen, AG AF Gerstner, Elizabeth R. Sorensen, A. Gregory TI Diffusion and Diffusion Tensor Imaging in Brain Cancer SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; RADIATION-INDUCED CHANGES; SQUAMOUS-CELL CARCINOMA; HIGH-GRADE GLIOMA; WHITE-MATTER; PROSTATE-CANCER; TUMOR RESPONSE; WEIGHTED MRI; CERVICAL-CANCER; THERAPY C1 [Gerstner, Elizabeth R.] Massachusetts Gen Hosp, Ctr Canc, Dept Neurol, Boston, MA 02114 USA. [Sorensen, A. Gregory] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Cambridge, MA USA. [Sorensen, A. Gregory] Massachusetts Gen Hosp, Div Hlth Sci & Technol, Cambridge, MA USA. [Sorensen, A. Gregory] Massachusetts Gen Hosp, Dept Radiol, Cambridge, MA USA. [Sorensen, A. Gregory] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Sorensen, A. Gregory] MIT, Cambridge, MA 02139 USA. RP Gerstner, ER (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Neurol, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM egerstner@partners.org NR 37 TC 18 Z9 18 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 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD APR PY 2011 VL 21 IS 2 BP 141 EP 146 DI 10.1016/j.semradonc.2010.10.005 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 736GY UT WOS:000288480200007 PM 21356481 ER PT J AU Schroeder, T Melo, MFV Venegas, JG AF Schroeder, Tobias Melo, Marcos F. Vidal Venegas, Jose G. TI Analysis of 2-[Fluorine-18]-Fluoro-2-deoxy-D-glucose Uptake Kinetics in PET Studies of Pulmonary Inflammation SO ACADEMIC RADIOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop for Pulmonary Functional Imaging CY SEP, 2009 CL Boston, MA DE Radionuclide imaging; positron emission tomography; FDG; lung inflammation; acute respiratory distress syndrome; cystic fibrosis; chronic obstructive pulmonary disease; compartmental modeling ID POSITRON-EMISSION-TOMOGRAPHY; ACUTE LUNG INJURY; CEREBRAL GLUCOSE-UTILIZATION; METABOLIC-ACTIVITY; F-18-FDG UPTAKE; DEOXYGLUCOSE UPTAKE; CYSTIC-FIBROSIS; INPUT FUNCTION; FDG-PET; DISSOCIATION AB Dynamic positron emission tomography (PET) imaging of the lung using the radiotracer 2-[fluorine-18]-fluoro-2-deoxy-D-glucose ((18)F-FDG) is an emerging method to assess noninvasively the metabolic activity of pulmonary inflammatory cells. Nevertheless, because of the distinct functional and structural characteristics of inflamed lung tissue standard methods of (18)F-FDG analysis can be substantially limited and there is no consensus about the best method for quantification of the (18)F-FDG signal for acute or chronic inflammatory lung diseases. This article gives an overview on recent advances in quantitative analysis of (18)F-FDG uptake kinetics in non-neoplastic inflamed lung tissue. C1 [Schroeder, Tobias; Melo, Marcos F. Vidal; Venegas, Jose G.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Melo, MFV (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM mvidalmelo@partners.org OI Schroeder, Tobias/0000-0002-4439-8060 FU NHLBI NIH HHS [4R01-HL086827-01, R01 HL086827-04, R01 HL068011, R01 HL086827-05, R01 HL086827, 5R01HL-068011-08] NR 40 TC 10 Z9 10 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD APR PY 2011 VL 18 IS 4 BP 418 EP 423 DI 10.1016/j.acra.2010.11.019 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 737MF UT WOS:000288572200003 PM 21292507 ER PT J AU Nishino, M Jackman, DM Hatabu, H Janne, PA Johnson, BE Van den Abbeele, AD AF Nishino, Mizuki Jackman, David M. Hatabu, Hiroto Jaenne, Pasi A. Johnson, Bruce E. Van den Abbeele, Annick D. TI Imaging of Lung Cancer in the Era of Molecular Medicine SO ACADEMIC RADIOLOGY LA English DT Article; Proceedings Paper CT 4th International Workshop for Pulmonary Functional Imaging CY SEP, 2009 CL Boston, MA DE Lung cancer; targeted therapy; computed tomography; dynamic-contrast-enhanced magnetic resonance imaging; positron emission tomography ID GROWTH-FACTOR-RECEPTOR; SOLITARY PULMONARY NODULES; CONTRAST-ENHANCED MRI; POSITRON-EMISSION-TOMOGRAPHY; PREVIOUSLY TREATED PATIENTS; TYROSINE KINASE INHIBITORS; SQUAMOUS-CELL CARCINOMAS; PHASE-II TRIAL; TUMOR RESPONSE; ACQUIRED-RESISTANCE AB Recent discoveries characterizing the molecular basis of lung cancer brought fundamental changes in lung cancer treatment. The authors review the molecular pathogenesis of lung cancer, including genomic abnormalities, targeted therapies, and resistance mechanisms, and discuss lung cancer imaging with novel techniques. Knowledge of the molecular basis of lung cancer is essential for radiologists to properly interpret imaging and assess response to therapy. Quantitative and functional imaging helps assessing the biologic behavior of lung cancer. C1 [Nishino, Mizuki; Van den Abbeele, Annick D.] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Jackman, David M.; Jaenne, Pasi A.; Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nishino, Mizuki; Hatabu, Hiroto; Van den Abbeele, Annick D.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Nishino, M (reprint author), Dana Farber Canc Inst, Dept Imaging, 44 Binney St, Boston, MA 02115 USA. EM mizuki_nishino@dfci.harvard.edu FU NCI NIH HHS [5R21 CA11627-02, P50 CA090578, R01 CA114465, P20 CA090578, 1R01CA114465-01, 2P50CA090578-06] NR 96 TC 18 Z9 18 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD APR PY 2011 VL 18 IS 4 BP 424 EP 436 DI 10.1016/j.acra.2010.10.020 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 737MF UT WOS:000288572200004 PM 21277232 ER PT J AU Lee, J Kosaras, B Del Signore, SJ Cormier, K Mckee, A Ratan, RR Kowall, NW Ryu, H AF Lee, Junghee Kosaras, Bela Del Signore, Steve J. Cormier, Kerry McKee, Ann Ratan, Rajiv R. Kowall, Neil W. Ryu, Hoon TI Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington's disease mice SO ACTA NEUROPATHOLOGICA LA English DT Article DE Huntington's disease; Mitochondria; Lipid peroxidation; 4-Hydroxy-2-nonenal (4-HNE); Neuronal survival ID FIBRILS IN-VITRO; OXIDATIVE STRESS; NORDIHYDROGUAIARETIC ACID; NEURODEGENERATIVE DISEASES; ALZHEIMERS-DISEASE; CORTICAL-NEURONS; TRANSGENIC MICE; MOUSE MODELS; CELL-DEATH; REPEAT AB Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Oxidative damage has been associated with pathological neuronal loss in HD. The therapeutic modulation of oxidative stress and mitochondrial function using low molecular weight compounds may be an important strategy for delaying the onset and slowing the progression of HD. In the present study, we found a marked increase of 4-hydroxy-2-nonenal (4-HNE) adducts, a lipid peroxidation marker, in the caudate and putamen of HD brains and in the striatum of HD mice. Notably, 4-HNE immunoreactivity was colocalized with mutant huntingtin inclusions in the striatal neurons of R6/2 HD mice. Administration of nordihydroguaiaretic acid (NDGA), an antioxidant that functions by inhibiting lipid peroxidation, markedly reduced 4-HNE adduct formation in the nuclear inclusions of R6/2 striatal neurons. NDGA also protected cultured neurons against oxidative stress-induced cell death by improving ATP generation and mitochondrial morphology and function. In addition, NDGA restored mitochondrial membrane potential, mitochondrial structure, and synapse structure in the striatum of R6/2 mice and increased their lifespan. The present findings suggest that further therapeutic studies using NDGA are warranted in HD and other neurodegenerative diseases characterized by increased oxidative stress and altered mitochondrial function. C1 [Lee, Junghee; Kowall, Neil W.; Ryu, Hoon] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Lee, Junghee; Del Signore, Steve J.; Cormier, Kerry; McKee, Ann; Kowall, Neil W.; Ryu, Hoon] Boston Univ, Sch Med, Dept Neurol & Pathol, Boston, MA 02118 USA. [Kosaras, Bela] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02115 USA. [Kosaras, Bela] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Del Signore, Steve J.; Cormier, Kerry; McKee, Ann] Bedford VA Med Ctr, Bedford, MA 01730 USA. [Ratan, Rajiv R.] Cornell Univ, Dept Neurol, Weill Med Coll, Burke Cornell Med Res Inst, White Plains, NY 10605 USA. RP Ryu, H (reprint author), VA Boston Healthcare Syst, Bldg 1A,Rm 109, Boston, MA 02130 USA. EM hoonryu@bu.edu RI Kowall, Neil/G-6364-2012 OI Kowall, Neil/0000-0002-6624-0213 FU NIH [NS52724] FX We thank to Katharine Karr and Yu Jin Hwang for the preparation of manuscript. This study was supported by NIH NS52724 (H.R.). NR 47 TC 37 Z9 37 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD APR PY 2011 VL 121 IS 4 BP 487 EP 498 DI 10.1007/s00401-010-0788-5 PG 12 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 735US UT WOS:000288446100005 PM 21161248 ER PT J AU Mohapatra, G Engler, DA Starbuck, KD Kim, JC Bernay, DC Scangas, GA Rousseau, A Batchelor, TT Betensky, RA Louis, DN AF Mohapatra, Gayatry Engler, David A. Starbuck, Kristen D. Kim, James C. Bernay, Derek C. Scangas, George A. Rousseau, Audrey Batchelor, Tracy T. Betensky, Rebecca A. Louis, David N. TI Genome-wide comparison of paired fresh frozen and formalin-fixed paraffin-embedded gliomas by custom BAC and oligonucleotide array comparative genomic hybridization: facilitating analysis of archival gliomas SO ACTA NEUROPATHOLOGICA LA English DT Article DE Array CGH; BAC aCGH; Glioma ID DNA COPY-NUMBER; HIGH-RESOLUTION ANALYSIS; IN-SITU HYBRIDIZATION; CELL-LINES; GLIOBLASTOMA-MULTIFORME; FFPE SAMPLES; TUMORS; OLIGOASTROCYTOMAS; SUBTYPES; OLIGODENDROGLIOMAS AB Array comparative genomic hybridization (aCGH) is a powerful tool for detecting DNA copy number alterations (CNA). Because diffuse malignant gliomas are often sampled by small biopsies, formalin-fixed paraffin-embedded (FFPE) blocks are often the only tissue available for genetic analysis; FFPE tissues are also needed to study the intratumoral heterogeneity that characterizes these neoplasms. In this paper, we present a combination of evaluations and technical advances that provide strong support for the ready use of oligonucleotide aCGH on FFPE diffuse gliomas. We first compared aCGH using bacterial artificial chromosome (BAC) arrays in 45 paired frozen and FFPE gliomas, and demonstrate a high concordance rate between FFPE and frozen DNA in an individual clone-level analysis of sensitivity and specificity, assuring that under certain array conditions, frozen and FFPE DNA can perform nearly identically. However, because oligonucleotide arrays offer advantages to BAC arrays in genomic coverage and practical availability, we next developed a method of labeling DNA from FFPE tissue that allows efficient hybridization to oligonucleotide arrays. To demonstrate utility in FFPE tissues, we applied this approach to biphasic anaplastic oligoastrocytomas and demonstrate CNA differences between DNA obtained from the two components. Therefore, BAC and oligonucleotide aCGH can be sensitive and specific tools for detecting CNAs in FFPE DNA, and novel labeling techniques enable the routine use of oligonucleotide arrays for FFPE DNA. In combination, these advances should facilitate genome-wide analysis of rare, small and/or histologically heterogeneous gliomas from FFPE tissues. C1 [Mohapatra, Gayatry; Starbuck, Kristen D.; Kim, James C.; Bernay, Derek C.; Scangas, George A.; Rousseau, Audrey; Louis, David N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mohapatra, Gayatry; Starbuck, Kristen D.; Kim, James C.; Bernay, Derek C.; Scangas, George A.; Rousseau, Audrey; Louis, David N.] Harvard Univ, Sch Med, Boston, MA USA. [Engler, David A.] Brigham Young Univ, Dept Stat, Provo, UT 84602 USA. [Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA 02114 USA. [Batchelor, Tracy T.; Louis, David N.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. RP Mohapatra, G (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM gmohapatra@partners.org; dlouis@partners.org RI Rousseau, Audrey/L-3193-2015 FU NIH [R21/R33 CA106695] FX This work was supported by NIH R21/R33 CA106695. NR 44 TC 8 Z9 8 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 EI 1432-0533 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD APR PY 2011 VL 121 IS 4 BP 529 EP 543 DI 10.1007/s00401-010-0773-z PG 15 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 735US UT WOS:000288446100009 PM 21080181 ER PT J AU Lee, JE Willett, WC Fuchs, CS Smith-Warner, SA Wu, K Ma, J Giovannucci, E AF Lee, Jung Eun Willett, Walter C. Fuchs, Charles S. Smith-Warner, Stephanie A. Wu, Kana Ma, Jing Giovannucci, Edward TI Folate intake and risk of colorectal cancer and adenoma: modification by time SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID FOLIC-ACID FORTIFICATION; COLON-CANCER; MULTIVITAMIN USE; DIETARY-FOLATE; CARCINOMA SEQUENCE; ALCOHOL; METAANALYSIS; PREVENTION; METHIONINE; DISEASE AB Background: Experimental and observational studies have suggested that folate may play dual roles in colorectal cancer risk depending on the timing and dose. Objective: We examined the latency between folate intake and the incidence of colorectal cancer. Design: We prospectively examined associations between folate intake assessed every 2 to 4 y by using validated food-frequency questionnaires and risk of colorectal cancer and adenoma in the Nurses' Health Study and Health Professionals Follow-Up Study, which included 2299 incident colorectal cancers and 5655 colorectal adenomas from 1980 to 2004. Results: There was an association between total folate intake 12-16 y before diagnosis and lower risk of colorectal cancer (relative risk: 0.69; 95% CI: 0.51, 0.94; >= 800 compared with <250 mu g folate/d), but there was no association between intake in the recent past and colorectal cancer risk. Long-and short-term intakes of total folate were associated with a lower risk of colorectal adenoma, with a strong association with intake 4-8 y before diagnosis (odds ratio: 0.68; 95% CI: 0.60, 0.78; >= 800 compared with <250 mu g folate/d). The current use of multivitamins for >15 y, but not a shorter duration of use, was associated with lower risk of colorectal cancer; and a shorter duration of use was related to lower risk of adenoma. We did not observe an adverse effect of total folate or synthetic folic acid on risk of colorectal cancer or adenoma even during the folic acid fortification era. Conclusion: Folate intake is inversely associated with risk of colorectal cancer only during early preadenoma stages. Am J Clin Nutr 2011; 93: 817-25. C1 [Willett, Walter C.; Fuchs, Charles S.; Ma, Jing; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Lee, Jung Eun] Sookmyung Womens Univ, Dept Food & Nutr, Seoul, South Korea. [Willett, Walter C.; Fuchs, Charles S.; Ma, Jing; Giovannucci, Edward] Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp,Dept Med, Boston, MA 02115 USA. [Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Willett, Walter C.; Smith-Warner, Stephanie A.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Giovannucci, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 667 Huntington Ave, Boston, MA 02115 USA. EM egiovann@hsph.harvard.edu OI Lee, Jung Eun/0000-0003-1141-878X FU National Institutes of Health/National Cancer Institute [CA87969, CA55075]; Conquer Cancer Coalition of Massachusetts; Prevent Cancer Foundation FX Supported by the National Institutes of Health/National Cancer Institute (grants CA87969 and CA55075), the Conquer Cancer Coalition of Massachusetts (EG), and the Prevent Cancer Foundation fellowship grant (JEL). NR 38 TC 58 Z9 64 U1 1 U2 15 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD APR PY 2011 VL 93 IS 4 BP 817 EP 825 DI 10.3945/ajcn.110.007781 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 736YS UT WOS:000288531600020 PM 21270374 ER PT J AU Mahon, PB Pirooznia, M Goes, FS Seifuddin, F Steele, J Lee, PH Huang, J Hamshere, ML DePaulo, JR Kelsoe, JR Rietschel, M Nothen, M Cichon, S Gurling, H Purcell, S Smoller, JW Craddock, N Schulze, TG McMahon, FJ Potash, JB Zandi, PP AF Mahon, Pamela Belmonte Pirooznia, Mehdi Goes, Fernando S. Seifuddin, Fayaz Steele, Jo Lee, Phil Hyoun Huang, Jie Hamshere, Marian L. DePaulo, J. Raymond, Jr. Kelsoe, John R. Rietschel, Marcella Noethen, Markus Cichon, Sven Gurling, Hugh Purcell, Shaun Smoller, Jordan W. Craddock, Nick Schulze, Thomas G. McMahon, Francis J. Potash, James B. Zandi, Peter P. CA Bipolar Genome Study BiGS Consort TI Genome-Wide Association Analysis of Age at Onset and Psychotic Symptoms in Bipolar Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article ID I AFFECTIVE-DISORDER; FAMILIAL AGGREGATION; DIAGNOSTIC INTERVIEW; EUROPEAN ANCESTRY; LINKAGE ANALYSES; METAANALYSIS; PEDIGREES; SCHIZOPHRENIA; LOCUS; GENE AB Genome-wide association studies (GWAS) have identified several susceptibility loci for bipolar disorder (BP), most notably ANK3. However, most of the inherited risk for BP remains unexplained. One reason for the limited success may be the genetic heterogeneity of BP. Clinical sub-phenotypes of BP may identify more etiologically homogeneous subsets of patients, which can be studied with increased power to detect genetic variation. Here, we report on a mega-analysis of two widely studied sub-phenotypes of BP, age at onset and psychotic symptoms, which are familial and clinically significant. We combined data from three GWAS: NIMH Bipolar Disorder Genetic Association Information Network (GAIN-BP), NIMH Bipolar Disorder Genome Study (BiGS), and a German sample. The combined sample consisted of 2,836 BP cases with information on sub-phenotypes and 2,744 controls. Imputation was performed, resulting in 2.3 million SNPs available for analysis. No SNP reached genome-wide significance for either sub-phenotype. In addition, no SNP reached genome-wide significance in a meta-analysis with an independent replication sample. We had 80% power to detect associations with a common SNP at an OR of 1.6 for psychotic symptoms and a mean difference of 1.8 years in age at onset. Age at onset and psychotic symptoms in BP may be influenced by many genes of smaller effect sizes or other variants not measured well by SNP arrays, such as rare alleles. (C) 2011 Wiley-Liss, Inc. C1 [Zandi, Peter P.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA. [Mahon, Pamela Belmonte; Pirooznia, Mehdi; Goes, Fernando S.; Seifuddin, Fayaz; DePaulo, J. Raymond, Jr.; Potash, James B.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Steele, Jo; Schulze, Thomas G.; McMahon, Francis J.] NIMH, US Dept HHS, NIH, Intramural Res Program, Bethesda, MD 20892 USA. [Lee, Phil Hyoun; Huang, Jie; Purcell, Shaun; Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Hamshere, Marian L.; Craddock, Nick] Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff, S Glam, Wales. [Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Rietschel, Marcella] Univ Gottingen, Univ Med Ctr, Dept Psychiat & Psychotherapy, Gottingen, Germany. [Rietschel, Marcella] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. [Noethen, Markus] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Noethen, Markus; Cichon, Sven] Univ Bonn, Life & Brain Ctr, Dept Genom, D-5300 Bonn, Germany. [Cichon, Sven] Res Ctr Juelich, Inst Neurosci & Med INM 1, Julich, Germany. [Gurling, Hugh] UCL, Dept Mental Hlth Sci, London, England. RP Zandi, PP (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Hampton House,Room 857,624 N Broadway, Baltimore, MD 21205 USA. EM pzandi@jhsph.edu RI Liu, Chunyu/G-7561-2012; Schulze, Thomas/H-2157-2013; Gurling, Hugh/A-5029-2010; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; OI Liu, Chunyu/0000-0002-5986-4415; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Pirooznia, Mehdi/0000-0002-4210-6458; McMahon, Francis/0000-0002-9469-305X; Nothen, Markus/0000-0002-8770-2464 FU [R01 MH079799] FX The authors express their profound appreciation to the families who participated in this project, and to the many clinicians who facilitated the referral of participants to the study. Data and biomaterials for the NIMH samples were collected as part of 10 projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1991 to 1998, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, U01 MH46282-John Nurnberger, M. D., Ph. D., Marvin Miller, M. D. and Elizabeth Bowman, M. D.; Washington University, St Louis, MO, U01 MH46280-Theodore Reich, M. D., Allison Goate, Ph. D. and John Rice, Ph. D.; Johns Hopkins University, Baltimore, MD U01 MH46274-J Raymond DePaulo Jr, M. D. Sylvia Simpson, M. D., MPH and Colin Stine, Ph. D.; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, M. D.-Elliot Gershon, M. D., Diane Kazuba, BA and Elizabeth Maxwell, M. S. W. From 1999 to 2003, the Principal Investigators and Co-Investigatorswere: Indiana University, Indianapolis, IN, R01 MH59545-John Nurn-berger, M. D., Ph. D., Marvin J. Miller, M. D., Elizabeth S. Bowman, M. D., N. Leela Rau, M. D., P. Ryan Moe, M. D., Nalini Samavedy, M. D., Rif El-Mallakh, M. D. (at University of Louisville), Husseini Manji, M. D. (at Wayne State University), Debra A. Glitz, M. D. (at Wayne State University), Eric T. Meyer, MS, Carrie Smiley, RN, Tatiana Foroud, Ph. D., Leah Flury, MS, Danielle M. Dick, Ph. D. and Howard Edenberg, Ph. D.; Washington University, St Louis, MO, R01 MH059534, John Rice, Ph. D., Theodore Reich, M. D., Allison Goate, Ph. D. and Laura Bierut, M. D.; Johns Hopkins University, Baltimore, MD, R01 MH59533-Melvin McInnis, M. D., J. Raymond DePaulo Jr, M. D., Dean F. MacKinnon, M. D., Francis M. Mondimore, M. D., James B. Potash, M. D., Peter P. Zandi, Ph. D., Dimitrios Avramopoulos and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553-Wade Berrettini, M. D., Ph. D.; University of California at Irvine, CA, R01 MH60068-William Byerley, M. D. and Mark Vawter, M. D.; University of Iowa, IA, R01 MH059548-William Coryell, M. D. and Raymond Crowe, M. D.; University of Chicago, Chicago, IL, R01 MH59535-Elliot Gershon, M. D., Judith Badner, Ph. D., Francis McMahon, M. D., Chunyu Liu, Ph. D., Alan Sanders, M. D., Maria Caserta, Steven Dinwiddie, M. D., Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567-John Kelsoe, M. D., Rebecca McKinney, B. A.; Rush University, IL, R01 MH059556-William Scheftner, M. D., Howard M. Kravitz, DO, MPH, Diana Marta, B. A., Annette Vaughn-Brown, MSN, RN and Laurie Bederow, MA; NIMH Intramural Research Program, Bethesda, M. D., 1Z01MH002810-01, Francis J. McMahon, M. D., Layla Kassem, PsyD, Sevilla Detera-Wadleigh, Ph. D., Lisa Austin, Ph. D., Dennis L. Murphy, M. D. From 2003 to 2007, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01 MH59545, John Nurnberger, M. D., Ph. D., Marvin J. Miller, M. D., Elizabeth S. Bowman, M. D., N. Leela Rau, M. D., P. Ryan Moe, M. D., Nalini Samavedy, M. D., Rif El-Mallakh, M. D. (at University of Louisville), Husseini Manji, M. D. (at Johnson and Johnson), Debra A. Glitz, M. D. (at Wayne State University), Eric T. Meyer, Ph. D., M. S. (at Oxford University, UK), Carrie Smiley, R. N., Tatiana Foroud, Ph. D., Leah Flury, M. S., Danielle M. Dick, Ph. D (at Virginia Commonwealth University), Howard Edenberg, Ph. D.; Washington University, St. Louis, MO, R01 MH059534, John Rice, Ph. D, Theodore Reich, M. D., Allison Goate, Ph. D.; , Laura Bierut M. D. K02 DA21237; Johns Hopkins University, Baltimore, MD, R01 MH59533, Melvin McInnis, M. D., J. Raymond DePaulo, Jr., M. D., Dean F. MacKinnon, M. D., Francis M. Mondimore, M. D., James B. Potash, M. D., Peter P. Zandi, Ph. D, Dimitrios Avramopoulos, and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini, M. D., Ph. D.; University of California at San Francisco, CA, R01 MH60068, William Byerley, M. D., and Sophia Vinogradov, M. D.; University of Iowa, IA, R01MH059548, WilliamCoryell, M. D., and Raymond Crowe, M. D.; University of Chicago, IL, R01 MH59535, Elliot Gershon, M. D., Judith Badner, Ph. D., Francis McMahon, M. D., Chunyu Liu, Ph. D., Alan Sanders, M. D., Maria Caserta, Steven Dinwiddie, M. D., Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, John Kelsoe, M. D., Rebecca McKinney, B. A.; Rush University, IL, R01 MH059556, William Scheftner, M. D., Howard M. Kravitz, D. O., M. P. H., Diana Marta, B. S., Annette Vaughn-Brown, M. S. N., R. N., and Laurie Bederow, M. A.; NIMH Intramural Research Program, Bethesda, M. D., 1Z01MH002810-01, Francis J. McMahon, M. D., Layla Kassem, Psy. D., Sevilla Detera-Wadleigh, Ph. D, Lisa Austin, Ph. D, Dennis L. Murphy, M. D.; Howard University, William B. Lawson, M. D., Ph. D., Evarista Nwulia, M. D., and Maria Hipolito, M. D. Control subjects from the National Institute of Mental Health Schizophrenia Genetics Initiative (NIMH-GI), data and biomaterials are being collected by the `` Molecular Genetics of Schizophrenia II'' (MGS-2) collaboration. The investigators and coinvestigators are: ENH/ Northwestern University, Evanston, IL, MH059571, Pablo V. Gejman, M. D. (Collaboration Coordinator; PI), Alan R. Sanders, M. D.; Emory University School of Medicine, Atlanta, GA, MH59587, Farooq Amin, M. D. (PI); Louisiana State University Health Sciences Center; New Orleans, Louisiana, MH067257, Nancy Buccola APRN, BC, MSN (PI); University of California-Irvine, Irvine, CA, MH60870, William Byerley, M. D. (PI); Washington University, St. Louis, MO, U01, MH060879, C. Robert Cloninger, M. D. (PI); University of Iowa, Iowa, IA, MH59566, Raymond Crowe, M. D. (PI), Donald Black, M. D.; University of Colorado, Denver, CO, MH059565, Robert Freedman, M. D. (PI); University of Pennsylvania, Philadelphia, PA, MH061675, Douglas Levinson M. D. (PI); University of Queensland, Queensland, Australia, MH059588, Bryan Mowry, M. D. (PI); Mt. Sinai School of Medicine, New York, NY, MH59586, Jeremy Silverman, Ph. D. (PI). Genome-wideSNPgenotyping of theNIMH samples was performed through the Genetic Association Information Network under the direction of the Bipolar Genetics Studies Collaboration. The Principal Investigators and Co-Investigators were: University of California San Diego, La Jolla, CA, John R. Kelsoe, M. D. (PI), Tiffany A. Greenwood, Ph. D., Paul D. Shilling, Ph. D., Caroline Nievergelt, Ph. D.; Scripps Research Institute, La Jolla, CA: Nicholas Schork, Ph. D. (PI), Erin N. Smith, Ph. D., Cinnamon Bloss, Ph. D.; Indiana University, Bloomington, IN, John Nurnberger, M. D. (PI), Howard J. Edenberg, Ph. D., Tatiana Foroud, Ph. D.; University of Chicago, Chicago, IL, Elliot Gershon, M. D. (PI), Chunyu Liu, Ph. D., Judith A. Badner, Ph. D.; Rush University Medical Center, Chicago, IL, William A. Scheftner, M. D.; Howard University, Washington, DC, William B. Lawson, M. D. (PI), Evaristus A. Nwulia, M. D., Maria Hipolito, M. D.; University of Iowa, Iowa City, IA, William Coryell, M. D. (PI); Washington University, St.; Louis, MO, John Rice, Ph D. (PI); University of California San Francisco, San Francisco, CA, William Byerley, M. D. (PI); National Institute of Mental Health, Bethesda, M. D., Francis McMahon, M. D. (PI), Thomas G. Schulze, M. D.; University of Pennsylvania, Philadelphia, PA, Wade Berrettini, M. D., Ph. D. (PI); JohnsHopkins University, Baltimore, MD, James B. Potash, M. D. (PI), Peter P. Zandi, Ph. D., Pamela Belmonte Mahon, Ph. D.; University of Michigan, Ann Arbor, MI, Melvin G. McInnis, M. D. (PI), Sebastian Zollner, Ph. D.; Translation Genomic Research Institute, Phoenix, AZ, David Craig, Ph. D. (PI), Szabolics Szelinger. Data and biomaterials for the subjects in the Wellcome Trust Case-Control Consortium were collected by: University of Aberdeen, Foresterhill, Aberdeen, UK, Gerome Breen, David St Clair; Birmingham University, Birmingham, UK, Sian Caesar, Katherine Gordon-Smith, Lisa Jones; Cardiff University, Cardiff, UK, Christine Fraser, Elaine K. Green, Detelina Grozeva, Marian L. Hamshere, Peter A. Holmans, Ian R. Jones, George Kirov, Valentina Moskvina, Ivan Nikolov, Michael C. O'Donovan, Michael J. Owen, Nick Craddock; The Institute of Psychiatry, King's College, London, UK, David A. Collier, Amanda Elkin, Anne Farmer, Richard Williamson, Peter McGuffin; Royal Victoria Infirmary, Newcastle upon Tyne, UK, Allan H. Young, I. Nicol Ferrier; Supported in part by R01 MH079799 (Smoller). NR 42 TC 23 Z9 23 U1 2 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD APR PY 2011 VL 156B IS 3 BP 370 EP 378 DI 10.1002/ajmg.b.31172 PG 9 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 734KI UT WOS:000288332600015 ER PT J AU Al-Agha, OM Huwait, HF Chow, C Yang, W Senz, J Kalloger, SE Huntsman, DG Young, RH Gilks, CB AF Al-Agha, Osama M. Huwait, Hassan F. Chow, Christine Yang, Winnie Senz, Janine Kalloger, Steve E. Huntsman, David G. Young, Robert H. Gilks, C. Blake TI FOXL2 Is a Sensitive and Specific Marker for Sex Cord-Stromal Tumors of the Ovary SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE FOXL2; alpha-inhibin; calretinin; sex cord-stromal tumors; immunohistochemistry ID GRANULOSA-CELL TUMOR; INHIBIN; CALRETININ; EXPRESSION; NEOPLASMS AB Sex cord-stromal tumors (SCSTs) of the ovary are relatively uncommon tumors. Diagnosis of SCST rests primarily on the histomorphology of these tumors, and tumors with an atypical or unconventional appearance can pose diagnostic challenges. Previously, we had identified FOXL2 (402C -> G) mutation as being characteristic of adult granulosa cell tumors (aGCTs). However, molecular screening for this mutation is not always possible and adds time and cost to the diagnostic process. In this study, we investigated the potential diagnostic use of immunostaining for FOXL2 on formalin-fixed paraffin-embedded tissue sections. Using a commercially available polyclonal antiserum against FOXL2 protein, immunoexpression of FOXL2 was tested in 501 ovarian tumor samples, including 119 SCSTs, using whole tissue sections and tissue microarrays. Staining was correlated with FOXL2 mutation status. In addition, we compared FOXL2 immunoexpression with that of alpha-inhibin and calretinin, the 2 traditional immunomarkers of SCST, in a subset of 89 SCSTs. FOXL2 immunostaining was present in 95 of 119 (80%) SCSTs, including > 95% of aGCTs, juvenile granulosa cell tumors, fibromas, and sclerosing stromal tumors. Only 50% of Sertoli-Leydig cell tumors (N = 40) expressed FOXL2. One of 11 steroid cell tumors and 3 of 3 female adnexal tumors of probable Wolffian origin showed FOXL2 immunoreactivity, whereas all other non-SCSTs tested (N = 368) were negative for FOXL2 expression. Thus, the sensitivity and specificity of FOXL2 immunoreactivity for SCST are 80% and 99%, respectively. The FOXL2 (402C -> G) mutation was confirmed to be both a sensitive and relatively specific indicator of aGCT. Forty-five of 119 SCSTs were mutation positive. These cases were 39 of 42 (93%) aGCTs, 3 of 40 Sertoli-Leydig cell tumors, 2 of 5 thecomas, and 1 of 4 (25%) SCSTs of unclassified type. SCSTs harboring a FOXL2 mutation consistently immunoexpressed FOXL2 (44 of 45, 98%), but FOXL2 immunostaining was also seen in many SCSTs that lacked a mutation (49 of 73, 67%). FOXL2 immunostaining showed higher sensitivity for the diagnosis of SCST, compared with alpha-inhibin and calretinin, and FOXL2 staining was typically more intense in positive cases compared with either alpha-inhibin or calretinin. In the SCSTs that were negative for FOXL2 expression, alpha-inhibin and/or calretinin immunostaining yielded positive results. In conclusion, FOXL2 is a relatively sensitive and highly specific marker for SCST. FOXL2 staining is present in almost all SCSTs with a FOXL2 mutation, and also in a majority of SCSTs without a mutation. FOXL2, together with alpha-inhibin and calretinin, forms an immunomarker panel that will result in positive staining with 1 or more markers in essentially all cases of SCST. C1 [Al-Agha, Osama M.; Yang, Winnie; Senz, Janine; Kalloger, Steve E.; Huntsman, David G.; Gilks, C. Blake] Vancouver Gen Hosp, Ctr Translat & Appl Genom, Vancouver, BC, Canada. [Al-Agha, Osama M.; Chow, Christine; Kalloger, Steve E.; Huntsman, David G.; Gilks, C. Blake] Vancouver Gen Hosp, Genet Pathol Evaluat Ctr, Vancouver, BC, Canada. [Huwait, Hassan F.; Gilks, C. Blake] Vancouver Gen Hosp, Dept Pathol, Vancouver, BC, Canada. [Young, Robert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Huntsman, DG (reprint author), British Columbia Canc Agcy, CTAG, 3427-600 W 10th Ave, Vancouver, BC V5Z 4E6, Canada. EM dhuntsma@bccancer.bc.ca FU CIHR [200281, 102198]; sanofiaventis FX Supported by grants from CIHR (#200281 and 102198) and an unrestricted educational grant from sanofiaventis. NR 24 TC 68 Z9 75 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD APR PY 2011 VL 35 IS 4 BP 484 EP 494 DI 10.1097/PAS.0b013e31820a406c PG 11 WC Pathology; Surgery SC Pathology; Surgery GA 736JT UT WOS:000288491600003 PM 21378549 ER PT J AU Rege, TA Wagner, AJ Corless, CL Heinrich, MC Hornick, JL AF Rege, Tanya A. Wagner, Andrew J. Corless, Christopher L. Heinrich, Michael C. Hornick, Jason L. TI "Pediatric-type" Gastrointestinal Stromal Tumors in Adults: Distinctive Histology Predicts Genotype and Clinical Behavior SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE gastrointestinal stromal tumor; KIT; PDGFRA; tyrosine kinase inhibitor; sarcoma; soft tissue tumor ID OF-THE-LITERATURE; TERM-FOLLOW-UP; CARNEY TRIAD; GERMLINE MUTATIONS; PDGFRA MUTATIONS; GASTRIC TUMORS; YOUNG-ADULTS; IMATINIB; PATHOLOGY; PARAGANGLIOMA AB Gastrointestinal stromal tumors (GISTs) rarely affect children, mainly girls. Pediatric GISTs typically arise in the stomach as multifocal tumors with a multinodular growth pattern, epithelioid morphology, lymph node metastases, an absence of KIT and PDGFRA gene mutations, and indolent behavior. Occasional GISTs in adults show similar features. Such tumors are not widely recognized. GISTs with a multinodular growth pattern in patients over the age of 18 years were retrieved from surgical and consultation files. Hematoxylin and eosin-stained slides were reviewed, immunohistochemistry was performed, and KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12, 14, and 18) genes were screened for mutations. Clinical follow-up was obtained. Sixteen cases were identified, affecting 13 women and 3 men (median age, 31.5 y; range, 19 to 56 y), all in the stomach. The mean tumor size was 5.4 cm (range, 1.8 to 11 cm); 4 were multifocal. All tumors showed a multinodular or plexiform architecture and epithelioid (N = 3) or mixed epithelioid and spindle cell (N = 13) morphology. Five tumors had vascular invasion; 6 had focal necrosis. Mitotic activity ranged from 3 to 156/50 high-power fields (8 tumors had <= 5/50 high-power fields). Using Armed Forces Institute of Pathology risk stratification, categories for primary tumors were: none (N = 2), very low risk (N = 3), low risk (N = 3), moderate risk (N = 3), and high risk (N = 5). By immunohistochemistry, all tumors were positive for KIT, 82% DOG1, 72% CD34, 18% caldesmon, 9% S-100, 8% smooth muscle actin, and 0% desmin. All tumors were wild type for KIT and PDGFRA in the exons that were screened. At primary resection, 9 patients (56%) had lymph node metastases and 3 patients had liver metastases. Follow-up ranged from 16 months to 16 years (median, 5 y). Two tumors recurred locally in the stomach and 7 patients developed subsequent metastases to the lymph nodes N = 5), liver (N = 3), and peritoneum/omentum (N = 3). Primary tumors from 7 patients with metastases were Armed Forces Institute of Pathology low risk, very low risk, or no risk of recurrence. None of the metastatic tumors responded to treatment with imatinib mesylate. One patient died of disseminated liver and intra-abdominal metastases and the remaining patients were alive at last follow-up. Gastric GISTs in adults with a multinodular or plexiform growth pattern and epithelioid or mixed morphology are similar to pediatric GISTs. Unlike conventional adult GISTs, this distinctive subset predominantly affects women, often metastasizes to lymph nodes, and lacks mutations in KIT and PDGFRA. Current risk assessment criteria do not reliably predict behavior for this group. Although metastases are common and most tumors are imatinib resistant, they pursue a relatively indolent clinical course. Recognition of "pediatric-type" GISTs in adults is critical for prognosis, appropriate therapy, and follow-up. C1 [Rege, Tanya A.; Hornick, Jason L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Rege, Tanya A.; Hornick, Jason L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Wagner, Andrew J.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Corless, Christopher L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Heinrich, Michael C.] Portland VA Med Ctr, Div Hematol & Oncol, Portland, OR USA. [Corless, Christopher L.; Heinrich, Michael C.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. RP Hornick, JL (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM jhornick@partners.org FU Department of Veterans Affairs; Life Raft Group; GIST FX Supported in part from a grant from the Merit Review Grant from the Department of Veterans Affairs (MCH) and funding from the Life Raft Group and GIST Cancer Research Fund (CLC and MCH). NR 24 TC 58 Z9 62 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD APR PY 2011 VL 35 IS 4 BP 495 EP 504 DI 10.1097/PAS.0b013e31820e5f7d PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 736JT UT WOS:000288491600004 PM 21358303 ER PT J AU Chaux, A Pfannl, R Rodriguez, IM Barreto, JE Velazquez, EF Lezcano, C Piris, A Netto, GJ Cubilla, AL AF Chaux, Alcides Pfannl, Rolf Rodriguez, Ingrid M. Barreto, Jose E. Velazquez, Elsa F. Lezcano, Cecilia Piris, Adriano Netto, George J. Cubilla, Antonio L. TI Distinctive Immunohistochemical Profile of Penile Intraepithelial Lesions: A Study of 74 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE penile intraepithelial neoplasia; carcinoma in situ; squamous hyperplasia; differentiated penile intraepithelial neoplasia; warty/basaloid penile intraepithelial neoplasia ID SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS; CANCER; NEOPLASIA; VULVA; ASSOCIATION; PREVENTION; P16(INK4A); VARIANTS; PATHWAYS AB Several classification schemes for penile precancerous lesions have been proposed, but none of them seems to correlate with the current understanding of penile cancer pathogenesis. Recently, a system, which takes into account morphologic features and purported etiopathogenesis, was proposed, separating penile intraepithelial neoplasia (PeIN) in differentiated and warty/basaloid subtypes. This study was designed to seek an immunohistochemical profile that can be helpful in the classification and differential diagnosis of penile epithelial abnormalities and precancerous lesions using the aforementioned system. The immunohistochemical panel included stains for p16(INK4a), p53, and Ki-67. For p16(INK4a) immunostaining, only full-thickness positivity in all epithelial cells was considered as positive; for p53 and Ki-67 immunostaining, patchy or diffuse nuclear positivity above the basal layer was considered as positive. Seventy-four lesions in 59 patients were selected and classified as follows: differentiated PeIN, 34 cases; squamous hyperplasia (SH), 21 cases; basaloid PeIN, 15 cases; and warty PeIN, 4 cases. The mean age of patients was 64 years. Forty-two lesions (56.8%) were located in the glans and 32 (43.2%) in the foreskin. Overexpression of p16(INK4a) was useful for distinguishing SH from warty/basaloid PeINs (0% vs. 94.7%, P < 0.0001) but not SH from differentiated PeINs (0% vs. 5.9%, P = 0.519). In addition, p16(INK4a) allowed the distinction of differentiated and warty/basaloid PeINs (5.9% vs. 94.7%, P < 0.0001). Immunohistochemistry results for p53 allowed the separation of SH and differentiated PeIN (9.5% vs. 44.1%, P = 0.0078) and SH and warty/basaloid PeIN (9.5% vs. 55.6%, P = 0.0042). Ki-67 immunostain was useful for distinguishing SH from differentiated PeIN (52.6% vs. 89.7%, P = 0.0062) and SH from PeIN with warty and/or basaloid features (52.6% vs. 100%, P = 0.0011). There seems to be a distinctive immunohistochemical profile for associated and precursor epithelial lesions of the penis. SH was p16(INK4a) and p53 negative, with variable Ki-67 positivity. Differentiated PeIN was p16(INK4a) negative and Ki-67 positive, with variable p53 positivity. Basaloid and warty PeINs were consistently p16(INK4a) and Ki-67 positive, with variable p53 positivity. The use of a triple p16(INK4a)/p53/Ki-67 immunohistochemical panel was found to be helpful in the classification, differential diagnosis, and morphologic standardization of penile intraepithelial lesions. C1 [Chaux, Alcides; Rodriguez, Ingrid M.; Barreto, Jose E.; Lezcano, Cecilia; Cubilla, Antonio L.] Inst Patol & Invest, Asuncion, Paraguay. [Chaux, Alcides; Netto, George J.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Pfannl, Rolf] Tufts Med Ctr, Boston, MA USA. [Lezcano, Cecilia; Piris, Adriano] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Velazquez, Elsa F.] Caris Life Sci, Caris Dx Div, Newton, MA USA. RP Cubilla, AL (reprint author), Inst Patol & Invest, Martin Brizuela 325, Asuncion, Paraguay. EM acubilla@institutodepatologia.com.py OI Chaux, Alcides/0000-0002-5824-9867 FU Johns Hopkins Medicine Patana Fund for Research FX Supported in part by The Johns Hopkins Medicine Patana Fund for Research. NR 26 TC 20 Z9 20 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD APR PY 2011 VL 35 IS 4 BP 553 EP 562 DI 10.1097/PAS.0b013e3182113402 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 736JT UT WOS:000288491600011 PM 21399489 ER PT J AU Wang, JH Wu, Q Yang, P Li, H Li, J Mountz, JD Hsu, HC AF Wang, John H. Wu, Qi Yang, PingAr Li, Hao Li, Jun Mountz, John D. Hsu, Hui-Chen TI Type I Interferon-Dependent CD86(high) Marginal Zone Precursor B Cells Are Potent T Cell Costimulators in Mice SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; PLASMACYTOID DENDRITIC CELLS; PATHOGENIC AUTOANTIBODIES; DISEASE-ACTIVITY; LYMPH-NODES; BXD2 MICE; BLOOD; ACTIVATION; EXPRESSION; RECEPTOR AB Objective. To investigate the role of CD86(high) marginal zone (MZ) precursor B cells in type I interferon (IFN)-induced T cell-dependent responses in autoimmune BXD2 mice. Methods. Confocal microscopic imaging was used to determine the location of plasmacytoid dendritic cells (DCs), MZ precursor B cells, and CD4 T cells in the spleens of BXD2 and BXD2-Ifnar(-/-) mice. Immunohistochemical staining was used to determine IgG(bright) cells in the spleens of BXD2 and BXD2-Ifnar(-/-) mice. Enzyme-linked immunosorbent assay was used to determine serum levels of IFN alpha and autoantibodies, and 4-hydroxy-3-nitrophenylacetyl hapten (NP)-chicken gamma-globulin (CGG) (NP-CGG)-or NP-Ficoll-induced anti-NP2 antibody titers. Real-time quantitative polymerase chain reaction was used to determine the levels of type I IFN transcripts. T cell proliferation was measured using H-3-thymidine. The expression of CD86 and CD80 was determined by fluorescence-activated cell sorting analysis. Results. The deletion of type I IFN receptor abrogated the development of IgGbright cells and sup-pressed a T cell-dependent antibody response. Type I IFN signaling was associated with the expression of CD86, but not CD80, on follicular, MZ, and MZ precursor B cells. However, MZ precursor B cells demonstrated the highest expression of CD86 and the highest capacity for T cell costimulation with intact type I IFN receptor. This effect was blocked by an antibody that neutralizes CD86. In IFN receptor-intact BXD2 mouse spleens, MZ precursor B cells clustered at the T cell-B cell border. CD86 deletion suppressed germinal center formation, autoantibody production, and development of autoimmune diseases in BXD2 mice. Conclusion. Type I IFN can promote autoimmune responses in BXD2 mice through up-regulation of CD86(high) expression on MZ precursor B cells and trafficking of MZ precursor B cells to the T cell-B cell border to provide costimulation of CD4 T cells. C1 [Hsu, Hui-Chen] Univ Alabama, Div Clin Immunol & Rheumatol, Dept Med, Birmingham, AL 35294 USA. [Mountz, John D.] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. RP Hsu, HC (reprint author), Univ Alabama, Div Clin Immunol & Rheumatol, Dept Med, 1825 Univ Blvd,SHELB 311, Birmingham, AL 35294 USA. EM rheu078@uab.edu RI Li, Hao/N-7406-2015 OI Li, Hao/0000-0002-2171-8826 FU American College of Rheumatology Research and Education Foundation; Alliance for Lupus Research; Department of Veterans Affairs [1I01BX000600-01]; Daiichi-Sankyo Co., Ltd; NIH [1-AI-071110-01A1, ARRA-3-R01-AI-71110-02S1, P30-AR-48311]; Lupus Research Institute; Arthritis Foundation FX Supported by grants to Dr. Mountz from the American College of Rheumatology Research and Education Foundation (Within Our Reach research grant), the Alliance for Lupus Research (Target Identification in Lupus program grant), the Department of Veterans Affairs (Merit Review grant 1I01BX000600-01), Daiichi-Sankyo Co., Ltd, and the NIH (grants 1-AI-071110-01A1, ARRA-3-R01-AI-71110-02S1, and P30-AR-48311) and by grants to Dr. Hsu from the Lupus Research Institute (Novel Research project grant) and the Arthritis Foundation (Arthritis Investigator Award). NR 32 TC 10 Z9 10 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD APR PY 2011 VL 63 IS 4 BP 1054 EP 1064 DI 10.1002/art.30231 PG 11 WC Rheumatology SC Rheumatology GA 748VO UT WOS:000289421100024 PM 21225691 ER PT J AU Boserup, MW Lichota, J Haile, D Moos, T AF Boserup, Michael W. Lichota, Jacek Haile, David Moos, Torben TI Heterogenous distribution of ferroportin-containing neurons in mouse brain SO BIOMETALS LA English DT Article DE Blood-brain barrier; Iron; Neurodegeneration; Oxidative stress; qPCR; Transferrin ID DIVALENT METAL TRANSPORTER-1; CENTRAL-NERVOUS-SYSTEM; TRANSFERRIN RECEPTOR; IRON-METABOLISM; RAT; EXPRESSION; CELLS; CERULOPLASMIN; PROTEINS; FERRITIN AB Iron is crucial for a variety of cellular functions in neuronal cells. Neuronal iron uptake is reflected in a robust and consistent expression of transferrin receptors and divalent metal transporter 1 (DMT 1). Conversely, the mechanisms by which neurons neutralize and possibly excrete iron are less clear. Studies indicate that neurons express ferroportin which could reflect a mechanism for iron export. We mapped the distribution of ferroportin in the adult mouse brain using an antibody prepared from a peptide representing amino acid sequences 223-303 of mouse ferroportin. The antibody specifically detected ferroportin in brain homogenates, whereas homogenates of cultured endothelial cells were devoid of immunoreactivity. In brain sections, ferroportin was confined to neuronal cell bodies and peripheral processes of cerebral cortex, hippocampus, thalamus, brain stem, and cerebellum. In brain stem ferroportin-labeling was particularly high in neurons of cranial nerve nuclei and reticular formation. Ferroportin was hardly detectable in striatum, pallidum, or hypothalamus. Among non-neuronal cells, ferroportin was detected in oligodendrocytes and choroid plexus epithelial cells. A comparison with previous studies on the distribution of transferrin receptors in neurons shows that many neuronal pools coincide with those expressing ferroportin. The data therefore indicate that neuronal iron homeostasis consists of a delicate balance between transferrin receptor-mediated uptake of iron-transferrin and ferroportin-related iron excretion. The findings also suggest a particular high turnover of iron in neuronal regions, such as habenula, hippocampus, reticular formation and cerebellum, as several neurons in these regions exhibit a prominent co-expression of transferrin receptors and ferroportin. C1 [Boserup, Michael W.; Lichota, Jacek; Moos, Torben] Univ Aalborg, Dept Hlth Sci & Technol, Neurobiol Sect, DK-9220 Aalborg, Denmark. [Haile, David] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Moos, T (reprint author), Univ Aalborg, Dept Hlth Sci & Technol, Neurobiol Sect, Fr Bajers Vej 3B,1-216, DK-9220 Aalborg, Denmark. EM tmoos@hst.aau.dk OI Moos, Torben/0000-0001-9989-0207 FU Lundbeck Fund; Danish Parkinson's Disease Fund; Carlsberg Foundation; Spar Nord Fund; Obelske Familiefond FX We would like to thank Susan Peters at University of Copenhagen, Denmark and Merete Fredsgaard, Aalborg University, Denmark for excellent technical assistance. Murine brain endothelioma cells, bEnd3, were kindly obtained from Dr. Sara Gosk, University of Bonn, Germany. This work was supported by grants from the Lundbeck Fund, the Danish Parkinson's Disease Fund, the Carlsberg Foundation, the Spar Nord Fund, and the Obelske Familiefond. NR 42 TC 13 Z9 15 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0966-0844 J9 BIOMETALS JI Biometals PD APR PY 2011 VL 24 IS 2 BP 357 EP 375 DI 10.1007/s10534-010-9405-2 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 735BF UT WOS:000288387700015 PM 21213119 ER PT J AU Lauenstein, HD Quarcoo, D Plappert, L Schleh, C Nassimi, M Pilzner, C Rochlitzer, S Brabet, P Welte, T Hoymann, HG Krug, N Muller, M Lerner, EA Braun, A Groneberg, DA AF Lauenstein, H. D. Quarcoo, D. Plappert, L. Schleh, C. Nassimi, M. Pilzner, C. Rochlitzer, S. Brabet, P. Welte, T. Hoymann, H. G. Krug, N. Mueller, M. Lerner, E. A. Braun, A. Groneberg, D. A. TI Pituitary adenylate cyclase-activating peptide receptor 1 mediates anti-inflammatory effects in allergic airway inflammation in mice SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE airway inflammation; allergy; asthma; mouse model; neuropeptides; PACAP; VIP ID VASOACTIVE-INTESTINAL-PEPTIDE; DENDRITIC CELL EXPRESSION; LATE ASTHMATIC RESPONSE; LUTZOMYIA-LONGIPALPIS; RESPIRATORY-TRACT; POLYPEPTIDE PACAP; FERRET TRACHEA; SEPTIC SHOCK; MURINE MODEL; T-CELLS AB P>Background Bronchial asthma is characterized by airway inflammation and reversible obstruction. Since the gold standard of therapy, a combination of anti-inflammatory corticosteroids and bronchodilatory beta(2) agonists, has recently been discussed to be related to an increased mortality, there is a need for novel therapeutic pathways. Objective A new experimental concept that encompasses the vasoactive intestinal peptide/pituitary adenylate cyclase activating peptide (PACAP) family of receptors by demonstrating the anti-inflammatory effects of the PACAP receptor 1 (PAC1R) in a murine model of allergic asthma is described. Methods PAC1R expression was investigated in lung tissue and isolated dendritic cells (DCs) via real-time PCR. Ovalbumin (OVA)-induced asthma models were used in PAC1R-deficient mice and BALB/c mice treated with PAC1R agonist maxadilan (MAX). Bronchoalveolar lavages have been performed and investigated at the cellular and cytokine levels. Fluorescence staining of a frozen lung section has been performed to detect eosinophil granulocytes in lung tissue. Plasma IgE levels have been quantified via the ELISA technique. Lung function was determined using head-out body plethysmography or whole-body plethysmography. Results Increased PAC1R mRNA expression in lung tissue was present under inflammatory conditions. PAC1R expression was detected on DCs. In OVA-induced asthma models, which were applied to PAC1R-deficient mice (PAC1R-/-) and to BALB/c mice treated with the specific PAC1R agonist MAX, PAC1R deficiency resulted in inflammatory effects, while agonistic stimulation resulted in anti-inflammatory effects. No effects on lung function were detected both in the gene-depletion and in the pharmacologic studies. In summary, here, we demonstrate that anti-inflammatory effects can be achieved via PAC1R. Conclusion PAC1R agonists may represent a promising target for an anti-inflammatory therapy in airway diseases such as bronchial asthma. C1 [Lauenstein, H. D.; Plappert, L.; Schleh, C.; Nassimi, M.; Pilzner, C.; Rochlitzer, S.; Hoymann, H. G.; Krug, N.; Mueller, M.; Braun, A.] Fraunhofer Inst Toxicol & Expt Med, Dept Immunol Allergol & Immuntoxikol, D-30625 Hannover, Germany. [Lauenstein, H. D.; Plappert, L.; Pilzner, C.; Welte, T.; Groneberg, D. A.] Hannover Med Sch, Clin Pneumol, D-3000 Hannover, Germany. [Quarcoo, D.; Groneberg, D. A.] Free Univ Berlin, Inst Occupat Med, Charite Univ Med Berlin, D-1000 Berlin, Germany. [Quarcoo, D.; Groneberg, D. A.] Humboldt Univ, Berlin, Germany. [Brabet, P.] INSERM, Inst Neurosci Montpellier, Montpellier, France. [Lerner, E. A.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. RP Braun, A (reprint author), Fraunhofer Inst Toxicol & Expt Med, Dept Immunol Allergol & Immuntoxikol, Nikolai Fuchs Str 1, D-30625 Hannover, Germany. EM armin.braun@item.fraunhofer.de RI Braun, Armin /B-8750-2009; OI Braun, Armin /0000-0002-1142-1463; Groneberg, David/0000-0001-8551-6556 FU Deutsche Forschungsgemeinschaft [DFG Br 2126/2-2, SFB 587, B4, B13] FX Funded by Deutsche Forschungsgemeinschaft (DFG Br 2126/2-2, SFB 587 'Immune reactions of the lung in infection and allergy', projects B4 and B13). NR 57 TC 11 Z9 11 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0954-7894 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD APR PY 2011 VL 41 IS 4 BP 592 EP 601 DI 10.1111/j.1365-2222.2010.03636.x PG 10 WC Allergy; Immunology SC Allergy; Immunology GA 735BA UT WOS:000288387200018 PM 21059121 ER PT J AU Colwell, AS Craft, RO AF Colwell, Amy S. Craft, Randall O. TI Near-Infrared Spectroscopy in Autologous Breast Reconstruction SO CLINICS IN PLASTIC SURGERY LA English DT Article DE Near-infrared spectroscopy; Autologous reconstruction; Breast cancer; Free flap monitoring ID FREE FLAPS; OXYGEN-SATURATION; PERFUSION; CANCER; RESUSCITATION; TRANSFERS; HEAD AB Autologous breast reconstruction is commonly performed after mastectomy and provides a natural replacement that mimics the native breast. Although current free flap success rates exceed 95%, total flap loss can be devastating for patients. As a result, new technologies have emerged to provide an objective means for flap monitoring, with the hope that vaso-occlusive events can be detected before the clinical manifestation of a microvascular complication and the no-reflow phenomenon. This article focuses on the available data for one new technology, near-infrared spectroscopy, and its current use in clinical practice. C1 [Colwell, Amy S.] Harvard Univ, Div Plast Surg, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Colwell, AS (reprint author), Harvard Univ, Div Plast Surg, Massachusetts Gen Hosp, Sch Med, 15 Parkman St,WACC 435, Boston, MA 02114 USA. EM acolwell@partners.org NR 26 TC 3 Z9 4 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 0094-1298 J9 CLIN PLAST SURG JI Clin. Plast. Surg. PD APR PY 2011 VL 38 IS 2 BP 301 EP + DI 10.1016/j.cps.2011.03.014 PG 8 WC Surgery SC Surgery GA 780YI UT WOS:000291896900013 PM 21620154 ER PT J AU Mattingly, G Surman, CB Mao, AR Eagan, CA Onofrey, M Lerner, M AF Mattingly, Greg Surman, Craig B. Mao, Alice R. Eagan, Corey A. Onofrey, Meaghan Lerner, Marc TI Improving Communication in ADHD Care: Results from In-office Linguistic Research SO CNS SPECTRUMS LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CLINICAL-PRACTICE GUIDELINE; CHILD; DIAGNOSIS; DOCTORS; TEAM AB Introduction: An in-office linguistic study was conducted to help improve understanding of how to better evaluate and treat attention-deficit/hyperactivity disorder (ADHD). Methods: Naturally occurring interactions were recorded among 7 psychiatrists and 23 patients and 8 pediatricians along with 22 patients and their parents. Participants were interviewed separately post-visit. Transcripts of interactions and interviews were analyzed using sociolinguistic techniques. Results: Visits were variable in length and lacked concrete treatment plans. In the pediatricsetting, children were typically excluded from dialogues, accounting for only 8% of words spoken. School was the primary metric used to evaluate symptoms. Pediatricians allayed parents' concerns about stimulant therapy by promising to prescribe the lowest possible dose, rather than discussing titrating to an optimal dose. Adults were evaluated idiosyncratically without the use of scales or tools. Stimulants were positioned as short-term "trials" without strong physician recommendations. Discussion: Conversations about stimulant therapy lacked goal- and expectation-setting. Also missing from conversations was a definitive treatment plan based on the core symptoms of ADHD. Incorporating open-ended questions and tools or rating scales may result in a more effective and efficient in-office dialogue. Conclusion: Further research is warranted to assess the efficacy of communication strategies to enhance in-office discussions of ADHD and stimulant therapy. C1 [Eagan, Corey A.; Onofrey, Meaghan] Ogilvy CommonHlth Insights & Analyt, Parsippany, NJ 07054 USA. [Mattingly, Greg] St Charles Psychiat Associates, St Charles, MO USA. [Surman, Craig B.] Massachusetts Gen Hosp, Clin & Res Programs Pediat Psychopharmacol & Adul, Adult ADHD Res Program, Boston, MA 02114 USA. [Surman, Craig B.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Mao, Alice R.] Baylor Coll Med, Houston, TX 77030 USA. [Lerner, Marc] Univ Calif Irvine, Sch Med, Dept Pediat, Irvine, CA 92717 USA. RP Eagan, CA (reprint author), Ogilvy CommonHlth Insights & Analyt, 440 Interpace Pkwy, Parsippany, NJ 07054 USA. EM corey.eagan@ogilvy.com FU AstraZeneca; Dainnpon-Sumitomo; Eli Lilly; Forest Laboratories; GlaxoSmithKline; Janssen; Johnson Johnson; Lundbeck; McNeil; Merck; New River; Novartis; Organon; Pfizer; sanofi-aventis; Schwabe/Ingenix; Sepracor; Shire; Solvay; Takeda; Vanda; Wyeth; Janssen-Ortho; Abbott; Alza; Cephalon; Hilda and Preston Davis Foundation; National Institutes of Health; Addrenex; NIMH; Next Wave; Psychgenics; Quintile; Shionogi; McNeil Pediatrics FX Dr. Mattingly has been a consultant for Eli Lilly, Forest Laboratories, McNeil, Pfizer, Shire, and Vanda; has been on speakers' bureaus for Abbott, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, McNeil, and Shire; and receives research support from AstraZeneca, Dainnpon-Sumitomo, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck, McNeil, Merck, New River, Novartis, Organon, Pfizer, sanofi-aventis, Schwabe/Ingenix, Sepracor, Shire, Solvay, Takeda, Vanda, and Wyeth. Dr. Surman has been a consultant/advisor to McNeil, Shire, and Takeda; has received support for speaking and other educational activities from Janssen-Ortho, McNeil, Novartis, and Shire; has received research support from Abbott, Alza, Cephalon, Eli Lilly, the Hilda and Preston Davis Foundation, McNeil, Merck, New River, the National Institutes of Health, Organon, Pfizer, Shire, and Takeda; and has received honoraria from Reed Medical Education (a logistics collaborator for the MGH Psychiatry Academy). Dr. Mao has received honoraria for being on the speaker bureaus for Bristol-Myers Squibb, Eli Lilly, Novartis, Pfizer, and Shire. Dr. Lerner is a consultant to McNeil and Shire; is on the speakers' bureaus for Eli Lilly, McNeil, and Shire; and receives research support from Addrenex, Eli Lilly, McNeil, the NIMH, Next Wave, Psychgenics, Quintile, Shionogi, and Shire. Ms. Onofrey has received research support from McNeil Pediatrics. Ms. Eagan reports no affiliations with or financial interest in any organization that may pose a conflict of interest. NR 31 TC 1 Z9 1 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1092-8529 J9 CNS SPECTRUMS JI CNS Spectr. PD APR PY 2011 VL 16 IS 4 BP 85 EP 94 DI 10.1017/S1092852912000235 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 951KD UT WOS:000304718500001 PM 24725370 ER PT J AU Chen, KT Malo, MS Beasley-Topliffe, LK Poelstra, K Millan, JL Mostafa, G Alam, SN Ramasamy, S Warren, HS Hohmann, EL Hodin, RA AF Chen, Kathryn T. Malo, Madhu S. Beasley-Topliffe, Laura Kline Poelstra, Klaas Millan, Jose Luis Mostafa, Golam Alam, Sayeda N. Ramasamy, Sundaram Warren, H. Shaw Hohmann, Elizabeth L. Hodin, Richard A. TI A Role for Intestinal Alkaline Phosphatase in the Maintenance of Local Gut Immunity SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Mucosal gut defense factor; Lipopolysaccharide; Tolerance; TLR4 ID SALMONELLA-TYPHIMURIUM LIPOPOLYSACCHARIDES; MAJOR HISTOCOMPATIBILITY COMPLEX; MONOPHOSPHORYL LIPID-A; ALCOHOLIC LIVER-INJURY; ENDOTOXIN TOLERANCE; KUPFFER CELLS; INTRAPERITONEAL INJECTION; ESCHERICHIA-COLI; T-CELLS; CLASS-I AB Intestinal alkaline phosphatase (IAP) is a gut mucosal defense factor known to dephosphorylate lipopolysaccharide (LPS); however, the role of IAP in the gut response to luminal bacteria remains poorly defined. We investigated immune responses of wild-type (WT) and IAP-knockout (IAP-KO) mice to LPS and Salmonella typhimurium challenges. Cryostat sectioning and standard indirect immunohistochemical staining for major histocompatibility complex (MHC) class II molecules were performed on liver tissue from WT and IAP-KO mice. WT and IAP-KO mice were orally gavaged with S. typhimurium; bacterial translocation to mesenteric nodes, liver, and spleen was determined by tissue homogenization and plating. In other experiments, WT and IAP-KO mice received intraperitoneal injections of LPS, with subsequent quantification of complete blood counts and serum interleukin (IL)-6 by enzyme-linked immunosorbent assay (ELISA). WT and IAP-KO whole blood were plated and stimulated with LPS and Pam-3-Cys, followed by cytokine assays. Immunohistologic liver examinations showed increased expression of MHC class II molecules in IAP-KO mice. Following S. typhimurium challenge, WT mice appeared moribund compared with IAP-KO mice, with increased bacterial translocation. WT mice had > 50% decrease (P < .005) in platelets and 1.8-fold (P < .05) increased serum IL-6 compared with IAP-KO mice in response to LPS injections. IAP-KO whole-blood stimulation with LPS and Pam-3-Cys resulted in increased IL-6 and tumor necrosis factor (TNF)-alpha secretion compared with WT. IAP-KO mice exhibit characteristics consistent with local LPS tolerance. Whole-blood response of IAP-KO mice did not reflect systemic tolerance. These data suggest that IAP is a local immunomodulating factor, perhaps regulating LPS-toll-like receptor 4 (TLR4) interaction between commensal microflora and intestinal epithelium. C1 [Chen, Kathryn T.; Malo, Madhu S.; Mostafa, Golam; Ramasamy, Sundaram; Hodin, Richard A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Chen, Kathryn T.] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. [Poelstra, Klaas] Univ Groningen, Dept Pharmacokinet Toxicol & Targeting, Groningen, Netherlands. [Millan, Jose Luis] Burnham Inst Med Res, Sanford Childrens Hlth Res Ctr, La Jolla, CA 92037 USA. [Beasley-Topliffe, Laura Kline; Warren, H. Shaw; Hohmann, Elizabeth L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Hodin, RA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. EM kathryn.chen@gmail.com; mmalo@partners.org; lbeasleytopliffe@gmail.com; k.poelstra@rug.nl; millan@burnham.org; gmostafa@partners.org; snalam@partners.org; ramasamy.sundaram@mgh.harvard.edu; warren@helix.mgh.harvard.edu; ehohmann@partners.org; rhodin@partners.org FU National Institutes of Health [R01DK050623, R01DK047186, T32DK007754] FX Grant support: (1) National Institutes of Health Grant R01DK050623; (2) National Institutes of Health Grant R01DK047186; (3) National Institutes of Health Grant T32DK007754. NR 44 TC 40 Z9 43 U1 1 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD APR PY 2011 VL 56 IS 4 BP 1020 EP 1027 DI 10.1007/s10620-010-1396-x PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 736RR UT WOS:000288512300012 PM 20844955 ER PT J AU Sonnenberg, A AF Sonnenberg, Amnon TI Time Trends of Mortality from Gastric Cancer in Europe SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Birth-cohorts; Duodenal ulcer; Epidemiology; Gastric cancer; Gastric ulcer; Helicobacter pylori; Mortality; Time trends ID PEPTIC-ULCER; HELICOBACTER-PYLORI; CENTURIES; DISEASE AB The time trends of gastric and duodenal ulcer disease are shaped by a birth-cohort phenomenon. The aim of this study was to assess the extent by which a birth-cohort phenomenon also affected the long-term time trends of gastric cancer among different European countries. Mortality data from France, Germany, Netherlands, Scotland, Spain, and Sweden of the past 56-85 years were analyzed. The age-specific death rates were plotted against the period of death as period-age contours and against the period of birth as cohort-age contours. The long-term time trends of gastric cancer mortality were found to have risen among generations born during the 18th century until the mid-19th century and then to have declined in all subsequent generations. The rise and fall of gastric cancer preceded similar birth-cohort patterns of gastric and duodenal ulcer by about 10-30 years. With the exception of gastric cancer in Germany, similar birth-cohort phenomena were found in all countries, as well as in men and women. The time trends of mortality from gastric cancer and peptic are shaped by birth-cohort patterns that have affected all countries of Europe. It remains an enigma why mortality associated with gastric cancer and peptic ulcer suddenly started to rise within a short time period during the 19th century. C1 [Sonnenberg, Amnon] Oregon Hlth & Sci Univ, 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 21 TC 12 Z9 13 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD APR PY 2011 VL 56 IS 4 BP 1112 EP 1118 DI 10.1007/s10620-010-1553-2 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 736RR UT WOS:000288512300023 PM 21234687 ER PT J AU Yasuhara, SE AF Yasuhara, S. E. TI EXPLORING THE ROLE OF PHOSPHODIESTERASE PDE5 INHIBITION IN THE TREATMENT OF MUSCULAR DYSTROPHY SO DRUGS OF THE FUTURE LA English DT Article ID NITRIC-OXIDE SYNTHASE; VASCULAR SMOOTH-MUSCLE; PROTEIN-KINASE-G; SARCOGLYCAN-SARCOSPAN COMPLEX; DEFICIENT SKELETAL-MUSCLE; MDX MOUSE; PULMONARY-HYPERTENSION; CHRONIC HEPATITIS; CREATINE-KINASE; CYCLIC-GMP AB Duchenne muscular dystrophy (DMD) is caused by a mutation of a single gene, dystrophin, and is characterized by a slow progression and the increased turnover of myofiber degeneration and regeneration. Despite the long history of scientific research, the full mechanisms of muscle damage still need to be clarified and the therapeutic choices are limited. Recent studies on blood flow regulation have led to the discovery of a novel pharmacological treatment for muscular dystrophies. Phosphodiesterase PDE5 inhibitors were originally designed to improve blood circulation by inducing vasodilation in target organs and are widely used to treat male erectile dysfunction. Recently, the range of potential clinical applications for PDE5 inhibitors has widened, with increasing reports of their efficacy against various conditions, including pulmonary hypertension. The potential efficacy against DMD was reported in animal studies using the murine equivalent model. In this review, I discuss the recent understanding of the role of blood flow regulation in the pathogenesis of muscular dystrophy. Therapeutic approaches with PDE5 inhibitors will be discussed and include citations from the recent publications with animal studies. Future considerations of PDE5 inhibitor therapies will be examined, including the evaluation of drug efficacy and potential side effects. C1 Harvard Univ, Massachusetts Gen Hosp, Dept Anesthesiol & Crit Care, Shriners Hosp,Sch Med, Boston, MA 02114 USA. RP Yasuhara, SE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Anesthesiol & Crit Care, Shriners Hosp,Sch Med, 51 Blossom St, Boston, MA 02114 USA. EM Shingo_yasuhara@yahoo.com RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 170 TC 2 Z9 2 U1 0 U2 1 PU PROUS SCIENCE, SA-THOMSON REUTERS PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0377-8282 J9 DRUG FUTURE JI Drug Future PD APR PY 2011 VL 36 IS 4 BP 321 EP 339 DI 10.1358/dof.2011.36.4.1579114 PG 19 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 782OT UT WOS:000292019700006 ER PT J AU LaPlante, JM Falardeau, JL Brown, EM Slaugenhaupt, SA Vassilev, PM AF LaPlante, Janice M. Falardeau, John L. Brown, Edward M. Slaugenhaupt, Susan A. Vassilev, Peter M. TI The cation channel mucolipin-1 is a bifunctional protein that facilitates membrane remodeling via its serine lipase domain SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Membrane remodeling; Phospholipase; TRPML1; Mucolipin; Mucolipidosis IV; Tubulo-vesicular ID IV CULTURED FIBROBLASTS; PHOSPHOLIPASE A(2); CA2+-INDEPENDENT FUSION; LYSOPHOSPHATIDIC ACID; LYSOSOMAL EXOCYTOSIS; GIANT LIPOSOMES; ENDOSOME FUSION; IN-VITRO; CELLS; IDENTIFICATION AB Phospholipase modulators have been shown to affect the topology of lipid bilayers and the formation of tubulo-vesicular structures, but the specific endogenous phospholipases involved have yet to be identified. Here we show that TRPML1 (MLN1), a Ca2+-permeable channel, contributes to membrane remodeling through a serine lipase consensus domain, and thus represents a novel type of bifunctional protein. Remarkably, this serine lipase active site determines the ability of MLN1 to generate tubulo-vesicular extensions in mucolipin-1-expressing oocytes, human fibroblasts and model membrane vesicles. Our demonstration that MLN1 is involved in membrane remodeling and the formation of extensions suggests that it may play a role in the formation of cellular processes linked to the late endosome/lysosome (LE/L) pathway. MLN1 is absent or mutated in patients with mucolipidosis IV (MLIV), a lysosomal disorder with devastating neurological and other consequences. This study provides potential insight into the pathophysiology of MLIV. (C) 2011 Elsevier Inc. All rights reserved. C1 [LaPlante, Janice M.; Brown, Edward M.; Vassilev, Peter M.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [LaPlante, Janice M.; Brown, Edward M.; Vassilev, Peter M.] Brigham & Womens Hosp, Membrane Biol Program, Dept Med, Boston, MA 02115 USA. [LaPlante, Janice M.; Falardeau, John L.; Brown, Edward M.; Slaugenhaupt, Susan A.; Vassilev, Peter M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Falardeau, John L.; Slaugenhaupt, Susan A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02115 USA. RP LaPlante, JM (reprint author), Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 75 Francis St, Boston, MA 02115 USA. EM jlaplante@rics.bwh.harvard.edu FU ML4 Foundation; National Institute of Neurological Disorders and Stroke [NS39995]; NIH; PKDF; Genzyme; NARSAD; Stanley Foundation FX The authors wish to kindly thank Dr. James Gusella for his helpful discussions during the preparation of this manuscript. This study was supported by the ML4 Foundation (J.M.L.), the National Institute of Neurological Disorders and Stroke NS39995 (S.A.S.), NIH, PKDF, Genzyme, NARSAD and Stanley Foundation (P.M.V.). NR 56 TC 8 Z9 8 U1 1 U2 5 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD APR 1 PY 2011 VL 317 IS 6 BP 691 EP 705 DI 10.1016/j.yexcr.2011.01.008 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 736VE UT WOS:000288522300001 PM 21256127 ER PT J AU Arena, R Guazzi, M Myers, J Grinnen, D Forman, DE Lavie, CJ AF Arena, Ross Guazzi, Marco Myers, Jonathan Grinnen, Daniel Forman, Daniel E. Lavie, Carl J. TI Cardiopulmonary exercise testing in the assessment of pulmonary hypertension SO EXPERT REVIEW OF RESPIRATORY MEDICINE LA English DT Review DE aerobic capacity; carbon dioxide production; diagnosis; minute ventilation; prognosis; pulmonary vasculopathy; ventilatory efficiency ID CHRONIC HEART-FAILURE; TIDAL CARBON-DIOXIDE; 6-MINUTE WALK TEST; ARTERIAL-HYPERTENSION; VENTILATORY EFFICIENCY; GAS-EXCHANGE; HYPERTROPHIC CARDIOMYOPATHY; SCIENTIFIC STATEMENT; SYSTEMIC-SCLEROSIS; VASCULAR-DISEASE AB The assessment of patients with suspected or confirmed pulmonary arterial hypertension (PAH) and secondary pulmonary hypertension (PH) continues to evolve and, in recent years, evidence demonstrating that cardiopulmonary exercise testing (CPX) provides valuable information has grown at an impressive rate. The key premise supporting the use of CPX is that certain variables obtained provide insight into the degree of ventilation/perfusion mismatching secondary to altered pulmonary hemodynamics. In this article, we discuss the pathophysiology of PAH and secondary PH and its impact on cardiac function, review the clinical presentation of patients with elevated pulmonary pressures and outline a case for the use of CPX as an integral assessment technique, discuss CPX technology and testing procedures, and review the current state of available evidence and provide clinical recommendations for CPX in the setting of known or suspected PAH and secondary PH. C1 [Arena, Ross; Grinnen, Daniel] Virginia Commonwealth Univ, Richmond, VA 23220 USA. [Guazzi, Marco] Univ Milan, San Paolo Hosp, Cardiopulm Lab, Div Cardiol, Milan, Italy. [Myers, Jonathan; Forman, Daniel E.] VA Palo Alto Hlth Care Syst, Div Cardiovasc, Palo Alto, CA USA. [Forman, Daniel E.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Forman, Daniel E.] VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [Lavie, Carl J.] Univ Queensland, Sch Med, Ochsner Clin Sch, John Ochsner Heart & Vasc Inst,Dept Cardiovasc Di, New Orleans, LA USA. RP Arena, R (reprint author), Virginia Commonwealth Univ, Richmond, VA 23220 USA. EM rarena70@gmail.com RI Arena, Ross/A-3141-2008; Lavie, Carl/A-6014-2011; Guazzi, Marco/J-3165-2016 OI Arena, Ross/0000-0002-6675-1996; Guazzi, Marco/0000-0002-8456-609X NR 88 TC 19 Z9 19 U1 0 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1747-6348 EI 1747-6356 J9 EXPERT REV RESP MED JI Expert Rev. Respir. Med. PD APR PY 2011 VL 5 IS 2 BP 281 EP 293 DI 10.1586/ERS.11.4 PG 13 WC Respiratory System SC Respiratory System GA 056RE UT WOS:000312508000021 PM 21510737 ER PT J AU Aronis, KN Fiorenza, CG Chamberland, JP Mantzoros, CS AF Aronis, Konstantinos N. Fiorenza, Christina G. Chamberland, John P. Mantzoros, Christos S. TI Leptin administered in physiologic or pharmacologic doses does not regulate circulating angiogenesis factors in humans SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Aronis, Konstantinos N.; Fiorenza, Christina G.; Chamberland, John P.; Mantzoros, Christos S.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Mantzoros, Christos S.] Boston VA Healthcare Syst, Sect Endocrinol, Boston, MA USA. RI Aronis, Konstantinos/F-3586-2012; Aronis, Konstantinos/J-6582-2014 OI Aronis, Konstantinos/0000-0001-7189-8434; NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708401216 ER PT J AU Beard, RS Henry, JN Price, TO Ercal, N Banks, WA Bearden, SE AF Beard, Richard Scott Henry, Jamie N. Price, Tulin Otamis Ercal, Nuran Banks, William A. Bearden, Shawn E. TI Homocysteine disrupts NO metabolism in brain microvascular endothelial cells by an mGluR5-dependent mechanism SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Beard, Richard Scott; Henry, Jamie N.; Bearden, Shawn E.] Idaho State Univ, Pocatello, ID 83209 USA. [Price, Tulin Otamis] St Louis Univ, St Louis, MO 63103 USA. [Ercal, Nuran] Missouri Univ Sci & Technol, Rolla, MO USA. [Banks, William A.] VA Puget Sound, Seattle, WA USA. [Banks, William A.] Univ Washington, Seattle, WA 98195 USA. RI Beard Jr., Richard/E-2051-2013 OI Beard Jr., Richard/0000-0001-8545-3014 NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708405604 ER PT J AU Bellani, MA Muniandy, P Paramasivam, M Smogorzewska, A Wang, WD de Winter, J Seidman, MM AF Bellani, Marina Andrea Muniandy, Parames Paramasivam, Manikandian Smogorzewska, Agata Wang, Weidong de Winter, Johan Seidman, Michael M. TI Dissecting cellular inter-strand crosslink repair pathways through the recruitment kinetics of Fanconi Anemia (FA) proteins to localized ICLs SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Bellani, Marina Andrea; Paramasivam, Manikandian; Seidman, Michael M.] LMG, Baltimore, MD USA. [Wang, Weidong] NIA, LG, NIH, Baltimore, MD 21224 USA. [Muniandy, Parames] Dana Farber Canc Inst, Boston, MA 02115 USA. [Smogorzewska, Agata] Rockefeller Univ, New York, NY 10021 USA. [de Winter, Johan] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708402580 ER PT J AU Chen, YX Gelfond, JA McManus, LM Shireman, PK AF Chen, Yongxin Gelfond, Jonathan A. McManus, Linda M. Shireman, Paula K. TI MiR-682 Antisense Inhibits Skeletal Muscle Regeneration SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Chen, Yongxin; McManus, Linda M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Shireman, Paula K.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708402405 ER PT J AU Clayton, CC Neve, KA AF Clayton, Cecilea C. Neve, Kim A. TI Analysis of dopamine D2 receptor mutants deficient in arrestin binding using bioluminescence resonance energy transfer SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 Oregon Hlth & Sci Univ, Portland, OR 97201 USA. Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708403585 ER PT J AU Cypess, AM AF Cypess, Aaron M. TI New Discoveries in Human Brown Adipose Tissue SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Cypess, Aaron M.] Joslin Diabet Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708404514 ER PT J AU Farrell, S Brecha, N Barnes, S AF Farrell, Spring Brecha, Nicholas Barnes, Steven TI Somatostatin receptor subtype 4 modulation of L-type Ca2+ channels in rat retinal ganglion cells SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Farrell, Spring; Barnes, Steven] Dalhousie Univ, Halifax, NS, Canada. [Brecha, Nicholas; Barnes, Steven] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Brecha, Nicholas] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708401102 ER PT J AU Feinstein, TN Vilardaga, JP AF Feinstein, Timothy N. Vilardaga, Jean-Pierre TI Retromer terminates the generation of cAMP by internalized G protein-coupled PTH receptors SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Feinstein, Timothy N.; Vilardaga, Jean-Pierre] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Vilardaga, Jean-Pierre] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Vilardaga, Jean-Pierre] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708403577 ER PT J AU Gohil, VM Sheth, SA Nilsson, R Lee, JH Wojtovich, A Perocchi, F Chen, W Clish, C Ayata, C Brookes, P Mootha, V AF Gohil, Vishal M. Sheth, Sunil A. Nilsson, Roland Lee, Jeong-Hyun Wojtovich, Andrew Perocchi, Fabiana Chen, William Clish, Clary Ayata, Cenk Brookes, Paul Mootha, Vamsi TI Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Gohil, Vishal M.; Sheth, Sunil A.; Nilsson, Roland; Perocchi, Fabiana; Chen, William; Mootha, Vamsi] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lee, Jeong-Hyun; Ayata, Cenk] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. [Wojtovich, Andrew; Brookes, Paul] Univ Rochester, Med Ctr, Dept Pharmacol & Physiol, Rochester, NY 14642 USA. [Clish, Clary; Mootha, Vamsi] Broad Inst MIT & Harvard, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708402712 ER PT J AU Harston, RK McKillop, JC Moschella, PC Van Laer, A Quinones, LS Baicu, CF Balasubramanian, S Zile, MR Kuppuswamy, D AF Harston, Rebecca Kate McKillop, John C. Moschella, Phillip C. Van Laer, An Quinones, Lakeya S. Baicu, Catalin F. Balasubramanian, Sundaravadivel Zile, Michael R. Kuppuswamy, Dhandapani TI Acute rapamycin treatment augments both protein ubiquitination and Akt activation in pressure-overloaded rat myocardium SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Harston, Rebecca Kate] ABL Inc, Prod Dev, Kensington, MD USA. [McKillop, John C.; Moschella, Phillip C.; Van Laer, An; Quinones, Lakeya S.; Baicu, Catalin F.; Balasubramanian, Sundaravadivel; Zile, Michael R.; Kuppuswamy, Dhandapani] Med Univ S Carolina, Charleston, SC 29425 USA. [Zile, Michael R.; Kuppuswamy, Dhandapani] Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708404524 ER PT J AU Hernandez-Corbacho, M Mather, AR Jenkins, R Clarke, C Hannun, Y Obeid, L Snider, A Siskind, L AF Hernandez-Corbacho, Maria Mather, Andrew R. Jenkins, Rusell Clarke, Christopher Hannun, Yusuf Obeid, Lina Snider, Ashley Siskind, Leah TI Long-Chain Glycosphingolipids Mediate Renal Aging SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Hernandez-Corbacho, Maria; Mather, Andrew R.; Jenkins, Rusell; Clarke, Christopher; Hannun, Yusuf; Obeid, Lina; Snider, Ashley; Siskind, Leah] Med Univ S Carolina, Charleston, SC 29425 USA. [Obeid, Lina; Snider, Ashley; Siskind, Leah] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708402724 ER PT J AU Hsiao, PYL Mitchell, DC Hartman, TJ Jensen, GL Coffman, DL Still, CD Allman, RM Sawyer, P AF Hsiao, Pao Ying Lin Mitchell, Diane C. Hartman, Terryl J. Jensen, Gordon L. Coffman, Donna L. Still, Christopher D. Allman, Richard M. Sawyer, Patricia TI Characterizing dietary patterns in older adults using a novel approach SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Hsiao, Pao Ying Lin; Mitchell, Diane C.; Hartman, Terryl J.; Jensen, Gordon L.] Penn State Univ, Dept Nutr Sci, University Pk, PA 16802 USA. [Coffman, Donna L.] Penn State Univ, Methodol Ctr, University Pk, PA 16802 USA. [Still, Christopher D.] Geisinger Med Ctr, Danville, PA 17822 USA. [Allman, Richard M.] Birmingham VA Med Ctr, Birmingham, AL USA. [Allman, Richard M.; Sawyer, Patricia] Univ Alabama Birmingham, Div Gerontol Geriatr & Palliat Care, Birmingham, AL USA. RI Coffman, Donna/C-3038-2013 OI Coffman, Donna/0000-0001-6305-6579 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708405192 ER PT J AU Jain, A Munn, LL AF Jain, Abhishek Munn, Lance L. TI Rare Blood Cell Separation on a Microfluidic Platform: A Case Study of Circulating Tumor Cells SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Jain, Abhishek] Boston Univ, Boston, MA 02215 USA. [Jain, Abhishek; Munn, Lance L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA USA. RI Munn, Lance/L-3950-2016 OI Munn, Lance/0000-0003-0698-7232 NR 0 TC 0 Z9 0 U1 1 U2 11 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708405516 ER PT J AU Korkmaz, B Jegot, G Derache, C Remold-O'Donnell, E Kellenberger, C Gauthier, F AF Korkmaz, Brice Jegot, Gwenhael Derache, Chrystelle Remold-O'Donnell, Eileen Kellenberger, Christine Gauthier, Francis TI A substrate-based approach to convert serpinB1 into a specific inhibitor of proteinase 3, the Wegener granulomatosis autoantigen SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Korkmaz, Brice; Jegot, Gwenhael; Gauthier, Francis] INSERM, Proteases & Vectorisat Pulm U618, Tours, France. [Derache, Chrystelle] CNRS, Ctr Biophys Mol, Orleans, France. [Remold-O'Donnell, Eileen] Immune Dis Inst, Boston, MA USA. [Kellenberger, Christine] CNRS, Marseille, France. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708403544 ER PT J AU Li, Y Si, R Feng, Y Zou, L Wang, E Chao, W AF Li, Yan Si, Rui Feng, Yan Zou, Lin Wang, E. Chao, Wei TI Myocardial ischemia induces a rapid activation of innate immune signaling via cardiac heat-shock protein-60 and Toll-like receptor 4 SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Li, Yan; Si, Rui; Feng, Yan; Zou, Lin; Wang, E.; Chao, Wei] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. [Li, Yan] Tongji Hosp, HUST, Wuhan, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708402288 ER PT J AU Moore, C Rosenblum, JL Kaplan, LM AF Moore, Carolyn Rosenblum, Jennifer L. Kaplan, Lee M. TI Calcium and vitamin D supplementation is associated with decreased intra-abdominal fat mass SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Moore, Carolyn] Texas Womans Univ, Houston, TX USA. [Rosenblum, Jennifer L.; Kaplan, Lee M.] MGH Weight Ctr, Boston, MA USA. [Rosenblum, Jennifer L.; Kaplan, Lee M.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708401851 ER PT J AU Munn, L Kunert, C Kamoun, W Tyrrell, JA AF Munn, Lance Kunert, Christian Kamoun, Walid Tyrrell, James Alex TI Simulating vascular remodeling and transport in tumors SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Munn, Lance; Kunert, Christian; Kamoun, Walid] Massachusetts Gen Hosp, Charlestown, MA USA. [Tyrrell, James Alex] Thomson Reuters, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708403694 ER PT J AU Munn, L Liao, S Wong, A Lacorre, D Jain, RK Fukumura, D Cheng, G AF Munn, Lance Liao, Shan Wong, Andus Lacorre, Delphine Jain, Rakesh K. Fukumura, Dai Cheng, Gang TI Wrapping-and-tapping anastomosis connects implanted endothelial networks to host vasculature SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Munn, Lance; Liao, Shan; Wong, Andus; Lacorre, Delphine; Jain, Rakesh K.; Fukumura, Dai; Cheng, Gang] Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708402313 ER PT J AU Naar, AM Walker, AK Yang, FJ Najafi-Shoushtari, SH Rottiers, V Kristo, F Li, YX Shioda, T Cohen, DE Gerszten, RE AF Naeaer, Anders M. Walker, Amy K. Yang, Fajun Najafi-Shoushtari, S. Hani Rottiers, Veerle Kristo, Fjoralba Li, Yingxia Shioda, Toshi Cohen, David E. Gerszten, Robert E. TI Conserved Gene Regulatory Mechanisms Controlling Cholesterol and Fat SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Naeaer, Anders M.; Walker, Amy K.; Yang, Fajun; Najafi-Shoushtari, S. Hani; Rottiers, Veerle; Shioda, Toshi] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Naeaer, Anders M.; Walker, Amy K.; Yang, Fajun; Najafi-Shoushtari, S. Hani; Rottiers, Veerle] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. [Kristo, Fjoralba; Gerszten, Robert E.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA USA. [Li, Yingxia; Cohen, David E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol, Boston, MA 02115 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708401739 ER PT J AU Nansel, TR Liu, AY Lipsky, LM Haynie, DL Mehta, SN Laffel, LMB AF Nansel, Tonja R. Liu, Aiyi Lipsky, Leah M. Haynie, Denise L. Mehta, Sanjeev N. Laffel, Lori M. B. TI Differences in diet quality between weekdays and weekends: utility of a random effects model SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Nansel, Tonja R.; Liu, Aiyi; Lipsky, Leah M.; Haynie, Denise L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Mehta, Sanjeev N.; Laffel, Lori M. B.] Joslin Diabet Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708403308 ER PT J AU Perez, KY Hyun-Park, J Tanwar, PS Teixeira, J AF Perez, Kayla Y. Hyun-Park, Joo Tanwar, Pradeep S. Teixeira, Jose TI The Expression of Pluripotent Genes in Normal Human Endometrium SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Perez, Kayla Y.] Interamer Univ Puerto Rico San German, Mayaguez, PR USA. [Hyun-Park, Joo; Tanwar, Pradeep S.; Teixeira, Jose] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708402864 ER PT J AU Ruan, YC Da Silva, N Belleannee, C Shum, WWC Breton, S AF Ruan, Ye Chun Da Silva, Nicolas Belleannee, Clemence Shum, Winnie W. C. Breton, Sylvie TI Involvement of CFTR in ATP and HCO3-secretion in epididymal principal cells SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 Massachusetts Gen Hosp, Div Nephrol, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708400501 ER PT J AU Sas, KM Amria, MY Bell, PD AF Sas, Kelli Margot Amria, May Y. Bell, P. Darwin TI Diabetes accelerates cystogenesis in the adult conditional ift88 knockout mouse SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Sas, Kelli Margot; Amria, May Y.; Bell, P. Darwin] Med Univ S Carolina, Charleston, SC 29425 USA. [Bell, P. Darwin] Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708404141 ER PT J AU Segal, RA AF Segal, Rosalind A. TI Retrograde Response Genes and Neuronal Survival SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Segal, Rosalind A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708401768 ER PT J AU Sengupta, A Molkentin, JD Paik, JH DePinho, RA Yutzey, KE AF Sengupta, Arunima Molkentin, Jeffery D. Paik, Ji-Hye DePinho, Ronald A. Yutzey, Katherine E. TI FOXO transcription factors promote cardiomyocyte survival upon induction of oxidative stress SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Sengupta, Arunima; Molkentin, Jeffery D.; Yutzey, Katherine E.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Paik, Ji-Hye; DePinho, Ronald A.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708404380 ER PT J AU Song, JW Munn, LL AF Song, Jonathan W. Munn, Lance L. TI Biomechanical Determinants of Endothelial Cell Sprouting in a Microfluidic Device SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 Massachusetts Gen Hosp, EL Steele Lab Tumor Biol Radiat Oncol, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. RI Munn, Lance/L-3950-2016; Song, Jonathan/C-1922-2013 OI Munn, Lance/0000-0003-0698-7232; Song, Jonathan/0000-0002-6991-5298 NR 0 TC 0 Z9 0 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708401218 ER PT J AU Soto-Pina, AE Kadapakkam, S Mehring, C Hinojosa-Laborde, C Strong, R AF Soto-Pina, Alexandra Estela Kadapakkam, Sheela Mehring, Cinthya Hinojosa-Laborde, Carmen Strong, Randy TI Inhibition of tyrosine hydroxylase reduces dexamethasone-induced hypertension SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Soto-Pina, Alexandra Estela; Kadapakkam, Sheela; Mehring, Cinthya; Hinojosa-Laborde, Carmen; Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Soto-Pina, Alexandra Estela; Kadapakkam, Sheela; Strong, Randy] S Texas Vet Hlth Care Syst, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708405701 ER PT J AU Soydan, G Waeber, C AF Soydan, Guray Waeber, Christian TI Sphingosine-1-phosphate-induced vasoconstriction is increased in basilar but not in peripheral arteries in type 2 diabetic mice SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Soydan, Guray; Waeber, Christian] Massachusetts Gen Hosp, Charlestown, MA USA. [Soydan, Guray] Hacettepe Univ, Sch Med, Ankara, Turkey. RI Waeber, Christian/A-8333-2009 OI Waeber, Christian/0000-0001-6078-0027 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708405414 ER PT J AU Soydan, G Waeber, C AF Soydan, Guray Waeber, Christian TI Sphingosine-1-phosphate mediate vasoconstriction in femoral and mesenteric arteries of mice via S1P3 receptors SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Soydan, Guray; Waeber, Christian] Massachusetts Gen Hosp, Charlestown, MA USA. [Soydan, Guray] Hacettepe Univ, Sch Med, Ankara, Turkey. RI Waeber, Christian/A-8333-2009 OI Waeber, Christian/0000-0001-6078-0027 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708400221 ER PT J AU Soydan, G Ferrari, MD van den Maagdenberg, AMJM Ayata, C AF Soydan, Guray Ferrari, Michel D. van den Maagdenberg, Arn M. J. M. Ayata, Cenk TI Functional changes of vascular responses in familial hemiplegic migraine type 1 SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Soydan, Guray; Ayata, Cenk] Massachusetts Gen Hosp, Charlestown, MA USA. [Soydan, Guray] Hacettepe Univ, Ankara, Turkey. [Ferrari, Michel D.; van den Maagdenberg, Arn M. J. M.] Leiden Univ, Med Ctr, Leiden, Netherlands. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708400213 ER PT J AU Soydan, G Xu, J Sims, JR AF Soydan, Guray Xu, Jian Sims, John Randall TI Dantrolene and nimodipine inhibits vasoconstriction of basilar artery in a rat subarachnoid hemorrhage model SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Soydan, Guray; Xu, Jian; Sims, John Randall] Massachusetts Gen Hosp, Charlestown, MA USA. [Soydan, Guray] Hacettepe Univ, Sch Med, Ankara, Turkey. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708400211 ER PT J AU Soydan, G Xu, J Sims, JR Waeber, C AF Soydan, Guray Xu, Jian Sims, John Randall Waeber, Christian TI S1P-induced vasoconstriction increased in basilar artery of a subarachnoid hemorrhage model in rats SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Soydan, Guray; Xu, Jian; Sims, John Randall; Waeber, Christian] Massachusetts Gen Hosp, Charlestown, MA USA. [Soydan, Guray] Hacettepe Univ, Sch Med, Ankara, Turkey. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708400212 ER PT J AU Spassieva, SD Rahmaniyan, M Bielawski, J Kraveka, JM Obeid, LM AF Spassieva, Stefka D. Rahmaniyan, Mehrdad Bielawski, Jacek Kraveka, Jacqueline M. Obeid, Lina M. TI Cell Density Dependent Inhibition of Dihydroceramide Desaturase SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Spassieva, Stefka D.; Rahmaniyan, Mehrdad; Bielawski, Jacek; Kraveka, Jacqueline M.; Obeid, Lina M.] Med Univ S Carolina, Charleston, SC 29425 USA. [Obeid, Lina M.] Ralph H Johnson Vet Affairs Hosp, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708404667 ER PT J AU Trager, RE Wills, L Lindsey, C Beeson, G Beeson, C Schnellmann, R Peterson, Y AF Trager, Richard Edwin Wills, Lauren Lindsey, Christopher Beeson, Gyda Beeson, Craig Schnellmann, Rick Peterson, Yuri TI High throughput identification of mitochondrial toxicophores SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Trager, Richard Edwin; Wills, Lauren; Lindsey, Christopher; Beeson, Gyda; Beeson, Craig; Schnellmann, Rick; Peterson, Yuri] Med Univ S Carolina, Charleston, SC 29425 USA. [Schnellmann, Rick] Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708403539 ER PT J AU Wang, HZ Porter, L Sarwar, ZU Wells, JT McManus, LM Shireman, PK AF Wang, Hanzhou Porter, Laurel Sarwar, Zaheer U. Wells, Jason T. McManus, Linda M. Shireman, Paula K. TI Macrophage Ablation in CD11b-diphtheria Toxin Receptor (DTR) Transgenic Mice Impairs Skeletal Muscle Regeneration SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Wang, Hanzhou; Porter, Laurel; Sarwar, Zaheer U.; Wells, Jason T.; McManus, Linda M.; Shireman, Paula K.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Shireman, Paula K.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708403413 ER PT J AU Wang, W Zhu, JQ Springer, TA Luo, BH AF Wang, Wei Zhu, Jieqing Springer, Timothy A. Luo, Binghao TI TESTS OF INTEGRIN TRANSMEMBRANE DOMAIN HOMO-OLIGOMERIZATION DURING INTEGRIN LIGAND BINDING AND SIGNALING SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Wang, Wei; Luo, Binghao] Louisiana State Univ, Baton Rouge, LA 70803 USA. [Zhu, Jieqing; Springer, Timothy A.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. [Zhu, Jieqing; Springer, Timothy A.] Childrens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708406731 ER PT J AU Wick, MJ Loomis, ZL Buesing, EJ Wehling, CA Cool, CD Hersh, LB Voelkel, NF Dempsey, EC AF Wick, Marilee J. Loomis, Zoe L. Buesing, Erica J. Wehling, Carol A. Cool, Carlyne D. Hersh, Louis B. Voelkel, Norbert F. Dempsey, Edward C. TI Decreased lung neprilysin gene expression in humans with COPD and pulmonary vascular remodeling SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Wick, Marilee J.; Loomis, Zoe L.; Buesing, Erica J.; Cool, Carlyne D.; Voelkel, Norbert F.; Dempsey, Edward C.] Univ Colorado Denver, CVP Res Lab, Aurora, CO USA. [Wick, Marilee J.; Loomis, Zoe L.; Buesing, Erica J.; Cool, Carlyne D.; Voelkel, Norbert F.; Dempsey, Edward C.] Univ Colorado Denver, Div Pulm, Aurora, CO USA. [Wick, Marilee J.; Loomis, Zoe L.; Wehling, Carol A.; Dempsey, Edward C.] Denver VAMC, Denver, CO USA. [Hersh, Louis B.] Univ Kentucky, Lexington, KY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708400449 ER PT J AU Zhong, Z Liu, QL Rehman, H He, SQ Shi, YJ Krishnasamy, Y Schnellmann, RG AF Zhong, Zhi Liu, Qinlong Rehman, Hasibur He, Songqing Shi, Yanjun Krishnasamy, Yasodha Schnellmann, Rick G. TI Supplementation of amphiregulin improves fatty liver regeneration after partial hepatectomy (PHX): the role of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases (ERK) SO FASEB JOURNAL LA English DT Meeting Abstract CT Experimental Biology Meeting 2011 CY APR 09-13, 2011 CL Washington, DC SP Amer Assoc Anatomists (AAA), Amer Physiolog Soc (APS), Amer Soc Biochem & Mol Biol (ASBMB), Amer Soc Investigat Pathol (ASIP), Amer Soc Nutrit (ASN), Amer Soc Pharmacol & Expt Therapeut (ASPET) C1 [Schnellmann, Rick G.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Zhong, Zhi; Liu, Qinlong; Rehman, Hasibur; He, Songqing; Shi, Yanjun; Krishnasamy, Yasodha; Schnellmann, Rick G.] Med Univ S Carolina, Charleston, SC 29425 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2011 VL 25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 032IE UT WOS:000310708407181 ER PT J AU Cacoub, PP Zeymer, U Limbourg, T Baumgartner, I Poldermans, D Rother, J Bhatt, DL Steg, PG AF Cacoub, Patrice P. Zeymer, Uwe Limbourg, Tobias Baumgartner, Iris Poldermans, Don Roether, Joachim Bhatt, Deepak L. Steg, Philippe Gabriel CA REACH Registry Investigators TI Effects of adherence to guidelines for the control of major cardiovascular risk factors on outcomes in the REduction of Atherothrombosis for Continued Health (REACH) Registry Europe SO HEART LA English DT Article ID PERIPHERAL-ARTERIAL-DISEASE; ASSOCIATION/AMERICAN-STROKE-ASSOCIATION; TRANSIENT ISCHEMIC ATTACK; CARE PROFESSIONALS; VASCULAR-DISEASE; EVENT RATES; CORONARY; STATEMENT; CHOLESTEROL; OUTPATIENTS AB Objectives To examine the impact of cardiovascular risk factor control on 3-year cardiovascular event rates in patients with stable symptomatic atherothrombotic disease in Europe. Methods The REduction of Atherothrombosis for Continued Health (REACH) Registry recruited patients aged >= 45 years with established atherothrombotic disease or three or more risk factors, of whom 20 588 symptomatic patients from 18 European countries were analysed in this study at baseline and 12, 24 and 36 months. 'Good control' of cardiovascular risk factors was defined as three to five risk factors at target values of international guideline recommendations (systolic blood pressure < 140 mm Hg, diastolic blood pressure < 90 mm Hg, fasting glycaemia < 110 mg/dl, total cholesterol < 200 mg/dl, non-smoking). Independent predictors of 'good control' of major risk factors were assessed by multivariate analysis. Results Among symptomatic patients in the REACH Registry Europe (mean age 67 years, 70.6% male), 59.4% had good control of risk factors at baseline. Good risk factor control was associated with lower cardiovascular death/non-fatal stroke/non-fatal myocardial infarction (OR 0.76; 95% CI 0.69 to 0.83) and mortality (OR 0.89; 95% CI 0.79 to 0.99) at 36 months, compared with poor control. Independent predictors of good control of risk factors included residence in western versus eastern Europe (OR 1.29), high level of education (OR 1.16), established coronary artery disease (OR 1.18), treatment with one or more antithrombotic (OR 1.59) and one or more lipid-lowering agent (OR 1.16). Conclusions In REACH, less than 60% of patients with stable atherothrombotic disease had good control of the five major cardiovascular risk factors. Improved risk factor control is associated with a positive impact on 3-year cardiovascular event rates and mortality. C1 [Cacoub, Patrice P.] Univ Paris 06, INSERM, U959, UMR Pierre & Marie Curie 7211, Paris, France. [Cacoub, Patrice P.] Hosp La Pitie Salpetriere, AP HP, Paris, France. [Zeymer, Uwe; Limbourg, Tobias] Heidelberg Univ, Inst Herzinfarktforsch Ludwigshafen, Ludwigshafen, Germany. [Baumgartner, Iris] Univ Hosp Bern, Inselspital, Div Clin & Intervent Angiol, Swiss Cardiovasc Ctr, CH-3010 Bern, Switzerland. [Poldermans, Don] Erasmus MC, Dept Vasc Surg, Rotterdam, Netherlands. [Roether, Joachim] Hannover Med Sch, Johannes Wesling Klinikum Minden, D-3000 Hannover, Germany. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Steg, Philippe Gabriel] Univ Paris 07, INSERM, U698, Paris, France. RP Cacoub, PP (reprint author), Grp Hosp La Pitie Salpetriere, AP HP, Serv Med Interne, 47-83 Blvd Hop, F-75013 Paris, France. EM patrice.cacoub@psl.aphp.fr OI ELISAF, MOSES/0000-0003-0505-078X FU Sanofi-Aventis (Paris, France); Bristol-Myers Squibb (Princeton, New Jersey, USA); Waksman Foundation (Tokyo, Japan); Sanofi-Aventis; Schering Plough; Servier and Roche; Bristol-Myers-Squibb; Lundbeck and Boehringer Ingelheim; Eisai; Ethicon; Heartscape; Medicines Company FX The REACH Registry is sponsored by Sanofi-Aventis (Paris, France), Bristol-Myers Squibb (Princeton, New Jersey, USA) and the Waksman Foundation (Tokyo, Japan). The sponsors provide logistical support. All manuscripts in the REACH Registry are led by independent authors who are not governed by the funding sponsors and are reviewed by an academic publication committee before submission. The funding sponsors have the opportunity to review manuscript submissions but do not have authority to change any aspect of a manuscript.; PPC has received research grants from Sanofi-Aventis, Schering Plough, Servier and Roche; honoraria from Sanofi-Aventis, Schering Plough, Servier, Roche, AstraZeneca and Bristol-Myers Squibb. UZ has received research grants and speaker honoraria from Bristol-Myers-Squibb and Sanofi Aventis. JR has received honoraria and consulting fees from Sanofi-Aventis, Bristol-Myers Squibb, Lundbeck and Boehringer Ingelheim. DLB has received research grants (to the institution) from: AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis and The Medicines Company; has served as a consultant (honoraria waived or donated for past three years) for Arena, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola, Sanofi-Aventis, Schering Plough, Scios, Takeda, The Medicines Company and Vertex. PGS has received a research grant from Sanofi-Aventis (1999 to 2008); is on the speaker's bureau for Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Menarini, Medtronic, Nycomed, Pierre Fabre, Sanofi-Aventis, Servier and The Medicines Company; is on the consulting/advisory boards for Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Endotis, GlaxoSmithKline, Medtronic, MSD, Nycomed, Sanofi-Aventis, Servier and The Medicines Company and is a stockholder for Aterovax. TL, IB and DP: No interests declared. NR 28 TC 34 Z9 37 U1 0 U2 4 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD APR PY 2011 VL 97 IS 8 BP 660 EP 667 DI 10.1136/hrt.2010.213710 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 737CA UT WOS:000288544700011 PM 21357372 ER PT J AU Oral, E Ghali, BW Muratoglu, OK AF Oral, Ebru Ghali, Bassem W. Muratoglu, Orhun K. TI The elimination of free radicals in irradiated UHMWPEs with and without vitamin E stabilization by annealing under pressure SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS LA English DT Article DE arthroplasty; bearing surfaces; crystallinity; polyethylene (UHMWPE); radiation ID MOLECULAR-WEIGHT POLYETHYLENE; TOTAL HIP-ARTHROPLASTY; ELECTRON-BEAM RADIATION; ALPHA-TOCOPHEROL; MECHANICAL-PROPERTIES; CROSS-LINKING; ACETABULAR COMPONENTS; ORTHOPEDIC UHMWPE; PHASE-TRANSITION; MEDICAL IMPLANTS AB Radiation crosslinking of ultrahigh molecular weight polyethylene (UHMWPE) has been used to decrease the wear of joint implant bearing surfaces. While radiation crosslinking has been successful in decreasing femoral head penetration into UHMWPE acetabular liners in vivo, postirradiation thermal treatment of the polymer is required to ensure the oxidative stability of joint implants in the long term. Two types of thermal treatment have been used: (i) annealing below the melting point preserves the mechanical properties but the residual free radicals trapped in the crystalline regions are not completely eliminated, leading to oxidation in the long-term and (ii) annealing above the melting point (melting) eliminates the free radicals but leads to a decrease in mechanical properties through loss of crystallinity during the melting process. In this study, we hypothe-sized that free radicals could be reduced by annealing below the melting point under pressure effectively without melting due to the elevation of the melting point. By avoiding the complete melting of UHMWPE, mechanical properties would be preserved. Our hypothesis tested positive in that we found the radiation-induced free radicals to be markedly reduced (below the detection limit of state-of-the-art electron spin resonance) by thermal annealing under pressure in radiation crosslinked virgin UHMWPE and UHMWPE/vitamin-E blends without loss of mechanical properties. (C) 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 97B: 167-174, 2011. C1 [Oral, Ebru; Ghali, Bassem W.; Muratoglu, Orhun K.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Oral, Ebru; Muratoglu, Orhun K.] Harvard Univ, Sch Med, Boston, MA USA. RP Muratoglu, OK (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. EM omuratoglu@partners.org FU NIH [AR051142]; Zimmer, Inc. FX Contract grant sponsor: NIH; contract grant number: AR051142; Contract grant sponsor: Zimmer, Inc. and laboratory funds NR 51 TC 10 Z9 12 U1 2 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4973 EI 1552-4981 J9 J BIOMED MATER RES B JI J. Biomed. Mater. Res. Part B PD APR PY 2011 VL 97B IS 1 BP 167 EP 174 DI 10.1002/jbm.b.31799 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 735KT UT WOS:000288413900019 PM 21381192 ER PT J AU Guyatt, GH Oxman, AD Kunz, R Atkins, D Brozek, J Vist, G Alderson, P Glasziou, P Falck-Ytter, Y Schunemann, HJ AF Guyatt, Gordon H. Oxman, Andrew D. Kunz, Regina Atkins, David Brozek, Jan Vist, Gunn Alderson, Philip Glasziou, Paul Falck-Ytter, Yngve Schuenemann, Holger J. TI GRADE guidelines: 2. Framing the question and deciding on important outcomes SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE GRADE; PICO; Patient-important outcomes; Surrogate; Guideline development; Quality of evidence; Indirectness ID PATIENT-IMPORTANT OUTCOMES; ATRIAL-FIBRILLATION; CONTROLLED-TRIALS; CLINICAL-TRIALS; METAANALYSIS; THERAPY AB GRADE requires a clear specification of the relevant setting, population, intervention, and comparator. It also requires specification of all important outcomes whether evidence from research studies is, or is not, available. For a particular management question, the population, intervention, and outcome should be sufficiently similar across studies that a similar magnitude of effect is plausible. Guideline developers should specify the relative importance of the outcomes before gathering the evidence and again when evidence summaries are complete. In considering the importance of a surrogate outcome, authors should rate the importance of the patient-important outcome for which the surrogate is a substitute and subsequently rate down the quality of evidence for indirectness of outcome. (C) 2011 Elsevier Inc. All rights reserved. C1 [Guyatt, Gordon H.; Brozek, Jan; Schuenemann, Holger J.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. [Oxman, Andrew D.; Vist, Gunn] Norwegian Knowledge Ctr Hlth Serv, Oslo, Norway. [Kunz, Regina] Univ Basel Hosp, Acad Swiss Insurance Med, CH-4031 Basel, Switzerland. [Atkins, David] US Dept Vet Affairs, Off Res & Dev, Washington, DC USA. [Alderson, Philip] Natl Inst Hlth & Clin Excellence, Ctr Clin Practice, Manchester, Lancs, England. [Glasziou, Paul] Bond Univ, Gold Coast, Qld, Australia. [Falck-Ytter, Yngve] Case Western Reserve Univ, Div Gastroenterol, Case & VA Med Ctr, Cleveland, OH 44106 USA. RP Guyatt, GH (reprint author), McMaster Univ, Dept Clin Epidemiol & Biostat, CLARITY Res Grp, Room 2C12,1200 Main St, W Hamilton, ON L8N 3Z5, Canada. EM guyatt@mcmaster.ca RI Glasziou, Paul/A-7832-2008 OI Glasziou, Paul/0000-0001-7564-073X NR 16 TC 298 Z9 311 U1 1 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-4356 EI 1878-5921 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD APR PY 2011 VL 64 IS 4 BP 395 EP 400 DI 10.1016/j.jclinepi.2010.09.012 PG 6 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 734UF UT WOS:000288364300008 PM 21194891 ER PT J AU Balshem, H Helfand, M Schunemann, HJ Oxman, AD Kunz, R Brozek, J Vist, GE Falck-Ytter, Y Meerpohl, J Norris, S Guyatt, GH AF Balshem, Howard Helfand, Mark Schuenemann, Holger J. Oxman, Andrew D. Kunz, Regina Brozek, Jan Vist, Gunn E. Falck-Ytter, Yngve Meerpohl, Joerg Norris, Susan Guyatt, Gordon H. TI GRADE guidelines: 3. Rating the quality of evidence SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE Quality assessment; Body of evidence; Imprecision; Indirectness; Inconsistency; Publication bias ID REYES-SYNDROME; VENOUS THROMBOEMBOLISM; 1ST EPISODE; RISK-FACTOR; ANTICOAGULATION AB This article introduces the approach of GRADE to rating quality of evidence. GRADE specifies four categories high, moderate, low, and very low that are applied to a body of evidence, not to individual studies. In the context of a systematic review, quality reflects our confidence that the estimates of the effect are correct. In the context of recommendations, quality reflects our confidence that the effect estimates are adequate to support a particular recommendation. Randomized trials begin as high-quality evidence, observational studies as low quality. "Quality" as used in GRADE means more than risk of bias and so may also be compromised by imprecision, inconsistency, indirectness of study results, and publication bias. In addition, several factors can increase our confidence in an estimate of effect. GRADE provides a systematic approach for considering and reporting each of these factors. GRADE separates the process of assessing quality of evidence from the process of making recommendations. Judgments about the strength of a recommendation depend on more than just the quality of evidence. (C) 2011 Elsevier Inc. All rights reserved. C1 [Balshem, Howard] Oregon Hlth & Sci Univ, BICC, Oregon Evidence Based Practice Ctr, Portland, OR 97239 USA. [Helfand, Mark] Portland VA Med Ctr, Portland, OR USA. [Schuenemann, Holger J.; Brozek, Jan; Guyatt, Gordon H.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON L8N 3Z5, Canada. [Oxman, Andrew D.; Vist, Gunn E.] Norwegian Knowledge Ctr Hlth Serv, N-0130 Oslo, Norway. [Kunz, Regina] Univ Basel Hosp, Basel Inst Clin Epidemiol, CH-4031 Basel, Switzerland. [Falck-Ytter, Yngve] Case Western Reserve Univ, Div Gastroenterol, Case Med Ctr & VA, Cleveland, OH 44106 USA. [Meerpohl, Joerg] Univ Med Ctr Freiburg, German Cochrane Ctr, Inst Med Biometry & Med Informat, D-79104 Freiburg, Germany. [Meerpohl, Joerg] Univ Med Ctr Freiburg, Div Pediat Hematol & Oncol, Dept Pediat & Adolescent Med, D-79106 Freiburg, Germany. [Norris, Susan] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97239 USA. RP Balshem, H (reprint author), Oregon Hlth & Sci Univ, BICC, Oregon Evidence Based Practice Ctr, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM balshemh@ohsu.edu RI Meerpohl, Joerg/J-4224-2013 OI Meerpohl, Joerg/0000-0002-1333-5403 NR 13 TC 963 Z9 991 U1 9 U2 48 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD APR PY 2011 VL 64 IS 4 BP 401 EP 406 DI 10.1016/j.jclinepi.2010.07.015 PG 6 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 734UF UT WOS:000288364300009 PM 21208779 ER PT J AU Guyatt, GH Oxman, AD Vist, G Kunz, R Brozek, J Alonso-Coello, P Montori, V Akl, EA Djulbegovic, D Falck-Ytter, Y Norris, SL Williams, JW Atkins, D Meerpohl, J Schunemann, HJ AF Guyatt, Gordon H. Oxman, Andrew D. Vist, Gunn Kunz, Regina Brozek, Jan Alonso-Coello, Pablo Montori, Victor Akl, Elie A. Djulbegovic, Ben Falck-Ytter, Yngve Norris, Susan L. Williams, John W., Jr. Atkins, David Meerpohl, Joerg Schuenemann, Holger J. TI GRADE guidelines: 4. Rating the quality of evidence-study limitations (risk of bias) SO JOURNAL OF CLINICAL EPIDEMIOLOGY LA English DT Article DE GRADE; quality of evidence; risk of bias; confidence in estimates; blinding; concealment ID RANDOMIZED CONTROLLED-TRIALS; OUTCOME REPORTING BIAS; SPINAL-CORD-INJURY; EMPIRICAL-EVIDENCE; VENOUS THROMBOEMBOLISM; CLINICAL-TRIALS; HEART-FAILURE; METAANALYSIS; THERAPY; BENEFIT AB In the GRADE approach, randomized trials start as high-quality evidence and observational studies as low-quality evidence, but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias. Well-established limitations of randomized trials include failure to conceal allocation, failure to blind, loss to follow-up, and failure to appropriately consider the intention-to-treat principle. More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results. Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance. Risk of bias may vary across outcomes (e.g., loss to follow-up may be far less for all-cause mortality than for quality of life), a consideration that many systematic reviews ignore. In deciding whether to rate down for risk of bias whether for randomized trials or observational studies-authors should not take an approach that averages across studies. Rather, for any individual outcome, when there are some studies with a high risk, and some with a low risk of bias, they should consider including only the studies with a lower risk of bias. (C) 2011 Elsevier Inc. All rights reserved. C1 [Guyatt, Gordon H.; Brozek, Jan; Schuenemann, Holger J.] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON L8N 3Z5, Canada. [Oxman, Andrew D.; Vist, Gunn] Norwegian Knowledge Ctr Hlth Serv, N-0130 Oslo, Norway. [Kunz, Regina] Univ Basel Hosp, Acad Swiss Insurance Med, CH-4031 Basel, Switzerland. [Kunz, Regina] Univ Basel Hosp, Basel Inst Clin Epidemiol & Biostat, CH-4031 Basel, Switzerland. [Alonso-Coello, Pablo] Univ Autonoma Barcelona, Iberoamer Cochrane Ctr, Serv Epidemiol Clin & Salud Publ, Hosp St Pau, Barcelona 08041, Spain. [Alonso-Coello, Pablo] Univ Autonoma Barcelona, CIBERESP, Hosp St Pau, Barcelona 08041, Spain. [Montori, Victor] Mayo Clin, Knowledge & Encounter Res Unit, Rochester, MN USA. [Akl, Elie A.] SUNY Buffalo, Dept Med, Buffalo, NY 14260 USA. [Djulbegovic, Ben] Univ S Florida, Ctr Evidence Based Med & Hlth Outcomes Res, Tampa, FL 33612 USA. [Djulbegovic, Ben] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Hematol, Tampa, FL 33612 USA. [Djulbegovic, Ben] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Hlth Outcomes & Behav, Tampa, FL 33612 USA. [Falck-Ytter, Yngve] Case Western Reserve Univ, Div Gastroenterol, Case & VA Med Ctr, Cleveland, OH 44106 USA. [Norris, Susan L.] Oregon Hlth & Sci Univ, Dept Med Informat & Clin Epidemiol, Portland, OR 97239 USA. [Williams, John W., Jr.] Duke Univ, Med Ctr, Durham, NC 27705 USA. [Williams, John W., Jr.] Durham Vet Affairs Ctr Hlth Serv Res Primary Care, Durham, NC 27705 USA. [Atkins, David] US Dept Vet Affairs, QUERI Program, Off Res & Dev, Washington, DC USA. [Meerpohl, Joerg] Univ Med Ctr Freiburg, German Cochrane Ctr, Inst Med Biometry & Med Informat, D-79104 Freiburg, Germany. [Meerpohl, Joerg] Univ Med Ctr Freiburg, Div Pediat Hematol & Oncol, Dept Pediat & Adolescent Med, D-79106 Freiburg, Germany. RP Guyatt, GH (reprint author), McMaster Univ, Dept Clin Epidemiol & Biostat, CLARITY Res Grp, Room 2C12,1200 Main St, W Hamilton, ON L8N 3Z5, Canada. EM guyatt@mcmaster.ea RI Djulbegovic, Benjamin/I-3661-2012; Meerpohl, Joerg/J-4224-2013; OI Djulbegovic, Benjamin/0000-0003-0671-1447; Meerpohl, Joerg/0000-0002-1333-5403; Montori, Victor/0000-0003-0595-2898 NR 37 TC 501 Z9 514 U1 6 U2 27 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-4356 J9 J CLIN EPIDEMIOL JI J. Clin. Epidemiol. PD APR PY 2011 VL 64 IS 4 BP 407 EP 415 DI 10.1016/j.jclinepi.2010.07.017 PG 9 WC Health Care Sciences & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 734UF UT WOS:000288364300010 PM 21247734 ER PT J AU Dalrymple, LS Katz, R Kestenbaum, B Shlipak, MG Sarnak, MJ Stehman-Breen, C Seliger, S Siscovick, D Newman, AB Fried, L AF Dalrymple, Lorien S. Katz, Ronit Kestenbaum, Bryan Shlipak, Michael G. Sarnak, Mark J. Stehman-Breen, Catherine Seliger, Stephen Siscovick, David Newman, Anne B. Fried, Linda TI Chronic Kidney Disease and the Risk of End-Stage Renal Disease versus Death SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE renal disease; cardiovascular disease; clinical epidemiology ID CARDIOVASCULAR HEALTH; COMPETING RISK; UNITED-STATES; OLDER-ADULTS; MORTALITY; OUTCOMES; EVENTS; POPULATION AB Among older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown. To compare the rates of ESRD, cardiovascular and non-cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants. The CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older. 1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m(2) were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003. The outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol. During 9.7 years of follow-up, 5% of the cohort progressed to ESRD, and 61% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non-cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD. Older adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD. C1 [Dalrymple, Lorien S.] Univ Calif Davis, Dept Med, Sacramento, CA 95817 USA. [Katz, Ronit] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Kestenbaum, Bryan] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Shlipak, Michael G.] Vet Affairs Med Ctr, Med Serv, Gen Internal Med Sect, San Francisco, CA 94121 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Sarnak, Mark J.] Tufts Med Ctr, Dept Med, Boston, MA USA. [Stehman-Breen, Catherine] Amgen Inc, Thousand Oaks, CA 91320 USA. [Seliger, Stephen] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Siscovick, David] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Newman, Anne B.; Fried, Linda] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Newman, Anne B.; Fried, Linda] Univ Pittsburgh, Sch Med, Dept Epidemiol, Pittsburgh, PA USA. [Fried, Linda] VA Pittsburgh Hlth Care Syst, Renal Sect, Pittsburgh, PA USA. RP Dalrymple, LS (reprint author), Univ Calif Davis, Dept Med, 4150V St,3500 PSSB, Sacramento, CA 95817 USA. EM lorien.dalrymple@ucdmc.ucdavis.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU Amgen Inc.; Tap Pharmaceuticals; Merck FX Drs. Dalrymple, Katz, Shlipak, Seliger, Siscovick, and Newman report no conflicts of interest. Dr. Kestenbaum has received honoraria from Shire, Abbott, and Genzyme Inc., and has received grant funding from Amgen Inc. Dr. Sarnak has received funding from Tap Pharmaceuticals. Dr. Stehman-Breen is an employee of Amgen. Dr. Fried has provided expert testimony for Bayer and received a grant from Merck. NR 25 TC 61 Z9 65 U1 0 U2 6 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 APR PY 2011 VL 26 IS 4 BP 379 EP 385 DI 10.1007/s11606-010-1511-x PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 733KD UT WOS:000288260700007 PM 20853156 ER PT J AU Walz, SE Smith, M Cox, E Sattin, J Kind, AJH AF Walz, Stacy E. Smith, Maureen Cox, Elizabeth Sattin, Justin Kind, Amy J. H. TI Pending Laboratory Tests and the Hospital Discharge Summary in Patients Discharged To Sub-Acute Care SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE laboratory tests; hospital discharge; sub-acute care ID MEDICAL REHABILITATION REPORT; UNIFORM DATA SYSTEM; BLOOD CULTURES; TIME; COMMUNICATION; PREVALENCE; BACTEREMIA; PHYSICIANS; ATTITUDES; PROGRAMS AB Previous studies have noted a high (41%) prevalence and poor discharge summary communication of pending laboratory (lab) tests at the time of hospital discharge for general medical patients. However, the prevalence and communication of pending labs within a high-risk population, specifically those patients discharged to sub-acute care (i.e., skilled nursing, rehabilitation, long-term care), remains unknown. To determine the prevalence and nature of lab tests pending at hospital discharge and their inclusion within hospital discharge summaries, for common sub-acute care populations. Retrospective cohort study. Stroke, hip fracture, and cancer patients discharged from a single large academic medical center to sub-acute care, 2003-2005 (N = 564) Pending lab tests were abstracted from the laboratory information system (LIS) and from each patient's discharge summary, then grouped into 14 categories and compared. Microbiology tests were sub-divided by culture type and number of days pending prior to discharge. Of sub-acute care patients, 32% (181/564) were discharged with pending lab tests per the LIS; however, only 11% (20/181) of discharge summaries documented these. Patients most often left the hospital with pending microbiology tests (83% [150/181]), particularly blood and urine cultures, and reference lab tests (17% [30/181]). However, 82% (61/74) of patients' pending urine cultures did not have 24-hour preliminary results, and 19% (13/70) of patients' pending blood cultures did not have 48-hour preliminary results available at the time of hospital discharge. Approximately one-third of the sub-acute care patients in this study had labs pending at discharge, but few were documented within hospital discharge summaries. Even after considering the availability of preliminary microbiology results, these omissions remain common. Future studies should focus on improving the communication of pending lab tests at discharge and evaluating the impact that this improved communication has on patient outcomes. C1 [Walz, Stacy E.; Smith, Maureen; Kind, Amy J. H.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI 53706 USA. [Smith, Maureen] Univ Wisconsin, Sch Med & Publ Hlth, Dept Family Med, Madison, WI USA. [Smith, Maureen] Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Madison, WI USA. [Cox, Elizabeth] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pediat, Madison, WI USA. [Sattin, Justin] Univ Wisconsin, Sch Med & Publ Hlth, Dept Neurol, Madison, WI USA. [Kind, Amy J. H.] Univ Wisconsin, Sch Med & Publ Hlth, Div Geriatr, Dept Med, Madison, WI USA. [Kind, Amy J. H.] William S Middleton Mem Vet Adm Med Ctr, GRECC, US Dept Vet Affairs, Madison, WI USA. RP Walz, SE (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Populat Hlth Sci, Madison, WI 53706 USA. EM sewalz@wisc.edu FU University of Wisconsin (UW) Hartford Center of Excellence in Geriatrics; UW; NIH [1KL2RR025012-01]; National Center for Research Resources, National Institute of Health [1UL1RR025011]; University of Wisconsin Institute for Clinical and Translational Research (UW ICTR); National Center for Research Resources, National Institutes of Health [1UL1RR025011]; National Institute on Aging [K23AG034551] FX Funding for this project was provided by the University of Wisconsin (UW) Hartford Center of Excellence in Geriatrics and the UW Health Innovation Program. Dr. Kind is supported by a K-L2 through the NIH grant 1KL2RR025012-01 [Institutional Clinical and Translational Science Award (UW-Madison) 1UL1RR025011 (KL2) program of the National Center for Research Resources, National Institute of Health]. Additional support was provided by the Health Innovation Program and the Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research (UW ICTR), grant 1UL1RR025011 from the Clinical and Translational Science Award (CTSA) program of the National Center for Research Resources, National Institutes of Health. The project described was supported by Award Number K23AG034551 from the National Institute on Aging. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health. NR 29 TC 14 Z9 14 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD APR PY 2011 VL 26 IS 4 BP 393 EP 398 DI 10.1007/s11606-010-1583-7 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 733KD UT WOS:000288260700009 PM 21116868 ER PT J AU Press, MJ Silber, JH Rosen, AK Romano, PS Itani, KMF Zhu, JS Wang, YL Even-Shoshan, O Halenar, MJ Volpp, KG AF Press, Matthew J. Silber, Jeffrey H. Rosen, Amy K. Romano, Patrick S. Itani, Kamal M. F. Zhu, Jingsan Wang, Yanli Even-Shoshan, Orit Halenar, Michael J. Volpp, Kevin G. TI The Impact of Resident Duty Hour Reform on Hospital Readmission Rates Among Medicare Beneficiaries SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE education; medical; graduate; hospital; readmission ID QUALITY-OF-CARE; ADMINISTRATIVE DATA; ACCREDITATION COUNCIL; COMORBIDITY MEASURES; PATIENT PREDICTORS; STATISTICAL-MODELS; REGULATIONS; INFORMATION; MORTALITY; TRANSITIONS AB A key goal of resident duty hour reform by the Accreditation Council for Graduate Medical Education (ACGME) in 2003 was to improve patient outcomes. To assess whether the reform led to a change in readmission rates. Observational study using multiple time series analysis with hospital discharge data from July 1, 2000 to June 30, 2005. Fixed effects logistic regression was used to examine the change in the odds of readmission in more versus less teaching-intensive hospitals before and after duty hour reform. All unique Medicare patients (n = 8,282,802) admitted to acute-care nonfederal hospitals with principal diagnoses of acute myocardial infarction, congestive heart failure, gastrointestinal bleeding, or stroke (combined medical group), or a DRG classification of general, orthopedic, or vascular surgery (combined surgical group). Primary outcome was 30-day all-cause readmission. Secondary outcomes were (1) readmission or death within 30 days of discharge, and (2) readmission, death during the index admission, or death within 30 days of discharge. For the combined medical group, there was no evidence of a change in readmission rates in more versus less teaching-intensive hospitals [OR = 0.99 (95% CI 0.94, 1.03) in post-reform year 1 and OR = 0.99 (95% CI 0.95, 1.04) in post-reform year 2]. There was also no evidence of relative changes in readmission rates for the combined surgical group: OR = 1.03 (95% CI 0.98, 1.08) for post-reform year 1 and OR = 1.02 (95% CI 0.98, 1.07) for post-reform year 2. Findings for the secondary outcomes combining readmission and death were similar. Among Medicare beneficiaries, there were no changes in hospital readmission rates associated with resident duty hour reform. C1 [Press, Matthew J.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY 10065 USA. [Press, Matthew J.] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA. [Halenar, Michael J.; Volpp, Kevin G.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Silber, Jeffrey H.; Zhu, Jingsan; Halenar, Michael J.; Volpp, Kevin G.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Silber, Jeffrey H.; Even-Shoshan, Orit; Volpp, Kevin G.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Silber, Jeffrey H.; Volpp, Kevin G.] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. [Silber, Jeffrey H.; Wang, Yanli; Even-Shoshan, Orit] Childrens Hosp Philadelphia, Ctr Outcomes Res, Philadelphia, PA 19104 USA. [Rosen, Amy K.; Itani, Kamal M. F.] VA Boston Hlth Care Syst, Boston, MA USA. [Itani, Kamal M. F.] Boston Univ, Boston, MA 02215 USA. [Romano, Patrick S.] UC Davis Sch Med, Div Gen Med, Sacramento, CA USA. [Romano, Patrick S.] UC Davis Sch Med, Ctr Healthcare Policy & Res, Sacramento, CA USA. [Itani, Kamal M. F.] Harvard Univ, Sch Med, Boston, MA USA. [Rosen, Amy K.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Res, Boston, MA 02215 USA. RP Press, MJ (reprint author), Weill Cornell Med Coll, Dept Publ Hlth, 402 E 67th St, New York, NY 10065 USA. EM map9069@med.cornell.edu RI Romano, Patrick/N-4225-2014 OI Romano, Patrick/0000-0001-6749-3979 FU National Heart, Lung, and Blood Institute FX Dr. Press was in the Robert Wood Johnson Foundation Clinical Scholars Program at the University of Pennsylvania and the Philadelphia VA Medical Center at the time this work was conducted. Funding for this work was provided by a grant from the National Heart, Lung, and Blood Institute. We presented an earlier version of the manuscript as an oral presentation at the 2010 SGIM Annual Meeting in Minneapolis. NR 47 TC 15 Z9 15 U1 0 U2 3 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 APR PY 2011 VL 26 IS 4 BP 405 EP 411 DI 10.1007/s11606-010-1539-y PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 733KD UT WOS:000288260700011 PM 21057883 ER PT J AU Barnett, L Goenka, R Silver, J O'Neill, P Hunter, C Cancro, M Laufer, T AF Barnett, Lisa Goenka, Radhika Silver, Jonathan O'Neill, Patrick Hunter, Christopher Cancro, Michael Laufer, Terri TI T follicular helper cells require cognate B cell interactions for acquisition of full effector function SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Barnett, Lisa; Goenka, Radhika; O'Neill, Patrick; Cancro, Michael; Laufer, Terri] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Silver, Jonathan; Hunter, Christopher] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. [Laufer, Terri] Philadelphia VA Med Ctr, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 63.4 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751702037 ER PT J AU Basher, F Harrell, M Richard, E Nowling, T AF Basher, Fahmin Harrell, Maria Richard, Erin Nowling, Tamara TI Effects of Fli1 on T cell function in systemic lupus erythematosus SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Basher, Fahmin; Harrell, Maria; Richard, Erin; Nowling, Tamara] Med Univ S Carolina, Med Rheumatol, Charleston, SC 29425 USA. [Nowling, Tamara] Ralph H Johnson VA Med, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 44.44 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751700006 ER PT J AU Bodhankar, S Wang, CH Vandenbark, A Offner, H AF Bodhankar, Sheetal Wang, Chunhe Vandenbark, Arthur Offner, Haling TI Indispensable role of B cells in mediating protective effects of estrogen against EAE SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Bodhankar, Sheetal; Wang, Chunhe; Vandenbark, Arthur; Offner, Haling] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Bodhankar, Sheetal; Vandenbark, Arthur; Offner, Haling] Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 167.20 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751708025 ER PT J AU Bu, X DeKruyff, R Umetsu, D Freeman, G AF Bu, Xia DeKruyff, Rosemarie Umetsu, Dale Freeman, Gordon TI TIM-3-and TIM-4-mediated phagocytosis of apoptotic cells induces cytokine production in peritoneal macrophages SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Bu, Xia; Freeman, Gordon] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [DeKruyff, Rosemarie; Umetsu, Dale] Childrens Hosp Boston, Boston, MA USA. [Bu, Xia; DeKruyff, Rosemarie; Umetsu, Dale; Freeman, Gordon] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 100.55 PG 2 WC Immunology SC Immunology GA V44LY UT WOS:000209751703080 ER PT J AU De Costala, AM Walker, D Schuyler, C Young, R AF De Costala, Anna-Maria Walker, David Schuyler, Corinne Young, Rita TI Administration of a vaccine composed of dendritic cells pulsed with premalignant oral lesion lysate stimulates Th1 and Th17 immunity in mice bearing carcinogen-induced premalignant oral lesions SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [De Costala, Anna-Maria; Young, Rita] Med Univ South Carolina, Microbiol & Immunol, Charleston, SC USA. [De Costala, Anna-Maria; Walker, David; Schuyler, Corinne; Young, Rita] Ralph H Johnson VA Med Ctr, Med Res Serv, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 165.13 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751708014 ER PT J AU Dileepan, T Linehan, J Moon, J Pepper, M Jenkins, M Cleary, P AF Dileepan, Thamotharampillai Linehan, Jonathan Moon, James Pepper, Marion Jenkins, Marc Cleary, Patrick TI Epitope-specific CD4(+) T cell response to Group A Streptococcal infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Dileepan, Thamotharampillai; Linehan, Jonathan; Pepper, Marion; Jenkins, Marc; Cleary, Patrick] Univ Minnesota, Microbiol, Minneapolis, MN USA. [Moon, James] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 99.27 PG 2 WC Immunology SC Immunology GA V44LY UT WOS:000209751703001 ER PT J AU Dileepan, T Kim, H Moon, J Linehan, J Jenkins, M Cleary, P Skinner, P AF Dileepan, Thamotharampillai Kim, Hyeon Moon, James Linehan, Jonathan Jenkins, Marc Cleary, Patrick Skinner, Pamela TI In situ peptide-MHC-II tetramer staining of antigen-specific CD4(+) T cells in tissues SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Dileepan, Thamotharampillai; Kim, Hyeon; Linehan, Jonathan; Jenkins, Marc; Cleary, Patrick; Skinner, Pamela] Univ Minnesota, Microbiol, Minneapolis, MN USA. [Moon, James] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 65.37 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751702121 ER PT J AU Ding, YN Hsu, HC Wu, Q Yang, P Mountz, J AF Ding, Yanna Hsu, Hui-Chen Wu, Qi Yang, Pingar Mountz, John TI Sequential effects of IL-21 and IL-17 to regulate spleen CXCR5(+) follicular T helper cells in autoimmune BXD2 mice SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Ding, Yanna; Hsu, Hui-Chen; Wu, Qi; Yang, Pingar; Mountz, John] Univ Alabama Birmingham, Birmingham, AL USA. [Mountz, John] Birmingham VA Med Ctr, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 101.44 PG 2 WC Immunology SC Immunology GA V44LY UT WOS:000209751703111 ER PT J AU Farley, K Stolley, J Cooley, J Remold-O'Donnelll, E AF Farley, Kalamo Stolley, James Cooley, Jessica Remold-O'Donnelll, Eileen TI SerpinB1 functions in generating neutrophil extracellular traps SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Farley, Kalamo; Stolley, James; Cooley, Jessica; Remold-O'Donnelll, Eileen] Harvard Univ, Childrens Hosp, Sch Med, Immune Dis Inst Program Cellular & Mol Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 111.11 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751704176 ER PT J AU Jiang, XD Wagers, A Clark, R Liu, LZ Fuhlbrigge, R Kupper, T AF Jiang, Xiaodong Wagers, Amy Clark, Rachael Liu, Luzheng Fuhlbrigge, Robert Kupper, Thomas TI CD8 T cells are rapidly recruited to both immunized and unimmunized skin after vaccinica virus skin scarification persist long-term as nonmigratory resident memory T cells (Trm), and provide rapid, effective, and specific local immunity SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Jiang, Xiaodong; Clark, Rachael; Liu, Luzheng; Fuhlbrigge, Robert; Kupper, Thomas] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wagers, Amy] Harvard Univ, Dept Stem Cell & Regenerat Biol, Howard Hughes Med Inst, Harvard Stem Cell Inst,Joslin Diabet Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 102.25 PG 2 WC Immunology SC Immunology GA V44LY UT WOS:000209751703150 ER PT J AU Kalsy, A Bhuiyan, M Charles, R Arifuzzaman, M Clemens, JD Larocque, RC Harris, JB Calderwood, SB Czerkinsky, C Qadri, F Ryan, E AF Kalsy, Anuj Bhuiyan, Md Charles, Richelle Arifuzzaman, Mohammad Clemens, John D. Larocque, Regina C. Harris, Jason B. Calderwood, Stephen B. Czerkinsky, Cecil Qadri, Firdausi Ryan, Edward TI Induction of memory responses following transcutaneous immunization requires presence of immunoadjuvantative cholera holotoxin SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Bhuiyan, Md; Qadri, Firdausi] Int Ctr Diarrheal Dis Res, Dhaka, Bangladesh. [Kalsy, Anuj; Charles, Richelle; Arifuzzaman, Mohammad; Larocque, Regina C.; Harris, Jason B.; Calderwood, Stephen B.; Ryan, Edward] Harvard Univ, Massachusetts Gen Hosp, Med, Boston, MA USA. [Kalsy, Anuj; Charles, Richelle; Larocque, Regina C.; Harris, Jason B.; Calderwood, Stephen B.; Ryan, Edward] Harvard Univ, Sch Med, Boston, MA USA. [Calderwood, Stephen B.] Harvard Univ, Sch Med, Dept Microbiol & Med Genet, Boston, MA USA. [Ryan, Edward] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Clemens, John D.; Czerkinsky, Cecil] Int Vaccine Inst, Seoul, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 53.4 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751701044 ER PT J AU Li, H Wu, Q Yang, PA Cua, D Hsu, HC Mountz, J AF Li, Hao Wu, Qi Yang, PingAr Cua, Daniel Hsu, Hui-Chen Mountz, John TI IL-23 induces apoptosis of self-reactive thymocytes in thymic negative selection by an Rorc dependent mechanism SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Li, Hao] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Li, Hao; Wu, Qi; Yang, PingAr; Hsu, Hui-Chen; Mountz, John] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Cua, Daniel] Merck Res Labs, Palo Alto, CA USA. [Mountz, John] Birmingham VA Med Ctr, Birmingham, AL USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 64.19 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751702078 ER PT J AU Li, J Hsu, HC Yang, PA Wu, Q Li, H Mountz, J AF Li, Jun Hsu, Hui-Chen Yang, PingAr Wu, Qi Li, Hao Mountz, John TI Anti-DR5 antibody eliminates inflammatory macrophages rebalancing IL-23/Th17 axis and regulatory T cells in arthritis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Li, Jun; Hsu, Hui-Chen; Yang, PingAr; Wu, Qi; Li, Hao; Mountz, John] Univ Alabama Birmingham, Dept Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. [Mountz, John] Birmingham VA Med Ctr, Birmigham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 147.26 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751705167 ER PT J AU Lukacs-Kornek, V Malhotra, D Fletcher, A Pinner, S Tayalia, P Turley, S AF Lukacs-Kornek, Veronika Malhotra, Deepali Fletcher, Anne Pinner, Sophie Tayalia, Prakriti Turley, Shannon TI Regulated release of nitric oxide by fibroblastic reticular cells controls the frequency and pathogenicity of autoreactive T cells in a model of intestinal tolerance SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Lukacs-Kornek, Veronika; Malhotra, Deepali; Fletcher, Anne; Pinner, Sophie; Turley, Shannon] Dana Farber Canc Inst, Boston, MA 02115 USA. [Turley, Shannon] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Tayalia, Prakriti] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 44.37 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751700022 ER PT J AU Nowling, T Richard, EM Harrell, M Basher, F Zhang, J AF Nowling, Tamara Richard, Erin Morris Harrell, Maria Basher, Fahmin Zhang, John TI Specific effects of Fli1 levels on T cells in the MRL/Ipr lupus prone model SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Nowling, Tamara; Richard, Erin Morris; Harrell, Maria; Basher, Fahmin; Zhang, John] Med Univ S Carolina, Med Rheumatol, Charleston, SC 29425 USA. [Nowling, Tamara; Zhang, John] Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 44.30 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751700025 ER PT J AU Paintlia, A Paintlia, M Singh, A Singh, I AF Paintlia, Ajaib Paintlia, Manjeet Singh, Avtar Singh, Inderjit TI Lovastatin exhibits synergy with Vitamin D hormone to confer protection from experimental autoimmune encephalomylitis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Paintlia, Ajaib; Paintlia, Manjeet; Singh, Inderjit] Med Univ S Carolina, Charleston, SC 29425 USA. [Singh, Avtar] Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 148.5 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751705190 ER PT J AU Paintlia, M Paintlia, A Singh, A Singh, I AF Paintlia, Manjeet Paintlia, Ajaib Singh, Avtar Singh, Inderjit TI Interleukin-17 exacerbates tumor necrosis Factor-alpha induced apoptotic cell death of oligodendrocytes SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Paintlia, Manjeet; Paintlia, Ajaib; Singh, Inderjit] MUSC, Charleston, SC USA. [Singh, Avtar] Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 148.8 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751705192 ER PT J AU Penaloza-MacMaster, P Araki, K Kamphorst, A Iyer, S West, E Konieczny, B Freeman, G Rudenski, A Ahmed, R AF Penaloza-MacMaster, Pablo Araki, Koichi Kamphorst, Alice Iyer, Smita West, Erin Konieczny, Bogna Freeman, Gordon Rudenski, Alexander Ahmed, Rafi TI FoxP3+CD4+cells promote CD8 T cell exhaustion during chronic infection SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Penaloza-MacMaster, Pablo; Araki, Koichi; Kamphorst, Alice; Iyer, Smita; West, Erin; Konieczny, Bogna; Ahmed, Rafi] Emory Univ, Atlanta, GA 30322 USA. [Rudenski, Alexander] Sloan Kettering Inst, New York, NY USA. [Freeman, Gordon] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 105.5 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751704002 ER PT J AU Pinner, S Turley, S AF Pinner, Sophie Turley, Shannon TI Podoplanin-rich stromal networks induce dendritic cell motility via activation of CLEC-2 SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Pinner, Sophie; Turley, Shannon] Dana Farber Canc Inst, Canc Immunol & AIDS, Boston, MA 02115 USA. [Pinner, Sophie] UCL, London, England. [Turley, Shannon] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 102.21 PG 2 WC Immunology SC Immunology GA V44LY UT WOS:000209751703148 ER PT J AU Suzuki, E Williams, S Karam, E Zhang, X AF Suzuki, Eiji Williams, Sarah Karam, Eva Zhang, Xian TI Transcription factor Fli-1 is involved in regulation of dendritic cell and monocyte development SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Suzuki, Eiji; Karam, Eva; Zhang, Xian] Med Univ S Carolina, Charleston, SC 29425 USA. [Williams, Sarah; Zhang, Xian] Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 153.33 PG 2 WC Immunology SC Immunology GA V44LY UT WOS:000209751706107 ER PT J AU Taniguchi, R Devoss, J Moon, J Jenkins, M Anderson, M AF Taniguchi, Ruth Devoss, Jason Moon, James Jenkins, Marc Anderson, Mark TI Aire mediates peptide epitope-specific thymic deletion of self reactive T cells to prevent autoimmune uveitis SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Taniguchi, Ruth; Devoss, Jason; Anderson, Mark] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Moon, James] Univ Minnesota, Minneapolis, MN USA. [Moon, James; Jenkins, Marc] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 148.3 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751705182 ER PT J AU Walker, D Reeves, T De Costa, AM Schuyler, C Young, MR AF Walker, David Reeves, Travis De Costa, Anna-Maria Schuyler, Corinne Young, M. Rita TI The effects of 1,25-dihydroxy vitamin D3 on tumor-associated immunosuppression in squamous cell carcinoma of the head and neck. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Walker, David; Reeves, Travis; Young, M. Rita] Med Univ S Carolina, Otolaryngol, Charleston, SC 29425 USA. [Schuyler, Corinne; Young, M. Rita] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [De Costa, Anna-Maria] Med Univ S Carolina, Microbiol & Immunol, Charleston, SC 29425 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 165.29 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751707188 ER PT J AU Wang, S Villablanca, E Gomes, D Nguyen, D Mizoguchi, E Kagan, J Reinecker, HC Hacohen, N Nagler, C Xavier, R Rossi-Bergmann, B Chen, YB Blomhoff, R Snapper, S Mora, R AF Wang, Sen Villablanca, Eduardo Gomes, Daniel Nguyen, Deanna Mizoguchi, Emiko Kagan, Jonathan Reinecker, Hans-Christian Hacohen, Nir Nagler, Cathryn Xavier, Ramnik Rossi-Bergmann, Bartira Chen, Yi-Bin Blomhoff, Rune Snapper, Scott Mora, Rodrigo TI MyD88-dependent TLR signals are necessary and sufficient to confer dendritic cells with gut-specific imprinting properties. SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Wang, Sen; Villablanca, Eduardo; Nguyen, Deanna; Mizoguchi, Emiko; Reinecker, Hans-Christian; Xavier, Ramnik; Snapper, Scott; Mora, Rodrigo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA. [Gomes, Daniel; Rossi-Bergmann, Bartira] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21941 Rio De Janeiro, Brazil. [Kagan, Jonathan] Childrens Hosp, Gastrointestinal Unit, Boston, MA 02115 USA. [Hacohen, Nir] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Nagler, Cathryn] Univ Chicago, Dept Pathol, Comm Immunol, BSD, Chicago, IL 60637 USA. [Chen, Yi-Bin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bone Marrow Transplantat, Boston, MA USA. [Blomhoff, Rune] Univ Oslo, Inst Basic Med Sci, Bostonoslo, Norway. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 161.2 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751707088 ER PT J AU Zhang, X Williams, S Suzuki, E Karam, E Gikeson, G AF Zhang, Xian Williams, Sarah Suzuki, Eiji Karam, Eva Gilkeson, Gary TI Fli-1 transcription factor affects inflammatory cell infiltration in the lupus nephritis development by regulating expression of inflammatory chemokines SO JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract C1 [Zhang, Xian; Suzuki, Eiji; Karam, Eva; Gilkeson, Gary] Med Univ S Carolina, Med, Charleston, SC 29425 USA. [Zhang, Xian; Williams, Sarah; Gilkeson, Gary] Ralph H Johnson VA Med Ctr, Charleston, SC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD APR PY 2011 VL 186 SU 1 MA 44.12 PG 1 WC Immunology SC Immunology GA V44LY UT WOS:000209751700040 ER PT J AU Hatano, H Hayes, TL Dahl, V Sinclair, E Lee, TH Hoh, R Lampiris, H Hunt, PW Palmer, S McCune, JM Martin, JN Busch, MP Shacklett, BL Deeks, SG AF Hatano, Hiroyu Hayes, Timothy L. Dahl, Viktor Sinclair, Elizabeth Lee, Tzong-Hae Hoh, Rebecca Lampiris, Harry Hunt, Peter W. Palmer, Sarah McCune, Joseph M. Martin, Jeffrey N. Busch, Michael P. Shacklett, Barbara L. Deeks, Steven G. TI A Randomized, Controlled Trial of Raltegravir Intensification in Antiretroviral-treated, HIV-infected Patients with a Suboptimal CD4(+) T Cell Response SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; LOW-LEVEL VIREMIA; POLYMERASE-CHAIN-REACTION; BLOOD MONONUCLEAR-CELLS; IMMUNE RECONSTITUTION; TYPE-1 INFECTION; THERAPY; ACTIVATION; SUPPRESSION; INDIVIDUALS AB Background. Some human immunodeficiency virus (HIV)-infected individuals are not able to achieve a normal CD4(+) T cell count despite prolonged, treatment-mediated viral suppression. We conducted an intensification study to assess whether residual viral replication contributes to replenishment of the latent reservoir and whether mucosal HIV-specific T cell responses limit the reservoir size. Methods. Thirty treated subjects with CD4(+) T cell counts of <350 cells/mm(3) despite viral suppression for >= 1 year were randomized to add raltegravir (400 mg twice daily) or matching placebo for 24 weeks. The primary end points were the proportion of subjects with undetectable plasma viremia (determined using an ultrasensitive assay with a lower limit of detection of <.3 copy/mL) and a change in the percentage of CD38(+)HLA-DR(+)CD8(+) T cells in peripheral blood mononuclear cells (PBMCs). Results. The proportion of subjects with undetectable plasma viremia did not differ between the 2 groups (P = .42). Raltegravir intensification did not have a significant effect on immune activation or HIV-specific responses in PBMCs or gut-associated lymphoid tissue. Conclusions. Low-level viremia is not likely to be a significant cause of suboptimal CD4(+) T cell gains during HIV treatment. C1 [Hatano, Hiroyu; Sinclair, Elizabeth; Hoh, Rebecca; Lampiris, Harry; Hunt, Peter W.; McCune, Joseph M.; Martin, Jeffrey N.; Busch, Michael P.; Deeks, Steven G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hayes, Timothy L.; Shacklett, Barbara L.] Univ Calif Davis, Davis, CA 95616 USA. [Dahl, Viktor; Palmer, Sarah] Karolinska Inst, Solna, Sweden. [Dahl, Viktor; Palmer, Sarah] Swedish Inst Infect Dis Control, Solna, Sweden. [Lee, Tzong-Hae; Busch, Michael P.] Blood Syst Res Inst, San Francisco, CA USA. [Lampiris, Harry] San Francisco VA Med Ctr, San Francisco, CA USA. RP Hatano, H (reprint author), San Francisco Gen Hosp, Bldg 80,Ward 84,995 Potrero Ave, San Francisco, CA 94110 USA. EM hhatano@php.ucsf.edu RI Shacklett, Barbara/A-7288-2009; OI Shacklett, Barbara/0000-0002-7067-732X; Dahl, Viktor/0000-0001-9921-5172 FU National Institute of Allergy and Infectious Diseases [K23AI075985, K24AI069994, AI052745, AI055273, RR16482, R01 AI087145, R01 AI057020]; American Foundation for AIDS Research [106710-40-RGRL, 107170-44-RGRL]; Universitywide AIDS Research Program [CC99-SF-001]; UCSF/Gladstone Institute of Virology and Immunology Center for AIDS Research [P30 AI027763]; UCSF Clinical and Translational Research Institute Clinical Research Center [UL1 RR024131]; Center for AIDS Prevention Studies [P30 MH62246]; Center for HIV/AIDS Vaccine Immunology [U01-AI067854]; NCRR [C06 RR - 12088]; Swedish Research Council; National Institutes of Health (NIH) [DPI OD00329] FX This work was supported by the National Institute of Allergy and Infectious Diseases (grant numbers K23AI075985, K24AI069994, AI052745, AI055273, RR16482, R01 AI087145, R01 AI057020), the American Foundation for AIDS Research (grant number 106710-40-RGRL), the Universitywide AIDS Research Program (grant number CC99-SF-001), the UCSF/Gladstone Institute of Virology and Immunology Center for AIDS Research (grant number P30 AI027763), the Clinical Research Center at San Francisco General Hospital, supported by the UCSF Clinical and Translational Research Institute Clinical Research Center (grant number UL1 RR024131), the Center for AIDS Prevention Studies (P30 MH62246), and the Center for HIV/AIDS Vaccine Immunology (grant number U01-AI067854). Mucosal samples were analyzed in a facility constructed with support from NCRR (grant number C06 RR - 12088). S. P. was funded, in part, by the Swedish Research Council and by the American Foundation for AIDS Research (grant number 107170-44-RGRL). J.M.M. is a recipient of the National Institutes of Health (NIH) Director's Pioneer Award Program, part of the NIH Roadmap for Medical Research (grant number DPI OD00329). NR 46 TC 116 Z9 116 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 1 PY 2011 VL 203 IS 7 BP 960 EP 968 DI 10.1093/infdis/jiq138 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 737FF UT WOS:000288553800011 PM 21402547 ER PT J AU Li, JZ Brumme, ZL Brumme, CJ Wang, HY Spritzler, J Robertson, MN Lederman, MM Carrington, M Walker, BD Schooley, RT Kuritzkes, DR AF Li, Jonathan Z. Brumme, Zabrina L. Brumme, Chanson J. Wang, Hongying Spritzler, John Robertson, Michael N. Lederman, Michael M. Carrington, Mary Walker, Bruce D. Schooley, Robert T. Kuritzkes, Daniel R. CA AIDS Clinical Trials Grp A5197 TI Factors Associated With Viral Rebound in HIV-1-Infected Individuals Enrolled in a Therapeutic HIV-1 gag Vaccine Trial SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELL RESPONSES; CLASS-I; DISEASE PROGRESSION; ESCAPE MUTATIONS; IMMUNE-RESPONSES; INFECTION; HLA; LOAD; VIREMIA AB Background. Human immunodeficiency virus type 1 (HIV-1) vaccines directed to the cell-mediated immune system could have a role in lowering the plasma HIV-1 RNA set point, which may reduce infectivity and delay disease progression. Methods. Randomized, placebo-controlled trial involving HIV-1-infected participants who received a recombinant adenovirus serotype 5 (rAd5) HIV-1 gag vaccine or placebo. Sequence-based HLA typing was performed for all 110 participants who initiated analytic treatment interruption (ATI) to assess the role of HLA types previously associated with HIV prognosis. Plasma HIV-1 gag and pol RNA sequences were obtained during the ATI. Virologic endpoints and HLA groups were compared between treatment arms using the 2-sample rank sum test. A linear regression model was fitted to derive independent correlates of ATI week 16 plasma viral load (w16 PVL). Results. Vaccinated participants with neutral HLA alleles had lower median w16 PVLs than did vaccinated participants with protective HLA alleles (P = .01) or placebo participants with neutral HLA alleles (P = .02). Factors independently associated with lower w16 PVL included lower pre-antiretroviral therapy PVL, greater Gag sequence divergence from the vaccine sequence, decreased proportion of HLA-associated polymorphisms in Gag, and randomization to the vaccine arm. Conclusions. Therapeutic vaccination with a rAd5-HIV gag vaccine was associated with lower ATI week 16 PVL even after controlling for viral and host genetic factors. C1 [Li, Jonathan Z.; Kuritzkes, Daniel R.] Brigham & Womens Hosp, Sect Retroviral Therapeut, Cambridge, MA 02139 USA. [Li, Jonathan Z.; Walker, Bruce D.; Kuritzkes, Daniel R.] Harvard Univ, Sch Med, Boston, MA USA. [Brumme, Zabrina L.; Brumme, Chanson J.; Carrington, Mary; Walker, Bruce D.] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Brumme, Zabrina L.; Brumme, Chanson J.; Carrington, Mary; Walker, Bruce D.] Harvard Univ, Cambridge, MA 02138 USA. [Brumme, Zabrina L.] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. [Wang, Hongying; Spritzler, John] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Robertson, Michael N.] Merck Res Labs, N Wales, PA USA. [Lederman, Michael M.] Case Western Reserve Univ, Div Infect Dis, Cleveland, OH 44106 USA. [Carrington, Mary] NCI Frederick, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Schooley, Robert T.] Univ Calif San Diego, Div Infect Dis, La Jolla, CA 92093 USA. RP Kuritzkes, DR (reprint author), Brigham & Womens Hosp, Sect Retroviral Therapeut, 65 Landsdowne St,Rm 449, Cambridge, MA 02139 USA. EM dkuritzkes@partners.org OI Brumme, Chanson/0000-0003-2722-5288 FU Canadian Institutes of Health Research; Intramural NIH HHS; NCRR NIH HHS [K24 RR016482]; NIAID NIH HHS [P30 AI60354, U01 AI068636, P30 AI060354, T32 AI007387, T32 AI07387, U01 AI068634]; PHS HHS [HHSN261200800001E] NR 43 TC 15 Z9 16 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 1 PY 2011 VL 203 IS 7 BP 976 EP 983 DI 10.1093/infdis/jiq143 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 737FF UT WOS:000288553800013 PM 21402549 ER PT J AU Branowicki, P Driscoll, M Hickey, P Renaud, K Sporing, E AF Branowicki, Patricia Driscoll, Margaret Hickey, Patricia Renaud, Kristen Sporing, Eileen TI Exemplary Professional Practice Through Nurse Peer Review SO JOURNAL OF PEDIATRIC NURSING-NURSING CARE OF CHILDREN & FAMILIES LA English DT Review DE Exemplary professional practice; Peer review; Nursing practice ID QUALITY; CARE AB The development and execution of a nurse peer review program to evaluate nursing practice associated with significant adverse events has resulted in systemic changes. Descriptive analyses were conducted for 23 peer-reviewed cases involving 41 RNs and 2 advanced practice nurses from 14 specialties over a 4-year period. Thematic analysis revealed four common event categories: assessment and monitoring, team communication, skin integrity, and vascular access. This approach demonstrates the impact of professional nurse accountability for improving the quality of care and may serve as an exemplar for professional practice. (C) 2011 Elsevier Inc. All rights reserved. C1 [Branowicki, Patricia; Hickey, Patricia; Renaud, Kristen; Sporing, Eileen] Childrens Hosp Boston, Dana Farber Canc Inst, Dept Nursing Patient Serv, Nursing Patient Care Serv, Boston, MA 02115 USA. [Driscoll, Margaret] Childrens Hosp Boston, Program Patient Safety & Qual, Boston, MA USA. RP Branowicki, P (reprint author), Childrens Hosp Boston, Dana Farber Canc Inst, Dept Nursing Patient Serv, Nursing Patient Care Serv, Boston, MA 02115 USA. EM patricia.branowicki@childrens.harvard.edu NR 24 TC 3 Z9 4 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0882-5963 J9 J PEDIATR NURS JI J. Pediatr. Nurs. PD APR PY 2011 VL 26 IS 2 SI SI BP 128 EP 136 DI 10.1016/j.pedn.2010.12.009 PG 9 WC Nursing; Pediatrics SC Nursing; Pediatrics GA 045OA UT WOS:000311704900005 PM 21419972 ER PT J AU Patti, JA AF Patti, John A. TI Clouds on Radiology's Research Horizon SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Patti, JA (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 202, Boston, MA 02114 USA. EM jpatti@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD APR PY 2011 VL 8 IS 4 BP 215 EP 215 DI 10.1016/j.jacr.2011.03.005 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 961FI UT WOS:000305449100001 PM 21458753 ER PT J AU Cuaron, JJ Hirsch, AE Medich, DC Hirsch, JA Rosenstein, BS AF Cuaron, John J. Hirsch, Ariel E. Medich, David C. Hirsch, Joshua A. Rosenstein, Barry S. TI Introduction to Radiation Safety and Monitoring SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Radiation safety; monitoring; radiology; precaution AB Ionizing radiation is used in diagnostic imaging, external-beam radiation therapy, brachytherapy, and nuclear medicine to diagnose and treat a number of common conditions. To ensure the safety of patients, providers, and surrounding staff members, it is important that the health care community become familiar with the terminology, common equipment, and standard practices used in radiation safety and monitoring. The authors aim to provide an introduction to radiation safety and monitoring so that health care providers and support personnel who may have contact with patients, equipment, and facilities that use radioactive material may be more aware of the policies and precautions that are in place to ensure their safety. C1 [Hirsch, Ariel E.] Boston Univ, Med Ctr, Dept Radiat Oncol, Sch Med, Boston, MA 02118 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept Radiol, Div Intervent Neuroradiol, Boston, MA 02114 USA. [Medich, David C.] Univ Massachusetts Lowell, Radiat Lab, Lowell, MA USA. [Rosenstein, Barry S.] Mt Sinai Sch Med, Dept Radiat Oncol, New York, NY USA. [Rosenstein, Barry S.] Mt Sinai Sch Med, Dept Dermatol, New York, NY USA. [Rosenstein, Barry S.] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. [Rosenstein, Barry S.] NYU, Sch Med, New York, NY USA. RP Hirsch, JA (reprint author), Boston Univ, Med Ctr, Dept Radiat Oncol, Sch Med, 830 Harrison Ave,Moakley Bldg LL, Boston, MA 02118 USA. EM ariel.hirsch@bmc.org RI Medich, David/B-6006-2013 NR 6 TC 3 Z9 3 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD APR PY 2011 VL 8 IS 4 BP 259 EP 264 DI 10.1016/j.jacr.2010.08.020 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 961FI UT WOS:000305449100012 PM 21458764 ER PT J AU Friedlander, AH AF Friedlander, Arthur H. TI OSTEONECROSIS OF THE JAW SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Letter C1 VA Greater Los Angeles Healthcare Syst, Grad Med Educ, Los Angeles, CA 90073 USA. RP Friedlander, AH (reprint author), VA Greater Los Angeles Healthcare Syst, Grad Med Educ, Los Angeles, CA 90073 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 EI 1943-4723 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD APR PY 2011 VL 142 IS 4 BP 370 EP 371 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 749EU UT WOS:000289447200006 PM 21454841 ER PT J AU Seliverstov, I AF Seliverstov, Irina TI Practical management approaches to anticoagulation non-compliance, health literacy, and limited English proficiency in the outpatient clinic setting SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article; Proceedings Paper CT 11th National Conference on Anticoagulant Therapy CY MAY 05-07, 2011 CL Boston, MA SP Anticoagulat Forum DE Warfarin; Non-compliance; Health literacy ID WARFARIN; ADHERENCE; QUALITY AB Warfarin is a widely used oral anticoagulant. It is highly efficacious for the treatment and prevention of thromboembolic disorders despite its narrow therapeutic window. Poor compliance with warfarin is common and a major contributor to poor anticoagulation control. A number of psychosocial issues (e.g. depressive symptoms, attitudinal and behavioral factors, cognitive function, lack of social support, limited English proficiency, health illiteracy) have been associated with warfarin non-compliance among patients in anticoagulation clinics. Patient-specific features, such as these, are important to identify in order to develop appropriate and practical interventions. Health literacy and limited English proficiency are the extension of issues related to culture, language, and ethnicity. A better understanding of patients' functioning level and health utilization factors may help to develop and target interventions for high risk patients and reduce complications from suboptimal therapy and poor warfarin management due to non-compliance. Four patient case scenarios will be used to illustrate these issues and identify potential interventions to optimize warfarin therapy. C1 Massachusetts Gen Hosp, Anticoagulat Management Serv, Boston, MA 02114 USA. RP Seliverstov, I (reprint author), Massachusetts Gen Hosp, Anticoagulat Management Serv, 275 Cambridge St,Suite 101, Boston, MA 02114 USA. EM iseliverstov@partners.org NR 7 TC 6 Z9 7 U1 1 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD APR PY 2011 VL 31 IS 3 SI SI BP 321 EP 325 DI 10.1007/s11239-011-0560-2 PG 5 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 733KZ UT WOS:000288262900012 PM 21337118 ER PT J AU Sullivan, K Sherman, O Eng, C Ribner, H Liao, S AF Sullivan, K. Sherman, O. Eng, C. Ribner, H. Liao, S. TI Management recommendations for subtherapeutic international normalized ratio (INR) and consecutive subtherapeutic INR in an anticoagulation clinic SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Meeting Abstract C1 [Sullivan, K.; Sherman, O.; Eng, C.; Ribner, H.; Liao, S.] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD APR PY 2011 VL 31 IS 3 SI SI BP 379 EP 379 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 733KZ UT WOS:000288262900043 ER PT J AU Oertel, LB O'Neil, JA AF Oertel, L. B. O'Neil, J. A. TI Impact of patient self testing on time in therapeutic range SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Meeting Abstract C1 [Oertel, L. B.; O'Neil, J. A.] Massachusetts Gen Hosp, Anticoagulat Management Serv, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD APR PY 2011 VL 31 IS 3 SI SI BP 380 EP 381 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 733KZ UT WOS:000288262900047 ER PT J AU Banerjee, I Sharma, N Yarmush, M AF Banerjee, Ipsita Sharma, Nripen Yarmush, Martin TI Impact of co-culture on pancreatic differentiation of embryonic stem cells SO JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE LA English DT Article DE embryonic stem cell; differentiation; pancreatic islet; co-culture; diabetes; endothelial cell ID INSULIN-PRODUCING CELLS; IN-VITRO DIFFERENTIATION; TRANS-RETINOIC ACID; BETA-CELLS; GENE-EXPRESSION; SECRETING CELLS; ENDOCRINE-CELLS; ISLETS; PRECURSORS; INDUCTION AB Promise of cellular therapy for type 1 diabetes has inspired the search for transplantable cell sources, and embryonic stem cells (ESCs) have emerged as strong candidates. We have developed a directed differentiation protocol to obtain insulin-producing cells from ESCs. The ESCs are first induced towards a homogeneous monolayer of definitive endoderm-like cells by co-culture with primary hepatocytes. Pancreatic commitment is induced by plating the ESC-derived endoderms on Matrigel, along with Sonic hedgehog inhibition and retinoid induction. More than 70% of differentiated cells positively upregulated Pdx-1, along with pro-endocrine transcription factors Ngn3, beta 2/neroD1, Nkx2.2 and Nkx6.1. Final maturation to islet-specific cells is achieved by co-culturing the ESC-derived pancreatic endocrine cells with endothelial cells, which resulted in Insulin 1 upregulation in 60% of the cell population, along with high levels of IAPP and Glut2. The differentiated cell population also secreted high levels of insulin. Our findings illustrate the significant effect of co-culture in different stages of differentiation and maturation of ESCs in vitro. Such a high yield of pancreatic islet cells has not yet been reported. Our findings establish a robust protocol for islet differentiation. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Banerjee, Ipsita; Sharma, Nripen; Yarmush, Martin] Harvard Univ, Sch Med, Ctr Engn Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Banerjee, Ipsita] Univ Pittsburgh, Dept Chem Engn, Pittsburgh, PA 15261 USA. [Yarmush, Martin] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. RP Banerjee, I (reprint author), Harvard Univ, Sch Med, Ctr Engn Med, Massachusetts Gen Hosp, 55 Blossom St, Boston, MA 02114 USA. EM ipb1@pitt.edu NR 43 TC 15 Z9 16 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1932-6254 J9 J TISSUE ENG REGEN M JI J. Tissue Eng. Regen. Med. PD APR PY 2011 VL 5 IS 4 BP 313 EP 323 DI 10.1002/term.317 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Engineering, Biomedical SC Cell Biology; Biotechnology & Applied Microbiology; Engineering GA 737HD UT WOS:000288558800013 PM 20717889 ER PT J AU Budde, ML Lhost, JJ Burwitz, BJ Becker, EA Burns, CM O'Connor, SL Karl, JA Wiseman, RW Bimber, BN Zhang, GL Hildebrand, W Brusic, V O'Connor, DH AF Budde, Melisa L. Lhost, Jennifer J. Burwitz, Benjamin J. Becker, Ericka A. Burns, Charles M. O'Connor, Shelby L. Karl, Julie A. Wiseman, Roger W. Bimber, Benjamin N. Zhang, Guang Lan Hildebrand, William Brusic, Vladimir O'Connor, David H. TI Transcriptionally Abundant Major Histocompatibility Complex Class I Alleles Are Fundamental to Nonhuman Primate Simian Immunodeficiency Virus-Specific CD8(+) T Cell Responses SO JOURNAL OF VIROLOGY LA English DT Article ID INFECTED RHESUS-MONKEYS; PEPTIDE-BINDING SPECIFICITY; CYNOMOLGUS MACAQUES; LYMPHOCYTE RESPONSES; MAMU-B-ASTERISK-08-POSITIVE MACAQUES; SIVMAC239 REPLICATION; DISEASE PROGRESSION; VIRAL PROTEIN; CTL EPITOPE; MOLECULE AB Simian immunodeficiency virus (SIV)-infected macaques are the preferred animal model for human immunodeficiency virus (HIV) vaccines that elicit CD8(+) T cell responses. Unlike humans, whose CD8(+) T cell responses are restricted by a maximum of six HLA class I alleles, macaques express up to 20 distinct major histocompatibility complex class I (MHC-I) sequences. Interestingly, only a subset of macaque MHC-I sequences are transcriptionally abundant in peripheral blood lymphocytes. We hypothesized that highly transcribed MHC-I sequences are principally responsible for restricting SIV-specific CD8(+) T cell responses. To examine this hypothesis, we measured SIV-specific CD8(+) T cell responses in MHC-I homozygous Mauritian cynomolgus macaques. Each of eight CD8(+) T cell responses defined by full-proteome gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay were restricted by four of the five transcripts that are transcriptionally abundant (>1% of total MHC-I transcripts in peripheral blood lymphocytes). The five transcriptionally rare transcripts shared by these animals did not restrict any detectable CD8(+) T cell responses. Further, seven CD8(+) T cell responses were defined by identifying peptide binding motifs of the three most frequent MHC-I transcripts on the M3 haplotype. Combined, these results suggest that transcriptionally abundant MHC-I transcripts are principally responsible for restricting SIV-specific CD8(+) T cell responses. Thus, only a subset of the thousands of known MHC-I alleles in macaques should be prioritized for CD8(+) T cell epitope characterization. C1 [Budde, Melisa L.; Lhost, Jennifer J.; Burwitz, Benjamin J.; Burns, Charles M.; O'Connor, Shelby L.; O'Connor, David H.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. [Becker, Ericka A.; Karl, Julie A.; Wiseman, Roger W.; Bimber, Benjamin N.; O'Connor, David H.] Wisconsin Natl Primate Res Ctr, Madison, WI 53706 USA. [Hildebrand, William] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. [Zhang, Guang Lan; Brusic, Vladimir] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. RP O'Connor, DH (reprint author), 555 Sci Dr, Madison, WI 53711 USA. EM doconnor@primate.wisc.edu OI o'connor, david/0000-0003-2139-470X FU National Institutes of Health [R01 AI077376-01, R21 AI082880-01]; National Institute of Allergy and Infectious Diseases [R01 5R01A1084787-02]; Research Facilities Improvement Program [RR15459-01, RR020141-01]; National Center for Research Resources, a component of the National Institutes of Health [P51 RR000167] FX This research was supported by National Institutes of Health grants R01 AI077376-01 and R21 AI082880-01 and grant R01 5R01A1084787-02 from the National Institute of Allergy and Infectious Diseases. Work for this manuscript was conducted in a facility constructed with support from Research Facilities Improvement Program grants RR15459-01 and RR020141-01.; We thank David Watkins and his lab members Shari Piaskowski, Matthew Reynolds, and Nancy Wilson. Additionally, we thank David Price and Emma Gostick for their aid in generating tetramers and Ann Detmer for her help with viral sequencing. We thank the staff at the Wisconsin National Primate Research Center, a facility supported by grant P51 RR000167 from the National Center for Research Resources, a component of the National Institutes of Health. NR 56 TC 25 Z9 25 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2011 VL 85 IS 7 BP 3250 EP 3261 DI 10.1128/JVI.02355-10 PG 12 WC Virology SC Virology GA 734WT UT WOS:000288373000020 PM 21270169 ER PT J AU Shtanko, O Watanabe, S Jasenosky, LD Watanabe, T Kawaoka, Y AF Shtanko, Olena Watanabe, Shinji Jasenosky, Luke D. Watanabe, Tokiko Kawaoka, Yoshihiro TI ALIX/AIP1 Is Required for NP Incorporation into Mopeia Virus Z-Induced Virus-Like Particles SO JOURNAL OF VIROLOGY LA English DT Article ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; ZINC-BINDING PROTEIN; FINGER Z-PROTEIN; MULTIVESICULAR BODY; LATE DOMAINS; ASSEMBLY DOMAIN; C-PROTEIN; ESCRT-III; ALIX; HIV-1 AB During virus particle assembly, the arenavirus nucleoprotein (NP) associates with the viral genome to form nucleocapsids, which ultimately become incorporated into new virions at the cell membrane. Virion release is facilitated by the viral matrix Z protein through its interaction with the cellular endosomal sorting complex required for transport (ESCRT) machinery. However, the mechanism of nucleocapsid incorporation into virions is not well understood. Here, we demonstrate that ALIX/AIP1, an ESCRT-associated host protein, is required for the incorporation of the NP of Mopeia virus, a close relative of Lassa virus, into Z-induced virus-like particles (VLPs). Furthermore, we show that the Bro1 domain of ALIX/AIP1 interacts with the NP and Z proteins simultaneously, facilitating their interaction, and we identify residues 342 to 399 of NP as being necessary for its interaction with ALIX/AIP1. Our observations suggest a potential role for ALIX/AIP1 in linking Mopeia virus NP to Z and the budding apparatus, thereby promoting NP incorporation into virions. C1 [Shtanko, Olena; Watanabe, Shinji; Watanabe, Tokiko; Kawaoka, Yoshihiro] Univ Wisconsin, Dept Pathobiol Sci, Sch Vet Med, Madison, WI 53711 USA. [Watanabe, Shinji; Watanabe, Tokiko; Kawaoka, Yoshihiro] Japan Sci & Technol Agcy, ERATO Infect Induced Host Responses Project, Kawaguchi, Saitama 3320012, Japan. [Jasenosky, Luke D.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Kawaoka, Yoshihiro] Univ Tokyo, Div Virol, Dept Microbiol & Immunol, Tokyo 1088639, Japan. [Kawaoka, Yoshihiro] Univ Tokyo, Int Res Ctr Infect Dis, Inst Med Sci, Tokyo 1088639, Japan. RP Watanabe, T (reprint author), Univ Wisconsin, Dept Pathobiol Sci, Sch Vet Med, 575 Sci Dr, Madison, WI 53711 USA. EM twatanabe@svm.vetmed.wisc.edu; kawaokay@svm.vetmed.wisc.edu FU U.S. National Institutes of Health; National Institute of Allergy and Infectious Diseases Public Health Service FX This work was supported by a U.S. National Institutes of Health and National Institute of Allergy and Infectious Diseases Public Health Service grant. NR 50 TC 19 Z9 19 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2011 VL 85 IS 7 BP 3631 EP 3641 DI 10.1128/JVI.01984-10 PG 11 WC Virology SC Virology GA 734WT UT WOS:000288373000054 PM 21248028 ER PT J AU Koh, Y Matreyek, KA Engelman, A AF Koh, Yasuhiro Matreyek, Kenneth A. Engelman, Alan TI Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS INTEGRASE; HIV-1 INTEGRASE; CRYSTAL-STRUCTURE; FOAMY VIRUS; IN-VITRO; RALTEGRAVIR; RESISTANCE; REPLICATION; INFECTION; EVOLUTION AB Integrase inhibitors are emerging anti-human immunodeficiency virus (HIV) drugs, and multiple retroviruses and transposable elements were evaluated here for susceptibilities to raltegravir (RAL) and elvitegravir (EVG). All viruses, including primate and nonprimate lentiviruses, a Betaretrovirus, a Gammaretrovirus, and the Alpharetrovirus Rous sarcoma virus (RSV), were susceptible to inhibition by RAL. EVG potently inhibited all lentiviruses and intermediately inhibited Betaretrovirus and Gammaretrovirus infections yet was basically ineffective against RSV. Substitutions based on HIV type 1 (HIV-1) resistance changes revealed that integrase residue Ser150 contributed significantly to the resistance of RSV. The drugs intermediately inhibited intracisternal A-particle retrotransposition but were inactive against Sleeping Beauty transposition and long interspersed nucleotide element 1 (LINE-1) retrotransposition. C1 [Engelman, Alan] Harvard Univ, Dept Canc Immunol & AIDS, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Engelman, A (reprint author), Harvard Univ, Dept Canc Immunol & AIDS, Sch Med, Dana Farber Canc Inst, 44 Binney St,CLS-1010, Boston, MA 02115 USA. EM alan_engelman@dfci.harvard.edu OI Matreyek, Kenneth/0000-0001-9149-551X FU U.S. NIH [AI039394]; Mitsubishi Pharma Foundation; Japanese Association for Infectious Diseases; Japanese Society of Chemotherapy; Harvard University Center for AIDS Research; NIH [P30AI060354]; NIAID; NCI; NIMH; NIDA; NICHD; NHLBI; NCCAM FX This work was supported by U.S. NIH grant AI039394 (A.E.), the Mitsubishi Pharma Foundation (Y.K.), the Japanese Association for Infectious Diseases (Y.K.), the Japanese Society of Chemotherapy (Y.K.), and the Harvard University Center for AIDS Research, an NIH-funded program (P30AI060354) that is supported by the following NIH institutes and centers: NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, and NCCAM. NR 54 TC 19 Z9 20 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2011 VL 85 IS 7 BP 3677 EP 3682 DI 10.1128/JVI.02541-10 PG 6 WC Virology SC Virology GA 734WT UT WOS:000288373000058 PM 21270168 ER PT J AU Popov, S Strack, B Sanchez-Merino, V Popova, E Rosin, H Gottlinger, HG AF Popov, Sergei Strack, Bettina Sanchez-Merino, Victor Popova, Elena Rosin, Heike Goettlinger, Heinrich G. TI Human Immunodeficiency Virus Type 1 and Related Primate Lentiviruses Engage Clathrin through Gag-Pol or Gag SO JOURNAL OF VIROLOGY LA English DT Article ID CATALYTIC DOMAIN; HIV-1 GAG; REVERSE-TRANSCRIPTASE; PARTICLE-PRODUCTION; INTEGRASE MUTANTS; ADAPTER COMPLEX; BINDING; PROTEIN; ALIX; REPLICATION AB The Gag-Pol polyprotein of human immunodeficiency virus type 1 (HIV-1) is not required for efficient viral particle production. However, premature termination codons in pol, particularly in the integrase (IN)-coding region, can markedly impair HIV-1 particle formation, apparently due to the premature activation of the viral protease (PR). We now report that the IN domain of Gag-Pol is required for the incorporation of clathrin into HIV-1 virions. Significantly, PR-dependent effects of point mutations in IN on particle production correlated strictly with their effects on clathrin incorporation. A possible interpretation of these findings is that certain IN mutations impair particle production in a PR-dependent manner by promoting Gag-Pol dimerization, which also occludes a binding site for clathrin. Consistently with this model, the reverse transcriptase (RT) inhibitor efavirenz, which is thought to promote Gag-Pol dimerization, inhibited the incorporation of clathrin into HIV-1 virions. Clathrin-depleted cells produced normal amounts of HIV-1 virions; however, their infectivity was reduced. We also observed that HIV-2 and the simian immunodeficiency virus SIVmac interact with clathrin through one or two copies of a peptide motif in the p6 domain of Gag that resembles the clathrin box of cellular adaptor proteins. Furthermore, the substitution of the hydrophobic residues in the single clathrin box motif of SIVmac caused a replication defect in primary cells. Taken together, our results indicate that primate lentiviruses from two different subgroups functionally interact with clathrin during assembly. C1 [Popov, Sergei; Popova, Elena; Goettlinger, Heinrich G.] Univ Massachusetts, Sch Med, Program Gene Funct & Express, Program Mol Med, Worcester, MA 01605 USA. [Strack, Bettina; Sanchez-Merino, Victor; Rosin, Heike; Goettlinger, Heinrich G.] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gottlinger, HG (reprint author), UMass Med Sch, LRB 526,364 Plantat St, Worcester, MA 01605 USA. EM heinrich.gottlinger@umassmed.edu FU National Institute of Allergy and Infectious Diseases [R37AI029873] FX This work was supported by grant number R37AI029873 from the National Institute of Allergy and Infectious Diseases. NR 49 TC 12 Z9 12 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2011 VL 85 IS 8 BP 3792 EP 3801 DI 10.1128/JVI.02329-10 PG 10 WC Virology SC Virology GA 736ZV UT WOS:000288536100009 PM 21289110 ER PT J AU Wright, JK Novitsky, V Brockman, MA Brumme, ZL Brumme, CJ Carlson, JM Heckerman, D Wang, BX Losina, E Leshwedi, M van der Stok, M Maphumulo, L Mkhwanazi, N Chonco, F Goulder, PJR Essex, M Walker, BD Ndung'u, T AF Wright, Jaclyn K. Novitsky, Vladimir Brockman, Mark A. Brumme, Zabrina L. Brumme, Chanson J. Carlson, Jonathan M. Heckerman, David Wang, Bingxia Losina, Elena Leshwedi, Mopo van der Stok, Mary Maphumulo, Lungile Mkhwanazi, Nompumelelo Chonco, Fundisiwe Goulder, Philip J. R. Essex, Max Walker, Bruce D. Ndung'u, Thumbi TI Influence of Gag-Protease-Mediated Replication Capacity on Disease Progression in Individuals Recently Infected with HIV-1 Subtype C SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ESCAPE MUTATIONS; CLASS-I; VIRAL LOAD; HLA; FITNESS; EPITOPE; PLASMA; AIDS; TRANSMISSION AB HLA class I-mediated selection of immune escape mutations in functionally important Gag epitopes may partly explain slower disease progression in HIV-1-infected individuals with protective HLA alleles. To investigate the impact of Gag function on disease progression, the replication capacities of viruses encoding Gag-protease from 60 individuals in early HIV-1 subtype C infection were assayed in an HIV-1-inducible green fluorescent protein reporter cell line and were correlated with subsequent disease progression. Replication capacities did not correlate with viral load set points (P = 0.37) but were significantly lower in individuals with below-median viral load set points (P = 0.03), and there was a trend of correlation between lower replication capacities and lower rates of CD4 decline (P = 0.09). Overall, the proportion of host HLA-specific Gag polymorphisms in or adjacent to epitopes was negatively associated with replication capacities (P = 0.04), but host HLA-B-specific polymorphisms were associated with higher viral load set points (P = 0.01). Further, polymorphisms associated with host-specific protective HLA alleles were linked with higher viral load set points (P = 0.03). These data suggest that transmission or early HLA-driven selection of Gag polymorphisms results in reduced early cytotoxic T-lymphocyte (CTL) responses and higher viral load set points. In support of the former, 46% of individuals with nonprotective alleles harbored a Gag polymorphism exclusively associated with a protective HLA allele, indicating a high rate of their transmission in sub-Saharan Africa. Overall, HIV disease progression is likely to be affected by the ability to mount effective Gag CTL responses as well as the replication capacity of the transmitted virus. C1 [Wright, Jaclyn K.; Leshwedi, Mopo; van der Stok, Mary; Maphumulo, Lungile; Mkhwanazi, Nompumelelo; Chonco, Fundisiwe; Walker, Bruce D.; Ndung'u, Thumbi] Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Nelson R Mandela Sch Med, ZA-4013 Durban, South Africa. [Novitsky, Vladimir; Essex, Max] Botswana Harvard Sch Publ Hlth, AIDS Initiat Partnership HIV Res & Educ, Gaborone, Botswana. [Novitsky, Vladimir; Essex, Max] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Brockman, Mark A.; Brumme, Zabrina L.] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. [Brockman, Mark A.; Brumme, Zabrina L.; Brumme, Chanson J.] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Carlson, Jonathan M.; Heckerman, David] Microsoft Res, ESci Grp, Redmond, WA USA. [Wang, Bingxia; Losina, Elena] Massachusetts Gen Hosp, Program HIV Outcomes Res, Boston, MA 02114 USA. [Goulder, Philip J. R.] Univ Oxford, Nuffield Dept Med, Dept Paediat, Oxford, England. [Goulder, Philip J. R.; Walker, Bruce D.; Ndung'u, Thumbi] MIT, Ragon Inst, Massachusetts Gen Hosp, Boston, MA USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Ndung'u, T (reprint author), Univ KwaZulu Natal, HIV Pathogenesis Programme, Doris Duke Med Res Inst, Nelson R Mandela Sch Med, 719 Umbilo Rd, ZA-4013 Durban, South Africa. EM ndungu@ukzn.ac.za OI Ndung'u, Thumbi/0000-0003-2962-3992; Brumme, Chanson/0000-0003-2722-5288; Brockman, Mark/0000-0001-6432-1426 FU NIH [RO1-AI067073, RO1-AI057027]; Bill and Melinda Gates Foundation; South African AIDS Vaccine Initiative; South African Department of Science and Technology through the National Research Foundation; Ragon Institute Fund for Innovation; New International Initiatives; National Research Foundation; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University; Canadian Institutes for Health Research (CIHR) FX This research was funded by NIH (RO1-AI067073 and RO1-AI057027), the Bill and Melinda Gates Foundation, the South African AIDS Vaccine Initiative, the South African Department of Science and Technology through the National Research Foundation, and the Ragon Institute Fund for Innovation and New International Initiatives. J.K.W. is funded by the National Research Foundation and the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University. Z.L.B. is supported by a New Investigator Award from the Canadian Institutes for Health Research (CIHR). T.N. holds the South African Department of Science and Technology/National Research Foundation Research Chair in Systems Biology of HIV/AIDS. Additional support was provided by the Mark and Lisa Schwartz Foundation. NR 49 TC 26 Z9 26 U1 2 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR PY 2011 VL 85 IS 8 BP 3996 EP 4006 DI 10.1128/JVI.02520-10 PG 11 WC Virology SC Virology GA 736ZV UT WOS:000288536100028 PM 21289112 ER PT J AU Baddley, JW AF Baddley, John W. TI Clinical risk factors for invasive aspergillosis SO MEDICAL MYCOLOGY LA English DT Article; Proceedings Paper CT 4th Advances Against Aspergillosis (AAA) Conference CY FEB 04-06, 2010 CL Rome, ITALY DE Aspergillus; clinical risk factors; invasive aspergillosis ID CRITICALLY-ILL PATIENTS; CELL TRANSPLANT RECIPIENTS; OBSTRUCTIVE PULMONARY-DISEASE; SOLID-ORGAN TRANSPLANTATION; INTENSIVE-CARE-UNIT; FUNGAL-INFECTIONS; RESPIRATORY-TRACT; IMMUNOCOMPROMISED PATIENTS; MOLD INFECTIONS; EPIDEMIOLOGY AB Despite improvements in the antifungal armamentarium and diagnostic modalities, invasive aspergillosis (IA) remains an important cause of morbidity and mortality in immunocompromised patients. There is an emergence of non-traditional groups at risk for IA, including intensive care unit (ICU) patients, post-operative patients, those with chronic pulmonary diseases, patients with AIDS and patients on immunomodulating drugs (TNF-alpha inhibitors). Identification of clinical risk factors for IA may help in determining which patients require risk modification and other prevention measures. C1 [Baddley, John W.] Univ Alabama, Dept Med, Div Infect Dis, Birmingham, AL 35294 USA. [Baddley, John W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Baddley, JW (reprint author), Univ Alabama, Dept Med, Div Infect Dis, 1900 Univ Blvd,229 Tinsley Harrison Tower, Birmingham, AL 35294 USA. EM jbaddley@uab.edu NR 57 TC 26 Z9 28 U1 1 U2 7 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 APR PY 2011 VL 49 SU 1 BP S7 EP S12 DI 10.3109/13693786.2010.505204 PG 6 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 734IE UT WOS:000288327000002 PM 20718606 ER PT J AU Williams, HJ Norton, N Dwyer, S Moskvina, V Nikolov, I Carroll, L Georgieva, L Williams, NM Morris, DW Quinn, EM Giegling, I Ikeda, M Wood, J Lencz, T Hultman, C Lichtenstein, P Thiselton, D Maher, BS Malhotra, AK Riley, B Kendler, KS Gill, M Sullivan, P Sklar, P Purcell, S Nimgaonkar, VL Kirov, G Holmans, P Corvin, A Rujescu, D Craddock, N Owen, MJ O'Donovan, MC AF Williams, H. J. Norton, N. Dwyer, S. Moskvina, V. Nikolov, I. Carroll, L. Georgieva, L. Williams, N. M. Morris, D. W. Quinn, E. M. Giegling, I. Ikeda, M. Wood, J. Lencz, T. Hultman, C. Lichtenstein, P. Thiselton, D. Maher, B. S. Malhotra, A. K. Riley, B. Kendler, K. S. Gill, M. Sullivan, P. Sklar, P. Purcell, S. Nimgaonkar, V. L. Kirov, G. Holmans, P. Corvin, A. Rujescu, D. Craddock, N. Owen, M. J. O'Donovan, M. C. CA Mol Genetics Schizophrenia ISC SGENE-Plus GROUP TI Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE ZNF804A; association; schizophrenia; bipolar disorder; meta-analysis ID GENE-EXPRESSION; COMMON VARIANTS; ASSOCIATION; RISK; PSYCHOSIS; INSIGHTS; LOCUS; TWIN AB A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P = 1.61 x 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P = 9.96 x 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N = 18 945, schizophrenia plus bipolar disorder N = 21 274 and controls N = 38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P = 2.5 x 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P = 4.1 x 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder. Molecular Psychiatry (2011) 16, 429-441; doi:10.1038/mp.2010.36; published online 6 April 2010 C1 [Williams, H. J.; Norton, N.; Dwyer, S.; Moskvina, V.; Nikolov, I.; Carroll, L.; Georgieva, L.; Williams, N. M.; Ikeda, M.; Kirov, G.; Holmans, P.; Craddock, N.; Owen, M. J.; O'Donovan, M. C.] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Dept Psychol Med & Neurol, Cardiff CF14 4XN, S Glam, Wales. [Morris, D. W.; Quinn, E. M.; Gill, M.; Corvin, A.] Trinity Coll Dublin, Sch Med, Neuropsychiat Genet Res Grp, Dublin, Ireland. [Giegling, I.; Rujescu, D.] Univ Munich, Div Mol & Clin Neurobiol, Munich, Germany. [Ikeda, M.] Fujita Hlth Univ, Sch Med, Dept Psychiat, Aichi, Japan. [Wood, J.; Nimgaonkar, V. L.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Wood, J.; Nimgaonkar, V. L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Lencz, T.; Malhotra, A. K.] N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Ctr Translat Psychiat, Manhasset, NY USA. [Lencz, T.; Malhotra, A. K.] Zucker Hillside Hosp, Div Res, Glen Oaks, NY USA. [Lencz, T.; Malhotra, A. K.] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10467 USA. [Hultman, C.; Lichtenstein, P.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Thiselton, D.; Maher, B. S.; Riley, B.; Kendler, K. S.] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Thiselton, D.; Maher, B. S.; Riley, B.; Kendler, K. S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [Maher, B. S.; Riley, B.; Kendler, K. S.] Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. [Sullivan, P.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sklar, P.; Purcell, S.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Sklar, P.; Purcell, S.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Sklar, P.; Purcell, S.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. RP O'Donovan, MC (reprint author), Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Dept Psychol Med & Neurol, Henry Wellcome Bldg, Cardiff CF14 4XN, S Glam, Wales. EM owenmj@Cardiff.ac.uk; odonovanmc@Cardiff.ac.uk RI Maher, Brion/F-9185-2010; Holmans, Peter/F-4518-2015; Lencz, Todd/J-3418-2014; OI Holmans, Peter/0000-0003-0870-9412; Lencz, Todd/0000-0001-8586-338X; Corvin, Aiden/0000-0001-6717-4089; O'Donovan, Michael/0000-0001-7073-2379; Morris, Derek/0000-0002-3413-570X; Gill, Michael/0000-0003-0206-5337; lichtenstein, paul/0000-0003-3037-5287; Escott-Price, Valentina/0000-0003-1784-5483 FU Wellcome Trust [076113]; MRC; NIMH (USA) [CONTE: 2 P50 MH066392-05A1] FX We thank all the families who contributed to the sample collections we used. We also thank The MRC London Neurodegenerative Diseases Brain Bank, UK; The Stanley Medical Research Institute Brain Bank, USA; and The Karolinska Institute, Sweden, that supplied the post-mortem brain tissue. This study makes use of control data generated by the Wellcome Trust Case/Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. The UK research was supported by grants from the MRC, the Wellcome Trust and by a NIMH (USA) CONTE: 2 P50 MH066392-05A1. NR 31 TC 43 Z9 49 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD APR PY 2011 VL 16 IS 4 BP 429 EP 441 DI 10.1038/mp.2010.36 PG 13 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 739TK UT WOS:000288740700010 PM 20368704 ER PT J AU Deng, XM Dzamko, N Prescott, A Davies, P Liu, QS Yang, QK Lee, JD Patricelli, MP Nomanbhoy, TK Alessi, DR Gray, NS AF Deng, Xianming Dzamko, Nicolas Prescott, Alan Davies, Paul Liu, Qingsong Yang, Qingkai Lee, Jiing-Dwan Patricelli, Matthew P. Nomanbhoy, Tyzoon K. Alessi, Dario R. Gray, Nathanael S. TI Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2 SO NATURE CHEMICAL BIOLOGY LA English DT Article ID CYTOPLASMIC LOCALIZATION; 14-3-3 BINDING; MUTATIONS; MAP AB Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. We employed a new, parallel, compound-centric approach to identify a potent and selective LRRK2 inhibitor, LRRK2-IN-1, and demonstrated that inhibition of LRRK2 induces dephosphorylation of Ser910 and Ser935 and accumulation of LRRK2 within aggregate structures. LRRK2-IN-1 will serve as a versatile tool to pharmacologically interrogate LRRK2 biology and study its role in Parkinson's disease. C1 [Deng, Xianming; Liu, Qingsong; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Deng, Xianming; Liu, Qingsong; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Dzamko, Nicolas; Davies, Paul; Alessi, Dario R.] Univ Dundee, MRC Prot Phosphorylat Unit, Coll Life Sci, Dundee, Scotland. [Prescott, Alan] Univ Dundee, Div Cell Biol & Immunol, Coll Life Sci, Dundee, Scotland. [Yang, Qingkai; Lee, Jiing-Dwan] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Patricelli, Matthew P.; Nomanbhoy, Tyzoon K.] ActivX Biosci, La Jolla, CA USA. RP Deng, XM (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. EM r.alessi@dundee.ac.uk; nathanael_gray@dfci.harvard.edu OI Alessi, Dario/0000-0002-2140-9185; Yang, Qingkai/0000-0001-6628-5393; Prescott, Alan/0000-0002-0747-7317; liu, qing song/0000-0002-7829-2547; Dzamko, Nicolas/0000-0002-9121-0294 FU US National Institutes of Health [P41 GM079575-03, CA079871, CA114059]; Medical Research Council; National Health and Medical Research Council; Michael J. Fox Foundation for Parkinson's Disease Research; University of California [19XT-0084] FX We wish to thank staff at the National Centre for Protein Kinase Profiling (http://www.kinase-screen.mrc.ac.uk) for undertaking Dundee kinase specificity screening, F. Hentati (Institut National de Neurologie, Tunisia) and A. Reith (GlaxoSmithKline Pharmaceuticals Research and Development) for providing EBV immortalized human lymphoblastoid cells, P. Bamborough (GlaxoSmithKline Pharmaceuticals Research and Development) for providing LRRK2 homology model and the antibody purification teams (Division of Signal Transduction Therapy (DSTT), University of Dundee) coordinated by H. McLauchlan and J. Hastie for generation of antibodies. This work was supported by US National Institutes of Health grant P41 GM079575-03 (N.S.G.), the Medical Research Council Technology Industry Collaboration Award and a National Health and Medical Research Council postdoctoral fellowship (N.D.), the Medical Research Council (D. R. A.), the Michael J. Fox Foundation for Parkinson's Disease Research (D. R. A.), the pharmaceutical companies supporting the DSTT (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA and Pfizer) (D. R. A.), the US National Institutes of Health grants CA079871 and CA114059 (J.-D.L.) and funds from the Tobacco-Related Disease Research Program of the University of California, 19XT-0084, (J.-D.L.). NR 22 TC 175 Z9 175 U1 2 U2 39 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD APR PY 2011 VL 7 IS 4 BP 203 EP 205 DI 10.1038/NCHEMBIO.538 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 737CC UT WOS:000288545000007 PM 21378983 ER PT J AU Zhu, H Lensch, MW Cahan, P Daley, GQ AF Zhu, Hao Lensch, M. William Cahan, Patrick Daley, George Q. TI Investigating monogenic and complex diseases with pluripotent stem cells SO NATURE REVIEWS GENETICS LA English DT Review ID QT INTERVAL DURATION; HUMAN SOMATIC-CELLS; MOTOR-NEURONS; MOUSE EMBRYOS; COMMON VARIANTS; DEFINED FACTORS; DOWNS-SYNDROME; ALS; CULTURE; MODELS AB Human genetic studies have revealed the molecular basis of countless monogenic diseases but have been less successful in associating phenotype to genotype in complex multigenic conditions. Pluripotent stem cells (PSCs), which can differentiate into any cell type, offer promise for defining the functional effects of genetic variation. Here, we recount the advantages and practical limitations of coupling PSCs to genome-wide analyses to probe complex genetics and discuss the ability to investigate epigenetic contributions to disease states. We also describe new ways of using mice and mouse embryonic stem cells (ESCs) in tandem with human stem cells to further define genotype-phenotype relationships. C1 [Zhu, Hao; Lensch, M. William; Cahan, Patrick; Daley, George Q.] Childrens Hosp, Howard Hughes Med Inst, Harvard Stem Cell Inst, Stem Cell Transplantat Program,Div Pediat Haemata, Boston, MA 02115 USA. [Zhu, Hao] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Childrens Hosp, Howard Hughes Med Inst, Harvard Stem Cell Inst, Stem Cell Transplantat Program,Div Pediat Haemata, 300 Longwood Ave, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu OI Zhu, Hao/0000-0002-8417-9698; Cahan, Patrick/0000-0003-3652-2540 FU US National Institutes of Health [RO1-DK70055, RO1-DK59279, UO1-HL100001]; American Recovery and Reinvestment Act (ARRA) [RC2-HL102815]; Roche Foundation for Anaemia Research; Alex's Lemonade Stand Foundation; Harvard Stem Cell Institute FX G. Q. D. is an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. G. Q. D. is supported by grants from the US National Institutes of Health (RO1-DK70055, RO1-DK59279 and UO1-HL100001, and special funds from the American Recovery and Reinvestment Act (ARRA) stimulus package (RC2-HL102815)), the Roche Foundation for Anaemia Research, Alex's Lemonade Stand Foundation and the Harvard Stem Cell Institute. NR 73 TC 72 Z9 73 U1 2 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 EI 1471-0064 J9 NAT REV GENET JI Nat. Rev. Genet. PD APR PY 2011 VL 12 IS 4 BP 266 EP 275 DI 10.1038/nrg2951 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 736YT UT WOS:000288531700010 PM 21386866 ER PT J AU Hazlett, EA Goldstein, KE Tajima-Pozo, K Speidel, ER Zelmanova, Y Entis, JJ Silverman, JM New, AS Koenigsberg, HW Haznedar, MM Byne, W Siever, LJ AF Hazlett, Erin A. Goldstein, Kim E. Tajima-Pozo, Kazuhiro Speidel, Elizabeth R. Zelmanova, Yuliya Entis, Jonathan J. Silverman, Jeremy M. New, Antonia S. Koenigsberg, Harold W. Haznedar, M. Mehmet Byne, William Siever, Larry J. TI Cingulate and temporal lobe fractional anisotropy in schizotypal personality disorder SO NEUROIMAGE LA English DT Article DE Diffusion tensor imaging; Schizotypal personality disorder; Dorsolateral prefrontal cortex; Temporal lobe; Cingulum; Fractional anisotropy ID WHITE-MATTER INTEGRITY; THALAMIC MEDIODORSAL NUCLEUS; DIFFUSION TENSOR ANISOTROPY; EARLY-ONSET SCHIZOPHRENIA; ANTERIOR CINGULATE; GYRUS VOLUME; GRAY-MATTER; ABNORMALITIES; MRI; SPECTRUM AB Background: Consistent with the clinical picture of milder symptomatology in schizotypal personality disorder (SPD) than schizophrenia, morphological studies indicate SPD abnormalities in temporal lobe regions but to a much lesser extent in prefrontal regions implicated in schizophrenia. Lower fractional anisotropy (FA), a measure of white-matter integrity within prefrontal, temporal, and cingulate regions has been reported in schizophrenia but has been little studied in SPD. Aims: The study aim was to examine temporal and prefrontal white matter FA in 30 neuroleptic-naive SPD patients and 35 matched healthy controls (HCs). We hypothesized that compared with HCs, SPD patients would exhibit lower FA in temporal lobe and anterior cingulum regions but relative sparing in prefrontal regions. Method: We acquired diffusion tensor imaging (DTI) in all participants and examined FA in the white matter underlying Brodmann areas (BAs) in dorsolateral prefrontal (BAs 44, 45, and 46), temporal lobe (BAs 22, 21, and 20), and cingulum (BAs 25, 24, 31, 23, and 29) regions with a series of analyses using multivariate analysis of variance. Results: Compared with HCs, the SPD group had significantly lower FA in the left temporal lobe but not prefrontal regions. In the cingulum. FA was lower in the SPD group in the posterior regions (BAs 31 and 23), higher in the anterior (BA 25) regions and lower overall in the right but not the left cingulum. Among the SPD group, lower FA in the cingulum was associated with more severe negative symptoms (e.g., odd speech). Conclusions: Similar to schizophrenia, our results indicate cingulum-temporal lobe FA abnormalities in SPD and suggest that cingulum abnormalities are associated with negative symptoms. Published by Elsevier Inc. C1 [Hazlett, Erin A.; Goldstein, Kim E.; Tajima-Pozo, Kazuhiro; Speidel, Elizabeth R.; Zelmanova, Yuliya; Entis, Jonathan J.; Silverman, Jeremy M.; New, Antonia S.; Koenigsberg, Harold W.; Haznedar, M. Mehmet; Byne, William; Siever, Larry J.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Hazlett, Erin A.; Silverman, Jeremy M.; New, Antonia S.; Koenigsberg, Harold W.; Haznedar, M. Mehmet; Byne, William; Siever, Larry J.] James J Peters Dept Vet Affairs Med Ctr, Mental Illness Res Educ & Clin Ctr MIRECC VISN3, Bronx, NY 10468 USA. RP Hazlett, EA (reprint author), James J Peters Dept Vet Adm Med Ctr, Mental Illness Res Educ & Clin Ctr MIRECC VISN3, 130 W Kingsbridge Rd,Room 6A-45, Bronx, NY 10468 USA. EM erin.hazlett@mssm.edu FU VA MERIT [7609-28]; NIMH [R01MH073911]; National Center for Research Resources (NCRR), NIH [M01-Patient Care RR-00071]; Mental Illness, Research, Education, and Clinical Center, VISN 3 Veterans Health Administration FX This study was supported by VA MERIT 7609-28 to Dr. Siever and NIMH grant R01MH073911 to Dr. Hazlett. Other support came from a grant (M01-Patient Care RR-00071) from the National Center for Research Resources (NCRR), a component of the NIH and the Mental Illness, Research, Education, and Clinical Center, VISN 3 Veterans Health Administration. NR 73 TC 16 Z9 17 U1 1 U2 3 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 APR 1 PY 2011 VL 55 IS 3 BP 900 EP 908 DI 10.1016/j.neuroimage.2010.12.082 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 734DQ UT WOS:000288313800006 PM 21223999 ER PT J AU Cohen-Adad, J El Mendili, MM Lehericy, S Pradat, PF Blancho, S Rossignol, S Benali, H AF Cohen-Adad, J. El Mendili, M-M. Lehericy, S. Pradat, P-F. Blancho, S. Rossignol, S. Benali, H. TI Demyelination and degeneration in the injured human spinal cord detected with diffusion and magnetization transfer MRI SO NEUROIMAGE LA English DT Article DE Spinal cord injury; Diffusion-weighted MRI; Magnetization transfer; Atrophy; ASIA ID MULTIPLE-SCLEROSIS BRAIN; INDUCED B-0 FLUCTUATIONS; WHITE-MATTER PATHOLOGY; ANGULAR RESOLUTION; AXONAL INJURY; WALLERIAN DEGENERATION; MULTIEXPONENTIAL T-2; TENSOR TRACTOGRAPHY; FIBER ORIENTATIONS; CORPUS-CALLOSUM AB Characterizing demyelination/degeneration of spinal pathways in traumatic spinal cord injured (SCI) patients is crucial for assessing the prognosis of functional rehabilitation. Novel techniques based on diffusion-weighted (DW) magnetic resonance imaging (MRI) and magnetization transfer (MT) imaging provide sensitive and specific markers of white matter pathology. In this paper we combined for the first time high angular resolution diffusion-weighted imaging (HARDI), MT imaging and atrophy measurements to evaluate the cervical spinal cord of fourteen SCI patients and age-matched controls. We used high in-plane resolution to delineate dorsal and ventrolateral pathways. Significant differences were detected between patients and controls in the normal-appearing white matter for fractional anisotropy (FA, p < 0.0001), axial diffusivity (p < 0.05), radial diffusivity (p < 0.05), generalized fractional anisotropy (GFA, p < 0.0001), magnetization transfer ratio (MTR, p < 0.0001) and cord area (p < 0.05). No significant difference was detected in mean diffusivity (p = 0.41), T1-weighted (p = 0.76) and 12-weighted (p = 0.09) signals. MRI metrics were remarkably well correlated with clinical disability (Pearson's correlations, FA: p < 0.01, GFA: p < 0.01, radial diffusivity: p = 0.01, MTR: p = 0.04 and atrophy: p < 0.01). Stepwise linear regressions showed that measures of MTR in the dorsal spinal cord predicted the sensory disability whereas measures of MTR in the ventrolateral spinal cord predicted the motor disability (ASIA score). However, diffusion metrics were not specific to the sensorimotor scores. Due to the specificity of axial and radial diffusivity and MT measurements, results suggest the detection of demyelination and degeneration in SCI patients. Combining HARDI with MT imaging is a promising approach to gain specificity in characterizing spinal cord pathways in traumatic injury. (C) 2011 Elsevier Inc. All rights reserved. C1 [Cohen-Adad, J.] Harvard Univ, AA Martinos Ctr Biomed Imaging, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Cohen-Adad, J.; El Mendili, M-M.; Benali, H.] Hop La Pitie Salpetriere, UMR 678, INSERM UPMC, Paris, France. [Lehericy, S.] Grp Hosp Pitie Salpetriere, Ctr Neuroimaging Res CENIR, Inst Cerveau & Moelle Epiniere,Ctr Rech, UPMC,UMR 5975,INSERM U975,CNRS UMR 7225, F-75634 Paris, France. [Pradat, P-F.] Hop La Pitie Salpetriere, AP HP, Paris, France. [Blancho, S.] Inst Rech Moelle Epiniere & Encephale, Paris, France. [Rossignol, S.] Univ Montreal, Fac Med, GRSNC, Montreal, PQ H3C 3J7, Canada. RP Cohen-Adad, J (reprint author), Harvard Univ, AA Martinos Ctr Biomed Imaging, Sch Med, Massachusetts Gen Hosp, 149 13 St, Charlestown, MA 02129 USA. EM jcohen@nmr.mgh.harvard.edu FU Association Francaise contre les Myopathies (AFM); Institut pour la Recherche sur la Moelle epiniere et l'Encephale (IRME) FX We thank Dr. Maxime Descoteaux for providing the code to compute the Q-Ball ODF and Dr. Henrik Lundell for providing the code to measure the cord area. We also thank Drs. Stephane Ouary, Olivier Freund, Kevin Nigaud, Alexandre Vignaud and Eric Bardinet for helping with the project. We thank Drs. Thierry Albert, Bertrand Baussart, Caroline Hugeron, Hugues Pascal Moussellard, Frederic Petit and Marc-Antoine Rousseau for helping with patient recruitment and we thank all subjects. We also thank the reviewers for their helpful comments that greatly improved the quality of the manuscript. This study was supported by the Association Francaise contre les Myopathies (AFM) and by the Institut pour la Recherche sur la Moelle epiniere et l'Encephale (IRME). S.R. received a special fellowship from the IRME to participate in these studies during a sabbatical leave in Paris. NR 96 TC 85 Z9 88 U1 0 U2 15 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 APR 1 PY 2011 VL 55 IS 3 BP 1024 EP 1033 DI 10.1016/j.neuroimage.2010.11.089 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 734DQ UT WOS:000288313800017 PM 21232610 ER PT J AU Harvey, PO Lee, J Cohen, MS Engel, SA Glahn, DC Nuechterlein, KH Wynn, JK Green, MF AF Harvey, Philippe-Olivier Lee, Junghee Cohen, Mark S. Engel, Stephen A. Glahn, David C. Nuechterlein, Keith H. Wynn, Jonathan K. Green, Michael F. TI Altered dynamic coupling of lateral occipital complex during visual perception in schizophrenia SO NEUROIMAGE LA English DT Article DE Functional connectivity/ Dynamic coupling; Lateral occipital complex; Backward visual masking; Schizophrenia; fMRI ID BACKWARD-MASKING DEFICITS; MULTIPLE TRIAL TYPES; EVENT-RELATED FMRI; FUNCTIONAL CONNECTIVITY; OBJECT RECOGNITION; CORTEX; MECHANISMS; PATTERNS; ENTROPY; HUMANS AB Introduction: There is mounting evidence that visual perception abnormalities in schizophrenia are partly explained by a dysfunction of the lateral occipital complex (LO). We previously demonstrated that schizophrenia patients had broader topography and reduced magnitude of activity of LO. However, the functional connectivity of LO with other brain regions during visual perception has not been directly investigated in schizophrenia. Materials and methods: Eighteen patients with schizophrenia and eighteen matched controls performed a backward masking task during functional magnetic resonance imaging (fMRI). Stimulus onset asynchronies were manipulated to change the level of target visibility. To examine connectivity with LO function we conducted psychophysiological interactions (PPI) analyses using: 1) a region of interest (ROI) approach and 2) a whole brain analysis. ROIs were defined based on a contrast of trials on which a target was presented versus null trials in which no stimuli were presented. Results: Eleven ROIs were identified. Both groups showed similar strength of coupling between LO and the 11 ROIs when visibility was not taken into account. Healthy controls showed clear changes in coupling between LO and prefrontal and parietal regions as a function of target visibility (higher coupling with more visible targets). In comparison, patients showed reduced dynamic coupling with LO in the right superior frontal gyrus (significant after correcting for multiple comparisons) and a trend for reduced coupling in the left precuneus and left inferior frontal regions. Whole brain analysis identified additional regions that showed dynamic coupling with LO in healthy controls, but not in patients. Discussion: The increased coupling between LO and higher-level parietal and prefrontal regions during visual awareness in healthy controls likely reflects visual reentrant processing. The lack of modulation of coupling between LO and key prefrontal and parietal regions found in schizophrenia may partly reflect abnormalities in LO tuning. The altered LO coupling may contribute to visual perception abnormalities in schizophrenia. (C) 2010 Elsevier Inc. All rights reserved. C1 [Harvey, Philippe-Olivier; Lee, Junghee; Cohen, Mark S.; Nuechterlein, Keith H.; Wynn, Jonathan K.; Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90073 USA. [Harvey, Philippe-Olivier; Lee, Junghee; Wynn, Jonathan K.; Green, Michael F.] VA Greater Los Angeles, Healthcare Ctr Syst, Los Angeles, CA USA. [Engel, Stephen A.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Glahn, David C.] Olin Neuropsychiat Res Ctr, New Haven, CT USA. [Glahn, David C.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Nuechterlein, Keith H.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. RP Harvey, PO (reprint author), Univ Calif Los Angeles, Semel Inst, W LA VA Healthcare Ctr, 11301 Wilshire Blvd,210A,Room 131, Los Angeles, CA 90073 USA. EM poharvey@ucla.edu RI Cohen, Mark/C-6610-2011; Lee, Junghee/C-5226-2014; Wynn, Jonathan/H-3749-2014 OI Cohen, Mark/0000-0001-6731-4053; Lee, Junghee/0000-0001-9567-8700; Wynn, Jonathan/0000-0002-1763-8540 FU Canadian Institutes of Health Research; William M. and Linda R Dietel Philanthropic Fund at the Northern Piedmont Community Foundation; Northstar Fund; [MH043292] FX This work was supported by grant MH043292 to Dr. Green. Poorang Non and Alisa Malin assisted in data collection. Dr. Harvey is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research. For generous support of the UCLA Brain Mapping Center, we also thank the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, The Ahmanson Foundation, William M. and Linda R Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, Tamkin Foundation, Jennifer Jones-Simon, Capital Group Companies Charitable Foundation, Robson Family, and Northstar Fund. NR 51 TC 16 Z9 17 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD APR 1 PY 2011 VL 55 IS 3 BP 1219 EP 1226 DI 10.1016/j.neuroimage.2010.12.045 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 734DQ UT WOS:000288313800035 PM 21194569 ER PT J AU Golfinopoulos, E Tourville, JA Bohland, JW Ghosh, SS Nieto-Castanon, A Guenther, FH AF Golfinopoulos, Elisa Tourville, Jason A. Bohland, Jason W. Ghosh, Satrajit S. Nieto-Castanon, Alfonso Guenther, Frank H. TI fMRI investigation of unexpected somatosensory feedback perturbation during speech SO NEUROIMAGE LA English DT Article DE Functional magnetic resonance imaging; Structural equation modeling; Speech motor control; Right hemisphere; Somatosensory feedback ID PHASE BIMANUAL MOVEMENTS; FUNCTIONAL IMAGING DATA; WORKING-MEMORY NETWORK; SURFACE-BASED ANALYSIS; FALSE DISCOVERY RATE; EVENT-RELATED FMRI; STRUCTURAL EQUATION; EFFECTIVE CONNECTIVITY; AUDITORY-FEEDBACK; MOTOR CONTROL AB Somatosensory feedback plays a critical role in the coordination of articulator movements for speech production. In response to unexpected resistance to lip or jaw movements during speech, fluent speakers can use the difference between the somatosensory expectations of a speech sound and the actual somatosensory feedback to adjust the trajectories of functionally relevant but unimpeded articulators. In an effort to investigate the neural substrates underlying the somatosensory feedback control of speech, we used an event-related sparse sampling functional magnetic resonance imaging paradigm and a novel pneumatic device that unpredictably blocked subjects' jaw movements. In comparison to speech, perturbed speech, in which jaw perturbation prompted the generation of compensatory speech motor commands, demonstrated increased effects in bilateral ventral motor cortex, right-lateralized anterior supramarginal gyrus, inferior frontal gyrus pars triangularis and ventral premotor cortex, and bilateral inferior posterior cerebellum (lobule VIII). Structural equation modeling revealed a significant increased influence from left anterior supramarginal gyrus to right anterior supramarginal gyrus and from left anterior supramarginal gyrus to right ventral premotor cortex as well as a significant increased reciprocal influence between right ventral premotor cortex and right ventral motor cortex and right anterior supramarginal gyrus and right inferior frontal gyrus pars triangularis for perturbed speech relative to speech. These results suggest that bilateral anterior supramarginal gyrus, right inferior frontal gyrus pars triangularis, right ventral premotor and motor cortices are functionally coupled and influence speech motor output when somatosensory feedback is unexpectedly perturbed during speech production. (C) 2011 Elsevier Inc. All rights reserved. C1 [Golfinopoulos, Elisa; Tourville, Jason A.; Bohland, Jason W.; Ghosh, Satrajit S.; Guenther, Frank H.] Boston Univ, Dept Cognit & Neural Syst, Boston, MA 02215 USA. [Bohland, Jason W.] Boston Univ, Dept Hlth Sci, Boston, MA 02215 USA. [Ghosh, Satrajit S.; Guenther, Frank H.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Nieto-Castanon, Alfonso] StatsANC LLC, Buenos Aires, DF, Argentina. [Guenther, Frank H.] Boston Univ, Dept Speech Language & Hearing Sci, Boston, MA 02215 USA. [Guenther, Frank H.] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Guenther, Frank H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Golfinopoulos, E (reprint author), Boston Univ, Dept Cognit & Neural Syst, 677 Beacon St, Boston, MA 02215 USA. EM egolfino@cns.bu.edu RI Bohland, Jason/L-4807-2016; OI Bohland, Jason/0000-0002-6305-5848; Ghosh, Satrajit/0000-0002-5312-6729 FU National Institute on Deafness and other Communication Disorders [R01 DC02852]; CELEST, an NSF Science of Learning Center [NSF SMA-0835976]; National Center for Research Resources [P41RR14075]; MIND Institute FX This research was supported by the National Institute on Deafness and other Communication Disorders (R01 DC02852, F. Guenther PI) and by CELEST, an NSF Science of Learning Center (NSF SMA-0835976). Imaging was made possible with support from the National Center for Research Resources grant P41RR14075 and the MIND Institute. The authors would like to thank Joseph Perkell, Mark Tiede, Kevin Reilly, Oren Civier, Bruce Fischl, Julie Goodman, Lawrence Wald and the anonymous reviewers for their time and consideration. NR 100 TC 37 Z9 38 U1 1 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD APR 1 PY 2011 VL 55 IS 3 BP 1324 EP 1338 DI 10.1016/j.neuroimage.2010.12.065 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 734DQ UT WOS:000288313800045 PM 21195191 ER PT J AU Wozniak, J AF Wozniak, Janet TI Challenges remain in the diagnosis and treatment of childhood-onset bipolar disorder SO NEUROPSYCHIATRY LA English DT Editorial Material C1 [Wozniak, Janet] Massachusetts Gen Hosp, Pediat Bipolar Disorder Clin & Res Program, Boston, MA 02114 USA. [Wozniak, Janet] Harvard Univ, Sch Med, Boston, MA USA. RP Wozniak, J (reprint author), Massachusetts Gen Hosp, Pediat Bipolar Disorder Clin & Res Program, Boston, MA 02114 USA. EM jwozniak@partners.org NR 10 TC 0 Z9 0 U1 1 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1758-2008 J9 NEUROPSYCHIATRY-LOND JI Neuropsychiatry PD APR PY 2011 VL 1 IS 2 BP 93 EP 95 DI 10.2217/NPY.11.14 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 961DD UT WOS:000305443200001 ER PT J AU Wilens, TE AF Wilens, Timothy Edwin TI Current controversies in ADHD: diagnosis, treatment and comorbid substance abuse SO NEUROPSYCHIATRY LA English DT Editorial Material ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; ADULTS; SYMPTOMS; EFFICACY; SUBTYPES; ABT-089; THERAPY C1 Massachusetts Gen Hosp, Child Psychiat Serv, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. RP Wilens, TE (reprint author), Massachusetts Gen Hosp, Child Psychiat Serv, Pediat Psychopharmacol Unit, YAW6A,55 Fruit St, Boston, MA 02114 USA. EM twilens@partners.org NR 10 TC 0 Z9 0 U1 1 U2 7 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1758-2008 J9 NEUROPSYCHIATRY-LOND JI Neuropsychiatry PD APR PY 2011 VL 1 IS 2 BP 115 EP 121 DI 10.2217/NPY.11.15 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 961DD UT WOS:000305443200009 ER PT J AU Garzon-Serrano, J Ryan, C Waak, K Hirschberg, R Tully, S Bittner, EA Chipman, DW Schmidt, U Kasotakis, G Benjamin, J Zafonte, R Eikermann, M AF Garzon-Serrano, Jaime Ryan, Cheryl Waak, Karen Hirschberg, Ronald Tully, Susan Bittner, Edward A. Chipman, Daniel W. Schmidt, Ulrich Kasotakis, Georgios Benjamin, John Zafonte, Ross Eikermann, Matthias TI Early Mobilization in Critically Ill Patients: Patients' Mobilization Level Depends on Health Care Provider's Profession SO PM&R LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; ACUTE RESPIRATORY-FAILURE; INTENSIVE-CARE; UNIT MOBILITY; OLDER-ADULTS; REHABILITATION; EXERCISE; THERAPY; PHYSIOTHERAPY; MEDICINE AB Objective: To evaluate whether the level of mobilization achieved and the barriers for progressing to the next mobilization level differ between nurses and physical therapists. Design: Prospective, observational study. Setting: Twenty-bed surgical intensive care unit (SICU) of the Massachusetts General Hospital. Participants: Sixty-three critically ill patients. Methods: Physical therapists and nurses performed 179 mobilization therapies with 63 patients. Outcome Measurement: Mobilization was defined as the process of enhancing mobility in the SICU, including bed mobility, edge of bed activities, transfers out of bed to a chair, and gait training; the mobilization level was measured on the SICU optimal mobilization scale, a 5-point (0-4) numerical rating scale. Results: Patients' level of mobilization achieved by physical therapists was significantly higher compared with that achieved by nurses (2.3 +/- 1.2 mean +/- SD versus 1.2 +/- 1.2, respectively P < .0001). Different barriers for mobilization were identified by physical therapists and nurses: hemodynamic instability (26% versus 12%, P = .03) and renal replacement therapy (12% versus 1%, P = .03) were barriers rated higher by nurses, whereas neurologic impairment was rated higher by physical therapists providers (18% versus 38%, P = .002). No mobilization-associated adverse events were observed in this study. Conclusions: This study showed that physical therapists mobilize their critically ill patients to higher levels compared with nurses. Nurse and physical therapists identify different barriers for mobilization. Routine involvement of physical therapists in directing mobilization treatment may promote early mobilization of critically ill patients. PM R 2011;3:307-313 C1 [Garzon-Serrano, Jaime; Ryan, Cheryl; Tully, Susan; Bittner, Edward A.; Schmidt, Ulrich; Benjamin, John; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02114 USA. [Garzon-Serrano, Jaime; Ryan, Cheryl; Hirschberg, Ronald; Tully, Susan; Bittner, Edward A.; Schmidt, Ulrich; Benjamin, John; Zafonte, Ross; Eikermann, Matthias] Harvard Univ, Sch Med, Boston, MA USA. [Chipman, Daniel W.; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. [Ryan, Cheryl; Tully, Susan] Massachusetts Gen Hosp, Dept Clin Nursing Serv, Boston, MA 02114 USA. [Waak, Karen] Massachusetts Gen Hosp, Dept Phys & Occupat Therapy, Boston, MA 02114 USA. [Hirschberg, Ronald; Zafonte, Ross] Massachusetts Gen Hosp, Dept Phys Med & Rehabil, Boston, MA 02114 USA. [Kasotakis, Georgios] Massachusetts Gen Hosp, Div Trauma & Surg Crit Care, Boston, MA 02114 USA. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA 02114 USA. EM meikermann@partners.org FU Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine, Boston, MA FX This work was supported by funds from the Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine, Boston, MA. NR 33 TC 48 Z9 50 U1 4 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 EI 1934-1563 J9 PM&R JI PM&R PD APR PY 2011 VL 3 IS 4 BP 307 EP 313 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 961AY UT WOS:000305437500005 PM 21497316 ER PT J AU Jackson, GL Lee, SYD Edelman, D Weinberger, M Yano, EM AF Jackson, George L. Lee, Shoou-Yih Daniel Edelman, David Weinberger, Morris Yano, Elizabeth M. TI Employment of mid-level providers in primary care and control of diabetes SO PRIMARY CARE DIABETES LA English DT Article DE Diabetes; Mid-level providers; United States Department of Veterans Affairs ID NURSE-PRACTITIONERS; NONPHYSICIAN CLINICIAN; PHYSICIAN ASSISTANTS; CONTROLLED-TRIAL; CASE-MANAGEMENT; UNITED-STATES; VETERANS; OUTCOMES; QUALITY; ORGANIZATION AB Aims: Examine potential associations between inclusion of mid-level providers in United States Veterans Affairs (VA) primary care programs and diabetes control. Methods: We established a cohort of diabetes patients (alive October 1, 1999) using the VA Diabetes Registry and VA corporate databases. 1999 VA Survey of Primary Care Practices data were combined with individual-patient information. We used a two-level hierarchical model to determine the relationship between staffing characteristics and hemoglobin A1c (HbAlc), among 88,682 patients from 198 clinics. Results: Inclusion of nurse practitioners (NPs) at relatively limited levels (% of all providers who are NPs) in the primary care program was significantly associated with HbA1c lower by 0.31 percentage points (95% CI, -0.50% to -0.12%) compared to programs that did not include NPs. Having some level of NP staffing vs. no NP staffing was associated HbA1c lower by 0.25%. Inclusion of physician assistants (PAs) in primary care programs was generally not associated with a statistically significant difference in HbA1c. The exception is that moderate levels of PA staffing were associated with slightly higher HbA1c [0.18%, 95% CI, 0.02-0.34)]. Conclusions: Diabetes control among primary care patients appeared to benefit from inclusion of NPs, while an analogous association was not found for PAs. Published by Elsevier Ltd on behalf of Primary Care Diabetes Europe. C1 [Jackson, George L.; Edelman, David; Weinberger, Morris] Vet Affairs Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Jackson, George L.; Edelman, David] Duke Univ, Med Ctr, Div Gen Internal Med, Durham, NC 27710 USA. [Lee, Shoou-Yih Daniel] Univ Michigan, Dept Hlth Management & Policy, Ann Arbor, MI 48109 USA. [Weinberger, Morris] Univ N Carolina, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Yano, Elizabeth M.] VA Greater Angeles Healthcare Syst, Ctr Study Healthcare Provider Behav, Sepulveda, CA USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Dept Hlth Serv, Los Angeles, CA USA. RP Jackson, GL (reprint author), Durham VA Med Ctr, HSR&D Serv 152, 508 Fulton St, Durham, NC 27705 USA. EM george.l.jackson@duke.edu OI Edelman, David/0000-0001-7112-6151 FU VA grant [MRP 05-312]; VA HSRD Service [MPC 97-012]; [2T32HS000079-06] FX Support: During part of this work, Dr. Jackson was a National Research Service Award-Agency for Healthcare Research and Quality Postdoctoral Fellow (institutional training grant 2T32HS000079-06) and a Veterans Affairs Health Services Research & Development (HSR&D) Merit Review Entry Program awardee (VA grant MRP 05-312). Dr. Weinberger is a VA HSR&D Senior Career Scientist awardee. Dr. Yano is a VA HSR&D Research Career Scientist awardee (RCS 05-195). Survey data collection was funded by the VA HSR&D Service (Project MPC 97-012). NR 39 TC 9 Z9 9 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1751-9918 J9 PRIM CARE DIABETES JI Prim. Care Diabetes PD APR PY 2011 VL 5 IS 1 BP 25 EP 31 DI 10.1016/j.pcd.2010.09.005 PG 7 WC Endocrinology & Metabolism; Primary Health Care SC Endocrinology & Metabolism; General & Internal Medicine GA 943MR UT WOS:000304128200004 PM 20980212 ER PT J AU Porkka-Heiskanen, T Kalinchuk, AV AF Porkka-Heiskanen, Tarja Kalinchuk, Anna V. TI Adenosine, energy metabolism and sleep homeostasis SO SLEEP MEDICINE REVIEWS LA English DT Review DE Adenosine; Caffeine; Energy metabolism; Glia; NF-kB; Sleep; SD; Recovery sleep ID BASAL FOREBRAIN NEURONS; ACTIVITY-DEPENDENT RELEASE; ACTIVATED PROTEIN-KINASE; EQUILIBRATIVE NUCLEOSIDE TRANSPORTERS; VENTROLATERAL PREOPTIC NEURONS; PONTINE RETICULAR-FORMATION; CENTRAL-NERVOUS-SYSTEM; MOUSE CEREBRAL-CORTEX; EYE-MOVEMENT SLEEP; NITRIC-OXIDE AB Adenosine is directly linked to the energy metabolism of cells. In the central nervous system (CNS) an increase in neuronal activity enhances energy consumption as well as extracellular adenosine concentrations. In most brain areas high extracellular adenosine concentrations, through A1 adenosine receptors, decrease neuronal activity and thus the need for energy. Adenosine may be a final common pathway for various sleep factors. We have identified a relatively specific area, the basal forebrain (BF), which appears to be central in the regulation/execution of recovery sleep after sleep deprivation (SD), or prolonged wakefulness. Adenosine concentration increases in this area during SD, and this increase induces sleep while prevention of the increase during SD abolishes recovery sleep. The increase in adenosine is associated with local changes in energy metabolism as indicated by increases in levels of pyruvate and lactate and increased phosphorylation of AMP-activated protein kinase. The increases in adenosine and sleep are associated with intact cholinergic system since specific lesion of the BF cholinergic cells abolishes both. Whether adenosine during SD is produced by the cholinergic neurons or astrocytes associated with them remains to be explored. An interesting, but so far unexplored question regards the relationship between the local, cortical regulation of sleep homeostasis and the global regulation of the state of sleep as executed by lower brain mechanisms, including the BF. The increase in adenosine concentration during SD also in cortical areas suggests that adenosine may have a role in the local regulation of sleep homeostasis. The core of sleep need is probably related to primitive functions of life, like energy metabolism. It can be noted that this assumption in no way excludes the possibility that later in evolution additional functions may have developed, e.g., related to complex neuronal network functions like memory and learning. (C) 2010 Published by Elsevier Ltd. C1 [Porkka-Heiskanen, Tarja] Univ Helsinki, Inst Biomed, FIN-00014 Helsinki, Finland. [Kalinchuk, Anna V.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Boston, MA 02132 USA. RP Porkka-Heiskanen, T (reprint author), Univ Helsinki, Inst Biomed, POB 63, FIN-00014 Helsinki, Finland. EM porkka@cc.helsinki.fi; anna_kalinchuk@hms.haivard.edu OI Stenberg, Tarja/0000-0003-1843-7625 FU Academy of Finland FX This work was supported by a grant from the Academy of Finland. NR 126 TC 92 Z9 94 U1 4 U2 45 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1087-0792 EI 1532-2955 J9 SLEEP MED REV JI Sleep Med. Rev. PD APR PY 2011 VL 15 IS 2 BP 123 EP 135 DI 10.1016/j.smrv.2010.06.005 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 737LV UT WOS:000288571200007 PM 20970361 ER PT J AU Agler, AH Kurth, T Gaziano, JM Buring, JE Cassano, PA AF Agler, Anne H. Kurth, Tobias Gaziano, J. Michael Buring, Julie E. Cassano, Patricia A. TI Randomised vitamin E supplementation and risk of chronic lung disease in the Women's Health Study SO THORAX LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; ANTIOXIDANT STATUS; ALPHA-TOCOPHEROL; CONTROLLED-TRIAL; COPD; MORTALITY; BURDEN; ASTHMA AB Background The oxidant/antioxidant balance in lung tissue is hypothesised to contribute to the risk of chronic obstructive pulmonary disease (COPD). Observational studies consistently report higher antioxidant status associated with lower COPD risk, but few randomised studies have been reported. Methods A post hoc analysis of 38 597 women without chronic lung disease at baseline was conducted in the Women's Health Study (WHS) to test the effect of vitamin E on the risk of incident chronic lung disease. The WHS is a randomised double-blind placebo-controlled factorial trial of vitamin E (600 IU every other day) and aspirin (100 mg every other day) in female health professionals aged >= 45 years. Using Cox proportional hazards models, the effect of randomised vitamin E assignment on self-reported physician-diagnosed chronic lung disease was evaluated. Results During 10 years of follow-up (376 710 person-years), 760 first occurrences of chronic lung disease were reported in the vitamin E arm compared with 846 in the placebo arm (HR 0.90; 95% CI 0.81 to 0.99; p=0.029). This 10% reduction in the risk of incident chronic lung disease was not modified by cigarette smoking, age, randomised aspirin assignment, multivitamin use or dietary vitamin E intake (minimum p for interaction=0.19). Current cigarette smoking was a strong predictor of chronic lung disease risk (HR 4.17; 95% CI 3.70 to 4.70; vs. never smokers). Conclusions In this large randomised trial, assignment to 600 IU vitamin E led to a 10% reduction in the risk of chronic lung disease in women. C1 [Agler, Anne H.; Cassano, Patricia A.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Kurth, Tobias; Gaziano, J. Michael; Buring, Julie E.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Kurth, Tobias] INSERM, Unit Neuroepidemiol 708, Paris, France. [Kurth, Tobias] Univ Paris 06, Paris, France. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, GRECC, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA. RP Cassano, PA (reprint author), Cornell Univ, Div Nutr Sci, 209 Savage Hall, Ithaca, NY 14853 USA. EM pac6@cornell.edu RI Kurth, Tobias/A-9243-2012 OI Kurth, Tobias/0000-0001-7169-2620 FU National Institutes for Health, USA [NIH HL071022, NIH HL043851, CA47988] FX This study was funded by grants from the National Institutes for Health, USA, grants NIH HL071022 (PAC); NIH HL043851 and CA47988 (Women's Health Study). NR 35 TC 18 Z9 18 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 EI 1468-3296 J9 THORAX JI Thorax PD APR PY 2011 VL 66 IS 4 BP 320 EP 325 DI 10.1136/thx.2010.155028 PG 6 WC Respiratory System SC Respiratory System GA 737WA UT WOS:000288598900012 PM 21257986 ER PT J AU Johnson, AS O'Sullivan, E D'Aoust, LN Omer, A Bonner-Weir, S Fisher, RJ Weir, GC Colton, CK AF Johnson, Amy S. O'Sullivan, Esther D'Aoust, Laura N. Omer, Abdulkadir Bonner-Weir, Susan Fisher, Robert J. Weir, Gordon C. Colton, Clark K. TI Quantitative Assessment of Islets of Langerhans Encapsulated in Alginate SO TISSUE ENGINEERING PART C-METHODS LA English DT Article ID STIMULATED INSULIN-SECRETION; ISOLATED PANCREATIC-ISLETS; SILICONE-RUBBER MEMBRANES; INTRACELLULAR ATP CONTENT; OXYGEN-CONSUMPTION RATE; BETA-CELL APOPTOSIS; ISOLATED RAT ISLETS; NUDE-MICE; DIFFERENT DONORS; ADP/ATP RATIO AB Improved methods have recently been developed for assessing islet viability and quantity in human islet preparations for transplantation, and these measurements have proven useful for predicting transplantation outcome. The objectives of this study were to adapt these methods for use with microencapsulated islets, to verify that they provide meaningful quantitative measurements, and to test them with two model systems: (1) barium alginate and (2) barium alginate containing a 70% (w/v) perfluorocarbon (PFC) emulsion, which presents challenges to use of these assays and is of interest in its own right as a means for reducing oxygen supply limitations to encapsulated tissue. Mitochondrial function was assessed by oxygen consumption rate measurements, and the analysis of data was modified to account for the increased solubility of oxygen in the PFC-alginate capsules. Capsules were dissolved and tissue recovered for nuclei counting to measure the number of cells. Capsule volume was determined from alginate or PFC content and used to normalize measurements. After low oxygen culture for 2 days, islets in normal alginate lost substantial viable tissue and displayed necrotic cores, whereas most of the original oxygen consumption rate was recovered with PFC alginate, and little necrosis was observed. All nuclei were recovered with normal alginate, but some nuclei from nonrespiring cells were lost with PFC alginate. Biocompatibility tests revealed toxicity at the islet periphery associated with the lipid emulsion used to provide surfactants during the emulsification process. We conclude that these new assay methods can be applied to islets encapsulated in materials as complex as PFC-alginate. Measurements made with these materials revealed that enhancement of oxygen permeability of the encapsulating material with a concentrated PFC emulsion improves survival of encapsulated islets under hypoxic conditions, but reformulation of the PFC emulsion is needed to reduce toxicity. C1 [Johnson, Amy S.; D'Aoust, Laura N.; Fisher, Robert J.; Colton, Clark K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [O'Sullivan, Esther; Omer, Abdulkadir; Bonner-Weir, Susan; Weir, Gordon C.] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Colton, CK (reprint author), MIT, Dept Chem Engn, Room 66-452,77 Massachusetts Ave, Cambridge, MA 02139 USA. EM ckcolton@mit.edu OI Bonner-Weir, Susan/0000-0003-4682-0656 FU NIH [R01DK50657, R01-DK063108-01A1, NCRR ICR U42 16606]; JDRF Center FX This work was supported by grants from the NIH (R01DK50657, R01-DK063108-01A1, and NCRR ICR U42 16606) and JDRF Center for Islet Transplantation at Harvard Medical School. Rat islet isolations were performed with the assistance of Jennifer Hollister-Lock, Vaja Tchipasvilli, and Vassileios Kostaras from Joslin Diabetes Center. Human islets used for DNA measurements were obtained from various Islet Cell Resource centers administered by the Administrative and Bioinformatics Coordinating Center at the City of Hope National Medical Center and supported by NCRR, NIDDK, and JDRF. Histology sections were prepared by Chris Cahill (Joslin DERC, NIH DK 36836). Bio-spherix provided the Xvivo System for use in these experiments. NR 68 TC 21 Z9 22 U1 2 U2 9 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3384 J9 TISSUE ENG PART C-ME JI Tissue Eng. Part C-Methods PD APR PY 2011 VL 17 IS 4 BP 435 EP 449 DI 10.1089/ten.tec.2009.0510 PG 15 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 744FD UT WOS:000289079400007 PM 21067465 ER PT J AU Cady, B Michaelson, JS Chung, MA AF Cady, Blake Michaelson, James S. Chung, Maureen A. TI The "Tipping Point" for Breast Cancer Mortality Decline Has Resulted from Size Reductions Due to Mammographic Screening SO ANNALS OF SURGICAL ONCOLOGY LA English DT Editorial Material ID US C1 [Cady, Blake] Cambridge Hosp, Cambridge Breast Ctr, Dept Surg, Cambridge, MA 02139 USA. [Michaelson, James S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Boston, MA USA. [Chung, Maureen A.] Brown Univ, Rhode Isl Hosp, Dept Surg, Sch Med, Providence, RI 02903 USA. RP Cady, B (reprint author), Cambridge Hosp, Cambridge Breast Ctr, Dept Surg, Cambridge, MA 02139 USA. EM bcady123@comcast.net NR 17 TC 10 Z9 10 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD APR PY 2011 VL 18 IS 4 BP 903 EP 906 DI 10.1245/s10434-011-1557-y PG 4 WC Oncology; Surgery SC Oncology; Surgery GA 732TW UT WOS:000288213600001 PM 21267787 ER PT J AU Oklu, R Hesketh, R Wicky, S Metcalfe, JC AF Oeklue, Rahmi Hesketh, Robin Wicky, Stephan Metcalfe, James C. TI Expression of mRNA Isoforms of Latent Transforming Growth Factor-beta Binding Protein-1 in Coronary Atherosclerosis and Human Tissues SO BIOCHEMICAL GENETICS LA English DT Article DE Latent transforming growth factor-beta binding protein; Q-RT-PCR; Alternative splicing; Genetic variation ID SMOOTH-MUSCLE-CELLS; AMERICAN-HEART-ASSOCIATION; TGF-BETA; VASCULAR-LESIONS; RECEPTOR; TGF-BETA-1; GROWTH-FACTOR-BETA-1; ARTERIOSCLEROSIS; IDENTIFICATION; DEFINITION AB Latent transforming growth factor-beta binding protein-1 (LTBP1) has been implicated in the control of secretion, localization, and activation of TGF beta (transforming growth factor-beta). We developed a quantitative reverse-transcriptase polymerase chain reaction (Q-RT-PCR) assay using an RNA internal standard to examine the expression of three alternatively spliced isoforms of LTBP1 (LTBP1 Delta 41, LTBP1 Delta 53, and LTBP1 Delta 55) in a variety of human tissues. The assays were also used to determine the expression of LTBP1L and LTBP1S isoforms and total LTBP1. The Q-RT-PCR assays were highly reproducible and showed that in most tissues LTBP1 Delta 55 and LTBP1L were minor components of LTBP1. The proportion of LTBP1 Delta 41 ranged from 2% of total LTBP1 mRNA in early coronary atherosclerotic lesions to 54% in advanced lesions. C1 [Oeklue, Rahmi; Wicky, Stephan] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02155 USA. [Hesketh, Robin; Metcalfe, James C.] Univ Cambridge, Dept Biochem, Sect Cardiovasc Biol, Cambridge CB2 1QW, England. RP Oklu, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02155 USA. EM roklu@partners.org FU British Heart Foundation; Ali Y. Koc, Koc Holding, Istanbul, Turkey FX This work was supported by a British Heart Foundation program grant to JCM. RO is the recipient of a Koc scholarship from Ali Y. Koc, Koc Holding, Istanbul, Turkey. We are grateful to Drs. Chris Byrne and Junlong Zhang for helpful discussion of their Q-RT-PCR method. NR 25 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0006-2928 J9 BIOCHEM GENET JI Biochem. Genet. PD APR PY 2011 VL 49 IS 3-4 BP 213 EP 225 DI 10.1007/s10528-010-9400-x PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 732EV UT WOS:000288168700007 PM 21161366 ER PT J AU Cigler, T Richardson, H Yaffe, MJ Fabian, CJ Johnston, D Ingle, JN Nassif, E Brunner, RL Wood, ME Pater, JL Hu, H Qi, S Tu, D Goss, PE AF Cigler, T. Richardson, H. Yaffe, M. J. Fabian, C. J. Johnston, D. Ingle, J. N. Nassif, E. Brunner, R. L. Wood, M. E. Pater, J. L. Hu, H. Qi, S. Tu, D. Goss, P. E. TI A randomized, placebo-controlled trial (NCIC CTG MAP.2) examining the effects of exemestane on mammographic breast density, bone density, markers of bone metabolism and serum lipid levels in postmenopausal women SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE Chemoprevention; Aromatase inhibitors; Breast density; Bone density ID HORMONE REPLACEMENT THERAPY; CANCER RISK; PARENCHYMAL PATTERNS; ADJUVANT TAMOXIFEN; MINERAL DENSITY; COMPLETING 5; LETROZOLE; CLASSIFICATION; PROLIFERATION; POLYMORPHISMS AB We hypothesized that exemestane (EXE) would reduce mammographic breast density and have unique effects on biomarkers of bone and lipid metabolism. Healthy postmenopausal women were randomized to EXE (25 mg daily) or placebo (PLAC) for 12 months and followed for a total of 24 months. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms and secondary endpoints were changes in serum lipid levels, bone biomarkers, and bone mineral density (BMD). Ninety-eight women were randomized (49 to EXE; 49 to PLAC) and 65 had PD data at baseline and 12 months. Among women treated with EXE, PD was not significantly changed from baseline at 6, 12, or 24 months and was not different from PLAC. EXE was associated with significant percentage increase from baseline in N-telopeptide at 12 months compared with PLAC. No differences in percent change from baseline in BMD (lumbar spine and femoral neck) were observed between EXE and PLAC at either 12 or 24 months. Patients on EXE had a significantly larger percent decrease in total cholesterol than in the PLAC arm at 6 months and in HDL cholesterol at 3, 6, and 12 months. No significant differences in percent change in LDL or triglycerides were noted at any time point between the two treatment arms. EXE administered for 1 year to healthy postmenopausal women did not result in significant changes in mammographic density. A reversible increase in the bone resorption marker N-telopeptide without significant change in bone specific alkaline phosphatase or BMD during the 12 months treatment period and 1 year later was noted. Changes in lipid parameters on this trial were modest and reversible. C1 [Hu, H.; Qi, S.; Goss, P. E.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Cigler, T.] Weill Cornell Med Coll, New York, NY USA. [Richardson, H.; Johnston, D.; Pater, J. L.; Tu, D.] NCIC Clin Trials Grp, Kingston, ON, Canada. [Yaffe, M. J.] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Fabian, C. J.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Ingle, J. N.] Mayo Clin, Rochester, MN USA. [Nassif, E.] Univ Montreal, Notre Dame Hosp, Montreal, PQ H3C 3J7, Canada. [Brunner, R. L.] Univ Nevada, Sch Med, Reno, NV 89557 USA. [Wood, M. E.] Fletcher Allen Hlth Care, Burlington, VT USA. RP Goss, PE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, 55 Fruit St,Lawrence House,LRH-302, Boston, MA 02114 USA. EM pgoss@partners.org FU The Avon Foundation, New York; Pfizer Inc; Canadian Cancer Society FX Paul Goss is supported in part by The Avon Foundation, New York. This project was supported by Pfizer Inc and the Canadian Cancer Society. We are also indebted to the hard-working investigators and staff at the participating MAP.2 centres and to all the women who generously agreed to participate in this trial. NR 42 TC 21 Z9 21 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD APR PY 2011 VL 126 IS 2 BP 453 EP 461 DI 10.1007/s10549-010-1322-0 PG 9 WC Oncology SC Oncology GA 733GK UT WOS:000288251000017 PM 21221773 ER PT J AU Choi, HR von Knoch, F Zurakowski, D Nelson, SB Malchau, H AF Choi, Ho-Rim von Knoch, Fabian Zurakowski, David Nelson, Sandra B. Malchau, Henrik TI Can Implant Retention be Recommended for Treatment of Infected TKA? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID TOTAL-KNEE-ARTHROPLASTY; PROSTHETIC JOINT INFECTION; TOTAL HIP; 2-STAGE REVISION; DEBRIDEMENT; COMPONENTS; SALVAGE; MANAGEMENT; SPACER; IRRIGATION AB Retention treatment is reportedly associated with lower infection control rates than two-stage revision. However, the studies on which this presumption are based depend on comparisons of historical rather than concurrent controls. We (1) asked whether the infection control rates, number of additional procedures, length of hospital stay, and treatment duration differed between implant retention and two-stage revision treatment; and (2) identified risk factors that can contribute to failure of infection control. We reviewed the records of 60 patients treated for 64 infected TKA from 2002 to 2007. Twenty-eight patients (32 knees) underwent d,bridement with retention of component, and 32 patients (32 knees) were treated with component removal and two-stage revision surgery. We determined patients' demographics, type of infection, causative organisms, and outcome of treatment. Mean followup was 36 months (range, 12-84 months). Infection control rate was 31% in retention and 59% in the removal group after initial surgical treatment, and 81% and 91% at latest followup, respectively. Treatment duration was shorter in the retention group and there was no difference in number of additional surgeries and length of hospital stay. Type of treatment (retention versus removal) was the only factor associated with infection control; subgroup analysis in the retention group showed Staphylococcus aureus infection and polyethylene nonexchange as contributing factors for failure of infection control. Although initial infection control rate was substantially lower in the retention group than the removal group, final results were comparable at latest followup. We believe retention treatment can be selectively considered for non-S. aureus infection, and when applied in selected patients, polyethylene exchange should be performed. Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. C1 [Choi, Ho-Rim; von Knoch, Fabian; Malchau, Henrik] Massachusetts Gen Hosp, Harris Orthoped Lab, Dept Orthoped Surg, Boston, MA 02114 USA. [Choi, Ho-Rim] SoonChunHyang Univ Hosp, Dept Orthoped Surg, Cheonan, South Korea. [Zurakowski, David] Harvard Univ, Dept Anesthesiol, Sch Med, Childrens Hosp Boston, Boston, MA USA. [Zurakowski, David] Harvard Univ, Dept Surg, Sch Med, Childrens Hosp Boston, Boston, MA USA. [Nelson, Sandra B.] Massachusetts Gen Hosp, Div Infect Dis, Dept Med, Boston, MA 02114 USA. RP Malchau, H (reprint author), Massachusetts Gen Hosp, Harris Orthoped Lab, Dept Orthoped Surg, 55 Fruit St,GRJ-1126, Boston, MA 02114 USA. EM hmalchau@partners.org NR 37 TC 28 Z9 30 U1 0 U2 2 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 APR PY 2011 VL 469 IS 4 BP 961 EP 969 DI 10.1007/s11999-010-1679-8 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 730HA UT WOS:000288023200006 PM 21080127 ER PT J AU Wuerz, TH Regenbogen, SE Ehrenfeld, JM Malchau, H Rubash, HE Gawande, AA Kent, DM AF Wuerz, Thomas H. Regenbogen, Scott E. Ehrenfeld, Jesse M. Malchau, Henrik Rubash, Harry E. Gawande, Atul A. Kent, David M. TI The Surgical Apgar Score in Hip and Knee Arthroplasty SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID ADVERSE EVENTS; BLOOD-PRESSURE; ERRORS; HANDWRITTEN; HOSPITALS; RECORDS; RISK AB A 10-point Surgical Apgar Score, based on patients' estimated blood loss, lowest heart rate, and lowest mean arterial pressure during surgery, was developed to rate patients' outcomes in general and vascular surgery but has not been tested for patients having orthopaedic surgery. For patients undergoing hip and knee arthroplasties, we asked (1) whether the score provides accurate risk stratification for major postoperative complications, and (2) whether it captures intraoperative variables contributing to postoperative risk based on the three parameters independent of preoperative risk. We retrospectively reviewed the electronic records for all 3511 patients who underwent a hip or knee arthroplasty from March 2003 to August 2006 and extracted data to calculate a Surgical Apgar Score. We evaluated the relationship between scores and likelihood of major postoperative in-hospital complications and assessed its discrimination and calibration. Complication rates increased monotonically as the score decreased. Even after controlling for preoperative risk, each 1-point decrease in the score was associated with a 34.0% increase (95% confidence interval, 0.66-0.84) in the odds of a complication. The overall discriminatory performance of the score was a c-statistic of 0.61. Seventy-six percent of all major complications occurred in patients classified as low risk with scores of 7 or greater. For patients undergoing hip and knee arthroplasties, the score captures important intraoperative information regarding risk of complications and contributes additional information to preoperative risk, but on its own is insufficient to provide comprehensive postoperative risk stratification for arthroplasties. Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. C1 [Wuerz, Thomas H.; Kent, David M.] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Ctr Predict Med Res, Boston, MA 02111 USA. [Wuerz, Thomas H.] Tufts Univ, Sackler Sch Grad Biomed Sci, Clin Res Program, Boston, MA 02111 USA. [Wuerz, Thomas H.; Malchau, Henrik; Rubash, Harry E.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Regenbogen, Scott E.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Regenbogen, Scott E.; Gawande, Atul A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Ehrenfeld, Jesse M.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Gawande, Atul A.] Brigham & Womens Hosp, Dept Surg, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. RP Wuerz, TH (reprint author), Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Ctr Predict Med Res, 35 Kneeland St, Boston, MA 02111 USA. EM twuerz@partners.org OI Ehrenfeld, Jesse/0000-0003-3427-0140; Gawande, Atul/0000-0002-1824-9176 FU National Institutes of Health [T32 HS00060] FX One of the authors (THW) has received funding from the National Institutes of Health under Ruth L. Kirschstein National Research Service Award (Agency for Healthcare Research and Quality Grant Number T32 HS00060). NR 22 TC 22 Z9 22 U1 1 U2 3 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 APR PY 2011 VL 469 IS 4 BP 1119 EP 1126 DI 10.1007/s11999-010-1721-x PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 730HA UT WOS:000288023200028 PM 21132410 ER PT J AU Clements, JL Bouchard, CS Lee, WB Dunn, SP Mannis, MJ Reidy, JJ John, T Hannush, SB Goins, KM Wagoner, MD Adi, MA Rubenstein, JB Udell, IJ Babiuch, AS AF Clements, John L. Bouchard, Charles S. Lee, W. Barry Dunn, Steven P. Mannis, Mark J. Reidy, James J. John, Thomas Hannush, Sadeer B. Goins, Kenneth M. Wagoner, Michael D. Adi, Marwa A. Rubenstein, Jonathan B. Udell, Ira J. Babiuch, Amy S. TI Retrospective Review of Graft Dislocation Rate Associated With Descemet Stripping Automated Endothelial Keratoplasty After Primary Failed Penetrating Keratoplasty SO CORNEA LA English DT Review DE cornea transplant; Descemet stripping endothelial keratoplasty; penetrating keratoplasty; endothelial keratoplasty ID CELL LOSS; UNITED-STATES; EYES; OUTCOMES; TRENDS AB Purpose: To report the rate of graft dislocation in patients who underwent Descemet stripping automated endothelial keratoplasty (DSAEK) after a previous penetrating keratoplasty (PKP). Methods: Institutional review board-approved, multicenter, retrospective chart review. Inclusion criteria included: prior failed PKP and subsequent DSAEK. The primary outcomes measured in this study were the presence of a graft dislocation, rate of rebubble, and graft attachment. Additional variables included: presence of a prior glaucoma drainage device, graft-to-host size disparity, number of sutures remaining in PKP, and stripping of the Descemet membrane at the time of DSAEK surgery. Results: Ninety patients (97 eyes) were included in the study. In 31% (30 of 97), the endothelial graft dislocated after surgery. All 30 cases required a rebubble except 1, which reattached spontaneously. Ninety-eight percent (95 of 97) of all grafts remained attached for the duration of the follow-up period. Only 2 eyes (2.2%) required repeat graft. Endothelial grafts dislocated in 67% of patients with glaucoma draining devices. The dislocation rate for grafts larger than the host was 12 of 49 (24%), equal to the host was 3 of 17 (18%), and smaller than the host was 8 of 19 (42%). Dislocations occurred in 5 of 21 (24%) of grafts with sutures remaining and 22 of 76 (29%) of those with all sutures out. Five of 12 (42%) cases of grafts performed without stripping the Descemet had dislocations. Conclusions: The graft dislocation rate in DSAEK procedures after PKP is comparable to that after primary DSAEK cases. Donor grafts that are smaller than the host PKP and the presence of prior glaucoma drainage devices are risk factors for higher rates of graft dislocation. C1 [Clements, John L.; Bouchard, Charles S.; John, Thomas] Loyola Univ, Dept Ophthalmol, Med Ctr, Maywood, IL 60153 USA. [Clements, John L.; Bouchard, Charles S.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Dept Ophthalmol, Hines, IL 60141 USA. [Lee, W. Barry] Eye Consultants Atlanta Piedmont Hosp, Dept Ophthalmol, Atlanta, GA USA. [Dunn, Steven P.] William Beaumont Hosp, Dept Ophthalmol, Royal Oak, MI 48072 USA. [Mannis, Mark J.] Univ Calif Davis, Dept Ophthalmol & Vis Sci, Sacramento, CA 95817 USA. [Reidy, James J.] SUNY Buffalo, Dept Ophthalmol, Buffalo, NY 14260 USA. [Hannush, Sadeer B.] Wills Eye Inst, Dept Ophthalmol, Philadelphia, PA USA. [Goins, Kenneth M.; Wagoner, Michael D.] Univ Iowa Hosp & Clin, Dept Ophthalmol & Visual Sci, Iowa City, IA 52242 USA. [Adi, Marwa A.] Georgetown Univ, Med Ctr, Dept Ophthalmol, Washington, DC 20007 USA. [Rubenstein, Jonathan B.; Babiuch, Amy S.] Rush Univ, Dept Ophthalmol, Med Ctr, Chicago, IL 60612 USA. [Udell, Ira J.] Albert Einstein Coll Med, Northshore Long Isl Jewish Hlth Syst, Dept Ophthalmol, Bronx, NY 10467 USA. RP Bouchard, CS (reprint author), Loyola Univ, Dept Ophthalmol, Med Ctr, 2160 S 1st Ave, Maywood, IL 60153 USA. EM cboucha@lumc.edu FU Richard A. Perritt Charitable Foundation FX Supported in part by the Richard A. Perritt Charitable Foundation. NR 21 TC 28 Z9 30 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 J9 CORNEA JI Cornea PD APR PY 2011 VL 30 IS 4 BP 414 EP 418 DI 10.1097/ICO.0b013e3181f7f163 PG 5 WC Ophthalmology SC Ophthalmology GA 732OJ UT WOS:000288196200009 PM 21099405 ER PT J AU Wessel, MM Sarkar, JS Jakobiec, FA Dang, NT Bhat, P Michaud, N Starr, CE AF Wessel, Matthew M. Sarkar, Jayati S. Jakobiec, Frederick A. Dang, Natasha Bhat, Pooja Michaud, Norman Starr, Christopher E. TI Treatment of Lisch Corneal Dystrophy With Photorefractive Keratectomy and Mitomycin C SO CORNEA LA English DT Article DE Lisch corneal dystrophy; photorefractive keratectomy; mitomycin C; electron microscopy ID WHORLED MICROCYSTIC DYSTROPHY; KERATOCYTES; EPITHELIUM AB Purpose: To describe a case of Lisch dystrophy; review the clinical, histopathologic, and electron microscopic features of this entity; and discuss a novel treatment approach using photorefractive keratectomy (PRK) and mitomycin C (MMC). Methods: A 45-year-old man with a feathery, comet-shaped, right-sided, corneal lesion was treated with excimer laser PRK and 20 seconds of MMC. The uninvolved fellow eye underwent traditional PRK without the use of MMC. Epithelial scrapings were sent for histopathologic analysis. Results: Histopathologic analysis showed vacuolated cells in the epithelial layer. Electron microscopy revealed empty intracytoplasmic vacuoles, electron-dense whorled inclusions, and reduced tonofilaments. Surface ablation and MMC was successful in treating the initial lesion, with only minimal recurrence noted in the affected eye. Surprisingly, a new asymptomatic lesion was noted in the unaffected eye but dissipated over time. Conclusions: Although the whorled inclusions represent a novel finding, the overall clinical and microscopic analysis was consistent with Lisch dystrophy. Surface ablation with MMC should be considered as a treatment option for this disease. C1 [Wessel, Matthew M.; Sarkar, Jayati S.; Starr, Christopher E.] Cornell Univ, Weill Cornell Med Coll, New York Presbyterian Hosp, Dept Ophthalmol, New York, NY 10021 USA. [Jakobiec, Frederick A.; Bhat, Pooja; Michaud, Norman] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Lab Ophthalm Pathol, Boston, MA USA. [Dang, Natasha] Univ Ottawa, Ottawa Hosp, Inst Eye, Dept Ophthalmol, Ottawa, ON, Canada. RP Starr, CE (reprint author), Cornell Univ, Weill Cornell Med Coll, New York Presbyterian Hosp, Dept Ophthalmol, 1305 York Ave,11th Floor, New York, NY 10021 USA. EM cestarr@med.cornell.edu NR 12 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 J9 CORNEA JI Cornea PD APR PY 2011 VL 30 IS 4 BP 481 EP 485 DI 10.1097/ICO.0b013e3181ec8e26 PG 5 WC Ophthalmology SC Ophthalmology GA 732OJ UT WOS:000288196200026 PM 21045666 ER PT J AU Mianowska, B Fendler, W Szadkowska, A Baranowska, A Grzelak-Agaciak, E Sadon, J Keenan, H Mlynarski, W AF Mianowska, B. Fendler, W. Szadkowska, A. Baranowska, A. Grzelak-Agaciak, E. Sadon, J. Keenan, H. Mlynarski, W. TI HbA(1c) levels in schoolchildren with type 1 diabetes are seasonally variable and dependent on weather conditions SO DIABETOLOGIA LA English DT Article DE Adolescents; Children; HbA(1c); Seasonal variation; Type 1 diabetes mellitus ID PHYSICAL-ACTIVITY; INTENSIVE TREATMENT; VITAMIN-D; MELLITUS; CHILDREN; INSULIN; MELATONIN; TIME; VALUES; MEN AB We evaluated seasonal HbA(1c) changes in children with type 1 diabetes and its relation with measures of weather conditions. HbA(1c) changes over more than 3 years were evaluated in type 1 diabetic patients who were younger than 18 years and had diabetes duration of more than 12 months, and correlated with measures of weather conditions (ambient temperature, hours of sunshine and solar irradiance). After comparison of autocorrelation patterns, patterns of metabolic control and meteorological data were evaluated using Spearman rank correlation. A total of 3,935 HbA(1c) measurements in 589 school (a parts per thousand yen7 years) and 88 preschool (< 7 years) children were analysed. Mean (+/- SD) HbA(1c) level for the whole study period was 7.65 +/- 1.12%. The lowest HbA(1c) levels were observed in late summer and the highest in winter months, with differences consistently exceeding 0.44%. Autocorrelation analysis of HbA(1c) levels in schoolchildren showed a sine-wave pattern with a cycle length of roughly 12 months, which mirrored changes in ambient temperature. Strong negative correlations of HbA(1c) with ambient temperature (R = -0.56; p = 0.0002), hours of sunshine (R = -0.52; p = 0.0007) and solar irradiance (R = -0.52; p = 0.0006) were present in schoolchildren, but not in preschoolers (p a parts per thousand yenaEuro parts per thousand 0.29 for each correlation). Seasonal changes of HbA(1c) levels in schoolchildren with type 1 diabetes are a significant phenomenon and should be considered in patient education and diabetes management. They may potentially affect the results of clinical trials using HbA(1c) levels as their primary outcome, as well as HbA(1c)-based diagnosis of diabetes. C1 [Mianowska, B.; Fendler, W.; Szadkowska, A.; Baranowska, A.; Mlynarski, W.] Med Univ Lodz, Dept Pediat Oncol Hematol & Diabetol, PL-91738 Lodz, Poland. [Grzelak-Agaciak, E.; Sadon, J.] Inst Meteorol & Water Management, Warsaw, Poland. [Keenan, H.] Harvard Univ, Sch Med, Dept Med, Clin Res Joslin Diabet Ctr, Boston, MA USA. RP Mlynarski, W (reprint author), Med Univ Lodz, Dept Pediat Oncol Hematol & Diabetol, 36-50 Sporna St, PL-91738 Lodz, Poland. EM Wojciech.Mlynarski@umed.lodz.pl RI Mianowska, Beata/S-9485-2016; Fendler, Wojciech/S-9592-2016 OI Fendler, Wojciech/0000-0002-5083-9168 FU Innovative Economy Operational Program; Foundation for Polish Science; Polish Ministry of Science and Higher Education [N407 022135, N407 099437]; Foundation for Development of Polish Pharmacy and Medicine FX The study was funded by TEAM programme 'Polish Registry for Pediatric and Adolescent Diabetes-nationwide genetic screening for monogenic diabetes' of the Innovative Economy Operational Program and Foundation for Polish Science. W. Fendler was supported by a research grant of the Polish Ministry of Science and Higher Education (N407 022135) and the Foundation for Development of Polish Pharmacy and Medicine. W. Mlynarski was supported by a research grant of the Polish Ministry of Science and Higher Education (N407 099437). NR 30 TC 22 Z9 22 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD APR PY 2011 VL 54 IS 4 BP 749 EP 756 DI 10.1007/s00125-010-2013-4 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 732VG UT WOS:000288217200006 PM 21188352 ER PT J AU Xavier, GD Farhan, H Kim, H Caxaria, S Johnson, P Hughes, S Bugliani, M Marselli, L Marchetti, P Birzele, F Sun, G Scharfmann, R Rutter, J Siniakowicz, K Weir, G Parker, H Reimann, F Gribble, FM Rutter, GA AF Xavier, G. da Silva Farhan, H. Kim, H. Caxaria, S. Johnson, P. Hughes, S. Bugliani, M. Marselli, L. Marchetti, P. Birzele, F. Sun, G. Scharfmann, R. Rutter, J. Siniakowicz, K. Weir, G. Parker, H. Reimann, F. Gribble, F. M. Rutter, G. A. TI Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion SO DIABETOLOGIA LA English DT Article DE Alpha cells; Glucagon secretion; Human islets of Langerhans; Knockout mouse; PASK ID GAMMA-AMINOBUTYRIC-ACID; PANCREATIC ALPHA-CELLS; SERINE/THREONINE KINASE; BETA-CELLS; GENE-EXPRESSION; IN-VIVO; INSULIN; GLUCOSE; MOUSE; SOMATOSTATIN AB We assessed whether per-arnt-sim (PAS) domain-containing protein kinase (PASK) is involved in the regulation of glucagon secretion. mRNA levels were measured in islets by quantitative PCR and in pancreatic beta cells obtained by laser capture microdissection. Glucose tolerance, plasma hormone levels and islet hormone secretion were analysed in C57BL/6 Pask homozygote knockout mice (Pask (-/-)) and control littermates. Alpha-TC1-9 cells, human islets or cultured E13.5 rat pancreatic epithelia were transduced with anti-Pask or control small interfering RNAs, or with adenoviruses encoding enhanced green fluorescent protein or PASK. PASK expression was significantly lower in islets from human type 2 diabetic than control participants. PASK mRNA was present in alpha and beta cells from mouse islets. In Pask (-/-) mice, fasted blood glucose and plasma glucagon levels were 25 +/- 5% and 50 +/- 8% (mean +/- SE) higher, respectively, than in control mice. At inhibitory glucose concentrations (10 mmol/l), islets from Pask (-/-) mice secreted 2.04 +/- 0.2-fold (p < 0.01) more glucagon and 2.63 +/- 0.3-fold (p < 0.01) less insulin than wild-type islets. Glucose failed to inhibit glucagon secretion from PASK-depleted alpha-TC1-9 cells, whereas PASK overexpression inhibited glucagon secretion from these cells and human islets. Extracellular insulin (20 nmol/l) inhibited glucagon secretion from control and PASK-deficient alpha-TC1-9 cells. PASK-depleted alpha-TC1-9 cells and pancreatic embryonic explants displayed increased expression of the preproglucagon (Gcg) and AMP-activated protein kinase (AMPK)-alpha2 (Prkaa2) genes, implying a possible role for AMPK-alpha2 downstream of PASK in the control of glucagon gene expression and release. PASK is involved in the regulation of glucagon secretion by glucose and may be a useful target for the treatment of type 2 diabetes. C1 [Xavier, G. da Silva; Farhan, H.; Kim, H.; Caxaria, S.; Sun, G.; Rutter, G. A.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Endocrinol Diabet & Metab, Sect Cell Biol, London SW7 2AZ, England. [Johnson, P.; Hughes, S.] Univ Oxford, Nuffield Dept Surg Sci, Oxford, England. [Bugliani, M.; Marselli, L.; Marchetti, P.] Univ Pisa, Dipartimento Endocrinol & Metab, Unita Metab, Pisa, Italy. [Birzele, F.] Boehringer Ingelheim Pharma GmbH & Co KG, Target Discovery Res, Ingelheim, Germany. [Scharfmann, R.] Univ Paris 05, INSERM U845, Ctr Rech Croissance & Signalisat, Hop Necker,Fac Med, Paris, France. [Rutter, J.] Univ Utah, Sch Med, Div Endocrinol, Salt Lake City, UT USA. [Siniakowicz, K.; Weir, G.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol,Res Div, Boston, MA 02115 USA. [Siniakowicz, K.; Weir, G.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Parker, H.; Reimann, F.; Gribble, F. M.] Addenbrookes Hosp, Cambridge Inst Med Res, Cambridge, England. [Parker, H.; Reimann, F.; Gribble, F. M.] Addenbrookes Hosp, Dept Clin Biochem, Cambridge, England. RP Xavier, GD (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Med, Div Endocrinol Diabet & Metab, Sect Cell Biol, Exhibit Rd, London SW7 2AZ, England. EM g.dasilva-xavier@imperial.ac.uk; g.rutter@imperial.ac.uk RI Marchetti, Piero/J-7439-2013; OI Marchetti, Piero/0000-0003-4907-0635; da Silva Xavier, Gabriela/0000-0002-0678-012X FU Juvenile Diabetes Research Foundation; European Foundation; Wellcome Trust [081958/2/07/2]; Medical Research Council [G0401641]; Imperial College London; Diabetes Research and Wellness Foundation FX The authors thank S. Vakhshouri for technical assistance, and F. Semplici and M. K. Loder for scientific input during manuscript preparation. This work was supported by a Juvenile Diabetes Research Foundation post-doctoral fellowship and an European Foundation for the Study of Diabetes Albert Renold travelling fellowship to G. da Silva Xavier, and by grants to G. A. Rutter from the Wellcome Trust (081958/2/07/2) and the Medical Research Council (G0401641). H. Farhan, H. Kim and S. Caxaria were supported by Imperial College London BSc and MSc project funds. The Diabetes Research and Wellness Foundation supported P. Johnson and S. Hughes. NR 37 TC 12 Z9 13 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD APR PY 2011 VL 54 IS 4 BP 819 EP 827 DI 10.1007/s00125-010-2010-7 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 732VG UT WOS:000288217200016 ER PT J AU Dubovsky, SL Dubovsky, AN AF Dubovsky, Steven L. Dubovsky, Amelia N. TI Ziprasidone for maintenance treatment of bipolar I disorder in adults SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE antipsychotic drug; bipolar; maintenance; mania; prophylaxis ID RANDOMIZED CONTROLLED-TRIALS; ATYPICAL ANTIPSYCHOTICS; DOUBLE-BLIND; MOOD STABILIZER; ACUTE MANIA; DE-POINTES; PLACEBO; EFFICACY; MANAGEMENT; LITHIUM AB Introduction: Antipsychotic drugs are increasingly used in the maintenance treatment of bipolar disorder. This review addresses the evidence supporting the use of one of these medications for this indication in order to place available data in perspective for the clinician. Areas covered: The approval of ziprasidone for maintenance treatment of bipolar I disorder was based on two open-label extensions of industry-sponsored 3-week monotherapy trials in mania, involving a total of 189 patients and an industry-sponsored study using sample enrichment of 584 outpatients who had either ziprasidone or a placebo added to lithium or valproate. Patients enrolled in maintenance studies did not have refractory mood disorders or comorbid conditions or risk of dangerousness, and they were able to give sustained consent. Ziprasidone is generally well tolerated, but should be taken with food. Primary interactions of concern are those with other serotonergic medications and other medications that prolong the QT interval. Expert opinion: Although antipsychotic drugs are used frequently for maintenance treatment, current guidelines recommend that an attempt be made to withdraw them after acute treatment. The use of these medications as part of a maintenance regimen is most appropriate in cases of persistent psychosis or failure to respond to standard mood stabilizer combinations. C1 [Dubovsky, Steven L.] SUNY Buffalo, Dept Psychiat, Buffalo, NY 14215 USA. [Dubovsky, Amelia N.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Dubovsky, Steven L.] Univ Colorado, Dept Med, Denver, CO USA. RP Dubovsky, SL (reprint author), SUNY Buffalo, Dept Psychiat, 462 Grider St, Buffalo, NY 14215 USA. EM dubovsky@buffalo.edu FU Pfizer; Biogen; Eli Lilly; Otsuka; Sumitomo FX SL Dubovsky has received research support from Pfizer, Biogen, Eli Lilly, Otsuka and Sumitomo. NR 45 TC 1 Z9 2 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD APR PY 2011 VL 12 IS 5 BP 817 EP 824 DI 10.1517/14656566.2011.563237 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 732VS UT WOS:000288218400013 PM 21385150 ER PT J AU Furukawa, T Hatori, T Fujita, I Yamamoto, M Kobayashi, M Ohike, N Morohoshi, T Egawa, S Unno, M Takao, S Osako, M Yonezawa, S Mino-Kenudson, M Lauwers, GY Yamaguchi, H Ban, S Shimizu, M AF Furukawa, Toru Hatori, Takashi Fujita, Izumi Yamamoto, Masakazu Kobayashi, Makio Ohike, Nobuyuki Morohoshi, Toshio Egawa, Shinichi Unno, Michiaki Takao, Sonshin Osako, Masahiko Yonezawa, Suguru Mino-Kenudson, Mari Lauwers, Gregory Y. Yamaguchi, Hiroshi Ban, Shinichi Shimizu, Michio TI Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas SO GUT LA English DT Article ID CYSTIC NEOPLASMS; EXPRESSION; TUMORS; CLASSIFICATION; MANAGEMENT; CONSENSUS AB Objective The clinicopathological significance of four morphological types of intraductal papillary mucinous neoplasms of the pancreas (IPMNs; gastric, intestinal, pancreatobiliary and oncocytic) was assessed. Design Retrospective multicentre analysis of 283 surgically resected IPMNs. Results Of the 283 IPMNs, 139 were of the gastric type, 101 were intestinal, 19 were pancreatobiliary and 24 were oncocytic. These types were significantly associated with clinicopathological factors including sex (p=0.0032), age (p=0.00924), ectatic duct size (p=0.0245), detection of mural nodules (p=4.09x10(-6)), histological grade (p < 2.20x10(-16)), macroscopic types with differential involvement of the pancreatic duct system (p=3.91x10(-5)), invasive phenotypes (p=3.34x10(-12)), stage (p < 2.20x10(-16)) and recurrence (p=0.00574). Kaplan-Meier analysis showed significant differences in patient survival by morphological type (p=5.24x10(-6)). Survival rates at 5 and 10 years, respectively, were 0.937 (95% CI 0.892 to 0.984) for patients with gastric-type IPMNs; 0.886 (95% CI 0.813 to 0.965) and 0.685 (95% CI 0.553 to 0.849) for those with intestinal-type IPMNs; 0.839 (95% CI 0.684 to 1.000) and 0.734 (95% CI 0.526 to 1.000) for those with oncocytic-type IPMNs; and 0.520 (95% CI 0.298 to 0.909) and undetermined for those with pancreatobiliary-type IPMNs. Analysis by the Cox proportional hazards model comparing prognostic risks determined by stage and the morphological and macroscopic types indicated that staging was the most significant predictor of survival (p=3.68x10(-8)) followed by the morphological type (p=0.0435). Furthermore, the morphological type remained a significant predictor in a subcohort of invasive cases (p=0.0089). Conclusion In this multicentre retrospective analysis, the morphological type of IPMN appears to be an independent predictor of patient prognosis. C1 [Furukawa, Toru] Tokyo Womens Med Univ, Inst Integrated Med Sci, Shinjuku Ku, Tokyo 1628666, Japan. [Furukawa, Toru; Kobayashi, Makio] Tokyo Womens Med Univ Hosp, Dept Surg Pathol, Tokyo, Japan. [Hatori, Takashi; Fujita, Izumi; Yamamoto, Masakazu] Tokyo Womens Med Univ, Dept Surg, Inst Gastroenterol, Tokyo 1628666, Japan. [Kobayashi, Makio] Tokyo Womens Med Univ, Dept Pathol, Tokyo 1628666, Japan. [Ohike, Nobuyuki; Morohoshi, Toshio] Showa Univ, Sch Med, Dept Pathol 1, Tokyo 142, Japan. [Egawa, Shinichi; Unno, Michiaki] Tohoku Univ, Div Hepatobiliary Pancreat Surg, Grad Sch Med, Sendai, Miyagi 980, Japan. [Takao, Sonshin] Kagoshima Univ, Frontier Sci Res Ctr, Kagoshima 890, Japan. [Osako, Masahiko] Kagoshima Shi Med Assoc Hosp, Dept Surg, Kagoshima, Japan. [Yonezawa, Suguru] Kagoshima Univ, Dept Human Pathol, Field Oncol, Grad Sch Med & Dent Sci, Kagoshima 890, Japan. [Mino-Kenudson, Mari; Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Yamaguchi, Hiroshi; Ban, Shinichi; Shimizu, Michio] Saitama Med Univ, Int Med Ctr, Dept Pathol, Hidaka, Saitama, Japan. RP Furukawa, T (reprint author), Tokyo Womens Med Univ, Inst Integrated Med Sci, Shinjuku Ku, 8-1 Kawada Cho, Tokyo 1628666, Japan. EM toru.furukawa@twmu.ac.jp RI Unno, Michiaki/A-8633-2010 OI Unno, Michiaki/0000-0002-2145-6416 FU Ministry of Education, Culture, Sports, Science and Technology; Ministry of Education, Culture, Sports, Science and Technology (Japan) FX This work was supported in part by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology and by the Program for Promoting the Establishment of Strategic Research Centers, Special Coordination Funds for Promoting Science and Technology, Ministry of Education, Culture, Sports, Science and Technology (Japan). NR 20 TC 90 Z9 92 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD APR PY 2011 VL 60 IS 4 BP 509 EP 516 DI 10.1136/gut.2010.210567 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 730CZ UT WOS:000288010600016 PM 21193453 ER PT J AU Pett, SL Carey, C Lin, E Wentworth, D Lazovski, J Miro, JM Gordin, F Angus, B Rodriguez-Barradas, M Rubio, R Tambussi, G Cooper, DA Emery, S AF Pett, S. L. Carey, C. Lin, E. Wentworth, D. Lazovski, J. Miro, J. M. Gordin, F. Angus, B. Rodriguez-Barradas, M. Rubio, R. Tambussi, G. Cooper, D. A. Emery, S. CA INSIGHT-ESPRIT Study Grp TI Predictors of bacterial pneumonia in Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT) SO HIV MEDICINE LA English DT Article DE bacterial pneumonia; combination antiretroviral therapy; ESPRIT; rIL-2 ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; INCREASED APOPTOSIS; THERAPY; RISK; INDIVIDUALS; SMOKING; CYCLES; PLASMA; COHORT AB Background and Objectives Bacterial pneumonia still contributes to morbidity/mortality in HIV infection despite effective combination antiretroviral therapy (cART). Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT), a trial of intermittent recombinant interleukin-2 (rIL-2) with cART vs. cART alone (control arm) in HIV-infected adults with CD4 counts >= 300 cells/mu L, offered the opportunity to explore associations between bacterial pneumonia and rIL-2, a cytokine that increases the risk of some bacterial infections. Methods Baseline and time-updated factors associated with first-episode pneumonia on study were analysed using multivariate proportional hazards regression models. Information on smoking/pneumococcal vaccination history was not collected. Results IL-2 cycling was most intense in years 1-2. Over approximate to 7 years, 93 IL-2 [rate 0.67/100 person-years (PY)] and 86 control (rate 0.63/100 PY) patients experienced a pneumonia event [hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.79, 1.42; P=0.68]. Median CD4 counts prior to pneumonia were 570 cells/mu L (IL-2 arm) and 463 cells/mu L (control arm). Baseline risks for bacterial pneumonia included older age, injecting drug use, detectable HIV viral load (VL) and previous recurrent pneumonia; Asian ethnicity was associated with decreased risk. Higher proximal VL (HR for 1 log(10) higher VL 1.28; 95% CI 1.11, 1.47; P < 0.001) was associated with increased risk; higher CD4 count prior to the event (HR per 100 cells/mu L higher 0.94; 95% CI 0.89, 1.0; P=0.04) decreased risk. Compared with controls, the hazard for a pneumonia event was higher if rIL-2 was received < 180 days previously (HR 1.66; 95% CI 1.07, 2.60; P=0.02) vs. >= 180 days previously (HR 0.98; 95% CI 0.70, 1.37; P=0.9). Compared with the control group, pneumonia risk in the IL-2 arm decreased over time, with HRs of 1.41, 1.71, 1.16, 0.62 and 0.84 in years 1, 2, 3-4, 5-6 and 7, respectively. Conclusions Bacterial pneumonia rates in cART-treated adults with moderate immunodeficiency are high. The mechanism of the association between bacterial pneumonia and recent IL-2 receipt and/or detectable HIV viraemia warrants further exploration. C1 [Pett, S. L.] Univ New S Wales, Fac Med, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW 2034, Australia. [Pett, S. L.; Cooper, D. A.] St Vincents Hosp, Ctr Appl Med Res, Sydney, NSW 2010, Australia. [Wentworth, D.] Univ Minnesota, Dept Biostat, Minneapolis, MN USA. [Lazovski, J.] Fdn ESPRIT, Buenos Aires, DF, Argentina. [Miro, J. M.] Univ Barcelona, Hosp Clin IDIBAPS, Barcelona, Spain. [Gordin, F.] VA Med Ctr, Dept Infect Dis, Washington, DC USA. [Angus, B.] John Radcliffe Hosp, Wellcome Trust Ctr Clin Trop Med, Oxford OX3 9DU, England. [Rodriguez-Barradas, M.] VA Med Ctr, Houston, TX USA. [Rubio, R.] Hosp 12 Octubre, E-28041 Madrid, Spain. [Tambussi, G.] Univ Milan, Osped San Raffaele, Div Malattie, I-20127 Milan, Italy. RP Pett, SL (reprint author), Univ New S Wales, Fac Med, Natl Ctr HIV Epidemiol & Clin Res, UNSW Coogee Campus,45 Beach St, Sydney, NSW 2034, Australia. EM spett@nchecr.unsw.edu.au RI Yee, Thynn Thynn/H-5862-2012; Beral, Valerie/B-2979-2013; Doerler, Martin/C-2015-2013; Pulido, Federico/B-8417-2009; Arribas, Jose/A-1595-2015; Victor, Moreno-Cuerda/G-3851-2016; Bouza, Emilio/D-8661-2014; Emery, Sean/H-4920-2013 OI Okhuysen, Pablo/0000-0002-1596-3411; Magenta, Lorenzo/0000-0002-7644-3647; Angus, Brian/0000-0003-3598-7784; Pulido, Federico/0000-0002-7414-8812; Arribas, Jose/0000-0002-7410-9450; Victor, Moreno-Cuerda/0000-0003-0262-8216; Bouza, Emilio/0000-0001-6967-9267; Emery, Sean/0000-0001-6072-8309 FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI46957, U01 AI068641] FX The Writing Group acknowledges the efforts of the many ESPRIT and SILCAAT investigators who collected these data, and the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) Executive Committee (J. D. Neaton, D. Abrams, A. Babiker, J. Baxter, D. A. Cooper, C. J. Cohen, D. Cohn, J. H. Darbyshire, W. El-Sadr, S. Emery, F. Gordin, H. C. Lane, G. Larson, M. H. Losso, J. D. Lundgren, J. Nadler and A. N. Phillips) for their oversight of the ESPRIT study and valuable editorial assistance. ESPRIT was supported by grants U01 AI46957 and U01 AI068641 from the National Institute of Allergy and Infectious Diseases (NIAID). rIL-2 was provided by Chiron and Novartis. This study is ClinicalTrials.gov number NCT00004978. NR 25 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-2662 J9 HIV MED JI HIV Med. PD APR PY 2011 VL 12 IS 4 BP 219 EP 227 DI 10.1111/j.1468-1293.2010.00875.x PG 9 WC Infectious Diseases SC Infectious Diseases GA 730GB UT WOS:000288020700005 PM 20812949 ER PT J AU Eyler, LT Prom-Wormley, E Fennema-Notestine, C Panizzon, MS Neale, MC Jernigan, TL Fischl, B Franz, CE Lyons, MJ Stevens, A Pacheco, J Perry, ME Schmitt, JE Spitzer, NC Seidman, LJ Thermenos, HW Tsuang, MT Dale, AM Kremen, WS AF Eyler, Lisa T. Prom-Wormley, Elizabeth Fennema-Notestine, Christine Panizzon, Matthew S. Neale, Michael C. Jernigan, Terry L. Fischl, Bruce Franz, Carol E. Lyons, Michael J. Stevens, Allison Pacheco, Jennifer Perry, Michele E. Schmitt, J. Eric Spitzer, Nicholas C. Seidman, Larry J. Thermenos, Heidi W. Tsuang, Ming T. Dale, Anders M. Kremen, William S. TI Genetic Patterns of Correlation Among Subcortical Volumes in Humans: Results From a Magnetic Resonance Imaging Twin Study SO HUMAN BRAIN MAPPING LA English DT Article DE behavioral genetics; hippocampus; amygdala; striatum; pallidum; caudate; putamen; thalamus; ventricles ID FACTOR VAL66MET POLYMORPHISM; VIETNAM ERA TWIN; HUMAN BRAIN; NEUROTROPHIC FACTOR; CEREBRAL-CORTEX; HIPPOCAMPAL VOLUMES; HEALTHY-SUBJECTS; OLDER-ADULTS; MORPHOLOGY; MRI AB Little is known about genetic influences on the volume of subcortical brain structures in adult humans, particularly whether there is regional specificity of genetic effects. Understanding patterns of genetic covariation among volumes of subcortical structures may provide insight into the development of individual differences that have consequences for cognitive and emotional behavior and neuropsychiatric disease liability. We measured the volume of 19 subcortical structures (including brain and ventricular regions) in 404 twins (110 monozygotic and 92 dizygotic pairs) from the Vietnam Era Twin Study of Aging and calculated the degree of genetic correlation among these volumes. We then examined the patterns of genetic correlation through hierarchical cluster analysis and by principal components analysis. We found that a model with four genetic factors best fit the data: a Basal Ganglia/Thalamus factor; a Ventricular factor; a Limbic factor; and a Nucleus Accumbens factor. Homologous regions from each hemisphere loaded on the same factors. The observed patterns of genetic correlation suggest the influence of multiple genetic influences. There is a genetic organization among structures which distinguishes between brain and cerebrospinal fluid spaces and between different subcortical regions. Further study is needed to understand this genetic patterning and whether it reflects influences on early development, functionally dependent patterns of growth or pruning, or regionally specific losses due to genes involved in aging, stress response, or disease. Hum Brain Mapp 32:641-653, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Eyler, Lisa T.; Fennema-Notestine, Christine; Panizzon, Matthew S.; Jernigan, Terry L.; Franz, Carol E.; Perry, Michele E.; Tsuang, Ming T.; Kremen, William S.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Eyler, Lisa T.] VA San Diego Healthcare Syst, Mental Illness Res Educ & Clin Ctr, San Diego, CA USA. [Prom-Wormley, Elizabeth; Neale, Michael C.; Schmitt, J. Eric] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Prom-Wormley, Elizabeth; Neale, Michael C.; Schmitt, J. Eric] Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. [Prom-Wormley, Elizabeth; Neale, Michael C.; Schmitt, J. Eric] Virginia Commonwealth Univ, Dept Mol Genet, Richmond, VA USA. [Jernigan, Terry L.; Perry, Michele E.] Univ Calif San Diego, Dept Cognit Sci, La Jolla, CA 92093 USA. [Fischl, Bruce; Stevens, Allison; Pacheco, Jennifer] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Fischl, Bruce; Stevens, Allison; Pacheco, Jennifer] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lyons, Michael J.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Spitzer, Nicholas C.] Univ Calif San Diego, Dept Biol, La Jolla, CA 92093 USA. [Seidman, Larry J.; Thermenos, Heidi W.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Tsuang, Ming T.; Kremen, William S.] Univ Calif San Diego, Ctr Behav Genom, La Jolla, CA 92093 USA. [Tsuang, Ming T.] Harvard Univ, Inst Psychiat Epidemiol & Genet, Boston, MA 02115 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Tsuang, Ming T.; Kremen, William S.] VA San Diego Healthcare Syst, Ctr Excellence Stress & Mental Hlth, San Diego, CA USA. RP Eyler, LT (reprint author), 9500 Gilman Dr,Mail Code 9151B, La Jolla, CA 92093 USA. EM lteyler@ucsd.edu RI Lyons, Michael/B-6119-2011; OI Prom-Wormley, Elizabeth/0000-0001-9230-9723; Lyons, Michael/0000-0001-6516-9219; Fennema-Notestine, Christine/0000-0002-6527-6361 FU National Institute on Aging, National Institutes of Health (NIH) [U24 RR021382, R01 AG18386, R01 AG18384, R01 AG22381, R01 AG 22982]; National Institute for Mental Health, NIH [R01 MH20030]; National Institute for Drug Abuse, NIH [R01 DA18673]; VA Desert Pacific Mental Illness Research Education and Clinical Center FX Contract grant sponsor: National Institute on Aging, National Institutes of Health (NIH); Contract grant numbers: U24 RR021382, R01 AG18386, R01 AG18384, R01 AG22381, R01 AG 22982; Contract grant sponsor: National Institute for Mental Health, NIH; Contract grant number: R01 MH20030; Contract grant sponsor: National Institute for Drug Abuse, NIH; Contract grant number: R01 DA18673; Contract grant sponsor: VA Desert Pacific Mental Illness Research Education and Clinical Center. NR 45 TC 19 Z9 19 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD APR PY 2011 VL 32 IS 4 BP 641 EP 653 DI 10.1002/hbm.21054 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 732ID UT WOS:000288177300012 PM 20572207 ER PT J AU Wang, MJ Tang, ST Stryhn, A Justesen, S Larsen, MV Dziegiel, MH Lewinsohn, DM Buus, S Lund, O Claesson, MH AF Wang, Mingjun Tang, Sheila T. Stryhn, Anette Justesen, Sune Larsen, Mette V. Dziegiel, Morten H. Lewinsohn, David M. Buus, Soren Lund, Ole Claesson, Mogens H. TI Identification of MHC class II restricted T-cell-mediated reactivity against MHC class I binding Mycobacterium tuberculosis peptides SO IMMUNOLOGY LA English DT Article DE cytotoxic T lymphocyte epitope; HLA-I; HLA-II; Mycobacterium tuberculosis; vaccine ID CD8-T-CELL MEMORY; IMMUNE-RESPONSES; CD4-T-CELL HELP; ACUTE INFECTION; CTL EPITOPES; GENOME-WIDE; MICE; VIVO; MACROPHAGES; VACCINATION AB P>Major histocompatibility complex (MHC) class I restricted cytotoxic T lymphocytes (CTL) are known to play an important role in the control of Mycobacterium tuberculosis infection so identification of CTL epitopes from M. tuberculosis is of importance for the development of effective peptide-based vaccines. In the present work, bioinformatics technology was employed to predict binding motifs of 9mer peptides derived from M. tuberculosis for the 12 HLA-I supertypes. Subsequently, the predicted peptides were synthesized and assayed for binding to HLA-I molecules in a biochemically based system. The antigenicity of a total of 157 peptides with measured affinity for HLA-I molecules of K(D) <= 500 nm were evaluated using peripheral blood T cells from strongly purified protein derivative reactive healthy donors. Of the 157 peptides, eight peptides (5%) were found to induce T-cell responses. As judged from blocking with HLA class I and II subtype antibodies in the ELISPOT assay culture, none of the eight antigenic peptides induced HLA class I restricted CD8(+) T-cell responses. Instead all responses were blocked by pan-HLA class II and anti-HLA-DR antibodies. In addition, CD4(+) T-cell depletion before the 10 days of expansion, resulted in total loss of reactivity in the ELISPOT culture for most peptide specificities. FACS analyses with intracellular interferon-gamma staining of T cells expanded in the presence of M. tuberculosis peptides confirmed that the responsive cells were indeed CD4(+). In conclusion, T-cell immunity against HLA-I binding 9mer M. tuberculosis-derived peptides might in many cases turn out to be mediated by CD4(+) T cells and restricted by HLA-II molecules. The use of 9mer peptides recognized by both CD8(+) and CD4(+) T cells might be of importance for the development of future M. tuberculosis peptide-based vaccines. C1 [Claesson, Mogens H.] Univ Copenhagen, Panum Inst, Dept Int Hlth Immunol & Microbiol, Fac Heath Sci, DK-2200 Copenhagen N, Denmark. [Tang, Sheila T.; Larsen, Mette V.; Lund, Ole] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, DK-2800 Lyngby, Denmark. [Dziegiel, Morten H.] Univ Copenhagen Hosp, HS Blood Bank KI 2034, DK-2100 Copenhagen, Denmark. [Lewinsohn, David M.] Portland VA Med Ctr, CCM, Portland, OR USA. RP Claesson, MH (reprint author), Univ Copenhagen, Panum Inst, Dept Int Hlth Immunol & Microbiol, Fac Heath Sci, Bldg 18-3,Blegdamsvej 3C, DK-2200 Copenhagen N, Denmark. EM claesson@sund.ku.dk RI Lund, Ole/F-4437-2014; Buus, Soren/F-5446-2010; Lewinsohn, David/I-4936-2013; OI Lund, Ole/0000-0003-1108-0491; Lewinsohn, David/0000-0001-9906-9494; Buus, Soren/0000-0001-8363-1999 FU National Institute of Allergy and Infectious Disease [HHSN266200400083C, HHSN266200400025C]; EU [503231]; National Institutes of Health [HHSN266200400081C] FX We are grateful to Ms Maja Udsen and Ms Trine Devantier for excellent technical assistance. This work was supported by National Institute of Allergy and Infectious Disease contracts HHSN266200400083C, HHSN266200400025C, EU 6FP 503231 and National Institutes of Health contract HHSN266200400081C (DML). NR 55 TC 11 Z9 13 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD APR PY 2011 VL 132 IS 4 BP 482 EP 491 DI 10.1111/j.1365-2567.2010.03383.x PG 10 WC Immunology SC Immunology GA 732UV UT WOS:000288216100004 PM 21294723 ER PT J AU Ananthakrishnan, AN McGinley, EL Saeian, K Binion, DG AF Ananthakrishnan, Ashwin N. McGinley, Emily L. Saeian, Kia Binion, David G. TI Temporal Trends in Disease Outcomes Related to Clostridium Difficile Infection in Patients with Inflammatory Bowel Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE inflammatory bowel disease; Crohn's disease; ulcerative colitis; Clostridium difficile; colectomy; hospitalization; severity ID TOXIN; DIARRHEA; IMPACT; HOSPITALIZATION; EPIDEMIOLOGY; OUTBREAK; COLITIS; STRAIN AB Background: Clostridium difficile has emerged as an important pathogen in patients with inflammatory bowel disease (IBD) and is associated with increased morbidity and mortality. No studies have examined the temporal change in severity of C. difficile infection (CDI) complicating IBD. Methods: Using data from the Nationwide Inpatient Sample, we identified all IBD-related hospitalizations during the years 1998, 2004, and 2007 and examined hospitalizations with a coexisting diagnosis of C. difficile. We compared the absolute outcomes of in-hospital mortality and colectomy in the C. difficile-IBD cohort during these timepoints, and also examined these outcomes relative to non-C. difficile IBD controls during each corresponding year. Results: During 1998, 2004, and 2007, approximately 1.4%, 2.3%, and 2.9% of all IBD hospitalizations nationwide were complicated by CDI (P < 0.001). The absolute mortality in the C. difficile-IBD cohort increased from 5.9%-7.2% (P = 0.052) with a nonsignificant increase in colectomy rate from 3.8%-4.5% between 1998 and 2007. Compared to non-C. difficile IBD controls, there was an increase in the relative mortality risk associated with C. difficile from 1998 (odds ratio [OR] 2.38, 95% confidence interval [CI]: 1.52-3.72) to 2007 (OR 3.38, 95% CI: 2.66-4.29) (P = 0.15) with a significant increase in total colectomy odds from 1998 (OR 1.39, 95% CI: 0.81-2.37) to 2007 (OR 2.51, 95% CI: 1.90-3.34) (P = 0.03). Conclusion: There has been a temporal increase nationwide in CDI complicating IBD hospitalizations. The excess morbidity associated with C. difficile infection in hospitalized IBD patients has increased between 1998 and 2007. C1 [Ananthakrishnan, Ashwin N.; Saeian, Kia] Med Coll Wisconsin, Div Gastroenterol & Hepatol, Milwaukee, WI 53226 USA. [McGinley, Emily L.] Med Coll Wisconsin, Div Epidemiol, Milwaukee, WI 53226 USA. [Binion, David G.] Univ Pittsburgh, Sch Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org NR 35 TC 58 Z9 58 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD APR PY 2011 VL 17 IS 4 BP 976 EP 983 DI 10.1002/ibd.21457 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 732GR UT WOS:000288173500012 PM 20824818 ER PT J AU Meade, CS Conn, NA Skalski, LM Safren, SA AF Meade, Christina S. Conn, Nina A. Skalski, Linda M. Safren, Steven A. TI Neurocognitive impairment and medication adherence in HIV patients with and without cocaine dependence SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; SUBSTANCE-ABUSE TREATMENT; SELF-REPORTED ADHERENCE; QUALITY-OF-LIFE; COGNITIVE IMPAIRMENT; DRUG-USE; NEUROPSYCHOLOGICAL PERFORMANCE; INFECTED PERSONS; VIROLOGICAL RESPONSE; DISEASE PROGRESSION AB Cocaine abuse among HIV patients is associated with faster disease progression and mortality. This study examined the relationship between neurocognitive functioning and medication adherence in HIV patients with (n = 25) and without (n = 39) current cocaine dependence. Active users had greater neurocognitive impairment (mean T-score = 35.16 vs. 40.97, p < .05) and worse medication adherence (mean z-score = -0.44 vs. 0.27, p < .001). In a multiple regression model, neurocognitive functioning (beta = .33, p < .01) and cocaine dependence (beta = -.36, p < .01) were predictive of poorer adherence. There was a significant indirect effect of cocaine dependence on medication adherence through neurocognitive impairment (estimate = -0.15, p < .05), suggesting that neurocognitive impairment partially mediated the relationship between cocaine dependence and poorer adherence. These results confirm that cocaine users are at high risk for poor HIV outcomes and underscore the importance of treating both neurocognitive impairment and cocaine dependence among HIV patients. C1 [Meade, Christina S.] Duke Univ, Dept Psychiat & Behav Sci, Sch Med, Durham, NC 27708 USA. [Meade, Christina S.; Skalski, Linda M.] Duke Global Hlth Inst, Durham, NC USA. [Meade, Christina S.; Conn, Nina A.] McLean Hosp, Behav Psychopharmacol Res Lab, Belmont, MA 02178 USA. [Meade, Christina S.; Safren, Steven A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Safren, Steven A.] Massachusetts Gen Hosp, Behav Med Serv, Boston, MA 02114 USA. RP Meade, CS (reprint author), Duke Univ, Dept Psychiat & Behav Sci, Sch Med, Box 90519, Durham, NC 27708 USA. EM christina.meade@duke.edu FU NIAID NIH HHS [R21 AI064519, P30 AI060354, P30 AI060354-04, P30 AI060354-05, P30 AI064518, P30 AI064518-04, P30 AI064518-05, P30-AI064519, P30-AI60354]; NIDA NIH HHS [T32 DA015036, T32 DA015036-06, T32 DA015036-07, T32-DA01536] NR 93 TC 23 Z9 23 U1 5 U2 9 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 J9 J BEHAV MED JI J. Behav. Med. PD APR PY 2011 VL 34 IS 2 BP 128 EP 138 DI 10.1007/s10865-010-9293-5 PG 11 WC Psychology, Clinical SC Psychology GA 730HZ UT WOS:000288025700006 PM 20857187 ER PT J AU Teo, KK Sleight, P Gao, P Yusuf, S Connolly, S Yusuf, S Swedberg, K Pfeffer, MA Granger, CB McMurray, JJV Sjoelie, AK Massie, BM Carson, P Lewis, JB Wachtell, K Dahlof, B Devereux, RB Kjeldsen, SE Julius, S Ibsen, H Lindholm, LH Olsen, MH Okin, PM Califf, R Holman, RR Haffner, SM Dagenais, G Probstfield, J Anderson, C Diaz, R Dans, A Levine, M Unger, T Fagard, R Diener, HC Sacco, RL Zanchetti, A Cohn, JN Weber, M AF Teo, Koon K. Sleight, Peter Gao, Peggy Yusuf, Salim Connolly, Stuart Yusuf, Salim Swedberg, Karl Pfeffer, Marc A. Granger, Christopher B. McMurray, John J. V. Sjoelie, Anne K. Massie, Barry M. Carson, Peter Lewis, Julia B. Wachtell, Kristian Dahlof, Bjorn Devereux, Richard B. Kjeldsen, Sverre E. Julius, Stevo Ibsen, Hans Lindholm, Lars H. Olsen, Michael H. Okin, Peter M. Califf, Robert Holman, Rury R. Haffner, Steven M. Dagenais, Gilles Probstfield, Jeffrey Anderson, Craig Diaz, Rafael Dans, Antonio Levine, Mark Unger, Thomas Fagard, Robert Diener, Hans-Christoph Sacco, Ralph L. Zanchetti, Alberto Cohn, Jay N. Weber, Michael CA ARB Trialists Collaboration TI Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals The ARB Trialists Collaboration SO JOURNAL OF HYPERTENSION LA English DT Review DE angiotensin receptor blockers; cancer incidence; candesartan; clinical trials; irbesartan; losartan; meta-analysis; telmisartan; valsartan ID CONVERTING-ENZYME-INHIBITORS; ANGIOTENSIN-RECEPTOR BLOCKER; LEFT-VENTRICULAR DYSFUNCTION; CHRONIC HEART-FAILURE; RANDOMIZED CONTROLLED-TRIALS; HIGH-RISK PATIENTS; CARDIOVASCULAR EVENTS; PROSTATE-CANCER; ANTIHYPERTENSIVE MEDICATION; MYOCARDIAL-INFARCTION AB Background Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) reduce cardiovascular disease (CVD) events, but a recent meta-analysis of selected studies suggested that ARBs may increase cancer risks. Objective Candesartan, irbesartan, telmisartan, valsartan, and losartan were assessed for incident cancers in 15 large parallel long-term multicenter double-blind clinical trials of these agents involving 138 769 participants. Patients and methods Individuals at high CVD risk were randomized to telmisartan (three trials, n=51 878), irbesartan (three trials, n=14 859), valsartan (four trials, n=44 264), candesartan (four trials, n=18 566), and losartan (one trial, n=9193) and followed for 23-60 months. Incident cancer cases were compared in patients randomized to ARBs versus controls. In five trials (n=42 403), the ARBs were compared to ACEi and in 11 trials (n=63 313) to controls without ACEi. In addition, in seven trials (n=47 020), the effect of ARBs with ACEi was compared to ACEi alone and in two trials ARBs with ACEi versus ARB alone (n=25 712). Results Overall, there was no excess of cancer incidence with ARB therapy compared to controls in the 15 trials [ 4549 (6.16%) cases of 73 808 allocated to ARB versus 3856 (6.31%) of 61 106 assigned to non-ARB controls; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.95-1.04] overall or when individual ARBs were examined. ORs comparing combination therapy with ARB along with ACEi versus ACEi was 1.01 (95% CI 0.94-1.10), combination versus ARB alone 1.02 (95% CI 0.91-1.13), ARB alone versus ACEi alone 1.06 (95% CI 0.97-1.16) and ARB versus placebo/control without ACEi 0.97 (95% CI 0.91-1.04). There was no excess of lung, prostate or breast cancer, or overall cancer deaths associated with ARB treatment. Conclusion There was no significant increase in the overall or site-specific cancer risk from ARBs compared to controls. J Hypertens 29: 623-635 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Teo, Koon K.; Gao, Peggy; Yusuf, Salim] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. [Sleight, Peter] Univ Oxford, John Radcliffe Hosp, Oxford OX3 9DU, England. [Connolly, Stuart; Yusuf, Salim] McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada. [Swedberg, Karl] Univ Gothenburg, Dept Emergency, Sahlgrenska Acad, Gothenburg, Sweden. [Swedberg, Karl] Univ Gothenburg, Dept Cardiovasc Med, Sahlgrenska Acad, Gothenburg, Sweden. [Pfeffer, Marc A.] Harvard Univ, Sch Med, Boston, MA USA. [McMurray, John J. V.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Granger, Christopher B.] Duke Univ, Med Ctr, Div Cardiovasc Med, Duke Clin Res Inst, Durham, NC USA. [McMurray, John J. V.] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland. [Sjoelie, Anne K.] Odense Hosp, Dept Ophthalmol, Odense, Denmark. [Massie, Barry M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Massie, Barry M.] San Francisco VA Med Ctr, San Francisco, CA USA. [Carson, Peter] Washington VAMC Georgetown Univ, Washington, DC USA. [Lewis, Julia B.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Wachtell, Kristian] Gentofte Univ Hosp, Dept Cardiol, Copenhagen, Denmark. [Dahlof, Bjorn] Sahlgrens Univ Hosp, Dept Med, Gothenburg, Sweden. [Okin, Peter M.] Weill Cornell Med Coll, Div Cardiol, Dept Med, New York, NY USA. [Kjeldsen, Sverre E.] Univ Oslo Hosp, Oslo, Norway. [Julius, Stevo] Univ Michigan, Ann Arbor, MI 48109 USA. [Ibsen, Hans] Aarhus Univ, DK-8000 Aarhus C, Denmark. [Ibsen, Hans] Univ Copenhagen, DK-1168 Copenhagen, Denmark. [Ibsen, Hans] Hlobaek Hosp, Hlobaek, Denmark. [Lindholm, Lars H.] Umea Univ, Dept Publ Hlth, S-90187 Umea, Sweden. [Lindholm, Lars H.] Umea Univ, Dept Clin Med, S-90187 Umea, Sweden. [Olsen, Michael H.] Glostrup Univ Hosp, Dept Internal Med, Div Cardiol, Glostrup, Denmark. [Cohn, Jay N.] Duke Univ, Med Ctr, Div Cardiovasc Med, Duke Clin Res Inst, Durham, NC USA. [Holman, Rury R.] Univ Oxford, OCDEM, Oxford OX1 2JD, England. [Haffner, Steven M.] Baylor Coll Med, Dept Med, San Antonio, TX USA. [Dagenais, Gilles] Univ Laval, Laval Hosp, Heart & Lung Inst, Ste Foy, PQ G1V 4G5, Canada. [Probstfield, Jeffrey] Univ Washington, Dept Med, Seattle, WA USA. [Anderson, Craig] Royal Prince Alfred Hosp, George Inst Int Hlth, Sydney, NSW, Australia. [Anderson, Craig] Univ Sydney, Sydney, NSW 2006, Australia. [Diaz, Rafael] Estudios Clin Latinoamer, Rosario, Santa Fe, Argentina. [Dans, Antonio] Univ Philippines, Coll Med, Manila, Philippines. [Levine, Mark] McMaster Univ, Dept Oncol, Hamilton, ON L8V 1C3, Canada. [Unger, Thomas] Charite, Cardiovasc Res Ctr, D-13353 Berlin, Germany. [Unger, Thomas] Charite, Inst Pharmacol, D-13353 Berlin, Germany. [Fagard, Robert] Univ Leuven KU Leuven, Hypertens & Cardiovasc Rehabil Unit, Leuven, Belgium. [Diener, Hans-Christoph] Univ Hosp Essen, Dept Neurol, Essen, Germany. [Diener, Hans-Christoph] Univ Hosp Essen, Stroke Ctr, Essen, Germany. [Sacco, Ralph L.] Univ Miami, Miami, FL USA. [Zanchetti, Alberto] Univ Milan, Ctr Clin Physiol & Hypertens, Milan, Italy. [Zanchetti, Alberto] Ist Auxol Italiano, Milan, Italy. [Cohn, Jay N.] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Weber, Michael] Suny Downstate Med Ctr, Coll Med, Brooklyn, NY 11203 USA. RP Teo, KK (reprint author), Hamilton Gen Hosp, Populat Hlth Res Inst, David Braley Cardiac Vasc Stroke Res Inst, Rm C2-106,237 Barton St E, Hamilton, ON L8L 2X2, Canada. EM koon.teo@phri.ca RI Granger, Christopher/D-3458-2014; Olsen, Michael/H-8176-2014 OI Granger, Christopher/0000-0002-0045-3291; FU Boehringer Ingelheim; Bristol-Myers Squibb; Sanofi-Aventis; Sanofi-Synthelabo; Novartis; AstraZenica; Takeda; Merck FX K.K.T. and P.S. received consulting and lecture fees and research grants from Boehringer Ingelheim; S.Y. received grants and honoraria from Boehringer Ingelheim, Bristol-Myers Squibb, and Sanofi-Aventis. P.G. does not have relevant information to disclose.; Boehringer-Ingelheim was the sponsor of the telmisartan trials. The irbesartan trials were sponsored by Bristol-Myers Squibb and Sanofi-Synthelabo, the valsartan trials by Novartis, the candesartan trials by AstraZenica (CHARM and DIRECT were also sponsored by Takeda) and the losartan trial by Merck. Data for this meta-analysis were obtained from the investigators and sponsors and were analyzed at PHRI independent of the sponsors. NR 44 TC 63 Z9 63 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD APR PY 2011 VL 29 IS 4 BP 623 EP 635 DI 10.1097/HJH.0b013e328344a7de PG 13 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 732PH UT WOS:000288199500001 ER PT J AU Liu, PA Zhang, C Chen, J Zhang, RG Ren, JH Huang, YH Zhu, F Li, ZY Wu, G AF Liu, Pian Zhang, Chen Chen, Jing Zhang, Ruiguang Ren, Jinghua Huang, Yuhui Zhu, Fang Li, Zhenyu Wu, Gang TI Combinational Therapy of Interferon-alpha and Chemotherapy Normalizes Tumor Vasculature by Regulating Pericytes Including the Novel Marker RGS5 in Melanoma SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE melanoma; chemoimmunotherapy; interferon-alpha; pericytes; RGS5 ID ANTI-ANGIOGENIC THERAPY; ORTHOTOPIC MOUSE MODEL; CANCER-THERAPY; GROWTH-FACTOR; PANCREATIC-ADENOCARCINOMA; ANTIANGIOGENIC THERAPY; METASTATIC MELANOMA; ENDOTHELIAL SPROUTS; DOWN-REGULATION; BLOOD-VESSELS AB Several large randomized clinical trials show that chemotherapy in combination with interferon-alpha (IFN-alpha) seems superior to single-agent chemotherapy, such as dacarbazine (DTIC) in melanoma, but the molecular mechanism of this better efficacy is unclear. IFN-alpha has antiangiogenic activity and could downregulate expression of regulator of G-protein signalling-5 (RGS5) recognized as a novel pericyte marker and a master gene loss of which results in pericyte maturation, vascular normalization, and consequent marked reductions in tumor hypoxia and vessel leakiness in pancreatic carcinoma. Here, we investigated the molecular mechanism of the effects of this combination therapy on melanoma tumor growth. In B16 tumor-bearing mice, the addition of IFN-alpha to DTIC treatment significantly reduced tumor volume, compared with control or DTIC alone. Consistently, Digital Radiography data showed less chaotic vessel morphology and a decrease in microvessel density and mean vessel diameter in the combinational treatment. Furthermore, the combination therapy showed a remarkable reduction in tumor hypoxia, downregulated RGS5 expression, and increased mature pericyte coverage. Our data suggest that the combination of IFN-alpha and DTIC therapy more efficiently inhibits tumor growth by normalizing tumor vasculature. This study shows a previously unrecognized role of IFN-alpha in melanoma vascular normalization and suggests that pericyte including its novel marker RGS5 is an important target of IFN-alpha. C1 [Liu, Pian; Chen, Jing; Zhang, Ruiguang; Ren, Jinghua; Zhu, Fang; Li, Zhenyu; Wu, Gang] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Ctr Canc, Wuhan 430022, Peoples R China. [Zhang, Chen] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Hepatobiliary Surg, Wuhan 430022, Peoples R China. [Huang, Yuhui] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Huang, Yuhui] Harvard Univ, Sch Med, Boston, MA USA. RP Wu, G (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Ctr Canc, 1277 Jiefang Ave, Wuhan 430022, Peoples R China. EM wugangzr@yahoo.com.cn FU National Natural Science Fund of China [30973473] FX Supported by the National Natural Science Fund of China (NO. 30973473). NR 41 TC 8 Z9 8 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD APR PY 2011 VL 34 IS 3 BP 320 EP 326 DI 10.1097/CJI.0b013e318213cd12 PG 7 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 733CO UT WOS:000288238200010 PM 21389866 ER PT J AU Ellis, KL Newton-Cheh, C Wang, TJ Frampton, CM Doughty, RN Whalley, GA Ellis, CJ Skelton, L Davis, N Yandle, TG Troughton, RW Richards, AM Cameron, VA AF Ellis, Katrina L. Newton-Cheh, Christopher Wang, Thomas J. Frampton, Chris M. Doughty, Rob N. Whalley, Gillian A. Ellis, Chris J. Skelton, Lorraine Davis, Nick Yandle, Tim G. Troughton, Richard W. Richards, A. Mark Cameron, Vicky A. TI Association of genetic variation in the natriuretic peptide system with cardiovascular outcomes SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Natriuretic peptides; Polymorphisms; Cardiovascular outcomes ID VENTRICULAR EJECTION FRACTION; ACUTE MYOCARDIAL-INFARCTION; SYMPATHETIC-NERVE ACTIVITY; RECEPTOR GENE; ESSENTIAL-HYPERTENSION; BLOOD-PRESSURE; HEART-FAILURE; 5'-FLANKING REGION; HUMAN-PLASMA; POLYMORPHISM AB Polymorphisms within individual natriuretic peptide genes have been associated with risk factors for cardiovascular disease, but their association with clinical outcomes was previously unknown. This study aimed to investigate the association between genetic variants in key genes of the natriuretic peptide system with cardiovascular outcomes in patients with coronary artery disease. Coronary disease patients (n = 1810) were genotyped for polymorphisms within NPPA, NPPB, NPPC, NPR1 and NPR2. Clinical history, natriuretic peptide concentrations, echocardiography, all-cause mortality and cardiovascular hospital readmissions were recorded over a median 2.8 years. Minor alleles of NPPA rs5068, rs5065 and rs198358 were associated with less history of hypertension; minor alleles of NPPA rs5068 and rs198358 was also associated with higher circulating natriuretic peptide levels (p = 0.003 to p = 0.04). Minor alleles of NPPB rs198388, rs198389, and rs632793 were associated with higher circulating BNP and NT-proBNP (p = 0.001 to p = 0.03), and reduced E/E-1 (p = 0.011), or LVESVI (p = 0.001) and LVEDVI (p = 0.004). Within NPPC, both rs11079028 and rs479651 were associated with higher NT-proBNP and CNP (p = 0.01 to p = 0.03), and rs479651 was associated with lower LVESVI (p = 0.008) and LVEDVI (p = 0.018). NPR2 rs10758325 was associated with smaller LVMI (p<0.02). A reduced rate of cardiovascular readmission was observed for minor alleles of NPPA rs5065 (p<0.0001), NPPB rs632793 (p<0.0001), rs198388 (p<0.0001), rs198389 (p<0.0001), and NPR2 rs10758325 (p<0.0001). There were no associations with all-cause mortality. In established cardiovascular disease, natriuretic peptide system polymorphisms were associated with natriuretic peptide levels, hypertension, echocardiographic indices and the incidence of hospital readmission for cardiovascular events. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Ellis, Katrina L.; Frampton, Chris M.; Skelton, Lorraine; Davis, Nick; Yandle, Tim G.; Troughton, Richard W.; Richards, A. Mark; Cameron, Vicky A.] Univ Otago, Christchurch Cardioendocrine Res Grp, Dept Med, Christchurch 8140, New Zealand. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Newton-Cheh, Christopher; Wang, Thomas J.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Div Cardiol, Boston, MA 02114 USA. [Newton-Cheh, Christopher; Wang, Thomas J.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Doughty, Rob N.; Whalley, Gillian A.; Ellis, Chris J.] Univ Auckland, Dept Med, Auckland, New Zealand. [Whalley, Gillian A.] Unitec Inst Technol, Dept Med Imaging, Auckland, New Zealand. RP Ellis, KL (reprint author), Univ Otago, Christchurch Cardioendocrine Res Grp, Dept Med, POB 4345, Christchurch 8140, New Zealand. EM katina.ellis@otago.ac.nz OI Whalley, Gillian/0000-0002-5713-6967 FU Health Research Council of New Zealand (Auckland, New Zealand); New Zealand Lotteries Grant Board (Wellington, New Zealand); National Heart Foundation of New Zealand (Auckland, New Zealand) FX This work was supported by the Health Research Council of New Zealand (Auckland, New Zealand); New Zealand Lotteries Grant Board (Wellington, New Zealand), and National Heart Foundation of New Zealand (Auckland, New Zealand). NR 42 TC 34 Z9 34 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD APR PY 2011 VL 50 IS 4 BP 695 EP 701 DI 10.1016/j.yjmcc.2011.01.010 PG 7 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 734CM UT WOS:000288310800014 PM 21276798 ER PT J AU Guimaraes, AR Ross, R Figuereido, JL Waterman, P Weissleder, R AF Guimaraes, Alexander R. Ross, Robert Figuereido, Jose L. Waterman, Peter Weissleder, Ralph TI MRI with Magnetic Nanoparticles Monitors Downstream Anti-Angiogenic Effects of mTOR Inhibition SO MOLECULAR IMAGING AND BIOLOGY LA English DT Article DE Magnetic resonance imaging; MRI; Magnetic nanoparticle imaging; Ultrasmall superparamagnetic iron oxide nanoparticle; Renal cell cancer; mTOR; Angiogenesis ID RENAL-CELL CARCINOMA; PROGRESSION-FREE SURVIVAL; IN-VIVO ASSESSMENT; TUMOR ANGIOGENESIS; ANTIANGIOGENIC ACTIVITY; RAD001 EVEROLIMUS; INTERFERON-ALPHA; COLON-CARCINOMA; CONTRAST; MODEL AB To study the effect of mammalian target of rapamycin (mTOR) inhibition on angiogenesis with magnetic resonance imaging (MRI) using magnetic iron oxide nanoparticles (MNP). One million CAK-1 renal cell carcinoma cells were subcutaneously implanted into each of 20 nude mice. When tumors reached similar to 750 mu l, four daily treatment arms began and continued for 4 weeks: rapamycin (mTOR inhibitor) 10 mg/kg/day; sorafenib (VEGF inhibitor) high dose (80 mg/kg/day) and low dose (30 mg/kg/day); and saline control. Weekly MRI (4.7 T Bruker Pharmascan) was performed before and after IV MION-48, a prototype MNP similar to MNP in clinical trials. Vascular volume fraction (VVF) was quantified as Delta R2 (from multi-contrast T2 sequences) and normalized to assumed muscle VVF of 3%. Linear regression compared VVF to microvascular density (MVD) as determined by histology. VVF correlated with MVD (R(2) = 0.95). VVF in all treatment arms differed from control (p < 0.05) and declined weekly with treatment. VVF changes with rapamycin were similar to high-dose sorafenib. This study demonstrates noninvasive, in vivo anti-angiogenic monitoring using MRI of mTOR inhibition. C1 [Guimaraes, Alexander R.; Figuereido, Jose L.; Waterman, Peter; Weissleder, Ralph] Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. [Guimaraes, Alexander R.; Figuereido, Jose L.; Waterman, Peter; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Ross, Robert] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Guimaraes, Alexander R.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging, Boston, MA 02114 USA. RP Guimaraes, AR (reprint author), Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. EM aguimaraes1@partners.org FU Renal Spore-Dana Farber Cancer Institute; MGH-AstraZeneca Strategic Alliance FX Funding provided by the Renal Spore-Dana Farber Cancer Institute & MGH-AstraZeneca Strategic Alliance NR 24 TC 9 Z9 9 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1536-1632 J9 MOL IMAGING BIOL JI Mol. Imaging. Biol. PD APR PY 2011 VL 13 IS 2 BP 314 EP 320 DI 10.1007/s11307-010-0357-2 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 732IH UT WOS:000288177700015 PM 20559742 ER PT J AU Sheehan, J Gaman, A Vangel, M Kuo, B AF Sheehan, J. Gaman, A. Vangel, M. Kuo, B. TI Pooled analysis of brain activity in irritable bowel syndrome and controls during rectal balloon distension SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE brain imaging; colo-rectal stimulation; irritable bowel syndrome; pooled analysis ID VISCERAL PAIN; CEREBRAL ACTIVATION; DESCENDING COLON; HEALTHY CONTROLS; GI DISORDERS; IBS PATIENTS; HYPERSENSITIVITY; RESPONSES; STIMULI; FMRI AB Background Brain-imaging literature of irritable bowel syndrome (IBS) suggests an abnormal brain-gut communication. We analyzed the literature to evaluate and compare the aspects of brain activity in individuals with IBS and control subjects experiencing controlled rectal stimulation. Methods PubMed was searched until September 2010. Data from 16 articles reporting brain activity during rectal balloon distensions in IBS compared to control groups was analyzed. Prevalence rates and pairwise activations were assessed using binomial distributions for 11 selected regions of interest. The data were aggregated to adjust for center effect. Key Results There was considerable variability in the literature regarding regions and their activity patterns in controls and individuals with IBS. There was no significant difference found in the thalamus, anterior cingulate cortex, posterior cingulate cortex, and prefrontal cortex, however, results show limited evidence of consensus for the anterior insula (AI) (P = 0.22). Pairwise activity results suggest that pairs involving the AI tend to have more consistent activity together than pairs which do not involve the AI (posterior insula and AI, P = 0.08; posterior cingulate cortex and AI, P = 0.16), however, no pairwise evaluation reached significance. Conclusions & Inferences Our pooled analysis demonstrates that the literature reports are quite heterogeneous but there is some evidence that there may be patterns of higher activity more common in individuals with IBS than in controls. A consensus, though, regarding study designs, analysis approach and reporting could create a clearer understanding of brain involvement in IBS pathophysiology. C1 [Sheehan, J.; Gaman, A.; Vangel, M.; Kuo, B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,GI Unit,Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Kuo, B (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,GI Unit,Martinos Ctr Biomed Imaging, 55 Fruit St, Boston, MA 02114 USA. EM bkuo@partners.org NR 54 TC 1 Z9 1 U1 3 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD APR PY 2011 VL 23 IS 4 DI 10.1111/j.1365-2982.2010.01635.x PG 12 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 733KR UT WOS:000288262100009 ER PT J AU Yang, XL Cao, WD Zhou, J Zhang, W Zhang, XA Lin, W Fei, Z Lin, H Wang, B AF Yang, Xiaoliang Cao, Weidong Zhou, Jie Zhang, Wei Zhang, Xiang Lin, Wei Fei, Zhou Lin, Hong Wang, Bo TI 14-3-3Zeta Positive Expression is Associated With a Poor Prognosis in Patients With Glioblastoma SO NEUROSURGERY LA English DT Article DE 14-3-3 zeta; Glioblastoma; Prognostic factor ID ISOFORM-SPECIFIC EXPRESSION; CANCER-CELL-SURVIVAL; LUNG-CANCER; BREAST-CANCER; PROMOTER METHYLATION; HUMAN ASTROCYTOMA; APOPTOTIC SIGNAL; DOWN-REGULATION; UP-REGULATION; 14-3-3-ZETA AB BACKGROUND: When identifying clinical markers predicting clinical outcome, disease recurrence and resistance to therapies often determine the diagnosis and therapy of some cancer types. OBJECTIVE: To investigate whether 14-3-3zeta positive expression is an indicator of prognosis in patients with glioblastoma. METHODS: Forty-seven patients treated with surgery, radiotherapy, and adjuvant chemotherapy between 2005 and 2007 were divided into 2 groups according to 14-3-3zeta expression in an immunohistochemical study: the 14-3-3zeta negative group (n = 12 patients) and the 14-3-3zeta positive group (n = 35 patients). The clinicopathologic features and survival data for patients in the 14-3-3zeta positive group were compared with data from the patients in the 14-3-3zeta negative group. Kaplan-Meier survival analysis and univariate and multivariate analyses were performed to determine the prognostic factors that influenced patient survival. RESULTS: 14-3-3zeta positive expression was observed in approximately 74.5% of patients with glioblastoma. Patients in the 14-3-3zeta positive group had lower overall survival rates and median survival time than those in the 14-3-3zeta negative group (overall 2-year actuarial survival rates, 8.6% for the 14-3-3zeta positive group vs 16.7% for the 14-3-3zeta negative group; overall 2-year median survival time, 12.9 months for the 14-3-3zeta positive group vs 17.9 months for the 14-3-3zeta negative group, P = .019). 14-3-3zeta positive expression in tumor cells also was correlated with a shorter interval to tumor recurrence (median interval to recurrence, 5.9 months in the 14-3-3zeta positive group vs 8.3 months in the 14-3-3zeta negative group, P = .002). Univariate and multivariate analyses showed that 14-3-3zeta positive expression was an independent prognostic factor. CONCLUSION: 14-3-3zeta positive expression can be used as a potential molecular risk factor in patients with glioblastoma. C1 [Yang, Xiaoliang; Cao, Weidong; Zhou, Jie; Zhang, Wei; Zhang, Xiang; Lin, Wei; Fei, Zhou; Lin, Hong] Fourth Mil Med Univ, Xijing Hosp, Inst Neurosurg, Xian 710032, Shaanxi Prov, Peoples R China. [Zhang, Wei] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Neurosurg, Mol Neurosurg Lab,Brain Tumor Res Ctr, Boston, MA USA. [Wang, Bo] Fourth Mil Med Univ, Sch Mil Prevent Med, Dept Epidemiol, Xian 710032, Shaanxi Prov, Peoples R China. RP Zhang, XA (reprint author), Fourth Mil Med Univ, Xijing Hosp, Inst Neurosurg, Xian 710032, Shaanxi Prov, Peoples R China. EM zhiyin100@163.com FU National Natural Science Foundation of China [81072083]; Scientific and Technological Project of ShaanXi Province [2008K09-09] FX This work is supported by National Natural Science Foundation of China (No. 81072083) and Scientific and Technological Project of ShaanXi Province (No. 2008K09-09). The auithors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. NR 38 TC 16 Z9 16 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD APR PY 2011 VL 68 IS 4 BP 932 EP 937 DI 10.1227/NEU.0b013e3182098c30 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 731QA UT WOS:000288123100044 PM 21242845 ER PT J AU Joffe, S Kodish, E AF Joffe, Steven Kodish, Eric TI Protecting the Rights and Interests of Pediatric Stem Cell SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material ID BONE-MARROW; TRANSPLANTATION; SIBLINGS; CHILDREN; DONORS C1 [Joffe, Steven] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Joffe, Steven] Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Kodish, Eric] Cleveland Clin, Ctr Eth Humanities & Spiritual Care, Cleveland, OH 44106 USA. RP Joffe, S (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Smith 207 450 Brookline Ave, Boston, MA 02215 USA. EM steven_joffe@dfci.harvard.edu OI Joffe, Steven/0000-0002-0667-7384 NR 10 TC 6 Z9 6 U1 2 U2 3 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD APR PY 2011 VL 56 IS 4 BP 517 EP 519 DI 10.1002/pbc.23028 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 729XD UT WOS:000287986700004 PM 21298734 ER PT J AU Badalian-Very, G Vergilio, JA Degar, BA Calicchio, M Fleming, MD Rollins, BJ AF Badalian-Very, Gayane Vergilio, Jo-Anne Degar, Barbara A. Calicchio, Monica Fleming, Mark D. Rollins, Barrett J. TI TOLL RECEPTORS AND LANGERHANS CELL HISTIOCYTOSIS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD APR PY 2011 VL 56 IS 4 BP 689 EP 690 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 729XD UT WOS:000287986700041 ER PT J AU Campbell, PK Abraham, A Jeng, M Cardenas-Cardos, R Rodriguez-Galindo, C AF Campbell, P. K. Abraham, A. Jeng, M. Cardenas-Cardos, R. Rodriguez-Galindo, C. TI USE OF CLOFARABINE IN THE TREATMENT OF REFRACTORY AND RECURRENT MULTISYSTEM LANGERHANS CELL HISTIOCYTOSIS SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 St Jude Childrens Hosp, Memphis, TN 38105 USA. Stanford Univ, Sch Med, Lucile Packard Childrens Hosp, Stanford, CA 94305 USA. Inst Nacl Pediat, Delegac Coyoacan, Mexico City, DF, Mexico. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD APR PY 2011 VL 56 IS 4 BP 691 EP 692 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 729XD UT WOS:000287986700048 ER PT J AU Akilov, OE Wu, MX Jin, YZ Zhou, ZY Geskin, LJ Falo, LD Hasan, T AF Akilov, Oleg E. Wu, Mei X. Jin, Yongzhu Zhou, Zhuoyan Geskin, Larisa J. Falo, Louis D. Hasan, Tayyaba TI Vaccination with photodynamic therapy-treated macrophages induces highly suppressive T-regulatory cells SO PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE LA English DT Article DE Leishmania; macrophage; tolerance; T regulatory cells; vaccination ID LEISHMANIA-MAJOR; IMMUNOREGULATORY FUNCTIONS; CUTANEOUS LEISHMANIASIS; DENDRITIC CELLS; NATURAL MODEL; NITRIC-OXIDE; RESPONSES; IMMUNITY; TOLERANCE; INFECTION AB Background/purpose The present study explores whether photodynamic therapy (PDT)-induced apoptosis can increase the number of tolerogenic regulatory T cells (Treg) and limit collateral tissue damage. Methods BALB/c mice were vaccinated subcutaneously three times with PDT-induced apoptotic or thaw-frozen, necrotic non-infected autologous macrophages (M). Two weeks after the last vaccination, mice were infected intradermally with 106 promastigotes of Leishmania major. Results Mice that received PDT-induced apoptotic M had fewer parasites and higher numbers of Treg than mice vaccinated with thaw-frozen necrotic M or phosphate-buffered saline (PBS). Interleukin (IL)-4 and IL-6 were significantly suppressed, while IL-10 was increased in mice that received the PDT-induced apoptotic M. The role of Treg in this process was confirmed through Treg transfer from vaccinated to naive mice. Mice receiving CD4+CD25+ cells from mice vaccinated with PDT-induced apoptotic M showed smaller lesions 3 weeks after infection and lower parasitic burdens than mice that received Tregs from mice of thaw-frozen necrotic M or PBS groups. These changes were mediated by the depletion of CD3+CD8+ and NKT cells and increased levels of IL-12p70 and interferon-gamma, IL-10, and TGF-beta in the cutaneous leishmaniasis lesions. Conclusion Vaccination with apoptotic M-induced tolerogenic Treg cells that limited collateral tissue damage and diminished parasitic burden. C1 [Akilov, Oleg E.; Geskin, Larisa J.; Falo, Louis D.] Univ Pittsburgh, Dept Dermatol, Pittsburgh, PA 15213 USA. [Akilov, Oleg E.; Wu, Mei X.; Jin, Yongzhu; Zhou, Zhuoyan; Hasan, Tayyaba] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp,Wellman Ctr Photomed, Boston, MA 02115 USA. RP Akilov, OE (reprint author), Univ Pittsburgh, Dept Dermatol, 200 Lothrop St,Presby S Tower,Suit 3880, Pittsburgh, PA 15213 USA. EM oea2@pitt.edu FU Department of Defense [FA9550-04-1-0079]; Harvard Skin Disease Research Center FX We are grateful to Mary Ann McDowell, PhD (University of Notre Dame, Notre Dame, IN, USA), for providing us with the L. major V1 strain. We are appreciative of the assistance of Andrea Johnston, Ezra Mirvish and Sue McCann with the manuscript preparation. We thank Kasper Hoebe (Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA) and Thomas A. Ferguson (Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA) for critically reading our manuscript. This work was supported by the Department of Defense Medical Free Electron Laser Program Grant No. FA9550-04-1-0079 (to T. Hasan), Harvard Skin Disease Research Center Pilot and Feasibility Grant (to O. Akilov). NR 43 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0905-4383 J9 PHOTODERMATOL PHOTO JI Photodermatol. Photoimmunol. Photomed. PD APR PY 2011 VL 27 IS 2 BP 97 EP 107 DI 10.1111/j.1600-0781.2011.00578.x PG 11 WC Dermatology SC Dermatology GA 733FT UT WOS:000288249300007 PM 21392113 ER PT J AU Rutemark, C Alicot, E Bergman, A Carroll, MC Heyman, B AF Rutemark, Christian Alicot, Elisabeth Bergman, Anna Carroll, Michael C. Heyman, Birgitta TI The Requirement for Classical Complement Activation in Antibody Responses is not Explained by IgM-Mediated Activation SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Meeting Abstract CT 40th Scandinavian-Society for Immunology Meeting CY 2011 CL Geilo, NORWAY SP Scandinavian-Soc Immunol C1 [Rutemark, Christian; Bergman, Anna; Heyman, Birgitta] Uppsala Univ, Dept Med Biochem & Microbiol, Uppsala, Sweden. [Alicot, Elisabeth; Carroll, Michael C.] Harvard Univ, Sch Med, Dept Pathol, Immune Dis Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD APR PY 2011 VL 73 IS 4 MA 25 BP 357 EP 357 PG 1 WC Immunology SC Immunology GA 728KA UT WOS:000287871800037 ER PT J AU Delmonico, FL AF Delmonico, Francis L. TI Striving to achieve a national self-sufficiency SO TRANSPLANT INTERNATIONAL LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Delmonico, FL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM francis_delmonico@neob.org NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0934-0874 J9 TRANSPL INT JI Transpl. Int. PD APR PY 2011 VL 24 IS 4 BP 315 EP 316 DI 10.1111/j.1432-2277.2011.01227.x PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 732SU UT WOS:000288210800004 PM 21276091 ER PT J AU Dominguez-Gil, B Delmonico, FL Shaheen, FAM Matesanz, R O'Connor, K Minina, M Muller, E Young, K Manyalich, M Chapman, J Kirste, G Al-Mousawi, M Coene, L Garcia, VD Gautier, S Hasegawa, T Jha, V Kwek, TK Chen, ZK Loty, B Costa, AN Nathan, HM Ploeg, R Reznik, O Rosendale, JD Tibell, A Tsoulfas, G Vathsala, A Noel, L AF Dominguez-Gil, Beatriz Delmonico, Francis L. Shaheen, Faissal A. M. Matesanz, Rafael O'Connor, Kevin Minina, Marina Muller, Elmi Young, Kimberly Manyalich, Marti Chapman, Jeremy Kirste, Guenter Al-Mousawi, Mustafa Coene, Leen Garcia, Valter Duro Gautier, Serguei Hasegawa, Tomonori Jha, Vivekanand Kwek, Tong Kiat Chen, Zhonghua Klaus Loty, Bernard Costa, Alessandro Nanni Nathan, Howard M. Ploeg, Rutger Reznik, Oleg Rosendale, John D. Tibell, Annika Tsoulfas, George Vathsala, Anantharaman Noel, Luc TI The critical pathway for deceased donation: reportable uniformity in the approach to deceased donation SO TRANSPLANT INTERNATIONAL LA English DT Review DE assessment; identification; possible deceased donors; referral ID DEATH AB P>The critical pathway of deceased donation provides a systematic approach to the organ donation process, considering both donation after cardiac death than donation after brain death. The pathway provides a tool for assessing the potential of deceased donation and for the prospective identification and referral of possible deceased donors. C1 [Delmonico, Francis L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dominguez-Gil, Beatriz; Matesanz, Rafael] Org Nacl Trasplantes, Madrid, Spain. [Shaheen, Faissal A. M.] Saudi Ctr Organ Transplantat SCOT, Minist Hlth, Riyadh, Saudi Arabia. [O'Connor, Kevin] LifeCtr NW, Bellevue, WA USA. [Minina, Marina] Moscow Coordinating Ctr Organ Donat, Moscow, Russia. [Muller, Elmi] Univ Cape Town, Dept Surg, Groote Schuur Hosp, ZA-7925 Cape Town, South Africa. [Young, Kimberly] Canadian Blood Serv, Ottawa, ON, Canada. [Manyalich, Marti] Hosp Clin Barcelona, Barcelona, Spain. [Chapman, Jeremy] Westmead Hosp, Sydney, NSW, Australia. [Kirste, Guenter] Deutsch Stiftung Organtransplantat, Frankfurt, Germany. [Al-Mousawi, Mustafa] Organ Transplant Ctr Kuwait, Kuwait, Kuwait. [Coene, Leen] Fed Serv Publ Hlth, Brussels, Belgium. [Garcia, Valter Duro] Brazilian Soc Organ Transplantat, Porto Alegre, RS, Brazil. [Gautier, Serguei] Russian Transplantat Soc, Natl Res Inst Transplantol & Artificial Organs, Moscow, Russia. [Hasegawa, Tomonori] Toho Univ, Sch Med, Dept Social Med, Tokyo, Japan. [Jha, Vivekanand] Postgrad Inst Med Educ & Res, Dept Nephrol, Chandigarh 160012, India. [Jha, Vivekanand] Indian Soc Nephrol, Chandigarh, India. [Kwek, Tong Kiat] Tan Tock Seng Hosp, Dept Anaesthesiol, Singapore, Singapore. [Chen, Zhonghua Klaus] Tongji Hosp, Tongji Med Coll, Inst Organ Transplantat, Wuhan, Peoples R China. [Loty, Bernard] Agence Biomed, La Plaine St Denis, France. [Costa, Alessandro Nanni] Italian Natl Transplant Ctr, Rome, Italy. [Nathan, Howard M.] Gift Life Donor Program, Philadelphia, PA USA. [Ploeg, Rutger] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Reznik, Oleg] Assoc Transplant Coordinators, Dept Transplantat, State Res Inst Emergency, St Petersburg, Russia. [Tibell, Annika] Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden. [Tsoulfas, George] Aristotele Univ Thessaloniki, Thessaloniki, Greece. [Vathsala, Anantharaman] Natl Univ Singapore, Dpt Med, Singapore 117548, Singapore. [Noel, Luc] WHO, Essential Hlth Technol, Clin Procedures, CH-1211 Geneva, Switzerland. RP Delmonico, FL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM francis_delmonico@neob.org RI Tsoulfas, Georgios/K-4801-2012; Muller, Elmi/I-3258-2014; OI Tsoulfas, Georgios/0000-0001-5043-7962; Muller, Elmi/0000-0003-4891-5296; Reznik, Oleg/0000-0003-2770-1432 NR 15 TC 43 Z9 45 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0934-0874 J9 TRANSPL INT JI Transpl. Int. PD APR PY 2011 VL 24 IS 4 BP 373 EP 378 DI 10.1111/j.1432-2277.2011.01243.x PG 6 WC Surgery; Transplantation SC Surgery; Transplantation GA 732SU UT WOS:000288210800011 PM 21392129 ER PT J AU Quinn, TM Taylor, JJ Magarik, JA Vought, E Kindy, MS Ellegala, DB AF Quinn, T. M. Taylor, J. J. Magarik, J. A. Vought, E. Kindy, M. S. Ellegala, D. B. TI Decompressive craniectomy: technical note SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Review DE cerebral edema; decompressive craniectomy; intracranial pressure; patient management; traumatic brain injury ID TRAUMATIC BRAIN-INJURY; CEREBRAL-ARTERY INFARCTION; INTRACRANIAL HYPERTENSION; ISCHEMIC-STROKE; MANAGEMENT; MULTICENTER; RECOVERY; PRESSURE; THERAPY AB Decompressive craniectomy is a neurosurgical technique in which a portion of the skull is removed to reduce intracranial pressure. The rationale for this procedure is based on the Monro-Kellie Doctrine; expanding the physical space confining edematous brain tissue after traumatic brain injury will reduce intracranial pressure. There is significant debate over the efficacy of decompressive craniectomy despite its sound rationale and historical significance. Considerable variation in the employment of decompressive craniectomy, particularly for secondary brain injury, explains the inconsistent results and mixed opinions of this potentially valuable technique. One way to address these concerns is to establish a consistent methodology for performing decompressive craniectomies. The purpose of this paper is to begin accomplishing this goal and to emphasize the critical points of the hemicraniectomy and bicoronal (Kjellberg type) craniectomy. C1 [Quinn, T. M.; Taylor, J. J.; Magarik, J. A.; Vought, E.; Ellegala, D. B.] Med Univ S Carolina, Div Neurosurg, Dept Neurosci, Charleston, SC 29425 USA. [Kindy, M. S.] Med Univ S Carolina, Div Res, Dept Neurosci, Charleston, SC 29425 USA. [Kindy, M. S.] Ralph H Johnson VA Med Ctr, Res Serv, Charleston, SC USA. RP Ellegala, DB (reprint author), Med Univ S Carolina, Div Neurosurg, Dept Neurosci, Room CSB 428,96 Jonathan Lucas St, Charleston, SC 29425 USA. EM ellegala@musc.edu FU Veterans Administration FX The authors do not have any conflicts of interest. This work was supported in part by grants from the Veterans Administration (MSK). NR 39 TC 12 Z9 14 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD APR PY 2011 VL 123 IS 4 BP 239 EP 244 DI 10.1111/j.1600-0404.2010.01397.x PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 728GR UT WOS:000287863100002 PM 20637010 ER PT J AU Franklin, TR Wang, Z Li, Y Suh, JJ Goldman, M Lohoff, FW Cruz, J Hazan, R Jens, W Detre, JA Berrettini, W O'Brien, CP Childress, AR AF Franklin, Teresa R. Wang, Ze Li, Yin Suh, Jesse J. Goldman, Marina Lohoff, Falk W. Cruz, Jeffrey Hazan, Rebecca Jens, Will Detre, John A. Berrettini, Wade O'Brien, Charles P. Childress, Anna Rose TI Dopamine transporter genotype modulation of neural responses to smoking cues: confirmation in a new cohort SO ADDICTION BIOLOGY LA English DT Article DE Addiction; dopamine transporter; genetic variability; neuroimaging; relapse vulnerability; smoking cues ID FAGERSTROM TOLERANCE QUESTIONNAIRE; RANDOMIZED CONTROLLED-TRIAL; RECEPTOR PARTIAL AGONIST; DRD4 VNTR POLYMORPHISM; FMRI-BOLD RESPONSES; NICOTINE-DEPENDENCE; CIGARETTE-SMOKING; ORBITOFRONTAL CORTEX; WITHDRAWAL SYMPTOMS; PREFRONTAL CORTEX AB Previously we demonstrated profound effects of dopamine transporter (DAT) SLC6A3 genotype on limbic responses to smoking cues (SCs). Probands carrying at least one copy of the 9-repeat allele (9-repeat carriers) had greater neural responses to SCs in the anatomically interconnected rostral ventral striatum/medial orbitofrontal cortex (VS/mOFC), compared with homozygotes for the 10-repeat allele (10/10-repeats). To test the reliability of the initial findings, we examined perfusion functional magnetic resonance images acquired during SC exposure in a new cohort of smokers (N = 26) who were genotyped for the SLC6A3 polymorphism. In smokers overall, activity was enhanced in the VS/mOFC (t = 3.77). Contrasts between allelic groups revealed that 9-repeat carriers had a greater response to SCs in the VS (t = 3.12) and mOFC (t = 3.19). In separate groups, 9-repeat carriers showed increased activity in the VS (t = 5.47) and mOFC (T = 4.96), while no increases were observed in 10-repeats. Subjective reports of craving correlated with increased activity in reward-related structures including the extended amygdala, insula and post-central gyrus, and decreased activity in the dorsolateral prefrontal cortex, and were DAT-genotype dependent (r = 0.63-0.96). In secondary analyses, we found that The Fagerstrom Test for Nicotine Dependence scores correlated with enhanced SC-induced perfusion in 10/10-repeats in the insula, mOFC, medial temporal and superior frontal gyri (r = 0.50-0.82), while correlations were absent in 9-repeat carriers. Despite heterogeneity introduced by a host of factors, including variance in other genes involved in smoking behavior, we confirm that DAT genotype predicts the direction and location of neural responses to SCs. C1 [Franklin, Teresa R.; Wang, Ze; Li, Yin; Suh, Jesse J.; Goldman, Marina; Lohoff, Falk W.; Cruz, Jeffrey; Hazan, Rebecca; Jens, Will; Berrettini, Wade; O'Brien, Charles P.; Childress, Anna Rose] Univ Penn, Philadelphia Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Detre, John A.] Univ Penn, Philadelphia Sch Med, Dept Radiol & Neurol, Philadelphia, PA 19104 USA. [Suh, Jesse J.; O'Brien, Charles P.; Childress, Anna Rose] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Franklin, TR (reprint author), Univ Penn, Dept Psychiat, Addict Treatment Res Ctr, Sch Med, 3900 Chestnut St, Philadelphia, PA 19104 USA. EM franklin_t@mail.trc.upenn.edu RI Wang, Ze/A-1043-2007; Lohoff, Falk/M-7951-2016; OI Jens, William/0000-0001-5201-1412 FU NIH [5-P60-DA-005186-18]; Pfizer Pharmaceuticals; Alexander Foundation FX Work supported by NIH 5-P60-DA-005186-18, Pfizer Pharmaceuticals (an Investigator-initiated research grant) and The Alexander Foundation. NR 82 TC 33 Z9 33 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD APR PY 2011 VL 16 IS 2 BP 308 EP 322 DI 10.1111/j.1369-1600.2010.00277.x PG 15 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 730HQ UT WOS:000288024800012 PM 21299752 ER PT J AU Izamis, ML Sharma, NS Uygun, B Bieganski, R Saeidi, N Nahmias, Y Uygun, K Yarmush, ML Berthiaume, F AF Izamis, Maria-Louisa Sharma, Nripen S. Uygun, Basak Bieganski, Robert Saeidi, Nima Nahmias, Yaakov Uygun, Korkut Yarmush, Martin L. Berthiaume, Francois TI In Situ Metabolic Flux Analysis to Quantify the Liver Metabolic Response to Experimental Burn Injury SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE hypermetabolism; metabolic flux analysis; liver; trauma and burns; rat; in vivo ID MASS ISOTOPOMER ANALYSIS; CITRIC-ACID CYCLE; AMINO-ACID; RAT-LIVER; HYPERMETABOLIC LIVERS; FAILURE MODEL; ENERGY; GLUCONEOGENESIS; CACHEXIA; SUPPORT AB Trauma such as burns induces a hypermetabolic response associated with altered central carbon and nitrogen metabolism. The liver plays a key role in these metabolic changes; however, studies to date have evaluated the metabolic state of liver using ex vivo perfusions or isotope labeling techniques targeted to specific pathways. Herein, we developed a unique mass balance approach to characterize the metabolic state of the liver in situ, and used it to quantify the metabolic changes to experimental burn injury in rats. Rats received a sham (control uninjured), 20% or 40% total body surface area (TBSA) scald burn, and were allowed to develop a hypermetabolic response. One day prior to evaluation, all animals were fasted to deplete glycogen stores. Four days post-burn, blood flow rates in major vessels of the liver were measured, and blood samples harvested. We combined measurements of metabolite concentrations and flow rates in the major vessels entering and leaving the liver with a steady-state mass balance model to generate a quantitative picture of the metabolic state of liver. The main findings were: (1) Sham-burned animals exhibited a gluconeogenic pattern, consistent with the fasted state; (2) the 20% TBSA burn inhibited gluconeogenesis and exhibited glycolytic-like features with very few other significant changes; (3) the 40% TBSA burn, by contrast, further enhanced gluconeogenesis and also increased amino acid extraction, urea cycle reactions, and several reactions involved in oxidative phosphorylation. These results suggest that increasing the severity of injury does not lead to a simple dose-dependent metabolic response, but rather leads to qualitatively different responses. Biotechnol. Bioeng. 2011;108: 839-852. (C) 2010 Wiley Periodicals, Inc. C1 [Izamis, Maria-Louisa; Sharma, Nripen S.; Uygun, Basak; Bieganski, Robert; Saeidi, Nima; Nahmias, Yaakov; Uygun, Korkut; Yarmush, Martin L.; Berthiaume, Francois] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Shriners Hosp Children,Ctr Engn Med, Boston, MA 02114 USA. [Sharma, Nripen S.; Yarmush, Martin L.; Berthiaume, Francois] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Berthiaume, F (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Shriners Hosp Children,Ctr Engn Med, Boston, MA 02114 USA. EM fberthia@rci.rutgers.edu RI Nahmias, Yaakov/H-4725-2013; Uygun, Basak/I-1792-2012; Lorkiewicz, Pawel/A-2126-2011; OI Uygun, Basak/0000-0002-2600-7900; Lorkiewicz, Pawel/0000-0002-1755-9826; Nahmias, Yaakov/0000-0002-6051-616X FU Shriners Hospitals for Children [8640, 8450, 8460, 8490, 8496, 8503]; National Institutes of Health [DK080942] FX This work was supported by the Shriners Hospitals for Children (8640, 8450, 8460, 8490, 8496, and 8503) and the National Institutes of Health grant # DK080942. NR 39 TC 7 Z9 10 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD APR PY 2011 VL 108 IS 4 BP 839 EP 852 DI 10.1002/bit.22998 PG 14 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 730LL UT WOS:000288034700013 PM 21404258 ER PT J AU Hamdy, O AF Hamdy, Osama TI Nonsurgical Diabetes Weight Management: Be Prepared for Sustainable and Practical Interventions SO CURRENT DIABETES REPORTS LA English DT Editorial Material ID LIFE-STYLE INTERVENTION; OUTCOMES C1 Joslin Diabet Ctr, Boston, MA 02481 USA. RP Hamdy, O (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02481 USA. EM Osama.hamdy@joslin.harvard.edu NR 8 TC 1 Z9 1 U1 0 U2 0 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 APR PY 2011 VL 11 IS 2 BP 75 EP 76 DI 10.1007/s11892-010-0172-9 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 729CI UT WOS:000287925200002 PM 21222057 ER PT J AU Arathuzik, GG Goebel-Fabbri, AE AF Arathuzik, Gillian G. Goebel-Fabbri, Ann E. TI Nutrition Therapy and the Management of Obesity and Diabetes: An Update SO CURRENT DIABETES REPORTS LA English DT Article DE Weight management; Obesity; Type 2 diabetes; Diet; Nutrition ID LOW-FAT DIET; WEIGHT-LOSS; LOW-CARBOHYDRATE; RISK-FACTORS; TYPE-2; INTERVENTION; PROTEIN; TRIAL; INDIVIDUALS; MELLITUS AB Diabetes and obesity have each become a national health crisis in recent years. The number of people who have diabetes and prediabetes continues to grow with a predicted number of 336 million people worldwide with type 2 diabetes by 2030. The prevalence of diabetes has risen in parallel with the increased prevalence of obesity. The optimal nutrition therapy for the treatment of both diabetes and obesity remains controversial. Health care practitioners are no longer solely prescribing the conventional low-fat, higher-carbohydrate diet approach that was used for over a decade. Lower-carbohydrate, higher-fat, or higher-protein diets are now being viewed as equally or sometimes more effective treatment plans for diabetes and obesity. In addition, there are other aspects of diet beyond macronutrient composition that are currently being investigated. This article will summarize research conducted over the past 2 years examining medical nutrition therapy for diabetes and obesity. It will also describe the unique challenges that come with treating this patient population. C1 [Arathuzik, Gillian G.; Goebel-Fabbri, Ann E.] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Arathuzik, GG (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM Gillian.arathuzik@joslin.harvard.edu; Ann.goebel-fabbri@joslin.harvard.edu NR 29 TC 9 Z9 9 U1 0 U2 17 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 APR PY 2011 VL 11 IS 2 BP 106 EP 110 DI 10.1007/s11892-011-0176-0 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 729CI UT WOS:000287925200007 PM 21240571 ER PT J AU Hamdy, O Horton, ES AF Hamdy, Osama Horton, Edward S. TI Protein Content in Diabetes Nutrition Plan SO CURRENT DIABETES REPORTS LA English DT Article DE Medical nutrition therapy; Diabetes; Protein; Nutrition ID GLUCOSE APPEARANCE RATE; WEIGHT-LOSS DIET; RENAL-FUNCTION; BARIATRIC SURGERY; ORAL GLUCOSE; RISK-FACTORS; FOLLOW-UP; TYPE-2; INGESTION; RESTRICTION AB Medical nutrition therapy plays a major role in diabetes management. Macronutrient composition has been debated for a long time. However, there is increasing evidence that a modest increase in dietary protein intake above the current recommendation is a valid option toward better diabetes control, weight reduction, and improvement in blood pressure, lipid profile, and markers of inflammation. Increasing the absolute protein intake to 1.5-2 g/kg (or 20-30% of total caloric intake) during weight reduction has been suggested for overweight and obese patients with type 2 diabetes and normal kidney function. Increased protein intake does not increase plasma glucose, but increases the insulin response and results in a significant reduction in hemoglobin A(1c). In addition, a higher dietary protein intake reduces hunger, improves satiety, increases thermogenesis, and limits lean muscle mass loss during weight reduction using a reduced calorie diet and increased physical activity. It is preferable to calculate protein intake for patients with diabetes as grams per kilogram of body weight and not as a fixed percentage of total energy intake to avoid protein malnutrition when a hypocaloric diet is used. The relationship between protein intake as grams per kilogram of body weight and albumin excretion rate is very weak, except in hypertensive patients and particularly in those with uncontrolled diabetes. A protein intake of 0.8-1 g/kg should be recommended only for patients with diabetes and chronic kidney disease. Other patients with diabetes should not reduce protein intake to less than 1 g/kg of body weight. This review discusses the effects of different amounts of protein intake in a diabetes meal plan. It particular, it discusses the effects of protein intake on renal function, the effects of protein content on diabetes control, and the effects of increased dietary protein on body weight. C1 [Hamdy, Osama; Horton, Edward S.] Harvard Univ, Sch Med, Dept Endocrinol, Joslin Diabet Ctr, Boston, MA 02481 USA. RP Hamdy, O (reprint author), Harvard Univ, Sch Med, Dept Endocrinol, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02481 USA. EM Osama.hamdy@joslin.harvard.edu RI Biguzzi, Felipe/E-4724-2015 NR 36 TC 7 Z9 7 U1 0 U2 6 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 APR PY 2011 VL 11 IS 2 BP 111 EP 119 DI 10.1007/s11892-010-0171-x PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 729CI UT WOS:000287925200008 PM 21207203 ER PT J AU Lo, J AF Lo, Janet TI Dyslipidemia and lipid management in HIV-infected patients SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Article DE cardiovascular risk factors; HIV; lipids ID IMMUNODEFICIENCY-VIRUS-INFECTION; COMBINATION ANTIRETROVIRAL THERAPY; CLINICAL-TRIALS GROUP; TREATMENT PANEL-III; PROTEASE INHIBITORS; RISK-FACTORS; MYOCARDIAL-INFARCTION; RANDOMIZED-TRIAL; DISEASE; CHOLESTEROL AB Purpose of review Dyslipidemia is highly prevalent among patients living with chronic HIV infection and may confer increased risk of cardiovascular disease in this patient population. This review summarizes recent data investigating lipid abnormalities and its management in HIV-infected patients. Recent findings Studies in the last year have evaluated the effects of various lipid-lowering therapies not previously investigated in the HIV patient population. Rosuvastatin is a potent statin that appears to be well tolerated and effective in HIV-infected patients with hypercholesterolemia. Summary Dyslipidemia is common in HIV-infected individuals. Medical therapy of lipid disorders needs to take potential drug-drug interactions of lipid-lowering medications and antiretroviral agents into consideration. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Program Nutr Metab, Boston, MA 02114 USA. RP Lo, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Program Nutr Metab, 55 Fruit St,LON 207, Boston, MA 02114 USA. EM jlo@partners.org FU NHLBI NIH HHS [K23 HL092792-04, K23 HL092792] NR 29 TC 15 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1752-296X J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD APR PY 2011 VL 18 IS 2 BP 144 EP 147 DI 10.1097/MED.0b013e328344556e PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 729AV UT WOS:000287919500008 PM 21297466 ER PT J AU Goldstein, JN Gilson, AJ AF Goldstein, Joshua N. Gilson, Aaron J. TI Critical Care Management of Acute Intracerebral Hemorrhage SO CURRENT TREATMENT OPTIONS IN NEUROLOGY LA English DT Review ID ASSOCIATION/AMERICAN-STROKE-ASSOCIATION; HYPERTENSIVE CEREBRAL-HEMORRHAGE; PREDICTS HEMATOMA EXPANSION; CT ANGIOGRAPHY; CLINICAL-TRIAL; BLOOD-PRESSURE; INTRAVENTRICULAR THROMBOLYSIS; CONSERVATIVE TREATMENT; AMYLOID ANGIOPATHY; HIGHEST RISK AB Intracerebral hemorrhage is a medical emergency. It is the most deadly and disabling form of stroke, and no individual therapy has been demonstrated to improve outcome. However, it appears that aggressive medical care in general, and management by neuroscience specialists in particular, offers substantial benefit. Therefore, providing the best supportive care based on currently available evidence may well improve outcomes. Airway management and management of blood pressure aimed at maximizing cerebral perfusion while minimizing ongoing bleeding, as well as rapid reversal of anticoagulation, are likely to be important in the early phase. Additionally, efforts should be undertaken to provide careful glucose management and temperature management and to maximize cerebral perfusion pressure. Selected patients are likely to benefit from external ventricular drainage or even hematoma evacuation. Except in rare circumstances, most patients should be managed in a neuroscience intensive care unit during the acute phase. Some patients appear to have no reasonable likelihood of recovery and can be considered for limitations of care such as Do Not Resuscitate orders or Comfort Measures Only orders. However, it can be difficult to accurately predict long-term outcome in the acute phase; formal prognostic tools should be used to offer information to patients and their families. After the hemorrhage has stabilized, efforts to minimize complications include thromboembolism prophylaxis, physical therapy, and acute rehabilitation. C1 [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Goldstein, JN (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Zero Emerson Pl,Suite 3B, Boston, MA 02114 USA. EM jgoldstein@partners.org; aaron.gilson@lmunet.edu RI Goldstein, Joshua/H-8953-2016 FU CSL Behring FX Conflicts of Interest: J. Goldstein: Consulting fees and travel expenses from CSL Behring; A. Gilson: None. NR 61 TC 7 Z9 9 U1 1 U2 3 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1092-8480 J9 CURR TREAT OPTION NE JI Curr. Treat. Options Neurol. PD APR PY 2011 VL 13 IS 2 BP 204 EP 216 DI 10.1007/s11940-010-0109-2 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 729CV UT WOS:000287926800007 PM 21222062 ER PT J AU Simard, JM Sahuquillo, J Sheth, KN Kahle, KT Walcott, BP AF Simard, J. Marc Sahuquillo, Juan Sheth, Kevin N. Kahle, Kristopher T. Walcott, Brian P. TI Managing Malignant Cerebral Infarction SO CURRENT TREATMENT OPTIONS IN NEUROLOGY LA English DT Review ID INTENSIVE-CARE-UNIT; ARTERY INFARCTION; DECOMPRESSIVE CRANIECTOMY; INTRACRANIAL-PRESSURE; ISCHEMIC-STROKE; HYPERTONIC SALINE; HEMISPHERIC INFARCTION; RANDOMIZED-TRIAL; HEAD-INJURY; HEMICRANIECTOMY AB Managing patients with malignant cerebral infarction remains one of the foremost challenges in medicine. These patients are at high risk for progressive neurologic deterioration and death due to malignant cerebral edema, and they are best cared for in the intensive care unit of a comprehensive stroke center. Careful initial assessment of neurologic function and of findings on MRI, coupled with frequent reassessment of clinical and radiologic findings using CT or MRI are mandatory to promote the prompt initiation of treatments that will ensure the best outcome in these patients. Significant deterioration in either neurologic function or radiologic findings or both demand timely treatment using the best medical management, which may include osmotherapy (mannitol or hypertonic saline), endotracheal intubation, and mechanical ventilation. Under appropriate circumstances, decompressive craniectomy may be warranted to improve outcome or to prevent death. C1 [Simard, J. Marc] Dept Neurosurg, Baltimore, MD 21201 USA. [Sahuquillo, Juan] Univ Autonoma Barcelona, Dept Neurosurg, Hosp Univ Vall dHebron, Barcelona 08035, Spain. [Sheth, Kevin N.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, DC 20201 USA. [Kahle, Kristopher T.; Walcott, Brian P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA 02114 USA. RP Simard, JM (reprint author), Dept Neurosurg, 22 S Greene St,Suite S12D, Baltimore, MD 21201 USA. EM msimard@smail.umaryland.edu RI Sahuquillo, Juan/B-3577-2008 OI Sahuquillo, Juan/0000-0003-0713-5875 FU NHLBI NIH HHS [R01 HL082517]; NINDS NIH HHS [R01 NS061808, R01 NS061808-04] NR 49 TC 18 Z9 20 U1 0 U2 6 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1092-8480 J9 CURR TREAT OPTION NE JI Curr. Treat. Options Neurol. PD APR PY 2011 VL 13 IS 2 BP 217 EP 229 DI 10.1007/s11940-010-0110-9 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 729CV UT WOS:000287926800008 PM 21190097 ER PT J AU Chung, JH Kradin, RL Greene, RE Shepard, JAO Digumarthy, SR AF Chung, Jonathan H. Kradin, Richard L. Greene, Reginald E. Shepard, Jo-Anne O. Digumarthy, Subba R. TI CT predictors of mortality in pathology confirmed ARDS SO EUROPEAN RADIOLOGY LA English DT Article DE Acute respiratory distress syndrome; Diffuse alveolar damage; Right-sided heart strain; Mortality; CT ID RESPIRATORY-DISTRESS-SYNDROME; ACUTE INTERSTITIAL PNEUMONIA; ACUTE LUNG INJURY; PULMONARY VASCULAR OBSTRUCTION; RIGHT-VENTRICULAR DYSFUNCTION; THIN-SECTION CT; COMPUTED-TOMOGRAPHY; CLINICAL-COURSE; FOLLOW-UP; EMBOLISM AB To identify CT findings that predict mortality in acute respiratory distress syndrome (ARDS) and to identify CT findings that differentiate diffuse alveolar damage (DAD) from DAD with prominent histopathological features of organizing pneumonia (DAD-OP). Twenty-eight patients with ARDS (corroborated by open biopsy) and chest CT within 2 weeks of biopsy were included in our study. Differences in CT findings in patients with survivors versus nonsurvivors as well as for DAD versus DAD-OP were compared using Fisher's exact test. Lung involvement of greater than 80%, RA/LA ratio > 1, and varicoid traction bronchiectasis were statistically more common in nonsurvivors than in survivors (respective p values of 0.001, 0.008, and 0.038). PA dilation greater than 3 cm and RV/LV ratio greater than 0.9 were also more common in nonsurvivors than in survivors but these factors did not achieve significance. CT findings did not differentiate DAD from DAD-OP. Our study suggests that > 80% of lung involvement, RA/LA ratio > 1, and varicoid bronchiectasis predict mortality in patients with ARDS/DAD. Signs of right-sided heart failure (PA dilation greater than 3 cm and RV/LV ratio greater than 0.9) approached significance. CT findings did not differentiate DAD from DAD-OP. C1 [Chung, Jonathan H.; Greene, Reginald E.; Shepard, Jo-Anne O.; Digumarthy, Subba R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kradin, Richard L.] Massachusetts Gen Hosp, Dept Pathol & Pulm Med, Boston, MA 02114 USA. RP Digumarthy, SR (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 202, Boston, MA 02114 USA. EM sdigumarthy@partners.org NR 35 TC 11 Z9 12 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 J9 EUR RADIOL JI Eur. Radiol. PD APR PY 2011 VL 21 IS 4 BP 730 EP 737 DI 10.1007/s00330-010-1979-0 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 729DI UT WOS:000287928200008 PM 20927526 ER PT J AU Matschke, S Wentzensen, A Ring, D Marent-Huber, M Audige, L Jupiter, JB AF Matschke, S. Wentzensen, A. Ring, D. Marent-Huber, M. Audige, L. Jupiter, J. B. TI Comparison of angle stable plate fixation approaches for distal radius fractures SO INJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJURED LA English DT Article DE Distal radius fractures; Dorsal plating; Volar plating; LCP; 2-Year follow-up ID INTERNAL-FIXATION; INTRAARTICULAR FRACTURES; UNSTABLE FRACTURES; LOCKING PLATES; PI PLATE; DORSAL; VOLAR; COMPLICATIONS; MANAGEMENT; CLASSIFICATION AB Introduction: The aim of the study was to compare radiological and functional outcomes between volar and dorsal surgical fixation of distal radius fractures using low-profile, fixed-angle implants. Patients and methods: A total of 305 distal radius fracture patients were treated with Synthes locking compression plate (LCP) 2.4- or 3.5-mm fixation using either a volar (n = 266) or dorsal (n = 39) approach. The patients were examined at 6 months, 1 and 2 years for radiological assessment of fracture healing, alignment, reduction and arthritis, as well as the determination of various functional outcome scores. Results: Both groups were comparable with respect to baseline and injury characteristics. The complication rate was higher for the volar approach (15%). No significant differences were observed for Disabilities of the Arm, Shoulder and Hand (DASH) and Short Form (36) Health Survey (SF-36) scores, pain, arthritis grade, grip strength and radiological measurements. However, a significantly better functional outcome represented by a low mean Gartland and Werley score was observed for the volar approach after 6 and 12 months. Significantly higher percentages of dorsal extension, palmar flexion, ulnar deviation and supination angle (relative to the mean contralateral healthy wrist) were also reported for volar approach patients at the 6-month follow-up. Conclusions: Volar internal fixation of distal radius fractures with LCP DR implants can result in earlier and better functional outcome compared with the dorsal approach, yet is associated with a higher incidence of complications. After 2 years, these differences are no longer observed between the two surgical methods. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Matschke, S.; Wentzensen, A.] Univ Heidelberg, Unfallchirurg Klin, Klin Unfallchirurg & Orthopad, Berufsgenossenschaftliche Unfallklin Ludwigshafen, D-67071 Ludwigshafen, Germany. [Ring, D.; Jupiter, J. B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Marent-Huber, M.; Audige, L.] AO Clin Invest & Documentat, Davos, Switzerland. RP Matschke, S (reprint author), Univ Heidelberg, Unfallchirurg Klin, Klin Unfallchirurg & Orthopad, Berufsgenossenschaftliche Unfallklin Ludwigshafen, Ludwig Guttmann Str 13, D-67071 Ludwigshafen, Germany. EM matschke@bgu-ludwigshafen.de RI AOCID, AO Foundation/R-6455-2016 NR 29 TC 16 Z9 24 U1 0 U2 3 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 APR PY 2011 VL 42 IS 4 BP 385 EP 392 DI 10.1016/j.injury.2010.10.010 PG 8 WC Critical Care Medicine; Emergency Medicine; Orthopedics; Surgery SC General & Internal Medicine; Emergency Medicine; Orthopedics; Surgery GA 730CM UT WOS:000288008500014 PM 21144514 ER PT J AU Baumueller, S Alkadhi, H Stolzmann, P Frauenfelder, T Goetti, R Schertler, T Plass, A Falk, V Feuchtner, G Scheffel, H Desbiolles, L Leschka, S AF Baumueller, Stephan Alkadhi, Hatem Stolzmann, Paul Frauenfelder, Thomas Goetti, Robert Schertler, Thomas Plass, Andre Falk, Volkmar Feuchtner, Gudrun Scheffel, Hans Desbiolles, Lotus Leschka, Sebastian TI Computed Tomography of the Lung in the High-Pitch Mode Is Breath Holding Still Required? SO INVESTIGATIVE RADIOLOGY LA English DT Article DE computed tomography scanner; lung; breathing ID HIGH-RESOLUTION CT; THIN-SECTION CT; ADAPTED EXAMINATION PROTOCOLS; SPIRAL VOLUMETRIC CT; RADIATION-EXPOSURE; PULMONARY NODULES; AORTIC-ANEURYSM; IMAGE QUALITY; HELICAL CT; REDUCTION AB Objectives: To prospectively investigate whether the high-pitch mode (HPM) for computed tomography (CT) enables the diagnostic visualization of the lung parenchyma without suspended respiration. Materials and Methods: A total of 40 consecutive patients (age, 67 +/- 11 years) underwent 128-slice dual-source CT of the chest including nonenhanced, arterial, and venous phase of contrast. CT was performed in the HPM with a pitch of 3.2 during continuous breathing (group A) and during breath-hold (group B), and at standard pitch of 1 during deep-inspiratory breath-hold (group C). The 3 protocols were scanned in a random order in each patient. Two blinded readers independently assessed the image quality of 5 regions in both the lungs using a semiquantitative 3-point score. Image noise was measured as the standard deviation of attenuation. Presence and size of pulmonary nodules were noted and measured on each CT dataset. Lung volume was measured using dedicated semi-automated segmentation software. Results: Interobserver agreement for image quality ratings was excellent (kappa = 0.91). There were no significant differences in the number of lung regions having an image quality other than excellent between group A (2.5%) and B (1.5%, P = 0.48), whereas significantly less regions had impaired image quality in group B compared with group C (5.5%, P < 0.01). Image quality impairment in group C was because of breathing in 36% and cardiac pulsation in 64%. Image noise in group C (9 +/- 2 HU) was significantly lower than that in group B (30 +/- 2 HU, P < 0.001) whereas no significant difference was found between group A and B (P = 0.52). There were no significant differences for the depiction (P = 1.0) and size (P = 0.94) of lung nodules among the 3 modes. Average lung volume in group A was 75% +/- 15% of that in deep inspiration (group B/C) being significantly smaller (P < 0.05). Estimated effective radiation doses in group C and group B were 5.8 +/- 0.5 mSv and 1.6 +/- 0.1 mSv, respectively. Conclusions: CT of the lung can be accomplished using the HPM at a low radiation dose with a diagnostic image quality even without suspended respiration. C1 [Leschka, Sebastian] Cantonal Hosp St Gallen, Inst Radiol, CH-9007 St Gallen, Switzerland. [Baumueller, Stephan; Alkadhi, Hatem; Stolzmann, Paul; Frauenfelder, Thomas; Goetti, Robert; Schertler, Thomas; Feuchtner, Gudrun; Scheffel, Hans; Desbiolles, Lotus] Univ Zurich Hosp, Inst Diagnost & Intervent Radiol, CH-8091 Zurich, Switzerland. [Alkadhi, Hatem; Stolzmann, Paul; Scheffel, Hans] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Alkadhi, Hatem; Stolzmann, Paul; Scheffel, Hans] Harvard Univ, Sch Med, Boston, MA USA. [Plass, Andre; Falk, Volkmar] Univ Zurich Hosp, Cardiovasc Surg Clin, CH-8091 Zurich, Switzerland. RP Leschka, S (reprint author), Cantonal Hosp St Gallen, Inst Radiol, Rorschacher Str 95, CH-9007 St Gallen, Switzerland. EM sebastian.leschka@kssg.ch RI Goetti, Robert/I-8961-2012; Frauenfelder, Thomas/O-1734-2016 OI Frauenfelder, Thomas/0000-0002-3295-6619 NR 37 TC 34 Z9 37 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD APR PY 2011 VL 46 IS 4 BP 240 EP 245 DI 10.1097/RLI.0b013e3181feee1a PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 729WK UT WOS:000287984600004 PM 21217528 ER PT J AU McCall, AA Linthicum, FH O'Malley, JT Adams, JC Merchant, SN Bassim, MK Gellibolian, R Fayad, JN AF McCall, Andrew A. Linthicum, Fred H., Jr. O'Malley, Jennifer T. Adams, Joe C. Merchant, Saumil N. Bassim, Marc K. Gellibolian, Robert Fayad, Jose N. TI Extralabyrinthine Manifestations of DFNA9 SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE cochlin; COCH; hearing loss; deafness ID SENSORINEURAL HEARING-LOSS; VESTIBULAR DYSFUNCTION; INNER-EAR; OTITIS-MEDIA; A DOMAIN; COCHLIN; DEAFNESS; GENE; MUTATIONS AB DFNA9 is an autosomal dominant cause of non-syndromic adult-onset sensorineural hearing loss with associated variable vestibular dysfunction caused by mutations in the COCH gene. DFNA9 has previously been characterized by the presence of unique histopathologic features limited to the cochlear and vestibular labyrinth. This report describes newly discovered extralabyrinthine findings within the middle ear in DFNA9 and discusses their implications. The histopathologic anatomy of extralabyrinthine structures was reviewed in 12 temporal bones from seven individuals with DFNA9 and compared with age-matched controls. All temporal bones with DFNA9 had abnormal deposits within the tympanic membrane, incudomalleal joint, and incudostapedial joint. Hematoxylin and eosin stain and Movat's pentachrome stain both revealed different staining patterns of the extralabyrinthine deposits compared with the intralabyrinthine deposits suggesting that the composition of the deposits varies with location. The deposits within the tympanic membrane resembled cartilage morphologically and stained positively for aggrecan, an extracellular matrix protein found in cartilage. However, the cellular component of the tympanic membrane deposits did not stain with immunomarkers for chondrocytes (s100 and connective tissue growth factor). These novel findings in DFNA9 have implications for the phenotypic expression of the disorder and the clinical workup of adult-onset sensorineural hearing loss. C1 [McCall, Andrew A.; O'Malley, Jennifer T.; Adams, Joe C.; Merchant, Saumil N.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [McCall, Andrew A.; O'Malley, Jennifer T.; Adams, Joe C.; Merchant, Saumil N.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Linthicum, Fred H., Jr.; Gellibolian, Robert; Fayad, Jose N.] House Ear Res Inst, Los Angeles, CA 90057 USA. [Bassim, Marc K.; Fayad, Jose N.] House Ear Clin, Los Angeles, CA 90057 USA. RP McCall, AA (reprint author), Univ Pittsburgh, Dept Otolaryngol, Inst Eye & Ear, 200 Lothrop St,Suite 500, Pittsburgh, PA 15213 USA. EM mccallaa@upmc.edu FU National Institutes of Health [U24 DC 008559, U24 DC 008625] FX This work was supported by the National Institutes of Health (grants U24 DC 008559 and U24 DC 008625 Human Temporal Bone Consortium for Research Resource Enhancement of the National Institute on Deafness and Other Communication Disorders). We acknowledge Diane Jones and Barbara Burgess from the Massachusetts Eye and Ear Infirmary temporal bone histopathology laboratory for technical assistance with the project. We thank Andrew E. Rosenberg, MD bone and soft tissue pathology specialist from the Department of Pathology at the Massachusetts General Hospital for providing his expertise and guidance as well as providing the s100 antibody utilized in this project. NR 26 TC 3 Z9 3 U1 0 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 J9 JARO-J ASSOC RES OTO JI JARO PD APR PY 2011 VL 12 IS 2 BP 141 EP 149 DI 10.1007/s10162-010-0245-0 PG 9 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 728FA UT WOS:000287858600002 PM 21052762 ER PT J AU McClintock, SM Husain, MM Wisniewski, SR Nierenberg, AA Stewart, JW Trivedi, MH Cook, I Morris, D Warden, D Rush, AJ AF McClintock, Shawn M. Husain, Mustafa M. Wisniewski, Stephen R. Nierenberg, Andrew A. Stewart, Jonathan W. Trivedi, Madhukar H. Cook, Ian Morris, David Warden, Diane Rush, Augustus John TI Residual Symptoms in Depressed Outpatients Who Respond by 50% But Do Not Remit to Antidepressant Medication SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE depression; STAR*D; residual; symptoms; treatment response ID STAR-ASTERISK-D; DIAGNOSTIC SCREENING QUESTIONNAIRE; SEQUENCED TREATMENT ALTERNATIVES; MAJOR DEPRESSION; COGNITIVE THERAPY; PARTIAL REMISSION; DISORDER; RELAPSE; RISK; SYMPTOMATOLOGY AB Little is known about the quantity or quality of residual depressive symptoms in patients with major depressive disorder (MDD) who have responded but not remitted with antidepressant treatment. This report describes the residual symptom domains and individual depressive symptoms in a large representative sample of outpatients with nonpsychotic MDD who responded without remitting after up to 12 weeks of citalopram treatment in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Response was defined as 50% or greater reduction in baseline 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR(16)) by treatment exit, and remission as a final QIDS-SR16 of less than 6. Residual symptom domains and individual symptoms were based on the QIDS-SR16 and classified as either persisting from baseline or emerging during treatment. Most responders who did not remit endorsed approximately 5 residual symptom domains and 6 to 7 residual depressive symptoms. The most common domains were insomnia (94.6%), sad mood (70.8%), and decreased concentration (69.6%). The most common individual symptoms were midnocturnal insomnia (79.0%), sad mood (70.8%), and decreased concentration/decision making (69.6%). The most common treatment-emergent symptoms were midnocturnal insomnia (51.4%) and decreased general interest (40.0%). The most common persistent symptoms were midnocturnal insomnia (81.6%), sad mood (70.8%), and decreased concentration/decision making (70.6%). Suicidal ideation was the least common treatment-emergent symptom (0.7%) and the least common persistent residual symptom (17.1%). These findings suggest that depressed outpatients who respond by 50% without remitting to citalopram treatment have a broad range of residual symptoms. Individualized treatments are warranted to specifically address each patient's residual depressive symptoms. C1 [McClintock, Shawn M.; Husain, Mustafa M.; Trivedi, Madhukar H.; Morris, David; Warden, Diane] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [McClintock, Shawn M.] Columbia Univ, Dept Psychiat, Div Brain Stimulat & Therapeut Modulat, New York State Psychiat Inst, New York, NY USA. [Wisniewski, Stephen R.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Pittsburgh, PA USA. [Nierenberg, Andrew A.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Stewart, Jonathan W.] New York State Psychiat Inst & Hosp, Depress Evaluat Serv, Dept Psychiat, New York, NY 10032 USA. [Cook, Ian] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Depress Res & Clin Program, Los Angeles, CA USA. [Rush, Augustus John] Duke Natl Univ Singapore, Off Clin Sci, Grad Sch Med, Singapore, Singapore. RP McClintock, SM (reprint author), Univ Texas SW Med Ctr Dallas, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM shawn.mcclintock@utsouthwestern.edu OI Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382 FU National Institute of Mental Health [N01MH90003]; National Institutes of Health; National Center for Research Resources; National Alliance for the Research of Schizophrenia and Depression; Aspect Medical Systems/Covidien; Cyberonics, Inc.; Eli Lilly Company; Neuronetics; Novartis; Sepracor; National Institutes of Health, National Institute of Mental Health; Stanley Medical Research Institute; St. Jude Medical Center; Brainsway; Pfizer, Inc.; Cephalor, Inc.; Cederroth; Cyberonics; Forest; Medtronics; National Alliance for Research on Schizophrenia and Depression; Ortho-McNeil-Janssen; Pamlab; Pfizer; Shire; Stanley Foundation through the Broad Institute; Bristol-Myers Squibb; Eli Lilly; GlaxoSmithKline; Janssen; Lictwer Pharma; Wyeth; AstraZeneca; Advanced Neuromodulation Systems; Best Practice Project Management; Bristol-Myers Squibb/Otsuka; Gerson Lehrman Group; Jazz Pharmaceuticals; Magellan Health Services; Merck Co.; Novartis Pharmaceuticals; Ono Pharmaceuticals; Organon; Otsuka Pharmaceuticals; Transcept Pharmaceuticals; Urban Institute; Wyeth Ayerst; University of Michigan; Brain Resource; Forest Pharmaceuticals; Society of Biological Psychiatry; Agency for Healthcare Research and Quality (AHRQ); Corcept Therapeutics, Inc.; National Institute on Drug Abuse; Pharmacia Upjohn; Predix Pharmaceuticals (Epix); Solvay Pharmaceuticals, Inc.; Targacept; ImaRx Therapeutics, Inc.; Case Western Reserve University; Singapore Clinical Research Institute; Dey Pharmaceuticals; Venebio; National Institute of Health, National Institute of Neurological Disorders and Stroke; National Institute of Health, National Institute of Aging FX This project was funded by the National Institute of Mental Health under contract N01MH90003 to the University of Texas Southwestern Medical Center at Dallas (A. J. Rush and M. H. Trivedi, principal investigators). The NIMH had no further role in the study design; collection, analysis, and interpretation of the data; writing of the report; or in the decision to submit the paper for publication. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.; Dr McClintock has received research support from the National Institutes of Health, the National Center for Research Resources, and the National Alliance for the Research of Schizophrenia and Depression. Dr Cook has served as an advisor and consultant for Ascend Media, Bristol-Meyers Squibb, Cyberonics, Inc, Lilly, and the US Department of Justice. He has served on the speaker's bureaus for Bristol-Meyers Squibb, Neuronetics, and Wyeth/Pfizer. He has received research support from Aspect Medical Systems/Covidien, Cyberonics, Inc., Eli Lilly & Company, Neuronetics, Novartis, Sepracor, and the National Institutes of Health. His patents on biomedical devices are assigned to the Regents of the University of California. Dr Husain has received research support from the National Institutes of Health (including National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, and National Institute of Aging), the Stanley Medical Research Institute, St. Jude Medical Center, Cyberonics, Inc., Brainsway, Neuronetics, and he has received equipment from Magstim, Inc. Dr Morris has received consultation fees from Pfizer, Inc. and Cephalor, Inc. Dr Nierenberg has consulted to or served on the advisory boards of Abbott, Appliance Computing, Brain Cells, Bristol-Myers Squibb, Eli Lilly, EpiQ, Forest, GlaxoSmithKline, Janssen, Jazz, Merck, Novartis, Pamlab, Pfizer, PGx Health, Pharmaceutica, Schering-Plough, Sepracor, Shire, Somerset, Takeda, and Targacept; has received research support from Cederroth, Cyberonics, Forest, Medtronics, the National Alliance for Research on Schizophrenia and Depression, the National Institute of Mental Health, Ortho-McNeil-Janssen, Pamlab, Pfizer, Shire, and the Stanley Foundation through the Broad Institute; has received past support from Bristol-Myers Squibb, Cederroth, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Lictwer Pharma, Pfizer, and Wyeth; has received honoraria from the Massachusetts General Hospital (MGH) Psychiatry Academy (MGHPA activities are supported through Independent Medical Education grants from AstraZeneca, Eli Lilly, and Janssen); earns fees for editorial functions for CNS Spectrums through MBL Communications, and Psychiatric Annals through Slack; receives honoraria as a CME executive director for the Journal of Clinical Psychiatry through Physicians Postgraduate Press; has been on the speaker's bureaus of Bristol-Myers Squibb, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, and Wyeth; has received royalties from Cambridge University Press and Belvoir Publishing; owns stock options in Appliance Computing; and owns the copyrights to the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery Asberg Depression Scale, exclusively licensed to the MGH Clinical Trials Network and Institute. Dr Rush has received consultation fees from Advanced Neuromodulation Systems, AstraZeneca, Best Practice Project Management, Bristol-Myers Squibb/Otsuka, the Gerson Lehrman Group, Jazz Pharmaceuticals, Magellan Health Services, Merck & Co., Neuronetics, Novartis Pharmaceuticals, Ono Pharmaceuticals, Organon, Otsuka Pharmaceuticals, Pamlab, Transcept Pharmaceuticals, Urban Institute, Wyeth Ayerst, University of Michigan, and Brain Resource. He has received consulting fee/honoraria from Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, and Pfizer. He has received royalties from Guilford Publications, Healthcare Technology Systems, and the University of Texas Southwestern Medical Center.; He has received research support from the National Institute of Mentl Health and the Stanley Medical Research Institute, and a stipend from the Society of Biological Psychiatry. Dr Stewart has received consultation fees from Merck & Co., study funding from Eli Lilly & Company and the National Institute of Mental Health, and study medication from Forest Pharmaceuticals. Dr Trivedi has acted as a paid consultant to or served on speaker's bureaus for Abbott Laboratories, Inc., Abdi Ibrahim, Akzo (Organon Pharmaceuticals, Inc.), AstraZeneca, Bristol-Meyers Squibb, Cephalon, Inc., Cyberonics, Inc., Eli Lilly & Company, Evotec, Fabre Kramer Pharmaceuticals, Inc., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceuticals Products, LP, Johnson & Johnson PRD, Mead Johnson, Medtronic, Neuronetics, Otsuka Pharmaceuticals, Parke-Davis Pharmaceuticals, Inc., Pfizer, Inc., Sepracor, SHIRE Development, Solvay Pharmaceuticals, VantagePoint, and Wyeth-Ayerst Laboratories. He has also received research funding from the Agency for Healthcare Research and Quality (AHRQ), Corcept Therapeutics, Inc., Cyberonics, Inc., Merck, National Alliance for Research in Schizophrenia and Depression, National Institute of Mental Health, National Institute on Drug Abuse, Novartis, Pharmacia & Upjohn, Predix Pharmaceuticals (Epix), Solvay Pharmaceuticals, Inc., and Targacept. Dr Warden has received research funding from the National Alliance for the Research of Schizophrenia and Depression, the National Institutes of Health, and has owned shares of stock in Pfizer, Inc. Dr Wisniewski has received consulting fees from Cyberonics, Inc. (2005-2009), ImaRx Therapeutics, Inc. (2006), Bristol-Myers Squibb (2007-08), Organon (2007), Case Western Reserve University (2007), Singapore Clinical Research Institute (2009), Dey Pharmaceuticals (2010), and Venebio (2010). NR 39 TC 60 Z9 64 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD APR PY 2011 VL 31 IS 2 BP 180 EP 186 DI 10.1097/JCP.0b013e31820ebd2c PG 7 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 729AJ UT WOS:000287917500008 PM 21346613 ER PT J AU Fan, XD Copeland, PM Liu, EY Chiang, EL Freudenreich, O Goff, DC Henderson, DC AF Fan, Xiaoduo Copeland, Paul M. Liu, Emily Y. Chiang, Elaine Freudenreich, Oliver Goff, Donald C. Henderson, David C. TI No Effect of Single-Dose Intranasal Insulin Treatment on Verbal Memory and Sustained Attention in Patients With Schizophrenia SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE intranasal insulin; cognition; attention; schizophrenia ID RAT HIPPOCAMPUS; DIABETIC-RATS; RECEPTOR; MODULATION; BRAIN; PERFORMANCE; COGNITION; HUMANS AB Background: Impairments in verbal memory and attention are among the most severe and disabling cognitive deficits in patients with schizophrenia. Whereas efficacy for cognition has not yet been established for any pharmacologic strategy in schizophrenia, an accumulating body of evidence suggests a possible beneficial role of insulin. Methods: We conducted a double-blind, placebo-controlled trial to examine the effect of single-dose intranasal insulin treatment on cognition in nondiabetic patients with schizophrenia. After fasting for 12 hours, subjects received either 40 IU regular human insulin or placebo administered by intranasal pump. The Hopkins Verbal Learning Test and the Continuous Performance Test-Identical Pairs were administered before and 30 minutes after intranasal treatment. Results: Thirty patients were enrolled and completed the study. The 2 treatment groups (insulin vs placebo, n = 15 in each group) did not differ on any demographic or general clinical variable (P > 0.40). There was no significant difference between the 2 treatment groups in change on Hopkins Verbal Learning Test immediate recall total score and delayed recall score, or on CPT d', hits rate, reaction time of hits, or false-alarm rate (P > 0.1). Conclusions: Results of the present study suggest that single-dose intranasal insulin treatment does not have a large-enough effect on verbal memory or sustained attention to be detected by a sample of this size in patients with schizophrenia but was safe and well tolerated. Longitudinal studies to explore cognitive benefits of repeated dosing of intranasal insulin treatment are needed. C1 [Fan, Xiaoduo; Freudenreich, Oliver; Goff, Donald C.; Henderson, David C.] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Fan, Xiaoduo; Copeland, Paul M.; Freudenreich, Oliver; Goff, Donald C.; Henderson, David C.] Harvard Univ, Sch Med, Boston, MA USA. [Copeland, Paul M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Liu, Emily Y.] Partners Community Healthcare Inc, Haverhill, MA USA. [Chiang, Elaine] George Washington Univ, Sch Med, Washington, DC USA. RP Fan, XD (reprint author), Freedom Trail Clin, 25 Staniford St, Boston, MA 02114 USA. EM xfan@partners.org FU Massachusetts General Hospital; Eli Lilly; AstraZeneca; Bristol-Myers Squibb; Janssen; Pfizer; Cephalon; Organon; Xytis; Wyeth; Forest Labs; Indevus; Schering Plough; Janssen and Bristol-Myers Squibb; Novartis; Takeda; Solvay; COVANCE FX The study was sponsored by an internal fund from the Massachusetts General Hospital Schizophrenia Program.; Dr Fan has received research support or honoraria from Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Janssen, and Pfizer. Dr Copeland has received honoraria from Amylin, Eli Lilly, Merck, Sanofi-Aventis, and Takeda. Dr Freudenreich has received research support or honoraria from AstraZeneca, Bristol-Myers Squibb, Janssen, Eli Lilly, Cephalon, and Pfizer. Dr Goff has received research support or honoraria from Organon, Xytis, Wyeth, Forest Labs, Eli Lilly, Pfizer, Indevus, Schering Plough, AstraZeneca, Janssen and Bristol-Myers Squibb, Novartis, and Cephalon. Dr Henderson has received research support or honoraria from Takeda, Bristol-Myers Squibb, Pfizer, AstraZeneca, Eli Lilly, Solvay, Janssen, and COVANCE. Dr Liu and Ms Chiang report no disclosures. NR 24 TC 8 Z9 8 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD APR PY 2011 VL 31 IS 2 BP 231 EP 234 DI 10.1097/JCP.0b013e31820ebd0e PG 4 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 729AJ UT WOS:000287917500016 PM 21346605 ER PT J AU Siddappa, NB Hemashettar, G Wong, YL Lakhashe, S Rasmussen, RA Watkins, JD Novembre, FJ Villinger, F Else, JG Montefiori, DC Ruprecht, RM AF Siddappa, Nagadenahalli B. Hemashettar, Girish Wong, Yin Ling Lakhashe, Samir Rasmussen, Robert A. Watkins, Jennifer D. Novembre, Francis J. Villinger, Francois Else, James G. Montefiori, David C. Ruprecht, Ruth M. TI Development of a tier 1 R5 clade C simian-human immunodeficiency virus as a tool to test neutralizing antibody-based immunoprophylaxis SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE clade C SHIV; neutralization sensitive; R5 SHIV; tier 1; vaccine development ID NEIGHBOR-JOINING METHOD; TYPE-1 SUBTYPE-C; CORECEPTOR SWITCH; HIV-1 INFECTION; MACAQUES; ENV; ENVELOPE; ISOLATE; TRANSMISSION; CELLS AB Background While some recently transmitted HIV clade C (HIV-C) strains exhibited tier 1 neutralization phenotypes, most were tier 2 strains (J Virol 2010; 84:1439). Because induction of neutralizing antibodies (nAbs) through vaccination against tier 2 viruses has proven difficult, we have generated a tier 1, clade C simian-human immunodeficiency virus (SHIV-C) to permit efficacy testing of candidate AIDS vaccines against tier 1 viruses. Methods SHIV-1157ipEL was created by swapping env of a late-stage virus with that of a tier 1, early form. Results After adaptation to rhesus macaques (RM), passaged SHIV-1157ipEL-p replicated vigorously in vitro and in vivo while maintaining R5 tropism. The virus was reproducibly transmissible intrarectally. Phylogenetically, SHIV-1157ipEL-p Env clustered with HIV-C sequences. All RM chronically infected with SHIV-1157ipEL-p developed high nAb titers against autologous as well as heterologous tier 1 strains. Conclusions SHIV-1157ipEL-p was reproducibly transmitted in RM, induced cross-clade nAbs, and represents a tool to evaluate anti-HIV-C nAb responses in primates. C1 [Siddappa, Nagadenahalli B.; Hemashettar, Girish; Wong, Yin Ling; Lakhashe, Samir; Rasmussen, Robert A.; Watkins, Jennifer D.; Ruprecht, Ruth M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Siddappa, Nagadenahalli B.; Lakhashe, Samir; Rasmussen, Robert A.; Watkins, Jennifer D.; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA USA. [Novembre, Francis J.; Villinger, Francois; Else, James G.] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Novembre, Francis J.] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Villinger, Francois; Else, James G.] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Siddappa, NB (reprint author), Dana Farber Canc Inst, JFB809,44 Binney St, Boston, MA 02115 USA. EM nb_siddappa@dfci.harvard.edu; ruth_ruprecht@dfci.harvard.edu RI Lakhashe, Samir/F-1150-2014; OI Byrareddy, Siddappa /0000-0002-7423-1763 FU National Institutes of Health [P01 AI048240, R01 DE016013, R37 AI034266]; [RR-00165] FX We thank Elizabeth Samit for assistance in the preparation of this manuscript and Stephanie Ehnert, Chris Souder and Kalpana Patel for coordinating sample collections. We thank Mahesh Bachu for help with phylogenetic analysis. This work was supported by National Institutes of Health grants P01 AI048240, R01 DE016013, and R37 AI034266 to R.M.R. Base grant RR-00165 provided support to the Yerkes National Primate Research Center. NR 26 TC 6 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD APR PY 2011 VL 40 IS 2 BP 120 EP 128 DI 10.1111/j.1600-0684.2010.00454.x PG 9 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 729QK UT WOS:000287965500007 PM 21044092 ER PT J AU Liu, XH Manzano, G Kim, HT Feeley, BT AF Liu, Xuhui Manzano, Givenchy Kim, Hubert T. Feeley, Brian T. TI A Rat Model of Massive Rotator Cuff Tears SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE rotator cuff tear; muscular atrophy; fat infiltration ID SKELETAL-MUSCLE ATROPHY; FACTOR-KAPPA-B; FATTY INFILTRATION; SUPRASPINATUS MUSCLE; FUNCTIONAL OUTCOMES; TENDON DETACHMENT; SINGLE-ROW; LONG-TERM; REPAIR; DEGENERATION AB Rotator cuff tears (RCTs) are the most common tendon injury seen in orthopedic patients. Massive RCT does not heal spontaneously and results in poor clinical outcomes. Muscle atrophy and fatty infiltration in rotator cuff muscles are major complications of chronic massive RCT and are thought to be the key factors responsible for the failure of attempted massive RCT repair. However, the pathophysiology of rotator cuff muscle atrophy and fat infiltration remains largely unknown, and no small animal model has been shown to reproduce the histologic and molecular changes seen in massive RCT. In this article, we report a novel rat massive RCT model, in which significant and consistent muscle atrophy and fat infiltration were observed in the rotator cuff muscles after rotator cuff tendon transection and denervation. The supraspinatus and infraspinatus muscle lost 25.4% and 28.9% of their wet weight 2 weeks after complete tendon transection, respectively. Six weeks after surgery, the average wet weight of supraspinatus and infraspinatus muscles decreased 13.2% and 28.3%, respectively. Significant fat infiltration was only observed in infraspinatus 6 weeks after tendon transection. (C) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:588-595, 2011 C1 [Liu, Xuhui; Manzano, Givenchy; Kim, Hubert T.; Feeley, Brian T.] Univ Calif San Francisco Sports Med & Shoulder Su, Dept Orthoped Surg, San Francisco, CA 94153 USA. [Liu, Xuhui; Manzano, Givenchy; Kim, Hubert T.] San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA. RP Feeley, BT (reprint author), Univ Calif San Francisco Sports Med & Shoulder Su, Dept Orthoped Surg, 1500 Owens Ave, San Francisco, CA 94153 USA. EM feeleyb@orthosurg.ucsf.edu FU Orthopaedic Research & Education Foundation FX This work was supported by the Orthopaedic Research & Education Foundation. The authors have no personal or financial affiliations that may have biased the presentation. NR 42 TC 41 Z9 41 U1 0 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD APR PY 2011 VL 29 IS 4 BP 588 EP 595 DI 10.1002/jor.21266 PG 8 WC Orthopedics SC Orthopedics GA 731LV UT WOS:000288109300018 PM 20949443 ER PT J AU Samelson, EJ Christiansen, BA Demissie, S Broe, KE Zhou, Y Meng, CA Yu, W Cheng, X O'Donnell, CJ Hoffmann, U Genant, HK Kiel, DP Bouxsein, ML AF Samelson, E. J. Christiansen, B. A. Demissie, S. Broe, K. E. Zhou, Y. Meng, C. A. Yu, W. Cheng, X. O'Donnell, C. J. Hoffmann, U. Genant, H. K. Kiel, D. P. Bouxsein, M. L. TI Reliability of vertebral fracture assessment using multidetector CT lateral scout views: the Framingham Osteoporosis Study SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Computed tomography; Lateral scout; Reliability; Scoutviews; Semiquantitative; Vertebral fracture ID X-RAY ABSORPTIOMETRY; COMPUTED-TOMOGRAPHY; PREVALENCE; WOMEN; HEART; IDENTIFICATION; RECOGNITION; RADIOGRAPHY; DIAGNOSIS; DEFORMITIES AB Two radiologists evaluated images of the spine from computed tomography (CT) scans on two occasions to diagnose vertebral fracture in 100 individuals. Agreement was fair to good for mild fractures, and agreement was good to excellent for more severe fractures. CT scout views are useful to assess vertebral fracture. We investigated inter-reader agreement between two radiologists and intra-reader agreement between duplicate readings for each radiologist, in assessment of vertebral fracture using a semi-quantitative method from lateral scout views obtained by CT. Participants included 50 women and 50 men (age 50-87 years, mean 70 years) in the Framingham Study. T4-L4 vertebrae were assessed independently by two radiologists on two occasions using a semi-quantitative scale as normal, mild, moderate, or severe fracture. Vertebra-specific prevalence of grade a parts per thousand yen1 (mild) fracture ranged from 3% to 5%. We found fair (kappa = 56-59%) inter-reader agreement for grade a parts per thousand yen1 vertebral fractures and good (kappa = 68-72%) inter-reader agreement for grade a parts per thousand yen2 fractures. Intra-reader agreement for grade a parts per thousand yen1 vertebral fracture was fair (kappa = 55%) for one reader and excellent for another reader (kappa = 77%), whereas intra-reader agreement for grade a parts per thousand yen2 vertebral fracture was excellent for both readers (kappa = 76% and 98%). Thoracic vertebrae were more difficult to evaluate than the lumbar region, and agreement was lowest (inter-reader kappa = 43%) for fracture at the upper (T4-T9) thoracic levels and highest (inter-reader kappa = 76-78%) for the lumbar spine (L1-L4). Based on a semi-quantitative method to classify vertebral fractures using CT scout views, agreement within and between readers was fair to good, with the greatest source of variation occurring for fractures of mild severity and for the upper thoracic region. Agreement was good to excellent for fractures of at least moderate severity. Lateral CT scout views can be useful in clinical research settings to assess vertebral fracture. C1 [Samelson, E. J.; O'Donnell, C. J.; Hoffmann, U.; Kiel, D. P.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Samelson, E. J.; Broe, K. E.; Meng, C. A.; Kiel, D. P.] Inst Aging Res Boston, Boston, MA USA. [Christiansen, B. A.; Bouxsein, M. L.] Beth Israel Deaconess Med Ctr, Ctr Adv Orthoped Studies, Boston, MA 02215 USA. [Christiansen, B. A.; Bouxsein, M. L.] Harvard Univ, Sch Med, Dept Orthoped Surg, Boston, MA 02115 USA. [Christiansen, B. A.] Univ Calif Davis, Dept Orthopaed, Sacramento, CA 95817 USA. [Demissie, S.; Zhou, Y.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Yu, W.] Beijing Union Med Coll Hosp, Beijing, Peoples R China. [Cheng, X.] Beijing Ji Shui Tan Hosp, Beijing, Peoples R China. [O'Donnell, C. J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hoffmann, U.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Genant, H. K.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Genant, H. K.] Synarc Inc, San Francisco, CA USA. RP Samelson, EJ (reprint author), Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. EM Samelson@hrca.harvard.edu; bchristiansen@ucdavis.edu; demissie@bu.edu; broe@hrca.harvard.edu; zyanhua@bu.edu; Ching-AnMeng@hrca.harvard.edu; weiyu5508@yahoo.com; xiao65@263.net; codonnell@nih.gov; uhoffmann@partners.org; harry.genant@ucsf.edu; kiel@hrca.harvard.edu; mbouxsei@bidmc.harvard.edu RI Christiansen, Blaine/F-9021-2010; OI Kiel, Douglas/0000-0001-8474-0310 FU NIH [R01AR053986, R01AR/AG041398, K01 AR053118, T32 AG023480]; National Heart, Lung, and Blood Institute (NHLBI) (NIH/NHLBI) [N01-HC-25195] FX This work was supported by NIH R01AR053986, R01AR/AG041398, K01 AR053118, T32 AG023480, and by the National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study (NIH/NHLBI Contract N01-HC-25195). NR 45 TC 17 Z9 20 U1 0 U2 1 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 APR PY 2011 VL 22 IS 4 BP 1123 EP 1131 DI 10.1007/s00198-010-1290-6 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 728DN UT WOS:000287854500012 PM 20495902 ER PT J AU Landman, AB Rokos, IC Burns, K Van Gelder, CM Fisher, RM Dunford, JV Cone, DC Bogucki, S AF Landman, Adam B. Rokos, Ivan C. Burns, Kevin Van Gelder, Carin M. Fisher, Roger M. Dunford, James V. Cone, David C. Bogucki, Sandy TI AN OPEN, INTEROPERABLE, AND SCALABLE PREHOSPITAL INFORMATION TECHNOLOGY NETWORK ARCHITECTURE SO PREHOSPITAL EMERGENCY CARE LA English DT Article DE emergency medical services communication systems; emergency medical services; information management; computer communication networks ID ELEVATION MYOCARDIAL-INFARCTION; TO-BALLOON TIME; HOSPITAL CARDIAC-ARREST; STANDARDIZED COMMUNICATION; SYNDROMIC SURVEILLANCE; MEDICINE PROJECT; UTSTEIN STYLE; EMERGENCY; SYSTEMS; INTEGRATION AB Some of the most intractable challenges in prehospital medicine include response time optimization, inefficiencies at the emergency medical services (EMS)-emergency department (ED) interface, and the ability to correlate field interventions with patient outcomes. Information technology (IT) can address these and other concerns by ensuring that system and patient information is received when and where it is needed, is fully integrated with prior and subsequent patient information, and is securely archived. Some EMS agencies have begun adopting information technologies, such as wireless transmission of 12-lead electrocardiograms, but few agencies have developed a comprehensive plan for management of their prehospital information and integration with other electronic medical records. This perspective article highlights the challenges and limitations of integrating IT elements without a strategic plan, and proposes an open, interoperable, and scalable prehospital information technology (PHIT) architecture. The two core components of this PHIT architecture are 1) routers with broadband network connectivity to share data between ambulance devices and EMS system information services and 2) an electronic patient care report to organize and archive all electronic prehospital data. To successfully implement this comprehensive PHIT architecture, data and technology requirements must be based on best available evidence, and the system must adhere to health data standards as well as privacy and security regulations. Recent federal legislation prioritizing health information technology may position federal agencies to help design and fund PHIT architectures. C1 [Landman, Adam B.] Yale Univ, Robert Wood Johnson Fdn Clin Scholars Program, New Haven, CT 06520 USA. [Landman, Adam B.; Burns, Kevin; Van Gelder, Carin M.; Cone, David C.; Bogucki, Sandy] Yale Univ, Dept Emergency Med, Sch Med, New Haven, CT 06520 USA. [Landman, Adam B.] US Dept Vet Affairs, West Haven, CT USA. [Rokos, Ivan C.] Olive View UCLA Med Ctr, Dept Emergency Med, Sylmar, CA 91342 USA. [Fisher, Roger M.] San Diego Med Serv, San Diego, CA USA. [Dunford, James V.] Univ Calif San Diego, Dept Emergency Med, San Diego Med Ctr, La Jolla, CA 92093 USA. RP Landman, AB (reprint author), Yale Univ, Robert Wood Johnson Fdn Clin Scholars Program, 333 Cedar St,IE 61 SHM,POB 208088, New Haven, CT 06520 USA. EM adam.landman@yahoo.com OI Cone, David/0000-0002-7437-959X; Landman, Adam/0000-0002-2166-0521 FU US Department of Veterans Affairs; Robert Wood Johnson Foundation FX Dr. Landman is a Robert Wood Johnson Foundation Clinical Scholar at Yale University, supported by the US Department of Veterans Affairs and the Robert Wood Johnson Foundation. NR 48 TC 8 Z9 8 U1 0 U2 15 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1090-3127 J9 PREHOSP EMERG CARE JI Prehosp. Emerg. Care PD APR-JUN PY 2011 VL 15 IS 2 BP 149 EP 157 DI 10.3109/10903127.2010.534235 PG 9 WC Emergency Medicine; Public, Environmental & Occupational Health SC Emergency Medicine; Public, Environmental & Occupational Health GA 729FG UT WOS:000287933400002 PM 21294627 ER PT J AU Coppadoro, A Berra, L Bigatello, LM AF Coppadoro, Andrea Berra, Lorenzo Bigatello, Luca M. TI Modifying endotracheal tubes to prevent ventilator-associated pneumonia SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE aspiration pneumonia; biofilm; endotracheal tube coating; endotracheal tube cuff; ventilator-associated pneumonia ID SUBGLOTTIC SECRETION DRAINAGE; REDUCES PULMONARY ASPIRATION; TRACHEAL TUBE; BACTERIAL-COLONIZATION; FLUID LEAKAGE; MUCUS SHAVER; CUFF; POLYURETHANE; TRIAL; BIOFILM AB Purpose of review The endotracheal tube (ETT) is the main avenue leading to airway contamination and subsequent ventilator-associated pneumonia (VAP) during mechanical ventilation. A number of modifications to the ETT are available, aimed at reducing the incidence of VAP. We review here available systems and devices, and clinical data regarding their efficacy. Recent findings Three main modifications of ETTs have been developed: coating with antimicrobials, adding a suction channel for the removal of oro-pharyngeal secretions, and modifying the design of the cuff. Each of these interventions has been shown to limit bacterial colonization of the distal airways and to decrease the incidence of VAP. Data on their ultimate effect on related clinical outcomes are still lacking. Summary Modifications of ETTs aimed at decreasing the onset of VAP show promising results. However, the lack of a significant effect on outcomes prompts us to use caution before recommending their widespread use. C1 [Bigatello, Luca M.] VA Boston Healthcare Syst, Anesthesia & Crit Care Serv, W Roxbury, MA 02132 USA. [Coppadoro, Andrea; Berra, Lorenzo; Bigatello, Luca M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Coppadoro, Andrea] Univ Milano Bicocca, Dipartimento Med Sperimentale, Milan, Italy. RP Bigatello, LM (reprint author), VA Boston Healthcare Syst, Anesthesia & Crit Care Serv, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM luca.bigatello@va.gov FU Covidien FX A.C. has no conflict of interest to declare. L. B. has no conflict of interest to declare. L. M. B. has received a consulting fee from Covidien. NR 39 TC 7 Z9 8 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD APR PY 2011 VL 24 IS 2 BP 157 EP 162 DI 10.1097/QCO.0b013e328343b733 PG 6 WC Infectious Diseases SC Infectious Diseases GA 726BO UT WOS:000287693500013 PM 21252657 ER PT J AU Messou, E Chaix, ML Gabillard, D Minga, A Losina, E Yapo, V Kouakou, M Danel, C Sloan, C Rouzioux, C Freedberg, KA Anglaret, X AF Messou, Eugene Chaix, Marie-Laure Gabillard, Delphine Minga, Albert Losina, Elena Yapo, Vincent Kouakou, Martial Danel, Christine Sloan, Caroline Rouzioux, Christine Freedberg, Kenneth A. Anglaret, Xavier TI Association Between Medication Possession Ratio, Virologic Failure and Drug Resistance in HIV-1-Infected Adults on Antiretroviral Therapy in Cote d'Ivoire SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article ID HIV-INFECTED ADULTS; SUB-SAHARAN AFRICA; ADHERENCE; ABIDJAN; STRAINS; OUTCOMES; DETERMINANTS; ASSESSMENTS; PERFORMANCE; PROGRESSION AB Background: Adherence is a strong determinant of viral suppression with antiretroviral therapy (ART) but measuring it is challenging. Medication delivery can be measured accurately in settings with computerized prescription databases. We studied the association between medication possession ratio (MPR), virologic suppression, and resistance to ART in Cote d'Ivoire. Methods: We conducted a prospective cohort study of HIV-1-infected adults initiating ART in 3 clinics using computerized monitoring systems. Patients had viral load (VL) tests at month 6 (M6) and month 12 (M12) after ART initiation and genotype tests if VL was detectable (>= 300 copies/mL). MPR was defined as the number of daily doses of antiretroviral drug actually provided divided by the total number of follow-up days since ART initiation. Results: Overall, 1573 patients started ART with stavudine/zidovudine plus lamivudine plus nevirapine/efavirenz. At M6 and M12, 996 and 942 patients were in active follow-up; 20% (M6) and 25% (M12) of patients had detectable VL, including 7% (M6) and 11% (M12) with >= 1 resistance mutation. Among patients with MPR of >= 95%, 80%-94%, 65%-79%, 50%-64%, and <50% at M12, the proportion with detectable VL [resistance] was 9% [4%], 17% [7%], 45% [24%], 67% [31%], and 85% [37%]. Among patients with >= 1 mutation at M12, 86% were resistant to lamivudine/emtricitabine and/or nevirapine/efavirenz but not to other drugs. Conclusions: MPR was strongly associated with virologic outcomes. Half of those with detectable VL at M12 had no resistance mutations. MPR should be used at M6 to identify patients who might benefit from early interventions to reinforce adherence. C1 [Messou, Eugene; Gabillard, Delphine; Minga, Albert; Danel, Christine; Anglaret, Xavier] Univ Bordeaux, INSERM, U897, Bordeaux, France. [Messou, Eugene; Gabillard, Delphine; Minga, Albert; Yapo, Vincent; Kouakou, Martial; Danel, Christine; Sloan, Caroline; Anglaret, Xavier] Programme PAC CI ANRS, Abidjan, Cote Ivoire. [Chaix, Marie-Laure; Rouzioux, Christine] Univ Paris 05, EA 3620, Paris, France. [Chaix, Marie-Laure; Rouzioux, Christine] CHU Necker, AP HP, Virol Lab, Paris, France. [Losina, Elena; Freedberg, Kenneth A.] Brigham & Womens Hosp, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Losina, Elena; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Boston, MA USA. [Yapo, Vincent] CHU Treichville, CeDReS, Abidjan, Cote Ivoire. RP Anglaret, X (reprint author), Univ Bordeaux 2, INSERM, Unite 897, 146 Rue Leo Saignat, F-33076 Bordeaux, France. EM xavier.anglaret@isped.u-bordeaux2.fr RI Anglaret, Xavier/F-7333-2013 FU Agence Nationale de Recherches sur le SIDA et les hepatitis virales [ANRS 12136, ANRS 12212]; National Institute of Allergy and Infectious Diseases [R01 AI058736, K24 AI062476]; Institute of International Education FX Supported by the Agence Nationale de Recherches sur le SIDA et les hepatitis virales (ANRS 12136, ANRS 12212), the National Institute of Allergy and Infectious Diseases (R01 AI058736, K24 AI062476), and the Institute of International Education Fulbright (Fellowship CS). NR 38 TC 30 Z9 31 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR PY 2011 VL 56 IS 4 BP 356 EP 364 DI 10.1097/QAI.0b013e3182084b5a PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 726QH UT WOS:000287740700019 PM 21191309 ER PT J AU Bogoch, II Andrews, JR Marty, FM Hohmann, EL AF Bogoch, Isaac I. Andrews, Jason R. Marty, Francisco M. Hohmann, Elizabeth L. TI HIV-1 and 2009 H1N1 Influenza A in Adults SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Letter C1 [Bogoch, Isaac I.; Andrews, Jason R.; Hohmann, Elizabeth L.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bogoch, Isaac I.; Andrews, Jason R.; Marty, Francisco M.; Hohmann, Elizabeth L.] Harvard Univ, Sch Med, Boston, MA USA. [Marty, Francisco M.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Bogoch, II (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. NR 8 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD APR PY 2011 VL 56 IS 4 BP E111 EP E113 DI 10.1097/QAI.0b013e31820a9afb PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 726QH UT WOS:000287740700003 PM 21350357 ER PT J AU Hirano, AA Brandstatter, JH Morgans, CW Brecha, NC AF Hirano, Arlene A. Brandstaetter, Johann Helmut Morgans, Catherine W. Brecha, Nicholas C. TI SNAP25 Expression in Mammalian Retinal Horizontal Cells SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE SNARE complex; exocytosis; immunocytochemistry; retina; vision ID SYNAPTOSOMAL-ASSOCIATED PROTEIN; CALCIUM-BINDING PROTEINS; ACTIVITY-DEPENDENT PHOSPHORYLATION; ACID TRANSPORTER EXPRESSION; VESICULAR GABA TRANSPORTER; SYNAPTIC CORE COMPLEX; MACAQUE MONKEY RETINA; T-SNARE SNAP-25; RIBBON SYNAPSES; DIFFERENTIAL EXPRESSION AB Horizontal cells mediate inhibitory feedforward and feedback lateral interactions in the outer retina at photoreceptor terminals and bipolar cell dendrites; however, the mechanisms that underlie synaptic transmission from mammalian horizontal cells are poorly understood. The localization of a vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) to horizontal cell processes in primate and rodent retinae suggested that mammalian horizontal cells release transmitter in a vesicular manner. Toward determining whether the molecular machinery for vesicular transmitter release is present in horizontal cells, we investigated the expression of SNAP25 (synaptosomal-associated protein of 25 kDa), a key SNARE protein, by immunocytochemistry with cell type-specific markers in the retinae of mouse, rat, rabbit, and monkey. Different commercial antibodies to SNAP25 were tested on vertical sections of retina. We report the robust expression of SNAP25 in both plexiform layers. Double labeling with SNAP25 and calbindin antibodies demonstrated that horizontal cell processes and their endings in photoreceptor triad synapses were strongly labeled for both proteins in mouse, rat, rabbit, and monkey retinae. Double labeling with parvalbumin antibodies in monkey retina verified SNAP25 immunoreactivity in all horizontal cells. Pre-embedding immunoelectron microscopy in rabbit retina confirmed expression of SNAP25 in lateral elements within photoreceptor triad synapses. The SNAP25 immunoreactivity in the plexiform layers and outer nuclear layer fell into at least three patterns depending on the antibody, suggesting a differential distribution of SNAP25 isoforms. The presence of SNAP25a and SNAP25b isoforms in mouse retina was established by reverse transcriptase-polymerase chain reaction. SNAP25 expression in mammalian horizontal cells along with other SNARE proteins is consistent with vesicular exocytosis. J. Comp. Neurol. 519:972-988, 2011. (C) 2010 Wiley-Liss, Inc. C1 [Hirano, Arlene A.; 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. [Hirano, Arlene A.; Brecha, Nicholas C.] Vet Adm Greater Los Angeles Hlth Syst, Los Angeles, CA 90073 USA. [Brandstaetter, Johann Helmut] Univ Erlangen Nurnberg, Dept Biol, D-91508 Erlangen, Germany. [Morgans, Catherine W.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97239 USA. RP Hirano, AA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, 10833 Le Conte Ave,Box 951763, Los Angeles, CA 90095 USA. EM ahirano@mednet.ucla.edu FU National Institutes of Health [EY15573]; Veterans Administration; University of California-Los Angeles; German Research Foundation [BR 1643/4-1] FX Grant sponsor: National Institutes of Health; Grant number: EY15573; Grant sponsors: Veterans Administration Career Scientist Award; University of California-Los Angeles Stein-Oppenheimer Award (to N.C.B.); German Research Foundation; Grant number: BR 1643/4-1 (to J.H.B.). NR 113 TC 23 Z9 23 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD APR PY 2011 VL 519 IS 5 BP 972 EP 988 DI 10.1002/cne.22562 PG 17 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 719MR UT WOS:000287209400010 PM 21280047 ER PT J AU Wang, Q Wu, PC Roberson, RS Luk, BV Ivanova, I Chu, E Wu, DY AF Wang, Qin Wu, Peter C. Roberson, Rachel S. Luk, Belinda V. Ivanova, Iana Chu, Elizabeth Wu, Daniel Y. TI Survivin and escaping in therapy-induced cellular senescence SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE survivin; accelerated senescence; Cdc2/Cdk1 ID GERANYLGERANYLTRANSFERASE-I INHIBITOR; TERMINAL PROLIFERATION ARREST; LUNG-CANCER CELLS; TUMOR-CELLS; MITOTIC CATASTROPHE; CARCINOMA-CELLS; DNA-DAMAGE; APOPTOSIS; PHOSPHORYLATION; EXPRESSION AB Therapy-induced accelerated cellular senescence (ACS) is a reversible tumor response to chemotherapy that is likely detrimental to the overall therapeutic efficacy of cancer treatment. To further understand the mechanism by which cancer cells can escape the sustained cell cycle arrest in ACS, we established a tissue culture model, in which the p53-null NCI-H1299 cells can be induced into senescence by an abbreviated exposure to a chemotherapeutic agent. Previously, we have reported that senescent cells overexpress Cdc2/Cdk1 when they bypassed the prolonged arrest and their viability is dependent on Cdc2/Cdk1 kinase activity. In our study, we show that human survivin is the immediate downstream effector of the Cdc2/Cdk1 mediated survival signal. Survivin cooperates with Cdc2/Cdk1 to inhibit apoptosis following chemotherapy and promote senescence escape. Using HIV-1 TAT peptides to disrupt survivin phosphorylation by Cdc2/Cdk1, we also found that phosphorylated survivin is necessary both for the escape of senescent cells and for maintenance of subsequent viability after bypassing senescence. These results further propose survivin as an important determinant of senescence reversibility and as a putative molecular target to enforce cell death in ACS. C1 [Wang, Qin; Wu, Peter C.; Roberson, Rachel S.; Luk, Belinda V.; Ivanova, Iana; Chu, Elizabeth; Wu, Daniel Y.] VA Puget Sound Hlth Care Syst, Seattle Inst Biomed & Clin Res, Seattle, WA 98108 USA. [Wu, Peter C.] VA Puget Sound Hlth Care Syst, Dept Surg, Seattle, WA 98108 USA. [Wu, Peter C.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Wu, Daniel Y.] Univ Washington, Dept Med, Div Oncol, Seattle, WA 98195 USA. [Wu, Daniel Y.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Wang, Q (reprint author), VA Puget Sound Hlth Care Syst, Seattle Inst Biomed & Clin Res, 1660 S Columbian Way, Seattle, WA 98108 USA. EM proteinss@hotmail.com FU National Cancer Institute [R01-CA113892-01] FX Grant sponsor: National Cancer Institute; Grant number: R01-CA113892-01 NR 41 TC 24 Z9 27 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD APR 1 PY 2011 VL 128 IS 7 BP 1546 EP 1558 DI 10.1002/ijc.25482 PG 13 WC Oncology SC Oncology GA 718XI UT WOS:000287159400005 PM 20503268 ER PT J AU Saboo, SS Krajewski, KM Jagannathan, JP O'Regan, KN Odze, R Ramaiya, N Wolpin, BM AF Saboo, Sachin S. Krajewski, Katherine M. Jagannathan, Jyothi P. O'Regan, Kevin N. Odze, Robert Ramaiya, Nikhil Wolpin, Brian M. TI Rapid progression of combined hepatocellular carcinoma and cholangiocarcinoma SO CANCER IMAGING LA English DT Article DE Combined hepatocellular carcinoma and cholangiocarcinoma; MRI ID CLINICOPATHOLOGICAL FEATURES; COMPUTED-TOMOGRAPHY; PROGNOSTIC-FACTORS; GEMCITABINE; CANCER; CT AB Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CC) is a rare entity comprising 1 - 14.2% of all primary liver carcinomas. In this report, we present a case of rapid progression of cHCC-CC, a rare tumor in a 77-year-old Caucasian male patient with hepatitis B-induced cirrhosis, moderately elevated alpha fetoprotein, and imaging and pathologic features of a mixed liver tumor. There was no evidence of metastatic disease in the chest, abdomen or pelvis by computed tomography (CT) scan at the time of diagnosis. Needle biopsy of the segment 8 lesion revealed two discrete histologic components to the tumor: well-differentiated HCC and poorly differentiated adenocarcinoma, consistent with intrahepatic CC. The patient rapidly developed metastatic disease after initial local therapy with hepatic arterial chemoembolization and percutaneous cryoablation, dying within 5 months of diagnosis. Radiofrequency ablation, cryoablation and radioembolization with yttrium-90 microspheres remain possible treatment strategies for patients with cHCC-CC unable to undergo surgical resection. The diagnosis and treatment of cHCC-CC can be challenging due to clinical, imaging and histological features that overlap with pure HCC and CC. C1 [Saboo, Sachin S.; Krajewski, Katherine M.; Jagannathan, Jyothi P.; O'Regan, Kevin N.; Ramaiya, Nikhil] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Odze, Robert] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Wolpin, Brian M.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Saboo, SS (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiol, 44 Binney St, Boston, MA 02115 USA. EM ssaboo@partners.org NR 25 TC 3 Z9 3 U1 0 U2 1 PU E-MED PI LONDON PA PO BOX 29761, LONDON, NW3 7ZS, ENGLAND SN 1470-7330 J9 CANCER IMAGING JI Cancer Imaging PD MAR 31 PY 2011 VL 11 IS 1 BP 37 EP 41 DI 10.1102/1470-7330.2011.0009 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 826DA UT WOS:000295330400001 PM 21507775 ER PT J AU Reeves, RK Evans, TI Gillis, J Wong, FE Connole, M Carville, A Johnson, RP AF Reeves, R. Keith Evans, Tristan I. Gillis, Jacqueline Wong, Fay E. Connole, Michelle Carville, Angela Johnson, R. Paul TI Quantification of mucosal mononuclear cells in tissues with a fluorescent bead-based polychromatic flow cytometry assay SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Fluorescent beads; Lymphocyte enumeration; Flow cytometry; Mucosal lymphocytes ID SIV INFECTION; LYMPHOCYTE; BLOOD; GUT AB Since the vast majority of infections occur at mucosal surfaces, accurate characterization of mucosal immune cells is critically important for understanding transmission and control of infectious diseases. Standard flow cytometric analysis of cells obtained from mucosal tissues can provide valuable information on the phenotype of mucosal leukocytes and their relative abundance, but does not provide absolute cell counts of mucosal cell populations. We developed a bead-based flow cytometry assay to determine the absolute numbers of multiple mononuclear cell types in colorectal biopsies of rhesus macaques. Using 10-color flow cytometry panels and pan-fluorescent beads, cells were enumerated in biopsy specimens by adding a constant ratio of beads per mg of tissue and then calculating cell numbers/mg of tissue based on cell-to-bead ratios determined at the time of sample acquisition. Testing in duplicate specimens showed the assay to be highly reproducible (Spearman R=0.9476, P<0.0001). Using this assay, we report enumeration of total CD45(+) leukocytes, CD4(+) and CD8(+) T cells, B cells, NK cells, CD14(+) monocytes, and myeloid and plasmacytoid dendritic cells in colorectal biopsies, with cell numbers in normal rhesus macaques varying from medians of 4486 cells/mg (T cells) to 3 cells/mg (plasmacytoid dendritic cells). This assay represents a significant advancement in rapid, accurate quantification of mononuclear cell populations in mucosal tissues and could be applied to provide absolute counts of a variety of different cell populations in diverse tissues. (C) 2011 Elsevier B.V. All rights reserved. C1 [Reeves, R. Keith; Evans, Tristan I.; Gillis, Jacqueline; Wong, Fay E.; Connole, Michelle; Johnson, R. Paul] Harvard Univ, Sch Med, Div Immunol, New England Primate Res Ctr, Southborough, MA 01772 USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Ragon Inst Massachusetts Gen Hosp MIT & Harvard, Boston, MA 02115 USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02115 USA. RP Johnson, RP (reprint author), Harvard Univ, Sch Med, Div Immunol, New England Primate Res Ctr, 1 Pine Hill Dr, Southborough, MA 01772 USA. EM paul_johnson@hms.harvard.edu FU NIH [AI071306, AI090735, RR00168]; CHAVI/HVTN Early Career Investigator award [U19 AI 067854-04] FX The authors thank Elaine Roberts for dedicated animal care and Yi Yu for quality technical assistance. This work was supported through NIH grants AI071306, AI090735, and RR00168, and a CHAVI/HVTN Early Career Investigator award, grant number U19 AI 067854-04, to R.K.R. NR 10 TC 4 Z9 4 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAR 31 PY 2011 VL 367 IS 1-2 BP 95 EP 98 DI 10.1016/j.jim.2011.02.002 PG 4 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 767CV UT WOS:000290833800012 PM 21315723 ER PT J AU Eccles, MP Weijer, C Mittman, B AF Eccles, Martin P. Weijer, Charles Mittman, Brian TI Requirements for ethics committee review for studies submitted to Implementation Science SO IMPLEMENTATION SCIENCE LA English DT Editorial Material AB The requirement for ethics review of studies submitted to Implementation Science has been unclear. Therefore, in this editorial, we set out our requirements for ethics committee review of experimental and non-experimental studies. For any study that meets the criteria of human subject research (which includes research on healthcare providers), irrespective of study design, we will require proof of either satisfactory ethics committee review or of the granting of an official exemption or waiver. C1 [Eccles, Martin P.] Inst Hlth & Soc, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England. [Weijer, Charles] Univ Western Ontario, Rotman Inst Philosophy, London, ON N6A 5B6, Canada. [Mittman, Brian] VA Greater Los Angeles Healthcare Syst, VA Ctr Implementat Practice & Res Support, Sepulveda, CA 91343 USA. RP Eccles, MP (reprint author), Inst Hlth & Soc, Baddiley Clark Bldg, Newcastle Upon Tyne NE2 4AX, Tyne & Wear, England. EM martin.eccles@ncl.ac.uk OI Mittman, Brian/0000-0003-3589-9178 NR 3 TC 2 Z9 2 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD MAR 31 PY 2011 VL 6 AR 32 DI 10.1186/1748-5908-6-32 PG 3 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 749NN UT WOS:000289475200001 PM 21453451 ER PT J AU Holodniy, M Brown, ST Cameron, DW Kyriakides, TC Angus, B Babiker, A Singer, J Owens, DK Anis, A Goodall, R Hudson, F Piaseczny, M Russo, J Schechter, M Deyton, L Darbyshire, J AF Holodniy, Mark Brown, Sheldon T. Cameron, D. William Kyriakides, Tassos C. Angus, Brian Babiker, Abdel Singer, Joel Owens, Douglas K. Anis, Aslam Goodall, Ruth Hudson, Fleur Piaseczny, Mirek Russo, John Schechter, Martin Deyton, Lawrence Darbyshire, Janet CA OPTIMA Team TI Results of Antiretroviral Treatment Interruption and Intensification in Advanced Multi-Drug Resistant HIV Infection from the OPTIMA Trial SO PLOS ONE LA English DT Article ID STRUCTURED TREATMENT INTERRUPTION; QUALITY-OF-LIFE; CROSS-RESISTANCE; CLINICAL PROGRESSION; VIROLOGICAL FAILURE; MEGA-HAART; COHORT; THERAPY; INHIBITORS; VIRUS AB Background: Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting. Methods and Findings: We conducted a 262 factorial randomized open label controlled trial in patients with a CD4 count <= 300 cells/mu l who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (<= 4 ARVs) or intensive (>= 5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/mu l, mean viral load was 4.74 log(10) copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86-1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68-1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options. Conclusions: We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options. C1 [Holodniy, Mark; Owens, Douglas K.] VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. [Holodniy, Mark; Owens, Douglas K.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Brown, Sheldon T.] James J Peters VA Med Ctr, Bronx, NY USA. [Brown, Sheldon T.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Cameron, D. William] Univ Ottawa, Ottawa Hosp, Res Inst, Ottawa, ON, Canada. [Cameron, D. William; Singer, Joel; Anis, Aslam; Piaseczny, Mirek; Schechter, Martin] St Pauls Hosp, Canadian HIV Trials Network, Vancouver, BC V6Z 1Y6, Canada. [Kyriakides, Tassos C.; Russo, John] VA Cooperat Studies Program Coordinating Ctr, West Haven, CT USA. [Angus, Brian] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Med, Oxford OX3 9DU, England. [Babiker, Abdel; Goodall, Ruth; Hudson, Fleur; Darbyshire, Janet] MRC Clin Trials Unit, London, England. [Deyton, Lawrence] Off Publ Hlth & Environm Hazards, Dept Vet Affairs, Washington, DC USA. RP Holodniy, M (reprint author), VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. EM bcameron@ohri.ca OI Schechter, Martin/0000-0001-6063-2155; Angus, Brian/0000-0003-3598-7784; Cameron, Bill/0000-0002-0090-3539; Goodall, Ruth/0000-0003-0622-5035 FU Ontario Ministry of Health/Ontario HIV Treatment Network; CIHR Canadian HIV Trials Network, Canada FX DWC is supported with a Career Scientist Award of the Ontario Ministry of Health/Ontario HIV Treatment Network. The study was supported in part in Canada through the CIHR Canadian HIV Trials Network. The study funders (MRC-UK, VACSP, CIHR) reviewed and approved the design and conduct of the trial, with external expert reviewers who were represented on the Trial Steering Committee. The OPTIMA Writing Committee and the OPTIMA team had full access to the statistical report and to the study data by request and the Writing Committee had final responsibility for the submitted manuscript. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 14 Z9 14 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 31 PY 2011 VL 6 IS 3 AR e14764 DI 10.1371/journal.pone.0014764 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 743YU UT WOS:000289057200001 PM 21483491 ER PT J AU Watkins, JD Siddappa, NB Lakhashe, SK Humbert, M Sholukh, A Hemashettar, G Wong, YL Yoon, JK Wang, W Novembre, FJ Villinger, F Ibegbu, C Patel, K Corti, D Agatic, G Vanzetta, F Bianchi, S Heeney, JL Sallusto, F Lanzavecchia, A Ruprecht, RM AF Watkins, Jennifer D. Siddappa, Nagadenahalli B. Lakhashe, Samir K. Humbert, Michael Sholukh, Anton Hemashettar, Girish Wong, Yin Ling Yoon, John K. Wang, Wendy Novembre, Francis J. Villinger, Francois Ibegbu, Chris Patel, Kalpana Corti, Davide Agatic, Gloria Vanzetta, Fabrizia Bianchi, Siro Heeney, Jonathan L. Sallusto, Federica Lanzavecchia, Antonio Ruprecht, Ruth M. TI An Anti-HIV-1 V3 Loop Antibody Fully Protects Cross-Clade and Elicits T-Cell Immunity in Macaques Mucosally Challenged with an R5 Clade C SHIV SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NEUTRALIZING ANTIBODIES; MONOCLONAL-ANTIBODIES; CHIMERIC VIRUS; HIV-1 VACCINE; TRANSMISSION; IMMUNIZATION; INFECTION; GP120; TRIAL AB Neutralizing antibodies have been shown to protect macaques against SHIV challenge. However, genetically diverse HIV-1 clades have evolved, and a key question left unanswered is whether neutralizing antibodies can confer cross-clade protection in vivo. The novel human monoclonal antibody HGN194 was isolated from an individual infected with an HIV-1 clade AG recombinant circulating recombinant form (CRF). HGN194 targets an epitope in the third hypervariable loop (V3) of HIV-1 gp120 and neutralizes a range of relatively neutralization-sensitive and resistant viruses. We evaluated the potential of HGN194 to protect infant rhesus monkeys against a SHIV encoding a primary CCR5-tropic HIV-1 clade C envelope. After high-dose mucosal challenge, all untreated controls became highly viremic while all HGN194-treated animals (50 mg/kg) were completely protected. When HGN194 was given at 1 mg/kg, one out of two monkeys remained aviremic, whereas the other had delayed, lower peak viremia. Interestingly, all protected monkeys given high-dose HGN194 developed Gagspecific proliferative responses of both CD4+ and CD8+ T cells. To test whether generation of the latter involved cryptic infection, we ablated CD8+ cells after HGN194 clearance. No viremia was detected in any protected monkeys, thus ruling out virus reservoirs. Thus, induction of CD8 T-cell immunity may have resulted from transient `` Hit and Run'' infection or cross priming via Ag-Ab-mediated cross-presentation. Together, our data identified the HGN194 epitope as protective and provide proof-of-concept that this anti-V3 loop mAb can prevent infection with sterilizing immunity after challenge with virus of a different clade, implying that V3 is a potential vaccine target. C1 [Watkins, Jennifer D.; Siddappa, Nagadenahalli B.; Lakhashe, Samir K.; Humbert, Michael; Sholukh, Anton; Hemashettar, Girish; Wong, Yin Ling; Yoon, John K.; Wang, Wendy; Ruprecht, Ruth M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Watkins, Jennifer D.; Siddappa, Nagadenahalli B.; Lakhashe, Samir K.; Humbert, Michael; Sholukh, Anton; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA USA. [Novembre, Francis J.; Villinger, Francois; Ibegbu, Chris; Patel, Kalpana] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Novembre, Francis J.] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Villinger, Francois] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Corti, Davide; Agatic, Gloria; Vanzetta, Fabrizia; Bianchi, Siro] Humabs SAGL, Bellinzona, Switzerland. [Heeney, Jonathan L.] Univ Cambridge, Dept Vet Med, Cambridge, England. [Sallusto, Federica; Lanzavecchia, Antonio] Inst Res Biomed, Bellinzona, Switzerland. RP Watkins, JD (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM ruth_ruprecht@dfci.harvard.edu RI Lakhashe, Samir/F-1150-2014; OI Byrareddy, Siddappa /0000-0002-7423-1763; Heeney, Jonathan/0000-0003-2702-1621; Bianchi, Siro/0000-0002-5100-8905 FU National Institutes of Health [R37 AI34266, P01 AI48240]; Bill and Melinda Gates Foundation [38637]; Center For AIDS Research Immunology Core [P30 A01050409]; [RR-00165] FX This work was supported in part by National Institutes of Health grant R37 AI34266 and P01 AI48240 to RMR, by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) UCL-VDC (Weiss) grant 38637, and by Center For AIDS Research Immunology Core P30 A01050409. Base grant RR-00165 provided support to the Yerkes National Primate Research Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 45 Z9 45 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 31 PY 2011 VL 6 IS 3 AR e18207 DI 10.1371/journal.pone.0018207 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 743YU UT WOS:000289057200043 PM 21483815 ER PT J AU Abel, GA AF Abel, Gregory A. TI The real world: CLL SO BLOOD LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; SEER-MEDICARE DATA; CANCER-TREATMENT C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Abel, GA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 11 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 31 PY 2011 VL 117 IS 13 BP 3481 EP 3482 PG 2 WC Hematology SC Hematology GA 743EH UT WOS:000288999800003 PM 21454464 ER PT J AU Morgan, BA AF Morgan, Bruce A. TI DEVELOPMENTAL BIOLOGY A hair-raising tale SO NATURE LA English DT Editorial Material ID FOLLICLE STEM-CELLS; NICHE C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Morgan, BA (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM bruce.morgan@cbrc2.mgh.harvard.edu FU NIAMS NIH HHS [R01 AR055256] NR 6 TC 1 Z9 1 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 31 PY 2011 VL 471 IS 7340 BP 586 EP 587 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 742NN UT WOS:000288951200029 PM 21455169 ER PT J AU Treadway, K Chatterjee, N AF Treadway, Katharine Chatterjee, Neal TI BECOMING A PHYSICIAN Into the Water - The Clinical Clerkships SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID MEDICAL-EDUCATION C1 [Treadway, Katharine] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Treadway, K (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 5 TC 18 Z9 18 U1 1 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 31 PY 2011 VL 364 IS 13 BP 1190 EP 1193 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 742NO UT WOS:000288951300003 PM 21449782 ER PT J AU Tierney, LM Thabet, A Nishino, H AF Tierney, Lawrence M., Jr. Thabet, Ashraf Nishino, Ha TI A Woman with Fever, Confusion, Liver Failure, Anemia, and Thrombocytopenia Hemophagocytic lymphohistiocytosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HEPATITIS-C VIRUS; EXTRAHEPATIC MANIFESTATIONS; INFECTION; VETERANS; DISEASES; THERAPY C1 [Tierney, Lawrence M., Jr.] Univ Calif San Francisco, Dept Med, Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Thabet, Ashraf] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Nishino, Ha] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Thabet, Ashraf] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Nishino, Ha] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Tierney, LM (reprint author), Univ Calif San Francisco, Dept Med, Vet Affairs Med Ctr, San Francisco, CA 94143 USA. NR 20 TC 10 Z9 10 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 MAR 31 PY 2011 VL 364 IS 13 BP 1259 EP 1270 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 742NO UT WOS:000288951300013 PM 21449790 ER PT J AU Bautista, PA Yagi, Y AF Bautista, Pinky A. Yagi, Yukako TI Localization of Eosinophilic Esophagitis from H&E stained images using multispectral imaging SO DIAGNOSTIC PATHOLOGY LA English DT Article; Proceedings Paper CT 10th European Congress on Telepathology/4th International Congress on Virtual Microscopy CY JUL 01-03, 2010 CL Vilnius, LITHUANIA AB This study is an initial investigation on the capability of multispectral imaging to capture subtle spectral information that would enable the automatic delineation between the eosinophilic esophagitis and other eosin stained tissue components, especially the RBCs. In the method, a principal component analysis (PCA) was performed on the spectral transmittance samples of the different tissue components, excluding however the transmittance samples of the eosinophilic esophagitis. From the average spectral error configuration of the eosinophilic esophagitis transmittance samples, i.e. the difference between the actual transmittance and the estimated transmittance using m PC vectors, we indentified two spectral bands by which we can localize the eosinophils. Initial results show the possibility of automatically localizing the eosinophilic esophagitis by utilizing spectral information. C1 [Bautista, Pinky A.; Yagi, Yukako] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Bautista, PA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM pbautista@partners.org NR 9 TC 2 Z9 3 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1746-1596 J9 DIAGN PATHOL JI Diagn. Pathol. PD MAR 30 PY 2011 VL 6 SU 1 AR S2 DI 10.1186/1746-1596-6-S1-S2 PG 8 WC Pathology SC Pathology GA 759IS UT WOS:000290234600002 PM 21489190 ER PT J AU Yagi, Y AF Yagi, Yukako TI Color standardization and optimization in Whole Slide Imaging SO DIAGNOSTIC PATHOLOGY LA English DT Article; Proceedings Paper CT 10th European Congress on Telepathology/4th International Congress on Virtual Microscopy CY JUL 01-03, 2010 CL Vilnius, LITHUANIA AB Introduction: Standardization and validation of the color displayed by digital slides is an important aspect of digital pathology implementation. While the most common reason for color variation is the variance in the protocols and practices in the histology lab, the color displayed can also be affected by variation in capture parameters (for example, illumination and filters), image processing and display factors in the digital systems themselves. Method: We have been developing techniques for color validation and optimization along two paths. The first was based on two standard slides that are scanned and displayed by the imaging system in question. In this approach, one slide is embedded with nine filters with colors selected especially for H&E stained slides (looking like tiny Macbeth color chart); the specific color of the nine filters were determined in our previous study and modified for whole slide imaging (WSI). The other slide is an H&E stained mouse embryo. Both of these slides were scanned and the displayed images were compared to a standard. The second approach was based on our previous multispectral imaging research. Discussion: As a first step, the two slide method (above) was used to identify inaccurate display of color and its cause, and to understand the importance of accurate color in digital pathology. We have also improved the multispectral-based algorithm for more consistent results in stain standardization. In near future, the results of the two slide and multispectral techniques can be combined and will be widely available. We have been conducting a series of researches and developing projects to improve image quality to establish Image Quality Standardization. This paper discusses one of most important aspects of image quality-color. C1 [Yagi, Yukako] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Yagi, Yukako] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Yagi, Y (reprint author), Massachusetts Gen Hosp, Dept Pathol, 101 Merrimac St,Suite 820, Boston, MA 02114 USA. EM yyagi@partners.org NR 4 TC 28 Z9 28 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1746-1596 J9 DIAGN PATHOL JI Diagn. Pathol. PD MAR 30 PY 2011 VL 6 SU 1 AR S15 DI 10.1186/1746-1596-6-S1-S15 PG 12 WC Pathology SC Pathology GA 759IS UT WOS:000290234600015 PM 21489185 ER PT J AU Mick, E McGough, JJ Middleton, FA Neale, B Faraone, SV AF Mick, Eric McGough, James J. Middleton, Frank A. Neale, Benjamin Faraone, Stephen V. TI Genome-wide association study of blood pressure response to methylphenidate treatment of attention-deficit/hyperactivity disorder SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE ADHD; Blood pressure; Genome-wide association study; Methylphenidate; Pharmacogenomic ID CORONARY-ARTERY-DISEASE; QT INTERVAL DURATION; COMMON VARIANTS; CARDIOVASCULAR HEALTH; LINKAGE ANALYSES; GENE VARIANTS; PR INTERVAL; HEART; IDENTIFICATION; POLYMORPHISMS AB Objective: We conducted a genome-wide association study of blood pressure in an open-label study of the methylphenidate transdermal system (MTS) for the treatment of attention-deficit/hyperactivity disorder (ADHD). Method: Genotyping was conducted with the Affymetrix Genome-Wide Human SNP Array 6.0. Multivariate association analyses were conducted using the software package PLINK. After data cleaning and quality control we tested 316,934 SNPs in 140 children with ADHD. Results: We observed no genome-wide statistically significant findings, but a SNP in a K(+)-dependent Na(+)/Ca(2+) exchanger expressed in vascular smooth muscle (SLC24A3) was included in our top associations at p<1E-04. Genetic enrichment analyses of genes with >= 1 SNP significant at p<0.01, implicated several functional categories (FERM domain, p = 5.0E-07; immunoglobulin domain, p = 8.1E-06; the transmembrane region, p = 4.4E-05; channel activity, p = 2.0E-04; and type-Ill fibronectins, p = 2.7E-05) harboring genes previously associated with related cardiovascular phenotypes. Conclusions: The hypothesis generating results from this study suggests that polymorphisms in several genes consistently associated with cardiovascular diseases may impact changes in blood pressure observed with methylphenidate pharmacotherapy in children with ADHD. (C) 2010 Elsevier Inc. All rights reserved. C1 [Mick, Eric] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Mick, Eric] Harvard Univ, Sch Med, Boston, MA 02114 USA. [McGough, James J.] UCLA Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Middleton, Frank A.; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Middleton, Frank A.; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. [Neale, Benjamin] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin] Harvard & MIT, Broad Inst, Cambridge Ctr 7, Cambridge, MA 02142 USA. RP Mick, E (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 55 Fruit St,Warren 705, Boston, MA 02114 USA. EM mick@helix.mgh.harvard.edu OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 NR 68 TC 8 Z9 11 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD MAR 30 PY 2011 VL 35 IS 2 SI SI BP 466 EP 472 DI 10.1016/j.pnpbp.2010.11.037 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 753WP UT WOS:000289811200023 PM 21130132 ER PT J AU Abbott, C Juarez, M White, T Gollub, RL Pearlson, GD Bustillo, J Lauriello, J Ho, B Bockholt, HJ Clark, VP Magnotta, V Calhoun, VD AF Abbott, C. Juarez, M. White, T. Gollub, R. L. Pearlson, G. D. Bustillo, J. Lauriello, J. Ho, B. Bockholt, H. J. Clark, V. P. Magnotta, V. Calhoun, V. D. TI Antipsychotic dose and diminished neural modulation: A multi-site fMRI study SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Antipsychotic; Default mode network; fMRI; Independent component analysis; Motor cortex ID INDEPENDENT COMPONENT ANALYSIS; RESONANCE-IMAGING DATA; SCHIZOPHRENIC-PATIENTS; WORKING-MEMORY; 1ST-EPISODE SCHIZOPHRENIA; SENSORIMOTOR CORTEX; PARKINSONS-DISEASE; CORTICAL RESPONSE; MOTOR STIMULATION; HEALTHY-SUBJECTS AB Background: The effect of antipsychotics on the blood oxygen level dependent signal in schizophrenia is poorly understood. The purpose of the present investigation is to examine the effect of antipsychotic medication on independent neural networks during a motor task in a large, multi-site functional magnetic resonance imaging investigation. Methods: Seventy-nine medicated patients with schizophrenia and 114 comparison subjects from the Mind Clinical Imaging Consortium database completed a paced, auditory motor task during functional magnetic resonance imaging (fMRI). Independent component analysis identified temporally cohesive but spatially distributed neural networks. The independent component analysis time course was regressed with a model time course of the experimental design. The resulting beta weights were evaluated for group comparisons and correlations with chlorpromazine equivalents. Results: Group differences between patients and comparison subjects were evident in the cortical and subcortical motor networks, default mode networks, and attentional networks. The chlorpromazine equivalents correlated with the unimotor/bitemporal (rho=-0.32, P=0.0039), motor/caudate (rho= -0.22, P=0.046), posterior default mode (rho=0.26, P=0.020), and anterior default mode networks (rho=0.24, P=0.03). Patients on typical antipsychotics also had less positive modulation of the motor/caudate network relative to patients on atypical antipsychotics (t(77)=2.01, P=0.048). Conclusion: The results suggest that antipsychotic dose diminishes neural activation in motor (cortical and subcortical) and default mode networks in patients with schizophrenia. The higher potency, typical antipsychotics also diminish positive modulation in subcortical motor networks. Antipsychotics may be a potential confound limiting interpretation of fMRI studies on the disease process in medicated patients with schizophrenia. (C) 2010 Elsevier Inc. All rights reserved. C1 [Abbott, C.; Bustillo, J.; Calhoun, V. D.] Univ New Mexico, Dept Psychiat, Albuquerque, NM 87131 USA. [Juarez, M.; Bockholt, H. J.; Clark, V. P.; Calhoun, V. D.] Mind Res Network, Albuquerque, NM 87131 USA. [Juarez, M.; Calhoun, V. D.] Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA. [Clark, V. P.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Gollub, R. L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Magnotta, V.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Ho, B.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Pearlson, G. D.; Calhoun, V. D.] Yale Univ, Sch Med, Dept Psychiat, Hartford, CT 06106 USA. [White, T.] Univ Minnesota, Div Child Psychiat, Minneapolis, MN 55454 USA. [Pearlson, G. D.; Calhoun, V. D.] Olin Neuropsychiat Res Ctr, Hartford, CT 06106 USA. [White, T.] Erasmus MC, Dept Child Psychiat, Rotterdam, Netherlands. [Lauriello, J.] Univ Missouri Columbia, Columbia, MO 65212 USA. RP Abbott, C (reprint author), Univ New Mexico, Dept Psychiat, Albuquerque, NM 87131 USA. EM cabbott@salud.unm.edu RI Ho, Beng-Choon/D-6959-2011; Calhoun, Vince/H-7146-2013; bustillo, juan/J-7067-2013; Clark, Vincent/B-3343-2010; OI Ho, Beng-Choon/0000-0003-3976-1555; Calhoun, Vince/0000-0001-9058-0747; Clark, Vincent/0000-0002-9151-2102; Gollub, Randy L./0000-0002-9434-4044 FU Department of Energy [DE-FG02-99ER62764]; NIH NCRR [P41RR14075, 5MO1-RR001066, U24 RR021992]; National Institutes of Health [R01 EB000840, K08 MH068540] FX The Department of Energy DE-FG02-99ER62764, NIH NCRR P41RR14075, 5MO1-RR001066, and U24 RR021992 funded data collection. National Institutes of Health grant R01 EB000840 and K08 MH068540 also funded this study. The authors would like to thank the Mind Research Network staff for their efforts during the data collection processes and Guilherme Machado for help with data organization and analysis. NR 63 TC 26 Z9 26 U1 4 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD MAR 30 PY 2011 VL 35 IS 2 SI SI BP 473 EP 482 DI 10.1016/j.pnpbp.2010.12.001 PG 10 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 753WP UT WOS:000289811200024 PM 21185903 ER PT J AU Bagrow, JP Wang, DS Barabasi, AL AF Bagrow, James P. Wang, Dashun Barabasi, Albert-Laszlo TI Collective Response of Human Populations to Large-Scale Emergencies SO PLOS ONE LA English DT Article ID MOBILE COMMUNICATION-NETWORKS; PREDICTABILITY; EPIDEMICS; BEHAVIOR; LAWS AB Despite recent advances in uncovering the quantitative features of stationary human activity patterns, many applications, from pandemic prediction to emergency response, require an understanding of how these patterns change when the population encounters unfamiliar conditions. To explore societal response to external perturbations we identified real-time changes in communication and mobility patterns in the vicinity of eight emergencies, such as bomb attacks and earthquakes, comparing these with eight non-emergencies, like concerts and sporting events. We find that communication spikes accompanying emergencies are both spatially and temporally localized, but information about emergencies spreads globally, resulting in communication avalanches that engage in a significant manner the social network of eyewitnesses. These results offer a quantitative view of behavioral changes in human activity under extreme conditions, with potential long-term impact on emergency detection and response. C1 [Bagrow, James P.; Wang, Dashun; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Ctr Complex Network Res, Boston, MA 02115 USA. [Bagrow, James P.; Wang, Dashun; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Bagrow, JP (reprint author), Northeastern Univ, Dept Phys, Ctr Complex Network Res, Boston, MA 02115 USA. EM bagrowjp@gmail.com FU James S. McDonnell Foundation 21st Century Initiative in Studying Complex Systems; National Science Foundation within the Information Technology Research [DMR-0426737]; Defense Threat Reduction Agency [HDTRA1-08-1-0027]; United States Army Research Laboratory [W911NF-09-2-0053]; United States Office of Naval Research [N000141010968]; [IIS-0513650] FX The authors were funded by the James S. McDonnell Foundation 21st Century Initiative in Studying Complex Systems, National Science Foundation within the Information Technology Research (DMR-0426737) and IIS-0513650 programs, the Defense Threat Reduction Agency award HDTRA1-08-1-0027, the Network Science Collaborative Technology Alliance sponsored by the United States Army Research Laboratory under agreement number W911NF-09-2-0053, and the United States Office of Naval Research Award (N000141010968). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 61 Z9 61 U1 1 U2 29 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 30 PY 2011 VL 6 IS 3 AR e17680 DI 10.1371/journal.pone.0017680 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 743YK UT WOS:000289055700014 PM 21479206 ER PT J AU Iwasa, Y Michor, F AF Iwasa, Yoh Michor, Franziska TI Evolutionary Dynamics of Intratumor Heterogeneity SO PLOS ONE LA English DT Article ID DNA POLYMORPHISM DATA; TUMOR HETEROGENEITY; DROSOPHILA-MELANOGASTER; GENETIC-VARIATION; CANCER; MODEL; PROGRESSION; CELLS; CARCINOGENESIS; POPULATIONS AB Intraneoplastic diversity in human tumors is a widespread phenomenon of critical importance for tumor progression and the response to therapeutic intervention. Insights into the evolutionary events that control tumor heterogeneity would be a major breakthrough in our comprehension of cancer development and could lead to more effective prevention methods and therapies. In this paper, we design an evolutionary mathematical framework to study the dynamics of heterogeneity over time. We consider specific situations arising during tumorigenesis, such as the emergence of positively selected mutations ("drivers") and the accumulation of neutral variation ("passengers"). We perform exact computer simulations of the emergence of diverse tumor cell clones over time, and derive analytical estimates for the extent of heterogeneity within a population of cancer cells. Our methods contribute to a quantitative understanding of tumor heterogeneity and the impact of heritable alterations on this tumor trait. C1 [Iwasa, Yoh] Kyushu Univ, Fac Sci, Dept Biol, Fukuoka 812, Japan. [Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Iwasa, Y (reprint author), Kyushu Univ, Fac Sci, Dept Biol, Fukuoka 812, Japan. EM michor@jimmy.harvard.edu RI Iwasa, Yoh/G-5368-2010 OI Iwasa, Yoh/0000-0003-0691-1852 FU National Cancer Institute (NCI) initiative [U54CA143798] FX This work was supported by the National Cancer Institute (NCI) initiative to fund Physical Science-Oncology Centers (grant U54CA143798) (F.M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 24 Z9 24 U1 0 U2 8 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 MAR 30 PY 2011 VL 6 IS 3 AR e17866 DI 10.1371/journal.pone.0017866 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 743YK UT WOS:000289055700016 PM 21479218 ER PT J AU Velez, JM Miriyala, S Nithipongvanitch, R Noel, T Plabplueng, CD Oberley, T Jungsuwadee, P Van Remmen, H Vore, M Clair, DKS AF Velez, Joyce M. Miriyala, Sumitra Nithipongvanitch, Ramaneeya Noel, Teresa Plabplueng, Chotiros D. Oberley, Terry Jungsuwadee, Paiboon Van Remmen, Holly Vore, Mary Clair, Daret K. St. TI p53 Regulates Oxidative Stress-Mediated Retrograde Signaling: A Novel Mechanism for Chemotherapy-Induced Cardiac Injury SO PLOS ONE LA English DT Article ID MANGANESE SUPEROXIDE-DISMUTASE; GLUTATHIONE TRANSFERASE; LIPID-PEROXIDATION; NITRIC-OXIDE; CELL-DEATH; ACTIVATION; MICE; AUTOPHAGY; PROTEINS; HEART AB The side effects of cancer therapy on normal tissues limit the success of therapy. Generation of reactive oxygen species (ROS) has been implicated for numerous chemotherapeutic agents including doxorubicin (DOX), a potent cancer chemotherapeutic drug. The production of ROS by DOX has been linked to DNA damage, nuclear translocation of p53, and mitochondrial injury; however, the causal relationship and molecular mechanisms underlying these events are unknown. The present study used wild-type (WT) and p53 homozygous knock-out (p53(-/-)) mice to investigate the role of p53 in the crosstalk between mitochondria and nucleus. Injecting mice with DOX (20 mg/kg) causes oxidative stress in cardiac tissue as demonstrated by immunogold analysis of the levels of 4-hydroxy-2'-nonenal (4HNE)-adducted protein, a lipid peroxidation product bound to proteins. 4HNE levels increased in both nuclei and mitochondria of WT DOX-treated mice but only in nuclei of DOX-treated p53((-/-)) mice, implicating a critical role for p53 in causing DOX-induced oxidative stress in mitochondria. The stress-activated protein c-Jun amino-terminal kinase (JNKs) was activated in response to increased 4HNE in WT mice but not p53((-/-)) mice receiving DOX treatment, as determined by co-immunoprecipitation of HNE and pJNK. The activation of JNK in DOX treated WT mice was accompanied by Bcl-2 dissociation from Beclin in mitochondria and induction of type II cell death (autophagic cell death), as evidenced by an increase in LC3-I/LC-3-II ratio and gamma-H2AX, a biomarker for DNA damage. The absence of p53 significantly reduces mitochondrial injury, assessed by quantitative morphology, and decline in cardiac function, assessed by left ventricular ejection fraction and fraction shortening. These results demonstrate that p53 plays a critical role in DOX-induced cardiac toxicity, in part, by the induction of oxidative stress mediated retrograde signaling. C1 [Velez, Joyce M.; Miriyala, Sumitra; Noel, Teresa; Jungsuwadee, Paiboon; Vore, Mary; Clair, Daret K. St.] Univ Kentucky, Grad Ctr Toxicol, Lexington, KY 40526 USA. [Oberley, Terry] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA. [Oberley, Terry] Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Pathol & Lab Med Serv, Madison, WI 53792 USA. [Nithipongvanitch, Ramaneeya; Plabplueng, Chotiros D.] Mahidol Univ, Fac Med Technol, Bangkok 10700, Thailand. [Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. RP Velez, JM (reprint author), Univ Kentucky, Grad Ctr Toxicol, Lexington, KY 40526 USA. EM DSTCL00@uky.edu RI Vore, Mary/E-2177-2012 FU National Institutes of Health [CA 139483, CA 139484, T32 HL072743]; Interdisciplinary Cardiovascular Training Program FX This work is supported by National Institutes of Health grants CA 139483, CA 139484 and T32 HL072743, Interdisciplinary Cardiovascular Training Program (Joyce M. Velez). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 30 Z9 31 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 30 PY 2011 VL 6 IS 3 AR e18005 DI 10.1371/journal.pone.0018005 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 743YK UT WOS:000289055700021 PM 21479164 ER PT J AU Vidwans, SJ Flaherty, KT Fisher, DE Tenenbaum, JM Travers, MD Shrager, J AF Vidwans, Smruti J. Flaherty, Keith T. Fisher, David E. Tenenbaum, Jay M. Travers, Michael D. Shrager, Jeff TI A Melanoma Molecular Disease Model SO PLOS ONE LA English DT Article ID P16 PROTEIN EXPRESSION; METASTATIC MELANOMA; MALIGNANT-MELANOMA; CUTANEOUS MELANOMA; SIGNALING PATHWAYS; BRAF MUTATIONS; HUMAN CANCER; CYCLIN D1; COMBINED INHIBITION; SEQUENCE VARIANTS AB While advanced melanoma remains one of the most challenging cancers, recent developments in our understanding of the molecular drivers of this disease have uncovered exciting opportunities to guide personalized therapeutic decisions. Genetic analyses of melanoma have uncovered several key molecular pathways that are involved in disease onset and progression, as well as prognosis. These advances now make it possible to create a "Molecular Disease Model" (MDM) for melanoma that classifies individual tumors into molecular subtypes (in contrast to traditional histological subtypes), with proposed treatment guidelines for each subtype including specific assays, drugs, and clinical trials. This paper describes such a Melanoma Molecular Disease Model reflecting the latest scientific, clinical, and technological advances. C1 [Vidwans, Smruti J.; Tenenbaum, Jay M.; Travers, Michael D.; Shrager, Jeff] CollabRx Inc, Palo Alto, CA 94301 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Fisher, David E.] Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. [Fisher, David E.] Massachusetts Gen Hosp, Melanoma Program, Boston, MA 02114 USA. [Shrager, Jeff] Stanford Univ, Symbol Syst Program Consulting, Stanford, CA 94305 USA. RP Vidwans, SJ (reprint author), CollabRx Inc, Palo Alto, CA 94301 USA. EM jshrager@stanford.edu FU NIAMS NIH HHS [R01 AR043369] NR 92 TC 43 Z9 44 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 MAR 30 PY 2011 VL 6 IS 3 AR e18257 DI 10.1371/journal.pone.0018257 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 743YK UT WOS:000289055700041 PM 21479172 ER PT J AU Sheth, SA Abuelem, T Gale, JT Eskandar, EN AF Sheth, Sameer A. Abuelem, Tarek Gale, John T. Eskandar, Emad N. TI Basal Ganglia Neurons Dynamically Facilitate Exploration during Associative Learning SO JOURNAL OF NEUROSCIENCE LA English DT Article ID FOREBRAIN CIRCUIT; STRIATAL NEURONS; CAUDATE; CORTEX; MONKEY; RESPONSES; DOPAMINE; MOVEMENT; PRIMATE; INPUTS AB The basal ganglia (BG) appear to play a prominent role in associative learning, the process of pairing external stimuli with rewarding responses. Accumulating evidence suggests that the contributions of various BG components may be described within a reinforcement learning model, in which a broad repertoire of possible responses to environmental stimuli are evaluated before the most profitable one is chosen. The striatum receives diverse cortical inputs, providing a rich source of contextual information about environmental cues. It also receives projections from midbrain dopaminergic neurons, whose phasic activity reflects a reward prediction error signal. These coincident information streams are well suited for evaluating responses and biasing future actions toward the most profitable response. Still lacking in this model is a mechanistic description of how initial response variability is generated. To investigate this question, we recorded the activity of single neurons in the globus pallidus internus (GPi), the primary BG output nucleus, in nonhuman primates ( Macaca mulatta) performing a motor associative learning task. A subset (29%) of GPi neurons showed learning-related effects, decreasing firing during the early stages of learning, then returning to higher baseline rates as associations were mastered. On a trial-by-trial basis, lower firing rates predicted exploratory behavior, whereas higher rates predicted an exploitive response. These results suggest that, during associative learning, BG output is initially permissive, allowing exploration of a variety of responses. Once a profitable response is identified, increased GPi activity suppresses alternative responses, sharpening the response profile and encouraging exploitation of the profitable learned behavior. C1 [Sheth, Sameer A.; Gale, John T.; Eskandar, Emad N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, Boston, MA 02114 USA. [Abuelem, Tarek] Baylor Coll Med, Dept Neurosurg, Houston, TX 77030 USA. RP Eskandar, EN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg, 55 Fruit St,White 502, Boston, MA 02114 USA. EM eeskandar@partners.org FU National Institutes of Health [R25 NS065743, R01 EY017658, R01 NS063249]; National Science Foundation [IOB 0645886]; Howard Hughes Medical Institute FX This work was supported by National Institutes of Health Grants R25 NS065743 (to S.A.S.) and R01 EY017658 and R01 NS063249 (to E.N.E.), National Science Foundation Grant IOB 0645886 (to E.N.E.), and Howard Hughes Medical Institute Early Career Award (to E.N.E.). NR 31 TC 25 Z9 26 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 30 PY 2011 VL 31 IS 13 BP 4878 EP 4885 DI 10.1523/JNEUROSCI.3658-10.2011 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 742JM UT WOS:000288938200014 PM 21451026 ER PT J AU Palva, S Kulashekhar, S Hamalainen, M Palva, JM AF Palva, Satu Kulashekhar, Shrikanth Haemaelaeinen, Matti Palva, J. Matias TI Localization of Cortical Phase and Amplitude Dynamics during Visual Working Memory Encoding and Retention SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SHORT-TERM-MEMORY; HUMAN CEREBRAL-CORTEX; SURFACE-BASED ANALYSIS; PREFRONTAL CORTEX; OSCILLATORY ACTIVITY; ALPHA OSCILLATIONS; EVOKED-RESPONSES; INDIVIDUAL-DIFFERENCES; OBJECT RECOGNITION; NEURONAL SYNCHRONY AB Several studies show that the amplitudes of human brain oscillations are modulated during the performance of visual working memory (VWM) tasks in a load-dependent manner. Less is known about the dynamics and identities of the cortical regions in which these modulations take place, and hence their functional significance has remained unclear. We used magnetoencephalography and electroencephalography together with minimum norm estimate-based source modeling to study the dynamics of ongoing brain activity during a parametric VWM task. Early stimulus processing and memory encoding were associated with a memory load-dependent spread of neuronal activity from occipital to temporal, parietal, and frontal cortical regions. During the VWM retention period, the amplitudes of oscillations in theta/alpha-(5-9 Hz), high-alpha-(10-14 Hz), beta-(15-30 Hz), gamma-(30-50 Hz), and high-gamma-(50-150 Hz) frequency bands were suppressed below baseline levels, and yet, in frontoparietal regions, load dependently strengthened. However, in occipital and occipitotemporal structures, only beta, gamma, and high-gamma amplitudes were robustly strengthened by memory load. Individual behavioral VWM capacity was predicted by both the magnitude of the N1 evoked response component in early visual regions and by the amplitudes of frontoparietal high-alpha and high-gamma band oscillations. Thus, both early stimulus processing and late retention period activities may influence the behavioral outcome in VWM tasks. These data support the notion that beta-and gamma-band oscillations support the maintenance of object representations in VWM whereas alpha-, beta-, and gamma-band oscillations together contribute to attentional and executive processing. C1 [Palva, Satu; Kulashekhar, Shrikanth; Palva, J. Matias] Univ Helsinki, Ctr Neurosci, FIN-00014 Helsinki, Finland. [Kulashekhar, Shrikanth] HUSLAB, BioMag Lab, Helsinki 00029, Finland. [Haemaelaeinen, Matti] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Haemaelaeinen, Matti] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Palva, S (reprint author), Univ Helsinki, Ctr Neurosci, POB 56, FIN-00014 Helsinki, Finland. EM satu.palva@helsinki.fi; matias.palva@helsinki.fi RI Palva, J. Matias/D-5837-2013; Palva, Satu/D-7400-2013; Hamalainen, Matti/C-8507-2013; OI Palva, Satu/0000-0001-9496-7391 FU Academy of Finland; Helsinki University; National Institutes of Health National Center for Research [P41 RR14075]; National Institute of Biomedical Imaging and Bioengineering [1R01EB009048, 1R01 EB006385] FX This study was supported by the Academy of Finland, by the Helsinki University Research Funds, the National Institutes of Health National Center for Research Resources Grant P41 RR14075, and National Institute of Biomedical Imaging and Bioengineering Grants 1R01EB009048 and 1R01 EB006385. NR 79 TC 54 Z9 58 U1 0 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 30 PY 2011 VL 31 IS 13 BP 5013 EP 5025 DI 10.1523/JNEUROSCI.5592-10.2011 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 742JM UT WOS:000288938200027 PM 21451039 ER PT J AU Biederman, J Petty, CR Wozniak, J Wilens, TE Fried, R Doyle, A Henin, A Bateman, C Evans, M Faraone, SV AF Biederman, Joseph Petty, Carter R. Wozniak, Janet Wilens, Timothy E. Fried, Ronna Doyle, Alysa Henin, Aude Bateman, Clancey Evans, Maggie Faraone, Stephen V. TI Impact of executive function deficits in youth with bipolar I disorder: A controlled study SO PSYCHIATRY RESEARCH LA English DT Article DE Mania; Children; Cognition; Neuropsychology ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; HYPERACTIVITY DISORDER; LEARNING-DISABILITIES; CHILDREN; ASSOCIATION; ADOLESCENTS; PERFORMANCE; DYSFUNCTION; SYMPTOMS; MANIA AB Although psychometrically-defined executive function deficits (EFDs) and ecologically valid functional outcomes have been documented among youth with bipolar I (BP-I) disorder, little is known about their association. We hypothesized that EFDs would be associated with significant ecologically valid impairments beyond those predicted by having BP-I disorder. Youth with BP-I disorder were ascertained from psychiatric clinics and community sources. We defined EFDs as having at least two out of eight EF measures impaired from a battery of six tests. Significantly more youth with BP-I disorder had EFDs than controls (45% versus 17%). Comparisons were made between controls without EFDs (N=81), controls with EFDs (N=17), BP-I youth without EFDs (N=76), and BP-I youth with EFDs (N=62). EFDs were associated with an increased risk for placement in a special class and a decrease in academic achievement (WRAT-3 reading and arithmetic). EFDs in BP-I subjects were associated with an increased risk for speech/language disorder (as assessed in the K-SADS-E) relative to BP-I subjects without EFDs. Youth with BP-I disorder and EFDs are at high risk for significant impairments in academic functioning. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Biederman, Joseph] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Biederman, Joseph; Wozniak, Janet; Wilens, Timothy E.; Henin, Aude] Harvard Univ, Dept Psychiat, Cambridge, MA 02138 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Clin & Res Program Pediat Psychopharmacol, Yawkey 6A,Fruit St, Boston, MA 02114 USA. EM jbiederman@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU NIH [R01MH066237, R01DA12945]; Neal-Kimmerly Fund for the Study of Cognition; Heinz C. Prechter Bipolar Research Fund; MGH Pediatric Psychopharmacology Council FX This work was supported by NIH grants R01MH066237 to Dr. Wozniak and R01DA12945 to Dr. Wilens. This work was also supported by the Neal-Kimmerly Fund for the Study of Cognition, a grant from the Heinz C. Prechter Bipolar Research Fund, and the support of members of the MGH Pediatric Psychopharmacology Council. NR 46 TC 14 Z9 14 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD MAR 30 PY 2011 VL 186 IS 1 BP 58 EP 64 DI 10.1016/j.psychres.2010.08.029 PG 7 WC Psychiatry SC Psychiatry GA 739OX UT WOS:000288728600011 PM 20864180 ER PT J AU Schoenfeld, DA Rajicic, N Ficociello, LH Finkelstein, DM AF Schoenfeld, David A. Rajicic, Natasa Ficociello, Linda H. Finkelstein, Dianne M. TI A test for the relationship between a time-varying marker and both recovery and progression with missing data SO STATISTICS IN MEDICINE LA English DT Article DE interval-censored failure time data; polychotomous logistic regression; longitudinal marker; random effects model; PRO logistic model ID LONGITUDINAL DATA; EVENT; MODEL; REGRESSION; COVARIATE AB For clinical studies of chronic diseases, patients are followed to determine whether treatment results in either improvement or decline in their clinical status. During periodic exams, laboratory specimens are collected that are believed to reflect both the progression and improvement in the disease status. Often patients miss visits and return with a changed disease status, resulting in interval-censored laboratory markers and indicators of disease status. The goal of this paper is to propose a single test that would evaluate the relationship between a longitudinal marker and clinical progression or recovery when missing visits result in interval-censored covariate and outcome data. We apply our test to evaluate the relationship between treatment compliance and progression and remission of renal disease in diabetic patients. Copyright (C) 2011 John Wiley & Sons, Ltd. C1 [Schoenfeld, David A.; Finkelstein, Dianne M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schoenfeld, David A.; Finkelstein, Dianne M.] Harvard Univ, Biostat Unit, Boston, MA 02114 USA. [Rajicic, Natasa] Pfizer Inc, New York, NY 10017 USA. [Ficociello, Linda H.] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Finkelstein, DM (reprint author), Massachusetts Gen Hosp, 50 Staniford St, Boston, MA 02114 USA. EM dfinkelstein@partners.org FU NIH [HD05520, CA 74302, CA 75971, DK-41526] FX We thank Andrej Krolewski for providing the diabetes data. This work was partially funded by grants from the NIH: HD05520, CA 74302, CA 75971, and DK-41526. NR 11 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAR 30 PY 2011 VL 30 IS 7 BP 718 EP 724 DI 10.1002/sim.4145 PG 7 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 736RV UT WOS:000288512700003 PM 21394748 ER PT J AU Granziera, C Hadjikhani, N Arzy, S Seeck, M Meuli, R Krueger, G AF Granziera, Cristina Hadjikhani, Nouchine Arzy, Shahar Seeck, Margitta Meuli, Reto Krueger, Gunnar TI In-vivo magnetic resonance imaging of the structural core of the Papez circuit in humans SO NEUROREPORT LA English DT Article DE diffusion spectrum imaging; Papez circuit; tractography ID TEMPORAL-LOBE EPILEPSY; ALZHEIMERS-DISEASE; ABNORMALITIES; MRI AB Papez circuit is one of the major pathways of the limbic system, and it is involved in the control of memory and emotion. Structural and functional alterations have been reported in psychiatric, neurodegenerative, and epileptic diseases. Despite the clinical interest, however, in-vivo imaging of the entire circuit remains a technological challenge. We used magnetic resonance diffusion spectrum imaging to comprehensively picture the Papez circuit in healthy humans: (i) the hippocampus-mammillary body pathway, (ii) the connections between the lateral subiculum and the cingulate cortex, and (iii) the mammillo-thalamic tract. The diagnostic and therapeutic implications of these results are discussed in the context of recent findings reporting the involvement of the Papez circuit in neurological and psychiatric diseases. NeuroReport 22:227-231 (C) 2011 Wolters KluwerHealth | Lippincott Williams & Wilkins. C1 [Granziera, Cristina] CHU Vaudois, Dept Neurol, CH-1011 Lausanne, Switzerland. [Meuli, Reto] CHU Vaudois, Dept Radiol, CH-1011 Lausanne, Switzerland. Univ Lausanne, Lausanne, Switzerland. [Granziera, Cristina; Hadjikhani, Nouchine; Arzy, Shahar] Ecole Polytech Fed Lausanne, Brain Mind Inst, Lausanne, Switzerland. [Arzy, Shahar; Seeck, Margitta] Univ Hosp Geneva, Dept Neurol, Geneva, Switzerland. [Krueger, Gunnar] Siemens Schweiz AG, Healthcare Sector IM&WS S, Renens, Switzerland. [Hadjikhani, Nouchine] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Granziera, C (reprint author), EPFL SV BMI GRHAD, Batiment AAB 1 32,Stn 15, CH-1015 Lausanne, Switzerland. EM cristina.granziera@chuv.ch RI Centre d'imagerie Biomedicale, CIBM/B-5740-2012; Hadjikhani, Nouchine/C-2018-2008; OI Hadjikhani, Nouchine/0000-0003-4075-3106; Arzy, Shahar/0000-0001-6500-8095; Granziera, Cristina/0000-0002-4917-8761 FU Centre d'Imagerie BioMedicale of the University of Lausanne; Swiss Federal Institute of Technology Lausanne (EPFL); University of Geneva; Centre Hospitalier Universitaire Vaudois; Hopitaux Universitaires de Geneve; Leenaards foundation; Jeantet foundation; Stoicescu fellowship; Swiss National Fund [33CM30-124089, 33CM30-124115, 320030-122073] FX This work was supported by the Centre d'Imagerie BioMedicale of the University of Lausanne, the Swiss Federal Institute of Technology Lausanne (EPFL), the University of Geneva, the Centre Hospitalier Universitaire Vaudois, the Hopitaux Universitaires de Geneve, the Leenaards and the Jeantet foundations, the Stoicescu fellowship, and the Swiss National Fund 33CM30-124089, 33CM30-124115, and 320030-122073. NR 20 TC 12 Z9 13 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD MAR 30 PY 2011 VL 22 IS 5 BP 227 EP 231 DI 10.1097/WNR.0b013e328344f75f PG 5 WC Neurosciences SC Neurosciences & Neurology GA 732BC UT WOS:000288155900007 PM 21346644 ER PT J AU Dias-Santagata, D Lam, Q Vernovsky, K Vena, N Lennerz, JK Borger, DR Batchelor, TT Ligon, KL Iafrate, AJ Ligon, AH Louis, DN Santagata, S AF Dias-Santagata, Dora Lam, Quynh Vernovsky, Kathy Vena, Natalie Lennerz, Jochen K. Borger, Darrell R. Batchelor, Tracy T. Ligon, Keith L. Iafrate, A. John Ligon, Azra H. Louis, David N. Santagata, Sandro TI BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications SO PLOS ONE LA English DT Article ID GIANT-CELL GLIOBLASTOMAS; LOW-GRADE ASTROCYTOMAS; PILOCYTIC ASTROCYTOMAS; ANAPLASTIC FEATURES; GENETIC ALTERATIONS; MAPK PATHWAY; FUSION GENE; EXPRESSION; GLIOMAS; TUMORS AB Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs. C1 [Dias-Santagata, Dora; Lam, Quynh; Lennerz, Jochen K.; Iafrate, A. John; Louis, David N.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Dias-Santagata, Dora; Lam, Quynh; Lennerz, Jochen K.; Iafrate, A. John; Louis, David N.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Vernovsky, Kathy; Borger, Darrell R.; Batchelor, Tracy T.] Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA USA. [Dias-Santagata, Dora; Lam, Quynh; Vernovsky, Kathy; Lennerz, Jochen K.; Borger, Darrell R.; Batchelor, Tracy T.; Ligon, Keith L.; Iafrate, A. John; Ligon, Azra H.; Louis, David N.; Santagata, Sandro] Harvard Univ, Sch Med, Boston, MA USA. [Vena, Natalie; Ligon, Keith L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Vena, Natalie; Ligon, Keith L.; Ligon, Azra H.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Ligon, Keith L.; Santagata, Sandro] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ligon, Keith L.; Ligon, Azra H.; Santagata, Sandro] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Dias-Santagata, D (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM ssantagata@partners.org OI Ligon, Keith/0000-0002-7733-600X FU Aid for Cancer Research Foundation; PLGA Foundation; National Institutes of Health (NIH) [CA095616, CA57683, K08NS064168]; Sontag Foundation; Goldhirsh Foundation; V Foundation for Cancer Research; Brain Science Foundation FX This work was supported by the Aid for Cancer Research Foundation and from an anonymous donor (to MGH) and the PLGA Foundation. KLL is supported by National Institutes of Health (NIH) grant CA095616, the Sontag Foundation, and the Goldhirsh Foundation. DNL is supported by NIH grant CA57683. SS is supported by NIH grant K08NS064168, the V Foundation for Cancer Research and the Brain Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 56 TC 119 Z9 122 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 29 PY 2011 VL 6 IS 3 AR e17948 DI 10.1371/journal.pone.0017948 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 743YC UT WOS:000289054600021 PM 21479234 ER PT J AU Gregory, MS Hackett, CG Abernathy, EF Lee, KS Saff, RR Hohlbaum, AM Moody, KSL Hobson, MW Jones, A Kolovou, P Karray, S Giani, A John, SWM Chen, DF Marshak-Rothstein, A Ksander, BR AF Gregory, Meredith S. Hackett, Caroline G. Abernathy, Emma F. Lee, Karen S. Saff, Rebecca R. Hohlbaum, Andreas M. Moody, Krishna-sulayman L. Hobson, Maura W. Jones, Alexander Kolovou, Paraskevi Karray, Saoussen Giani, Andrea John, Simon W. M. Chen, Dong Feng Marshak-Rothstein, Ann Ksander, Bruce R. TI Opposing Roles for Membrane Bound and Soluble Fas Ligand in Glaucoma-Associated Retinal Ganglion Cell Death SO PLOS ONE LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; FIBER LAYER THICKNESS; OCULAR IMMUNE PRIVILEGE; OPEN-ANGLE GLAUCOMA; INFLAMMATORY RESPONSES; INDUCED APOPTOSIS; GENE-EXPRESSION; DBA/2J MICE; ALPHA; ACTIVATION AB Glaucoma, the most frequent optic neuropathy, is a leading cause of blindness worldwide. Death of retinal ganglion cells (RGCs) occurs in all forms of glaucoma and accounts for the loss of vision, however the molecular mechanisms that cause RGC loss remain unclear. The pro-apoptotic molecule, Fas ligand, is a transmembrane protein that can be cleaved from the cell surface by metalloproteinases to release a soluble protein with antagonistic activity. Previous studies documented that constitutive ocular expression of FasL maintained immune privilege and prevented neoangeogenesis. We now show that FasL also plays a major role in retinal neurotoxicity. Importantly, in both TNF alpha triggered RGC death and a spontaneous model of glaucoma, gene-targeted mice that express only full-length FasL exhibit accelerated RGC death. By contrast, FasL-deficiency, or administration of soluble FasL, protected RGCs from cell death. These data identify membrane-bound FasL as a critical effector molecule and potential therapeutic target in glaucoma. C1 [Gregory, Meredith S.; Hackett, Caroline G.; Abernathy, Emma F.; Hobson, Maura W.; Jones, Alexander; Kolovou, Paraskevi; Chen, Dong Feng; Ksander, Bruce R.] Harvard Univ, Sch Med, Dept Ophthalmol, Schepens Eye Res Inst, Boston, MA 02163 USA. [Lee, Karen S.; Hohlbaum, Andreas M.; Moody, Krishna-sulayman L.; Hobson, Maura W.] Boston Univ, Sch Med, Dept Microbiol, Boston, MA 02118 USA. [Saff, Rebecca R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Moody, Krishna-sulayman L.; Marshak-Rothstein, Ann] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Karray, Saoussen] Hop Necker Enfants Malad, INSERM, U580, Paris, France. [Giani, Andrea] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [John, Simon W. M.] Jackson Lab, Howard Hughes Med Inst, Bar Harbor, ME 04609 USA. RP Gregory, MS (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Schepens Eye Res Inst, Boston, MA 02163 USA. EM ann.rothstein@umassmed.edu; bruce.ksander@schepens.harvard.edu FU Lions Research Foundation; American Health Assistance Foundation; NEI [EY016486, EY016145]; NCI [CA90691]; Glaucoma Foundation; [EY11721] FX Funding sources: Lions Research Foundation (BRK), American Health Assistance Foundation (MSG), NEI EY016486 (BRK), NEI EY016145 (MSG), NCI CA90691 (AMR), EY11721 (SWMJ), the Glaucoma Foundation (BRK) and SWMJ is an investigator of the Howard Hughes Medical Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 37 Z9 38 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 29 PY 2011 VL 6 IS 3 AR e17659 DI 10.1371/journal.pone.0017659 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 743YC UT WOS:000289054600014 PM 21479271 ER PT J AU Konstantinopoulos, PA Cannistra, SA Fountzilas, H Culhane, A Pillay, K Rueda, B Cramer, D Seiden, M Birrer, M Coukos, G Zhang, L Quackenbush, J Spentzos, D AF Konstantinopoulos, Panagiotis A. Cannistra, Stephen A. Fountzilas, Helen Culhane, Aedin Pillay, Kamana Rueda, Bo Cramer, Daniel Seiden, Michael Birrer, Michael Coukos, George Zhang, Lin Quackenbush, John Spentzos, Dimitrios TI Integrated Analysis of Multiple Microarray Datasets Identifies a Reproducible Survival Predictor in Ovarian Cancer SO PLOS ONE LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; GENE-EXPRESSION; GENOMIC SIGNATURES; STAGE-III; PACLITAXEL; CISPLATIN; PATTERNS; PATHWAY; CELL; CARBOPLATIN AB Background: Public data integration may help overcome challenges in clinical implementation of microarray profiles. We integrated several ovarian cancer datasets to identify a reproducible predictor of survival. Methodology/Principal Findings: Four microarray datasets from different institutions comprising 265 advanced stage tumors were uniformly reprocessed into a single training dataset, also adjusting for inter-laboratory variation ("batcheffect"). Supervised principal component survival analysis was employed to identify prognostic models. Models were independently validated in a 61-patient cohort using a custom array genechip and a publicly available 229-array dataset. Molecular correspondence of high-and low-risk outcome groups between training and validation datasets was demonstrated using Subclass Mapping. Previously established molecular phenotypes in the 2(nd) validation set were correlated with high and low-risk outcome groups. Functional representational and pathway analysis was used to explore gene networks associated with high and low risk phenotypes. A 19-gene model showed optimal performance in the training set (median OS 31 and 78 months, p < 0.01), 1(st) validation set (median OS 32 months versus not-yet-reached, p=0.026) and 2(nd) validation set (median OS 43 versus 61 months, p=0.013) maintaining independent prognostic power in multivariate analysis. There was strong molecular correspondence of the respective high-and low-risk tumors between training and 1(st) validation set. Low and high-risk tumors were enriched for favorable and unfavorable molecular subtypes and pathways, previously defined in the public 2(nd) validation set. Conclusions/Significance: Integration of previously generated cancer microarray datasets may lead to robust and widely applicable survival predictors. These predictors are not simply a compilation of prognostic genes but appear to track true molecular phenotypes of good-and poor-outcome. C1 [Konstantinopoulos, Panagiotis A.; Cannistra, Stephen A.; Fountzilas, Helen; Pillay, Kamana; Spentzos, Dimitrios] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Dept Med,Sch Med, Boston, MA 02215 USA. [Culhane, Aedin; Quackenbush, John] Harvard Univ, Dept Biostat & Computat Biol, Dana Farber Canc Inst, Dept Biostat,Sch Publ Hlth, Boston, MA 02215 USA. [Rueda, Bo] Harvard Univ, Dept Obstet Gynecol & Reprod Biol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02215 USA. [Cramer, Daniel] Harvard Univ, Dept Obstet Gynecol & Reprod Biol, Brigham & Womens Hosp, Sch Med, Boston, MA 02215 USA. [Seiden, Michael] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Birrer, Michael] Harvard Univ, Div Gynecol Med Oncol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02215 USA. [Coukos, George; Zhang, Lin] Univ Penn, Dept Gynecol Oncol, Philadelphia, PA 19104 USA. [Quackenbush, John] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Konstantinopoulos, PA (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Dept Med,Sch Med, Boston, MA 02215 USA. EM dspentzo@bidmc.harvard.edu FU NIH/NCI [P50CA105009]; Clinical Investigation Training Program; Beth Israel Deaconess Medical Center; Harvard-MIT Division of Health Sciences and Technology, Boston; Bernice Shopkin Weisman Fund; Ovarian Cancer Research Fund in memory of Amy Sachs Simon; LeAnn's Fund; Sisters Against Ovarian Cancer FX This study was supported via the NIH/NCI P50CA105009 Ovarian Cancer SPORE (Career Development Award to Dimitrios Spentzos, and Project 4 to Daniel Cramer/Stephen Cannistra), the Clinical Investigation Training Program, Beth Israel Deaconess Medical Center and Harvard-MIT Division of Health Sciences and Technology, Boston, to Panagiotis Konstantinopoulos, the Bernice Shopkin Weisman Fund, the Ovarian Cancer Research Fund in memory of Amy Sachs Simon, LeAnn's Fund, and the Sisters Against Ovarian Cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 15 Z9 15 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 29 PY 2011 VL 6 IS 3 AR e18202 DI 10.1371/journal.pone.0018202 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 743YC UT WOS:000289054600033 PM 21479231 ER PT J AU Budin, I Szostak, JW AF Budin, Itay Szostak, Jack W. TI Physical effects underlying the transition from primitive to modern cell membranes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE origin of life; ribozymes; coevolution ID LIPID-BILAYERS; VESICLES; RNA; PHOSPHOLIPIDS; AMPHIPHILES; TRANSPORTER; COMPETITION; KINETICS; EXCHANGE; FLUIDITY AB To understand the emergence of Darwinian evolution, it is necessary to identify physical mechanisms that enabled primitive cells to compete with one another. Whereas all modern cell membranes are composed primarily of diacyl or dialkyl glycerol phospholipids, the first cell membranes are thought to have self-assembled from simple, single-chain lipids synthesized in the environment. We asked what selective advantage could have driven the transition from primitive to modern membranes, especially during early stages characterized by low levels of membrane phospholipid. Here we demonstrate that surprisingly low levels of phospholipids can drive protocell membrane growth during competition for single-chain lipids. Growth results from the decreasing fatty acid efflux from membranes with increasing phospholipid content. The ability to synthesize phospholipids from single-chain substrates would have therefore been highly advantageous for early cells competing for a limited supply of lipids. We show that the resulting increase in membrane phospholipid content would have led to a cascade of new selective pressures for the evolution of metabolic and transport machinery to overcome the reduced membrane permeability of diacyl lipid membranes. The evolution of phospholipid membranes could thus have been a deterministic outcome of intrinsic physical processes and a key driving force for early cellular evolution. C1 [Budin, Itay; Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Budin, Itay; Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Budin, Itay; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU NASA [EXB02-0031-0018]; Howard Hughes Medical Institute FX We thank R. Bruckner, A. Ricardo, S. Tobe, T. Zhu, and C. Blain for discussions and S. Tobe for assistance with nucleotide permeability experiments. This work was supported by a grant from the NASA Exobiology Program (EXB02-0031-0018 to J.W.S.). J.W.S. is an Investigator of the Howard Hughes Medical Institute. NR 36 TC 75 Z9 79 U1 55 U2 125 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 MAR 29 PY 2011 VL 108 IS 13 BP 5249 EP 5254 DI 10.1073/pnas.1100498108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 741VY UT WOS:000288894800026 PM 21402937 ER PT J AU Tinoco, AD Kim, YG Tagore, DM Wiwczar, J Lane, WS Danial, NN Saghatelian, A AF Tinoco, Arthur D. Kim, Yun-Gon Tagore, Debarati M. Wiwczar, Jessica Lane, William S. Danial, Nika N. Saghatelian, Alan TI A Peptidomics Strategy To Elucidate the Proteolytic Pathways That Inactivate Peptide Hormones SO BIOCHEMISTRY LA English DT Article ID ENHANCED INSULIN-SECRETION; IMPROVED GLUCOSE-TOLERANCE; GLUCAGON-LIKE PEPTIDE-1; INTESTINAL POLYPEPTIDE; SUBSTRATE-SPECIFICITY; MASS-SPECTROMETRY; IV INHIBITOR; HUMAN PLASMA; IN-VIVO; MICE AB Proteolysis plays a key role in regulating the levels and activity of peptide hormones. Characterization of the proteolytic pathways that cleave peptide hormones is of basic interest and can, in some cases, spur the development of novel therapeutics. The lack, however, of an efficient approach to identify endogenous fragments of peptide hormones has hindered the elucidation of these proteolytic pathways. Here, we apply a mass spectrometry (MS) based peptidomics approach to characterize the intestinal fragments of peptide histidine isoleucine (PHI), a hormone that promotes glucose-stimulated insulin secretion (GSIS). Our approach reveals a proteolytic pathway in the intestine that truncates PHI at its C-terminus to produce a PHI fragment that is inactive in a GSIS assay, a result that provides a potential mechanism of PHI regulation in vivo. Differences between these in vivo peptidomics studies and in vitro lysate experiments, which showed N- and C-terminal processing of PHI, underscore the effectiveness of this approach to discover physiologically relevant proteolytic pathways. Moreover, integrating this peptidomics approach with bioassays (i.e., GSIS) provides a general strategy to reveal proteolytic pathways that may regulate the activity of peptide hormones. C1 [Tinoco, Arthur D.; Kim, Yun-Gon; Tagore, Debarati M.; Saghatelian, Alan] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Wiwczar, Jessica; Danial, Nika N.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Wiwczar, Jessica; Danial, Nika N.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Lane, William S.] Harvard Univ, Ctr Syst Biol, Mass Spectrometry & Prote Resource Lab, Cambridge, MA 02138 USA. RP Saghatelian, A (reprint author), Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA. EM saghatelian@chemistry.harvard.edu FU Mary Fieser Postdoctoral Fellowship; Searle Scholar Award; Burroughs Wellcome Fund Career Award in the Biomedical Sciences; National Institutes of Health [5 R01 DK078081, 1DP2OD002374] FX This work was supported by the Mary Fieser Postdoctoral Fellowship (A.D.T.), Searle Scholar Award (A.S.), Burroughs Wellcome Fund Career Award in the Biomedical Sciences (N.N.D. and A.S.), National Institutes of Health Grant 5 R01 DK078081 (N.N.D.), and National Institutes of Health Grant 1DP2OD002374 (A.S.). NR 37 TC 11 Z9 11 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 29 PY 2011 VL 50 IS 12 BP 2213 EP 2222 DI 10.1021/bi2000033 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 737MS UT WOS:000288573500024 PM 21299233 ER PT J AU Rolland, M Frahm, N Nickle, DC Jojic, N Deng, WJ Allen, TM Brander, C Heckerman, DE Mullins, JI AF Rolland, Morgane Frahm, Nicole Nickle, David C. Jojic, Nebojsa Deng, Wenjie Allen, Todd M. Brander, Christian Heckerman, David E. Mullins, James I. TI Increased Breadth and Depth of Cytotoxic T Lymphocytes Responses against HIV-1-B Nef by Inclusion of Epitope Variant Sequences SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CELLULAR IMMUNE-RESPONSES; INFECTION; LOAD; HIV; RECOGNITION; PROTEINS; VIREMIA; AIDS; CTL AB Different vaccine approaches cope with HIV-1 diversity, ranging from centralized(1-4) to variability-encompassing(5-7) antigens. For all these strategies, a concern remains: how does HIV-1 diversity impact epitope recognition by the immune system? We studied the relationship between HIV-1 diversity and CD8(+) T Lymphocytes (CTL) targeting of HIV-1 subtype B Nef using 944 peptides (10-mers overlapping by nine amino acids (AA)) that corresponded to consensus peptides and their most common variants in the HIV-1-B virus population. IFN-gamma ELISpot assays were performed using freshly isolated PBMC from 26 HIV-1-infected persons. Three hundred and fifty peptides elicited a response in at least one individual. Individuals targeted a median of 7 discrete regions. Overall, 33% of responses were directed against viral variants but not elicited against consensus-based test peptides. However, there was no significant relationship between the frequency of a 10-mer in the viral population and either its frequency of recognition (Spearman's correlation coefficient rho = 0.24) or the magnitude of the responses (rho = 0.16). We found that peptides with a single mutation compared to the consensus were likely to be recognized (especially if the change was conservative) and to elicit responses of similar magnitude as the consensus peptide. Our results indicate that cross-reactivity between rare and frequent variants is likely to play a role in the expansion of CTL responses, and that maximizing antigenic diversity in a vaccine may increase the breadth and depth of CTL responses. However, since there are few obvious preferred pathways to virologic escape, the diversity that may be required to block all potential escape pathways may be too large for a realistic vaccine to accommodate. Furthermore, since peptides were not recognized based on their frequency in the population, it remains unclear by which mechanisms variability-inclusive antigens (i.e., constructs enriched with frequent variants) expand CTL recognition. C1 [Rolland, Morgane; Nickle, David C.; Deng, Wenjie; Mullins, James I.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Frahm, Nicole; Allen, Todd M.; Brander, Christian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Jojic, Nebojsa; Brander, Christian] Hosp Badalona Germans Trias & Pujol, AIDS Res Inst IrsiCaixa HIVACAT, Barcelona, Spain. [Brander, Christian] ICREA, Barcelona, Spain. [Heckerman, David E.] Microsoft Res, Redmond, WA USA. RP Rolland, M (reprint author), Henry M Jackson Fdn, Mil HIV Res Program, Rockville, MD 20852 USA. EM mrolland@hivresearch.org RI Allen, Todd/F-5473-2011; OI Brander, Christian/0000-0002-0548-5778 FU Microsoft Research; Bill and Melinda Gates Foundation [43437]; amfAR [107005-43-RFNT]; Computational Biology Core of the University of Washington Centers for AIDS Research and STD (National Institutes of Health) [AI27757]; University of Washington Center for AIDS Research [P30 AI27757] FX This work was supported by an unrestricted gift from Microsoft Research, the Bill and Melinda Gates Foundation (43437) and by grants to MR from amfAR (Mathilde Krim Fellowship - 107005-43-RFNT), the Computational Biology Core of the University of Washington Centers for AIDS Research and STD (National Institutes of Health AI27757), and a grant to JIM from the University of Washington Center for AIDS Research (P30 AI27757)(bioinformatics core). These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. DEH is an employee of Microsoft Research and MR is currently employed by the Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF) (this study was completed prior to MR's employment at HJF). NR 24 TC 15 Z9 15 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 28 PY 2011 VL 6 IS 3 AR e17969 DI 10.1371/journal.pone.0017969 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 743XV UT WOS:000289053800009 PM 21464919 ER PT J AU Yamin, CK Emani, S Williams, DH Lipsitz, SR Karson, AS Wald, JS Bates, DW AF Yamin, Cyrus K. Emani, Srinivas Williams, Deborah H. Lipsitz, Stuart R. Karson, Andrew S. Wald, Jonathan S. Bates, David W. TI The Digital Divide in Adoption and Use of a Personal Health Record SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article AB Background: Personal health records (PHRs) offer the potential to improve the patient experience and the quality of patient care. However, the "digital divide," the population-level gap in Internet and computer access, may prevent certain groups from accessing the PHR. Methods: We conducted a cross-sectional analysis of a PHR within a northeastern health system. We compared adopters (ie, those activating a PHR account online) with nonadopters (ie, those who see a physician offering the PHR but do not activate an account). We further categorized adopters by intensity of PHR use, measured by number of log-ins and number of messages sent to physicians' practices. Results: As of September 30, 2009, among 75 056 patients, 43% had adopted the PHR since 2002. Blacks and Hispanics were less likely to adopt the PHR compared with whites (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.45-0.55; and 0.64; 0.57-0.73, respectively), and those with lower annual income were less likely to adopt the PHR than were those with higher income. Compared with nonadopters, adopters were more likely to have more than 2 comorbidities (OR, 1.27; 95% CI, 1.17-1.30). Use of an aggressive marketing strategy for PHR enrollment increased adoption nearly 3-fold (OR, 2.92; 95% CI, 1.58-5.40). Intensity of use was best predicted by increasing number of comorbidities, followed by race/ethnicity (whites more than blacks and Hispanics) and insurance status. We found no association between income and log-in frequency or secure messages sent. Conclusions: Despite increasing Internet availability, racial/ethnic minority patients adopted a PHR less frequently than white patients, and patients with the lowest annual income adopted a PHR less often than those with higher incomes. Among adopters, however, income did not have an effect on PHR use. C1 [Yamin, Cyrus K.; Emani, Srinivas; Williams, Deborah H.; Lipsitz, Stuart R.; Wald, Jonathan S.; Bates, David W.] Brigham & Womens Hosp, Div Gen Internal Med, Dept Med, Boston, MA 02120 USA. [Yamin, Cyrus K.; Emani, Srinivas; Karson, Andrew S.] Harvard Univ, Sch Med, Boston, MA USA. [Karson, Andrew S.] Massachusetts Gen Hosp, Dept Med, Div Gen Internal Med, Boston, MA 02114 USA. [Wald, Jonathan S.; Bates, David W.] Partners HealthCare, Partners Informat Syst, Boston, MA USA. RP Bates, DW (reprint author), Brigham & Womens Hosp, Div Gen Internal Med, Dept Med, 1620 Tremont St, Boston, MA 02120 USA. EM dbates@partners.org FU Harvard Medical School FX Dr Bates reported owning stock in Medicalis, which makes radiology ordering applications. Mr Yamin reported receiving funding from Harvard Medical School. NR 20 TC 97 Z9 97 U1 5 U2 27 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 28 PY 2011 VL 171 IS 6 BP 568 EP 574 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 741LB UT WOS:000288864100014 PM 21444847 ER PT J AU Mendelson, TB Meltzer, M Campbell, EG Caplan, AL Kirkpatrick, JN AF Mendelson, Todd B. Meltzer, Michele Campbell, Eric G. Caplan, Arthur L. Kirkpatrick, James N. TI Conflicts of Interest in Cardiovascular Clinical Practice Guidelines SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID ASSOCIATION STROKE COUNCIL; PHARMACEUTICAL COMPANY PAYMENTS; INTERDISCIPLINARY-WORKING-GROUP; PERIPHERAL-VASCULAR-DISEASE; CARDIOLOGY-COUNCIL; HEART-ASSOCIATION; ISCHEMIC-STROKE; HEALTH-POLICY; TASK-FORCE; MANAGEMENT AB Background: Clinical practice guidelines (CPGs) serve as standards of care in practice, quality improvement, and reimbursement. The extent of conflicts of interest (COIs) in cardiology guideline production has not been well studied. Herein, we describe the scope of COIs in CPGs. Methods: We examined the 17 most recent American College of Cardiology/American Heart Association guidelines through 2008. Using disclosure lists, we cataloged COIs for each participant as receiving a research grant, being on a speaker's bureau and/or receiving honoraria, owning stock, or being a consultant or member of an advisory board. We also cataloged the companies and institutions reported in each disclosure. "Episode" describes 1 instance of participation in 1 guideline by 1 person. "Individual" describes 1 person who may be involved in multiple episodes. "Company" describes a commercial or industry affiliation reported by an individual in a single episode. Analysis involved descriptive statistics and correlation analyses (Pearson correlation coefficient, chi(2) and R(2)). Results: Fifty-six percent of the 498 individuals reported a COI, corresponding to 56% of the 651 episodes. Being a consultant or member of an advisory board was the most common type. The percentage of episodes involving a COI varied between guidelines (range, 13%-87%). The number of episodes per individual was associated with both presence and number of disclosures (P < .001 for both comparisons). Of 478 companies, the number per guideline ranged from 2 to 242 companies (mean, 38 companies). One company was the most frequently reported company in 7 of 17 guidelines. Conclusion: Conflicts of interest are prevalent in cardiology guidelines, but there seems to be a significant number of experienced experts without COIs. C1 [Kirkpatrick, James N.] Univ Penn, Dept Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Mendelson, Todd B.; Caplan, Arthur L.; Kirkpatrick, James N.] Univ Penn, Ctr Bioeth, Philadelphia, PA 19104 USA. [Mendelson, Todd B.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Meltzer, Michele] Thomas Jefferson Univ, Dept Med, Div Rheumatol, Philadelphia, PA 19107 USA. [Campbell, Eric G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mongan Inst Hlth Policy, Boston, MA USA. RP Kirkpatrick, JN (reprint author), Univ Penn, Dept Med, Div Cardiovasc Med, 3400 Spruce St,9021 Gates Pavil, Philadelphia, PA 19104 USA. EM James.kirkpatrick@uphs.upenn.edu NR 49 TC 74 Z9 74 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 28 PY 2011 VL 171 IS 6 BP 577 EP 584 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 741LB UT WOS:000288864100016 PM 21444849 ER PT J AU Lo, B Kelch, RP Grady, D AF Lo, Bernard Kelch, Robert P. Grady, Deborah TI Illuminating Physicians' Financial Relationships With Industry SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Lo, Bernard] Univ Calif San Francisco, Program Med Eth, San Francisco, CA 94143 USA. [Lo, Bernard; Grady, Deborah] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Grady, Deborah] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Kelch, Robert P.] Univ Michigan, Off Execut Vice President Med Affairs Emeritus, Ann Arbor, MI 48109 USA. [Grady, Deborah] San Francisco VA Med Ctr, San Francisco, CA USA. RP Lo, B (reprint author), Univ Calif San Francisco, Program Med Eth, 521 Parnassus Ave,Box 0903,Room C-126, San Francisco, CA 94143 USA. EM bernie@medicine.ucsf.edu FU NCRR NIH HHS [1UL1RR024131-01]; NIMH NIH HHS [MH062246] NR 9 TC 5 Z9 5 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 28 PY 2011 VL 171 IS 6 BP 587 EP 589 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 741LB UT WOS:000288864100019 PM 21444852 ER PT J AU Pop-Eleches, C Thirumurthy, H Habyarimana, JP Zivin, JG Goldstein, MP de Walque, D MacKeen, L Haberer, J Kimaiyo, S Sidle, J Ngare, D Bangsberg, DR AF Pop-Eleches, Cristian Thirumurthy, Harsha Habyarimana, James P. Zivin, Joshua G. Goldstein, Markus P. de Walque, Damien MacKeen, Leslie Haberer, Jessica Kimaiyo, Sylvester Sidle, John Ngare, Duncan Bangsberg, David R. TI Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders SO AIDS LA English DT Article DE adherence; antiretroviral therapy; HIV/AIDS; mobile phones; randomized controlled trial; sub-Saharan Africa; text message reminders ID SUB-SAHARAN AFRICA; HIV-INFECTED PATIENTS; MEDICATION ADHERENCE; THERAPY ADHERENCE; BEHAVIOR-CHANGE; INTERVENTIONS; HEALTH; KENYA; CARE; NONADHERENCE AB Objective: There is limited evidence on whether growing mobile phone availability in sub-Saharan Africa can be used to promote high adherence to antiretroviral therapy (ART). This study tested the efficacy of short message service (SMS) reminders on adherence to ART among patients attending a rural clinic in Kenya. Design: A randomized controlled trial of four SMS reminder interventions with 48 weeks of follow-up. Methods: Four hundred and thirty-one adult patients who had initiated ART within 3 months were enrolled and randomly assigned to a control group or one of the four intervention groups. Participants in the intervention groups received SMS reminders that were either short or long and sent at a daily or weekly frequency. Adherence was measured using the medication event monitoring system. The primary outcome was whether adherence exceeded 90% during each 12-week period of analysis and the 48-week study period. The secondary outcome was whether there were treatment interruptions lasting at least 48 h. Results: In intention-to-treat analysis, 53% of participants receiving weekly SMS reminders achieved adherence of at least 90% during the 48 weeks of the study, compared with 40% of participants in the control group (P = 0.03). Participants in groups receiving weekly reminders were also significantly less likely to experience treatment interruptions exceeding 48 h during the 48-week follow-up period than participants in the control group (81 vs. 90%, P = 0.03). Conclusion: These results suggest that SMS reminders may be an important tool to achieve optimal treatment response in resource-limited settings. (c) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Thirumurthy, Harsha; Goldstein, Markus P.; de Walque, Damien] World Bank, Dev Res Grp, Washington, DC 20433 USA. [Pop-Eleches, Cristian] Columbia Univ, Sch Int & Publ Affairs, New York, NY USA. [Pop-Eleches, Cristian] Columbia Univ, Dept Econ, New York, NY 10027 USA. [Thirumurthy, Harsha] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Policy & Management, Chapel Hill, NC USA. [Habyarimana, James P.] Georgetown Univ, Publ Policy Inst, Washington, DC USA. [Zivin, Joshua G.] Univ Calif San Diego, Sch Int Relat & Pacific Studies, San Diego, CA 92103 USA. [MacKeen, Leslie] US Agcy Int Dev, Bur Global Hlth, Washington, DC 20523 USA. [Haberer, Jessica] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kimaiyo, Sylvester] Moi Univ, Sch Med, Eldoret, Kenya. [Sidle, John] Indiana Univ Sch Med, Div Gen Internal Med, Indianapolis, IN USA. [Sidle, John] Moi Univ, Fac Hlth Sci, Dept Med, Eldoret, Kenya. [Ngare, Duncan] Moi Univ, Sch Publ Hlth, Eldoret, Kenya. [Bangsberg, David R.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Haberer, Jessica] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. RP Thirumurthy, H (reprint author), World Bank, Dev Res Grp, 1818 H St NW, Washington, DC 20433 USA. EM hthirumurthy@worldbank.org RI de Walque, Damien/K-7049-2012; Emchi, Karma/Q-1952-2016; OI de Walque, Damien/0000-0003-1592-7602; Graff Zivin, Joshua/0000-0002-0820-4900 FU Bank Netherlands Partnership Program (BNPP) [71 44 565, 7 142 349]; United States Agency for International Development; National Institute of Mental Health [87228, 87227] FX The World Bank Research Group provided financial support for this study under contracts 7 142 349 and 71 44 565 funded by the Bank Netherlands Partnership Program (BNPP). This research was also supported in part by a grant to the USAID-AMPATH Partnership from the United States Agency for International Development as part of the President's Emergency Plan for AIDS Relief (PEPFAR). J.H. and D. R. B. received support from the National Institute of Mental Health (87228 and 87227, respectively). NR 43 TC 315 Z9 320 U1 1 U2 54 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 27 PY 2011 VL 25 IS 6 BP 825 EP 834 DI 10.1097/QAD.0b013e32834380c1 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 736IR UT WOS:000288487400013 PM 21252632 ER PT J AU Eggert, US AF Eggert, Ulrike S. TI Chemical approach to understanding cell division SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 241st National Meeting and Exposition of the American-Chemical-Society (ACS) CY MAR 27-31, 2011 CL Anaheim, CA SP Amer Chem Soc C1 [Eggert, Ulrike S.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 27 PY 2011 VL 241 MA 33-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 782BO UT WOS:000291982801533 ER PT J AU Karajanagi, SS Lopez-Guerra, G Park, H Kobler, JB Galindo, M Aanestad, J Mehta, DD Kumai, Y Giordano, N d'Almeida, A Heaton, JT Langer, RS Herrera, VLM Faquin, W Hillman, RE Zeitels, SM AF Karajanagi, Sandeep S. Lopez-Guerra, Gerardo Park, Hyoungshin Kobler, James B. Galindo, Marilyn Aanestad, Jon Mehta, Daryush D. Kumai, Yoshihiko Giordano, Nicholas d'Almeida, Anthony Heaton, James T. Langer, Robert S. Herrera, Victoria L. M. Faquin, William Hillman, Robert E. Zeitels, Steven M. TI Assessment of a new biomaterial designed to restore pliability to scarred vocal folds SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 241st National Meeting and Exposition of the American-Chemical-Society (ACS) CY MAR 27-31, 2011 CL Anaheim, CA SP Amer Chem Soc C1 Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Surg, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. MIT, Dept Chem Engn, Cambridge, MA 02139 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Boston Univ, Sch Engn, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 27 PY 2011 VL 241 MA 10-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 782BO UT WOS:000291982801857 ER PT J AU Shur, O Szilvay, GR Blenner, MA Cropek, DM Banta, SA AF Shur, Oren Szilvay, Geza R. Blenner, Mark A. Cropek, Donald M. Banta, Scott A. TI Beta roll motifs as a novel scaffold for engineering biomolecular recognition SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 241st National Meeting and Exposition of the American-Chemical-Society (ACS) CY MAR 27-31, 2011 CL Anaheim, CA SP Amer Chem Soc C1 Columbia Univ, New York, NY USA. Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. USA, Construct Engn Res Lab, Engineer Res & Dev Ctr, Champaign, IL 61824 USA. VTT Tech Res Ctr, Espoo, Finland. NR 0 TC 0 Z9 0 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 27 PY 2011 VL 241 MA 511-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 782BO UT WOS:000291982801961 ER PT J AU Tena, A Vallabhajosyula, P Hawley, RJ Griesemer, A Yamada, K Sachs, DH AF Tena, Aseda Vallabhajosyula, Prashanth Hawley, Robert J. Griesemer, Adam Yamada, Kazuhiko Sachs, David H. TI Quantification of Baboon Thymopoiesis in Porcine Thymokidney Xenografts by the Signal-Joining T-Cell Receptor Excision Circle Assay SO TRANSPLANTATION LA English DT Article DE Thymokidney; Thymopoiesis; Signal joint TCR excision circles (sjTREC); Xenograft ID THYMIC LOBE TRANSPLANTATION; SKIN-GRAFT TOLERANCE; MINIATURE SWINE; INDUCTION; BARRIER; TISSUE; MODEL; MICE AB Background. Transplantation of vascularized donor thymic tissue along with a kidney transplant has markedly improved graft survival across the discordant pig-to-baboon xenogeneic barrier. To quantify the production of baboon T cells by the porcine thymic tissue, we recently developed an assay to measure the excised DNA products of baboon T-cell receptor (TCR) gene rearrangement (signal-joining TCR excision circles, sjTREC). Methods. Initial polymerase chain reaction (PCR) analysis documented that TCR delta REC-psi J alpha rearrangement occurs in baboons. Primers, specific to baboon sjTREC sequence were designed and used to quantify sjTREC molecules in peripheral blood mononuclear cells and thymic tissue using a quantitative PCR assay. Results. sjTREC levels were higher in phenotypically naive (CD3(+) CD45RA(+) (+)) T cells (650 copies/100,000 cells) than in phenotypically memory (CD3(+)CD45RA(low)) T cells, with sjTREC below the limit of detection (40 copies/100,000 cells). Surgical removal of the native thymus in two baboons led to a significant decrease of sjTREC in peripheral blood (from 1104 and 920 copies to 184 and 190 copies/100,000 cells, respectively), confirming the role of the thymus in maintaining the peripheral T-cell pool. In two thymectomized baboons that received porcine thymokidney xenografts, sjTREC levels remained low in the peripheral blood (< 40 copies/100,000 cells), but increased to 52 and 192 copies/100,000 cells in thymic biopsies, implying that baboon thymopoiesis had begun to occur in the porcine thymic xenografts. Conclusions. Baboon sjTREC can be quantified by quantitative PCR using primers specific to baboon sequence. Initial results suggest that baboon thymopoiesis occurs in vascularized porcine thymus xenografts. C1 [Tena, Aseda; Vallabhajosyula, Prashanth; Hawley, Robert J.; Griesemer, Adam; Yamada, Kazuhiko; Sachs, David H.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Sachs, DH (reprint author), Massachusetts Gen Hosp E, Transplantat Biol Res Ctr, Bldg 149-9019,13th St, Boston, MA 02129 USA. EM david.sachs@tbrc.mgh.harvard.edu FU NIH/NIAID [5PO1A145897-09]; NIH/NIAID/NIDDK [1U01DK080653-02] FX This work was supported in part by grants from NIH/NIAID 5PO1A145897-09 and NIH/NIAID/NIDDK 1U01DK080653-02. NR 17 TC 8 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAR 27 PY 2011 VL 91 IS 6 BP 639 EP 644 DI 10.1097/TP.0b013e31820b6b52 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 731NM UT WOS:000288115800017 PM 21285918 ER PT J AU Spitzer, TR Sykes, M Tolkoff-Rubin, N Kawai, T McAfee, SL Dey, BR Ballen, K Delmonico, F Saidman, S Sachs, DH Cosimi, AB AF Spitzer, Thomas R. Sykes, Megan Tolkoff-Rubin, Nina Kawai, Tatsuo McAfee, Steven L. Dey, Bimalangshu R. Ballen, Karen Delmonico, Francis Saidman, Susan Sachs, David H. Cosimi, A. Benedict TI Long-Term Follow-Up of Recipients of Combined Human Leukocyte Antigen-Matched Bone Marrow and Kidney Transplantation for Multiple Myeloma With End-Stage Renal Disease SO TRANSPLANTATION LA English DT Article DE Bone marrow; Kidney transplant; Multiple myeloma ID MIXED LYMPHOHEMATOPOIETIC CHIMERISM; HEMATOPOIETIC-CELL TRANSPLANTATION; ANTITUMOR RESPONSES; CONDITIONING REGIMEN; DONOR CHIMERISM; IFN-GAMMA; TOLERANCE; INFUSIONS; THERAPY; HOST AB Background. Specific tolerance after combined kidney and bone marrow transplantation for multiple myeloma with end-stage renal disease through mixed lymphohematopoietic chimerism has been achieved, as evidenced by prolonged normal renal function without ongoing immunosuppression. Methods. To achieve potent antimyeloma responses and induce tolerance for the renal allograft, seven patients (median age: 48 years [range: 34-55 years]) with multiple myeloma and end-stage renal disease underwent a combined human leukocyte antigen-matched kidney and bone marrow transplant with lead follow-up time of more than 12 years. Preparative therapy for the transplant consisted of high-dose cyclophosphamide, equine antithymocyte globulin and pretransplant thymic irradiation. Cyclosporine as the sole posttransplant immunosuppressive therapy was tapered and discontinued as early as day 73 posttransplant. Results. All seven patients achieved mixed chimerism. One patient developed acute graft-versus-host disease and two chronic graft-versus-host disease. Five of seven patients are alive, four with no evidence of myeloma from 4 to 12.1 years posttransplant. Three patients have normal or near-normal renal function without needing systemic immunosuppression. Two patients with normal renal function off immunosuppression were returned to immunosuppressive therapy without evidence of rejection because of the occurrence of chronic graft-versus-host disease. Conclusions. These long-term follow-up data show that sustained renal allograft tolerance and prolonged antimyeloma responses are achievable after human leukocyte antigen-matched kidney and bone marrow transplantation and the induction of mixed lymphohematopoietic chimerism. C1 [Spitzer, Thomas R.] Massachusetts Gen Hosp, Bone Marrow Transplant Program, Bone Marrow Transplant Unit, Dept Med, Boston, MA 02114 USA. [Sykes, Megan; Sachs, David H.] Massachusetts Gen Hosp, Transplant Biol Res Ctr, Dept Surg, Boston, MA 02114 USA. [Tolkoff-Rubin, Nina] Massachusetts Gen Hosp, Renal Unit, Dept Med, Boston, MA 02114 USA. [Kawai, Tatsuo; Delmonico, Francis; Cosimi, A. Benedict] Massachusetts Gen Hosp, Dept Surg, Transplantat Unit, Boston, MA 02114 USA. [Saidman, Susan] Massachusetts Gen Hosp, Dept Pathol, Histocompatibil Lab, Boston, MA 02114 USA. RP Spitzer, TR (reprint author), Massachusetts Gen Hosp, Bone Marrow Transplant Program, Bone Marrow Transplant Unit, Dept Med, 0 Emerson Pl,Suite 118, Boston, MA 02114 USA. EM tspitzer@partners.org FU Immune Tolerance Network (NIH) [N01 AI15416]; National Institute of Allergy and Infectious Diseases; Juvenile Diabetes Research Foundation FX This research was performed with the support of the Immune Tolerance Network (NIH Contract #N01 AI15416), an international clinical research consortium headquartered at the University of California San Francisco and supported by the National Institute of Allergy and Infectious Diseases and the Juvenile Diabetes Research Foundation (M.S.). NR 21 TC 63 Z9 67 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAR 27 PY 2011 VL 91 IS 6 BP 672 EP 676 DI 10.1097/TP.0b013e31820a3068 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 731NM UT WOS:000288115800022 PM 21217460 ER PT J AU Ascierto, PA De Maio, E Bertuzzi, S Palmieri, G Halaban, R Hendrix, M Kashani-Sabet, M Ferrone, S Wang, E Cochran, A Rivoltini, L Lee, PP Fox, BA Kirkwood, JM Ullmann, CD Lehmann, FF Sznol, M Schwartzentruber, DJ Maio, M Flaherty, K Galon, J Ribas, A Yang, J Stroncek, DF Mozzillo, N Marincola, FM AF Ascierto, Paolo A. De Maio, Eleonora Bertuzzi, Stefano Palmieri, Giuseppe Halaban, Ruth Hendrix, Mary Kashani-Sabet, Mohamed Ferrone, Soldano Wang, Ena Cochran, Alistair Rivoltini, Licia Lee, Peter P. Fox, Bernard A. Kirkwood, John M. Ullmann, Claudio Dansky Lehmann, Frederic F. Sznol, Mario Schwartzentruber, Douglas J. Maio, Michele Flaherty, Keith Galon, Jerome Ribas, Antoni Yang, James Stroncek, David F. Mozzillo, Nicola Marincola, Franco M. TI Future perspectives in melanoma research. Meeting report from the "Melanoma Research: a bridge Naples-USA. Naples, December 6(th)-7(th) 2010" SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID PRIMARY CUTANEOUS MELANOMA; PROGNOSTIC-SIGNIFICANCE; COLORECTAL-CANCER; CELLS; PROTEIN; TUMORS AB Progress in understanding the molecular basis of melanoma has made possible the identification of molecular targets with important implications in clinical practice. In fact, new therapeutic approaches are emerging from basic science and it will be important to implement their rapid translation into clinical practice by active clinical investigation. The first meeting of Melanoma Research: a bridge Naples-USA, organized by Paolo A. Ascierto (INT, Naples, Italy) and Francesco Marincola (NIH, Bethesda, USA) took place in Naples, on 6-7 December 2010. This international congress gathered more than 30 international and Italian faculty members and was focused on recent advances in melanoma molecular biology, immunology and therapy, and created an interactive discussion across Institutions belonging to Government, Academy and Pharmaceutical Industry, in order to stimulate new approaches in basic, translational and clinical research. Four topics of discussion were identified: New pathways in Melanoma, Biomarkers, Clinical Trials and New Molecules and Strategies. C1 [Ascierto, Paolo A.; De Maio, Eleonora; Mozzillo, Nicola] Fdn Pascale, Ist Nazl Tumori, Dept Melanoma Sarcoma & Head & Neck Dis, Naples, Italy. [Bertuzzi, Stefano] NIH, Off Director, Off Sci Policy Anal, Off Sci Policy, Bethesda, MD 20892 USA. [Palmieri, Giuseppe] CNR, Inst Biomol Chem, Unit Canc Genet, Sassari, Italy. [Halaban, Ruth] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA. [Hendrix, Mary] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA. [Kashani-Sabet, Mohamed] Calif Pacific Med Ctr, Res Inst, Ctr Melanoma Res & Treatment, San Francisco, CA USA. [Ferrone, Soldano] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Wang, Ena; Stroncek, David F.; Marincola, Franco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Stroncek, David F.; Marincola, Franco M.] NIH, Ctr Human Immunol, Bethesda, MD 20892 USA. [Cochran, Alistair] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Rivoltini, Licia] IRCCS Fdn, Ist Nazl Tumori, Unit Immunotherapy Human Tumors, Milan, Italy. [Lee, Peter P.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Fox, Bernard A.] Providence Portland Med Ctr, Lab Mol & Tumor Immunol, Robert W Franz Canc Res Ctr, Earle A Chiles Res Inst, Portland, OR USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA. [Kirkwood, John M.] Univ Pittsburgh, Dept Med, Div Hematol Oncol, Inst Canc, Pittsburgh, PA USA. [Kirkwood, John M.] Pittsburgh Canc Inst, Melanoma Program, Pittsburgh, PA 15213 USA. [Ullmann, Claudio Dansky] NCI, Clin Invest Branch, Canc Therapy Evaluat Program DCTD, Bethesda, MD 20892 USA. [Lehmann, Frederic F.] GlaxoSmithKline Biol, Canc Immunotherapeut Business Unit, Rixensart, Belgium. [Sznol, Mario] Yale Canc Ctr, New Haven, CT USA. [Schwartzentruber, Douglas J.] Indiana Univ, Hlth Goshen Ctr Canc Care, Goshen, IN USA. [Maio, Michele] Univ Siena, Hosp Siena, Ist Toscano Tumori, I-53100 Siena, Italy. [Flaherty, Keith] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Galon, Jerome] INSERM, U872, Cordeliers Res Ctr, Inserm Grp Leader,Team 15, Paris, France. [Ribas, Antoni] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Med, Los Angeles, CA 90024 USA. [Yang, James] NIH, Bethesda, MA USA. RP Ascierto, PA (reprint author), Fdn Pascale, Ist Nazl Tumori, Dept Melanoma Sarcoma & Head & Neck Dis, Naples, Italy. EM paolo.ascierto@gmail.com RI altomonte, maresa/G-7734-2011 FU Italian Ministry of Health [M2/11]; Fondazione Melanoma Onlus; Bristol Myers Squibb FX This work was supported by the Italian Ministry of Health "Progetto Ricerca Corrente Istituto Nazionale Tumori Pascale M2/11 Approccio multidisciplinare dalla ricerca alla cura del melanoma" and by Fondazione Melanoma Onlus. Authors would like to thank authors who have provided Tables originally published in Cancer Vaccines, Second Edition (2011) edited by Adrian Bot, Mihail Obrocea, and Franco Marincola; available from Informa Healthcare http://informahealthcare.com/.; PAA participated in advisory board for Bristol Myers Squibb, Merck/Schering-Plough, GlaxoSmithKline and Roche. MKS has served on the Merck/Schering-Plough Advisory Board and Speakers' Bureau, and owns stock in Melanoma Diagnostics. Myriad Genetics has licensed intellectual property developed by MKS. JMK is consultant to GSKbio and Morphotek. FFL is employee of GlaxoSmithKline Biologicals. MS received consulting fees from Bristol Myers Squibb. KF is consultant to Roche/Genentech and GlaxoSmithKline. AR participated in advisory board for Roche-Genentech and Bristol Myers Squibb. NR 28 TC 8 Z9 8 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAR 26 PY 2011 VL 9 AR 32 DI 10.1186/1479-5876-9-32 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 750RE UT WOS:000289564900001 PM 21439082 ER PT J AU Huynh, H Zheng, JK Umikawa, M Silvany, R Xie, XJ Wu, CJ Holzenberger, M Wang, QM Zhang, CC AF Huynh, HoangDinh Zheng, Junke Umikawa, Masato Silvany, Robert Xie, Xian-Jin Wu, Catherine J. Holzenberger, Martin Wang, Qianming Zhang, Cheng Cheng TI Components of the Hematopoietic Compartments in Tumor Stroma and Tumor-Bearing Mice SO PLOS ONE LA English DT Article ID EX-VIVO EXPANSION; STEM-CELLS; GROWTH-FACTOR; PROGENITOR CELLS; NICHE; POPULATION; CANCER; LIVER; IGF-1 AB Solid tumors are composed of cancerous cells and non-cancerous stroma. A better understanding of the tumor stroma could lead to new therapeutic applications. However, the exact compositions and functions of the tumor stroma are still largely unknown. Here, using a Lewis lung carcinoma implantation mouse model, we examined the hematopoietic compartments in tumor stroma and tumor-bearing mice. Different lineages of differentiated hematopoietic cells existed in tumor stroma with the percentage of myeloid cells increasing and the percentage of lymphoid and erythroid cells decreasing over time. Using bone marrow reconstitution analysis, we showed that the tumor stroma also contained functional hematopoietic stem cells. All hematopoietic cells in the tumor stroma originated from bone marrow. In the bone marrow and peripheral blood of tumor-bearing mice, myeloid populations increased and lymphoid and erythroid populations decreased and numbers of hematopoietic stem cells markedly increased with time. To investigate the function of hematopoietic cells in tumor stroma, we co-implanted various types of hematopoietic cells with cancer cells. We found that total hematopoietic cells in the tumor stroma promoted tumor development. Furthermore, the growth of the primary implanted Lewis lung carcinomas and their metastasis were significantly decreased in mice reconstituted with IGF type I receptor-deficient hematopoietic stem cells, indicating that IGF signaling in the hematopoietic tumor stroma supports tumor outgrowth. These results reveal that hematopoietic cells in the tumor stroma regulate tumor development and that tumor progression significantly alters the host hematopoietic compartment. C1 [Huynh, HoangDinh; Zheng, Junke; Umikawa, Masato; Silvany, Robert; Zhang, Cheng Cheng] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA. [Huynh, HoangDinh; Zheng, Junke; Umikawa, Masato; Silvany, Robert; Zhang, Cheng Cheng] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA. [Xie, Xian-Jin] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Wu, Catherine J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Holzenberger, Martin] Hop St Antoine, INSERM, U515, F-75571 Paris, France. [Wang, Qianming] S China Normal Univ, Sch Chem & Environm, Guangzhou, Guangdong, Peoples R China. RP Huynh, H (reprint author), Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA. EM Alec.Zhang@UTSouthwestern.edu FU American Cancer Society [ACS-IRG-02-196]; NIH [K01CA120099]; Welch Foundation [I-1701]; March of Dimes Foundation; DOD [PR093256]; Cancer Prevention and Research Institute of Texas [RP100402] FX American Cancer Society grant ACS-IRG-02-196 (http://www.cancer.org/), NIH grant K01CA120099 (http://grants1.nih.gov/grants/funding/funding.htm), Welch Foundation I-1701 ( http://www.welch1.org/), Basil O'Connor Award from the March of Dimes Foundation (http://www.marchofdimes.com/research/research.html), DOD Peer Reviewed Medical Research Program PR093256 (https://cdmrp.org/), and Cancer Prevention and Research Institute of Texas RP100402 (http://www.cprit.state.tx.us/funding-opportunities/) supported this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 5 Z9 5 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 25 PY 2011 VL 6 IS 3 AR e18054 DI 10.1371/journal.pone.0018054 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 740SE UT WOS:000288813900030 PM 21464968 ER PT J AU Levis, M Ravandi, F Wang, ES Baer, MR Perl, A Coutre, S Erba, H Stuart, RK Baccarani, M Cripe, LD Tallman, MS Meloni, G Godley, LA Langston, AA Amadori, S Lewis, ID Nagler, A Stone, R Yee, K Advani, A Douer, D Wiktor-Jedrzejczak, W Juliusson, G Litzow, MR Petersdorf, S Sanz, M Kantarjian, HM Sato, T Tremmel, L Bensen-Kennedy, DM Small, D Smith, BD AF Levis, Mark Ravandi, Farhad Wang, Eunice S. Baer, Maria R. Perl, Alexander Coutre, Steven Erba, Harry Stuart, Robert K. Baccarani, Michele Cripe, Larry D. Tallman, Martin S. Meloni, Giovanna Godley, Lucy A. Langston, Amelia A. Amadori, Sergio Lewis, Ian D. Nagler, Arnon Stone, Richard Yee, Karen Advani, Anjali Douer, Dan Wiktor-Jedrzejczak, W. Juliusson, Gunnar Litzow, Mark R. Petersdorf, Stephen Sanz, Miguel Kantarjian, Hagop M. Sato, Takashi Tremmel, Lothar Bensen-Kennedy, Debra M. Small, Donald Smith, B. Douglas TI Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; TYROSINE KINASE INHIBITOR; ACUTE MYELOGENOUS LEUKEMIA; IN-VITRO; MUTATIONS; SORAFENIB; CEP-701; PKC412; COMBINATIONS AB In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 mu M. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482. (Blood. 2011;117(12): 3294-3301) C1 [Levis, Mark; Sato, Takashi; Smith, B. Douglas] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Ravandi, Farhad; Kantarjian, Hagop M.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Wang, Eunice S.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Baer, Maria R.] Univ Maryland, Baltimore, MD 21201 USA. [Perl, Alexander] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Coutre, Steven] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Erba, Harry] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Stuart, Robert K.] Med Univ S Carolina, Charleston, SC 29425 USA. [Baccarani, Michele] Univ Bologna, Seragnoli Inst Hematol & Med Oncol, Bologna, Italy. [Cripe, Larry D.] Indiana Univ, Simon Canc Ctr, Indianapolis, IN 46204 USA. [Tallman, Martin S.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Meloni, Giovanna] Univ Roma La Sapienza, Rome, Italy. [Godley, Lucy A.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Langston, Amelia A.] Emory Univ, Sch Med, Atlanta, GA USA. [Amadori, Sergio] Univ Roma Tor Vergata, Dept Hematol, Rome, Italy. [Lewis, Ian D.] Inst Med & Vet Sci, Div Haematol, Adelaide, SA 5000, Australia. [Nagler, Arnon] Chaim Sheba Med Ctr, Div Hematol & Bone Marrow Transplantat, IL-52621 Tel Hashomer, Israel. [Stone, Richard] Dana Farber Canc Inst, Boston, MA 02115 USA. [Yee, Karen] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Advani, Anjali] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. [Douer, Dan] Univ So Calif, Keck Sch Med, Norris Canc Ctr, Los Angeles, CA 90033 USA. [Wiktor-Jedrzejczak, W.] Med Univ Warsaw, Dept Hematol Oncol, Warsaw, Poland. [Wiktor-Jedrzejczak, W.] Med Univ Warsaw, Dept Internal Dis, Warsaw, Poland. [Juliusson, Gunnar] Lund Stem Cell Ctr, Dept Hematol, Lund, Sweden. [Litzow, Mark R.] Mayo Clin, Rochester, MN USA. [Petersdorf, Stephen] Seattle Canc Care Alliance, Seattle, WA USA. [Sanz, Miguel] Hosp Univ La Fe, Valencia, Spain. [Tremmel, Lothar; Bensen-Kennedy, Debra M.] Cephalon Inc, Frazer, PA USA. RP Levis, M (reprint author), Kimmel Canc Ctr Johns Hopkins, 1650 Orleans St,Rm 243, Baltimore, MD 21231 USA. EM levisma@jhmi.edu OI Stuart, Robert/0000-0001-7549-8008; Amadori, Sergio/0000-0002-2356-8681 FU National Cancer Institute (NCI) [P50 CA100632-06, R01 CA128864]; American Society of Clinical Oncology FX This work was supported the National Cancer Institute (NCI; Leukemia SPORE P50 CA100632-06, R01 CA128864) and the American Society of Clinical Oncology (M.L.). M.L. is a Clinical Scholar of the Leukemia & Lymphoma Society. NR 31 TC 156 Z9 160 U1 2 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 24 PY 2011 VL 117 IS 12 BP 3294 EP 3301 DI 10.1182/blood-2010-08-301796 PG 8 WC Hematology SC Hematology GA 741FJ UT WOS:000288848500012 PM 21270442 ER PT J AU Weisenburger, DD Savage, KJ Harris, NL Gascoyne, RD Jaffe, ES MacLennan, KA Rudiger, T Pileri, S Nakamura, S Nathwani, B Campo, E Berger, F Coiffier, B Kim, WS Holte, H Federico, M Au, WY Tobinai, K Armitage, JO Vose, JM AF Weisenburger, Dennis D. Savage, Kerry J. Harris, Nancy Lee Gascoyne, Randy D. Jaffe, Elaine S. MacLennan, Kenneth A. Ruediger, Thomas Pileri, Stefano Nakamura, Shigeo Nathwani, Bharat Campo, Elias Berger, Francoise Coiffier, Bertrand Kim, Won-Seog Holte, Harald Federico, Massimo Au, Wing Y. Tobinai, Kensei Armitage, James O. Vose, Julie M. CA Int Peripheral T-Cell Lymphoma Pro TI Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; PROGNOSTIC-FACTORS; CLINICAL-FEATURES; CLINICOPATHOLOGICAL FEATURES; REAL CLASSIFICATION; JAPANESE PATIENTS; UNITED-STATES; SINGLE-CENTER; EXPRESSION; OUTCOMES AB The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P < .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (>= 10 cm), thrombocytopenia (< 150 x 10(9)/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies. (Blood. 2011;117(12):3402-3408) C1 [Savage, Kerry J.] British Columbia Canc Agcy, Dept Med Oncol, Vancouver, BC V5Z 4E6, Canada. [Harris, Nancy Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Harris, Nancy Lee] Harvard Univ, Sch Med, Boston, MA USA. [Gascoyne, Randy D.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. [Jaffe, Elaine S.] NCI, Dept Hematopathol, Bethesda, MD 20892 USA. [MacLennan, Kenneth A.] St James Univ Hosp, Sect Pathol, Leeds LS9 7TF, W Yorkshire, England. [MacLennan, Kenneth A.] St James Univ Hosp, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England. [Ruediger, Thomas] Stadt Klinikum Karlsruhe, Inst Pathol, Karlsruhe, Germany. [Pileri, Stefano] Univ Bologna Hosp, Dept Pathol, Bologna, Italy. [Weisenburger, Dennis D.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. [Nakamura, Shigeo] Nagoya Univ Hosp, Dept Pathol & Lab Med, Nagoya, Aichi, Japan. [Nathwani, Bharat] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. [Nathwani, Bharat] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Campo, Elias] Univ Barcelona, Hosp Clin, Dept Pathol, Barcelona, Spain. [Berger, Francoise] Ctr Hosp Lyon Sud, Dept Pathol, Lyon, France. [Coiffier, Bertrand] Ctr Hosp Lyon Sud, Dept Med, Lyon, France. [Kim, Won-Seog] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Div Hematol Oncol, Seoul, South Korea. [Holte, Harald] Norwegian Radium Hosp, Dept Oncol, Oslo, Norway. [Holte, Harald] Oslo Univ Hosp, Oslo, Norway. [Federico, Massimo] Modena Hosp, Dept Med, Modena, Italy. [Au, Wing Y.] Queen Mary Hosp, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Tobinai, Kensei] Natl Canc Ctr, Hematol & Stem Cell Transplantat Div, Tokyo, Japan. [Armitage, James O.; Vose, Julie M.] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE 68198 USA. RP Weisenburger, DD (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, 983135 Nebraska Med Ctr, Omaha, NE 68198 USA. EM dweisenb@unmc.edu RI Federico, Massimo/A-6801-2012; Nakamura, Shigeo/I-1571-2012; Federico, Massimo/J-5984-2014; Cuadros, Marta/K-1576-2014; Zinzani, Pier Luigi/J-9182-2016; OI Federico, Massimo/0000-0002-9889-3796; Federico, Massimo/0000-0002-5074-3262; Cuadros, Marta/0000-0002-8329-4854; Zinzani, Pier Luigi/0000-0002-2112-2651; Jaffe, Elaine/0000-0003-4632-0301; Campo, elias/0000-0001-9850-9793 NR 39 TC 121 Z9 129 U1 0 U2 10 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 24 PY 2011 VL 117 IS 12 BP 3402 EP 3408 DI 10.1182/blood-2010-09-310342 PG 7 WC Hematology SC Hematology GA 741FJ UT WOS:000288848500023 PM 21270441 ER PT J AU Nelson, EA Walker, SR Weisberg, E Bar-Natan, M Barrett, R Gashin, LB Terrell, S Klitgaard, JL Santo, L Addorio, MR Ebert, BL Griffin, JD Frank, DA AF Nelson, Erik A. Walker, Sarah R. Weisberg, Ellen Bar-Natan, Michal Barrett, Rosemary Gashin, Laurie B. Terrell, Shariya Klitgaard, Josephine L. Santo, Loredana Addorio, Martha R. Ebert, Benjamin L. Griffin, James D. Frank, David A. TI The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors SO BLOOD LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; DNA-BINDING ACTIVITY; BCR-ABL; CONSTITUTIVE ACTIVATION; STEM-CELLS; CONFER RESISTANCE; CANCER-THERAPY; BCR/ABL; IMATINIB; PHOSPHORYLATION AB The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, although CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we used a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, although it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes and induces cell cycle arrest and apoptosis in CML cell lines. Pimozide also selectively inhibits colony formation of CD34(+) bone marrow cells from CML patients. Importantly, pimozide induces similar effects in the presence of the T315I BCR/ABL mutation that renders the kinase resistant to presently available inhibitors. Simultaneously inhibiting STAT5 with pimozide and the kinase inhibitors imatinib or nilotinib shows enhanced effects in inhibiting STAT5 phosphorylation and in inducing apoptosis. Thus, targeting STAT5 may be an effective strategy for the treatment of CML and other myeloproliferative diseases. (Blood. 2011;117(12):3421-3429) C1 [Nelson, Erik A.; Walker, Sarah R.; Weisberg, Ellen; Bar-Natan, Michal; Barrett, Rosemary; Gashin, Laurie B.; Terrell, Shariya; Klitgaard, Josephine L.; Santo, Loredana; Addorio, Martha R.; Ebert, Benjamin L.; Griffin, James D.; Frank, David A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nelson, Erik A.; Walker, Sarah R.; Weisberg, Ellen; Bar-Natan, Michal; Ebert, Benjamin L.; Griffin, James D.; Frank, David A.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Klitgaard, Josephine L.] Symphogen AS, Lyngby, Denmark. [Klitgaard, Josephine L.] Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark. RP Frank, DA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Mayer 522B,44 Binney St, Boston, MA 02115 USA. EM david_frank@dfci.harvard.edu OI Grossberg, Laurie/0000-0003-3676-868X FU National Cancer Institute; Initiative for Chemical Genetics (Bethesda, MD); Multiple Myeloma Research Foundation (Norwalk, CT); Kittredge Foundation (Dana-Farber Cancer Institute); Dana-Farber Cancer Institute; Gabrielle's Angel Foundation (NewYork, NY) FX This work was supported by the National Cancer Institute and the Initiative for Chemical Genetics (Bethesda, MD) and was assisted by the Chemical Biology Platform of the Broad Institute of Harvard and MIT (Boston, MA). Tissue samples were obtained from the Ted and Eileen Pasquarello Tissue Bank for Hematologic Malignancies (Dana-Farber Cancer Institute). This work was also supported by the Multiple Myeloma Research Foundation (Norwalk, CT), the Kittredge Foundation (Dana-Farber Cancer Institute), the Brent Leahey Fund (Dana-Farber Cancer Institute), Gabrielle's Angel Foundation (NewYork, NY), and the Claudia Adams Barr Program in Innovative Basic Cancer Research (Dana-Farber Cancer Institute). NR 34 TC 104 Z9 108 U1 1 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 24 PY 2011 VL 117 IS 12 BP 3421 EP 3429 DI 10.1182/blood-2009-11-255232 PG 9 WC Hematology SC Hematology GA 741FJ UT WOS:000288848500025 PM 21233313 ER PT J AU Chapman, MA Lawrence, MS Keats, JJ Cibulskis, K Sougnez, C Schinzel, AC Harview, CL Brunet, JP Ahmann, GJ Adli, M Anderson, KC Ardlie, KG Auclair, D Baker, A Bergsagel, PL Bernstein, BE Drier, Y Fonseca, R Gabriel, SB Hofmeister, CC Jagannath, S Jakubowiak, AJ Krishnan, A Levy, J Liefeld, T Lonial, S Mahan, S Mfuko, B Monti, S Perkins, LM Onofrio, R Pugh, TJ Rajkumar, SV Ramos, AH Siegel, DS Sivachenko, A Stewart, AK Trudel, S Vij, R Voet, D Winckler, W Zimmerman, T Carpten, J Trent, J Hahn, WC Garraway, LA Meyerson, M Lander, ES Getz, G Golub, TR AF Chapman, Michael A. Lawrence, Michael S. Keats, Jonathan J. Cibulskis, Kristian Sougnez, Carrie Schinzel, Anna C. Harview, Christina L. Brunet, Jean-Philippe Ahmann, Gregory J. Adli, Mazhar Anderson, Kenneth C. Ardlie, Kristin G. Auclair, Daniel Baker, Angela Bergsagel, P. Leif Bernstein, Bradley E. Drier, Yotam Fonseca, Rafael Gabriel, Stacey B. Hofmeister, Craig C. Jagannath, Sundar Jakubowiak, Andrzej J. Krishnan, Amrita Levy, Joan Liefeld, Ted Lonial, Sagar Mahan, Scott Mfuko, Bunmi Monti, Stefano Perkins, Louise M. Onofrio, Robb Pugh, Trevor J. Rajkumar, S. Vincent Ramos, Alex H. Siegel, David S. Sivachenko, Andrey Stewart, A. Keith Trudel, Suzanne Vij, Ravi Voet, Douglas Winckler, Wendy Zimmerman, Todd Carpten, John Trent, Jeff Hahn, William C. Garraway, Levi A. Meyerson, Matthew Lander, Eric S. Getz, Gad Golub, Todd R. TI Initial genome sequencing and analysis of multiple myeloma SO NATURE LA English DT Article ID B-CELL LYMPHOMA; HUMAN CANCER; SOMATIC MUTATIONS; STRESS-RESPONSE; GENE; PATHOGENESIS; BLIMP-1; EXOSOME; DIFFERENTIATION; CLASSIFICATION AB Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-kappa B signalling was indicated by mutations in 11 members of the NF-kappa B pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge. C1 [Chapman, Michael A.; Lawrence, Michael S.; Cibulskis, Kristian; Sougnez, Carrie; Harview, Christina L.; Brunet, Jean-Philippe; Adli, Mazhar; Ardlie, Kristin G.; Bernstein, Bradley E.; Drier, Yotam; Gabriel, Stacey B.; Liefeld, Ted; Mahan, Scott; Monti, Stefano; Onofrio, Robb; Pugh, Trevor J.; Ramos, Alex H.; Sivachenko, Andrey; Voet, Douglas; Winckler, Wendy; Hahn, William C.; Garraway, Levi A.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Golub, Todd R.] Eli & Edythe L Broad Inst, Cambridge Ctr 7, Cambridge, MA 02412 USA. [Keats, Jonathan J.; Ahmann, Gregory J.; Bergsagel, P. Leif; Fonseca, Rafael; Stewart, A. Keith] Mayo Clin Arizona, Scottsdale, AZ 85259 USA. [Keats, Jonathan J.; Ahmann, Gregory J.; Anderson, Kenneth C.; Auclair, Daniel; Bergsagel, P. Leif; Fonseca, Rafael; Hofmeister, Craig C.; Jagannath, Sundar; Jakubowiak, Andrzej J.; Krishnan, Amrita; Levy, Joan; Lonial, Sagar; Mfuko, Bunmi; Perkins, Louise M.; Rajkumar, S. Vincent; Siegel, David S.; Stewart, A. Keith; Trudel, Suzanne; Vij, Ravi; Zimmerman, Todd] Multiple Myeloma Res Consortium, Norwalk, CT 06581 USA. [Schinzel, Anna C.; Anderson, Kenneth C.; Hahn, William C.; Garraway, Levi A.; Meyerson, Matthew; Golub, Todd R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Adli, Mazhar; Bernstein, Bradley E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Auclair, Daniel; Levy, Joan; Mfuko, Bunmi; Perkins, Louise M.] Multiple Myeloma Res Fdn, Norwalk, CT 06581 USA. [Baker, Angela; Carpten, John; Trent, Jeff] Translat Genom Res Inst, Phoenix, AZ 85004 USA. [Bernstein, Bradley E.; Hahn, William C.; Meyerson, Matthew; Lander, Eric S.; Golub, Todd R.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Bernstein, Bradley E.; Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Drier, Yotam] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel. [Hofmeister, Craig C.] Ohio State Univ, Med Ctr, Columbus, OH 43210 USA. [Jagannath, Sundar] St Vincents Comprehens Canc Ctr, New York, NY 11001 USA. [Jakubowiak, Andrzej J.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Krishnan, Amrita] City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA. [Lonial, Sagar] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Rajkumar, S. Vincent] Mayo Clin Rochester, Rochester, MN 55905 USA. [Siegel, David S.] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ 07601 USA. [Trudel, Suzanne] Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. [Vij, Ravi] Washington Univ, Sch Med, St Louis, MO 63110 USA. [Zimmerman, Todd] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Lander, Eric S.] MIT, Cambridge, MA 02142 USA. RP Golub, TR (reprint author), Eli & Edythe L Broad Inst, Cambridge Ctr 7, Cambridge, MA 02412 USA. EM gadgetz@broadinstitute.org; golub@broadinstitute.org RI Bergsagel, Peter/A-7842-2011; Meyerson, Matthew/E-7123-2012; Hofmeister, Craig/E-3256-2011; Drier, Yotam/K-5208-2012; OI Bergsagel, Peter/0000-0003-1523-7388; Hofmeister, Craig/0000-0003-4816-1607; Drier, Yotam/0000-0003-1725-2995; Monti, Stefano/0000-0002-9376-0660; Fonseca, Rafael/0000-0002-5938-3769; Rajkumar, S. Vincent/0000-0002-5862-1833 FU Multiple Myeloma Research Foundation; Leukaemia and Lymphoma Research (UK) FX This project was funded by a grant from the Multiple Myeloma Research Foundation. M.A.C. was supported by a Clinician Scientist Fellowship from Leukaemia and Lymphoma Research (UK). We are grateful to all members of the Broad Institute's Biological Samples Platform, Genetic Analysis Platform, and Genome Sequencing Platform, without whom this work would not have been possible. NR 47 TC 649 Z9 661 U1 18 U2 101 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 24 PY 2011 VL 471 IS 7339 BP 467 EP 472 DI 10.1038/nature09837 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 739GJ UT WOS:000288702200053 PM 21430775 ER PT J AU Ceol, CJ Houvras, Y Jane-Valbuena, J Bilodeau, S Orlando, DA Battisti, V Fritsch, L Lin, WM Hollmann, TJ Ferre, F Bourque, C Burke, CJ Turner, L Uong, A Johnson, LA Beroukhim, R Mermel, CH Loda, M Ait-Si-Ali, S Garraway, LA Young, RA Zon, LI AF Ceol, Craig J. Houvras, Yariv Jane-Valbuena, Judit Bilodeau, Steve Orlando, David A. Battisti, Valentine Fritsch, Lauriane Lin, William M. Hollmann, Travis J. Ferre, Fabrizio Bourque, Caitlin Burke, Christopher J. Turner, Laura Uong, Audrey Johnson, Laura A. Beroukhim, Rameen Mermel, Craig H. Loda, Massimo Ait-Si-Ali, Slimane Garraway, Levi A. Young, Richard A. Zon, Leonard I. TI The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset SO NATURE LA English DT Article ID MALIGNANT-MELANOMA; BRAF MUTATIONS; HUMAN CANCER; GENES; NEVI; SENESCENCE; EXPRESSION; REPRESSION; LYSINE-9; CELLS AB The most common mutation in human melanoma, BRAF(V600E), activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway(1,2). BRAF(V600E) mutations are also present in benign melanocytic naevi(3), highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes(4,5). For certain amplifications, the large number of genes in the interval has precluded an understanding of the cooperating oncogenic events. Here we have used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes, that are transcriptionally dysregulated in response to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis. C1 [Ceol, Craig J.; Houvras, Yariv; Bourque, Caitlin; Burke, Christopher J.; Turner, Laura; Uong, Audrey; Zon, Leonard I.] Harvard Univ, Stem Cell Program & Hematol Oncol, Childrens Hosp Boston,Med Sch, Howard Hughes Med Inst,Harvard Stem Cell Inst, Boston, MA 02115 USA. [Houvras, Yariv] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Jane-Valbuena, Judit; Lin, William M.; Johnson, Laura A.; Beroukhim, Rameen; Mermel, Craig H.; Garraway, Levi A.] Harvard Univ, Dept Med Oncol, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. [Jane-Valbuena, Judit; Lin, William M.; Johnson, Laura A.; Beroukhim, Rameen; Mermel, Craig H.; Garraway, Levi A.] Harvard Univ, Ctr Canc Genome Discovery, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. [Jane-Valbuena, Judit; Lin, William M.; Johnson, Laura A.; Beroukhim, Rameen; Mermel, Craig H.; Garraway, Levi A.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Bilodeau, Steve; Orlando, David A.; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Battisti, Valentine; Fritsch, Lauriane; Ait-Si-Ali, Slimane] Univ Paris Diderot, Epigenet & Destin Cellulaire UMR7216, CNRS, F-75013 Paris, France. [Hollmann, Travis J.; Loda, Massimo] Harvard Univ, Ctr Mol Oncol Pathol, Brigham & Womens Hosp, Dana Farber Canc Inst,Med Sch, Boston, MA 02115 USA. [Ferre, Fabrizio] Univ Roma La Sapienza, A Rossi Fanelli Biochem Sci Dept, I-00185 Rome, Italy. RP Zon, LI (reprint author), Harvard Univ, Stem Cell Program & Hematol Oncol, Childrens Hosp Boston,Med Sch, Howard Hughes Med Inst,Harvard Stem Cell Inst, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu RI Young, Richard/F-6495-2012; OI Young, Richard/0000-0001-8855-8647; FERRE', FABRIZIO/0000-0003-2768-5305 FU Damon Runyon Cancer Research Foundation [DRG-1855-05]; Charles A. King Trust Foundation; American Society of Clinical Oncology; Canadian Institutes of Health Research; National Institutes of Health [K99AR056899-02, K08DK075432-04, CA146455, HG002668, CA103846, DK055381] FX We thank D. Harrington, R. White and Y. Zhou for discussions; C. Lawrence, I. Adatto and L.-K. Zhang for expert fish care; G. Frampton for bioinformatics assistance; and K. Kwan, C.-B. Chien, and J. Boehm for reagents. This work was supported by grants from the Damon Runyon Cancer Research Foundation (C.J.C., DRG-1855-05), the Charles A. King Trust Foundation (C.J.C.), a Young Investigator Award from the American Society of Clinical Oncology (Y.H.), the Canadian Institutes of Health Research (S.B.) and the National Institutes of Health (C.J.C., K99AR056899-02; Y.H., K08DK075432-04; R.A.Y., CA146455, HG002668; and L.I.Z., CA103846 and DK055381). NR 23 TC 184 Z9 187 U1 2 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 MAR 24 PY 2011 VL 471 IS 7339 BP 513 EP + DI 10.1038/nature09806 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 739GJ UT WOS:000288702200062 PM 21430779 ER PT J AU White, RM Cech, J Ratanasirintrawoot, S Lin, CY Rahl, PB Burke, CJ Langdon, E Tomlinson, ML Mosher, J Kaufman, C Chen, F Long, HK Kramer, M Datta, S Neuberg, D Granter, S Young, RA Morrison, S Wheeler, GN Zon, LI AF White, Richard Mark Cech, Jennifer Ratanasirintrawoot, Sutheera Lin, Charles Y. Rahl, Peter B. Burke, Christopher J. Langdon, Erin Tomlinson, Matthew L. Mosher, Jack Kaufman, Charles Chen, Frank Long, Hannah K. Kramer, Martin Datta, Sumon Neuberg, Donna Granter, Scott Young, Richard A. Morrison, Sean Wheeler, Grant N. Zon, Leonard I. TI DHODH modulates transcriptional elongation in the neural crest and melanoma SO NATURE LA English DT Article ID CARBAMOYL-PHOSPHATE SYNTHETASE; ZEBRAFISH; LEFLUNOMIDE; EXPRESSION; INHIBITOR; DISCOVERY; KINASE; CELLS; GENE AB Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma(1). We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation. C1 [White, Richard Mark; Cech, Jennifer; Ratanasirintrawoot, Sutheera; Burke, Christopher J.; Langdon, Erin; Kaufman, Charles; Datta, Sumon; Zon, Leonard I.] Harvard Univ, Stem Cell Program & Hematol Oncol, Childrens Hosp Boston,Med Sch, Howard Hughes Med Inst,Harvard Stem Cell Inst, Boston, MA 02115 USA. [White, Richard Mark; Kaufman, Charles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Lin, Charles Y.; Rahl, Peter B.; Young, Richard A.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Lin, Charles Y.; Young, Richard A.] MIT, Dept Biol, Cambridge, MA 02142 USA. [Tomlinson, Matthew L.; Wheeler, Grant N.] Univ E Anglia, Sch Biol Sci, Norwich NR4 7TJ, Norfolk, England. [Mosher, Jack; Morrison, Sean] Univ Michigan, Howard Hughes Med Inst, Ctr Stem Cell Biol, Ann Arbor, MI 48109 USA. [Chen, Frank] Harvard Univ, Cambridge, MA 02138 USA. [Long, Hannah K.] Univ Cambridge, Cambridge CB2 1TN, England. [Kramer, Martin] Genzyme Corp, Cambridge, MA 02142 USA. [Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Granter, Scott] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Zon, LI (reprint author), Harvard Univ, Stem Cell Program & Hematol Oncol, Childrens Hosp Boston,Med Sch, Howard Hughes Med Inst,Harvard Stem Cell Inst, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu RI Wheeler, Grant/D-3023-2009; Young, Richard/F-6495-2012; Long, Hannah/A-6301-2013 OI Young, Richard/0000-0001-8855-8647; FU Howard Hughes Medical Institute; National Cancer Institute (National Institutes of Health); American Society for Clinical Oncology; National Institute of Arthritis and Musculoskeletal and SkinDiseases (National Institutes of Health); Biotechnology and Biological Sciences Research Council/Pfizer FX We thank G. Bollag and P. Lin for supplying PLX4720. The melanoma xenografts were performed with the assistance of T. Venezia-Bowman. In situ hybridization probes for crestin were supplied by P. Henion. We thank S. Lacadie, C. Ceol, Y. Houvras, T. Bowman, X. Bai and R. Field for discussions and/or comments on the manuscript. This work was supported by the Howard Hughes Medical Institute and the National Cancer Institute (National Institutes of Health) (L.I.Z.), Aid for Cancer Research, the American Society for Clinical Oncology and the National Institute of Arthritis and Musculoskeletal and SkinDiseases (National Institutes of Health) (R.M.W.). M.L.T. was a Biotechnology and Biological Sciences Research Council/Pfizer Industrial CASE award recipient. NR 26 TC 154 Z9 157 U1 2 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 MAR 24 PY 2011 VL 471 IS 7339 BP 518 EP 522 DI 10.1038/nature09882 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 739GJ UT WOS:000288702200063 PM 21430780 ER PT J AU Negre, N Brown, CD Ma, LJ Bristow, CA Miller, SW Wagner, U Kheradpour, P Eaton, ML Loriaux, P Sealfon, R Li, ZR Ishii, H Spokony, RF Chen, J Hwang, L Cheng, C Auburn, RP Davis, MB Domanus, M Shah, PK Morrison, CA Zieba, J Suchy, S Senderowicz, L Victorsen, A Bild, NA Grundstad, AJ Hanley, D MacAlpine, DM Mannervik, M Venken, K Bellen, H White, R Gerstein, M Russell, S Grossman, RL Ren, B Posakony, JW Kellis, M White, KP AF Negre, Nicolas Brown, Christopher D. Ma, Lijia Bristow, Christopher Aaron Miller, Steven W. Wagner, Ulrich Kheradpour, Pouya Eaton, Matthew L. Loriaux, Paul Sealfon, Rachel Li, Zirong Ishii, Haruhiko Spokony, Rebecca F. Chen, Jia Hwang, Lindsay Cheng, Chao Auburn, Richard P. Davis, Melissa B. Domanus, Marc Shah, Parantu K. Morrison, Carolyn A. Zieba, Jennifer Suchy, Sarah Senderowicz, Lionel Victorsen, Alec Bild, Nicholas A. Grundstad, A. Jason Hanley, David MacAlpine, David M. Mannervik, Mattias Venken, Koen Bellen, Hugo White, Robert Gerstein, Mark Russell, Steven Grossman, Robert L. Ren, Bing Posakony, James W. Kellis, Manolis White, Kevin P. TI A cis-regulatory map of the Drosophila genome SO NATURE LA English DT Article ID TRANSCRIPTION FACTOR; ENHANCERS; MELANOGASTER; EXPRESSION; BLASTODERM; PROTEINS AB Systematic annotation of gene regulatory elements is a major challenge in genome science. Direct mapping of chromatin modification marks and transcriptional factor binding sites genome-wide(1,2) has successfully identified specific subtypes of regulatory elements(3). In Drosophila several pioneering studies have provided genome-wide identification of Polycomb response elements(4), chromatin states(5), transcription factor binding sites(6-9), RNA polymerase II regulation(8) and insulator elements(10); however, comprehensive annotation of the regulatory genome remains a significant challenge. Here we describe results from the modENCODE cis-regulatory annotation project. We produced a map of the Drosophila melanogaster regulatory genome on the basis of more than 300 chromatin immunoprecipitation data sets for eight chromatin features, five histone deacetylases and thirty-eight site-specific transcription factors at different stages of development. Using these data we inferred more than 20,000 candidate regulatory elements and validated a subset of predictions for promoters, enhancers and insulators in vivo. We identified also nearly 2,000 genomic regions of dense transcription factor binding associated with chromatin activity and accessibility. We discovered hundreds of new transcription factor co-binding relationships and defined a transcription factor network with over 800 potential regulatory relationships. C1 [Negre, Nicolas; Brown, Christopher D.; Ma, Lijia; Spokony, Rebecca F.; Davis, Melissa B.; Domanus, Marc; Morrison, Carolyn A.; Zieba, Jennifer; Suchy, Sarah; Senderowicz, Lionel; Victorsen, Alec; Bild, Nicholas A.; Grundstad, A. Jason; Grossman, Robert L.; White, Kevin P.] Univ Chicago, Inst Genom & Syst Biol, Dept Human Genet, Chicago, IL 60637 USA. [Bristow, Christopher Aaron; Kheradpour, Pouya; Sealfon, Rachel; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Broad Inst MIT & Harvard, Cambridge, MA 02139 USA. [Miller, Steven W.; Ishii, Haruhiko; Posakony, James W.] Univ Calif San Diego, Div Biol Sci CDB, La Jolla, CA 92093 USA. [Wagner, Ulrich; Li, Zirong; Hwang, Lindsay; Ren, Bing] Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Eaton, Matthew L.] Duke Univ, Dept Pharmacol & Canc Biol, Med Ctr, Durham, NC 27710 USA. [Loriaux, Paul] Univ Calif San Diego, Signaling Syst Lab, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Chen, Jia; Hanley, David; Grossman, Robert L.] Univ Illinois, Natl Ctr Data Min, Chicago, IL 60607 USA. [Cheng, Chao; Gerstein, Mark] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA. [Cheng, Chao; Gerstein, Mark] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Cheng, Chao] Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA. [Auburn, Richard P.; Russell, Steven] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Auburn, Richard P.; Russell, Steven] Univ Cambridge, Cambridge Syst Biol Ctr, Cambridge CB2 3EH, England. [Shah, Parantu K.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Mannervik, Mattias] Stockholm Univ, Dept Dev Biol, Wenner Gren Inst, Arrhenius Labs E3, S-10691 Stockholm, Sweden. [Venken, Koen; Bellen, Hugo] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [White, Robert] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3DY, England. [Grossman, Robert L.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Ren, Bing] Inst Genom Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Ren, Bing] Moores Canc Ctr, La Jolla, CA 92093 USA. RP White, KP (reprint author), Univ Chicago, Inst Genom & Syst Biol, Dept Human Genet, 900 E 57th St, Chicago, IL 60637 USA. EM kpwhite@uchicago.edu RI Eaton, Matthew/C-4408-2011; White, Rob/G-4835-2012; Russell, Steve/A-4072-2011; Venken, Koen/B-9909-2013; OI Russell, Steve/0000-0003-0546-3031; Venken, Koen/0000-0003-0741-4698; Mannervik, Mattias/0000-0003-4999-9655; Grossman, Robert/0000-0003-3741-5739; Bellen, Hugo/0000-0001-5992-5989; Negre, Nicolas/0000-0001-9727-3416; Brown, Christopher/0000-0002-3785-5008 FU National Human Genome Research Institute [U01HG004264]; Chicago Biomedical Consortium; Chicago Community Trust; Lilly-Life Sciences Research Foundation; NIH NRSA; Isaac Newton Trust; Department of Energy; NHGRI [U01 HG004279] FX This work was supported by U01HG004264 from the National Human Genome Research Institute to K.P.W. and also funded by the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Human Genome Research Institute (NHGRI) or the National Institutes of Health (NIH). C.D.B. is supported by a Lilly-Life Sciences Research Foundation fellowship. C.A.B. is supported by a NIH NRSA postdoctoral fellowship. R.P.A. is in part supported by an Isaac Newton Trust award to R.W.P.L. was supported by a grant from the Department of Energy Computational Sciences Graduate Fellowship (DOE CSGF). M.E.L. and D.M.M. work was supported by NHGRI grant U01 HG004279. We thank the Functional Genomics Facility at the University of Chicago and the High-Throughput Genome Analysis Core at Argonne National Laboratory for processing of microarrays and of Illumina sequence. We thank T.-R. Li, J.D. Lambert, S. Rifkin, T. Herreman, C. Mason, L. Sun and Z. Gauhar for producing the developmental expression microarray data. We also thank the many members of the Drosophila community who contributed to this work by providing reagents. A complete list of community participants is included in the Supplementary Methods. NR 27 TC 249 Z9 254 U1 1 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 24 PY 2011 VL 471 IS 7339 BP 527 EP 531 DI 10.1038/nature09990 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 739GJ UT WOS:000288702200065 PM 21430782 ER PT J AU Flynn, RL Centore, RC O'Sullivan, RJ Rai, R Tse, A Zhou, SY Chang, S Karlseder, J Zou, L AF Flynn, Rachel Litman Centore, Richard C. O'Sullivan, Roderick J. Rai, Rekha Tse, Alice Zhou Songyang Chang, Sandy Karlseder, Jan Zou, Lee TI TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA SO NATURE LA English DT Article ID REPLICATION PROTEIN-A; REPEAT-CONTAINING RNA; FISSION YEAST; CHROMOSOME ENDS; BINDING PROTEIN; ATR; DAMAGE; POT1; RPA; ELONGATION AB Maintenance of telomeres requires both DNA replication and telomere 'capping' by shelterin. These two processes use two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomeres 1 (POT1). Although RPA and POT1 each have a critical role at telomeres, how they function in concert is not clear. POT1 ablation leads to activation of the ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase at telomeres(1,2), suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. Unexpectedly, we found that purified POT1 and its functional partner TPP1 are unable to prevent RPA binding to telomeric ssDNA efficiently. In cell extracts, we identified a novel activity that specifically displaces RPA, but not POT1, from telomeric ssDNA. Using purified protein, here we show that the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) recapitulates the RPA displacing activity. The RPA displacing activity is inhibited by the telomeric repeat-containing RNA (TERRA) in early S phase, but is then unleashed in late S phase when TERRA levels decline at telomeres(3). Interestingly, TERRA also promotes POT1 binding to telomeric ssDNA by removing hnRNPA1, suggesting that the reaccumulation of TERRA after S phase helps to complete the RPA-to-POT1 switch on telomeric ssDNA. Together, our data suggest that hnRNPA1, TERRA and POT1 act in concert to displace RPA from telomeric ssDNA after DNA replication, and promote telomere capping to preserve genomic integrity. C1 [Flynn, Rachel Litman; Centore, Richard C.; Tse, Alice; Zou, Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA. [Zou, Lee] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [O'Sullivan, Roderick J.; Karlseder, Jan] Salk Inst Biol Studies, Mol & Cellular Lab, La Jolla, CA 92037 USA. [Rai, Rekha; Chang, Sandy] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. [Zhou Songyang] Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA. RP Zou, L (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA. EM zou.lee@mgh.harvard.edu RI rai, rekha/A-3680-2012 FU National Institutes of Health (NIH) [5T32CA009216-28, F32-GM089150, CA133249, CA129037, GM06525, AG025837, GM076388]; American Cancer Society [0902501]; George E. Hewitt Foundation for Medical Research; Welch Foundation [Q-1673]; ACS [RSG-08-297] FX We thank T. de Lange, A. Krainer, B. Chabot and M. Wold for reagents, and members of the Zou laboratory for discussion. L.Z. is an Ellison New Scholar on Aging. R.L.F. is supported by National Institutes of Health (NIH) fellowship 5T32CA009216-28 and American Cancer Society fellowship 0902501. R.C.C. is supported by NIH fellowship F32-GM089150. R.J.O. is supported by the George E. Hewitt Foundation for Medical Research. This work is supported by a Welch Foundation grant (Q-1673) to Z.S., an ACS grant (RSG-08-297) to L.Z., and NIH grants CA133249 to Z.S., CA129037 to S.C., GM06525 and AG025837 to J.K. and GM076388 to L.Z. NR 30 TC 126 Z9 131 U1 2 U2 23 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 24 PY 2011 VL 471 IS 7339 BP 532 EP + DI 10.1038/nature09772 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 739GJ UT WOS:000288702200066 PM 21399625 ER PT J AU Chabner, BA AF Chabner, Bruce A. TI Early Accelerated Approval for Highly Targeted Cancer Drugs SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CELL LUNG-CANCER; INHIBITION C1 Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Chabner, BA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 7 TC 46 Z9 47 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 24 PY 2011 VL 364 IS 12 BP 1087 EP 1089 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 739FY UT WOS:000288701100002 PM 21428763 ER PT J AU McCormack, M Alfirevic, A Bourgeois, S Farrell, JJ Kasperaviciute, D Carrington, M Sills, GJ Marson, T Jia, XM de Bakker, PIW Chinthapalli, K Molokhia, M Johnson, MR O'Connor, GD Chaila, E Alhusaini, S Shianna, KV Radtke, RA Heinzen, EL Walley, N Pandolfo, M Pichler, W Park, BK Depondt, C Sisodiya, SM Goldstein, DB Deloukas, P Delanty, N Cavalleri, GL Pirmohamed, M AF McCormack, Mark Alfirevic, Ana Bourgeois, Stephane Farrell, John J. Kasperaviciute, Dalia Carrington, Mary Sills, Graeme J. Marson, Tony Jia, Xiaoming de Bakker, Paul I. W. Chinthapalli, Krishna Molokhia, Mariam Johnson, Michael R. O'Connor, Gerard D. Chaila, Elijah Alhusaini, Saud Shianna, Kevin V. Radtke, Rodney A. Heinzen, Erin L. Walley, Nicole Pandolfo, Massimo Pichler, Werner Park, B. Kevin Depondt, Chantal Sisodiya, Sanjay M. Goldstein, David B. Deloukas, Panos Delanty, Norman Cavalleri, Gianpiero L. Pirmohamed, Munir TI HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STEVENS-JOHNSON-SYNDROME; TOXIC EPIDERMAL NECROLYSIS; ADVERSE DRUG-REACTIONS; HUMAN-LEUKOCYTE ANTIGEN-B-ASTERISK-5701; GENERALIZED EXANTHEMATOUS PUSTULOSIS; INDUCED LIVER-INJURY; HLA-B; ABACAVIR HYPERSENSITIVITY; COST-EFFECTIVENESS; DRESS SYNDROME AB BACKGROUND Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P = 3.5x10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLAA*3101 allele (P = 1.1x10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS The presence of the HLA-A* 3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. C1 [Alfirevic, Ana] Univ Liverpool, Wolfson Ctr Personalised Med, Dept Mol & Clin Pharmacol, Inst Translat Med, Liverpool L69 3GL, Merseyside, England. [McCormack, Mark; Alhusaini, Saud; Delanty, Norman; Cavalleri, Gianpiero L.] Royal Coll Surgeons Ireland, Dublin 2, Ireland. [O'Connor, Gerard D.; Chaila, Elijah; Delanty, Norman] Beaumont Hosp, Div Neurol, Dublin 9, Ireland. [Marson, Tony] Walton Ctr Neurol, Liverpool, Merseyside, England. [Bourgeois, Stephane; Deloukas, Panos] Wellcome Trust Sanger Inst, Hinxton, England. [Chinthapalli, Krishna; Sisodiya, Sanjay M.] Natl Soc Epilepsy, Gerrards Cross, Bucks, England. [Farrell, John J.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Carrington, Mary] Harvard Univ, Massachusetts Gen Hosp, MIT, Sch Med,Ragon Inst, Boston, MA USA. [Jia, Xiaoming] Harvard Univ, Sch Med, Harvard MIT Div Hlth Sci & Technol, Boston, MA 02115 USA. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Div Genet, Dept Med,Med Sch, Boston, MA 02115 USA. [Kasperaviciute, Dalia; Chinthapalli, Krishna; Sisodiya, Sanjay M.] UCL, Dept Clin & Expt Epilepsy, Inst Neurol, London, England. [Molokhia, Mariam] Kings Coll London, Dept Primary Care & Publ Hlth Sci, Div Hlth & Social Care Res, London WC2R 2LS, England. [Johnson, Michael R.] Univ London Imperial Coll Sci Technol & Med, Dept Med, Ctr Neurosci, London, England. [Carrington, Mary] NCI, Canc & Inflammat Program, Lab Expt Immunol, SAIC Frederick, Frederick, MD 21701 USA. [de Bakker, Paul I. W.] Harvard & MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [de Bakker, Paul I. W.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [de Bakker, Paul I. W.] Univ Med Ctr, Dept Med Genet, Div Biomed Genet, Utrecht, Netherlands. [Shianna, Kevin V.; Heinzen, Erin L.; Walley, Nicole; Goldstein, David B.] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC USA. [Radtke, Rodney A.] Duke Univ, Sch Med, Dept Med Neurol, Durham, NC USA. [Pandolfo, Massimo; Depondt, Chantal] Univ Libre Bruxelles, Dept Neurol, Hop Erasme, Brussels, Belgium. [Pichler, Werner] Univ Bern, Dept Rheumatol Clin Immunol & Allergol, Bern, Switzerland. RP Alfirevic, A (reprint author), Univ Liverpool, Wolfson Ctr Personalised Med, Dept Mol & Clin Pharmacol, Inst Translat Med, Block A,Waterhouse Bldgs,1-5 Brownlow St, Liverpool L69 3GL, Merseyside, England. EM ana.alfirevic@liv.ac.uk RI Cavalleri, Gianpiero/A-6632-2010; Pirmohamed, Munir/H-6004-2011; Deloukas, Panos/B-2922-2013; de Bakker, Paul/B-8730-2009; McCormack, Mark/A-5482-2010; OI Pirmohamed, Munir/0000-0002-7534-7266; Deloukas, Panos/0000-0001-9251-070X; de Bakker, Paul/0000-0001-7735-7858; McCormack, Mark/0000-0002-8213-6141; Delaney, Norman/0000-0002-3953-9842; Cavalleri, Gianpiero/0000-0002-9802-0506 FU U.K. Department of Health; Department of Health; National Health Service Chair of Pharmacogenetics; Medical Research Council Centre for Drug Safety Science; Wolfson Foundation; Wellcome Trust Sanger Institute; National Institute for Health Research; Medical Research Council [G0400126]; Wellcome Trust [084730]; University College London Hospitals Charity; Clinical Research and Development Committee [F136]; National Institute for Health Research [08-08-SCC]; Brainwave-the Irish Epilepsy Association [2009/001]; Medical Research Charities Group of Ireland; Health Research Board; National Society for Epilepsy; Fonds National de la Recherche Scientifique; Fonds Erasme pour la Recherche Medicale; Universite Libre de Bruxelles (Belgium); Health Research Board of Ireland; Department of Health National Institute for Health Research Biomedical Research Centres; National Cancer Institute [HHS-N261200800001E]; National Cancer Institute, National Institutes of Health FX Funded by the U.K. Department of Health and others.; Supported by grants to the Liverpool collaborators from the Department of Health, the National Health Service Chair of Pharmacogenetics, the Medical Research Council Centre for Drug Safety Science, the Wolfson Foundation, the Wellcome Trust Sanger Institute, and the National Institute for Health Research (to Dr. Pirmohamed); by grants to the EPIGEN consortium from the Medical Research Council (G0400126), the Wellcome Trust (084730), University College London Hospitals Charity, Clinical Research and Development Committee (F136), and the National Institute for Health Research (08-08-SCC); by an award (2009/001) from Brainwave-the Irish Epilepsy Association; by the Medical Research Charities Group of Ireland, the Health Research Board, the National Society for Epilepsy, Fonds National de la Recherche Scientifique, and Fonds Erasme pour la Recherche Medicale, Universite Libre de Bruxelles (Belgium); by a Translational Research Scholars award from the Health Research Board of Ireland (to Mr. McCormack); by the Department of Health National Institute for Health Research Biomedical Research Centres; and by a contract from the National Cancer Institute (HHS-N261200800001E) and the Intramural Research Program at the National Cancer Institute, National Institutes of Health. NR 40 TC 327 Z9 344 U1 6 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 MAR 24 PY 2011 VL 364 IS 12 BP 1134 EP 1143 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 739FY UT WOS:000288701100008 PM 21428769 ER PT J AU Murali, MR Castells, MC Song, JY Dudzinski, DM Hasserjian, RP AF Murali, Mandakolathur R. Castells, Mariana C. Song, James Y. Dudzinski, David M. Hasserjian, Robert P. TI A Man with Flushing and Hypotension Indolent systemic mastocytosis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID KOUNIS-SYNDROME; SM-AHNMD; TRYPTASE; ANAPHYLAXIS; DISEASE C1 [Murali, Mandakolathur R.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Dudzinski, David M.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Song, James Y.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Hasserjian, Robert P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Castells, Mariana C.] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Murali, Mandakolathur R.; Castells, Mariana C.; Dudzinski, David M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Song, James Y.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Hasserjian, Robert P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Murali, MR (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. NR 26 TC 4 Z9 4 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 24 PY 2011 VL 364 IS 12 BP 1155 EP 1165 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 739FY UT WOS:000288701100012 PM 21428772 ER PT J AU Sequist, LV Waltman, BA Dias-Santagata, D Digumarthy, S Turke, AB Fidias, P Bergethon, K Shaw, AT Gettinger, S Cosper, AK Akhavanfard, S Heist, RS Temel, J Christensen, JG Wain, JC Lynch, TJ Vernovsky, K Mark, EJ Lanuti, M Iafrate, AJ Mino-Kenudson, M Engelman, JA AF Sequist, Lecia V. Waltman, Belinda A. Dias-Santagata, Dora Digumarthy, Subba Turke, Alexa B. Fidias, Panos Bergethon, Kristin Shaw, Alice T. Gettinger, Scott Cosper, Arjola K. Akhavanfard, Sara Heist, Rebecca S. Temel, Jennifer Christensen, James G. Wain, John C. Lynch, Thomas J. Vernovsky, Kathy Mark, Eugene J. Lanuti, Michael Iafrate, A. John Mino-Kenudson, Mari Engelman, Jeffrey A. TI Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID GROWTH-FACTOR-RECEPTOR; TYROSINE KINASE INHIBITORS; NONSMALL CELL; MESENCHYMAL TRANSITION; GEFITINIB RESISTANCE; MET AMPLIFICATION; NEUROENDOCRINE TUMORS; ACTIVATING MUTATIONS; T790M MUTATIONS; GENE MUTATION AB Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors, but drug resistance invariably emerges. To elucidate mechanisms of acquired drug resistance, we performed systematic genetic and histological analyses of tumor biopsies from 37 patients with drug-resistant non-small cell lung cancers (NSCLCs) carrying EGFR mutations. All drug-resistant tumors retained their original activating EGFR mutations, and some acquired known mechanisms of resistance including the EGFR T790M mutation or MET gene amplification. Some resistant cancers showed unexpected genetic changes including EGFR amplification and mutations in the PIK3CA gene, whereas others underwent a pronounced epithelial-to-mesenchymal transition. Surprisingly, five resistant tumors (14%) transformed from NSCLC into small cell lung cancer (SCLC) and were sensitive to standard SCLC treatments. In three patients, serial biopsies revealed that genetic mechanisms of resistance were lost in the absence of the continued selective pressure of EGFR inhibitor treatment, and such cancers were sensitive to a second round of treatment with EGFR inhibitors. Collectively, these results deepen our understanding of resistance to EGFR inhibitors and underscore the importance of repeatedly assessing cancers throughout the course of the disease. C1 [Sequist, Lecia V.; Turke, Alexa B.; Fidias, Panos; Shaw, Alice T.; Cosper, Arjola K.; Heist, Rebecca S.; Temel, Jennifer; Wain, John C.; Vernovsky, Kathy; Lanuti, Michael; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Sequist, Lecia V.; Waltman, Belinda A.; Dias-Santagata, Dora; Digumarthy, Subba; Turke, Alexa B.; Fidias, Panos; Shaw, Alice T.; Akhavanfard, Sara; Heist, Rebecca S.; Temel, Jennifer; Wain, John C.; Mark, Eugene J.; Lanuti, Michael; Iafrate, A. John; Mino-Kenudson, Mari; Engelman, Jeffrey A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Dias-Santagata, Dora; Bergethon, Kristin; Akhavanfard, Sara; Mark, Eugene J.; Iafrate, A. John; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Digumarthy, Subba] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Gettinger, Scott; Lynch, Thomas J.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Gettinger, Scott; Lynch, Thomas J.] Yale Canc Ctr, New Haven, CT 06520 USA. [Christensen, James G.] Pfizer Oncol, Translat Pharmacol, La Jolla, CA 92121 USA. [Wain, John C.; Lanuti, Michael] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Sequist, LV (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM lvsequist@partners.org; jengelman@partners.org FU Uniting Against Lung Cancer; UALC: New England; Marjorie E. Korff Fund; NIH [P50 CA127003, CA120060-01, R01CA137008-01, R01CA140594, 1U01CA141457-01]; National Cancer Institute [P50CA090578]; Dana-Farber/Harvard Cancer Center; American Association for Cancer Research; V Foundation; American Cancer Society [RSG-06-102-01-CCE]; Ellison Foundation; Doris Duke Charitable Foundation; Daniel Crane Foundation FX This study is supported by grants from Uniting Against Lung Cancer, sponsored by UALC: New England and the Marjorie E. Korff Fund (L. V. S.), the NIH Gastrointestinal Cancer SPORE P50 CA127003 (J.A.E. and M.M.-K.), K08 grant CA120060-01 (J.A.E.), R01CA137008-01 (J.A.E.), R01CA140594 (J.A.E.), 1U01CA141457-01 (J.A.E.), National Cancer Institute Lung SPORE P50CA090578 (J.A.E.), Dana-Farber/Harvard Cancer Center, the American Association for Cancer Research (J.A.E.), the V Foundation (J.A.E.), American Cancer Society RSG-06-102-01-CCE (J.A.E.), the Ellison Foundation Scholar (J.A.E.), and the Doris Duke Charitable Foundation (B. A. W.). This work was supported by a gift from the Daniel Crane Foundation. NR 64 TC 832 Z9 875 U1 18 U2 80 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 MAR 23 PY 2011 VL 3 IS 75 AR 75ra26 DI 10.1126/scitranslmed.3002003 PG 12 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 795LD UT WOS:000292974800004 PM 21430269 ER PT J AU Jackevicius, CA Tu, JV Ross, JS Ko, DT Carreon, D Krumholz, HM AF Jackevicius, Cynthia A. Tu, Jack V. Ross, Joseph S. Ko, Dennis T. Carreon, Daniel Krumholz, Harlan M. TI Use of Fibrates in the United States and Canada SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID TYPE-2 DIABETES-MELLITUS; CORONARY-HEART-DISEASE; TREATMENT PANEL-III; RHABDOMYOLYSIS; GEMFIBROZIL; CHOLESTEROL; TRIAL; PREVENTION; THERAPY; EVENTS AB Context Interest in the role of fibrates intensified after the publication of the negative results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which assessed therapy with fenofibrate plus statins. The evidence for clinical benefit in outcomes with the use of fibrates is heavily weighted on the use of the older fibrates such as gemfibrozil and clofibrate. Objectives To examine trends in the current use of fibrates and to examine the relationship between differences in the availability and use of brand-name vs generic formulations of fenofibrate and the economic implications in the United States compared with Canada. Design, Setting, and Patients Population-level, observational cohort study using IMS Health data from the United States and Canada of patients prescribed fibrates between January 2002 and December 2009. Main Outcome Measures Fibrate prescriptions dispensed and expenditures. Results In the United States, fibrate prescriptions dispensed increased from 336 prescriptions/100 000 population in January 2002 to 730 prescriptions/100 000 population in December 2009, an increase of 117.1% (95% confidence interval [CI], 116.0%-117.9%), whereas in Canada, fibrate prescriptions increased from 402 prescriptions/100 000 population in January 2002 to 474 prescriptions/100 000 population in December 2009, an increase of 18.1% (95% CI, 17.9%-18.3%) (P<.001). In the United States, fenofibrate prescriptions dispensed increased from 150 prescriptions/100 000 population in January 2002 to 440 prescriptions/100 000 population in December 2009, an increase of 159.3% (95% CI, 157.7%-161.0%), comprising 47.9% of total fibrate prescriptions in 2002 and 65.2% in 2009. In Canada, fenofibrate prescriptions increased from 321 prescriptions/100 000 population in January 2002 to 429 prescriptions/100 000 population in December 2009. The annual ratio of generic to brand-name fenofibrate use in the United States ranged from 0:1 to 0.09:1 between 2002 and 2008, while the ratio in Canada steadily increased from 0.51:1 to 1.89:1 between 2005 and 2008. In the United States, crude fenofibrate expenditures increased from $11 535/100 000 population/month in 2002 to $44 975/100 000 population/month in 2009, while the rates in Canada declined from $17 695/100 000 population/month in 2002 to $16 112/100 000 population/month in 2009. Fibrate expenditures per 100 000 population were 3-fold higher in 2009 in the United States compared with Canada. Conclusion During the past decade, prescriptions for fibrates (particularly fenofibrate) increased in the United States, while prescriptions for fibrates in Canada remained stable. JAMA. 2011; 305(12): 1217-1224 C1 [Jackevicius, Cynthia A.; Carreon, Daniel] Western Univ Hlth Sci, Coll Pharm, Dept Pharm Practice & Adm, Pomona, CA 91766 USA. [Jackevicius, Cynthia A.; Tu, Jack V.; Ko, Dennis T.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Jackevicius, Cynthia A.; Tu, Jack V.] Univ Toronto, Fac Med, Dept Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Tu, Jack V.; Ko, Dennis T.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Schulich Heart Ctr, Div Cardiol, 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. [Ross, Joseph S.] Yale Univ, Sch Med, Dept Med,Sect Gen Internal Med, Ctr Outcomes Res & Evaluat,Yale New Haven Hosp, New Haven, CT 06510 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth,Sect Hlth Policy & Adm, Ctr Outcomes Res & Evaluat,Yale New Haven Hosp, New Haven, CT 06510 USA. [Ross, Joseph S.; Krumholz, Harlan M.] Yale Univ, Sch Med, Sect Cardiovasc Med, Ctr Outcomes Res & Evaluat,Yale New Haven Hosp, New Haven, CT USA. [Krumholz, Harlan M.] Robert Wood Johnson Clin Scholars Program, New Haven, CT USA. RP Jackevicius, CA (reprint author), Western Univ Hlth Sci, Coll Pharm, Dept Pharm Practice & Adm, 309 E 2nd St, Pomona, CA 91766 USA. EM cjackevicius@westernu.edu OI Ko, Dennis/0000-0001-6840-8051; Tu, Jack/0000-0003-0111-722X FU College of Pharmacy of Western University of Health Sciences, Pomona, California; Canadian Institutes of Health Research; Canada Research Chair in Health Services Research; Heart and Stroke Foundation of Ontario, Toronto; National Institute on Aging [K08 AG032886]; American Federation of Aging Research; National Heart, Lung, and Blood Institute [U01-HL105270]; Ontario Ministry of Health and Long-Term Care, Toronto FX This study was funded in part by the College of Pharmacy of Western University of Health Sciences, Pomona, California, and in part by a Canadian Institutes of Health Research team grant in cardiovascular outcomes research awarded to the Canadian Cardiovascular Outcomes Research Team. Dr Tu is supported by a Canada Research Chair in Health Services Research and by a Career Investigator award of the Heart and Stroke Foundation of Ontario, Toronto. Dr Ross is currently supported by the National Institute on Aging grant K08 AG032886 and by the American Federation of Aging Research through the Paul B. Beeson Career Development Award Program. Dr Ko is supported by a new investigator award from the Canadian Institutes of Health Research. Dr Krumholz is supported by grant U01-HL105270 (awarded to the Center for Cardiovascular Outcomes Research at Yale University) from the National Heart, Lung, and Blood Institute. The Institute for Clinical Evaluative Sciences is supported by an operating grant from the Ontario Ministry of Health and Long-Term Care, Toronto. NR 35 TC 46 Z9 46 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 23 PY 2011 VL 305 IS 12 BP 1217 EP 1224 DI 10.1001/jama.2011.353 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 738PA UT WOS:000288652100017 PM 21427374 ER PT J AU Resnik, DB Koski, G AF Resnik, David B. Koski, Greg TI A National Registry for Healthy Volunteers in Phase 1 Clinical Trials SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Resnik, David B.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Koski, Greg] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Mongan Inst Hlth Policy, Boston, MA USA. [Koski, Greg] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. RP Resnik, DB (reprint author), NIEHS, NIH, POB 12233,Mail Drop CU03, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-01, ZIA ES102646-02] NR 9 TC 17 Z9 17 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 23 PY 2011 VL 305 IS 12 BP 1236 EP 1237 DI 10.1001/jama.2011.354 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 738PA UT WOS:000288652100020 PM 21406636 ER PT J AU Duncan, DT Wolin, KY Scharoun-Lee, M Ding, EL Warner, ET Bennett, GG AF Duncan, Dustin T. Wolin, Kathleen Y. Scharoun-Lee, Melissa Ding, Eric L. Warner, Erica T. Bennett, Gary G. TI Does perception equal reality? Weight misperception in relation to weight-related attitudes and behaviors among overweight and obese US adults SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article ID PREVALENCE ODDS RATIO; BODY-MASS INDEX; SELF-PERCEPTION; PHYSICAL-ACTIVITY; UNITED-STATES; LOSE WEIGHT; UNIVERSITY-STUDENTS; GENDER-DIFFERENCES; RACIAL-DIFFERENCES; IDEAL WEIGHT AB Background: Weight misperception might preclude the adoption of healthful weight-related attitudes and behaviors among overweight and obese individuals, yet limited research exists in this area. We examined associations between weight misperception and several weight-related attitudes and behaviors among a nationally representative sample of overweight and obese US adults. Methods: Data from the 2003-2006 National Health and Nutrition Examination Survey (NHANES) were used. Analyses included non-pregnant, overweight and obese (measured body mass index >= 25) adults aged 20 and older. Weight misperception was identified among those who reported themselves as "underweight" or "about the right weight". Outcome variables and sample sizes were: weight-loss attitudes/behaviors (wanting to weigh less and having tried to lose weight; n = 4,784); dietary intake (total energy intake; n = 4,894); and physical activity (meets 2008 US physical activity recommendations, insufficiently active, and sedentary; n = 5,401). Multivariable regression models were stratified by gender and race/ethnicity. Analyses were conducted in 2009-2010. Results: These overweight/obese men and women who misperceived their weight were 71% (RR 0.29, 95% CI 0.25-0.34) and 65% (RR 0.35, 95% CI 0.29-0.42) less likely to report that they want to lose weight and 60% (RR 0.40, 95% CI 0.30-0.52) and 56% (RR 0.44, 95% CI 0.32-0.59) less likely to have tried to lose weight within the past year, respectively, compared to those who accurately perceived themselves as overweight. Blacks were particularly less likely to have tried to lose weight. Weight misperception was not a significant predictor of total energy intake among most subgroups, but was associated with lower total energy intake among Hispanic women (change -252.72, 95% CI -433.25, -72.18). Men who misperceived their weight were less likely (RR 0.68, 95% CI 0.52-0.89) to be insufficiently active (the strongest results were among Black men) and women who misperceived their weight were less likely (RR 0.74, 95% CI 0.54, 1.00, p = 0.047) to meet activity recommendations compared to being sedentary. Conclusion: Overall, weight misperception among overweight and obese adults was associated with less likelihood of interest in or attempts at weight loss and less physical activity. These associations varied by gender and race/ethnicity. This study highlights the importance of focusing on inaccurate weight perceptions in targeted weight loss efforts. C1 [Duncan, Dustin T.; Bennett, Gary G.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Duncan, Dustin T.] Harvard Univ, Sch Publ Hlth, Harvard Prevent Res Ctr Nutr & Phys Act, Boston, MA 02115 USA. [Wolin, Kathleen Y.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Wolin, Kathleen Y.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. [Scharoun-Lee, Melissa; Bennett, Gary G.] Duke Univ, Duke Global Hlth Inst, Durham, NC USA. [Ding, Eric L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Ding, Eric L.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ding, Eric L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Warner, Erica T.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Warner, Erica T.; Bennett, Gary G.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Bennett, Gary G.] Duke Univ, Dept Psychol & Neurosci, Durham, NC USA. RP Bennett, GG (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM gary.bennett@duke.edu RI Wolin, Kathleen/I-2154-2014 OI Ding, Eric/0000-0002-5881-8097; Wolin, Kathleen/0000-0001-7950-9042 FU Association of Schools of Public Health/Centers for Disease Control and Prevention/Prevention Research Center Minority Health; National Cancer Institute [CA091842, 5K22CA126992-04]; American Diabetes Association; National Institute of Diabetes and Digestive and Kidney Diseases [5R01DK078798-03] FX DTD was supported in part by an Association of Schools of Public Health/Centers for Disease Control and Prevention/Prevention Research Center Minority Health Fellowship. KYW was supported in part by grant CA091842 from the National Cancer Institute. ELD was supported in part by an American Diabetes Association Postoctoral Fellowship. GGB was supported by grants 5K22CA126992-04 from the National Cancer Institute and 5R01DK078798-03 from the National Institute of Diabetes and Digestive and Kidney Diseases. We are especially gratefully to two anonymous reviewers who offered very helpful comments. NR 75 TC 79 Z9 79 U1 6 U2 18 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD MAR 22 PY 2011 VL 8 AR 20 DI 10.1186/1479-5868-8-20 PG 9 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 747XU UT WOS:000289355400001 PM 21426567 ER PT J AU Singh, JP Klein, HU Huang, DT Reek, S Kuniss, M Quesada, A Barsheshet, A Cannom, D Goldenberg, I McNitt, S Daubert, JP Zareba, W Moss, AJ AF Singh, Jagmeet P. Klein, Helmut U. Huang, David T. Reek, Sven Kuniss, Malte Quesada, Aurelio Barsheshet, Alon Cannom, David Goldenberg, Ilan McNitt, Scott Daubert, James P. Zareba, Wojciech Moss, Arthur J. TI Left Ventricular Lead Position and Clinical Outcome in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) Trial SO CIRCULATION LA English DT Article DE biventricular pacing; cardiac resynchronization therapy; congestive heart failure; heart failure; resynchronization ID HEART-FAILURE PATIENTS; BUNDLE-BRANCH BLOCK; DELAY; SITE; HEMODYNAMICS; ACTIVATION; CONDUCTION AB Background-An important determinant of successful cardiac resynchronization therapy for heart failure is the position of the left ventricular (LV) pacing lead. The aim of this study was to analyze the impact of the LV lead position on outcome in patients randomized to cardiac resynchronization-defibrillation in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) study. Methods and Results--The location of the LV lead was assessed by means of coronary venograms and chest x-rays recorded at the time of device implantation. The LV lead location was classified along the short axis into an anterior, lateral, or posterior position and along the long axis into a basal, midventricular, or apical region. The primary end point of MADIT-CRT was heart failure (HF) hospitalization or death, whichever came first. The LV lead position was assessed in 799 patients, (55% patients >= 65 years of age, 26% female, 10% LV ejection fraction <= 25%, 55% ischemic cardiomyopathy, and 71% left bundle-branch block) with a follow-up of 29 +/- 11 months. The extent of cardiac resynchronization therapy benefit was similar for leads in the anterior, lateral, or posterior position (P=0.652). The apical lead location compared with leads located in the nonapical position (basal or midventricular region) was associated with a significantly increased risk for heart failure/death (hazard ratio=1.72; 95% confidence interval, 1.09 to 2.71; P=0.019) after adjustment for the clinical covariates. The apical lead position was also associated with an increased risk for death (hazard ratio=2.91; 95% confidence interval, 1.42 to 5.97; P=0.004). Conclusion-LV leads positioned in the apical region were associated with an unfavorable outcome, suggesting that this lead location should be avoided in cardiac resynchronization therapy. C1 [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv,Heart Ctr, Boston, MA 02114 USA. [Klein, Helmut U.; Huang, David T.; Barsheshet, Alon; McNitt, Scott; Zareba, Wojciech; Moss, Arthur J.] Univ Rochester, Med Ctr, Dept Med, Cardiol Unit, Rochester, NY 14627 USA. [Kuniss, Malte] Max Planck Inst Physiol & Clin Res, Kerckhoff Klin, D-6350 Bad Nauheim, Germany. [Reek, Sven] Univ Hosp, Magdeburg, Germany. [Quesada, Aurelio] Hosp Gen Valencia, Valencia, Spain. [Cannom, David] Good Samaritan Hosp, Los Angeles, CA USA. [Daubert, James P.] Duke Univ, Durham, NC USA. RP Singh, JP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Arrhythmia Serv,Heart Ctr, GRB 109,55 Fruit St, Boston, MA 02114 USA. EM jsingh@partners.org FU Boston Scientific; University of Rochester; St. Jude Medical; Medtronic Inc.; Boston Scientific Corp; Biotronik; Guidant Corp; Sorin Group; Medtronic; CV Therapeutics; Biosense Webster; St. Jude FX This study was supported by a research grant from Boston Scientific to the University of Rochester, with funds distributed to the coordination and data center, enrolling centers, core laboratories, committees, and boards under subcontracts from the University of Rochester. Dr Singh reports receiving research grants from St. Jude Medical, Medtronic Inc., Boston Scientific Corp, and Biotronik; serving on advisory boards or as a consultant for Boston Scientific Corp, Medtronic Inc., Sorin Group, and St. Jude Medical; and receiving lecture fees from Medtronic Inc., Biotronik, Guidant Corp, St. Jude Medical, and Sorin Group. Dr Klein has received grant support and lecture fees from Boston Scientific. Dr Huang has received research grants and lecture fees from Boston Scientific. Dr Reek reports receiving consulting fees from St. Jude Medical. Dr Kuniss has received lecture fees from Boston Scientific. Dr Quesada has received consulting fees from Medtronic and Boston Scientific. Dr Cannom reports receiving consulting and lecture fees from Medtronic and lecture fees from Boston Scientific. Dr Goldenberg has received research grants from Boston Scientific. Dr Daubert has received lecture fees from Boston Scientific; consulting fees from Medtronic, CV Therapeutics, and Biosense Webster; and institutional fellowship support from Boston Scientific, Medtronic, St. Jude, Biosense Webster, and Biotronik. Dr Zareba has received lecture fees from Boston Scientific and grant support from Medtronic. Dr Moss reports receiving grant support from Boston Scientific and lecture fees from Boston Scientific, Medtronic, and St. Jude Medical. The other authors report no conflicts. NR 25 TC 209 Z9 224 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 22 PY 2011 VL 123 IS 11 BP 1159 EP 1166 DI 10.1161/CIRCULATIONAHA.110.000646 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 741GM UT WOS:000288852200009 PM 21382893 ER PT J AU Lau, KS Juchheim, AM Cavaliere, KR Philips, SR Lauffenburger, DA Haigis, KM AF Lau, Ken S. Juchheim, Alwin M. Cavaliere, Kimberly R. Philips, Sarah R. Lauffenburger, Douglas A. Haigis, Kevin M. TI In Vivo Systems Analysis Identifies Spatial and Temporal Aspects of the Modulation of TNF-alpha-Induced Apoptosis and Proliferation by MAPKs SO SCIENCE SIGNALING LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; KINASE INHIBITORS; EPITHELIAL-CELLS; ACTIVATE ERK; CROSS-TALK; RECEPTORS; INDUCTION; COLITIS; SIGNALS AB Cellular responses to external stimuli depend on dynamic features of multipathway network signaling; thus, cell behavior is influenced in a complex manner by the environment and by intrinsic properties. Methods of multivariate systems analysis have provided an understanding of these convoluted effects, but only for relatively simplified examples in vitro. To determine whether such approaches could be successfully used in vivo, we analyzed the signaling network that determines the response of intestinal epithelial cells to tumor necrosis factor-alpha (TNF-alpha). We built data-driven, partial least-squares discriminant analysis (PLSDA) models based on signaling, apoptotic, and proliferative responses in the mouse small intestinal epithelium after systemic exposure to TNF-alpha. The extracellular signal-regulated kinase (ERK) signaling axis was a critical modulator of the temporal variation in apoptosis at different doses of TNF-alpha and of the spatial variation in proliferation in distinct intestinal regions. Inhibition of MEK, a mitogen-activated protein kinase kinase upstream of ERK, altered the signaling network and changed the temporal and spatial phenotypes consistent with model predictions. Our results demonstrate the dynamic, adaptive nature of in vivo signaling networks and identify natural, tissue-level variation in responses that can be deconvoluted only with quantitative, multivariate computational modeling. This study lays a foundation for the use of systems-based approaches to understand how dysregulation of the cellular network state underlies complex diseases. C1 [Lau, Ken S.; Juchheim, Alwin M.; Cavaliere, Kimberly R.; Philips, Sarah R.; Haigis, Kevin M.] Massachusetts Gen Hosp, Ctr Canc Res, Mol Pathol Unit, Charlestown, MA 02129 USA. [Lau, Ken S.; Juchheim, Alwin M.; Cavaliere, Kimberly R.; Philips, Sarah R.; Haigis, Kevin M.] Massachusetts Gen Hosp, Ctr Syst Biol, Charlestown, MA 02129 USA. [Lau, Ken S.; Juchheim, Alwin M.; Haigis, Kevin M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Lau, Ken S.; Lauffenburger, Douglas A.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Lau, Ken S.; Lauffenburger, Douglas A.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. RP Haigis, KM (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Mol Pathol Unit, Charlestown, MA 02129 USA. EM khaigis@partners.org OI Lau, Ken/0000-0001-8438-0319 FU National Institute of General Medical Sciences [R01-GM088827]; National Cancer Institute [U54-CA112967] FX We thank J. Pritchard, L. Kleiman, D. Clarke, and B. Cosgrove for comments on the manuscript. Funding: This work was supported by grants from the National Institute of General Medical Sciences (R01-GM088827 to K. M. H. and D. A. L.) and the National Cancer Institute (U54-CA112967 to D. A. L.). K. S. L. is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation. Author contributions: K. S. L., D. A. L., and K. M. H. designed the experiments; K. S. L., A. M. J., K. R. C., and S. R. P. conducted the experiments; K. S. L. performed computational analyses; K. S. L., D. A. L., and K. M. H. wrote the manuscript; all of the authors discussed the results and edited the manuscript; and K. M. H. coordinated all aspects of the project. Competing interests: The authors declare that they have no competing financial interests. NR 36 TC 46 Z9 46 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 22 PY 2011 VL 4 IS 165 AR ra16 DI 10.1126/scisignal.2001338 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 738OR UT WOS:000288651000002 PM 21427409 ER PT J AU Albers, J Schulze, J Beil, FT Gebauer, M Baranowsky, A Keller, J Marshall, RP Wintges, K Friedrich, FW Priemel, M Schilling, AF Rueger, JM Cornils, K Fehse, B Streichert, T Sauter, G Jakob, F Insogna, KL Pober, B Knobeloch, KP Francke, U Amling, M Schinke, T AF Albers, Joachim Schulze, Jochen Beil, F. Timo Gebauer, Matthias Baranowsky, Anke Keller, Johannes Marshall, Robert P. Wintges, Kristofer Friedrich, Felix W. Priemel, Matthias Schilling, Arndt F. Rueger, Johannes M. Cornils, Kerstin Fehse, Boris Streichert, Thomas Sauter, Guido Jakob, Franz Insogna, Karl L. Pober, Barbara Knobeloch, Klaus-Peter Francke, Uta Amling, Michael Schinke, Thorsten TI Control of bone formation by the serpentine receptor Frizzled-9 SO JOURNAL OF CELL BIOLOGY LA English DT Article ID WILLIAMS-SYNDROME DELETION; PROTEIN-COUPLED RECEPTORS; NEGATIVE REGULATOR; ISG15 MODIFICATION; SIGNALING PATHWAY; OSTEOBLAST DIFFERENTIATION; BETA-CATENIN; MICE; GENE; MASS AB Although Wnt signaling in osteoblasts is of critical importance for the regulation of bone remodeling, it is not yet known which specific Wnt receptors of the Frizzled family are functionally relevant in this process. In this paper, we show that Fzd9 is induced upon osteoblast differentiation and that Fzd9(-/-) mice display low bone mass caused by impaired bone formation. Our analysis of Fzd9(-/-) primary osteoblasts demonstrated defects in matrix mineralization in spite of normal expression of established differentiation markers. In contrast, we observed a reduced expression of chemokines and interferon-regulated genes in Fzd9(-/-) osteoblasts. We also identified the ubiquitin-like modifier Isg15 as one potential downstream mediator of Fzd9 in these cells. Importantly, our molecular analysis further revealed that canonical Wnt signaling is not impaired in the absence of Fzd9, thus explaining the absence of a bone resorption phenotype. Collectively, our results reveal a previously unknown function of Fzd9 in osteoblasts, a finding that may have therapeutic implications for bone loss disorders. C1 [Albers, Joachim; Schulze, Jochen; Beil, F. Timo; Baranowsky, Anke; Keller, Johannes; Marshall, Robert P.; Wintges, Kristofer; Friedrich, Felix W.; Schilling, Arndt F.; Amling, Michael; Schinke, Thorsten] Univ Med Ctr Hamburg Eppendorf, Dept Osteol & Biomech, D-20246 Hamburg, Germany. [Gebauer, Matthias; Priemel, Matthias; Rueger, Johannes M.] Univ Med Ctr Hamburg Eppendorf, Dept Trauma Hand & Reconstruct Surg, D-20246 Hamburg, Germany. [Cornils, Kerstin; Fehse, Boris] Univ Med Ctr Hamburg Eppendorf, Dept Stem Cell Transplantat, D-20246 Hamburg, Germany. [Streichert, Thomas] Univ Med Ctr Hamburg Eppendorf, Inst Clin Chem, D-20246 Hamburg, Germany. [Sauter, Guido] Univ Med Ctr Hamburg Eppendorf, Dept Pathol, D-20246 Hamburg, Germany. [Jakob, Franz] Univ Wurzburg, Dept Orthoped, D-97074 Wurzburg, Germany. [Insogna, Karl L.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06519 USA. [Pober, Barbara] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Knobeloch, Klaus-Peter] Univ Clin Freiburg, Dept Neurol, D-79106 Freiburg, Germany. [Francke, Uta] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. RP Schinke, T (reprint author), Univ Med Ctr Hamburg Eppendorf, Dept Osteol & Biomech, D-20246 Hamburg, Germany. EM schinke@uke.uni-hamburg.de RI Fehse, Boris/A-8721-2012; Jakob, Franz/D-8526-2015; Jakob, Prof. Dr. Franz/F-9894-2015; OI Fehse, Boris/0000-0001-9780-7211 FU Deutsche Forschungsgemeinschaft within the transregional research group Mechanisms of Fracture Healing and Bone Regeneration in Osteoporosis [SCHI 504/5-1, SCHI 504/5-2] FX This work was supported by grants from the Deutsche Forschungsgemeinschaft (SCHI 504/5-1 and SCHI 504/5-2) within the transregional research group Mechanisms of Fracture Healing and Bone Regeneration in Osteoporosis. NR 68 TC 41 Z9 42 U1 0 U2 12 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAR 21 PY 2011 VL 192 IS 6 BP 1057 EP 1072 DI 10.1083/jcb.201008012 PG 16 WC Cell Biology SC Cell Biology GA 743AD UT WOS:000288986200015 PM 21402791 ER PT J AU Nanthakumar, N Meng, D Goldstein, AM Zhu, WS Lu, L Uauy, R Llanos, A Claud, EC Walker, WA AF Nanthakumar, Nanda Meng, Di Goldstein, Allan M. Zhu, Weishu Lu, Lei Uauy, Ricardo Llanos, Adolfo Claud, Erika C. Walker, W. Allan TI The Mechanism of Excessive Intestinal Inflammation in Necrotizing Enterocolitis: An Immature Innate Immune Response SO PLOS ONE LA English DT Article ID EPITHELIAL-CELLS; ENDOTOXIN TOLERANCE; BACTERIAL LIGANDS; UP-REGULATION; CORTICOSTEROIDS; ENTEROCYTES; EXPRESSION AB Necrotizing enterocolitis (NEC) is a devastating neonatal intestinal inflammatory disease, occurring primarily in premature infants, causing significant morbidity and mortality. The pathogenesis of NEC is associated with an excessive inflammatory IL-8 response. In this study, we hypothesized that this excessive inflammatory response is related to an immature expression of innate immune response genes. To address this hypothesis, intestinal RNA expression analysis of innate immune response genes was performed after laser capture microdissection of resected ileal epithelium from fetuses, NEC patients and children and confirmed in ex vivo human intestinal xenografts. Changes in mRNA levels of toll-like receptors (TLR)-2 and -4, their signaling molecules and transcription factors (MyD88, TRAF-6 and NF kappa B1) and negative regulators (SIGIRR, IRAK-M, A-20 and TOLLIP) and the effector IL-8 were characterized by qRT-PCR. The expression of TLR2, TLR4, MyD88, TRAF-6, NFkB1 and IL-8 mRNA was increased while SIGIRR, IRAK-M, A-20 and TOLLIP mRNA were decreased in fetal vs. mature human enterocytes and further altered in NEC enterocytes. Similar changes in mRNA expression were observed in immature, but not mature, human intestinal xenografts. Confirmation of gene expression was also validated with selective protein measurements and with suggested evidence that immature TRL4 enterocyte surface expression was internalized in mature enterocytes. Cortisone, an intestinal maturation factor, treatment corrected the mRNA differences only in the immature intestinal xenograft. Using specific siRNA to attenuate expression of primary fetal enterocyte cultures, both TOLLIP and A-20 were confirmed to be important when knocked down by exhibiting the same excessive inflammatory response seen in the NEC intestine. We conclude that the excessive inflammatory response of the immature intestine, a hallmark of NEC, is due to a developmental immaturity in innate immune response genes. C1 [Nanthakumar, Nanda; Meng, Di; Zhu, Weishu; Lu, Lei; Walker, W. Allan] Harvard Univ, Sch Med, Dev Gastroenterol Lab, Boston, MA 02115 USA. [Goldstein, Allan M.] Harvard Univ, Sch Med, Pediat Surg Res Lab, MassGen Hosp Children, Boston, MA USA. [Uauy, Ricardo; Llanos, Adolfo] Univ Chile, Inst Nutr & Food Technol, Santiago, Chile. [Claud, Erika C.] Univ Chicago, Dept Pediat & Med, Sect Neonatol, Chicago, IL 60637 USA. RP Nanthakumar, N (reprint author), Harvard Univ, Sch Med, Dev Gastroenterol Lab, Boston, MA 02115 USA. EM wwalker@partners.org FU National Institutes of Health (NIH) [R01 HD059126, R01-HD012437, R01 DK070260, P01 DK033506, P30 DK040561, R01 DK080914, R01 HD059123, R21 HD055237, R21 AT004044]; March of Dimes Basil O'Connor Starter Award FX This work was supported by grants from National Institutes of Health (NIH): R01 HD059126 (Nanda Nanthakumar); R01-HD012437, R01 DK070260, P01 DK033506 and P30 DK040561 (W. Allan Walker); R01 DK080914 (Allan Goldstein); R01 HD059123, R21 HD055237, R21 AT004044 and the March of Dimes Basil O'Connor Starter Award (Erika Claud). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 115 Z9 121 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 21 PY 2011 VL 6 IS 3 AR e17776 DI 10.1371/journal.pone.0017776 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 738BC UT WOS:000288613300015 PM 21445298 ER PT J AU Tu, DQ Li, YQ Song, HK Toms, AV Gould, CJ Ficarro, SB Marto, JA Goode, BL Eck, MJ AF Tu, Daqi Li, Yiqun Song, Hyun Kyu Toms, Angela V. Gould, Christopher J. Ficarro, Scott B. Marto, Jarrod A. Goode, Bruce L. Eck, Michael J. TI Crystal Structure of a Coiled-Coil Domain from Human ROCK I SO PLOS ONE LA English DT Article ID RHO-ASSOCIATED KINASE; MYOSIN LIGHT-CHAIN; SMOOTH-MUSCLE CONTRACTION; BINDING PROTEIN RHO; FOCAL ADHESIONS; SERINE/THREONINE KINASE; STRESS FIBERS; PHOSPHORYLATION; ACTIVATION; REORGANIZATION AB The small GTPase Rho and one of its targets, Rho-associated kinase (ROCK), participate in a variety of actin-based cellular processes including smooth muscle contraction, cell migration, and stress fiber formation. The ROCK protein consists of an N-terminal kinase domain, a central coiled-coil domain containing a Rho binding site, and a C-terminal pleckstrin homology domain. Here we present the crystal structure of a large section of the central coiled-coil domain of human ROCK I (amino acids 535-700). The structure forms a parallel alpha-helical coiled-coil dimer that is structurally similar to tropomyosin, an actin filament binding protein. There is an unusual discontinuity in the coiled-coil; three charged residues (E613, R617 and D620) are positioned at what is normally the hydrophobic core of coiled-coil packing. We speculate that this conserved irregularity could function as a hinge that allows ROCK to adopt its autoinhibited conformation. C1 [Tu, Daqi; Toms, Angela V.; Ficarro, Scott B.; Marto, Jarrod A.; Eck, Michael J.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Tu, Daqi; Li, Yiqun; Toms, Angela V.; Ficarro, Scott B.; Marto, Jarrod A.; Eck, Michael J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Song, Hyun Kyu] Korea Univ, Sch Life Sci & Biotechnol, Seoul, South Korea. [Gould, Christopher J.; Goode, Bruce L.] Brandeis Univ, Dept Biol, Waltham, MA 02254 USA. [Gould, Christopher J.; Goode, Bruce L.] Brandeis Univ, Rosenstiel Basic Med Sci Res Ctr, Waltham, MA 02254 USA. RP Tu, DQ (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM eck@red.dfci.harvard.edu RI Song, Hyun Kyu/D-6763-2016 OI Song, Hyun Kyu/0000-0001-5684-4059 FU National Institutes of Health (NIH) [GM071834]; Ministry of Education, Science and Technology [R33-10108] FX This research was supported by National Institutes of Health (NIH) grant GM071834 to M.J.E. and by WCU (World Class University) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R33-10108) to M.J.E. and H.K.S. NR 48 TC 17 Z9 20 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 21 PY 2011 VL 6 IS 3 AR e18080 DI 10.1371/journal.pone.0018080 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 738BC UT WOS:000288613300035 PM 21445309 ER PT J AU Roditi, LD Michor, F AF Roditi, Laura De Vargas Michor, Franziska TI Evolutionary dynamics of BRCA1 alterations in breast tumorigenesis SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Stochastic modeling; Breast cancer; Moran model ID TUMOR-SUPPRESSOR GENE; OVARIAN-CANCER; MUTATION; IRRADIATION; INSTABILITY; HYPOTHESIS; REPAIR; DAMAGE AB Cancer results from the accumulation of alterations in oncogenes and tumor suppressor genes. Tumor suppressors are classically defined as genes which contribute to tumorigenesis if their function is lost. Genetic or epigenetic alterations inactivating such genes may arise during somatic cell divisions or alternatively may be inherited from a parent. One notable exception to this rule is the BACA] tumor suppressor that predisposes to hereditary breast cancer when lost. Genetic alterations of this gene are hardly ever observed in sporadic breast cancer, while individuals harboring a germline mutation readily accumulate a second alteration inactivating the remaining allele a finding which represents a conundrum in cancer genetics. In this paper, we present a novel mathematical framework of sporadic and hereditary breast tumorigenesis. We study the dynamics of genetic alterations driving breast tumorigenesis and explore those scenarios which can explain the absence of somatic BRCA1 alterations while replicating all other disease statistics. Our results support the existence of a heterozygous phenotype of BRCA1 and suggest that the loss of one BRCA1 allele may suppress the fitness advantage caused by the inactivation of other tumor suppressor genes. This paper contributes to the mathematical investigation of breast tumorigenesis. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Michor, Franziska] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Michor, Franziska] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Roditi, Laura De Vargas] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA. [Roditi, Laura De Vargas] Weill Cornell Med Coll, Tri Inst Training Program Computat Biol & Med, New York, NY 10065 USA. RP Michor, F (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM michor@jimmy.harvard.edu FU NCI [U54CA143798] FX The authors would like to thank the Michor laboratory for helpful comments and discussions. This work is supported by NCI Grant U54CA143798. NR 34 TC 3 Z9 3 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD MAR 21 PY 2011 VL 273 IS 1 BP 207 EP 215 DI 10.1016/j.jtbi.2010.12.033 PG 9 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 725XX UT WOS:000287681300021 ER PT J AU Tamura, Y Watanabe, K Kantani, T Hayashi, J Ishida, N Kaneki, M AF Tamura, Yoshiaki Watanabe, Keiichi Kantani, Tomomi Hayashi, Junichi Ishida, Nobuhiko Kaneki, Masao TI Upregulation of circulating IL-15 by treadmill running in healthy individuals: Is IL-15 an endocrine mediator of the beneficial effects of endurance exercise? SO ENDOCRINE JOURNAL LA English DT Article DE IL-15; Myokine; Endurance exercise; Treadmill ID HUMAN SKELETAL-MUSCLE; CARBOHYDRATE INGESTION; INSULIN ACTION; INTERLEUKIN-15; ADIPOCYTES; ASSOCIATION; EXPRESSION; ADIPOSE; OBESITY; MASS AB The beneficial effects of endurance exercise include insulin-sensitization and reduction of fat mass. Limited knowledge is available about the mechanisms by which endurance exercise exerts the salutary effects. Myokines, cytokines secreted by skeletal muscle, have been recognized as a potential mediator. Recently, a role of skeletal muscle-derived interleukin-15 (IL-15) in improvement of fat-lean body mass composition and insulin sensitivity has been proposed. Yet, previous studies have reported that endurance training does not increase production or secretion of IL-15 in skeletal muscle. Here, we show that in opposition to previous findings, 30-min treadmill running at 70% of age-predicted maximum heart rate resulted in a significant increase in circulating IL-15 level in untrained healthy young men. These findings suggest that IL-15 might play a role in the systemic anti-obesogenic and insulin-sensitizing effects of endurance exercise, not only as a paracrine and autocrine but also as an endocrine factor. C1 [Tamura, Yoshiaki; Kaneki, Masao] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Shriners Hosp Children,Dept Anesthesia Crit Care, Charlestown, MA 02129 USA. [Watanabe, Keiichi; Ishida, Nobuhiko] Wafukai Med Corp, Tama Rehabil Acad, Ome 1980004, Japan. [Kantani, Tomomi] Wafukai Tama Rehabil Hosp, Ome 1980052, Japan. [Hayashi, Junichi] Kyorin Univ, Sch Med, Dept Gen Med, Mitaka, Tokyo 1818611, Japan. RP Kaneki, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Shriners Hosp Children,Dept Anesthesia Crit Care, 149 13th St,Rm 6604, Charlestown, MA 02129 USA. EM mkaneki@helix.mgh.harvard.edu FU National Institutes of Health [R01DK05827]; American Diabetes Association [7-08-RA-77] FX This work was supported by research grants to M.K. from the National Institutes of Health (R01DK05827) and American Diabetes Association (7-08-RA-77). NR 18 TC 32 Z9 38 U1 1 U2 16 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR 20 PY 2011 VL 58 IS 3 BP 211 EP 215 DI 10.1507/endocrj.K10E-400 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 764MS UT WOS:000290634300009 PM 21307608 ER PT J AU Finkelstein, DM Schoenfeld, DA AF Finkelstein, Dianne M. Schoenfeld, David A. TI Correcting for Discretionary Treatment Crossover in an Analysis of Survival in the Breast International Group BIG 1-98 Trial by Using the Inverse Probability of Censoring Weighted Method SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID CLINICAL-TRIAL C1 [Finkelstein, Dianne M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Boston, MA 02115 USA. RP Finkelstein, DM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 4 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2011 VL 29 IS 9 BP 1093 EP 1095 DI 10.1200/JCO.2010.33.9374 PG 3 WC Oncology SC Oncology GA 736YZ UT WOS:000288532500018 PM 21321297 ER PT J AU Ganz, PA Land, SR Geyer, CE Cecchini, RS Costantino, JP Pajon, ER Fehrenbacher, L Atkins, JN Polikoff, JA Vogel, VG Erban, JK Livingston, RB Perez, EA Mamounas, EP Wolmark, N Swain, SM AF Ganz, Patricia A. Land, Stephanie R. Geyer, Charles E., Jr. Cecchini, Reena S. Costantino, Joseph P. Pajon, Eduardo R. Fehrenbacher, Louis Atkins, James N. Polikoff, Jonathan A. Vogel, Victor G. Erban, John K. Livingston, Robert B. Perez, Edith A. Mamounas, Eleftherios P. Wolmark, Norman Swain, Sandra M. TI Menstrual History and Quality-of-Life Outcomes in Women With Node-Positive Breast Cancer Treated With Adjuvant Therapy on the NSABP B-30 Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MUSTARD L-PAM; PREMENOPAUSAL WOMEN; FUNCTIONAL ASSESSMENT; PREVENTION TRIAL; CHEMOTHERAPY; SYMPTOMS; MANAGEMENT; AMENORRHEA; PRESERVATION; FERTILITY AB Purpose Premenopausal women with breast cancer receiving adjuvant chemotherapy are at risk for amenorrhea. The National Surgical Adjuvant Breast and Bowel Project B-30 trial included menstrual history (MH) and quality-of-life (QOL) studies to compare treatments on these outcomes. Patients and Methods Patients were randomly assigned to sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T; AC -> T), concurrent TAC, or AT, which varied in duration (24, 12, 12 weeks, respectively), and use of C. Endocrine therapy was prescribed for women with hormone receptor-positive tumors. MH and QOL were assessed with standardized questionnaires at baseline; cycle 4, day 1; and every 6 months through 24 months. Prespecified analyses examined rates of amenorrhea by treatment arm, the relationship between amenorrhea and QOL, and QOL by treatment arm. Results Amenorrhea 12 months after random assignment was significantly different between treatment groups: 69.8% for AC -> T, 57.7% for TAC, and 37.9% for AT (P < .001). The AT group without tamoxifen had the lowest rate of amenorrhea. QOL was poorer for patients receiving AC -> T at 6 months but similar to others by 12 months. Post-treatment symptoms were increased above baseline for all treatments. Multivariable repeated measures modeling demonstrated that treatment arm, time point, age, and tamoxifen use were significantly associated with symptom severity (all P values < .002). Conclusion Amenorrhea rates differed significantly by treatment arm, with the AT arm having the lowest rate. Patients treated with longer duration therapy (AC -> T) had greater symptom severity and poorer QOL at 6 months, but did not differ from shorter duration treatments at 12 months. J Clin Oncol 29: 1110-1116. (C) 2011 by American Society of Clinical Oncology C1 Univ Pittsburgh, Sch Publ Hlth, NSABP Biostat Ctr, Pittsburgh, PA 15260 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Eastern Cooperat Oncol Grp, Philadelphia, PA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Div Canc Prevent & Control Res, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. Kaiser Permanente No Calif, Vallejo, CA USA. So Calif Kaiser Permanente, San Diego, CA USA. Colorado Canc Res Program, Denver, CO USA. SE Canc Control Consortium Community Clin, Goldsboro, NC USA. Amer Canc Soc, Atlanta, GA 30329 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Arizona, Arizona Canc Ctr, Arizona Hlth Sci Ctr, Tucson, AZ USA. SW Oncol Grp, Ann Arbor, MI USA. Mayo Clin, Jacksonville, FL 32224 USA. N Cent Canc Treatment Grp, Rochester, MN USA. Aultman Hlth Fdn, Canton, OH USA. Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20010 USA. Univ Pittsburgh, Ctr Canc, Pittsburgh, PA 15260 USA. RP Ganz, PA (reprint author), Univ Calif Los Angeles, Div Canc Prevent & Control Res, Jonsson Comprehens Canc Ctr, 650 Charles Young Dr S,Room A2-125 CHS, Los Angeles, CA 90095 USA. EM pganz@mednet.ucla.edu OI Cecchini, Reena/0000-0002-9075-9357; Swain, Sandra/0000-0002-1320-3830 FU AstraZeneca FX Research Funding: Victor G. Vogel, AstraZeneca NR 24 TC 53 Z9 57 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2011 VL 29 IS 9 BP 1110 EP 1116 DI 10.1200/JCO.2010.29.7689 PG 7 WC Oncology SC Oncology GA 736YZ UT WOS:000288532500022 PM 21300930 ER PT J AU Colleoni, M Giobbie-Hurder, A Regan, MM Thurlimann, B Mouridsen, H Mauriac, L Forbes, JF Paridaens, R Lang, I Smith, I Chirgwin, J Pienkowski, T Wardley, A Price, KN Gelber, RD Coates, AS Goldhirsch, A AF Colleoni, Marco Giobbie-Hurder, Anita Regan, Meredith M. Thuerlimann, Beat Mouridsen, Henning Mauriac, Louis Forbes, John F. Paridaens, Robert Lang, Istvan Smith, Ian Chirgwin, Jacquie Pienkowski, Tadeusz Wardley, Andrew Price, Karen N. Gelber, Richard D. Coates, Alan S. Goldhirsch, Aron TI Analyses Adjusting for Selective Crossover Show Improved Overall Survival With Adjuvant Letrozole Compared With Tamoxifen in the BIG 1-98 Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID EARLY BREAST-CANCER; POSTMENOPAUSAL WOMEN; AROMATASE INHIBITORS; INVERSE PROBABILITY; THERAPY; TRIAL; ANASTROZOLE; NONCOMPLIANCE; ARNO-95; TESTS AB Purpose Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged overall survival (OS) compared with tamoxifen monotherapy. Patients and Methods Of 8,010 postmenopausal women with hormone receptor-positive, early breast cancer enrolled on the Breast International Group (BIG) 1-98 study, 4,922 were randomly assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen. Of 2,459 patients enrolled in the tamoxifen treatment arm, 619 (25.2%) selectively crossed over to either adjuvant or extended letrozole after initial trial results were presented in January 2005. To gain better estimates of relative treatment effects in the presence of selective crossover, we used inverse probability of censoring weighted (IPCW) modeling. Results Weighted Cox models, by using IPCW, estimated a statistically significant, 18% reduction in the hazard of an OS event with letrozole treatment (hazard ratio [HR], 0.82; 95% CI, 0.70 to 0.95). Estimates of 5-year OS on the basis of IPCW were 91.8% and 90.4% for letrozole and tamoxifen, respectively. The HRs of DFS and TDR events by using IPCW modeling were 0.83 (95% CI, 0.74 to 0.94) and 0.80 (95% CI, 0.67 to 0.94), respectively (P < .05 for DFS, OS, and TDR). Median follow-up was 74 months. Conclusion Adjuvant treatment with letrozole, compared with tamoxifen, significantly reduces the risk of death, the risk of recurrent disease, and the risk of recurrence at distant sites in postmenopausal women with hormone receptor-positive breast cancer. J Clin Oncol 29: 1117-1124. (C) 2011 by American Society of Clinical Oncology C1 [Colleoni, Marco] Ist Europeo Oncol, I-20141 Milan, Italy. Dana Farber Canc Inst, Int Breast Canc Study Grp Stat Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Kantonsspital, Breast Ctr, St Gallen, Switzerland. Swiss Grp Clin Canc Res, Int Breast Canc Study Grp, Bern, Switzerland. Oncol Inst So Switzerland, Bellinzona, Switzerland. Rigshosp, Danish Breast Canc Cooperat Grp, DK-2100 Copenhagen, Denmark. Inst Bergonie, French Breast Canc Grp, Bordeaux, France. Univ Newcastle, Calvary Mater Hosp, Australian New Zealand Breast Canc Trials Grp, Newcastle, NSW 2308, Australia. Box Hill Hosp, Melbourne, Vic, Australia. Maroondah Hosp, Melbourne, Vic, Australia. Univ Sydney, Sydney, NSW 2006, Australia. Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Louvain, Belgium. Natl Inst Oncol, Budapest, Hungary. Royal Marsden Hosp, London, England. Inst Canc Res, London SW3 6JB, England. S Manchester Univ Hosp Trust, Christie Hosp Natl Hlth Serv Trust, Manchester, Lancs, England. Canc Ctr Maria Sklodowska Curie Mem, Inst Oncol, Warsaw, Poland. RP Colleoni, M (reprint author), Ist Europeo Oncol, Via Ripamonti 435, I-20141 Milan, Italy. EM marco.colleoni@ieo.it RI Wardley, ANdrew/N-8135-2015 OI Wardley, ANdrew/0000-0002-9639-0888 FU Novartis; AstraZeneca; Pfizer FX Research Funding: Jacquie Chirgwin, Novartis, AstraZeneca, Pfizer; Tadeusz Pienkowski, Novartis; Richard D. Gelber, Novartis NR 20 TC 74 Z9 77 U1 1 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 MAR 20 PY 2011 VL 29 IS 9 BP 1117 EP 1124 DI 10.1200/JCO.2010.31.6455 PG 8 WC Oncology SC Oncology GA 736YZ UT WOS:000288532500023 PM 21321298 ER PT J AU O'Connor, OA Pro, B Pinter-Brown, L Bartlett, N Popplewell, L Coiffier, B Lechowicz, MJ Savage, KJ Shustov, AR Gisselbrecht, C Jacobsen, E Zinzani, PL Furman, R Goy, A Haioun, C Crump, M Zain, JM Hsi, E Boyd, A Horwitz, S AF O'Connor, Owen A. Pro, Barbara Pinter-Brown, Lauren Bartlett, Nancy Popplewell, Leslie Coiffier, Bertrand Lechowicz, Mary Jo Savage, Kerry J. Shustov, Andrei R. Gisselbrecht, Christian Jacobsen, Eric Zinzani, Pier Luigi Furman, Richard Goy, Andre Haioun, Corinne Crump, Michael Zain, Jasmine M. Hsi, Eric Boyd, Adam Horwitz, Steven TI Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results From the Pivotal PROPEL Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NON-HODGKINS-LYMPHOMA; CLASSIFICATION; METHOTREXATE; MALIGNANCIES; MANAGEMENT; SUPERIOR; WORKSHOP; FEATURES; MODELS; REAL AB Purpose Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non-Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of pralatrexate, a novel antifolate with promising activity. Patients and Methods Patients with independently confirmed PTCL who progressed following >= 1 line of prior therapy received pralatrexate intravenously at 30 mg/m(2)/wk for 6 weeks in 7-week cycles. Primary assessment of response was made by independent central review using the International Workshop Criteria. The primary end point was overall response rate. Secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS). Results Of 115 patients enrolled, 111 were treated with pralatrexate. The median number of prior systemic therapies was three (range, 1 to 12). The response rate in 109 evaluable patients was 29% (32 of 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median DoR of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The most common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), and anemia (18%). Conclusion To our knowledge, PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study conducted in patients with relapsed or refractory PTCL. Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant. These data formed the basis for the US Food and Drug Administration approval of pralatrexate, the first drug approved for this disease. J Clin Oncol 29:1182-1189. (C) 2011 by American Society of Clinical Oncology C1 [O'Connor, Owen A.] NYU, Inst Canc, NYU Langone Med Ctr, New York, NY 10003 USA. New York Weill Cornell Med Ctr, New York, NY USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Calif Los Angeles, Los Angeles, CA USA. City Hope Natl Med Ctr, Duarte, CA USA. Washington Univ, Siteman Canc Ctr, St Louis, MO USA. Ctr Hosp Lyon Sud, F-69310 Pierre Benite, France. Emory Univ, Atlanta, GA 30322 USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Princess Margaret Hosp, Toronto Univ Hlth Network, Toronto, ON M4X 1K9, Canada. Seattle Canc Care Alliance, Seattle, WA USA. Hop St Louis, Paris, France. Hop Henri Mondor, F-94010 Creteil, France. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Bologna, Bologna, Italy. Hackensack Univ, Med Ctr, Hackensack, NJ USA. Clin Univ UCL Mt Godinne, Yvoir, Belgium. Cleveland Clin, Cleveland, OH 44106 USA. Allos Therapeut Inc, Westminster, CO USA. RP O'Connor, OA (reprint author), NYU, Inst Canc, NYU Langone Med Ctr, 550 1st Ave,Suite 1121, New York, NY 10003 USA. EM owen.o'connor@nyumc.org RI Zinzani, Pier Luigi/J-9182-2016 OI Zinzani, Pier Luigi/0000-0002-2112-2651 FU Allos Therapeutics; Allos Therapeutics, Inc FX Owen A. O'Connor, Allos Therapeutics; Barbara Pro, Allos Therapeutics, Inc; Lauren Pinter-Brown, Allos Therapeutics; Nancy Bartlett, Allos Therapeutics, Inc; Leslie Popplewell, Allos Therapeutics, Inc.; Andrei R. Shustov, Allos Therapeutics, Inc; Christian Gisselbrecht, Allos Therapeutics, Inc; Andre Goy, Allos Therapeutics, Inc; Eric Hsi, Allos Therapeutics; Steven Horwitz, Gloucester Pharmaceuticals, Allos Therapeutics NR 21 TC 197 Z9 208 U1 2 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2011 VL 29 IS 9 BP 1182 EP 1189 DI 10.1200/JCO.2010.29.9024 PG 8 WC Oncology SC Oncology GA 736YZ UT WOS:000288532500032 PM 21245435 ER PT J AU Wen, PY Van den Bent, MJ Macdonald, DR Vogelbaum, MA Chang, SM AF Wen, Patrick Y. Van den Bent, Martin J. Macdonald, David R. Vogelbaum, Michael A. Chang, Susan M. TI New Agents and New End Points for Recurrent Gliomas Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. [Van den Bent, Martin J.] Erasmus Univ Hosp, Daniel den Hoed Canc Ctr, Rotterdam, Netherlands. [Macdonald, David R.] Univ Western Ontario, London Reg Canc Program, London, ON, Canada. [Vogelbaum, Michael A.] Cleveland Clin, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44106 USA. [Chang, Susan M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2011 VL 29 IS 9 BP E247 EP E247 DI 10.1200/JCO.2010.33.4383 PG 1 WC Oncology SC Oncology GA 736YZ UT WOS:000288532500013 ER PT J AU Drucker, DJ Goldfine, AB AF Drucker, Daniel J. Goldfine, Allison B. TI Cardiovascular safety and diabetes drug development SO LANCET LA English DT Editorial Material ID EXENATIDE TWICE; OPEN-LABEL; TYPE-2; LIRAGLUTIDE; THERAPIES; OUTCOMES; WEIGHT; RISK C1 [Drucker, Daniel J.] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Med, Toronto, ON M5G 1X5, Canada. [Goldfine, Allison B.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Drucker, DJ (reprint author), Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Med, Toronto, ON M5G 1X5, Canada. EM d.drucker@utoronto.ca RI Drucker, Daniel/A-4092-2010 NR 14 TC 19 Z9 20 U1 0 U2 1 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 MAR 19 PY 2011 VL 377 IS 9770 BP 977 EP 979 DI 10.1016/S0140-6736(10)62299-4 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 740FA UT WOS:000288775800009 PM 21316097 ER PT J AU Pe'er, D Hacohen, N AF Pe'er, Dana Hacohen, Nir TI Principles and Strategies for Developing Network Models in Cancer SO CELL LA English DT Article ID HUMAN B-CELLS; TRANSCRIPTIONAL NETWORK; GENE-EXPRESSION; IDENTIFICATION; INHIBITION; MAP; ACTIVATION; REGULATORS; PATHWAYS; DYNAMICS AB The flood of genome-wide data generated by high-throughput technologies currently provides biologists with an unprecedented opportunity: to manipulate, query, and reconstruct functional molecular networks of cells. Here, we outline three underlying principles and six strategies to infer network models from genomic data. Then, using cancer as an example, we describe experimental and computational approaches to infer "differential" networks that can identify genes and processes driving disease phenotypes. In conclusion, we discuss how a network-level understanding of cancer can be used to predict drug response and guide therapeutics. C1 [Pe'er, Dana] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA. [Pe'er, Dana] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA. [Hacohen, Nir] Broad Inst MIT & Harvard, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Hacohen, Nir] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Pe'er, D (reprint author), Columbia Univ, Dept Biol Sci, 1212 Amsterdam Ave, New York, NY 10027 USA. EM dpeer@biology.columbia.edu OI Pe'er, Dana/0000-0002-9259-8817 FU NIH [DP2-OD002414-01, DP2 OD002230]; NIAID [U54 AI057159]; Burroughs Wellcome Fund; Packard Fellowship for Science and Engineering FX The authors would like to thank Arnon Arazi, Andrea Califano, William Hahn, Andreja Jovic, Oren Litvin, Neal Rosen, Sagi Shapira, and Cathy Wu for valuable comments. The authors would like to thank Oren Litvin for help with the illustrations. This research was supported by the NIH Director's New Innovator Award Program through grant numbers DP2-OD002414-01 (D.P.) and DP2 OD002230 (N.H.), as well as NIAID U54 AI057159 (N.H.). D.P. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund and Packard Fellowship for Science and Engineering. NR 48 TC 91 Z9 92 U1 3 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 18 PY 2011 VL 144 IS 6 BP 864 EP 873 DI 10.1016/j.cell.2011.03.001 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 737BQ UT WOS:000288543500006 PM 21414479 ER PT J AU Vidal, M Cusick, ME Barabasi, AL AF Vidal, Marc Cusick, Michael E. Barabasi, Albert-Laszlo TI Interactome Networks and Human Disease SO CELL LA English DT Review ID PROTEIN-PROTEIN INTERACTIONS; YEAST SACCHAROMYCES-CEREVISIAE; DNA INTERACTION NETWORK; GENE-EXPRESSION; C-ELEGANS; CAENORHABDITIS-ELEGANS; ESCHERICHIA-COLI; TRANSCRIPTION FACTORS; METABOLIC NETWORKS; INTERACTION MAP AB Complex biological systems and cellular networks may underlie most genotype to phenotype relationships. Here, we review basic concepts in network biology, discussing different types of interactome networks and the insights that can come from analyzing them. We elaborate on why interactome networks are important to consider in biology, how they can be mapped and integrated with each other, what global properties are starting to emerge from interactome network models, and how these properties may relate to human disease. C1 [Vidal, Marc; Cusick, Michael E.; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA. [Vidal, Marc; Cusick, Michael E.; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Vidal, Marc; Cusick, Michael E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res CCNR, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Northeastern Univ, Dept Biol & Comp Sci, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Vidal, M (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol CCSB, Boston, MA 02215 USA. EM marc_vidal@dfci.harvard.edu; alb@neu.edu FU National Institutes of Health [R01-HG001715] FX We thank David E. Hill, Matija Dreze, Anne-Ruxandra Carvunis, Benoit Charloteaux, Quan Zhong, Balaji Santhanam, Sam Pevzner, Song Yi, Nidhi Sahni, Jean Vandenhaute, and Roseann Vidal for careful reading of the manuscript. Interactome mapping efforts at CCSB have been supported mainly by National Institutes of Health grant R01-HG001715. M.V. is grateful to Nadia Rosenthal for the peaceful Suttonian environment. We apologize to those in the field whose important work was not cited here due to space limitation. NR 156 TC 550 Z9 563 U1 26 U2 194 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 18 PY 2011 VL 144 IS 6 BP 986 EP 998 DI 10.1016/j.cell.2011.02.016 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 737BQ UT WOS:000288543500015 PM 21414488 ER PT J AU Uljon, SN Richardson, PG Schur, PH Anderson, KC Tanasijevic, MJ Lindeman, NI AF Uljon, Sacha N. Richardson, Paul G. Schur, Peter H. Anderson, Kenneth C. Tanasijevic, Milenko J. Lindeman, Neal I. TI Serial serum free light chain measurements do not detect changes in disease status earlier than electrophoretic M-spike measurements in patients with intact immunoglobulin myeloma SO CLINICA CHIMICA ACTA LA English DT Article DE Serum free light chains; Serum protein electrophoresis; Myeloma ID MULTIPLE-MYELOMA; PROTEIN; CATABOLISM AB Background: Serum free light chains (SFLC) are used to manage patients with light chain or hyposecretory myeloma, and may also be useful in patients with intact immunoglobulin myeloma (IIMM), because their shorter half-life may enable earlier indication of relapse/response than electrophoretic M-spikes or heavy chain (IgGA) immunonephelometry. Methods: One thousand five SFLC, M-spike, and IgGA concentrations were compared at multiple time points during the treatment of 17 myeloma patients, followed over 7.7-63.4 months. Changes in these analytes were evaluated in context with changes in disease status and treatment. Results: 14/17 (82%) patients showed synchrony between M-spike, IgGA, and SFLC measurements. SFLC changes preceded M-spike/IgGA in 1 patient, and lagged behind M-spike/IgGA in 2 patients. In eight patients, SFLC showed short-term fluctuations unaccompanied by changes in M-spike, IgGA, or clinical treatment. Conclusions: In 16/17 intact immunoglobulin myeloma patients tested frequently over similar to 3 years, SFLC performed no better than M-spike and did not add value to conventional serum electrophoresis. (C) 2010 Elsevier B.V. All rights reserved. C1 [Uljon, Sacha N.; Tanasijevic, Milenko J.; Lindeman, Neal I.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Richardson, Paul G.; Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Schur, Peter H.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Uljon, Sacha N.; Richardson, Paul G.; Schur, Peter H.; Anderson, Kenneth C.; Tanasijevic, Milenko J.; Lindeman, Neal I.] Harvard Univ, Sch Med, Boston, MA USA. RP Lindeman, NI (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St,Amory 2-217D, Boston, MA 02115 USA. EM nlindeman@partners.org NR 17 TC 7 Z9 7 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD MAR 18 PY 2011 VL 412 IS 7-8 BP 562 EP 568 DI 10.1016/j.cca.2010.12.002 PG 7 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 727YZ UT WOS:000287840600014 PM 21144845 ER PT J AU Illerhaus, G Batchelor, T AF Illerhaus, Gerald Batchelor, Tracy TI PCNSL: biomarker better than biopsy? SO BLOOD LA English DT Editorial Material C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 8 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 17 PY 2011 VL 117 IS 11 BP 2987 EP 2989 PG 5 WC Hematology SC Hematology GA 736LN UT WOS:000288496300003 PM 21415274 ER PT J AU Ringman, JM Gylys, KH Medina, LD Fox, M Kepe, V Flores, DL Apostolova, LG Barrio, JR Small, G Silverman, DH Siu, E Cederbaum, S Hecimovic, S Malnar, M Chakraverty, S Goate, AM Bird, TD Leverenz, JB AF Ringman, John M. Gylys, Karen H. Medina, Luis D. Fox, Michelle Kepe, Vladimir Flores, Deborah L. Apostolova, Liana G. Barrio, Jorge R. Small, Gary Silverman, Daniel H. Siu, Erin Cederbaum, Stephen Hecimovic, Silva Malnar, Martina Chakraverty, Suma Goate, Alison M. Bird, Thomas D. Leverenz, James B. TI Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer's disease due to a novel PSEN1 mutation (vol 487, pg 287, 2011) SO NEUROSCIENCE LETTERS LA English DT Correction C1 [Ringman, John M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Mary S Easton Ctr Alzheimers Dis Res, Los Angeles, CA 90095 USA. [Fox, Michelle; Cederbaum, Stephen] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90095 USA. [Kepe, Vladimir; Barrio, Jorge R.; Silverman, Daniel H.; Siu, Erin] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Flores, Deborah L.] Harbor UCLA Med Ctr, Dept Psychiat, Torrance, CA 90509 USA. [Small, Gary; Cederbaum, Stephen] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Psychiat, Los Angeles, CA 90095 USA. [Hecimovic, Silva; Malnar, Martina] Rudjer Boskovic Inst, Dept Mol Med, Zogreb, Croatia. [Chakraverty, Suma; Goate, Alison M.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Bird, Thomas D.; Leverenz, James B.] Univ Washington, Clin Ctr, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Ringman, JM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Mary S Easton Ctr Alzheimers Dis Res, 10911 Weyburn Ave,200, Los Angeles, CA 90095 USA. EM jringman@mednet.ucla.edu NR 1 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 17 PY 2011 VL 491 IS 2 BP 163 EP 163 DI 10.1016/j.neulet.2011.01.021 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 739QF UT WOS:000288732200015 ER PT J AU Damrauer, SM Studer, P da Silva, CG Longo, CR Ramsey, HE Csizmadia, E Shrikhande, GV Scali, ST Libermann, TA Bhasin, MK Ferran, C AF Damrauer, Scott M. Studer, Peter da Silva, Cleide G. Longo, Christopher R. Ramsey, Haley E. Csizmadia, Eva Shrikhande, Gautam V. Scali, Salvatore T. Libermann, Towia A. Bhasin, Manoj K. Ferran, Christiane TI A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration SO PLOS ONE LA English DT Article ID ACTIVATED-RECEPTOR-ALPHA; NF-KAPPA-B; ENDOTHELIAL-CELL ACTIVATION; GENE-EXPRESSION PATTERNS; ZINC-FINGER PROTEIN; PARTIAL-HEPATECTOMY; ACID SYNTHESIS; MOUSE LIVERS; PPAR-ALPHA; MICE AB Background: Liver Regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-kappa B inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR) in mice. In this study, we explored the Systems Biology modulated by A20 following extended LR in mice. Methodology and Principal Findings: We performed transcriptional profiling using Affymetrix-Mouse 430.2 arrays on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.beta galactosidase treated livers, before and 24 hours after 78% LR. A20 overexpression impacted 1595 genes that were enriched for biological processes related to inflammatory and immune responses, cellular proliferation, energy production, oxidoreductase activity, and lipid and fatty acid metabolism. These pathways were modulated by A20 in a manner that favored decreased inflammation, heightened proliferation, and optimized metabolic control and energy production. Promoter analysis identified several transcriptional factors that implemented the effects of A20, including NF-kappa B, CEBPA, OCT-1, OCT-4 and EGR1. Interactive scale-free network analysis captured the key genes that delivered the specific functions of A20. Most of these genes were affected at basal level and after resection. We validated a number of A20's target genes by real-time PCR, including p21, the mitochondrial solute carriers SLC25a10 and SLC25a13, and the fatty acid metabolism regulator, peroxisome proliferator activated receptor alpha. This resulted in greater energy production in A20-expressing livers following LR, as demonstrated by increased enzymatic activity of cytochrome c oxidase, or mitochondrial complex IV. Conclusion: This Systems Biology-based analysis unravels novel mechanisms supporting the pro-regenerative function of A20 in the liver, by optimizing energy production through improved lipid/fatty acid metabolism, and down-regulated inflammation. These findings support pursuit of A20-based therapies to improve patients' outcomes in the context of extreme liver injury and extensive LR for tumor treatment or donation. C1 [Damrauer, Scott M.; Studer, Peter; da Silva, Cleide G.; Longo, Christopher R.; Ramsey, Haley E.; Csizmadia, Eva; Shrikhande, Gautam V.; Scali, Salvatore T.; Ferran, Christiane] Harvard Univ, Sch Med, Div Vasc Surg, Vasc Biol Res Ctr, Boston, MA USA. [Damrauer, Scott M.; Studer, Peter; da Silva, Cleide G.; Longo, Christopher R.; Ramsey, Haley E.; Csizmadia, Eva; Shrikhande, Gautam V.; Scali, Salvatore T.; Ferran, Christiane] Harvard Univ, Sch Med, Dept Surg, Beth Israel Deaconess Med Ctr,Transplant Inst, Boston, MA 02115 USA. [Libermann, Towia A.; Bhasin, Manoj K.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Interdisciplinary Med & Biotechnol,Dept Med, Boston, MA 02215 USA. RP Damrauer, SM (reprint author), Massachusetts Gen Hosp, Div Vasc Surg, Boston, MA 02114 USA. EM mbhasin@bidmc.harvard.edu; cferran@bidmc.harvard.edu OI Libermann, Towia/0000-0002-4006-8179 FU NIH [RO1 DK063275, RO1 HL080130, HL057791, T32 HL07734]; Juvenile Diabetes Research Foundation [1-2007-567]; National Swiss Foundation FX research was supported by NIH grants RO1 DK063275, RO1 HL080130, HL057791 and Juvenile Diabetes Research Foundation grant 1-2007-567 to CF. SMD, CRL, GVS, STS, are recipients of a fellowship award from the NIH T32 HL07734. PS is the recipient of a grant from the National Swiss Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 18 Z9 20 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 MAR 17 PY 2011 VL 6 IS 3 AR e17715 DI 10.1371/journal.pone.0017715 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 736SO UT WOS:000288514600011 PM 21437236 ER PT J AU Zhao, Y Sharma, N Ledoux, MS AF Zhao, Y. Sharma, N. Ledoux, M. S. TI THE DYT1 CARRIER STATE INCREASES ENERGY DEMAND IN THE OLIVOCEREBELLAR NETWORK SO NEUROSCIENCE LA English DT Article DE dystonia; globus pallidus; glucose utilization; cytochrome oxidase histochemistry; inferior olive; Purkinje cells ID CYTOCHROME-OXIDASE HISTOCHEMISTRY; CEREBRAL GLUCOSE-UTILIZATION; GENETICALLY DYSTONIC RAT; INFERIOR OLIVE; 2-DEOXYGLUCOSE METHOD; NEURONAL-ACTIVITY; BASAL GANGLIA; MOUSE MODEL; HORSERADISH-PEROXIDASE; DESCENDING CONNECTIONS AB DYT1 dystonia is caused by a GAG deletion in TOR1A, the gene which encodes torsinA. Gene expression studies in rodents and functional imaging studies in humans suggest that DYT1 dystonia may be a network disorder of neurodevelopmental origin. To generate high resolution metabolic maps of DYT1 dystonia and pinpoint dysregulated network elements, we performed 2-deoxyglucose autoradiography and cytochrome oxidase (CO) histochemistry in transgenic mice expressing human mutant (hMT1) torsinA and wild-type littermates. In comparison with controls, hMT1 mice showed increased glucose utilization (GU) in the inferior olive (IO) medial nucleus (IOM), IO dorsal accessory nucleus and substantia nigra compacta, and decreased GU in the medial globus pallidus (MGP) and lateral globus pallidus. The hMT1 mice showed increased CO activity in the IOM and Purkinje cell layer of cerebellar cortex, and decreased CO activity in the caudal caudate-putamen, substantia nigra reticulata and MGP. These findings suggest that (1) the DYT1 carrier state increases energy demand in the olivocerebellar network and (2) the IO may be a pivotal node for abnormal basal ganglia-cerebellar interactions in dystonia. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Zhao, Y.; Ledoux, M. S.] Univ Tennessee, Hlth Sci Ctr, Dept Neurol, Memphis, TN 38163 USA. [Zhao, Y.; Ledoux, M. S.] Univ Tennessee, Hlth Sci Ctr, Dept Anat & Neurobiol, Memphis, TN 38163 USA. [Sharma, N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sharma, N.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Ledoux, MS (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Neurol, Memphis, TN 38163 USA. EM mledoux@uthsc.edu RI LeDoux, Mark/I-1390-2013 OI LeDoux, Mark/0000-0002-1748-3390 FU Dystonia Medical Research Foundation; National Institute of Neurological Diseases and Stroke [R01NS048458, R03NS050185, R01NS069936] FX This work was supported by the Dystonia Medical Research Foundation and National Institute of Neurological Diseases and Stroke (R01NS048458, R03NS050185, R01NS069936). NR 58 TC 15 Z9 15 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD MAR 17 PY 2011 VL 177 BP 183 EP 194 DI 10.1016/j.neuroscience.2011.01.015 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 734DR UT WOS:000288313900018 PM 21241782 ER PT J AU Palumbo, A Anderson, K AF Palumbo, Antonio Anderson, Kenneth TI MEDICAL PROGRESS Multiple Myeloma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID STEM-CELL TRANSPLANTATION; PREDNISONE PLUS THALIDOMIDE; RANDOMIZED CONTROLLED-TRIAL; GROUP CONSENSUS STATEMENT; WORKING GROUP GUIDELINES; HIGH-DOSE DEXAMETHASONE; LONG-TERM SURVIVAL; ELDERLY-PATIENTS; PHASE-III; MOLECULAR CLASSIFICATION AB Multiple myeloma is a neoplastic plasma-cell disorder that is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, and associated organ dysfunction.(1) It accounts for approximately 1% of neoplastic diseases and 13% of hematologic cancers. In Western countries, the annual ageadjusted incidence is 5.6 cases per 100,000 persons.(2) The median age at diagnosis is approximately 70 years; 37% of patients are younger than 65 years, 26% are between the ages of 65 and 74 years, and 37% are 75 years of age or older.(2,3) In recent years, the introduction of autologous stem-cell transplantation and the availability of agents such as thalidomide, lenalidomide, and bortezomib have changed the management of myeloma and extended overall survival. 3-5 In patients presenting at an age under 60 years, 10-year survival is approximately 30%.(4) C1 [Palumbo, Antonio] Univ Turin, Div Hematol, Myeloma Unit, AOU S Giovanni Battista, I-10126 Turin, Italy. [Anderson, Kenneth] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Hematolg Neoplasia,Dept Med, Boston, MA 02115 USA. RP Palumbo, A (reprint author), Univ Turin, Div Hematol, Myeloma Unit, AOU S Giovanni Battista, Via Genova 3, I-10126 Turin, Italy. EM appalumbo@yahoo.com FU Celgene; Janssen-Cilag; Merck; Amgen FX Dr. Palumbo reports receiving fees for advisory board membership, consulting fees, and payment for the development of educational presentations from Celgene and Janssen-Cilag and lecture fees from Celgene, Janssen-Cilag, Merck, and Amgen; and Dr. Anderson, receiving fees for advisory board membership from Bristol-Myers Squibb, Celgene, Novartis, Onyx, Merck, and Millennium and being a founder of Acetylon. No other potential conflict of interest relevant to this article was reported. NR 103 TC 713 Z9 746 U1 10 U2 100 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 MAR 17 PY 2011 VL 364 IS 11 BP 1046 EP 1060 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 735SX UT WOS:000288439000010 PM 21410373 ER PT J AU Sims, KB Cole, AJ Sherman, JC Caruso, PA Snuderl, M AF Sims, Katherine B. Cole, Andrew J. Sherman, Janet C. Caruso, Paul A. Snuderl, Matija TI Case 8-2011: A 32-Year-Old Woman with Seizures and Cognitive Decline Kufs' disease (autosomal dominant, Parry type, young-adult-onset neuronal ceroid lipofuscinosis) SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PROGRESSIVE MYOCLONUS EPILEPSIES; THERAPEUTIC ASPECTS; DIAGNOSIS; INHERITANCE; CHILDHOOD; GENES; FORM C1 [Sims, Katherine B.; Cole, Andrew J.; Sherman, Janet C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sherman, Janet C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Caruso, Paul A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Snuderl, Matija] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sims, Katherine B.; Cole, Andrew J.; Sherman, Janet C.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Caruso, Paul A.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Snuderl, Matija] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Sims, KB (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 25 TC 7 Z9 7 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 17 PY 2011 VL 364 IS 11 BP 1062 EP 1074 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 735SX UT WOS:000288439000013 PM 21410375 ER PT J AU Simpson, JL Greene, MF AF Simpson, Joe Leigh Greene, Michael F. TI Fetal Surgery for Myelomeningocele? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Simpson, Joe Leigh] Florida Int Univ, Herbert Wertheim Coll Med, Dept Human & Mol Genet, Miami, FL 33199 USA. [Simpson, Joe Leigh] Florida Int Univ, Herbert Wertheim Coll Med, Dept Obstet & Gynecol, Miami, FL 33199 USA. [Greene, Michael F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Simpson, JL (reprint author), Florida Int Univ, Herbert Wertheim Coll Med, Dept Human & Mol Genet, Miami, FL 33199 USA. NR 5 TC 15 Z9 17 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 MAR 17 PY 2011 VL 364 IS 11 BP 1076 EP 1077 DI 10.1056/NEJMe1101228 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 735SX UT WOS:000288439000014 PM 21306233 ER PT J AU Xu, J Orkin, SH AF Xu, Jian Orkin, Stuart H. TI The erythroid/myeloid lineage fate paradigm takes a new player SO EMBO JOURNAL LA English DT Editorial Material ID CELL FATE; ZEBRAFISH; PU.1 AB The erythroid versus myeloid lineage fate decision controlled by cross-antagonism between GATA1 and PU.1 serves as a mechanistic paradigm for transcription factor interplay during lineage specification. In this issue of The EMBO Journal, Monteiro et al (2011) examined this paradigm in blood populations in zebrafish embryos, and demonstrated that, unexpectedly, the regulatory interactions between GATA1 and PU.1 lead to different outcomes depending on the cellular contexts and the development stages. GATA1/PU.1 cross-antagonism is also modulated by a third factor transcriptional intermediate factor 1 gamma (TIF1 gamma), a chromatin-associated haematopoietic regulator. C1 [Xu, Jian; Orkin, Stuart H.] Childrens Hosp, Howard Hughes Med Inst, Div Hematol Oncol, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Childrens Hosp, Howard Hughes Med Inst, Div Hematol Oncol, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu FU Howard Hughes Medical Institute NR 10 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAR 16 PY 2011 VL 30 IS 6 BP 983 EP 985 DI 10.1038/emboj.2011.45 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 752ER UT WOS:000289672900001 PM 21407249 ER PT J AU Bot, AGJ Doornberg, JN Lindenhovius, ALC Ring, D Goslings, JC van Dijk, CN AF Bot, Arjan G. J. Doornberg, Job N. Lindenhovius, Anneluuk L. C. Ring, David Goslings, J. Carel van Dijk, C. Niek TI Long-Term Outcomes of Fractures of Both Bones of the Forearm SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID COMPRESSION-PLATE FIXATION; HEALTH-STATUS; CHILDREN; RADIUS; ULNA; ADULTS; ARM; COMPLICATIONS; TRAUMA; VALUES AB Background: Previous studies identified limited impairment and disability several years after diaphyseal fractures of both the radius and ulna, although the relationship between impairment and disability was inconsistent. This investigation studied skeletally mature and immature patients more than ten years after injury and addressed the hypotheses that (1) objective measurements of impairment correlate with disability, (2) depression and misinterpretation of nociception correlate with disability, and (3) patients injured when skeletally mature or immature have comparable impairment and disability. Methods: Seventy-one patients with diaphyseal fractures of the radius and ulna were evaluated at an average of twenty-one years after injury. Twenty-five of the thirty-five patients who were skeletally immature at the time of injury were treated nonoperatively, and thirty-one of the thirty-six skeletally mature patients were treated operatively. Objective evaluation included radiographs, functional assessment, and grip strength. Validated questionnaires were used to measure arm-specific disability (the Disabilities of the Arm, Shoulder and Hand [DASH] score), misinterpretation of pain (Pain Catastrophizing Scale [PCS]), and depression (the validated Dutch form of the Center for Epidemiologic Studies-Depression scale [CES-D]). Results: The average DASH score was 8 points (range, 0 to 54); 97% of patients had excellent or satisfactory results according to the criteria of Anderson et al., and 72% reported no pain. Both the forearm rotation and the writ flexion/extension arc was 91% of that seen on the uninjured side; grip strength was 94%. There were small but significant differences in rotation (151 versus 169, p = 0.004) and wrist flexion-extension (123 degrees versus 142 degrees, p = 0.002) compared with the results in the uninjured arm. There was no difference in disability between patients who were skeletally mature or immature at the time of injury. Pain, pain catastrophizing (misinterpretation of nociception), and grip strength were the most important predictors of disability. Conclusions: An average of twenty-one years after sustaining diaphyseal fractures of both the radius and the ulna, patients who were skeletally immature or mature at the time of fracture have comparable disability. Disability correlates better with subjective and psychosocial aspects of illness, such as pain and pain catastrophizing, than with objective measurements of impairment. C1 [Bot, Arjan G. J.; Doornberg, Job N.; Lindenhovius, Anneluuk L. C.; Ring, David; Goslings, J. Carel; van Dijk, C. Niek] Acad Med Ctr, Dept Orthopaed Surg, NL-1100 DD Amsterdam, Netherlands. Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. Acad Med Ctr, Dept Surg, Trauma Unit, NL-1100 DD Amsterdam, Netherlands. RP Bot, AGJ (reprint author), Acad Med Ctr, Dept Orthopaed Surg, Meibergdreef 9, NL-1100 DD Amsterdam, Netherlands. EM a.g.j.bot@gmail.com NR 32 TC 18 Z9 19 U1 0 U2 1 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD MAR 16 PY 2011 VL 93A IS 6 BP 527 EP 532 DI 10.2106/JBJS.J.00581 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 734AN UT WOS:000288305700003 PM 21411702 ER PT J AU Ozdinler, PH Benn, S Yamamoto, TH Guzel, M Brown, RH Macklis, JD AF Oezdinler, P. Hande Benn, Susanna Yamamoto, Ted H. Guezel, Mine Brown, Robert H., Jr. Macklis, Jeffrey D. TI Corticospinal Motor Neurons and Related Subcerebral Projection Neurons Undergo Early and Specific Neurodegeneration in hSOD1(G93A) Transgenic ALS Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; HEREDITARY SPASTIC PARAPLEGIA; SPINAL MUSCULAR-ATROPHY; SUBTYPE-SPECIFIC GENES; PROGRAMMED CELL-DEATH; MOUSE MODEL; SUPEROXIDE-DISMUTASE; CEREBRAL-CORTEX; FAMILIAL ALS; IN-VIVO AB Amyotrophic lateral sclerosis (ALS) is characterized by predominant vulnerability and central degeneration of both corticospinal/corticobulbar motor neurons (CSMN; "upper motor neurons") in cerebral cortex, and spinal/bulbar motor neurons (SMN; "lower motor neurons") in spinal cord and brainstem. Increasing evidence indicates broader cerebral cortex pathology in cognitive, sensory, and association systems in select cases. It remains unclear whether widely accepted transgenic ALS models, in particular hSOD1(G93A) mice, undergo degeneration of CSMN and molecularly/developmentally closely related populations of nonmotor projection neurons [e.g., other subcerebral projection neurons (SCPN)], and whether potential CSMN/SCPN degeneration is specific and early. This relative lack of knowledge regarding upper motor neuron pathology in these ALS model mice has hindered both molecular-pathophysiologic understanding of ALS and their use toward potential CSMN therapeutic approaches. Here, using a combination of anatomic, cellular, transgenic labeling, and newly available neuronal subtype-specific molecular analyses, we identify that CSMN and related nonmotor SCPN specifically and progressively degenerate in hSOD1(G93A) mice. Degeneration starts quite early and presymptomatically, by postnatal day 30. Other neocortical layers, cortical interneurons, and other projection neuron populations, even within layer V, are not similarly affected. Nonneuronal pathology in neocortex (activated astroglia and microglia) is consistent with findings in human ALS cortex and in affected mouse and human spinal cord. These results indicate previously unknown neuron type-specific vulnerability of CSMN/sensory and association SCPN, and identify that characteristic dual CSMN and SMN degeneration is conserved in hSOD1(G93A) mice. These results provide a foundation for detailed investigation of CSMN/SCPN vulnerability and toward potential CSMN therapeutics in ALS. C1 [Oezdinler, P. Hande; Yamamoto, Ted H.; Guezel, Mine; Macklis, Jeffrey D.] Harvard Univ, Sch Med, Dept Neurosurg, MGH HMS Ctr Nervous Syst Repair, Boston, MA 02114 USA. [Oezdinler, P. Hande; Yamamoto, Ted H.; Guezel, Mine; Macklis, Jeffrey D.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Oezdinler, P. Hande; Yamamoto, Ted H.; Guezel, Mine; Macklis, Jeffrey D.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02114 USA. [Oezdinler, P. Hande; Yamamoto, Ted H.; Guezel, Mine; Macklis, Jeffrey D.] Harvard Univ, Massachusetts Gen Hosp, Nayef Al Rodhan Labs, Boston, MA 02114 USA. [Oezdinler, P. Hande; Yamamoto, Ted H.; Guezel, Mine; Macklis, Jeffrey D.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Boston, MA 02114 USA. [Oezdinler, P. Hande; Yamamoto, Ted H.; Guezel, Mine; Macklis, Jeffrey D.] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02114 USA. [Benn, Susanna; Brown, Robert H., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,MassGeneral Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. RP Macklis, JD (reprint author), Harvard Univ, Sch Med, Dept Neurosurg, MGH HMS Ctr Nervous Syst Repair, Boston, MA 02114 USA. EM ozdinler@northwestern.edu; jeffrey_macklis@hms.harvard.edu FU National Institutes of Health [NS49553, NS41590, NS45523]; ALS Association; Harvard Stem Cell Institute; Les Turner ALS Foundation; Harvard NeuroDiscovery Center FX This work was supported by grants from the National Institutes of Health (NS49553; additional infrastructure provided by NS41590 and NS45523), the ALS Association, and the Harvard Stem Cell Institute to J.D.M., and the Les Turner ALS Foundation to P.H.O. P.H.O. was partially supported by a fellowship from the Harvard NeuroDiscovery Center, and by a program grant from the Harvard Stem Cell Institute to J.D.M. We thank K. Billmers, A. Palmer, A. Sanders, M. Jonathan for technical assistance; members of the Macklis and Brown laboratories for important input and suggestions; and E. Azim, S. Sohur, and J. Emsley for critical reading of an earlier version of this manuscript. NR 72 TC 59 Z9 59 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 16 PY 2011 VL 31 IS 11 BP 4166 EP 4177 DI 10.1523/JNEUROSCI.4184-10.2011 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 735YC UT WOS:000288455700024 PM 21411657 ER PT J AU Luikart, BW Schnell, E Washburn, EK Bensen, AL Tovar, KR Westbrook, GL AF Luikart, Bryan W. Schnell, Eric Washburn, Eric K. Bensen, AeSoon L. Tovar, Kenneth R. Westbrook, Gary L. TI Pten Knockdown In Vivo Increases Excitatory Drive onto Dentate Granule Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AUTISM SPECTRUM DISORDERS; LHERMITTE-DUCLOS-DISEASE; SOCIAL-INTERACTION; SOMA SIZE; INHIBITION; MUTATION; GENE; MICE; PROLIFERATION; TRANSMISSION AB Some cases of autism spectrum disorder have mutations in the lipid phosphatase, phosphatase and tensin homolog on chromosome 10 (Pten). Tissue specific deletion of Pten in the hippocampus and cortex of mice causes anatomical and behavioral abnormalities similar to human autism. However, the impact of reductions in Pten on synaptic and circuit function remains unexplored. We used in vivo stereotaxic injections of lentivirus expressing a short hairpin RNA to knock down Pten in mouse neonatal and young adult dentate granule cells. We then assessed the morphology and synaptic physiology between 2 weeks and 4 months later. Confocal imaging of the hippocampus revealed a marked increase in granule cell size and an increase in dendritic spine density. The onset of morphological changes occurred earlier in neonatal mice than in young adults. We used whole-cell recordings from granule cells in acute slices to assess synaptic function after Pten knockdown. Consistent with the increase in dendritic spines, the frequency of excitatory miniature and spontaneous postsynaptic currents increased. However, there was little or no effect on IPSCs. Thus, Pten knockdown results in an imbalance between excitatory and inhibitory synaptic activity. Because reductions in Pten affected mature granule cells as well as developing granule cells, we suggest that the disruption of circuit function by Pten hypofunction may be ongoing well beyond early development. C1 [Luikart, Bryan W.; Washburn, Eric K.; Bensen, AeSoon L.; Tovar, Kenneth R.; Westbrook, Gary L.] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. [Schnell, Eric] Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Portland, OR 97239 USA. [Schnell, Eric] Oregon Hlth & Sci Univ, Dept Anesthesia & Perioperat Med, Portland, OR 97239 USA. RP Luikart, BW (reprint author), Dartmouth Med Sch, Dept Neurobiol & Physiol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM bryan.w.luikart@dartmouth.edu RI Luikart, Bryan/D-2683-2012; OI Schnell, Eric/0000-0002-5623-5015 FU National Institutes of Health [T32NS007381, F32MH079548, MH46613] FX This work was supported by National Institutes of Health Grants T32NS007381, F32MH079548 (B.W.L.), and MH46613 (G.L.W.). We thank Cooper French, Stephen Magill, Mike Walogorsky, and Karin Mullendorff for their contributions to this work. NR 34 TC 61 Z9 61 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 16 PY 2011 VL 31 IS 11 BP 4345 EP 4354 DI 10.1523/JNEUROSCI.0061-11.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 735YC UT WOS:000288455700041 PM 21411674 ER PT J AU Sachs, DH AF Sachs, David H. TI Mark Pescovitz, M.D. (1955-2010) IN MEMORIAM SO TRANSPLANTATION LA English DT Biographical-Item C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. RP Sachs, DH (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Bldg 149-9019,13th St, Boston, MA 02129 USA. EM david.sachs@tbrc.mgh.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAR 15 PY 2011 VL 91 IS 5 BP 487 EP 488 DI 10.1097/TP.0b013e31821060d1 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 722ZJ UT WOS:000287474300001 PM 21343875 ER PT J AU Magnani, JW Johnson, VM Sullivan, LM Gorodeski, EZ Schnabel, RB Lubitz, SA Levy, D Ellinor, PT Benjamin, EJ AF Magnani, Jared W. Johnson, Victor M. Sullivan, Lisa M. Gorodeski, Eiran Z. Schnabel, Renate B. Lubitz, Steven A. Levy, Daniel Ellinor, Patrick T. Benjamin, Emelia J. TI P Wave Duration and Risk of Longitudinal Atrial Fibrillation in Persons >= 60 Years Old (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID FAILURE; INTERVAL; PROFILE; INDEXES; DISEASE; STROKE AB Long-term risk prediction is a priority for the prevention of atrial fibrillation (AF). P wave indices are electrocardiographic measurements describing atrial conduction. The role of P wave indices in the prospective determination of AF and mortality risk has had limited assessment. We quantified by digital caliper the P wave indices of maximum duration and dispersion in 1,550 Framingham Heart Study participants >= 60 years old (58% women) from single-channel electrocardiograms recorded from 1968 through 1971. We examined the association of selected P wave indices and long-term outcomes using Cox proportional hazards regression incorporating age, gender, body mass index, systolic blood pressure, treatment for hypertension, significant murmur, heart failure, and PR interval. Over a median follow-up of 15.8 years (range 0 to 38.7), 359 participants developed AF and 1,525 died. Multivariable-adjusted hazard ratios (HRs) per SD increase in maximum P wave duration were 1.15 (95% confidence interval [CI] 0.90 to 1.47, p = 0.27) for AF and 1.02 (95% CI 0.96 to 1.08, p = 0.18) for mortality. The upper 5% of P wave maximum duration had a multivariable-adjusted HR of 2.51 (95% CI 1.13 to 5.57, p = 0.024) for AF and an HR of 1.11 (95% CI 0.87 to 1.40, p = 0.20) for mortality. We found no significant associations between P wave dispersion with incidence of AF or mortality. In conclusion, maximum P wave duration at the upper fifth percentile was associated with long-term AF risk in an elderly community-based cohort. P wave duration is an electrocardiographic endophenotype for AF. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107: 917-921) C1 [Magnani, Jared W.; Benjamin, Emelia J.] Boston Univ, Sch Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Magnani, Jared W.; Levy, Daniel; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Johnson, Victor M.; Sullivan, Lisa M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Gorodeski, Eiran Z.] Cleveland Clin, Inst Heart & Vasc, Cleveland, OH 44106 USA. [Schnabel, Renate B.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Mainz, Germany. [Schnabel, Renate B.] Gutenberg Heart Study Div Prevent Med, Mainz, Germany. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Magnani, JW (reprint author), Boston Univ, Sch Med, Sect Cardiovasc Med, Boston, MA 02118 USA. EM jmagnani@bu.edu RI Schnabel, Renate/F-6527-2014; OI Gorodeski, Eiran/0000-0003-3756-8831; Sullivan, Lisa/0000-0003-0726-7149; Benjamin, Emelia/0000-0003-4076-2336 FU American Heart Association, Dallas, Texas [09FTF2190028]; National Institutes of Health, Bethesda, Maryland [N01-HC 25195, RC1HL101056, 1R01HL102214, 1HL104156, HL092577] FX This research was funded by Award 09FTF2190028 from the American Heart Association, Dallas, Texas to Dr. Magnani and Grants N01-HC 25195, RC1HL101056, and 1R01HL102214 (Dr. Benjamin), 1HL104156 (Dr. Ellinor), and HL092577 (Dr. Ellinor and Dr. Benjamin) from the National Institutes of Health, Bethesda, Maryland. NR 19 TC 60 Z9 64 U1 1 U2 7 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 MAR 15 PY 2011 VL 107 IS 6 BP 917 EP 921 DI 10.1016/j.amjcard.2010.10.075 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 740WO UT WOS:000288825300019 PM 21255761 ER PT J AU Tsao, CW Gona, P Salton, C Danias, PG Blease, S Hoffmann, U Fox, CS Albert, M Levy, D O'Donnell, CJ Manning, WJ Yeon, SB AF Tsao, Connie W. Gona, Philimon Salton, Carol Danias, Peter G. Blease, Susan Hoffmann, Udo Fox, Caroline S. Albert, Mark Levy, Daniel O'Donnell, Christopher J. Manning, Warren J. Yeon, Susan B. TI Subclinical and Clinical Correlates of Left Ventricular Wall Motion Abnormalities in the Community SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY CALCIUM; MAGNETIC-RESONANCE; MYOCARDIAL-INFARCTION; HEART-DISEASE; PROGNOSTIC-SIGNIFICANCE; CARDIOVASCULAR-DISEASE; COMPUTED-TOMOGRAPHY; FOLLOW-UP; POPULATION; ATHEROSCLEROSIS AB The prevalence and clinical correlates of left ventricular (LV) wall motion abnormalities (WMAs), associated with morbidity and mortality, have not been well-characterized in the population. Framingham Heart Study Offspring Cohort participants (n = 1,794, 844 men, age 65 9 years) underwent cine cardiovascular magnetic resonance for evaluation of LV function. A subset (n = 1,009, 460 men) underwent cardiac multidetector computed tomography for analysis of coronary artery calcium. The presence of coronary heart disease and heart failure (CHD-HF) were assessed in relation to the presence of WMAs. WMAs were present in 117 participants (6.5%) and were associated with male gender, elevated hemoglobin Ale, LV mass, LV end-diastolic volume, and lower LV ejection fraction. Of the 1,637 participants without CHD-HF, 68 (4.2%) had WMAs. In this group, WMAs were associated with obesity, hypertension, and Framingham coronary heart disease risk score in the age- and gender-adjusted analyses and were associated with male gender and hypertension on multivariate analysis. Most subjects with WMAs were in the greatest coronary artery calcium groups. The presence of coronary artery calcium greater than the seventy-fifth percentile and Agatston score > 100. were associated with a greater than twofold risk of WMAs in the age- and gender-adjusted analysis but were no longer significant when additionally adjusted for CHD-HF. Previous Q-wave myocardial infarction was present in 29% of the 117 participants with WMAs. In conclusion, in the present longitudinally followed free-living population, 4.2% of the participants without CHD-HF had WMAs. WMAs were associated with the clinical parameters associated with cardiovascular disease risk. Aggressive risk factor modification may be prudent for subjects with WMAs, particularly those free of clinical CHD-HF. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:949-955) C1 [Tsao, Connie W.; Salton, Carol; Danias, Peter G.; Manning, Warren J.; Yeon, Susan B.] Beth Israel Deaconess Med Ctr, Harvard Thorndike Lab, Boston, MA 02215 USA. [Tsao, Connie W.; Salton, Carol; Danias, Peter G.; Manning, Warren J.; Yeon, Susan B.] Beth Israel Deaconess Med Ctr, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. [Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. [Gona, Philimon] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Gona, Philimon; Blease, Susan; Fox, Caroline S.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Metab & Diabet, Boston, MA 02115 USA. [Albert, Mark] Michigan State Univ, Coll Human Med, Grand Rapids, MI USA. [O'Donnell, Christopher J.] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. RP Yeon, SB (reprint author), Beth Israel Deaconess Med Ctr, Harvard Thorndike Lab, Boston, MA 02215 USA. EM syeon@bidmc.harvard.edu FU National Heart, Lung, and Blood Institute, Bethesda, Maryland [N01-HC-25195]; National Institutes of Health, Bethesda, Maryland [1RO1 HL70279, T32 HL07374] FX The Framingham Heart Study was supported by contract N01-HC-25195 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. The present study was supported in part by grant 1RO1 HL70279 and training grant T32 HL07374 (to C. W. Tsao) from the National Institutes of Health, Bethesda, Maryland. NR 25 TC 5 Z9 5 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 MAR 15 PY 2011 VL 107 IS 6 BP 949 EP 955 DI 10.1016/j.amjcard.2010.11.014 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 740WO UT WOS:000288825300025 PM 21247548 ER PT J AU Maire, CL Ligon, KL AF Maire, Cecile L. Ligon, Keith L. TI Glioma Models: New GEMMs Add "Class" with Genomic and Expression Correlations SO CANCER CELL LA English DT Editorial Material ID GLIOBLASTOMA; MEDULLOBLASTOMA; SUBTYPES AB Malignant gliomas are characterized by accumulated aberrations affecting TP53, PTEN, and RB1 signaling. In this issue, Chow et al. discover that combinatorial loss of these tumor suppressors in mice induces gliomas with unexpected degrees of similarity to human pathologic, genomic, and expression subclasses recently revealed by large-scale genomic studies. C1 [Maire, Cecile L.; Ligon, Keith L.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Dept Med Oncol, Boston, MA 02215 USA. [Ligon, Keith L.] Brigham & Womens Hosp, Dept Pathol, Div Neuropathol, Boston, MA 02115 USA. [Ligon, Keith L.] Childrens Hosp Boston, Dept Pathol, Div Neuropathol, Boston, MA 02115 USA. [Ligon, Keith L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Ligon, KL (reprint author), Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM keith_ligon@dfci.harvard.edu OI Ligon, Keith/0000-0002-7733-600X NR 10 TC 2 Z9 2 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD MAR 15 PY 2011 VL 19 IS 3 BP 295 EP 297 DI 10.1016/j.ccr.2011.02.018 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 738LY UT WOS:000288642500001 PM 21397851 ER PT J AU Mehta, S Huillard, E Kesari, S Maire, CL Golebiowski, D Harrington, EP Alberta, JA Kane, MF Theisen, M Ligon, KL Rowitch, DH Stiles, CD AF Mehta, Shwetal Huillard, Emmanuelle Kesari, Santosh Maire, Cecile L. Golebiowski, Diane Harrington, Emily P. Alberta, John A. Kane, Michael F. Theisen, Matthew Ligon, Keith L. Rowitch, David H. Stiles, Charles D. TI The Central Nervous System-Restricted Transcription Factor Olig2 Opposes p53 Responses to Genotoxic Damage in Neural Progenitors and Malignant Glioma SO CANCER CELL LA English DT Article ID INTEGRATED GENOMIC ANALYSIS; GROWTH-FACTOR RECEPTOR; CANCER STEM-CELLS; LOW-GRADE GLIOMAS; IN-VIVO; SUCCESSFUL CHEMOTHERAPY; SELF-RENEWAL; GENES; PATHWAY; OLIGODENDROGLIOMA AB High-grade gliomas are notoriously insensitive to radiation and genotoxic drugs. Paradoxically, the p53 gene is structurally intact in the majority of these tumors. Resistance to genotoxic modalities in p53-positive gliomas is generally attributed to attenuation of p53 functions by mutations of other components within the p53 signaling axis, such as p14(Arf), MDM2, and ATM, but this explanation is not entirely satisfactory. We show here that the central nervous system (CNS)-restricted transcription factor Olig2 affects a key posttranslational modification of p53 in both normal and malignant neural progenitors and thereby antagonizes the interaction of p53 with promoter elements of multiple target genes. In the absence of Olig2 function, even attenuated levels of p53 are adequate for biological responses to genotoxic damage. C1 [Huillard, Emmanuelle; Harrington, Emily P.; Rowitch, David H.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Huillard, Emmanuelle; Harrington, Emily P.; Rowitch, David H.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Huillard, Emmanuelle; Harrington, Emily P.; Rowitch, David H.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Mehta, Shwetal; Golebiowski, Diane; Alberta, John A.; Kane, Michael F.; Stiles, Charles D.] Dept Canc Biol, Boston, MA 02115 USA. [Kesari, Santosh; Maire, Cecile L.; Theisen, Matthew; Ligon, Keith L.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kesari, Santosh] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92093 USA. [Ligon, Keith L.] Brigham & Womens Hosp, Div Neuropathol, Dept Pathol, Boston, MA 02115 USA. RP Rowitch, DH (reprint author), Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. EM rowitchd@peds.ucsf.edu; charles_stiles@dfci.harvard.edu RI Kesari, Santosh/E-8461-2013 FU NINDS [NS05563, NS040511, NS057727, NS047213]; Pediatric Low-Grade Astrocytoma Foundation FX recipient of the NRSA fellowship NS05563 from NINDS. This work was supported by grants from the NINDS (NS040511, NS057727, and NS047213 to D.H.R., C.D.S., and K.L.L respectively) and from the Pediatric Low-Grade Astrocytoma Foundation. D.H.R is a Howard Hughes Medical Institute Investigator. NR 70 TC 61 Z9 65 U1 1 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD MAR 15 PY 2011 VL 19 IS 3 BP 359 EP 371 DI 10.1016/j.ccr.2011.01.035 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 738LY UT WOS:000288642500009 PM 21397859 ER PT J AU Anderson, KC AF Anderson, Kenneth C. TI Oncogenomics to Target Myeloma in the Bone Marrow Microenvironment SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEASOME INHIBITOR PS-341; DIAGNOSED MULTIPLE-MYELOMA; LENALIDOMIDE PLUS DEXAMETHASONE; UNDETERMINED SIGNIFICANCE MGUS; RANDOMIZED CONTROLLED-TRIAL; OVERCOMES DRUG-RESISTANCE; IN-VIVO CYTOTOXICITY; MONOCLONAL GAMMOPATHY; PHASE-III; MOLECULAR CLASSIFICATION AB Multiple myeloma (MM) is an example of rapid bench-to-bedside translation in new drug development. Bortezomib and lenalidamide target the tumor cell in the bone marrow microenvironment to overcome drug resistance in laboratory and animal models; each is effective to treat relapsed and/or refractory, relapsed, and newly diagnosed MM, and both are now showing promise as maintenance therapy. Major ongoing translational research efforts include improved classification and personalized therapies; identification and validation of next-generation agents targeting the tumor cell in its microenvironment; novel immune therapies; rationally based combination therapies; and use of novel agents to delay or prevent development of active MM. This paradigm of targeting the tumor in its microenvironment has already extended median survival in MM from 3 to 7 to 8 years and has great potential to improve patient outcome in other hematologic malignancies and solid tumors as well. Clin Cancer Res; 17(6); 1225-33. (C)2011 AACR. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM kenneth_anderson@dfci.harvard.edu NR 80 TC 38 Z9 41 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 MAR 15 PY 2011 VL 17 IS 6 BP 1225 EP 1233 DI 10.1158/1078-0432.CCR-10-3366 PG 9 WC Oncology SC Oncology GA 735RR UT WOS:000288435300004 PM 21411438 ER PT J AU Munshi, NC Avet-Loiseau, H AF Munshi, Nikhil C. Avet-Loiseau, Herve TI Genomics in Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID IN-SITU HYBRIDIZATION; STEM-CELL TRANSPLANTATION; HIGH-DOSE THERAPY; ADVERSE PROGNOSTIC-FACTOR; GROWTH-FACTOR RECEPTOR-3; P53 GENE DELETION; CHROMOSOME-13 ABNORMALITIES; MOLECULAR CLASSIFICATION; INTERGROUPE FRANCOPHONE; COMPLETE REMISSIONS AB Multiple myeloma (MM) is a complex disease that is driven by numerous genetic and epigenetic alterations. Comprehensive oncogenomic analysis indicates the presence of many highly recurrent and highly focal amplifications and/or deletions in the MM genome. Integrated oncogenomic analyses of human MM have identified candidates resident within regions of amplification and/or deletions that are predicted to be involved in MM pathogenesis and progression. The biological behavior and clinical outcome in MM are dependent on these molecular determinants, which are also attractive therapeutic targets. The data obtained from extensive analysis of patient samples, with annotated clinical outcomes, are providing insights into molecular mechanisms of disease behavior, helping to develop sensitive prognostic models, identifying novel therapeutic targets, providing the framework for the development of molecularly based therapies, and, eventually, will help in developing individualized therapy to improve outcomes, with reduced toxicity. Clin Cancer Res; 17(6); 1234-42. (C)2011 AACR. C1 [Munshi, Nikhil C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Munshi, Nikhil C.] VA Boston Healthcare Syst, Boston, MA USA. [Avet-Loiseau, Herve] Univ Hosp, Hematol Lab, Nantes, France. [Avet-Loiseau, Herve] INSERM, U892, Nantes, France. RP Munshi, NC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,D1B28, Boston, MA 02115 USA. EM nikhil_munshi@dfci.harvard.edu; havetloiseau@chu-nantes.fr FU NIH [PO1 CA155258-01, RO1-124929, P50-100007, PO1-78378]; Department of Veterans Affairs; Intergroupe Francophone du Myelome; French Institut National du [R09076NN] FX This study was supported in part by the NIH grant PO1 CA155258-01 (N.C. Munshi and H. Avet-Loiseau), RO1-124929, P50-100007, PO1-78378, and Department of Veterans Affairs Merit Review Awards (N.C. Munshi); Intergroupe Francophone du Myelome; and the French Institut National du Cancer grant R09076NN (H. Avet-Loiseau). NR 60 TC 48 Z9 50 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 MAR 15 PY 2011 VL 17 IS 6 BP 1234 EP 1242 DI 10.1158/1078-0432.CCR-10-1843 PG 9 WC Oncology SC Oncology GA 735RR UT WOS:000288435300005 PM 21411439 ER PT J AU Lonial, S Mitsiades, CS Richardson, PG AF Lonial, Sagar Mitsiades, Constantine S. Richardson, Paul G. TI Treatment Options for Relapsed and Refractory Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID PEGYLATED LIPOSOMAL DOXORUBICIN; STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; EXTENDED FOLLOW-UP; HISTONE-DEACETYLASE INHIBITORS; HIGH-DOSE DEXAMETHASONE; PHASE-II; ORAL CYCLOPHOSPHAMIDE; CLINICAL-IMPLICATIONS; COMBINATION THERAPY AB Treatment options for patients with relapsed myeloma have benefited from the development of new targeted agents. The use of bortezomib, thalidomide, and lenalidomide have dramatically changed outcomes for patients with relapsed myeloma. New agents are also in development, on the basis of preclinical rationale, as well as combinations of conventional and novel agents. Together each of these treatment approaches are being tested in phase I, II, and III clinical trials, with the goal of prolonged duration of remission and, ultimately, improved overall survival. Clin Cancer Res; 17(6); 1264-77. (C)2011 AACR. C1 [Lonial, Sagar] Emory Univ, Sch Med, Winship Canc Inst, Dept Hematol & Med Oncol, Atlanta, GA USA. [Mitsiades, Constantine S.; Richardson, Paul G.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Dept Med Oncol, Boston, MA 02115 USA. RP Lonial, S (reprint author), 1365 Clifton Rd,Bldg C,Room 4004, Atlanta, GA 30322 USA. EM sloni01@emory.edu FU PharmaMar; OSI Pharmaceuticals, Amgen; AVEO Pharma; EMD Serono; Sunesis; Gloucester Pharmaceuticals, Genzyme; Johnson Johnson; Rick Corman Multiple Myeloma Research Fund FX S. Lonial, consultant, Millennium, Celgene, BMS, Novartis, Merck, Onyx. P.G. Richardson, consultant, Millennium, Celgene, Johnson & Johnson, Novartis. C.S. Mitsiades, consultant honoraria from Millennium Pharmaceuticals, Novartis Pharmaceuticals, Bristol-Myers Squibb, Merck & Co., Kosan Pharmaceuticals, Pharmion and Centocor; licensing royalties from PharmaMar; and research funding from OSI Pharmaceuticals, Amgen, AVEO Pharma, EMD Serono, Sunesis, Gloucester Pharmaceuticals, Genzyme, and Johnson & Johnson.; The authors would like to express their sincere thanks to Katherine Redman for administrative and editorial assistance with this article, which was in part supported by the Rick Corman Multiple Myeloma Research Fund. NR 142 TC 78 Z9 83 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2011 VL 17 IS 6 BP 1264 EP 1277 DI 10.1158/1078-0432.CCR-10-1805 PG 14 WC Oncology SC Oncology GA 735RR UT WOS:000288435300008 PM 21411442 ER PT J AU Raje, N Roodman, GD AF Raje, Noopur Roodman, G. David TI Advances in the Biology and Treatment of Bone Disease in Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; KAPPA-B LIGAND; CELL-ACTIVATING FACTOR; MARROW STROMAL CELLS; IN-VIVO; OSTEOCLAST FORMATION; INHIBITS OSTEOCLASTOGENESIS; MICRODAMAGE ACCUMULATION; THERAPEUTIC IMPLICATIONS; RECEPTOR ACTIVATOR AB Osteolytic bone disease is pathognomonic of multiple myeloma (MM) and affects more than 80% of patients. Bone disease results in skeletal-related events (SRE) such as vertebral compression fractures, which may cause cord compression, hypercalcemia, pathologic fractures that require radiation or surgical fixation, and severe pain. All of these not only result in a negative impact on quality of life but also adversely impact overall survival. Osteolytic disease is a consequence of increased osteoclast (OC) activation along with osteoblast (OB) inhibition, resulting in altered bone remodeling. OC number and activity are increased in MM via cytokine deregulation within the bone marrow (BM) milieu, whereas negative regulators of OB differentiation suppress bone formation. Bisphosphonates are a well-established treatment of myeloma-related skeletal disease and are the current standard of care. However, complications arising from their long-term use have prompted studies of schedule optimization and alternate strategies. Several novel agents are currently under investigation for their positive effect on bone remodeling via OC inhibition. The identification of negative regulators of OB differentiation has prompted the use of anabolic agents. In addition to restoring bone remodeling, these drugs may inhibit tumor growth in vivo. Future studies will look to combine or sequence all of these agents with the goal of not only alleviating morbidity from bone disease but also capitalizing on the resultant antitumor activity. Clin Cancer Res; 17(6); 1278-86. (C)2011 AACR. C1 [Raje, Noopur] Massachusetts Gen Hosp, MGH Canc Ctr, Div Hematol Oncol, Boston, MA 02114 USA. [Raje, Noopur] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Roodman, G. David] Univ Pittsburgh, Sch Med, Div Hematol Oncol, Pittsburgh, PA USA. [Roodman, G. David] Virginia Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Raje, N (reprint author), Massachusetts Gen Hosp, MGH Canc Ctr, Div Hematol Oncol, 55 Fruit St, Boston, MA 02114 USA. EM nraje@partners.org FU Acetylon; AstraZeneca FX N. Raje, commercial research grant, Acetylon, AstraZeneca; consultant, Celgene, Amgen, Novartis. G. D. Roodman disclosed no potential conflicts of interest. NR 88 TC 68 Z9 73 U1 1 U2 6 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 MAR 15 PY 2011 VL 17 IS 6 BP 1278 EP 1286 DI 10.1158/1078-0432.CCR-10-1804 PG 9 WC Oncology SC Oncology GA 735RR UT WOS:000288435300009 PM 21411443 ER PT J AU Rudd, ML Price, JC Fogoros, S Godwin, AK Sgroi, DC Merino, MJ Bell, DW AF Rudd, Meghan L. Price, Jessica C. Fogoros, Sarah Godwin, Andrew K. Sgroi, Dennis C. Merino, Maria J. Bell, Daphne W. TI A Unique Spectrum of Somatic PIK3CA (p110 alpha) Mutations Within Primary Endometrial Carcinomas SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN CANCER; TUMOR-SUPPRESSOR; POOR-PROGNOSIS; GENE-MUTATIONS; HIGH-FREQUENCY; PATHWAY; DOMAIN; PTEN; CARCINOGENESIS; PHOSPHATASE AB Purpose: The goal of this study was to comprehensively define the incidence of mutations in all exons of PIK3CA in both endometrioid endometrial cancer (EEC) and nonendometrioid endometrial cancer (NEEC). Experimental Design: We resequenced all coding exons of PIK3CA and PTEN, and exons 1 and 2 of KRAS, from 108 primary endometrial tumors. Somatic mutations were confirmed by sequencing matched normal DNAs. The biochemical properties of a subset of novel PIK3CA mutations were determined by exogenously expressing wild type and mutant constructs in U2OS cells and measuring levels of AKT(Ser473) phosphorylation. Results: Somatic PIK3CA mutations were detected in 52.4% of 42 EECs and 33.3% of 66 NEECs. Half (29 of 58) of all nonsynonymous PIK3CA mutations were in exons 1-7 and half were in exons 9 and 20. The exons 1-7 mutations localized to the ABD, ABD-RBD linker and C2 domains of p110 alpha. Within these regions, Arg88, Arg93, Gly106, Lys111, Glu365, and Glu453, were recurrently mutated; Arg88, Arg93, and Lys111 formed mutation hotspots. The p110 alpha-R93W, -G106R, -G106V, -K111E, -delP449-L455, and -E453K mutants led to increased levels of phospho-AKT(Ser473) compared to wild-type p110 alpha. Overall, 62% of exons 1-7 PIK3CA mutants and 64% of exons 9-20 PIK3CA mutants were activating; 72% of exon 1-7 mutations have not previously been reported in endometrial cancer. Conclusions: Our study identified a new subgroup of endometrial cancer patients with activating mutations in the amino-terminal domains of p110 alpha; these patients might be appropriate for consideration in clinical trials of targeted therapies directed against the PI3K pathway. Clin Cancer Res; 17(6); 1331-40. (C)2011 AACR. C1 [Rudd, Meghan L.; Price, Jessica C.; Fogoros, Sarah; Bell, Daphne W.] NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. [Merino, Maria J.] NCI, NIH, Bethesda, MD 20892 USA. [Godwin, Andrew K.] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. [Sgroi, Dennis C.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. RP Bell, DW (reprint author), NHGRI, Canc Genet Branch, 50 South Dr,MSC-8000, Bethesda, MD 20892 USA. EM belldaph@mail.nih.gov FU National Human Genome Research Institute/NIH; NIH [R01 CA140323, U01 CA113916, R01-1CA112021-01]; NCI SPORE in breast cancer at Massachusetts General Hospital; Ovarian Cancer Research Fund; Avon Foundation FX The Intramural Program of the National Human Genome Research Institute/NIH (D. W. Bell); NIH R01 CA140323 (A. K. Godwin), U01 CA113916 (A. K. Godwin), NIH R01-1CA112021-01 (D. C. Sgroi), NCI SPORE in breast cancer at Massachusetts General Hospital (D. C. Sgroi), the Ovarian Cancer Research Fund (A. K. Godwin), and the Avon Foundation (D. C. Sgroi). NR 41 TC 99 Z9 99 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 MAR 15 PY 2011 VL 17 IS 6 BP 1331 EP 1340 DI 10.1158/1078-0432.CCR-10-0540 PG 10 WC Oncology SC Oncology GA 735RR UT WOS:000288435300014 PM 21266528 ER PT J AU Liao, S Liu, JQ Lin, PC Shi, T Jain, RK Xu, L AF Liao, Shan Liu, Jieqiong Lin, Peichun Shi, Tony Jain, Rakesh K. Xu, Lei TI TGF-beta Blockade Controls Ascites by Preventing Abnormalization of Lymphatic Vessels in Orthotopic Human Ovarian Carcinoma Models SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; ALTERED EXPRESSION; TUMOR VASCULATURE; MALIGNANT ASCITES; INHIBITS TUMOR; CANCER MODEL; MOUSE MODEL; ANGIOGENESIS; METASTASIS; THERAPY AB Purpose: Ovarian cancer patients with malignant ascites have poor prognosis. The accumulation of ascites is caused by an imbalance between fluid extravasation from the blood vessels and reabsorption by lymphatic vessels. Whereas, the role of TGF-beta in tumor progression has been well studied, the role of TGF-beta in lymphatic vessel function is far from understood. Here, we sought to dissect the role of TGF-beta blockade in the formation of ascites. Experimental Design: We used soluble TGF-beta Receptor II (sT beta RII) to block TGF-beta signaling in two orthotopic human ovarian carcinoma models: SKOV3ip1 and Hey-A8. We measured tumor proliferation, apoptosis, lymphangiogenesis, and angiogenesis by immunohistochemical staining, and examined diaphragm lymphatic vessel network by intraperitoneal injection of a fluorescent dye. Diaphragm lymphatic vessel function was assessed by tracking fluorescent beads in the diaphragm and measuring their drainage rate. Results: TGF-beta blockade impaired tumor growth in both models, accompanied by a decreased tumor cell proliferation and angiogenesis. More strikingly, TGF-beta blockade almost completely abolished ascites formation. TGF-beta blockade significantly inhibited the expression of VEGF, which is the major contributor to ascites formation. At the same time, TGF-beta blockade prevent 'abnormalization' of diaphragm lymphatic vessels and improved ascites drainage. Conclusions: TGF-beta blockade decreased ascites by both inhibiting ascites formation and improving ascites drainage. Based on our finding, it is reasonable to consider the use of TGF-beta blockade as a palliative treatment for symptomatic ascites. Clin Cancer Res; 17(6); 1415-24. (C)2011 AACR. C1 [Liao, Shan; Liu, Jieqiong; Lin, Peichun; Jain, Rakesh K.; Xu, Lei] Massachusetts Gen Hosp, Edwin L Steele Lab, Dept Radiat Oncol, Boston, MA 02114 USA. [Liu, Jieqiong] Cent S Univ, Xiangya Hosp 2, Dept Breast Surg, Changsha, Hunan, Peoples R China. [Shi, Tony] NYU, Coll Arts & Sci, New York, NY USA. RP Xu, L (reprint author), Massachusetts Gen Hosp, Edwin L Steele Lab, Dept Radiat Oncol, 100 Blossom St,Cox 734, Boston, MA 02114 USA. EM lei@steele.mgh.harvard.edu RI Lin, Pei-Chun/A-3200-2013 FU Genzyme; Noxxon; Harvard Medical School; NCI [P01-CA80124]; Federal Share/NCI; Massachusetts Biomedical Research Corporation FX R.K. Jain, consultant, Genzyme and Noxxon. Neither reagent nor financial support from these two companies was used in the current study.; This work was supported in part by Clafflin Distinguished Scholar Award, Harvard Medical School (L. Xu), Program Project Grant P01-CA80124 from NCI (to R.K. Jain) and Federal Share/NCI Proton Beam Program (R.K. Jain) and Tosteson Postdoctoral Fellowship from the Massachusetts Biomedical Research Corporation (S. Liao.). NR 41 TC 25 Z9 26 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2011 VL 17 IS 6 BP 1415 EP 1424 DI 10.1158/1078-0432.CCR-10-2429 PG 10 WC Oncology SC Oncology GA 735RR UT WOS:000288435300022 PM 21278244 ER PT J AU Morikawa, T Baba, Y Yamauchi, M Kuchiba, A Nosho, K Shima, K Tanaka, N Huttenhower, C Frank, DA Fuchs, CS Ogino, S AF Morikawa, Teppei Baba, Yoshifumi Yamauchi, Mai Kuchiba, Aya Nosho, Katsuhiko Shima, Kaori Tanaka, Noriko Huttenhower, Curtis Frank, David A. Fuchs, Charles S. Ogino, Shuji TI STAT3 Expression, Molecular Features, Inflammation Patterns, and Prognosis in a Database of 724 Colorectal Cancers SO CLINICAL CANCER RESEARCH LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; GROWTH-SUPPRESSIVE ACTIVITY; COLON-CANCER; MICROSATELLITE INSTABILITY; SIGNAL TRANSDUCER; TRANSCRIPTION-3 ACTIVATION; FACTOR RECEPTOR; BRAF MUTATION; BETA-CATENIN; CELLS AB Purpose: STAT3 is a transcription factor that is constitutively activated in some cancers. It seems to play crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation, and suppression of antitumor host immune response in the tumor microenvironment. Although the STAT3 signaling pathway is a potential drug target, clinical, pathologic, molecular, or prognostic features of STAT3-activated colorectal cancer remain uncertain. Experimental Design: Utilizing a database of 724 colon and rectal cancer cases, we evaluated phosphorylated STAT3 (p-STAT3) expression by immunohistochemistry. The Cox proportional hazards model was used to compute mortality HR, adjusting for clinical, pathologic, and molecular features, including microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), LINE-1 methylation, 18q LOH, TP53 (p53), CTNNB1 (beta-catenin), JC virus T-antigen, and KRAS, BRAF, and PIK3CA mutations. Results: Among the 724 tumors, 131 (18%) showed high-level p-STAT3 expression (p-STAT3-high), 244 (34%) showed low-level expression (p-STAT3-low), and the remaining 349 (48%) were negative for p-STAT3. p-STAT3 overexpression was associated with significantly higher colorectal cancer-specific mortality [ log-rank P - 0.0020; univariate HR (p-STAT3-high vs. p-STAT3-negative): 1.85, 95% CI: 1.30-2.63, P(trend) = 0.0005; multivariate HR: 1.61, 95% CI: 1.11-2.34, P(trend) = 0.015]. p-STAT3 expression was positively associated with peritumoral lymphocytic reaction (multivariate OR: 3.23; 95% CI: 1.89-5.53, P < 0.0001). p-STAT3 expression was not associated with MSI, CIMP, or LINE-1 hypomethylation. Conclusions: STAT3 activation in colorectal cancer is associated with adverse clinical outcome, supporting its potential roles as a prognostic biomarker and a chemoprevention and/or therapeutic target. Clin Cancer Res; 17(6); 1452-62. (C)2011 AACR. C1 [Ogino, Shuji] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Ctr Mol Oncol Pathol,Dept M, Boston, MA 02115 USA. [Huttenhower, Curtis] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA USA. RP Ogino, S (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Ctr Mol Oncol Pathol,Dept M, 44 Binney St,Room JF-215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu OI Huttenhower, Curtis/0000-0002-1110-0096 FU U.S. NIH [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826, R01 CA151993]; Bennett Family Fund; Entertainment Industry Foundation through National Colorectal Cancer Research Alliance; Japan Society for Promotion of Science FX This work was supported by U.S. NIH grants P01 CA87969 (to S. Hankinson), P01 CA55075 (to W. Willett), P50 CA127003 (to C.S. Fuchs), K07 CA122826 (to S. Ogino), and R01 CA151993 (to S. Ogino) and by grants from the Bennett Family Fund and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. T. Morikawa and K. Nosho were supported by fellowship grants from the Japan Society for Promotion of Science. NR 50 TC 75 Z9 79 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2011 VL 17 IS 6 BP 1452 EP 1462 DI 10.1158/1078-0432.CCR-10-2694 PG 11 WC Oncology SC Oncology GA 735RR UT WOS:000288435300025 PM 21310826 ER PT J AU Sun, T Lee, GSM Oh, WK Freedman, ML Pomerantz, M Pienta, KJ Kantoff, PW AF Sun, Tong Lee, Gwo-Shu Mary Oh, William K. Freedman, Matthew L. Pomerantz, Mark Pienta, Kenneth J. Kantoff, Philip W. TI Inherited Variants in the Chemokine CCL2 Gene and Prostate Cancer Aggressiveness in a Caucasian Cohort SO CLINICAL CANCER RESEARCH LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; ANDROGEN-DEPRIVATION THERAPY; SINGLE-NUCLEOTIDE POLYMORPHISMS; CUMULATIVE ASSOCIATION; PROMOTER POLYMORPHISM; PLASMA-CONCENTRATIONS; IN-VIVO; MCP-1; MACROPHAGE; GROWTH AB Purpose: Though C-C chemokine ligand 2 (CCL2) has been shown to play a pivotal role in prostate cancer tumorigenesis and invasion, the role of inherited variation in the CCL2 gene in prostate cancer progression and metastases remains unanswered. This study is aimed to determine the influence of CCL2 germline variants on prostate cancer aggressiveness. Experimental Design: We performed an association study between six single nucleotide polymorphisms (SNP) in the CCL2 gene and prostate cancer clinicopathologic variables in a large hospital-based Caucasian patient cohort (N = 4,073). Results: Genetic variation at CCL2 is associated with markers of disease aggressiveness. Three SNPs, each in strong linkage disequilibrium, are associated with a higher (>7) biopsy Gleason score: CCL2 - 1811 A/G, -2835 A/C, and +3726 T/C (P = 0.01, 0.03, and 0.04, respectively). The CCL2 - 1811 G allele is addionally associated with advanced pathologic stages in patients who underwent radical prostatectomy (P = 0.04). In haplotype analysis, we found that the frequency of a common haplotype, H5, was higher among patients with D'Amico good risk features (P(permutation) = 0.04). Conclusions: These results support the influence of CCL2 variants on prostate cancer development and progression. Clin Cancer Res; 17(6); 1546-52. (C) 2010 AACR. C1 [Pienta, Kenneth J.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Pienta, Kenneth J.] Michigan Ctr Translat Pathol, Dept Med & Urol, Ann Arbor, MI USA. [Sun, Tong; Lee, Gwo-Shu Mary; Oh, William K.; Freedman, Matthew L.; Pomerantz, Mark; Kantoff, Philip W.] Harvard Univ, Sch Med, Boston, MA USA. [Sun, Tong; Lee, Gwo-Shu Mary; Oh, William K.; Freedman, Matthew L.; Pomerantz, Mark; Kantoff, Philip W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Pienta, KJ (reprint author), Univ Michigan, Ctr Comprehens Canc, Room 7308,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM kpienta@umich.edu; philip_kantoff@dfci.harvard.edu RI Oh, William/B-9163-2012; Pienta, Kenneth/E-7679-2015 OI Oh, William/0000-0001-5113-8147; Pienta, Kenneth/0000-0002-4138-2186 FU SPORE in Prostate Cancer [2 P50 CA090381-06, 2 P50 CA69568-06]; Prostate Cancer Foundation; Department of Defense (DoD) [W81XWH-09-1-0372] FX This work was supported by a SPORE in Prostate Cancer 2 P50 CA090381-06, SPORE in Prostate Cancer 2 P50 CA69568-06, the Prostate Cancer Foundation, and Department of Defense (DoD) Prostate Cancer Training Award W81XWH-09-1-0372. NR 38 TC 8 Z9 9 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 MAR 15 PY 2011 VL 17 IS 6 BP 1546 EP 1552 DI 10.1158/1078-0432.CCR-10-2015 PG 7 WC Oncology SC Oncology GA 735RR UT WOS:000288435300034 PM 21135144 ER PT J AU Janket, SJ Jethwani, K Meurman, JH AF Janket, Sok-Ja Jethwani, Kamal Meurman, Jukka H. TI Invasive Dental Treatment and Risk for Vascular Events SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID DISEASE C1 [Janket, Sok-Ja] Boston Univ, Henry M Goldman Sch Dent Med, Boston, MA 02118 USA. [Jethwani, Kamal] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Meurman, Jukka H.] Univ Helsinki, Cent Hosp, FIN-00290 Helsinki, Finland. RP Janket, SJ (reprint author), Boston Univ, Henry M Goldman Sch Dent Med, Boston, MA 02118 USA. OI Janket, Sok-Ja/0000-0003-0078-3992 NR 5 TC 1 Z9 1 U1 0 U2 3 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 MAR 15 PY 2011 VL 154 IS 6 BP 441 EP 441 DI 10.7326/0003-4819-154-6-201103150-00014 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 734WA UT WOS:000288370000012 PM 21403083 ER PT J AU Dotto, GP AF Dotto, G. Paolo TI Calcineurin Signaling as a Negative Determinant of Keratinocyte Cancer Stem Cell Potential and Carcinogenesis SO CANCER RESEARCH LA English DT Review ID EPITHELIAL-CELLS; INHIBITOR DSCR1; TUMOR-GROWTH; SKIN-CANCER; P53; GENE; NFAT; EXPRESSION; CARCINOMA; NOTCH1 AB Calcineurin is the only known serine-threonine phosphatase under calcium-calmodulin control and key regulator of the immune system. Treatment of patients with calcineurin-inhibitory drugs like cyclosporin A and FK506 to prevent graft rejection dramatically increases the risk of cutaneous squamous cell carcinoma, which is a major cause of death after organ transplants. Recent evidence indicates that suppression of calcineurin signaling, together with its impact on the immune system, exerts direct tumor-promoting effects in keratinocytes, enhancing cancer stem cell potential. The underlying mechanism involves interruption of a double negative regulatory axis, whereby calcineurin and nuclear factors of activated T-cell signaling inhibits expression of ATF3, a negative regulator of p53. The resulting suppression of keratinocyte cancer cell senescence is of likely clinical significance for the many patients under treatment with calcineurin inhibitors and may be of relevance for other cancer types in which altered calcium-calcineurin signaling plays a role. Cancer Res; 71(6); 2029-33. (C) 2011 AACR. C1 [Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Dotto, G. Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. RP Dotto, GP (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. EM Paolo.Dotto@unil.ch FU NIH [AR39190, AR054856]; Swiss National Foundation; Oncosuisse [02361-02-2009] FX This work was supported by grants from NIH (grants AR39190 and AR054856), the Swiss National Foundation, and Oncosuisse (grant 02361-02-2009). NR 41 TC 11 Z9 11 U1 1 U2 6 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 MAR 15 PY 2011 VL 71 IS 6 BP 2029 EP 2033 DI 10.1158/0008-5472.CAN-10-3750 PG 5 WC Oncology SC Oncology GA 734YZ UT WOS:000288381300002 PM 21406393 ER PT J AU Wolfer, A Ramaswamy, S AF Wolfer, Anita Ramaswamy, Sridhar TI MYC and Metastasis SO CANCER RESEARCH LA English DT Review ID TO-MESENCHYMAL TRANSITION; BREAST-CANCER; COLORECTAL-CANCER; GENE-EXPRESSION; STEM-CELLS; AMPLIFICATION; REPRESSION; OVEREXPRESSION; TRANSFORMATION; PROLIFERATION AB Aggressive primary tumors express transcriptional signatures that correlate with their metastatic propensity. A number of these signatures have been deployed in the clinic as risk stratification tools. However, the molecular basis of these clinically useful prognostic signatures has remained a largely unresolved area of controversy. We recently found that many prognostic signatures reflect the activity of the MYC oncogene, which in turn regulates tumor metastasis through specific effects on cancer cell invasion and migration. These findings offer a general framework for understanding the molecular basis of clinically prognostic transcriptional signatures and suggest potentially new avenues for studying metastasis. Cancer Res; 71(6); 2034-7. (C) 2011 AACR. C1 [Wolfer, Anita; Ramaswamy, Sridhar] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Wolfer, Anita; Ramaswamy, Sridhar] Harvard Univ, Sch Med, Boston, MA USA. [Ramaswamy, Sridhar] Broad Inst, Cambridge, MA USA. [Ramaswamy, Sridhar] Harvard Stem Cell Inst, Cambridge, MA USA. RP Ramaswamy, S (reprint author), Massachusetts Gen Hosp, Ctr Canc, 185 Cambridge St, Boston, MA 02114 USA. EM sridhar@mgh.harvard.edu FU Astra Zeneca FX S. Ramaswamy is a recipient of a commercial research grant by Astra Zeneca. NR 39 TC 62 Z9 64 U1 0 U2 6 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 MAR 15 PY 2011 VL 71 IS 6 BP 2034 EP 2037 DI 10.1158/0008-5472.CAN-10-3776 PG 4 WC Oncology SC Oncology GA 734YZ UT WOS:000288381300003 PM 21406394 ER PT J AU Hu, WG Ge, XW You, T Xu, T Zhang, JY Wu, GX Peng, ZH Chorev, M Aktas, BH Halperin, JA Brown, JR Qin, XB AF Hu, Weiguo Ge, Xiaowen You, Tao Xu, Ting Zhang, Jinyan Wu, Gongxiong Peng, Zhihai Chorev, Michael Aktas, Bertal H. Halperin, Jose A. Brown, Jennifer R. Qin, Xuebin TI Human CD59 Inhibitor Sensitizes Rituximab-Resistant Lymphoma Cells to Complement-Mediated Cytolysis SO CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; DECAY-ACCELERATING FACTOR; ANTI-CD20 MONOCLONAL-ANTIBODIES; DEPENDENT CELLULAR CYTOTOXICITY; IN-VIVO; CANCER-IMMUNOTHERAPY; THERAPEUTIC ACTIVITY; EFFECTOR MECHANISMS; REGULATORY PROTEIN; EXPRESSION AB Rituximab efficacy in cancer therapy depends in part on induction of complement-dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulatory protein that restricts the formation of the membrane attack complex, thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell non-Hodgkin's lymphoma (NHL), and upregulation of hCD59 is an important determinant of the sensitivity of NHL cells to rituximab treatment. Here, we report that the potent hCD59 inhibitor rILYd4 enhances CDC in vitro and in vivo, thereby sensitizing rituximab-resistant lymphoma cells and primary chronic lymphocytic leukemia cells (CLL) to rituximab treatment. By defining pharmcokinetic/pharmacodynamic profiles of rILYd4 in mice, we showed that by itself rILYd4 does not adversely mediate in vivo hemolysis of hCD59-expressing erythrocytes. Increasing expression levels of the complement regulators CD59 and CD55 in rituximab-resistant cells occur due to selection of preexisting clones rather than de novo induction of these proteins. Moreover, lymphoma cells overexpressing CD59 were directly responsible for the resistance to rituximab-mediated CDC therapy. Our results rationalize the use of rILYd4 as a therapeutic adjuvant for rituximab treatment of rituximab-resistant lymphoma and CLL. Furthermore, they suggest that preemptive elimination of CD59-overexpressing subpopulations along with rituximab treatment may be a useful approach to ablate or conquer rituximab resistance. Cancer Res; 71(6); 2298-307. (C)2011 AACR. C1 [Hu, Weiguo; Ge, Xiaowen; You, Tao; Zhang, Jinyan; Wu, Gongxiong; Chorev, Michael; Aktas, Bertal H.; Halperin, Jose A.; Qin, Xuebin] Harvard Univ, Lab Translat Res, Sch Med, Cambridge, MA 02139 USA. [Hu, Weiguo; Wu, Gongxiong; Chorev, Michael; Aktas, Bertal H.; Halperin, Jose A.; Qin, Xuebin] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Brown, Jennifer R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Xu, Ting] Sino Recombi Pharma, Suzhou, Peoples R China. [Zhang, Jinyan; Peng, Zhihai] Shanghai Jiao Tong Univ, Dept Gen Surg, Shanghai Peoples Hosp 1, Sch Med, Shanghai 200030, Peoples R China. RP Hu, WG (reprint author), Harvard Univ, Lab Translat Res, Sch Med, 1 Kendall Sq,Bldg 600,3rd Floor, Cambridge, MA 02139 USA. EM weiguo_hu@hms.harvard.edu; xuebin_qin@hms.harvard.edu FU Harvard Technology Development Accelerator Fund [NIHRO1AI061174, NIHR21CA141324]; Natural Science Foundation of China [30972952]; China National Key Technology RD Program [2008BAI60B03]; China Scholarship Council [2009628090]; NIH [K23]; ASH; Leukemia and Lymphoma Society FX NIHRO1AI061174 (to X.B. Qin) and NIHR21CA141324 (to X. B. Qin), Harvard Technology Development Accelerator Fund (to X. B. Qin), and Natural Science Foundation of China (30972952; to Z. Peng), China National Key Technology R&D Program (2008BAI60B03; to Z. Peng), and China Scholarship Council (2009628090 (to X. Ge). J.R. Brown is supported by NIH K23 and an ASH Scholar Award and the Leukemia and Lymphoma Society Scholar in Clinical Research Award. NR 46 TC 35 Z9 39 U1 0 U2 7 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 MAR 15 PY 2011 VL 71 IS 6 BP 2298 EP 2307 DI 10.1158/0008-5472.CAN-10-3016 PG 10 WC Oncology SC Oncology GA 734YZ UT WOS:000288381300029 PM 21252115 ER PT J AU Bin Hafeez, B Zhong, WX Weichert, J Dreckschmidt, NE Jamal, MS Verma, AK AF Bin Hafeez, Bilal Zhong, Weixiong Weichert, Jamey Dreckschmidt, Nancy E. Jamal, Mohammad Sarwar Verma, Ajit K. TI Genetic Ablation of PKC Epsilon Inhibits Prostate Cancer Development and Metastasis in Transgenic Mouse Model of Prostate Adenocarcinoma SO CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE-C; CONSTITUTIVE ACTIVATION; STAT3; PHOSPHORYLATION; INTERACTS; SURVIVAL; INTERLEUKIN-6; STAT3SER727; PROGRESSION; EXPRESSION AB Protein kinase C epsilon (PKC epsilon), a novel PKC isoform, is overexpressed in prostate cancer (PCa) and correlates with disease aggressiveness. However, the functional contribution of PKCe to development or progression of PCa remained to be determined. Here we present the first in vivo genetic evidence that PKCe is essential for both the development and metastasis of PCa in the transgenic mouse model of prostate adenocarcinoma (TRAMP). Heterozygous or homozygous genetic deletions of PKC epsilon in FVB/N TRAMP inhibited PCa development and metastasis as analyzed by positron emission tomography/computed tomography, tumor weight determinations, and histopathology. We also examined biomarkers associated with tumor progression in this model, including markers of survival, proliferation, angiogenesis, inflammation, and metastatic progression. To find clues about the genes regulated by PKC epsilon and linked to the Stat3 signaling pathway, we carried out focused PCR arrays of JAK/STAT signaling in excised PCa tissues from PKCe wild-type and nullizygous TRAMP mice. Notably, PKC epsilon loss was associated with significant downregulation of proliferative and metastatic genes C/EBP beta (CCAAT/enhancer binding protein beta), CRP (C-reactive protein), CMK, EGFR (epidermal growth factor receptor), CD64, Jun B, and gp130. Taken together, our findings offer the first genetic evidence of the role of PKCe in PCa development and metastasis. PKCe may be potential target for prevention and/or treatment of PCa. Cancer Res; 71(6); 2318-27. (C)2011 AACR. C1 [Bin Hafeez, Bilal; Dreckschmidt, Nancy E.; Jamal, Mohammad Sarwar; Verma, Ajit K.] Univ Wisconsin, Dept Human Oncol, Sch Med & Publ Hlth, Paul Carbone Comprehens Canc Ctr,Wisconsin Inst M, Madison, WI 53792 USA. [Zhong, Weixiong] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53792 USA. [Zhong, Weixiong] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Weichert, Jamey] Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, Madison, WI 53792 USA. RP Verma, AK (reprint author), Univ Wisconsin, Dept Human Oncol, Sch Med & Publ Hlth, Paul Carbone Comprehens Canc Ctr,Wisconsin Inst M, Madison, WI 53792 USA. EM akverma@facstaff.wisc.edu RI Jamal, Mohammad/I-1230-2012; Jamal, Mohammad/K-3842-2013 FU DOD [W81XWH]; NIH [CA35368]; UWCCC Cancer Center [2 P30 CA014520-34] FX This study was supported by DOD grant (W81XWH), NIH grant CA35368, and UWCCC Cancer Center Support grant 2 P30 CA014520-34 for small animal imaging facility. NR 27 TC 0 Z9 0 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2011 VL 71 IS 6 BP 2318 EP 2327 DI 10.1158/0008-5472.CAN-10-4170 PG 10 WC Oncology SC Oncology GA 734YZ UT WOS:000288381300031 ER PT J AU Gavathiotis, E Walensky, LD AF Gavathiotis, Evripidis Walensky, Loren D. TI Tracking BAX once its trigger is pulled SO CELL CYCLE LA English DT Editorial Material ID MITOCHONDRIAL-MEMBRANE; ACTIVATION; APOPTOSIS; HELIX; PUMA C1 [Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. Childrens Hosp Boston, Div Hematol Oncol, Boston, MA USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM Loren_Walensky@dfci.harvard.edu FU NCI NIH HHS [R01 CA050239]; NHLBI NIH HHS [K99 HL095929-01A1, K99 HL095929, K99 HL095929-02, R00 HL095929] NR 11 TC 4 Z9 4 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 15 PY 2011 VL 10 IS 6 BP 868 EP 870 DI 10.4161/10.6.15034 PG 3 WC Cell Biology SC Cell Biology GA 734UX UT WOS:000288366400006 PM 21325897 ER PT J AU Joukov, V AF Joukov, Vladimir TI Aurora kinases and spindle assembly Variations on a common theme? SO CELL CYCLE LA English DT Article DE aurora kinases; Cep192; chromosome passenger complex; spindle assembly; microtubule-organizing center; centrosome; kinetochore ID MICROTUBULE-ORGANIZING CENTERS; CHROMOSOMAL PASSENGER COMPLEX; MITOTIC SPINDLE; CELL-DIVISION; B KINASE; A KINASE; CAENORHABDITIS-ELEGANS; CENTROSOME MATURATION; INNER CENTROMERE; PROTEIN-KINASES AB The Aurora A (AurA) serine/threonine kinase controls multiple aspects of cell division and plays a key role in centrosome maturation and bipolar spindle assembly. The pleiotropic functions of AurA depend on its interaction with several cofactors, the best known of which is TPX2. TPX2 targets AurA to spindle microtubules (MTs) and activates it, both allosterically and by protecting the activation loop (T-loop) of the kinase domain from dephosphorylation. Although several factors have been implicated in the regulation of AurA at centrosomes, the underlying mechanism has remained elusive, and the existence of a distinct centrosome-specific AurA activator has been proposed. Our recent study has identified this activator as Cep192/Spd-2, one of the key factors in centrosome biogenesis. Cep192 targets AurA to centrosomes, where it promotes its activation by a novel, oligomerization-dependent mechanism characterized by extensive T-loop phosphorylation and high kinase activity. This process is key to the function of centrosomes as microtubule-organizing centers. Here, our findings are discussed in the context of other recent studies on the Aurora kinases, with an emphasis on their role in spindle assembly. The collected evidence suggests that the 'hot spots' of MT nucleation, centrosomes and kinetochores, rely on the oligomerization-mediated mechanism of activation of AurA and Aurora B, respectively. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol,Dept Genet, Boston, MA 02115 USA. RP Joukov, V (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol,Dept Genet, 44 Binney St, Boston, MA 02115 USA. EM vladimir_joukov@dfci.harvard.edu NR 102 TC 11 Z9 11 U1 1 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 15 PY 2011 VL 10 IS 6 BP 895 EP 903 DI 10.4161/cc.10.6.14909 PG 9 WC Cell Biology SC Cell Biology GA 734UX UT WOS:000288366400015 PM 21325891 ER PT J AU Chin, L Hahn, WC Getz, G Meyerson, M AF Chin, Lynda Hahn, William C. Getz, Gad Meyerson, Matthew TI Making sense of cancer genomic data SO GENES & DEVELOPMENT LA English DT Review ID ARRAY CGH DATA; CELL LUNG-CANCER; NUCLEOTIDE POLYMORPHISM ARRAYS; CONSENSUS CODING SEQUENCES; LINEAGE-SURVIVAL ONCOGENE; AMINO-ACID SUBSTITUTIONS; GENE-EXPRESSION ANALYSIS; ACUTE MYELOID-LEUKEMIA; GROWTH-FACTOR RECEPTOR; TYROSINE KINASE JAK2 AB High-throughput tools for nucleic acid characterization now provide the means to conduct comprehensive analyses of all somatic alterations in the cancer genomes. Both large-scale and focused efforts have identified new targets of translational potential. The deluge of information that emerges from these genome-scale investigations has stimulated a parallel development of new analytical frameworks and tools. The complexity of somatic genomic alterations in cancer genomes also requires the development of robust methods for the interrogation of the function of genes identified by these genomics efforts. Here we provide an overview of the current state of cancer genomics, appraise the current portals and tools for accessing and analyzing cancer genomic data, and discuss emerging approaches to exploring the functions of somatically altered genes in cancer. C1 [Chin, Lynda; Hahn, William C.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chin, Lynda; Hahn, William C.; Getz, Gad; Meyerson, Matthew] Broad Inst Harvard, Cambridge, MA 02142 USA. [Chin, Lynda; Hahn, William C.; Getz, Gad; Meyerson, Matthew] MIT, Cambridge, MA 02142 USA. RP Chin, L (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM lynda_chin@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012 FU NIH [U24CA143845, U24CA144025, U24CA143867]; Cancer Target Discovery and Development) network investigators [NIH RC2CA148268] FX We apologize to colleagues whose studies, algorithms, or portals are not cited in this review due to limitation in space. L.C., G.G., and M.M. are TCGA-funded investigators (NIH U24CA143845, U24CA144025, and U24CA143867). L.C. and W. C.H. are CTD2 (Cancer Target Discovery and Development) network investigators (NIH RC2CA148268). NR 224 TC 136 Z9 138 U1 3 U2 23 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 MAR 15 PY 2011 VL 25 IS 6 BP 534 EP 555 DI 10.1101/gad.2017311 PG 22 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 734VA UT WOS:000288366800002 PM 21406553 ER PT J AU Ng, ACY Eisenberg, JM Heath, RJW Huett, A Robinson, CM Nau, GJ Xavier, RJ AF Ng, Aylwin C. Y. Eisenberg, Jason M. Heath, Robert J. W. Huett, Alan Robinson, Cory M. Nau, Gerard J. Xavier, Ramnik J. TI Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE pathogen-response; anti-bacterial; inflammation; pathogen sensors; autophagy ID CROHNS-DISEASE; SUSCEPTIBILITY; RECOGNITION; DIVERSITY; GENES; CONTRIBUTES; ASSOCIATION; ACTIVATION; EVOLUTION; REVEALS AB In innate immune sensing, the detection of pathogen-associated molecular patterns by recognition receptors typically involve leucine-rich repeats (LRRs). We provide a categorization of 375 human LRR-containing proteins, almost half of which lack other identifiable functional domains. We clustered human LRR proteins by first assigning LRRs to LRR classes and then grouping the proteins based on these class assignments, revealing several of the resulting protein groups containing a large number of proteins with certain non-LRR functional domains. In particular, a statistically significant-number of LRR proteins in the typical (T) and bacterial + typical (S+T) categories have transmembrane domains, whereas most of the LRR proteins in the cysteine-containing (CC) category contain an F-box domain (which mediates interactions with the E3 ubiquitin ligase complex). Furthermore, by examining the evolutionary profiles of the LRR proteins, we identified a subset of LRR proteins exhibiting strong conservation in fungi and an enrichment for "nucleic acid-binding" function. Expression analysis of LRR genes identifies a subset of pathogen-responsive genes in human primary macrophages infected with pathogenic bacteria. Using functional RNAi, we show that MFHAS1 regulates Toll-like receptor (TLR)-dependent signaling. By using protein interaction network analysis followed by functional RNAi, we identified LRSAM1 as a component of the antibacterial autophagic response. C1 [Ng, Aylwin C. Y.; Eisenberg, Jason M.; Heath, Robert J. W.; Huett, Alan; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Ng, Aylwin C. Y.; Eisenberg, Jason M.; Heath, Robert J. W.; Huett, Alan; Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Ng, Aylwin C. Y.; Eisenberg, Jason M.; Heath, Robert J. W.; Huett, Alan; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ng, Aylwin C. Y.; Eisenberg, Jason M.; Xavier, Ramnik J.] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA 02142 USA. [Robinson, Cory M.; Nau, Gerard J.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15261 USA. RP Xavier, RJ (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. EM xavier@molbio.mgh.harvard.edu OI Nau, Gerard/0000-0001-7921-8317 FU National Institutes of Health [AI062773, DK83756, DK060049]; Crohn's and Colitis Foundation of America FX We thank Mark Daly and Fred Ausubel for helpful discussions. This work was supported by National Institutes of Health Grants AI062773, DK83756, DK060049, and DK060049 (to R.J.X., R.J.W.H., and J.E.) and a Research Fellowship Award from the Crohn's and Colitis Foundation of America (to A.C.Y.N.). NR 42 TC 52 Z9 54 U1 1 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 MAR 15 PY 2011 VL 108 SU 1 BP 4631 EP 4638 DI 10.1073/pnas.1000093107 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 735WM UT WOS:000288451300017 PM 20616063 ER PT J AU Li, XA Krishnan, L Cherepanov, P Engelman, A AF Li, Xiang Krishnan, Lavanya Cherepanov, Peter Engelman, Alan TI Structural biology of retroviral DNA integration SO VIROLOGY LA English DT Review DE HIV-1; Prototype foamy virus; Integrase; Integration; AIDS; Integrase strand transfer inhibitor; Raltegravir; Structural biology; X-ray crystallography ID HUMAN-IMMUNODEFICIENCY-VIRUS; STRAND TRANSFER INHIBITORS; PROTEIN IN-VITRO; REFINED SOLUTION STRUCTURE; CARBOXYL-TERMINAL DOMAINS; SITE-DIRECTED MUTAGENESIS; ZINC-BINDING DOMAIN; HIV-1 INTEGRASE; CATALYTIC DOMAIN; AVIAN-SARCOMA AB Three-dimensional macromolecular structures shed critical light on biological mechanism and facilitate development of small molecule inhibitors. Clinical success of raltegravir, a potent inhibitor of HIV-1 integrase, demonstrated the utility of this viral DNA recombinase as an antiviral target. A variety of partial integrase structures reported in the past 16 years have been instrumental and very informative to the field. Nonetheless, because integrase protein fragments are unable to functionally engage the viral DNA substrate critical for strand transfer inhibitor binding, the early structures did little to materially impact drug development efforts. However, recent results based on prototype foamy virus integrase have fully reversed this trend, as a number of X-ray crystal structures of active integrase-DNA complexes revealed key mechanistic details and moreover established the foundation of HIV-1 integrase strand transfer inhibitor action. In this review we discuss the landmarks in the progress of integrase structural biology during the past 17 years. (C) 2010 Elsevier Inc. All rights reserved. C1 [Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, Div Infect Dis, London W2 1PG, England. [Li, Xiang; Krishnan, Lavanya; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol, Boston, MA 02115 USA. [Li, Xiang; Krishnan, Lavanya; Engelman, Alan] Dana Farber Canc Inst, AIDS, Boston, MA 02115 USA. RP Cherepanov, P (reprint author), Univ London Imperial Coll Sci Technol & Med, Div Infect Dis, St Marys Campus,Norfolk Pl, London W2 1PG, England. EM p.cherepanov@imperial.ac.uk; alan_engelman@dfci.harvard.edu RI Li, Xiang/C-4588-2011; Cherepanov, Peter/F-6859-2010 OI Cherepanov, Peter/0000-0002-0634-538X FU UK Medical Research Council [G0900116]; US National Institutes of Health [AI70042] FX This work was supported by UK Medical Research Council Grant G0900116 (to P.C.) and US National Institutes of Health Grant AI70042 (to A.E.). The content of this paper does not necessarily reflect the views or policies of these funding agencies. NR 142 TC 60 Z9 61 U1 2 U2 15 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 MAR 15 PY 2011 VL 411 IS 2 SI SI BP 194 EP 205 DI 10.1016/j.virol.2010.12.008 PG 12 WC Virology SC Virology GA 734OI UT WOS:000288343000005 PM 21216426 ER PT J AU Smoller, JW AF Smoller, Jordan W. TI Who's Afraid of Anxiety Genetics? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 [Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat Genet Program Mood & Anxiety Disorders, Dept Psychiat, Boston, MA 02114 USA. RP Smoller, JW (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Psychiat & Neurodev Genet Unit, Simches Res Bldg,185 Cambridge St,Room 2298, Boston, MA 02114 USA. EM jsmoller@hms.harvard.edu NR 8 TC 7 Z9 7 U1 0 U2 4 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 MAR 15 PY 2011 VL 69 IS 6 BP 506 EP 507 DI 10.1016/j.biopsych.2011.01.020 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 732NW UT WOS:000288193400001 PM 21353834 ER PT J AU Apfel, BA Ross, J Hlavin, J Meyerhoff, DJ Metzler, TJ Marmar, CR Weiner, MW Schuff, N Neylan, TC AF Apfel, Brigitte A. Ross, Jessica Hlavin, Jennifer Meyerhoff, Dieter J. Metzler, Thomas J. Marmar, Charles R. Weiner, Michael W. Schuff, Norbert Neylan, Thomas C. TI Hippocampal Volume Differences in Gulf War Veterans with Current Versus Lifetime Posttraumatic Stress Disorder Symptoms SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Depression; Gulf War veterans; hippocampus; magnetic resonance imaging; posttraumatic stress disorder ID MAJOR DEPRESSIVE DISORDER; ADMINISTERED PTSD SCALE; ANTIDEPRESSANT TREATMENT; CHILDHOOD MALTREATMENT; PSYCHIATRIC-DISORDERS; ADULT NEUROGENESIS; ALCOHOL DEPENDENCE; RAT HIPPOCAMPUS; DENTATE GYRUS; METAANALYSIS AB Background: Decreased hippocampal volume is described in posttraumatic stress disorder (PTSD) and depression. However, it is not known whether it is a risk factor for the development of PTSD or a consequence of PTSD. We sought to determine the effects of PTSD and depressive symptoms on hippocampal volume. Methods: Clinical and magnetic resonance imaging data were collected in a cross sectional study of 244 Gulf War veterans. Measures included lifetime and current Clinician Administered PTSD Scale, Hamilton Depression Scale, Life Stressor Checklist, and Lifetime Drinking History. Magnetic resonance imaging data were acquired with a 1.5-T scanner and analyzed with automated and semiautomated image processing techniques. Results: Eighty-two veterans had lifetime PTSD, 44 had current PTSD, and 38 had current depression. In the linear regression analysis, current PTSD symptoms (standardized coefficient beta = -.25, p = .03) but neither lifetime PTSD symptoms nor current depression were associated with smaller hippocampal volume. Gender, age, history of early life trauma, education, lifetime and current alcohol use, current marijuana use, and treatment with antidepressants did not have independent effects. Participants with chronic PTSD had, on average, a smaller hippocampus compared with those with remitted PTSD. Conclusions: The finding that current but not lifetime PTSD symptom severity explains hippocampal size raises two possibilities: either a small hippocampus is a risk factor for lack of recovery from PTSD (trait) or PTSD effects on hippocampal volume are reversible once PTSD symptoms remit and the patient recovers (state). C1 [Apfel, Brigitte A.; Ross, Jessica; Neylan, Thomas C.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Meyerhoff, Dieter J.; Weiner, Michael W.; Schuff, Norbert] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Apfel, Brigitte A.; Ross, Jessica; Metzler, Thomas J.; Neylan, Thomas C.] Vet Affairs Med Ctr, Mental Hlth Serv, San Francisco, CA 94121 USA. [Hlavin, Jennifer; Meyerhoff, Dieter J.; Weiner, Michael W.; Schuff, Norbert] Vet Affairs Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94121 USA. [Marmar, Charles R.] NYU, Dept Psychiat, New York, NY 10016 USA. RP Apfel, BA (reprint author), San Francisco VA Med Ctr, Dept Psychiat, 116A,4150 Clement St, San Francisco, CA 94121 USA. EM brigitte.apfel@ucsf.edu RI Schueter, nicos/A-3625-2014 FU Department of Defense [DAMD17-01-1-0764]; US Army Medical Research and Materiel Command; National Institutes of Health/National Institute of Environmental Health Sciences [ES09883]; Mental Illness Research, Education, and Clinical Center of the Department of Veterans Affairs; Office of Academic Affiliations; Department of Veterans Affairs; [R01 AA 10788] FX This study was supported by Department of Defense Grant DAMD17-01-1-0764, entitled, "Magnetic Resonance and Spectroscopy of the Human Brain in GulfWarIllness," awarded to the Northern California Institute for Research and Education from the Department of Defense Gulf War Illnesses Research Program, US Army Medical Research and Materiel Command. This study was also supported by National Institutes of Health/National Institute of Environmental Health Sciences Grant ES09883 and the Mental Illness Research, Education, and Clinical Center of the Department of Veterans Affairs. Resources and the use of facilities were provided by the Veterans Administration Medical Center, San Francisco, California. Writing of this manuscript was supported by the Office of Academic Affiliations, Advanced Fellowship Program in Mental Illness Research and Treatment, Department of Veterans Affairs, and R01 AA 10788 (DJM). We are grateful to Karl Friedl, Ph.D., for his support, and last but not least we thank Diana Truran and her staff for MRI scanning. All authors report no biomedical financial interests or potential conflicts of interest. NR 74 TC 44 Z9 47 U1 6 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 MAR 15 PY 2011 VL 69 IS 6 BP 541 EP 548 DI 10.1016/j.biopsych.2010.09.044 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 732NW UT WOS:000288193400008 PM 21094937 ER PT J AU Anees, M Horak, P El-Gazzar, A Susani, M Heinze, G Perco, P Loda, M Lis, R Krainer, M Oh, WK AF Anees, Mariam Horak, Peter El-Gazzar, Ahmed Susani, Martin Heinze, Georg Perco, Paul Loda, Massimo Lis, Rosina Krainer, Michael Oh, William K. TI Recurrence-Free Survival in Prostate Cancer Is Related to Increased Stromal TRAIL Expression SO CANCER LA English DT Article DE Prostate cancer; tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); death receptors; recurrence-free survival ID NF-KAPPA-B; APOPTOSIS-INDUCING LIGAND; DEATH RECEPTORS; TARGETING DEATH; OVARIAN-CANCER; CYTOCHROME-C; TRANSCRIPTION; INHIBITOR; PROTEIN; FLIP AB BACKGROUND: TRAIL (tumor necrosis factor related apoptosis-inducing ligand) is involved in tumor immune surveillance and, thus, may be a potential cancer therapy. TRAIL expression in the tumor microenvironment has been shown to impact cancer survival in multiple tumor types, including ovarian cancer. We studied TRAIL expression and outcomes in patients with prostate cancer. METHODS: A tissue microarray (TMA) of 200 prostate cancer patients and benign prostate tissue controls was used to assess the epithelial and stromal protein expression of TRAIL, death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and the FLICE inhibitory protein (FLIP(L)). We correlated these expression patterns with clinicopathological parameters and determined its impact on recurrence-free survival. RESULTS: Nearly all (99.5%) prostate cancer tissues examined displayed either decreased expression of pro-apoptotic TRAIL receptors, increased FLIPL expression, or both. We observed elevated death receptor, decoy receptor, FLIP(L), and epithelial TRAIL expression in prostate cancer epithelium. TRAIL expression in the stromal tumor microenvironment surrounding the prostate cancer was markedly lower. Elevated TRAIL expression in the tumor microenvironment was also significantly associated with increased recurrence-free survival (P = .014), after controlling for other prognostic markers. In contrast, epithelial expression of TRAIL did not have an effect on overall survival. CONCLUSIONS: Expression of the components of the pro-apoptotic TRAIL pathway is altered in prostate cancer. Moreover, TRAIL expression in the tumor microenvironment may affect recurrence-free survival rate of prostate cancer patients. Consequently, these results may be useful in devising future therapeutic strategies targeting the TRAIL pathway in prostate cancer. Cancer 2011;117:1172-82. (C) 2070 American Cancer Society C1 [Anees, Mariam; Horak, Peter; El-Gazzar, Ahmed; Krainer, Michael] Med Univ Vienna, Dept Med 1, Div Oncol, A-1090 Vienna, Austria. [Susani, Martin] Med Univ Vienna, Dept Clin Pathol, A-1090 Vienna, Austria. [Heinze, Georg] Med Univ Vienna, Ctr Med Stat Informat & Intelligent Syst, A-1090 Vienna, Austria. [Perco, Paul] Univ Vienna, Inst Theoret Chem, Vienna, Austria. [Loda, Massimo; Lis, Rosina] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Oh, William K.] Mt Sinai Sch Med, Tisch Canc Inst, Div Hematol & Med Oncol, New York, NY USA. RP Krainer, M (reprint author), Med Univ Vienna, Dept Med 1, Div Oncol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM michael.krainer@meduniwien.ac.at RI Oh, William/B-9163-2012; OI Oh, William/0000-0001-5113-8147; Krainer, Michael/0000-0002-7011-4957 FU FWF [P20715-B12]; HEC Pakistan FX FWF Grant P20715-B12, HEC Pakistan Scholarship to M.A. NR 45 TC 10 Z9 11 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD MAR 15 PY 2011 VL 117 IS 6 BP 1172 EP 1182 DI 10.1002/cncr.25504 PG 11 WC Oncology SC Oncology GA 734PZ UT WOS:000288349300009 PM 21381010 ER PT J AU Chen, YZ Kong, JA Sun, T Li, G Szeto, FL Liu, WC Deb, DK Wang, YL Zhao, Q Thadhani, R Li, YC AF Chen, Yunzi Kong, Juan Sun, Tao Li, George Szeto, Frances L. Liu, Weicheng Deb, Dilip K. Wang, Youli Zhao, Qun Thadhani, Ravi Li, Yan Chun TI 1,25-Dihydroxyvitamin D-3 suppresses inflammation-induced expression of plasminogen activator inhibitor-1 by blocking nuclear factor-kappa B activation SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Vitamin D; PAI-1; NF-kappa B; Gene regulation ID VITAMIN-D-RECEPTOR; CHRONIC KIDNEY-DISEASE; NECROSIS-FACTOR-ALPHA; GROWTH-FACTOR-BETA; DIABETIC-NEPHROPATHY; GENE-EXPRESSION; D ANALOGS; CARDIOVASCULAR-DISEASE; COMBINATION THERAPY; RENAL INFLAMMATION AB Plasminogen activator inhibitor (PAI)-1 is a major fibrinolytic inhibitor. High PAI-1 is associated with increased renal and cardiovascular disease risk. Previous studies demonstrated PAI-1 down-regulation by 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), but the molecular mechanism remains unknown. Here we show that exposure of mouse embryonic fibroblasts to TNF alpha or LPS led to a marked induction of PAI-1, which was blunted by 1,25(OH)(2)D-3, NF-kappa B inhibitor or p65 siRNA, suggesting the involvement of NF-kappa B in 1,25(OH)(2)D-3-induced repression. In mouse Pai-1 promoter a putative cis-kappa B element was identified at -299. EMSA and ChIP assays showed that TNE-alpha increased p50/p65 binding to this kappa B site, which was disrupted by 1,25(OH)(2)D-3. Luciferase reporter assays showed that PAI-1 promoter activity was induced by TNF alpha or LPS, and the induction was blocked by 1,25(OH)(2)D-3. Mutation of the kappa B site blunted TNF alpha, LPS or 1,25(OH)(2)D-3 effects. 1,25(OH)(2)D-3 blocked 1 kappa B alpha degradation and arrested p50/p65 nuclear translocation. In mice LPS stimulated PAI-1 expression in the heart and macrophages, and the stimulation was blunted by pre-treatment with a vitamin D analog. Together these data demonstrate that 1,25(OH)(2)D-3 down-regulates PAI-1 by blocking NE-kappa B activation. Inhibition of PAI-1 production may contribute to the reno- and cardio-protective effects of vitamin D. (C) 2010 Elsevier Inc. All rights reserved. C1 [Li, Yan Chun] Univ Chicago, Dept Med, KCBD, Div Biol Sci, Chicago, IL 60637 USA. [Szeto, Frances L.; Li, Yan Chun] Univ Chicago, Div Biol Sci, Comm Mol Metab & Nutr, Chicago, IL 60637 USA. [Kong, Juan; Li, Yan Chun] China Med Univ, Lab Metab Dis Res & Drug Dev, Shenyang, Peoples R China. [Zhao, Qun] China Med Univ, Key Lab Congenital Malformat, Minist Hlth, Shenyang, Peoples R China. [Thadhani, Ravi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, Boston, MA USA. RP Li, YC (reprint author), Univ Chicago, Dept Med, KCBD, Div Biol Sci, 900 E 57th St,Mailbox 9-9110, Chicago, IL 60637 USA. EM cyan@medicine.bsd.uchicago.edu RI Sun, Tao/F-8233-2012; liu, weicheng/D-4173-2013 FU NIH [HL085793]; Center for D-Receptor Activation Research; Abbott Laboratory; American Heart Association [10SDG4280066] FX This work was supported in part by NIH grant HL085793, a research grant from the Center for D-Receptor Activation Research (to YCL), and a research grant from Abbott Laboratory (to RT). JK is support by American Heart Association Scientist Development Grant (10SDG4280066). NR 50 TC 40 Z9 42 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD MAR 15 PY 2011 VL 507 IS 2 BP 241 EP 247 DI 10.1016/j.abb.2010.12.020 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 730TR UT WOS:000288058000005 PM 21176770 ER PT J AU Campbell-Yesufu, OT Gandhi, RT AF Campbell-Yesufu, Omobolaji T. Gandhi, Rajesh T. TI Update on Human Immunodeficiency Virus (HIV)-2 Infection SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID PLASMA VIRAL LOAD; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; HIV-ASSOCIATED NEPHROPATHY; TO-CHILD TRANSMISSION; HIV-2-INFECTED PATIENTS; GUINEA-BISSAU; ANTIRETROVIRAL THERAPY; WEST-AFRICA; IN-VITRO; DRUG-RESISTANCE AB Infection with human immunodeficiency virus type 2 (HIV-2) occurs mainly in West Africa, but an increasing number of cases have been recognized in Europe, India, and the United States. In this era of global integration, clinicians must be aware of when to consider the diagnosis of HIV-2 infection and how to test for this virus. Although there is debate regarding when therapy should be initiated and which regimen should be chosen, recent trials have provided important information on treatment options for HIV-2 infection. In this review, we present information on recent clinical advances in our understanding of HIV-2 infection and highlight remaining diagnostic and therapeutic challenges. C1 [Gandhi, Rajesh T.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Gandhi, Rajesh T.] Harvard Univ, Boston, MA 02115 USA. RP Gandhi, RT (reprint author), MIT, Massachusetts Gen Hosp, Ragon Inst, GRJ 504,55 Fruit St, Boston, MA 02114 USA. EM rgandhi@partners.org FU Tibotec; Gilead; NIH [R01 AI066992-04A1, G08LM008830-01]; AIDS Clinical Trials Group [NIH U01 AI 694722]; Harvard University Center for AIDS Research [NIH 2P30 AI060354-06] FX We would like to thank Drs Kimon Zachary and Joseph Yao for their review of and comments on sections of this paper and Dr Eric Rosenberg for information regarding HIV-1 and HIV-2 diagnostic testing. We would like to acknowledge Betsy Wonderly and Rishabh Phukan for assistance in preparing this paper. R.T.G. has received grant support from Tibotec and Gilead.; R.T.G. is supported by NIH R01 AI066992-04A1 and NIH G08LM008830-01 and by grants to the AIDS Clinical Trials Group (NIH U01 AI 694722) and the Harvard University Center for AIDS Research (NIH 2P30 AI060354-06). NR 71 TC 56 Z9 57 U1 2 U2 13 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 MAR 15 PY 2011 VL 52 IS 6 BP 780 EP 787 DI 10.1093/cid/ciq248 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 730FX UT WOS:000288020300013 PM 21367732 ER PT J AU Kim, BM Woo, J Kanellopoulou, C Shivdasani, RA AF Kim, Byeong-Moo Woo, Janghee Kanellopoulou, Chryssa Shivdasani, Ramesh A. TI Regulation of mouse stomach development and Barx1 expression by specific microRNAs SO DEVELOPMENT LA English DT Article DE Barx1; Stomach development; MicroRNA; Mouse ID CAENORHABDITIS-ELEGANS; ANIMAL MICRORNAS; CELL FATE; DIFFERENTIATION; INITIATION; EVOLUTION; MIR-145; IMPACT; GENES AB Although microRNAs (miRNAs) are postulated to fine-tune many developmental processes, their relationships with specific targets and tissues remain largely undefined. The mesenchymal transcription factor Barx1 controls spleen and stomach morphogenesis and is required to specify stomach-specific epithelium in adjacent endoderm. Barx1 expression is precisely regulated in space and time, with a sharp drop in stomach levels after epithelial specification. We tested the hypothesis that specific miRNAs mediate this marked decline in Barx1 levels. Depletion of the miRNA-processing enzyme Dicer in cultured stomach mesenchyme and conditional Dicer gene deletion in mice significantly increased Barx1 levels, disrupted stomach and intestine development and caused spleen agenesis. Computational and experimental studies identified miR-7a and miR-203 as candidate miRNAs that regulate Barx1 and are expressed in inverse proportion to it in the fetal mouse stomach. Through specific interactions with cognate sequences in the Barx1 3' untranslated region, miR-7a and miR-203 repress Barx1 expression in stomach mesenchymal cells and its function in inducing gastric epithelium. These results indicate that miRNAs are required for proper digestive tract organogenesis and that miR-7a and miR-203 control expression of the stomach homeotic regulator Barx1. C1 [Kim, Byeong-Moo; Woo, Janghee; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kim, Byeong-Moo; Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Kim, Byeong-Moo; Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Woo, Janghee] Harvard Univ, Sch Med, Grad Program Biol & Biomed Sci, Boston, MA 02115 USA. [Kanellopoulou, Chryssa] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. EM ramesh_shivdasani@dfci.harvard.edu FU National Institutes of Health [R01DK081113]; Harvard Stem Cell Institute FX We thank Warren Zimmer for providing Bapx1+/Cre mice and Andrew McMahon for providing the pCIG vector. Supported by National Institutes of Health grant R01DK081113 (to R.A.S.) and a predoctoral training grant from the Harvard Stem Cell Institute (to J.W.). Deposited in PMC for release after 12 months. NR 31 TC 13 Z9 13 U1 0 U2 4 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 MAR 15 PY 2011 VL 138 IS 6 BP 1081 EP 1086 DI 10.1242/dev.056317 PG 6 WC Developmental Biology SC Developmental Biology GA 724KP UT WOS:000287575300006 PM 21307095 ER PT J AU Altfeld, M Goulder, PJ AF Altfeld, Marcus Goulder, Philip J. TI The STEP Study Provides a Hint That Vaccine Induction of the Right CD8(+) T Cell Responses Can Facilitate Immune Control of HIV SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID IMMUNODEFICIENCY VIRUS-REPLICATION; RHESUS-MONKEYS; VIRAL LOAD; CLASS-I; ESCAPE; TRANSMISSION; CHALLENGE; INFECTION; EXPANSION; FAILURE C1 [Goulder, Philip J.] Univ Oxford, Dept Paediat, Oxford, England. [Altfeld, Marcus] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA USA. RP Altfeld, M (reprint author), Harvard Univ, Sch Med, Bldg 149,13th St,Rm 6003, Boston, MA 02129 USA. EM maltfeld@partners.org FU NIAID NIH HHS [R01 AI046995] NR 30 TC 5 Z9 5 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2011 VL 203 IS 6 BP 753 EP 755 DI 10.1093/infdis/jiq119 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 726RB UT WOS:000287742700002 PM 21343145 ER PT J AU Chen, JJ Rosas, HD Salat, DH AF Chen, J. Jean Rosas, H. Diana Salat, David H. TI Age-associated reductions in cerebral blood flow are independent from regional atrophy SO NEUROIMAGE LA English DT Article DE Cerebral blood flow (CBF); Aging; Arterial-spin labelling (ASL); Magnetic resonance imaging (MRI); Quantitative perfusion; Alzheimer's disease; Dementia; Cortical thickness; Cerebral cortex ID VASCULAR RISK-FACTORS; MILD COGNITIVE IMPAIRMENT; MAGNETIC-RESONANCE IMAGES; PARTIAL-VOLUME CORRECTION; BRAIN PERFUSION SPECT; SPIN-LABELING MRI; ALZHEIMERS-DISEASE; WHITE-MATTER; AGING BRAIN; IN-VIVO AB Prior studies have demonstrated decreasing cerebral blood flow (CBF) in normal aging, but the full spatial pattern and potential mechanism of changes in CBF remain to be elucidated. Specifically, existing data have not been entirely consistent regarding the spatial distribution of such changes, potentially a result of neglecting the effect of age-related tissue atrophy in CBF measurements. In this work, we use pulsed arterial-spin labelling to quantify regional CBF in 86 cognitively and physically healthy adults, aged 23 to 88 years. Surface-based analyses were utilized to map regional decline in CBF and cortical thickness with advancing age, and to examine the spatial associations and dissociations between these metrics. Our results demonstrate regionally selective age-related reductions in cortical perfusion, involving the superior-frontal, orbito-frontal, superior-parietal, middle-inferior temporal, insular, precuneus, supramarginal, lateral-occipital and cingulate regions, while subcortical CBF was relatively preserved in aging. Regional effects of age on CBF differed from that of grey-matter atrophy. In addition, the pattern of CBF associations with age displays an interesting similarity with the default-mode network These findings demonstrate the dissociation between regional CBF and structural alterations specific to normal aging, and augment our understanding of mechanisms of pathology in older adults. (C) 2010 Elsevier Inc. All rights reserved. C1 [Chen, J. Jean; Rosas, H. Diana; Salat, David H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging,MGH MIT HMS, Charlestown, MA 02129 USA. [Chen, J. Jean; Salat, David H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. [Rosas, H. Diana] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Charlestown, MA 02129 USA. [Salat, David H.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA USA. RP Chen, JJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, AA Martinos Ctr Biomed Imaging,MGH MIT HMS, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM jjchen@nmr.mgh.harvard.edu RI Chen, J. Jean/A-2846-2013 OI Chen, J. Jean/0000-0001-5469-7542 FU NIH [K01AG024898, R01NR010827, NS042861, P41RR14075]; Canadian Institutes of Health Research (CIHR); Athinoula A. Martinos Center for Biomedical Imaging FX This research was supported by NIH grants K01AG024898, R01NR010827, NS042861, and P41RR14075, as well as the Canadian Institutes of Health Research (CIHR) and the Athinoula A. Martinos Center for Biomedical Imaging. We also thank Dr. Doug Greve for his input on multi-modal image registration, and Mr. Robert McInnis for help with cognitive testing. NR 127 TC 76 Z9 78 U1 3 U2 21 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 MAR 15 PY 2011 VL 55 IS 2 BP 468 EP 478 DI 10.1016/j.neuroimage.2010.12.032 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 724DL UT WOS:000287556200005 PM 21167947 ER PT J AU Triantafyllou, C Polimeni, JR Wald, LL AF Triantafyllou, Christina Polimeni, Jonathan R. Wald, Lawrence L. TI Physiological noise and signal-to-noise ratio in fMRI with multi-channel array coils SO NEUROIMAGE LA English DT Article DE Physiological noise; Parallel imaging; Array coils; fMRI; GRAPPA; SNR; 32-channel coil; Resolution ID MRI; RECONSTRUCTIONS; IMAGES; GRAPPA AB Sensitivity in BOLD fMRI is characterized by the signal to noise ratio (SNR) of the time-series (tSNR), which contains fluctuations from thermal and physiological noise sources. Alteration of an ecquisition parameter can affect the tSNR differently depending on the relative magnitude of the physiological and thermal noise, therefore knowledge of this ratio is essential for optimizing fMRI acquisitions. In this study, we compare image and time-series SNR from array coils at 3 T with and without parallel imaging (GRAPPA) as a function of image resolution and acceleration. We use the "absolute unit" SNR method of Kellman and McVeigh to calculate the image SNR (SNR(0)) in a way that renders it comparable to tSNR, allowing determination of the thermal to physiological noise ratio, and the pseudo-multiple replica method to quantify the image noise alterations due to the GRAPPA reconstruction. The Kruger and Glover noise model, in which the physiological noise standard deviation is proportional to signal strength, was found to hold for the accelerated and non-accelerated array coil data. Thermal noise dominated the EPI time-series for medium to large voxel sizes for single-channel and 12-channel head coil configurations, but physiological noise dominated the 32-channel array acquisition even at 1 mm x 1 mm x 3 mm resolution. At higher acceleration factors, image SNR is reduced and the time-series becomes increasingly thermal noise dominant. However, the tSNR reduction is smaller than the reduction in image SNR due to the presence of physiological noise. (C) 2010 Elsevier Inc. All rights reserved. C1 [Triantafyllou, Christina] MIT, AA Martinos Imaging Ctr, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Triantafyllou, Christina; Polimeni, Jonathan R.; Wald, Lawrence L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA USA. [Wald, Lawrence L.] Harvard Massachusetts Inst Technol MIT, Div Hlth Sci & Technol, Cambridge, MA USA. RP Triantafyllou, C (reprint author), MIT, AA Martinos Imaging Ctr, McGovern Inst Brain Res, 77 Massachusetts Ave,Bldg 46,Room 46-1165, Cambridge, MA 02139 USA. EM ctrianta@mit.edu RI Triantafyllou, Christina/E-7724-2011; Polimeni, Jonathan/P-1395-2014; Wald, Lawrence/D-4151-2009 OI Polimeni, Jonathan/0000-0002-1348-1179; FU McGovern Institute for Brain Research at MIT; NIH [P41RR14075] FX The authors would like to thank the McGovern Institute for Brain Research at MIT for the funding, Steve Shannon and Sheeba Arnold for the technical support, and Michael Hamm and Thomas Witzel for their assistance with computational resources. This work was supported by NIH grant P41RR14075. NR 18 TC 49 Z9 49 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAR 15 PY 2011 VL 55 IS 2 BP 597 EP 606 DI 10.1016/j.neuroimage.2010.11.084 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 724DL UT WOS:000287556200018 PM 21167946 ER PT J AU Wilson, LB Tregellas, JR Slason, E Pasko, BE Rojas, DC AF Wilson, Lisa B. Tregellas, Jason R. Slason, Erin Pasko, Bryce E. Rojas, Donald C. TI Implicit phonological priming during visual word recognition SO NEUROIMAGE LA English DT Article DE fMRI; Phonology; Priming; Implicit memory; Superior temporal gyrus; Supramarginal gyrus; Default-mode network ID SUPERIOR TEMPORAL GYRUS; VERBAL WORKING-MEMORY; DEFAULT-MODE; FUNCTIONAL NEUROANATOMY; SENTENCE COMPREHENSION; SPEECH PRODUCTION; LEXICAL ACCESS; BRAIN-FUNCTION; TIME-COURSE; ACTIVATION AB Phonology is a lower-level structural aspect of language involving the sounds of a language and their organization in that language. Numerous behavioral studies utilizing priming, which refers to an increased sensitivity to a stimulus following prior experience with that or a related stimulus, have provided evidence for the role of phonology in visual word recognition. However, most language studies utilizing priming in conjunction with functional magnetic resonance imaging (fMRI) have focused on lexical-semantic aspects of language processing. The aim of the present study was to investigate the neurobiological substrates of the automatic, implicit stages of phonological processing. While undergoing fMRI, eighteen individuals performed a lexical decision task (LOT) on prime-target pairs including word-word homophone and pseudoword-word pseudohomophone pairs with a prime presentation below perceptual threshold. Whole-brain analyses revealed several cortical regions exhibiting hemodynamic response suppression due to phonological priming including bilateral superior temporal gyri (STG), middle temporal gyri (MTG), and angular gyri (AG) with additional region of interest (ROI) analyses revealing response suppression in the left lateralized supramarginal gyrus (SMG). Homophone and pseudohomophone priming also resulted in different patterns of hemodynamic responses relative to one another. These results suggest that phonological processing plays a key role in visual word recognition. Furthermore, enhanced hemodynamic responses for unrelated stimuli relative to primed stimuli were observed in midline cortical regions corresponding to the default-mode network (DMN) suggesting that DMN activity can be modulated by task requirements within the context of an implicit task. (C) 2010 Elsevier Inc. All rights reserved. C1 [Wilson, Lisa B.; Tregellas, Jason R.; Slason, Erin; Pasko, Bryce E.; Rojas, Donald C.] Univ Colorado Denver, Dept Psychiat, Aurora, CO 80045 USA. [Tregellas, Jason R.] Denver VA Med Ctr, Res Serv, Denver, CO 80220 USA. RP Rojas, DC (reprint author), Univ Colorado Denver, Dept Psychiat, 13001 E 17th Pl, Aurora, CO 80045 USA. EM lisa.wilson@ucdenver.edu; jason.tregellas@ucdenver.edu; erin.slason@gmail.com; bryce.pasko@ucdenver.edu; don.rojas@ucdenver.edu RI Rojas, Don/F-4296-2012; Tregellas, Jason/J-3637-2015; OI Rojas, Don/0000-0001-6560-9616 FU Autism Speaks [2090]; Autism Speaks Weatherstone [6291]; National Institutes of Health (NIH) [PHS R01 MH082020]; NIH/NCRR Colorado CTSI [TL1 RR025778]; National Institute of Child Health and Human Development (NICHHD) [HD041697] FX Funding for this study was provided by Autism Speaks Grant 2090, Autism Speaks Weatherstone Grant 6291, the National Institutes of Health (NIH) Grant PHS R01 MH082020, NIH/NCRR Colorado CTSI Grant TL1 RR025778, and the National Institute of Child Health and Human Development (NICHHD) Grant HD041697. The funding sources had no further role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. NR 64 TC 12 Z9 14 U1 0 U2 13 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 MAR 15 PY 2011 VL 55 IS 2 BP 724 EP 731 DI 10.1016/j.neuroimage.2010.12.019 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 724DL UT WOS:000287556200031 PM 21159322 ER PT J AU Majic, T Rentzsch, J Gudlowski, Y Ehrlich, S Juckel, G Sander, T Lang, UE Winterer, G Gallinat, J AF Majic, Tomislav Rentzsch, Johannes Gudlowski, Yehonala Ehrlich, Stefan Juckel, Georg Sander, Thomas Lang, Undine E. Winterer, Georg Gallinat, Juergen TI COMT Val(108/158)Met genotype modulates human sensory gating SO NEUROIMAGE LA English DT Article DE COMT polymorphism; P50; N100; Auditory sensory gating; Endophenotypes; Dopamine ID METHYLTRANSFERASE VAL(158)MET GENOTYPE; UNMEDICATED SCHIZOPHRENIC-PATIENTS; AUDITORY-EVOKED POTENTIALS; EVENT-RELATED POTENTIALS; TEST-RETEST RELIABILITY; POOR P50 SUPPRESSION; GAMMA-BAND RESPONSES; PREPULSE INHIBITION; FRONTAL-CORTEX; PREFRONTAL CORTEX AB Background: The catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism of the dopamine system is essential for prefrontal cortex processing capacity and efficiency. In addition, dopaminergic neurotransmission is also associated with the sensory gating phenomenon protecting the cerebral cortex from information overload. It is however unclear if COMT genotype as a predictor of prefrontal efficiency modulates sensory gating on the level of the auditory cortex, i.e. the gating of the auditory evoked P50 and N100 components. Methods: P50 and N100 gating and COMT Val(108/158)Met genotype were determined in 282 healthy subjects of German descent carefully screened for psychiatric or neurological disorders. Results: A significant effect of the COMT genotype was observed for N100 gating (F = 4.510, df = 2, p = 0.012) but not for P50 gating (F = 0.376, df = 2, p = 0.687). Contrast analysis showed that Met/Met individuals had poorer N100 gating compared to Val/Met (F = -12.931, p = 0.003) and the Val/Val individuals (F = -11.056, p = 0.057). Conclusion: The results indicate that a high prefrontal efficiency as suggested by the COMT Met/Met genotype is associated with to a poor sensory gating of the N100 component. This would fit in a model where a high prefrontal processing capacity allows a pronounced afferent input of sensory information from the auditory cortex as reflected by a poor sensory gating. The more pronounced prefrontal contribution to the N100 compared to the P50 component may explain the exclusive genotype association with the N100 sensory gating. This preliminary model should be replicated and validated in future investigations. (C) 2010 Elsevier Inc. All rights reserved. C1 [Majic, Tomislav] Charite, Hosp St Hedwig, Dept Psychiat & Psychotherapy, Clin Psychiat & Psychotherapy, D-10115 Berlin, Germany. [Rentzsch, Johannes; Gudlowski, Yehonala; Ehrlich, Stefan; Lang, Undine E.] Charite, Dept Psychiat & Psychotherapy, D-10117 Berlin, Germany. [Ehrlich, Stefan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. [Juckel, Georg] Ruhr Univ Bochum, Dept Psychiat Psychotherapy Psychosomat & Prevent, LWL Univ Hosp, D-44791 Bochum, Germany. [Sander, Thomas; Winterer, Georg] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany. [Sander, Thomas; Winterer, Georg] Res Ctr Juelich, Inst Neurosci & Biophys, D-52425 Julich, Germany. RP Majic, T (reprint author), Charite, Hosp St Hedwig, Dept Psychiat & Psychotherapy, Clin Psychiat & Psychotherapy, 2rosse Hamburger Str 5-11, D-10115 Berlin, Germany. EM tomislav.majic@charite.de RI Lang, Undine Emmi/K-5553-2015; OI Lang, Undine Emmi/0000-0002-3585-6533; Ehrlich, Stefan/0000-0003-2132-4445 NR 91 TC 14 Z9 14 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAR 15 PY 2011 VL 55 IS 2 BP 818 EP 824 DI 10.1016/j.neuroimage.2010.12.031 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 724DL UT WOS:000287556200041 PM 21184832 ER PT J AU Shlipak, M AF Shlipak, Michael TI Diabetic Nephropathy: Preventing Progression SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material C1 San Francisco VA Med Ctr, San Francisco, CA USA. RP Shlipak, M (reprint author), San Francisco VA Med Ctr, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD MAR 15 PY 2011 VL 83 IS 6 BP 732 EP 733 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 979ZM UT WOS:000306863400011 ER PT J AU Weiss, A Grueninger, S Abramowski, D Di Giorgio, FP Lopatin, MM Rosas, HD Hersch, S Paganetti, P AF Weiss, Andreas Grueninger, Stephan Abramowski, Dorothee Di Giorgio, Francesco Paolo Lopatin, Miriam Moscovitch Rosas, H. Diana Hersch, Steven Paganetti, Paolo TI Microtiter plate quantification of mutant and wild-type huntingtin normalized to cell count SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID DISEASE AB Huntington's disease is caused by a gain-of-function neurotoxic mutation in normally neuroprotective huntingtin. Sensitive assays are required to discriminate mutant huntingtin from wild-type huntingtin. We have developed a normalized 384-plate assay for determination of mutant and wild-type huntingtin. Based on a single pipetting step, the sensitive assay uses two antibody pairs for simultaneous mutant and wild-type huntingtin time-resolved fluorescence resonance energy transfer detection combined with PicoGreen quantification of double-stranded DNA. The assay can be used for discovery of drugs reducing mutant huntingtin over wild-type huntingtin and for assessing the value of huntingtin as a disease progression marker, and it is adaptable to other proteins of interest. (C) 2010 Elsevier Inc. All rights reserved. C1 [Weiss, Andreas; Grueninger, Stephan; Abramowski, Dorothee; Di Giorgio, Francesco Paolo] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland. [Lopatin, Miriam Moscovitch; Rosas, H. Diana; Hersch, Steven] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Paganetti, Paolo] AC Immune, CH-1015 Lausanne, Switzerland. RP Weiss, A (reprint author), Novartis Inst Biomed Res, CH-4002 Basel, Switzerland. EM andreas-1.weiss@novartis.com FU NINDS NIH HHS [U01 NS071789] NR 13 TC 7 Z9 7 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAR 15 PY 2011 VL 410 IS 2 BP 304 EP 306 DI 10.1016/j.ab.2010.11.044 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 718EN UT WOS:000287103900019 PM 21134349 ER PT J AU Johansen, KL AF Johansen, Kirsten L. TI Time to Rethink the Timing of Dialysis Initiation SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material C1 [Johansen, Kirsten L.] Univ Calif San Francisco, Nephrol Sect, San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94121 USA. RP Johansen, KL (reprint author), Univ Calif San Francisco, Nephrol Sect, San Francisco VA Med Ctr, 111J,4150 Clement St, San Francisco, CA 94121 USA. EM Kirsten.johansen@ucsf.edu NR 10 TC 4 Z9 4 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 14 PY 2011 VL 171 IS 5 BP 382 EP U182 DI 10.1001/archinternmed.2010.413 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 734IW UT WOS:000288328800002 PM 21059965 ER PT J AU Zhang, YT Zhou, L Gellad, WF AF Zhang, Yuting Zhou, Lei Gellad, Walid F. TI Potential Savings From Greater Use of $4 Generic Drugs SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter C1 [Zhang, Yuting; Zhou, Lei] Univ Pittsburgh, Dept Hlth Policy & Management, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Gellad, Walid F.] Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, Div Gen Med, Pittsburgh, PA 15261 USA. [Gellad, Walid F.] RAND Corp, Santa Monica, CA 90406 USA. RP Zhang, YT (reprint author), Univ Pittsburgh, Dept Hlth Policy & Management, Grad Sch Publ Hlth, 130 De Soto St,Crabtree Hall A664, Pittsburgh, PA 15261 USA. EM ytzhang@pitt.edu OI Zhang, Yuting/0000-0002-6460-6779 FU NCATS NIH HHS [KL2 TR000146]; NCRR NIH HHS [UL1 RR024153, KL2 RR024154, KL2 RR024154-04] NR 5 TC 9 Z9 9 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 14 PY 2011 VL 171 IS 5 BP 468 EP 469 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 734IW UT WOS:000288328800018 PM 21403045 ER PT J AU Chang, J Lindsay, RJ Kulkarni, S Lifson, JD Carrington, M Altfeld, M AF Chang, Judy Lindsay, Robert J. Kulkarni, Smita Lifson, Jeffrey D. Carrington, Mary Altfeld, Marcus TI Polymorphisms in interferon regulatory factor 7 reduce interferon-alpha responses of plasmacytoid dendritic cells to HIV-1 SO AIDS LA English DT Article ID SIV INFECTION; IMMUNE ACTIVATION; VIRUS-INFECTIONS; NATURAL HOSTS; TLR7 AB Recognition of HIV-1 ssRNA by Toll-like receptor 7 induces the production of the pro-inflammatory cytokines that may contribute to the systemic immune activation associated with HIV-1 disease progression. Here, we describe a novel association between polymorphisms in interferon regulatory factor 7 (IRF7), a master regulator of interferon-alpha (IFN-alpha), and the ability of plasmacytoid dendritic cells to produce IFN-alpha in response to HIV-1. IRF7 polymorphisms may, therefore, affect the ability of individuals to respond to HIV-1 and modulate HIV-1 disease progression. C1 [Chang, Judy; Lindsay, Robert J.; Carrington, Mary; Altfeld, Marcus] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Kulkarni, Smita; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, Frederick, MD 21701 USA. [Lifson, Jeffrey D.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Altfeld, M (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Bldg 149,13th St,6th Floor, Navy Yard, MA 02129 USA. EM maltfeld@partners.org FU Doris Duke Charitable Foundation; Phillip T. and Susan M. Ragon Foundation; Bill and Melinda Gates Foundation; National Health and Medical Research Council of Australia [519578]; Ragon Fellowship; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; [RO1 216753] FX The authors thank the Brigham and Women's Hospital PhenoGenetic Project for providing DNA samples from healthy individuals that were used in the replication effort of this study. These studies were supported by RO1 216753 and the Doris Duke Charitable Foundation. They also thank the Phillip T. and Susan M. Ragon Foundation and the Bill and Melinda Gates Foundation for their support. J.J.C. is supported by a fellowship awarded from the National Health and Medical Research Council of Australia (519578) and a Ragon Fellowship and M. A. is a Doris Duke Distinguished Clinical Scientist. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 14 TC 12 Z9 12 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 13 PY 2011 VL 25 IS 5 BP 715 EP 717 DI 10.1097/QAD.0b013e328343c186 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 729PT UT WOS:000287963600023 PM 21297422 ER PT J AU Lin, NU Burstein, HJ AF Lin, Nancy U. Burstein, Harold J. TI EMBRACE, eribulin, and new realities of advanced breast cancer SO LANCET LA English DT Editorial Material ID HALICHONDRIN B ANALOG; PHASE-II; ANTHRACYCLINE; CHEMOTHERAPY; MESYLATE; TAXANE C1 [Burstein, Harold J.] Dana Farber Canc Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Burstein, HJ (reprint author), Dana Farber Canc Inst, Boston, MA 02215 USA. EM hburstein@partners.org NR 7 TC 5 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAR 12 PY 2011 VL 377 IS 9769 BP 878 EP 880 DI 10.1016/S0140-6736(11)60280-8 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 738GR UT WOS:000288628800005 PM 21376386 ER PT J AU Eekhoff, A Bonakdar, N Alonso, JL Hoffmann, B Goldmann, WH AF Eekhoff, Alexander Bonakdar, Navid Alonso, Jose Luis Hoffmann, Bernd Goldmann, Wolfgang H. TI Glomerular podocytes: A study of mechanical properties and mechano-chemical signaling SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Podocytes; Cell mechanics and signaling; Magnetic tweezer; Magnetic twisting cytometry; Cell stretcher; Actin cytoskeleton; AT1 receptor; Angiotensin II; Calcium ID SMOOTH-MUSCLE-CELLS; CULTURED ENDOTHELIAL-CELLS; CYCLIC STRETCH; IN-VITRO; CYTOSKELETON; PROTEINURIA; ACTIN; EXPRESSION; INCREASES; DYNAMICS AB Kidney glomeruli function as filters, allowing the passage of small solutes and waste products into the urinary tract, while retaining essential proteins and macromolecules in the blood stream. These structures are under constant mechanical stress due to fluid pressure, driving filtration across the barrier. We mechanically stimulated adherent wildtype podocytes using the methods of magnetic tweezer and twisting as well as cell stretching. Attaching collagen IV-coated or poly-L-lysine-coated magnetic beads to cell receptors allowed for the determination of cellular stiffness. Angiotensin II-treated podocytes showed slightly higher stiffness than untreated cells, the cell fluidity (i.e. internal dynamics) remained similar, and showed an increase with force. The bead detachment (a measure of the binding strength) was higher in angiotensin II-treated compared to untreated podocytes. Magnetic twisting confirmed that angiotensin II treatment of podocytes increases and CDTA treatment decreases cell stiffness. However, treatment with both angiotensin II and CDTA increased the cell stiffness only slightly compared to solely CDTA-treated cells. Exposing podocytes to cyclic, uniaxial stretch showed an earlier onset of ERK(1/2) phosphorylation compared to MEF (control) cells. These results indicate that angiotensin II might free intracellularly stored calcium and affects actomyosin contraction, and that mechanical stimulation influences cell signaling. (C) 2011 Elsevier Inc. All rights reserved. C1 [Eekhoff, Alexander; Bonakdar, Navid; Goldmann, Wolfgang H.] Univ Erlangen Nurnberg, Ctr Med Phys & Technol, Biophys Grp, D-91052 Erlangen, Germany. [Alonso, Jose Luis] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02129 USA. [Hoffmann, Bernd] Forschungszentrum Julich GmbH, Inst Complex Syst 7, Biomech, Julich, Germany. RP Goldmann, WH (reprint author), Univ Erlangen Nurnberg, Ctr Med Phys & Technol, Biophys Grp, Henkestr 91, D-91052 Erlangen, Germany. EM wgoldmann@biomed.uni-erlangen.de RI Alonso, Jose Luis/G-7961-2012; Goldmann, Wolfgang/H-5572-2013; Hoffmann, Bernd/I-7237-2013; OI Hoffmann, Bernd/0000-0002-3803-8835 FU Bayerisch-Franzosisches Hochschulzentrum; Deutscher Akademischer Austausch Dienst, Bavaria California Technology Center; Deutsche Forschungsgemeinschaft FX We thank Drs. Ben Fabry, Rudolf Merkel, Gerold Diez, James Smith, and Anna Klemm for helpful comments, Tim Feichtmeier for the cyclic stretch experiments on human umbilical cord fibroblasts, Andrea Zang for helping with OMTC, and Wolfgang Rubner for building a new cell stretcher. This work was supported by grants from Bayerisch-Franzosisches Hochschulzentrum, Deutscher Akademischer Austausch Dienst, Bavaria California Technology Center, and Deutsche Forschungsgemeinschaft. NR 29 TC 10 Z9 10 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 11 PY 2011 VL 406 IS 2 BP 229 EP 233 DI 10.1016/j.bbrc.2011.02.022 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 738CF UT WOS:000288616200013 PM 21315064 ER PT J AU Edderkaoui, M Nitsche, C Zheng, L Pandol, SJ Gukovsky, I Gukovskaya, AS AF Edderkaoui, Mouad Nitsche, Claudia Zheng, Ling Pandol, Stephen J. Gukovsky, Ilya Gukovskaya, Anna S. TI NADPH Oxidase Activation in Pancreatic Cancer Cells Is Mediated through Akt-dependent Up-regulation of p22(phox) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; AORTIC SMOOTH-MUSCLE; FACTOR-I RECEPTOR; ENDOTHELIAL-CELLS; GROWTH; NOX4; APOPTOSIS; ALPHA; EXPRESSION; GENERATION AB We recently showed that Nox4 NADPH oxidase is highly expressed in pancreatic ductal adenocarcinoma and that it is activated by growth factors and plays a pro-survival, antiapoptotic role. Here we investigate the mechanisms through which insulin-like growth factor I and serum (FBS) activate NADPH oxidase in pancreatic cancer (PaCa) cells. We show that in PaCa cells, NADPH oxidase is composed of Nox4 and p22(phox) catalytic subunits, which are both required for NADPH oxidase activity. Insulin-like growth factor I and FBS activate NADPH oxidase through transcriptional up-regulation of p22(phox). This involves activation of the transcription factor NF-kappa B mediated by Akt kinase. Up-regulation of p22(phox) by the growth factors results in increased Nox4-p22(phox) complex formation and activation of NADPH oxidase. This mechanism is different from that for receptor-induced activation of phagocytic NADPH oxidase, which is mediated by phosphorylation of its regulatory subunits. Upregulation of p22(phox) represents a novel pro-survival mechanism through which growth factors and Akt inhibit apoptosis in PaCa cells. C1 [Gukovskaya, Anna S.] Vet Affairs Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Los Angeles, CA 90073 USA. RP Gukovskaya, AS (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, 11301 Wilshire Blvd,Bldg 258,Rm 340, Los Angeles, CA 90073 USA. EM agukovsk@ucla.edu FU National Institutes of Health through NCI [R01CA119025]; NCCAM [AT003960]; Department of Veterans Affairs Merit Review; CURE-Digestive Diseases Research Center FX This work was supported, in whole or in part, by National Institutes of Health Grants R01CA119025 through the NCI (to A. S. G.) and AT003960 through the NCCAM (to S. J. P.). This study was also supported by the Department of Veterans Affairs Merit Review (to A. S. G.) and the CURE-Digestive Diseases Research Center Pilot and Feasibility Award (to M. E.). NR 32 TC 34 Z9 34 U1 0 U2 0 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 MAR 11 PY 2011 VL 286 IS 10 BP 7779 EP 7787 DI 10.1074/jbc.M110.200063 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 730DQ UT WOS:000288013300009 PM 21118808 ER PT J AU Kim, DY Gersbacher, MT Inquimbert, P Kovacs, DM AF Kim, Doo Yeon Gersbacher, Manuel T. Inquimbert, Perrine Kovacs, Dora M. TI Reduced Sodium Channel Na(v)1.1 Levels in BACE1-null Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMYLOID PRECURSOR PROTEIN; BETA-SECRETASE BACE1; APP TRANSGENIC MICE; ALZHEIMERS-DISEASE; MOLECULAR-MECHANISMS; MULTIPLE-SCLEROSIS; NEURONAL-ACTIVITY; GAMMA-SECRETASE; CELL-ADHESION; MOUSE MODEL AB The Alzheimer BACE1 enzyme cleaves numerous substrates, with largely unknown physiological consequences. We have previously identified the contribution of elevated BACE1 activity to voltage-gated sodium channel Na(v)1.1 density and neuronal function. Here, we analyzed physiological changes in sodium channel metabolism in BACE1-null mice. Mechanistically, we first confirmed that endogenous BACE1 requires its substrate, the beta-subunit Na-v beta 2, to regulate levels of the pore-forming alpha-subunit Na(v)1.1 in cultured primary neurons. Next, we analyzed sodium channel alpha-subunit levels in brains of BACE1-null mice at 1 and 3 months of age. At both ages, we found that Na(v)1.1 protein levels were significantly decreased in BACE1-null versus wild-type mouse brains, remaining unchanged in BACE1-heterozygous mouse brains. Interestingly, levels of Na(v)1.2 and Na(v)1.6 alpha-subunits also decreased in 1-month-old BACE1-null mice. In the hippocampus of BACE1-null mice, we found a robust 57% decrease of Na(v)1.1 levels. Next, we performed surface biotinylation studies in acutely dissociated hippocampal slices from BACE1-null mice. Hippocampal surface Na(v)1.1 levels were significantly decreased, but Na(v)1.2 surface levels were increased in BACE1-null mice perhaps as a compensatory mechanism for reduced surface Na(v)1.1. We also found that Na-v beta(2) processing and Na(v)1.1 mRNA levels were significantly decreased in brains of BACE1-null mice. This suggests a mechanism consistent with BACE1 activity regulating mRNA levels of the alpha-subunit Na(v)1.1 via cleavage of cell-surface Na-v beta(2). Together, our data show that endogenous BACE1 activity regulates total and surface levels of voltage-gated sodium channels in mouse brains. Both decreased Na(v)1.1 and elevated surface Na(v)1.2 may result in a seizure phenotype. Our data caution that therapeutic BACE1 activity inhibition in Alzheimer disease patients may affect Na(v)1 metabolism and alter neuronal membrane excitability in Alzheimer disease patients. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Neurobiol Dis Lab,Genet & Aging Res Unit, Massachusetts Gen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Inquimbert, Perrine] Childrens Hosp, Dept Neurol, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. EM dora_kovacs@hms.harvard.edu FU National Institutes of Health, NIA FX This work was supported, in whole or in part, by National Institutes of Health grants from NIA (to D. M. K. and D. Y. K.). NR 48 TC 40 Z9 40 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 11 PY 2011 VL 286 IS 10 BP 8106 EP 8116 DI 10.1074/jbc.M110.134692 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 730DQ UT WOS:000288013300041 PM 21190943 ER PT J AU Wang, XV Verhaak, RGW Purdom, E Spellman, PT Speed, TP AF Wang, Xin Victoria Verhaak, Roel G. W. Purdom, Elizabeth Spellman, Paul T. Speed, Terence P. TI Unifying Gene Expression Measures from Multiple Platforms Using Factor Analysis SO PLOS ONE LA English DT Article ID PROBE LEVEL DATA; MICROARRAY DATA; REPRODUCIBILITY; DISCOVERY; GENOME AB In the Cancer Genome Atlas (TCGA) project, gene expression of the same set of samples is measured multiple times on different microarray platforms. There are two main advantages to combining these measurements. First, we have the opportunity to obtain a more precise and accurate estimate of expression levels than using the individual platforms alone. Second, the combined measure simplifies downstream analysis by eliminating the need to work with three sets of expression measures and to consolidate results from the three platforms. We propose to use factor analysis (FA) to obtain a unified gene expression measure (UE) from multiple platforms. The UE is a weighted average of the three platforms, and is shown to perform well in terms of accuracy and precision. In addition, the FA model produces parameter estimates that allow the assessment of the model fit. The R code is provided in File S2. Gene-level FA measurements for the TCGA data sets are available from http://tcga-data.nci.nih.gov/docs/publications/unified_expression/. C1 [Wang, Xin Victoria] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Wang, Xin Victoria] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Verhaak, Roel G. W.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Verhaak, Roel G. W.] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA USA. [Purdom, Elizabeth] Univ Calif Berkeley, Dept Stat, Berkeley, CA 94720 USA. [Spellman, Paul T.] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA 94720 USA. [Speed, Terence P.] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic 3050, Australia. RP Wang, XV (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM vwang@jimmy.harvard.edu FU National Institutes of Health [U24 CA126551]; Dutch Cancer Society KWF FX This work was supported by the National Institutes of Health [U24 CA126551 to XVW, EP, PTS, and TPS] and Dutch Cancer Society KWF [fellowship to RGWV]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 24 TC 7 Z9 7 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 MAR 11 PY 2011 VL 6 IS 3 AR e17691 DI 10.1371/journal.pone.0017691 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 733FF UT WOS:000288247800025 PM 21436879 ER PT J AU Feng, D Liu, T Sun, Z Bugge, A Mullican, SE Alenghat, T Liu, XS Lazar, MA AF Feng, Dan Liu, Tao Sun, Zheng Bugge, Anne Mullican, Shannon E. Alenghat, Theresa Liu, X. Shirley Lazar, Mitchell A. TI A Circadian Rhythm Orchestrated by Histone Deacetylase 3 Controls Hepatic Lipid Metabolism SO SCIENCE LA English DT Article ID FATTY LIVER-DISEASE; RECEPTOR COREPRESSOR; CLOCK; TRANSCRIPTION; MICE; OSCILLATOR; TISSUE AB Disruption of the circadian clock exacerbates metabolic diseases, including obesity and diabetes. We show that histone deacetylase 3 ( HDAC3) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Although amounts of HDAC3 are constant, its genomic recruitment in liver corresponds to the expression pattern of the circadian nuclear receptor Rev-erb alpha. Rev-erb alpha colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erb alpha in mouse liver causes hepatic steatosis. Thus, genomic recruitment of HDAC3 by Rev-erb alpha directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis. C1 [Feng, Dan; Sun, Zheng; Bugge, Anne; Mullican, Shannon E.; Alenghat, Theresa; Lazar, Mitchell A.] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Dept Med,Dept Genet, Philadelphia, PA 19104 USA. [Feng, Dan; Sun, Zheng; Bugge, Anne; Mullican, Shannon E.; Alenghat, Theresa; Lazar, Mitchell A.] Univ Penn, Sch Med, Inst Diabet Obes & Metab IDOM, Philadelphia, PA 19104 USA. [Liu, Tao; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Liu, Tao; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Lazar, MA (reprint author), Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Dept Med,Dept Genet, Philadelphia, PA 19104 USA. EM lazar@mail.med.upenn.edu RI Liu, Tao/G-3585-2010; Sun, Zheng/C-1146-2012; Feng, Dan/F-7205-2013; OI Liu, Tao/0000-0002-8818-8313; Sun, Zheng/0000-0002-6858-0633; Liu, Tao/0000-0003-0446-9001 FU NIH [DK19525, DK49210, DK45586, DK43806, RC1DK08623, HG4069] FX ChIP-seq and microarray data have been deposited in the Gene Expression Omnibus (GSE25937 and GSE26345) database. We thank B. Vennstrom for providing Rev-erba KO mice; M. Brown, D. Steger, and members of the Lazar lab for helpful discussions; D. Zhuo for technical assistance; the Penn IDOM Metabolism Resource (J. Millar) for help with de novo lipogenesis experiments; the Functional Genomics Core (J. Schug and K. Kaestner) and the Viral Vector Core (J. Johnston) of the Penn Diabetes Endocrinology Research Center (NIH DK19525) for deep sequencing and virus preparation; the Morphology Core (J. Katz and G. Swain) (NIH DK49210) for tissue preparation and staining; and the Penn Bioinformatics Core (J. Tobias) and Microarray Core (D. Baldwin) for gene expression analysis. Supported by the Cox Institute, NIH DK45586, DK43806, and RC1DK08623 (to M. A. L.) and NIH HG4069 (to X. S. L.). NR 30 TC 255 Z9 261 U1 8 U2 49 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 MAR 11 PY 2011 VL 331 IS 6022 BP 1315 EP 1319 DI 10.1126/science.1198125 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 732UM UT WOS:000288215200044 PM 21393543 ER PT J AU Shen, WL Kwon, Y Adegbola, AA Luo, JJ Chess, A Montell, C AF Shen, Wei L. Kwon, Young Adegbola, Abidemi A. Luo, Junjie Chess, Andrew Montell, Craig TI Function of Rhodopsin in Temperature Discrimination in Drosophila SO SCIENCE LA English DT Article ID NUCLEOTIDE-GATED CHANNEL; C-ELEGANS; CAENORHABDITIS-ELEGANS; PHOSPHOLIPASE-C; G-PROTEIN; PHOTOTRANSDUCTION; THERMOSENSATION; RECEPTORS; NEURONS AB Many animals, including the fruit fly, are sensitive to small differences in ambient temperature. The ability of Drosophila larvae to choose their ideal temperature (18 degrees C) over other comfortable temperatures (19 degrees to 24 degrees C) depends on a thermosensory signaling pathway that includes a heterotrimeric guanine nucleotide-binding protein (G protein), a phospholipase C, and the transient receptor potential TRPA1 channel. We report that mutation of the gene (ninaE) encoding a classical G protein-coupled receptor (GPCR), Drosophila rhodopsin, eliminates thermotactic discrimination in the comfortable temperature range. This role for rhodopsin in thermotaxis toward 18 degrees C was light-independent. Introduction of mouse melanopsin restored normal thermotactic behavior in ninaE mutant larvae. We propose that rhodopsins represent a class of evolutionarily conserved GPCRs that are required for initiating thermosensory signaling cascades. C1 [Shen, Wei L.; Kwon, Young; Luo, Junjie; Montell, Craig] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. [Shen, Wei L.; Kwon, Young; Luo, Junjie; Montell, Craig] Johns Hopkins Univ, Sch Med, Dept Neurosci, Ctr Sensory Biol, Baltimore, MD 21205 USA. [Adegbola, Abidemi A.; Chess, Andrew] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Adegbola, Abidemi A.; Chess, Andrew] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. [Chess, Andrew] Broad Inst, Cambridge, MA 02142 USA. [Chess, Andrew] Mt Sinai Sch Med, Dept Dev & Regenerat Biol, New York, NY 10029 USA. [Chess, Andrew] Mt Sinai Sch Med, Fishberg Dept Neurosci, New York, NY 10029 USA. RP Montell, C (reprint author), Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. EM cmontell@jhmi.edu RI shen, wei/C-2311-2013; OI Montell, Craig/0000-0001-5637-1482 FU National Institute of General Medical Sciences, NIH [GM085335] FX We thank Y. Liu for advice with the statistical analyses, the Bloomington Stock Center, FlyBase, and the Harvard TRiP. A. A. A. received support from a NARSAD Young Investigator Award. This study was supported by a grant to C. M. from the National Institute of General Medical Sciences, NIH (GM085335). NR 21 TC 78 Z9 80 U1 3 U2 30 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 MAR 11 PY 2011 VL 331 IS 6022 BP 1333 EP 1336 DI 10.1126/science.1198904 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 732UM UT WOS:000288215200049 PM 21393546 ER PT J AU Lin, AE Alexander, ME Colan, SD Kerr, B Rauen, KA Noonan, J Baffa, J Hopkins, E Sol-Church, K Limongelli, G Digilio, MC Marino, B Innes, AM Aoki, Y Silberbach, M Delrue, MA White, SM Hamilton, RM O'Connor, W Grossfeld, PD Smoot, LB Padera, RF Gripp, KW AF Lin, Angela E. Alexander, Mark E. Colan, Steven D. Kerr, Bronwyn Rauen, Katherine A. Noonan, Jacqueline Baffa, Jeanne Hopkins, Elizabeth Sol-Church, Katia Limongelli, Giuseppe Digilio, Maria Christina Marino, Bruno Innes, A. Micheil Aoki, Yoko Silberbach, Michael Delrue, Marie-Ange White, Susan M. Hamilton, Robert M. O'Connor, William Grossfeld, Paul D. Smoot, Leslie B. Padera, Robert F. Gripp, Karen W. TI Clinical, Pathological, and Molecular Analyses of Cardiovascular Abnormalities in Costello Syndrome: A Ras/MAPK Pathway Syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE aortic dilation; arrhythmias; cardiovascular malformation; chaotic atrial rhythm; congenital heart defect; ectopic atrial tachycardia; HRAS; hypertrophic cardiomyopathy; multifocal atrial tachycardia; Noonan-spectrum syndromes; RASopathy ID FACIO-CUTANEOUS SYNDROME; CAUSE NOONAN-SYNDROME; GENOTYPE-PHENOTYPE CORRELATION; GERMLINE KRAS MUTATIONS; OF-FUNCTION MUTATIONS; HYPERTROPHIC CARDIOMYOPATHY; LEOPARD-SYNDROME; HRAS MUTATION; PTPN11 MUTATIONS; CARDIAC-HYPERTROPHY AB Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes ("RASopathies'"). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients(44%), usually non-progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%), and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow-up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction. Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one-fourth of those with arrhythmia, but is generally self-limited in the remaining three-fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated. (C) 2011 Wiley-Liss, Inc. C1 [Lin, Angela E.] MassGen Hosp Children, Genet Unit, Boston, MA 02114 USA. [Alexander, Mark E.; Colan, Steven D.; Smoot, Leslie B.] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Kerr, Bronwyn] Cent Manchester Fdn Trust Manchester, Acad Hlth Sci Ctr, Manchester, Lancs, England. [Rauen, Katherine A.] Ctr Comprehens Canc, San Francisco, CA USA. [Rauen, Katherine A.] Univ Calif San Francisco, Dept Pediat, Div Med Genet, San Francisco, CA 94143 USA. [Noonan, Jacqueline] Univ Kentucky, Med Ctr, Dept Pediat, Lexington, KY USA. [Baffa, Jeanne] Nemours Cardiac Ctr, Wilmington, DE USA. [Hopkins, Elizabeth; Gripp, Karen W.] Div Med Genet, Wilmington, DE USA. [Sol-Church, Katia] Alfred I DuPont Hosp Children, Dept Biomed Res, Wilmington, DE USA. [Limongelli, Giuseppe] Univ Naples 2, Monaldi Hosp, Naples, Italy. [Digilio, Maria Christina] Bambino Gesu Pediat Hosp, Rome, Italy. [Marino, Bruno] Univ Roma La Sapienza, Dept Pediat, Rome, Italy. [Innes, A. Micheil] Univ Calgary, Dept Med Genet, Calgary, AB, Canada. [Aoki, Yoko] Tohoku Univ, Sch Med, Dept Med Genet, Sendai, Miyagi 980, Japan. [Silberbach, Michael] Doernbecher Childrens Hosp, Dept Pediat, Div Cardiol, Portland, OR USA. [Delrue, Marie-Ange] CHU Bordeaux, Serv Genet Med, Bordeaux, France. [White, Susan M.] Royal Childrens Hosp, Genet Hlth Serv Victoria, Melbourne, Vic, Australia. [Hamilton, Robert M.] Hosp Sick Children, Div Cardiol, Toronto, ON M5G 1X8, Canada. [O'Connor, William] Univ Kentucky, Med Ctr, Dept Pathol, Lexington, KY 40536 USA. [Grossfeld, Paul D.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Padera, Robert F.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Lin, AE (reprint author), MassGen Hosp Children, Genet Unit, 185 Cambridge St,Simches 2222, Boston, MA 02114 USA. EM lin.angela@mgh.harvard.edu RI innes, allan micheil/A-9955-2017; OI Innes, Micheil/0000-0001-9881-5467; LImongelli, Giuseppe/0000-0002-8291-9517 NR 109 TC 40 Z9 40 U1 1 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR 11 PY 2011 VL 155A IS 3 BP 486 EP 507 DI 10.1002/ajmg.a.33857 PG 22 WC Genetics & Heredity SC Genetics & Heredity GA 730KX UT WOS:000288033300008 PM 21344638 ER PT J AU Hartman, RJ Riehle-Colarusso, T Lin, A Frias, JL Patel, SS Duwe, K Correa, A Rasmussen, SA AF Hartman, Robert J. Riehle-Colarusso, Tiffany Lin, Angela Frias, Jaime L. Patel, Sonali S. Duwe, Kara Correa, Adolfo Rasmussen, Sonja A. CA Natl Birth Defects Prevention TI Descriptive Study of Nonsyndromic Atrioventricular Septal Defects in the National Birth Defects Prevention Study, 1997-2005 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE atrioventricular septal defect; endocardial cushion defect; atrioventricular canal defect; prevalence; congenital heart defect; congenital abnormalities; birth defects; chromosomal abnormalities; ethnicity; nonsyndromic ID CONGENITAL HEART-DEFECTS; DOWN-SYNDROME; CANAL DEFECT; INFANTS; DISEASE; MALFORMATIONS; POPULATIONS; PREVALENCE; ANOMALIES; REGION AB Nonsyndromic atrioventricular septal defects (AVSDs) are serious congenital heart defects for which information on prevalence and descriptive characteristics based on large, geographically, and ethnically diverse populations has been limited. To describe the birth prevalence and phenotype of nonsyndromic AVSDs, we used data from the National Birth Defects Prevention Study (NBDPS), a multisite, population-based case-control study aimed at identifying genetic and environmental risk factors for birth defects. For this analysis, infants born during the period 1997-2005 and meeting the NBDPS case definition for AVSDs were included. Infants with an AVSD associated with recognized or strongly suspected chromosomal abnormalities or single-gene disorders (syndromic case infants) were excluded. We identified 302 infants with a nonsyndromic AVSD for a birth prevalence of 0.83/10,000 livebirths. Over 20% of infants with an AVSD had an additional major birth defect, with gastrointestinal, renal or urinary, and central nervous system defects being the most common. A lower prevalence of AVSDs was seen among infants born to Hispanic mothers compared with those born to non-Hispanic White mothers [prevalence ratio = 0.63 (95% confidence interval: 0.46-0.86)]. Understanding the prevalence of nonsyndromic AVSDs, demographic factors associated with their occurrence, and associated defects could help guide clinical care, as well as contribute to a better understanding of pathogenesis. (C) 2011 Wiley-Liss, Inc. C1 [Hartman, Robert J.; Riehle-Colarusso, Tiffany; Frias, Jaime L.; Duwe, Kara; Correa, Adolfo; Rasmussen, Sonja A.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. [Hartman, Robert J.; Duwe, Kara] Oak Ridge Inst Sci & Educ, Oak Ridge, TN USA. [Lin, Angela] Massachusetts Ctr Birth Defects Res & Prevent, Massachusetts Dept Publ Hlth, Boston, MA USA. [Lin, Angela] MassGen Hosp Children, Genet Unit, Boston, MA USA. [Frias, Jaime L.] McKing Consulting Corp, Fairfax, VA USA. [Patel, Sonali S.] Univ Iowa, Childrens Hosp, Iowa City, IA USA. RP Rasmussen, SA (reprint author), CDC, 1600 Clifton Rd,MS E-86, Atlanta, GA 30333 USA. EM skr9@cdc.gov RI Publications, NBDPS/B-7692-2013 FU Centers for Disease Control and Prevention (CDC) FX We thank Chris Cosper and Dr. Suzanne Gilboa for their assistance in data analysis. We thank Cathleen Higgins and Marques Merri-weather for their assistance with the supplemental surveillance study. The authors acknowledge the contributions and dedication of the abstractors from the MACDP, the IRCID, and the MBDMP, as well as the staff and scientists who contribute to the NBDPS. This research was supported in part by an appointment to the Research Participation Program at the Centers for Disease Control and Prevention (CDC) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and CDC. NR 31 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR 11 PY 2011 VL 155A IS 3 BP 555 EP 564 DI 10.1002/ajmg.a.33874 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 730KX UT WOS:000288033300015 PM 21337694 ER PT J AU Phulwani, P Bergwitz, C Jaureguiberry, G Rasoulpour, M Estrada, E AF Phulwani, Priya Bergwitz, Clemens Jaureguiberry, Graciana Rasoulpour, Majjid Estrada, Elizabeth TI Hereditary Hypophosphatemic Rickets With Hypercalciuria and Nephrolithiasis-Identification of a Novel SLC34A3/NaPi-IIc Mutation SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE rickets; hypophosphatemia; hypercalciuria; NaPi ID PHOSPHATE HOMEOSTASIS; SLC34A3; OSTEOMALACIA; CHILDREN AB Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is characterized by rickets, hyperphosphaturia, hypophosphatemia, elevated 1,25-dihydroxyvitamin-D, increased gastrointestinal calcium absorption and hypercalciuria. Serum calcium, 25-hydroxyvitamin-D and PTH levels are normal. Here we describe a boy with HHRH, nephrolithiasis, and compound heterozygosity for one previously described mutation (g. 4225_50del) and a novel splice mutation (g. 1226G > A) in SLC34A3, the gene encoding the renal sodium-phosphate cotransporter NaPi-IIc. The patient's mother and grandmother are carriers of g. 4225_50del, and both have a history of nephrolithiasis associated with hypercalciuria and elevated 1,25-dihydroxyvitamin-D. His three siblings (2-6 years old), who are also carriers of g. 4225_50del, have hypercalciuria but so far their renal ultrasounds are normal. Thus, SLC34A3/NaPi-IIc mutations appear to be associated with variable phenotypic changes at presentation, which can include recurrent nephrolithiasis. (C) 2011 Wiley-Liss, Inc. C1 [Phulwani, Priya; Estrada, Elizabeth] Connecticut Childrens Med Ctr, Dept Pediat Endocrinol & Diabet, Hartford, CT 06106 USA. [Bergwitz, Clemens; Jaureguiberry, Graciana] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Bergwitz, Clemens; Jaureguiberry, Graciana] Harvard Univ, Sch Med, Boston, MA USA. [Rasoulpour, Majjid] Connecticut Childrens Med Ctr, Dept Pediat Nephrol, Hartford, CT 06106 USA. RP Phulwani, P (reprint author), Connecticut Childrens Med Ctr, Dept Pediat Endocrinol & Diabet, 85 Seymour St,Suite 500, Hartford, CT 06106 USA. EM pphulwa@ccmckids.org FU NIDDK NIH HHS [K08 DK078361, R03 DK089127] NR 22 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR 11 PY 2011 VL 155A IS 3 BP 626 EP 633 DI 10.1002/ajmg.a.33832 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 730KX UT WOS:000288033300029 PM 21344632 ER PT J AU Letai, A AF Letai, Anthony TI A new face of BCL-2 inhibition in CLL SO BLOOD LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; APOPTOSIS; RECEPTOR; ABT-737; MCL-1 C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 10 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 10 PY 2011 VL 117 IS 10 BP 2750 EP 2751 DI 10.1182/blood-2011-01-328658 PG 3 WC Hematology SC Hematology GA 732SJ UT WOS:000288209600005 PM 21393499 ER PT J AU Grass, S Preuss, KD Wikowicz, A Terpos, E Ziepert, M Nikolaus, D Yang, Y Fadle, N Regitz, E Dimopoulos, MA Treon, SP Hunter, ZR Pfreundschuh, M AF Grass, Sandra Preuss, Klaus-Dieter Wikowicz, Alexandra Terpos, Evangelos Ziepert, Marita Nikolaus, Diana Yang, Yin Fadle, Natalie Regitz, Evi Dimopoulos, Meletios A. Treon, Steven P. Hunter, Zachary R. Pfreundschuh, Michael TI Hyperphosphorylated paratarg-7: a new molecularly defined risk factor for monoclonal gammopathy of undetermined significance of the IgM type and Waldenstrom macroglobulinemia SO BLOOD LA English DT Article ID NON-HODGKIN-LYMPHOMA; MHC CLASS-I; MULTIPLE-MYELOMA; IDENTIFICATION; GENE; IMMUNOGLOBULIN; PARAPROTEINS; STIMULATION; DISORDERS; PATTERNS AB We recently described paratarg-7 (P-7), a protein of unknown function, as the target of 15% of immunoglobulin A (IgA) and IgG paraproteins in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. To determine the frequency of P-7 as a paraprotein target in IgM-MGUS and Waldenstrom macroglobulinemia (WM), sera from patients with IgM-MGUS/WM were tested for reactivity with recombinant P-7 by enzyme-linked immunoabsorbent assay. The specificity of the paraprotein-mediated reaction was shown by absorption studies and cloning of the respective B-cell receptor. The paraproteins of 18 (9 WM and 9 IgM-MGUS) of 161 patients (11%) reacted with P-7. Isoelectric focusing and phosphatase treatment showed that P-7 was hyperphosphorylated (pP-7) in all patients with an anti-P-7-specific IgM paraprotein tested. Because only 4 of 200 healthy controls (2%) were carriers of pP-7, pP-7 carrier state is associated with a significantly increased risk (odds ratio = 6.2; P = .001) for developing IgM-MGUS/MW. Family analyses showed that the pP-7 carrier state is inherited as a dominant trait. After IgA/IgG-MGUS and multiple myeloma, IgM-MGUS/WM is the second neoplasia associated with pP-7 carrier state. The dominant inheritance of pP-7 explains cases of familial IgM-MGUS/WM and enables the identification of family members at increased risk. (Blood. 2011;117(10):2918-2923) C1 [Grass, Sandra; Preuss, Klaus-Dieter; Wikowicz, Alexandra; Nikolaus, Diana; Yang, Yin; Fadle, Natalie; Regitz, Evi; Pfreundschuh, Michael] Univ Saarland, Sch Med, Dept Internal Med 1, Jose Carreras Ctr Immuno & Gene Therapy, D-66421 Homburg, Saar, Germany. [Terpos, Evangelos; Dimopoulos, Meletios A.] Univ Athens, Sch Med, Dept Clin Therapeut, GR-11527 Athens, Greece. [Ziepert, Marita] Univ Leipzig, IMISE, Leipzig, Germany. [Treon, Steven P.; Hunter, Zachary R.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. RP Pfreundschuh, M (reprint author), Univ Saarland, Sch Med, Dept Internal Med 1, Jose Carreras Ctr Immuno & Gene Therapy, D-66421 Homburg, Saar, Germany. EM michael.pfreundschuh@uks.eu RI Hunter, Zachary/H-3018-2013 OI Hunter, Zachary/0000-0002-1689-1691 FU Forderverein Krebsforschung Saar-Pfalz-Mosel; HOMFOR; Wilhelm Sander-Stiftung FX This work was supported by Forderverein Krebsforschung Saar-Pfalz-Mosel, HOMFOR, and Wilhelm Sander-Stiftung. NR 28 TC 11 Z9 12 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 10 PY 2011 VL 117 IS 10 BP 2918 EP 2923 DI 10.1182/blood-2010-09-306076 PG 6 WC Hematology SC Hematology GA 732SJ UT WOS:000288209600029 PM 21220746 ER PT J AU Sun, Y Meijer, DH Alberta, JA Mehta, S Kane, MF Tien, AC Fu, H Petryniak, MA Potter, GB Liu, ZJ Powers, JF Runquist, IS Rowitch, DH Stiles, CD AF Sun, Yu Meijer, Dimphna H. Alberta, John A. Mehta, Shwetal Kane, Michael F. Tien, An-Chi Fu, Hui Petryniak, Magdalena A. Potter, Gregory B. Liu, Zijing Powers, James F. Runquist, I. Sophie Rowitch, David H. Stiles, Charles D. TI Phosphorylation State of Olig2 Regulates Proliferation of Neural Progenitors SO NEURON LA English DT Article ID LOOP-HELIX FACTORS; NERVOUS-SYSTEM; MOTOR-NEURON; STEM-CELLS; OLIGODENDROCYTE DIFFERENTIATION; TRANSCRIPTION FACTORS; SPECIFICATION; ACETYLATION; GLIOMA; GENES AB The bHLH transcription factors that regulate early development of the central nervous system can generally be classified as either antineural or proneural. Initial expression of antineural factors prevents cell cycle exit and thereby expands the pool of neural progenitors. Subsequent (and typically transient) expression of proneural factors promotes cell cycle exit, subtype specification, and differentiation. Against this backdrop, the bHLH transcription factor Olig2 in the oligodendrocyte lineage is unorthodox, showing antineural functions in multipotent CNS progenitor cells but also sustained expression and proneural functions in the formation of oligodendrocytes. We show here that the proliferative function of Olig2 is controlled by developmentally regulated phosphorylation of a conserved triple serine motif within the amino-terminal domain. In the phosphorylated state, Olig2 maintains antineural (i.e., promitotic) functions that are reflected in human glioma cells and in a genetically defined murine model of primary glioma. C1 [Tien, An-Chi; Petryniak, Magdalena A.; Potter, Gregory B.; Rowitch, David H.] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Pediat, San Francisco, CA 94143 USA. [Sun, Yu; Meijer, Dimphna H.; Alberta, John A.; Mehta, Shwetal; Kane, Michael F.; Fu, Hui; Liu, Zijing; Runquist, I. Sophie; Stiles, Charles D.] Harvard Univ, Sch Med, Dept Canc Biol, Boston, MA 02115 USA. [Sun, Yu; Meijer, Dimphna H.; Alberta, John A.; Mehta, Shwetal; Kane, Michael F.; Fu, Hui; Liu, Zijing; Runquist, I. Sophie; Stiles, Charles D.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Powers, James F.] Tufts Med Ctr, Dept Pathol, Boston, MA 02111 USA. [Tien, An-Chi; Petryniak, Magdalena A.; Potter, Gregory B.; Rowitch, David H.] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Neurol Surg, San Francisco, CA 94143 USA. RP Rowitch, DH (reprint author), Univ Calif San Francisco, Howard Hughes Med Inst, Dept Pediat, 513 Parnassus Ave, San Francisco, CA 94143 USA. EM rowitchd@peds.ucst.edu; charles_stiles@dfci.harvard.edu RI Fu, Hui/C-2881-2011; OI Fu, Hui/0000-0003-0252-6009; Potter, Gregory/0000-0002-0585-6575; Liu, Zijing/0000-0001-7790-0590 FU NINDS [NS040511, NS057727]; Pediatric Low-Grade Astrocytoma Foundation; [KO8 NS062744] FX The authors gratefully acknowledge Dr. Ross Tomaino at the Taplin Biological Mass Spectrometry Facility of Harvard Medical School for helpful suggestions in the proteolytic digestions and mass spectroscopy analysis of Olig2. Excellent technical assistance was provided by Diane Goleblowski, Maria Murray, Jessica Weatherbee, and Gizelle Robinson. Finally, we are grateful to Drs. Qiufu Ma and Rosalind Segal at Dana-Farber for support and helpful suggestions. M.A.P. acknowledges KO8 NS062744 for support. This work was supported by grants from the NINDS (NS040511 and NS057727 to D.H.R. and C.D.S., respectively) and from the Pediatric Low-Grade Astrocytoma Foundation. D.H.R is a Howard Hughes Medical Institute Investigator. NR 41 TC 56 Z9 59 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 10 PY 2011 VL 69 IS 5 BP 906 EP 917 DI 10.1016/j.neuron.2011.02.005 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 739RU UT WOS:000288736500009 PM 21382551 ER PT J AU Chou, CW Wong, GTC Lim, G McCabe, MF Wang, SX Irwin, MG Mao, JR AF Chou, Chiu-Wen Wong, Gordon T. C. Lim, Grewo McCabe, Michael F. Wang, Shuxing Irwin, Michael G. Mao, Jianren TI Peripheral nerve injury alters the expression of NF-kappa B in the rat's hippocampus SO BRAIN RESEARCH LA English DT Article DE Neuropathic pain; NF-kappa B; Hippocampus ID DENTATE GYRUS; NEUROPATHIC PAIN; GENE-EXPRESSION; FORMALIN PAIN; RECONSOLIDATION; MONONEUROPATHY; MICROINJECTION; STIMULATION; DISORDERS; ANALGESIA AB The hippocampus plays an important role in learning and memory and possibly contributes to the formation of pain-related memory and emotional responses. However, there is currently little data linking the hippocampus to neuropathic pain. It has been reported that NF-kappa B is an important regulatory factor in memory consolidation within the hippocampus. This study aims to examine a possible relationship between the hippocampal NF-kappa B expression and nerve injury-induced thermal hyperalgesia using a rat model of constriction sciatic nerve injury (CCI). Immunofluorescence and Western blot analysis were performed to detect and quantify the hippocampal NF-kappa B expression. Thermal hyperalgesia was examined on day 0 and postoperative days 1, 7 and 14. The nuclear portion of the p65 NF-kappa B expression was significantly increased on the contralateral side on days 7 and 14 as well as significantly increased on the ipsilateral side on day 14 as compared to the sham control group. Intraperitoneal administration of MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, reduced hyperalgesia and modulated the NF-kappa B expression in the contralateral side of hippocampus. These results suggest an association between the hippocampal NF-kappa B expression and the behavioral manifestation of thermal hyperalgesia, which is likely to be mediated through activation of the NMDA receptor. (C) 2011 Elsevier B.V. All rights reserved. C1 [Chou, Chiu-Wen; Lim, Grewo; McCabe, Michael F.; Wang, Shuxing; Mao, Jianren] Harvard Univ, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care,Sch Med, MGH Ctr Translat Pain Res,WACC 324, Boston, MA 02114 USA. [Chou, Chiu-Wen; Wong, Gordon T. C.; Irwin, Michael G.] Univ Hong Kong, Dept Anaesthesiol, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China. RP Mao, JR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care,Sch Med, MGH Ctr Translat Pain Res,WACC 324, Boston, MA 02114 USA. EM jmao@partners.org FU NIH [DE18214, DE18538, N545681] FX This study is supported by NIH RO1 grants DE18214, DE18538, and N545681. The authors claim no conflict of interest. NR 28 TC 12 Z9 13 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAR 10 PY 2011 VL 1378 BP 66 EP 71 DI 10.1016/j.brainres.2011.01.006 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 739PN UT WOS:000288730300007 PM 21223950 ER PT J AU Groom, JR Luster, AD AF Groom, Joanna R. Luster, Andrew D. TI CXCR3 in T cell function SO EXPERIMENTAL CELL RESEARCH LA English DT Review DE Chemokines; Chemokine receptors; T cell trafficking ID CHEMOKINE RECEPTOR CXCR3; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; GAMMA-INDUCIBLE PROTEIN-10; SYSTEMIC-LUPUS-ERYTHEMATOSUS; CENTRAL-NERVOUS-SYSTEM; CHRONIC HEPATITIS-C; CARDIAC ALLOGRAFT-REJECTION; MURINE CEREBRAL MALARIA; VIRUS TYPE-2 INFECTION; IFN-GAMMA AB CXCR3 is a chemokine receptor that is highly expressed on effector T cells and plays an important role in T cell trafficking and function. CXCR3 is rapidly induced on naive cells following activation and preferentially remains highly expressed on Th1-type CD4(+) T cells and effector CD8(+) T cells. CXCR3 is activated by three interferon-inducible ligands CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC). Early studies demonstrated a role for CXCR3 in the trafficking of Th1 and CD8 T cells to peripheral sites of Th1-type inflammation and the establishment of a Thl amplification loop mediated by IFN gamma and the IFN gamma-inducible CXCR3 ligands. More recent studies have also suggested that CXCR3 plays a role in the migration of T cells in the microenvironment of the peripheral tissue and lymphoid compartment, facilitating the interaction of T cells with antigen presenting cells leading to the generation of effector and memory cells. (C) 2011 Elsevier Inc. All rights reserved. C1 [Groom, Joanna R.; Luster, Andrew D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02115 USA. RP Luster, AD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02115 USA. EM aluster@mgh.harvard.edu FU Australian Government National Health; Medical Research Counsel and Overseas Biomedical Based Fellowship; NIH [CA69212] FX JRG was supported by Australian Government National Health and Medical Research Counsel and Overseas Biomedical Based Fellowship and ADL was supported by NIH grant CA69212. NR 166 TC 160 Z9 166 U1 7 U2 23 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD MAR 10 PY 2011 VL 317 IS 5 SI SI BP 620 EP 631 DI 10.1016/j.yexcr.2010.12.017 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 735KU UT WOS:000288414000008 PM 21376175 ER PT J AU Kumar, V Ogilvy, CS AF Kumar, Vishesh Ogilvy, Christopher S. TI Giant Intracranial Aneurysm SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Kumar, Vishesh] N Shore Med Ctr, Salem, MA USA. [Ogilvy, Christopher S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kumar, V (reprint author), N Shore Med Ctr, Salem, MA USA. EM vkumar3@partners.org NR 0 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 10 PY 2011 VL 364 IS 10 BP 956 EP 956 DI 10.1056/NEJMicm1008509 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 732FL UT WOS:000288170300012 PM 21388313 ER PT J AU Pallais, JC Mackool, BT Pitman, MB AF Pallais, J. Carl Mackool, Bonnie T. Pitman, Martha Bishop TI Case 7-2011: A 52-Year-Old Man with Upper Respiratory Symptoms and Low Oxygen Saturation Levels SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GLUTEN-FREE DIET; DERMATITIS-HERPETIFORMIS; CELIAC-DISEASE; DIABETIC-PATIENT; PULSE OXIMETRY; BLOOD-GLUCOSE; A1C ASSAY; METHEMOGLOBINEMIA; DAPSONE; DIAGNOSIS C1 [Pallais, J. Carl] Massachusetts Gen Hosp, Dept Med, Div Endocrinol, Boston, MA 02114 USA. [Mackool, Bonnie T.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Pitman, Martha Bishop] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mackool, Bonnie T.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Pallais, J. Carl] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Pitman, Martha Bishop] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Pallais, JC (reprint author), Massachusetts Gen Hosp, Dept Med, Div Endocrinol, Boston, MA 02114 USA. NR 58 TC 10 Z9 10 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 10 PY 2011 VL 364 IS 10 BP 957 EP 966 DI 10.1056/NEJMcpc1013923 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 732FL UT WOS:000288170300014 PM 21388314 ER PT J AU Liu, QS Wang, JH Kang, SA Thoreen, CC Hur, W Ahmed, T Sabatini, DM Gray, NS AF Liu, Qingsong Wang, Jinhua Kang, Seong A. Thoreen, Carson C. Hur, Wooyoung Ahmed, Tausif Sabatini, David M. Gray, Nathanael S. TI Discovery of 9-(6-Aminopyridin-3-yl)-1-(3-(trifluoromethyl)-phenyl)benzo[h][1,6]napht hyridin-2(1H)-one (Torin2) as a Potent, Selective, and Orally Available Mammalian Target of Raparnycin (mTOR) Inhibitor for Treatment of Cancer SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTITUMOR-ACTIVITY; RAPAMYCIN MTOR; THERAPY AB The mTOR mediated PI3K/AKT/mTOR signal transduction pathway has been demonstrated to play a key role in a broad spectrum of cancers. Starting from the mTOR selective inhibitor 1 (Torin1), a focused medicinal chemistry effort led to the discovery of an improved mTOR inhibitor 3 (Torin2), which possesses an EC(50) of 0.25 nM for inhibiting cellular mTOR activity. Compound 3 exhibited 800-fold selectivity over PI3K (EC(50): 200 nM) and over 100-fold binding selectivity relative to 440 other protein kinases. Compound 3 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure relative to compound 1. C1 [Liu, Qingsong; Wang, Jinhua; Thoreen, Carson C.; Hur, Wooyoung; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Liu, Qingsong; Wang, Jinhua; Thoreen, Carson C.; Hur, Wooyoung; Gray, Nathanael S.] Harvard Univ, Dept Biol Chem & Mol Pharmacol, Sch Med, Boston, MA 02115 USA. [Kang, Seong A.; Sabatini, David M.] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA. [Ahmed, Tausif] Sai Advantium Pharma Ltd, Hyderabad 500033, Andhra Pradesh, India. [Sabatini, David M.] MIT, Dept Biol, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Sabatini, David M.] MIT, Koch Ctr Integrat Canc Res, Cambridge, MA 02139 USA. RP Gray, NS (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM Nathanael_gray@dfci.harvard.edu FU NIH [GM079575-03] FX We thank Life Technologies Corporation, SelectScreen Kinase Profiling Service for performing enzymatic biochemical kinase profiling, and Ambit Bioscience for performing KinomeScan profiling. We also want to thank Sai Advantium Pharma Ltd. (India) for the pharmacokinetic studies and Michael Cameron for performing in vitro microsome stability studies. This work was partially supported by NIH Grant GM079575-03. NR 24 TC 81 Z9 84 U1 4 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 10 PY 2011 VL 54 IS 5 BP 1473 EP 1480 DI 10.1021/jm101520v PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 727WJ UT WOS:000287833300033 PM 21322566 ER PT J AU Amin, SB Shah, PK Yan, AM Adamia, S Minvielle, S Avet-Loiseau, H Munshi, NC Li, C AF Amin, Samir B. Shah, Parantu K. Yan, Aimin Adamia, Sophia Minvielle, Stephane Avet-Loiseau, Herve Munshi, Nikhil C. Li, Cheng TI The dChip survival analysis module for microarray data SO BMC BIOINFORMATICS LA English DT Article ID COPY-NUMBER ALTERATIONS; GENE-EXPRESSION; BREAST-CANCER; MICRORNA EXPRESSION; MULTIPLE-MYELOMA; PREDICTION; SIGNATURE; ARRAYS AB Background: Genome-wide expression signatures are emerging as potential marker for overall survival and disease recurrence risk as evidenced by recent commercialization of gene expression based biomarkers in breast cancer. Similar predictions have recently been carried out using genome-wide copy number alterations and microRNAs. Existing software packages for microarray data analysis provide functions to define expression-based survival gene signatures. However, there is no software that can perform survival analysis using SNP array data or draw survival curves interactively for expression-based sample clusters. Results: We have developed the survival analysis module in the dChip software that performs survival analysis across the genome for gene expression and copy number microarray data. Built on the current dChip software's microarray analysis functions such as chromosome display and clustering, the new survival functions include interactive exploring of Kaplan-Meier (K-M) plots using expression or copy number data, computing survival p-values from the log-rank test and Cox models, and using permutation to identify significant chromosome regions associated with survival. Conclusions: The dChip survival module provides user-friendly way to perform survival analysis and visualize the results in the context of genes and cytobands. It requires no coding expertise and only minimal learning curve for thousands of existing dChip users. The implementation in Visual C++ also enables fast computation. The software and demonstration data are freely available at http://dchip-surv.chenglilab.org. C1 [Amin, Samir B.; Shah, Parantu K.; Yan, Aimin; Li, Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Amin, Samir B.; Shah, Parantu K.; Yan, Aimin; Li, Cheng] Harvard Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Amin, Samir B.; Adamia, Sophia; Munshi, Nikhil C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Minvielle, Stephane; Avet-Loiseau, Herve] Univ Hosp, Dept Hematol, Nantes, France. [Minvielle, Stephane; Avet-Loiseau, Herve] INSERM, Ctr Rech Cancerol, U892, Nantes, France. [Munshi, Nikhil C.] Vet Adm Boston Healthcare Syst, W Roxbury, MA 02132 USA. [Munshi, Nikhil C.] Harvard Univ, Sch Med, W Roxbury, MA 02132 USA. RP Li, C (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA. EM lch3000@gmail.com RI Minvielle, Stephane/K-8251-2015; OI Amin, Samir/0000-0002-3207-9505 FU NIH [1R01GM077122]; Claudia Adams Barr Program in Innovative Basic Cancer Research FX We thank Cheng Li Lab members for constructive discussion. This work has been supported by NIH grant 1R01GM077122. P. K. S. has been supported by the Claudia Adams Barr Program in Innovative Basic Cancer Research. NR 20 TC 6 Z9 6 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAR 9 PY 2011 VL 12 AR 72 DI 10.1186/1471-2105-12-72 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 742ZH UT WOS:000288983600001 PM 21388547 ER PT J AU Meyer-Luehmann, M Mora, JR Mielke, M Spires-Jones, TL de Calignon, A von Andrian, UH Hyman, BT AF Meyer-Luehmann, Melanie Mora, J. Rodrigo Mielke, Matthew Spires-Jones, Tara L. de Calignon, Alix von Andrian, Ulrich H. Hyman, Bradley T. TI T cell mediated cerebral hemorrhages and microhemorrhages during passive A beta immunization in APPPS1 transgenic mice SO MOLECULAR NEURODEGENERATION LA English DT Article ID AMYLOID PRECURSOR PROTEIN; CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; MOUSE MODEL; COGNITIVE DECLINE; MEMORY DEFICITS; IN-VIVO; PEPTIDE; PLAQUES; NEUROPATHOLOGY AB Background: Immunization against amyloid-beta (A beta), the peptide that accumulates in the form of senile plaques and in the cerebrovasculature in Alzheimer's disease (AD), causes a dramatic immune response that prevents plaque formation and clears accumulated A beta in transgenic mice. In a clinical trial of A beta immunization, some patients developed meningoencephalitis and hemorrhages. Neuropathological investigations of patients who died after the trial showed clearance of amyloid pathology, but also a powerful immune response involving activated T cells probably underlying the negative effects of the immunization. Results: To define the impact of T cells on this inflammatory response we used passive immunization and adoptive transfer to separate the effect of IgG and T cell mediated effects on microhemorrhage in APPPS1 transgenic mice. Neither anti A beta IgG nor adoptively transferred T cells, alone, led to increased cerebrovascular damage. However, the combination of adoptively transferred T cells and passive immunization led to massive cerebrovascular bleeding that ranged from multiple microhemorrhages in the parenchyma to large hematomas. Conclusions: Our results indicate that vaccination can lead to A beta and T cell induced cerebral micro-hemorrhages and acute hematomas, which are greatly exacerbated by T cell mediated activity. C1 [Meyer-Luehmann, Melanie; Mielke, Matthew; Spires-Jones, Tara L.; de Calignon, Alix; Hyman, Bradley T.] Harvard Univ, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Med Sch,Dept Neurol,Alzheimers Dis Res Lab, Charlestown, MA 02129 USA. [Meyer-Luehmann, Melanie] German Ctr Neurodegenerat Dis DZNE, D-80336 Munich, Germany. [Meyer-Luehmann, Melanie] Univ Munich, Adolf Butenandt Inst, D-80336 Munich, Germany. [Mora, J. Rodrigo; von Andrian, Ulrich H.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Mora, J. Rodrigo; von Andrian, Ulrich H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Mora, J. Rodrigo] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Hyman, BT (reprint author), Harvard Univ, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Med Sch,Dept Neurol,Alzheimers Dis Res Lab, Charlestown, MA 02129 USA. EM bhyman@partners.org RI von Andrian, Ulrich/A-5775-2008 FU NIH [AG08487, K99 AG033670-01A1]; Alzheimer's Association [EB00768]; Dana Foundation FX This work was supported by NIH Grant AG08487, K99 AG033670-01A1 and the Alzheimer's Association Pioneer Award EB00768 and the Dana Foundation. NR 41 TC 11 Z9 11 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD MAR 9 PY 2011 VL 6 AR 22 DI 10.1186/1750-1326-6-22 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 742SS UT WOS:000288965400001 PM 21388539 ER PT J AU Nelissen, K Borra, E Gerbella, M Rozzi, S Luppino, G Vanduffel, W Rizzolatti, G Orban, GA AF Nelissen, Koen Borra, Elena Gerbella, Marzio Rozzi, Stefano Luppino, Giuseppe Vanduffel, Wim Rizzolatti, Giacomo Orban, Guy A. TI Action Observation Circuits in the Macaque Monkey Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SUPERIOR TEMPORAL SULCUS; LATERAL INTRAPARIETAL AREA; CORTICAL CONNECTIONS; PREMOTOR CORTEX; BIOLOGICAL MOTION; RETINOTOPIC ORGANIZATION; FUNCTIONAL-ORGANIZATION; NEURAL REPRESENTATION; POLYSENSORY AREA; VENTRAL PREMOTOR AB In both monkeys and humans, the observation of actions performed by others activates cortical motor areas. An unresolved question concerns the pathways through which motor areas receive visual information describing motor acts. Using functional magnetic resonance imaging (fMRI), we mapped the macaque brain regions activated during the observation of grasping actions, focusing on the superior temporal sulcus region (STS) and the posterior parietal lobe. Monkeys viewed either videos with only the grasping hand visible or videos with the whole actor visible. Observation of both types of grasping videos activated elongated regions in the depths of both lower and upper banks of STS, as well as parietal areas PFG and anterior intraparietal (AIP). The correlation of fMRI data with connectional data showed that visual action information, encoded in the STS, is forwarded to ventral premotor cortex (F5) along two distinct functional routes. One route connects the upper bank of the STS with area PFG, which projects, in turn, to the premotor area F5c. The other connects the anterior part of the lower bank of the STS with premotor areas F5a/p via AIP. Whereas the first functional route emphasizes the agent and may relay visual information to the parieto-frontal mirror circuit involved in understanding the agent's intentions, the second route emphasizes the object of the action and may aid in understanding motor acts with respect to their immediate goal. C1 [Nelissen, Koen; Vanduffel, Wim; Orban, Guy A.] Katholieke Univ Leuven, Sch Med, Neuro & Psychofysiol Lab, B-3000 Louvain, Belgium. [Nelissen, Koen; Vanduffel, Wim] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Borra, Elena; Gerbella, Marzio; Rozzi, Stefano; Luppino, Giuseppe; Rizzolatti, Giacomo] Univ Parma, Dept Neurosci, I-43100 Parma, Italy. [Rizzolatti, Giacomo] Italian Inst Technol, Brain Ctr Motor & Social Cognit, I-43100 Parma, Italy. RP Nelissen, K (reprint author), Katholieke Univ Leuven, Sch Med, Neuro & Psychofysiol Lab, Herestr 49,Bus 1021, B-3000 Louvain, Belgium. EM koen.nelissen@med.kuleuven.be OI gerbella, marzio/0000-0002-1204-3484; Rozzi, Stefano/0000-0002-6147-1530 FU Fonds voor Wetenschappelijk Onderzoek (FWO) [G151.04, G.0.593.09]; Excellentie Financiering Katholieke Universiteit Leuven [EF 05/14]; Interuniversity Attraction Pole Grant [6/29]; National Institutes of Health [R21 NS064432-01]; Ministero dell' Universita e della Ricerca (MUR) [PRIN 2006052343-002]; Agenzia Spaziale Italiana; region Flanders FX This work was supported by Fonds voor Wetenschappelijk Onderzoek (FWO) Grant G151.04 (G.A.O.), Excellentie Financiering Katholieke Universiteit Leuven Grant EF 05/14 (G.A.O.), Interuniversity Attraction Pole Grant 6/29 (G.A.O.); FWO Grant G.0.593.09 and National Institutes of Health Grant R21 NS064432-01 (W. V., K.N.); Ministero dell' Universita e della Ricerca (MUR) Grant PRIN 2006052343-002 (G. L.); and grants from Agenzia Spaziale Italiana and MUR (G. R.). The 3T scanner was purchased with a "Zware Apparatuur" 2004 grant from the region Flanders. Laboratoire Guerbet (Roissy, France) provided the contrast agent Sinerem. K.N. is a postdoctoral research fellow of the FWO. We thank A. Coeman, W. Depuydt, M. De Paep, C. Fransen, P. Kayenbergh, G. Meulemans, R. Peeters, S. Verstraeten, and Dr. H. Kolster for technical assistance. NR 58 TC 87 Z9 87 U1 3 U2 20 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 MAR 9 PY 2011 VL 31 IS 10 BP 3743 EP 3756 DI 10.1523/JNEUROSCI.4803-10.2011 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 732CJ UT WOS:000288160500024 PM 21389229 ER PT J AU Moulton, EA Elman, I Pendse, G Schmahmann, J Becerra, L Borsook, D AF Moulton, Eric A. Elman, Igor Pendse, Gautam Schmahmann, Jeremy Becerra, Lino Borsook, David TI Aversion-Related Circuitry in the Cerebellum: Responses to Noxious Heat and Unpleasant Images SO JOURNAL OF NEUROSCIENCE LA English DT Article ID COGNITIVE-AFFECTIVE SYNDROME; HUMAN BRAIN; PAIN; INVOLVEMENT; EMOTION; ACTIVATION; LESIONS; HUMANS; METAANALYSIS; ANXIETY AB The cerebellum is reliably activated during both acute and chronic pain conditions, but it is unclear whether the response to aversive painful stimuli can be generalized to other aversive stimuli. We hypothesized that cerebellar activation during pain reflects higher-level encoding of aversive stimuli. We used functional magnetic resonance imaging (fMRI) to compare cerebellar responses in 11 healthy volunteers to noxious heat (46 degrees C) applied to the hand and to the passive viewing of images selected from the International Affective Picture System. Aversive stimuli in the form of noxious heat and unpleasant pictures (unpleasant vs neutral) activated overlapping areas in the posterior cerebellum, specifically in hemispheric lobule VI, Crus I, and VIIb. Pleasant pictures (pleasant vs neutral) did not share the same pattern of activation as observed with the aversive stimuli. Cerebellar areas that showed functional overlap with both heat pain and unpleasant picture viewing were significantly inversely correlated with fMRI signals measured in limbic system structures, including the anterior hypothalamus, subgenual anterior cingulate cortex, and the parahippocampal gyrus. Heat-specific functional connectivity was detected in many regions including primary motor cortex, secondary somatosensory cortex, anterior insula, and the periaqueductal gray. The overlap between cerebellar lobuli reactive to noxious heat and passive viewing of unpleasant images suggest that the cerebellum may contain specific regions involved in encoding generalized aversive processing. The separate cortical networks suggest that noxious heat-evoked responses in the cerebellum can be divided into sensorimotor and emotional networks. C1 [Moulton, Eric A.; Pendse, Gautam; Becerra, Lino; Borsook, David] Harvard Univ, McLean Hosp, Sch Med, PAIN Grp, Belmont, MA 02478 USA. [Elman, Igor] Harvard Univ, McLean Hosp, Sch Med, Clin Psychopathol Lab, Belmont, MA 02478 USA. [Schmahmann, Jeremy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ataxia Unit,Cognit Behav Neurol Unit,Dept Neurol, Boston, MA 02114 USA. RP Moulton, EA (reprint author), Harvard Univ, McLean Hosp, Sch Med, PAIN Grp, 115 Mill St, Belmont, MA 02478 USA. EM emoulton@mclean.harvard.edu FU National Institutes of Health (National Institute on Drug Abuse) [K01DA024289, R01DA017959]; National Institutes of Health (National Institute of Neurological Disorders and Stroke) [K24NS064050]; Birmingham and MINDlink Foundations FX This work was supported by the National Institutes of Health (National Institute on Drug Abuse Grant K01DA024289 to E.A.M. and Grant R01DA017959 to I.E.; and National Institute of Neurological Disorders and Stroke Grant K24NS064050 to D.B.), and the Birmingham and MINDlink Foundations (J.S.). We acknowledge Susie Morris, Sadie Cole, and Won Chi for their assistance in subject recruitment and data collection. NR 73 TC 64 Z9 64 U1 1 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 9 PY 2011 VL 31 IS 10 BP 3795 EP 3804 DI 10.1523/JNEUROSCI.6709-10.2011 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 732CJ UT WOS:000288160500029 PM 21389234 ER PT J AU Roseman, M Milette, K Bero, LA Coyne, JC Lexchin, J Turner, EH Thombs, BD AF Roseman, Michelle Milette, Katherine Bero, Lisa A. Coyne, James C. Lexchin, Joel Turner, Erick H. Thombs, Brett D. TI Reporting of Conflicts of Interest in Meta-analyses of Trials of Pharmacological Treatments SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID CELL LUNG-CANCER; PHARMACEUTICAL-INDUSTRY; RANDOMIZED-TRIALS; DRUG TRIALS; CARDIOVASCULAR-DISEASE; COMPETING INTERESTS; DIABETES-MELLITUS; CLINICAL-TRIALS; FINANCIAL TIES; RISK AB Context Disclosure of conflicts of interest (COIs) from pharmaceutical industry study funding and author-industry financial relationships is sometimes recommended for randomized controlled trials (RCTs) published in biomedical journals. Authors of meta-analyses, however, are not required to report COIs disclosed in original reports of included RCTs. Objective To investigate whether meta-analyses of pharmacological treatments published in high-impact biomedical journals report COIs disclosed in included RCTs. Data Sources and Study Selection We selected the 3 most recent meta-analyses of patented pharmacological treatments published January 2009 through October 2009 in each general medicine journal with an impact factor of at least 10; in high-impact journals in each of the 5 specialty medicine areas with the greatest 2008 global therapeutic sales (oncology, cardiology, respiratory medicine, endocrinology, and gastroenterology); and in the Cochrane Database of Systematic Reviews. Data Extraction Two investigators independently extracted data on disclosed study funding, author-industry financial ties, and author employment from each meta-analysis, from RCTs included in each meta-analysis, and on whether meta-analyses reported disclosed COIs of included RCTs. Results Of 29 meta-analyses reviewed, which included 509 RCTs, only 2 meta-analyses (7%) reported RCT funding sources; and 0 reported RCT author-industry ties or employment by the pharmaceutical industry. Of 318 meta-analyzed RCTs that reported funding sources, 219 (69%) were industry funded; and 91 of 132 (69%) that reported author financial disclosures had 1 or more authors with pharmaceutical industry financial ties. In 7 of the 29 meta-analyses reviewed, 100% of included RCTs had at least 1 form of disclosed COI (pharmaceutical industry funding, author-industry financial ties, or employment), yet only 1 of these 7 meta-analyses reported RCT funding sources, and 0 reported RCT author-industry ties or employment. Conclusion Among a group of meta-analyses of pharmacological treatments published in high-impact biomedical journals, information concerning primary study funding and author COIs for the included RCTs were only rarely reported. JAMA. 2011;305(10):1008-1017 www.jama.com C1 [Roseman, Michelle; Milette, Katherine; Thombs, Brett D.] Jewish Gen Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E4, Canada. [Roseman, Michelle; Milette, Katherine; Thombs, Brett D.] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Thombs, Brett D.] McGill Univ, Dept Epidemiol, Montreal, PQ, Canada. [Thombs, Brett D.] McGill Univ, Dept Biostat, Montreal, PQ, Canada. [Thombs, Brett D.] McGill Univ, Dept Occupat Hlth, Montreal, PQ, Canada. [Thombs, Brett D.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Bero, Lisa A.] Univ Calif San Francisco, Sch Pharm, Dept Clin Pharm, San Francisco, CA 94143 USA. [Bero, Lisa A.] Univ Calif San Francisco, Sch Med, Inst Hlth Policy Studies, San Francisco, CA 94143 USA. [Coyne, James C.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Coyne, James C.] Univ Groningen, Univ Med Ctr Groningen, Dept Hlth Sci, Hlth Psychol Sect, NL-9700 AB Groningen, Netherlands. [Lexchin, Joel] Univ Toronto, Univ Hlth Network, Emergency Dept, Toronto, ON, Canada. [Lexchin, Joel] Univ Toronto, Dept Family & Community Med, Toronto, ON M5S 1A1, Canada. [Lexchin, Joel] York Univ, Sch Hlth Policy & Management, N York, ON M3J 1P3, Canada. [Turner, Erick H.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Turner, Erick H.] Portland VA Med Ctr, Portland, OR USA. RP Thombs, BD (reprint author), Jewish Gen Hosp, Lady Davis Inst Med Res, 4333 Cote Ste Catherine Rd, Montreal, PQ H3T 1E4, Canada. EM brett.thombs@mcgill.ca OI Turner, Erick/0000-0002-3522-3357 FU Canadian Institutes of Health Research; McGill University; Canadian Institutes of Health Research Strategic Training Initiative [SKI 83345]; Fonds de la Recherche en Sante Quebec; Etablissement de Jeunes Chercheurs FX Ms Roseman and Ms Milette were supported by Frederick Banting and Charles Best Canadian Graduate Scholarships-Master's Awards from the Canadian Institutes of Health Research. Ms Roseman was also supported by a McGill University Provost's Graduate Fellowship and a McGill University Principal's Graduate Fellowship. Ms. Milette was also supported by a Canadian Scleroderma Research Group Studentship (Canadian Institutes of Health Research Strategic Training Initiative in Health Research Grant, SKI 83345) and a McGill University Provost's Graduate Fellowship. Dr Thombs was supported by a New Investigator Award from the Canadian Institutes of Health Research and an Etablissement de Jeunes Chercheurs award from the Fonds de la Recherche en Sante Quebec. Funds from the Etablissement de Jeunes Chercheurs award supported this project. NR 69 TC 68 Z9 69 U1 1 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 9 PY 2011 VL 305 IS 10 BP 1008 EP 1017 DI 10.1001/jama.2011.257 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 731SM UT WOS:000288129600020 PM 21386079 ER PT J AU Li, SQ Moffett, HF Lu, J Werner, L Zhang, H Ritz, J Neuberg, D Wucherpfennig, KW Brown, JR Novina, CD AF Li, Shuqiang Moffett, Howell F. Lu, Jun Werner, Lillian Zhang, Hao Ritz, Jerome Neuberg, Donna Wucherpfennig, Kai W. Brown, Jennifer R. Novina, Carl D. TI MicroRNA Expression Profiling Identifies Activated B Cell Status in Chronic Lymphocytic Leukemia Cells SO PLOS ONE LA English DT Article ID CLL PATIENTS; DISEASE PROGRESSION; MIRNA EXPRESSION; DOWN-REGULATION; PHENOTYPE; APOPTOSIS; LYMPHOMA; REVEALS; DIFFERENTIATION; PROLIFERATION AB Chronic lymphocytic leukemia (CLL) is thought to be a disease of resting lymphocytes. However, recent data suggest that CLL cells may more closely resemble activated B cells. Using microRNA (miRNA) expression profiling of highly-enriched CLL cells from 38 patients and 9 untransformed B cells from normal donors before acute CpG activation and 5 matched B cells after acute CpG activation, we demonstrate an activated B cell status for CLL. Gene set enrichment analysis (GSEA) identified statistically-significant similarities in miRNA expression between activated B cells and CLL cells including upregulation of miR-34a, miR-155, and miR-342-3p and downregulation of miR-103, miR-181a and miR-181b. Additionally, decreased levels of two CLL signature miRNAs miR-29c and miR-223 are associated with ZAP70(+) and IgVH unmutated status and with shorter time to first therapy. These data indicate an activated B cell status for CLL cells and suggest that the direction of change of individual miRNAs may predict clinical course in CLL. C1 [Li, Shuqiang; Moffett, Howell F.; Wucherpfennig, Kai W.; Novina, Carl D.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Moffett, Howell F.] Harvard Univ, Sch Med, Div Med Sci, Boston, MA USA. [Lu, Jun; Zhang, Hao; Novina, Carl D.] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA USA. [Werner, Lillian; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ritz, Jerome; Brown, Jennifer R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ritz, Jerome; Brown, Jennifer R.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Novina, Carl D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Li, SQ (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM carl_novina@dfci.harvard.edu OI Ritz, Jerome/0000-0001-5526-4669 FU NIH [PO1-CA081534, K23 CA115682]; NRSA [DFCI/NCI T32 CA70083]; Carreras International Leukemia; Doris Duke Clinical Scientist Development Awards FX The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The funders of the study include NIH grant (PO1-CA081534), NIH grant (K23 CA115682), NRSA Fellowship (DFCI/NCI T32 CA70083), Carreras International Leukemia and Doris Duke Clinical Scientist Development Awards. NR 43 TC 36 Z9 40 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 8 PY 2011 VL 6 IS 3 AR e16956 DI 10.1371/journal.pone.0016956 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 732FI UT WOS:000288170000012 PM 21408091 ER PT J AU Sasaki, AT Carracedo, A Locasale, JW Anastasiou, D Takeuchi, K Kahoud, ER Haviv, S Asara, JM Pandolfi, PP Cantley, LC AF Sasaki, Atsuo T. Carracedo, Arkaitz Locasale, Jason W. Anastasiou, Dimitrios Takeuchi, Koh Kahoud, Emily Rose Haviv, Sasson Asara, John M. Pandolfi, Pier Paolo Cantley, Lewis C. TI Ubiquitination of K-Ras Enhances Activation and Facilitates Binding to Select Downstream Effectors SO SCIENCE SIGNALING LA English DT Article ID HUMAN COLORECTAL-CANCER; SIGNAL-TRANSDUCTION; COSTELLO-SYNDROME; KRAS MUTATIONS; POINT MUTATION; H-RAS; PROTEINS; REGION; SWITCH; CODON-146 AB The guanosine triphosphate (GTP)-loaded form of the guanosine triphosphatase (GTPase) Ras initiates multiple signaling pathways by binding to various effectors, such as the kinase Raf and phosphatidylinositol 3-kinase (PI3K). Ras activity is increased by guanine nucleotide exchange factors that stimulate guanosine diphosphate release and GTP loading and is inhibited by GTPase-activating proteins that stimulate GTP hydrolysis. KRAS is the most frequently mutated RAS gene in cancer. Here, we report that monoubiquitination of lysine-147 in the guanine nucleotide-binding motif of wild-type K-Ras could lead to enhanced GTP loading. Furthermore, ubiquitination increased the binding of the oncogenic Gly12Val mutant of K-Ras to the downstream effectors PI3K and Raf. Thus, monoubiquitination could enhance GTP loading on K-Ras and increase its affinity for specific downstream effectors, providing a previously unidentified mechanism for Ras activation. Downloaded from stke. sciencemag. org on March 8, 2011 C1 [Sasaki, Atsuo T.; Locasale, Jason W.; Anastasiou, Dimitrios; Kahoud, Emily Rose; Haviv, Sasson; Asara, John M.; Cantley, Lewis C.] Harvard Univ, Sch Med, Div Signal Transduct, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Sasaki, Atsuo T.; Locasale, Jason W.; Anastasiou, Dimitrios; Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Carracedo, Arkaitz; Pandolfi, Pier Paolo] Harvard Univ, Beth Israel Deaconess Med Ctr, Beth Israel Deaconess Canc Ctr,Sch Med, Div Genet,Dept Med & Pathol,Canc Genet Program, Boston, MA 02215 USA. [Carracedo, Arkaitz] Technol Pk Bizkaia, CIC bioGUNE, Derio 48160, Bizkaia, Spain. [Takeuchi, Koh] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Takeuchi, Koh] Natl Inst Adv Ind Sci & Technol, Biomed Informat Res Ctr, Koto Ku, Tokyo 1350064, Japan. [Asara, John M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Cantley, LC (reprint author), Harvard Univ, Sch Med, Div Signal Transduct, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. EM lcantley@hms.harvard.edu RI Carracedo, Arkaitz/F-7029-2011; cancer, biogune/H-7276-2012; Cantley, Lewis/D-1800-2014; OI Carracedo, Arkaitz/0000-0001-5957-1260; Cantley, Lewis/0000-0002-1298-7653; Locasale, Jason/0000-0002-7766-3502 FU NCI NIH HHS [1P01CA120964-01A1, 5P01CA117969, 5P30CA006516-43, P01 CA089021, P01 CA117969, P01 CA120964, P01CA089021, P30 CA006516]; NIGMS NIH HHS [R01 GM041890, R01 GM056203, R01-GM41890, R37 GM041890] NR 31 TC 54 Z9 55 U1 2 U2 14 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1945-0877 EI 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 8 PY 2011 VL 4 IS 163 AR ra13 DI 10.1126/scisignal.2001518 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 731PS UT WOS:000288122300001 PM 21386094 ER PT J AU Fradley, MG Picard, MH AF Fradley, Michael G. Picard, Michael H. TI Rupture of the Posteromedial Papillary Muscle Leading to Partial Flail of the Anterior Mitral Leaflet SO CIRCULATION LA English DT Editorial Material ID ACUTE MYOCARDIAL-INFARCTION C1 [Fradley, Michael G.; Picard, Michael H.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Fradley, MG (reprint author), Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. EM mfradley@partners.org OI Picard, Michael/0000-0002-9264-3243 NR 4 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 8 PY 2011 VL 123 IS 9 BP 1044 EP 1045 DI 10.1161/CIRCULATIONAHA.110.984724 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 731OL UT WOS:000288118900019 PM 21382906 ER PT J AU Bhatt, DL AF Bhatt, Deepak L. TI Glycoprotein IIb/IIIa Inhibitors Do They Still Have a Role? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE adverse outcomes; glycoprotein IIb/IIIa inhibitors; meta-analysis; myocardial infarction; PCI ID PERCUTANEOUS CORONARY INTERVENTION; ACUITY TRIAL; MYOCARDIAL-INFARCTION; RANDOMIZED-TRIAL; PCI; BIVALIRUDIN; MORTALITY; RISK; STRATEGIES; ELEVATION C1 [Bhatt, Deepak L.] Brigham & Womens Hosp, Dept Cardiol, VA Boston Healthcare Syst, Boston, MA 02132 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA 02132 USA. RP Bhatt, DL (reprint author), Brigham & Womens Hosp, Dept Cardiol, VA Boston Healthcare Syst, 1400 VFW Pkwy, Boston, MA 02132 USA. EM DLBHATTMD@post.harvard.edu NR 20 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 8 PY 2011 VL 57 IS 10 BP 1200 EP 1201 DI 10.1016/j.jacc.2010.10.031 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 729PI UT WOS:000287962500005 PM 21371636 ER PT J AU Sun, QA Chen, XX Ma, JH Peng, HY Wang, F Zha, XJ Wang, YN Jing, YL Yang, HW Chen, RR Chang, L Zhang, Y Goto, J Onda, H Chen, T Wang, MR Lu, YY You, H Kwiatkowski, D Zhang, HB AF Sun, Qian Chen, Xinxin Ma, Jianhui Peng, Haiyong Wang, Fang Zha, Xiaojun Wang, Yanan Jing, Yanling Yang, Hongwang Chen, Rongrong Chang, Long Zhang, Yu Goto, June Onda, Hiroaki Chen, Tong Wang, Ming-Rong Lu, Youyong You, Han Kwiatkowski, David Zhang, Hongbing TI Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE PTEN; tuberous sclerosis 1; hexokinase II; lactate dehydrogenase-B; glyceraldehyde 3-phosphate dehydrogenase ID TUBEROUS SCLEROSIS COMPLEX; CELL-GROWTH; SIGNALING PATHWAYS; RENAL-CARCINOMA; VEGF EXPRESSION; CANCER-CELLS; NULL-CELLS; MTOR; TSC2; METABOLISM AB Although aerobic glycolysis (the Warburg effect) is a hallmark of cancer, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear. For a largely unknown regulatory mechanism, a rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and tumor cells, and plays an essential role in tumor metabolism and growth. Because the receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a frequently altered pathway in cancer, we explored its potential role in cancer metabolism. We identified mTOR as a central activator of the Warburg effect by inducing PKM2 and other glycolytic enzymes under normoxic conditions. PKM2 level was augmented in mouse kidney tumors due to deficiency of tuberous sclerosis complex 2 and consequent mTOR activation, and was reduced in human cancer cells by mTOR suppression. mTOR up-regulation of PKM2 expression was through hypoxia-inducible factor 1 alpha (HIF1 alpha)-mediated transcription activation, and c-Myc-heterogeneous nuclear ribonucleoproteins (hnRNPs)-dependent regulation of PKM2 gene splicing. Disruption of PKM2 suppressed oncogenic mTOR-mediated tumorigenesis. Unlike normal cells, mTOR hyperactive cells were more sensitive to inhibition of mTOR or glycolysis. Dual suppression of mTOR and glycolysis synergistically blunted the proliferation and tumor development of mTOR hyperactive cells. Even though aerobic glycolysis is not required for breach of senescence for immortalization and transformation, the frequently deregulated mTOR signaling during multistep oncogenic processes could contribute to the development of the Warburg effect in many cancers. Components of the mTOR/HIF1 alpha/Myc-hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway. C1 [Sun, Qian; Chen, Xinxin; Peng, Haiyong; Wang, Fang; Zha, Xiaojun; Wang, Yanan; Jing, Yanling; Yang, Hongwang; Chen, Rongrong; Chang, Long; Zhang, Hongbing] Peking Union Med Coll, Inst Basic Med Sci, Dept Physiol & Pathophysiol, State Key Lab Med Mol Biol, Beijing 100005, Peoples R China. [Sun, Qian; Chen, Xinxin; Peng, Haiyong; Wang, Fang; Zha, Xiaojun; Wang, Yanan; Jing, Yanling; Yang, Hongwang; Chen, Rongrong; Chang, Long; Zhang, Hongbing] Peking Union Med Coll, Sch Basic Med, Beijing 100005, Peoples R China. [Sun, Qian; Chen, Xinxin; Peng, Haiyong; Wang, Fang; Zha, Xiaojun; Wang, Yanan; Jing, Yanling; Yang, Hongwang; Chen, Rongrong; Chang, Long; Zhang, Hongbing] Chinese Acad Med Sci, Beijing 100005, Peoples R China. [Ma, Jianhui; You, Han] Xia Men Univ, Sch Life Sci, Xiamen 361005, Peoples R China. [Zhang, Yu; Wang, Ming-Rong] Chinese Acad Med Sci, Beijing 100021, Peoples R China. [Zhang, Yu; Wang, Ming-Rong] Peking Union Med Coll, Canc Inst Hosp, State Key Lab Mol Oncol, Beijing 100021, Peoples R China. [Goto, June; Kwiatkowski, David] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Goto, June; Kwiatkowski, David] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Translat Med, Boston, MA 02115 USA. [Onda, Hiroaki] Jackson Lab, Mouse Genome Informat Team, Bar Harbor, ME 04609 USA. [Chen, Tong] Ohio State Univ, Dept Internal Med, Div Med Oncol, Columbus, OH 43210 USA. [Lu, Youyong] Peking Univ, Sch Oncol, Beijing Canc Hosp Inst, Mol Oncol Lab, Beijing 100142, Peoples R China. RP Zhang, HB (reprint author), Peking Union Med Coll, Inst Basic Med Sci, Dept Physiol & Pathophysiol, State Key Lab Med Mol Biol, Beijing 100005, Peoples R China. EM hyou@xmu.edu.cn; hbzhang2006@gmail.com RI Chen, Tong/E-2879-2011; Peng, Haiyong/S-8045-2016 FU National Natural Science Foundation of China [30788004]; National Basic Research Program of China 973 Program [2009CB522202, 2009CB522203]; Ministry of Education of China [B08007] FX This study was supported by National Natural Science Foundation of China Grant 30788004, the National Basic Research Program of China 973 Program Grants 2009CB522202 and 2009CB522203, and Ministry of Education of China 111 Project B08007. NR 51 TC 207 Z9 220 U1 9 U2 61 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 8 PY 2011 VL 108 IS 10 BP 4129 EP 4134 DI 10.1073/pnas.1014769108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 731PA UT WOS:000288120400059 PM 21325052 ER PT J AU Valm, AM Welch, JLM Rieken, CW Hasegawa, Y Sogin, ML Oldenbourg, R Dewhirst, FE Borisy, GG AF Valm, Alex M. Welch, Jessica L. Mark Rieken, Christopher W. Hasegawa, Yuko Sogin, Mitchell L. Oldenbourg, Rudolf Dewhirst, Floyd E. Borisy, Gary G. TI Systems-level analysis of microbial community organization through combinatorial labeling and spectral imaging SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell biology; fluorescence; microbial diversity; oral biofilm ID TARGETED OLIGONUCLEOTIDE PROBES; HUMAN ORAL BACTERIA; DENTAL PLAQUE; COAGGREGATION; BIOFILMS; IDENTIFICATION; COADHESION; FISH AB Microbes in nature frequently function as members of complex multitaxon communities, but the structural organization of these communities at the micrometer level is poorly understood because of limitations in labeling and imaging technology. We report here a combinatorial labeling strategy coupled with spectral image acquisition and analysis that greatly expands the number of fluorescent signatures distinguishable in a single image. As an imaging proof of principle, we first demonstrated visualization of Escherichia coli labeled by fluorescence in situ hybridization (FISH) with 28 different binary combinations of eight fluorophores. As a biological proof of principle, we then applied this Combinatorial Labeling and Spectral Imaging FISH (CLASI-FISH) strategy using genus-and family-specific probes to visualize simultaneously and differentiate 15 different phylotypes in an artificial mixture of laboratory-grown microbes. We then illustrated the utility of our method for the structural analysis of a natural microbial community, namely, human dental plaque, a microbial biofilm. We demonstrate that 15 taxa in the plaque community can be imaged simultaneously and analyzed and that this community was dominated by early colonizers, including species of Streptococcus, Prevotella, Actinomyces, and Veillonella. Proximity analysis was used to determine the frequency of inter- and intrataxon cell-to-cell associations which revealed statistically significant intertaxon pairings. Cells of the genera Prevotella and Actinomyces showed the most interspecies associations, suggesting a central role for these genera in establishing and maintaining biofilm complexity. The results provide an initial systems-level structural analysis of biofilm organization. C1 [Valm, Alex M.; Welch, Jessica L. Mark; Rieken, Christopher W.; Hasegawa, Yuko; Sogin, Mitchell L.; Oldenbourg, Rudolf; Borisy, Gary G.] Marine Biol Lab, Woods Hole, MA 02543 USA. [Valm, Alex M.; Hasegawa, Yuko; Sogin, Mitchell L.; Oldenbourg, Rudolf] Brown Univ, Providence, RI 02912 USA. [Dewhirst, Floyd E.] Forsyth Inst, Cambridge, MA 02142 USA. [Dewhirst, Floyd E.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Borisy, GG (reprint author), Marine Biol Lab, Woods Hole, MA 02543 USA. EM gborisy@mbl.edu OI Borisy, Gary/0000-0002-0266-8018 FU Alfred P. Sloan Foundation [2007-3-13]; National Institutes of Health, National Institute of Dental and Craniofacial Research (NIDCR) [1RC1-DE020630, 1F31-DE019576] FX We are grateful to Louis M. Kerr for invaluable assistance with microscopy. We thank Nikon Instruments and Carl Zeiss for gracious instrumentation support. This work was supported by Grant 2007-3-13 from the Alfred P. Sloan Foundation (to G.G.B.), National Institutes of Health Grant 1RC1-DE020630 from the National Institute of Dental and Craniofacial Research (NIDCR) (to G.G.B. and F.E.D.) and by National Institutes of Health Fellowship 1F31-DE019576 from NIDCR (to A.M.V.). NR 32 TC 90 Z9 90 U1 5 U2 34 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 MAR 8 PY 2011 VL 108 IS 10 BP 4152 EP 4157 DI 10.1073/pnas.1101134108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 731PA UT WOS:000288120400063 PM 21325608 ER PT J AU Ahveninen, J Hamalainen, M Jaaskelainen, IP Ahlfors, SP Huang, S Lin, FH Raij, T Sams, M Vasios, CE Belliveau, JW AF Ahveninen, Jyrki Haemaelaeinen, Matti Jaaskelainen, Iiro P. Ahlfors, Seppo P. Huang, Samantha Lin, Fa-Hsuan Raij, Tommi Sams, Mikko Vasios, Christos E. Belliveau, John W. TI Attention-driven auditory cortex short-term plasticity helps segregate relevant sounds from noise SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE processing negativity; cocktail party phenomenon; event-related potentials; negative difference; auditory scene analysis ID SURFACE-BASED ANALYSIS; SELECTIVE ATTENTION; CORTICAL SURFACE; RECEPTIVE-FIELDS; HUMAN BRAIN; COORDINATE SYSTEM; SPATIAL ATTENTION; TASK-DIFFICULTY; SINGLE NEURONS; FREQUENCY AB How can we concentrate on relevant sounds in noisy environments? A "gain model" suggests that auditory attention simply amplifies relevant and suppresses irrelevant afferent inputs. However, it is unclear whether this suffices when attended and ignored features overlap to stimulate the same neuronal receptive fields. A "tuning model" suggests that, in addition to gain, attention modulates feature selectivity of auditory neurons. We recorded magnetoencephalography, EEG, and functional MRI (fMRI) while subjects attended to tones delivered to one ear and ignored opposite-ear inputs. The attended ear was switched every 30 s to quantify how quickly the effects evolve. To produce overlapping inputs, the tones were presented alone vs. during white-noise masking notch-filtered +/- 1/6 octaves around the tone center frequencies. Amplitude modulation (39 vs. 41 Hz in opposite ears) was applied for "frequency tagging" of attention effects on maskers. Noise masking reduced early (50-150 ms; N1) auditory responses to unattended tones. In support of the tuning model, selective attention canceled out this attenuating effect but did not modulate the gain of 50-150 ms activity to nonmasked tones or steady-state responses to the maskers themselves. These tuning effects originated at nonprimary auditory cortices, purportedly occupied by neurons that, without attention, have wider frequency tuning than +/- 1/6 octaves. The attentional tuning evolved rapidly, during the first few seconds after attention switching, and correlated with behavioral discrimination performance. In conclusion, a simple gain model alone cannot explain auditory selective attention. In nonprimary auditory cortices, attention-driven short-term plasticity retunes neurons to segregate relevant sounds from noise. C1 [Ahveninen, Jyrki; Haemaelaeinen, Matti; Ahlfors, Seppo P.; Huang, Samantha; Lin, Fa-Hsuan; Raij, Tommi; Vasios, Christos E.; Belliveau, John W.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp,Dept Radiol, Charlestown, MA 02129 USA. [Haemaelaeinen, Matti; Ahlfors, Seppo P.; Belliveau, John W.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Jaaskelainen, Iiro P.; Sams, Mikko] Aalto Univ, Dept Biomed Engn & Computat Sci, Mind & Brain Lab, FI-00076 Espoo, Finland. [Lin, Fa-Hsuan] Natl Taiwan Univ, Inst Biomed Engn, Taipei 106, Taiwan. RP Ahveninen, J (reprint author), Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp,Dept Radiol, Charlestown, MA 02129 USA. EM jyrki@nmr.mgh.harvard.edu RI Jaaskelainen, Iiro/C-7392-2012; Sams, Mikko/G-7060-2012; Hamalainen, Matti/C-8507-2013; Lin, Fa-Hsuan/G-6988-2012; Ahlfors, Seppo/P-3644-2016 OI Jaaskelainen, Iiro/0000-0001-6001-6950; Lin, Fa-Hsuan/0000-0002-9539-1731; FU National Institutes of Health [R01MH083744, R21DC010060, R01HD040712, R01NS037462, R01NS057500, R01NS048279, S10RR014798, P41RR14075]; National Center for Research Resources; Academy of Finland FX We thank Deirdre Foxe, Natsuko Mori, and Dan Wakeman for their help. This work was supported by National Institutes of Health Awards R01MH083744, R21DC010060, R01HD040712, R01NS037462, R01NS057500, R01NS048279, S10RR014798, and P41RR14075, the National Center for Research Resources, and the Academy of Finland. NR 52 TC 51 Z9 52 U1 0 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 8 PY 2011 VL 108 IS 10 BP 4182 EP 4187 DI 10.1073/pnas.1016134108 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 731PA UT WOS:000288120400068 PM 21368107 ER PT J AU Keliher, EJ Reiner, T Turetsky, A Hilderbrand, SA Weissleder, R AF Keliher, Edmund J. Reiner, Thomas Turetsky, Anna Hilderbrand, Scott A. Weissleder, Ralph TI High-Yielding, Two-Step F-18 Labeling Strategy for F-18-PARP1 Inhibitors SO CHEMMEDCHEM LA English DT Article DE F-18 labeling; cycloadditions; PARP1; PET imaging; tetrazines ID POSITRON-EMISSION-TOMOGRAPHY; FREE CLICK CHEMISTRY; POLY(ADP-RIBOSE) POLYMERASE-1; INTEGRATED MICROFLUIDICS; KINASE INHIBITORS; LIVING CELLS; CYCLOADDITION; CANCER; ATHEROSCLEROSIS; NANOPARTICLES C1 [Keliher, Edmund J.; Reiner, Thomas; Turetsky, Anna; Hilderbrand, Scott A.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol Dept, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol Dept, 185 Cambridge St, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu OI Reiner, Thomas/0000-0002-7819-5480 FU US National Institutes of Health (NIH) [CA86355, EB-010011]; NIGMS [T32 GM008313]; German National Academy of Sciences Leopoldina [LPDS 2009-24] FX We thank Drs. Ralph Mazitschek and Neal Devaraj for helpful discussions. This research was supported in part by the US National Institutes of Health (NIH) (grants CA86355 and EB-010011). AT was supported by NIH grant NIGMS T32 GM008313. TR was supported by a grant from the German National Academy of Sciences Leopoldina (LPDS 2009-24). NR 39 TC 51 Z9 51 U1 0 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1860-7179 J9 CHEMMEDCHEM JI ChemMedChem PD MAR 7 PY 2011 VL 6 IS 3 BP 424 EP 427 DI 10.1002/cmdc.201000426 PG 4 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 737WG UT WOS:000288599600005 PM 21360818 ER PT J AU Chen, X Tukachinsky, H Huang, CH Jao, C Chu, YR Tang, HY Mueller, B Schulman, S Rapoport, TA Salic, A AF Chen, Xin Tukachinsky, Hanna Huang, Chih-Hsiang Jao, Cindy Chu, Yue-Ru Tang, Hsiang-Yun Mueller, Britta Schulman, Sol Rapoport, Tom A. Salic, Adrian TI Processing and turnover of the Hedgehog protein in the endoplasmic reticulum SO JOURNAL OF CELL BIOLOGY LA English DT Article ID INTEGRAL MEMBRANE-PROTEINS; ER-ASSOCIATED DEGRADATION; UBIQUITIN LIGASE COMPLEX; HMG-COA REDUCTASE; SONIC-HEDGEHOG; MISFOLDED GLYCOPROTEINS; AUTOPROCESSING DOMAIN; QUALITY-CONTROL; DISLOCATION; CYTOSOL AB T he Hedgehog (Hh) signaling pathway has important functions during metazoan development. The Hh ligand is generated from a precursor by self-cleavage, which requires a free cysteine in the C-terminal part of the protein and results in the production of the cholesterol-modified ligand and a C-terminal fragment. In this paper, we demonstrate that these reactions occur in the endoplasmic reticulum (ER). The catalytic cysteine needs to form a disulfide bridge with a conserved cysteine, which is subsequently reduced by protein disulfide isomerase. Generation of the C-terminal fragment is followed by its ER-associated degradation (ERAD), providing the first example of an endogenous luminal ERAD substrate that is constitutively degraded. This process requires the ubiquitin ligase Hrd1, its partner Sel1, the cytosolic adenosine triphosphatase p97, and degradation by the proteasome. Processing-defective mutants of Hh are degraded by the same ERAD components. Thus, processing of the Hh precursor competes with its rapid degradation, explaining the impaired Hh signaling of processing-defective mutants, such as those causing human holoprosencephaly. C1 [Chen, Xin; Schulman, Sol; Rapoport, Tom A.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Chen, Xin; Tukachinsky, Hanna; Jao, Cindy; Salic, Adrian] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Mueller, Britta] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02115 USA. [Chen, Xin; Huang, Chih-Hsiang; Chu, Yue-Ru; Tang, Hsiang-Yun] Natl Hlth Res Inst, Div Biotechnol & Pharmaceut Res, Miaoli 115, Taiwan. RP Salic, A (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. EM asalic@hms.harvard.edu RI Chen, Xin/D-2073-2010; OI schulman, sol/0000-0002-5229-3592 FU American Heart Association; National Science Foundation; National Institutes of Health [GM052586]; Howard Hughes Medical Institute; National Research Program for Genomic Medicine; National Science Council; National Health Research Institutes (Taiwan); Rita Allen Foundation; Beckman Foundation FX H. Tukachinsky and C. Jao are supported by predoctoral fellowships from the American Heart Association and from the National Science Foundation, respectively. T.A. Rapoport is supported by the National Institutes of Health grant GM052586 and is a Howard Hughes Medical Institute Investigator. X. Chen is supported by funds from the National Research Program for Genomic Medicine, National Science Council, and National Health Research Institutes (Taiwan). A. Salic acknowledges the support from the Rita Allen Foundation and the Beckman Foundation. NR 56 TC 56 Z9 56 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD MAR 7 PY 2011 VL 192 IS 5 BP 825 EP 838 DI 10.1083/jcb.201008090 PG 14 WC Cell Biology SC Cell Biology GA 730XI UT WOS:000288070300011 PM 21357747 ER PT J AU Ackerman, ME Moldt, B Wyatt, RT Dugast, AS McAndrew, E Tsoukas, S Jost, S Berger, CT Sciaranghella, G Liu, QQ Irvine, DJ Burton, DR Alter, G AF Ackerman, Margaret E. Moldt, Brian Wyatt, Richard T. Dugast, Anne-Sophie McAndrew, Elizabeth Tsoukas, Stephen Jost, Stephanie Berger, Christoph T. Sciaranghella, Gaia Liu, Qingquan Irvine, Darrell J. Burton, Dennis R. Alter, Galit TI A robust, high-throughput assay to determine the phagocytic activity of clinical antibody samples SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Phagocytosis; Antibody; ADCC; Antibody-dependent phagocytosis; Monocytes; Fc receptor; Effector function ID FC-GAMMA-RI; HUMAN MONOCYTIC CELLS; MYCOBACTERIUM-TUBERCULOSIS; CYTOKINE PRODUCTION; IMMUNOGLOBULIN-G; THP-1 CELLS; ENHANCING ANTIBODIES; GENE-EXPRESSION; TUMOR-CELLS; LINE THP-1 AB Phagocytosis can be induced via the engagement of Fc gamma receptors by antibody-opsonized material. Furthermore, the efficiency of antibody-induced effector functions has been shown to be dramatically modulated by changes in antibody glycosylation. Because infection can modulate antibody glycans, which in turn modulate antibody functions, assays capable of determining the induction of effector functions rather than neutralization or titer provide a valuable opportunity to more fully characterize the quality of the adaptive immune response. Here we describe a robust and high-throughput flow cytometric assay to define the phagocytic activity of antigen-specific antibodies from clinical samples. This assay employs a monocytic cell line that expresses numerous Fc receptors: including inhibitory and activating, and high and low affinity receptors allowing complex phenotypes to be studied. We demonstrate the adaptability of this high-throughput, flow-based assay to measure antigen-specific antibody-mediated phagocytosis against an array of viruses, including influenza, HIV, and dengue. The phagocytosis assay format further allows for simultaneous analysis of cytokine release, as well as determination of the role of specific Fry-receptor subtypes, making it a highly useful system for parsing differences in the ability of clinical and vaccine induced antibody samples to recruit this critical effector function. (C) 2010 Elsevier B.V. All rights reserved. C1 [Moldt, Brian; Wyatt, Richard T.; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Moldt, Brian; Wyatt, Richard T.; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Consortium, La Jolla, CA 92037 USA. [Ackerman, Margaret E.; Dugast, Anne-Sophie; McAndrew, Elizabeth; Tsoukas, Stephen; Jost, Stephanie; Berger, Christoph T.; Sciaranghella, Gaia; Liu, Qingquan; Irvine, Darrell J.; Burton, Dennis R.; Alter, Galit] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Boston, MA USA. [Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. RP Ackerman, ME (reprint author), 149 13th St,Room 6616, Charlestown, MA 02129 USA. EM meackerman@partners.org RI Ackerman, Margaret/B-5944-2012; Dugast, AnneSophie/L-9541-2015 FU International AIDS Vaccine Initiative through the Neutralizing Antibody Consortium; Ragon Institute of MGH; MIT; Harvard; NIH [A1055332, A1080289]; NIAID FX The authors wish to acknowledge funding from the International AIDS Vaccine Initiative through the Neutralizing Antibody Consortium; NIAID, NIH A1055332, NIH A1080289, and The Ragon Institute of MGH, MIT, and Harvard. BM acknowledges fellowship support from the Alfred Benzon Foundation. We thank the Phillip T and Susan M Ragon Foundation for their support. NR 49 TC 61 Z9 61 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 EI 1872-7905 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD MAR 7 PY 2011 VL 366 IS 1-2 BP 8 EP 19 DI 10.1016/j.jim.2010.12.016 PG 12 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 749FY UT WOS:000289450600002 PM 21192942 ER PT J AU Kacimi, R Giffard, RG Yenari, MA AF Kacimi, Rachid Giffard, Rona G. Yenari, Midori A. TI Endotoxin-activated microglia injure brain derived endothelial cells via NF-kappa B, JAK-STAT and JNK stress kinase pathways SO JOURNAL OF INFLAMMATION-LONDON LA English DT Article ID NITRIC-OXIDE SYNTHASE; INDUCED INOS EXPRESSION; EXPERIMENTAL STROKE; MILD HYPOTHERMIA; PROTEIN-KINASE; IMMUNE-SYSTEM; INFLAMMATION; DISEASES; HYPOXIA; BARRIER AB Background: We previously showed that microglia damage blood brain barrier (BBB) components following ischemic brain insults, but the underlying mechanism(s) is/are not well known. Recent work has established the contribution of toll-like receptor 4 (TLR4) activation to several brain pathologies including ischemia, neurodegeneration and sepsis. The present study established the requirement of microglia for lipopolysaccharide (LPS) mediated endothelial cell death, and explored pathways involved in this toxicity. LPS is a classic TLR4 agonist, and is used here to model aspects of brain conditions where TLR4 stimulation occurs. Methods/Results: In monocultures, LPS induced death in microglia, but not brain derived endothelial cells (EC). However, LPS increased EC death when cocultured with microglia. LPS led to nitric oxide (NO) and inducible NO synthase (iNOS) induction in microglia, but not in EC. Inhibiting microglial activation by blocking iNOS and other generators of NO or blocking reactive oxygen species (ROS) also prevented injury in these cocultures. To assess the signaling pathway(s) involved, inhibitors of several downstream TLR-4 activated pathways were studied. Inhibitors of NF-kappa B, JAK-STAT and JNK/SAPK decreased microglial activation and prevented cell death, although the effect of blocking JNK/SAPK was rather modest. Inhibitors of PI3K, ERK, and p38 MAPK had no effect. Conclusions: We show that LPS-activated microglia promote BBB disruption through injury to endothelial cells, and the specific blockade of JAK-STAT, NF-kappa B may prove to be especially useful anti-inflammatory strategies to confer cerebrovascular protection. C1 [Kacimi, Rachid; Yenari, Midori A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Kacimi, Rachid; Yenari, Midori A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Giffard, Rona G.] Stanford Univ, Med Ctr, Dept Anesthesia Dept, Stanford, CA 94305 USA. RP Yenari, MA (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. EM yenari@alum.mit.edu FU Department of Veterans Affairs [NIH P50 NS014543, R01 NS 40156, GM049831]; Department of Defense [DAMD17-03-1-0532] FX This work was supported by the Department of Veterans Affairs (MAY), grants from the NIH P50 NS014543 (RGG, MAY), R01 NS 40156 (MAY), GM049831 (RGG) and the Department of Defense DAMD17-03-1-0532 (MAY). NR 40 TC 65 Z9 71 U1 0 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-9255 J9 J INFLAMM-LOND JI J. Inflamm.-Lond. PD MAR 7 PY 2011 VL 8 AR 7 DI 10.1186/1476-9255-8-7 PG 15 WC Immunology SC Immunology GA 738BT UT WOS:000288615000001 PM 21385378 ER PT J AU Scott, JA AF Scott, James A. TI Loneliness SO LANCET LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Scott, JA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM scott@helix.mgh.harvard.edu NR 1 TC 0 Z9 0 U1 1 U2 1 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 MAR 5 PY 2011 VL 377 IS 9768 BP 812 EP 812 DI 10.1016/S0140-6736(11)60308-5 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 738GO UT WOS:000288628500027 PM 21377570 ER PT J AU Fizazi, K Carducci, M Smith, M Damiao, R Brown, J Karsh, L Milecki, P Shore, N Rader, M Wang, HI Jiang, Q Tadros, S Dansey, R Goessl, C AF Fizazi, Karim Carducci, Michael Smith, Matthew Damiao, Ronaldo Brown, Janet Karsh, Lawrence Milecki, Piotr Shore, Neal Rader, Michael Wang, Huei Jiang, Qi Tadros, Sylvia Dansey, Roger Goessl, Carsten TI Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study SO LANCET LA English DT Article ID CONTROLLED PHASE-II; BREAST-CANCER; SKELETAL COMPLICATIONS; CONTROLLED-TRIALS; LONG-TERM; THERAPY; MULTICENTER; PREVENTION; CARCINOMA; SURVIVAL AB Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal. related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12.2 months (IQR 5.9-18.5) for patients on denosumab and 11.2 months (IQR 5.6-17.4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20.7 months (95% CI 18.8-24.9) with denosumab compared with 17.1 months (15-0-19.4) with zoledronic acid (hazard ratio 0.82, 95% CI 0.71-0.95; p=0.0002 for non-inferiority; p=0.008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0.0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p=0.09). Interpretation Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. C1 [Fizazi, Karim] Univ Paris 11, Inst Gustave Roussy, Dept Canc Med, F-94805 Villejuif, France. [Carducci, Michael] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Smith, Matthew] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Damiao, Ronaldo] Hosp Univ Pedro Ernesto, Rio De Janeiro, Brazil. [Brown, Janet] Canc Res UK Clin Ctr, Leeds, W Yorkshire, England. [Karsh, Lawrence] Urol Ctr Colorado, Denver, CO USA. [Milecki, Piotr] Wielkopolskie Ctr Onkol, Poznan, Poland. [Shore, Neal] Carolina Urol Res Ctr, Myrtle Beach, SC USA. [Rader, Michael] Nyack Hosp, Union State Bank, Ctr Canc, Nyack, NY USA. [Wang, Huei; Jiang, Qi; Tadros, Sylvia; Dansey, Roger; Goessl, Carsten] Amgen Inc, Thousand Oaks, CA USA. RP Fizazi, K (reprint author), Univ Paris 11, Inst Gustave Roussy, Dept Canc Med, 39 Rue Camille Desmoulins, F-94805 Villejuif, France. EM fizazi@igr.fr OI Krainer, Michael/0000-0002-7011-4957 FU Amgen; Novartis; Center of Research in Urology Sergio Aguinaga (CEPUSA); Amgen, Thousand Oaks, CA, USA FX KF has received consultancy fees and travel support from Amgen for this study and from Novartis; participated in speakers' bureaux and advisory boards for Amgen and Novartis; and provided expert testimony for Amgen. MC has received consultancy fees from Amgen for this study and for other agents in development, and from Novartis; and received research funding from Amgen. MS has received consultancy fees from Amgen; and participated in sponsored clinical research with Amgen and Novartis. RDam has received research funding from Amgen and the Center of Research in Urology Sergio Aguinaga (CEPUSA). JB has received travel support and payment for lectures from Amgen and Novartis; JB has received payment for membership of advisory boards from Amgen. Novartis, and GlaxoSmithKline; and JB and JB's institution have received consultancy fees from Amgen. LK has received consultancy fees, travel support, and honoraria for lectures and development of educational presentations from Amgen; and LK's institution has received research funding from Amgen. PM has received research funding from Amgen; and been a board member and principal investigator for, and received travel support from, Amgen. NS has received consultancy fees and travel support from Amgen for this study; and received research funding and honoraria from Amgen. MR has received travel support and honoraria for membership of advisory boards and lectures from Amgen; and MR's institution has received research funding from Amgen for this study. HW, QJ, ST, RDan, and CG are employees of Amgen, and have received stock or stock options from Amgen.; We thank the patients and investigators at all participating sites who made important contributions to this study; Geoffrey Smith, supported by Amgen, for medical writing assistance in preparation of this report; and the DMC for its diligence in monitoring of the study. The DMC wishes to remain anonymous because it is monitoring other trials of denosumab. This report is presented in memory of study investigator Lina Barbosa Cassol and study coordinator Carla Fioratti. This study was funded by Amgen, Thousand Oaks, CA, USA. Primary results of the data in this report were presented on June, 6, 2010, at the American Society of Clinical Oncology Annual Meeting in Chicago, IL, USA. NR 33 TC 715 Z9 732 U1 11 U2 84 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 MAR 5 PY 2011 VL 377 IS 9768 BP 813 EP 822 DI 10.1016/S0140-6736(10)62344-6 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 738GO UT WOS:000288628500029 PM 21353695 ER PT J AU Vunjak-Novakovic, G Scadden, DT AF Vunjak-Novakovic, Gordana Scadden, David T. TI Biomimetic Platforms for Human Stem Cell Research SO CELL STEM CELL LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; BONE-MARROW; EXTRACELLULAR-MATRIX; ADULT-MOUSE; ELECTRICAL-STIMULATION; SKELETAL-MUSCLE; PRECURSOR CELLS; HAIR FOLLICLE; SELF-RENEWAL; IN-VITRO AB Stem cells are central to developing new treatment options for tissue regeneration and constructing controllable models for biological research. Bioengineered cell culture environments that combine microenvironmental control with tissue-specific transport and signaling are critical tools in our efforts to study tissue development, regeneration, and disease under conditions that predict the human in vivo context. We propose that experimentation at the interfaces of biology, engineering, and medical sciences is critical for unlocking the full potential of stem cells. Here, we focus on the design and utilization of in vitro platforms that recapitulate the environments associated with tissue development, disease, and regeneration. C1 [Vunjak-Novakovic, Gordana] Columbia Univ, Dept Biomed Engn, New York, NY 10032 USA. [Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Harvard Stem Cell Inst, Boston, MA 02114 USA. RP Vunjak-Novakovic, G (reprint author), Columbia Univ, Dept Biomed Engn, New York, NY 10032 USA. EM gv2131@columbia.edu RI vunjak-novakovic, gordana/J-9279-2012; OI Vunjak-Novakovic, Gordana/0000-0002-9382-1574 FU NIH [HL076485, DE16525, HL089913, EB002520, HL044851, HL097794, HL100402, DK050234] FX The fusion of the fields of cell biology and bioengineering has been driven by the pioneering efforts of many contributors working at the interface of the two disciplines. We acknowledge their collective contributions and regret that space constraints prevented us from citing many meritorious studies that will continue to inspire future efforts. We also acknowledge research funding by NIH (HL076485, DE16525, HL089913, and EB002520 to G.V.-N. and HL044851, HL097794, HL100402, and DK050234 to D.T.S.) and thank Dr. N. Mirkovic for his expert help with illustrations. NR 90 TC 59 Z9 61 U1 2 U2 36 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 MAR 4 PY 2011 VL 8 IS 3 BP 252 EP 261 DI 10.1016/j.stem.2011.02.014 PG 10 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 735HI UT WOS:000288404400007 PM 21362565 ER PT J AU Chen, MH Colan, SD Diller, L AF Chen, Ming Hui Colan, Steven D. Diller, Lisa TI Cardiovascular Disease Cause of Morbidity and Mortality in Adult Survivors of Childhood Cancers SO CIRCULATION RESEARCH LA English DT Review DE anthracycline; radiation; cardiotoxicity; cancer survivor; childhood ID LONG-TERM SURVIVORS; ANTHRACYCLINE-INDUCED CARDIOTOXICITY; ACUTE LYMPHOBLASTIC-LEUKEMIA; CONGESTIVE-HEART-FAILURE; DOXORUBICIN-INDUCED CARDIOTOXICITY; LEFT-VENTRICULAR DYSFUNCTION; ASSOCIATION TASK-FORCE; RABBIT EAR ARTERY; HODGKINS-DISEASE; BREAST-CANCER AB Although important advances have been made in curing childhood cancer in the last several decades, long-term survivors face considerable morbidity and mortality because of late effects from their initial anticancer therapy. By 30 years after treatment, the cumulative mortality from treatment-related medical illness actually exceeds that of mortality from cancer recurrence. Cardiovascular disease, in particular, is a leading threat to the well-being of adult survivors of childhood cancers. Unfortunately, the mechanisms of these late cardiac effects are understudied and poorly understood. This article reviews cardiotoxicity associated with 2 major anticancer regimens used in treating childhood cancer patients: anthracycline treatment and radiation therapy. The known pathophysiology and clinical cardiac risk factors that further predispose these patients to late-onset cardiac events are discussed. Basic and translational research is urgently needed to clarify pathophysiologic mechanisms of late cardiac effects and to develop therapies to improve both long-term survival and quality of life of adults cured of pediatric cancers. (Circ Res. 2011; 108: 619-628.) C1 [Chen, Ming Hui; Colan, Steven D.] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Diller, Lisa] Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Chen, Ming Hui] Brigham & Womens Hosp, Dept Med, Div Womens Hlth, Boston, MA 02115 USA. [Chen, Ming Hui] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Chen, Ming Hui] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Diller, Lisa] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Chen, Ming Hui] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Colan, Steven D.; Diller, Lisa] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Chen, MH (reprint author), Childrens Hosp, Dept Cardiol, 300 Longwood Ave, Boston, MA 02115 USA. EM minghui.chen@cardio.chboston.org FU Translational Fund for Cardiology and Oncology; Department of Cardiology at Children's Hospital Boston FX M.H.C. is supported by the Translational Fund for Cardiology and Oncology and the Department of Cardiology at Children's Hospital Boston. NR 104 TC 43 Z9 45 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAR 4 PY 2011 VL 108 IS 5 BP 619 EP 628 DI 10.1161/CIRCRESAHA.110.224519 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 729PW UT WOS:000287963900015 PM 21372293 ER PT J AU Sengupta, A Molkentin, JD Paik, JH DePinho, RA Yutzey, KE AF Sengupta, Arunima Molkentin, Jeffery D. Paik, Ji-Hye DePinho, Ronald A. Yutzey, Katherine E. TI FoxO Transcription Factors Promote Cardiomyocyte Survival upon Induction of Oxidative Stress SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; ISCHEMIA-REPERFUSION INJURY; TRANSGENIC MICE; HEART-FAILURE; MOUSE HEART; CELL-DEATH; IN-VIVO; HYPERTROPHY; APOPTOSIS; PROLIFERATION AB Transcriptional regulatory mechanisms of cardiac oxidative stress resistance are not well defined. FoxO transcription factors are critical mediators of oxidative stress resistance in multiple cell types, but cardioprotective functions have not been reported previously. FoxO function in oxidative stress resistance was investigated in cultured cardiomyocytes and in mice with cardiomyocyte-specific combined deficiency of FoxO1 and FoxO3 subjected to myocardial infarction (MI) or acute ischemia/reperfusion (I/R) injury. Induction of oxidative stress in cardiomyocytes promotes FoxO1 and FoxO3 nuclear localization and target gene activation. Infection of cardiomyocytes with a dominant-negative FoxO1(Delta 256) adenovirus results in a significant increase in reactive oxygen species and cell death, whereas increased FoxO1 or FoxO3 expression reduces reactive oxygen species and cell death. Mice generated with combined conditional deletion of FoxO1 and FoxO3 specifically in cardiomyocytes were subjected to I/R or MI. Loss of FoxO1 and FoxO3 in cardiomyocytes results in a significant increase in infarct area with decreased expression of the antiapoptotic molecules, PTEN-induced kinase1 (PINK1) and CBP/P300-interacting transactivator (CITED2). Expressions of the antioxidants catalase and manganese superoxide dismutase-2 (SOD2) and the autophagy-related proteins LC3II and Gabarapl1 also are decreased following I/R compared with controls. Mice with cardiomyocyte-specific FoxO deficiency subjected to MI have reduced cardiac function, increased scar formation, induction of stress-responsive signaling, and increased apoptotic cell death relative to controls. These data support a critical role for FoxOs in promoting cardiomyocyte survival during conditions of oxidative stress through induction of antioxidants and cell survival pathways. C1 [Sengupta, Arunima; Molkentin, Jeffery D.; Yutzey, Katherine E.] Cincinnati Childrens Med Ctr, Div Mol Cardiovasc Biol, Inst Heart, Cincinnati, OH 45229 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci,Dept Med Oncol, Boston, MA 02115 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci,Dept Med, Boston, MA 02115 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci,Dept Genet, Boston, MA 02115 USA. RP Yutzey, KE (reprint author), Cincinnati Childrens Med Ctr ML 7020, Div Mol Cardiovasc Biol, 240 Albert Sabin Way, Cincinnati, OH 45229 USA. EM katherine.yutzey@cchmc.org FU National Institutes of Health [PO1 HL069779] FX This work was supported, in whole or in part, by National Institutes of Health Grant PO1 HL069779 (to K. E. Y. and J. D. M.). NR 42 TC 126 Z9 133 U1 5 U2 22 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 4 PY 2011 VL 286 IS 9 BP 7468 EP 7478 DI 10.1074/jbc.M110.179242 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 726PH UT WOS:000287737300061 PM 21159781 ER PT J AU Ando, K Uemura, K Kuzuya, A Maesako, M Asada-Utsugi, M Kubota, M Aoyagi, N Yoshioka, K Okawa, K Inoue, H Kawamata, J Shimohama, S Arai, T Takahashi, R Kinoshita, A AF Ando, Koichi Uemura, Kengo Kuzuya, Akira Maesako, Masato Asada-Utsugi, Megumi Kubota, Masakazu Aoyagi, Nobuhisa Yoshioka, Katsuji Okawa, Katsuya Inoue, Haruhisa Kawamata, Jun Shimohama, Shun Arai, Tetsuaki Takahashi, Ryosuke Kinoshita, Ayae TI N-cadherin Regulates p38 MAPK Signaling via Association with JNK-associated Leucine Zipper Protein IMPLICATIONS FOR NEURODEGENERATION IN ALZHEIMER DISEASE SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMYLOID-BETA; SCAFFOLDING PROTEIN; MISSENSE MUTATIONS; NEURITE OUTGROWTH; SYNAPSE LOSS; KINASE; ACTIVATION; PATHWAY; ADHESION; PRESENILIN-1 AB Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer disease. N-cadherin is a cell adhesion molecule essential for synaptic contact and is involved in the intracellular signaling pathway at the synapse. Here we report that the functional disruption of N-cadherin-mediated cell contact activated p38 MAPK in murine primary neurons, followed by neuronal death. We further observed that treatment with A beta(42) decreased cellular N-cadherin expression through NMDA receptors accompanied by increased phosphorylation of both p38 MAPK and Tau in murine primary neurons. Moreover, expression levels of phosphorylated p38 MAPK were negatively correlated with that of N-cadherin in human brains. Proteomic analysis of human brains identified a novel interaction between N-cadherin and JNK-associated leucine zipper protein (JLP), a scaffolding protein involved in the p38 MAPK signaling pathway. We demonstrated that N-cadherin expression had an inhibitory effect on JLP-mediated p38 MAPK signal activation by decreasing the interaction between JLP and p38 MAPK in COS7 cells. Also, this study demonstrated a novel physical and functional association between N-cadherin and p38 MAPK and suggested neuroprotective roles of cadherin-based synaptic contact. The dissociation of N-cadherin-mediated synaptic contact by A beta may underlie the pathological basis of neurodegeneration such as neuronal death, synaptic loss, and Tau phosphorylation in Alzheimer disease brain. C1 [Kinoshita, Ayae] Kyoto Univ, Grad Sch Med, Sch Human Hlth Sci, Sakyo Ku, Kyoto 6068507, Japan. [Aoyagi, Nobuhisa; Kawamata, Jun; Takahashi, Ryosuke] Kyoto Univ, Grad Sch Med, Dept Neurol, Kyoto 6068507, Japan. [Uemura, Kengo] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Yoshioka, Katsuji] Kanazawa Univ, Canc Res Inst, Div Mol Cell Signaling, Kanazawa, Ishikawa 9201192, Japan. [Okawa, Katsuya] Kyowa Hakko Kirin Co, Tokyo 1008185, Japan. [Inoue, Haruhisa] Kyoto Univ, Ctr iPS Cell Res & Applicat, Kyoto 6068507, Japan. [Shimohama, Shun] Sapporo Med Univ, Dept Neurol, Sapporo, Hokkaido 0608556, Japan. [Arai, Tetsuaki] Tokyo Inst Psychiat, Tokyo 1568585, Japan. RP Kinoshita, A (reprint author), Kyoto Univ, Grad Sch Med, Sch Human Hlth Sci, Sakyo Ku, 53 Shogoinkawahara Cho, Kyoto 6068507, Japan. EM akinoshita@hs.med.kyoto-u.ac.jp NR 40 TC 28 Z9 32 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 4 PY 2011 VL 286 IS 9 BP 7619 EP 7628 DI 10.1074/jbc.M110.158477 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 726PH UT WOS:000287737300075 PM 21177868 ER PT J AU Stamm, LM Goldberg, MB AF Stamm, Luisa M. Goldberg, Marcia B. TI Establishing the Secretion Hierarchy SO SCIENCE LA English DT Editorial Material ID III SECRETION; SALMONELLA-TYPHIMURIUM; SYSTEM C1 [Stamm, Luisa M.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Stamm, LM (reprint author), Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Cambridge, MA 02139 USA. EM mgoldberg1@partners.org FU NIAID NIH HHS [R01 AI081724, T32 AI007061] NR 9 TC 12 Z9 12 U1 0 U2 5 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 MAR 4 PY 2011 VL 331 IS 6021 BP 1147 EP 1148 DI 10.1126/science.1203195 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 729SN UT WOS:000287971200030 PM 21385706 ER PT J AU Schlegelmilch, K Mohseni, M Kirak, O Pruszak, J Rodriguez, JR Zhou, DW Kreger, BT Vasioukhin, V Avruch, J Brummelkamp, TR Camargo, FD AF Schlegelmilch, Karin Mohseni, Morvarid Kirak, Oktay Pruszak, Jan Rodriguez, J. Renato Zhou, Dawang Kreger, Bridget T. Vasioukhin, Valera Avruch, Joseph Brummelkamp, Thijn R. Camargo, Fernando D. TI Yap1 Acts Downstream of alpha-Catenin to Control Epidermal Proliferation SO CELL LA English DT Article ID ORGAN SIZE CONTROL; TUMOR-SUPPRESSOR; CELL-PROLIFERATION; PROMOTES APOPTOSIS; SIGNALING PATHWAY; HIPPO PATHWAY; PROGENITOR CELLS; TEAD/TEF FAMILY; PROTEIN-KINASE; GROWTH-CONTROL AB During development and regeneration, proliferation of tissue-specific stem cells is tightly controlled to produce organs of a predetermined size. The molecular determinants of this process remain poorly understood. Here, we investigate the function of Yap1, the transcriptional effector of the Hippo signaling pathway, in skin biology. Using gain- and loss-of-function studies, we show that Yap1 is a critical modulator of epidermal stem cell proliferation and tissue expansion. Yap1 mediates this effect through interaction with TEAD transcription factors. Additionally, our studies reveal that alpha-catenin, a molecule previously implicated in tumor suppression and cell density sensing in the skin, is an upstream negative regulator of Yap1. alpha-catenin controls Yap1 activity and phosphorylation by modulating its interaction with 14-3-3 and the PP2A phosphatase. Together, these data identify Yap1 as a determinant of the proliferative capacity of epidermal stem cells and as an important effector of a "crowd control" molecular circuitry in mammalian skin. C1 [Schlegelmilch, Karin; Mohseni, Morvarid; Camargo, Fernando D.] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Schlegelmilch, Karin; Mohseni, Morvarid; Camargo, Fernando D.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Schlegelmilch, Karin; Mohseni, Morvarid; Pruszak, Jan; Camargo, Fernando D.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Schlegelmilch, Karin] FU Berlin, Inst Chem Biochem, D-14195 Berlin, Germany. [Kirak, Oktay; Pruszak, Jan; Rodriguez, J. Renato; Brummelkamp, Thijn R.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Zhou, Dawang; Avruch, Joseph] Massachusetts Gen Hosp, Dept Mol & Cellular Biol, Boston, MA 02114 USA. [Kreger, Bridget T.; Vasioukhin, Valera] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Camargo, FD (reprint author), Childrens Hosp, Stem Cell Program, 300 Longwood Ave, Boston, MA 02115 USA. EM fernando.camargo@childrens.harvard.edu RI Kirak, Oktay/H-6347-2013; Pruszak, Jan/G-6972-2015; OI Kirak, Oktay/0000-0002-6524-4685; Pruszak, Jan/0000-0003-4297-4009; Zhou, Dawang/0000-0002-9053-5249 FU Stand Up to Cancer-AACR initiative, NIH [R01 CA131426]; Whitehead Institute FX We thank K. Shrestha and S. Zaghlul for their technical assistance; L. Zon and A. von Giese and members of the Camargo lab for critical discussion; and members of the Gregory laboratory for advice on mass spectrometry experiments. This work was supported by grants from the Stand Up to Cancer-AACR initiative, NIH grant R01 CA131426, and funds from the Whitehead Institute Fellows Program. F. D. C. is a V Foundation Scholar and Pew Scholar in the Biomedical Sciences. NR 58 TC 354 Z9 366 U1 11 U2 66 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 4 PY 2011 VL 144 IS 5 BP 782 EP 795 DI 10.1016/j.cell.2011.02.031 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 730CE UT WOS:000288007100016 PM 21376238 ER PT J AU Suzuki, A Stern, SA Bozdagi, O Huntley, GW Walker, RH Magistretti, PJ Alberini, CM AF Suzuki, Akinobu Stern, Sarah A. Bozdagi, Ozlem Huntley, George W. Walker, Ruth H. Magistretti, Pierre J. Alberini, Cristina M. TI Astrocyte-Neuron Lactate Transport Is Required for Long-Term Memory Formation SO CELL LA English DT Article ID ELEMENT-BINDING PROTEIN; IMMEDIATE-EARLY GENE; D-SERINE; RAT HIPPOCAMPUS; GLYCOGEN; GLUCOSE; POTENTIATION; PLASTICITY; ACTIN; CONSOLIDATION AB We report that, in the rat hippocampus, learning leads to a significant increase in extracellular lactate levels that derive from glycogen, an energy reserve selectively localized in astrocytes. Astrocytic glycogen breakdown and lactate release are essential for long-term but not short-term memory formation, and for the maintenance of long-term potentiation (LTP) of synaptic strength elicited in vivo. Disrupting the expression of the astrocytic lactate transporters monocarboxylate transporter 4 (MCT4) or MCT1 causes amnesia, which, like LTP impairment, is rescued by L-lactate but not equicaloric glucose. Disrupting the expression of the neuronal lactate transporter MCT2 also leads to amnesia that is unaffected by either L-lactate or glucose, suggesting that lactate import into neurons is necessary for long-term memory. Glycogenolysis and astrocytic lactate transporters are also critical for the induction of molecular changes required for memory formation, including the induction of phospho-CREB, Arc, and phospho-cofilin. We conclude that astrocyte-neuron lactate transport is required for long-term memory formation. C1 [Magistretti, Pierre J.] Univ Lausanne CHUV, Lab Neuroenerget & Cellular Dynam, Brain Mind Inst, EPFL, Lausanne, Switzerland. [Magistretti, Pierre J.] Univ Lausanne CHUV, Ctr Psychiat Neurosci, Lausanne, Switzerland. [Suzuki, Akinobu; Stern, Sarah A.; Bozdagi, Ozlem; Huntley, George W.; Alberini, Cristina M.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Bozdagi, Ozlem; Alberini, Cristina M.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Walker, Ruth H.] James J Peters VAMC, Dept Neurol, Bronx, NY 10468 USA. [Walker, Ruth H.] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. RP Magistretti, PJ (reprint author), Univ Lausanne CHUV, Lab Neuroenerget & Cellular Dynam, Brain Mind Inst, EPFL, Lausanne, Switzerland. EM pierre.magistretti@epfl.ch; cristina.alberini@mssm.edu FU Department of Veterans Affairs; [R01-MH065635]; [R01-MH074736]; [T32-MH087004] FX This work was supported by grants R01-MH065635 and R01-MH074736 to C. M. A., Department of Veterans Affairs Merit Award to R. H. W. and T32-MH087004 to S. A. S. We thank Rick Koch, Dhananjay Bambah-Mukku, Dillon Chen, Gabriella Pollonini, and Virginia Gao for technical support; and Reginald Miller and the Center for Comparative Medicine and Surgery facility at Mount Sinai School of Medicine for technical support. P.J.M. is the recipient of the Asterion Chair at Ecole Polytechnique Federale de Lausanne (EPFL). NR 64 TC 374 Z9 390 U1 7 U2 52 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 4 PY 2011 VL 144 IS 5 BP 810 EP 823 DI 10.1016/j.cell.2011.02.018 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 730CE UT WOS:000288007100018 PM 21376239 ER PT J AU Leuschner, F Nahrendorf, M AF Leuschner, Florian Nahrendorf, Matthias TI Molecular Imaging of Coronary Atherosclerosis and Myocardial Infarction Considerations for the Bench and Perspectives for the Clinic SO CIRCULATION RESEARCH LA English DT Review DE molecular imaging; hybrid imaging; atherosclerosis; myocardial infarction; heart failure ID POSITRON-EMISSION-TOMOGRAPHY; CARDIOVASCULAR MAGNETIC-RESONANCE; MATRIX-METALLOPROTEINASE ACTIVITY; AMERICAN-HEART-ASSOCIATION; CELL-ADHESION MOLECULE-1; IN-VIVO; CONTRAST AGENT; VASCULAR INFLAMMATION; NONINVASIVE DETECTION; COMPUTED-TOMOGRAPHY AB Motivated by the promise to transform preclinical research and clinical care, cardiovascular molecular imaging has made advances toward targeting coronary atherosclerosis and heart failure. Here, we discuss recent progress in the field, highlight how molecular imaging may facilitate preventive patient care, and review specific challenges associated with coronary and heart failure imaging. Practical considerations stress the potential of fluorescence imaging for basic research and discuss hybrid protocols such as FMT-CT and PET-MRI. (Circ Res. 2011; 108: 593-606.) C1 [Leuschner, Florian; Nahrendorf, Matthias] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Nahrendorf, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM mnahrendorf@mgh.harvard.edu FU NIH [R01HL095629, R01HL096576, R01EB006432, HHSN268201000044C]; American Heart Association [SDG0835623D]; Deutsche Herzstiftung e. V. FX This work was supported, in part, by NIH grants R01HL095629, R01HL096576, R01EB006432, HHSN268201000044C; American Heart Association Grant SDG0835623D; and the Deutsche Herzstiftung e. V. NR 114 TC 58 Z9 59 U1 1 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAR 4 PY 2011 VL 108 IS 5 BP 593 EP 606 DI 10.1161/CIRCRESAHA.110.232678 PG 14 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 729PW UT WOS:000287963900013 PM 21372291 ER PT J AU Pitman, RK AF Pitman, Roger K. TI Will reconsolidation blockade offer a novel treatment for posttraumatic stress disorder? SO FRONTIERS IN BEHAVIORAL NEUROSCIENCE LA English DT Editorial Material C1 [Pitman, Roger K.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Pitman, Roger K.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Pitman, RK (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. EM roger_pitman@hms.harvard.edu NR 15 TC 18 Z9 18 U1 0 U2 3 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5153 J9 FRONT BEHAV NEUROSCI JI Front. Behav. Neurosci. PD MAR 4 PY 2011 VL 5 AR 11 DI 10.3389/fnbeh.2011.00011 PG 2 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA V29VS UT WOS:000208776500001 PM 21427793 ER PT J AU Nakamura, K Kato, A Kobayashi, J Yanagihara, H Sakamoto, S Oliveira, DVNP Shimada, M Tauchi, H Suzuki, H Tashiro, S Zou, L Komatsu, K AF Nakamura, Kyosuke Kato, Akihiro Kobayashi, Junya Yanagihara, Hiromi Sakamoto, Shuichi Oliveira, Douglas V. N. P. Shimada, Mikio Tauchi, Hiroshi Suzuki, Hidekazu Tashiro, Satoshi Zou, Lee Komatsu, Kenshi TI Regulation of Homologous Recombination by RNF20-Dependent H2B Ubiquitination SO MOLECULAR CELL LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; CHROMATIN REMODELING COMPLEXES; REPAIR PROTEINS; HISTONE H2B; DISTINCT ROLES; CELL-CYCLE; IN-VIVO; UBIQUITYLATION; TRANSCRIPTION AB The E3 ubiquitin ligase RNF20 regulates chromatin structure by monoubiquitinating histone H2B in transcription. Here, we show that RNF20 is localized to double-stranded DNA breaks (DSBs) independently of H2AX and is required for the DSB-induced H2B ubiquitination. In addition, RNF20 is required for the methylation of H3K4 at DSBs and the recruitment of the chromatin-remodeling factor SNF2h. Depletion of RNF20, depletion of SNF2h, or expression of the H2B mutant lacking the ubiquitination site (K120R) compromises resection of DNA ends and recruitment of RAD51 and BRCA1. Consequently, cells lacking RNF20 or SNF2h and cells expressing H2B K120R exhibit pronounced defects in homologous recombination repair (HRR) and enhanced sensitivity to radiation. Finally, the function of RNF20 in HRR can be partially bypassed by forced chromatin relaxation. Thus, the RNF20-mediated H2B ubiquitination at DSBs plays a critical role in HRR through chromatin remodeling. C1 [Nakamura, Kyosuke; Kato, Akihiro; Kobayashi, Junya; Yanagihara, Hiromi; Sakamoto, Shuichi; Oliveira, Douglas V. N. P.; Shimada, Mikio; Komatsu, Kenshi] Kyoto Univ, Ctr Radiat Biol, Sakyo Ku, Kyoto 6068501, Japan. [Tauchi, Hiroshi] Ibaraki Univ, Dept Biol Sci, Mito, Ibaraki 3108512, Japan. [Suzuki, Hidekazu; Tashiro, Satoshi] Hiroshima Univ, Res Inst Radiat Biol & Med, Minami Ku, Hiroshima 7348553, Japan. [Zou, Lee] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA. RP Komatsu, K (reprint author), Kyoto Univ, Ctr Radiat Biol, Sakyo Ku, Yoshida Konoecho, Kyoto 6068501, Japan. EM komatsu@house.rbc.kyoto-u.ac.jp RI Shimada, Mikio/E-1565-2015 OI Shimada, Mikio/0000-0003-1980-9187 FU Ministry of Education, Culture, Sports, Science and Technology, Japan FX The authors thank S.J. Elledge and H. Kimura for providing the anti-MDC1 antibody and the cDNA for H2B used in this study. We also thank Y. Hayuka and M. Hiraga for their excellent technical assistance in this work. This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. NR 55 TC 133 Z9 135 U1 3 U2 31 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 MAR 4 PY 2011 VL 41 IS 5 BP 515 EP 528 DI 10.1016/j.molcel.2011.02.002 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 731ZU UT WOS:000288150700005 PM 21362548 ER PT J AU Vitek, WS Akers, A Meyn, LA Switzer, GE Lee, BY Beigi, RH AF Vitek, Wendy S. Akers, Aletha Meyn, Leslie A. Switzer, Galen E. Lee, Bruce Y. Beigi, Richard H. TI Vaccine eligibility and acceptance among ambulatory obstetric and gynecologic patients SO VACCINE LA English DT Article; Proceedings Paper CT 35th Annual Scientific Meeting of the Infectious-Diseases-Society-for-Obstetrics-and-Gynecology CY AUG 14-16, 2008 CL Seattle, WA SP Infect Dis Soc Obstetr & Gynecol DE Patient acceptance of health care; Vaccine; Obstetrics; Gynecology ID PREGNANCY AB Objective: To assess vaccine eligibility and factors associated with vaccine acceptance among ambulatory obstetric and gynecologic patients. Methods: An anonymous office-based survey was administered to women seeking ambulatory obstetric and gynecologic care at a large women's hospital from December 2007 to July 2008. Information collected included: demographics, medical and vaccination history, interest in receiving vaccines and attitudes towards vaccine providers. Vaccine eligibility was based on age and/or self-reported risk factors in accord with the 2007-2008 Center for Disease Control and Prevention (CDC) adult immunization schedule. Vaccine eligibility was examined using descriptive statistics, and demographic characteristics were compared using chi-squared analysis. A multivariable logistic regression model was developed to assess factors associated with participants' willingness to accept vaccines from their obstetrician-gynecologist. Results: A total of 1441 women completed the survey. The majority of participants (87%) would accept vaccines if recommended by their obstetrician-gynecologist. The primary factors associated with vaccine acceptance were having less than a high school education, being privately insured, currently being pregnant, reporting a history of vaccinations and previously receiving vaccinations from an obstetrician-gynecologist. A significant portion of participants were eligible for the hepatitis B. influenza and HPV vaccines (>= 50% for each). The type of vaccine did not influence willingness to accept vaccines from an obstetrician-gynecologist. Conclusion: A majority of women appear eligible for, and will accept, vaccinations regardless of specific vaccine, if recommended by their obstetrician-gynecologist. These findings justify ongoing efforts to expand immunization services offered by obstetrician-gynecologists. (C) 2011 Elsevier Ltd. All rights reserved. C1 [Vitek, Wendy S.] Women & Infants Hosp Rhode Isl, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, Providence, RI 02908 USA. [Akers, Aletha; Beigi, Richard H.] Univ Pittsburgh, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Med Ctr,Div Gynecol Specialties, Pittsburgh, PA 15213 USA. [Akers, Aletha; Beigi, Richard H.] Univ Pittsburgh, Magee Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Med Ctr,Div Reprod Infect Dis, Pittsburgh, PA 15213 USA. [Meyn, Leslie A.] Magee Womens Res Inst, Pittsburgh, PA USA. [Switzer, Galen E.] Univ Pittsburgh, Sch Med, Dept Med & Psychiat, Pittsburgh, PA USA. [Switzer, Galen E.] Univ Pittsburgh, Sch Med, Dept Clin & Translat Sci, Pittsburgh, PA USA. [Switzer, Galen E.] VA Pittsburgh Hlth Syst, Ctr Hlth Equ & Promot, Pittsburgh, PA USA. [Lee, Bruce Y.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Lee, Bruce Y.] Univ Pittsburgh, Dept Epidemiol, Sch Med, Pittsburgh, PA 15261 USA. [Lee, Bruce Y.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. RP Vitek, WS (reprint author), Women & Infants Hosp Rhode Isl, Div Reprod Endocrinol & Infertil, Dept Obstet & Gynecol, 90 Plain St, Providence, RI 02908 USA. EM wvitek@wihri.org NR 16 TC 13 Z9 13 U1 1 U2 2 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 MAR 3 PY 2011 VL 29 IS 11 BP 2024 EP 2028 DI 10.1016/j.vaccine.2011.01.026 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 739PU UT WOS:000288731000007 PM 21272604 ER PT J AU Smith, AR Majhail, NS MacMillan, ML DeFor, TE Jodele, S Lehmann, LE Krance, R Davies, SM AF Smith, Angela R. Majhail, Navneet S. MacMillan, Margaret L. DeFor, Todd E. Jodele, Sonata Lehmann, Leslie E. Krance, Robert Davies, Stella M. TI Hematopoietic cell transplantation comorbidity index predicts transplantation outcomes in pediatric patients SO BLOOD LA English DT Article ID HCT-CI; REDUCED-INTENSITY; MORBIDITY; MORTALITY; RISK; VALIDATION; LYMPHOMA; MYELOMA; MODELS AB Quantifying the risk of hematopoietic cell transplantation (HCT)-related mortality for pediatric patients is challenging. The HCT-specific comorbidity index (HCT-CI) has been confirmed as a useful tool in adults, but has not yet been validated in children. We conducted a retrospective cohort study of 252 pediatric patients undergoing their first allogeneic HCT between January 2008 and May 2009. Pretransplantation comorbidities were scored prospectively using the HCT-CI. Median age at transplantation was 6 years (range, 0.1-20) and median follow-up was 343 days (range, 110-624). HCT-CI scores were distributed as follows: 0, n = 139; 1-2, n = 52; and 3+, n = 61. The 1-year cumulative incidence of nonrelapse mortality (NRM) increased (10%, 14%, and 28%, respectively; P < .01) and overall survival (OS) decreased (88%, 67%, and 62%, respectively; P < .01) with increasing HCT-CI score. Multivariate analysis showed that compared with score 0, those with scores of 1-2 and 3+ had relative risks of NRM of 1.5 (95% confidence interval, 0.5-4.3, P = .48) and 4.5 (95% confidence interval, 1.7-12.1, P < .01), respectively. These results indicate that the HCT-CI score predicts NRM and OS in pediatric patients undergoing HCT and is a useful tool to assess risk, guide counseling in the pre-transplantation setting, and devise innovative therapies for the highest risk groups. (Blood. 2011; 117(9): 2728-2734) C1 [Smith, Angela R.; Majhail, Navneet S.; MacMillan, Margaret L.; DeFor, Todd E.] Univ Minnesota, Blood & Marrow Transplant Program, Minneapolis, MN 55455 USA. [Jodele, Sonata; Davies, Stella M.] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplant & Immune Deficiency, Cincinnati, OH USA. [Lehmann, Leslie E.] Childrens Hosp, Dana Farber Canc Inst, Pediat Stem Cell Transplant Program, Boston, MA 02115 USA. [Krance, Robert] Texas Childrens Canc Ctr, Pediat Stem Cell Transplant Program, Houston, TX USA. RP Smith, AR (reprint author), Univ Minnesota, Blood & Marrow Transplant Program, 420 Delaware St SE,MMC 484, Minneapolis, MN 55455 USA. EM smith719@umn.edu NR 17 TC 25 Z9 26 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 3 PY 2011 VL 117 IS 9 BP 2728 EP 2734 DI 10.1182/blood-2010-08-303263 PG 7 WC Hematology SC Hematology GA 732RR UT WOS:000288207400025 PM 21228326 ER PT J AU Ring, DC Herndon, JH Meyer, GS AF Ring, David C. Herndon, James H. Meyer, Gregg S. TI Case 34-2010: A Woman with an Incorrect Operation REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Ring, David C.; Herndon, James H.; Meyer, Gregg S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ring, DC (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 3 PY 2011 VL 364 IS 9 BP 883 EP 883 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 729DJ UT WOS:000287928400023 ER PT J AU Farrar, CT Kamoun, WS Ley, CD Kim, YR Catana, C Kwon, SJ Rosen, BR Jain, RK Sorensen, AG AF Farrar, Christian T. Kamoun, Walid S. Ley, Carsten D. Kim, Young R. Catana, Ciprian Kwon, Seon J. Rosen, Bruce R. Jain, Rakesh K. Sorensen, A. Gregory TI Sensitivity of MRI Tumor Biomarkers to VEGFR Inhibitor Therapy in an Orthotopic Mouse Glioma Model SO PLOS ONE LA English DT Article ID CEREBRAL BLOOD-VOLUME; CONTRAST-ENHANCED MRI; BRAIN-BARRIER PERMEABILITY; TYROSINE KINASE INHIBITOR; ARTERIAL INPUT FUNCTION; EARLY SURROGATE MARKER; IN-VIVO; GRADIENT-ECHO; VESSEL SIZE; GLIOBLASTOMA PATIENTS AB MRI biomarkers of tumor edema, vascular permeability, blood volume, and average vessel caliber are increasingly being employed to assess the efficacy of tumor therapies. However, the dependence of these biomarkers on a number of physiological factors can compromise their sensitivity and complicate the assessment of therapeutic efficacy. Here we examine the response of these MRI tumor biomarkers to cediranib, a potent vascular endothelial growth factor receptor (VEGFR) inhibitor, in an orthotopic mouse glioma model. A significant increase in the tumor volume and relative vessel caliber index (rVCI) and a slight decrease in the water apparent diffusion coefficient (ADC) were observed for both control and cediranib treated animals. This contrasts with a clinical study that observed a significant decrease in tumor rVCI, ADC and volume with cediranib therapy. While the lack of a difference between control and cediranib treated animals in these biomarker responses might suggest that cediranib has no therapeutic benefit, cediranib treated mice had a significantly increased survival. The increased survival benefit of cediranib treated animals is consistent with the significant decrease observed for cediranib treated animals in the relative cerebral blood volume (rCBV), relative microvascular blood volume (rMBV), transverse relaxation time (T2), blood vessel permeability (K(trans)), and extravascular-extracellular space (v(e)). The differential response of pre-clinical and clinical tumors to cediranib therapy, along with the lack of a positive response for some biomarkers, indicates the importance of evaluating the whole spectrum of different tumor biomarkers to properly assess the therapeutic response and identify and interpret the therapy-induced changes in the tumor physiology. C1 [Farrar, Christian T.; Kim, Young R.; Catana, Ciprian; Kwon, Seon J.; Rosen, Bruce R.; Sorensen, A. Gregory] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Kamoun, Walid S.; Ley, Carsten D.; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Charlestown, MA USA. RP Farrar, CT (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. EM cfarrar@nmr.mgh.harvard.edu FU National Institutes of Health [P41-RR14075, P01-CA80124, R01-CA115767]; AstraZeneca Pharmaceuticals; National Cancer Institute [T32-CA009502]; National Institute on Aging [K25-AG029415] FX This research was supported by the National Institutes of Health (P41-RR14075, P01-CA80124, R01-CA115767) and by AstraZeneca Pharmaceuticals. CTF gratefully acknowledges support from the National Cancer Institute (T32-CA009502) and the National Institute on Aging (K25-AG029415). WSK gratefully acknowledges support from the Susan G. Komen foundation. CDL gratefully acknowledges support from the Harboe Foundation, the A.P. Moller Foundation, and the Dagmar-Marshall Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 19 Z9 20 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 3 PY 2011 VL 6 IS 3 AR e17228 DI 10.1371/journal.pone.0017228 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 729QI UT WOS:000287965200013 PM 21390238 ER PT J AU McKinney, SM Thien, TDV Buxton, OM Solet, JM Ellenbogen, JM AF McKinney, Scott M. Thien Thanh Dang-Vu Buxton, Orfeu M. Solet, Jo M. Ellenbogen, Jeffrey M. TI Covert Waking Brain Activity Reveals Instantaneous Sleep Depth SO PLOS ONE LA English DT Article ID AROUSAL THRESHOLD; ALPHA OSCILLATIONS; STIMULUS DETECTION; POWER SPECTRUM; HUMAN CORTEX; EEG SPECTRA; PERFORMANCE; ELECTROENCEPHALOGRAM; FREQUENCY; COHERENCE AB The neural correlates of the wake-sleep continuum remain incompletely understood, limiting the development of adaptive drug delivery systems for promoting sleep maintenance. The most useful measure for resolving early positions along this continuum is the alpha oscillation, an 8-13 Hz electroencephalographic rhythm prominent over posterior scalp locations. The brain activation signature of wakefulness, alpha expression discloses immediate levels of alertness and dissipates in concert with fading awareness as sleep begins. This brain activity pattern, however, is largely ignored once sleep begins. Here we show that the intensity of spectral power in the alpha band actually continues to disclose instantaneous responsiveness to noise-a measure of sleep depth-throughout a night of sleep. By systematically challenging sleep with realistic and varied acoustic disruption, we found that sleepers exhibited markedly greater sensitivity to sounds during moments of elevated alpha expression. This result demonstrates that alpha power is not a binary marker of the transition between sleep and wakefulness, but carries rich information about immediate sleep stability. Further, it shows that an empirical and ecologically relevant form of sleep depth is revealed in real-time by EEG spectral content in the alpha band, a measure that affords prediction on the order of minutes. This signal, which transcends the boundaries of classical sleep stages, could potentially be used for real-time feedback to novel, adaptive drug delivery systems for inducing sleep. C1 [McKinney, Scott M.; Thien Thanh Dang-Vu; Ellenbogen, Jeffrey M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Thien Thanh Dang-Vu; Buxton, Orfeu M.; Solet, Jo M.; Ellenbogen, Jeffrey M.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA USA. [Thien Thanh Dang-Vu] Univ Liege, Cyclotron Res Ctr, Liege, Belgium. [Buxton, Orfeu M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Solet, Jo M.] Cambridge Hlth Alliance, Dept Med, Cambridge, MA USA. RP McKinney, SM (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM jeffrey_ellenbogen@hms.harvard.edu RI Sanguansri, Luz/B-6630-2011; OI Sanguansri, Luz/0000-0003-1908-7604; Dang Vu, Thien Thanh/0000-0002-7235-2721 FU Academy of Architecture for Health; Facilities Guidelines Institute; Center for Health Design; Massachusetts General Hospital FX This study was funded by the Academy of Architecture for Health, the Facilities Guidelines Institute, the Center for Health Design, and the Massachusetts General Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 22 Z9 22 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 3 PY 2011 VL 6 IS 3 AR e17351 DI 10.1371/journal.pone.0017351 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 729QI UT WOS:000287965200014 PM 21408616 ER PT J AU Nehme, NT Quintin, J Cho, JH Lee, J Lafarge, MC Kocks, C Ferrandon, D AF Nehme, Nadine T. Quintin, Jessica Cho, Ju Hyun Lee, Janice Lafarge, Marie-Celine Kocks, Christine Ferrandon, Dominique TI Relative Roles of the Cellular and Humoral Responses in the Drosophila Host Defense against Three Gram-Positive Bacterial Infections SO PLOS ONE LA English DT Article ID PEPTIDOGLYCAN RECOGNITION PROTEIN; IMMUNE-RESPONSE; TOLL-PATHWAY; PSEUDOMONAS-AERUGINOSA; ANTIMICROBIAL PEPTIDES; FUNGAL-INFECTIONS; IMD PATHWAYS; PGRP-SD; PHAGOCYTOSIS; RESISTANCE AB Background: Two NF-kappaB signaling pathways, Toll and immune deficiency (imd), are required for survival to bacterial infections in Drosophila. In response to septic injury, these pathways mediate rapid transcriptional activation of distinct sets of effector molecules, including antimicrobial peptides, which are important components of a humoral defense response. However, it is less clear to what extent macrophage-like hemocytes contribute to host defense. Methodology/Principal Findings: In order to dissect the relative importance of humoral and cellular defenses after septic injury with three different Gram-positive bacteria (Micrococcus luteus, Enterococcus faecalis, Staphylococcus aureus), we used latex bead pre-injection to ablate macrophage function in flies wildtype or mutant for various Toll and imd pathway components. We found that in all three infection models a compromised phagocytic system impaired fly survival independently of concomitant Toll or imd pathway activation. Our data failed to confirm a role of the PGRP-SA and GNBP1 Pattern Recognition Receptors for phagocytosis of S. aureus. The Drosophila scavenger receptor Eater mediates the phagocytosis by hemocytes or S2 cells of E. faecalis and S. aureus, but not of M. luteus. In the case of M. luteus and E. faecalis, but not S. aureus, decreased survival due to defective phagocytosis could be compensated for by genetically enhancing the humoral immune response. Conclusions/Significance: Our results underscore the fundamental importance of both cellular and humoral mechanisms in Drosophila immunity and shed light on the balance between these two arms of host defense depending on the invading pathogen. C1 [Nehme, Nadine T.; Quintin, Jessica; Cho, Ju Hyun; Lee, Janice; Lafarge, Marie-Celine; Kocks, Christine; Ferrandon, Dominique] Univ Strasbourg, CNRS, Inst Biol Mol & Cellulaire, Equipe Fdn Rech Med,UPR 9022, Strasbourg, France. [Cho, Ju Hyun; Lee, Janice; Kocks, Christine] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Nehme, NT (reprint author), Hop Necker Enfants Malad, INSERM, U768, Paris, France. EM D.Ferrandon@ibmc.u-strasbg.fr OI FERRANDON, Dominique/0000-0001-7680-7773 FU Conseil National de la Recherche Scientifique du Liban; CNRS; NIH [PO1 AI44220]; Fondation pour la Recherche Medicale FX N.N. was partially supported by a fellowship from the Conseil National de la Recherche Scientifique du Liban. This work was supported financially by the CNRS, a NIH Program grant PO1 AI44220, and a DROSELEGANS grant from the Agence Nationale de la Recherche. The Strasbourg team is an "Equipe FRM", a label awarded by the Fondation pour la Recherche Medicale. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 37 Z9 38 U1 2 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 3 PY 2011 VL 6 IS 3 AR e14743 DI 10.1371/journal.pone.0014743 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 729QI UT WOS:000287965200003 PM 21390224 ER PT J AU Dutt, S Narla, A Lin, K Mullally, A Abayasekara, N Megerdichian, C Wilson, FH Currie, T Khanna-Gupta, A Berliner, N Kutok, JL Ebert, BL AF Dutt, Shilpee Narla, Anupama Lin, Katherine Mullally, Ann Abayasekara, Nirmalee Megerdichian, Christine Wilson, Frederick H. Currie, Treeve Khanna-Gupta, Arati Berliner, Nancy Kutok, Jeffery L. Ebert, Benjamin L. TI Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells SO BLOOD LA English DT Article ID DIAMOND-BLACKFAN ANEMIA; HUMAN 5Q-SYNDROME; PIFITHRIN-ALPHA; CANCER-THERAPY; MARROW FAILURE; P73 FUNCTION; DNA-DAMAGE; PATHWAY; CLASSIFICATION; IDENTIFICATION AB Haploinsufficiency for ribosomal protein genes has been implicated in the pathophysiology of Diamond-Blackfan anemia (DBA) and the 5q- syndrome, a subtype of myelodysplastic syndrome. The p53 pathway is activated by ribosome dysfunction, but the molecular basis for selective impairment of the erythroid lineage in disorders of ribosome function has not been determined. We found that p53 accumulates selectively in the erythroid lineage in primary human hematopoietic progenitor cells after expression of shRNAs targeting RPS14, the ribosomal protein gene deleted in the 5q- syndrome, or RPS19, the most commonly mutated gene in DBA. Induction of p53 led to lineage-specific accumulation of p21 and consequent cell cycle arrest in erythroid progenitor cells. Pharmacologic inhibition of p53 rescued the erythroid defect, whereas nutlin-3, a compound that activates p53 through inhibition of HDM2, selectively impaired erythropoiesis. In bone marrow biopsies from patients with DBA or del(5q) myelodysplastic syndrome, we found an accumulation of nuclear p53 staining in erythroid progenitor cells that was not present in control samples. Our findings indicate that the erythroid lineage has a low threshold for the induction of p53, providing a basis for the failure of erythropoiesis in the 5q- syndrome, DBA, and perhaps other bone marrow failure syndromes. (Blood. 2011; 117(9): 2567-2576) C1 [Dutt, Shilpee; Narla, Anupama; Lin, Katherine; Mullally, Ann; Abayasekara, Nirmalee; Megerdichian, Christine; Wilson, Frederick H.; Khanna-Gupta, Arati; Berliner, Nancy; Ebert, Benjamin L.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Narla, Anupama; Ebert, Benjamin L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Narla, Anupama] Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Currie, Treeve; Kutok, Jeffery L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ebert, Benjamin L.] Harvard Stem Cell Inst, Cambridge, MA USA. RP Ebert, BL (reprint author), 1 Blackfan Circle,Karp 5-210, Boston, MA 02115 USA. EM bebert@partners.org FU National Institutes of Health [5R01 HL082945, P01 CA108631]; Burroughs-Wellcome Fund FX This work was supported by the National Institutes of Health (grants 5R01 HL082945 and P01 CA108631) and the Burroughs-Wellcome Fund (Career Award for Medical Scientists; B.L.E.). NR 42 TC 148 Z9 153 U1 1 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 3 PY 2011 VL 117 IS 9 BP 2567 EP 2576 DI 10.1182/blood-2010-07-295238 PG 10 WC Hematology SC Hematology GA 732RR UT WOS:000288207400008 PM 21068437 ER PT J AU Ehrlich, LIR Serwold, T Weissman, IL AF Ehrlich, Lauren I. Richie Serwold, Thomas Weissman, Irving L. TI In vitro assays misrepresent in vivo lineage potentials of murine lymphoid progenitors SO BLOOD LA English DT Article ID T-CELL PROGENITORS; BONE-MARROW; STEM-CELLS; HEMATOPOIETIC PROGENITORS; CONVERSION; DIFFERENTIATION; SPECIFICATION; GENERATION; ALPHA; BLOOD AB The identity of T-cell progenitors that seed the thymus has remained controversial, largely because many studies differ over whether these progenitors retain myeloid potential. Contradictory reports diverge in their use of various in vitro and in vivo assays. To consolidate these discordant findings, we compared the myeloid potential of 2 putative thymus seeding populations, common lymphoid progenitors (CLPs) and multipotent progenitors (MPPs), and the earliest intrathymic progenitor (DN1), using 2 in vitro assays and in vivo readouts. These assays gave contradictory results: CLP and DN1 displayed surprisingly robust myeloid potential on OP9-DL1 in vitro stromal cocultures but displayed little myeloid potential in vivo, as well as in methylcellulose cultures. MPP, on the other hand, displayed robust myeloid potential in all settings. We conclude that stromal cocultures reveal cryptic, but non-physiologic, myeloid potentials of lymphoid progenitors, providing an explanation for contradictory findings in the field and underscoring the importance of using in vivo assays for the determination of physiologic lineage potentials. (Blood. 2011; 117(9): 2618-2624) C1 [Ehrlich, Lauren I. Richie; Serwold, Thomas; Weissman, Irving L.] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA. [Serwold, Thomas] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Ehrlich, LIR (reprint author), 2506 Speedway,NMS 2-314, Austin, TX 78712 USA. EM lehrlich@mail.utexas.edu FU Leukemia & Lymphoma Society; National Institutes of Health [5R01A1047457, 5R01A1047458]; Joslin Diabetes Endocrinology Research Center [P30DK36836] FX This work was supported by the Leukemia & Lymphoma Society (Special Fellow Career Development award; L.I.R.E.) and the National Institutes of Health grants 5R01A1047457 and 5R01A1047458 (to I.L.W.) and Joslin Diabetes Endocrinology Research Center grant P30DK36836 (to T.S.). NR 21 TC 34 Z9 34 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 3 PY 2011 VL 117 IS 9 BP 2618 EP 2624 DI 10.1182/blood-2010-05-287102 PG 7 WC Hematology SC Hematology GA 732RR UT WOS:000288207400014 ER PT J AU Gore, A Li, Z Fung, HL Young, JE Agarwal, S Antosiewicz-Bourget, J Canto, I Giorgetti, A Israel, MA Kiskinis, E Lee, JH Loh, YH Manos, PD Montserrat, N Panopoulos, AD Ruiz, S Wilbert, ML Yu, JY Kirkness, EF Belmonte, JCI Rossi, DJ Thomson, JA Eggan, K Daley, GQ Goldstein, LSB Zhang, K AF Gore, Athurva Li, Zhe Fung, Ho-Lim Young, Jessica E. Agarwal, Suneet Antosiewicz-Bourget, Jessica Canto, Isabel Giorgetti, Alessandra Israel, Mason A. Kiskinis, Evangelos Lee, Je-Hyuk Loh, Yuin-Han Manos, Philip D. Montserrat, Nuria Panopoulos, Athanasia D. Ruiz, Sergio Wilbert, Melissa L. Yu, Junying Kirkness, Ewen F. Izpisua Belmonte, Juan Carlos Rossi, Derrick J. Thomson, James A. Eggan, Kevin Daley, George Q. Goldstein, Lawrence S. B. Zhang, Kun TI Somatic coding mutations in human induced pluripotent stem cells SO NATURE LA English DT Article ID IPS CELLS; GENOME; DNA; TRANSFORMATION; FIBROBLASTS; GENERATION; SEQUENCES; EFFICIENT; SELECTION; VARIANTS AB Defined transcription factors can induce epigenetic reprogramming of adult mammalian cells into induced pluripotent stem cells. Although DNA factors are integrated during some reprogramming methods, it is unknown whether the genome remains unchanged at the single nucleotide level. Here we show that 22 human induced pluripotent stem (hiPS) cell lines reprogrammed using five different methods each contained an average of five protein-coding point mutations in the regions sampled (an estimated six protein-coding point mutations per exome). The majority of these mutations were non-synonymous, nonsense or splice variants, and were enriched in genes mutated or having causative effects in cancers. At least half of these reprogramming-associated mutations pre-existed in fibroblast progenitors at low frequencies, whereas the rest occurred during or after reprogramming. Thus, hiPS cells acquire genetic modifications in addition to epigenetic modifications. Extensive genetic screening should become a standard procedure to ensure hiPS cell safety before clinical use. C1 [Young, Jessica E.; Canto, Isabel; Israel, Mason A.; Wilbert, Melissa L.; Goldstein, Lawrence S. B.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Young, Jessica E.; Canto, Isabel; Israel, Mason A.; Wilbert, Melissa L.; Goldstein, Lawrence S. B.] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA. [Gore, Athurva; Li, Zhe; Fung, Ho-Lim; Zhang, Kun] Univ Calif San Diego, Inst Genom Med, Dept Bioengn, La Jolla, CA 92093 USA. [Gore, Athurva; Li, Zhe; Fung, Ho-Lim; Zhang, Kun] Univ Calif San Diego, Inst Engn Med, La Jolla, CA 92093 USA. [Agarwal, Suneet; Loh, Yuin-Han; Manos, Philip D.; Daley, George Q.] Childrens Hosp Boston, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Agarwal, Suneet; Loh, Yuin-Han; Manos, Philip D.; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Antosiewicz-Bourget, Jessica; Yu, Junying; Thomson, James A.] Univ Wisconsin, Dept Anat, Madison, WI 53705 USA. [Giorgetti, Alessandra; Montserrat, Nuria; Izpisua Belmonte, Juan Carlos] Ctr Regenerat Med, Barcelona 08003, Spain. [Kiskinis, Evangelos; Eggan, Kevin] Harvard Univ, Howard Hughes Med Inst, Harvard Stem Cell Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Lee, Je-Hyuk] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02135 USA. [Panopoulos, Athanasia D.; Ruiz, Sergio; Izpisua Belmonte, Juan Carlos] Salk Inst Biol Studies, La Jolla, CA 92037 USA. [Kirkness, Ewen F.] J Craig Venter Inst, Rockville, MD 20850 USA. [Rossi, Derrick J.] Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA. RP Goldstein, LSB (reprint author), Univ Calif San Diego, Dept Cellular & Mol Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM lgoldstein@ucsd.edu; kzhang@bioeng.ucsd.edu RI Loh, Yuin-Han/E-1096-2014; Montserrat, Nuria/F-3136-2016; Ruiz, Sergio/G-1561-2016; Giorgetti, Alessandra/D-3784-2016 OI Loh, Yuin-Han/0000-0002-4715-6454; Montserrat, Nuria/0000-0002-1603-1755; Ruiz, Sergio/0000-0002-0177-6965; Giorgetti, Alessandra/0000-0002-2747-6514 FU NIH [R01 HL094963]; UCSD; California Institute for Regenerative Medicine [TG2-01154]; CIRM [RC1-00116]; Focht-Powell Fellowship; National Institute of General Medical Sciences [T32 GM008666]; A*Star Institute of Medical Biology; Singapore Stem Cell Consortium; MICINN; Sanofi-Aventis; G. Harold and Leila Y. Mathers Foundation; Cellex Foundation FX We thank J. M. Akey, G. M. Church, S. Ding, J. B. Li and J. Shendure for discussions and suggestions, S. Vassallo for assistance with DNA shearing, and G. L. Boulting and S. Ratansirintrawoot for assistance with hiPS cell culture. This study is supported by NIH R01 HL094963 and a UCSD new faculty start-up fund (to K.Z.), a training grant from the California Institute for Regenerative Medicine (TG2-01154) and a CIRM grant (RC1-00116) (to L.S.B.G.). L.S.B.G. is an Investigator of the Howard Hughes Medical Institute. A. Gore is supported by the Focht-Powell Fellowship and a CIRM predoctoral fellowship. M.L.W. is supported by an institutional training grant from the National Institute of General Medical Sciences (T32 GM008666). Y.-H.L. is supported by the A*Star Institute of Medical Biology and the Singapore Stem Cell Consortium. Work in the laboratory of J.C.I.B. was supported by grants from MICINN, Sanofi-Aventis, the G. Harold and Leila Y. Mathers Foundation and the Cellex Foundation. G.Q.D. is an investigator of the Howard Hughes Medical Institute and supported by grants from the NIH. NR 41 TC 627 Z9 661 U1 18 U2 147 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 3 PY 2011 VL 471 IS 7336 BP 63 EP U76 DI 10.1038/nature09805 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 729BY UT WOS:000287924100034 PM 21368825 ER PT J AU Inuzuka, H Shaik, S Onoyama, I Gao, DM Tseng, A Maser, RS Zhai, B Wan, LX Gutierrez, A Lau, AW Xiao, YH Christie, AL Aster, J Settleman, J Gygi, SP Kung, AL Look, T Nakayama, KI DePinho, RA Wei, WY AF Inuzuka, Hiroyuki Shaik, Shavali Onoyama, Ichiro Gao, Daming Tseng, Alan Maser, Richard S. Zhai, Bo Wan, Lixin Gutierrez, Alejandro Lau, Alan W. Xiao, Yonghong Christie, Amanda L. Aster, Jon Settleman, Jeffrey Gygi, Steven P. Kung, Andrew L. Look, Thomas Nakayama, Keiichi I. DePinho, Ronald A. Wei, Wenyi TI SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction SO NATURE LA English DT Article ID FBW7 UBIQUITIN LIGASE; TUMOR-SUPPRESSOR; PHOSPHORYLATION; DEGRADATION; DIFFERENTIATION; COMPLEX; CANCERS; PROTEIN AB The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer(1) and T-cell acute lymphoblastic leukaemia (T-ALL)(2). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL(3-5), validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun(6), Myc(7), cyclin E-8 and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth(10), overexpression of Jun, Myc or notch 1 can also induce programmed cell death(11). Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCFFBW7 (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL. C1 [Inuzuka, Hiroyuki; Shaik, Shavali; Gao, Daming; Tseng, Alan; Wan, Lixin; Lau, Alan W.; Wei, Wenyi] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Onoyama, Ichiro; Nakayama, Keiichi I.] Kyushu Univ, Dept Mol & Cellular Biol, Med Inst Bioregulat, Fukuoka 8128582, Japan. [Maser, Richard S.; Xiao, Yonghong; DePinho, Ronald A.] Harvard Univ, Belfer Inst Appl Canc Sci, Dana Farber Canc Inst, Dept Med Oncol,Sch Med, Boston, MA 02115 USA. [Maser, Richard S.] Jackson Lab, Bar Harbor, ME 04609 USA. [Zhai, Bo; Gygi, Steven P.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Gutierrez, Alejandro; Christie, Amanda L.; Kung, Andrew L.; Look, Thomas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Christie, Amanda L.; Kung, Andrew L.] Dana Farber Canc Inst, Lurie Family Imaging Ctr, Boston, MA 02115 USA. [Aster, Jon] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Settleman, Jeffrey] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc,Dept Med, Boston, MA 02129 USA. RP Wei, WY (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA. EM wwei2@bidmc.harvard.edu RI Maser, Richard/B-2970-2012; Wan, Lixin/F-2124-2011; OI Gutierrez, Alejandro/0000-0002-0249-9007; Kung, Andrew/0000-0002-9091-488X FU Emerald Foundation; Leukemia and Lymphoma Society; National Institutes of Health [GM089763]; Robert A. and Renee E. Belfer Foundation Institute for Applied Cancer Science FX We thank J. Lawler, C. Schorl, Q. Zhang and S. Glueck for critical reading of the manuscript, J. DeCaprio, M.-C. Hung, M. A. Kelliher, W. Harper and W. Hahn for providing reagents, L. Cantley and A. Toker for suggestions, I. Wertz and V. Dixit for sharing unpublished data, and members of the Wei and DePinho labs for useful discussions. W.W. is a Kimmel Scholar and V Scholar. This work was supported in part by the Emerald Foundation New Investigator award (W.W.), the Leukemia and Lymphoma Society Special Fellow award (W.W.) and a grant from the National Institutes of Health (W.W.; GM089763). R.A.D. is an American Cancer Society Research Professor and is supported by the Robert A. and Renee E. Belfer Foundation Institute for Applied Cancer Science. NR 29 TC 246 Z9 255 U1 5 U2 37 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 3 PY 2011 VL 471 IS 7336 BP 104 EP U128 DI 10.1038/nature09732 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 729BY UT WOS:000287924100043 PM 21368833 ER PT J AU Felker, GM Lee, KL Bull, DA Redfield, MM Stevenson, LW Goldsmith, SR LeWinter, MM Deswal, A Rouleau, JL Ofili, EO Anstrom, KJ Hernandez, AF McNulty, SE Velazquez, EJ Kfoury, AG Chen, HH Givertz, MM Semigran, MJ Bart, BA Mascette, AM Braunwald, E O'Connor, CM AF Felker, G. Michael Lee, Kerry L. Bull, David A. Redfield, Margaret M. Stevenson, Lynne W. Goldsmith, Steven R. LeWinter, Martin M. Deswal, Anita Rouleau, Jean L. Ofili, Elizabeth O. Anstrom, Kevin J. Hernandez, Adrian F. McNulty, Steven E. Velazquez, Eric J. Kfoury, Abdallah G. Chen, Horng H. Givertz, Michael M. Semigran, Marc J. Bart, Bradley A. Mascette, Alice M. Braunwald, Eugene O'Connor, Christopher M. CA NHLBI Heart Failure Clinical Res N TI Diuretic Strategies in Patients with Acute Decompensated Heart Failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONTINUOUS-INFUSION; LOOP DIURETICS; INTRAVENOUS DIURETICS; RENAL-FUNCTION; ESCAPE TRIAL; FUROSEMIDE; OUTCOMES; DIURESIS; REGISTRY; DYSPNEA AB BACKGROUND Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. METHODS In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. RESULTS In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236 +/- 1440 and 4373 +/- 1404, respectively; P = 0.47) or in the mean change in the creatinine level (0.05 +/- 0.3 mg per deciliter [4.4 +/- 26.5 mu mol per liter] and 0.07 +/- 0.3 mg per deciliter [6.2 +/- 26.5 mu mol per liter], respectively; P = 0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430 +/- 1401 vs. 4171 +/- 1436; P = 0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08 +/- 0.3 mg per deciliter [7.1 +/- 26.5 mu mol per liter] with the high-dose strategy and 0.04 +/- 0.3 mg per deciliter [3.5 +/- 26.5 mu mol per liter] with the low-dose strategy, P = 0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. CONCLUSIONS Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. C1 [Felker, G. Michael; Lee, Kerry L.; Anstrom, Kevin J.; Hernandez, Adrian F.; McNulty, Steven E.; Velazquez, Eric J.] Duke Clin Res Inst, Durham, NC 27705 USA. [Felker, G. Michael; O'Connor, Christopher M.] Duke Univ, Sch Med, Durham, NC USA. [Felker, G. Michael; O'Connor, Christopher M.] Duke Univ, Med Ctr, Duke Heart Ctr, Durham, NC 27710 USA. [Bull, David A.; Kfoury, Abdallah G.] Univ Utah, Salt Lake City, UT USA. [Redfield, Margaret M.; Chen, Horng H.] Mayo Clin, Rochester, MN USA. [Stevenson, Lynne W.; Givertz, Michael M.; Braunwald, Eugene] Brigham & Womens Hosp, Boston, MA 02115 USA. [Semigran, Marc J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Goldsmith, Steven R.; Bart, Bradley A.] Univ Minnesota, Minneapolis, MN USA. [LeWinter, Martin M.] Univ Vermont, Burlington, VT 05405 USA. [Deswal, Anita] Baylor Coll Med, Houston, TX 77030 USA. [Deswal, Anita] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Rouleau, Jean L.] Univ Montreal, Montreal, PQ, Canada. [Rouleau, Jean L.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Ofili, Elizabeth O.] Morehouse Sch Med, Atlanta, GA 30310 USA. [Mascette, Alice M.] NHLBI, Bethesda, MD 20892 USA. RP Felker, GM (reprint author), Duke Clin Res Inst, 2400 Pratt St,Rm 0311 Terrace Level, Durham, NC 27705 USA. EM michael.felker@duke.edu RI Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 FU National Heart, Lung, and Blood Institute [HL084861, HL084875, HL084877, HL084889, HL084890, HL084891, HL084899, HL084904, HL084907, HL084931]; Amgen; Cytokinetics; Corthera; Otsuka; Novartis; Roche Diagnostics; Medtronic; Johnson Johnson; Pfizer; Boehringer Ingelheim; XDx; Scios; Anexon; Nile Therapeutics; GE Healthcare; Forest Pharmaceuticals; Novella Clinical; Medpace; Roche; Actelion Pharmaceuticals; Trevena; Martek Biosciences FX The Heart Failure Clinical Research Network is supported by grants (HL084861, HL084875, HL084877, HL084889, HL084890, HL084891, HL084899, HL084904, HL084907, and HL084931) from the National Heart, Lung, and Blood Institute.; Dr. Felker reports receiving consulting fees from Amgen, Cytokinetics, Corthera, Otsuka, Novartis, and Roche Diagnostics and grant support from Amgen, Cytokinetics, Otsuka, and Roche Diagnostics; Dr. LeWinter, receiving consulting fees from Novartis, grant support from Medtronic, and lecture fees from Medtronic and Novartis; Dr. Anstrom, receiving consulting fees from Johnson & Johnson and Pfizer; Dr. Hernandez, receiving consulting fees from Amgen and grant support from Johnson & Johnson and serving on a clinical end points committee for Corthera; Dr. Velazquez, receiving consulting fees from Novartis and Boehringer Ingelheim, grant support from Johnson & Johnson, and lecture fees from Novartis; Dr. Kfoury, receiving grant support from Novartis and XDx; Dr. Chen, receiving grant support from Scios, Anexon, and Nile Therapeutics, being named as a coinventor on patents for chimeric natriuretic peptides, and receiving royalties from Nile Therapeutics; and Dr. O'Connor, receiving consulting fees from Merck, GE Healthcare, Forest Pharmaceuticals, Medtronic, Novella Clinical, Medpace, Roche, Actelion Pharmaceuticals, Amgen, Trevena, and Martek Biosciences and grant support from Johnson & Johnson. No other potential conflict of interest relevant to this article was reported. NR 26 TC 418 Z9 438 U1 2 U2 27 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 MAR 3 PY 2011 VL 364 IS 9 BP 797 EP 805 DI 10.1056/NEJMoa1005419 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 729DJ UT WOS:000287928400005 PM 21366472 ER PT J AU Rosenheck, RA Krystal, JH Lew, R Barnett, PG Fiore, L Valley, D Thwin, SS Vertrees, JE Liang, MH AF Rosenheck, Robert A. Krystal, John H. Lew, Robert Barnett, Paul G. Fiore, Louis Valley, Danielle Thwin, Soe Soe Vertrees, Julia E. Liang, Matthew H. CA CSP555 Res Grp TI Long-Acting Risperidone and Oral Antipsychotics in Unstable Schizophrenia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INJECTABLE RISPERIDONE; OPEN-LABEL; SCALE; EFFICACY; SAFETY; RELIABILITY; THERAPY; RELAPSE; DEPOT; ACCEPTABILITY AB BACKGROUND Long-acting injectable risperidone, a second-generation antipsychotic agent, may improve adherence to treatment and outcomes in schizophrenia, but it has not been tested in a long-term randomized trial involving patients with unstable disease. METHODS We randomly assigned patients in the Veterans Affairs (VA) system who had schizophrenia or schizoaffective disorder and who had been hospitalized within the previous 2 years or were at imminent risk for hospitalization to 25 to 50 mg of long-acting injectable risperidone every two weeks or to a psychiatrist's choice of an oral antipsychotic. All patients were followed for up to 2 years. The primary end point was hospitalization in a VA or non-VA psychiatric hospital. Symptoms, quality of life, and functioning were assessed in blinded videoconference interviews. RESULTS Of 369 participants, 40% were hospitalized at randomization, 55% were hospitalized within the previous 2 years, and 5% were at risk for hospitalization. The rate of hospitalization after randomization was not significantly lower among patients who received long-acting injectable risperidone than among those who received oral antipsychotics (39% after 10.8 months vs. 45% after 11.3 months; hazard ratio, 0.87; 95% confidence interval, 0.63 to 1.20). Psychiatric symptoms, quality of life, scores on the Personal and Social Performance scale of global functioning, and neurologic side effects were not significantly improved with long-acting injectable risperidone as compared with control treatments. Patients who received long-acting injectable risperidone reported more adverse events at the injection site and more extrapyramidal symptoms. CONCLUSIONS Long-acting injectable risperidone was not superior to a psychiatrist's choice of oral treatment in patients with schizophrenia and schizoaffective disorder who were hospitalized or at high risk for hospitalization, and it was associated with more local injection-site and extrapyramidal adverse effects. C1 [Rosenheck, Robert A.; Krystal, John H.] VA Connecticut Healthcare Syst, Res Educ & Clin Ctr, VA New England Mental Illness, West Haven, CT USA. [Rosenheck, Robert A.; Krystal, John H.] Yale Univ, Sch Med, New Haven, CT USA. [Lew, Robert; Fiore, Louis; Valley, Danielle; Thwin, Soe Soe; Liang, Matthew H.] Massachusetts Vet Epidemiol & Res Informat Ctr, VA Cooperat Studies Program, Coordinating Ctr, Boston, MA USA. [Barnett, Paul G.] VA Hlth Econ Resource Ctr, Menlo Pk, CA USA. [Vertrees, Julia E.] Clin Res Pharm Coordinating Ctr, VA Cooperat Studies Program, Albuquerque, NM USA. RP Rosenheck, RA (reprint author), VA Connecticut Healthcare Syst 151D, Res Educ & Clin Ctr, VA New England Mental Illness, 950 Campbell Ave, West Haven, CT 06516 USA. EM robert.rosenheck@va.gov FU Veterans Affairs Cooperative Studies Program; Ortho-McNeil Janssen Scientific Affairs FX Supported by the Veterans Affairs Cooperative Studies Program and an unrestricted grant from Ortho-McNeil Janssen Scientific Affairs. NR 36 TC 118 Z9 121 U1 5 U2 14 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 3 PY 2011 VL 364 IS 9 BP 842 EP 851 DI 10.1056/NEJMoa1005987 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 729DJ UT WOS:000287928400009 PM 21366475 ER PT J AU Eguchi, J Wang, X Yu, ST Kershaw, EE Chiu, PC Dushay, J Estall, JL Klein, U Maratos-Flier, E Rosen, ED AF Eguchi, Jun Wang, Xun Yu, Songtao Kershaw, Erin E. Chiu, Patricia C. Dushay, Joanne Estall, Jennifer L. Klein, Ulf Maratos-Flier, Eleftheria Rosen, Evan D. TI Transcriptional Control of Adipose Lipid Handling by IRF4 SO CELL METABOLISM LA English DT Article ID INTERFERON-REGULATORY FACTOR-4; INSULIN-INDUCED PHOSPHORYLATION; ACTIVATED PROTEIN-KINASE; BINDING-PROTEIN; TRIGLYCERIDE LIPASE; GENE-EXPRESSION; PHOSPHODIESTERASE 3B; PPAR-GAMMA; ADIPOCYTES; LIPOLYSIS AB Adipocytes store triglyceride during periods of nutritional affluence and release free fatty acids during fasting through coordinated cycles of lipogenesis and lipolysis. While much is known about the acute regulation of these processes during fasting and feeding, less is understood about the transcriptional basis by which adipocytes control lipid handling. Here, we show that interferon regulatory factor 4 (IRF4) is a critical determinant of the transcriptional response to nutrient availability in adipocytes. Fasting induces IRF4 in an insulin- and FoxO1-dependent manner. IRF4 is required for lipolysis, at least in part due to direct effects on the expression of adipocyte triglyceride lipase and hormone-sensitive lipase. Conversely, reduction of IRF4 enhances lipid synthesis. Mice lacking adipocyte IRF4 exhibit increased adiposity and deficient lipolysis. These studies establish a link between IRF4 and the disposition of calories in adipose tissue, with consequences for systemic metabolic homeostasis. C1 [Eguchi, Jun; Wang, Xun; Chiu, Patricia C.; Dushay, Joanne; Maratos-Flier, Eleftheria; Rosen, Evan D.] Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA. [Yu, Songtao] Northwestern Univ, Feinberg Sch Med, Childrens Mem Res Ctr, Dept Pediat, Chicago, IL 60614 USA. [Kershaw, Erin E.] Univ Pittsburgh, Div Endocrinol, Pittsburgh, PA 15261 USA. [Estall, Jennifer L.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Klein, Ulf] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. RP Rosen, ED (reprint author), Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA. EM erosen@bidmc.harvard.edu RI Kershaw, Erin/G-9587-2013 FU Kanae Foundation for the Promotion of Medical Science; American Heart Association [AHA0825928D]; National Institutes of Health [NIH R01 DK63906, NIH R01 DK085171] FX The authors wish to thank C.R. Kahn for use of samples from FIRKO mice, Tak Mak for Irf4-/- mice, Shingo Kajimura, Tetsuya Hosooka, Choel Son, Junji Kawashima, Linh Vong, and Mark Herman for technical advice, Domenico Accili for FoxO1 adenoviral constructs, and members of the Rosen lab for helpful discussion. We thank Leo Otterbein and Eva Csizmadia for help with alveolar lavage and immunohistochemistry. This work was funded by the Kanae Foundation for the Promotion of Medical Science, American Heart Association Award AHA0825928D (to J.E.), and National Institutes of Health grants NIH R01 DK63906 and NIH R01 DK085171 (to E.D.R.). NR 53 TC 139 Z9 140 U1 1 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD MAR 2 PY 2011 VL 13 IS 3 BP 249 EP 259 DI 10.1016/j.cmet.2011.02.005 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 731ZQ UT WOS:000288150200006 PM 21356515 ER PT J AU Brink, JA Goske, MJ Patti, JA AF Brink, James A. Goske, Marilyn J. Patti, John A. TI Informed Consent for Radiologic Procedures SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Brink, James A.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Goske, Marilyn J.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Patti, John A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Brink, JA (reprint author), Yale Univ, Sch Med, New Haven, CT 06520 USA. EM james.brink@yale.edu NR 5 TC 6 Z9 6 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 2 PY 2011 VL 305 IS 9 BP 888 EP 889 DI 10.1001/jama.2011.222 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 728DP UT WOS:000287854700015 PM 21364135 ER PT J AU Moye, J Naik, AD AF Moye, Jennifer Naik, Aanand D. TI Preserving Rights for Individuals Facing Guardianship SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Moye, Jennifer] VA Boston Healthcare Syst, Boston, MA USA. [Moye, Jennifer] Harvard Univ, Sch Med, Boston, MA USA. [Naik, Aanand D.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Naik, Aanand D.] Baylor Coll Med, Houston, TX 77030 USA. RP Moye, J (reprint author), VA Boston Healthcare Syst, Psychiat, Brockton Campus,940 Belmont St, Brockton, MA 02301 USA. EM jennifer.moye@va.gov RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X FU NIA NIH HHS [K23 AG027144, K23AG027144]; NIMH NIH HHS [R29 MH057104] NR 9 TC 17 Z9 17 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 2 PY 2011 VL 305 IS 9 BP 936 EP 937 DI 10.1001/jama.2011.247 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 728DP UT WOS:000287854700029 PM 21364144 ER PT J AU Henderson, ER Groundland, JS Pala, E Dennis, JA Wooten, R Cheong, D Windhager, R Kotz, RI Mercuri, M Funovics, PT Hornicek, FJ Temple, HT Ruggieri, P Letson, GD AF Henderson, Eric R. Groundland, John S. Pala, Elisa Dennis, Jeremy A. Wooten, Rebecca Cheong, David Windhager, Reinhard Kotz, Rainer I. Mercuri, Mario Funovics, Philipp T. Hornicek, Francis J. Temple, H. Thomas Ruggieri, Pietro Letson, G. Douglas TI Failure Mode Classification for Tumor Endoprostheses: Retrospective Review of Five Institutions and a Literature Review SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Review ID PROXIMAL FEMORAL REPLACEMENT; TOTAL KNEE ARTHROPLASTY; TOTAL HIP-ARTHROPLASTY; LIMB SALVAGE SURGERY; TOTAL FEMUR REPLACEMENT; MALIGNANT BONE-TUMOR; MORREY TOTAL ELBOW; QUALITY-OF-LIFE; TERM-FOLLOW-UP; PROSTHETIC REPLACEMENT AB Background: Massive endoprostheses provide orthopaedic oncologists with many reconstructive options after tumor resection, although failure rates are high. Because the number of these procedures is limited, failure of these devices has not been studied or classified adequately. This investigation is a multicenter review of the use of segmental endoprostheses with a focus on the modes, frequency, and timing of failure. Methods: Retrospective reviews of the operative databases of five institutions identified 2174 skeletally mature patients who received a large endoprosthesis for tumor resection. Patients who had failure of the endoprosthesis were identified, and the etiology and timing of failure were noted. Similar failures were tabulated and classified on the basis of the risk of amputation and urgency of treatment. Statistical analysis was performed to identify dependent relationships among mode of failure, anatomic location, and failure timing. A literature review was performed, and similar analyses were done for these data. Results: Five hundred and thirty-four failures were identified. Five modes of failure were identified and classified: soft-tissue failures (Type 1), aseptic loosening (Type 2), structural failures (Type 3), infection (Type 4), and tumor progression (Type 5). The most common mode of failure in this series was infection; in the literature, it was aseptic loosening. Statistical dependence was found between anatomic location and mode of failure and between mode of failure and time to failure. Significant differences were found in the incidence of failure mode Types 1, 2, 3, and 4 when polyaxial and uniaxial joints were compared. Significant dependence was also found between failure mode and anatomic location in the literature data. Conclusions: There are five primary modes of endoprosthetic failure, and their relative incidences are significantly different and dependent on anatomic location. Mode of failure and time to failure also show a significant dependence. Because of these relationships, cumulative reporting of segmental failures should be avoided because anatomy-specific trends will be missed. Endoprosthetic design improvements should address failure modes specific to the anatomic location. C1 [Henderson, Eric R.] H Lee Moffitt Canc Ctr & Res Inst, Sarcoma Program, Tampa, FL 33612 USA. Univ Bologna, Ist Ortoped Rizzoli, I-40136 Bologna, Italy. Univ Miami, Orthopaed Oncol Div, Dept Orthopaed Surg, Miami, FL 33136 USA. Med Univ Vienna, Dept Orthopaed Surg, A-1090 Vienna, Austria. Massachusetts Gen Hosp, Div Orthopaed Oncol, Boston, MA 02114 USA. RP Henderson, ER (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Sarcoma Program, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM eric.r.henderson@gmail.com FU DePuy; Johnson Johnson; Stryker FX The authors did not receive any outside funding or grants in support of their research for or preparation of this work. One or more of the authors, or a member of his or her immediate family, received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from commercial entities (DePuy [Johnson & Johnson] and Stryker). NR 93 TC 98 Z9 104 U1 7 U2 24 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD MAR 2 PY 2011 VL 93A IS 5 BP 418 EP 429 DI 10.2106/JBJSJ.00834 PG 12 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 727UB UT WOS:000287827000002 PM 21368074 ER PT J AU Buijze, GA Richardson, S Jupiter, JB AF Buijze, Geert A. Richardson, Shawn Jupiter, Jesse B. TI Successful Reconstruction for Complex Malunions and Nonunions of the Tibia and Femur SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID TRAUMA-RELATED AMPUTATIONS; LOWER-EXTREMITY TRAUMA; FREE-TISSUE TRANSFER; LOWER-LIMB INJURY; SALVAGE; FRACTURES; AMPUTEES; OUTCOMES; REHABILITATION; SATISFACTION AB Background: Information regarding the long-term outcomes of the treatment of lower-extremity fracture malunion and nonunion is lacking. Methods: Twenty-nine secondarily referred patients with complex malunion or nonunion of the tibia or femur, treated by a single surgeon, were followed for a median of twenty years (range, twelve to thirty-five years) after injury. The patients were referred at a median of twenty months (range, 1.5 to 360 months) postinjury and had undergone a median of three prior surgical procedures (range, zero to twenty-eight). At the time of final follow-up, patient-based outcomes, patient satisfaction, and pain were evaluated. Results: All twenty-nine patients had healing following treatment of the complex malunion or nonunion of the tibia or femur and were able to bear full weight and walk one block or more. The Lower Extremity Functional Scale (LEES) outcome tool revealed that twenty patients (69%) experienced moderate-to-severe difficulties in carrying out activities because of their lower-limb disability. The median Short Form-36 (SF-36) score was 67, with a median physical component score of 61 and a median mental component score of 71, indicating substantial impact on physical health status when compared with the norm. Conclusions: Reconstruction can be a worthwhile endeavor and should be considered for all patients with complex malunion or nonunion of the tibia or femur. C1 [Buijze, Geert A.] Harvard Univ, Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv,Med Sch, Boston, MA 02114 USA. RP Buijze, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv,Med Sch, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM gbuijze@partners.org FU Netherlands Organisation for Scientific Research (NWO) FX In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the Netherlands Organisation for Scientific Research (NWO). Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. NR 30 TC 4 Z9 6 U1 0 U2 1 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD MAR 2 PY 2011 VL 93A IS 5 BP 485 EP 492 DI 10.2106/JBJS.J.00342 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 727UB UT WOS:000287827000010 PM 21368081 ER PT J AU Rask-Madsen, C King, GL AF Rask-Madsen, Christian King, George L. TI Endothelium-Dependent Delivery of Insulin to Muscle Interstitium SO CELL METABOLISM LA English DT Editorial Material ID RESISTANCE; TRANSPORT; CELLS; MICE AB Insulin contributes to skeletal muscle glucose uptake by increasing blood flow and recruiting perfused capillaries. In this issue of Cell Metabolism, Kubota et al. (2011) show that deletion of IRS-2 in endothelial cells in mice causes impaired transcapillary insulin transport, decreased insulin-stimulated glucose uptake in muscle, and mild glucose intolerance. C1 [Rask-Madsen, Christian; King, George L.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. RP King, GL (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM george.king@joslin.harvard.edu FU NEI NIH HHS [K08 EY018677-04, K08 EY018677]; NIDDK NIH HHS [R01 DK053105, R01 DK053105-11] NR 10 TC 7 Z9 7 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD MAR 2 PY 2011 VL 13 IS 3 BP 236 EP 238 DI 10.1016/j.cmet.2011.02.008 PG 3 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 731ZQ UT WOS:000288150200003 PM 21356512 ER PT J AU Michael, I Walton, DS Levenberg, S AF Michael, Inbal Walton, David S. Levenberg, Shulamit TI Infantile Aphakic Glaucoma: A Proposed Etiologic Role of IL-4 and VEGF SO JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS LA English DT Article ID LENS EPITHELIAL-CELLS; TRABECULAR MESHWORK CELLS; ENDOTHELIAL GROWTH-FACTOR; CONGENITAL CATARACT-SURGERY; AQUEOUS-HUMOR; SURVIVAL; EXPRESSION; CYTOKINES; BETA; PROLIFERATION AB Purpose: To identify the factors secreted by lens epithelial cells (LECs) responsible for the altered trabecular meshwork (TM) cells and to compare their effect on monocultured TM cells with that of TM cells co-cultured with LECs. Methods: Such factors were isolated using cytokine antibody array membranes, and their effect on TM cells was assessed by analyzing changes in morphology and gene expression. In addition, inhibition of the isolated factors was performed in the co-culture model by adding specific antibodies to the cell culture media. Results: Transforming growth factor beta-2, interleukin-4 (IL-4), and vascular endothelial growth factor (VEGF) are presented as candidate cytokines responsible for the observed changes in LEC-TM co-cultures. Culturing TM cells in the presence of VEGF and IL-4 triggered alterations closely reflecting those observed in the LEC-TM co-culture model, where their inhibition significantly hindered the alteration of the TM cells. Conclusion: These findings suggest a possible explanation for the development of infantile aphakic glaucoma, based on residual LECs secreting IL-4 and VEGF after removal of congenital cataract, which then alter trabecular meshwork cell morphology and gene expression. [J Pediatr Ophthalmol Strabismus 2011;48:98-107.] C1 [Michael, Inbal; Levenberg, Shulamit] Technion Israel Inst Technol, Fac Biomed Engn, IL-32000 Haifa, Israel. [Walton, David S.] Massachusetts Eye & Ear Infirm, Glaucoma Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Levenberg, S (reprint author), Technion Israel Inst Technol, Fac Biomed Engn, IL-32000 Haifa, Israel. FU Children's Glaucoma Foundation, Boston, Massachusetts FX Supported by The Children's Glaucoma Foundation, Boston, Massachusetts. NR 32 TC 3 Z9 4 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0191-3913 J9 J PEDIAT OPHTH STRAB JI J. Pediatr. Ophthalmol. Strabismus. PD MAR-APR PY 2011 VL 48 IS 2 BP 98 EP 107 DI 10.3928/01913913-20100518-04 PG 10 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 879PM UT WOS:000299343900006 PM 20506964 ER PT J AU Tefferi, A Abdel-Wahab, O Cervantes, F Crispino, JD Finazzi, G Girodon, F Gisslinger, H Gotlib, J Kiladjian, JJ Levine, RL Licht, JD Mullally, A Odenike, O Pardanani, A Silver, RT Solary, E Mughal, T AF Tefferi, A. Abdel-Wahab, O. Cervantes, F. Crispino, J. D. Finazzi, G. Girodon, F. Gisslinger, H. Gotlib, J. Kiladjian, J-J Levine, R. L. Licht, J. D. Mullally, A. Odenike, O. Pardanani, A. Silver, R. T. Solary, E. Mughal, T. TI Mutations with epigenetic effects in myeloproliferative neoplasms and recent progress in treatment: Proceedings from the 5th International Post-ASH Symposium SO BLOOD CANCER JOURNAL LA English DT Article DE myeloproliferative; myelofibrosis; polycythemia; thrombocythemia; mastocytosis ID ACUTE MYELOID-LEUKEMIA; JAK2 46/1 HAPLOTYPE; CHRONIC MYELOMONOCYTIC LEUKEMIA; METHYLTRANSFERASE GENE EZH2; WORLD-HEALTH-ORGANIZATION; TYROSINE KINASE JAK2; POLYCYTHEMIA-VERA; ESSENTIAL THROMBOCYTHEMIA; PRIMARY MYELOFIBROSIS; MYELODYSPLASTIC SYNDROMES AB Immediately following the 2010 annual American Society of Hematology (ASH) meeting, the 5th International Post-ASH Symposium on Chronic Myelogenous Leukemia and BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) took place on 7-8 December 2010 in Orlando, Florida, USA. During this meeting, the most recent advances in laboratory research and clinical practice, including those that were presented at the 2010 ASH meeting, were discussed among recognized authorities in the field. The current paper summarizes the proceedings of this meeting in BCR-ABL1-negative MPN. We provide a detailed overview of new mutations with putative epigenetic effects (TET oncogene family member 2 (TET2), additional sex comb-like 1 (ASXL1), isocitrate dehydrogenase (IDH) and enhancer of zeste homolog 2 (EZH2)) and an update on treatment with Janus kinase (JAK) inhibitors, pomalidomide, everolimus, interferon-alpha, midostaurin and cladribine. In addition, the new 'Dynamic International Prognostic Scoring System (DIPSS)-plus' prognostic model for primary myelofibrosis (PMF) and the clinical relevance of distinguishing essential thrombocythemia from prefibrotic PMF are discussed. Blood Cancer Journal (2011) 1, e7; doi:10.1038/bcj.2011.4; published online 4 March 2011 C1 [Tefferi, A.; Pardanani, A.] Mayo Clin, Dept Med, Div Hematol, Rochester, MN 55905 USA. [Abdel-Wahab, O.; Levine, R. L.] Mem Sloan Kettering Canc Ctr, Dept Med, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Abdel-Wahab, O.; Levine, R. L.] Mem Sloan Kettering Canc Ctr, Leukemia Serv, New York, NY 10021 USA. [Cervantes, F.] Univ Barcelona, Dept Hematol, Hosp Clin, Inst Invest Biomed August Pi & Sunyer, Barcelona, Spain. [Crispino, J. D.; Licht, J. D.] Northwestern Univ, Dept Hematol, Chicago, IL 60611 USA. [Finazzi, G.] Osped Riuniti Bergamo, Dept Hematol, I-24100 Bergamo, Italy. [Girodon, F.] Hop Bocage, Hematol Lab, Dijon, France. [Gisslinger, H.] Med Univ Vienna, Dept Internal Med 1, Div Hematol & Blood Coagulat, Vienna, Austria. [Gotlib, J.] Stanford Univ, Sch Med, Div Hematol, Stanford, CA 94305 USA. [Kiladjian, J-J] Univ Paris 07, Hop St Louis, AP HP, Ctr Invest Clin 9504, Paris, France. [Mullally, A.] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Div Hematol,Dept Med,Med Sch, Boston, MA 02115 USA. [Odenike, O.] Univ Chicago, Sect Hematol & Oncol, Chicago, IL 60637 USA. [Silver, R. T.] Cornell Univ, Div Hematol & Med Oncol, Dept Med, Weill Med Coll, New York, NY 10021 USA. [Solary, E.] Univ Paris 11, Inst Gustave Roussy, INSERM, U1009, Villejuif, France. [Mughal, T.] Guys Hosp, Sch Med, Dept Haematol, London SE1 9RT, England. RP Tefferi, A (reprint author), Mayo Clin, Dept Med, Div Hematol, 200 1st St SW, Rochester, MN 55905 USA. EM tefferi.ayalew@mayo.edu OI Abdel-Wahab, Omar/0000-0002-3907-6171; Kiladjian, Jean-Jacques/0000-0002-8121-438X; Crispino, John/0000-0002-8182-8306 NR 147 TC 4 Z9 4 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2044-5385 J9 BLOOD CANCER J JI Blood Cancer J. PD MAR PY 2011 VL 1 AR e7 DI 10.1038/bcj.2011.4 PG 10 WC Oncology SC Oncology GA 872NC UT WOS:000298815400001 PM 23471017 ER PT J AU Harris, RD Marks, WM AF Harris, Robert D. Marks, William M. TI Donation and Training of Medical Personnel in Compact Ultrasound in Low-Resource Settings How We Do It SO ULTRASOUND QUARTERLY LA English DT Article DE compact ultrasound; portable ultrasound; obstetric ultrasound screening; low-resource settings; ultrasound training; perinatal mortality; maternal morbidity and mortality; rural clinics AB The authors offer a concise summary of dos and don'ts for the radiologist/sonologist wishing to expand his horizons and join those physicians donating ultrasound equipment and training medical personnel in low-resource countries. Topics include choosing a site, obtaining ultrasound equipment, preparing to travel, and starting a training program. The most important points to keep in mind are: (1) be prepared for any circumstance; (2) do your homework ahead of time; (3) make sure there is a local group "on the ground" that can ensure the machine's sustainability; and (4) allow for much more time to get things accomplished than in the developed world. C1 [Harris, Robert D.] Dartmouth Hitchcock Med Ctr, Dartmouth Med Sch, Dept Radiol, Lebanon, NH 03756 USA. [Harris, Robert D.] Dartmouth Hitchcock Med Ctr, Dartmouth Med Sch, Dept OB GYN, Lebanon, NH 03756 USA. [Marks, William M.] Massachusetts Gen Hosp, Div Global Hlth & Human Right, Boston, MA 02114 USA. [Marks, William M.] Radia Imaging Inc, Swedish Med Ctr, Seattle, WA USA. RP Harris, RD (reprint author), Dartmouth Hitchcock Med Ctr, Dartmouth Med Sch, Dept Radiol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM Robert.D.Harris@hitchcock.org NR 4 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-8771 J9 ULTRASOUND Q JI Ultrasound Q. PD MAR PY 2011 VL 27 IS 1 BP 3 EP 6 DI 10.1097/RUQ.0b013e31820e1598 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 854XD UT WOS:000297527200002 PM 21343798 ER PT J AU Manchikanti, L Giordano, J Fellows, B Hirsch, JA AF Manchikanti, Laxmaiah Giordano, James Fellows, Bert Hirsch, Joshua A. TI Placebo and Nocebo in Interventional Pain Management: A Friend or a Foe - Or Simply Foes? SO PAIN PHYSICIAN LA English DT Review DE Placebo; placebo analgesia; placebo treatment; placebo effect; nocebo; nocebo hyperalgesia; psychophysiological mediators; neurobiological mediators; inert agent ID LOW-BACK-PAIN; EVIDENCE-BASED MEDICINE; CAUDAL EPIDURAL INJECTIONS; LUMBAR SURGERY SYNDROME; MEDIAL BRANCH BLOCKS; CLINICAL-PRACTICE GUIDELINE; FACET JOINT INTERVENTIONS; TRIALS COMPARING PLACEBO; IRRITABLE-BOWEL-SYNDROME; ACTIVE CONTROLLED-TRIAL AB The present evidence illustrates that the placebo effect depends on a variety of neurochemical and neurophysiological mechanisms, which are measurable and modifiable. However, the placebo response is inexorably tied to the treatment context. All medical treatments take place in a particular context; this context includes the therapist's attitudes, psychosocial factors affecting the therapeutic relationship, and the patient's mindset. Therapeutic efficacy at least in part is attributable to the concordance between the proposed treatment and the patient's belief system. It is this fraction of the therapeutic response that is commonly called the placebo effect. More formally, the placebo effect is defined as that part of the therapeutic response that is not attributable to the properties of active ingredients. A proposed model of the placebo effect includes a complex reaction with induction, psychophysiological mediators, neurobiological mediators, and actualization of effects. Similarly, nocebo hyperalgesia is also explained by neurobiological mechanisms resulting in anxiety and nocebo hyperalgesia. Functional neuroanatomy of placebo indicates an anticipation phase and modulation phase or placebo response. In modern medicine it is well recognized that the treatment effect of many active interventions is related to both an active treatment component and the placebo component. Thus, clinical implications are enormous as such placebo analgesia and nocebo hyperalgesia are not simply response biases. Instead, they are the product of neurophysiological processes that modulate the integration of the nociceptive signals throughout the central nervous system. Thus, it has been suggested that clinicians should not try to avoid the placebo effect. On the contrary, they should try to potentiate it, since this is a very important clinical implication. From the research perspective, the emerging knowledge of placebo continues to cast doubts on the appropriateness of the double-blind placebo-control design in assessing efficacy of treatment - specifically involving interventional techniques or surgery. The research setting itself may introduce nocebo hyperalgesia. C1 [Manchikanti, Laxmaiah; Fellows, Bert] Pain Management Ctr Paducah, Paducah, KY USA. [Giordano, James] Potomac Inst Policy Studies, Ctr Neurotechnol Studies, Arlington, VA USA. [Giordano, James] Univ Oxford, Wellcome Ctr Neuroeth, Oxford, England. [Hirsch, Joshua A.] Massachusetts Gen Hosp, 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 192 TC 55 Z9 57 U1 3 U2 17 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 MAR-APR PY 2011 VL 14 IS 2 BP E157 EP E175 PG 19 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 857IV UT WOS:000297712700005 PM 21412379 ER PT J AU Boehmer, A Pfafferott, K Humphreys, IS Lucas, M Swadling, L Lauer, GM Gaudieri, S Klenerman, P Barnes, E AF Boehmer, A. Pfafferott, K. Humphreys, I. S. Lucas, M. Swadling, L. Lauer, G. M. Gaudieri, S. Klenerman, P. Barnes, E. TI MULTIPLE NOVEL PEPTIDE EPITOPES IN HCV GENOTYPE-3A IDENTIFIED USING TWO PARALLEL APPROACHES SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 46th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL) CY 2011 CL Berlin, GERMANY SP European Assoc Study Liver (EASL) C1 [Boehmer, A.; Humphreys, I. S.; Swadling, L.; Klenerman, P.; Barnes, E.] Univ Oxford, Nuffield Dept Clin Med, Oxford, England. [Pfafferott, K.; Lucas, M.; Gaudieri, S.] Royal Perth Hosp, Ctr Clin Immunol & Biomed Stat, Perth, WA, Australia. [Pfafferott, K.; Lucas, M.; Gaudieri, S.] Murdoch Univ, Perth, WA, Australia. [Lauer, G. M.] Massachusetts Gen Hosp, GI Unit, Boston, MA 02114 USA. [Lauer, G. M.] Harvard Univ, Sch Med, Boston, MA USA. [Gaudieri, S.] Univ Western Australia, Sch Anat & Human Biol, Perth, WA 6009, Australia. [Gaudieri, S.] Univ Western Australia, Ctr Forens Sci, Perth, WA 6009, Australia. [Klenerman, P.; Barnes, E.] Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England. EM annette.boehmer@chch.ox.ac.uk NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2011 VL 54 SU 1 MA 276 BP S113 EP S113 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 856GC UT WOS:000297625600277 ER PT J AU Corradini, E Meynard, D Montosi, G Garuti, C Wu, Q Ventura, P Babitt, JL Lin, HY Pietrangelo, A AF Corradini, E. Meynard, D. Montosi, G. Garuti, C. Wu, Q. Ventura, P. Babitt, J. L. Lin, H. Y. Pietrangelo, A. TI THE MOLECULAR BASIS FOR THE HEPATIC REGULATION OF HEPCIDIN, THE IRON HORMONE, BY BONE MORPHOGENETIC PROTEINS SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 46th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL) CY 2011 CL Berlin, GERMANY SP European Assoc Study Liver (EASL) C1 [Corradini, E.; Montosi, G.; Garuti, C.; Ventura, P.; Pietrangelo, A.] Univ Modena & Reggio Emilia, Dept Internal Med, Ctr Hemochromatosis, Modena, Italy. [Meynard, D.; Wu, Q.; Babitt, J. L.; Lin, H. Y.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol,Div Nephrol,Program Membrane Biol, Boston, MA USA. EM elena.corradini75@unimore.it RI meynard, delphine/B-4236-2014; Corradini, Elena/O-4167-2016; Pietrangelo, Antonello/K-1517-2016 OI Corradini, Elena/0000-0001-9477-2164; Pietrangelo, Antonello/0000-0002-7411-935X NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2011 VL 54 SU 1 MA 92 BP S41 EP S41 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 856GC UT WOS:000297625600093 ER PT J AU Hu, W Nevzorova, YA Nowak, JR Haas, U Moro, N Geng, Y Sicinski, P Barbacid, M Trautwein, C Liedtke, C AF Hu, W. Nevzorova, Y. A. Nowak, J. R. Haas, U. Moro, N. Geng, Y. Sicinski, P. Barbacid, M. Trautwein, C. Liedtke, C. TI CYCLIN E1 AND D1 CAN DRIVE LIVER REGENERATION IN MICE WITHOUT CDK2 SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 46th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL) CY 2011 CL Berlin, GERMANY SP European Assoc Study Liver (EASL) C1 [Hu, W.; Nevzorova, Y. A.; Nowak, J. R.; Haas, U.; Moro, N.; Trautwein, C.; Liedtke, C.] Rhein Westfal TH Aachen, Univ Hosp Aachen, Dept Med 3, Aachen, Germany. [Geng, Y.; Sicinski, P.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Barbacid, M.] CNIO, Madrid, Spain. EM whu@ukaachen.de NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2011 VL 54 SU 1 MA 1084 BP S428 EP S428 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 856GC UT WOS:000297625602223 ER PT J AU Kuntzen, T Neumann-Haefelin, C Lennon, N Talal, AH Carlson, J Brumme, C Timm, J Schmidt, J Wunsch, K Berical, A Berlin, AM Adams, S Young, SK Reyor, LL Kleyman, M McMahon, CM Birch, C zur Wiesch, JS Ledlie, T Michael, K Kodira, C Roberts, AD Schneidewind, A Lauer, GM Kim, AY Rosen, HR Bihl, F Cerny, A Spengler, U Brander, C Galagan, JE Nusbaum, C Walker, BD Lake-Bakaar, GV Daar, ES Jacobson, IM Gomperts, ED Edlin, BR Donfield, SM Chung, RT Marion, T Birren, BW Marincola, F Thimme, R Carrington, M Heckerman, D Henn, MR Allen, TM AF Kuntzen, T. Neumann-Haefelin, C. Lennon, N. Talal, A. H. Carlson, J. Brumme, C. Timm, J. Schmidt, J. Wunsch, K. Berical, A. Berlin, A. M. Adams, S. Young, S. K. Reyor, L. L. Kleyman, M. McMahon, C. M. Birch, C. zur Wiesch, J. Schulze Ledlie, T. Michael, K. Kodira, C. Roberts, A. D. Schneidewind, A. Lauer, G. M. Kim, A. Y. Rosen, H. R. Bihl, F. Cerny, A. Spengler, U. Brander, C. Galagan, J. E. Nusbaum, C. Walker, B. D. Lake-Bakaar, G. V. Daar, E. S. Jacobson, I. M. Gomperts, E. D. Edlin, B. R. Donfield, S. M. Chung, R. T. Marion, T. Birren, B. W. Marincola, F. Thimme, R. Carrington, M. Heckerman, D. Henn, M. R. Allen, T. M. TI POPULATIONAL ANALYSIS REVEALS A LINK BETWEEN COMPLEX VIRAL ESCAPE FROM CD8+T-CELL RESPONSES AND PROTECTION IN HCV INFECTION SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 46th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL) CY 2011 CL Berlin, GERMANY SP European Assoc Study Liver (EASL) C1 [Kuntzen, T.; Berical, A.; Reyor, L. L.; Kleyman, M.; McMahon, C. M.; Birch, C.; Schneidewind, A.; Lauer, G. M.; Kim, A. Y.; Walker, B. D.; Carrington, M.; Allen, T. M.] Ragon Inst MGH MIT & Harvard, Boston, MA USA. [Kuntzen, T.] Univ Zurich Hosp, Dept Gastroenterol & Hepatol, CH-8091 Zurich, Switzerland. [Neumann-Haefelin, C.; Schmidt, J.; Wunsch, K.; Thimme, R.] Univ Freiburg, Freiburg, Germany. [Lennon, N.; Berlin, A. M.; Young, S. K.; Michael, K.; Kodira, C.; Roberts, A. D.; Nusbaum, C.; Birren, B. W.; Henn, M. R.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Talal, A. H.; Lake-Bakaar, G. V.; Jacobson, I. M.; Edlin, B. R.] Weill Cornell Med Coll, New York, NY USA. [Carlson, J.; Heckerman, D.] Microsoft Res, Redmond, WA USA. [Brumme, C.] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada. [Timm, J.; Ledlie, T.] Univ Essen Gesamthsch, Essen, Germany. [Adams, S.; Marincola, F.] NIH, Bethesda, MD 20892 USA. [zur Wiesch, J. Schulze] Univ Hamburg Eppendorf, Hamburg, Germany. [Rosen, H. R.] Univ Cologne, Denver, CO USA. [Bihl, F.] Univ Geneva, Geneva, Switzerland. [Cerny, A.] Clin Moncucco, Lugano, Switzerland. [Spengler, U.] Univ Bonn, D-5300 Bonn, Germany. [Brander, C.] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain. [Daar, E. S.] Univ Calif Los Angeles, Los Angeles, CA USA. [Gomperts, E. D.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Donfield, S. M.] Rho Inc, Chapel Hill, NC USA. [Chung, R. T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Marion, T.] Univ Tennessee, Memphis, TN USA. EM christoph.neumann-haefelin@uniklinik-freiburg.de RI Neumann-Haefelin, Christoph/E-5550-2011 NR 0 TC 0 Z9 0 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2011 VL 54 SU 1 MA 3 BP S2 EP S2 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 856GC UT WOS:000297625600004 ER PT J AU O'Brien, TR Morgan, TR Pfeiffer, RM Chung, RT Lok, AS Shiffman, ML Dotrang, M Sninsky, JJ Bonkovsky, HL AF O'Brien, T. R. Morgan, T. R. Pfeiffer, R. M. Chung, R. T. Lok, A. S. Shiffman, M. L. Dotrang, M. Sninsky, J. J. Bonkovsky, H. L. CA HALT-C Trial Grp TI IL28B GENETIC ATTRIBUTABLE RISK IN HEPATITIS C-ASSOCIATED HEPATOCELLULAR CARCINOMA AND DECOMPENSATED LIVER DISEASE SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 46th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL) CY 2011 CL Berlin, GERMANY SP European Assoc Study Liver (EASL) C1 [O'Brien, T. R.; Pfeiffer, R. M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Morgan, T. R.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Morgan, T. R.] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA. [Chung, R. T.] Massachusetts Gen Hosp, Med Serv, Gastrointestinal Unit, Boston, MA 02114 USA. [Chung, R. T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Lok, A. S.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Shiffman, M. L.] Bon Secours Hlth Syst, Liver Inst Virginia, Newport News, VA USA. [Dotrang, M.] CSC, Rockville, MD USA. [Sninsky, J. J.] Celera Corp, Alameda, CA USA. [Bonkovsky, H. L.] Univ Connecticut, Dept Med, Ctr Hlth, Farmington, CT 06032 USA. [Bonkovsky, H. L.] Univ Connecticut, Ctr Hlth, Dept Mol & Struct Biol, Farmington, CT USA. [Bonkovsky, H. L.] Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT USA. [Bonkovsky, H. L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. EM timothy.morgan@va.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2011 VL 54 SU 1 MA 1336 BP S527 EP S528 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 856GC UT WOS:000297625603020 ER PT J AU Rodriguez-Torres, M Bacon, B Gordon, S Rubin, R Box, T Kugelmas, M Vierling, J Yoffe, B Pockros, P Everson, G Jonas, M Balart, L Bohm, O Castelloe, E Huyghe, MR Mento, S Spada, A Fox, AW Chojkier, M AF Rodriguez-Torres, M. Bacon, B. Gordon, S. Rubin, R. Box, T. Kugelmas, M. Vierling, J. Yoffe, B. Pockros, P. Everson, G. Jonas, M. Balart, L. Bohm, O. Castelloe, E. Huyghe, M. R. Mento, S. Spada, A. Fox, A. W. Chojkier, M. TI UNIQUE PATTERN OF VIROLOGIC RESPONSE IN PATIENTS WITH GENOTYPE-1 HCV: A PHASE II STUDY OF CTS-1027 IN COMBINATION WITH PEGINTERFERON/RIBAVIRIN (SOC) IN NULL RESPONDERS SO JOURNAL OF HEPATOLOGY LA English DT Meeting Abstract CT 46th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL) CY 2011 CL Berlin, GERMANY SP European Assoc Study Liver (EASL) C1 [Rodriguez-Torres, M.] Fdn Invest Diego, San Juan, PR USA. [Bacon, B.] St Louis Univ, St Louis, MO 63103 USA. [Gordon, S.] Henry Ford Hosp, Detroit, MI 48202 USA. [Rubin, R.] Liver Ctr Atlanta, Atlanta, GA USA. [Box, T.] Univ Utah, Salt Lake City, UT USA. [Kugelmas, M.] S Denver Gastroenterol, Denver, CO USA. [Vierling, J.] Baylor Coll Med, Houston, TX 77030 USA. [Yoffe, B.] VA Med Ctr, Houston, TX USA. [Pockros, P.] Scripps Clin, La Jolla, CA USA. [Everson, G.] Univ Colorado, Aurora, CO USA. [Jonas, M.] Consultants Clin Res, Cincinnati, OH USA. [Balart, L.] Tulane Univ Hlth Serv, New Orleans, LA USA. [Bohm, O.] FGK Clin Res, Munich, Germany. [Fox, A. W.] EBD Grp, Carlsbad, CA USA. [Castelloe, E.; Huyghe, M. R.; Mento, S.; Spada, A.] Conatus Pharmaceut, San Diego, CA USA. [Chojkier, M.] Univ Calif San Diego, San Diego, CA 92103 USA. EM rodztorres@coqui.net NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAR PY 2011 VL 54 SU 1 MA 468 BP S191 EP S191 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 856GC UT WOS:000297625601048 ER PT J AU Unal-Cevik, I Oaklander, AL AF Unal-Cevik, Isin Oaklander, Anne Louise TI Comparing Partial and Total Tibial-Nerve Axotomy: Long-Term Effects on Prevalence and Location of Evoked Pain Behaviors SO PAIN PRACTICE LA English DT Article DE rat; preclinical pain model; human; complex regional pain syndrome; neuropathic pain; diagnostic criteria; hyperalgesia; tibial neuropathy; partial tibial axotomy ID NEUROPATHIC PAIN; SCIATIC-NERVE; DORSAL-HORN; SPINAL-CORD; PERIPHERAL MONONEUROPATHY; POSTHERPETIC NEURALGIA; ADULT-RAT; INJURY; MODEL; SKIN AB Monophasic (one-time) nerve injuries heal without clinically significant residua in most cases, but rare individuals are left with neuropathic pain, even after seemingly minor lesions. The effects of lesion size on risk for chronic pain persistence are not well understood, particularly as concerns the complex regional pain syndrome, which is defined in part by pain "disproportionate" to the severity of the causative lesion, and extending outside the autonomous territory of a single nerve. To better clarify the expected prevalence of pain behaviors after nerve injury, we compared the effects in rats of different-sized axotomies on the prevalence and location of evoked pain behaviors. To highlight clinical relevance, we also describe a patient with iatrogenic tibial-nerve injury causing similar chronic neuralgia. Adult male Sprague-Dawley rats were anesthetized and had either 1/3, 2/3 or their entire left tibial nerves tightly ligated at two sites just below the sciatic trifurcation and the interposed nerve was cut. Unoperated rats provided controls. Sensory function in the tibial and sural-innervated territories of both plantar hindpaws was assessed for as long as 6 months post-operatively. Soon after surgery, evoked pain behavior developed in the ipsilesional sural-innervated site in a subset of axotomized rats and recovery was variable. The relationship between lesion size and prevalence and severity of hyperalgesia varied for different pain behaviors, with pinprick hyperalgesia clearly more likely after larger axotomies. In summary, partial tibial-nerve injury in rats models human disease and suggests that expectations of proportionality between lesion size and development of neuropathic pain may need revision. C1 Harvard Univ, Sch Med, Dept Neurol, Nerve Injury Unit,Massachusetts Gen Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Nerve Injury Unit,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Unal-Cevik, I (reprint author), Ufuk Univ, Dept Neurol, Fac Med, TR-06520 Ankara, Turkey. EM isin.unalcevik@gmail.com FU Reflex Sympathetic Dystrophy Association; National Organization for Rare Disorders; Public Health Service [R01NS42866, K24NS059892] FX This study is supported in part by the Reflex Sympathetic Dystrophy Association, the National Organization for Rare Disorders, the Public Health Service (R01NS42866, K24NS059892). It was presented in abstract form to the Society for Neuroscience. The technical assistance of Ralph Gott, MA, and the statistical assistance of E. Burcu Mamak-Ekinci, MS, are greatly appreciated. NR 32 TC 1 Z9 1 U1 0 U2 1 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1530-7085 J9 PAIN PRACT JI Pain Pract. PD MAR-APR PY 2011 VL 11 IS 2 BP 109 EP 119 DI 10.1111/j.1533-2500.2010.00429.x PG 11 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 840UD UT WOS:000296465900002 PM 21199309 ER PT J AU Mohamad, T Bernal, JM Kondur, A Hari, P Nelson, K Niraj, A Badheka, A Hassna, S Kiernan, T Elder, MD Gardi, D Schreiber, T AF Mohamad, Tamam Bernal, Juan M. Kondur, Ashok Hari, Pawan Nelson, Katrina Niraj, Ashutosh Badheka, Apurva Hassna, Samer Kiernan, Tom Elder, Mahir D. Gardi, Delair Schreiber, Theodore TI Coronary Revascularization Strategy for ST Elevation Myocardial Infarction with Multivessel Disease: Experience and Results at 1-Year Follow-Up SO AMERICAN JOURNAL OF THERAPEUTICS LA English DT Article DE ST elevation myocardial infarction (STEMI); coronary revascularization; culprit lesions; nonculprit (non-CL) lesions ID ISCHEMIC-HEART-DISEASE; ARTERY-DISEASE; UNSTABLE ANGINA; CARDIOGENIC-SHOCK; INVASIVE THERAPY; CULPRIT LESION; ANGIOPLASTY; VESSEL; INTERVENTION; REGISTRY AB Primary percutaneous coronary intervention (PCI) of culprit lesions (CLs) is the standard of care in patients presenting with ST elevation myocardial infarction (STEMI). However, optimal revascularization strategy for significant nonculprit lesions (non-CLs) in the setting of STEMI remains controversial. The importance of defining of such a strategy lies in the fact that approximately 50% of patients with STEMI have multivessel disease (MVD). The aim of this study was to describe characteristics, therapeutic strategies, and 1-year outcomes in a cohort of patients with STEMI and MVD. We retrospectively analyzed a cohort of 63 patients with STEMI and MVD obtained from a 5-year catheterization database. MVD was defined as >= 70% stenosis of >= 2 epicardial coronary arteries. This cohort was followed for a period of 1 year for major adverse cardiac events (MACE was defined as acute coronary syndrome, new onset heart failure, or death) and all-cause mortality. PCI with stent placement was the major therapeutic procedure (87.5%) performed for CLs. Non-CLs did not undergo interventions in a majority of individuals (47.6%), while the remaining patients underwent PCI (29%) and coronary artery bypass graft surgery (22%) for non-CLs. At 1-year follow-up, prevalence of MACE events and death in the entire cohort were 30% and 15%, respectively. A trend for better outcomes (1-year cumulative MACE events but not mortality) was observed in CL-only intervention cohort compared with non-CL intervention. The PCI and Coronary artery bypass graft surgery cohorts did not show any significant difference in clinical outcomes. In this retrospective cohort of patients with MVD who presented with STEMI, no intervention of noncritical lesions was the prevalent approach, reflecting guideline recommendations. CL-only intervention strategy showed a better clinical outcome than non-CL intervention. Intervention of noncritical lesions therefore did not seem to improve MACEs or all-cause mortality at 1-year of follow-up and might in fact have had a detrimental effect on outcomes. C1 [Mohamad, Tamam; Kondur, Ashok; Hari, Pawan; Nelson, Katrina; Niraj, Ashutosh; Badheka, Apurva; Hassna, Samer; Elder, Mahir D.; Gardi, Delair; Schreiber, Theodore] Wayne State Univ, Detroit, MI 48201 USA. [Bernal, Juan M.; Kiernan, Tom] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Mohamad, T (reprint author), Wayne State Univ, Div Cardiol, Harper Univ Hosp, 8 Brush,3990 John R, Detroit, MI 48201 USA. EM tamamns@yahoo.com OI Hari, Pawan/0000-0003-1579-8476 NR 42 TC 17 Z9 19 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1075-2765 J9 AM J THER JI Am. J. Ther. PD MAR-APR PY 2011 VL 18 IS 2 BP 92 EP 100 DI 10.1097/MJT.0b013e3181b809ee PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 733CP UT WOS:000288238300006 PM 20027110 ER PT J AU Conrad, C Husemann, Y Niess, H von Luettichau, I Huss, R Bauer, C Jauch, KW Klein, CA Bruns, C Nelson, PJ AF Conrad, Claudius Huesemann, Yves Niess, Hanno von Luettichau, Irene Huss, Ralf Bauer, Christian Jauch, Karl-Walter Klein, Christoph A. Bruns, Christiane Nelson, Peter J. TI Linking Transgene Expression of Engineered Mesenchymal Stem Cells and Angiopoietin-1-induced Differentiation to Target Cancer Angiogenesis SO ANNALS OF SURGERY LA English DT Article ID TUMOR ANGIOGENESIS; PERIPHERAL-BLOOD; GENE; THERAPY; DELIVERY; VECTORS; PROGENITORS; TISSUE; GLIOMA; NICHE AB Objective: To specifically target tumor angiogenesis by linking transgene expression of engineered mesenchymal stem cells to angiopoietin-1-induced differentiation. Background: Mesenchymal stem cells (MSCs) have been used to deliver therapeutic genes into solid tumors. These strategies rely on their homing mechanisms only to deliver the therapeutic agent. Methods: We engineered murine MSC to express reporter genes or therapeutic genes under the selective control of the Tie2 promoter/enhancer. This approach uses the differentiative potential of MSCs induced by the tumor microenvironment to drive therapeutic gene expression only in the context of angiogenesis. Results: When injected into the peripheral circulation of mice with either, orthotopic pancreatic or spontaneous breast cancer, the engineered MSCs were actively recruited to growing tumor vasculature and induced the selective expression of either reporter red florescent protein or suicide genes [herpes simplex virus-thymidine kinase (TK) gene] when the adoptively transferred MSC developed endothelial-like characteristics. The TK gene product in combination with the prodrug ganciclovir (GCV) produces a potent toxin, which affects replicative cells. The homing of engineered MSC with selective induction of TK in concert with GCV resulted in a toxic tumor-specific environment. The efficacy of this approach was demonstrated by significant reduction in primary tumor growth and prolongation of life in both tumor models. Conclusion: This "Trojan Horse" combined stem cell/gene therapy represents a novel treatment strategy for tailored therapy of solid tumors. C1 [Conrad, Claudius] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Conrad, Claudius] Massachusetts Gen Hosp, Harvard Stem Cell Inst, Boston, MA 02114 USA. [Huesemann, Yves; Klein, Christoph A.] Univ Regensburg, Chair Expt Med, Dept Pathol, D-8400 Regensburg, Germany. [Niess, Hanno; Jauch, Karl-Walter; Bruns, Christiane] Univ Munich, Dept Surg, Munich, Germany. [von Luettichau, Irene] Tech Univ Munich, Dept Pediat, D-8000 Munich, Germany. [von Luettichau, Irene] Tech Univ Munich, Pediat Oncol Ctr, D-8000 Munich, Germany. [Huss, Ralf] Univ Munich, Inst Pathol, D-8000 Munich, Germany. [Bauer, Christian] Univ Munich, Med Klin Innenstadt, Gastroenterol Sect, D-8000 Munich, Germany. [Nelson, Peter J.] Univ Munich, Med Policlin, Clin Biochem Grp, D-8000 Munich, Germany. RP Conrad, C (reprint author), Harvard Univ, Sch Med, Dept Surg, 55 Fruit St,GRB 425, Boston, MA 02114 USA. EM CConrad1@partners.org FU Deutsche Forschungsgemeinschaft [SFB 571 C2, SFB-TR36/B6, SPP1190]; Sander Stiftung FX Supported by grants from the Deutsche Forschungsgemeinschaft (SFB 571 C2 and SFB-TR36/B6 to PJN, and SPP1190 to CAK, CB, and PJN). This work has been supported by a grant from Sander Stiftung. NR 35 TC 17 Z9 19 U1 3 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD MAR PY 2011 VL 253 IS 3 BP 566 EP 571 DI 10.1097/SLA.0b013e3181fcb5d8 PG 6 WC Surgery SC Surgery GA 719VF UT WOS:000287238900019 PM 21169810 ER PT J AU Raval, MV Hamilton, BH Ingraham, AM Ko, CY Hall, BL AF Raval, Mehul V. Hamilton, Barton H. Ingraham, Angela M. Ko, Clifford Y. Hall, Bruce L. TI The Importance of Assessing Both Inpatient and Outpatient Surgical Quality SO ANNALS OF SURGERY LA English DT Article ID IMPROVEMENT PROGRAM; RISK ADJUSTMENT; PATIENT SAFETY; AMERICAN-COLLEGE; SURGERY; CARE; MORTALITY; HOSPITALS; MORBIDITY; CENTERS AB Objective: We aimed to determine whether hospital-level surgical performance was similar across outpatient and inpatient settings. Background: The majority of surgical procedures in the United States are performed in an outpatient setting but most quality improvement focuses on inpatient care. Methods: Using data from the 2006 to 2008 American College of Surgeons-National Surgical Quality Improvement Program, risk-adjusted hospital observed to expected ratios for morbidity and mortality were compared for inpatient and outpatient cases. In addition, hospital outpatient performance in each year was compared with performances in subsequent years. Results: Hospitals demonstrated variation in outcomes for outpatient morbidity with both good and poor outliers in each year. Outpatient mortality was so rare as to not support robust modeling. There was a lack of congruence between hospital performance for outpatient morbidity and either inpatient morbidity or inpatient mortality in each year, indicating that inpatient performance is not interchangeable with outpatient performance. Outpatient morbidity performance correlation between years was only moderate (correlations 0.449-0.534, all P < 0.001) indicating that although outcomes from 1 year mildly predict subsequent years, substitution of data would likely lead to missed opportunities for improvement. Conclusions: Assessments of risk-adjusted hospital-level outpatient morbidity performance demonstrate (1) variability across American College of Surgeons-National Surgical Quality Improvement Program sites; (2) a lack of congruence between outpatient morbidity performance and either inpatient morbidity or mortality performance; (3) year-to-year variation of outpatient morbidity performance at individual institutions. Continuing evaluation of both outpatient and inpatient outcomes is supported. Given the substantial volume of outpatient care delivered, outpatient assessments are likely to be an important component of ongoing quality improvement efforts. C1 [Raval, Mehul V.; Ingraham, Angela M.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL 60611 USA. [Raval, Mehul V.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. [Hamilton, Barton H.; Hall, Bruce L.] Washington Univ, John M Olin Sch Business, St Louis, MO 63130 USA. [Ingraham, Angela M.] Univ Cincinnati, Coll Med, Dept Surg, Cincinnati, OH 45267 USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Hall, Bruce L.] Washington Univ, Dept Surg, John Cochran Vet Affairs Med Ctr, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. RP Raval, MV (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, 633 N St Clair,22nd Floor, Chicago, IL 60611 USA. EM mraval@facs.org RI Hamilton, Barton/P-5187-2015; OI Raval, Mehul/0000-0002-1527-2661 FU John Gray Research Fellowship; Daniel F. and Ada L. Rice Foundation; Health Policy FX M.V.R is supported by the John Gray Research Fellowship and the Daniel F. and Ada L. Rice Foundation. B. L. H was supported by the Center for Health Policy, under the direction of Dr. William Peck, Washington University in St. Louis, St. Louis, MO. NR 37 TC 30 Z9 30 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD MAR PY 2011 VL 253 IS 3 BP 611 EP 618 DI 10.1097/SLA.0b013e318208fd50 PG 8 WC Surgery SC Surgery GA 719VF UT WOS:000287238900026 PM 21183845 ER PT J AU Kim, SJ Giugliano, RP Jang, IK AF Kim, Soo-Joong Giugliano, Robert P. Jang, Ik-Kyung TI Adjunctive pharmacologic therapy in percutaneous coronary intervention: Part I antiplatelet therapy SO CORONARY ARTERY DISEASE LA English DT Article DE angioplasty; anticoagulant; antiplatelet therapy; antithrombotic therapy; platelet; thrombin ID PLATELET GLYCOPROTEIN-IIB/IIIA; ELEVATION MYOCARDIAL-INFARCTION; PLACEBO-CONTROLLED TRIAL; RANDOMIZED-TRIAL; UNSTABLE ANGINA; DOUBLE-BLIND; CLOPIDOGREL PRETREATMENT; CARDIOVASCULAR-DISEASE; ASPIRIN RESISTANCE; PRASUGREL CS-747 AB Ischemic heart disease is a major cause of morbidity and mortality throughout the world. Percutaneous coronary intervention (PCI) has rapidly evolved from balloon angioplasty to drug-eluting stents over the past 25 years and has become an important treatment option for coronary heart disease. During PCI, atherosclerotic plaque disruption and the endothelium denudation stimulate both platelet aggregation and the thrombus generation. Therefore, pharmacological adjuvant therapies to protect the procedure-related thrombotic complication during PCI are indispensable. In addition to aspirin, whose benefit has been clearly shown in ischemic heart disease, clopidogrel and prasugrel have shown to dramatically reduce the rate of thrombosis after stent placement. The introduction of glycoprotein IIb/IIIa inhibitors has further improved the results of PCI especially in high-risk patients. In addition, several new drugs with antiplatelet or with antithrombin activities are currently under development. Coron Artery Dis 22:100-112 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Jang, Ik-Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. [Kim, Soo-Joong] Kyung Hee Univ, Coll Med, Dept Cardiol, Seoul, South Korea. [Giugliano, Robert P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02114 USA. RP Jang, IK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. EM ijang@partners.org NR 58 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0954-6928 EI 1473-5830 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD MAR PY 2011 VL 22 IS 2 BP 100 EP 112 DI 10.1097/MCA.0b013e32833729e3 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 719GD UT WOS:000287188700010 PM 20926950 ER PT J AU Schwab, P Scalapino, K AF Schwab, Pascale Scalapino, Kenneth TI Exercise for bone health: rationale and prescription SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review DE bone mass; exercise; mechano-transduction; osteocyte; osteoporosis ID RANDOMIZED CONTROLLED-TRIALS; QUALITY-OF-LIFE; MECHANICAL SIGNALS; HIGH-FREQUENCY; OSTEOPOROTIC FRACTURES; PHYSICAL-ACTIVITY; MUSCLE-ACTIVITY; RISK-FACTORS; IN-VIVO; STRENGTH AB Purpose of review Patients frequently inquire about exercise as a means to improve bone strength and reduce osteoporotic fracture. Understanding the biologic mechanisms and the available clinical evidence supporting the role of exercise in bone health is the key to an educated discussion. Recent findings Exercise downregulates sclerostin expression by the osteocyte favoring osteoblastogenesis. These changes are enhanced by dynamic cyclical load with rest periods and may be promoted by low-amplitude high-frequency stimuli. In the prepubertal years, exercise results in periosteal gains, whereas exercise later in life maintains bone mass, reduces falls and probably associated fractures, and improves quality-of-life measures. Summary Future studies should examine the effect of exercise on bone strength and determine the minimum quantity and frequency and the exercise type most effective to reduce osteoporotic fractures. C1 [Schwab, Pascale; Scalapino, Kenneth] Oregon Hlth & Sci Univ, Portland Vet Affairs Med Ctr, Portland, OR 97201 USA. RP Schwab, P (reprint author), 3710 SW Vet Hosp Rd, Portland, OR 97239 USA. EM schwabp@ohsu.edu NR 44 TC 8 Z9 8 U1 0 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 J9 CURR OPIN RHEUMATOL JI Curr. Opin. Rheumatol. PD MAR PY 2011 VL 23 IS 2 BP 137 EP 141 DI 10.1097/BOR.0b013e3283434501 PG 5 WC Rheumatology SC Rheumatology GA 715JB UT WOS:000286879200003 PM 21178629 ER PT J AU Campling, BG Collins, BN Algazy, KM Schnoll, RA Lam, M AF Campling, Barbara G. Collins, Bradley N. Algazy, Kenneth M. Schnoll, Robert A. Lam, Miu TI Spontaneous Smoking Cessation Before Lung Cancer Diagnosis SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Lung neoplasms; Prostate cancer; Myocardial infarction; Smoking cessation; Veterans ID CELL-LINES; NICOTINE DEPENDENCE; MORTALITY; CARCINOMA; GROWTH; RISK; ACETYLCHOLINE; ANGIOGENESIS; TACHYKININS; EXPRESSION AB Introduction: We have observed that many patients with lung cancer stop smoking before diagnosis, usually before clinical symptoms, and often without difficulty. This led us to speculate that spontaneous smoking cessation may be a presenting symptom of lung cancer. Methods: Patients from the Philadelphia Veterans Affairs Medical Center with lung cancer and for comparison, prostate cancer and myocardial infarction underwent a structured interview about their smoking habits preceding diagnosis. Severity of nicotine addiction was graded using the Fagerstrom Test for Nicotine Dependence. Among former smokers, dates of cessation, onset of symptoms, and diagnosis were recorded. Difficulty quitting was rated on a scale of 0 to 10. Distributions of intervals from cessation to diagnosis were compared between groups. Results: All 115 patients with lung cancer had been smokers. Fifty-five (48%) quit before diagnosis, and only six of these (11%) were symptomatic at quitting. Patients with lung cancer who quit were as dependent on nicotine, when smoking the most, as those who continued to smoke, unlike the other groups. Despite this, 31% quit with no difficulty. The median interval from cessation to diagnosis was 2.7 years for lung cancer, 24.3 years for prostate cancer, and 10.0 years for patients with myocardial infarction. Conclusions: These results challenge the notion that patients with lung cancer usually quit smoking because of disease symptoms. The hypothesis that spontaneous smoking cessation may be a presenting symptom of lung cancer warrants further investigation. C1 [Campling, Barbara G.; Algazy, Kenneth M.] Univ Penn, Dept Med, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Collins, Bradley N.] Temple Univ, Dept Publ Hlth, Philadelphia, PA 19122 USA. [Collins, Bradley N.] Temple Univ, Dept Pediat, Philadelphia, PA 19122 USA. [Schnoll, Robert A.] Univ Penn, Dept Psychiat, Transdisciplinary Tobacco Use Res Ctr, Philadelphia, PA 19104 USA. [Lam, Miu] Queens Univ, Dept Community Hlth & Epidemiol, Kingston, ON, Canada. RP Campling, BG (reprint author), 834 Chestnut St,Suite 314, Philadelphia, PA 19107 USA. EM Campling@jefferson.edu FU Veterans Affairs Healthcare Network FX Supported by a Veterans Affairs Healthcare Network Competitive Pilot Project Grant. The sponsor had no involvement in the study design, interpretation of results, or preparation of the manuscript. The opinions expressed herein are those of the authors and do not represent the views of the Department of Veterans Affairs or the United States Government. NR 36 TC 4 Z9 4 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD MAR PY 2011 VL 6 IS 3 BP 517 EP 524 DI 10.1097/JTO.0b013e318208c7da PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 719VR UT WOS:000287240100015 PM 21258255 ER PT J AU Lo, K Nguyen, J Fay, A AF Lo, Kristine Nguyen, John Fay, Aaron TI Customized Jones Tube Using a Surgical Drill SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article AB Purpose: To describe a technique for modifying a Jones tube length in the operating room. Methods: The required length of the Jones tube is determined using an 18-gauge needle passed from the conjunctiva posterior to the caruncle to the middle meatus. A longer Jones tube is ground to the proper length with a 4-mm diamond burr on a saber drill. Results: This procedure results in shortening of an oversized Jones tube in the operating room with no gross or microscopic defects in the glass surface. Conclusions: This technique allows modification of a Jones tube when the appropriate size is not available and may reduce the number of sizes that must be maintained in the operating room. C1 [Lo, Kristine; Nguyen, John; Fay, Aaron] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Fay, A (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM aaron_fay@meei.harvard.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD MAR-APR PY 2011 VL 27 IS 2 BP 130 EP 131 DI 10.1097/IOP.0b013e3181cd6320 PG 2 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 730BL UT WOS:000288003800016 PM 20639784 ER PT J AU Windsor, JS Rodway, GW Mukherjee, R Firth, PG Shattock, M Montgomery, HE AF Windsor, J. S. Rodway, G. W. Mukherjee, R. Firth, P. G. Shattock, M. Montgomery, H. E. TI Prolongation of the Corrected QT Complex - A Cause of Sudden Cardiac Death in the Mountain Environment? SO JOURNAL OF THE ROYAL ARMY MEDICAL CORPS LA English DT Article ID HIGH-RISK PATIENTS; HIGH-ALTITUDE; DYNAMIC ELECTROCARDIOGRAPHY; UNITED-STATES; WEIGHT-LOSS; HEART-RATE; LONG; INTERVAL; MANAGEMENT; HYPOTHERMIA AB In the mountain environment sudden cardiac death (SCD) has been shown to be responsible for the deaths of up to 52% of downhill skiers and 30% of hikers. The majority of SCD's are precipitated by a ventricular arrhythmia. Although most are likely to result from structural abnormalities associated with conditions such as ischaemic heart disease, a small but significant number may be due to abnormalities in ion channel activity, commonly known as, "channelopathies". Channelopathies have the potential to lengthen the time between ventricular depolarisation and repolarisation that can result in prolongation of the corrected QT interval (QTc) and episodes of polymorphic ventricular tachycardia (PVT) and eventually, ventricular fibrillation. This review examines the factors that prolong the QTc interval in the mountain environment and outlines a practical framework for preventing the life threatening arrhythmias that are associated with this condition. C1 [Windsor, J. S.; Mukherjee, R.; Montgomery, H. E.] UCL, UCL Ctr Altitude Space & Extreme Environm Med, Inst Human Hlth & Performance, London N19 5LW, England. [Rodway, G. W.] Univ Utah, Coll Nursing, Salt Lake City, UT 84112 USA. [Rodway, G. W.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Firth, P. G.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Shattock, M.] St Thomas Hosp, Div Cardiovasc, Rayne Inst, London, England. RP Windsor, JS (reprint author), UCL, UCL Ctr Altitude Space & Extreme Environm Med, Inst Human Hlth & Performance, Charterhouse Bldg,Archway Campus,Highgate Hill, London N19 5LW, England. RI Montgomery, Hugh/C-2592-2008; OI Montgomery, Hugh/0000-0001-8797-5019; Family Name Deactivated, Given Names Deactivated/0000-0001-6242-7585 NR 50 TC 0 Z9 0 U1 2 U2 2 PU RAMC JOURNAL PUBLICATIONS PI CAMBERELY SURREY PA HQ AMS, FASC, SLIM RD, CAMBERELY SURREY, GU15 4NP, ENGLAND SN 0035-8665 J9 J ROY ARMY MED CORPS JI J. R. Army Med. Corps PD MAR PY 2011 VL 157 IS 1 BP 63 EP 67 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 812FN UT WOS:000294276600012 PM 21465913 ER PT J AU Neto, JFL Kuhl, G Smith, MM de Souza, PA Vieira, LR AF Lubianca Neto, Jose Faibes Kuhl, Gabriel Smith, Mariana Magnus de Souza, Person Antunes Vieira, Leonardo Raduenz TI Association between congenital nasolacrimal duct cyst and bilateral choanal atresia SO BRAZILIAN JOURNAL OF OTORHINOLARYNGOLOGY LA English DT Editorial Material DE nasal obstruction; choanal atresia; nasolacrimal duct C1 [Lubianca Neto, Jose Faibes] Univ Fed Rio Grande do Sul, UFRGS, BR-90046900 Porto Alegre, RS, Brazil. [Lubianca Neto, Jose Faibes] Hosp Clin Porto Alegre, ENT Residency, Porto Alegre, RS, Brazil. [Lubianca Neto, Jose Faibes] Harvard Univ, Massachusetts Eye & Ear Infirm, Pediat ENT Div, Sch Med, Boston, MA 02114 USA. [Lubianca Neto, Jose Faibes] Fed Univ Hlth Sci, Porto Alegre, RS, Brazil. [Lubianca Neto, Jose Faibes] Univ Fed Rio Grande do Sul, Grad Program Med Sci, Porto Alegre, RS, Brazil. [Kuhl, Gabriel] Univ Coimbra, P-3000 Coimbra, Portugal. [Kuhl, Gabriel] Univ Caxias Sul, Caxias Do Sul, RS, Brazil. [Kuhl, Gabriel] Soc Otorhinolaryngol Rio Grande Sul, Porto Alegre, RS, Brazil. [Smith, Mariana Magnus] Pontificia Univ Catolica Rio Grande do Sul, Porto Alegre, RS, Brazil. [de Souza, Person Antunes] Univ Fed Pelotas, Pelotas, Brazil. [Vieira, Leonardo Raduenz] Univ Fed Ciencias Saude Porto Alegre, Porto Alegre, RS, Brazil. RP Neto, JFL (reprint author), Univ Fed Rio Grande do Sul, UFRGS, BR-90046900 Porto Alegre, RS, Brazil. NR 5 TC 3 Z9 4 U1 0 U2 2 PU ASSOC BRASILEIRA OTORRINOLARINGOLOGIA & CIRURGIA CERVICOFACIAL PI SAO PAULO PA AV INDIANOPOLOS 740, MOEMA, SAO PAULO, SP 04062-001, BRAZIL SN 1808-8694 J9 BRAZ J OTORHINOLAR JI Braz. J. Otorhinolaryngol. PD MAR-APR PY 2011 VL 77 IS 2 BP 267 EP 267 PG 1 WC Otorhinolaryngology SC Otorhinolaryngology GA 803JV UT WOS:000293578500019 PM 21537631 ER PT J AU Shin, JJ Rauch, SD Wasserman, J Coblens, O Randolph, GW AF Shin, Jennifer J. Rauch, Steven D. Wasserman, Jared Coblens, Orly Randolph, Gregory W. TI Evidence-Based Medicine in Otolaryngology, Part 2: The Current State of Affairs SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE evidence-based medicine; evidence-based practice; otolaryngology; systematic reviews; levels of evidence ID CLINICAL-PRACTICE GUIDELINE; RANDOMIZED CONTROLLED-TRIALS; JOURNALS; PERCEPTIONS; ASSOCIATION; COMPETENCE; SURGEONS AB What is the current state of evidence-based medicine in otolaryngology? This question inquires about the state of our literature, our attitudes and capabilities, and our patients' desires. Thus, this installment of "Evidence-Based Medicine in Otolaryngology" focuses on these 3 topics. First, the authors consider the literature relative to benchmarks for study design. Second, the data regarding otolaryngologists' and other surgical specialists' attitudes and understanding of clinical data are discussed. Third, patient-based efforts to promote and participate in evidence-based practice are explored. In addition, a discussion of the relevant supportive efforts made by our professional organizations is included. C1 [Shin, Jennifer J.] Harvard Univ, Sch Med, Div Otolaryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Shin, Jennifer J.] So Calif Permanente Med Grp, Los Angeles Med Ctr, Div Head & Neck Surg, Los Angeles, CA 90027 USA. [Rauch, Steven D.] Harvard Univ, Sch Med, Div Otol, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Wasserman, Jared] ENT & Allergy Associates, Englewood, NJ USA. [Coblens, Orly] New York State Amer Program, Sackler Sch Med, New York, NY USA. [Randolph, Gregory W.] Harvard Univ, Sch Med, Div Gen Otolaryngol & Endocrine Surg, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Shin, JJ (reprint author), Harvard Univ, Sch Med, Div Otolaryngol, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM jennifer_shin@meei.harvard.edu RI Shin, Jennifer/A-3169-2016 FU Springer; Otonomy, Inc FX Jennifer J. Shin is an editor of Evidence-Based Otolaryngology and receives book royalties from Springer. Steven D. Rauch received grant support from Otonomy, Inc and is a section editor of Evidence-Based Otolaryngology. Gregory W. Randolph is an editor of Evidence-Based Otolaryngology. (Shin J, Hartnick CJ, Randolph G, eds. Evidence-Based Otolaryngology. New York, NY: Springer Science + Business Media, LLC; 2008.) NR 47 TC 6 Z9 6 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD MAR PY 2011 VL 144 IS 3 BP 331 EP 337 DI 10.1177/0194599810393856 PG 7 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 808RZ UT WOS:000293997400001 PM 21493192 ER PT J AU Divi, V Lin, DT Emerick, K Rocco, J Deschler, DG AF Divi, Vasu Lin, Derrick T. Emerick, Kevin Rocco, James Deschler, Daniel G. TI Primary TEP Placement in Patients with Laryngopharyngeal Free Tissue Reconstruction and Salivary Bypass Tube Placement SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE voice; head and neck cancer; reconstructive surgery; free flaps ID PHARYNGOESOPHAGEAL RECONSTRUCTION; FLAP AB The authors examined the feasibility and advantages of primary tracheoesophageal puncture (TEP) with intraoperative placement of the voice prosthesis for patients undergoing laryngopharyngectomy requiring free tissue reconstruction and salivary bypass tube placement. Six patients were identified; 4 underwent total laryngopharyngectomy, and 2 underwent total laryngectomy with partial pharyngectomy. All 6 required free tissue reconstruction, and a salivary bypass tube was placed in all cases. All patients had a 20F Indwelling Blom-Singer prosthesis (InHealth Technologies, Carpinteria, California) placed. No complications were noted with intraoperative prosthesis placement. No prostheses were dislodged in the postoperative period. At 6 months, 4 patients available for evaluation had successful voice outcomes, and 3 were disease free. This study demonstrates the effectiveness of voice prosthesis placement at the time of primary TEP associated with free tissue reconstruction of a laryngopharyngeal defect with salivary bypass tube placement. C1 [Divi, Vasu; Lin, Derrick T.; Emerick, Kevin; Rocco, James; Deschler, Daniel G.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Divi, V (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM vasudivi@med.umich.edu NR 4 TC 6 Z9 6 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD MAR PY 2011 VL 144 IS 3 BP 474 EP 476 DI 10.1177/0194599810391960 PG 3 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 808RZ UT WOS:000293997400025 PM 21493216 ER PT J AU Naramura, M Nadeau, S Mohapatra, B Ahmad, G Mukhopadhyay, C Sattler, M Raja, SM Natarajan, A Band, V Band, H AF Naramura, Mayumi Nadeau, Scott Mohapatra, Bhopal Ahmad, Gulzar Mukhopadhyay, Chandrani Sattler, Martin Raja, Srikumar M. Natarajan, Amarnath Band, Vimla Band, Hamid TI Mutant Cbl proteins as oncogenic drivers in myeloproliferative disorders SO ONCOTARGET LA English DT Article DE Cbl; E3 ubiquitin ligase; leukemia; protein tyrosine kinase; signal transduction ID JUVENILE MYELOMONOCYTIC LEUKEMIA; ACUTE MYELOID-LEUKEMIA; ACQUIRED UNIPARENTAL DISOMY; HEMATOPOIETIC STEM-CELLS; GROWTH-FACTOR RECEPTOR; LIGASE C-CBL; RING FINGER; TYROSINE PHOSPHORYLATION; NEGATIVE REGULATION; MUTATIONS AB Casitas B-lineage lymphoma (Cbl) family proteins are evolutionarily-conserved attenuators of protein tyrosine kinase (PTK) signaling. Biochemical analyses over the past two decades have firmly established that the negative regulatory functions of Cbl proteins are mediated through their ability to facilitate ubiquitination and thus promote degradation of PTKs. As aberrant activation of PTKs is frequently associated with oncogenesis, it has long been postulated that loss of normal Cbl functions may lead to unregulated activation of PTKs and cellular transformation. In the last few years, mutations in the CBL gene have been identified in a subset of human patients with myeloid malignancies. Here we discuss insights gained from the analyses of Cbl mutants both in human patients and in animal models and propose potential mechanisms of oncogenesis through this pathway. C1 [Naramura, Mayumi; Nadeau, Scott; Mohapatra, Bhopal; Ahmad, Gulzar; Mukhopadhyay, Chandrani; Raja, Srikumar M.; Natarajan, Amarnath; Band, Vimla; Band, Hamid] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Naramura, Mayumi; Nadeau, Scott; Band, Vimla; Band, Hamid] Univ Nebraska Med Ctr, Dept Genet Cell Biol & Anat, Coll Med, Omaha, NE USA. [Mohapatra, Bhopal; Band, Hamid] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Coll Med, Omaha, NE USA. [Natarajan, Amarnath] Univ Nebraska Med Ctr, Dept Pharmaceut Sci, Coll Pharm, Omaha, NE USA. [Sattler, Martin] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Naramura, M (reprint author), Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. EM mnaramura@unmc.edu; hband@unmc.edu FU US National Institutes of Health [CA87986, CA99163, CA105489, CA116552, CA96844, CA127239, CA134660]; US Department of Defense [W81XWH-11-1-0166, W81XWH-07-1-0351, W81XWH-11-1-0171, W81XWH-10-1-0740]; University of Nebraska Medical Center (UNMC)-Eppley Cancer Center; Nebraska Department of Health and Human Services [LB-506]; Nebraska Center for Nanomedicine-Center for Biomedical Research Excellence (NCN-COBRE) FX Work in the authors' laboratories was supported by grants from the US National Institutes of Health (CA87986, CA99163, CA105489 and CA116552 to H.B.; CA96844 to V.B.; CA127239 to A.N.; CA134660 to M.S.), the US Department of Defense Breast Cancer Research Program (W81XWH-11-1-0166 to H.B; W81XWH-07-1-0351 and W81XWH-11-1-0171 to V.B; W81XWH-10-1-0740 to M.N.), University of Nebraska Medical Center (UNMC)-Eppley Cancer Center (Pilot Grants to M.N. and V.B.), Nebraska Department of Health and Human Services (LB-506 grant to S.M.R.) and Nebraska Center for Nanomedicine-Center for Biomedical Research Excellence (NCN-COBRE; seed grant to S.M.R.). NR 44 TC 22 Z9 23 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR PY 2011 VL 2 IS 3 BP 245 EP 250 PG 6 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 802KH UT WOS:000293509000016 PM 21422499 ER PT J AU Ory, B Ellisen, LW AF Ory, Benjamin Ellisen, Leif W. TI A microRNA-dependent circuit controlling p63/p73 homeostasis: p53 family cross-talk meets therapeutic opportunity SO ONCOTARGET LA English DT Article DE p63; p73; microRNA; apoptosis; cisplatin; squamous cell carcinoma; triple-negative breast cancer; chemosensitivity ID SQUAMOUS-CELL CARCINOMA; DNA-DAMAGE; P63; P73; APOPTOSIS; NETWORK; CANCER; EXPRESSION; CISPLATIN; CHEMOSENSITIVITY AB The p53 family transcription factors p53, p63 and p73 make diverse contributions in development and cancer. Mutation or deletion of p53 is observed in the majority of human cancers. In contrast, p63 and p73 are not lost in cancer but mediate distinct genetic roles in normal and tumor-specific contexts: p73 promotes genome stability and mediates chemosensitivity, while p63 largely lacks these p53-like functions and instead promotes proliferation and cell survival. We recently uncovered a mechanism which maintains p63/p73 homeostasis within the epithelium through direct transcriptional regulation of microRNAs (miRs). We discovered that several of the top p63-regulated miRs target p73 for inhibition, including miR-193a-5p, a direct p63/p73 transcriptional target which is repressed by p63 and activated by p73 both in vitro and in vivo. The resulting feed-forward circuit involving p63, miR-193a-5p and p73 controls p73 levels, cell viability and DNA damage susceptibility in certain cancers including squamous cell carcinoma. Here, we discuss the evolutionary implications of this regulatory circuit, which may point to a general mechanism of miR-mediated cross-talk within transcription factor gene families. Additionally, we suggest that inducible chemoresistance mediated by this miR-dependent mechanism might be an attractive target for therapeutic intervention. C1 [Ory, Benjamin] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Ellisen, LW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. EM ellisen@helix.mgh.harvard.edu RI Xie, Huangming/B-2260-2012; ory, benjamin/K-8231-2015 FU NIH [RO1 DE-015945]; Avon Foundation; Susan G. Komen for the Cure [KG091277] FX The work described herein was supported by NIH RO1 DE-015945, by the Avon Foundation, and by Susan G. Komen for the Cure KG091277. We thank members of the Ellisen laboratory for helpful comments on the manuscript. NR 38 TC 37 Z9 41 U1 0 U2 1 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR PY 2011 VL 2 IS 3 BP 259 EP 264 PG 6 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 802KH UT WOS:000293509000018 PM 21436470 ER PT J AU Erkan, EP Breakefield, XO Saydam, O AF Erkan, Erdogan Pekcan Breakefield, Xandra O. Saydam, Okay TI miRNA signature of schwannomas: Possible role(s) of "tumor suppressor" miRNAs in benign tumors SO ONCOTARGET LA English DT Article DE miR-7; Tumor suppressor miRNAs; Benign tumors; Schwannomas; Neurofibromatosis 2 (NF2); Ack1 ID GROWTH-FACTOR RECEPTOR; CHRONIC LYMPHOCYTIC-LEUKEMIA; BREAST-CANCER CELLS; P21-ACTIVATED KINASES; MICROPROCESSOR COMPLEX; EXPRESSION; MICRORNAS; GENE; FAMILY; MYC AB miRNAs have been recently implicated as drivers in several carcinogenic processes, where they can act either as oncogenes or as tumor suppressors. Schwannomas arise from Schwann cells, the myelinating cells of the peripheral nervous system. These benign tumors typically result from loss of the neurofibromatosis type 2 (NF2) tumor suppressor gene. We have recently carried out high-throughput miRNA expression profiling of human vestibular schwannomas using an array representing 407 known miRNAs in order to explore the role of miRNAs in the tumorigenesis of schwannomas. We found that miR-7 functions as a "tumor suppressor" by targeting proteins in three major oncogenic pathways - EGFR, Pak1, and Ack1. Interestingly, in this study, we also observed that several previously described potential tumor suppressor miRNAs that are down-regulated in malignant tumors were up-regulated in schwannomas. Here we discuss the possibility that "tumor suppressor" miRNAs may play a role in the transition stage(s) of cancer from benign to malignant forms. C1 [Erkan, Erdogan Pekcan; Saydam, Okay] Med Univ Vienna, Mol Oncol Res Unit, Div Oncol, Dept Pediat, A-1090 Vienna, Austria. [Breakefield, Xandra O.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02129 USA. [Breakefield, Xandra O.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02129 USA. [Breakefield, Xandra O.] Harvard Univ, Neurosci Program, Sch Med, Boston, MA 02129 USA. RP Saydam, O (reprint author), Med Univ Vienna, Mol Oncol Res Unit, Div Oncol, Dept Pediat, A-1090 Vienna, Austria. EM okay.saydam@meduniwien.ac.at FU Children's Tumor Foundation [2007-01-043, NINDS NS24279, NCI CA69246, CA86355]; Forschungsgesellschaft for Brain Tumors FX This study was supported by the Children's Tumor Foundation "Young Investigator Award" 2007-01-043 (O.S.), NINDS NS24279 (X.O.B., O.S.), NCI CA69246 (X.O.B.), CA86355 (X.O.B.) and Forschungsgesellschaft for Brain Tumors (O. S.). NR 47 TC 13 Z9 15 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR PY 2011 VL 2 IS 3 BP 265 EP 270 PG 6 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 802KH UT WOS:000293509000019 PM 21454924 ER PT J AU Zhang, ZG Kolm, P Boden, WE Hartigan, PM Maron, DJ Spertus, JA O'Rourke, RA Shaw, LJ Sedlis, SP Mancini, GBJ Berman, DS Dada, M Teo, KK Weintraub, WS AF Zhang, Zugui Kolm, Paul Boden, William E. Hartigan, Pamela M. Maron, David J. Spertus, John A. O'Rourke, Robert A. Shaw, Leslee J. Sedlis, Steven P. Mancini, G. B. John Berman, Daniel S. Dada, Marcin Teo, Koon K. Weintraub, William S. TI The Cost-Effectiveness of Percutaneous Coronary Intervention as a Function of Angina Severity in Patients With Stable Angina SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE angina; cost effectiveness; quality of life; questionnaires ID EVALUATION COURAGE TRIAL; OUTCOMES UTILIZING REVASCULARIZATION; OPTIMAL MEDICAL THERAPY; QUALITY-OF-LIFE; ARTERY-DISEASE; MYOCARDIAL-INFARCTION; HEART-DISEASE; ANGIOPLASTY; ECONOMICS; SURVIVAL AB Background-The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial compared percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) to OMT alone in reducing the risk of cardiovascular events in 2287 patients with stable coronary disease. We examined the cost-effectiveness of PCI as a function of angina severity at the time of randomization. Methods and Results-Angina severity was assessed with the Seattle Angina Questionnaire (SAQ). Patients were grouped into tertiles based on the distribution of baseline scores such that higher tertiles represented better health status. Clinically significant improvement from baseline within individual patients was defined as score increases of > 8 for physical limitation, > 20 for angina frequency, and > 16 for quality-of-life domains. The incremental cost-effectiveness ratio for PCI was calculated as the difference in costs divided by the difference in proportion of patients with clinically significant improvement. Improvement in angina severity was significantly greater for PCI patients in the lowest and middle tertiles. The number of patients needed to treat was much larger for the highest tertile. The added in-trial cost of PCI ranged from $7300 to $13 000. Incremental cost-effectiveness ratios ranged from $80 000 to $330 000 for the lowest and middle tertiles and from $520 000 to > $3 million for the highest tertile for 1 additional patient to achieve significant clinical improvement in health status. Conclusions-The incremental cost of PCI to provide meaningful clinical benefit above that achieved by OMT alone was lower for patients with severe angina than for those with mild or no angina. However, it is uncertain that at any level of angina severity that PCI as an initial strategy would achieve a socially acceptable cost threshold. C1 [Zhang, Zugui; Kolm, Paul; Weintraub, William S.] Christiana Care Hlth Syst, Newark, DE USA. [Boden, William E.] Western New York Vet Affairs Healthcare Network, Buffalo, NY USA. [Hartigan, Pamela M.] VA Connecticut Healthcare, Cooperat Studies Program Coordinating Ctr, West Haven, CT USA. [Maron, David J.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Spertus, John A.] Univ Missouri, Mid Amer Heart Inst, Kansas City, MO 64110 USA. [O'Rourke, Robert A.] San Antonio Vet Affairs Med Ctr, San Antonio, TX USA. [Shaw, Leslee J.] Emory Univ, Atlanta, GA 30322 USA. [Sedlis, Steven P.] NYU, New York, NY USA. [Sedlis, Steven P.] Vet Affairs New York Harbor Hlth Care Network, New York, NY USA. [Mancini, G. B. John] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Berman, Daniel S.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Dada, Marcin] Hartford Hosp, Hartford, CT 06115 USA. [Teo, Koon K.] McMaster Univ, Hamilton, ON, Canada. [Boden, William E.] Kaleida Hlth Syst, Buffalo, NY USA. RP Zhang, ZG (reprint author), Christiana Care Ctr Outcomes Res, 131 Continental Dr,Ste 202, Newark, DE 19713 USA. EM zzgfang@hotmail.com RI Library, Woodruff Health/A-6096-2012; OI Sedlis, Steven/0000-0002-8194-8017 FU Sanofi-Aventis; AstraZeneca; Institutions Network for Biomedical Research Excellence; Bristol-Myers Squibb; Pfizer; Merck; PDL Biopharma; Abbott; Cardiovascular Therapeutics; Kos Pharmaceuticals; Novartis; CAD; United Healthcare; Amgen; Lilly; GlaxoSmithKline; Merck Frosst-Schering (Canada); Boehringer-Ingelheim; Indigo Pharmaceuticals; Otsuka FX Dr Kolm reports receiving grant support from Sanofi-Aventis, AstraZeneca, Institutions Network for Biomedical Research Excellence, Otsuka, and Bristol-Myers Squibb. Dr Boden reports receiving consulting fees from Pfizer, Merck, PDL Biopharma, Bristol-Myers Squibb, Abbott, and Cardiovascular Therapeutics and receiving lecture fees from Sanofi-Aventis, Kos Pharmaceuticals, and Novartis. Dr Maron reports receiving fees from reviewing a case for a defendant who recommended medical therapy for patients with CAD. Dr Spertus reports receiving consulting fees from Otsuka and United Healthcare and grant support from Amgen, Bristol-Myers Squibb, Sanofi-Aventis, and Lilly and holds a copyright to the SAQ. Dr Mancini reports receiving grant support from GlaxoSmithKline, Pfizer, AstraZeneca, and Merck Frosst-Schering (Canada). Dr Teo reports receiving grant support from Boehringer-Ingelheim. Dr Weintraub reports receiving consulting fees from Sanofi-Aventis, GlaxoSmithKline, Indigo Pharmaceuticals, and Cardiovascular Therapeutics and receiving grant support from Sanofi-Aventis, AstraZeneca, Otsuka, and Bristol-Myers Squibb. Drs Zhang, Hartigan, O'Rourke, Shaw, Sedlis, Berman, Dada, and Weintraub report no conflicts. NR 29 TC 7 Z9 7 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7705 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD MAR PY 2011 VL 4 IS 2 BP 172 EP U72 DI 10.1161/CIRCOUTCOMES.110.940502 PG 22 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 734WN UT WOS:000288372200008 PM 21304091 ER PT J AU Ganis, G Rosenfeld, JP Meixner, J Kievit, RA Schendan, HE AF Ganis, Giorgio Rosenfeld, J. Peter Meixner, John Kievit, Rogier A. Schendan, Haline E. TI Lying in the scanner: Covert countermeasures disrupt deception detection by functional magnetic resonance imaging SO NEUROIMAGE LA English DT Article ID EVENT-RELATED FMRI; CONCEALED INFORMATION; PREFRONTAL CORTEX; MEMORY IMPAIRMENT; GUILTY KNOWLEDGE; BRAIN ACTIVITY; LIE DETECTION; NEUROSCIENCE; PROTOCOL; TESTS AB Functional magnetic resonance imaging (fMRI) studies have documented differences between deceptive and honest responses. Capitalizing on this research, companies marketing fMRI-based lie detection services have been founded, generating methodological and ethical concerns in scientific and legal communities. Critically, no fMRI study has examined directly the effect of countermeasures, methods used by prevaricators to defeat deception detection procedures. An fMRI study was conducted to fill this research gap using a concealed information paradigm in which participants were trained to use countermeasures. Robust group fMRI differences between deceptive and honest responses were found without, but not with countermeasures. Furthermore, in single participants, deception detection accuracy was 100% without countermeasures, using activation in ventrolateral and medial prefrontal cortices, but fell to 33% with countermeasures. These findings show that fMRI-based deception detection measures can be vulnerable to countermeasures, calling for caution before applying these methods to real-world situations. (C) 2010 Elsevier Inc. All rights reserved. C1 [Ganis, Giorgio; Schendan, Haline E.] Massachusetts Gen Hosp, Martinos Ctr, Charlestown, MA 02129 USA. [Ganis, Giorgio; Schendan, Haline E.] Univ Plymouth, Sch Psychol, Plymouth PL4 8AA, Devon, England. [Rosenfeld, J. Peter; Meixner, John] Northwestern Univ, Dept Psychol, Evanston, IL 60208 USA. [Kievit, Rogier A.] Univ Amsterdam, Dept Psychol, NL-1018 WB Amsterdam, Netherlands. RP Ganis, G (reprint author), Massachusetts Gen Hosp, Martinos Ctr, Bldg 149, Charlestown, MA 02129 USA. EM ganis@nmr.mgh.harvard.edu OI Ganis, Giorgio/0000-0001-6175-2618; Schendan, Haline/0000-0001-8925-5605; Kievit, Rogier/0000-0003-0700-4568 FU National Science Foundation [BCS0322611] FX This research was supported in part by the National Science Foundation (BCS0322611). NR 47 TC 51 Z9 56 U1 3 U2 39 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 MAR 1 PY 2011 VL 55 IS 1 BP 312 EP 319 DI 10.1016/j.neuroimage.2010.11.025 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 716YH UT WOS:000287008900030 PM 21111834 ER PT J AU Fujitani, S George, WL Murthy, AR AF Fujitani, Shigeki George, W. Lance Murthy, A. Rekha TI Comparison of Clinical Severity Score Indices for Clostridium difficile Infection SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID HOSPITALIZED-PATIENTS; DISEASE; DIARRHEA; STRAIN; METRONIDAZOLE; VANCOMYCIN; MORTALITY; EPIDEMIC; OUTBREAK; COLITIS AB OBJECTIVE. To compare 8 severity score indices for Clostridium difficile infection (CDI). DESIGN. Prospective observational study. METHODS. This study was conducted from July through October 2006. All hospitalized patients in 3 university-affiliated hospitals with a positive fecal Clostridium difficile toxin assay result were evaluated. Infection was considered severe if patients had at least 1 of the following clinical events during their hospitalization: (1) death attributed to CDI within 30 days after diagnosis, (2) colectomy necessitated by CDI, or (3) intensive care unit admission for management of complications attributed to CDI. Severity was assessed on the basis of 8 severity score indices, using published criteria for severe CDI as the benchmark. The 8 severity score indices studied were Beth Israel, University of Pittsburgh Medical Center version 1, University of Pittsburgh Medical Center version 2, Hines VA, modified University of Illinois, University of Calgary version 1, University of Calgary version 2, and University of Temple. RESULTS. Of 184 patients with CDI evaluated, 19 had severe cases and 165 had nonsevere cases, as assessed on the basis of the defined severe CDI criteria. Sensitivities of the 8 severity score indices studied ranged from 63.2% to 84.2%, and specificities ranged from 59.4% to 93.9%. The Hines VA index had the highest kappa score (0.69 [95% confidence interval, 0.54-0.83]), followed by the University of Pittsburgh Medical Center version 1 index. Independent risk factors for severe CDI determined by multivariate analysis were abdominal distention (P=.007), fever (temperature, 38.0 degrees C or above; P=.042), white blood cell count of at least 20,000 cells/mm(3) (P=.035), and hypoalbuminemia (serum albumin level less than 3 mg/dL; P=.029). CONCLUSION. The Hines VA CDI severity score index appeared to display the strongest correlation for predicting more severe forms of CDI. C1 [Fujitani, Shigeki] Marianna Univ Hosp, Dept Emergency & Crit Care Med, Miyamae Ku, Kawasaki, Kanagawa 2168511, Japan. [George, W. Lance] VA Greater Los Angeles Healthcare Syst, Infect Dis Sect, Los Angeles, CA USA. [George, W. Lance; Murthy, A. Rekha] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Murthy, A. Rekha] Cedars Sinai Med Ctr, Div Infect Dis, Dept Hosp Epidemiol, Los Angeles, CA 90048 USA. RP Fujitani, S (reprint author), Marianna Univ Hosp, Dept Emergency & Crit Care Med, Miyamae Ku, 2-16-1 Sugao, Kawasaki, Kanagawa 2168511, Japan. EM shigekifujitani@hotmail.com NR 20 TC 56 Z9 56 U1 1 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD MAR PY 2011 VL 32 IS 3 BP 220 EP 228 DI 10.1086/658336 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 790UH UT WOS:000292614200004 PM 21460506 ER PT J AU Irazoqui, JE AF Irazoqui, Javier E. TI Transparent worms help survey the fortress of innate immunity SO VIRULENCE LA English DT Editorial Material ID CAENORHABDITIS-ELEGANS; PSEUDOMONAS-AERUGINOSA; C. ELEGANS; INFECTION; SALMONELLA; INFLAMMATION C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Dev Immunol,Dept Pediat, Boston, MA 02115 USA. RP Irazoqui, JE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Dev Immunol,Dept Pediat, Boston, MA 02115 USA. EM javier@molbio.mgh.harvard.edu RI Irazoqui, Javier/A-8028-2013; OI Irazoqui, Javier/0000-0001-6553-1329 NR 26 TC 1 Z9 1 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD MAR-APR PY 2011 VL 2 IS 2 BP 83 EP 85 DI 10.4161/viru.2.2.15665 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 789NW UT WOS:000292523500001 PM 21460640 ER PT J AU Muhammed, M Coleman, JJ Carneiro, HA Mylonakis, E AF Muhammed, Maged Coleman, Jeffrey J. Carneiro, Herman A. Mylonakis, Eleftherios TI The challenge of managing fusariosis SO VIRULENCE LA English DT Review DE amphotericin B; fusariosis; Fusarium; invasive fungal infection; posaconazole; voriconazole ID INVASIVE FUNGAL-INFECTIONS; ACUTE LYMPHOBLASTIC-LEUKEMIA; LIPOSOMAL AMPHOTERICIN-B; CELL TRANSPLANT RECIPIENTS; IN-VITRO; ANTIFUNGAL SUSCEPTIBILITY; HEMATOLOGIC MALIGNANCIES; IMMUNOCOMPROMISED PATIENTS; MOLD INFECTIONS; LIPID COMPLEX AB Fusarium is the second most frequent mold involved in fungal infections and is particularly important among immunocompromised patients. Culture methods and microscopy are still routinely used in clinical laboratories to identify Fusarium spp., and more sophisticated, timely, and effective methods for detecting Fusarium spp. in laboratory samples could improve the outcome for the patient. These investigational diagnostic approaches include serological assays and specific nested PCR assays that can yield positive and negative predictive values of over 90%. Other assays in development, such as mass spectroscopy techniques, can provide accurate and consistent results. The treatment of fusariosis in immunocompromised patients remains a challenge and the prognosis of systemic fusariosis in this population remains poor. Successful treatment is highly dependent on the particular Fusarium species involved in the infection. High dose intravenous amphotericin B formulation is recommended as the first line of therapy in management of fusariosis in patients. Voriconazole is also effective in treating fusariosis. Intolerance, contraindication, or failure of the amphotericin B formulation warrants the use of voriconazole as an alternative agent, and posaconazole is licensed as salvage therapy against invasive fusariosis. Adjunctive therapies such as surgical debridement of infected tissue, granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) infusions, or granulocyte transfusions are also tools for managing fusariosis. In conclusion, Fusarium infection is considered an emerging problem and should be suspected in immunocompromised patients experiencing systemic infection and should be treated accordingly. C1 [Muhammed, Maged; Coleman, Jeffrey J.; Carneiro, Herman A.; Mylonakis, Eleftherios] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Coleman, JJ (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM jjcoleman@partners.org RI Coleman, Jeffrey/E-2981-2015 FU NIH [P01 AI 083214, R01 AI075286, R21 AI079569, T32 AI007061] FX This work was supported by NIH grants P01 AI 083214, R01 AI075286 and R21 AI079569 to E.M. and a T32 AI007061 to J.J.C. NR 77 TC 34 Z9 36 U1 1 U2 11 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD MAR-APR PY 2011 VL 2 IS 2 BP 91 EP 96 DI 10.4161/viru.2.2.15015 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 789NW UT WOS:000292523500003 PM 21304267 ER PT J AU Mendez, MF Shapira, JS Saul, RE AF Mendez, Mario F. Shapira, Jill S. Saul, Ronald E. TI The Spectrum of Sociopathy in Dementia SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID VENTROMEDIAL PREFRONTAL CORTEX; ANTISOCIAL PERSONALITY-DISORDER; POSITRON-EMISSION-TOMOGRAPHY; INCREASED GREY-MATTER; FRONTOTEMPORAL DEMENTIA; ALZHEIMERS-DISEASE; BRAIN ABNORMALITIES; CONDUCT PROBLEMS; DECISION-MAKING; MORAL JUDGMENTS AB Although well-known from head trauma and acute strokes, sociopathic behavior from dementia is less known and understood. This study reviewed 33 dementia patients who had been in trouble with the law. They were divided into two groups: 22 who committed impulsive sociopathic acts and 11 who committed non-impulsive acts. The impulsive patients demonstrated nonviolent acts, such as dis-inhibited sexual behavior or pathological stealing, and had disproportionate frontal-caudate atrophy on neuroimaging. The majority of non-impulsive patients demonstrated agitation-paranoia, sometimes with reactive aggression, delusional beliefs, or aphasic paranoia, and had advanced memory and other cognitive impairment. The impulsive patients tended to have frontally predominant illnesses such as frontotemporal dementia or Huntington's disease, whereas the non-impulsive group tended to have Alzheimer's disease or prominent aphasia. Sociopathy has different causes in dementia. Two common mechanisms are disinhibition, with frontally predominant disease, and agitation-paranoia, with greater cognitive impairment. These forms of sociopathy differ significantly from the antisocial/psychopathic personality. (The Journal of Neuropsychiatry and Clinical Neurosciences 2011; 23: 132-140) C1 [Mendez, Mario F.] VA Greater Los Angeles Healthcare Ctr, Neurobehav Unit 691 116AF, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Mendez, MF (reprint author), VA Greater Los Angeles Healthcare Ctr, Neurobehav Unit 691 116AF, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM mmendez@UCLA.edu FU NIMH [R01AG034499-02] FX This work was supported by NIMH Grant # R01AG034499-02. NR 69 TC 9 Z9 10 U1 7 U2 16 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD SPR PY 2011 VL 23 IS 2 BP 132 EP 140 PG 9 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 777VF UT WOS:000291652500127 PM 21677240 ER PT J AU Ducharme, S Flaherty, AW Seiner, SJ Dougherty, DD Morales, OG AF Ducharme, Simon Flaherty, Alice W. Seiner, Stephen J. Dougherty, Darin D. Morales, Oscar G. TI Temporary Interruption of Deep Brain Stimulation for Parkinson's Disease During Outpatient Electroconvulsive Therapy for Major Depression: A Novel Treatment Strategy SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID TREATMENT-RESISTANT DEPRESSION; PATIENT; ECT; EFFICACY; DAMAGE AB The safety of electroconvulsive therapy (ECT) in patients with deep brain stimulation (DBS) has not been established. Cases reported had no adverse events, but DBS was withheld throughout the weeks of the ECT course. The authors report the first case of temporary interruption of DBS only during the minutes of each outpatient ECT. (The Journal of Neuropsychiatry and Clinical Neurosciences 2011; 23: 194-197) C1 [Morales, Oscar G.] Harvard Univ, McLean Hosp, Sch Med, Belmont, MA 02478 USA. McGill Univ, Montreal, PQ, Canada. Harvard Univ, Sch Med, Dept Psychiat, Div Neurotherapeut,Massachusetts Gen Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Morales, OG (reprint author), Harvard Univ, McLean Hosp, Sch Med, 115 Mill St, Belmont, MA 02478 USA. EM ogmorales@partners.org FU NIMH; NARSAD; TSA; OCF; Wyeth; Jazz Pharmaceuticals; Bristol-Myers Squibb; Medtronic; Eli Lilly; Northstar; McNeil; Brand Ideas; Reed Elsevier; Cyberonics FX Dr. Ducharme, Dr. Flaherty, and Dr. Seiner have no disclosure or conflict of interest related to this topic. Dr. Dougherty's research has been funded by NIMH, NARSAD, TSA, and OCF. He has received honoraria, consultation fees, and/or royalties from Wyeth, Jazz Pharmaceuticals, Bristol-Myers Squibb, Medtronic, Eli Lilly, Northstar, McNeil, Brand Ideas, and Reed Elsevier. He has also participated in research funded by Medtronic, Cyberonics, Eli Lilly, McNeil and Northstar. NR 19 TC 13 Z9 13 U1 0 U2 5 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD SPR PY 2011 VL 23 IS 2 BP 194 EP 197 PG 4 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 777VF UT WOS:000291652500136 PM 21677249 ER PT J AU Yeh, B Ferrucci, S AF Yeh, Brenda Ferrucci, Steven TI Retinal pigment epithelium tears after bevacizumab injection SO OPTOMETRY-JOURNAL OF THE AMERICAN OPTOMETRIC ASSOCIATION LA English DT Article DE Age-related macular degeneration; Bevacizumab; Avastin; Choroidal neovascularization (CNV); Vascular endothelial growth factor; Pigment epithelial detachment; Retinal pigment epithelial tear ID OPTICAL COHERENCE TOMOGRAPHY; CHOROIDAL NEOVASCULARIZATION SECONDARY; INTRAVITREAL BEVACIZUMAB; MACULAR DEGENERATION; RANIBIZUMAB THERAPY; LASER TREATMENT; DETACHMENT; AVASTIN; PATHOGENESIS; PREDICTORS AB BACKGROUND: The advent of anti-vascular endothelial growth factor (VEGF) treatment for choroidal neovascularization has become the standard of care for wet age-related macular degeneration (AMD). Among the choices, intravitreal bevacizumab, for off-label use, has gained popularity. Recent attention has been on the complications of anti-VEGF treatment, one of them being a retinal pigment epithelial (RPE) tear. A tear in the RPE is a visually devastating complication, most commonly associated with fibrovascular pigment epithelial detachments (PED) in AMD, and may develop during the course of intravitreal bevacizumab treatment. CASE REPORT: We report a case of an 85-year-old white man with decreased visual acuities of 20/70 in the right eye (O.D.) and 20/150 in the left eye (O.S.) secondary to dry AMD O.D. and wet AMD with a fibrovascular PED O.S. The patient underwent treatment with an intravitreal bevacizumab injection O.S. Six weeks after the initial injection, the patient returned with further declining vision in the left eye secondary to an RPE tear. CONCLUSION: Intravitreal bevacizumab has proven to be an effective treatment for choroidal neovascularization and shows a significant improvement of vision for wet AMD patients. However, there are risks associated with the procedure. One of the most visually significant is an RPE tear, which can occur at an incidence rate as high as 17%. Optometrists should be aware of this rare, but serious, complication associated with anti-VEGF treatment for wet AMD. Optometry 2011;82:152-157 C1 [Yeh, Brenda; Ferrucci, Steven] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Yeh, Brenda; Ferrucci, Steven] Sepulveda Vet Affairs Ambulatory Care Ctr Nursing, Sepulveda, CA USA. [Ferrucci, Steven] So Calif Coll Optometry, Fullerton, CA USA. RP Ferrucci, S (reprint author), Sepulveda Vet Affairs Ambulatory Care Ctr, 16111 Plummer St 112E, Sepulveda, CA 91343 USA. EM Steven.Ferrucci@va.gov NR 44 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 1529-1839 J9 OPTOMETRY JI Optometry PD MAR PY 2011 VL 82 IS 3 BP 152 EP 157 DI 10.1016/j.optm.2010.09.010 PG 6 WC Ophthalmology SC Ophthalmology GA 778MO UT WOS:000291708600006 PM 21130699 ER PT J AU Shahlaie, K Larson, PS Starr, PA AF Shahlaie, Kiarash Larson, Paul S. Starr, Philip A. TI Intraoperative Computed Tomography for Deep Brain Stimulation Surgery: Technique and Accuracy Assessment SO NEUROSURGERY LA English DT Article DE Computed tomography; Deep brain stimulation; Intraoperative imaging; Lead location; Neuronavigation ID SUBTHALAMIC NUCLEUS; ELECTRODE PLACEMENT; PARKINSONS-DISEASE; LOCALIZATION; IMPLANTATION; CANCER; EXPERIENCE; LOCATIONS; OUTCOMES; SHIFT AB BACKGROUND: The efficacy of deep brain stimulation (DBS) is highly dependent on the accuracy of lead placement. OBJECTIVE: To describe the use of intraoperative computed tomography (iCT) to confirm lead location before surgical closure and to study the accuracy of this technique. METHODS: Fifteen patients underwent awake microelectrode-guided DBS surgery in a stereotactic frame. A portable iCT scanner (Medtronic O-arm) was positioned around the patient's head throughout the procedure and was used to confirm lead location before fixation of the lead to the skull. Images were computationally fused with pre-operative magnetic resonance imaging (MRI), and lead tip coordinates with respect to the midpoint of the anterior commissure-posterior commissure line were measured. Tip coordinates were compared with those obtained from postoperative MRI. RESULTS: iCT was integrated into standard frame-based microelectrode-guided DBS surgery with a minimal increase in surgical time or complexity. Technically adequate 2-dimensional and 3-dimensional images were obtained in all cases. Head positioning and fixation techniques that allow unobstructed imaging are described. Lead tip measurements on iCT fused with preoperative MRI were statistically indistinguishable from those obtained with postoperative MRI. CONCLUSION: iCT can be easily incorporated into standard DBS surgery, replaces the need for C-arm fluoroscopy, and provides accurate intraoperative 3-dimensional confirmation of electrode tip locations relative to preoperative images and surgical plans. iCT fused to preoperative MRI may obviate the need for routine postoperative MRI in DBS surgery. Technical nuances that must be mastered for the efficient use of iCT during DBS implantation are described. C1 [Starr, Philip A.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, Parkinsons Dis Res Educ & Care Ctr, San Francisco, CA USA. RP Starr, PA (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 533 Parnassus Ave,Box 0445, San Francisco, CA 94143 USA. EM starrp@neurosurg.ucsf.edu NR 25 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD MAR PY 2011 VL 68 SU 1 AR ons114 DI 10.1227/NEU.0b013e31820781bc PG 11 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 773KU UT WOS:000291307000032 ER PT J AU Basko-Plluska, JL Thyssen, JP Schalock, PC AF Basko-Plluska, Juliana L. Thyssen, Jacob P. Schalock, Peter C. TI Cutaneous and Systemic Hypersensitivity Reactions to Metallic Implants SO DERMATITIS LA English DT Review ID TOTAL KNEE REPLACEMENT; TOTAL HIP-ARTHROPLASTY; PACEMAKER CONTACT SENSITIVITY; CORONARY-ARTERY-DISEASE; GOLD SODIUM THIOSULFATE; FORAMEN OVALE OCCLUDER; BONE-CEMENT COMPONENTS; ORAL LICHENOID LESIONS; BURNING MOUTH SYNDROME; IN-STENT RESTENOSIS AB Cutaneous reactions to metal implants, orthopedic or otherwise, are well documented in the literature. The first case of a dermatitis reaction over a stainless steel fracture plate was described in 1966. Most skin reactions are eczematous and allergic in nature, although urticarial, bullous, and vasculitic eruptions may occur. Also, more complex immune reactions may develop around the implants, resulting in pain, inflammation, and loosening. Nickel, cobalt, and chromium are the three most common metals that elicit both cutaneous and extracutaneous allergic reactions from chronic internal exposure. However, other metal ions as well as bone cement components can cause such hypersensitivity reactions. To complicate things, patients may also develop delayed-type hypersensitivity reactions to metals lie, in-stent restenosis, prosthesis loosening, inflammation, pain, or allergic contact dermatitis) following the insertion of intravascular stents, dental implants, cardiac pacemakers, or implanted gynecologic devices. Despite repeated attempts by researchers and clinicians to further understand this difficult area of medicine, the association between metal sensitivity and cutaneous allergic reactions remains to be fully understood. This review provides an update of the current knowledge in this field and should be valuable to health care providers who manage patients with conditions related to this field. C1 [Basko-Plluska, Juliana L.] Univ Chicago, Dept Med, Dermatol Sect, Chicago, IL 60637 USA. Univ Copenhagen, Gentofte Hosp, Natl Allergy Res Ctr, Dept Dermato Allergol, DK-1168 Copenhagen, Denmark. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA USA. RP Basko-Plluska, JL (reprint author), Univ Chicago, Dept Med, Dermatol Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA. NR 130 TC 54 Z9 56 U1 3 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1710-3568 EI 2162-5220 J9 DERMATITIS JI Dermatitis PD MAR-APR PY 2011 VL 22 IS 2 BP 65 EP 79 DI 10.2310/6620.2011.10055 PG 15 WC Dermatology SC Dermatology GA 768XS UT WOS:000290973500001 PM 21504692 ER PT J AU Chandra, A Jena, AB Skinner, JS AF Chandra, Amitabh Jena, Anupam B. Skinner, Jonathan S. TI The Pragmatist's Guide to Comparative Effectiveness Research SO JOURNAL OF ECONOMIC PERSPECTIVES LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; STABLE CORONARY-DISEASE; COST-EFFECTIVENESS ANALYSIS; US HEALTH-CARE; DRUG DEVELOPMENT; REIMBURSEMENT; MORTALITY; MEDICINE; IMPACT; TRIAL C1 [Chandra, Amitabh] Harvard Univ, Harvard Kennedy Sch Govt, Cambridge, MA 02138 USA. [Jena, Anupam B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Skinner, Jonathan S.] Dartmouth Coll, Dartmouth Inst Hlth Care Policy & Clin Practice, Hanover, NH 03755 USA. [Chandra, Amitabh; Skinner, Jonathan S.] Natl Bur Econ Res, Cambridge, MA 02138 USA. RP Chandra, A (reprint author), Harvard Univ, Harvard Kennedy Sch Govt, Cambridge, MA 02138 USA. EM amitabh_chandra@harvard.edu; jena.anupam@mgh.harvard.edu; jonathan.skinner@dartmouth.edu FU NIA NIH HHS [P01 AG019783, P01 AG019783-10, P01 AG19783] NR 60 TC 25 Z9 26 U1 3 U2 8 PU AMER ECONOMIC ASSOC PI NASHVILLE PA 2014 BROADWAY, STE 305, NASHVILLE, TN 37203 USA SN 0895-3309 EI 1944-7965 J9 J ECON PERSPECT JI J. Econ. Perspect. PD SPR PY 2011 VL 25 IS 2 BP 27 EP 46 DI 10.1257/jep.25.2.27 PG 20 WC Economics SC Business & Economics GA 764GW UT WOS:000290618900002 PM 21595324 ER PT J AU LeBoeuf, NR Schmults, CD AF LeBoeuf, Nicole R. Schmults, Chrysalyne D. TI Update on the Management of High-Risk Squamous Cell Carcinoma SO SEMINARS IN CUTANEOUS MEDICINE AND SURGERY LA English DT Article ID NONMELANOMA SKIN-CANCER; ORGAN TRANSPLANT RECIPIENTS; POSITRON-EMISSION-TOMOGRAPHY; CHRONIC LYMPHOCYTIC-LEUKEMIA; PHASE-II TRIAL; BASAL-CELL; EPIDERMOLYSIS-BULLOSA; PERINEURAL INVASION; CALCINEURIN INHIBITORS; PROGNOSTIC FACTORS AB Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy occurring in white patients in the United States and incidence rates are increasing. While the majority of the 87,000-760,000 cases that occur yearly in the U.S. are curable, 4% develop lymph node metastases and 1.5% die from the disease. Given the frequency of occurrence of CSCC, it is estimated to cause as many deaths yearly as melanoma, with the majority occurring in patients with high risk tumors or in those at high risk for metastasis due to a variety of host factors, most commonly systemic immunosuppression. There are currently no standardized prognostic or treatment models to assist clinicians in most effectively identifying and managing these patients. Identification of patients at risk for poor outcomes as well as standardization regarding classification, staging, and treatment of high-risk tumors is critical for optimizing patient care. In this article, available literature on the classification and management of high risk CSCC is briefly summarized, emphasizing new information. Semin Cutan Med Surg 30:26-34 (C) 2011 Elsevier Inc. All rights reserved. C1 [LeBoeuf, Nicole R.; Schmults, Chrysalyne D.] Harvard Univ, Brigham & Womens Hosp, Dept Dermatol, Dana Farber Canc Inst,Med Sch, Boston, MA 02115 USA. RP Schmults, CD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp,Dept Dermatol, 1153 Ctr St, Jamaica Plain, MA 02130 USA. EM cschmults@partners.org NR 102 TC 11 Z9 14 U1 1 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1085-5629 J9 SEMIN CUTAN MED SURG JI Semin. Cutan. Med. Surg. PD MAR PY 2011 VL 30 IS 1 BP 26 EP 34 DI 10.1016/j.sder.2011.02.002 PG 9 WC Dermatology; Surgery SC Dermatology; Surgery GA 764RL UT WOS:000290649900005 PM 21540018 ER PT J AU Boruta, D McCann, C Growdon, W AF Boruta, D. McCann, C. Growdon, W. TI Single-incision laparoscopic staging surgery for endometrial cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Boruta, D.; McCann, C.; Growdon, W.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 16 BP S9 EP S9 DI 10.1016/j.ygyno.2010.12.023 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300017 ER PT J AU Campos, S Atkinson, T Berlin, S Roche, M Whalen, C Matulonis, U Horowitz, N Birrer, M Penson, R AF Campos, S. Atkinson, T. Berlin, S. Roche, M. Whalen, C. Matulonis, U. Horowitz, N. Birrer, M. Penson, R. TI STAC: A phase II study of carboplatin/paclitaxel/bevacizumab followed by randomization to either bevacizumab alone or erlotinib and bevacizumab in the upfront management of patients with ovarian, fallopian tube or peritoneal cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Campos, S.; Atkinson, T.; Berlin, S.; Whalen, C.; Matulonis, U.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Roche, M.; Birrer, M.; Penson, R.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Horowitz, N.] Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 181 BP S79 EP S79 DI 10.1016/j.ygyno.2010.12.188 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300182 ER PT J AU Garrett, L Zhang, L Guo, L Therrien, V Growdon, W Foster, R Rueda, B AF Garrett, L. Zhang, L. Guo, L. Therrien, V. Growdon, W. Foster, R. Rueda, B. TI Influence of the novel histone deacetylase inhibitor panobinostat (LBH589) on the growth of ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Garrett, L.; Zhang, L.; Guo, L.; Therrien, V.; Growdon, W.; Foster, R.; Rueda, B.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 163 BP S71 EP S71 DI 10.1016/j.ygyno.2010.12.170 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300164 ER PT J AU Growdon, W Garrett, L Rousel, B Scialabba, V Ellisen, L Dias-Santagata, D Foster, R Tambouret, R Rueda, B Borger, D AF Growdon, W. Garrett, L. Rousel, B. Scialabba, V. Ellisen, L. Dias-Santagata, D. Foster, R. Tambouret, R. Rueda, B. Borger, D. TI Activating PIK3CA and RAS mutations identified exclusively in carcinosarcomas of uterine origin SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Growdon, W.; Garrett, L.; Rousel, B.; Scialabba, V.; Ellisen, L.; Dias-Santagata, D.; Foster, R.; Tambouret, R.; Rueda, B.; Borger, D.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 97 BP S42 EP S43 DI 10.1016/j.ygyno.2010.12.104 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300098 ER PT J AU McCann, C Bradford, L Boruta, D Del Carmen, M Goodman, A Growdon, W Schorge, J AF McCann, C. Bradford, L. Boruta, D. Del Carmen, M. Goodman, A. Growdon, W. Schorge, J. TI Secondary cytoreductive surgery for recurrent endometrial cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [McCann, C.; Bradford, L.; Boruta, D.; Del Carmen, M.; Goodman, A.; Growdon, W.; Schorge, J.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 215 BP S93 EP S94 DI 10.1016/j.ygyno.2010.12.222 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300216 ER PT J AU Moore, R Miller, C DiSilvestro, P Landrum, L Gajewski, W Renneisen, P Skates, S AF Moore, R. Miller, C. DiSilvestro, P. Landrum, L. Gajewski, W. Renneisen, P. Skates, S. TI Evaluation of the risk of ovarian malignancy algorithm in women with a pelvic mass presenting to general gynecologists SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Moore, R.; DiSilvestro, P.] Brown Univ, Women & Infants Hosp, Providence, RI USA. [Landrum, L.] Univ Oklahoma, Oklahoma City, OK USA. [Gajewski, W.] New Hanover Reg Med Ctr, Wilmington, NC USA. [Renneisen, P.] Fujirebio Diagnost, Malvern, PA USA. [Skates, S.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 156 BP S68 EP S68 DI 10.1016/j.ygyno.2010.12.163 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300157 ER PT J AU Rauh-Hain, I Growdon, W Rodriguez, N Goodman, A Boruta, D Horowitz, N Del Carmen, M Schorge, J AF Rauh-Hain, I. Growdon, W. Rodriguez, N. Goodman, A. Boruta, D. Horowitz, N. Del Carmen, M. Schorge, J. TI Primary debulking surgery versus neoadjuvant chemotherapy in stage IV ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Rauh-Hain, I.; Growdon, W.; Goodman, A.; Boruta, D.; Del Carmen, M.; Schorge, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rauh-Hain, I.; Rodriguez, N.; Horowitz, N.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Rauh-Hain, I.; Growdon, W.; Rodriguez, N.; Goodman, A.; Boruta, D.; Horowitz, N.; Del Carmen, M.; Schorge, J.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 26 BP S12 EP S13 DI 10.1016/j.ygyno.2010.12.033 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300027 ER PT J AU Rauh-Hain, J Growdon, W Rodriguez, N Goodman, A Schorge, J Boruta, D Horowitz, N Del Carmen, M AF Rauh-Hain, J. Growdon, W. Rodriguez, N. Goodman, A. Schorge, J. Boruta, D. Horowitz, N. Del Carmen, M. TI Carcinosarcoma of the ovary: A case-control study SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Rauh-Hain, J.; Growdon, W.; Goodman, A.; Schorge, J.; Boruta, D.; Del Carmen, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rauh-Hain, J.; Rodriguez, N.; Horowitz, N.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Rauh-Hain, J.; Growdon, W.; Rodriguez, N.; Goodman, A.; Schorge, J.; Boruta, D.; Horowitz, N.; Del Carmen, M.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 149 BP S65 EP S65 DI 10.1016/j.ygyno.2010.12.156 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300150 ER PT J AU Rodriguez, N Rauh-Hain, J Feltmate, C Del Carmen, M Penson, R Goodman, A Matulonis, U Muto, M Schorge, J Horowitz, N AF Rodriguez, N. Rauh-Hain, J. Feltmate, C. Del Carmen, M. Penson, R. Goodman, A. Matulonis, U. Muto, M. Schorge, J. Horowitz, N. TI CA-125 changes can predict optimal interval cytoreduction in patients with advanced-stage epithelial ovarian cancer treated with neoadjuvant chemotherapy SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Rodriguez, N.; Rauh-Hain, J.; Feltmate, C.; Muto, M.; Horowitz, N.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Rauh-Hain, J.; Del Carmen, M.; Penson, R.; Goodman, A.; Schorge, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Del Carmen, M.; Penson, R.; Goodman, A.; Schorge, J.] Harvard Univ, Boston, MA 02115 USA. [Matulonis, U.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 146 BP S63 EP S64 DI 10.1016/j.ygyno.2010.12.153 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300147 ER PT J AU Spencer, R Schorge, J Del Carmen, M Goodman, A Growdon, W Boruta, D AF Spencer, R. Schorge, J. Del Carmen, M. Goodman, A. Growdon, W. Boruta, D. TI Laparoscopic surgery for endometrial cancer: Why don't all patients go home the day after surgery? SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Spencer, R.; Schorge, J.; Del Carmen, M.; Goodman, A.; Growdon, W.; Boruta, D.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 205 BP S89 EP S89 DI 10.1016/j.ygyno.2010.12.212 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300206 ER PT J AU Zaid, T Thompson, M Wong, K Yeung, T Yeung, Z Kwan, S Co, C Schmandt, R Birrer, M Mok, S AF Zaid, T. Thompson, M. Wong, K. Yeung, T. Yeung, Z. Kwan, S. Co, C. Schmandt, R. Birrer, M. Mok, S. TI Overexpression of fibroblast growth factor 1 and fibroblast growth factor receptor 4 in high-grade serous ovarian carcinoma: Correlation with survival and implications for therapeutic targeting SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Zaid, T.; Thompson, M.; Wong, K.; Yeung, T.; Yeung, Z.; Kwan, S.; Co, C.; Schmandt, R.; Mok, S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Birrer, M.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2011 VL 121 IS 1 SU 1 MA 120 BP S52 EP S52 DI 10.1016/j.ygyno.2010.12.127 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 760AF UT WOS:000290292300121 ER PT J AU Ahmadi, N Nabavi, V Hajsadeghi, F Flores, F Azmoon, S Ismaeel, H Shavelle, D Mao, SS Ebrahimi, R Budoff, MJ AF Ahmadi, Naser Nabavi, Vahid Hajsadeghi, Fereshteh Flores, Ferdinand Azmoon, Shahdad Ismaeel, Hussain Shavelle, David Mao, Song S. Ebrahimi, Ramin Budoff, Matthew J. TI Impaired aortic distensibility measured by computed tomography is associated with the severity of coronary artery disease SO INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING LA English DT Article DE Aortic distensibility index; Computed tomographic angiography; Coronary artery calcium score; 2D Trans-thoracic echocardiography ID HEART-DISEASE; ENDOTHELIAL DYSFUNCTION; ELASTIC PROPERTIES; CLINICAL-PRACTICE; PROGNOSTIC VALUE; III GUIDELINES; ELECTRON-BEAM; SMOOTH-MUSCLE; STIFFNESS; ATHEROSCLEROSIS AB Impaired aortic distensibility index (ADI) is associated with cardiovascular risk factors. This study evaluates the relation of ADI measured by computed tomographic angiography (CTA) with the severity of coronary atherosclerosis in subjects with suspected coronary artery disease (CAD). Two hundred and twenty-nine subjects,age 63 +/- A 9 years, 42% female, underwent coronary artery calcium (CAC) scanning and CTA, and their ADI and Framingham risk score (FRS) were measured. End-systolic and end-diastolic (ED) cross-sectional-area(CSA) of ascending-aorta (AAo) was measured 15-mm above the left-main coronary ostium. ADI was defined as: [(Delta lumen-CSA)/(lumen-CSA in ED x systemic-pulse-pressure) x 10(3)]. ADI measured by 2D-trans-thoracic echocardiography (TTE) was compared with CTA-measured ADI in 26 subjects without CAC. CAC was defined as 0, 1-100, 101-400 and 400+. CAD was defined as luminal stenosis 0, 1-49% and 50%+. There was an excellent correlation between CTA- and TTE-measured ADI (r (2) = 0.94, P = 0.0001). ADI decreased from CAC 0 to CAC 400+; similarly from FRS 1-9% to FRS 20% + (P < 0.05). After adjustment for risk factors, the relative risk for each standard deviation decrease in ADI was 1.66 for CAC 1-100, 2.26 for CAC 101-400 and 2.32 for CAC 400+ as compared to CAC 0; similarly, 2.36 for non-obstructive CAD and 2.67 for obstructive CAD as compared to normal coronaries. The area under the ROC-curve to predict significant CAD was 0.68 for FRS, 0.75 for ADI, 0.81 for CAC and 0.86 for the combination (P < 0.05). Impaired aortic distensibility strongly correlates with the severity of coronary atherosclerosis. Addition of ADI to CAC and traditional risk factors provides incremental value to predict at-risk individuals. C1 [Ahmadi, Naser; Nabavi, Vahid; Hajsadeghi, Fereshteh; Flores, Ferdinand; Ismaeel, Hussain; Mao, Song S.; Budoff, Matthew J.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA. [Ebrahimi, Ramin] Univ Calif Los Angeles, Sch Med, Greater Los Angeles VA Med Ctr, Los Angeles, CA USA. [Shavelle, David] Univ So Calif, Los Angeles, CA USA. [Azmoon, Shahdad] New York Med Coll, Valhalla, NY 10595 USA. RP Ahmadi, N (reprint author), Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, 1124 W Carson St,RB2, Torrance, CA 90502 USA. EM nahmadi@labiomed.org NR 52 TC 14 Z9 15 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1569-5794 J9 INT J CARDIOVAS IMAG JI Int. J. Cardiovasc. Imaging PD MAR PY 2011 VL 27 IS 3 BP 459 EP 469 DI 10.1007/s10554-010-9680-6 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 762OU UT WOS:000290490100017 PM 20711815 ER PT J AU Wang, JC Cunningham, MJ AF Wang, James C. Cunningham, Michael J. TI Congenital dacryocystocele: Is there a familial predisposition? SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Dacryocystocele; Congenital nasolacrimal obstruction; Familial ID NASOLACRIMAL DUCT; OBSTRUCTION; MANAGEMENT; MUCOCELE AB Congenital impatency of the nasolacrimal drainage system is relatively common. Dacryocystocele formation is an infrequent variant of such congenital nasolacrimal duct obstruction (NLDO). Congenital dacryocystocele typically manifests as a mass in the medial canthal region; alternatively the nasolacrimal expansion may present solely intranasally as a nasolacrimal duct cyst. Despite the relative frequency of congenital NLDO, there have been few reported familial cases. We report here two female siblings with congenital dacryocystocele, and review the etiology and potential inherited predisposition to this comparatively rare entity. Published by Elsevier Ireland Ltd. C1 [Wang, James C.; Cunningham, Michael J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Dept Otolaryngol,Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Cunningham, MJ (reprint author), Harvard Univ, Sch Med, Dept Otol & Laryngol, Dept Otolaryngol,Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Michael_Cunningham@meei.harvard.edu NR 15 TC 8 Z9 10 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-5876 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD MAR PY 2011 VL 75 IS 3 BP 430 EP 432 DI 10.1016/j.ijporl.2010.11.026 PG 3 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA 764BY UT WOS:000290604600025 PM 21185090 ER PT J AU Mimiaga, MJ Thomas, B Mayer, KH Reisner, SL Menon, S Swaminathan, S Periyasamy, M Johnson, CV Safren, SA AF Mimiaga, M. J. Thomas, B. Mayer, K. H. Reisner, S. L. Menon, S. Swaminathan, S. Periyasamy, M. Johnson, C. V. Safren, S. A. TI Alcohol use and HIV sexual risk among MSM in Chennai, India SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE men who have sex with men (MSM); alcohol; HIV; sexually transmitted infections (STI); prevention; intervention; India ID HUMAN-IMMUNODEFICIENCY-VIRUS; BASE-LINE DATA; BRIEF INTERVENTIONS; TRANSMITTED INFECTIONS; WINE SHOPS; URBAN-POOR; CONDOM USE; MEN; PREVENTION; HEALTH AB Men who have sex with men (MSM) in India are a core risk group for HIV. Heavy alcohol consumption is associated with increased sexual risk-taking behaviours in many cultures, in particular among MSM. However, no studies to date have explored alcohol use and HIV risk among MSM in India. MSM in Chennai, India (n = 210) completed an interviewer-administered behavioural and psychosocial assessment. Bivariate and multivariable logistic regression procedures examined behavioural and demographic associations with weekly alcohol consumption. Twenty-eight percent of the sample (n = 58) reported using alcohol at least weekly to the point of being buzzed/intoxicated, which was associated with older age, being married to a woman, being panthi (masculine appearing, predominantly insertive partners) versus kothi (feminine acting/appearing and predominantly receptive partners), weekly tobacco use, unprotected anal sex and unprotected vaginal sex in the three months prior to study enrolment (all P < 0.05). In a multivariable model, unprotected vaginal sex in the previous three months and being married to a women were unique variables associated with weekly alcohol use (all P < 0.01). Further investigation of alcohol use within the context of sexual risk taking is warranted among Indian MSM. Panthis and MSM who are married to women may be particularly likely to benefit from interventions to decrease alcohol intake and concurrent unsafe sex. C1 [Mimiaga, M. J.; Reisner, S. L.; Safren, S. A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Mimiaga, M. J.; Mayer, K. H.; Johnson, C. V.; Safren, S. A.] Fenway Community Hlth, Fenway Inst, Boston, MA USA. [Thomas, B.; Swaminathan, S.; Periyasamy, M.] Indian Council Med Res, TB Res Ctr, Madras, Tamil Nadu, India. [Mayer, K. H.] Brown Univ, Miriam Hosp, Providence, RI USA. [Menon, S.] Sahodaran, Madras, Tamil Nadu, India. RP Mimiaga, MJ (reprint author), MGH Behav Med, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM mmimiaga@partners.org FU Lifespan/Tufts/Brown University Center for AIDS [NIH P30 AI42853]; [P30A1060354] FX Funding for this project was supported by a supplement to parent grant P30A1060354 on which Bruce Walker MD is the PI, and Steven A Safren PhD was the PI of the supplement. Support for some staff time (Mayer) was from the Lifespan/Tufts/Brown University Center for AIDS Research grant: NIH P30 AI42853. NR 42 TC 26 Z9 26 U1 1 U2 5 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0956-4624 J9 INT J STD AIDS JI Int. J. STD AIDS PD MAR PY 2011 VL 22 IS 3 BP 121 EP 125 DI 10.1258/ijsa.2009.009059 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 761UL UT WOS:000290426400001 PM 21464447 ER PT J AU Weintraub, D Morgan, JC AF Weintraub, Daniel Morgan, John C. TI Both the Body and Brain Benefit from Exercise: Potential Win-Win for Parkinson's Disease Patients SO MOVEMENT DISORDERS LA English DT Editorial Material ID COGNITIVE IMPAIRMENT; HIPPOCAMPAL; DEMENTIA C1 [Weintraub, Daniel] Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Morgan, John C.] Georgia Hlth Sci Univ, Augusta, GA USA. RP Weintraub, D (reprint author), Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RI AUDIFFREN, MICHEL/H-5649-2011 NR 10 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAR PY 2011 VL 26 IS 4 BP 607 EP 607 DI 10.1002/mds.23726 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 762AO UT WOS:000290444800008 PM 21506145 ER PT J AU Gallagher, CL Oakes, TR Johnson, SC Chung, MK Holden, JE Bendlin, BB McLaren, DG Xu, GF Nickles, RJ Pyzalski, R DeJesus, O Brown, WD AF Gallagher, Catherine L. Oakes, Terrence R. Johnson, Sterling C. Chung, Moo K. Holden, James E. Bendlin, Barbara B. McLaren, Donald G. Xu, Guofan Nickles, Robert J. Pyzalski, Robert DeJesus, Onofre Brown, W. Douglas TI Rate of 6-[18F]Fluorodopa Uptake Decline in Striatal Subregions in Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; Fluorodopa positron emission tomography; disease progression; aging; gender ID POSITRON-EMISSION-TOMOGRAPHY; BRAIN TRANSFER CONSTANTS; TIME UPTAKE DATA; GRAPHICAL EVALUATION; DOPAMINE TURNOVER; CLINICAL-TRIALS; PROGRESSION; PET; LEVODOPA AB Background: Rate of decline in 6-L[(18)F]fluorodopa (FDOPA) uptake within the striatum has been reported as showing regional differences in Parkinson's disease (PD). Methods: We acquired longitudinal brain FDOPA positron emission tomography (PET) studies in 26 PD subjects and 11 controls over 4.5 years. We analyzed both spatially normalized voxel-wise maps of radiotracer influx (Kocc) and average Kocc values for six non-overlapping volumes of interest (VOIs) encompassing the striatum. Results: The voxel-wise analysis showed that in PD, FDOPA Kocc decline spanned the striatum but was greatest in the posterior putamen ipsilateral and anterior putamen contralateral to initial symptoms. The VOI approached showed that absolute rates of Kocc decline were significantly greater in PD than control subjects, but that the slope of decline did not differ between subregions. In PD, ratios of uptake between subregions did not change during the study with the exception of the ipsilateral putamen/caudate ratio. Decline rates were marginally greater during earlier time segments. Both male gender and advancing age were associated with lower baseline FDOPA uptake, but no difference in decline rates. VOI Kocc values were significantly correlated with disease duration, but only moderately correlated with clinical measures. Discussion: We conclude that FDOPA uptake in subregions of the striatum is strongly correlated with disease duration and age, and declines approximately equally from symptom onset in PD. This implies that in idiopathic PD, relative preservation of uptake in the anterior striatum reflects a delay in pathologic involvement of nigrostriatal projections to this region. (C)2011 Movement Disorder Society C1 [Gallagher, Catherine L.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. [Gallagher, Catherine L.] Univ Wisconsin, Dept Neurol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Oakes, Terrence R.; Chung, Moo K.] Univ Wisconsin, Waisman Ctr Brain Imaging Lab, Madison, WI USA. [Johnson, Sterling C.; Bendlin, Barbara B.; Xu, Guofan] William S Middleton Mem Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Madison, WI USA. [Johnson, Sterling C.; Bendlin, Barbara B.; McLaren, Donald G.; Xu, Guofan] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Chung, Moo K.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. [Holden, James E.] Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA. [McLaren, Donald G.; Nickles, Robert J.; DeJesus, Onofre] Univ Wisconsin, Neurosci Training Program, Madison, WI 53706 USA. [Pyzalski, Robert] Univ Wisconsin, Dept Radiol, Madison, WI 53706 USA. [Brown, W. Douglas] Med Coll Wisconsin, Dept Radiol, Milwaukee, WI 53226 USA. RP Gallagher, CL (reprint author), William S Middleton VA Hosp, 6112B,2500 Overlook Terrace Dr, Madison, WI 53792 USA. EM gallagher@neurology.wisc.edu RI McLaren, Donald/G-9906-2011; OI Bendlin, Barbara/0000-0002-0580-9875; Johnson, Sterling/0000-0002-8501-545X FU William S. Middleton Memorial Veterans Hospital Geriatric Research Education and Clinical Center; Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA FX This work was supported with use of facilities at the William S. Middleton Memorial Veterans Hospital Geriatric Research Education and Clinical Center, and the Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA. Figure preparation by Jennifer Broihahn, University of Wisconsin Department of Neurology Media Specialist. NR 31 TC 6 Z9 6 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAR PY 2011 VL 26 IS 4 BP 614 EP 620 DI 10.1002/mds.23503 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 762AO UT WOS:000290444800010 PM 21449008 ER PT J AU Byers, AL Vittinghoff, E Lui, LY Hoang, T Covinsky, KE Cauley, JA Ensrud, KE Hillier, TA Fredman, L Yaffe, K AF Byers, Amy L. Vittinghoff, Eric Lui, Li-Yung Hoang, Tina Covinsky, Kenneth E. Cauley, Jane A. Ensrud, Kristine E. Hillier, Teresa A. Fredman, Lisa Yaffe, Kristine TI Characterization of Long-term Depressive Trajectories Among Elderly Women SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 18-21, 2011 CL San Antonio, TX SP Amer Assoc Geriat Psychiat C1 [Byers, Amy L.; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Vittinghoff, Eric; Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Covinsky, Kenneth E.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Byers, Amy L.; Hoang, Tina; Covinsky, Kenneth E.; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Cauley, Jane A.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ensrud, Kristine E.] Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. [Ensrud, Kristine E.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Hillier, Teresa A.] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Fredman, Lisa] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Lui, Li-Yung] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2011 VL 19 IS 3 SU 1 BP S104 EP S105 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PD UT WOS:000289791000117 ER PT J AU Calleo, JS Bush, A Kraus-Schuman, C Snow, L Wilson, N Kunik, ME Pauker, A Stanley, MA AF Calleo, Jessica S. Bush, Amy Kraus-Schuman, Cynthia Snow, Lynn Wilson, Nancy Kunik, Mark E. Pauker, Amber Stanley, Melinda A. TI Clinical Characteristics and Associated Anxiety Symptoms in Anxious Patients with Dementia SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 18-21, 2011 CL San Antonio, TX SP Amer Assoc Geriat Psychiat C1 [Calleo, Jessica S.; Bush, Amy; Wilson, Nancy; Kunik, Mark E.; Stanley, Melinda A.] Houston VA HSR&D Ctr Excellence, Houston, TX USA. [Kraus-Schuman, Cynthia; Kunik, Mark E.] Michael E Debakay Vet Affairs Med Ctr, Houston, TX USA. [Calleo, Jessica S.; Bush, Amy; Wilson, Nancy; Stanley, Melinda A.] Baylor Coll Med, Houston, TX 77030 USA. [Snow, Lynn] Univ Alabama, Tuscaloosa, AL USA. [Pauker, Amber] Puget Sound Hlth Care Syst, Dept Vet Affairs, Seatle, WA USA. [Snow, Lynn] Tuscaloosa Vet Affairs Med Ctr, Tuscaloosa, AL USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2011 VL 19 IS 3 SU 1 BP S79 EP S80 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PD UT WOS:000289791000084 ER PT J AU Calleo, JS York, M Bush, A Wilson, N Kraus-Schuman, C Kunik, ME Stanley, MA AF Calleo, Jessica S. York, Michele Bush, Amy Wilson, Nancy Kraus-Schuman, Cynthia Kunik, Mark E. Stanley, Melinda A. TI Problem Solving Confidence and Executive Functioning in Older Adults with Generalized Anxiety Disorder SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 18-21, 2011 CL San Antonio, TX SP Amer Assoc Geriat Psychiat C1 [Calleo, Jessica S.; York, Michele; Bush, Amy; Wilson, Nancy; Kraus-Schuman, Cynthia; Kunik, Mark E.; Stanley, Melinda A.] Baylor Coll Med, Houston, TX 77030 USA. [Calleo, Jessica S.; York, Michele; Kraus-Schuman, Cynthia] Michael E Debakay Vet Affairs Med Ctr, Houston, TX USA. [Bush, Amy; Wilson, Nancy; Kunik, Mark E.; Stanley, Melinda A.] Houston VA HRS&D Ctr Excellence, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2011 VL 19 IS 3 SU 1 BP S65 EP S66 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PD UT WOS:000289791000063 ER PT J AU Chu, SH Ferrell, R Roeder, K Devlin, B DeMichele-Sweet, MAA Lopez, OL Sweet, RA AF Chu, Su H. Ferrell, Robert Roeder, Kathryn Devlin, Bernie DeMichele-Sweet, Mary Ann A. Lopez, Oscar L. Sweet, Robert A. TI TOMM40 Poly-T Repeat Length Polymorphism is Independently Associated with Psychosis Risk, But Not Age of Onset, in Late Onset Alzheimer Disease SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 18-21, 2011 CL San Antonio, TX SP Amer Assoc Geriat Psychiat C1 [Chu, Su H.; Roeder, Kathryn] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. [Ferrell, Robert; Devlin, Bernie; DeMichele-Sweet, Mary Ann A.; Lopez, Oscar L.; Sweet, Robert A.] Univ Pittsburgh, Pittsburgh, PA USA. [Sweet, Robert A.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2011 VL 19 IS 3 SU 1 BP S125 EP S125 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PD UT WOS:000289791000149 ER PT J AU Espinoza, R Jarvik, L Read, S Kaufman, AH AF Espinoza, Randall Jarvik, Lissy Read, Stephen Kaufman, Aaron H. TI EDUCATING THE NEXT GENERATION OF PHYSICIANS IN GERIATRIC PSYCHIATRY SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 18-21, 2011 CL San Antonio, TX SP Amer Assoc Geriat Psychiat C1 [Espinoza, Randall; Kaufman, Aaron H.] Univ Calif Los Angeles, Los Angeles, CA USA. [Jarvik, Lissy; Read, Stephen] Greater Los Angeles VA Hlth Syst, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2011 VL 19 IS 3 SU 1 BP S9 EP S9 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PD UT WOS:000289791000003 ER PT J AU Feil, D Rajan, M Soroka, O Miller, DR Pogach, L AF Feil, Denise Rajan, Mangala Soroka, Orysya Miller, Donald R. Pogach, Leonard TI Increased Risk of Hypoglycemia in Older Patients with Dementia and Cognitive Impairment: Is More Intensive Glycemic Control at the Expense of Safety? SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 18-21, 2011 CL San Antonio, TX SP Amer Assoc Geriat Psychiat C1 [Feil, Denise] W Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. [Feil, Denise; Rajan, Mangala; Soroka, Orysya; Miller, Donald R.; Pogach, Leonard] East Orange REAP, E Orange, NJ USA. [Miller, Donald R.] Bedford VA Ctr Hlth Outcomes, Bedford, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2011 VL 19 IS 3 SU 1 BP S114 EP S114 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PD UT WOS:000289791000133 ER EF