FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Dawson, C Mudgal, CS AF Dawson, Courtney Mudgal, Chaitanya S. TI Staged Description of the Finkelstein Test SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Finkelstein; de Quervain's disorder; tenosynovitis; wrist AB We have revisited the original description of the Finkelstein test and review the reasons for its subsequent erroneous description. We have also outlined a staged description of this test, which we have found to be reliable and minimally painful for the diagnosis of de Quervain's tendonitis within our clinical practice. (J Hand Surg 2010;35A:1513-1515. (C) 2010 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand.) C1 [Mudgal, Chaitanya S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Orthopaed Hand Serv, Boston, MA 02114 USA. Harvard Combined Orthopaed Residency Program, Boston, MA USA. RP Mudgal, CS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Orthopaed Hand Serv, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM cmudgal@partners.org NR 5 TC 8 Z9 9 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 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD SEP PY 2010 VL 35A IS 9 BP 1513 EP 1515 DI 10.1016/j.jhsa.2010.05.022 PG 3 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 646GK UT WOS:000281526400021 PM 20709467 ER PT J AU King, L Mancini, M Priest, K Wilhelm, J Kaul, M Rinehart, K Karl, A Mader, S Horak, F AF King, Laurie Mancini, Martina Priest, Kelsey Wilhelm, Jenny Kaul, Matt Rinehart, Katie Karl, Andrea Mader, Scott Horak, Fay TI Instrumented Tests of Postural Control for Mild TBI SO JOURNAL OF HEAD TRAUMA REHABILITATION LA English DT Meeting Abstract C1 [King, Laurie; Mancini, Martina; Priest, Kelsey; Wilhelm, Jenny; Horak, Fay] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Kaul, Matt; Karl, Andrea; Mader, Scott] Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0885-9701 EI 1550-509X J9 J HEAD TRAUMA REHAB JI J. Head Trauma Rehabil. PD SEP-OCT PY 2010 VL 25 IS 5 BP 403 EP 403 PG 1 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 649JR UT WOS:000281765400064 ER PT J AU Bhatt, DL AF Bhatt, Deepak L. TI Acute Coronary Syndrome Update for Hospitalists SO JOURNAL OF HOSPITAL MEDICINE LA English DT Review DE acute coronary syndrome; non-ST-segment elevation myocardial infarction; ST-segment elevation myocardial infarction ID ELEVATION MYOCARDIAL-INFARCTION; ORAL ANTIPLATELET THERAPY; EARLY INVASIVE MANAGEMENT; STRATEGY ACUITY TRIAL; DRUG-ELUTING STENTS; ACUTE CATHETERIZATION; PLATELET INHIBITION; HEART-ASSOCIATION; INTERVENTION; CLOPIDOGREL AB Acute coronary syndromes (ACSs)-unstable angina, non-ST-segment (ST, part of an electrocardiogram between the QRS complex and the T wave) or ST-segment elevation myocardial infarction (MI)-remain extremely common and clinically challenging. In addition to electrocardiography and biomarkers, formal risk stratification using risk scores has become an important part of the initial evaluation of patients with ACS. On the basis of the estimated risk of subsequent ischemic events, the optimal use and timing of cardiac catheterization and revascularization procedures can be determined. Additionally, antiplatelet and anticoagulant therapy can be instituted, with consideration given to both the ischemic and bleeding risks in an individual patient. A particular challenge in ACS management has been the rapid evolution of guidelines in response to new randomized clinical trial and registry data. Understanding and implementing the recommendations in these evidence-based guidelines are important parts of hospitalists' practice. Journal of Hospital Medicine 2010; 5: S15-S21. (C) 2010 Society of Hospital Medicine. C1 [Bhatt, Deepak L.] Brigham & Womens Hosp, Cardiovasc Program, Boston, MA 02115 USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. RP Bhatt, DL (reprint author), Brigham & Womens Hosp, Cardiovasc Program, 75 Francis St, Boston, MA 02115 USA. EM dlbhattmd@post.harvard.edu NR 28 TC 2 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1553-5592 J9 J HOSP MED JI J. Hosp. Med. PD SEP PY 2010 VL 5 SU 4 BP S15 EP S21 DI 10.1002/jhm.830 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 654EM UT WOS:000282151300003 PM 20842746 ER PT J AU Truong, QA Ptaszek, LM Charipar, EM Taylor, C Fontes, JD Kriegel, M Irlbeck, T Toepker, M Schlett, CL Bamberg, F Blankstein, R Brady, TJ Nagurney, JT Hoffmann, U AF Truong, Quynh A. Ptaszek, Leon M. Charipar, Elizabeth M. Taylor, Carolyn Fontes, Joao D. Kriegel, Matthias Irlbeck, Thomas Toepker, Michael Schlett, Christopher L. Bamberg, Fabian Blankstein, Ron Brady, Thomas J. Nagurney, John T. Hoffmann, Udo TI Performance of electrocardiographic criteria for left ventricular hypertrophy as compared with cardiac computed tomography: from the Rule Out Myocardial Infarction Using Computer Assisted Tomography trial SO JOURNAL OF HYPERTENSION LA English DT Article DE computed tomography; electrocardiography; left ventricular hypertrophy; left ventricular mass ID ESSENTIAL-HYPERTENSION; CARDIOVASCULAR EVENTS; MASS; DIAGNOSIS; PREDICTION; RISK; VALIDATION; MORTALITY; PATTERNS; STANDARD AB Objective Cardiac computed tomography (CT) is a state-of-the- art technology that provides an accurate noninvasive method to quantify left ventricular mass for analysis of left ventricular hypertrophy (LVH). We aimed to examine seven ECG-based LVH criteria against two CT indexation criteria for LVH: a CT-specific body surface area cutoff and the obesity-independent height(2.7) criteria. Methods In 333 patients (mean age 53 +/- 12 years, 61% men), 64-slice contrast-enhanced CT was performed and 12-lead surface ECG within 24 h. Left ventricular mass was measured at end-diastole. Using both CT indexation criteria, the cohort was subdivided into patients with LVH and without LVH. The seven ECG criteria for LVH were the Cornell voltage index, Cornell voltage duration product, Cornell/strain index, Sokolow-Lyon index, Romhilt-Estes scores at least 4 and at least 5, and Gubner-Ungerleider. Results The ECG parameters had high specificities (85-97%) and variable low sensitivities (4-43%) when compared to either CT criteria of LVH. The three Cornell-based methods performed the best (test-positive likelihood ratio: 4.5-6.7), followed by the Sokolow-Lyon and Romhilt-Estes scores (test-positive likelihood ratio: 2.3-4.0). With the exception of the Gubner-Ungerleider criterion, the other six ECG criteria were associated with at least one of the CT-based LVH (adjusted odds ratio 2.4-9.5) and had incremental predictive value beyond that of hypertension history. Conclusion Using cardiac CT as a gold standard for LVH assessment, ECG criteria for LVH have high specificities with the three Cornell-based criteria providing the best test performance for identifying patients with LVH. J Hypertens 28:1959-1967 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Truong, Quynh A.; Charipar, Elizabeth M.; Taylor, Carolyn; Fontes, Joao D.; Kriegel, Matthias; Irlbeck, Thomas; Schlett, Christopher L.; Bamberg, Fabian; Blankstein, Ron; Brady, Thomas J.; Hoffmann, Udo] Harvard Univ, Sch Med, Cardiac MR PET CT Program, Massachusetts Gen Hosp,Dept Radiol, Boston, MA 02114 USA. [Truong, Quynh A.; Ptaszek, Leon M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Toepker, Michael] Univ Hosp Vienna, Dept Radiol, Vienna, Austria. [Bamberg, Fabian] Univ Munich, Klinikum Grosshadern, Dept Clin Radiol, D-8000 Munich, Germany. [Blankstein, Ron] Brigham & Womens Hosp, Noninvas Cardiovasc Imaging Program, Div Cardiovasc, Boston, MA 02115 USA. [Blankstein, Ron] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Nagurney, John T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Truong, QA (reprint author), Harvard Univ, Sch Med, Cardiac MR PET CT Program, Massachusetts Gen Hosp,Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM qtruong@partners.org FU NIH [R01 HL080053, T32HL076136, L30HL093896]; Siemens Medical Solutions and General Electrics Healthcare FX The present work was supported by the NIH R01 HL080053 and in part supported by Siemens Medical Solutions and General Electrics Healthcare. R.B. and Q.A.T. received support from NIH grant T32HL076136. Dr Q.A.T. also received support from NIH grant L30HL093896. NR 35 TC 7 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0263-6352 EI 1473-5598 J9 J HYPERTENS JI J. Hypertens. PD SEP PY 2010 VL 28 IS 9 BP 1959 EP 1967 DI 10.1097/HJH.0b013e32833b49cb PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 647GE UT WOS:000281605300025 PM 20498615 ER PT J AU Rudd, CE Trevillyan, JM Dasgupta, JD Wong, LL Schlossman, SF AF Rudd, Christopher E. Trevillyan, James M. Dasgupta, Jai Dev Wong, Linda L. Schlossman, Stuart F. TI The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes (Reprinted from Proceedings of the National Academy of Sciences, vol 85, pg 5190-5194, 1988) SO JOURNAL OF IMMUNOLOGY LA English DT Reprint ID CELL ANTIGEN RECEPTOR; AVIAN-SARCOMA VIRUS; CROSS-LINKING; ANTI-L3T4 ANTIBODIES; ACCESSORY CELLS; GENE-PRODUCT; ACTIVATION; PHOSPHORYLATION; RETROVIRUS; IDENTIFICATION AB The CD4 (T4) antigen is a cell-surface glyco-protein that is expressed predominantly on the surface of helper T cells and has been implicated in the regulation of T-cell activation and in the associative recognition of class II antigens of the major histocompatibility complex. In addition, the CD4 antigen appears to serve as a receptor for the human immunodeficiency virus (HIV). An important question has been whether the CD4 receptor is linked to an intracellular mediator that could regulate the activation of the CD4(+) subset. In this paper, we provide preliminary evidence that the CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (PTK) of 55-60 kDa, which is expressed specifically in T cells. The PTK is the human analogue of the murine pp56(LSTRA) (pp56(lck)) and has significant homology with c-src, c-yes, and other members of the src family. The identification of the PTK associated with CD4 receptor was made by use of an antiserum to a synthetic peptide that was deduced from the DNA sequence of PTK. Two-dimensional nonequilibrium pH gradient gel electrophoresis/NaDodSO(4)/PAGE revealed the kinase to focus as a heterogeneous collection of spots in the pH range of 4.0-5.0. Furthermore, in vitro phosphorylation revealed the phosphorylation of two additional polypeptides at 40 and 80 kDa, in addition to the autophosphorylation of the PTK at 55-60 kDa. The potential importance of the association between the CD4 receptor and the PTK of T cells is discussed in relation to T-cell activation and HIV infectivity. C1 [Rudd, Christopher E.; Wong, Linda L.; Schlossman, Stuart F.] Dana Farber Canc Inst, Div Tumor Immunol, Boston, MA 02115 USA. [Dasgupta, Jai Dev] Dana Farber Canc Inst, Div Immunogenet, Boston, MA 02115 USA. [Rudd, Christopher E.; Dasgupta, Jai Dev] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Schlossman, Stuart F.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Trevillyan, James M.] Texas Tech Univ, Hlth Sci Ctr, Dept Internal Med, Amarillo, TX 79106 USA. RP Rudd, CE (reprint author), Dana Farber Canc Inst, Div Tumor Immunol, 44 Binney St, Boston, MA 02115 USA. FU Wellcome Trust [092627] NR 45 TC 1 Z9 1 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2010 VL 185 IS 5 BP 2645 EP 2649 PG 5 WC Immunology SC Immunology GA 641JX UT WOS:000281122600003 PM 20724730 ER PT J AU Gonzalez, SF Lukacs-Kornek, V Kuligowski, MP Pitcher, LA Degn, SE Turley, SJ Carroll, MC AF Gonzalez, Santiago F. Lukacs-Kornek, Veronika Kuligowski, Michael P. Pitcher, Lisa A. Degn, Soren E. Turley, Shannon J. Carroll, Michael C. TI Complement-Dependent Transport of Antigen into B Cell Follicles SO JOURNAL OF IMMUNOLOGY LA English DT Review ID FOLLICULAR DENDRITIC CELLS; SUBCAPSULAR SINUS MACROPHAGES; INFLUENZA-VIRUS INFECTION; MARGINAL ZONE MACROPHAGES; HUMORAL IMMUNE-RESPONSE; HERPES-SIMPLEX-VIRUS; LYMPH-NODE CORTEX; ANTIBODY-RESPONSE; GERMINAL-CENTERS; LYMPHOCYTES-B AB Since the original proposal by Fearon and Locksley (Fearon and Locksley. 1996. Science 272: 50-53) that the complement system linked innate and adaptive immunity, there has been a rapid expansion of studies on this topic. With the advance of intravital imaging, a number of recent papers revealed an additional novel pathway in which complement C3 and its receptors enhance humoral immunity through delivery of Ag to the B cell compartment. In this review, we discuss this pathway and highlight several novel exceptions recently found with a model influenza vaccine, such as mannose-binding lectin opsonization of influenza and uptake by macrophages, and the capture of virus by dendritic cells residing in the medullary compartment of peripheral lymph nodes. The Journal of Immunology, 2010, 185: 2659-2664. C1 [Carroll, Michael C.] Childrens Hosp, Immune Dis Inst, WAB, Boston, MA 02115 USA. [Gonzalez, Santiago F.; Kuligowski, Michael P.; Pitcher, Lisa A.; Degn, Soren E.; Carroll, Michael C.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Gonzalez, Santiago F.; Lukacs-Kornek, Veronika; Kuligowski, Michael P.; Pitcher, Lisa A.; Degn, Soren E.; Turley, Shannon J.; Carroll, Michael C.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Lukacs-Kornek, Veronika; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Degn, Soren E.] Aarhus Univ, Dept Med Microbiol & Immunol, Aarhus, Denmark. RP Carroll, MC (reprint author), Childrens Hosp, Immune Dis Inst, WAB, 200 Longwood Ave,Room 251, Boston, MA 02115 USA. EM carroll@idi.harvard.edu OI Degn, Soren/0000-0001-5409-045X FU National Institutes of Health [5 RO1 AI039246, 1 PO1 AI078897, 5 RO1 AI067706, RO1 DK074500]; Glaxo-Smith Kline; Marie Curie International Outgoing Fellowship [220044]; National Institutes of Health Transfusion Biology and Medicine [5T32HL066987-09] FX This work was supported by National Institutes of Health Grants 5 RO1 AI039246, 1 PO1 AI078897, 5 RO1 AI067706 (to M.C.C.), and RO1 DK074500 (to S.J.T.); a Glaxo-Smith Kline postdoctoral fellowship award (to M. K.); Marie Curie International Outgoing Fellowship for Career Development Award 220044 (to S.F.G.); and National Institutes of Health Transfusion Biology and Medicine Training Grant 5T32HL066987-09 (to L.A.P.). NR 73 TC 14 Z9 14 U1 1 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2010 VL 185 IS 5 BP 2659 EP 2664 DI 10.4049/jimmunol.1000522 PG 6 WC Immunology SC Immunology GA 641JX UT WOS:000281122600005 PM 20724732 ER PT J AU Kim, ST Touma, M Takeuchi, K Sun, ZYJ Dave, VP Kappes, DJ Wagner, G Reinherz, EL AF Kim, Sun Taek Touma, Maki Takeuchi, Koh Sun, Zhen-Yu J. Dave, Vibhuti P. Kappes, Dietmar J. Wagner, Gerhard Reinherz, Ellis L. TI Distinctive CD3 Heterodimeric Ectodomain Topologies Maximize Antigen-Triggered Activation of alpha beta T Cell Receptors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CRYSTAL-STRUCTURE; ZETA-CHAIN; CD3-EPSILON-GAMMA HETERODIMER; STEPWISE EVOLUTION; THYMIC SELECTION; FG LOOP; COMPLEX; MICE; CD3-GAMMA; FRAGMENT AB The alpha beta TCR has recently been suggested to function as an anisotropic mechanosensor during immune surveillance, converting mechanical energy into a biochemical signal upon specific peptide/MHC ligation of the alpha beta clonotype. The heterodimeric CD3 epsilon gamma and CD3 epsilon delta subunits, each composed of two Ig-like ectodomains, form unique side-to-side hydrophobic interfaces involving their paired G-strands, rigid connectors to their respective transmembrane segments. Those dimers are laterally disposed relative to the alpha beta heterodimer within the TCR complex. In this paper, using structure-guided mutational analysis, we investigate the functional consequences of a striking asymmetry in CD3 gamma and CD3 delta G-strand geometries impacting ectodomain shape. The uniquely kinked conformation of the CD3 gamma G-strand is crucial for maximizing Ag-triggered TCR activation and surface TCR assembly/expression, offering a geometry to accommodate juxtaposition of CD3 gamma and TCR beta ectodomains and foster quaternary change that cannot be replaced by the isologous CD3 delta subunit's extracellular region. TCR beta and CD3 subunit protein sequence analyses among Gnathostomata species show that the C beta FG loop and CD3 gamma subunit coevolved, consistent with this notion. Furthermore, restoration of T cell activation and development in CD3 gamma(-/-) mouse T lineage cells by interspecies replacement can be rationalized from structural insights on the topology of chimeric mouse/human CD3 epsilon delta dimers. Most importantly, our findings imply that CD3 gamma and CD3 delta evolved from a common precursor gene to optimize peptide/MHC-triggered alpha beta TCR activation. The Journal of Immunology, 2010, 185: 2951-2959. C1 [Kim, Sun Taek; Touma, Maki; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. [Kim, Sun Taek; Touma, Maki; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kim, Sun Taek; Touma, Maki; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Takeuchi, Koh; Sun, Zhen-Yu J.; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Dave, Vibhuti P.] Clin Res Inst Montreal, Lymphocyte Dev Lab, Montreal, PQ H2W 1R7, Canada. [Kappes, Dietmar J.] Fox Chase Canc Ctr, Blood Cell Dev & Canc Program, Philadelphia, PA 19111 USA. RP Reinherz, EL (reprint author), 77 Ave Louis Pasteur,HIM 419, Boston, MA 02115 USA. EM ellis_reinherz@dfci.harvard.edu FU National Institutes of Health Research [AI19807, CA74620, AI37581, GM47467, EB002026]; Canadian Institutes of Health [81145] FX This work was supported by National Institutes of Health Grants AI19807 (to E.L.R.), CA74620 (to D.J.K.), AI37581, GM47467, and EB002026 (to G.W.), and Canadian Institutes of Health Research Grant 81145 (to V.P.D.). NR 49 TC 19 Z9 21 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2010 VL 185 IS 5 BP 2951 EP 2959 DI 10.4049/jimmunol.1000732 PG 9 WC Immunology SC Immunology GA 641JX UT WOS:000281122600038 PM 20660709 ER PT J AU Nemeth, T Futosi, K Hably, C Brouns, MR Jakob, SM Kovacs, M Kertesz, Z Walzog, B Settleman, J Mocsai, A AF Nemeth, Tamas Futosi, Krisztina Hably, Csilla Brouns, Madeleine R. Jakob, Sascha M. Kovacs, Miklos Kertesz, Zsuzsanna Walzog, Barbara Settleman, Jeffrey Mocsai, Attila TI Neutrophil Functions and Autoimmune Arthritis in the Absence of p190RhoGAP: Generation and Analysis of a Novel Null Mutation in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SRC FAMILY KINASES; GTPASE-ACTIVATING PROTEINS; GAP-ASSOCIATED PROTEINS; FC-GAMMA-RIII; RHO-GTPASE; RESPIRATORY BURST; REGULATES CELL; NADPH OXIDASE; ACTIN CYTOSKELETON; MURINE NEUTROPHILS AB beta(2) integrins of neutrophils play a critical role in innate immune defense, but they also participate in tissue destruction during autoimmune inflammation. p190RhoGAP (ArhGAP35), a regulator of Rho family small GTPases, is required for integrin signal transduction in fibroblasts. Prior studies have also suggested a role for p190RhoGAP in beta(2) integrin signaling in neutrophils. To directly test that possibility, we have generated a novel targeted mutation completely disrupting the p190RhoGAP-encoding gene in mice. p190RhoGAP deficiency led to perinatal lethality and defective neural development, precluding the analysis of neutrophil functions in adult p190RhoGAP(-/-) animals. This was overcome by transplantation of fetal liver cells from p190RhoGAP(-/-) fetuses into lethally irradiated wild-type recipients. Neutrophils from such p190RhoGAP(-/-) bone marrow chimeras developed normally and expressed normal levels of various cell surface receptors. Although p190RhoGAP(-/-) neutrophils showed moderate reduction of beta(2) integrin-mediated adherent activation, they showed mostly normal migration in beta(2) integrin-dependent in vitro and in vivo assays and normal beta(2) integrin-mediated killing of serum-opsonized Staphylococcus aureus and Escherichia coli. A neutrophil-and beta(2) integrin-dependent transgenic model of the effector phase of autoimmune arthritis also proceeded normally in p190RhoGAP(-/-) bone marrow chimeras. In contrast, all the above responses were completely blocked in CD18(-/-) neutrophils or CD18(-/-) bone marrow chimeras. These results suggest that p190RhoGAP likely does not play a major indispensable role in beta(2) integrin-mediated in vitro and in vivo neutrophil functions or the effector phase of experimental autoimmune arthritis. The Journal of Immunology, 2010, 185: 3064-3075. C1 [Nemeth, Tamas; Futosi, Krisztina; Hably, Csilla; Kovacs, Miklos; Kertesz, Zsuzsanna; Mocsai, Attila] Semmelweis Univ, Sch Med, Dept Physiol, H-1444 Budapest, Hungary. [Futosi, Krisztina] Semmelweis Univ, Sch Med, Dept Med Chem, H-1444 Budapest, Hungary. [Brouns, Madeleine R.; Settleman, Jeffrey] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Jakob, Sascha M.; Walzog, Barbara] Univ Munich, Walter Brendel Ctr Expt Med, Munich, Germany. RP Mocsai, A (reprint author), Semmelweis Univ, Sch Med, Dept Physiol, POB 259, H-1444 Budapest, Hungary. EM mocsai@eok.sote.hu RI Mocsai, Attila/B-2792-2008; OI Kovacs, Miklos/0000-0001-9650-3363; Nemeth, Tamas/0000-0001-6854-4301; Mocsai, Attila/0000-0002-0512-1157 FU European Research Council [206283]; Hungarian Office for Research and Technology [NKFP-A1-0069/2006]; Wellcome Trust [087782]; Deutsche Forschungsgemeinschaft [Wa 1048/2-3] FX This work was supported by the European Research Council (Starting Independent Investigator Award No. 206283 to A. M.), the Hungarian Office for Research and Technology (Anyos Jedlik Award No. NKFP-A1-0069/2006 to A. M.), the Wellcome Trust (International Senior Research Fellowship No. 087782 to A. M.), and the Deutsche Forschungsgemeinschaft (Wa 1048/2-3 to B.W.). NR 91 TC 18 Z9 18 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2010 VL 185 IS 5 BP 3064 EP 3075 DI 10.4049/jimmunol.0904163 PG 12 WC Immunology SC Immunology GA 641JX UT WOS:000281122600051 PM 20675588 ER PT J AU Cassol, E Malfeld, S Mahasha, P van der Merwe, S Cassol, S Seebregts, C Alfano, M Poli, G Rossouw, T AF Cassol, Edana Malfeld, Susan Mahasha, Phetole van der Merwe, Schalk Cassol, Sharon Seebregts, Chris Alfano, Massimo Poli, Guido Rossouw, Theresa TI Persistent Microbial Translocation and Immune Activation in HIV-1-Infected South Africans Receiving Combination Antiretroviral Therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIV-INFECTED PATIENTS; T-CELL-ACTIVATION; VIRUS TYPE-1 INFECTION; MONOCYTE SUBSET; RNA LEVELS; PLASMA-LIPOPROTEINS; DISEASE PROGRESSION; INNATE IMMUNITY; AIDS PATIENTS; VIRAL LOAD AB Background. Microbial translocation contributes to immune activation and disease progression during chronic human immunodeficiency virus type 1 (HIV-1) infection. However, its role in the African AIDS epidemic remains controversial. Here, we investigated the relationship between markers of monocyte activation, plasma lipopolysaccharide (LPS), and HIV-1 RNA in South Africans prioritized to receive combination antiretroviral therapy (cART). Methods. Ten HIV-1-negative African controls and 80 HIV-1-infected patients with CD4 T cell counts <200 cells/mu L were sampled prior to (n = 60) or during (n = 20) receipt of effective cART. Viral load was measured by Nuclisens; LPS by the Limulus amoebocyte lysate assay; monocyte and T cell subsets by flow cytometry; and soluble CD14, cytokines, and chemokines by enzyme-linked immunosorbent assay and customized Bio-Plex plates. Results. Three distinct sets of markers were identified. CCL2, CXCL10, and CD14(+)CD16(+) monocyte levels were positively correlated with HIV-1 viremia. This finding, together with cART-induced normalization of these markers, suggests that their upregulation was driven by HIV-1. Plasma interleukin-6 was associated with the presence of opportunistic coinfections. Soluble CD14 and tumor necrosis factor were linked to plasma LPS levels and, as observed for LPS, remained elevated in patients receiving effective cART. Conclusions. Microbial translocation is a major force driving chronic inflammation in HIV-infected Africans receiving cART. Prevention of monocyte activation may be especially effective at enhancing therapeutic outcomes. C1 [Cassol, Edana; Malfeld, Susan; Mahasha, Phetole; van der Merwe, Schalk; Cassol, Sharon; Rossouw, Theresa] Univ Pretoria, Fac Hlth Sci, MRC Unit Inflammat & Immun, Dept Immunol, ZA-0002 Pretoria, South Africa. [van der Merwe, Schalk] Univ Pretoria, Fac Hlth Sci, Hepatol & GI Res Lab, Dept Immunol, ZA-0002 Pretoria, South Africa. Natl Hlth Lab Serv, Tshwane Acad Div, Pretoria, South Africa. [Seebregts, Chris] MRC, Tygerberg, South Africa. [Cassol, Edana; Alfano, Massimo; Poli, Guido] Ist Sci San Raffaele, Div Immunol Transplantat & Infect Dis, AIDS Immunopathogenesis Unit, I-20132 Milan, Italy. [Cassol, Edana; Poli, Guido] Univ Vita Salute San Raffaele, Sch Med, Milan, Italy. RP Cassol, E (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,CLS 1017, Boston, MA 02115 USA. EM edana_cassol@dfci.harvard.edu FU EU [2007 174-790]; National Research Council of South Africa [61509] FX EU Grant Sante 2007 174-790 (to C. S. and S. C.) and National Research Council of South Africa, Unlocking the Future 61509 (to S. C. and S.v.d.M.). NR 49 TC 105 Z9 106 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 1 PY 2010 VL 202 IS 5 BP 723 EP 733 DI 10.1086/655229 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 634ZB UT WOS:000280623800010 PM 20629534 ER PT J AU Teten, AL Schumacher, JA Taft, CT Stanley, MA Kent, TA Bailey, SD Dunn, NJ White, DL AF Teten, Andra L. Schumacher, Julie A. Taft, Casey T. Stanley, Melinda A. Kent, Thomas A. Bailey, Sara D. Dunn, Nancy Jo White, Donna L. TI Intimate Partner Aggression Perpetrated and Sustained by Male Afghanistan, Iraq, and Vietnam Veterans With and Without Posttraumatic Stress Disorder SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE posttraumatic stress disorder; intimate partner aggression; domestic violence; veterans ID COMBAT VETERANS; INTERGENERATIONAL TRANSMISSION; RISK-FACTORS; MILITARY VETERANS; ALCOHOL-PROBLEMS; PHYSICAL ABUSE; VIOLENCE; ANGER; HOSTILITY; WAR AB Veterans with posttraumatic stress disorder (PTSD) consistently evidence higher rates of intimate partner aggression perpetration than veterans without PTSD, but most studies have examined rates of aggression among Vietnam veterans several years after their deployment. The primary aim of this study was to examine partner aggression among male Afghanistan or Iraq veterans who served during Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) and compare this aggression to that reported by Vietnam veterans with PTSD. Three groups were recruited, OEF/OIF veterans with PTSD (n = 27), OEF/OIF veterans without PTSD (n = 31), and Vietnam veterans with PTSD (n = 28). Though only a few comparisons reached significance, odds ratios suggested that male OEF/OIF veterans with PTSD were approximately 1.9 to 3.1 times more likely to perpetrate aggression toward their female partners and 1.6 to 6 times more likely to report experiencing female perpetrated aggression than the other two groups. Significant correlations among reports of violence perpetrated and sustained suggested many men may have been in mutually violent relationships. Taken together, these results suggest that partner aggression among Iraq and Afghanistan veterans with PTSD may be an important treatment consideration and target for prevention. C1 [Stanley, Melinda A.; White, Donna L.] Michael E DeBakey VA Med Ctr, HCQCUS, Houston, TX USA. [Bailey, Sara D.; Dunn, Nancy Jo] Michael E DeBakey VA Med Ctr, Trauma Recovery Program, Houston, TX USA. [Teten, Andra L.; Stanley, Melinda A.; Kent, Thomas A.; Bailey, Sara D.; Dunn, Nancy Jo] S Cent Mental Illness Res Educ & Clin Ctr MIRECC, Houston, TX USA. [Stanley, Melinda A.] Baylor Coll Med, Div Psychol, Houston, TX 77030 USA. [Bailey, Sara D.; Dunn, Nancy Jo] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [White, Donna L.] Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [White, Donna L.] Baylor Coll Med, Gastroenterol Sect, Houston, TX 77030 USA. [Schumacher, Julie A.] Univ Mississippi, Med Ctr, University, MS 38677 USA. [Taft, Casey T.] VA Boston Healthcare Syst, Natl Ctr PTSD, Behav Sci Div, Boston, MA USA. [Taft, Casey T.] Boston Univ, Sch Med, Boston, MA 02215 USA. RP Teten, AL (reprint author), Ctr Dis Control & Prevent, Div Violence Prevent, Natl Ctr Injury Prevent & Control, 4770 Buford Hwy MS F-64, Atlanta, GA 30341 USA. EM ateten@cdc.gov OI Kent, Thomas/0000-0002-9877-7584 NR 43 TC 50 Z9 50 U1 2 U2 15 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD SEP PY 2010 VL 25 IS 9 BP 1612 EP 1630 DI 10.1177/0886260509354583 PG 19 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA 635OT UT WOS:000280665800004 PM 20023200 ER PT J AU Tian, F Lee, SW AF Tian, Fang Lee, Sam W. TI X-Linked Inhibitor of Apoptosis Protein as a Therapeutic Target in Metastatic Melanoma SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID ENDOPLASMIC-RETICULUM-STRESS; XIAP; DEATH; CELLS AB Melanoma is the most dangerous type of skin cancer, with notorious resistance to current chemotherapy and immunotherapy. In this issue, Hiscutt et al. report on the prognostic significance of X-linked inhibitor of apoptosis protein (XIAP) in melanoma. The finding that XIAP inhibition significantly increases endoplasmic reticulum stress-mediated apoptosis in melanoma cells suggests that XIAP is a potential therapeutic target for melanoma therapy. C1 [Tian, Fang; Lee, Sam W.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. [Tian, Fang; Lee, Sam W.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Lee, SW (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. EM swlee@partners.org FU NCI NIH HHS [R01 CA085681] NR 13 TC 4 Z9 6 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2010 VL 130 IS 9 BP 2169 EP 2172 DI 10.1038/jid.2010.205 PG 5 WC Dermatology SC Dermatology GA 638RA UT WOS:000280912100004 PM 20711206 ER PT J AU Pena-Cruz, V McDonough, SM Diaz-Griffero, F Crum, CP Carrasco, RD Freeman, GJ AF Pena-Cruz, Victor McDonough, Sean M. Diaz-Griffero, Felipe Crum, Christopher P. Carrasco, Ruben D. Freeman, Gordon J. TI PD-1 on Immature and PD-1 Ligands on Migratory Human Langerhans Cells Regulate Antigen-Presenting Cell Activity SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID PROGRAMMED DEATH-1 PD-1; ACTIVATED T-CELLS; DENDRITIC CELLS; STEADY-STATE; CONTACT HYPERSENSITIVITY; SIGNAL-TRANSDUCTION; TYROSINE KINASE; EXPRESSION; RECEPTOR; TOLERANCE AB Langerhans cells (LCs) are known as "sentinels'' of the immune system that function as professional antigen-presenting cells (APCs) after migration to draining lymph node. LCs are proposed to have a role in tolerance and the resolution of cutaneous immune responses. The Programmed Death-1 (PD-1) receptor and its ligands, PD-L1 and PD-L2, are a co-inhibitory pathway that contributes to the negative regulation of T-lymphocyte activation and peripheral tolerance. Surprisingly, we found PD-1 to be expressed on immature LCs (iLCs) in situ. PD-1 engagement on iLCs reduced IL-6 and macrophage inflammatory protein (MIP)-1 alpha cytokine production in response to TLR2 signals but had no effect on LC maturation. PD-L1 and PD-L2 were expressed at very low levels on iLCs. Maturation of LCs upon migration from epidermis led to loss of PD-I expression and gain of high expression of PD-L1 and PD-L2 as well as co-stimulatory molecules. Blockade of PD-L1 and/or PD-L2 on migratory LCs (mLCs) and DDCs enhanced T-cell activation, as has been reported for other APCs. Thus the PD-1 pathway is active in iLCs and inhibits iLC activities, but expression of receptor and ligands reverses upon maturation and PD-L1 and PD-L2 on mLC function to inhibit T-cell responses. C1 [Pena-Cruz, Victor; McDonough, Sean M.; Carrasco, Ruben D.; Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Diaz-Griffero, Felipe] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Crum, Christopher P.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Freeman, GJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,Meyer Bldg,Room 5, Boston, MA 02115 USA. EM gordon_freeman@dfci.harvard.edu FU NIH [A108080192, A1056299, BAA-05-11] FX We thank Dr Branch D. Moody for providing us with the Pam3Cys. This work was supported by NIH grants A108080192, A1056299, and BAA-05-11. NR 49 TC 13 Z9 13 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2010 VL 130 IS 9 BP 2222 EP 2230 DI 10.1038/jid.2010.127 PG 9 WC Dermatology SC Dermatology GA 638RA UT WOS:000280912100010 PM 20445553 ER PT J AU Mairhofer, D Kitzwogerer, M Nazarian, RM Lobo, A Geller, RJ Mihm, MC Jonak, C Trautinger, F AF Mairhofer, Daniela Kitzwoegerer, Melitta Nazarian, Rosalynne M. Lobo, Alice Geller, Richard J. Mihm, Martin C. Jonak, Constanze Trautinger, Franz TI Expression of the 27kD and 90kD heat shock proteins in psoriatic skin SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Society-for-Dermatological-Research (ESDR 2010) CY SEP 08-11, 2010 CL Helsinki, FINLAND SP European Soc Dermatolog Res C1 [Mairhofer, Daniela; Kitzwoegerer, Melitta; Trautinger, Franz] Karl Landsteiner Inst Derm Res, St Polten, Austria. [Mairhofer, Daniela; Trautinger, Franz] Landesklinikum, Dept Dermatol, St Polten, Austria. [Kitzwoegerer, Melitta] Landesklinikum, Dept Pathol, St Polten, Austria. [Nazarian, Rosalynne M.; Lobo, Alice; Mihm, Martin C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Jonak, Constanze] Med Univ Vienna, Dept Dermatol, Vienna, Austria. [Geller, Richard J.] Emerson Hosp, Concord, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2010 VL 130 SU 2 BP S13 EP S13 PG 1 WC Dermatology SC Dermatology GA 641FL UT WOS:000281110100075 ER PT J AU Wu, XW Nguyen, BC Dziunycz, P Chang, SE Brooks, Y Lefort, K Hofbauer, G Dotto, GP AF Wu, Xunwei Nguyen, Bach-Cuc Dziunycz, Piotr Chang, Sungeun Brooks, Yang Lefort, Karine Hofbauer, Guenther Dotto, G. Paolo TI Calcineurin and ATF3: opposite role in keratinocyte cancer development versus senescence SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Meeting Abstract CT 40th Annual Meeting of the European-Society-for-Dermatological-Research (ESDR 2010) CY SEP 08-11, 2010 CL Helsinki, FINLAND SP European Soc Dermatolog Res C1 [Wu, Xunwei; Nguyen, Bach-Cuc; Chang, Sungeun; Brooks, Yang; Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Dziunycz, Piotr; Hofbauer, Guenther] Univ Zurich Hosp, Dermatol Dpt, CH-8091 Zurich, Switzerland. [Lefort, Karine; Dotto, G. Paolo] Univ Lausanne, Biochem Dpt, Lausanne, Switzerland. RI Hofbauer, Gunther/B-2671-2010 OI Hofbauer, Gunther/0000-0003-0542-7989 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2010 VL 130 SU 2 BP S51 EP S51 PG 1 WC Dermatology SC Dermatology GA 641FL UT WOS:000281110100303 ER PT J AU Tanaka, N Abe-Dohmae, S Iwamoto, N Fitzgerald, ML Yokoyama, S AF Tanaka, Nobukiyo Abe-Dohmae, Sumiko Iwamoto, Noriyuki Fitzgerald, Michael L. Yokoyama, Shinji TI Helical apolipoproteins of high-density lipoprotein enhance phagocytosis by stabilizing ATP-binding cassette transporter A7 SO JOURNAL OF LIPID RESEARCH LA English DT Article DE ABCA7; apoA-I; HDL; phagocytosis; ABCA1; cholesterol ID CELLULAR CHOLESTEROL; TANGIER-DISEASE; APOA-I; SJOGRENS-SYNDROME; APOPTOTIC CELLS; UNILAMELLAR VESICLES; HDL GENERATION; LIPID RELEASE; HUMAN ABCA7; X RECEPTOR AB We previously reported that the endogenous ATP-binding cassette transporter (ABC)A7 strongly associates with phagocytic function rather than biogenesis of high-density lipoprotein (HDL), being regulated by sterol-regulatory element binding protein (SREBP)2. Phagocytic activity was found enhanced by apolipoprotein (apo) A-I and apoA-II more than twice the maximum in J774 and mouse peritoneal macrophages. Therefore we investigated the molecular basis of this reaction in association with the function of ABCA7. Similar to ABCA1, ABCA7 was degraded, likely by calpain, and apoA-I and apoA-II stabilize ABCA7 against degradation. Cell surface biotinylation experiments demonstrated that endogenous ABCA7 predominantly resides on the cell surface and that the apolipoproteins increase the surface ABCA7. The increase of phagocytosis by apolipoproteins was retained in the J774 cells treated with ABCA1 siRNA and in the peritoneal macrophages from ABCA1-knockout mice, but it was abolished in the J774 cells treated with ABCA7 siRNA and in the peritoneal macrophages from ABCA7-knockout mice. Phagocytosis was decreased in the cells in the peritoneal cavity of the ABCA7-knockout mouse compared with the wild-type control. We thus concluded that extracellular helical apolipoproteins augment ABCA7-associated phagocytosis by stabilizing ABCA7. The results demonstrated direct enhancement of the host defense system by HDL components.-Tanaka, N., S. Abe-Dohmae, N. Iwamoto, M. L. Fitzgerald, and S. Yokoyama. Helical apolipoproteins of high-density lipoprotein enhance phagocytosis by stabilizing ATP-binding cassette transporter A7. J. Lipid Res. 2010. 51: 2591-2599. C1 [Tanaka, Nobukiyo; Abe-Dohmae, Sumiko; Iwamoto, Noriyuki; Yokoyama, Shinji] Nagoya City Univ, Grad Sch Med Sci, Dept Biochem, Nagoya, Aichi, Japan. [Fitzgerald, Michael L.] Massachusetts Gen Hosp, Lipid Metab Unit, Boston, MA 02114 USA. [Fitzgerald, Michael L.] Harvard Univ, Sch Med, Partners Healthcare Ctr Genet & Genom, Boston, MA USA. RP Abe-Dohmae, S (reprint author), Nagoya City Univ, Grad Sch Med Sci, Dept Biochem, Nagoya, Aichi, Japan. EM bc.abedo@med.nagoya-cu.ac.jp FU Ministry of Education, Science, Technology, Culture and Sports; Ministry of Health, Welfare and Labor of Japan; National Institute of Biomedical Innovation of Japan; Nagoya City University of Japan; National Institutes of Health [HL-074136] FX This study was supported by grants-in-aid and by the program for developing the supporting system for upgrading the education and research from the Ministry of Education, Science, Technology, Culture and Sports and Ministry of Health, Welfare and Labor of Japan; by the program for promotion of fundamental studies in health sciences of the National Institute of Biomedical Innovation of Japan; and by grant-in-aid for research at Nagoya City University of Japan. Generation of the ABCA7-knockout mice was funded by National Institutes of Health Grant HL-074136 (M.L.F.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or other granting agencies. NR 42 TC 21 Z9 22 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD SEP PY 2010 VL 51 IS 9 BP 2591 EP 2599 DI 10.1194/jlr.M006049 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 637FA UT WOS:000280800200010 PM 20495215 ER PT J AU Lee, MH Hammad, SM Semler, AJ Luttrell, LM Lopes-Virella, MF Klein, RL AF Lee, Mi-Hye Hammad, Samar M. Semler, Andrea J. Luttrell, Louis M. Lopes-Virella, Maria F. Klein, Richard L. TI HDL3, but not HDL2, stimulates plasminogen activator inhibitor-1 release from adipocytes: the role of sphingosine-1-phosphate SO JOURNAL OF LIPID RESEARCH LA English DT Article DE plasminogen activator inhibitor-1; fibrinolysis; lipoprotein; high-density lipoprotein ID SPHINGOSINE 1-PHOSPHATE RECEPTORS; DENSITY-LIPOPROTEIN BINDING; CORONARY-ARTERY-DISEASE; VEIN ENDOTHELIAL-CELLS; NITRIC-OXIDE SYNTHASE; SCAVENGER RECEPTOR; BIOLOGICAL-ACTIVITIES; GENE-EXPRESSION; ADIPOSE-TISSUE; CLASS-B AB Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that regulates numerous key cardiovascular functions. High-density lipoproteins (HDLs) are the major plasma lipoprotein carriers of S1P. Fibrinolysis is a physiological process that allows fibrin clot dissolution, and decreased fibrinolytic capacity may result from increased circulating levels of plasminogen activator inhibitor-1 (PAI-1). We examined the effect of S1P associated with HDL sub-fractions on PAI-1 secretion from 3T3 adipocytes. S1P concentration in HDL3 averaged twice that in HDL2. Incubation of adipocytes with increasing concentrations of S1P in HDL3, but not HDL2, or with S1P complexed to albumin stimulated PAI-I secretion in a concentration-dependent manner. Quantitative RT-PCR revealed that S1P(1-3) are expressed in 3T3 adipocytes, with S1P(2) expressed in the greatest amount. Treatment of adipocytes with the S1P(1) and S1P(3) antagonist VPC23019 did not block PAI-1 secretion. Inhibiting S1P(2) with JTE-013 or reducing the expression of the gene coding for S1P(2) using silencing RNA (siRNA) technology blocked PAI-1 secretion, suggesting that the S1P(2) receptor mediates PAI-1 secretion from adipocytes exposed to HDL3 or S1P. Treatment with the phospholipase C (PLC) inhibitor U73122, the protein kinase C (PKC) inhibitor RO-318425, or the Rho-associated protein kinase (ROCK) inhibitor Y27632 all significantly inhibited HDL3- and S1P-mediated PAI-1 release, suggesting that HDL3- and/or S1P-stimulated PAI-1 secretion from 3T3 cells is mediated by activation of multiple, downstream signaling pathways of S1P(2).-Lee, M-H., S. M. Hammad, A. J. Semler, L M. Luttrell, M. F. Lopes-Virella, and R. L. Klein. HDL3, but not HDL2, stimulates plasminogen activator inhibitor-1 release from adipocytes: the role of sphingosine-1-phosphate. J. Lipid Res. 2010. 51: 2619-2628. C1 [Lee, Mi-Hye; Semler, Andrea J.; Luttrell, Louis M.; Lopes-Virella, Maria F.; Klein, Richard L.] Med Univ S Carolina, Div Endocrinol Metab & Med Genet, Charleston, SC 29425 USA. [Hammad, Samar M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Hammad, Samar M.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Luttrell, Louis M.; Lopes-Virella, Maria F.; Klein, Richard L.] Ralph H Johnson Dept Vet Affairs Med Ctr, Res Serv, Charleston, SC USA. RP Klein, RL (reprint author), Med Univ S Carolina, Div Endocrinol Metab & Med Genet, Charleston, SC 29425 USA. EM kleinrl@musc.edu FU National Institutes of Health [P01 HL-55782, DK-081352, HL-079274]; Department of Veterans Affairs; National Center for Research Resources (NCRR) [P20 RR-17677]; Medical University of South Carolina FX This work was supported by National Institutes of Health Grants P01 HL-55782 (M.L.V), DK-081352 (M.L.V.), and HL-079274 (S.M.H.). This work was also supported by the Merit Review Program of the Department of Veterans Affairs (R.L.K. and M.L.V.), the South Carolina COBRE in Lipidomics and Pathobiology (P20 RR-17677 from the National Center for Research Resources (NCRR) (S.M.H.), and the Lipidomics Core Facility at the Medical University of South Carolina. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or other granting agencies. NR 51 TC 21 Z9 21 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD SEP PY 2010 VL 51 IS 9 BP 2619 EP 2628 DI 10.1194/jlr.M003988 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 637FA UT WOS:000280800200013 PM 20522601 ER PT J AU Cho, JH Cho, G Song, Y Lee, C Park, BW Lee, CK Kim, N Park, SB Kang, JS Kang, MR Kim, HM Kim, YR Cho, KS Kim, JK AF Cho, Jee-Hyun Cho, Gyunggoo Song, Youngkyu Lee, Chulhyun Park, Bum-Woo Lee, Chang Kyung Kim, Namkug Park, Sung Bin Kang, Jong Soon Kang, Moo Rim Kim, Hwan Mook Kim, Young Ro Cho, Kyoung-Sik Kim, Jeong Kon TI Feasibility of FAIR Imaging for Evaluating Tumor Perfusion SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE flow-sensitive alternating inversion recovery; arterial spin labeling; blood flow; angiogenesis; magnetic resonance imaging ID CEREBRAL-BLOOD-FLOW; KINETIC-PARAMETERS; ANGIOGENESIS; MRI; QUANTIFICATION; TRACER; IMAGES; TIME AB Purpose: To evaluate the feasibility of flow-sensitive alternating inversion recovery (FAIR) for measuring blood flow in tumor models. Materials and Methods: In eight mice tumor models, FAIR and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed. The reliability for measuring blood flow on FAIR was evaluated using the coefficient of variation of blood flow on psoas muscle. Three regions of interest (ROIs) were drawn in the peripheral, intermediate, and central portions within each tumor. The location of ROI was the same on FAIR and DCE-MR images. The correlation between the blood flow on FAIR and perfusion-related parameters on DCE-MRI was evaluated using the Pearson correlation coefficient. Results: The coefficient of variation for measuring blood flow was 9.8%. Blood flow on FAIR showed a strong correlation with Kep (r = 0.77), percent relative enhancement (r = 0.731, and percent enhancement ratio (r = 0.81). The mean values of blood flow (mL/100 g/min) (358 vs. 207), Kep (sec(-1)) (7.46 vs. 1.31), percent relative enhancement (179% vs. 134%), and percent enhancement ratio (42% vs. 26%) were greater in the peripheral portion than in the central portion (P < 0.01). Conclusion: As blood flow measurement on FAIR is reliable and closely related with that on DCE-MR, FAIR is feasible for measuring tumor blood flow. C1 [Park, Bum-Woo; Lee, Chang Kyung; Kim, Namkug; Cho, Kyoung-Sik; Kim, Jeong Kon] Univ Ulsan, Coll Med, Dept Radiol, Res Inst Radiol,Med Imaging Lab,Asan Med Ctr, Seoul 138736, South Korea. [Cho, Jee-Hyun; Cho, Gyunggoo; Song, Youngkyu; Lee, Chulhyun] Korea Basic Sci Inst, Div Magnet Resonance, Cheongwon 363883, Chungbuk, South Korea. [Park, Sung Bin] Univ Ulsan, Ulsan Univ Hosp, Dept Radiol, Seoul 138736, South Korea. [Kang, Jong Soon; Kang, Moo Rim; Kim, Hwan Mook] Korean Res Inst Biosci & Biotechnol, Bioevaluat Ctr, Cheongwon, Chungbuk, South Korea. [Kim, Young Ro] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Kim, JK (reprint author), Univ Ulsan, Coll Med, Dept Radiol, Res Inst Radiol,Med Imaging Lab,Asan Med Ctr, 388-1 Poongnap Dong, Seoul 138736, South Korea. EM rialto@amc.seoul.kr FU Ministry for Health, Welfare Family Affairs [A090754]; Ministry of Education, Science and Technology [2009-0066963]; Korean Basic Science Institute [T30403] FX Contract grant sponsor: Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs; Contract grant number: A090754; Contract grant sponsor: Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology; Contract grant number: 2009-0066963; Contract grant sponsor: Korean Basic Science Institute; Contract grant number: T30403. NR 20 TC 7 Z9 9 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD SEP PY 2010 VL 32 IS 3 BP 738 EP 744 DI 10.1002/jmri.22298 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 646IK UT WOS:000281532700028 PM 20815076 ER PT J AU Dovydaitis, T AF Dovydaitis, Tiffany TI Human Trafficking: The Role of the Health Care Provider SO JOURNAL OF MIDWIFERY & WOMENS HEALTH LA English DT Article DE case study; human trafficking; immigrant; sex trafficking; women's health care AB Human trafficking is a major public health problem, both domestically and internationally. Health care providers are often the only professionals to interact with trafficking victims who are still in captivity. The expert assessment and interview skills of providers contribute to their readiness to identify victims of trafficking. The purpose of this article is to provide clinicians with knowledge on trafficking and give specific tools that they may use to assist victims in the clinical setting. Definitions, statistics, and common health care problems of trafficking victims are reviewed. The role of the health care provider is outlined through a case study and clinical practice tools are provided. Suggestions for future research are also briefly addressed. J Midwifery Womens Health 2010; 55: 462-467 (C) 2010 by the American College of Nurse-Midwives. C1 Univ Penn, Sch Nursing, Ctr Hlth Equ Res, Philadelphia, PA 19104 USA. RP Dovydaitis, T (reprint author), Univ Penn, Sch Nursing, Ctr Hlth Equ Res, Claire M Fagin Hall,418 Curie Blvd,Floor 2L, Philadelphia, PA 19104 USA. EM dtiffany@nursing.upenn.edu FU NINR NIH HHS [T32 NR007100, T32 NR007100-13] NR 28 TC 25 Z9 25 U1 3 U2 39 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1526-9523 J9 J MIDWIFERY WOM HEAL JI J. Midwifery Women Health PD SEP-OCT PY 2010 VL 55 IS 5 BP 462 EP 467 DI 10.1016/j.jmwh.2009.12.017 PG 6 WC Nursing SC Nursing GA 641PV UT WOS:000281142200011 PM 20732668 ER PT J AU Brooks, WW Shen, S Conrad, CH Goldstein, RH Deng, LL Bing, OHL AF Brooks, Wesley W. Shen, Steven Conrad, Chester H. Goldstein, Ronald H. Deng, Lingyi Lynn Bing, Oscar H. L. TI Transcriptional changes associated with recovery from heart failure in the SHR SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Heart failure; Hypertension; Cardiac hypertrophy; Gene expression profiling; Angiotensin converting enzyme inhibition; Phenylbutyrate ID SPONTANEOUSLY HYPERTENSIVE-RAT; TUMOR-NECROSIS-FACTOR; CONVERTING ENZYME-INHIBITION; MATRIX-METALLOPROTEINASE ACTIVITY; LEFT-VENTRICULAR HYPERTROPHY; CARDIAC GENE-EXPRESSION; MYOCARDIAL FIBROSIS; MICROARRAY ANALYSIS; FAILING MYOCARDIUM; ENERGY-METABOLISM AB To identify biological pathways associated with myocardial recovery from heart failure (HF), gene profiling and gene set enrichment analysis (GSEA) were examined in left ventricle of spontaneously hypertensive rats with HF (SHR-F) with no treatment, following treatment with the angiotensin converting enzyme inhibitor captopril, and treatment with captopril combined with the short chain fatty acid derivative phenylbutyrate. Failing hearts demonstrated depressed left ventricular ejection fraction, while ventricular volume and mass increased. Captopril treatment alone prevented further deterioration but did not improve myocardial function; relatively few transcripts were differentially expressed relative to untreated SHR-F. Gene sets identified by GSEA as downregulated with captopril treatment compared to SHR-F group included those related to hypoxia and reactive oxygen species, while upregulated gene sets included G protein signaling. Treatment with phenylbutyrate alone did not improve survival (no animals in this group survived the 30 day treatment period), while phenylbutyrate combined with captopril increased survival and significantly improved cardiac function in vivo and in vitro. Normalized microarray data identified 780 genes that demonstrated a combined treatment effect of which 258 genes were modified with HF. Fatty acid metabolism and ion transport were among the most significantly upregulated pathways in the combined treatment group compared to untreated SHR with HF, whereas those related to oxidative stress, growth, inflammation, protein degradation, and TGF-beta signaling were downregulated. These findings demonstrate improved myocardial function and regression of cardiac hypertrophy, and identify many HF related gene sets altered with phenylbutyrate and captopril treatment, but not captopril alone. These results characterize gene sets associated with recovery from HF, and suggest that phenylbutyrate may be a potentially effective adjunctive treatment, together with captopril, by synergistically modulating pathways that contribute to restoration of contractile function of the failing SHR heart. Published by Elsevier Ltd. C1 [Brooks, Wesley W.; Conrad, Chester H.; Goldstein, Ronald H.; Deng, Lingyi Lynn; Bing, Oscar H. L.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Brooks, Wesley W.; Conrad, Chester H.; Goldstein, Ronald H.; Deng, Lingyi Lynn; Bing, Oscar H. L.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Shen, Steven] Boston Univ, Sch Med, Clin & Translat Sci Inst, Boston, MA 02118 USA. RP Brooks, WW (reprint author), VA Boston Hlth Care Syst 151, Res Bldg R-124,150 S Huntington Ave, Boston, MA 02130 USA. EM brooksww@bu.edu; chester.conrad@va.gov OI Shen, Steven/0000-0001-7725-1260 FU Department of Veterans Affairs FX This work was supported by Medical Research Funds from the Department of Veterans Affairs. NR 55 TC 2 Z9 2 U1 0 U2 1 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 SEP PY 2010 VL 49 IS 3 BP 390 EP 401 DI 10.1016/j.yjmcc.2010.06.002 PG 12 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 640VU UT WOS:000281082900008 PM 20547165 ER PT J AU Lennerz, JK Timmerman, RJ Grange, DK DeBaun, MR Feinberg, AP Zehnbauer, BA AF Lennerz, Jochen K. Timmerman, Robert J. Grange, Dorothy K. DeBaun, Michael R. Feinberg, Andrew P. Zehnbauer, Barbara A. TI Addition of H19 'Loss of Methylation Testing' for Beckwith-Wiedemann Syndrome (BWS) Increases the Diagnostic Yield SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID ASSISTED REPRODUCTIVE TECHNOLOGIES; MONOZYGOTIC TWINS DISCORDANT; NEONATAL DIABETES-MELLITUS; POLYMERASE-CHAIN-REACTION; IN-VITRO FERTILIZATION; UNIPARENTAL DISOMY; DNA METHYLATION; WILMS-TUMOR; ISOLATED HEMIHYPERPLASIA; IMPRINTED GENES AB Beckwith-Wiedemann syndrome (BWS) is a clinical diagnosis; however, molecular confirmation via abnormal methylation of DMR2(LIT1) and/or DMR1(H19) has clinical utility due to epigenotype-tumor association. Despite the strong link between H19 hypermethylation and tumor risk, several diagnostic laboratories only test for hypomethylation of LIT1 We assessed the added diagnostic value of combined LIT1 and H19 testing in a large series of referred samples from 1298 patients, including 53 well-characterized patients from the St. Louis Children's Hospital BWS-Registry (validation samples) and 1245 consecutive nationwide referrals (practice samples). Methylation-sensitive enzymatic digestion with Southern hybridization assessed loss of normal imprinting. In the validation group, abnormal LIT1 hypomethylation was detected in 60% (32/52) of patients but LIT1/H19-combined testing was abnormal in 68% (36/53); sensitivity in the practice setting demonstrated 27% (342/1245) abnormal LIT1 and 32% (404/1245) abnormal LIT1/H19-combined. In addition, H19 methylation was abnormal in 7% of LIT1-normal patients. We observed absence of uniparental disomy (UPD) in 27% of combined LIT1/H19-abnormal samples, diagnostic of multilocus methylation abnormalities; in contrast to studies implicating that combined LIT1/H19 abnormalities are diagnostic of UPD. The overall low detection rate, even in validated patient samples and despite characterization of both loci and UPD status, emphasizes the importance of clinical diagnosis in BWS. (J Mol Diagn 2010, 12:576-588 DOI: 10.2353/jmoldx.2010.100005) C1 [Zehnbauer, Barbara A.] Ctr Dis Control & Prevent, CDC, Div Lab Syst, Lab Practice Evaluat, Atlanta, GA 30329 USA. [Lennerz, Jochen K.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Lennerz, Jochen K.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Grange, Dorothy K.] Washington Univ, Sch Med, Dept Pediat, Div Genet & Genom Med, St Louis, MO 63110 USA. [DeBaun, Michael R.] Washington Univ, Sch Med, Div Hematol Oncol, St Louis, MO 63110 USA. [Timmerman, Robert J.] St Johns Mercy Med Ctr, Mol Diagnost Lab, Des Moines, IA USA. [Feinberg, Andrew P.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Zehnbauer, Barbara A.] Ctr Dis Control & Prevent, CDC, Div Lab Syst, Genom Branch, Atlanta, GA 30329 USA. RP Zehnbauer, BA (reprint author), Ctr Dis Control & Prevent, CDC, Div Lab Syst, Lab Practice Evaluat, 1600 Clifton Rd NE,Mail Stop G23, Atlanta, GA 30329 USA. EM bzehnbauer@cdc.gov FU National Institutes of Health [CA54358] FX Supported by National Institutes of Health grant CA54358 (to A.P.F.). NR 129 TC 3 Z9 4 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD SEP PY 2010 VL 12 IS 5 BP 576 EP 588 DI 10.2353/jmoldx.2010.100005 PG 13 WC Pathology SC Pathology GA 648JW UT WOS:000281690800005 PM 20616360 ER PT J AU Wen, PY Quant, E Drappatz, J Beroukhim, R Norden, AD AF Wen, Patrick Y. Quant, Eudocia Drappatz, Jan Beroukhim, Rameen Norden, Andrew D. TI Medical therapies for meningiomas SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE Meningiomas; Chemotherapy; Hormonal therapy; Antiangiogenic therapies; Targeted molecular therapies ID EPIDERMAL-GROWTH-FACTOR; SIGNAL-TRANSDUCTION PATHWAYS; OF-THE-LITERATURE; PHASE-II TRIAL; FACTOR RECEPTOR; RECURRENT MENINGIOMAS; MALIGNANT MENINGIOMAS; IN-VIVO; INTERFERON-ALPHA; INTRACRANIAL MENINGIOMAS AB Meningiomas are the most common primary brain tumor in adults. Although the majority of these tumors can be effectively treated with surgery and radiation therapy, an important subset of patients have inoperable tumors, or develop recurrent disease after surgery and radiotherapy, and require some form of medical therapy. There are increasing numbers of studies evaluating various medical therapies but the results remain disappointing. Chemotherapies and hormonal therapies have been generally ineffective, although somatostatin analogues may have therapeutic potential. There is also increasing interest in targeted molecular therapies. Agents inhibiting platelet derived growth factor receptors and epidermal growth factor receptors have shown little efficacy, but molecular agents inhibiting vascular endothelial growth factor receptors appear to have some promise. As with other tumors, advances in the medical therapies for meningiomas will require improved understanding of the molecular pathogenesis of these tumors, more predictive preclinical models, and efficient mechanisms for conducting clinical trials, given the small population of eligible patients. C1 [Wen, Patrick Y.; Quant, Eudocia; Drappatz, Jan; Beroukhim, Rameen; Norden, Andrew D.] Dana Farber Brigham & Womens Canc Ctr, Dept Med Oncol, Ctr Neurooncol, Boston, MA 02115 USA. [Wen, Patrick Y.; Quant, Eudocia; Drappatz, Jan; Norden, Andrew D.] Brigham & Womens Hosp, Dept Neurol, Div Neurooncol, Boston, MA 02115 USA. [Wen, Patrick Y.; Quant, Eudocia; Drappatz, Jan; Beroukhim, Rameen; Norden, Andrew D.] Harvard Univ, Sch Med, Boston, MA USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Beroukhim, Rameen] Brigham & Womens Hosp, Dept Med, Cambridge, MA USA. [Beroukhim, Rameen] Broad Inst, Canc Program, Cambridge, MA USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womens Canc Ctr, Dept Med Oncol, Ctr Neurooncol, 44 Binney St, Boston, MA 02115 USA. EM pwen@partners.org; equant@partners.org; jdrappatz@partners.org; rberoukhim@partners.org; anorden@partners.org FU Steven and Kathleen Haley Foundation; Brain Science Foundation FX We greatly acknowledge the support of the Steven and Kathleen Haley and the Brain Science Foundation. NR 160 TC 53 Z9 53 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X EI 1573-7373 J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD SEP PY 2010 VL 99 IS 3 SI SI BP 365 EP 378 DI 10.1007/s11060-010-0349-8 PG 14 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 655BC UT WOS:000282215200008 PM 20820875 ER PT J AU Zlotnick, D Kalkanis, SN Quinones-Hinojosa, A Chung, K Linskey, ME Jensen, RL DeMonte, F Barker, FG Racine, CA Berger, MS Black, PM Cusimano, M Sekhar, LN Parsa, A Aghi, M McDermott, MW AF Zlotnick, D. Kalkanis, S. N. Quinones-Hinojosa, A. Chung, K. Linskey, M. E. Jensen, R. L. DeMonte, F. Barker, F. G. Racine, C. A. Berger, M. S. Black, P. M. Cusimano, M. Sekhar, L. N. Parsa, A. Aghi, M. McDermott, Michael W. TI FACT-MNG: tumor site specific web-based outcome instrument for meningioma patients SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE Meningioma; Intracranial surgery; Radiotherapy; Quality of life ID QUALITY-OF-LIFE; GAMMA-KNIFE RADIOSURGERY; TUBERCULUM-SELLAE MENINGIOMAS; TERM-FOLLOW-UP; INTRACRANIAL MENINGIOMAS; PETROCLIVAL MENINGIOMAS; FUNCTIONAL ASSESSMENT; SURGICAL-MANAGEMENT; SURGERY; RESECTION AB To formulate Functional Assessment of Cancer Therapy-Meningioma (FACT-MNG), a web-based tumor site-specific outcome instrument for assessing intracranial meningioma patients following surgical resection or stereotactic radiosurgery. We surveyed the relevant literature available on intracranial meningioma surgery and subsequent outcomes (38 papers), making note of which, if any, QOL/outcome instruments were utilized. None of the surgveyed papers included QOL assessment specific to tumor site. We subsequently developed questions that were relevant to the signs and symptoms that characterize each of 11 intracranial meningioma sites, and incorporated them into a modified combination of the Functional Assessment of Cancer Therapy-Brain (FACT-BR) and SF36 outcome instruments, thereby creating a new tumor site-specific outcome instrument, FACT-MNG. With outcomes analysis of surgical and radiosurgical treatments becoming more important, measures of the adequacy and success of treatment are needed. FACT-MNG represents a first effort to formalize such an instrument for meningioma patients. Questions specific to tumor site will allow surgeons to better assess specific quality of life issues not addressed in the past by more general questionnaires. C1 [McDermott, Michael W.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Sekhar, L. N.] Harborview Med Ctr UW Med, Dept Neurosurg, Seattle, WA 98104 USA. [Cusimano, M.] Univ Toronto, Dept Neurosurg, Toronto, ON M5C 3G7, Canada. [Black, P. M.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Barker, F. G.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [DeMonte, F.] Univ Texas MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. [Jensen, R. L.] Univ Utah Hlth Sci Ctr, Huntsman Canc Inst, Dept Neurosurg, Clin Neurosci Ctr, Salt Lake City, UT 84132 USA. [Linskey, M. E.] Univ Calif Irvine Med Ctr, Dept Neurosurg, Orange, CA USA. [Chung, K.; Racine, C. A.; Berger, M. S.; Parsa, A.; Aghi, M.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Quinones-Hinojosa, A.] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21231 USA. [Kalkanis, S. N.] Henry Ford Hosp, Henry Ford Dept Neurosurg, Detroit, MI 48201 USA. [Zlotnick, D.] Univ Calif Irvine, Irvine, CA 92697 USA. RP McDermott, MW (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 505 Parnassus Ave,M-780, San Francisco, CA 94143 USA. EM mcdermottm@neurosurg.ucsf.edu FU Meningioma Mommas FX The authors thank Meningioma Mommas for their financial support with this project and Vision Tree Software for their role in developing FACT-MNG into a web-based application. NR 55 TC 4 Z9 4 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD SEP PY 2010 VL 99 IS 3 SI SI BP 423 EP 431 DI 10.1007/s11060-010-0394-3 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 655BC UT WOS:000282215200013 PM 20853019 ER PT J AU Stacy, RC Jakobiec, FA Hochberg, FH Hochberg, EP Cestari, DM AF Stacy, Rebecca C. Jakobiec, Frederick A. Hochberg, Fred H. Hochberg, Ephraim P. Cestari, Dean M. TI Orbital Involvement in Bing-Neel Syndrome SO JOURNAL OF NEURO-OPHTHALMOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; TOXI-INFECTIOUS BASIS; WALDENSTROMS-MACROGLOBULINEMIA; MULTIPLE-MYELOMA; TUMOR-FORMATION; HYPERGLOBULINEMIA; AFFECTION AB Bing-Neel syndrome (BNS) is defined as intracranial involvement of Waldenstrom macroglobulinemia (WM). Few cases of orbital involvement have been reported. A 51-year-old man with a history of WM developed bilateral orbitopathy and optic neuropathy. Orbital biopsy, cerebrospinal fluid studies, and neuroimaging confirmed the diagnosis of BNS involving the orbital soft tissues, optic nerves, meninges, and cauda equina. The neuro-ophthalmic manifestations resolved after parenteral and intrathecal chemotherapy in addition to autologous stem cell transplantation. The rare neuro-ophthalmic manifestations of BNS may require a multifaceted approach to therapy. Journal of Neuro-Ophthalmology 2010;30:255-259 doi: 10.1097/WNO.0b013e3181dee96c (C) 2010 by North American Neuro-Ophthalmology Society C1 [Stacy, Rebecca C.; Jakobiec, Frederick A.; Cestari, Dean M.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Hochberg, Fred H.; Hochberg, Ephraim P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Cestari, DM (reprint author), 243 Charles St, Boston, MA 02116 USA. EM Dean_Cestari@meei.harvard.edu NR 24 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1070-8022 J9 J NEURO-OPHTHALMOL JI J. Neuro-Ophthal. PD SEP PY 2010 VL 30 IS 3 BP 255 EP 259 DI 10.1097/WNO.0b013e3181dee96c PG 5 WC Clinical Neurology; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 647EU UT WOS:000281601400011 PM 20548243 ER PT J AU Pasinetti, GM Ksiezak-Reding, H Santa-Maria, I Wang, J Ho, L AF Pasinetti, Giulio Maria Ksiezak-Reding, Hanna Santa-Maria, Ismael Wang, Jun Ho, Lap TI Development of a grape seed polyphenolic extract with anti-oligomeric activity as a novel treatment in progressive supranuclear palsy and other tauopathies SO JOURNAL OF NEUROCHEMISTRY LA English DT Review DE botanical medicine; grape seed polyphenolic extract; neurodegeneration; progressive supranuclear palsy; tau ID PAIRED HELICAL FILAMENTS; ALZHEIMERS-DISEASE; TAU-PROTEIN; NEURODEGENERATIVE TAUOPATHIES; CORTICOBASAL DEGENERATION; IN-VITRO; EXON 10; AGGREGATION; ISOFORMS; PHOSPHORYLATION AB A diverse group of neurodegenerative diseases - including progressive supranuclear palsy (PSP), corticobasal degeneration and Alzheimer's disease among others, collectively referred to as tauopathies - are characterized by progressive, age-dependent intracellular formations of misfolded protein aggregates that play key roles in the initiation and progression of neuropathogenesis. Recent studies from our laboratory reveal that grape seed-derived polyphenolic extracts (GSPE) potently prevent tau fibrillization into neurotoxic aggregates and therapeutically promote the dissociation of preformed tau aggregates [J. Alzheimer's Dis. (2009) vol. 16, pp. 433]. Based on our extensive bioavailability, bioactivity and functional preclinical studies, combined with the safety of GSPE in laboratory animals and in humans, we initiated a series of studies exploring the role of GSPE (Meganatural-Az (R) GSPE) as a potential novel botanical drug for the treatment of certain forms of tauopathies including PSP, a neurodegenerative disorder involving the accumulation and deposition of misfolded tau proteins in the brain characterized, in part, by abnormal intracellular tau inclusions in specific anatomical areas involving astrocytes, oligodendrocytes and neurons [J. Neuropathol. Exp. Neurol. (2002) vol. 61, pp. 33]. In this mini-review article, we discuss the biochemical characterization of GSPE in our laboratory and its potential preventative and therapeutic role in model systems of abnormal tau processing pertinent to PSP and related tauopathies. C1 [Pasinetti, Giulio Maria; Ksiezak-Reding, Hanna; Santa-Maria, Ismael; Wang, Jun; Ho, Lap] Mt Sinai Sch Med, Ctr Excellence Novel Approaches Neurodiagnost & N, Ctr Excellence Res Complementary & Alternat Med A, Brain Inst,Dept Neurol, New York, NY 10029 USA. [Pasinetti, Giulio Maria] James J Peters Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. RP Pasinetti, GM (reprint author), Mt Sinai Sch Med, Ctr Excellence Novel Approaches Neurodiagnost & N, Ctr Excellence Res Complementary & Alternat Med A, Brain Inst,Dept Neurol, 1 Gustave L Levy Pl,Box 1137, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu FU NIH [P01AT004511-01] FX Supported by NIH P01AT004511-01 to GMP. NR 49 TC 11 Z9 11 U1 2 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2010 VL 114 IS 6 BP 1557 EP 1568 DI 10.1111/j.1471-4159.2010.06875.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 646NQ UT WOS:000281549600003 PM 20569300 ER PT J AU Bao, L Patel, JC Walker, RH Shashidharan, P Rice, ME AF Bao, Li Patel, Jyoti C. Walker, Ruth H. Shashidharan, Pullanipally Rice, Margaret E. TI Dysregulation of striatal dopamine release in a mouse model of dystonia SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE acetylcholine; basal ganglia; brain slices; early-onset dystonia; voltammetry ID NICOTINIC ACETYLCHOLINE-RECEPTORS; IDIOPATHIC TORSION DYSTONIA; FAMILIAL PARKINSONS-DISEASE; EXERCISE-INDUCED DYSTONIA; DYT1 DYSTONIA; BASAL GANGLIA; MIDBRAIN DOPAMINE; NUCLEUS-ACCUMBENS; NEURONAL-ACTIVITY; HUMAN BRAIN AB Dystonia is a neurological disorder characterized by involuntary movements. We examined striatal dopamine (DA) function in hyperactive transgenic (Tg) mice generated as a model of dystonia. Evoked extracellular DA concentration was monitored with carbon-fiber microelectrodes and fast-scan cyclic voltammetry in striatal slices from non-Tg mice, Tg mice with a positive motor phenotype, and phenotype-negative Tg litter-mates. Peak single-pulse evoked extracellular DA concentration was significantly lower in phenotype-positive mice than in non-Tg or phenotype-negative mice, but indistinguishable between non-Tg and phenotype-negative mice. Phenotype-positive mice also had higher functional D2 DA autoreceptor sensitivity than non-Tg mice, which would be consistent with lower extracellular DA concentration in vivo. Multiple-pulse (phasic) stimulation (five pulses, 10-100 Hz) revealed an enhanced frequency dependence of evoked DA release in phenotype-positive versus non-Tg or phenotype-negative mice, which was exacerbated when extracellular Ca(2+) concentration was lowered. Enhanced sensitivity to phasic stimulation in phenotype-positive mice was reminiscent of the pattern seen with antagonism of nicotinic acetylcholine receptors. Consistent with a role for altered cholinergic regulation, the difference in phasic responsiveness among groups was lost when nicotinic receptors were blocked by mecamylamine. Together, these data implicate compromised DA release regulation, possibly from cholinergic dysfunction, in the motor symptoms of this dystonia model. C1 [Bao, Li; Rice, Margaret E.] NYU, Sch Med, Dept Physiol & Neurosci, New York, NY 10016 USA. [Bao, Li; Patel, Jyoti C.; Rice, Margaret E.] NYU, Sch Med, Dept Neurosurg, New York, NY 10016 USA. [Walker, Ruth H.] James J Peters Vet Affairs Med Ctr, Dept Neurol, Bronx, NY USA. [Walker, Ruth H.; Shashidharan, Pullanipally] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. RP Rice, ME (reprint author), NYU, Sch Med, Dept Physiol & Neurosci, 550 1st Ave, New York, NY 10016 USA. EM margaret.rice@nyu.edu OI Patel, Jyoti/0000-0003-0295-6180; Rice, Margaret/0000-0003-1793-2798 FU Bachmann-Strauss Dystonia and Parkinson Foundation; NIH/NINDS [NS036362, NS043038] FX This work was supported by the Bachmann-Strauss Dystonia and Parkinson Foundation (M. E. R. and P. S.), and by NIH/NINDS grants NS036362 (M. E. R) and NS043038 (P. S.). The authors declare no conflicts of interest. NR 90 TC 14 Z9 14 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2010 VL 114 IS 6 BP 1781 EP 1791 DI 10.1111/j.1471-4159.2010.06890.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 646NQ UT WOS:000281549600023 PM 20626557 ER PT J AU Yoo, AJ Hakimelahi, R Rost, NS Schaefer, PW Hirsch, JA Gonzalez, RG Rabinov, JD AF Yoo, Albert J. Hakimelahi, Reza Rost, Natalia S. Schaefer, Pamela W. Hirsch, Joshua A. Gonzalez, R. Gilberto Rabinov, James D. TI Diffusion weighted imaging reversibility in the brainstem following successful recanalization of acute basilar artery occlusion SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID INTRAARTERIAL THROMBOLYSIS; ISCHEMIC-INJURY; STROKE PATIENTS; REVERSAL AB Acute basilar artery occlusion (ABAO) is a devastating disease that can produce significant brainstem injury. Pretreatment diffusion weighted imaging (DWI) demonstrating extensive brainstem involvement has been shown to predict a poor outcome regardless of reperfusion. This case report describes a patient presenting with coma secondary to ABAO. MRI at presentation demonstrated significant DWI abnormality in the majority of the bilateral pons. The basilar artery was endovascularly recanalized 8 h after stroke onset, and the patient had a marked clinical recovery with no deficit at 3 months. Follow-up imaging revealed significant reversal of the pontine lesion. This finding of brainstem DWI reversibility cautions against the use of DWI to select ABAO patients for intra-arterial stroke therapy. The degree of apparent diffusion coefficient reduction on pretreatment MRI may not adequately identify which DWI abnormal brainstem tissue is potentially reversible. C1 [Yoo, Albert J.; Hakimelahi, Reza; Schaefer, Pamela W.; Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. [Yoo, Albert J.; Hirsch, Joshua A.; Rabinov, James D.] Massachusetts Gen Hosp, Dept Intervent Neuroradiol, Boston, MA 02114 USA. [Rost, Natalia S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Yoo, AJ (reprint author), Massachusetts Gen Hosp, Dept Neuroradiol & Intervent Neuroradiol, 55 Fruit St,Gray 241, Boston, MA 02114 USA. EM ajyoo@partners.org FU Neuroradiology Education and Research Foundation FX AJY was the 2007 recipient of the Neuroradiology Education and Research Foundation/Boston Scientific Fellowship in Cerebrovascular Disease Research. NR 11 TC 7 Z9 8 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD SEP PY 2010 VL 2 IS 3 BP 195 EP 197 DI 10.1136/jnis.2009.002048 PG 3 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 644FC UT WOS:000281357900003 PM 21990621 ER PT J AU Hirsch, JA Hirsch, AE Zoarski, GH Brook, AL Stone, JA Heck, DV Yoo, AJ AF Hirsch, Joshua A. Hirsch, Ariel E. Zoarski, Gregg H. Brook, Allan L. Stone, Jeffrey A. Heck, Donald V. Yoo, Albert J. TI Social responsibility in medical reporting SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID RESEARCH TRIAL SPORT; VERTEBRAL AUGMENTATION; RANDOMIZED-TRIAL; VERTEBROPLASTY; FRACTURES; OUTCOMES C1 [Hirsch, Joshua A.; Yoo, Albert J.] Massachusetts Gen Hosp, Dept Intervent Neuroradiol Endovasc Neurosurg, Boston, MA 02114 USA. [Hirsch, Ariel E.] Massachusetts Gen Hosp, Boston Med Ctr, Boston, MA 02114 USA. [Zoarski, Gregg H.] Univ Maryland, Dept Diagnost Imaging, Med Ctr, College Pk, MD 20742 USA. [Brook, Allan L.] Montefiore Med Ctr, Bronx, NY 10467 USA. [Stone, Jeffrey A.] Mayo Clin Florida, Jacksonville, FL USA. RP Hirsch, JA (reprint author), Massachusetts Gen Hosp, Dept Intervent Neuroradiol Endovasc Neurosurg, 55 Fruit St,Gray 241, Boston, MA 02114 USA. EM hirsch@snisonline.org NR 15 TC 4 Z9 4 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD SEP PY 2010 VL 2 IS 3 BP 217 EP 218 DI 10.1136/jnis.2010.002857 PG 2 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 644FC UT WOS:000281357900011 PM 21990629 ER PT J AU Hirsch, JA Hirsch, AE Jha, R Growney, M Rabinov, JD Nogueira, RG Pryor, JC Yoo, AJ AF Hirsch, Joshua A. Hirsch, Ariel E. Jha, Ruchira Growney, Marion Rabinov, James D. Nogueira, Raul G. Pryor, Johnny C. Yoo, Albert J. TI Practical management of malignant compression fractures SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID QUALITY-OF-LIFE; RANDOMIZED-TRIAL; CANCER-PATIENTS; VERTEBROPLASTY; SYMPTOMS C1 [Hirsch, Joshua A.; Growney, Marion; Rabinov, James D.; Nogueira, Raul G.; Pryor, Johnny C.; Yoo, Albert J.] Massachusetts Gen Hosp, Div Neurointervent Radiol, Boston, MA 02114 USA. [Hirsch, Ariel E.] Boston Med Ctr, Dept Radiat Oncol, Boston, MA USA. [Jha, Ruchira] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Hirsch, JA (reprint author), Massachusetts Gen Hosp, Div Neurointervent Radiol, Boston, MA 02114 USA. EM hirsch@snisonline.org NR 11 TC 3 Z9 3 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD SEP PY 2010 VL 2 IS 3 BP 219 EP 220 DI 10.1136/jnis.2010.002394 PG 2 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 644FC UT WOS:000281357900012 PM 21990630 ER PT J AU Jha, RM Hirsch, AE Yoo, AJ Ozonoff, A Growney, M Hirsch, JA AF Jha, Ruchira M. Hirsch, Ariel E. Yoo, Albert J. Ozonoff, Al Growney, Marion Hirsch, Joshua A. TI Palliation of compression fractures in cancer patients by vertebral augmentation: a retrospective analysis SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID TREATMENT OPTIONS; RANDOMIZED-TRIAL; SINGLE-CENTER; VERTEBROPLASTY; KYPHOPLASTY; MANAGEMENT; EFFICACY; FUTURE AB Aim To evaluate the efficacy of vertebral augmentation (VA) in cancer patients. Materials and methods From a retrospectively compiled database, 147 cancer cases (236 levels) were treated with VA. Mean age was 71+/-12 years and 56.5% were female. Variables evaluated include age, sex, procedure type, vertebral level treated, number of levels treated per procedure and technical approach. Outcomes were assessed by a previously described method retrospectively applied from medical records: a binary system of 'responders' versus 'non-responders' and further subcategorization with a four level pain scale. Two patient groups were analyzed: (1) 147 cancer patients with either osteoporotic or malignant vertebral compression fractures (all compression fractures (ACFs)) and (2) 102 cases with documented metastatic compression fractures (MCFs). Univariate and multivariate analyses determined outcomes. Results 93% of MCFs and 88.5% of ACFs showed response to treatment (pain improvement or resolution): 30% of ACFs and 31% of MCFs experienced pain resolution. MCFs showed increasing age to be a predictor of response to treatment in univariate (OR = 1.79, p = 0.04) and multivariate (OR = 2.05, p = 0.03) analysis. In ACFs, bipedicular needle approach decreased the odds of pain resolution (OR = 0.28, p = 0.01). In MCFs, lung cancer (OR = 0.06, p = 0.03) and multiple myeloma (OR = 0.10, p = 0.01) decreased the odds of pain resolution. Conclusions VA provides pain relief for a majority of ACFs and MCFs. Increasing age may be predictive of pain relief outcomes in MCFs. There are special planning, imaging and technical considerations (eg, needle placement) in using VA to treat cancer patients. C1 [Jha, Ruchira M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Hirsch, Ariel E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Yoo, Albert J.; Growney, Marion; Hirsch, Joshua A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol,Div Neurointervent Radiol, Boston, MA 02114 USA. [Ozonoff, Al] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. RP Jha, RM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Internal Med, 9 Hawthorne Pl,Unit 6F, Boston, MA 02114 USA. EM rjha@partners.org OI Ozonoff, Al/0000-0003-4233-5899 NR 27 TC 11 Z9 11 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD SEP PY 2010 VL 2 IS 3 BP 221 EP 228 DI 10.1136/jnis.2010.002675 PG 8 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 644FC UT WOS:000281357900013 PM 21990631 ER PT J AU Lundgren, K Helm-Estabrooks, N Klein, R AF Lundgren, Kristine Helm-Estabrooks, Nancy Klein, Reva TI Stuttering following acquired brain damage: A review of the literature SO JOURNAL OF NEUROLINGUISTICS LA English DT Review DE Neurogenic stuttering; Stuttering; Traumatic brain injury; Aphasia; Acquired stuttering ID CLINICAL ENTITY; SPEECH; LESIONS; ONSET AB Communication problems resulting from acquired brain damage are most frequently manifested as motor speech disorders such as dysarthria, syndromes of aphasia, and impairments of pragmatics. A much less common phenomenon is the onset of stuttering in adults who sustain a stroke, traumatic brain injury, or other neurologic events. When stuttering occurs in association with neuropathology, precise characterization and explanation of observed behaviors is often difficult. Among the clinical challenges presented by acquired stuttering are the problem of distinguishing this form of dysfluency from those associated with dysarthria and aphasia, and identifying the neuropathological condition(s) and brain lesion site(s) giving rise to this speech disorder. Another challenge to the precise characterization of acquired stuttering is the fact that some cases of acquired stuttering apparently have a psychological or neuropsychiatric genesis rather than a neuropathological one. In this paper we provide a review of the literature pertaining to the complicated phenomenon of acquired stuttering in adults and draw some tentative explanatory conclusions regarding this disorder. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Lundgren, Kristine] Univ N Carolina, Dept Commun Disorders & Sci, Greensboro, NC 27402 USA. [Lundgren, Kristine; Klein, Reva] Boston Univ, Sch Med, Boston, MA 02215 USA. [Lundgren, Kristine; Klein, Reva] Boston VA Healthcare Syst, Boston, MA USA. [Helm-Estabrooks, Nancy] Western Carolina Univ, Cullowhee, NC USA. RP Lundgren, K (reprint author), Univ N Carolina, Dept Commun Disorders & Sci, 323 Ferguson Bldg,POB 26170, Greensboro, NC 27402 USA. EM k_lundgr@uncg.edu FU NIH [P30DC005207, R21DC007165, R01DC009045] FX The preparation of this chapter was supported by NIH grants P30DC005207, R21DC007165, and R01DC009045. We would like to thank Martin Albert, William Milberg, Lorraine Obler, and Rossie Clark-Cotton for their insightful comments about this case. We thank Ellen McCracken for editorial assistance. NR 44 TC 20 Z9 20 U1 5 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0911-6044 J9 J NEUROLINGUIST JI J. Neurolinguist. PD SEP PY 2010 VL 23 IS 5 SI SI BP 447 EP 454 DI 10.1016/j.jneuroling.2009.08.008 PG 8 WC Linguistics; Neurosciences; Psychology, Experimental SC Linguistics; Neurosciences & Neurology; Psychology GA 635MI UT WOS:000280659400002 PM 20628582 ER PT J AU Baxa, M Juhas, S Pavlok, A Vodicka, P Juhasova, J Hruska-Plochan, M Miyanohara, A Marsala, M Cattaneo, E Difiglia, M Motlik, J AF Baxa, M. Juhas, S. Pavlok, A. Vodicka, P. Juhasova, J. Hruska-Plochan, M. Miyanohara, A. Marsala, M. Cattaneo, E. Difiglia, M. Motlik, J. TI TRANSGENIC MINIATURE PIG AS AN ANIMAL MODEL FOR HUNTINGTON'S DISEASE SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract C1 [Baxa, M.; Juhas, S.; Pavlok, A.; Vodicka, P.; Juhasova, J.; Hruska-Plochan, M.; Motlik, J.] Inst Anim Physiol & Genet AS CR, Libechov, Czech Republic. [Miyanohara, A.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Marsala, M.] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA. [Cattaneo, E.] Univ Milan, Dept Pharmacol Sci, Milan, Italy. [Cattaneo, E.] Univ Milan, Ctr Stem Cell Res, Milan, Italy. [Difiglia, M.] Massachussets Gen Hosp, Dept Neurol, Boston, MA USA. RI Juhasova, Jana/G-7144-2014; Vodicka, Pavel/H-3370-2014; Motlik, Jan/G-7148-2014; Juhas, Stefan/G-7141-2014; Hruska-Plochan, Marian/I-3982-2014; Pavlok, Antonin/H-8398-2014; Baxa, Monika/H-8396-2014 OI Juhasova, Jana/0000-0001-7022-6812; Juhas, Stefan/0000-0002-2866-0727; NR 0 TC 0 Z9 0 U1 2 U2 5 PU BMJ 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 SEP PY 2010 VL 81 SU 1 BP A8 EP A9 DI 10.1136/jnnp.2010.222570.26 PG 3 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA V29BR UT WOS:000208724400027 ER PT J AU Hruska-Plochan, M Juhas, S Juhasova, J Galik, J Miyanohara, A Marsala, M Bjarkam, CR Cattaneo, E DiFiglia, M Li, XJ Motlik, J AF Hruska-Plochan, M. Juhas, S. Juhasova, J. Galik, J. Miyanohara, A. Marsala, M. Bjarkam, C. R. Cattaneo, E. DiFiglia, M. Li, X-J Motlik, J. TI EXPRESSION OF THE HUMAN MUTANT HUNTINGTIN IN MINIPIG STRIATUM INDUCED FORMATION OF EM48+INCLUSIONS IN THE NEURONAL NUCLEI, CYTOPLASM AND PROCESSES SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract C1 [Hruska-Plochan, M.; Juhas, S.; Juhasova, J.; Motlik, J.] Inst Anim Physiol & Genet AS CR, Libechov, Czech Republic. [Galik, J.] Inst Neurobiol SAV, Kosice, Slovakia. [Miyanohara, A.] Univ Calif San Diego, Sch Med, Vector Dev Lab, La Jolla, CA 92093 USA. [Marsala, M.] Univ Calif San Diego, Neuroregenerat Lab, La Jolla, CA 92093 USA. [Bjarkam, C. R.] Univ Aarhus, Inst Anat, Aarhus C, Denmark. [Cattaneo, E.] Univ Milan, Lab Stem Cell Biol & Pharmacol Neurodegenerat Dis, Milan, Italy. [DiFiglia, M.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Li, X-J] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. RI Juhasova, Jana/G-7144-2014; Motlik, Jan/G-7148-2014; Juhas, Stefan/G-7141-2014; Hruska-Plochan, Marian/I-3982-2014 OI Juhasova, Jana/0000-0001-7022-6812; Juhas, Stefan/0000-0002-2866-0727; NR 0 TC 0 Z9 0 U1 0 U2 2 PU BMJ 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 SEP PY 2010 VL 81 SU 1 BP A9 EP A9 DI 10.1136/jnnp.2010.222570.27 PG 1 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA V29BR UT WOS:000208724400028 ER PT J AU Lindenberg, KS Davranche, A Klein, F Thomas, AV Lill, C Lenk, T Orlando, LR Kama, J Young, AB Landwehrmeyer, GB Trottier, Y AF Lindenberg, K. S. Davranche, A. Klein, F. Thomas, A. V. Lill, C. Lenk, T. Orlando, L. R. Kama, J. Young, A. B. Landwehrmeyer, G. B. Trottier, Y. TI INTERACTION OF HUNTINGTIN AND THE RYANODINE RECEPTOR SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract C1 [Lindenberg, K. S.; Lenk, T.; Landwehrmeyer, G. B.] Univ Ulm, D-89069 Ulm, Germany. [Lindenberg, K. S.; Thomas, A. V.; Lill, C.; Orlando, L. R.; Kama, J.; Young, A. B.] Massachusetts Gen Hosp, MIND, Charlestown, MA USA. [Davranche, A.; Klein, F.; Trottier, Y.] IGBMC, Illkirch Graffenstaden, France. [Thomas, A. V.] Alexiana Hosp, Cologne, Germany. [Thomas, A. V.] Johannes Gutenberg Univ Mainz, Dept Neurol, D-55122 Mainz, Germany. [Lill, C.] Max Planck Inst Mol Genet, Neuropsychiat Genet Grp, D-14195 Berlin, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ 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 SEP PY 2010 VL 81 SU 1 BP A6 EP A7 DI 10.1136/jnnp.2010.222570.20 PG 3 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA V29BR UT WOS:000208724400021 ER PT J AU Ramos, EM Gillis, T Mysore, J Abuelneel, K Gusella, J MacDonald, M Lee, JM Alonso, I Sequeiros, J AF Ramos, E. M. Gillis, T. Mysore, J. Abuelneel, K. Gusella, J. MacDonald, M. Lee, J-M Alonso, I. Sequeiros, J. TI MODIFIERS OF INSTABILITY AND AGE AT ONSET IN HD: HAPLOTYPE STUDY IN THE PORTUGUESE POPULATION SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract C1 [Ramos, E. M.; Gillis, T.; Mysore, J.; Abuelneel, K.; Gusella, J.; MacDonald, M.; Lee, J-M] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Ramos, E. M.; Alonso, I.; Sequeiros, J.] Univ Porto, UnIGENe, IBMC Inst Mol & Cell Biol, P-4100 Oporto, Portugal. [Alonso, I.; Sequeiros, J.] Univ Porto, CGPP, IBMC Inst Mol & Cell Biol, P-4100 Oporto, Portugal. [Sequeiros, J.] Univ Porto, ICBAS, P-4100 Oporto, Portugal. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ 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 SEP PY 2010 VL 81 SU 1 BP A16 EP A17 DI 10.1136/jnnp.2010.222588.3 PG 3 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA V29BR UT WOS:000208724400053 ER PT J AU Tabrizi, SJ Durr, A Roos, RAC Leavitt, BR Jones, R Landwehrmeyer, GB Johnson, H Hicks, SL Kennard, C Reilmann, R Craufurd, D Rosas, HD Frost, C Langbehn, DR Scahill, RI Stout, JC AF Tabrizi, S. J. Duerr, A. Roos, R. A. C. Leavitt, B. R. Jones, R. Landwehrmeyer, G. B. Johnson, H. Hicks, S. L. Kennard, C. Reilmann, R. Craufurd, D. Rosas, H. D. Frost, C. Langbehn, D. R. Scahill, R. I. Stout, J. C. CA TRACK-HD Investigators TI SIGNIFICANT BIOLOGICAL AND CLINICAL CHANGE DETECTED OVER 1 YEAR IN PREMANIFEST AND EARLY STAGE HUNTINGTON'S DISEASE IN THE TRACK-HD STUDY SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract C1 [Tabrizi, S. J.; Scahill, R. I.] UCL, UCL Inst Neurol, London, England. [Duerr, A.] Hop La Pitie Salpetriere, APHP, Dept Genet & Cytogenet, Paris, France. [Duerr, A.] Hop La Pitie Salpetriere, APHP, INSERM, UMR S679, Paris, France. [Roos, R. A. C.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. [Leavitt, B. R.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Jones, R.; Frost, C.] London Sch Hyg & Trop Med, London WC1, England. [Landwehrmeyer, G. B.] Univ Ulm, Dept Neurol, D-89069 Ulm, Germany. [Johnson, H.; Langbehn, D. R.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Hicks, S. L.; Kennard, C.] Univ Oxford, Dept Clin Neurol, Oxford, England. [Reilmann, R.] Univ Munster, Dept Neurol, D-48149 Munster, Germany. [Craufurd, D.] Univ Manchester, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Craufurd, D.] Cent Manchester Univ Hosp NHS Fdn Trust, St Marys Hosp, Manchester, Lancs, England. [Rosas, H. D.] Harvard, Dept Neurol, Massachusetts Gen Hosp, Charlestown, MA USA. [Langbehn, D. R.] Univ Iowa, Dept Biostat Secondary, Iowa City, IA USA. [Stout, J. C.] Monash Univ, Sch Psychol Psychiat & Psychol Med, Clayton, Vic 3800, Australia. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BMJ 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 SEP PY 2010 VL 81 SU 1 BP A33 EP A33 DI 10.1136/jnnp.2010.222653.1 PG 1 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA V29BR UT WOS:000208724400104 ER PT J AU Zucker, B Kama, JA Kuhn, A Thu, D Orlando, LR Dunah, AW Gokce, O Taylor, DM Lambeck, J Friedrich, B Lindenberg, KS Faull, RLM Weiller, C Young, AB Luthi-Carter, R AF Zucker, Birgit Kama, Jibrin A. Kuhn, Alexandre Thu, Doris Orlando, Lianna R. Dunah, Anthone W. Gokce, Ozgun Taylor, David M. Lambeck, Johann Friedrich, Bernd Lindenberg, Katrin S. Faull, Richard L. M. Weiller, Cornelius Young, Anne B. Luthi-Carter, Ruth TI Decreased Lin7b Expression in Layer 5 Pyramidal Neurons May Contribute to Impaired Corticostriatal Connectivity in Huntington Disease SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Corticostriatal projection; DNA microarray; Huntingtin; LIN7; Polyglutamine disease; Striatum ID MOUSE MODEL; NEUROTRANSMITTER RELEASE; GENE-EXPRESSION; CEREBRAL-CORTEX; PROJECTION-NEURONS; CORTICAL-NEURONS; SUBSTANCE-P; R6/2 MODEL; CELL LOSS; BRAIN AB Motor dysfunction, cognitive impairment, and regional cortical atrophy indicate cerebral cortical involvement in Huntington disease (HD). To address the hypothesis that abnormal corticostriatal connectivity arises from polyglutamine-related alterations in cortical gene expression, we isolated layer 5 cortical neurons by laser-capture microdissection and analyzed transcriptome-wide mRNA changes in them. Enrichment of transcription factor mRNAs including foxp2, tbr1, and neuroD6, and neurotransmission- and plasticity-related RNAs including sema5A, pclo, ntrk2, cntn1, and Lin7b were observed. Layer 5 motor cortex neurons of transgenic R6/2 HD mice also demonstrated numerous transcriptomic changes, including decreased expression of mRNAs encoding the Lin7 homolog b ([Lin7b] also known as veli-2 and mals2). Decreases in LIN7B and CNTN1 RNAs were also detected in human HD layer 5 motor cortex neurons. Lin7 homolog b, a scaffold protein implicated in synaptic plasticity, neurite outgrowth, and cellular polarity, was decreased at the protein level in layer 5 cortical neurons in R6/2 mice and human HD brains. Decreases in Lin7b and Lin7a mRNAs were detected in R6/2 cortex as early as 6 weeks of age, suggesting that this is an early pathogenetic event. Thus, decreased cortical LIN7 expression may contribute to abnormal corticostriatal connectivity in HD. C1 [Kuhn, Alexandre; Thu, Doris; Gokce, Ozgun; Taylor, David M.; Luthi-Carter, Ruth] Ecole Polytech Fed Lausanne, Brain Mind Inst, Lausanne, Switzerland. [Zucker, Birgit; Lambeck, Johann; Friedrich, Bernd; Weiller, Cornelius] Univ Hosp Freiburg, Dept Neurol, Freiburg, Germany. [Zucker, Birgit; Kama, Jibrin A.; Orlando, Lianna R.; Dunah, Anthone W.; Young, Anne B.; Luthi-Carter, Ruth] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Lindenberg, Katrin S.] Univ Ulm, Dept Neurol, D-7900 Ulm, Germany. [Faull, Richard L. M.] Univ Auckland, Fac Med & Hlth Sci, Ctr Brain Res, Auckland 1, New Zealand. [Faull, Richard L. M.] Univ Auckland, Fac Med & Hlth Sci, Dept Anat Radiol, Auckland 1, New Zealand. RP Luthi-Carter, R (reprint author), Ecole Polytech Fed Lausanne, Brain Mind Inst, Stn 15, Lausanne, Switzerland. EM ruth.luthi-carter@epfl.ch FU Hereditary Disease Foundation; Ecole Polytechnique Federale de Lausanne; National Institutes of Health [NS045242, AG13617]; Deutsche Forschungsgemeinschaft [ZU125/1-1]; Neurological Foundation of New Zealand; Health Research Council of New Zealand FX This study was supported by the Hereditary Disease Foundation, the Ecole Polytechnique Federale de Lausanne, the National Institutes of Health (Grant NS045242 to Ruth Luthi-Carter and AG13617 to Anne B. Young), the Deutsche Forschungsgemeinschaft Grant ZU125/1-1 (to Birgit Zucker), and the Neurological Foundation of New Zealand and the Health Research Council of New Zealand. NR 64 TC 9 Z9 10 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD SEP PY 2010 VL 69 IS 9 BP 880 EP 895 DI 10.1097/NEN.0b013e3181ed7a41 PG 16 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 648RT UT WOS:000281712300002 PM 20720508 ER PT J AU McKee, AC Gavett, BE Stern, RA Nowinski, CJ Cantu, RC Kowall, NW Perl, DP Hedley-Whyte, ET Price, B Sullivan, C Morin, P Lee, HS Kubilus, CA Daneshvar, DH Wulff, M Budson, AE AF McKee, Ann C. Gavett, Brandon E. Stern, Robert A. Nowinski, Christopher J. Cantu, Robert C. Kowall, Neil W. Perl, Daniel P. Hedley-Whyte, E. Tessa Price, Bruce Sullivan, Chris Morin, Peter Lee, Hyo-Soon Kubilus, Caroline A. Daneshvar, Daniel H. Wulff, Megan Budson, Andrew E. TI TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Amyotrophic lateral sclerosis; Chronic brain injury; Motor neuron disease; Sports; Tau proteins; TDP-43 ID AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; PROFESSIONAL FOOTBALL PLAYERS; PARKINSONISM-DEMENTIA COMPLEX; LOU-GEHRIGS-DISEASE; GULF-WAR VETERANS; HEAD-INJURY; ALZHEIMERS-DISEASE; ANTECEDENT EVENTS; CIGARETTE-SMOKING AB Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of beta-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43 kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43-positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease. C1 [McKee, Ann C.; Sullivan, Chris; Morin, Peter; Budson, Andrew E.] Bedford Vet Adm Hosp, Geriatr Res Educ Clin Ctr, Bedford, MA USA. [McKee, Ann C.; Gavett, Brandon E.; Stern, Robert A.; Nowinski, Christopher J.; Cantu, Robert C.; Kowall, Neil W.; Daneshvar, Daniel H.; Wulff, Megan] Ctr Study Traumat Encephalopathy, Boston, MA USA. [McKee, Ann C.; Gavett, Brandon E.; Stern, Robert A.; Sullivan, Chris; Morin, Peter; Lee, Hyo-Soon; Kubilus, Caroline A.; Budson, Andrew E.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [McKee, Ann C.; Kowall, Neil W.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [McKee, Ann C.] Natl VA ALS Biorepository, Tucson, AZ USA. [Nowinski, Christopher J.; Cantu, Robert C.] Sports Legacy Inst, Waltham, MA USA. [Cantu, Robert C.] Boston Univ, Sch Med, Dept Neurosurg, Boston, MA 02118 USA. [Cantu, Robert C.] Emerson Hosp, Dept Neurosurg, Concord, MA USA. [Kowall, Neil W.] Vet Adm Med Ctr Jamaica Plain, Geriatr Res Educ Clin Ctr, Boston, MA 02130 USA. [Perl, Daniel P.] Mt Sinai Sch Med, Dept Pathol Neuropathol, New York, NY USA. [Hedley-Whyte, E. Tessa] Harvard Univ, Sch Med, Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA USA. [Hedley-Whyte, E. Tessa] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. [Price, Bruce] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA USA. [Price, Bruce] McLean Hosp, Dept Neurol, Belmont, MA 02178 USA. RP McKee, AC (reprint author), Bedford Vet Adm Med Ctr, 182-B 200 Springs Rd, Bedford, MA 01730 USA. EM amckee@bu.edu RI Kowall, Neil/G-6364-2012; OI Kowall, Neil/0000-0002-6624-0213; Stern, Robert/0000-0002-5008-077X; Daneshvar, Daniel/0000-0003-3691-9513; Gavett, Brandon/0000-0003-1938-1854 FU Boston University Alzheimer's Disease Center [NIA P30 AG13846, 0572063345-5]; Mount Sinai Alzheimer's Disease Research Center [P50AG05138, P01AG02219]; Massachusetts Alzheimer's Disease Research Center [P50AG05134]; VA Biorepository [CSP 501]; Department of Veterans Affairs; Sports Legacy Institute; National Operating Committee on Standards for Athletic Equipment; National Football League FX This study was supported by the Boston University Alzheimer's Disease Center NIA P30 AG13846, supplement 0572063345-5; the Mount Sinai Alzheimer's Disease Research Center Grants P50AG05138 and P01AG02219; the Massachusetts Alzheimer's Disease Research Center Grant P50AG05134; the VA Biorepository (CSP 501), funded by the Department of Veterans Affairs; the Sports Legacy Institute; the National Operating Committee on Standards for Athletic Equipment; and by an unrestricted gift from the National Football League. The authors acknowledge the use of resources and facilities at the Edith Nourse Rogers Memorial Veterans Hospital in Bedford, Massachusetts. NR 73 TC 236 Z9 239 U1 4 U2 45 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD SEP PY 2010 VL 69 IS 9 BP 918 EP 929 DI 10.1097/NEN.0b013e3181ee7d85 PG 12 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 648RT UT WOS:000281712300005 PM 20720505 ER PT J AU Farrell, SR Raymond, ID Foote, M Brecha, NC Barnes, S AF Farrell, Spring R. Raymond, Iona D. Foote, Michael Brecha, Nicholas C. Barnes, Steven TI Modulation of Voltage-Gated Ion Channels in Rat Retinal Ganglion Cells Mediated by Somatostatin Receptor Subtype 4 SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID CALCIUM INFLUX; MOUSE RETINA; SST(2) RECEPTORS; RABBIT RETINA; NITRIC-OXIDE; NEURONS; EXPRESSION; CURRENTS; ROD AB Farrell SR, Raymond ID, Foote M, Brecha NC, Barnes S. Modulation of voltage-gated ion channels in rat retinal ganglion cells mediated by somatostatin receptor subtype 4. J Neurophysiol 104: 1347-1354, 2010. First published June 23, 2010; doi:10.1152/jn.00098.2010. Somatostatin (somatotropin release-inhibiting factor [SRIF]) is known to modulate the excitability of retinal ganglion cells, but the membrane mechanisms responsible and the extent to which intracellular calcium signaling is affected have not been determined. We show that somatostatin receptor subtype 4 (sst(4)) is expressed specifically in rat ganglion cells and that the generation of repetitive action potentials by isolated ganglion cells is reduced in the presence of L-803,087, a selective sst(4) agonist (10 nM). Under voltage clamp, L-803,087 increased outward K+ currents by 51.1 +/- 13.1% at 0 mV and suppressed Ca2+ channel currents by 32.5 +/- 9.4% at -10 mV in whole cell patch-clamped ganglion cells. The N-type Ca2+ channel blocker omega-conotoxin GVIA (CTX, 1 mu M) reduced L-type Ca2+ current (I Ca) in ganglion cells by 43.5 +/- 7.2% at -10 mV, after which addition of L-803,087 further reduced I Ca by 28.0 +/- 16.0%. In contrast, ganglion cells treated first with nifedipine (NIF, 10 mu M), which blocked 46.1 +/- 3.5% of the control current at -10 mV, did not undergo any further reduction in I Ca in the presence of L-803,087 (-3.5 +/- 3.8% vs. NIF), showing that stimulation of sst(4) reduces Ca2+ influx through L-type Ca2+ channels. To assess the effects of sst(4) stimulation on intracellular Ca2+ levels ([Ca2+](i)) in ganglion cells, fura-2 was used to measure changes in [Ca2+](i) in response to depolarization induced by elevated [K+](o). [Ca2+](i) was increased to a lesser extent (86%) in the presence of L-803,087 compared with recordings made in the absence of the sst(4) agonist and this effect was blocked by NIF (10 mu M). Suppression of spiking and Ca2+ signaling via sst(4) may contribute to the reported neuroprotective actions of somatostatin and promote ganglion cell survival following ischemia and axonal trauma. C1 [Farrell, Spring R.; Foote, Michael; Barnes, Steven] Dalhousie Univ, Dept Physiol & Biophys, Halifax, NS B3H 4H7, Canada. [Farrell, Spring R.; Foote, Michael; Barnes, Steven] Dalhousie Univ, Inst Neurosci, Halifax, NS B3H 4H7, Canada. [Barnes, Steven] Dalhousie Univ, Dept Ophthalmol & Visual Sci, Halifax, NS B3H 4H7, Canada. [Raymond, Iona D.; Brecha, Nicholas C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Brecha, Nicholas C.] Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Barnes, S (reprint author), Dalhousie Univ, Dept Physiol & Biophys, Halifax, NS B3H 4H7, Canada. EM sbarnes@dal.ca FU Plum Foundation; National Eye Institute [EY-15573]; Veterans Administration; Canadian Institutes for Health Research [MT-10968] FX This work was supported by a Plum Foundation grant to S. Barnes and N. Brecha, National Eye Institute Grant EY-15573 to N. Brecha, a Veterans Administration Senior Career Scientist Award to N. Brecha, and Canadian Institutes for Health Research Grant MT-10968 to S. Barnes. NR 29 TC 12 Z9 13 U1 0 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD SEP PY 2010 VL 104 IS 3 BP 1347 EP 1354 DI 10.1152/jn.00098.2010 PG 8 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 651FH UT WOS:000281910600014 PM 20573967 ER PT J AU Sadri-Vakili, G Kumaresan, V Schmidt, HD Famous, KR Chawla, P Vassoler, FM Overland, RP Xia, E Bass, CE Terwilliger, EF Pierce, RC Cha, JHJ AF Sadri-Vakili, Ghazaleh Kumaresan, Vidhya Schmidt, Heath D. Famous, Katie R. Chawla, Prianka Vassoler, Fair M. Overland, Ryan P. Xia, Eva Bass, Caroline E. Terwilliger, Ernest F. Pierce, R. Christopher Cha, Jang-Ho J. TI Cocaine-Induced Chromatin Remodeling Increases Brain-Derived Neurotrophic Factor Transcription in the Rat Medial Prefrontal Cortex, Which Alters the Reinforcing Efficacy of Cocaine SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ADENOASSOCIATED VIRUS VECTORS; MESOLIMBIC DOPAMINE SYSTEM; GENE-EXPRESSION; BDNF-GENE; MOLECULAR-MECHANISMS; HUNTINGTONS-DISEASE; NUCLEUS-ACCUMBENS; DRUG-ADDICTION; PROTEIN-LEVELS; D-3 RECEPTOR AB Cocaine self-administration alters patterns of gene expression in the brain that may underlie cocaine-induced neuronal plasticity. In the present study, male Sprague Dawley rats were allowed to self-administer cocaine (0.25 mg/infusion) 2 h/d for 14 d, followed by 7 d of forced abstinence. Compared with yoked saline control rats, cocaine self-administration resulted in increased brain-derived neurotrophic factor (BDNF) protein levels in the rat medial prefrontal cortex (mPFC). To examine the functional relevance of this finding, cocaine self-administration maintained under a progressive ratio schedule of reinforcement was assessed after short hairpin RNA-induced suppression of BDNF expression in the mPFC. Decreased BDNF expression in the mPFC increased the cocaine self-administration breakpoint. Next, the effect of cocaine self-administration on specific BDNF exons was assessed; results revealed selectively increased BDNF exon IV-containing transcripts in the mPFC. Moreover, there were significant cocaine-induced increases in acetylated histone H3 (AcH3) and phospho-cAMP response element binding protein (pCREB) association with BDNF promoter IV. In contrast, there was decreased methyl-CpG-binding protein 2 (MeCP2) association with BDNF promoter IV in the mPFC of rats that previously self-administered cocaine. Together, these results indicate that cocaine-induced increases in BDNF promoter IV transcript in the mPFC are driven by increased binding of AcH3 and pCREB as well as decreased MeCP2 binding at this BDNF promoter. Collectively, these results indicate that cocaine self-administration remodels chromatin in the mPFC, resulting in increased expression of BDNF, which appears to represent a compensatory neuroadaptation that reduces the reinforcing efficacy of cocaine. C1 [Sadri-Vakili, Ghazaleh; Overland, Ryan P.; Xia, Eva; Cha, Jang-Ho J.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Boston, MA 02129 USA. [Sadri-Vakili, Ghazaleh; Overland, Ryan P.; Xia, Eva; Cha, Jang-Ho J.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Kumaresan, Vidhya; Famous, Katie R.; Chawla, Prianka] Boston Univ, Sch Med, Dept Pharmacol, Boston, MA 02118 USA. [Schmidt, Heath D.; Vassoler, Fair M.; Pierce, R. Christopher] Univ Penn, Sch Med, Dept Psychiat, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. [Bass, Caroline E.] Wake Forest Univ, Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA. [Terwilliger, Ernest F.] Beth Israel Deaconess Med Ctr, Div Expt Med, Harvard Inst Med, Boston, MA 02115 USA. [Terwilliger, Ernest F.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Sadri-Vakili, G (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, 114 16th St, Charlestown, MA 02129 USA. EM gsadrivakili@partners.org OI Vassoler, Fair/0000-0001-5317-7174 FU National Institute on Drug Abuse [DA22339, DA18678, DA017543, DA024763, DA18333-02]; Glendorn Foundation; National Institutes of Health (NIH) [F30 DA19304, GM008541-7, DA16824] FX This work was supported by National Institute on Drug Abuse Grants DA22339, DA18678 (R.C.P.), DA017543 and DA024763 (C.E.B.), and DA18333-02 (E.F.T.) and the Glendorn Foundation (J.-H.J.C.). K.R.F. was partially supported by National Institutes of Health (NIH) National Research Service Award (NRSA) F30 DA19304, as well as NIH Training Grant T32 GM008541-7. H.D.S. was also partially supported by NIH NRSA Award DA16824. We thank Dr. Caroline Benn for valuable discussions. NR 59 TC 89 Z9 92 U1 0 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 1 PY 2010 VL 30 IS 35 BP 11735 EP 11744 DI 10.1523/JNEUROSCI.2328-10.2010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 647GV UT WOS:000281607300020 PM 20810894 ER PT J AU Dzhala, VI Kuchibhotla, KV Glykys, JC Kahle, KT Swiercz, WB Feng, G Kuner, T Augustine, GJ Bacskai, BJ Staley, KJ AF Dzhala, Volodymyr I. Kuchibhotla, Kishore V. Glykys, Joseph C. Kahle, Kristopher T. Swiercz, Waldemar B. Feng, Guoping Kuner, Thomas Augustine, George J. Bacskai, Brian J. Staley, Kevin J. TI Progressive NKCC1-Dependent Neuronal Chloride Accumulation during Neonatal Seizures SO JOURNAL OF NEUROSCIENCE LA English DT Article ID K-CL COTRANSPORTER; TEMPORAL-LOBE EPILEPSY; EXTRACELLULAR POTASSIUM ACTIVITY; IN-VITRO; RAT HIPPOCAMPUS; EPILEPTIFORM ACTIVITY; GABA(A) RECEPTOR; NA+-K+-2CL(-) COTRANSPORTER; INTRACELLULAR CHLORIDE; DEVELOPMENTAL-CHANGES AB Seizures induce excitatory shifts in the reversal potential for GABA(A)-receptor-mediated responses, which may contribute to the intractability of electro-encephalographic seizures and preclude the efficacy of widely used GABAergic anticonvulsants such as phenobarbital. We now report that, in intact hippocampi prepared from neonatal rats and transgenic mice expressing Clomeleon, recurrent seizures progressively increase the intracellular chloride concentration ([Cl(-)](i)) assayed by Clomeleon imaging and invert the net effect of GABA(A) receptor activation from inhibition to excitation assayed by the frequency of action potentials and intracellular Ca(2+) transients. These changes correlate with increasing frequency of seizure-like events and reduction in phenobarbital efficacy. The Na(+)-K(+)-2Cl(-) (NKCC1) cotransporter blocker bumetanide inhibited seizure-induced neuronal Cl(-) accumulation and the consequent facilitation of recurrent seizures. Our results demonstrate a novel mechanism by which seizure activity leads to [Cl(-)](i) accumulation, thereby increasing the probability of subsequent seizures. This provides a potential mechanism for the early crescendo phase of neonatal seizures. C1 [Dzhala, Volodymyr I.; Kuchibhotla, Kishore V.; Glykys, Joseph C.; Swiercz, Waldemar B.; Bacskai, Brian J.; Staley, Kevin J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kahle, Kristopher T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kuchibhotla, Kishore V.] Harvard Univ, Program Biophys, Cambridge, MA 02138 USA. [Feng, Guoping; Kuner, Thomas; Augustine, George J.] Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. RP Staley, KJ (reprint author), Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Dept Neurol, 16th St,CNYB 114,Room 2600, Charlestown, MA 02129 USA. EM kstaley@partners.org RI Augustine, George/J-9228-2013 FU National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke [NS 40109-06]; NIH [EB000768, NS580752]; American Epilepsy Society; Hearst Foundation FX This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke Grant NS 40109-06 (K.J.S.), NIH Grants EB000768 (B.J.B.) and NS580752 (K.V.K.), an American Epilepsy Society grant (J.C.G.), and a Hearst Foundation grant (V.I.D.). NR 92 TC 76 Z9 76 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 1 PY 2010 VL 30 IS 35 BP 11745 EP 11761 DI 10.1523/JNEUROSCI.1769-10.2010 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 647GV UT WOS:000281607300021 PM 20810895 ER PT J AU Simard, JM Kahle, KT Gerzanich, V AF Simard, J. Marc Kahle, Kristopher T. Gerzanich, Volodymyr TI Molecular mechanisms of microvascular failure in central nervous system injury-synergistic roles of NKCC1 and SUR1/TRPM4 A review SO JOURNAL OF NEUROSURGERY LA English DT Review DE traumatic brain injury; ischemia; capillary; NKCC1; SUR1; TRPM4 ID TRAUMATIC BRAIN-INJURY; K+-CL-COTRANSPORTER; NONSELECTIVE CATION CHANNEL; CEREBRAL-ARTERY OCCLUSION; SPINAL-CORD-INJURY; ADULT-RAT BRAIN; ISCHEMIC-STROKE; NA-K-2CL COTRANSPORTER; ENDOTHELIAL-CELLS; EDEMA FORMATION AB Microvascular failure largely underlies the damaging secondary events that accompany traumatic brain injury (TBI). Changes in capillary permeability result in the extravasation of extracellular fluid, inflammatory cells, and blood, thereby producing cerebral edema, inflammation, and progressive secondary hemorrhage (PSH). Recent work in rat models of TBI and stroke have implicated 2 ion transport proteins expressed in brain endothelial cells as critical mediators of edema formation: the constitutively expressed Na(+)-K(+)-2Cl(-) cotransporter, NKCC1, and the trauma/ischemia-induced SUR1-regulated NC(Ca-ATP) (SUR1/TRPM4) channel. Whereas NKCC1 function requires adenosine 5'-triphosphate (ATP), activation of SUR1/TRPM4 occurs only after ATP depletion. This opposite dependence on intracellular ATP levels implies that one or the other mechanism will activate/deactivate as ATP concentrations rise and fall during periods of ischemia/reperfusion, resulting in continuous edema formation regardless of cellular energy status. Moreover, with critical ATP depletion, sustained opening of SUR1/TRPM4 channels results in the oncotic death of endothelial cells, leading to capillary fragmentation and PSH. Bumetanide and glibenclamide are 2 well-characterized, safe, FDA-approved drugs that inhibit NKCC1 and the SUR1/TRPM4 channel, respectively. When used alone, these drugs have provided documented beneficial effects in animal models of TBI- and ischemia-associated cerebral edema and PSH. Given the mechanistic and temporal differences by which NKCC1 and the SUR1/TRPM4 channel contribute to the pathophysiological mechanisms of these events, combination therapy with bumetanide and glibenclamide may yield critical synergy in preventing injury-associated capillary failure. (DOI: 10.3171/2009.11.JNS081052) C1 [Simard, J. Marc; Gerzanich, Volodymyr] Univ Maryland, Sch Med, Dept Neurosurg, Baltimore, MD 21201 USA. [Simard, J. Marc] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Simard, J. Marc] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Kahle, Kristopher T.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Kahle, Kristopher T.] Harvard Univ, Sch Med, Boston, MA USA. RP Simard, JM (reprint author), Univ Maryland, Sch Med, Dept Neurosurg, 22 S Greene St,Suite S-12-D, Baltimore, MD 21201 USA. EM msimard@smail.umaryland.edu FU National Heart, Lung, and Blood Institute [HL082517]; National Institute of Neurological Disorders and Stroke [NS061808, NS060801, NS061934]; Department of Veterans Affairs (Baltimore, Maryland); Christopher and Dana Reeve Foundation FX This work was supported by grants to Dr. Simard from the National Heart, Lung, and Blood Institute (HL082517), the National Institute of Neurological Disorders and Stroke (NS061808, NS060801), the Department of Veterans Affairs (Baltimore, Maryland), and the Christopher and Dana Reeve Foundation; and to Dr. Gerzanich from the National Institute of Neurological Disorders and Stroke (NS061934). The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. NR 57 TC 41 Z9 42 U1 3 U2 10 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2010 VL 113 IS 3 BP 622 EP 629 DI 10.3171/2009.11.JNS081052 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 641FV UT WOS:000281111100028 PM 20035575 ER PT J AU Wong, JM Chi, SN Marcus, KJ Levine, BS Ullrich, NJ MacDonald, S Lechpammer, M Goumnerova, LC AF Wong, Judith M. Chi, Susan N. Marcus, Karen J. Levine, Bat-Sheva Ullrich, Nicole J. MacDonald, Shannon Lechpammer, Mirna Goumnerova, Liliana C. TI Germinoma with malignant transformation to nongerminomatous germ cell tumor Case report SO JOURNAL OF NEUROSURGERY-PEDIATRICS LA English DT Article DE germinoma; nongerminomatous germ cell tumor; tumor marker; alpha-fetoprotein; beta-human chorionic gonadotropin ID CHEMOTHERAPY; IRRADIATION; MANAGEMENT; DIAGNOSIS; THERAPY AB The authors describe the case of a young girl with suprasellar germinoma. Six weeks after this diagnosis, just prior to initiation of therapy, scrum and CSF marker analysis revealed sudden and marked elevation of a-fetoprotein, indicating transformation of her germinoma to a nongerminomatous germ cell tumor. She underwent chemotherapy and radiation therapy per the national treatment approach for the new diagnosis, with subsequent return of her serum and CSF tumor markers to normal levels. To the authors' knowledge, this is the first case in the English-language literature of a nongerminomatous germ cell tumor resulting from conversion of germinoma at the original site of presentation. (DOI: 10.3171/2010.6.PEDS09541) C1 [Goumnerova, Liliana C.] Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Wong, Judith M.] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Chi, Susan N.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Marcus, Karen J.] Childrens Hosp, Div Radiat Oncol, Boston, MA 02115 USA. [Levine, Bat-Sheva] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Ullrich, Nicole J.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [MacDonald, Shannon] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Lechpammer, Mirna] Brigham & Womens Hosp, Dept Pathol, Div Neuropathol, Boston, MA 02115 USA. RP Goumnerova, LC (reprint author), Childrens Hosp, Dept Neurosurg, 300 Longwood Ave,Hunnewell 2, Boston, MA 02115 USA. EM Liliana.Goumnerova@childrens.harvard.edu NR 17 TC 6 Z9 6 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 SEP PY 2010 VL 6 IS 3 BP 295 EP 298 DI 10.3171/2010.6.PEDS09541 PG 4 WC Clinical Neurology; Pediatrics; Surgery SC Neurosciences & Neurology; Pediatrics; Surgery GA 641FT UT WOS:000281110900018 PM 20809716 ER PT J AU Catana, C van der Kouwe, A Benner, T Michel, CJ Hamm, M Fenchel, M Fischl, B Rosen, B Schmand, M Sorensen, AG AF Catana, Ciprian van der Kouwe, Andre Benner, Thomas Michel, Christian J. Hamm, Michael Fenchel, Matthias Fischl, Bruce Rosen, Bruce Schmand, Matthias Sorensen, A. Gregory TI Toward Implementing an MRI-Based PET Attenuation-Correction Method for Neurologic Studies on the MR-PET Brain Prototype SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE simultaneous MR-PET; attenuation correction; ultrashort echo time MRI sequence; brain imaging; head segmentation ID POSITRON-EMISSION-TOMOGRAPHY; 3D PET; SEGMENTATION; PET/MRI; BONE AB Several factors have to be considered for implementing an accurate attenuation-correction (AC) method in a combined MR-PET scanner. In this work, some of these challenges were investigated, and an AC method based entirely on the MRI data obtained with a single dedicated sequence was developed and used for neurologic studies performed with the MR-PET human brain scanner prototype. Methods: The focus was on the problem of bone-air segmentation, selection of the linear attenuation coefficient for bone, and positioning of the radiofrequency coil. The impact of these factors on PET data quantification was studied in simulations and experimental measurements performed on the combined MR-PET scanner. A novel dual-echo ultrashort echo time (DUTE) MRI sequence was proposed for head imaging. Simultaneous MR-PET data were acquired, and the PET images reconstructed using the proposed DUTE MRI-based AC method were compared with the PET images that had been reconstructed using a CT-based AC method. Results: Our data suggest that incorrectly accounting for the bone tissue attenuation can lead to large underestimations (>20%) of the radiotracer concentration in the cortex. Assigning a linear attenuation coefficient of 0.143 or 0.151 cm(-1) to bone tissue appears to give the best trade-off between bias and variability in the resulting images. Not identifying the internal air cavities introduces large overestimations (>20%) in adjacent structures. On the basis of these results, the segmented CT AC method was established as the silver standard for the segmented MRI-based AC method. For an integrated MR-PET scanner, in particular, ignoring the radiofrequency coil attenuation can cause large underestimations (i.e., <= 50%) in the reconstructed images. Furthermore, the coil location in the PET field of view has to be accurately known. High-quality bone-air segmentation can be performed using the DUTE data. The PET images obtained using the DUTE MRI- and CT-based AC methods compare favorably in most of the brain structures. Conclusion: A DUTE MRI-based AC method considering all these factors was implemented. Preliminary results suggest that this method could potentially be as accurate as the segmented CT method and could be used for quantitative neurologic MR-PET studies. C1 [Catana, Ciprian; van der Kouwe, Andre; Benner, Thomas; Fischl, Bruce; Rosen, Bruce; Sorensen, A. Gregory] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Catana, C (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,Room 2301,13th St, Charlestown, MA 02129 USA. EM ccatana@nmr.mgh.harvard.edu FU NIH [1R01CA137254-01A1] FX We gratefully acknowledge Larry Byars from Siemens for many extremely useful discussions and for his invaluable contribution to the MR-PET project. This work was partly supported by NIH grant 1R01CA137254-01A1. NR 26 TC 168 Z9 171 U1 1 U2 13 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD SEP 1 PY 2010 VL 51 IS 9 BP 1431 EP 1438 DI 10.2967/jnumed.109.069112 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 646RN UT WOS:000281559900019 PM 20810759 ER PT J AU Vickers, SM Gotterbarm, T Spector, M AF Vickers, Scott M. Gotterbarm, Tobias Spector, Myron TI Cross-Linking Affects Cellular Condensation and Chondrogenesis in Type II Collagen-GAG Scaffolds Seeded with Bone Marrow-Derived Mesenchymal Stem Cells SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE stem cells; chondrogenesis; tissue engineering; condensation; collagen scaffolds ID SMOOTH-MUSCLE ACTIN; CANINE ARTICULAR CHONDROCYTES; MATRICES IN-VITRO; GLYCOSAMINOGLYCAN SCAFFOLDS; PROGENITOR CELLS; CARTILAGE; CONTRACTION; LIMB; PROLIFERATION; EXPRESSION AB The formation of cartilaginous tissue by chondroprogenitor cells, whether in vivo or in vitro, appears to require a critical initial stage of "condensation" in which intercellular space is reduced through an aggregation of cells, leading to development of cell-to-cell junctions followed by chondrocytic differentiation. The objective of this study was to investigate the association of aggregation (condensation) of mesenchymal stem cell (MSCs) and chondrogenesis in vitro. Previous work with chondrocytes indicated that the cross-link density and related cell-mediated contraction of collagen scaffolds significantly affects cartilaginous tissue formation within the cell-seeded construct. Based on this finding, we hypothesized that the cell-aggregating effect of the contraction of MSC-seeded collagen scaffolds of lower cross-link density favors chondrogenesis; scaffolds of higher cross-link density, which resist cell-mediated contraction, would demonstrate a lower cell number density (i.e., subcritical packing density) and less cartilage formation. Type II collagen GAG scaffolds, chemically cross-linked to achieve a range of cross-link densities, were seeded with caprine MSCs and cultured for 4 weeks. Constructs with low cross-link densities experienced cell-mediated contraction, increased cell number densities, and a greater degree of chondrogenesis (indicated by the chondrocytic morphology of cells, and synthesis of GAG and type II collagen) compared to more highly cross-linked scaffolds that resisted cellular contraction. These results provide a foundation for further investigation of the mechanisms by which condensation of mesenchymal cells induces chondrogenesis in this in vitro model, and may inform cross-linking protocols for collagen scaffolds for use in cartilage tissue engineering. (C) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1184-1192, 2010 C1 [Vickers, Scott M.; Spector, Myron] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Vickers, Scott M.; Gotterbarm, Tobias; Spector, Myron] VA Boston Healthcare Syst, Tissue Engn, Boston, MA 02130 USA. [Gotterbarm, Tobias; Spector, Myron] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthopaed Surg, Boston, MA 02115 USA. [Gotterbarm, Tobias] Stiftung Orthopad Univ Klin Heidelberg, D-69118 Heidelberg, Germany. RP Spector, M (reprint author), MIT, Dept Mech Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM mspector@rics.bwh.harvard.edu FU Office of Research and Development, Rehabilitation Research and Development Service, Department of Veterans Affairs; German Research Foundation (DFG) FX This material is based upon work supported by the Office of Research and Development, Rehabilitation Research and Development Service, Department of Veterans Affairs and the German Research Foundation (DFG). M. Spector is a VA Research Career Scientist. The authors are grateful to Mix Weaver and Lily Jeng for their technical assistance. NR 39 TC 42 Z9 45 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 EI 1554-527X J9 J ORTHOP RES JI J. Orthop. Res. PD SEP PY 2010 VL 28 IS 9 BP 1184 EP 1192 DI 10.1002/jor.21113 PG 9 WC Orthopedics SC Orthopedics GA 638LT UT WOS:000280897100011 PM 20225321 ER PT J AU Brochmann, EJ Simon, RJ Jawien, J Behnam, K Sintuu, C Wang, JC Murray, SS AF Brochmann, Elsa J. Simon, Robert J. Jawien, Janusz Behnam, Keyvan Sintuu, Chananit Wang, Jeffrey C. Murray, Samuel S. TI Carboxy Terminus of Secreted Phosphoprotein-24 kDa (spp24) Is Essential for Full Inhibition of BMP-2 Activity SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE bone morphogenetic proteins; BMP-binding proteins; surface plasmon resonance; spp24 ID BONE MORPHOGENETIC PROTEINS; BINDING PEPTIDE; ANTAGONISTS; SEQUENCE; GENE AB Secreted phosphoprotein-24 kDa (spp24) is a bone morphogenetic protein (BMP)-binding protein isolated from bone. It exists in a number of size forms and is hypothesized to function as a BMP latency protein and/or a "slow release" mechanism for BMPs involved in bone turnover and repair. We have examined the hypothesis that proteolytic modification of the C-terminus of spp24 affects its BMP-2-binding properties and bioactivity in the BMP-2-stimulated ectopic bone forming bioassay. Three different size forms of recombinant spp24 that correspond to predicted 18.1 kDa, 16.0 kDa, and 14.5 kDa proteolytic products were compared to full-length (fl) spp24. One of these forms (spp18.1) we hypothesize to be the protein which Urist initially, but apparently inaccurately, called "BMP." Only full-length spp24 completely inhibited BMP-2-induced bone formation. The 18.1 kD a truncated isoform of spp24 which we hypothesize to be Urist's protein did not. The inhibitory capacity of the proteins was correlated with their kinetic constants, assessed by surface plasmon resonance. At the highest, inhibitory, dose of spp24 and its derivatives, k(d) ("stability") best predicted the extent of ectopic bone formation whereas at the lowest dose, which was not inhibitory, k(a) ("recognition") best predicted the extent of ectopic bone formation. We conclude that proteolytic processing of spp24 affects the interaction of this protein with BMP-2 and this affects the function of the protein. (C) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1200-1207, 2010 C1 [Brochmann, Elsa J.; Murray, Samuel S.] VA Greater Los Angeles Hlth Care Syst, VA Med Ctr, Geriatr Res Educ & Clin Ctr 11 E, Sepulveda, CA 91343 USA. [Brochmann, Elsa J.; Murray, Samuel S.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Simon, Robert J.; Jawien, Janusz; Behnam, Keyvan; Sintuu, Chananit] VA Greater Los Angeles Hlth Care Syst, Res Serv, Sepulveda, CA 91343 USA. [Behnam, Keyvan] Lanx Inc, Broomfield, CO 80021 USA. [Sintuu, Chananit; Wang, Jeffrey C.] Univ Calif Los Angeles, Dept Orthopaed Surg, Los Angeles, CA 90024 USA. [Sintuu, Chananit; Wang, Jeffrey C.; Murray, Samuel S.] Univ Calif Los Angeles, Biomed Engn Interdept Program, Los Angeles, CA 90024 USA. RP Murray, SS (reprint author), VA Greater Los Angeles Hlth Care Syst, VA Med Ctr, Geriatr Res Educ & Clin Ctr 11 E, 16111 Plummer St, Sepulveda, CA 91343 USA. EM Samuel.Murray@va.gov FU Department of Veteran Affairs; Lanx, Inc. FX This work was supported by the Department of Veteran Affairs and Lanx, Inc. NR 20 TC 13 Z9 13 U1 0 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD SEP PY 2010 VL 28 IS 9 BP 1200 EP 1207 DI 10.1002/jor.21102 PG 8 WC Orthopedics SC Orthopedics GA 638LT UT WOS:000280897100013 PM 20162696 ER PT J AU Chapman, CR Lipschitz, DL Angst, MS Chou, R Denisco, RC Donaldson, GW Fine, PG Foley, KM Gallagher, RM Gilson, AM Haddox, JD Horn, SD Inturrisi, CE Jick, SS Lipman, AG Loeser, JD Noble, M Porter, L Rowbotham, MC Schoelles, KM Turk, DC Volinn, E Von Korff, MR Webster, LR Weisner, CM AF Chapman, C. Richard Lipschitz, David L. Angst, Martin S. Chou, Roger Denisco, Richard C. Donaldson, Gary W. Fine, Perry G. Foley, Kathleen M. Gallagher, Rollin M. Gilson, Aaron M. Haddox, J. David Horn, Susan D. Inturrisi, Charles E. Jick, Susan S. Lipman, Arthur G. Loeser, John D. Noble, Meredith Porter, Linda Rowbotham, Michael C. Schoelles, Karen M. Turk, Dennis C. Volinn, Ernest Von Korff, Michael R. Webster, Lynn R. Weisner, Constance M. TI Opioid Pharmacotherapy for Chronic Non-Cancer Pain in the United States: A Research Guideline for Developing an Evidence-Base SO JOURNAL OF PAIN LA English DT Article DE Opioid pharmacotherapy; chronic pain; evidence-based medicine; guideline; effectiveness; efficacy ID CHRONIC NONMALIGNANT PAIN; LOW-BACK-PAIN; CLINICAL-PRACTICE GUIDELINE; PRIMARY-CARE PHYSICIANS; DRUG-RELATED BEHAVIORS; TORSADES-DE-POINTES; INDUCED HYPERALGESIA; MORPHINE REQUIREMENTS; WORKERS-COMPENSATION; RANDOMIZED-TRIALS AB This document reports the consensus of an interdisciplinary panel of research and clinical experts charged with reviewing the use of opioids for chronic noncancer pain (CNCP) and formulating guidelines for future research. Prescribing opioids for chronic noncancer pain has recently escalated in the United States. Contrasting with increasing opioid use are: 1) The lack of evidence supporting long-term effectiveness; 2) Escalating misuse of prescription opioids including abuse and diversion; and 3) Uncertainty about the incidence and clinical salience of multiple, poorly characterized adverse drug events (ADEs) including endocrine dysfunction, immunosuppression and infectious disease, opioid-induced hyperalgesia and xerostomia, overdose, falls and fractures, and psychosocial complications. Chief among the limitations of current evidence are: 1) Sparse evidence on long-term opioid effectiveness in chronic pain patients due to the short-term time frame of clinical trials; 2) Insufficiently comprehensive outcome assessment; and 3) Incomplete identification and quantification of ADEs. The panel called for a strategic interdisciplinary approach to the problem domain in which basic scientists and clinicians cooperate to resolve urgent issues and generate a comprehensive evidence base. It offered 4 recommendations in 3 areas: 1) A research strategy for studying the effectiveness of long-term opioid pharmacotherapy; 2) Improvements in evidence-generation methodology; and 3) Potential research topics for generating new evidence. Perspective: Prescribing opioids for CNCP has outpaced the growth of scientific evidence bearing on the benefits and harms of these interventions. The need for a strong evidence base is urgent. This guideline offers a strategic approach to creating a comprehensive evidence base to guide safe and effective management of CNCP. (C) 2010 by the American Pain Society C1 [Chapman, C. Richard] Univ Utah, Pain Res Ctr, Dept Anesthesiol, Sch Med, Salt Lake City, UT 84108 USA. [Angst, Martin S.] Stanford Univ, Dept Anesthesiol, Palo Alto, CA 94304 USA. [Chou, Roger] Oregon Hlth & Sci Univ, Sch Med, Portland, OR 97201 USA. [Denisco, Richard C.] Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, NIH, Bethesda, MD USA. [Foley, Kathleen M.; Inturrisi, Charles E.] Mem Sloan Kettering Canc Ctr, Pain & Palliat Care Serv, New York, NY 10021 USA. [Gallagher, Rollin M.] Univ Penn, Sch Med, Dept Psychiat, Penn Pain Med Ctr, Philadelphia, PA 19104 USA. [Gallagher, Rollin M.] Univ Penn, Sch Med, Dept Anesthesiol & Crit Care, Penn Pain Med Ctr, Philadelphia, PA 19104 USA. [Gallagher, Rollin M.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Gilson, Aaron M.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Inturrisi, Charles E.] Cornell Univ, Dept Pharmacol, Joan & Sanford I Weill Med Sch, New York, NY 10021 USA. [Haddox, J. David] Purdue Pharma, Risk Management & Hlth Policy, Stamford, CT USA. [Jick, Susan S.] Boston Univ, Dept Epidemiol, Boston, MA 02215 USA. [Horn, Susan D.] Univ Utah, Sch Med, Dept Med Informat, ICOR, Salt Lake City, UT 84108 USA. [Horn, Susan D.] Univ Utah, Sch Med, Dept Med Informat, Int Sever Informat Syst Inc, Salt Lake City, UT 84108 USA. [Lipman, Arthur G.] Univ Utah, Dept Pharmacotherapy, LS Skaggs Pharm, Salt Lake City, UT 84108 USA. [Loeser, John D.] Univ Washington, Dept Neurol Surg, Seattle, WA 98195 USA. [Porter, Linda] Natl Inst Neurol Disorders & Stroke Syst & Cognit, NIH, Bethesda, MD USA. [Rowbotham, Michael C.] Univ Calif San Francisco, Pain Clin Res Ctr, San Francisco, CA 94143 USA. [Noble, Meredith; Schoelles, Karen M.] ECRI Inst, Plymouth Meeting, PA USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol, Seattle, WA 98195 USA. [Von Korff, Michael R.] Ctr Hlth Studies Grp Hlth Cooperat, Seattle, WA USA. [Webster, Lynn R.] Lifetree Pain Clin, Salt Lake City, UT USA. [Weisner, Constance M.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. RP Chapman, CR (reprint author), Univ Utah, Pain Res Ctr, Dept Anesthesiol, Sch Med, 615 Arapeen Dr,Suite 200, Salt Lake City, UT 84108 USA. EM crc20@utah.edu RI Inturrisi, Charles/E-7365-2013; OI Jick, Susan/0000-0002-2215-1067 FU Milbank Foundation; Mayday Fund FX Supported by a grant to the first author from the Milbank Foundation. A grant from The Mayday Fund supported the work necessary for this document. NR 143 TC 79 Z9 81 U1 3 U2 14 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD SEP PY 2010 VL 11 IS 9 BP 807 EP 829 DI 10.1016/j.jpain.2010.02.019 PG 23 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 652TW UT WOS:000282033900001 PM 20430701 ER PT J AU Hiers, RH Long, DL North, RB Oaklander, AL AF Hiers, Reta Honey Long, Donlin North, Richard B. Oaklander, Anne Louise TI Hiding in Plain Sight: A Case of Tarlov Perineural Cysts SO JOURNAL OF PAIN LA English DT Review DE Tarlov cyst; chronic pelvic pain; perineural and sacral nerve root cyst; neuropathic pain; treatment; mechanisms ID SACRAL MENINGEAL CYSTS; CHRONIC PAIN C1 [Hiers, Reta Honey] Tarlov Cyst Dis Fdn, Knoxville, TN USA. [Oaklander, Anne Louise] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Long, Donlin] Johns Hopkins Univ, Dept Neurosurg, Baltimore, MD USA. [North, Richard B.] Johns Hopkins Univ, Sch Med, Sandra & Malcolm Berman Brain & Spine Inst, Baltimore, MD USA. RP Hiers, RH (reprint author), Care of Paice JA, Northwestern Univ, Sch Med, 676 N St Clair St,Suite 850, Chicago, IL 60611 USA. EM j-paice@northwestern.edu OI Paice, Judith/0000-0001-7534-1756 NR 17 TC 10 Z9 12 U1 0 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD SEP PY 2010 VL 11 IS 9 BP 833 EP 837 DI 10.1016/j.jpain.2010.07.007 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 652TW UT WOS:000282033900003 PM 20800797 ER PT J AU Fijal, B Perlis, RH Heinloth, AN Houston, JP AF Fijal, Bonnie Perlis, Roy H. Heinloth, Alexandra N. Houston, John P. TI The Association of Single Nucleotide Polymorphisms in the Catechol-O-Methyltransferase Gene and Pain Scores in Female Patients With Major Depressive Disorder SO JOURNAL OF PAIN LA English DT Article DE COMT; visual analog scale; pain sensitivity; MDD; gender ID HAPLOTYPES; PERCEPTION; EXPRESSION AB We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene are associated with baseline pain levels in patients with major depressive disorder (MDD). Pain levels were quantified using a visual analog scale (VAS) for pain. Data from 159 female and 93 male self-reported white patients with MDD were analyzed. The associations between a haplotype previously associated with pain sensitivity created using COMT SNPs rs6269, rs4633, rs4818, and rs4680, and the proportion of female patients with "Pain While Awake" and "Overall Pain" at baseline were statistically significant (P < .05). In male patients, no statistically significant associations between COMT haplotypes and baseline pain scores were seen. The rs165599 SNP, which has previously been associated with response of depressive symptoms to treatment in patients with MDD, did not impact baseline pain in either gender. In conclusion, baseline pain levels appear to be associated with the COMT pain sensitivity haplotype in female patients with MDD. Perspective: This article presents associations of the COMT pain sensitivity haplotype and baseline pain levels in female patients with MDD. This finding could potentially help clinicians who seek to assess how genetic polymorphisms may contribute to a patient's pain experience. (C) 2010 by the American Pain Society C1 [Houston, John P.] Lilly USA LLC, Indianapolis, IN 46285 USA. [Fijal, Bonnie] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. [Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Lab Pharmacogenom, Boston, MA 02114 USA. [Heinloth, Alexandra N.] i3Statprobe, UnitedHlth Grp, Ann Arbor, MI USA. RP Houston, JP (reprint author), Lilly USA LLC, Mail Code 4103, Indianapolis, IN 46285 USA. EM HOUSTON_JOHN_P@LILLY.COM FU Lilly USA, LLC, Indianapolis, IN; Eli Lilly and Company; AstraZeneca; Bristol-Myers Squibb; GlaxoSmithKline; Pfizer; Proteus FX This study was sponsored by Lilly USA, LLC, Indianapolis, IN. Drs Fijal and Houston are full-time employees and minor stockholders of Lilly USA, LLC. Dr Perlis has received honoraria or consulting fees from Eli Lilly and Company, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, and Proteus, and is a stockholder in Concordant Rater Systems, LLC. Dr Heinloth is a fulltime employee of i3 Statprobe, a division of Ingenix, which is a subsidiary of UnitedHealth Group. Lilly contracted editorial assistance for this manuscript with i3 Statprobe. The authors thank Teri Tucker and Caron Modeas, i3 Statprobe, for editorial assistance. NR 17 TC 11 Z9 12 U1 0 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD SEP PY 2010 VL 11 IS 9 BP 910 EP 915 DI 10.1016/j.jpain.2009.12.016 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 652TW UT WOS:000282033900012 PM 20627703 ER PT J AU Jackson, V Arnold, RM AF Jackson, Vicki Arnold, Robert M. TI Introduction SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Editorial Material ID FELLOWSHIP C1 [Jackson, Vicki] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Jackson, V (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM VJackson@partners.org NR 5 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD SEP PY 2010 VL 13 IS 9 BP 1139 EP 1139 DI 10.1089/jpm.2010.9789 PG 1 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 649IJ UT WOS:000281762000014 PM 20836639 ER PT J AU Weckmann, MT Block, S AF Weckmann, Michelle T. Block, Susan TI Strategies for Finding and Negotiating a First Position in Hospice and Palliative Medicine SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID ACADEMIC MEDICINE; FACULTY; CAREER; WOMEN AB Securing a first job following training is an exciting and daunting task. Little formal guidance is available and trainees often find themselves confused, uncertain, and overwhelmed. This article is designed to provide a basic framework for fellows and new graduates to search for positions, apply, interview, and negotiate. The article focuses on securing an academic position; however, much of the advice is generalizable to a private-sector position. A short case example will be used to illustrate key points. C1 [Weckmann, Michelle T.] Univ Iowa, Dept Family Med Psychiat, Iowa City, IA 52242 USA. [Block, Susan] Dana Farber Canc Inst, Dept Psychosocial Olcol & Palliat Care, Boston, MA 02115 USA. [Block, Susan] Bringhan & Womens Hosp, Boston, MA USA. RP Weckmann, MT (reprint author), Univ Iowa, Dept Family Med Psychiat, Iowa City, IA 52242 USA. EM michelle-weckmann@uiowa.edu NR 27 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD SEP PY 2010 VL 13 IS 9 BP 1141 EP 1147 DI 10.1089/jpm.2010.0002 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 649IJ UT WOS:000281762000015 PM 20836640 ER PT J AU Chen, EY Mehra, K Mehrad, M Ning, G Miron, A Mutter, GL Monte, N Quade, B McKeon, FD Yassin, Y Xian, W Crum, CP AF Chen, Eleanor Y. Mehra, Karishma Mehrad, Mitra Ning, Gang Miron, Alexander Mutter, George L. Monte, Nicholas Quade, Bradley McKeon, Frank D. Yassin, Yosuf Xian, Wa Crum, Christopher P. TI Secretory cell outgrowth, PAX2 and serous carcinogenesis in the Fallopian tube SO JOURNAL OF PATHOLOGY LA English DT Article DE p53; PAX2; SCOUT; ovary; Fallopian tube; serous; carcinoma; BRCA1; BRCA2 ID OVARIAN-CANCER; INTRAEPITHELIAL CARCINOMA; BRCA MUTATIONS; EPITHELIUM; WOMEN; EXPRESSION; PREVENTION; PHENOTYPE; PRECURSOR; CARRIERS AB The 'p53 signature is a benign secretory cell outgrowth in the distal Fallopian tube that shares properties with ovarian serous cancer-including p53 mutations-and is a putative serous cancer precursor. We expanded the precursor definition to all secretory cell outgrowths (SCOUTs) of 30 or more cells and scored normal (N) and altered (A) expression of both p53 and PAX2, a gene down-regulated in ovarian and endometrial cancer. SCOUTs were identified by BCL2/p73 staining in tubes from women with serous carcinoma, inherited mutations in BRCA1 or BRCA2 and controls. SCOUTs were prevalent in both proximal and distal tube and significantly associated with serous carcinoma versus the others (p < 0.001); 89% were PAX2 (A) and 26% were PAX2 (A)/p53 (A) (p53 signatures). PAX2 (A)/p53 (N) SCOUTs were free of p53 mutations; however, 12 of 13 p53 signatures were PAX2 (A). A tubal carcinoma and contiguous SCOUT were p53 (A)/PAX2 (A) and shared the same p53 mutation. SCOUTs are discretely localized alterations commonly containing altered expression of multiple genes within histologically benign tubal epithelium. Geographic distribution in the tube varies by genotype and immunophenotype, from regionally unrestricted (PAX2) to greater likelihood specific area (fimbria) of shared prevalence (PAX2 and p53). This study reveals, for the first time, an entity (SCOUT) that is associated with serous cancer, expands the topography of altered PAX2 expression in the female genital tract mucosa and highlights another potential pathway disturbance involved in early serous carcinogenesis in the Fallopian tube. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Chen, Eleanor Y.; Mehra, Karishma; Mehrad, Mitra; Mutter, George L.; Monte, Nicholas; Quade, Bradley; Xian, Wa; Crum, Christopher P.] Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, Boston, MA 02115 USA. [Ning, Gang; McKeon, Frank D.] Harvard Univ, Sch Med, Dana Farber Canc Res Inst, Dept Cell Biol, Boston, MA 02115 USA. [Miron, Alexander; Yassin, Yosuf] Harvard Univ, Sch Med, Dana Farber Canc Res Inst, Div Canc Biol, Boston, MA 02115 USA. [Xian, Wa] ASTAR, Inst Biol, Singapore, Singapore. RP Crum, CP (reprint author), Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, 75 Francis St, Boston, MA 02115 USA. EM ccrum@partners.org FU NCI [1R21CA124688-01A1, P50 CA105009]; Columbia Hospital for Women Research Foundation; Division of Women's and Perinatal Pathology, Brigham and Women's Hospital FX This study was supported by grants from the NCI [Grant No. 1R21CA124688-01A1 to CPC, and P50 CA105009 (SPORE) to DC], the Columbia Hospital for Women Research Foundation (to CPC) and the Francis Ward Paine and TSA Pemberton Funds from the Division of Women's and Perinatal Pathology, Brigham and Women's Hospital. The authors are grateful to Dr Ross S Berkowitz, Dr Michael G Muto, Dr Colleen Feltmate and Dr Judy Garber of Brigham and Women's Hospital and the Dana Farber Cancer Institute for their clinical contributions. NR 28 TC 53 Z9 60 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3417 J9 J PATHOL JI J. Pathol. PD SEP PY 2010 VL 222 IS 1 BP 110 EP 116 DI 10.1002/path.2739 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA 638FQ UT WOS:000280879300011 PM 20597068 ER PT J AU Barnes, VM Teles, R Trivedi, HM Devizio, W Xu, T Lee, DP Mitchell, MW Wulff, JE Milburn, MV Guo, LN AF Barnes, Virginia M. Teles, Ricardo Trivedi, Harsh M. Devizio, William Xu, Tao Lee, Douglas P. Mitchell, Matthew W. Wulff, Jacob E. Milburn, Michael V. Guo, Lining TI Assessment of the Effects of Dentifrice on Periodontal Disease Biomarkers in Gingival Crevicular Fluid SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Biological markers; gingivitis; metabolomics; periodontitis ID HEALTH; TRICLOSAN/COPOLYMER AB Background: Periodontal disease has been studied primarily from clinical outcomes in lengthy human studies. Comprehensive biochemical profiling (metabolomics) has become a powerful tool for disease characterization and biomarker discovery. In a previous study, we performed a metabolomic analysis of gingival crevicular fluid collected from healthy, gingivitis, and periodontitis sites. Many metabolites associated with inflammation, oxidative stress, tissue degradation, and bacterial metabolism were found to be significantly induced by the diseases. Methods: A panel of 10 markers was selected from the previous metabolomic study based on their statistical significance. Thirty-nine chronic periodontitis subjects were randomly assigned to a toothpaste regimen: control dentifrice (n = 21) or triclosan-containing dentifrice ([CT] n = 18). Subjects were instructed to use their assigned dentifrice twice daily for 6 weeks. Gingival crevicular fluid samples from six healthy, six gingivitis, and three periodontitis sites were collected from each subject at baseline, 1 week, and 6 weeks. The relative levels of the markers in the samples were determined by mass spectrometry. One-sided matched-paired t tests were performed to compare data from healthy, gingivitis, and periodontitis sites. Results: Statistical analysis indicates that CT significantly decreased the levels of inosine, lysine, putrescine, and xanthine at the gingivitis sites as early as week 1. In contrast, control dentifrice had little effect. Conclusions: This result provides biochemical confirmation for the therapeutic effects of CT on gingivitis. Biomarkers were significantly altered by CT before clinical changes were observed, suggesting that the markers have predicative value for disease state assessment. J Periodontol 2010;81:12731279. C1 [Barnes, Virginia M.; Trivedi, Harsh M.; Devizio, William; Xu, Tao] Colgate Palmol Technol Ctr, Piscataway, NJ USA. [Teles, Ricardo] Forsyth Inst, Boston, MA USA. [Mitchell, Matthew W.; Wulff, Jacob E.; Milburn, Michael V.; Guo, Lining] Metabolon, Durham, NC USA. RP Guo, LN (reprint author), Metabolon, POB 110407, Res Triangle Pk, NC 27709 USA. EM lguo@metabolon.com OI Mitchell, Matthew/0000-0002-2681-4091 FU Colgate-Palmolive Company FX This investigation was supported by a research grant from Colgate-Palmolive Company to the Forsyth Institute and Metabolon. Virginia M. Barnes (Manager of Clinical Dental Research), Harsh M. Trivedi (Senior Technical Associate), William Devizio (Vice President), and Tao Xu (Director of Clinical Dental Research) are or were employees of Colgate-Palmolive Company, Piscataway, New Jersey. Ricardo Teles (Associate Member of the Staff, Department of Periodontology) is an employee of the Forsyth Institute, Boston, Massachusetts. Lining Guo (Senior Director), Matthew W. Mitchell (Senior Research Statistician), Michael V. Milburn (Chief Scientific Officer), Jacob E. Wulff (Statistician), and Douglas P. Lee (Study Director) are employees of Metabolon, Durham, North Carolina. NR 24 TC 11 Z9 11 U1 1 U2 1 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 J9 J PERIODONTOL JI J. Periodont. PD SEP PY 2010 VL 81 IS 9 BP 1273 EP 1279 DI 10.1902/jop.2010.100070 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 665GJ UT WOS:000283023100005 PM 20450373 ER PT J AU Rescala, B Rosalem, W Teles, RP Fischer, RG Haffajee, AD Socransky, SS Gustafsson, A Figueredo, CM AF Rescala, Bruno Rosalem, Wilson, Jr. Teles, Ricardo P. Fischer, Ricardo G. Haffajee, Anne D. Socransky, Sigmund S. Gustafsson, Anders Figueredo, Carlos Marcelo TI Immunologic and Microbiologic Profiles of Chronic and Aggressive Periodontitis Subjects SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Cytokines; gingival crevicular fluid; microbiology; periodontal diseases ID GINGIVAL CREVICULAR FLUID; SUBGINGIVAL MICROFLORA; ADULT PERIODONTITIS; INTERFERON-GAMMA; HOST RESPONSE; INTERLEUKIN-4; PATHOGENS; ELASTASE; NEUTROPHILS; CYTOKINES AB Background: This study determines the gingival crevicular fluid (GCF) levels of interleukin (IL)-1 beta, IL-2, IL-4, IL-8, interferon (IFN)-gamma and elastase activity in inflamed shallow and deep periodontal sites from patients with generalized chronic (GCP) and generalized aggressive periodontitis (GAgP), and to compare them to shallow sites from subjects with gingivitis. A secondary aim analyzes the microbiologic profile of these subjects. Methods: Cross-sectional clinical data were obtained from 20 GCP, 17 GAgP, and 10 gingivitis subjects. GCF samples were collected with paper strips and the levels of 1L-1 beta, IL-2, IL-4, IL-8, and IFN-gamma were measured using a multiplexed bead immunoassay. Elastase activity was assessed by an enzymatic assay. Subgingival plaque samples were analyzed using checkerboard DNA-DNA hybridization. Significance of differences among groups for immunologic and microbiologic data was examined using Kruskal-Wallis adjusting for multiple comparisons. Results: Mean clinical parameters and GCF volumes were higher in patients with GCP and GAgP compared to the gingivitis group. Higher levels of IL-1 beta and higher elastase activity were found in deep sites compared to shallow sites in both periodontitis groups (P<0.05). The microbiologic data showed significantly higher levels of the red complex species in patients with GCP and GAgP compared to gingivitis (P<0.05). There were no statistically significant differences in levels of GCF biomarkers and in levels of subgingival bacterial species between subjects with GCP and GAgP. Conclusion: There were no statistically significant differences in the measured immunologic and microbiologic parameters between subjects with GCP and GAgP. J Periodontol 2010;81:1308-1316. C1 [Rescala, Bruno; Rosalem, Wilson, Jr.; Fischer, Ricardo G.; Figueredo, Carlos Marcelo] Rio De Janeiro State Univ UERJ, Dept Periodontol, Rio De Janeiro, Brazil. [Teles, Ricardo P.; Haffajee, Anne D.; Socransky, Sigmund S.] Forsyth Inst, Dept Periodontol, Boston, MA USA. [Gustafsson, Anders; Figueredo, Carlos Marcelo] Karolinska Inst, Inst Odontol, Div Periodontol, Huddinge, Sweden. RP Figueredo, CM (reprint author), Fac Odontol Secretaria Posgrad & Pesquisa, Av 28 Setembro,157 Vila Isabel, BR-20551030 Rio De Janeiro, Brazil. EM cmfigueredo@hotmail.com RI Fischer, Ricardo/F-8788-2012; Figueredo, Carlos Marcelo/H-3356-2013 OI Figueredo, Carlos Marcelo/0000-0003-0222-9231 NR 35 TC 36 Z9 36 U1 1 U2 8 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 J9 J PERIODONTOL JI J. Periodont. PD SEP PY 2010 VL 81 IS 9 BP 1308 EP 1316 DI 10.1902/jop.2010.090643 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 665GJ UT WOS:000283023100009 PM 20450404 ER PT J AU Qian, WJ Petritis, BO Kaushal, A Finnerty, CC Jeschke, MG Monroe, ME Moore, RJ Schepmoes, AA Xiao, WZ Moldawer, LL Davis, RW Tompkins, RG Herndon, DN Camp, DG Smith, RD AF Qian, Wei-Jun Petritis, Brianne O. Kaushal, Amit Finnerty, Celeste C. Jeschke, Marc G. Monroe, Matthew E. Moore, Ronald J. Schepmoes, Athena A. Xiao, Wenzhong Moldawer, Lyle L. Davis, Ronald W. Tompkins, Ronald G. Herndon, David N. Camp, David G., II Smith, Richard D. CA Inflammation Host Response Injury TI Plasma Proteome Response to Severe Burn Injury Revealed by O-18-Labeled "Universal" Reference-Based Quantitative Proteomics SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE human plasma; quantitative proteomics; O-18 labeling; LC-MS; burn; inflammation; "universal" reference ID CHROMATOGRAPHY-MASS SPECTROMETRY; TIME TAG APPROACH; LIQUID-CHROMATOGRAPHY; METABOLIC-RESPONSE; ORGAN DYSFUNCTION; ACCURATE MASS; EXPRESSION; INFLAMMATION; ACTIVATION; LIPOPOLYSACCHARIDE AB A burn injury represents one of the most severe forms of human trauma and is responsible for significant mortality worldwide. Here, we present the first quantitative proteomics investigation of the blood plasma proteome response to severe burn injury by comparing the plasma protein concentrations of 10 healthy control subjects with those of 15 severe burn patients at two time-points following the injury. The overall analytical strategy for this work integrated immunoaffinity depletion of the 12 most abundant plasma proteins with cysteinyl-peptide enrichment-based fractionation prior to LC-MS analyses of individual patient samples. Incorporation of an O-18-labeled "universal" reference among the sample sets enabled precise relative quantification across samples. In total, 313 plasma proteins confidently identified with two or more unique peptides were quantified. Following statistical analysis, 110 proteins exhibited significant abundance changes in response to the burn injury. The observed changes in protein concentrations suggest significant inflammatory and hypermetabolic response to the injury, which is supported by the fact that many of the identified proteins are associated with acute phase response signaling, the complement system, and coagulation system pathways. The regulation of similar to 35 proteins observed in this study is in agreement with previous results reported for inflammatory or burn response, but approximately 50 potentially novel proteins previously not known to be associated with burn response or inflammation are also found. Elucidating proteins involved in the response to severe burn injury may reveal novel targets for therapeutic interventions as well as potential predictive biomarkers for patient outcomes such as multiple organ failure. C1 [Qian, Wei-Jun; Petritis, Brianne O.; Monroe, Matthew E.; Moore, Ronald J.; Schepmoes, Athena A.; Camp, David G., II; Smith, Richard D.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Qian, Wei-Jun; Petritis, Brianne O.; Monroe, Matthew E.; Moore, Ronald J.; Schepmoes, Athena A.; Camp, David G., II; Smith, Richard D.] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Kaushal, Amit; Xiao, Wenzhong; Davis, Ronald W.] Stanford Univ, Sch Med, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. [Finnerty, Celeste C.; Jeschke, Marc G.; Herndon, David N.] Univ Texas Med Branch, Shriners Burns Hosp, Dept Surg, Galveston, TX 77550 USA. [Moldawer, Lyle L.] Univ Florida, Coll Med, Dept Surg, Gainesville, FL 32610 USA. [Tompkins, Ronald G.] Harvard Univ, Shriners Burn Ctr, Dept Surg, Sch Med, Boston, MA 02114 USA. [Tompkins, Ronald G.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Smith, RD (reprint author), Pacific NW Natl Lab, Environm Mol Sci Lab, POB 999,MSIN K8-98, Richland, WA 99352 USA. EM rds@pnl.gov RI Qian, Weijun/C-6167-2011; Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; xiao, wenzhong/0000-0003-4944-6380 FU National Institute of General Medical Sciences (NIGMS) [U54 GM-62119-02, T32 GM-008256]; NIH National Center for Research Resources [RR18522]; EMSL (Environmental Molecular Science Laboratory); U.S. Department of Energy (DOE) Office of Biological and Environmental Research on the Pacific Northwest National Laboratory (PNNL) campus in Richland, Washington; Battelle [DE-AC05-76RLO-1830] FX Portions of this research were supported by the National Institute of General Medical Sciences (NIGMS; Large Scale Collaborative Research Grants U54 GM-62119-02 and T32 GM-008256), the NIH National Center for Research Resources (RR18522), and EMSL (Environmental Molecular Science Laboratory). EMSL is a national scientific user facility sponsored by the U.S. Department of Energy (DOE) Office of Biological and Environmental Research on the Pacific Northwest National Laboratory (PNNL) campus in Richland, Washington. PNNL is operated by Battelle for the DOE under contract DE-AC05-76RLO-1830. Additional participating investigators in the Large Scale Collaborative Research Program entitled Inflammation and the Host Response to Injury: Henry V. Baker, Ph.D., Ulysses Balis, M.D., Paul Bankey, M.D., Timothy R. Billiar, M.D., Bernard H. Brownstein, Ph.D., Steven E. Calvano, Ph.D., Irshad H. Chaudry, Ph.D., J. Perren Cobb, M.D., Joseph Cuschieri, M.D., Asit K. De, Ph.D., Bradley Freeman, M.D., Richard L. Gamelli, M.D., Nicole S. Gibran, M.D., Brian G. Harbrecht, M.D., Douglas L. Hayden, M.A., Laura Hennessy, R.N., Jureta W. Horton, Ph.D., Jeffrey Johnson, M.D., Matthew B. Klein, M.D., Stephen F. Lowry, M.D., Ronald V. Maier, M.D., John A. Mannick, M.D., Philip H. Mason, Ph.D., Grace P. McDonald-Smith, M.Ed., Carol L. Miller-Graziano, Ph.D., Michael N. Mindrinos, Ph.D., Joseph P. Minei, M.D., Ernest E. Moore, M.D., Avery B. Nathens, M.D., Ph.D., M.P.H., Grant E. O'Keefe, M.D., M.P.H., Laurence G. Rahme, Ph.D., Daniel G. Remick, Jr. M.D., David A. Schoenfeld, Ph.D., Michael B. Shapiro, M.D., Geoffrey M. Silver, M.D., John Storey, Ph.D., Robert Tibshirani, Ph.D., Mehmet Toner, Ph.D., H. Shaw Warren, M.D., Michael A. West, M.D. NR 59 TC 29 Z9 30 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD SEP PY 2010 VL 9 IS 9 BP 4779 EP 4789 DI 10.1021/pr1005026 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 645HS UT WOS:000281443700041 PM 20698492 ER PT J AU Sinclair, SJ Antonius, D Shiva, A Siefert, CJ Kehl-Fie, K Lama, S Shorey, HS Blais, MA AF Sinclair, Samuel J. Antonius, Daniel Shiva, Andrew Siefert, Caleb J. Kehl-Fie, Kendra Lama, Stephanie Shorey, Hal S. Blais, Mark A. TI The Psychometric Properties of the Personality Assessment Inventory-Short Form (PAI-SF) in Inpatient Forensic and Civil Samples SO JOURNAL OF PSYCHOPATHOLOGY AND BEHAVIORAL ASSESSMENT LA English DT Article DE Personality Assessment Inventory short-form; PAI-SF; Psychometric; Forensic assessment ID PCL-R; RELIABILITY; DISORDERS; INMATES; SCALES AB Research focusing on the Personality Assessment Inventory (PAI) has increased substantially over the past decade. However, there has been relatively little focus on the PAI short-form (PAISF). The current study evaluated the psychometric characteristics of the PAI-SF clinical scales using participants admitted to a large northeastern hospital under forensic (N = 178) and civil (N = 320) statutes. Results indicate that the internal consistency of the PAI-SF clinical scales is adequate for both the Forensic (range of alphas: 0.74 to 0.88) and Civil (0.79 to 0.91) samples, and assumptions of item-scale convergence and divergence were generally met with some exceptions. Finally, the PAI-SF exhibited strong agreement with the full-form PAI scores overall, and at the upper extreme (T a parts per thousand yenaEuro parts per thousand 70) of the distributions for both samples. The results are discussed in terms of how they extend prior research on the PAI-SF. C1 [Sinclair, Samuel J.; Siefert, Caleb J.; Blais, Mark A.] Massachusetts Gen Hosp, Psychol Evaluat & Res Lab, Dept Psychiat, Boston, MA 02114 USA. [Sinclair, Samuel J.; Siefert, Caleb J.; Blais, Mark A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Antonius, Daniel] NYU, Sch Med, Dept Psychiat, New York, NY USA. [Shiva, Andrew] NYU, Sch Med, New York, NY USA. [Shiva, Andrew] CUNY John Jay Coll Criminal Justice, New York, NY 10019 USA. [Kehl-Fie, Kendra; Lama, Stephanie] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Shorey, Hal S.] Widener Univ, Inst Grad Clin Psychol, Chester, PA 19013 USA. RP Sinclair, SJ (reprint author), Massachusetts Gen Hosp, Psychol Evaluat & Res Lab, Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM SJSinclair@Partners.org OI Shiva, Andrew/0000-0001-5069-239X NR 26 TC 7 Z9 7 U1 17 U2 19 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0882-2689 J9 J PSYCHOPATHOL BEHAV JI J. Psychopathol. Behav. Assess. PD SEP PY 2010 VL 32 IS 3 BP 406 EP 415 DI 10.1007/s10862-009-9165-x PG 10 WC Psychology, Clinical SC Psychology GA 634QK UT WOS:000280597800012 ER PT J AU Crisafulli, MA Thompson-Brenner, H Franko, DL Eddy, KT Herzog, DB AF Crisafulli, Michele A. Thompson-Brenner, Heather Franko, Debra L. Eddy, Kamryn T. Herzog, David B. TI Stigmatization of Anorexia Nervosa: Characteristics and Response to Intervention SO JOURNAL OF SOCIAL AND CLINICAL PSYCHOLOGY LA English DT Article ID EATING-DISORDERS; MENTAL ILLNESSES; ATTITUDES; PEOPLE; WOMEN; DISCRIMINATION AB The present study aimed to investigate the effects of different etiological explanations of anorexia nervosa (AN) on stigmatization of those with the disorder. College students (N = 173) were randomly assigned to view one of three videos describing AN as the product of either biology, culture, or an interaction of the two. In general, those who viewed the interaction video exhibited less stigma than those who viewed the sociocultural video, though more than those who viewed the biological video. These findings are consistent with attribution theory, as well as previous empirical findings, and may represent a preliminary step towards guiding those conducting campaigns to destigmatize eating disorders. C1 [Crisafulli, Michele A.; Thompson-Brenner, Heather] Boston Univ, Boston, MA 02215 USA. [Franko, Debra L.; Eddy, Kamryn T.; Herzog, David B.] Massachusetts Gen Hosp, Harris Ctr, Boston, MA 02114 USA. [Franko, Debra L.] Northeastern Univ, Boston, MA USA. RP Crisafulli, MA (reprint author), Boston Univ, Boston, MA 02215 USA. EM michele.a.crisafulli@gmail.com NR 20 TC 15 Z9 15 U1 0 U2 18 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0736-7236 J9 J SOC CLIN PSYCHOL JI J. Soc. Clin. Psychol. PD SEP PY 2010 VL 29 IS 7 BP 756 EP 770 PG 15 WC Psychology, Clinical; Psychology, Social SC Psychology GA 649HO UT WOS:000281759200002 ER PT J AU Williams, EC Achtmeyer, CE Kivlahan, DR Greenberg, D Merrill, JO Wickizer, TM Koepsell, TD Heagerty, PJ Bradley, KA AF Williams, Emily C. Achtmeyer, Carol E. Kivlahan, Daniel R. Greenberg, Diane Merrill, Joseph O. Wickizer, Thomas M. Koepsell, Thomas D. Heagerty, Patrick J. Bradley, Katharine A. TI Evaluation of an Electronic Clinical Reminder to Facilitate Brief Alcohol-Counseling Interventions in Primary Care SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID DECISION-SUPPORT-SYSTEMS; HEALTH-CARE; PROBLEM DRINKING; AUDIT-C; BARRIERS; IMPLEMENTATION; PERFORMANCE; OUTCOMES; PATIENT; TRIALS AB Objective: Brief intervention for patients with unhealthy alcohol use is a prevention priority in the United States, but most eligible patients do not receive it. This study evaluated an electronic alcohol-counseling clinical reminder at a single Veterans Affairs general medicine clinic. Method: The systems-level intervention evaluated in this study consisted of making the clinical reminder, which facilitated medical record documentation of brief intervention among patients who screened positive for unhealthy alcohol use, available to providers on one (of two) randomly selected hallways. Secondary electronic data were extracted for all patients who visited the clinic (October 1, 2002, to September 30, 2005). The proportion of patients with clinical-reminder use was evaluated among patients who screened positive for unhealthy drinking and were assigned to intervention hallway providers ("descriptive cohort"). Adjusted logistic regression evaluated the association between the intervention and resolution of unhealthy drinking at follow-up among all screen-positive patients who completed a second Alcohol Use Disorders Identification Test Consumption questionnaire 18 months or longer after the first ("outcomes cohort"). Results: Eligible patients (N = 22,863) included 10,392 controls and 12,471 in the intervention group. Fifteen percent (398 of 2,640) of descriptive cohort patients with unhealthy drinking had clinical-reminder use, which varied by severity (14% [n = 302 of 2,165] with mild/moderate and 20% [n = 96 of 475] with severe unhealthy drinking, p = .001). Only 39% (156 of 398) of patients with clinical-reminder use had documented brief intervention; advice to abstain was most common. Access to the clinical reminder was not significantly associated with resolution of unhealthy drinking in 1,358 patients in the outcomes cohort. Conclusions: Availability of a clinical reminder to facilitate brief intervention did not, alone, result in substantial use of the clinical reminder. More active implementation efforts may be needed to get brief interventions onto the agenda of busy primary care providers. (J. Stud. Alcohol Drugs, 71, 720-725, 2010) C1 [Williams, Emily C.] Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA 98101 USA. [Williams, Emily C.; Bradley, Katharine A.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Achtmeyer, Carol E.; Bradley, Katharine A.] Vet Affairs Puget Sound Hlth Care Syst, Primary & Specialty Med Care Serv, Seattle, WA 98101 USA. [Kivlahan, Daniel R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Bradley, Katharine A.] Univ Washington, Dept Med, Seattle, WA 98195 USA. Vet Affairs Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA 98101 USA. RP Williams, EC (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM emily.williams3@va.gov FU National Institute on Alcohol Abuse and Alcoholism [K23AA00313]; Veterans Affairs (VA) Substance Use Disorders Quality Enhancement Research Initiative (SUD QuERI); VA's Northwest Center of Excellence for Health Services Research and Development FX Dr. Bradley was a Robert Wood Johnson Generalist Physician Faculty Scholar and supported by a National Institute on Alcohol Abuse and Alcoholism career development award (K23AA00313) at the time this research was initiated. This study was also supported by the Veterans Affairs (VA) Substance Use Disorders Quality Enhancement Research Initiative (SUD QuERI) and the VA's Northwest Center of Excellence for Health Services Research and Development. Views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, the University of Washington, the National Institute on Alcohol Abuse and Alcoholism, or the Robert Wood Johnson Foundation. Preliminary versions of this work were presented at the Annual Scientific Meeting of the Research Society on Alcoholism, Washington, DC, June 28-July 2, 2008, and included in the dissertation of Emily C. Williams that was submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy from the University of Washington. NR 30 TC 10 Z9 10 U1 1 U2 3 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD SEP PY 2010 VL 71 IS 5 BP 720 EP 725 PG 6 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 645UE UT WOS:000281490900010 PM 20731977 ER PT J AU Del Prete, JC Bakaeen, FG Dao, TK Huh, J LeMaire, SA Coselli, JS Chu, D AF Del Prete, Jennifer C. Bakaeen, Faisal G. Dao, Tam K. Huh, Joseph LeMaire, Scott A. Coselli, Joseph S. Chu, Danny TI The Impact of Obesity on Long-term Survival After Coronary Artery Bypass Grafting SO JOURNAL OF SURGICAL RESEARCH LA English DT Article; Proceedings Paper CT 5th Annual Academic-Surgical Congress CY JAN-FEB -, 2010 CL San Antonio, TX DE body mass index; coronary artery bypass grafting; obesity; outcomes; survival ID BODY-MASS INDEX; AMERICAN-HEART-ASSOCIATION; CARDIAC-SURGERY; CARDIOVASCULAR-DISEASE; SECONDARY PREVENTION; EXTREME OBESITY; EARLY OUTCOMES; VALVE SURGERY; UNITED-STATES; MORTALITY AB Background. Obesity is a well-known risk factor for coronary artery disease. The objective of our study was to examine the impact of obesity on long-term survival after coronary artery bypass grafting (CABG). Materials and Methods. Using prospectively gathered data, we reviewed records of 1163 consecutive patients who underwent isolated primary CABG between 1997 and 2007. We compared outcomes of obese patients (body mass index [BMI] >= 30 kg/m(2); n = 472) and non-obese patients (BMI < 30 kg/m(2); n = 691). Long-term survival was assessed by using Kaplan-Meier curves generated by log-rank tests and adjusted for confounding factors with Cox logistic regression analysis. Results. Obese patients were slightly younger (60 +/- 8 versus 63 +/- 9y; P < 0.0001), were less likely to be current tobacco smokers (30% versus 41%; P < 0.0001), had a higher incidence of diabetes (51% versus 33%; P < 0.0001), and had a lower incidence of cerebral vascular disease (18% versus 24%; P = 0.009) than non-obese patients. The two groups of patients had similar 30-d rates of mortality (1.3% versus 1.5%; P = 0.8) and major adverse cardiac events (2.3% versus 2.5%; P = 0.9). Adjusted Cox regression survival curves were also similar between the two groups of patients (adjusted hazard ratio, 1.2; 95% confidence interval, 0.8-1.8; P = 0.28). Conclusions. Obese patients who underwent CABG had 30-d mortality rates and early outcomes similar to those of non-obese patients. Long-term survival was also similar between these two groups of patients after adjustment for confounding variables. Published by Elsevier Inc. C1 [Chu, Danny] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Del Prete, Jennifer C.; Huh, Joseph; LeMaire, Scott A.; Coselli, Joseph S.] St Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX USA. [Dao, Tam K.] Univ Houston, Houston, TX USA. RP Chu, D (reprint author), Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, 2002 Holcombe Blvd,OCL 112, Houston, TX 77030 USA. EM dchumd@gmail.com NR 29 TC 8 Z9 8 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD SEP PY 2010 VL 163 IS 1 BP 7 EP 11 DI 10.1016/j.jss.2010.02.014 PG 5 WC Surgery SC Surgery GA 640TT UT WOS:000281076300002 PM 20452615 ER PT J AU Fukudome, EY Kochanek, AR Li, YQ Smith, EJ Liu, BL Kheirbek, T Lu, J Kim, K Hamwi, K Velmahos, GC Alam, HB AF Fukudome, Eugene Y. Kochanek, Ashley R. Li, Yongqing Smith, Eleanor J. Liu, Baoling Kheirbek, Tareq Lu, Jennifer Kim, Kyuseok Hamwi, Kristopher Velmahos, George C. Alam, Hasan B. TI Pharmacologic Resuscitation Promotes Survival and Attenuates Hemorrhage-Induced Activation of Extracellular Signal-Regulated Kinase 1/2 SO JOURNAL OF SURGICAL RESEARCH LA English DT Article; Proceedings Paper CT 5th Annual Academic-Surgical Congress CY JAN-FEB -, 2010 CL San Antonio, TX DE hemorrhage; shock; resuscitation; valproic acid; acetylation; survival; ERK; lung ID HISTONE DEACETYLASE INHIBITORS; FOCAL CEREBRAL-ISCHEMIA; INDUCED CELL-DEATH; VALPROIC ACID; FLUID RESUSCITATION; CARDIAC HISTONES; PROTEIN-KINASES; LUNG INJURY; SHOCK; ACETYLATION AB Background. Hemorrhage is the leading cause of preventable trauma-related deaths, and histone deacetylase inhibitors (HDACI) such as valproic acid (VPA) can improve survival following lethal hemorrhage. HDACI acetylate proteins, and acetylation regulates many cellular functions. Here we have investigated the effects of VPA treatment on extracellular signal-regulated kinase 1/2 (ERK) activation, as ERK is well known to modulate cell death, gene expression, and inflammation. Materials and Methods. Anesthetized Wistar-Kyoto rats were subjected to lethal (60%) blood loss, and then randomized (n = 5-6/group) to (1) VPA 300 mg/kg or (2) vehicle control. Survival was monitored for 24 h. A separate group of rats were subjected to sublethal (40%) hemorrhage and were treated with VPA or vehicle. Rats were sacrificed at 1, 4, and 20 h, and lung tissue was assessed for the degree of acetylation of histone 3, and activation (phosphorylation) of ERK. Sham animals served as normal controls. Results. Sixty percent hemorrhage resulted in severe shock. Only 17% of the vehicle-treated animals survived (most died within 1 h), whereas 80% of the VPA-treated animals survived (P < 0.05). Hemorrhage resulted in a significant increase in phosphorylated ERK (activated form) compared with sham at the 1 and 4 h time points, but not at the 20 h time point. VPA treatment significantly attenuated these changes, while increasing histone protein acetylation. Conclusions. VPA treatment significantly improves survival following lethal hemorrhagic shock. Hemorrhage induces ERK activation, which is significantly attenuated by VPA treatment. This may represent one mechanism through which VPA promotes survival in otherwise lethal hemorrhagic shock. (C) 2010 Elsevier Inc. All rights reserved. C1 [Alam, Hasan B.] Harvard Univ, Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Sch Med,Dept Surg, Boston, MA 02114 USA. [Kheirbek, Tareq; Hamwi, Kristopher] Washington Hosp Ctr, Dept Surg, Washington, DC 20010 USA. RP Alam, HB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Sch Med,Dept Surg, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM hbalam@partners.org OI Kim, Kyuseok/0000-0002-7991-9428 FU NIGMS NIH HHS [R01 GM084127-02, R01 GM084127, R01 GM084127-01A1] NR 43 TC 23 Z9 26 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 0022-4804 J9 J SURG RES JI J. Surg. Res. PD SEP PY 2010 VL 163 IS 1 BP 118 EP 126 DI 10.1016/j.jss.2010.04.013 PG 9 WC Surgery SC Surgery GA 640TT UT WOS:000281076300020 PM 20599213 ER PT J AU Finkelstein, RA Li, YQ Liu, BL Shuja, F Fukudome, E Velmahos, GC Demoya, M Alam, HB AF Finkelstein, Robert A. Li, Yongqing Liu, Baoling Shuja, Fahad Fukudome, Eugene Velmahos, George C. deMoya, Marc Alam, Hasan B. TI Treatment with Histone Deacetylase Inhibitor Attenuates MAP Kinase Mediated Liver Injury in a Lethal Model of Septic Shock SO JOURNAL OF SURGICAL RESEARCH LA English DT Article; Proceedings Paper CT 5th Annual Academic-Surgical Congress CY JAN-FEB -, 2010 CL San Antonio, TX DE septic shock; acetylation; LPS; suberoylanilide hydroxamic acid; histone; MAP kinase; p38; ERK; IL-10; IL-6; liver ID TUMOR-NECROSIS-FACTOR; SUBEROYLANILIDE HYDROXAMIC ACID; CRITICALLY ILL PATIENTS; PROTEIN-KINASE; TNF-ALPHA; RESUSCITATION STRATEGIES; SIGNAL-TRANSDUCTION; CYTOKINE PRODUCTION; HUMAN ENDOTOXEMIA; CARDIAC HISTONES AB Background. Despite global efforts to improve the treatment of sepsis, it remains a leading cause of morbidity and mortality in intensive care units. We have previously shown that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, markedly improves survival in a murine model of lipopolysaccharide (LPS) -induced shock. SAHA has anti-inflammatory properties that have not been fully characterized. The liver plays an important role in the production of acute phase reactants involved in the inflammatory cascade and is also one of the major organs that can become dysfunctional in septic shock. The purpose of this study was to assess the effect of SAHA treatment on MAP kinases and associated inflammatory markers in murine liver after LPS-induced injury. Methods. C57B1/6J mice were randomly divided into three groups: (A) experimental-given intraperitoneal (i.p.) SAHA (50 mg/kg) in dimethyl sulfoxide (DMSO) vehicle solution (n = 12); (B) control- given vehicle only (n = 12), and; (C) sham-given no treatment (n = 7). Two hours later, experimental and control mice were injected with LPS (20 mg/kg, i.p.) and experimental mice received a second dose of SAHA. Livers were harvested at 3, 24, and 48 h for analysis of inflammatory markers using Western Blot, Polymerase Chain Reaction (PCR), and Enzyme-Linked Immunosorbent Assay (ELISA) techniques. Results. After 3 h, the livers of animals treated with SAHA showed significantly (P < 0.05) decreased expression of the pro-inflammatory MAP kinases phosphorylated p38, phosphorylated ERK, myeloperoxidase and interleukin-6, and increased levels of the anti-inflammatory interleukin-10 compared with controls. Phospho-p38 expression remained low in the SAHA treated groups at 24 and 48 h. Conclusion. Administration of SAHA is associated with attenuation of MAPK activation and alteration of inflammatory and anti-inflammatory markers in murine liver after a lethal LPS insult. The suppression of MAPK activity is rapid (within 3 h), and is sustained for up to 48 h post-treatment. These results may in part account for the improvement in survival shown in this model. (C) 2010 Elsevier Inc. All rights reserved. C1 [Alam, Hasan B.] Harvard Univ, Div Trauma Emergency Surg & Surg Crit Care, Massachusetts Gen Hosp, Sch Med,Dept Surg, Boston, MA 02114 USA. [Finkelstein, Robert A.] Harvard Univ, Dept Pediat, Massachusetts Gen Hosp, Sch Med,Div Pediat Crit Care Med, Boston, MA 02114 USA. RP Alam, HB (reprint author), Harvard Univ, Div Trauma Emergency Surg & Surg Crit Care, Massachusetts Gen Hosp, Sch Med,Dept Surg, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM hbalam@partners.org FU NIGMS NIH HHS [R01GM084127, R01 GM084127] NR 57 TC 19 Z9 23 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD SEP PY 2010 VL 163 IS 1 BP 146 EP 154 DI 10.1016/j.jss.2010.04.024 PG 9 WC Surgery SC Surgery GA 640TT UT WOS:000281076300024 PM 20599223 ER PT J AU Ortmann, AJ Palmer, CV Prattt, SR AF Ortmann, Amanda J. Palmer, Catherine V. Prattt, Sheila R. TI Impact of Spectrally Asynchronous Delays on Consonant Voicing Perception SO JOURNAL OF THE AMERICAN ACADEMY OF AUDIOLOGY LA English DT Article DE Assistive listening devices; hearing aids; speech perception ID HEARING-AID DELAYS; SPEECH PRODUCTION; IMPAIRED SUBJECTS; STOP CONSONANTS; LIMITS; IDENTIFICATION; RECOGNITION; SENTENCES; ENGLISH; ADULTS AB Background: A possible voicing cue used to differentiate voiced and voiceless cognate pairs is envelope onset asynchrony (EOA). EOA is the time between the onsets of two frequency bands of energy (in this study one band was high-pass filtered at 3000 Hz, the other low-pass filtered at 350 Hz). This study assessed the perceptual impact of manipulating EOA on voicing perception of initial stop consonants, and whether normal-hearing and hearing-impaired listeners were sensitive to changes in EOA as a cue for voicing. Purpose: The purpose of this study was to examine the effect of spectrally asynchronous auditory delay on the perception of voicing associated with initial stop consonants by normal-hearing and hearing-impaired listeners. Research Design: Prospective experimental study comparing the perceptual differences of manipulating the EOA cues for two groups of listeners. Study Sample: Thirty adults between the ages of 21 and 60yr completed the study: 17 listeners with normal hearing and 13 listeners with mild-moderate sensorineural hearing loss. Data Collection and Analysis: The participants listened to voiced and voiceless stop consonants within a consonant-vowel syllable structure. The EOA of each syllable was varied along a continuum, and identification and discrimination tasks were used to determine if the EOA manipulation resulted in categorical shifts in voicing perception. In the identification task the participants identified the consonants as belonging to one of two categories (voiced or voiceless cognate). They also completed a same-different discrimination task with the same set of stimuli. Categorical perception was confirmed with a d-prime sensitivity measure by examining how accurately the results from the identification task predicted the discrimination results. The influence of EOA manipulations on the perception of voicing was determined from shifts in the identification functions and discrimination peaks along the EOA continuum. The two participant groups were compared in order to determine the impact of EOA on voicing perception as a function of syllable and hearing status. Results: Both groups of listeners demonstrated a categorical shift in voicing perception with manipulation of EOA for some of the syllables used in this study. That is, as the temporal onset asynchrony between low-and high-frequency bands of speech was manipulated, the listeners' perception of consonant voicing changed between voiced and voiceless categories. No significant differences were found between listeners with normal hearing and listeners with hearing loss as a result of the EOA manipulation. Conclusions: The results of this study suggested that both normal-hearing and hearing-impaired listeners likely use spectrally asynchronous delays found in natural speech as a cue for voicing distinctions. While delays in modern hearing aids are less than those used in this study, possible implications are that additional asynchronous delays from digital signal processing or open-fitting amplification schemes might cause listeners with hearing loss to misperceive voicing cues. C1 [Ortmann, Amanda J.; Palmer, Catherine V.; Prattt, Sheila R.] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA 15260 USA. [Prattt, Sheila R.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Ortmann, AJ (reprint author), Washington Univ, Sch Med, Dept Otolaryngol, Campus Box 8115,660 S Euclid Ave, St Louis, MO 63110 USA. EM ortmanna@ent.wustl.edu FU Veterans Affairs; University of Pittsburgh School of Health; Rehabilitation Sciences Research Development Fund FX The primary author was funded through a Veterans Affairs predoctoral traineeship. This study was supported in part by the University of Pittsburgh School of Health and Rehabilitation Sciences Research Development Fund. NR 27 TC 1 Z9 1 U1 0 U2 1 PU AMER ACAD AUDIOLOGY PI RESTON PA 11730 PLAZA DR, STE 300, RESTON, VA 20190 USA SN 1050-0545 J9 J AM ACAD AUDIOL JI J. Am. Acad. Audiol. PD SEP PY 2010 VL 21 IS 8 BP 493 EP 511 DI 10.3766/jaaa.21.8.2 PG 19 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 674AK UT WOS:000283705300002 PM 21034697 ER PT J AU Neale, BM Medland, SE Ripke, S Asherson, P Franke, B Lesch, KP Faraone, SV Nguyen, TT Schafer, H Holmans, P Daly, M Steinhausen, HC Freitag, C Reif, A Renner, TJ Romanos, M Romanos, J Walitza, S Warnke, A Meyer, J Palmason, H Buitelaar, J Vasquez, AA Lambregts-Rommelse, N Gill, M Anney, RJL Langely, K O'Donovan, M Williams, N Owen, M Thapar, A Kent, L Sergeant, J Roeyers, H Mick, E Biederman, J Doyle, A Smalley, S Loo, S Hakonarson, H Elia, J Todorov, A Miranda, A Mulas, F Ebstein, RP Rothenberger, A Banaschewski, T Oades, RD Sonuga-Barke, EJS McGough, J Nisenbaum, L Middleton, F Hu, XL Nelson, S AF Neale, Benjamin M. Medland, Sarah E. Ripke, Stephan Asherson, Philip Franke, Barbara Lesch, Klaus-Peter Faraone, Stephen V. Nguyen, Thuy Trang Schaefer, Helmut Holmans, Peter Daly, Mark Steinhausen, Hans-Christoph Freitag, Christine Reif, Andreas Renner, Tobias J. Romanos, Marcel Romanos, Jasmin Walitza, Susanne Warnke, Andreas Meyer, Jobst Palmason, Haukur Buitelaar, Jan Vasquez, Alejandro Arias Lambregts-Rommelse, Nanda Gill, Michael Anney, Richard J. L. Langely, Kate O'Donovan, Michael Williams, Nigel Owen, Michael Thapar, Anita Kent, Lindsey Sergeant, Joseph Roeyers, Herbert Mick, Eric Biederman, Joseph Doyle, Alysa Smalley, Susan Loo, Sandra Hakonarson, Hakon Elia, Josephine Todorov, Alexandre Miranda, Ana Mulas, Fernando Ebstein, Richard P. Rothenberger, Aribert Banaschewski, Tobias Oades, Robert D. Sonuga-Barke, Edmund J. S. McGough, James Nisenbaum, Laura Middleton, Frank Hu, Xiaolan Nelson, Stan CA Psychiat GWAS Consortium ADHD Subg TI Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; meta-analysis; association; GWAS; genetics ID DEFICIT HYPERACTIVITY DISORDER; INTERNATIONAL HAPMAP PROJECT; MOLECULAR-GENETICS; ADULT ADHD; SCAN; LINKAGE; IDENTIFICATION; PREVALENCE; COMPONENTS; IMPUTATION AB Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method: We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results: No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions: Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability. J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(9):884-897. C1 [Neale, Benjamin M.; Ripke, Stephan; Daly, Mark] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin M.; Ripke, Stephan] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Daly, Mark] MIT, Cambridge, MA 02139 USA. [Medland, Sarah E.] Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld 4006, Australia. [Asherson, Philip; Sonuga-Barke, Edmund J. S.] Kings Coll London, MRC Social Genet & Dev Psychiat, London, England. [Franke, Barbara; Buitelaar, Jan; Vasquez, Alejandro Arias] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA. [Nguyen, Thuy Trang; Schaefer, Helmut] Univ Marburg, Inst Med Biometrie & Epidemiol, Marburg, Germany. [Holmans, Peter; Langely, Kate; Owen, Michael; Thapar, Anita] MRC, Ctr Neuropsychiat Genet & Gen, Cardiff, S Glam, Wales. [Steinhausen, Hans-Christoph; Walitza, Susanne] Univ Zurich, Zurich, Switzerland. [Steinhausen, Hans-Christoph] Aarhus Univ Hosp, Aalborg Psychiat Hosp, Aarhus, Denmark. [Steinhausen, Hans-Christoph] Univ Basel, Inst Psychol, CH-4003 Basel, Switzerland. [Lesch, Klaus-Peter; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas] Univ Wurzburg, Wurzburg, Germany. [Freitag, Christine; Banaschewski, Tobias] Goethe Univ Frankfurt, Frankfurt, Germany. [Meyer, Jobst; Palmason, Haukur] Univ Trier, Inst Psychobiol, Trier, Germany. [Gill, Michael; Anney, Richard J. L.] St James Hosp, Trinity Ctr Hlth Sci, Dublin, Ireland. [O'Donovan, Michael; Williams, Nigel] Cardiff Univ, Sch Med, Cardiff, S Glam, Wales. [Kent, Lindsey; Doyle, Alysa] Bute Med Sch, St Andrews, Fife, Scotland. [Sergeant, Joseph; Mick, Eric; Doyle, Alysa] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Roeyers, Herbert] Univ Ghent, B-9000 Ghent, Belgium. [Mick, Eric; Biederman, Joseph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program, Pediat Psychopharmacol Adult ADHD, Boston, MA 02114 USA. [Smalley, Susan; Loo, Sandra; McGough, James] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Hakonarson, Hakon; Elia, Josephine] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Hakonarson, Hakon] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Todorov, Alexandre] Washington Univ, Sch Med, St Louis, MO USA. [Miranda, Ana] Univ Valencia, E-46003 Valencia, Spain. [Mulas, Fernando] La Fe Univ Hosp, Fac Med, Valencia, Spain. [Ebstein, Richard P.] Singapore & Hebrew Univ, Jerusalem, Israel. [Rothenberger, Aribert] Univ Gottingen, D-3400 Gottingen, Germany. [Oades, Robert D.] Univ Duisburg Essen, Clin Child & Adolescent Psychiat, Essen, Germany. [Sonuga-Barke, Edmund J. S.] Univ Southampton, Sch Psychol, Inst Disorder Impulse & Attent, Southampton, NY USA. [Sonuga-Barke, Edmund J. S.] NYU, Ctr Child Study, New York, NY USA. [Nisenbaum, Laura] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Hu, Xiaolan] Pfizer, Mol Med, Groton, CT USA. RP Faraone, SV (reprint author), SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, 750 E Adams St, Syracuse, NY 13210 USA. EM sfaraone@childpsychresearch.org RI Lesch, Klaus-Peter/J-4906-2013; Sonuga-Barke, Edmund/D-9137-2011; Holmans, Peter/F-4518-2015; Miranda, Ana/G-8619-2015; Romanos, Marcel/D-7695-2017; turton, miranda/F-4682-2011; Nelson, Stanley/D-4771-2009; Franke, Barbara/D-4836-2009; Arias Vasquez, Alejandro/E-4762-2012; Buitelaar, Jan/E-4584-2012; Renner, Tobias/I-2120-2013; Medland, Sarah/C-7630-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X; O'Donovan, Michael/0000-0001-7073-2379; Walitza, Susanne/0000-0002-8161-8683; Gill, Michael/0000-0003-0206-5337; Kent, Lindsey/0000-0002-5315-3399; Mick, Eric/0000-0001-8505-8145; Anney, Richard/0000-0002-6083-407X; Thapar, Anita/0000-0002-3689-737X; Faraone, Stephen/0000-0002-9217-3982; Holmans, Peter/0000-0003-0870-9412; Miranda, Ana/0000-0001-6998-5686; Franke, Barbara/0000-0003-4375-6572; Arias Vasquez, Alejandro/0000-0002-4786-0169; Buitelaar, Jan/0000-0001-8288-7757; Medland, Sarah/0000-0003-1382-380X FU US National of Institute of Health [R13MH059126, R01MH62873, U01MH085518, R01MH081803, U01MH085515, K23MH066275-01, R01MH58277]; Children's Hospital of Philadelphia [200710 B]; NHMRC (Australia); Sidney Sax Public Health Fellowship [443036]; UMC Utrecht Genvlag Grant; Radboud University, Nijmegen Medical Centre; Deutsche Forschungsgemeinschaft [KFO 125, SFB 581, GRK 1156, ME 1923/5-1, ME 1923/5-3, GRK 1389, SCHA 542/10-3]; Bundesministerium fur Bildung und Forschung [BMBF 01GV0605]; Foundation for the NIH [R01MH080403]; NWO [480-05-003]; Dutch Brain Foundation FX This project was supported by the following grants: US National of Institute of Health Grants R13MH059126, R01MH62873, U01MH085518 and R01MH081803 to S.V. Faraone, U01MH085515 to M. Daly K23MH066275-01 to J. Elia; and R01MH58277 to S. Smalley; Institutional Development Award lathe Center for Applied Genomics from the Children's Hospital of Philadelphia to H. Hakonorson, Affymetrix Power Award, 200710 B. Franke; NHMRC (Australia) and Sidney Sax Public Health Fellowship (443036) to S.E. Medland; Wellcome Trust, UK for sample collection to L Kent. UMC Utrecht Genvlag Grant and Internal Grant of Radboud University, Nijmegen Medical Centre to J. Buitelaar, the Deutsche Forschungsgemeinschaft (KFO 125, SFB 581, GRK 1156 to K.P. Lesch, ME 1923/5-1, ME 1923/5-3, GRK 1389 to C. Freitag and J. Meyer, SCHA 542/10-3 to H. Schafer) and the Bundesministerium fur Bildung und Forschung (BMBF 01GV0605 to K.P. Lesch). Additional analytical support was from Foundation for the NIH and R01MH080403 (PI Sullivan). All computational work was conducted on the Genetic Cluster Computer the Netherlands) which is funded by on NWO Medium Investment grant (480-05-003, PI Posthumal, the Faculty of Psychology and Education of VU University (Amsterdam), and by the Dutch Brain Foundation (PI Ophoff) and is hosted by the Dutch National Computing and Networking Services. NR 37 TC 173 Z9 173 U1 6 U2 44 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 EI 1527-5418 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD SEP PY 2010 VL 49 IS 9 BP 884 EP 897 DI 10.1016/j.jaac.2010.06.008 PG 14 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 643WT UT WOS:000281331400003 PM 20732625 ER PT J AU Mick, E Todorov, A Smalley, S Hu, XL Loo, S Todd, RD Biederman, J Byrne, D Dechairo, B Guiney, A McCracken, J McGough, J Nelson, SF Reiersen, AM Wilens, TE Wozniak, J Neale, BM Faraone, SV AF Mick, Eric Todorov, Alexandre Smalley, Susan Hu, Xiaolan Loo, Sandra Todd, Richard D. Biederman, Joseph Byrne, Deirdre Dechairo, Bryan Guiney, Allan McCracken, James McGough, James Nelson, Stanley F. Reiersen, Angela M. Wilens, Timothy E. Wozniak, Janet Neale, Benjamin M. Faraone, Stephen V. TI Family-Based Genome-Wide Association Scan of Attention-Deficit/Hyperactivity Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; genome-wide association study; SLC9A9 ID DEFICIT HYPERACTIVITY DISORDER; POPULATION-BASED SAMPLE; DSM-IV; MOLECULAR-GENETICS; ADOLESCENT TWINS; CANDIDATE GENE; BLOOD-PRESSURE; ADHD; LINKAGE; METAANALYSIS AB Objective: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD. Method: Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St. Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo Bead Chip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families. Results: Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p = 6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9. Conclusions: We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders. J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(9):898-905. C1 [Mick, Eric; Neale, Benjamin M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Mick, Eric; Biederman, Joseph; Byrne, Deirdre; Guiney, Allan; Wilens, Timothy E.; Wozniak, Janet] Harvard Univ, Sch Med, Boston, MA USA. [Todorov, Alexandre; Todd, Richard D.; Reiersen, Angela M.] Washington Univ, Sch Med, St Louis, MO USA. [Smalley, Susan; Loo, Sandra; McCracken, James; McGough, James; Nelson, Stanley F.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Hu, Xiaolan; Dechairo, Bryan] Pfizer Inc, Mol Med, New York, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Syracuse, NY USA. RP Mick, E (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 55 Fruit St,Warren 705, Boston, MA 02114 USA. EM emick1@partners.org RI Nelson, Stanley/D-4771-2009; OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU Pfizer Inc.; National Institutes of Health (NIH) [R13MH059126, R01MH62873, U01MH085518, R01MH081803]; National Institute of Neurological Disorders and Stroke (NINDS) [NS054124]; National Institute of Mental Health (NIMH) [MH01966, MH63706, K08MH001503, R01MH066237]; National Institute on Drug Abuse (NIDA) [K24 DA016264] FX Genotyping was conducted by Genizon BioSciences Inc. with the financial support of Pfizer Inc. Subject ascertainment and assessment was supported by the following sources: National Institutes of Health (NIH) grants R13MH059126, R01MH62873, U01MH085518 and R01MH081803 to S.V.Faraone; National Institute of Neurological Disorders and Stroke (NINDS) grant NS054124 S. Loo; National Institute of Mental Health (NIMH) grant MH01966 to J. McGough; National Institute on Drug Abuse (NIDA) grant K24 DA016264 to T. Wilens; NIMH grant MH63706 to S. Smalley; and NIMH grants K08MH001503 and R01MH066237 to J. Wozniak. NR 29 TC 62 Z9 62 U1 3 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD SEP PY 2010 VL 49 IS 9 BP 898 EP 905 DI 10.1016/j.jaac.2010.02.014 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 643WT UT WOS:000281331400004 PM 20732626 ER PT J AU Neale, BM Medland, S Ripke, S Anney, RJL Asherson, P Buitelaar, J Franke, B Gill, M Kent, L Holmans, P Middleton, F Thapar, A Lesch, KP Faraone, SV Daly, M Nguyen, TT Schafer, H Steinhausen, HC Reif, A Renner, TJ Romanos, M Romanos, J Warnke, A Walitza, S Freitag, C Meyer, J Palmason, H Rothenberger, A Hawi, Z Sergeant, J Roeyers, H Mick, E Biederman, J AF Neale, Benjamin M. Medland, Sarah Ripke, Stephan Anney, Richard J. L. Asherson, Philip Buitelaar, Jan Franke, Barbara Gill, Michael Kent, Lindsey Holmans, Peter Middleton, Frank Thapar, Anita Lesch, Klaus-Peter Faraone, Stephen V. Daly, Mark Nguyen, Thuy Trang Schaefer, Helmut Steinhausen, Hans-Christoph Reif, Andreas Renner, Tobias J. Romanos, Marcel Romanos, Jasmin Warnke, Andreas Walitza, Susanne Freitag, Christine Meyer, Jobst Palmason, Haukur Rothenberger, Aribert Hawi, Ziarih Sergeant, Joseph Roeyers, Herbert Mick, Eric Biederman, Joseph CA IMAGE II Consortium TI Case-Control Genome-Wide Association Study of Attention-Deficit/Hyperactivity Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE ADHD; genetics; genome-wide association; imputation ID DEFICIT HYPERACTIVITY DISORDER; PROTEIN-KINASE-I; INTERNATIONAL HAPMAP PROJECT; SUBSTANCE USE DISORDERS; LONG-TERM POTENTIATION; MOLECULAR-GENETICS; SUSCEPTIBILITY LOCI; BIPOLAR DISORDER; COMMON VARIANTS; CANDIDATE GENES AB Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genomewide association studies (GWAS) are needed. Method: We used case-control analyses of 896 cases with DSM-IV ADHD genotvped using the Affymetrix 5.0 array and 2,455 repository controls screened for psychotic and bipolar symptoms genotyped using Affymetrix 6.0 arrays. A consensus SNP set was imputed using BEAGLE 3.0, resulting in an analysis dataset of 1,033,244 SNPs. Data were analyzed using a generalized linear model. Results: No genomewide significant associations were found. The most significant results implicated the following genes: PRKG1, FLNC, TCERG1L, PPM1H, NXPH1, PPM1H, CDH13, HK1, and HKDC1. Conclusions: The current analyses are a useful addition to the present literature and will make a valuable contribution to future meta-analyses. The candidate gene findings are consistent with a prior meta-analysis in suggesting that the effects of ADHD risk variants must, individually, be very small and/or include multiple rare alleles. J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(9):906-920. C1 [Neale, Benjamin M.; Ripke, Stephan; Daly, Mark] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Medland, Sarah] Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld 4006, Australia. [Neale, Benjamin M.; Medland, Sarah; Ripke, Stephan; Daly, Mark] Broad Inst Harvard, Cambridge, MA USA. [Neale, Benjamin M.; Medland, Sarah; Ripke, Stephan; Daly, Mark] MIT, Cambridge, MA 02139 USA. [Anney, Richard J. L.; Gill, Michael; Hawi, Ziarih] St James Hosp, Trinity Ctr Hlth Sci, Dublin, Ireland. [Asherson, Philip; Holmans, Peter] Kings Coll London, Med Res Council Social Genet & Dev Psychiat, London, England. [Buitelaar, Jan; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Kent, Lindsey] Bute Med Sch, St Andrews, Fife, Scotland. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA. [Thapar, Anita] Cardiff Univ, Sch Med, Med Res Council Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Nguyen, Thuy Trang; Schaefer, Helmut] Univ Marburg, Inst Med Biometrie & Epidemiol, Marburg, Germany. [Steinhausen, Hans-Christoph; Walitza, Susanne] Univ Zurich, Zurich, Switzerland. [Lesch, Klaus-Peter; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Warnke, Andreas; Walitza, Susanne] Univ Wurzburg, Wurzburg, Germany. [Freitag, Christine] Goethe Univ Frankfurt, Frankfurt, Germany. [Meyer, Jobst; Palmason, Haukur] Univ Trier, Inst Psychobiol, Trier, Germany. [Rothenberger, Aribert] Univ Gottingen, D-3400 Gottingen, Germany. [Sergeant, Joseph] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Roeyers, Herbert] Univ Ghent, B-9000 Ghent, Belgium. [Mick, Eric; Biederman, Joseph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program, Pediat Psychopharmacol Adult ADHD, Boston, MA 02114 USA. RP Faraone, SV (reprint author), SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, 750 E Adams St, Syracuse, NY 13210 USA. EM faraones@upstate.edu RI Franke, Barbara/D-4836-2009; Buitelaar, Jan/E-4584-2012; Renner, Tobias/I-2120-2013; Medland, Sarah/C-7630-2013; Holmans, Peter/F-4518-2015; Lesch, Klaus-Peter/J-4906-2013; Romanos, Marcel/D-7695-2017; OI Anney, Richard/0000-0002-6083-407X; Thapar, Anita/0000-0002-3689-737X; Faraone, Stephen/0000-0002-9217-3982; Hawi, Ziarih/0000-0002-0814-9112; Kent, Lindsey/0000-0002-5315-3399; Mick, Eric/0000-0001-8505-8145; Franke, Barbara/0000-0003-4375-6572; Buitelaar, Jan/0000-0001-8288-7757; Medland, Sarah/0000-0003-1382-380X; Holmans, Peter/0000-0003-0870-9412; Lesch, Klaus-Peter/0000-0001-8348-153X; Walitza, Susanne/0000-0002-8161-8683; Gill, Michael/0000-0003-0206-5337 FU US National Institutes of Health [R13MH059126, R01MH62873, U01MH085518, R01MH081803]; Affymetrix Power Award, 2007; NHMRC (Australia); Sidney Sax Public Health [443036]; Wellcome Trust, UK; Internal Grant of Radboud University Nijmegen Medical Centre; Deutsche Forschungsgemeinschaft [KFO 125, SFB 581, GRK 1156, RE 1632/5-1, SFB TRR58, ME 1923/5-1, ME 1923/5-3, SCHA 542/10-3]; Bundesministerium fur Bildung und Forschung BMBF [01GV0605] FX This work was supported by the following grants: US National Institutes of Health grants R13MH059126, R01MH62873, U01MH085518, and R01MH081803 to S.V. Faraone; Affymetrix Power Award, 2007, to B. Franke; NHMRC (Australia); a Sidney Sax Public Health Fellowship (443036) to S.E. Medland; Wellcome Trust, UK to L Kent; an Internal Grant of Radboud University Nijmegen Medical Centre to J. Buitelaar; a Wellcome Trust, UK, grant to A. Thapar, M. O'Donovan, and M. Owen; Deutsche Forschungsgemeinschaft grant KFO 125 to K.P. Lesch and A. Reif; SFB 581 and GRK 1156 to K.P. Lesch; RE 1632/5-1 to A. Reif; SFB TRR58 to K.P. Lesch and A. Reif; ME 1923/5-1 and ME 1923/5-3 to C. Freitag and J. Meyer; SCHA 542/10-3 to H. Schafer; and the Bundesministerium fur Bildung und Forschung BMBF grant 01GV0605 to K.P. Lesch. NR 65 TC 81 Z9 83 U1 7 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD SEP PY 2010 VL 49 IS 9 BP 906 EP 920 DI 10.1016/j.jaac.2010.06.007 PG 15 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 643WT UT WOS:000281331400005 PM 20732627 ER PT J AU Britton, JC Rauch, SL Rosso, IM Killgore, WDS Price, LM Ragan, J Chosak, A Hezel, DM Pine, DS Leibenluft, E Pauls, DL Jenike, MA Stewart, SE AF Britton, Jennifer C. Rauch, Scott L. Rosso, Isabelle M. Killgore, William D. S. Price, Lauren M. Ragan, Jennifer Chosak, Anne Hezel, Dianne M. Pine, Daniel S. Leibenluft, Ellen Pauls, David L. Jenike, Michael A. Stewart, S. Evelyn TI Cognitive Inflexibility and Frontal-Cortical Activation in Pediatric Obsessive-Compulsive Disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE anxiety; set-shifting; fMRI; inferior frontal gyrus; striatum ID DEFICIT HYPERACTIVITY DISORDER; RESPONSE-INHIBITION DEFICITS; PREFRONTAL CORTEX; BRAIN ACTIVATION; NEUROPSYCHOLOGICAL PERFORMANCE; EXECUTIVE FUNCTIONS; TOURETTES-SYNDROME; MOTOR INHIBITION; FUNCTIONAL MRI; TIC SEVERITY AB Objective: Deficits in cognitive flexibility and response inhibition have been linked to perturbations in cortico-striatal-thalamic circuitry in adult obsessive-compulsive disorder (OCD). Although similar cognitive deficits have been identified in pediatric OCD, few neuroimaging studies have been conducted to examine its neural correlates in the developing brain. In this study, we tested hypotheses regarding group differences in the behavioral and neural correlates of cognitive flexibility in a pediatric OCD and a healthy comparison (HC) sample. Method: In this functional magnetic resonance imaging (fMRI) study, a pediatric sample of 10- to 17-year-old subjects, 15 with OCD and 20 HC, completed a set-shifting task. The task, requiring an extradimensional shift to identify a target, examines cognitive flexibility. Within each block, the dimension (color or shape) that identified the target either alternated (i.e., mixed) or remained unchanged (i.e., repeated). Results: Compared with the HC group, the OCD group tended to be slower to respond to trials within mixed blocks. Compared with the HC group, the OCD group exhibited less left inferior frontal gyrus/BA47 activation in the set-shifting contrast (i.e., HC > OCD, mixed versus repeated); only the HC group exhibited significant activation in this region. The correlation between set shifting-induced right caudate activation and shift cost (i.e., reaction time differential in response to mixed versus repeated trials) was significantly different between HC and OCD groups, in that we found a positive correlation in HC and a negative correlation in OCD. Conclusions: In pediatric OCD, less fronto-striatal activation may explain previously identified deficits in shifting cognitive sets. J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(9): 944-953. C1 [Britton, Jennifer C.; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Rauch, Scott L.; Rosso, Isabelle M.; Killgore, William D. S.; Price, Lauren M.] McLean Hosp, Brain Imaging Ctr, Belmont, MA 02178 USA. [Stewart, S. Evelyn] Massachusetts Gen Hosp, Dept Psychiat, Richard B Simches Res Ctr, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. RP Stewart, SE (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Richard B Simches Res Ctr, Psychiat & Neurodev Genet Unit, 185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM estewart1@partners.org RI Britton, Jennifer/J-4501-2013; Stewart, Evelyn/K-6961-2014; OI Killgore, William/0000-0002-5328-0208; Stewart, S. Evelyn/0000-0002-0994-6383 FU Massachusetts General Hospital (MGH); Novartis; Neurogen; Sepracor; Primedia; Medtronics, Inc.; Board at the Massachusetts Society for Medical Research (MSMR); National Foundation of Mental Health (NFMH) Board; Department of Defense Contractor, GovSource, Inc.; Brain Institute, University of Utah; U.S. Army Medical Research and Material Command; Sleep History and Readiness Predictor (SHARP); U.S. Army Reserve; National Institutes of Health (National Institute of Neurological Disorders and Stroke, and National Institute of Mental Health); Autism Consortium; Ellison Foundation; Anonymous Donor FX Dr. Rauch has received funds for research through Massachusetts General Hospital (MGH) from Medtronics, Cyberonics, and Cephalon. He has received honoraria from Novartis, Neurogen, Sepracor, Primedia, and Medtronics, Inc. Dr. Rauch is a trustee at Mclean Hospital and serves on the Board at the Massachusetts Society for Medical Research (MSMR) as well as on the National Foundation of Mental Health (NFMH) Board. Dr. Killgore works as a part-time contract researcher at the Department of Defense Contractor, GovSource, Inc., and does contract work for the Brain Institute, University of Utah. He has a U.S. Army Medical Research and Material Command grant and a patent pending: The Sleep History and Readiness Predictor (SHARP), a computer program developed for predicting cognitive performance from sleep and circadian rhythms. Dr. Killgore is affiliated with the U.S. Army Reserve. Dr. Pauls has obtained funds from the following sources: National Institutes of Health (National Institute of Neurological Disorders and Stroke, and National Institute of Mental Health), Autism Consortium, Ellison Foundation, Anonymous Donor, and has received an honorarium from the Mayo Clinic for giving course lectures. Drs. Britton, Rosso, Ragan, Chosak, Pine, Leibenluft, Jenike, and Stewart, and Ms. Price, and Ms. Hezel report no biomedical financial interests or potential conflicts of interest. NR 57 TC 29 Z9 30 U1 7 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD SEP PY 2010 VL 49 IS 9 BP 944 EP 953 DI 10.1016/j.jaac.2010.05.006 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 643WT UT WOS:000281331400008 PM 20732630 ER PT J AU Ruchelsman, DE Hall, MP Youm, T AF Ruchelsman, David E. Hall, Michael P. Youm, Thomas TI Osteochondritis Dissecans of the Capitellum: Current Concepts SO JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LA English DT Review ID ADOLESCENT BASEBALL PLAYERS; HUMERAL CAPITELLUM; FOLLOW-UP; NONOPERATIVE TREATMENT; ARTICULAR-CARTILAGE; ELBOW JOINT; INJURIES; LESIONS; TRANSPLANTATION; CLASSIFICATION AB Osteochondritis dissecans (OCD) of the capitellum is an uncommon disorder seen primarily in the adolescent overhead athlete. Unlike Fanner disease, a self-limiting condition of the immature capitellum, OCD is multifactorial and likely results from microtrauma in the setting of cartilage mismatch and vascular susceptibility. The natural history of OCD is poorly understood, and degenerative joint disease may develop over time. Multiple modalities aid in diagnosis, including radiography, MRI, and magnetic resonance arthrography. Lesion size, location, and grade determine management, which should attempt to address subchondral bone loss and articular cartilage damage. Early, stable lesions are managed with rest. Surgery should be considered for unstable lesions. Most investigators advocate arthroscopic debridement with marrow stimulation. Fragment fixation and bone grafting also have provided good short-term results, but concerns persist regarding the healing potential of advanced lesions. Osteochondral autograft transplantation appears to be promising and should be reserved for larger, higher grade lesions. Clinical outcomes and return to sport are variable. Longer-term follow-up studies are necessary to fully assess surgical management, and patients must be counseled appropriately. C1 [Ruchelsman, David E.] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Ruchelsman, David E.] Harvard Univ, Sch Med, Boston, MA USA. [Ruchelsman, David E.] Newton Wellesley Hosp, Newton, MA USA. [Ruchelsman, David E.] Tufts Univ, Sch Med, Newton, MA USA. [Hall, Michael P.; Youm, Thomas] NYU, Hosp Joint Dis, Dept Orthopaed Surg, New York, NY USA. RP Ruchelsman, DE (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. NR 54 TC 23 Z9 23 U1 0 U2 6 PU AMER ACAD ORTHOPAEDIC SURGEONS PI ROSEMENT PA 6300 N RIVER ROAD, ROSEMENT, IL 60018-4262 USA SN 1067-151X J9 J AM ACAD ORTHOP SUR JI J. Am. Acad. Orthop. Surg. PD SEP PY 2010 VL 18 IS 9 BP 557 EP 567 PG 11 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 645KL UT WOS:000281454900007 PM 20810937 ER PT J AU Camacho, JN Britz, W Perlman, JE Sorrells, A AF Camacho, J. N. Britz, W. Perlman, J. E. Sorrells, A. TI Interactive Enrichment Housing for Nonhuman Primates SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Camacho, J. N.] Massachusetts Gen Hosp, Charlestown, MA USA. [Britz, W.] Britz & Co, Wheatland, WY USA. [Perlman, J. E.] Emory Univ, Yerkes Natl Primate Ctr, Atlanta, GA 30322 USA. [Sorrells, A.] Univ Calif San Francisco, Dept Lab Anim Resources, San Francisco, CA 94143 USA. NR 0 TC 0 Z9 0 U1 2 U2 7 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2010 VL 49 IS 5 BP 666 EP 666 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 652CG UT WOS:000281977900052 ER PT J AU Beisele, M Shen, Z Parry, N Fortin, M Taylor, NS Buckley, E Abedin, MZ Dewhirst, FE Fox, JG AF Beisele, M. Shen, Z. Parry, N. Fortin, M. Taylor, N. S. Buckley, E. Abedin, M. Z. Dewhirst, F. E. Fox, J. G. TI Novel Helicobacter spp. and Campylobacter spp. Isolated from Liver, Cecum, and Feces of Prairie Dogs SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Beisele, M.; Shen, Z.; Parry, N.; Fortin, M.; Taylor, N. S.; Buckley, E.; Fox, J. G.] MIT, Div Comparat Med, Cambridge, MA 02139 USA. [Dewhirst, F. E.] Forsyth Inst, Boston, MA USA. [Abedin, M. Z.] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2010 VL 49 IS 5 BP 676 EP 676 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 652CG UT WOS:000281977900084 ER PT J AU Bell, I Sedlacek, RS Young, SH Niemi, SM AF Bell, I. Sedlacek, R. S. Young, S. H. Niemi, S. M. TI Validation of a Novel Dry Heat Sterilizer SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Bell, I.; Sedlacek, R. S.; Young, S. H.; Niemi, S. M.] Massachusetts Gen Hosp, Ctr Comparat Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2010 VL 49 IS 5 BP 720 EP 721 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 652CG UT WOS:000281977900231 ER PT J AU Duran-Struuck, R Huang, C Sachs, DH Bronson, R Spitzer, T AF Duran-Struuck, R. Huang, C. Sachs, D. H. Bronson, R. Spitzer, T. TI Graft versus Host Disease in Miniature Swine: Development of a Scoring System to Correlate Swine and Human Clinical Disease Manifestations SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Meeting Abstract C1 [Spitzer, T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Bronson, R.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD SEP PY 2010 VL 49 IS 5 BP 732 EP 732 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 652CG UT WOS:000281977900267 ER PT J AU Patti, JA AF Patti, John A. TI ACR CHAIR'S MEMO Radiation Dose: Walmart or Mom and Pop? 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 2 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2010 VL 7 IS 9 BP 661 EP 662 DI 10.1016/j.jacr.2010.07.011 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V23SS UT WOS:000208363100001 PM 20816623 ER PT J AU Yee, J Rosen, MP Blake, MA Baker, ME Cash, BD Fidler, JL Grant, TH Greene, FL Jones, B Katz, DS Lalani, T Miller, FH Small, WC Sudakoff, GS Warshauer, DM AF Yee, Judy Rosen, Max Paul Blake, Michael A. Baker, Mark E. Cash, Brooks D. Fidler, Jeff L. Grant, Thomas H. Greene, Frederick L. Jones, Bronwyn Katz, Douglas S. Lalani, Tasneem Miller, Frank H. Small, William C. Sudakoff, Gary S. Warshauer, David M. TI ACR Appropriateness Criteria (R) on Colorectal Cancer Screening SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Colorectal cancer; adenoma; screening; CT colonography; barium enema; Appropriateness Criteria (R) AB Colorectal cancer remains one of the most common causes of cancer death in this country. This malignancy is ideally suited for screening because the detection and removal of the precursor adenomatous polyp can prevent most colorectal cancers from ever forming. The choice of a test for screening involves consideration of various individual parameters, including patient age and the presence of risk factors for the development of colorectal cancer. Computed tomographic colonography (CTC) has emerged as the leading imaging technique for colorectal cancer screening in average-risk individuals on the basis of the evidence presented in this paper. The double-contrast barium enema is an alternative imaging test that is appropriate particularly when CTC is not available. In 2008, the American Cancer Society guideline for colorectal cancer screening was revised jointly with the US Multi-Society Task Force on Colorectal Cancer and the ACR to include CTC every 5 years as an option for average-risk individuals. Computed tomographic colonography is also the preferred test for colon evaluation after an incomplete colonoscopy. Imaging tests including CTC and the double-contrast barium enema are usually not indicated for colorectal cancer screening in high-risk patients with polyposis syndromes or inflammatory bowel disease. This paper presents the new colorectal cancer imaging test ratings and is the result of evidence-based consensus by the ACR Appropriateness Criteria (R) Expert Panel on Gastrointestinal Imaging. C1 [Yee, Judy] Univ Calif San Francisco, VA Med Ctr, San Francisco, CA 94121 USA. [Rosen, Max Paul] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Blake, Michael A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Baker, Mark E.] Cleveland Clin, Cleveland, OH 44106 USA. [Cash, Brooks D.] Natl Naval Med Ctr, Bethesda, MD USA. [Cash, Brooks D.] Amer Gastroenterol Assoc, Bethesda, MD USA. [Fidler, Jeff L.] Mayo Clin, Rochester, MN USA. [Grant, Thomas H.] NW Med Fac, Chicago, IL USA. [Greene, Frederick L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Greene, Frederick L.] Amer Coll Surg, Chicago, IL USA. [Jones, Bronwyn] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Katz, Douglas S.] Winthrop Univ Hosp, Mineola, NY 11501 USA. [Lalani, Tasneem] Inland Imaging Associates, Seattle, WA USA. [Lalani, Tasneem] Univ Washington, Seattle, WA 98195 USA. [Miller, Frank H.] Northwestern Univ, Feinberg Sch Med, NMH, Chicago, IL 60611 USA. [Small, William C.] Emory Univ, Atlanta, GA 30322 USA. [Sudakoff, Gary S.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Warshauer, David M.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. RP Yee, J (reprint author), Univ Calif San Francisco, VA Med Ctr, 4150 Clement St,114, San Francisco, CA 94121 USA. EM judy.yee@radiology.ucsf.edu NR 78 TC 10 Z9 10 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 SEP PY 2010 VL 7 IS 9 BP 670 EP 678 DI 10.1016/j.jacr.2010.05.005 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V23SS UT WOS:000208363100005 PM 20816627 ER PT J AU Kaewlai, R Greene, RE Asrani, AV Abujudeh, HH AF Kaewlai, Rathachai Greene, Reginald E. Asrani, Ashwin V. Abujudeh, Hani H. TI The Impact of an Early-Morning Radiologist Work Shift on the Timeliness of Communicating Urgent Imaging Findings on Portable Chest Radiography SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Urgent finding; communication of finding; portable chest radiography; critical test results; staggered work shifts; early-morning shift AB Purpose: The aim of this study was to assess the potential impact of staggered radiologist work shifts on the timeliness of communicating urgent imaging findings that are detected on portable overnight chest radiography of hospitalized patients. Methods: The authors conducted a retrospective study that compared the interval between the acquisition and communication of urgent findings on portable overnight critical care chest radiography detected by art early-morning shift for radiologists (3 AM to 11 Am) with historical experience with a standard daytime shift (8 Am to 5 Pm) in the detection and communication of urgent findings in a similar patient population a year earlier. Results: During a 4-month period, 6,448 portable chest radiographic studies were interpreted on the early-morning radiologist shift. Urgent findings requiring immediate communication were detected in 308 (4.8%) studies. The early-morning shift of radiologists, on average, communicated these findings 2 hours earlier compared with the historical control group (P < .001). Conclusion: Staggered radiologist work shifts that include an early-morning shift can improve the timeliness of reporting urgent findings on overnight portable chest radiography of hospitalized patients. C1 [Kaewlai, Rathachai] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kaewlai, R (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 210, Boston, MA 02114 USA. EM rathachai@gmail.com OI Kaewlai, Rathachai/0000-0002-0650-9380 NR 18 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD SEP PY 2010 VL 7 IS 9 BP 715 EP 721 DI 10.1016/j.jacr.2010.02.009 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V23SS UT WOS:000208363100012 PM 20816634 ER PT J AU Kerfoot, BP Fu, YN Baker, H Connelly, D Ritchey, ML Genega, EM AF Kerfoot, B. Price Fu, Yineng Baker, Harley Connelly, Donna Ritchey, Michael L. Genega, Elizabeth M. TI Online Spaced Education Generates Transfer and Improves Long-Term Retention of Diagnostic Skills: A Randomized Controlled Trial SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID MEMORY; TESTS AB BACKGROUND: Retention of learning from surgical training is often limited, especially if the knowledge and skills are used infrequently. Using histopathology diagnostic skills as an experimental system, we compared knowledge transfer and retention between bolus Web-based teaching (WBT) modules and online spaced education, a novel email-based method of online education founded on the spacing effect. STUDY DESIGN: All.US urology residents were eligible to participate. Enrollees were randomized to 1 of 2 cohorts. Cohort 1 residents received 3 cycles/repetitions of spaced education on prostate-testis histopathology (weeks 1 to 16) and 3 WBT modules on bladder-kidney (weeks 14 to 16). Cohort 2 residents received 3 cycles of spaced education on bladder-kidney (weeks 1 to 16) and 3 WBT modules on prostate-testis (weeks 14 to 16). Each daily spaced education email presented a clinical scenario with histopathology image and asked for a diagnosis. Participants received immediate feedback after submitting their answers. Each cycle/repetition was 4 weeks long and consisted of 20 questions with unique images. WBT used the identical content and delivery system, with questions aggregated into three 20-question modules. Long-term retention of all 4 topics was assessed during weeks 18 to 45. RESULTS: Seven-hundred and twenty-four urology residents enrolled. Spaced education and WBT were completed by 77% and 66% of residents, respectively. Spaced education and WBT generated mean long-term score increases of 15.2% (SD 15.3%) and 3.4% (SD 16.3%), respectively (p < 0.01). Spaced education increased long-term learning efficiency 4-fold. CONCLUSIONS: Online spaced education generates transfer of histopathology diagnostic skills and substantially improves their long-term retention. Additional research is needed to determine how spaced education can optimize learning, transfer, and retention of surgical skills. ( J Am Coll Surg 2010; 211:331-337. (C) 2010 by the American College of Surgeons) C1 [Kerfoot, B. Price] Vet Affairs Boston Healthcare Syst, Surg Serv, Urol, Jamaica Plain, MA 02130 USA. [Kerfoot, B. Price; Fu, Yineng; Genega, Elizabeth M.] Harvard Univ, Sch Med, Boston, MA USA. [Fu, Yineng; Genega, Elizabeth M.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Baker, Harley] Calif State Univ Channel Isl, Camarillo, CA USA. [Connelly, Donna] Amer Urol Assoc, Linthicum, MD USA. [Ritchey, Michael L.] Mayo Clin, Dept Urol, Phoenix, AZ USA. RP Kerfoot, BP (reprint author), Vet Affairs Boston Healthcare Syst, Surg Serv, Urol, 150 S Huntington Ave,151DIA, Jamaica Plain, MA 02130 USA. EM price.kerfoot@gmail.com FU American Urological Association; American Urological Association Foundation; Astellas Pharma US, Inc.; United States Agency for Healthcare Research and Quality FX This study was supported in part by the American Urological Association, the American Urological Association Foundation, Astellas Pharma US, Inc., and the United States Agency for Healthcare Research and Quality. NR 19 TC 34 Z9 34 U1 2 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2010 VL 211 IS 3 BP 331 EP 337 DI 10.1016/j.jamcollsurg.2010.04.023 PG 7 WC Surgery SC Surgery GA 648QH UT WOS:000281708500005 PM 20800189 ER PT J AU Ereso, AQ Garcia, P Tseng, E Gauger, G Kim, H Dua, MM Victorino, GP Guy, TS AF Ereso, Alexander Q. Garcia, Pablo Tseng, Elaine Gauger, Grant Kim, Hubert Dua, Monica M. Victorino, Gregory P. Guy, T. Sloane TI Live Transference of Surgical Subspecialty Skills Using Telerobotic Proctoring to Remote General Surgeons SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID COLORECTAL SURGERY; OPERATING-ROOM AB BACKGROUND: Certain clinical environments, including military field hospitals or rural medical centers, lack readily available surgical subspecialists. We hypothesized that telementoring by a surgical sub-specialist using a robotic platform is feasible and can convey subspecialty knowledge and skill to a remotely located general surgeon. STUDY DESIGN: Eight general surgery residents evaluated the effect of remote surgical telementoring by performing 3 operative procedures, first unproctored and then again when teleproctored by a surgical subspecialist. The clinical scenarios consisted of a penetrating right ventricular injury requiring suture repair, an open tibial fracture requiring external fixation, and a traumatic subdural hematoma requiring craniectomy. A robotic platform consisting of a pan-and-tilt camera with laser pointer attached to an overhead surgical light with integrated audio allowed surgical subspecialists the ability to remotely teleproctor residents. Performance was evaluated using an Operative Performance Scale. Satisfaction surveys were given after performing the scenario unproctored and again after proctoring. RESULTS: Overall mean performance scores were superior in all scenarios when residents were proctored than when they were not (4.30 +/- 0.25 versus 2.43 +/- 0.20; p < 0.001). Mean performance scores for individual metrics, including tissue handling, instrument handling, speed of completion, and knowledge of anatomy, were all superior when residents were proctored (p < 0.001). Satisfaction surveys showed greater satisfaction and comfort among residents when proctored. Proctored residents believed the robotic platform facilitated learning and would be feasible if used clinically. CONCLUSIONS: This study supports the use of surgical teleproctoring in guiding remote general surgeons by a surgical subspecialist in the care of a wounded patient in need of an emergency subspecialty operation. (J Am Coll Surg 2010;211:400-411. (C) 2010 by the American College of Surgeons) C1 [Victorino, Gregory P.] Univ Calif, Dept Surg, Oakland, CA 94602 USA. [Garcia, Pablo] SRI Int, Menlo Pk, CA 94025 USA. [Tseng, Elaine; Gauger, Grant; Kim, Hubert; Guy, T. Sloane] Univ Calif San Francisco, Dept Surg, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. RP Victorino, GP (reprint author), Univ Calif, Dept Surg, 1411 E 31st St, Oakland, CA 94602 USA. EM gregory.victorino@ucsfmedctr.org FU US Army Medical Research and Materiel Command under MIPR [7K036M7082] FX This work was supported by the US Army Medical Research and Materiel Command under MIPR No.7K036M7082. NR 16 TC 25 Z9 25 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2010 VL 211 IS 3 BP 400 EP 411 DI 10.1016/j.jamcollsurg.2010.05.014 PG 12 WC Surgery SC Surgery GA 648QH UT WOS:000281708500014 PM 20800198 ER PT J AU Chitsaz, S Jaussaud, N Chau, E Azadani, AN Guy, TS Ratcliffe, MB Tseng, EE AF Chitsaz, Sam Jaussaud, Nicolas Chau, Edward Azadani, Ali N. Guy, T. Sloane Ratcliffe, Mark B. Tseng, Elaine E. TI Veteran patients with severe aortic stenosis: Outcomes with and without aortic valve replacement SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT Annual Clinical Congress of American-College-of-Surgeons CY 2010 CL Chicago, IL SP Amer Coll Surg C1 [Chitsaz, Sam; Jaussaud, Nicolas; Chau, Edward; Azadani, Ali N.; Guy, T. Sloane; Ratcliffe, Mark B.; Tseng, Elaine E.] San Francisco VA Med Ctr, San Francisco, CA USA. RI Chitsaz, Sam/C-4586-2008 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 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2010 VL 211 IS 3 SU S BP S30 EP S30 PG 1 WC Surgery SC Surgery GA 648QI UT WOS:000281708600050 ER PT J AU Conrad, C Schuetz, C Clippinger, B Vacanti, JP Markmann, JF Ott, HC AF Conrad, Claudius Schuetz, Christian Clippinger, Benjamin Vacanti, Joseph P. Markmann, James F. Ott, Harald C. TI Bio-engineered endocrine pancreas based on decellularized pancreatic matrix and mesenchymal stem cell/islet cell coculture SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT Annual Clinical Congress of American-College-of-Surgeons CY 2010 CL Chicago, IL SP Amer Coll Surg C1 [Conrad, Claudius; Schuetz, Christian; Clippinger, Benjamin; Vacanti, Joseph P.; Markmann, James F.; Ott, Harald C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Schuetz, Christian/K-5234-2013 OI Schuetz, Christian/0000-0002-6828-4543 NR 0 TC 6 Z9 6 U1 0 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2010 VL 211 IS 3 SU S BP S62 EP S62 PG 1 WC Surgery SC Surgery GA 648QI UT WOS:000281708600128 ER PT J AU Kochanek, AR Fukudome, EY Kheirbek, T Liu, BL Li, YQ Velmahos, GC Demoya, MA King, DR Alam, HB AF Kochanek, Ashley R. Fukudome, Eugene Y. Kheirbek, Tareq Liu, Baoling Li, Yongqing Velmahos, George C. demoya, Marc A. King, David R. Alam, Hasan B. TI Pharmacologic resuscitation attenuates pulmonary injury following hemorrhagic shock in a rodent model SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT Annual Clinical Congress of American-College-of-Surgeons CY 2010 CL Chicago, IL SP Amer Coll Surg C1 [Kochanek, Ashley R.; Fukudome, Eugene Y.; Kheirbek, Tareq; Liu, Baoling; Li, Yongqing; Velmahos, George C.; demoya, Marc A.; King, David R.; Alam, Hasan B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2010 VL 211 IS 3 SU S BP S45 EP S45 PG 1 WC Surgery SC Surgery GA 648QI UT WOS:000281708600087 ER PT J AU Nehs, MA Nagarkatti, SS Nucera, C Hodin, RA Parangi, S AF Nehs, Matthew A. Nagarkatti, Sushruta S. Nucera, Carmelo Hodin, Richard A. Parangi, Sareh TI PLX4720 induces tumor regression, reverses cachexia, and extends survival in a mouse model of late-stage anaplastic thyroid cancer SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT Annual Clinical Congress of American-College-of-Surgeons CY 2010 CL Chicago, IL SP Amer Coll Surg C1 [Nehs, Matthew A.; Nagarkatti, Sushruta S.; Nucera, Carmelo; Hodin, Richard A.; Parangi, Sareh] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 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 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2010 VL 211 IS 3 SU S BP S124 EP S124 PG 1 WC Surgery SC Surgery GA 648QI UT WOS:000281708600281 ER PT J AU Nguyen, BNH Albadawi, H Houbballah, R Haurani, MJ Yoo, HJ AF Nguyen, Bao-Ngoc H. Albadawi, Hassan Houbballah, Rabih Haurani, Mounir J. Yoo, Hyung-Jin TI Inducible nitric oxide synthase modulates the expression of molecular markers of muscle regeneration following hind limb ischemia reperfusion SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Meeting Abstract CT Annual Clinical Congress of American-College-of-Surgeons CY 2010 CL Chicago, IL SP Amer Coll Surg C1 [Nguyen, Bao-Ngoc H.; Albadawi, Hassan; Houbballah, Rabih; Haurani, Mounir J.; Yoo, Hyung-Jin] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD SEP PY 2010 VL 211 IS 3 SU S BP S139 EP S139 PG 1 WC Surgery SC Surgery GA 648QI UT WOS:000281708600320 ER PT J AU Rovner, AJ Mehta, SN Haynie, DL Robinson, EM Pound, HJ Butler, DA Laffel, LM Nansel, TR AF Rovner, Alisha J. Mehta, Sanjeev N. Haynie, Denise L. Robinson, Elizabeth M. Pound, Heidi J. Butler, Deborah A. Laffel, Lori M. Nansel, Tonja R. TI Perceived Benefits, Barriers, and Strategies of Family Meals among Children with Type 1 Diabetes Mellitus and Their Parents: Focus-Group Findings SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID MEALTIME INTERACTIONS; DIETARY-INTAKE; ADOLESCENTS; PATTERNS; QUALITY AB Dietary management of type 1 diabetes mellitus has become much less restrictive and more flexible in recent years due to contemporary insulin regimens, which may afford families of children with type 1 diabetes mellitus greater ease in sharing family meals. Although these treatment advancements might facilitate family meals, overall demands of diabetes management can influence family's perceived or actual ability to do so Youths with type 1 diabetes mellitus (ages 8 to 20 years) and parents participated in separate focus groups Thirty-five youths with type 1 diabetes mellitus (mean age=15 1 +/- 3 6 years) and their parents participated in 21 focus groups (12 youth groups, nine parent groups) Although there was substantial variability in how often family meals occurred, both parents and youths consistently perceived family meals as valuable and enjoyable. The major barrier to family meals discussed by both youths and parents was busy schedules Strategies for having family meals that were discussed by parents included shopping to ensure availability of the foods needed to prepare meals, planning, and cooking meals in advance, and using simplified cooking methods. These findings suggest that a family-focused approach to nutrition interventions in this population, as opposed to one targeting the child with diabetes only, can improve the chance for successful dietary change J AM Diet Assoc. 2010,110 1302-1306. C1 [Rovner, Alisha J.; Nansel, Tonja R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Mehta, Sanjeev N.; Pound, Heidi J.; Laffel, Lori M.] Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Boston, MA 02215 USA. [Mehta, Sanjeev N.; Laffel, Lori M.] Joslin Diabet Ctr, Genet & Epidemiol Sect, Boston, MA 02215 USA. [Mehta, Sanjeev N.; Butler, Deborah A.; Laffel, Lori M.] Harvard Univ, Sch Med, Boston, MA USA. [Butler, Deborah A.] Joslin Diabet Ctr, Pediat Programs, Boston, MA 02215 USA. [Robinson, Elizabeth M.] Virginia Commonwealth Univ, Dept Psychol, Richmond, VA 23284 USA. RP Nansel, TR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent, NIH, Dept Hlth & Human Serv, 6100 Execut Blvd,7B13R,MSC 7510, Bethesda, MD 20892 USA. OI Nansel, Tonja/0000-0002-8298-7595; Haynie, Denise/0000-0002-8270-6079 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health [HHSN267200703434C] FX This study was supported by the Intramural Research Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, contract number HHSN267200703434C NR 15 TC 8 Z9 8 U1 2 U2 7 PU AMER DIETETIC ASSOC PI CHICAGO PA 120 S RIVERSIDE PLZ, STE 2000, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD SEP PY 2010 VL 110 IS 9 BP 1302 EP 1306 DI 10.1016/j.jada.2010.06.010 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 645YG UT WOS:000281501500007 PM 20800121 ER PT J AU Wang, YF Jahns, L Tussing-Humphreys, L Xie, B Rockett, H Liang, HF Johnson, L AF Wang, Youfa Jahns, Lisa Tussing-Humphreys, Lisa Xie, Bin Rockett, Helaine Liang, Huifang Johnson, Luann TI Dietary Intake Patterns of Low-Income Urban African-American Adolescents SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID HEALTHY EATING INDEX; NUTRIENT INTAKE; RISK-FACTORS; VITAMIN-D; OBESITY; GIRLS; CONSUMPTION; BEVERAGES; CALCIUM; DESIGN AB Unhealthy eating increases risks for chronic disease. Few studies have examined the multifaceted aspects of dietary intake of low-income, urban African-American adolescents This study aimed to describe dietary patterns including energy, nutrients, food groups, and diet quality and to identify areas to guide future interventions Baseline data for a school-based obesity prevention study were collected from 382 African-American adolescents (10- to 14-year-olds) from four Chicago, IL, public schools in 2003. Diet was assessed using a 152-item food frequency questionnaire. Diet quality was measured using a modified version of the US Department of Agriculture Healthy Eating Index (HEI) and compared to published estimates for a nationwide sample Participants reported high energy intakes and several unhealthy eating patterns 58 6% consumed one or more servings of sweetened beverages per day and 15 7% consumed three or more servings per day; average fried food consumption was high (1 4 servings/day), 58.4% consumed one or more serving per day; and 75% consumed three or more three snacks per day. Only 49% of participants met the recommended three servings of dairy foods per day. Compared to a national, mostly white sample, participants had lower HEI scores (P<0.05), mean score was 66 0=12.8 (100= maximum HEI score) vs 70 3 13 0 in boys vs girls, one third had scores <60 ("needs improvement") and only 15% scored >80 ("good") This study reveals key areas of problematic dietary patterns for future interventions targeting low-income African-American adolescents, including frequent intakes of calorie-dense, low nutrient-rich foods, such as fried foods, snacks, and sweetened beverages. J Am Diet Assoc 2070,110.1340-1345 C1 [Wang, Youfa] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, Baltimore, MD 21205 USA. [Jahns, Lisa; Johnson, Luann] ARS, Grand Forks Human Nutr Res Ctr, USDA, Grand Forks, ND USA. [Jahns, Lisa] Univ Tennessee, Dept Nutr, Knoxville, TN 37996 USA. [Tussing-Humphreys, Lisa] ARS, USDA, Baton Rouge, LA USA. [Tussing-Humphreys, Lisa; Liang, Huifang] Univ Illinois, Dept Kinesiol & Nutr, Chicago, IL USA. [Xie, Bin] Claremont Grad Univ, Sch Community & Global Hlth, San Dimas, CA USA. [Xie, Bin] Univ So Calif, Sch Social Work, Hamovitch Res Ctr, Los Angeles, CA 90089 USA. [Rockett, Helaine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rockett, Helaine] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Rockett, Helaine] Harvard Univ, Brigham & Womens Hosp, Channing Lab, Sch Med, Boston, MA 02115 USA. [Liang, Huifang] Takeda Global Res & Dev Ctr Inc, Deerfield, IL USA. RP Wang, YF (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, 615 N Wolfe St,E2546, Baltimore, MD 21205 USA. EM ywang@jhsph.edu OI Jahns, Lisa/0000-0002-1828-6962 FU National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [1R01DK63383, R01DK81335-01A1]; National Institute of Child Health and Human Development [1R03HD058077-01A1] FX The study was supported in part by research grants from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK63383, R01DK81335-01A1) and National Institute of Child Health and Human Development (1R03HD058077-01A1). NR 40 TC 22 Z9 22 U1 0 U2 4 PU AMER DIETETIC ASSOC PI CHICAGO PA 120 S RIVERSIDE PLZ, STE 2000, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD SEP PY 2010 VL 110 IS 9 BP 1340 EP 1345 DI 10.1016/j.jada.2010.06.005 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 645YG UT WOS:000281501500012 PM 20800126 ER PT J AU Qureshi, SU Kimbrell, T Pyne, JM Magruder, KM Hudson, TJ Petersen, NJ Yu, HJ Schulz, PE Kunik, ME AF Qureshi, Salah U. Kimbrell, Timothy Pyne, Jeffrey M. Magruder, Kathy M. Hudson, Teresa J. Petersen, Nancy J. Yu, Hong-Jen Schulz, Paul E. Kunik, Mark E. TI Greater Prevalence and Incidence of Dementia in Older Veterans with Posttraumatic Stress Disorder SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE posttraumatic stress disorder; dementia; veterans ID ALZHEIMERS-DISEASE; RISK-FACTORS; AFFAIRS; MEMORY; PTSD; CARE; EDUCATION; INJURY; IRAQ AB OBJECTIVES To explore the association between posttraumatic stress disorder (PTSD) and dementia in older veterans. DESIGN Administrative database study of individuals seen within one regional division of the Veterans Affairs healthcare network. SETTING Veterans Integrated Service Network 16. PARTICIPANTS Veterans aged 65 and older who had a diagnosis of PTSD or who were recipients of a Purple Heart (PH) and a comparison group of the same age with no PTSD diagnosis or PH were divided into four groups: those with PTSD and no PH (PTSD+/PH-, n=3,660), those with PH and no PTSD (PTSD-/PH+, n=1,503), those with PTSD and a PH (PTSD+/PH+, n=153), and those without PTSD or a PH (PTSD-/PH-, n=5,165). MEASUREMENTS Incidence and prevalence of dementia after controlling for confounding factors in multivariate logistic regression. RESULTS The PTSD+/PH- group had a significantly higher incidence and prevalence of dementia than the groups without PTSD with or without a PH. The prevalence and incidence of a dementia diagnosis remained two times as high in the PTSD+/PH- group as in the PTSD-/PH+ or PTSD-/PH- group after adjusting for the confounding factors. There were no statistically significant differences between the other groups. CONCLUSION The incidence and prevalence of dementia is greater in veterans with PTSD. It is unclear whether this is due to a common risk factor underlying PTSD and dementia or to PTSD being a risk factor for dementia. Regardless, this study suggests that veterans with PTSD should be screened more closely for dementia. Because PTSD is so common in veterans, this association has important implications for veteran care. C1 [Qureshi, Salah U.; Petersen, Nancy J.; Yu, Hong-Jen; Kunik, Mark E.] Houston Ctr Qual Care & Utilizat Studies, Hlth Serv Res & Dev Serv, Houston, TX 77030 USA. [Qureshi, Salah U.; Schulz, Paul E.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Qureshi, Salah U.; Schulz, Paul E.] Baylor Coll Med, Neurosensory Ctr, Houston, TX 77030 USA. [Qureshi, Salah U.; Schulz, Paul E.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Petersen, Nancy J.; Kunik, Mark E.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Kunik, Mark E.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Qureshi, Salah U.; Kimbrell, Timothy; Kunik, Mark E.] Cent Arkansas Vet Healthcare Syst, Vet Affairs S Cent Mental Illness Res Educ & Clin, Little Rock, AR USA. [Kimbrell, Timothy; Pyne, Jeffrey M.; Hudson, Teresa J.] Cent Arkansas Vet Healthcare Syst, Ctr Mental Hlth & Outcomes Res, Little Rock, AR USA. [Kimbrell, Timothy; Pyne, Jeffrey M.; Hudson, Teresa J.] Univ Arkansas Med Sci, Dept Psychiat, Coll Med, Little Rock, AR 72205 USA. [Magruder, Kathy M.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. RP Kunik, ME (reprint author), Houston Ctr Qual Care & Utilizat Studies, Hlth Serv Res & Dev Serv, Michael DeBakey VAMC 152,2002 Holcombe, Houston, TX 77030 USA. EM mkunik@bcm.tmc.edu FU Houston Center for Quality of Care and Utilization Studies [HFP90-020] FX This work was supported in part by the Houston Center for Quality of Care and Utilization Studies (Houston VA Health Services Research and Development Center of Excellence [HFP90-020]). NR 31 TC 45 Z9 45 U1 4 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2010 VL 58 IS 9 BP 1627 EP 1633 DI 10.1111/j.1532-5415.2010.02977.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 646NM UT WOS:000281549000001 PM 20863321 ER PT J AU Ishii, S Streim, JE Saliba, D AF Ishii, Shinya Streim, Joel E. Saliba, Debra TI Potentially Reversible Resident Factors Associated with Rejection of Care Behaviors SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE rejection of care; nursing home; modifiable characteristics ID NURSING-HOME RESIDENTS; CONFUSION ASSESSMENT METHOD; LONG-TERM-CARE; AGGRESSIVE-BEHAVIOR; PSYCHOLOGICAL SYMPTOMS; ALZHEIMERS-DISEASE; DEMENTIA; DELIRIUM; DEPRESSION; AGITATION AB OBJECTIVES To identify the potentially modifiable resident-level factors associated with rejection of care in nursing home (NH) residents. DESIGN Secondary analysis of a 3.0 national field test to revise the Minimum Data Set (MDS). SETTING Seventy-one NHs in eight states. PARTICIPANTS Three thousand two hundred thirty NH residents scheduled for MDS assessments from September 2006 through February 2007. MEASUREMENTS The potentially mutable characteristics assessed were mood (Patient Health Questionnaire-9), delirium (Confusion Assessment Method), delusions, hallucinations or illusions, hearing impairment, vision impairment, pain severity, and infection diagnoses. Characteristics considered as covariates were cognition, communication abilities, and impairment in activities of daily living. RESULTS Of 3,230 residents assessed, 312 (9.7%) had demonstrated rejection of care in the preceding 5 days. In multiple regression analysis adjusted for covariates, rejection of care was associated with delusions (odds ratio (OR)=3.9; 95% confidence interval (CI)=2.5-6.0), delirium (OR=1.8, 95% CI=1.3-2.4), minor (OR=2.1, 95% CI=1.5-2.8) and major (OR=2.3, 95% CI=1.5-3.4) depression, and severe to horrible pain (OR=1.6, 95% CI=1.1-2.3). Infection diagnoses were not significant in bivariate analysis. Hallucinations or illusions, mild to moderate pain, and hearing and vision impairment were not significant in multiple regression analysis. CONCLUSION In this population, delirium, delusions, depression, and severe pain were associated with rejection of care, suggesting that some care rejection behaviors may resolve with appropriate interventions for the identified target conditions if the associations observed are causal. C1 [Ishii, Shinya; Saliba, Debra] VA Greater Los Angeles Healthcare Syst, Ctr Geriatr Res Educ & Clin, Los Angeles, CA 90073 USA. [Streim, Joel E.] Mental Illness Res Educ & Clin Ctr, Vet Integrated Serv Network 4, Philadelphia, PA USA. [Streim, Joel E.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Streim, Joel E.] Univ Penn, Dept Psychiat, Geriatr Psychiat Sect, Philadelphia, PA 19104 USA. [Saliba, Debra] Hlth Serv Res & Dev Ctr Excellence Study Healthca, Dept Vet Affairs, Los Angeles, CA USA. [Saliba, Debra] Univ Calif Los Angeles, Jewish Home Borun Ctr Gerontol Res, Los Angeles, CA USA. [Saliba, Debra] RAND, Santa Monica, CA USA. RP Ishii, S (reprint author), VA Greater Los Angeles Healthcare Syst, Ctr Geriatr Res Educ & Clin, 11301 Wilshire Blvd,Bldg 220,Room 302 11G, Los Angeles, CA 90073 USA. EM sishii@mednet.ucla.edu FU U.S. Department of Veterans Affairs; Veterans Health Administration; VA Health Services Research and Development (HSRD) [SDR 03-217] FX This work was funded by the U.S. Department of Veterans Affairs, Veterans Health Administration, VA Health Services Research and Development (HSR&D) Service through the VA Greater Los Angeles HSR&D Center of Excellence (Project SDR 03-217), the VA Office of Academic Affairs, and the Centers for Medicare and Medicaid Services and supported by the University of California at Los Angeles/Jewish Home Borun Center for Gerontological Research. NR 54 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2010 VL 58 IS 9 BP 1693 EP 1700 DI 10.1111/j.1532-5415.2010.03020.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 646NM UT WOS:000281549000010 PM 20863329 ER PT J AU Cherubini, A Del Signore, S Ouslander, J Semla, T Michel, JP AF Cherubini, Antonio Del Signore, Susanna Ouslander, Joe Semla, Todd Michel, Jean-Pierre TI Fighting Against Age Discrimination in Clinical Trials SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE older participant; clinical trial; regulatory agency; geriatric medicine; exclusion ID ISOLATED SYSTOLIC HYPERTENSION; RANDOMIZED CONTROLLED-TRIALS; FRAIL OLDER PERSONS; HEART-FAILURE; RESEARCH PARTICIPATION; PEOPLE; SPIRONOLACTONE; GUIDELINES; MORTALITY; BARRIERS AB At the American Geriatrics Society 2008 Annual Meeting, representatives of two geriatric societies, the European Union Geriatric Medicine Societies and the American Geriatrics Society, and two regulatory agencies, the U.S. Food and Drug Administration and the European Medicine Agency, conducted a roundtable discussion aimed at reviewing the participation of older people in clinical trials. This article summarizes the important issues discussed at the meeting. Historically, regulatory agencies started to promote the inclusion of older participants in clinical trials in the late 1980s. The identification of the causes of delay in including older participants in clinical trials, as well as of the ongoing bias against including older participants with multiple comorbidities, is important to help geriatricians fight against age discrimination in clinical trials. To overcome this problem, geriatrics societies and regulatory agencies must work together to propose new definitions, study designs, and technologies aimed at improving the evaluation of drugs in older people with multiple comorbidities and polypharmacy. C1 [Cherubini, Antonio] Univ Perugia, Sch Med, Policlin Santa Maria Misericordia, Inst Gerontol & Geriatr, I-06156 Perugia, Italy. [Del Signore, Susanna] Sanofi Aventis Rech & Dev, Massy, France. [Ouslander, Joe] Univ Miami, Miller Sch Med, Div Gerontol & Geriatr Med, Miami, FL 33136 USA. [Semla, Todd] US Dept Vet Affairs, Pharm Benefit Management Serv, Washington, DC USA. [Semla, Todd] Northwestern Univ, Dept Med, Div Geriatr Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Michel, Jean-Pierre] Geneva Sch Med, Dept Rehabil & Geriatr, Geneva, Switzerland. [Michel, Jean-Pierre] Univ Hosp Geneva, Geneva, Switzerland. RP Cherubini, A (reprint author), Univ Perugia, Sch Med, Policlin Santa Maria Misericordia, Inst Gerontol & Geriatr, Piazzale Menghini 1, I-06156 Perugia, Italy. EM cherubin_9@yahoo.com OI Cherubini, Antonio/0000-0003-0261-9897 NR 27 TC 57 Z9 59 U1 0 U2 12 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2010 VL 58 IS 9 BP 1791 EP 1796 DI 10.1111/j.1532-5415.2010.03032.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 646NM UT WOS:000281549000024 PM 20863340 ER PT J AU Wald, JS Businger, A Gandhi, TK Grant, RW Poon, EG Schnipper, JL Volk, LA Middleton, B AF Wald, Jonathan S. Businger, Alexandra Gandhi, Tejal K. Grant, Richard W. Poon, Eric G. Schnipper, Jeffrey L. Volk, Lynn A. Middleton, Blackford TI Implementing practice-linked pre-visit electronic journals in primary care: patient and physician use and satisfaction SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID DIABETES CARE; INFORMATION-TECHNOLOGY; DECISION-SUPPORT; AMBULATORY-CARE; HEALTH; QUALITY; RECORDS; EXPERIENCES; ACCESS; MODEL AB Electronic health records (EHRs) and EHR-connected patient portals offer patient provider collaboration tools for visit-based care. During a randomized controlled trial, primary care patients completed pre-visit electronic journals (eJournals) containing EHR-based medication, allergies, and diabetes (study arm 1) or health maintenance, personal history, and family history (study arm 2) topics to share with their provider. Assessment with surveys and usage data showed that among 2027 patients invited to complete an eJournal, 70.3% submitted one and 71.1% of submitters had one opened by their provider. Surveyed patients reported they felt more prepared for the visit (55.9%) and their provider had more accurate information about them (58.0%). More arm 1 versus arm 2 providers reported that eJournals were visit-time neutral (100% vs 53%; p<0.013), helpful to patients in visit preparation (66% vs 20%; p=0.082), and would recommend them to colleagues (78% vs 22%; p=0.0143). eJournal integration into practice warrants further study. C1 [Wald, Jonathan S.; Volk, Lynn A.; Middleton, Blackford] Partners Healthcare, Informat Syst, Wellesley, MA 02481 USA. [Wald, Jonathan S.; Gandhi, Tejal K.; Grant, Richard W.; Poon, Eric G.; Schnipper, Jeffrey L.; Middleton, Blackford] Harvard Univ, Sch Med, Boston, MA USA. [Wald, Jonathan S.; Businger, Alexandra; Gandhi, Tejal K.; Poon, Eric G.; Schnipper, Jeffrey L.; Middleton, Blackford] Brigham & Womens Hosp, Boston, MA 02115 USA. [Grant, Richard W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wald, JS (reprint author), Partners Healthcare, Informat Syst, 93 Worcester St,Suite 201, Wellesley, MA 02481 USA. EM jwald@partners.org OI Middleton, Blackford/0000-0002-1819-1234; Grant, Richard/0000-0002-6164-8025 FU Agency for Healthcare Research and Quality [R01 HS 13326-03]; Partners HealthCare FX Provided in part by the Agency for Healthcare Research and Quality (grant R01 HS 13326-03) and by Partners HealthCare through matching funds. NR 25 TC 19 Z9 19 U1 1 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP PY 2010 VL 17 IS 5 BP 502 EP 506 DI 10.1136/jamia.2009.001362 PG 5 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 652AM UT WOS:000281972200003 PM 20819852 ER PT J AU Joseph, WS Lipsky, BA AF Joseph, Warren S. Lipsky, Benjamin A. TI Medical Therapy of Diabetic Foot Infections SO JOURNAL OF THE AMERICAN PODIATRIC MEDICAL ASSOCIATION LA English DT Article ID STAPHYLOCOCCUS-AUREUS; CLASSIFICATION-SYSTEM; VALIDATION; DIAGNOSIS; RISK AB Diabetic foot infections are a common and often serious problem, accounting for more hospital bed days than any other complication of diabetes. Despite advances in antibiotic drug therapy and surgical management, these infections continue to be a major risk factor for amputations of the lower extremity. Although a variety of wound size and depth classification systems have been adapted for use in codifying diabetic foot ulcerations, none are specific to infection. In 2003, the International Working Group on the Diabetic Foot developed guidelines for managing diabetic foot infections, including the first severity scale specific to these infections. The following year, the Infectious Diseases Society of America published their diabetic foot infection guidelines. Herein, we review some of the critical points from the Executive Summary of the Infectious Diseases Society of America document and provide a commentary following each issue to update the reader on any pertinent changes that have occurred since publication of the original document in 2004. The importance of a multidisciplinary limb salvage team, apropos of this special issue jointly published by the American Podiatric Medical Association and the Society for Vascular Surgery, cannot be overstated. (J Am Podiatr Med Assoc 100(5): 395-400, 2010) C1 [Joseph, Warren S.] Roxborough Mem Hosp, Philadelphia, PA USA. [Lipsky, Benjamin A.] Univ Washington, Seattle, WA 98195 USA. [Lipsky, Benjamin A.] VA Puget Sound HCS, Primary Care Clin, Seattle, WA USA. RP Joseph, WS (reprint author), Amer Podiatr Med Assoc, 1109 Old Ford Rd, Huntingdon Valley, PA 19006 USA. EM wsjoseph@comcast.net OI Lipsky, Benjamin A./0000-0001-9886-5114 NR 17 TC 5 Z9 5 U1 0 U2 0 PU AMER PODIATRIC MED ASSOC PI BETHESDA PA 9312 OLD GEORGETOWN ROAD, BETHESDA, MD 20814-1621 USA SN 8750-7315 J9 J AM PODIAT MED ASSN JI J. Am. Podiatr. Med. Assoc. PD SEP-OCT PY 2010 VL 100 IS 5 BP 395 EP 400 PG 6 WC Orthopedics SC Orthopedics GA 655LF UT WOS:000282250800010 PM 20847353 ER PT J AU Chan, KE Lazarus, JM Hakim, RM AF Chan, Kevin E. Lazarus, J. Michael Hakim, Raymond M. TI Digoxin Associates with Mortality in ESRD SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID IMPAIRED RENAL-FUNCTION; CHRONIC HEART-FAILURE; HEMODIALYSIS-PATIENTS; PRACTICE GUIDELINES; TASK-FORCE; DIG TRIAL; HOSPITALIZATION; MANAGEMENT; DIGITALIS; THERAPY AB The safety of prescribing digoxin in ESRD is unknown. Hypokalemia, which frequently occurs among dialysis patients, may enhance the toxicity of digoxin. Here, we analyzed the association between digoxin prescription and survival in a retrospective cohort using covariate- and propensity score adjusted Cox models to minimize the potential for confounding by indication. Among 120,864 incident hemodialysis patients, digoxin use associated with a 28% increased risk for death (hazard ratio [HR] 1.28; 95% confidence interval 1.25 to 1.31). Increasing serum digoxin level was also significantly associated with mortality (HR 1.19 per ng/ml increase; 95% confidence interval 1.05 to 1.35). This increased mortality risk with level was most pronounced in patients with lower predialysis serum potassium (K) levels (HR 2.53 [P = 0.01] for K <4.3 mEq/L versus HR 0.86 [P = 0.35] for K >4.6 mEq/L). In conclusion, digoxin use among patients who are on hemodialysis associates with increased mortality, especially among those with low predialysis K concentrations. C1 [Chan, Kevin E.; Lazarus, J. Michael; Hakim, Raymond M.] Fresenius Med Care NA, Waltham, MA USA. [Chan, Kevin E.] Massachusetts Gen Hosp, Dept Med, Div Nephrol, Boston, MA 02114 USA. RP Chan, KE (reprint author), 920 Winter St, Waltham, MA 02451 USA. EM kevin.chan@fmc-na.com NR 41 TC 35 Z9 38 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD SEP PY 2010 VL 21 IS 9 BP 1550 EP 1559 DI 10.1681/ASN.2009101047 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 669JZ UT WOS:000283345000022 PM 20576808 ER PT J AU Greenberg, DL Verfaellie, M AF Greenberg, Daniel L. Verfaellie, Mieke TI Interdependence of episodic and semantic memory: Evidence from neuropsychology SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Review DE Semantic dementia; Memory disorders; Temporal lobe; Hippocampus; Review; Amnesia ID TEMPORAL-LOBE LESIONS; ALZHEIMERS-DISEASE; AUTOBIOGRAPHICAL MEMORY; RETROGRADE-AMNESIA; DEMENTIA; CONSCIOUSNESS; KNOWLEDGE; PATTERNS; ACTIVATION; CONTEXT AB Tulving's (1972) theory of memory draws a distinction between general knowledge (semantic memory) and memory for events (episodic memory). Neuropsychological studies have generally examined each type of memory in isolation, but theorists have long argued that these two forms of memory are interdependent. Here we review several lines of neuropsychological research that have explored the interdependence of episodic and semantic memory. The studies show that these forms of memory can affect each other both at encoding and at retrieval. We suggest that theories of memory should be revised to account for all of the interdependencies between episodic and semantic memory; they should also incorporate forms of memory that do not fit neatly into either category. (JINS, 2010, 16, 748-753.) C1 [Greenberg, Daniel L.] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA 02130 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Greenberg, DL (reprint author), VA Boston Healthcare Syst, Memory Disorders Res Ctr, 150 S Huntington Ave 151-A, Boston, MA 02130 USA. EM dlg@bu.edu OI Verfaellie, Mieke/0000-0001-5535-4584 FU NIH [MH71783]; Office of Research and Development, Medical Research Service, Department of Veterans Affairs FX This research was supported by NIH grant MH71783 and the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The authors have no financial or other relationships that could be interpreted as a conflict of interest affecting this manuscript. NR 49 TC 52 Z9 53 U1 4 U2 46 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD SEP PY 2010 VL 16 IS 5 BP 748 EP 753 DI 10.1017/S1355617710000676 PG 6 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 670HA UT WOS:000283410600003 PM 20561378 ER PT J AU Stricker, NH Tybur, JM Sadek, JR Haaland, KY AF Stricker, Nikki H. Tybur, Joshua M. Sadek, Joseph R. Haaland, Kathleen Y. TI Utility of the Neuropsychological Assessment Battery in detecting cognitive impairment after unilateral stroke SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Neuropsychology; Neuropsychological tests; Aging; Cerebrovascular disorders; Cognition disorders; Hemiparesis ID SCREENING MODULE; CLINICAL DETERMINANTS; PROGNOSTIC VALUE; 1ST-EVER STROKE; ISCHEMIC-STROKE; DEMENTIA; FREQUENCY; NAB; PERFORMANCE; DISORDERS AB This study evaluated the clinical utility of the Neuropsychological Assessment Battery (NAB) in a stroke sample by examining the NAB's ability to differentiate a chronic stroke group with radiologically confirmed unilateral damage (n = 42) and a demographically matched healthy control (HC) group (n = 36). The stroke group performed more poorly than the control group across NAB Total score and all five Domain scores. Receiver operator curves (ROC) were derived and area under the curve (AUC) showed moderate diagnostic effectiveness (AUC .70 to .90) for NAB Total score, all five Domain scores, a motor composite, and a Global Deficit Score (GDS) that has been shown to closely approximate clinical ratings of neuropsychological impairment. The NAB Total, GDS, and motor composite had comparable clinical utility, whereas the Attention and Executive domain scores demonstrated better classification utility compared with the Memory domain. Because 90.5% of our stroke sample had middle cerebral artery territory strokes, the comparison of motor and cognitive classification utility may be biased. However, follow-up analyses showed that the NAB accounted for additional variance even when motor composite was included in the model. Sensitivity, specificity, and odds ratios at various clinical cutoffs are provided. These results suggest that the NAB is a useful clinical tool for detection of cognitive deficits in individuals with chronic unilateral stroke, although lenient clinical cutoffs appear warranted to maximize sensitivity. (JINS, 2010, 16, 813-821.) C1 [Haaland, Kathleen Y.] New Mexico VA Healthcare Syst, Res Serv, Albuquerque, NM 87108 USA. [Stricker, Nikki H.] Boston VA Healthcare Syst, Psychol Serv, Boston, MA USA. [Stricker, Nikki H.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Tybur, Joshua M.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Sadek, Joseph R.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. [Sadek, Joseph R.; Haaland, Kathleen Y.] Univ New Mexico, Sch Med, Dept Psychiat, Albuquerque, NM 87131 USA. [Haaland, Kathleen Y.] Univ New Mexico, Sch Med, Dept Neurol, Albuquerque, NM 87131 USA. RP Haaland, KY (reprint author), New Mexico VA Healthcare Syst, Res Serv 151, 1501 San Pedro SE, Albuquerque, NM 87108 USA. EM khaaland@unm.edu RI Tybur, Joshua/P-5435-2014 OI Tybur, Joshua/0000-0002-0462-6508 FU Department of Veterans Affairs [B4125R] FX This work was supported by the Department of Veterans Affairs (Rehabilitation Research and Development Merit Review grant B4125R and Clinical Services Research and Development Merit Review grant). The authors thank Dr. Robert T. Knight for neuroimaging consultation. The authors report no conflicts of interest. Dr. Thomas Hammeke acted as the editor for this study to avoid a conflict of interest because the senior author, Dr. Haaland, is the current editor-in-chief of JINS. Information in this manuscript and the manuscript itself has never been published either electronically or in print. NR 36 TC 10 Z9 10 U1 1 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD SEP PY 2010 VL 16 IS 5 BP 813 EP 821 DI 10.1017/S1355617710000652 PG 9 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 670HA UT WOS:000283410600010 PM 20594388 ER PT J AU Hoos, A Eggermont, AMM Janetzki, S Hodi, FS Ibrahim, R Anderson, A Humphrey, R Blumenstein, B Old, L Wolchok, J AF Hoos, Axel Eggermont, Alexander M. M. Janetzki, Sylvia Hodi, F. Stephen Ibrahim, Ramy Anderson, Aparna Humphrey, Rachel Blumenstein, Brent Old, Lloyd Wolchok, Jedd TI Improved Endpoints for Cancer Immunotherapy Trials SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID RANDOMIZED PHASE-III; VACCINE-CONSORTIUM; PROSTATE-CANCER; SOLID TUMORS; HARMONIZATION GUIDELINES; METASTATIC MELANOMA; FOLLICULAR LYMPHOMA; RESPONSE CRITERIA; CLINICAL BENEFIT; IV MELANOMA AB Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan-Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation. C1 [Hoos, Axel; Janetzki, Sylvia; Old, Lloyd; Wolchok, Jedd] Columbia Univ, Inst Canc Res, Canc Immunotherapy Consortium, New York, NY 10032 USA. [Hoos, Axel; Ibrahim, Ramy; Anderson, Aparna; Humphrey, Rachel] Bristol Myers Squibb Co, Global Clin Res Oncol, Wallingford, CT 06492 USA. [Eggermont, Alexander M. M.] Erasmus Univ, Med Ctr, Dept Surg, Rotterdam, Netherlands. [Janetzki, Sylvia] ZellNet Consulting, Ft Lee, NJ USA. [Hodi, F. Stephen] Dana Farber Canc Inst, Dept Med Oncool, Boston, MA 02115 USA. [Blumenstein, Brent] TriArc Consulting, Washington, DC USA. [Old, Lloyd] Ludwig Inst Canc Res, New York, NY USA. [Wolchok, Jedd] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. RP Hoos, A (reprint author), Bristol Myers Squibb Co, Global Clin Res, 5 Res Pkwy, Wallingford, CT 06492 USA. EM axel.hoos@bms.com FU Cancer Immunotherapy Consortium of the Cancer Research Institute FX Funding for scientific meetings, workshops, and the immune monitoring proficiency panels was provided by the Cancer Immunotherapy Consortium of the Cancer Research Institute, a nonprofit organization. NR 54 TC 258 Z9 271 U1 5 U2 35 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP PY 2010 VL 102 IS 18 BP 1388 EP 1397 DI 10.1093/jnci/djq310 PG 10 WC Oncology SC Oncology GA 654OA UT WOS:000282176600008 PM 20826737 ER PT J AU Tempero, MA Arnoletti, JP Behrman, S Ben-Josef, E Benson, AB Berlin, JD Cameron, JL Casper, ES Cohen, SJ Duff, M Ellenhorn, JDI Hawkins, WG Hoffman, JP Kuvshinoff, BW Malafa, MP Muscarella, P Nakakura, EK Sasson, AR Thayer, SP Tyler, DS AF Tempero, Margaret A. Arnoletti, J. Pablo Behrman, Stephen Ben-Josef, Edgar Benson, Al B., III Berlin, Jordan D. Cameron, John L. Casper, Ephraim S. Cohen, Steven J. Duff, Michelle Ellenhorn, Joshua D. I. Hawkins, William G. Hoffman, John P. Kuvshinoff, Boris W., II Malafa, Mokenge P. Muscarella, Peter, II Nakakura, Eric K. Sasson, Aaron R. Thayer, Sarah P. Tyler, Douglas S. TI Pancreatic Adenocarcinoma SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review DE NCCN Clinical Practice Guidelines; NCCN Guidelines; pancreas; adenocarcinoma; ductal carcinoma; endoscopic retrograde cholangiopancreatography; ultrasonography; gemcitabine ID PHASE-III TRIAL; PROSPECTIVE RANDOMIZED-TRIAL; COOPERATIVE-ONCOLOGY-GROUP; GEMCITABINE-BASED CHEMORADIATION; IN-HOSPITAL MORTALITY; EXTENDED RETROPERITONEAL LYMPHADENECTOMY; PREOPERATIVE BILIARY DRAINAGE; PORTAL-VEIN CONFLUENCE; DOSE RATE GEMCITABINE; LONG-TERM SURVIVAL AB An estimated 36,800 people will die of pancreatic cancer in the United States in 2010. This disease is the fourth most common cause of cancer-related death among men and women in the United States. Its peak incidence is in the seventh and eighth decades of life. Although incidence is roughly equal for the sexes, African Americans seem to have a higher incidence than white Americans. Although the associated increase in risk is small, the development of pancreatic cancer is firmly linked to cigarette smoking. Some evidence shows that increased consumption of red meat and dairy products is associated with an elevation in pancreatic cancer risk, although other studies have failed to identify dietary risk factors. An increased body mass index is also associated with increased risk. Occupational exposure to chemicals, such as beta-naphthylamine and benzidine, is also associated with an increased risk of pancreatic cancer. These guidelines only discuss tumors of the exocrine pancreas; neuroendocrine tumors are not included. Important changes in the updated 2010 NCCN Guidelines include the addition of leucovorin to 5-FU chemotherapy for some cases and revised principles of diagnosis and staging. C1 [Tempero, Margaret A.; Nakakura, Eric K.] UCSF Helen Diller Family Compreheens Canc Ctr, San Francisco, CA USA. [Arnoletti, J. Pablo] Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. [Behrman, Stephen] Univ Tennessee, Inst Canc, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Ben-Josef, Edgar] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Benson, Al B., III] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Berlin, Jordan D.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Cameron, John L.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Casper, Ephraim S.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Cohen, Steven J.; Hoffman, John P.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Duff, Michelle] Pancreat Canc Act Network, Cleveland, OH USA. [Hawkins, William G.] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO USA. [Hawkins, William G.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Kuvshinoff, Boris W., II] Roswell Pk Canc Inst, Buffalo, NY USA. [Malafa, Mokenge P.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Muscarella, Peter, II] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Sasson, Aaron R.] Univ Nebraska Med Ctr, UNMC Eppley Canc Ctr, Lincoln, NE USA. [Thayer, Sarah P.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Tyler, Douglas S.] Duke Comprehens Canc Ctr, Durham, NC USA. RP Tempero, MA (reprint author), UCSF Helen Diller Family Compreheens Canc Ctr, San Francisco, CA USA. FU NCI NIH HHS [P50 CA127003-03, P01 CA117969, P01 CA117969-04, P01 CA117969-04S1, P01 CA117969-05, P50 CA127003, P50 CA127003-04, P50 CA127003-05]; NIDDK NIH HHS [K08 DK071329, K08 DK071329-04, K08 DK071329-05] NR 249 TC 78 Z9 81 U1 0 U2 10 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD SEP PY 2010 VL 8 IS 9 BP 972 EP + PG 47 WC Oncology SC Oncology GA 660AG UT WOS:000282608800002 PM 20876541 ER PT J AU Swarm, R Abernethy, AP Anghelescu, DL Benedetti, C Blinderman, CD Boston, B Cleeland, C Coyle, N DeLeon-Casasola, OA Eilers, JG Ferrell, B Janjan, NA Karver, SB Levy, MH Lynch, M Moryl, N Murphy, BA Nesbit, SA Oakes, L Obbens, EA Paice, JA Rabow, MW Syrjala, KL Urba, S Weinstein, SM AF Swarm, Robert Abernethy, Amy Pickar Anghelescu, Doralina L. Benedetti, Costantino Blinderman, Craig D. Boston, Barry Cleeland, Charles Coyle, Nessa deLeon-Casasola, Oscar A. Eilers, June G. Ferrell, Betty Janjan, Nora A. Karver, Sloan Beth Levy, Michael H. Lynch, Maureen Moryl, Natalie Murphy, Barbara A. Nesbit, Suzanne A. Oakes, Linda Obbens, Eugenie A. Paice, Judith A. Rabow, Michael W. Syrjala, Karen L. Urba, Susan Weinstein, Sharon M. TI Adult Cancer Pain SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review DE NCCN Clinical Practice Guidelines; NCCN Guidelines; cancer; pain; malignancy; pain assessment; pain intensity rating ID NEUROPATHIC PAIN; DOUBLE-BLIND; BREAKTHROUGH PAIN; MANAGEMENT; MORPHINE; MORPHINE-6-GLUCURONIDE; DEXTROPROPOXYPHENE; PATHOPHYSIOLOGY; EPIDEMIOLOGY; ANALGESICS AB Pain is one of the most common symptoms associated with cancer. Cancer pain or cancer-related pain is distinct from pain experienced by patients without malignancies. Pain occurs in approximately one quarter of patients with newly diagnosed malignancies, one third of patients undergoing treatment, and three quarters of patients with advanced disease, and is one of the symptoms patients fear most. Unrelieved pain denies patients comfort and greatly affects their activities, motivation, interactions with family and friends, and overall quality of life. The importance of relieving pain and availability of effective therapies make it imperative that physicians and nurses caring for these patients be adept at the assessment and treatment of cancer pain. This requires familiarity with the pathogenesis of cancer pain; pain assessment techniques; common barriers to the delivery of appropriate analgesia; and pertinent pharmacologic, anesthetic, neurosurgical, and behavioral approaches to the treatment of cancer pain. The NCCN Guidelines on adult cancer pain underwent significant revision for 2010. Noteworthy updates include the addition of steps with case examples for converting/rotating one opioid to another, oral morphine to methadone, and any opioid to transdermal fentanyl. C1 [Swarm, Robert] Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO USA. [Swarm, Robert] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Abernethy, Amy Pickar] Duke Comprehens Canc Ctr, Durham, NC USA. [Anghelescu, Doralina L.; Boston, Barry; Oakes, Linda] Univ Tennessee, Inst Canc, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Benedetti, Costantino] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Blinderman, Craig D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Cleeland, Charles; Janjan, Nora A.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Coyle, Nessa; Moryl, Natalie; Obbens, Eugenie A.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [deLeon-Casasola, Oscar A.] Roswell Pk Canc Inst, Buffalo, NY USA. [Eilers, June G.] Univ Nebraska Med Ctr, UNMC Eppley Canc Ctr, Lincoln, NE USA. [Karver, Sloan Beth] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Levy, Michael H.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Lynch, Maureen] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Murphy, Barbara A.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Nesbit, Suzanne A.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. [Paice, Judith A.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Rabow, Michael W.] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Syrjala, Karen L.] Seattle Canc Care Alliance, Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Urba, Susan] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Weinstein, Sharon M.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. RP Swarm, R (reprint author), Barnes Jewish Hosp, Siteman Canc Ctr, St Louis, MO USA. FU NCI NIH HHS [R01 CA112631] NR 65 TC 50 Z9 52 U1 0 U2 7 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD SEP PY 2010 VL 8 IS 9 BP 1046 EP + PG 42 WC Oncology SC Oncology GA 660AG UT WOS:000282608800005 PM 20876544 ER PT J AU Ellis, C Zhao, YM Egede, LE AF Ellis, Charles Zhao, Yumin Egede, Leonard E. TI Racial/Ethnic Disparities in Poststroke Outpatient Rehabilitation Among Veterans SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE stroke; rehabilitation; race/ethnicity ID INPATIENT STROKE REHABILITATION; HEALTH-CARE SYSTEM; RACIAL DISPARITIES; UNITED-STATES; ETHNIC-DIFFERENCES; OUTCOMES; SERVICES; MORTALITY; SEVERITY; AFFAIRS AB Objective: To examine racial/ethnic differences in the use of poststroke outpatient rehabilitation in veterans. Methods: We examined data from 4115 veterans with a diagnosis of stroke who were seen at a VA Medical Center in the southeastern United States. We compared the receipt of physical therapy (PT) and occupational therapy (OT) evaluations, visits, and procedures among 3 racial/ethnic groups. Multiple logistic regression was used to assess the independent effect of race/ethnicity on the receipt of a PT or OT evaluation and Poisson regression to estimate the effect of race/ethnicity on treatment visits and procedures received. Results: In univariate comparisons, a higher proportion of blacks received PT and OT evaluations than whites and others. Similarly, blacks received a higher mean number of PT/OT treatments than whites and others. In multivariate logistic models with whites as reference, blacks were more likely to receive PT evaluations (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.24-1.74) and OT evaluations (OR, 1.23; 95% CI, 1.01-1.51). In multivariate Poisson models with whites as reference, blacks received more PT/OT visits (OR, 7.22; 95% CI, 5.95-8.76) than non-Hispanic whites (OR, 5.28; 95% CI, 4.41-6.33), while others received fewer visits (OR, 4.39; 95% CI, 3.58-5.39) than the reference group. No significant differences were observed across groups in the number of procedures completed during each treatment visit. Conclusions: In an equal-access system, blacks were more likely to receive outpatient PT/OT evaluations and higher mean number of PT/OT treatments. Future studies need to examine sociodemographic and disease-specific factors that account for these differences. C1 [Ellis, Charles] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Zhao, Yumin; Egede, Leonard E.] Med Univ S Carolina, Dept Med, Ctr Hlth Dispar Res, Charleston, SC 29425 USA. [Egede, Leonard E.] Ralph H Johnson VA Med Ctr, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC USA. RP Ellis, C (reprint author), Med Univ S Carolina, Dept Hlth Sci & Res, 77 President St, Charleston, SC 29425 USA. EM ellisc@musc.edu FU Charleston, South Carolina, Veterans Administration Health Services Research and Development [REA 08-261]; Veterans Administration Health Services Research and Development [CDA 07-012-3] FX The contents of this paper are the result of work supported by the use of facilities at the Charleston, South Carolina, Veterans Administration Health Services Research and Development-funded Center for Disease Prevention and Health Interventions for Diverse Populations (REA 08-261). Dr Ellis is supported by a career development award (CDA 07-012-3) from the Veterans Administration Health Services Research and Development program. NR 31 TC 1 Z9 1 U1 1 U2 3 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD SEP PY 2010 VL 102 IS 9 BP 817 EP 822 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 670XK UT WOS:000283463100008 PM 20922926 ER PT J AU Denlinger, CE Ikonomidis, JS Reed, CE Spinale, FG AF Denlinger, Chadrick E. Ikonomidis, John S. Reed, Carolyn E. Spinale, Francis G. TI Epithelial to mesenchymal transition: The doorway to metastasis in human lung cancers SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Review ID BREAST-CANCER; TUMOR PROGRESSION; MATRIX-METALLOPROTEINASE; PROTEIN EXPRESSION; BETA-CATENIN; CELLS; CARCINOMA; CADHERIN; INVASION; RECEPTOR C1 Univ S Carolina, Charleston, SC USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Denlinger, CE (reprint author), 25 Courtenay Dr,Suite 7018, Charleston, SC 29425 USA. EM denlinge@musc.edu NR 49 TC 23 Z9 23 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2010 VL 140 IS 3 BP 505 EP 513 DI 10.1016/j.jtcvs.2010.02.061 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 641HS UT WOS:000281116000003 PM 20723721 ER PT J AU Dao, TK Chu, D Springer, J Gopaldas, RR Menefee, DS Anderson, T Hiatt, E Nguyen, Q AF Dao, Tam K. Chu, Danny Springer, Justin Gopaldas, Raja R. Menefee, Deleene S. Anderson, Thomas Hiatt, Emily Nguyen, Quang TI Clinical depression, posttraumatic stress disorder, and comorbid depression and posttraumatic stress disorder as risk factors for in-hospital mortality after coronary artery bypass grafting surgery SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID HEART-RATE-VARIABILITY; PLASMA NOREPINEPHRINE; ADMINISTRATIVE DATABASES; DISEASE; INDEX; MORBIDITY; CABG AB Objective: The goal of this study was to examine the effect of clinical depression, posttraumatic stress disorder, and comorbid depression and posttraumatic stress disorder on in-hospital mortality after a coronary artery bypass grafting surgery. It is hypothesized that depression, posttraumatic stress disorder, and comorbid depression and posttraumatic stress disorder will independently contribute to an increased risk for in-hospital mortality rates after coronary artery bypass grafting surgery. Methods: We performed a retrospective analysis of the 2006 Nationwide Inpatient Sample database. The Nationwide Inpatient Sample database provides information on approximately 8 million US inpatient stays from about 1000 hospitals. We performed c 2 and unpaired t tests to evaluate potential confounding group demographic and medical variables. Hierarchic logistic regression was used with forced order entry of depression, posttraumatic stress disorder, and comorbid depression and posttraumatic stress disorder. Results: Deceased patients were more likely to have had depression (alive, 24.8%; deceased, 60.3%; P < .001), posttraumatic stress disorder (alive, 13.4%; deceased, 56.1%; P < .001), and cormorbid depression and posttraumatic stress disorder (alive, 7.8%; deceased, 48.5%; P < .001). After adjusting for potential confounding factors, patients with depression (odds ratio, 1.24; 95% confidence interval, 1.02-1.50), posttraumatic stress disorder (odds ratio, 2.09; 95% confidence interval, 1.65-2.64), and comorbid depression and posttraumatic stress disorder (odds ratio, 4.66; 95% confidence interval, 3.46-6.26) had an increased likelihood of in-hospital mortality compared with that seen in patients who were alive. Conclusions: Two findings were noteworthy. First, depression, posttraumatic stress disorder, and comorbid depression and posttraumatic stress disorder are prevalent in patients undergoing coronary artery bypass grafting procedures. Second, depression, posttraumatic stress disorder, and comorbid depression and posttraumatic stress disorder increase the risk of death by magnitudes comparable with well-established physical health risk factors after coronary artery bypass grafting surgery. The implications for clinical practice and future directions are discussed. (J Thorac Cardiovasc Surg 2010;140:606-10) C1 [Dao, Tam K.; Hiatt, Emily] Univ Houston, Baylor Coll Med, Houston, TX 77030 USA. [Dao, Tam K.; Chu, Danny; Springer, Justin; Menefee, Deleene S.; Anderson, Thomas; Nguyen, Quang] Baylor Coll Med, Dept Educ Psychol, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Dao, Tam K.; Springer, Justin; Menefee, Deleene S.; Anderson, Thomas; Nguyen, Quang] Baylor Coll Med, Mental Hlth Serv Line, Houston, TX 77030 USA. [Chu, Danny] Baylor Coll Med, Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Gopaldas, Raja R.] Baylor Coll Med, Div Cardiothorac Surg, Houston, TX 77030 USA. St Lukes Episcopal Hosp, Texas Heart Inst, USA Sect Adult Cardiac Surg, Houston, TX USA. RP Dao, TK (reprint author), Univ Houston, Baylor Coll Med, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM tdao@mail.coe.uh.edu FU Mental Illness Research, Education, and Clinical Center FX Supported by the Mental Illness Research, Education, and Clinical Center. NR 23 TC 13 Z9 14 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2010 VL 140 IS 3 BP 606 EP 610 DI 10.1016/j.jtcvs.2009.10.046 PG 5 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 641HS UT WOS:000281116000017 PM 20074753 ER PT J AU Kubota, K Otsuji, Y Ueno, T Koriyama, C Levine, RA Sakata, R Tei, C AF Kubota, Kayoko Otsuji, Yutaka Ueno, Tetsuya Koriyama, Chihaya Levine, Robert A. Sakata, Ryuzo Tei, Chuwa TI Functional mitral stenosis after surgical annuloplasty for ischemic mitral regurgitation: Importance of subvalvular tethering in the mechanism and dynamic deterioration during exertion SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; PAPILLARY-MUSCLE DYSFUNCTION; RESTRICTIVE ANNULOPLASTY; VALVE; CARDIOMYOPATHY; RECONSTRUCTION; DETERMINANTS; EXERCISE; INSIGHTS; GEOMETRY AB Objective: Diastolic subvalvular mitral leaflet tethering by left ventricular remodeling that restricts leaflet opening in the presence of annular size reduction by surgery for ischemic mitral regurgitation potentially causes functional mitral stenosis in the absence of organic leaflet lesions. Exercise, known to worsen systolic tethering and ischemic mitral regurgitation, might also dynamically exacerbate such mitral stenosis by increasing tethering. This study evaluates the mechanism and response of such mitral stenosis to exercise. Methods: We measured the diastolic mitral valve area, annular area, and peak and mean transmitral pressure gradient by echocardiography in 20 healthy individuals and 31 patients who underwent surgical annuloplasty for ischemic mitral regurgitation. Results: Although the mitral valve area and annular area did not significantly differ in healthy individuals (4.7 +/- 0.6 cm(2) vs 5.2 +/- 0.6 cm(2), not significant), mitral valve area was significantly smaller than the annular area in patients after annuloplasty (1.6 +/- 0.2 cm(2) vs 3.3 +/- 0.5 cm(2), P < .01). The mitral valve area was less than 1.5 cm(2) only after the surgery (P < .01) and was significantly correlated with restricted leaflet opening (r(2) = 0.74, P < .001), left ventricular dilatation (r(2) = 0.17, P < .05), and New York Heart Association functional class (P < .05). Exercise stress echocardiography of 12 patients demonstrated dynamic worsening in functional mitral stenosis (mitral valve area: 2.0 +/- 0.5 cm(2) to 1.4 +/- 0.2 cm(2), P < .01; mean pressure gradient: 1.5 +/- 0.9 mm Hg to 6.0 +/- 2.2 mm Hg, P < .01). Conclusions: Persistent subvalvular leaflet tethering in the presence of annular size reduction by surgery in ischemic mitral regurgitation frequently causes functional mitral stenosis at the leaflet tip level, which is related to heart failure symptoms and can be dynamic with significant exercise-induced worsening. (J Thorac Cardiovasc Surg 2010; 140: 617-23) C1 [Otsuji, Yutaka] Univ Occupat & Environm Hlth, Sch Med, Dept Internal Med 2, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan. [Kubota, Kayoko; Tei, Chuwa] Kagoshima Univ, Dept Cardiovasc Med, Grad Sch Med, Kagoshima 890, Japan. [Ueno, Tetsuya; Sakata, Ryuzo] Kagoshima Univ, Dept Cardiovasc Surg, Grad Sch Med, Kagoshima 890, Japan. [Koriyama, Chihaya] Kagoshima Univ, Dept Publ Hlth, Grad Sch Med, Kagoshima 890, Japan. [Levine, Robert A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Otsuji, Y (reprint author), Univ Occupat & Environm Hlth, Sch Med, Dept Internal Med 2, Yahatanishi Ku, Iseigaoka 1-1, Kitakyushu, Fukuoka 8078555, Japan. EM otsujiy@med.uoeh-u.ac.jp FU Japan Society for the Promotion of Science, Tokyo, Japan [19500431, 21500458] FX Dr Otsuji was supported by Grants-in-Aid for Scientific Research 19500431 and 21500458 from the Japan Society for the Promotion of Science, Tokyo, Japan. NR 25 TC 34 Z9 35 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2010 VL 140 IS 3 BP 617 EP 623 DI 10.1016/j.jtcvs.2009.11.003 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 641HS UT WOS:000281116000019 PM 20122701 ER PT J AU Jones, JA Zavadzkas, JA Chang, EI Sheats, N Koval, C Stroud, RE Spinale, FG Ikonomidis, JS AF Jones, Jeffrey A. Zavadzkas, Juozas A. Chang, Eileen I. Sheats, Nina Koval, Christine Stroud, Robert E. Spinale, Francis G. Ikonomidis, John S. TI Cellular phenotype transformation occurs during thoracic aortic aneurysm development SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID MATRIX METALLOPROTEINASES; MURINE MODEL; ASCENDING AORTA; UP-REGULATION; EXPRESSION; INHIBITORS; PATTERNS; VALVES; CELLS AB Objective: Thoracic aortic aneurysms result from dysregulated remodeling of the vascular extracellular matrix, which may occur as a result of altered resident cellular function. The present study tested the hypothesis that aortic fibroblasts undergo a stable change in cellular phenotype during thoracic aortic aneurysm formation. Methods: Primary murine aortic fibroblasts were isolated from normal and thoracic aortic aneurysm-induced aortas (4 weeks post induction with 0.5 mol/L CaCl(2) 15 minutes) by the outgrowth method. Normal and thoracic aortic aneurysm cultures were examined using a focused polymerase chain reaction array to determine fibroblast-specific changes in gene expression in the absence and presence of biological stimulation (endothelin-1, phorbol-12-myristate-13-acetate, angiotensin-II). The relative expression of 38 genes, normalized to 4 housekeeping genes, was determined, and genes displaying a minimum 2-fold increase/decrease or genes with significantly different normalized cycle threshold values were considered to have altered expression. Results: At steady state, thoracic aortic aneurysm fibroblasts revealed elevated expression of several matrix metalloproteinases (Mmp2, Mmp11, Mmp14), collagen genes/elastin (Col1a1, Col1a2, Col3a1, Eln), and other matrix proteins, as well as decreased expression of Mmp3, Timp3, and Ltbp1. Moreover, gene expression profiles in thoracic aortic aneurysm fibroblasts were different than normal fibroblasts after equivalent biological stimuli. Conclusions: This study demonstrated for the first time that isolated primary aortic fibroblasts from thoracic aortic aneurysm-induced mice possess a unique and stable gene expression profile, and when challenged with biological stimuli, induce a transcriptional response that is different from normal aortic fibroblasts. Together, these data suggest that aortic fibroblasts undergo a stable phenotypic change during thoracic aortic aneurysm development, which may drive the enhancement of extracellular matrix proteolysis in thoracic aortic aneurysm progression. (J Thorac Cardiovasc Surg 2010;140:653-9) C1 [Jones, Jeffrey A.] Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Div Cardiothorac Surg, Dept Surg, Charleston, SC 29425 USA. RP Jones, JA (reprint author), Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Div Cardiothorac Surg, Dept Surg, Strom Thurmond Res Bldg,114 Doughty St,Suite 625,, Charleston, SC 29425 USA. EM jonesja@musc.edu OI Chang, Eileen/0000-0002-3444-7260 FU National Institutes of Health/National Health, Lung, and Blood Institute [R01 HL075488, R01 HL81692]; Department of Veterans Affairs [BLRD-CDA-2] FX This work was supported by the National Institutes of Health/National Health, Lung, and Blood Institute R01 HL075488 (to J.S.I.) and R01 HL81692 (to F. G. S.), and by the Department of Veterans Affairs through a Career Development Award to J.A.J. (BLRD-CDA-2) and a Merit Award to F. G. S. NR 27 TC 11 Z9 13 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2010 VL 140 IS 3 BP 653 EP 659 DI 10.1016/j.jtcvs.2009.12.033 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 641HS UT WOS:000281116000024 PM 20219212 ER PT J AU Ready, N Janne, PA Bogart, J DiPetrillo, T Garst, J Graziano, S Gu, L Wang, XF Green, MR Vokes, EE AF Ready, Neal Jaenne, Pasi A. Bogart, Jeffrey DiPetrillo, Thomas Garst, Jennifer Graziano, Stephen Gu, Lin Wang, Xiaofei Green, Mark R. Vokes, Everett E. CA Canc Leukemia Grp B TI Chemoradiotherapy and Gefitinib in Stage III Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor and KRAS Mutation Analysis Cancer and Leukemia Group B (CALEB) 30106, a CALGB-Stratified Phase II Trial SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Gefitinib; Non-small cell lung cancer; Chemoradiotherapy; Epidermal growth factor receptor ID PREVIOUSLY TREATED PATIENTS; SOUTHWEST-ONCOLOGY-GROUP; ACQUIRED-RESISTANCE; IONIZING-RADIATION; COMBINATION; CONCURRENT; ERLOTINIB; CARBOPLATIN; DOCETAXEL; CISPLATIN AB Introduction: This study evaluated the addition of gefitinib to sequential or concurrent chemoradiotherapy (CRT) in unresectable stage III non-small cell lung. cancer Methods: Between May 2002 and April 2005, 63 patients were entered before the study closing early All received two cycles paclitaxel 200 mg/m(2) and carboplatin area under the curve 6 Intravenous plus gefitinib 250 mg daily Poor risk stratum 1 (>= 5% weight loss and/or performance status 2) received radiotherapy 200 cGy for 33 fractions (6600 cGy) and gefitinib 250 mg daily Good-risk stratum 2 (performance status 0-1 weight loss and <5%) received the same RT with gefitinib 250 mg daily and weekly paclitaxel 50 mg/m(2) plus carboplatin AUC 2 Consolidation gefitinib until progression was started after all toxicities were grade Results: Acute high-grade infield toxicities were not clearly increased compared with historical CRT data Poor-risk (N = 21) median progression-free survival was 13 4 months (95% confidence interval [Cl] 6 4-25 2) and median overall survival 19 0 months (95% Cl 9 9-28 4) Good-risk (N = 39) median progression-free survival was 9 2 months (95% CI 6 7-12 2). and median overall survival was 13 months (95% CI 8 5-17 2) Thirteen of 45 tumors analyzed had activating epidermal growth factor receptor (EGFR) mutations. and 2 of 13 also had T790M mutations Seven tumors of 45 had KRAS mutations There was no apparent survival difference with EGFR-activating mutations versus wild type or KRAS mutation versus wild type Conclusions: Survival of poor-risk patients with wild type or mutated EGFR receiving sequential CRT with gefitinib was promising Survival for good-risk patients receiving concurrent CRT plus gefitinib was disappointing even for tumors with activating EGFR mutations C1 [Ready, Neal] Duke Univ, Med Ctr, Div Med Oncol, Durham, NC 27710 USA. [Jaenne, Pasi A.] Dana Farber Canc Ctr, Boston, MA USA. [Bogart, Jeffrey] SUNY Syracuse, Syracuse, NY USA. [DiPetrillo, Thomas; Graziano, Stephen] Rhode Isl Hosp, Providence, RI USA. [Gu, Lin; Wang, Xiaofei] Duke Univ, Med Ctr, Canc & Leukemia Grp Stat Ctr B, Durham, NC 27710 USA. [Green, Mark R.] Med Univ S Carolina, Charleston, SC 29425 USA. [Vokes, Everett E.] Univ Chicago, Chicago, IL 60637 USA. RP Ready, N (reprint author), Duke Univ, Med Ctr, Div Med Oncol, Durham, NC 27710 USA. FU Lilly; Bristol Myers Squibb; Amgen; Novartis FX Neal Ready. PhD. MD, received research grants from Lilly, Bristol Myers Squibb, Amgen, and Novartis to cover the cost of the clinical trials and was previously on the speaker bureau for Bristol Myers Squibb NR 42 TC 68 Z9 72 U1 0 U2 5 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 SEP PY 2010 VL 5 IS 9 BP 1382 EP 1390 PG 9 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 647FJ UT WOS:000281602900011 PM 20686428 ER PT J AU Sandler, A Yi, J Dahlberg, S Kolb, MM Wang, LS Hambleton, J Schiller, J Johnson, DH AF Sandler, Alan Yi, Jing Dahlberg, Suzanne Kolb, Margaret M. Wang, Lisa Hambleton, Julie Schiller, Joan Johnson, David H. TI Treatment Outcomes by Tumor Histology in Eastern Cooperative Group Study E4599 of Bevacizumab with Paclitaxel/Carboplatin for Advanced Non-small Cell Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Non-small cell lung cancer; Bevacizumab; Nonsquamous; Histology; Adenocarcinoma ID CHEMOTHERAPY; TRIAL; GEMCITABINE; CARBOPLATIN; PACLITAXEL AB Introduction: The combination of paclitaxel/carboplatin (PC) and bevacizumab ( B) was previously shown to extend overall survival (OS) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) An analysis of survival and safety outcomes based on histology is presented here Methods: Patients with cytologically or histologically confirmed metastatic NSCLC were treated with PC + B (PCB) or PC Median OS for all patients was determined using Kaplan-Meier methodology Hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained using an unstratified Cox proportional hazards model Histology-by-treatment interaction was tested with an unstratified multivariate Cox regression model Results: A total of 444 patients were randomized to PC, and 434 patients were randomized to PCB (the intent-to-treat population) Median OS times were 10 3 and 12 3 months for PC and PCB, respectively, with an HR for PCB of 0 80 (95% Cl 0 69-0 93) A total of 68 8% of patients had adenocarcinoma histology. 18 9% had "not otherwise specified", 5 5% had large cell undifferentiated, 2 6% had bronchoalveolar carcinoma. and 3 9% "other" For adenocarcinoma, median OS was 10 3 months for PC treatment (n = 302) and 14 2 months for PCB (n = 300), HR 0 69 (95% CI 0 58-0 83) Sample sizes for other specific histologic subtypes were too small for meaningful comparisons Safety profiles among histologies were consistent with the overall safety profile, and there were no unexpected adverse event trends Conclusions: Addition of B to PC is associated with increased survival in previously untreated patients with nonsquamous NSCLC Adenocarcinoma was associated with an increased survival benefit of PCB treatment Data for other histologies are inconclusive, primarily because of small patient sample sizes and lame CIs C1 [Sandler, Alan] Oregon Hlth & Sci Univ, Div Hematol Oncol, Dept Med, Portland, OR 97239 USA. [Yi, Jing; Kolb, Margaret M.; Wang, Lisa; Hambleton, Julie] Genentech Inc, San Francisco, CA 94080 USA. [Dahlberg, Suzanne] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Schiller, Joan] Univ Texas SW Med Ctr Dallas, Dept Med, Div Hematol Oncol, Dallas, TX 75390 USA. [Johnson, David H.] Vanderbilt Ingram Canc Ctr, Div Hematol Oncol, Dept Med, Nashville, TN USA. RP Sandler, A (reprint author), Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, 3181 SW Sam Jackson Pk Rd,Mail Code L586, Portland, OR 97239 USA. FU NCI NIH HHS [U10 CA021115, U10 CA023318, U10 CA066636] NR 16 TC 73 Z9 77 U1 1 U2 3 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 SEP PY 2010 VL 5 IS 9 BP 1416 EP 1423 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 647FJ UT WOS:000281602900016 PM 20686429 ER PT J AU Fernandes, AT Shinohara, ET Guo, MY Mitra, N Wilson, LD Rengan, R Metz, JM AF Fernandes, Annemarie T. Shinohara, Eric T. Guo, Mengye Mitra, Nandita Wilson, Lynn D. Rengan, Ramesh Metz, James M. TI The Role of Radiation Therapy in Malignant Thymoma A Surveillance, Epidemiology, and End Results Database Analysis SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Thymoma; Radiation; Secondary malignancy; Cardiac toxicity ID THYMIC EPITHELIAL TUMORS; INVASIVE THYMOMA; HODGKINS-DISEASE; POSTOPERATIVE RADIOTHERAPY; SURGICAL RESECTION; PROGNOSTIC-FACTORS; HEART-DISEASE; STAGE-II; CANCER; IRRADIATION AB Introduction: The potential benefits and long-term complications of radiotherapy treatment for malignant thymoma are unclear This is a retrospective analysis of outcome in patients with malignant thymoma from the Surveillance. Epidemiology. and End Results database between 1973 and 2005 Methods: Of the 1987 patients identified. 1334 were analyzed Patients were categorized according to the Masaoka staging system as stage I to IIA, III or IV to IV The primary end points were overall survival, cardiac mortality, and the development of secondary malignancies Results: Patients received surgery and radiation (50%), surgery alone (26%). radiation alone (12%), or no treatment (12%) The median follow-up time for survivors was 65 months (range, 1-361 months) There was no significant increase in the 12-year cumulative incidence rate of death from heart disease (10 2% radiation versus 7 5% no radiation, p = 0 83) or incidence of secondary malignancies (11 7% versus 12 4%, p = 0 70) with radiation Compared with surgery alone, adjuvant radiation significantly improved overall survival in patients with stage III to IV disease (p = 0 04) and demonstrated a nonsignificant trend in patients with stage IIIB disease (p = 0 09) However, after excluding patients surviving less than 4 months to account for surgical mortality, the benefit with radiation was no longer significant (stage IIIB p = 045. stage III-IV p = 0 44) Conclusions: Radiation does not seem to increase the risk of cardiac mortality or secondary malignancy in patients with malignant thymoma Although the routine use of postoperative radiotherapy in malignant thymoma does not appear warranted, high-risk patients may benefit from adjuvant radiation This study can help to design prospective trials to further establish the role of radiotherapy in malignant thymoma C1 [Fernandes, Annemarie T.; Shinohara, Eric T.; Mitra, Nandita; Rengan, Ramesh; Metz, James M.] Univ Penn, Philadelphia, PA 19104 USA. [Guo, Mengye] Dana Farber Canc Inst, Boston, MA 02115 USA. [Wilson, Lynn D.] Yale Univ, Sch Med, New Haven, CT USA. RP Fernandes, AT (reprint author), Univ Penn, 2 Donner,3400 Spruce St, Philadelphia, PA 19104 USA. FU Doris Duke Charitable Research Foundation FX Supported by the Doris Duke Charitable Research Foundation NR 32 TC 18 Z9 20 U1 0 U2 0 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 SEP PY 2010 VL 5 IS 9 BP 1454 EP 1460 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 647FJ UT WOS:000281602900022 PM 20651611 ER PT J AU Dylewski, ML Bender, JC Smith, AM Prelack, K Lydon, M Weber, JM Sheridan, RL AF Dylewski, Maggie L. Bender, Jodi C. Smith, Anne M. Prelack, Kathy Lydon, Martha Weber, Joan M. Sheridan, Robert L. TI The Selenium Status of Pediatric Patients With Burn Injuries SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the American-Burn-Association CT Annual Meeting of the American-Burn-Association CY MAR 22-25, 2007 CY MAR 22-25, 2007 CL San Diego, CA CL San Diego, CA SP Amer Burn Assoc SP Amer Burn Assoc DE Selenium; Glutathione peroxidase; Burns; Nutrition ID TRACE-ELEMENT SUPPLEMENTATION; MAJOR BURNS; SERUM AB Background: Dietary selenium (Se) requirements during critical illness are not well known. The objective of this study was to assess the longitudinal Se status of pediatric patients with burns. Methods: Twenty patients admitted to our hospital with burns exceeding 10% of their total body surface area were studied longitudinally during the first 8 weeks of admission or until 95% wound closure was achieved. Dietary Se intake was calculated daily, and plasma and urine samples were collected weekly for analyses of plasma Se, urinary Se, and glutathione peroxidase activity. Results: Patients included in this study were individuals with an average age of 6.5 years +/- 5.3 years and with burn injury of a mean total body surface area of 42% +/- 21%. Dietary Se intake throughout the study (mean = 60 mu g/d +/- 39 mu g/d) was consistent with established standards for healthy children and did not change throughout the study. Plasma Se (mean = 1.08 mu mol/L +/- 0.34 mu mol/L) and plasma glutathione peroxidase (mean = 3.2 U/g protein +/- 1.42 U/g protein) were below reported normal values for healthy American children. Mean urinary Se excretion (65.9 mu g/L +/- 50 mu g/L) exceed dietary Se intake. Plasma Se was inversely related to incidence of total infection (p = 0.04). Conclusions: Results from this study indicate that Se status is depressed among pediatric patients with burns and that recommended Se intake for healthy children is likely insufficient for this population. Further studies are necessary to elucidate the amount of dietary Se required to maximize Se stores among pediatric patients with burn injuries. C1 [Dylewski, Maggie L.; Prelack, Kathy; Lydon, Martha; Weber, Joan M.; Sheridan, Robert L.] Shriners Hosp Children, Dept Surg, Boston, MA 02114 USA. [Bender, Jodi C.; Smith, Anne M.] Ohio State Univ, Dept Human Nutr, Columbus, OH 43210 USA. [Sheridan, Robert L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dylewski, ML (reprint author), Shriners Hosp Children, Dept Surg, 51 Blossom St, Boston, MA 02114 USA. EM mdylewski@shrinenet.org NR 20 TC 13 Z9 15 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0022-5282 EI 1529-8809 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD SEP PY 2010 VL 69 IS 3 BP 584 EP 588 DI 10.1097/TA.0b013e3181e74c54 PG 5 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 649HX UT WOS:000281760800021 PM 20838129 ER PT J AU Karaosmanoglu, AD Gee, MS AF Karaosmanoglu, A. Devrim Gee, Michael S. TI Sonographic Findings of an Adrenal Leiomyosarcoma SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article ID FEATURES AB Mesenchymal tumors of the adrenal gland are rare clinical entities. Most of these tumors are benign and include angiomyolipomas, leiomyomas, neurofibromas, osteomas, and schwannomas.(1) Malignant mesenchymal tumors of the adrenal gland are even rarer and include angiosarcomas and leiomyosarcomas. The imaging features of a primary leiomyosarcoma of the adrenal gland are not well described in the radiologic literature. In this report, we try to increase the awareness of practicing radiologists to this extremely rare primary adrenal malignancy. C1 [Karaosmanoglu, A. Devrim; Gee, Michael S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Abdominal Imaging & Intervent,Dept Radiol, Boston, MA 02114 USA. RP Karaosmanoglu, AD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Abdominal Imaging & Intervent,Dept Radiol, 55 Fruit St,White 2, Boston, MA 02114 USA. EM alidevrim76@yahoo.com RI Karaosmanoglu, Ali/D-8624-2015 OI Karaosmanoglu, Ali/0000-0003-0027-9593 NR 9 TC 1 Z9 2 U1 0 U2 1 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD SEP PY 2010 VL 29 IS 9 BP 1369 EP 1373 PG 5 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 656RX UT WOS:000282355400016 PM 20733196 ER PT J AU Saylor, PJ AF Saylor, Philip J. TI Fracture Types and Risk Factors in Men With Prostate Cancer on Androgen Deprivation Therapy: A Matched Cohort Study of 19,079 Men EDITORIAL COMMENT SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA 02114 USA. RP Saylor, PJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD SEP PY 2010 VL 184 IS 3 BP 923 EP 923 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 636IP UT WOS:000280725600028 PM 20643451 ER PT J AU Kilpatrick, LA Ornitz, E Ibrahimovic, H Hubbard, CS Rodriguez, LV Mayer, EA Naliboff, BD AF Kilpatrick, Lisa Ann Ornitz, Edward Ibrahimovic, Hana Hubbard, Catherine S. Rodriguez, Larissa V. Mayer, Emeran A. Naliboff, Bruce D. TI Gating of Sensory Information Differs in Patients With Interstitial Cystitis/Painful Bladder Syndrome SO JOURNAL OF UROLOGY LA English DT Article DE urinary bladder; cystitis, interstitial; startle reaction; female; sensory gating ID PREPULSE INHIBITION; STARTLE; STRESS; SENSORIMOTOR; MODULATION; BRAIN; MEN AB Purpose: Altered sensory processing in interstitial cystitis/painful bladder syndrome cases may result from a deficiency of the central nervous system to adequately filter incoming visceral afferent information. We used prepulse inhibition as an operational measure of sensorimotor gating to examine early pre-attentive stages of information processing in females with interstitial cystitis/painful bladder syndrome and healthy controls. Materials and Methods: We assessed prepulse inhibition in 14 female patients with interstitial cystitis/painful bladder syndrome and 17 healthy controls at 60 and 120-millisecond prepulse-to-startle stimulus intervals. We evaluated group differences in prepulse inhibition, and relationships between prepulse inhibition, neuroticism and acute stress ratings. Results: Patients showed significantly decreased prepulse inhibition at 60 and 120-millisecond prepulse intervals. The prepulse inhibition deficit was related to acute stress ratings in the patients. However, increased neuroticism appeared to mitigate the prepulse inhibition deficit in those with interstitial cystitis/painful bladder syndrome, possibly reflecting greater vigilance. Conclusions: Compared to healthy controls, female patients with interstitial cystitis/painful bladder syndrome had decreased ability to adequately filter incoming information and perform appropriate sensorimotor gating. These results suggest that a possible mechanism for altered interoceptive information processing in interstitial cystitis/painful bladder syndrome cases may be a general deficit in filtering mechanisms due to altered pre-attentive processing. C1 [Rodriguez, Larissa V.] Univ Calif Los Angeles, Dept Urol, Los Angeles, CA 90024 USA. [Ornitz, Edward; Mayer, Emeran A.] Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA. [Kilpatrick, Lisa Ann; Hubbard, Catherine S.; Mayer, Emeran A.] Univ Calif Los Angeles, Dept Physiol & Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Ornitz, Edward; Mayer, Emeran A.; Naliboff, Bruce D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Kilpatrick, Lisa Ann; Ornitz, Edward; Ibrahimovic, Hana; Hubbard, Catherine S.; Mayer, Emeran A.; Naliboff, Bruce D.] Univ Calif Los Angeles, Ctr Neurobiol Stress, Los Angeles, CA 90095 USA. [Hubbard, Catherine S.; Naliboff, Bruce D.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Rodriguez, LV (reprint author), Univ Calif Los Angeles, Dept Urol, Los Angeles, CA 90024 USA. EM naliboff@ucla.edu RI Kilpatrick, Lisa/E-6995-2015; OI Hubbard, Catherine/0000-0002-9139-2198 FU National Institutes of Health [NR007768, P50 DK64539, R24 AT002681]; Veterans Affairs Medical Research, National Institutes of Health [T32-DK07180-34]; Astellas FX Supported by National Institutes of Health Grants NR007768, P50 DK64539 and R24 AT002681, Veterans Affairs Medical Research, National Institutes of Health GI Training Grant T32-DK07180-34 and a gift from the Virginia Friedhofer Charitable Trust.; Financial interest and/or other relationship with Astellas. NR 30 TC 15 Z9 15 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD SEP PY 2010 VL 184 IS 3 BP 958 EP 963 DI 10.1016/j.juro.2010.04.083 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 636IP UT WOS:000280725600039 PM 20643444 ER PT J AU Joseph, WS Lipsky, BA AF Joseph, Warren S. Lipsky, Benjamin A. TI Medical therapy of diabetic foot infections SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID STAPHYLOCOCCUS-AUREUS; CLASSIFICATION-SYSTEM; VALIDATION; DIAGNOSIS; RISK AB Diabetic foot infections are a common and often serious problem, accounting for a greater number of hospital bed days than any other complication of diabetes. Despite advances in both antibiotic therapy and surgical management, these infections continue to be a major risk factor for amputations of the lower extremity. Although a number of wound size and depth classification systems have been adapted for use in codifying diabetic foot ulcerations, none are specific for infection. In 2003, the International Working Group on the Diabetic Foot developed guidelines for managing diabetic foot infections, including the first severity scale specific for these infections. The following year, the Infectious Diseases Society of America (IDSA) published their Diabetic Foot Infection Guidelines. In this article, we review some of the critical points from the Executive Summary of the IDSA document and provide a commentary following each issue to update the reader on any pertinent changes that have occurred since the publication of the original document in 2004. The importance of a multidisciplinary limb salvage team, apropos this special joint issue of the American Podiatric Medical Association and the Society for Vascular Surgery, cannot be overstated. (J Vase Surg 2010;52:67S-71S.) C1 [Joseph, Warren S.] Roxborough Mem Hosp, Philadelphia, PA USA. Univ Washington, Seattle, WA 98195 USA. [Lipsky, Benjamin A.] VA Puget Sound HCS, Primary Care Clin, Seattle, WA 98195 USA. RP Joseph, WS (reprint author), 1109 Old Ford Rd, Huntingdon Valley, PA 19006 USA. EM wsjoseph@comcast.net OI Lipsky, Benjamin A./0000-0001-9886-5114 NR 16 TC 9 Z9 10 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2010 VL 52 SU S BP 67S EP 71S DI 10.1016/j.jvs.2010.06.010 PG 5 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 646VC UT WOS:000281570200010 PM 20804935 ER PT J AU Finzi, A Pacheco, B Zeng, X Do Kwon, Y Kwong, PD Sodroski, J AF Finzi, Andres Pacheco, Beatriz Zeng, Xin Do Kwon, Young Kwong, Peter D. Sodroski, Joseph TI Conformational characterization of aberrant disulfide-linked HIV-1 gp120 dimers secreted from overexpressing cells SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HIV-1; Virus entry; CD4; Envelope glycoprotein; Conformational change ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN TRIMERS; TRANSMEMBRANE GLYCOPROTEIN; MONOCLONAL-ANTIBODIES; OLIGOMERIC STRUCTURE; RECEPTOR-BINDING; AIDS PATIENTS; INNER DOMAIN; T4 MOLECULE; HTLV-III AB The envelope (Env) glycoproteins of human immunodeficiency virus (HIV-1) mediate viral entry and are also the primary target of neutralizing antibodies. The gp160 envelope glycoprotein precursor undergoes proteolytic cleavage in the Golgi complex to produce the gp120 exterior glycoprotein and the gp41 transmembrane glycoprotein, which remain associated non-covalently in the trimeric Env complex. Monomeric soluble gp120 has been used extensively to investigate conformational states, structure, antigenicity and immunogenicity of the HIV-1 Env glycoproteins. Expression of gp120 alone (without gp41) leads to the accumulation not only of monomeric gp120 but also an aberrant dimeric form. The gp120 dimers were sensitive to reducing agents. The formation of gp120 dimers was disrupted by a single amino acid change in the inner domain, and was reduced by removal of the V1/V2 variable loops or the N and C termini. Epitopes on the gp120 inner domain and the chemokine receptor-binding surface were altered or occluded by gp120 dimerization. Awareness of the existence and properties of gp120 dimers should assist interpretation of studies of this key viral protein. (C) 2010 Elsevier B.V. All rights reserved. C1 [Finzi, Andres; Pacheco, Beatriz; Zeng, Xin; Sodroski, Joseph] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Finzi, Andres; Pacheco, Beatriz; Sodroski, Joseph] Harvard Univ, Sch Med, Div Aids, Dept Pathol, Boston, MA 02115 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Do Kwon, Young; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Sodroski, J (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,CLS 1010, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu RI Kwon, Young Do/A-6957-2010 FU National Institutes of Health [AI24755, GM56550, AI67854]; International AIDS Vaccine Initiative FX The authors would like to thank Ms. Yvette McLaughlin and Ms. Elizabeth Carpelan for manuscript preparation. This work was supported by grants from the National Institutes of Health (AI24755, GM56550 and AI67854), by the International AIDS Vaccine Initiative, and by the late William F. McCarty-Cooper. The authors have no conflicts of interest to report. NR 47 TC 25 Z9 26 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD SEP PY 2010 VL 168 IS 1-2 BP 155 EP 161 DI 10.1016/j.jviromet.2010.05.008 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 638CS UT WOS:000280869400027 PM 20471426 ER PT J AU Reeves, RK Evans, TI Gillis, J Johnson, RP AF Reeves, R. Keith Evans, Tristan I. Gillis, Jacqueline Johnson, R. Paul TI Simian Immunodeficiency Virus Infection Induces Expansion of alpha 4 beta 7(+) and Cytotoxic CD56(+) NK Cells SO JOURNAL OF VIROLOGY LA English DT Article ID NATURAL-KILLER-CELLS; ACUTE HIV-1 INFECTION; RHESUS MACAQUES; DENDRITIC CELLS; SIV INFECTION; HLA-B; EXPRESSION; RESPONSES; INNATE; SUBPOPULATIONS AB Herein we demonstrate that chronic simian immunodeficiency virus (SIV) infection induces significant upregulation of the gut-homing marker alpha 4 beta 7 on macaque NK cells, coupled with downregulation of the lymph node-trafficking marker, CCR7. Interestingly, in naive animals, alpha 4 beta 7 expression was associated with increased NK cell activation and, on CD16(+) NK cells, delineated a unique dual-function cytotoxic-CD107a(+)/gamma interferon (IFN-gamma)-secreting population. However, while SIV infection increased CD107a expression on stimulated CD56(+) NK cells, alpha 4 beta 7(+) and alpha 4 beta 7(-) NK cells were affected similarly. These findings suggest that SIV infection redirects NK cells away from the lymph nodes to the gut mucosae but alters NK cell function independent of trafficking repertoires. C1 [Reeves, R. Keith; Evans, Tristan I.; Gillis, Jacqueline; Johnson, R. Paul] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Immunol, Southborough, MA 01772 USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02115 USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Harvard & Infect Dis Unit, Boston, MA 02115 USA. RP Johnson, RP (reprint author), Harvard Univ, Sch Med, New England Primate Res Ctr, Div Immunol, Southborough Campus,POB 9102,Pine Hill Dr, Southborough, MA 01772 USA. EM paul_johnson@hms.harvard.edu FU NIH [AI062412, AI071306, RR00168]; CHAVI/HVTN [U19 AI 067854-04] FX This research was supported by NIH grants AI062412, AI071306, and RR00168, as well as a CHAVI/HVTN Early Career Investigator award, grant number U19 AI 067854-04, to R. K. R. NR 36 TC 28 Z9 28 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2010 VL 84 IS 17 BP 8959 EP 8963 DI 10.1128/JVI.01126-10 PG 5 WC Virology SC Virology GA 634SJ UT WOS:000280605300055 PM 20554780 ER PT J AU Choi, AI Li, YM Parikh, C Volberding, PA Shlipak, MG AF Choi, Andy I. Li, Yongmei Parikh, Chirag Volberding, Paul A. Shlipak, Michael G. TI Long-term clinical consequences of acute kidney injury in the HIV-infected SO KIDNEY INTERNATIONAL LA English DT Article DE acute kidney injury; cardiovascular disease; end-stage renal disease; HIV; mortality ID ACUTE-RENAL-FAILURE; ACUTE MYOCARDIAL-INFARCTION; OF-VETERANS-AFFAIRS; T-CELL-ACTIVATION; PERITUBULAR CAPILLARIES; ANTIRETROVIRAL THERAPY; CARDIOVASCULAR EVENTS; SERUM CREATININE; DEATH; OUTCOMES AB To evaluate the long-term consequences of acute kidney injury (AKI) in human immunodeficiency virus (HIV)-infected persons, we studied 17,325 patients in a national HIV registry during their first hospitalization. We determined the association of AKI with risk for heart failure, cardiovascular events, end-stage renal disease (ESRD), and mortality beginning 90 days after discharge. Based on AKI Network criteria, 2453 had stage 1; 273 had stage 2 or 3; and 334 had dialysis-requiring AKI. Over a mean follow-up period of 5.7 years, 333 had heart failure, 673 had cardiovascular diseases (CVDs), 348 developed ESRD, and 8405 deaths occurred. In multivariable-adjusted analyses, AKI stage 1 was associated with death and ESRD, but not heart failure or other CVD. Dialysis-requiring AKI had much stronger and significant associations with increased risk for long-term ESRD, and death in addition to heart failure and cardiovascular events. When AKI was reclassified to account for recovery, stage 1 with recovery was still associated with death, but not ESRD. Thus, in this national sample of HIV-infected persons, we found the clinical repercussions of AKI appear to extend beyond the hospital setting contributing to excess cardiovascular risks, ESRD, and mortality. Additionally, AKI affected almost one of six patients with HIV who survived at least 90 days following discharge. Kidney International (2010) 78, 478-485; doi: 10.1038/ki.2010.171; published online 2 June 2010 C1 [Choi, Andy I.; Li, Yongmei; Volberding, Paul A.; Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Choi, Andy I.; Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Parikh, Chirag] Yale Univ, New Haven, CT USA. RP Choi, AI (reprint author), San Francisco VA Med Ctr, Dept Med, Box 111J,4150 Clement St, San Francisco, CA 94121 USA. EM andy.choi@ucsf.edu FU National Institutes of Health [K23DK080645-01A1, K23AI65244, R01 DK066488-01]; National Center for Research Resources [KL2 RR024130]; American Heart Association; VA Public Health Strategic Health Care Group FX This study was supported by the National Institutes of Health (K23DK080645-01A1, K23AI65244, R01 DK066488-01), the National Center for Research Resources (KL2 RR024130), the American Heart Association Early Investigator Award, and the VA Public Health Strategic Health Care Group. These funding sources had no involvement in the design or execution of this study. NR 42 TC 54 Z9 56 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2010 VL 78 IS 5 BP 478 EP 485 DI 10.1038/ki.2010.171 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 637YX UT WOS:000280856200009 PM 20520594 ER PT J AU Astolfi, A Nannini, M Pantaleo, MA Di Battista, M Heinrich, MC Santini, D Catena, F Corless, CL Maleddu, A Saponara, M Lolli, C Di Scioscio, V Formica, S Biasco, G AF Astolfi, Annalisa Nannini, Margherita Pantaleo, Maria Abbondanza Di Battista, Monica Heinrich, Michael C. Santini, Donatella Catena, Fausto Corless, Christopher L. Maleddu, Alessandra Saponara, Maristella Lolli, Cristian Di Scioscio, Valerio Formica, Serena Biasco, Guido TI A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number SO LABORATORY INVESTIGATION LA English DT Article DE gastrointestinal stromal tumors; gene expression profiling; SNPs array ID POTENTIAL THERAPEUTIC TARGET; PROGNOSTIC IMPLICATIONS; CHROMOSOME 14; MUTATIONS; GISTS; 22Q; AGGRESSIVENESS; ABERRATIONS; DELETIONS; IMATINIB AB In addition to KIT and PDGFRA mutations, sequential accumulation of other genetic events is involved in the development and progression of gastrointestinal stromal tumors (GISTs). Until recently, the significance of these other alterations has not been thoroughly investigated. We report the first study that integrates gene expression profiling and high-resolution genomic copy number analyses in GIST. Fresh tissue specimens from 25 patients with GIST were collected, and gene expression profiling and high-resolution genomic copy number analyses were performed, using Affymetrix U133Plus and SNP array 6.0. We found that all 21 mutant GIST patients showed both macroscopic cytogenetic alterations and cryptic microdeletions or amplifications, whereas 75% (three of four) of wild-type patients with GIST did not show genomic imbalances. The most frequently observed chromosomal alterations in patients with mutant GIST included 14q complete or partial deletion (17 of 25), 1p deletion (14 of 25) and 22q deletion (10 of 25). Genetic targets of the chromosomal aberrations were selected by integrated analysis of copy number and gene expression data. We detected the involvement of known oncogenes and tumor suppressors including KRAS in chr 12p amplification and KIF1B, PPM1A, NF2 in chr 1p, 14q and 22p deletions, respectively. The genomic segment most frequently altered in mutated samples was the 14q23.1 region, which contains potentially novel tumor suppressors, including DAAM1, RTN1 and DACT1. siRNA-mediated RTN1 downregulation showed evidence for the potential role in GIST pathogenesis. The combination of gene expression profiling and high-resolution genomic copy number analysis offers a detailed molecular portrait of GISTs, providing an essential comprehensive knowledge necessary to guide the discovery of novel target genes involved in tumor development and progression. Laboratory Investigation (2010) 90, 1285-1294; doi:10.1038/labinvest.2010.110; published online 14 June 2010 C1 [Nannini, Margherita; Pantaleo, Maria Abbondanza; Di Battista, Monica; Maleddu, Alessandra; Saponara, Maristella; Lolli, Cristian; Biasco, Guido] Univ Bologna, S Orsola Malpighi Hosp, Dept Hematol & Oncol Sci LA Seragnoli, I-40138 Bologna, Italy. [Astolfi, Annalisa; Pantaleo, Maria Abbondanza; Formica, Serena; Biasco, Guido] Univ Bologna, Interdept Ctr Canc Res G Prodi, I-40138 Bologna, Italy. [Heinrich, Michael C.] Oregon Hlth & Sci Univ, Dept Med, Portland VA Med Ctr, Portland, OR 97201 USA. [Heinrich, Michael C.; Corless, Christopher L.] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA. [Santini, Donatella] Univ Bologna, S Orsola Malpighi Hosp, Pathol Unit, I-40138 Bologna, Italy. [Catena, Fausto] Univ Bologna, S Orsola Malpighi Hosp, Emergency Surg & Transplant Dept, I-40138 Bologna, Italy. [Corless, Christopher L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland VA Med Ctr, Portland, OR 97201 USA. [Di Scioscio, Valerio] Univ Bologna, Univ Hosp S Orsola Malpighi, Div Pneumonefro, Dept Radiol, I-40138 Bologna, Italy. RP Pantaleo, MA (reprint author), Univ Bologna, S Orsola Malpighi Hosp, Dept Hematol & Oncol Sci, Via Massarenti 9, I-40138 Bologna, Italy. EM maria.pantaleo@unibo.it RI Saponara, Maristella/J-9904-2016; nannini, margherita/J-9866-2016; OI Saponara, Maristella/0000-0003-0715-171X; PANTALEO, MARIA ABBONDANZA/0000-0002-0177-6957; NANNINI, MARGHERITA/0000-0002-2103-1960; astolfi, annalisa/0000-0002-2732-0747 FU Fondazione Cassa di Risparmio of Bologna (CARISBO); Fondazione Giuseppe Alazio, Palermo; Vanini-Cavagnino; VA; Life Raft Group FX Research programs on GISTs are supported by Fondazione Cassa di Risparmio of Bologna (CARISBO), Fondazione Giuseppe Alazio, Palermo, and Vanini-Cavagnino grant. This research was also supported in part by A VA Merit Review grant (MCH) and funding from the Life Raft Group (MCH). NR 35 TC 45 Z9 47 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD SEP PY 2010 VL 90 IS 9 BP 1285 EP 1294 DI 10.1038/labinvest.2010.110 PG 10 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 645NN UT WOS:000281467800002 PM 20548289 ER PT J AU Mashima, R Honda, K Yang, Y Morita, Y Inoue, A Arimura, S Nishina, H Ema, H Nakauchi, H Seed, B Oda, H Yamanashi, Y AF Mashima, Ryuichi Honda, Kazuho Yang, Yi Morita, Yohei Inoue, Akane Arimura, Sumimasa Nishina, Hiroshi Ema, Hideo Nakauchi, Hiromitsu Seed, Brian Oda, Hideaki Yamanashi, Yuji TI Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma SO LABORATORY INVESTIGATION LA English DT Article DE adaptor protein; Dok; macrophage; tumor ID NEGATIVE REGULATION; TUMOR SUPPRESSORS; DOCKING PROTEIN; FAMILY; LEUKEMIA; CELLS; IDENTIFICATION; HOMEOSTASIS; MACROPHAGE; P62(DOK) AB Histiocytic sarcoma (HS), a rare hematological malignancy, is an aggressive neoplasm that responds poorly to therapy. The molecular etiology and pathology of this disease remain unclear, hampering the development of an effective therapy, and there remains a need for more, and more realistic, animal models. HS cells typically show a histiocytic (ie, tissue macrophage-like) morphology and express histiocyte/macrophage markers in the absence of lymphocyte markers. In this study, we report that Dok-1(-/-) Dok-2(-/-) Dok-3(-/-) mice develop HS, but do not exhibit elevated incidence of other types of tumors. These mutant mice showed earlier mortality than wild-type (WT) or the other mutant mice, and this mortality was associated with HS. In total, 17 of 21 tumor-bearing Dok-1(-/-) Dok-2(-/-) Dok-3(-/-) mice necropsied at 25-66 weeks of age showed multiple organ spread, with osteolytic lesions and orthotopic invasion from the bone marrow to skeletal muscle. Tumors from the mice were transplantable. In addition, all Dok-1(-/-) Dok-2(-/-) Dok-3(-/-) mice, but only a small proportion of Dok-3(-/-) mice and no Dok-1(-/-) Dok-2(-/-) mice, exhibited abnormal accumulation of macrophages in the lung on necropsy at 8-12 weeks of age. Macrophages derived from Dok-1(-/-) Dok-2(-/-) Dok-3(-/-) mice displayed an exaggerated proliferative response to macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) compared with WT and mutant controls. Together, these findings indicate that Dok-1, Dok-2, and Dok-3 cooperatively suppress aggressive HS, and commend Dok-1(-/-) Dok-2(-/-) Dok-3(-/-) mice as a useful model for the study of this neoplasia. Laboratory Investigation (2010) 90, 1357-1364; doi:10.1038/labinvest.2010.121; published online 14 June 2010 C1 [Yamanashi, Yuji] Univ Tokyo, Div Genet, Inst Med Sci, Dept Canc Biol,Minato Ku, Tokyo 1088639, Japan. [Honda, Kazuho; Oda, Hideaki] Tokyo Womens Med Univ, Dept Pathol, Tokyo, Japan. [Yang, Yi] Novartis Inst Biomed Res, Cambridge, MA USA. [Morita, Yohei; Ema, Hideo; Nakauchi, Hiromitsu] Univ Tokyo, Lab Stem Cell Therapy, Inst Med Sci, Tokyo 1088639, Japan. [Nishina, Hiroshi] Tokyo Med & Dent Univ, Med Res Inst, Dept Dev & Regenerat Biol, Tokyo, Japan. [Seed, Brian] Massachusetts Gen Hosp, Dept Pediat, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Yamanashi, Y (reprint author), Univ Tokyo, Div Genet, Inst Med Sci, Dept Canc Biol,Minato Ku, 4-6-1 Shirokanedai, Tokyo 1088639, Japan. EM yyamanas@ims.u-tokyo.ac.jp RI Morita, Yohei/N-1260-2014 OI Morita, Yohei/0000-0003-4163-5080 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan FX We thank Drs RF Whittier and T Yasuda for critically reading the paper and/or for thoughtful discussions; and Ms N Ogawa for animal care. This work was supported by Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. NR 31 TC 20 Z9 22 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD SEP PY 2010 VL 90 IS 9 BP 1357 EP 1364 DI 10.1038/labinvest.2010.121 PG 8 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 645NN UT WOS:000281467800008 PM 20548287 ER PT J AU Sonpavde, G Sternberg, CN Rosenberg, JE Hahn, NM Galsky, MD Vogelzang, NJ AF Sonpavde, Guru Sternberg, Cora N. Rosenberg, Jonathan E. Hahn, Noah M. Galsky, Matthew D. Vogelzang, Nicholas J. TI Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium SO LANCET ONCOLOGY LA English DT Review ID PHASE-II TRIAL; GROWTH-FACTOR RECEPTOR; COOPERATIVE-ONCOLOGY-GROUP; ADVANCED BLADDER-CANCER; PLATINUM-CONTAINING REGIMEN; PROGNOSTIC-FACTORS; M-VAC; NEOADJUVANT CHEMOTHERAPY; KINASE INHIBITOR; TRACT CARCINOMA AB Front-line platinum-based combination chemotherapy leads to high response rates but suboptimum overall survival for patients with advanced transitional-cell carcinoma of the urothelium. Bevacizumab is being assessed in combination with platinum-based first-line chemotherapy in a large phase 3 trial. Current second-line systemic therapies, including taxanes, yield disappointing outcomes. Vinflunine, a novel vinca alkaloid, showed some activity and was recently approved in Europe based on results of the first completed phase 3 trial in the second-line setting. Better understanding of molecular biology and the emergence of novel biological agents now offer the possibility of improved outcomes. Neoadjuvant therapy before cystectomy and consolidation therapy with biological agents after first-line therapy provide a framework for the development of new drugs. We propose that trials to approve new drugs target two separate populations; multicentre non-randomised phase 2 trials should include patients with chemotherapy-resistant disease progressing within 6 months of first-line therapy, and randomised trials might be appropriate for chemotherapy-sensitive disease progressing more than 6 months after first-line therapy. A multidisciplinary approach is necessary to make therapeutic advances. This review discusses current second-line therapy and emerging drugs for advanced transitional-cell carcinoma. C1 [Sonpavde, Guru] Texas Oncol & Vet Affairs Med Ctr, Houston, TX USA. [Sonpavde, Guru] Baylor Coll Med, Houston, TX 77030 USA. [Sternberg, Cora N.] San Camillo Forlanini Hosp, Rome, Italy. [Rosenberg, Jonathan E.] Harvard Univ, Sch Med, Boston, MA USA. [Rosenberg, Jonathan E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hahn, Noah M.] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. [Galsky, Matthew D.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Vogelzang, Nicholas J.] Comprehens Canc Ctr Nevada, Las Vegas, NV USA. RP Sonpavde, G (reprint author), Baylor Coll Med, 501 Med Ctr Blvd, Webster, TX 77598 USA. EM guru.sonpavde@usoncology.com RI Mendez, Pedro /J-8955-2016 OI Mendez, Pedro /0000-0001-6713-7907 FU Eli Lilly; Bristol-Myers Squibb; Pfizer; Novartis; AstraZeneca; Cougar Biotech and honoraria; Sanofi-Aventis; Bayer; Novartis and Genentech; Tokai; Algeta; Arqule; Can Bas; Mannkind; Wilex FX GS has received research support from Eli Lilly, Bristol-Myers Squibb, Pfizer, Novartis, and AstraZeneca, and participated in a speakers bureau for Pfizer, Novartis, Wyeth, and Sanofi-Aventis. CNS has received research support from Cougar Biotech and honoraria from Sanofi-Aventis, Pfizer, and Bayer. JER has participated in a speakers bureau for Novartis, received research support from Novartis and Genentech, and been a consultant for Abbott, Genentech, and Novartis. NMH has participated in a speakers bureau for Sanofi-Aventis and received research support from Celgene. MDG has participated in a speakers bureau for Wyeth and Novartis. NJV has received research support from Tokai, Algeta, Arqule, AstraZeneca, Can Bas, Mannkind, Wilex, and Veridex; is on the speakers bureau for Genentech, Novartis, Sanofi-Aventis, Lilly, Wyeth, and Pfizer, and serves as a consultant to Allos, Ambit, Amgen, GlaxoSmithKline, Celgene, Cougar, Genome Pharmaceuticals Corporation, and ChemGene. NR 87 TC 70 Z9 70 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD SEP PY 2010 VL 11 IS 9 BP 861 EP 870 DI 10.1016/S1470-2045(10)70086-3 PG 10 WC Oncology SC Oncology GA 657KQ UT WOS:000282412000026 PM 20537950 ER PT J AU Shargorodsky, J Curhan, SG Eavey, R Curhan, GC AF Shargorodsky, Josef Curhan, Sharon G. Eavey, Roland Curhan, Gary C. TI A Prospective Study of Cardiovascular Risk Factors and Incident Hearing Loss in Men SO LARYNGOSCOPE LA English DT Article; Proceedings Paper CT Conference on Triological-Society/Combined Otolaryngology Spring Meeting CY APR 28-MAY 02, 2010 CL Las Vegas, NV SP Triol Soc DE Hearing loss; cardiovascular; smoking; cholesterol ID NUTRITION EXAMINATION SURVEY; HEALTH-PROFESSIONALS; DIABETES-MELLITUS; PHYSICAL-ACTIVITY; NATIONAL-HEALTH; UNITED-STATES; OLDER-ADULTS; IMPAIRMENT; PREVALENCE; DISEASE AB Objectives/Hypothesis: Hearing loss is the most common sensory disorder in the United States, affecting more than 36 million people. Cardiovascular risk factors have been associated with the risk of hearing loss in cross-sectional studies, but prospective data are currently lacking. Study Design: Prospective cohort study. Methods: We prospectively evaluated the association between diagnosis of hypertension, diabetes mellitus, hypercholesterolemia, smoking, or body mass index (BMI) and incident hearing loss. Participants were 26,917 men in the Health Professionals Follow-up Study, aged 40 to 74 years at baseline in 1986. Study participants completed questionnaires about lifestyle and medical history every 2 years. Information on self-reported professionally diagnosed hearing loss and year of diagnosis was obtained from the 2004 questionnaire, and cases were defined as hearing loss diagnosed between 1986 and 2004. Multivariable-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression models. Results: A total of 3,488 cases of hearing loss were identified. History of hypertension (HR 0.96; 95% confidence interval [CI], 0.88-1.03), diabetes mellitus (HR 0.92; 95% CI, 0.78-1.08), or obesity (HR 1.02; 95% CI, 0.90-1.15 for BMI >= 30 compared to normal range of 19-24.9) was not significantly associated with hearing-loss risk. Hypercholesterolemia (HR -1.10; 95% CI, 1.02-1.18) and past smoking history (HR 1.09; 95% CI, 1.01-1.17) were associated with a significantly increased risk of hearing loss after multivariate adjustment. Conclusions: A history of hypertension, diabetes mellitus, or obesity is not associated with increased risk of hearing loss; a history of past smoking or hypercholesterolemia has a small but statistically significant association with increased risk of hearing loss in adult males. C1 [Shargorodsky, Josef; Curhan, Sharon G.; Curhan, Gary C.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Shargorodsky, Josef] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Eavey, Roland] Vanderbilt Univ, Sch Med, Vanderbilt Bill Wilkerson Ctr Otolaryngol & Commu, Nashville, TN 37212 USA. [Curhan, Gary C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Curhan, Gary C.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. RP Shargorodsky, J (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM josef_shargorodsky@meei.harvard.edu FU NCI NIH HHS [P01 CA055075]; NHLBI NIH HHS [R01 HL035464] NR 29 TC 37 Z9 38 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD SEP PY 2010 VL 120 IS 9 BP 1887 EP 1891 DI 10.1002/lary.21039 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 645DH UT WOS:000281430600027 PM 20715090 ER PT J AU Izikson, L Farinelli, W Sakamoto, F Tannous, Z Anderson, RR AF Izikson, Leonid Farinelli, William Sakamoto, Fernanda Tannous, Zeina Anderson, R. Rox TI Safety and Effectiveness of Black Tattoo Clearance in a Pig Model After a Single Treatment With a Novel 758 nm 500 Picosecond Laser: A Pilot Study SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE tattoo; removal; laser; nanosecond; picosecond; pigment; porcine; carbon; iron oxide ID PLASMA; PIGMENTS; REMOVAL; PULSES AB Background: Optimal selective photothermolysis of a pigment particle requires pulse durations equal to or less than the particle's thermal relaxation time (t(1/2)). Since tattoo particles in skin range in diameter from 40 to 300 nm, picosecond pulses would approximate t(1/2) more closely and, therefore, might be more effective at tattoo particle fragmentation. Materials and Methods: India Ink (carbon) or iron oxide tattoos were placed on the back of a Yorkshire pig. Six weeks later, each tattoo was treated with either a 758 nm 500 picosecond laser (Cynosure), a 755 nm 30-50 nanoseconds laser, or left untreated. After 4 weeks, clinical responses were evaluated by three dermatologists based on pre- and post-treatment photographs; histopathologic findings were evaluated by a dermatopathologist; and electron microscopic findings were analyzed for treated and non-treated carbon tattoos. Results: After a single treatment, picosecond-domain pulses at 758 nm produced a significantly greater degree of carbon tattoo clearance compared to nanosecond-domain pulses at 755 nm. For iron oxide tattoos, both modalities produced minimal-to-poor clearance that was generally comparable. Neither modality resulted in scarring, textural changes, or hypopigmentation, and there was no histopathologic evidence of scarring. Electron micrographs revealed the presence of amorphous material (treated pigment) in picosecond and nanosecond laser-treated tattoos, consistent with effective targeting of India Ink pigment. Conclusions: The 758 nm 500 picosecond laser is more effective at carbon tattoo clearance after one session in a porcine model than the 30-50 nanosecond laser emitting at a similar wavelength. Both lasers cleared carbon tattoos more effectively than iron oxide tattoos. Both lasers have a comparable safety profile, and neither produced clinical or histopathologic scarring. Further studies in humans are necessary to evaluate whether repeated treatments with picosecond versus nanosecond domain modalities might yield superior tattoo pigment clearance with a comparable safety profile. Lasers Surg. Med. 42:640-646, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Izikson, Leonid; Farinelli, William; Sakamoto, Fernanda; Tannous, Zeina; Anderson, R. Rox] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Izikson, L (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, BHX 630,Bartlett Hall, Boston, MA 02114 USA. EM lizikson@partners.org FU Wellman Center for Photomedicine FX Contract grant sponsor: Cynosure to the Wellman Center for Photomedicine. NR 18 TC 27 Z9 30 U1 2 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD SEP PY 2010 VL 42 IS 7 BP 640 EP 646 DI 10.1002/lsm.20942 PG 7 WC Dermatology; Surgery SC Dermatology; Surgery GA 645US UT WOS:000281492300006 PM 20740618 ER PT J AU Phipps, AI Ichikawa, L Bowles, EJA Carney, PA Kerlikowske, K Miglioretti, DL Buist, DSM AF Phipps, Amanda I. Ichikawa, Laura Bowles, Erin J. A. Carney, Patricia A. Kerlikowske, Karla Miglioretti, Diana L. Buist, Diana S. M. TI Defining menopausal status in epidemiologic studies: A comparison of multiple approaches and their effects on breast cancer rates SO MATURITAS LA English DT Article DE Menopause; Breast cancer; Incidence; Concordance ID MENSTRUAL FACTORS; RISK; TRANSITION; WOMEN AB Objectives: Menopausal status is a common covariate in epidemiologic studies. Still, there are no standard definitions for menopausal status using observational data. This study assesses distinctions between menopausal status definitions using commonly collected epidemiologic data, and explores their impact on study outcomes using breast cancer rates as an example. Study design: Using survey data from 227,700 women aged 40-64 who received screening mammograms from the Breast Cancer Surveillance Consortium, we classified menopausal status under five different definitions: one complex definition combining multiple variables, two definitions using age as a proxy for menopausal status, one based only on menstrual period status, and one based on age and menstrual period status. Main outcome measures: We compared the distribution of menopausal status and menopausal status-specific breast cancer incidence and detection rates across definitions for menopausal status. Results: Overall, 36% and 29% of women were consistently classified as postmenopausal and premenopausal, respectively, across all definitions. Menopausal status-specific breast cancer incidence and detection rates were similar across definitions. Rates were unchanged when information regarding natural menopause, bilateral oophorectomy, hormone therapy, and timing of last menstrual period were sequentially added to definitions of postmenopausal status. Conclusions: Distinctions in menopausal status definitions contribute to notable differences in how women are classified, but translate to only slight differences in menopausal status-specific breast cancer rates. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Phipps, Amanda I.; Buist, Diana S. M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Ichikawa, Laura; Bowles, Erin J. A.; Miglioretti, Diana L.; Buist, Diana S. M.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Carney, Patricia A.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97239 USA. [Carney, Patricia A.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Med, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Epidemiol, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Biostat, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Miglioretti, Diana L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Phipps, AI (reprint author), Univ Washington, Dept Epidemiol, 1959 NE Pacific St,Hlth Sci Bldg F-262,Box 357236, Seattle, WA 98195 USA. EM aiphipps@u.washington.edu FU National Cancer Institute (NCI), NIH [T32 CA09168]; NCI [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040] FX Data collection for this work was supported by a NCI-funded Breast Cancer Surveillance Consortium co-operative agreement (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040). This publication was supported by grant number T32 CA09168 from the National Cancer Institute (NCI), NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI, NIH. NR 16 TC 27 Z9 27 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-5122 J9 MATURITAS JI Maturitas PD SEP PY 2010 VL 67 IS 1 BP 60 EP 66 DI 10.1016/j.maturitas.2010.04.015 PG 7 WC Geriatrics & Gerontology; Obstetrics & Gynecology SC Geriatrics & Gerontology; Obstetrics & Gynecology GA 651QU UT WOS:000281943000013 PM 20494530 ER PT J AU Schwarz, EB Longo, LS Zhao, XH Stone, RA Cunningham, F Good, CB AF Schwarz, Eleanor Bimla Longo, Lisa S. Zhao, Xinhua Stone, Roslyn A. Cunningham, Francesca Good, Chester B. TI Provision of Potentially Teratogenic Medications to Female Veterans of Childbearing Age SO MEDICAL CARE LA English DT Article DE women; preconception counseling; medication safety; contraception ID UNITED-STATES; BIRTH-DEFECTS; CARE; PREGNANCY; HEALTH; WOMEN; PRECONCEPTION; PRESCRIPTION AB Background: Certain medications increase the risk of birth defects whether used during pregnancy or immediately preconception. Objectives: To describe dispensing of potentially teratogenic medications (Food and Drug Administration classes D or X) to female Veterans treated by the Veterans Affairs (VA) Healthcare System, and assess whether documented provision of family planning services is more common when potentially teratogenic medications are prescribed. Research Design: We examined all 2,634,441 prescriptions filled in fiscal year 2007 or 2008 by 78,232 female Veterans, aged 18 to 45, who made >= 2 visits to VA clinics within the year prior to medication dispensing from VA pharmacies. Measures: Medications dispensed, contraceptive counseling, and pregnancy testing. Results: Prescriptions for potentially teratogenic medications were filled by 48.8% of female Veterans who received medications from a VA pharmacy. Women who filled prescriptions for potentially teratogenic medications were only slightly more likely to have documented family planning services (eg, contraception, contraceptive counseling, or pregnancy testing) than women who filled class C, but not class D or X, prescriptions (55.7% vs. 51.8%). Women filling only class A or B prescriptions were least likely to have documented family planning services (35.9%). Among women dispensed potentially teratogenic medications, family planning services were significantly more likely to be documented for women who were >= 25 years (odds ratio [OR], 2.82; 95% confidence interval [CI], 2.57-3.11), unmarried (OR, 1.30; 95% CI, 1.23-1.35), non-White (OR, 1.17; 95% CI, 1.09-1.26), seen at a women's clinic (OR, 1.96; 95% CI, 1.88-2.05), received a retinoid medication (OR, 7.72; 95% CI, 3.02- 19.7), or had serious mental illness (OR, 1.26; 95% CI, 1.18-1.34). Conclusions: Medications that may cause birth defects if used during pregnancy are dispensed frequently to female Veterans by VA pharmacies without documented receipt of contraceptive counseling or pregnancy testing. C1 [Schwarz, Eleanor Bimla] Univ Pittsburgh, Ctr Res Hlth Care, Dept Obstet, Pittsburgh, PA 15213 USA. [Schwarz, Eleanor Bimla] Univ Pittsburgh, Dept Gynecol, Pittsburgh, PA 15213 USA. [Schwarz, Eleanor Bimla] Univ Pittsburgh, Dept Reprod Sci, Pittsburgh, PA 15213 USA. [Schwarz, Eleanor Bimla; Stone, Roslyn A.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Schwarz, Eleanor Bimla; Good, Chester B.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. [Longo, Lisa S.] Vet Affairs Pharm Benefits Management Serv, Pittsburgh, PA USA. [Zhao, Xinhua; Stone, Roslyn A.; Good, Chester B.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Cunningham, Francesca] Vet Affairs Pharm Benefits Management Serv, Vet Affairs Ctr Medicat Safety, Hines, IL USA. RP Schwarz, EB (reprint author), Univ Pittsburgh, Ctr Res Hlth Care, Dept Obstet, 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM schwarzeb@upmc.edu OI Schwarz, Eleanor Bimla/0000-0002-9912-8236 FU National Institute of Child Health and Development [K23HD051585]; Department of Veterans Affairs (VA Pittsburgh Healthcare System, Pittsburgh, PA; VA Hospital, Hines, IL FX Supported by a career development award from the National Institute of Child Health and Development, K23HD051585. Also supported in part by the Department of Veterans Affairs (VA Pittsburgh Healthcare System, Pittsburgh, PA and Edward Hines, Jr. VA Hospital, Hines, IL). NR 22 TC 17 Z9 17 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD SEP PY 2010 VL 48 IS 9 BP 834 EP 842 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 641JZ UT WOS:000281122800011 PM 20706159 ER PT J AU Fagerlin, A Sepucha, KR Couper, MP Levin, CA Singer, E Zikmund-Fisher, BJ AF Fagerlin, Angela Sepucha, Karen R. Couper, Mick P. Levin, Carrie A. Singer, Eleanor Zikmund-Fisher, Brian J. TI Patients' Knowledge about 9 Common Health Conditions: The DECISIONS Survey SO MEDICAL DECISION MAKING LA English DT Article DE informed decision making; patient education; knowledge ID LUMBAR SPINAL STENOSIS; LOW-BACK-PAIN; RANDOMIZED CONTROLLED-TRIAL; INFORMED DECISION; NONOPERATIVE TREATMENT; CATARACT-SURGERY; DISK HERNIATION; SCREENING MAMMOGRAPHY; PRIMARY PREVENTION; AMERICAN-COLLEGE AB Background. To make informed decisions, patients must have adequate knowledge of key decision-relevant facts. Objective. To determine adults' knowledge about information relevant to common types of medication, screening, or surgery decisions they recently made. Setting. National sample of US adults identified by random-digit dialing. Design. Cross-sectional survey conducted between November 2006 and May 2007. Participants. A total of 2575 English-speaking adults aged 40 y or older who reported having discussed the following medical decisions with a health care provider within the previous 2 y: prescription medications for hypertension, hypercholesterolemia, or depression; screening tests for colorectal, breast, or prostate cancer; or surgeries for knee/hip replacement, cataracts, or lower back pain. Measurements. Participants answered knowledge questions and rated the importance of their health care provider, family/friends, and the media as sources of information. Results. Accuracy rates varied widely across questions and decision contexts. For example, patients considering cataract surgery were more likely to correctly estimate recovery time than those patients considering lower back pain or knee/hip replacement (78% v. 29% and 39%, P < 0.001). Similarly, participants were more knowledgeable of facts about colorectal cancer screening than those who were asked about breast or prostate cancer. Finally, respondents were consistently more knowledgeable on comparable questions about blood pressure medication than cholesterol medication or antidepressants. The impact of demographic characteristics and sources of information also varied substantially. For example, blacks had lower knowledge than whites about cancer screening decisions (odds ratio [OR] = 0.57; 95% confidence interval [CI] = 0.43, 0.75; P = 0.001) and medication (OR = 0.77; 95% CI = 0.60, 0.97; P = 0.03) even after we controlled for other demographic factors. The same was not true for surgical decisions. Limitations. The questions did not measure all knowledge relevant to informed decision making, were subject to recall biases, and may have assessed numeracy more than knowledge. Conclusions. Patient knowledge of key facts relevant to recently made medical decisions is often poor and varies systematically by decision type and patient characteristics. Improving patient knowledge about risks, benefits, and characteristics of medical procedures is essential to support informed decision making. C1 [Fagerlin, Angela; Couper, Mick P.; Zikmund-Fisher, Brian J.] Ctr Behav & Decis Sci Med, Ann Arbor, MI 48109 USA. [Fagerlin, Angela; Zikmund-Fisher, Brian J.] VA Ann Arbor Healthcare Syst, VA Hlth Serv Res & Dev Ctr Excellence, Ann Arbor, MI USA. [Fagerlin, Angela; Zikmund-Fisher, Brian J.] Univ Michigan, Div Gen Internal Med, Ann Arbor, MI 48109 USA. [Sepucha, Karen R.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Sepucha, Karen R.] Massachusetts Gen Hosp, Hlth Decis Res Unit, Boston, MA 02114 USA. [Couper, Mick P.; Singer, Eleanor] Univ Michigan, Survey Res Ctr, Inst Social Res, Ann Arbor, MI 48109 USA. [Levin, Carrie A.] Fdn Informed Med Decis Making, Boston, MA USA. RP Fagerlin, A (reprint author), Ctr Behav & Decis Sci Med, 300 N Ingalls Bldg,Rm 7C27, Ann Arbor, MI 48109 USA. EM fagerlin@med.umich.edu RI Zikmund-Fisher, Brian/A-7677-2009; OI Zikmund-Fisher, Brian/0000-0002-1637-4176 FU American Cancer Society [MRSG-06-130-01-CPPB]; Foundation for Informed Medical Decision Making (FIMDM) FX Dr. Zikmund-Fisher supported by an MRSG career development award from the American Cancer Society (MRSG-06-130-01-CPPB). The Foundation for Informed Medical Decision Making (FIMDM) provided the funding for this research. Although the research involved substantial collaboration between the University of Michigan (UM) research team and FIMDM representatives, the research grant was awarded in compliance with UM's policies, which bar funder interference in scholarly work. Design of the survey and control of the research data rested with the UM investigator team, and Dr. Fagerlin had final authority regarding the content of the article. During this research, Dr. Levin was director of research at FIMDM. She provided input on the research design, feedback on analyses, and constructive comments on manuscript drafts consistent with her listed coauthorship role. Portions of this research were presented at the annual meeting of the Society for Medical Decision Making, Philadelphia, Pennsylvania, 20 October 2008. Dr. Zikmund-Fisher is now at the Department of Health Behavior and Health Education, University of Michigan. Revision accepted for publication 13 June 2010. NR 66 TC 27 Z9 28 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD SEP-OCT PY 2010 VL 30 SU 5 BP 35S EP 52S DI 10.1177/0272989X10378700 PG 18 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 656JG UT WOS:000282326400007 PM 20881153 ER PT J AU Hoffman, RM Lewis, CL Pignone, MP Couper, MP Barry, MJ Elmore, JG Levin, CA Van Hoewyk, J Zikmund-Fisher, BJ AF Hoffman, Richard M. Lewis, Carmen L. Pignone, Michael P. Couper, Mick P. Barry, Michael J. Elmore, Joann G. Levin, Carrie A. Van Hoewyk, John Zikmund-Fisher, Brian J. TI Decision-Making Processes for Breast, Colorectal, and Prostate Cancer Screening: The DECISIONS Survey SO MEDICAL DECISION MAKING LA English DT Article DE prostatic neoplasms; breast neoplasms; colorectal neoplasms; early detection of cancer; decision making ID HEALTH INTERVIEW SURVEY; PHYSICIAN-PATIENT DISCUSSIONS; UNITED-STATES; PRIMARY-CARE; MAMMOGRAPHY; PREFERENCES; AIDS; TRIAL AB Background. Patients should understand the risks and benefits of cancer screening in order to make informed screening decisions. Objectives. To evaluate the extent of informed decision making in patient-provider discussions for colorectal (CRC), breast (BrCa), and prostate (PCa) cancer screening. Setting. National sample of US adults identified by random-digit dialing. Design. Cross-sectional survey conducted between November 2006 and May 2007. Participants. English-speaking US adults aged 50 y and older who had discussed cancer screening with a health care provider within the previous 2 y. Measurements. Cancer screening survey modules that asked about demographic characteristics, cancer knowledge, the importance of various sources of information, and self-reported cancer screening decision-making processes. Results. Overall, 1082 participants completed 1 or more of the 3 cancer modules. Although participants generally considered themselves well informed about screening tests, half or more could not correctly answer even 1 open-ended knowledge question for any given module. Participants consistently overestimated risks for being diagnosed with and dying from each cancer and overestimated the positive predictive values of prostate-specific antigen tests and mammography. Providers were the most highly rated information source, usually initiated screening discussions (64%-84%), and often recommended screening (73%-90%). However, participants reported that providers elicited their screening preferences in only 31% (CRC women) to 57% (PCa) of discussions. Although more than 90% of the discussions addressed the pros of screening, only 19% (BrCa) to 30% (PCa) addressed the cons of screening. Limitations. Recall bias is possible because screening process reports were not independently validated. Conclusions. Cancer screening decisions reported by patients who discussed screening with their health care providers consistently failed to meet criteria for being informed. Given the high ratings for provider information and frequent recommendations for screening, providers have important opportunities to ensure that informed decision making occurs for cancer screening decisions. C1 [Hoffman, Richard M.] Univ New Mexico, Sch Med, Med Serv, New Mexico VA Hlth Care Syst, Albuquerque, NM 87131 USA. [Hoffman, Richard M.] Univ New Mexico, Sch Med, Dept Med, Albuquerque, NM 87131 USA. [Lewis, Carmen L.; Pignone, Michael P.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Couper, Mick P.; Van Hoewyk, John; Zikmund-Fisher, Brian J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Barry, Michael J.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Elmore, Joann G.] Univ Washington, Dept Med, Seattle, WA USA. [Levin, Carrie A.] Fdn Informed Med Decis Making, Boston, MA USA. [Zikmund-Fisher, Brian J.] Ann Arbor VA Hlth Care Syst, Ann Arbor, MI USA. RP Hoffman, RM (reprint author), 1501 San Pedro Dr SE,Mailstop 111, Albuquerque, NM 87108 USA. EM rhoffman@unm.edu RI Zikmund-Fisher, Brian/A-7677-2009; OI Pignone, Michael/0000-0002-6657-7342; Zikmund-Fisher, Brian/0000-0002-1637-4176 FU New Mexico VA Health Care System, Albuquerque, NM; National Cancer Institute [5K07CA104128, K05CA129166]; American Cancer Society [MRSG-06-130-01-CPPB] FX Dr. Hoffman is supported by the New Mexico VA Health Care System, Albuquerque, NM. Dr. Lewis is supported by a K07 Mentored Career Development Award (5K07CA104128) from the National Cancer Institute. Dr. Pignone is supported by a National Cancer Institute Established Investigator Award K05CA129166. Dr. Elmore is supported by 1K05 CA104699 from the National Cancer Institute. Dr. Zikmund-Fisher is supported by a grant from the American Cancer Society (MRSG-06-130-01-CPPB). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Foundation for Informed Medical Decision Making or the Department of Veterans Affairs. Revision accepted for publication 21 January 2010. NR 41 TC 56 Z9 56 U1 0 U2 9 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD SEP-OCT PY 2010 VL 30 SU 5 BP 53S EP 64S DI 10.1177/0272989X10378701 PG 12 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 656JG UT WOS:000282326400008 PM 20881154 ER PT J AU Sepucha, KR Fagerlin, A Couper, MP Levin, CA Singer, E Zikmund-Fisher, BJ AF Sepucha, Karen R. Fagerlin, Angela Couper, Mick P. Levin, Carrie A. Singer, Eleanor Zikmund-Fisher, Brian J. TI How Does Feeling Informed Relate to Being Informed? The DECISIONS Survey SO MEDICAL DECISION MAKING LA English DT Article DE shared decision making; provider decision making; patient decision making; decision aids; decision analysis; performance measures; pay-for-performance; physician-patient communication ID KNOWLEDGE; PROGRAM AB Background. An important part of delivering high-quality, patient-centered care is making sure patients are informed about decisions regarding their health care. The objective was to examine whether patients' perceptions about how informed they were about common medical decisions are related to their ability to answer various knowledge questions. Methods. A cross-sectional survey was conducted November 2006 to May 2007 of a national sample of US adults identified by random-digit dialing. Participants were 2575 English-speaking US adults aged 40 and older who had made 1 of 9 medication, cancer screening, or elective surgery decisions within the previous 2 years. Participants rated how informed they felt on a scale of 0 (not at all informed) to 10 (extremely well-informed), answered decision-specific knowledge questions, and completed standard demographic questions. Results. Overall, 36% felt extremely well informed (10), 30% felt well informed (8-9), and 33% felt not at all to somewhat informed (0-7). Multivariate logistic regression analyses showed no overall relationship between knowledge scores and perceptions of being extremely well informed (odds ratio [OR] = 0.94, 95% confidence interval [CI] 0.63-1.42, P = 0.78). Three patterns emerged for decision types: a negative relationship for cancer screening decisions (OR = 0.58, CI 0.33-1.02, P = 0.06), no relationship for medication decisions (OR = 0.99, CI 0.54-1.83, P = 0.98), and a positive relationship for surgery decisions (OR = 3.07, 95% CI 0.90-10.54, P = 0.07). Trust in the doctor was associated with feeling extremely well-informed for all 3 types of decisions. Lower education and lower income were also associated with feeling extremely well informed for medication and screening decisions. Retrospective survey data are subject to recall bias, and participants may have had different perspectives or more factual knowledge closer to the time of the decision. Conclusions. Patients facing common medical decisions are not able to accurately assess how well informed they are. Clinicians need to be proactive in providing adequate information to patients and testing patients' understanding to ensure informed decisions. C1 [Sepucha, Karen R.] Massachusetts Gen Hosp, Hlth Decis Res Unit, Boston, MA 02114 USA. [Sepucha, Karen R.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Fagerlin, Angela; Zikmund-Fisher, Brian J.] VA Ann Arbor Healthcare Syst, VA Hlth Serv Res & Dev Ctr Excellence, Ann Arbor, MI USA. [Fagerlin, Angela; Zikmund-Fisher, Brian J.] Univ Michigan, Div Gen Internal Med, Ann Arbor, MI 48109 USA. [Fagerlin, Angela; Couper, Mick P.; Zikmund-Fisher, Brian J.] Ctr Behav & Decis Sci Med, Ann Arbor, MI USA. [Couper, Mick P.; Singer, Eleanor] Univ Michigan, Inst Social Res, Survey Res Ctr, Ann Arbor, MI USA. [Levin, Carrie A.] Fdn Informed Med Decis Making, Boston, MA USA. RP Sepucha, KR (reprint author), Massachusetts Gen Hosp, Hlth Decis Res Unit, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM ksepucha@partners.org RI Zikmund-Fisher, Brian/A-7677-2009; OI Zikmund-Fisher, Brian/0000-0002-1637-4176 NR 16 TC 33 Z9 33 U1 1 U2 13 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD SEP-OCT PY 2010 VL 30 SU 5 BP 77S EP 84S DI 10.1177/0272989X10379647 PG 8 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 656JG UT WOS:000282326400010 PM 20881156 ER PT J AU Hahn, JO Reisner, AT Asada, HH AF Hahn, Jin-Oh Reisner, Andrew T. Asada, H. Harry TI Estimation of pulse transit time using two diametric blood pressure waveform measurements SO MEDICAL ENGINEERING & PHYSICS LA English DT Article DE Pulse transit time; Blind system identification; Blood pressure; Cardiovascular system ID ARTERIAL STIFFNESS; VELOCITY; MODEL; ECG AB This paper presents a novel method to estimate the aortic-to-peripheral pulse transit time (PTT) using the blood pressure waveforms measured at two diametric peripheral locations, for instance, one on an upper extremity and the other on a lower extremity. The method is based on a computational relationship between the two peripheral blood pressures, which is derived by first relating each peripheral blood pressure to a common central aortic blood pressure. The parameters of the computational relationship for an individual subject can be identified by fitting them to two peripheral blood pressure waveform measurements, thereby characterizing the cardiovascular dynamics, from which absolute changes in the PTT between the central aorta and each peripheral measurement site can be determined. The strength of the method is that it does not require any a priori knowledge of the peripheral measurement locations nor of the physiologic condition of the cardiovascular system. Experimental results are provided from five healthy swine subjects whose actual PTT experimentally varied from 44.9 ms to 163.0 ms (76.7 ms mean +/- 26.4 ms SD). Compared to the reference PTT measurement, the novel method proposed in this paper estimated PTT within 3.7 ms mean +/- 4.2 ms SD after initial calibration. (C) 2010 IPEM. Published by Elsevier Ltd. All rights reserved. C1 [Hahn, Jin-Oh] Univ British Columbia, Dept Elect & Comp Engn, Vancouver, BC V6T 1Z4, Canada. [Reisner, Andrew T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Asada, H. Harry] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Hahn, JO (reprint author), Univ British Columbia, Dept Elect & Comp Engn, 373-2366 Main Mall, Vancouver, BC V6T 1Z4, Canada. EM jinoh.hahn@alum.mit.edu; areisner@partners.org; asada@mit.edu FU Sharp Corporation FX This research was supported in part by the Sharp Corporation. NR 25 TC 17 Z9 17 U1 1 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1350-4533 J9 MED ENG PHYS JI Med. Eng. Phys. PD SEP PY 2010 VL 32 IS 7 BP 753 EP 759 DI 10.1016/j.medengphy.2010.04.017 PG 7 WC Engineering, Biomedical SC Engineering GA 642TC UT WOS:000281239800009 PM 20537933 ER PT J AU Sun, HY Alexander, BD Lortholary, O Dromer, F Forrest, GN Lyon, GM Somani, J Gupta, KL Del Busto, R Pruett, TL Sifri, CD Limaye, AP John, GT Klintmalm, GB Pursell, K Stosor, V Morris, MI Dowdy, LA Munoz, P Kalil, AC Garcia-Diaz, J Orloff, SL House, AA Houston, SH Wray, D Huprikar, S Johnson, LB Humar, A Razonable, RR Fisher, RA Husain, S Wagener, MM Singh, N AF Sun, Hsin-Yun Alexander, Barbara D. Lortholary, Olivier Dromer, Francoise Forrest, Graeme N. Lyon, G. Marshall Somani, Jyoti Gupta, Krishan L. Del Busto, Ramon Pruett, Timothy L. Sifri, Costi D. Limaye, Ajit P. John, George T. Klintmalm, Goran B. Pursell, Kenneth Stosor, Valentina Morris, Michele I. Dowdy, Lorraine A. Munoz, Patricia Kalil, Andre C. Garcia-Diaz, Julia Orloff, Susan L. House, Andrew A. Houston, Sally H. Wray, Dannah Huprikar, Shirish Johnson, Leonard B. Humar, Atul Razonable, Raymund R. Fisher, Robert A. Husain, Shahid Wagener, Marilyn M. Singh, Nina CA CRYPTOCOCCAL COLLABORATIVE TI Cutaneous cryptococcosis in solid organ transplant recipients SO MEDICAL MYCOLOGY LA English DT Article DE Cryptococcus; transplants; fungal infections ID IMMUNE RECONSTITUTION SYNDROME; RENAL-ALLOGRAFT RECIPIENT; HEMATOPOIETIC STEM-CELL; NEOFORMANS INFECTION; CLINICAL-RELEVANCE; CELLULITIS; TUBERCULOSIS; THERAPY; MYCOSES AB Clinical manifestations, treatment, and outcomes of cutaneous cryptococcosis in solid organ transplant (SOT) recipients are not fully defined. In a prospective cohort comprising 146 SOT recipients with cryptococcosis, we describe the presentation, antifungal therapy, and outcome of cutaneous cryptococcal disease. Cutaneous cryptococcosis was documented in 26/146 (17.8%) of the patients and manifested as nodular/mass (34.8%), maculopapule (30.4%), ulcer/pustule/abscess (30.4%), and cellulitis (30.4%) with 65.2% of the skin lesions occurred in the lower extremities. Localized disease developed in 30.8% (8/26), and disseminated disease in 69.2% (18/26) with involvement of the central nervous system (88.9%, 16/18), lung (33.3%, 6/18), or fungemia (55.6%, 10/18). Fluconazole (37.5%) was employed most often for localized and lipid formulations of amphotericin B (61.1%) for disseminated disease. Overall mortality at 90 days was 15.4% (4/26) with 16.7% in disseminated and 12.5% in localized disease (P = 0.78). SOT recipients who died were more likely to have renal failure (75.0% vs. 13.6%, P = 0.028), longer time to onset of disease after transplantation (87.5 vs. 22.6 months, P = 0.023), and abnormal mental status (75% vs. 13.6%, P = 0.028) than those who survived. Cutaneous cryptococcosis represents disseminated disease in most SOT recipients and preferentially involves the extremities. Outcomes with appropriate management were comparable between SOT recipients with localized and disseminated cryptococcosis. C1 [Singh, Nina] VA Pittsburgh Healthcare Syst, Infect Dis Sect, Pittsburgh, PA 15240 USA. [Sun, Hsin-Yun] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Sun, Hsin-Yun] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. [Alexander, Barbara D.] Duke Univ, Med Ctr, Durham, NC USA. [Lortholary, Olivier; Dromer, Francoise] Inst Pasteur, Paris, France. [Lortholary, Olivier] Hop Necker Enfants Malad, Fac Med Paris Descartes, Paris, France. [Forrest, Graeme N.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Lyon, G. Marshall; Somani, Jyoti] Emory Univ, Atlanta, GA 30322 USA. [Gupta, Krishan L.] Postgrad Inst Med Educ & Res, Chandigarh 160012, India. [Del Busto, Ramon] Henry Ford Hosp, Detroit, MI 48202 USA. [Pruett, Timothy L.; Sifri, Costi D.] Univ Virginia, Charlottesville, VA USA. [Limaye, Ajit P.] Univ Washington, Seattle, WA 98195 USA. [John, George T.] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Klintmalm, Goran B.] Baylor Univ, Med Ctr, Dallas, TX USA. [Pursell, Kenneth] Univ Chicago, Chicago, IL 60637 USA. [Stosor, Valentina] Northwestern Univ, Chicago, IL 60611 USA. [Morris, Michele I.; Dowdy, Lorraine A.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Munoz, Patricia] Hosp Gen Univ Gregorio Maranon, Madrid, Spain. [Munoz, Patricia] CIBER Enfermedades Respiratorias CIBERES, Madrid, Spain. [Kalil, Andre C.] Univ Nebraska, Omaha, NE 68182 USA. [Garcia-Diaz, Julia] Ochsner Clin & Alton Ochsner Med Fdn, Orleans, LA USA. [Orloff, Susan L.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [House, Andrew A.] Univ Western Ontario, London, ON, Canada. [Houston, Sally H.] Tampa Gen Hosp, Tampa, FL 33606 USA. [Wray, Dannah] Med Univ S Carolina, Charleston, SC 29425 USA. [Huprikar, Shirish] Mt Sinai Med Ctr, New York, NY 10029 USA. [Johnson, Leonard B.] St Johns Hosp, Detroit, MI USA. [Humar, Atul] Toronto Gen Hosp, Univ Hlth Network, Toronto, ON, Canada. [Razonable, Raymund R.] Mayo Clin, Rochester, MN USA. [Fisher, Robert A.] Virginia Commonwealth Univ, Richmond, VA USA. [Husain, Shahid; Wagener, Marilyn M.; Singh, Nina] Univ Pittsburgh, Pittsburgh, PA USA. RP Singh, N (reprint author), VA Pittsburgh Healthcare Syst, Infect Dis Sect, Univ Dr C, Pittsburgh, PA 15240 USA. EM nis5@pitt.edu RI khan, raja/B-5726-2012; OI Munoz Garcia, Patricia Carmen/0000-0001-5706-5583; SUN, HSIN-YUN/0000-0003-0074-7721 FU National Institutes of Health; National Institute of Allergy and Infectious Diseases [R01 AI 054719-01] FX National Institutes of Health, National Institute of Allergy and Infectious Diseases (R01 AI 054719-01 to Nina Singh). NR 26 TC 17 Z9 17 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD SEP PY 2010 VL 48 IS 6 BP 785 EP 791 DI 10.3109/13693780903496617 PG 7 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 654WA UT WOS:000282200500001 PM 20100136 ER PT J AU Kirkpatrick, WR Zimmerman, JD Haikal, FP Broker, MJ Brockway, E Fothergill, AW McCarthy, DI Patterson, TF Redding, SW AF Kirkpatrick, William R. Zimmerman, Joseph D. Haikal, Fadi P. Broker, Michael J. Brockway, Erin Fothergill, Annette W. McCarthy, Dora I. Patterson, Thomas F. Redding, Spencer W. TI Screening for drug-resistant Candida yeasts with chromogenic agar SO MEDICAL MYCOLOGY LA English DT Article DE Candida; resistance; echinocandin; azole ID PATIENTS RECEIVING RADIATION; DISK DIFFUSION METHODS; IN-VITRO ACTIVITIES; ANTIFUNGAL SUSCEPTIBILITY; ORAL COLONIZATION; SEPSIS SECONDARY; AMPHOTERICIN-B; NECK-CANCER; CASPOFUNGIN; GLABRATA AB We examined the utility of agar dilution to screen yeasts for reduced susceptibility to several newer antifungal drugs including echinocandins and azoles. We compared agar dilution susceptibility screening with the Clinical and Laboratory Standards Institute (CLSI) method for Candida isolates. We added echinocandins and azoles to CHROMagar Candida medium prior to its solidification. Assessment of resistance was based on growth characteristics, wherein decreased colony size in the presence of antifungal drugs was used as an indicator of susceptibility. Clinical Candida isolates of C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. guilliermondii, C. lusitaniae, C. rugosa and C. dubliniensis were screened for drug susceptibility. Overall, antifungal susceptibility of the yeasts to anidulafungin, caspofungin, micafungin, posaconazole and voriconazole, determined using CHROMagar agar dilution, were shown to be 96, 80, 94, 90 and 97% as accurate, respectively, as those determined by the CLSI method, i.e., within one tube dilution of CLSI MICs. Categorical errors by percentage had a broader range. Major errors noted with anidulafungin, caspofungin and micafungin were 3, 6 and 0%, respectively, while very major errors were 15, 55 and 38%, respectively. Major errors with posaconazole and voriconazole were 12 and 0%, respectively, while very major errors were 0 and 22%, respectively, compared to CLSI standards. Most of the assessment errors were found with C. glabrata and C. parapsilosis. Agar dilution screening for drug susceptibility with the current panel of antifungal drugs is rapid, accurate and effective. However, the determination of resistance or non-susceptibility in yeasts may be more problematic, and may be species dependent. C1 [Zimmerman, Joseph D.; Haikal, Fadi P.; Broker, Michael J.; Redding, Spencer W.] Univ Texas Hlth Sci Ctr San Antonio, Dept Dent Diagnost Sci, San Antonio, TX 78229 USA. [Kirkpatrick, William R.; Brockway, Erin; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Fothergill, Annette W.; McCarthy, Dora I.; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Redding, Spencer W.] S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Redding, SW (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Dent Diagnost Sci, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM redding@uthscsa.edu FU National Institute of Dental and Craniofacial Research; National Institutes of Health NIH [DE14318, NIH NIDCR 5R01-DE018096] FX This project was funded in part by federal funds from the National Institute of Dental and Craniofacial Research, National Institutes of Health, under Contract No. NIH NIDCR 5R01-DE018096 and NIH Grant #DE14318 for the COSTAR Program. NR 21 TC 2 Z9 2 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD SEP PY 2010 VL 48 IS 6 BP 807 EP 816 DI 10.3109/13693780903514542 PG 10 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 654WA UT WOS:000282200500004 PM 20109095 ER PT J AU Palacio-Bedoya, F Cadena, JA Thompson, GR Sutton, DA Owens, AD Patterson, TF AF Palacio-Bedoya, Federico Cadena, Jose A. Thompson, George R., III Sutton, Deanna A. Owens, Aaron D. Patterson, Thomas F. TI A noninvasive renal fungus ball caused by Rhizopus - a previously unreported manifestation of zygomycosis SO MEDICAL MYCOLOGY LA English DT Article DE zygomycetes; Rhizopus; fungus ball; renal; mucormycosis ID SALVAGE THERAPY; POSACONAZOLE; ASPERGILLUS; MANAGEMENT; CANDIDIASIS; DISEASE AB We describe the first reported case of renal zygomycosis presenting as an isolated fungus ball (bezoar) without renal parenchymal invasion. Since all previous descriptions of renal involvement have discussed tissue invasion, our case is unique in that the infection was confined solely in the renal pelvis and extended to the distal ureter without signs of contiguous renal infection. Our patient later developed renal insufficiency while receiving amphotericin B Lipid Complex (ABLC). The therapy was changed to posaconazole with subsequent clinical, mycologic, and radiographic improvement and the patient has remained free of recurrence 5 years after diagnosis. C1 [Thompson, George R., III] Univ Calif Davis, Dept Internal Med, Div Infect Dis, Sacramento, CA 95817 USA. [Palacio-Bedoya, Federico; Owens, Aaron D.] Univ Texas Hlth Sci Ctr San Antonio, Dept Internal Med, Div Hosp Med, San Antonio, TX USA. [Palacio-Bedoya, Federico; Cadena, Jose A.; Thompson, George R., III; Owens, Aaron D.; Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Internal Med, Div Infect Dis, San Antonio, TX USA. [Sutton, Deanna A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol, Fungus Testing Lab, San Antonio, TX USA. [Palacio-Bedoya, Federico; Cadena, Jose A.; Thompson, George R., III; Patterson, Thomas F.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Thompson, GR (reprint author), Univ Calif Davis, Dept Internal Med, Div Infect Dis, 4150 V St, Sacramento, CA 95817 USA. EM george.thompson@ucdmc.ucdavis.edu FU Basilea; Merck; Pfizer FX G.R.T. has served as a consultant for Basilea. T.F.P. has received research support from Basilea, Merck, Pfizer, and Schering-Plough, has received speaking fees from Merck and Pfizer, and as a consultant for Basilea, Merck, Nektar, Pfizer, and Toyama. NR 20 TC 2 Z9 2 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1369-3786 EI 1460-2709 J9 MED MYCOL JI Med. Mycol. PD SEP PY 2010 VL 48 IS 6 BP 866 EP 869 DI 10.3109/13693781003694796 PG 4 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 654WA UT WOS:000282200500014 PM 20353310 ER PT J AU Chen, W Craft, D Madden, TM Zhang, K Kooy, HM Herman, GT AF Chen, Wei Craft, David Madden, Thomas M. Zhang, Kewu Kooy, Hanne M. Herman, Gabor T. TI A fast optimization algorithm for multicriteria intensity modulated proton therapy planning SO MEDICAL PHYSICS LA English DT Article DE projection method; multi-criteria; optimization; numerical evaluation ID FLUENCE MAP OPTIMIZATION; RADIATION-THERAPY; ITERATIVE ALGORITHMS; FEASIBILITY PROBLEM; RADIOTHERAPY; IMRT; CONSTRAINTS; PROJECTIONS; MODELS AB Purpose: To describe a fast projection algorithm for optimizing intensity modulated proton therapy (IMPT) plans and to describe and demonstrate the use of this algorithm in multicriteria IMPT planning. Methods: The authors develop a projection-based solver for a class of convex optimization problems and apply it to IMPT treatment planning. The speed of the solver permits its use in multicriteria optimization, where several optimizations are performed which span the space of possible treatment plans. The authors describe a plan database generation procedure which is customized to the requirements of the solver. The optimality precision of the solver can be specified by the user. Results: The authors apply the algorithm to three clinical cases: A pancreas case, an esophagus case, and a tumor along the rib cage case. Detailed analysis of the pancreas case shows that the algorithm is orders of magnitude faster than industry-standard general purpose algorithms (MOSEK's interior point optimizer, primal simplex optimizer, and dual simplex optimizer). Additionally, the projection solver has almost no memory overhead. Conclusions: The speed and guaranteed accuracy of the algorithm make it suitable for use in multicriteria treatment planning, which requires the computation of several diverse treatment plans. Additionally, given the low memory overhead of the algorithm, the method can be extended to include multiple geometric instances and proton range possibilities, for robust optimization. (C) 2010 American Association of Physicists in Medicine. [DOI: 10.1118/1.3481566] C1 [Chen, Wei; Herman, Gabor T.] CUNY, Grad Ctr, Dept Comp Sci, New York, NY 10016 USA. [Craft, David; Madden, Thomas M.; Zhang, Kewu; Kooy, Hanne M.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Craft, David; Madden, Thomas M.; Zhang, Kewu; Kooy, Hanne M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Chen, W (reprint author), CUNY, Grad Ctr, Dept Comp Sci, New York, NY 10016 USA. EM dcraft@partners.org FU NCI [1 R01 CA103904-01A1]; National Heart, Lung And Blood Institute [R01HL070472] FX The authors thank Thomas Bortfeld and Yair Censor for their support of this work. Also, the authors are grateful for the insightful suggestions of the anonymous referees. This work was supported in part by NCI Grant No. 1 R01 CA103904-01A1, Multicriteria IMRT Optimization and Award No. R01HL070472 from the National Heart, Lung And Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung And Blood Institute or the National Institutes of Health. NR 30 TC 20 Z9 20 U1 0 U2 4 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 SEP PY 2010 VL 37 IS 9 BP 4938 EP 4945 DI 10.1118/1.3481566 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 651DY UT WOS:000281906000045 PM 20964213 ER PT J AU Joffe, H Partridge, A Giobbie-Hurder, A Li, XC Habin, K Goss, P Winer, E Garber, J AF Joffe, Hadine Partridge, Ann Giobbie-Hurder, Anita Li, Xiaochun Habin, Karleen Goss, Paul Winer, Eric Garber, Judy TI Augmentation of venlafaxine and selective serotonin reuptake inhibitors with zolpidem improves sleep and quality of life in breast cancer patients with hot flashes: a randomized, double-blind, placebo-controlled trial SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Insomnia; Sleep; Quality of life; Hot flashes; Vasomotor symptoms; Breast cancer; Zolpidem; Selective serotonin reuptake inhibitor; Serotonin-norepinephrine reuptake inhibitor; Antidepressant ID MENOPAUSAL SYMPTOMS; NEWER ANTIDEPRESSANTS; POSTMENOPAUSAL WOMEN; MAJOR DEPRESSION; CIRCADIAN-RHYTHM; CHRONIC INSOMNIA; ASSOCIATION; TAMOXIFEN; PERIMENOPAUSAL; EFFICACY AB Objective: Hot flashes are a major quality-of-life issue for breast cancer survivors, interrupting sleep, reducing quality of life, and diminishing treatment adherence to adjuvant endocrine therapies. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) are used widely but are only partially effective for hot flashes. Alternative strategies are needed. We hypothesized that augmentation of SSRI/SNRI therapy with hypnotic agents would optimize hot flash therapy by improving sleep and quality of life. Methods: Women with breast cancer or at high risk for developing the disease who had hot flashes in association with nocturnal awakenings were randomized to double-blinded treatment with zolpidem 10 mg or placebo for 5 weeks. SSRI/SNRI nonusers (81%) started venlafaxine XR 75 mg/day concurrently, whereas SSRI/SNRI users continued that therapy. We compared the proportion of responders, defined as study completers with improved subjective sleep quality (Pittsburgh Sleep Quality Index) and/or objectively assessed wake time after sleep onset on actigraphy, between groups. Results: Of 53 women (aged 51 +/- 8 y) randomized to zolpidem augmentation (n = 25) or placebo augmentation (n = 28), 38 completed the protocol (57% on placebo, 88% on zolpidem). More women augmented with zolpidem than placebo were responders on the sleep outcome (40% vs 14%; P = 0.035). Quality of life improved more with zolpidem than with placebo (P = 0.01). Treatment effects on hot flashes and mood did not differ between groups. Conclusions: Augmentation of SSRI/SNRI with zolpidem improves sleep and quality of life in breast cancer survivors with hot flashes and associated sleep disturbance. Adding a hypnotic agent to an SSRI/SNRI helps women to sleep through nighttime hot flashes. Treatments targeting sleep may be an important supplemental strategy to optimize well-being. C1 [Joffe, Hadine] Massachusetts Gen Hosp, Perinatal & Reprod Psychiat Program, Dept Psychiat, Boston, MA 02114 USA. [Partridge, Ann; Winer, Eric; Garber, Judy] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Giobbie-Hurder, Anita; Li, Xiaochun] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Habin, Karleen; Goss, Paul] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. RP Joffe, H (reprint author), Massachusetts Gen Hosp, Perinatal & Reprod Psychiat Program, Dept Psychiat, 185 Cambridge St,Suite 2286, Boston, MA 02114 USA. EM hjoffe@partners.org FU Susan G. Komen Breast Cancer Foundation; Bayer HealthCare Pharmaceuticals; Forest Laboratories, Inc.; GlaxoSmithKline; Sepracor Inc.; Astra Zeneca FX This study was supported by the Susan G. Komen Breast Cancer Foundation. Study medication was provided by Wyeth-Ayerst Pharmaceuticals and Sanofi-Aventis.; Dr. Joffe-Research/product support for this protocol: Study medication provided by Wyeth-Ayerst Pharmaceuticals and Sanofi-Aventis. Research support/coinvestigator: Bayer HealthCare Pharmaceuticals, Forest Laboratories, Inc., GlaxoSmithKline, and Sepracor Inc. Advisory/Consulting: Sanofi-Aventis. Dr. Garber-Consultant for Generation Health. Coinvestigator on a trial sponsored by Astra Zeneca. NR 50 TC 17 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD SEP-OCT PY 2010 VL 17 IS 5 BP 908 EP 916 DI 10.1097/gme.0b013e3181dbee1b PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 647JL UT WOS:000281614700009 PM 20581724 ER PT J AU Nagrath, D Avila-Elchiver, M Berthiaume, F Tilles, AW Messac, A Yarmush, ML AF Nagrath, Deepak Avila-Elchiver, Marco Berthiaume, Francois Tilles, Arno W. Messac, Achille Yarmush, Martin L. TI Soft constraints-based multiobjective framework for flux balance analysis SO METABOLIC ENGINEERING LA English DT Article DE Bioartificial liver; Hepatocytes/linear physical programming; Metabolic networks; Multiobjective optimization; Pareto optimality ID METABOLIC OBJECTIVE FUNCTIONS; SANDWICH CONFIGURATION; CULTURED-HEPATOCYTES; OPTIMIZATION; IDENTIFICATION; NETWORKS; PLASMA; CELLS; GLUTAMINE; SELECTION AB The current state of the art for linear optimization in Flux Balance Analysis has been limited to single objective functions. Since mammalian systems perform various functions, a multiobjective approach is needed when seeking optimal flux distributions in these systems. In most of the available multiobjective optimization methods, there is a lack of understanding of when to use a particular objective, and how to combine and/or prioritize mutually competing objectives to achieve a truly optimal solution. To address these limitations we developed a soft constraints based linear physical programming-based flux balance analysis (LPPFBA) framework to obtain a multiobjective optimal solutions. The developed framework was first applied to compute a set of multiobjective optimal solutions for various pairs of objectives relevant to hepatocyte function (urea secretion, albumin, NADPH, and glutathione syntheses) in bioartificial liver systems. Next, simultaneous analysis of the optimal solutions for three objectives was carried out. Further, this framework was utilized to obtain true optimal conditions to improve the hepatic functions in a simulated bioartificial liver system. The combined quantitative and visualization framework of LPPFBA is applicable to any large-scale metabolic network system, including those derived by genomic analyses. (C) 2010 Elsevier Inc. All rights reserved. C1 [Avila-Elchiver, Marco; Berthiaume, Francois; Tilles, Arno W.; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med Surg Serv, Boston, MA 02114 USA. [Avila-Elchiver, Marco; Berthiaume, Francois; Tilles, Arno W.; Yarmush, Martin L.] Shriners Hosp Children, Boston, MA 02114 USA. [Nagrath, Deepak] Rice Univ, Dept Chem & Biomol Engn, Houston, TX 77005 USA. [Avila-Elchiver, Marco] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Messac, Achille] Rensselaer Polytech Inst, Dept Mech Engn, Troy, NY USA. [Berthiaume, Francois; Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Yarmush, ML (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med Surg Serv, Boston, MA 02114 USA. EM ireis@sbi.org OI Nagrath, Deepak/0000-0002-8999-2282 FU National Institutes of Health [DK059766, EB008678] FX Financial Support: This work was partially supported by the National Institutes of Health Grant nos. DK059766 and EB008678 NR 30 TC 15 Z9 17 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7176 J9 METAB ENG JI Metab. Eng. PD SEP PY 2010 VL 12 IS 5 BP 429 EP 445 DI 10.1016/j.ymben.2010.05.003 PG 17 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 640TI UT WOS:000281074900003 PM 20553945 ER PT J AU Goedecke, JH Utzschneider, K Faulenbach, MV Rizzo, M Berneis, K Spinas, GA Dave, JA Levitt, NS Lambert, EV Olsson, T Kahn, SE AF Goedecke, Julia H. Utzschneider, Kristina Faulenbach, Mirjam V. Rizzo, Manfredi Berneis, Kaspar Spinas, Giatgen A. Dave, Joel A. Levitt, Naomi S. Lambert, Estelle V. Olsson, Tommy Kahn, Steven E. TI Ethnic differences in serum lipoproteins and their determinants in South African women SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID INSULIN-RESISTANCE; METABOLIC SYNDROME; RISK-FACTORS; MYOCARDIAL-INFARCTION; TRIGLYCERIDE LEVELS; FAT DISTRIBUTION; ADIPOSE-TISSUE; CHOLESTEROL; OBESITY; LIPASE AB The objective of the study was to characterize ethnic differences in lipid levels and low-density lipoprotein (LDL) particle size and subclasses in black and white South African women and to explore the associations with insulin sensitivity (S-1), body composition, and lifestyle factors Fasting scrum lipids and LDL size and subclasses, body composition (dual-energy x-ray absorptiometry), and S-1 (frequently sampled intravenous glucose tolerance test) were measured in normal-weight (body mass index <25 kg/m(2)) black (n = 15) and white (n = 15), and obese (body mass index >30 kg/m(2)) black (n = 13) and white (n = 13) women. Normal-weight and obese black women had lower triglycerides (0 59 +/- 0 09 and 0 77 +/- 0 10 vs 0.89 +/- 0 09 and 0.93 +/- 0 10 mmol/L, P < 05) and high-density lipoprotein cholesterol (1 2 +/- 0 1 and 1 1 +/- 0.1 vs 1 7 +/- 0 1 and 1 6 +/- 0 3 mmol/L, P < 01) than white women. The LDL particle size was not different, but obese black women had more LDL subclass IV (17 3% +/- 1 0% vs 12 5% +/- 1.0%, P < 01) In white women, triglycerides and LDL particle size correlated with S-1 (P < 01), whereas cholesterol levels correlated with body fat (P < .05) Low socioeconomic status, low dietary protein intake, and injectable contraceptive use were the major determinants of unfavorable lipid profiles in black women Black women had lower triglyceride and high-density lipoprotein cholesterol levels and more small dense LDL particles than white women The major determinants of serum lipids in black women were socioeconomic status and lifestyle factors, whereas in white women, S-1 and body composition most closely correlated with scrum lipids (C) 2010 Elsevier Inc All rights reserved C1 [Goedecke, Julia H.; Lambert, Estelle V.] Univ Cape Town, Dept Human Biol, UCT MRC Res Unit Exercise Sci & Sports Med, ZA-7700 Rondebosch, South Africa. [Goedecke, Julia H.] S African MRC, Cape Town, South Africa. [Utzschneider, Kristina; Faulenbach, Mirjam V.; Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Utzschneider, Kristina; Faulenbach, Mirjam V.; Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. [Rizzo, Manfredi] Univ Palermo, Dept Clin Med & Emerging Dis, I-90133 Palermo, Italy. [Berneis, Kaspar; Spinas, Giatgen A.] Univ Zurich Hosp, Div Endocrinol Diabet & Clin Nutr, Zurich, Switzerland. [Berneis, Kaspar] Zurich Ctr Integrat Human Physiol, Zurich, Switzerland. [Dave, Joel A.; Levitt, Naomi S.] Univ Cape Town, Dept Med, Endocrine Unit, ZA-7700 Rondebosch, South Africa. [Olsson, Tommy] Umea Univ, Dept Med, S-90187 Umea, Sweden. RP Goedecke, JH (reprint author), Univ Cape Town, UCT MRC Res Unit Exercise Sci & Sports Med, 3rd Floor Sports Sci Inst S Africa,POB 115, ZA-7725 Newlands, South Africa. RI Goedecke, Julia/J-8628-2013; Goedecke, Julia/E-1820-2016; OI Goedecke, Julia/0000-0001-6795-4771; Goedecke, Julia/0000-0001-6795-4771; Olsson, Tommy/0000-0001-7768-1076; RIZZO, Manfredi/0000-0002-9549-8504; Kahn, Steven/0000-0001-7307-9002 FU Medical Research Council of South Africa; International Atomic Energy Agency; National Research Foundation of South Africa; Royal Society SA-UK; University of Cape Town; United States Department of Veterans Affairs FX This study was funded by the Medical Research Council of South Africa, the International Atomic Energy Agency, the National Research Foundation of South Africa and Royal Society SA-UK Science Networks Programme, the University of Cape Town, and the United States Department of Veterans Affairs. There are no conflicts of interest. NR 36 TC 21 Z9 21 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0026-0495 EI 1532-8600 J9 METABOLISM JI Metab.-Clin. Exp. PD SEP PY 2010 VL 59 IS 9 BP 1341 EP 1350 DI 10.1016/j.metabol.2009.12.018 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 645SY UT WOS:000281487700015 PM 20096899 ER PT J AU Szymczak, JE Brooks, JV Volpp, KG Bosk, CL AF Szymczak, Julia E. Brooks, Joanna Veazey Volpp, Kevin G. Bosk, Charles L. TI To Leave or to Lie? Are Concerns about a Shift-Work Mentality and Eroding Professionalism as a Result of Duty-Hour Rules Justified? SO MILBANK QUARTERLY LA English DT Article DE Internship; residency; duty-hour regulations; professionalism ID HOURS REFORM; RESIDENTS; REGULATIONS; MORTALITY; RESTRICTIONS; ATTITUDES; EDUCATION; MEDICINE; SURGEONS; LIMITS AB Methods: In 2008, we conducted three months of ethnographic observation of internal medicine and general surgery residents as they went about their everyday work in two hospitals affiliated with the same training program, as well as in-depth interviews with seventeen residents. Field notes and interview transcripts were analyzed for perceptions and behaviors in regard to beginning and leaving work, reporting duty hours, and expressing opinions about DHR. Findings: The respondents did not exhibit a "shift work" mentality in relation to their work. We found that residents: (1) occasionally stay in the hospital in order to complete patient care tasks even when, according to the clock, they are required to leave, because the organizational culture stresses performing work thoroughly, (2) do not blindly embrace noncompliance with DHR but are thoughtful about the tradeoffs inherent in the regulations, and (3) express nuanced and complex reasons for erroneously reporting duty hours, suggesting that reporting hours worked is not a simple issue of lying or truth telling. Conclusions: Concerns about DHR and the erosion of resident professionalism resulting from the development of a "shift work" mentality likely have been overstated. Instead, the influence of DHR on professionalism is more complex than the conventional wisdom suggests and requires additional assessment. C1 [Bosk, Charles L.] Univ Penn, Dept Sociol, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Bosk, CL (reprint author), Univ Penn, Dept Sociol, 3718 Locust Walk,Suite 113, Philadelphia, PA 19104 USA. EM cbosk@sas.upenn.edu FU U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development [SHP 08-178]; Robert Wood Johnson Health Investigator Award FX This work was supported by the U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (SHP 08-178). Charles L. Bosk received additional support from a Robert Wood Johnson Health Investigator Award. We thank Jacob Avery and Keri Monahan for their substantial data collection efforts. Without their commitment, we would have offered only a thin, rather than a thick, description. Mary Dixon-Woods of the University of Leicester anticipated one of our reviewers' objections, which speeded up the revision. Finally, we would like to thank the editor and reviewers of The Milbank Quarterly for their insightful comments and suggestions. NR 40 TC 25 Z9 25 U1 1 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-378X J9 MILBANK Q JI Milbank Q. PD SEP PY 2010 VL 88 IS 3 BP 350 EP 381 PG 32 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 654QA UT WOS:000282181900004 PM 20860575 ER PT J AU Santiago-Lastra, YA Eisner, BH AF Santiago-Lastra, Y. A. Eisner, B. H. TI Predictors of success in shock wave lithotripsy of renal and ureteral stones SO MINERVA UROLOGICA E NEFROLOGICA LA English DT Review DE Calculi; Lithotripsy; Ureteral calculi AB In many centers, shock wave lithotripsy (SWL) is a commonly used modality for the treatment of both renal and ureteral calculi. It is non-invasive, may be performed using minimal anesthesia, and has a high level of patient acceptance. The focus of the present review is to highlight patient and stone characteristics which affect the outcomes of SWL, in order to define which patients are proper candidates for this treatment. C1 [Santiago-Lastra, Y. A.; Eisner, B. H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. RP Eisner, BH (reprint author), Massachusetts Gen Hosp, Dept Urol, GRB 1102,55 Fruit St, Boston, MA 02114 USA. EM beisner@partners.org NR 88 TC 0 Z9 0 U1 0 U2 2 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0393-2249 J9 MINERVA UROL NEFROL JI Minerva Urol. Nefrol. PD SEP PY 2010 VL 62 IS 3 BP 283 EP 294 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA V28DM UT WOS:000208661500009 PM 20940697 ER PT J AU Zhang, HB Schulz, TJ Espinoza, DO Huang, TL Emanuelli, B Kristiansen, K Tseng, YH AF Zhang, Hongbin Schulz, Tim J. Espinoza, Daniel O. Huang, Tian Lian Emanuelli, Brice Kristiansen, Karsten Tseng, Yu-Hua TI Cross Talk between Insulin and Bone Morphogenetic Protein Signaling Systems in Brown Adipogenesis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID 3T3-L1 ADIPOCYTE DIFFERENTIATION; GROWTH-FACTOR-I; ADIPOSE-TISSUE; MITOCHONDRIAL BIOGENESIS; TRANSCRIPTIONAL CONTROL; GENE-EXPRESSION; ADULT HUMANS; SERINE/THREONINE KINASE; METABOLIC SYNDROME; RECEPTOR-ALPHA AB Both insulin and bone morphogenetic protein (BMP) signaling systems are important for adipocyte differentiation. Analysis of gene expression in BMP7-treated fibroblasts revealed a coordinated change in insulin signaling components by BMP7. To further investigate the cross talk between insulin and BMP signaling systems in brown adipogenesis, we examined the effect of BMP7 in insulin receptor substrate 1 (IRS-1)-deficient brown preadipocytes, which exhibit a severe defect in differentiation. Treatment of these cells with BMP7 for 3 days prior to adipogenic induction restored differentiation and expression of brown adipogenic markers. The high level of adipogenic inhibitor preadipocyte factor 1 (Pref-1) in IRS-1-null cells was markedly reduced by 3 days of BMP7 treatment, and analysis of the 1.3-kb pref-1 promoter revealed 9 putative Smad binding elements (SBEs), suggesting that BMP7 could directly suppress Pref-1 expression, thereby allowing the initiation of the adipogenic program. Using a series of sequential deletion mutants of the pref-1 promoter linked to the luciferase gene and chromatin immunoprecipitation, we demonstrate that the promoter-proximal SBE (-192/-184) was critical in mediating BMP7's suppressive effect on pref-1 transcription. Together, these data suggest cross talk between the insulin and BMP signaling systems by which BMP7 can rescue brown adipogenesis in cells with insulin resistance. C1 [Zhang, Hongbin; Schulz, Tim J.; Espinoza, Daniel O.; Huang, Tian Lian; Emanuelli, Brice; Tseng, Yu-Hua] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Zhang, Hongbin; Kristiansen, Karsten] Univ So Denmark, Dept Biochem & Mol Biol, Copenhagen, Denmark. [Zhang, Hongbin; Kristiansen, Karsten] Univ Copenhagen, Dept Biol, Copenhagen, Denmark. RP Tseng, YH (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. EM yu-hua.tseng@joslin.harvard.edu RI Schulz, Tim/F-4842-2013; Kristiansen, Karsten/J-5148-2014; Emanuelli, Brice/M-2097-2016 OI Schulz, Tim/0000-0002-8413-3972; Kristiansen, Karsten/0000-0002-6024-0917; FU NIH [R01 DK077097, R21 DK070722, UL1 RR 025758-01]; Eli Lilly Research Foundation; Harvard Stem Cell Institute; NIDDK, Joslin Diabetes and Endocrinology Research Center [P30DK036836]; Danish Natural Science Research Council; Novo Nordisk Foundation; Carlsberg Foundation FX This work was supported in part by grants R01 DK077097, R21 DK070722, and UL1 RR 025758-01 from NIH (Harvard Catalyst/The Harvard Clinical and Translational Science Center) and research grants from the Eli Lilly Research Foundation and Harvard Stem Cell Institute (to Y.-H.T.), by the Joslin Diabetes and Endocrinology Research Center (P30DK036836 from the NIDDK), the Danish Natural Science Research Council, the Novo Nordisk Foundation, and the Carlsberg Foundation (to K.K.). NR 60 TC 31 Z9 33 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2010 VL 30 IS 17 BP 4224 EP 4233 DI 10.1128/MCB.00363-10 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 636TF UT WOS:000280762900011 PM 20584981 ER PT J AU Lin, CI Whang, EE Donner, DB Du, JY Lorch, J He, F Jiang, XF Price, BD Moore, FD Ruan, DT AF Lin, Chi-Iou Whang, Edward E. Donner, David B. Du, Jinyan Lorch, Jochen He, Frank Jiang, Xiaofeng Price, Brendan D. Moore, Francis D., Jr. Ruan, Daniel T. TI Autophagy Induction with RAD001 Enhances Chemosensitivity and Radiosensitivity through Met Inhibition in Papillary Thyroid Cancer SO MOLECULAR CANCER RESEARCH LA English DT Article ID CELL-DEATH; MAMMALIAN TARGET; LUNG-CANCER; HEPATOCELLULAR-CARCINOMA; ANTITUMOR-ACTIVITY; EVEROLIMUS RAD001; OVARIAN-CANCER; MOUSE MODEL; THERAPY; MTOR AB Although autophagy is generally considered a prosurvival mechanism that preserves viability, there is evidence that it could drive an alternative programmed cell death pathway in cells with defects in apoptosis. Because the inhibition of autophagic activity promotes resistance to both chemotherapy and external beam radiation in papillary thyroid cancer (PTC), we determined if RAD001, a potent activator of autophagy, improves the efficacy of either therapy. We found that RAD001 increased the expression level of light chain 3-II, a marker for autophagy, as well as autophagosome formation in cell lines and in human PTC ex vivo. RAD001 sensitized PTC to doxorubicin and external beam radiation in a synergistic fashion, suggesting that combination therapy could improve therapeutic response at less toxic concentrations. The effects of RAD001 were abrogated by RNAi knockdown of the autophagy-related gene 5, suggesting that RAD001 acts, in part, by enhancing autophagy. Because the synergistic activity of RAD001 with doxorubicin and external radiation suggests distinct and complementary mechanisms of action, we characterized how autophagy modulates signaling pathways in PTC. To do so, we performed kinome profiling and discovered that autophagic activation resulted in Src phosphorylation and Met dephosphorylation. Src inhibition did not reverse the effects of RAD001, whereas Met inhibition reversed the effects of autophagy blockade on chemosensitivity. These results suggest that the anticancer effects of autophagic activation are mediated largely through Met. We conclude that RAD001 induces autophagy, which enhances the therapeutic response to cytotoxic chemotherapy and external beam radiation in PTC. Mol Cancer Res; 8(9); 1217-26. (C)2010 AACR. C1 [Lin, Chi-Iou; Whang, Edward E.; Moore, Francis D., Jr.; Ruan, Daniel T.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Lorch, Jochen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jiang, Xiaofeng; Price, Brendan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Genom Stabil & DNA Repair,Dept Radiat Oncol, Boston, MA 02115 USA. [Donner, David B.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Du, Jinyan; He, Frank] MIT, Broad Inst, Cambridge, MA 02139 USA. RP Ruan, DT (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM druan@partners.org FU Department of Surgery at Brigham and Women's Hospital FX Osteen Junior Faculty Research Grant from the Department of Surgery at Brigham and Women's Hospital. NR 47 TC 57 Z9 61 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD SEP PY 2010 VL 8 IS 9 BP 1217 EP 1226 DI 10.1158/1541-7786.MCR-10-0162 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 650RI UT WOS:000281868700005 PM 20736296 ER PT J AU Weisberg, E Choi, HG Barrett, R Zhou, WJ Zhang, JM Ray, A Nelson, EA Jiang, JR Moreno, D Stone, R Galinsky, I Fox, E Adamia, S Kung, AL Gray, NS Griffin, JD AF Weisberg, Ellen Choi, Hwan Geun Barrett, Rosemary Zhou, Wenjun Zhang, Jianming Ray, Arghya Nelson, Erik A. Jiang, Jingrui Moreno, Daisy Stone, Richard Galinsky, Ilene Fox, Edward Adamia, Sophia Kung, Andrew L. Gray, Nathanael S. Griffin, James D. TI Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID INTERNAL TANDEM DUPLICATION; ACUTE MYELOID-LEUKEMIA; TYROSINE KINASE; BCR-ABL; ACTIVATING MUTATION; FLT3-EXPRESSING CELLS; QUANTITATIVE-ANALYSIS; THERAPEUTIC TARGET; GENE; RESISTANCE AB For a subpopulation of acute myeloid leukemia (AML) patients, the constitutively activated tyrosine kinase, mutant FLT3, has emerged as a promising target for therapy. The development of drug resistance, however, is a growing concern for mutant FLT3 inhibitors, such as PKC412. Potential therapeutic benefit can arise from the combination of two structurally diverse inhibitors that target-but bind differently to-the same protein or from two inhibitors with completely different mechanisms of action. Thus, there is a need for identification and development of novel FLT3 inhibitors that have the ability to positively combine with PKC412 or standard chemotherapeutic agents used to treat AML as a way to suppress the development of drug resistance and consequently prolong disease remission. Here, we report the effects of the novel type II ATP-competitive inhibitors, HG-7-85-01 and HG-7-86-01, which potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3-ITD or FLT3 kinase domain point mutants via induction of apoptosis and cell cycle inhibition. Antileukemic activity of HG-7-85-01 was shown in vivo to be comparable with that observed with PKC412 in a bioluminescence assay using NCr nude mice harboring Ba/F3-FLT3-ITD-luc+ cells. HG-7-85-01 was also observed to override PKC412 resistance. Finally, HG-7-85-01 and HG-7-86-01 synergized with PKC412 and standard chemotherapeutic agents against mutant PKC412-sensitive and some PKC412-resistant, FLT3-positive cells. Thus, we present a structurally novel class of FLT3 inhibitors that warrants consideration for clinical testing against drug-resistant disease in AML patients. Mol Cancer Ther; 9(9); 2468-77. (C) 2010 AACR. C1 [Weisberg, Ellen; Barrett, Rosemary; Ray, Arghya; Nelson, Erik A.; Jiang, Jingrui; Stone, Richard; Galinsky, Ilene; Adamia, Sophia; Griffin, James D.] Dana Farber Canc Inst, Dept Med Oncol Hematol Neoplasia, Boston, MA 02115 USA. [Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Moreno, Daisy] Dana Farber Canc Inst, Anim Resources Facil, Boston, MA 02115 USA. [Fox, Edward] Dana Farber Canc Inst, Mol Diagnost Lab, Boston, MA 02115 USA. [Choi, Hwan Geun; Zhou, Wenjun; Zhang, Jianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Stone, Richard] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Stone, Richard] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Weisberg, E (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM ellen_weisberg@dfci.harvard.edu; nathanael_gray@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X FU NIH [CA66996, CA36167, DK50654]; Leukemia and Lymphoma Society Specialized Center of Research Award FX NIH grants CA66996, CA36167, and DK50654 and Leukemia and Lymphoma Society Specialized Center of Research Award (J.D. Griffin). NR 34 TC 10 Z9 10 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP PY 2010 VL 9 IS 9 BP 2468 EP 2477 DI 10.1158/1535-7163.MCT-10-0232 PG 10 WC Oncology SC Oncology GA 648HN UT WOS:000281683000004 PM 20807780 ER PT J AU Yao, JK Dougherty, GG Reddy, RD Keshavan, MS Montrose, DM Matson, WR Rozen, S Krishnan, RR McEvoy, J Kaddurah-Daouk, R AF Yao, J. K. Dougherty, G. G., Jr. Reddy, R. D. Keshavan, M. S. Montrose, D. M. Matson, W. R. Rozen, S. Krishnan, R. R. McEvoy, J. Kaddurah-Daouk, R. TI Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia SO MOLECULAR PSYCHIATRY LA English DT Article DE Trp; N-acetylserotonin; 5-hydroxyindoleacetic acid; schizophrenia; first-episode neuroleptic naive; targeted metabolomics ID PERFORMANCE LIQUID-CHROMATOGRAPHY; PLATELET SEROTONIN CONCENTRATION; ENDOGENOUS KYNURENIC ACID; CEREBROSPINAL-FLUID; LIPID-PEROXIDATION; N-ACETYLSEROTONIN; 5-HYDROXYINDOLEACETIC ACID; METABOLOMIC ANALYSIS; DIETARY TRYPTOPHAN; OXIDATIVE DAMAGE AB Schizophrenia is characterized by complex and dynamically interacting perturbations in multiple neurochemical systems. In the past, evidence for these alterations has been collected piecemeal, limiting our understanding of the interactions among relevant biological systems. Earlier, both hyper- and hyposerotonemia were variously associated with the longitudinal course of schizophrenia, suggesting a disturbance in the central serotonin (5-hydroxytryptamine (5-HT)) function. Using a targeted electrochemistry-based metabolomics platform, we compared metabolic signatures consisting of 13 plasma tryptophan (Trp) metabolites simultaneously between first-episode neuroleptic-naive patients with schizophrenia (FENNS, n = 25) and healthy controls (HC, n = 30). We also compared these metabolites between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. N-acetylserotonin was increased in FENNS-BL compared with HC (P = 0.0077, which remained nearly significant after Bonferroni correction). N-acetylserotonin/Trp and melatonin (Mel)/serotonin ratios were higher, and Mel/N-acetylserotonin ratio was lower in FENNS-BL (all P-values < 0.0029), but not after treatment, compared with HC volunteers. All three groups had highly significant correlations between Trp and its metabolites, Mel, kynurenine, 3-hydroxykynurenine and tryptamine. However, in the HC, but in neither of the FENNS groups, serotonin was highly correlated with Trp, Mel, kynurenine or tryptamine, and 5-hydroxyindoleacetic acid (5HIAA) was highly correlated with Trp, Mel, kynurenine or 3-hydroxykynurenine. A significant difference between HC and FENNS-BL was further shown only for the Trp-5HIAA correlation. Thus, some metabolite interactions within the Trp pathway seem to be altered in the FENNS-BL patients. Conversion of serotonin to N-acetylserotonin by serotonin N-acetyltransferase may be upregulated in FENNS patients, possibly related to the observed alteration in Trp-5HIAA correlation. Considering N-acetylserotonin as a potent antioxidant, such increases in N-acetylserotonin might be a compensatory response to increased oxidative stress, implicated in the pathogenesis of schizophrenia. Molecular Psychiatry (2010) 15, 938-953; doi:10.1038/mp.2009.33;published online 28 April 2009 C1 [Yao, J. K.] VA Pittsburgh Healthcare Syst, Neurochem & Psychopharmacol Lab, Pittsburgh, PA 15206 USA. [Yao, J. K.; Dougherty, G. G., Jr.; Reddy, R. D.; Keshavan, M. S.; Montrose, D. M.] Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Med Ctr, Pittsburgh, PA 15213 USA. [Yao, J. K.] Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Keshavan, M. S.] Wayne State Univ, Dept Psychiat & Behav Neurosci, Detroit, MI USA. [Keshavan, M. S.] Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02215 USA. [Keshavan, M. S.] Harvard Univ, Boston, MA 02115 USA. [Matson, W. R.] Bedford VA Med Ctr, Bedford, MA USA. [Rozen, S.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Krishnan, R. R.; McEvoy, J.; Kaddurah-Daouk, R.] Duke Univ, Med Ctr, Durham, NC USA. RP Yao, JK (reprint author), VA Pittsburgh Healthcare Syst, Neurochem & Psychopharmacol Lab, Bldg 13,151R2-H,7180 Highland Dr, Pittsburgh, PA 15206 USA. EM jkyao@pitt.edu OI Rozen, Steven G./0000-0002-4288-0056 FU Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory RD; Senior Research Career Scientist Award; VA Pittsburgh Healthcare System; National Institute of Health [MH58141, MH64118, MH45203, R24 GM078233, UL1 RR024153]; NIH/NCRR/GCRC [M01 RR00056]; Metabolomics Research Network; Stanley Medical Research Institute; NARSAD FX This material is based on work supported in part by the grants from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory R&D (Merit Reviews (JKY) and Senior Research Career Scientist Award (JKY)), VA Pittsburgh Healthcare System (JKY, GGD, RDR), National Institute of Health (MH58141 (JKY), MH64118 (RDR), MH45203 (MSK), R24 GM078233 (RKD), c UL1 RR024153 and NIH/NCRR/GCRC Grant M01 RR00056), Metabolomics Research Network (RKD); Stanley Medical Research Institute (RKD), and NARSAD (RKD). The authors are grateful to Drs Nina Schooler, Cameron Carter and Gretchen Haas, and the clinical core staff of the Center for the Neuroscience of Mental Disorders (MH45156, David Lewis MD, Director) for their assistance in diagnostic and psychopathological assessments, and to P Cheng, C Korbanic and J Haflett for their technical assistance. NR 94 TC 45 Z9 47 U1 2 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2010 VL 15 IS 9 BP 938 EP 953 DI 10.1038/mp.2009.33 PG 16 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 648EB UT WOS:000281672100009 PM 19401681 ER PT J AU Maestrini, E Pagnamenta, AT Lamb, JA Bacchelli, E Sykes, NH Sousa, I Toma, C Barnby, G Butler, H Winchester, L Scerri, TS Minopoli, F Reichert, J Cai, G Buxbaum, JD Korvatska, O Schellenberg, GD Dawson, G de Bildt, A Minderaa, RB Mulder, EJ Morris, AP Bailey, AJ Monaco, AP AF Maestrini, E. Pagnamenta, A. T. Lamb, J. A. Bacchelli, E. Sykes, N. H. Sousa, I. Toma, C. Barnby, G. Butler, H. Winchester, L. Scerri, T. S. Minopoli, F. Reichert, J. Cai, G. Buxbaum, J. D. Korvatska, O. Schellenberg, G. D. Dawson, G. de Bildt, A. Minderaa, R. B. Mulder, E. J. Morris, A. P. Bailey, A. J. Monaco, A. P. CA IMGSAC TI High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility SO MOLECULAR PSYCHIATRY LA English DT Article DE autistic disorder; disease susceptibility; single nucleotide polymorphisms; linkage disequilibrium; chromosome 7; chromosome 2 ID LINKED MENTAL-RETARDATION; PERVASIVE DEVELOPMENTAL DISORDERS; MULTILOCUS GENOTYPE DATA; CANDIDATE GENES; SPECTRUM DISORDERS; LINKAGE ANALYSES; CHROMOSOME 7Q; ARRAY-CGH; GENOME; MUTATIONS AB Autism spectrum disorders are a group of highly heritable neurodevelopmental disorders with a complex genetic etiology. The International Molecular Genetic Study of Autism Consortium previously identified linkage loci on chromosomes 7 and 2, termed AUTS1 and AUTS5, respectively. In this study, we performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences. SNP genotype data were also used to investigate copy number variation within these regions. The study sample consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls. Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals. Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7. Evidence for the involvement of DOCK4 in autism susceptibility was supported by independent replication of association at rs2217262 and the finding of a deletion segregating in a sib-pair family. Molecular Psychiatry (2010) 15, 954-968; doi:10.1038/mp.2009.34; published online 28 April 2009 C1 [Pagnamenta, A. T.; Lamb, J. A.; Sykes, N. H.; Sousa, I.; Barnby, G.; Butler, H.; Winchester, L.; Scerri, T. S.; Morris, A. P.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Maestrini, E.; Bacchelli, E.; Toma, C.; Minopoli, F.] Univ Bologna, Dept Biol, I-40126 Bologna, Italy. [Lamb, J. A.] Univ Manchester, Ctr Integrated Genom Med Res, Manchester, Lancs, England. [Reichert, J.; Cai, G.; Buxbaum, J. D.] Mt Sinai Sch Med, Seaver Autism Res Ctr, Dept Psychiat, New York, NY USA. [Korvatska, O.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Schellenberg, G. D.] Univ Penn, Sch Med, Dept Pathol, Philadelphia, PA 19104 USA. [Schellenberg, G. D.] Univ Penn, Sch Med, Lab Med, Philadelphia, PA 19104 USA. [Dawson, G.] Autism Speaks, New York, NY USA. [Dawson, G.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [de Bildt, A.; Minderaa, R. B.; Mulder, E. J.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 AV Groningen, Netherlands. [Bailey, A. J.] Univ Dept Psychiat, Warneford Hosp, Oxford, England. RP Monaco, AP (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, S Parks Rd, Oxford OX3 7BN, England. EM Anthony.Bailey@psych.ox.ac.uk; anthony.monaco@well.ox.ac.uk RI Monaco, Anthony/A-4495-2010; Bolton, Patrick/E-8501-2010; Maestrini, Elena/K-7508-2012; Bailey, Anthony/J-2860-2014; Toma, Claudio/L-7853-2014; OI Girao Meireles de Sousa, Ines/0000-0001-6983-8870; Monaco, Anthony/0000-0001-7480-3197; Bolton, Patrick/0000-0002-5270-6262; Bailey, Anthony/0000-0003-4257-972X; Toma, Claudio/0000-0003-3901-7507; Buxbaum, Joseph/0000-0001-8898-8313 FU UK Medical Research Council; Wellcome Trust; BIOMED 2 [CT-97-2759]; EC [QLG2-CT-1999-0094]; Deutsche Forschungsgemeinschaft; Fondation France Telecom; Conseil Regional Midi-Pyrenees; Child Mental Health Research of Copenhagen; Danish Natural Science Research Council [9802210]; National Institutes of Health [U19 HD35482, MO1 RR06022, K05 MH01196, K02 MH01389]; Fondazione Telethon FX We thank all the families who have participated in the study and the professionals who made this study possible. We also thank John Broxholme for bioinformatics support, Joseph Trakalo and Chris Allan at the WTCHG core genomics facility for Illumina and Sequenom genotyping, respectively. We especially thank Professor Giovanni Romeo at the Medical Genetics Unit, S Orsola-Malpighi Hospital, University of Bologna for his generous provision of laboratory space and equipment to EM, EB and CT. The CPEA (Collaborative Program of Excellence in Autism) thank Jeffery Munson, and Raphael Bernier and Annette Estes. This work was funded by the Nancy Lurie Marks Family Foundation; the Simons Foundation; the EC Sixth FP AUTISM MOLGEN, TelethonItaly; the Korczak Foundation for Autism and Related Disorders; the Netherlands Organization for Scientific Research (NWO). The IMGSAC was funded by UK Medical Research Council, Wellcome Trust, BIOMED 2 (CT-97-2759), EC Fifth Framework (QLG2-CT-1999-0094), Deutsche Forschungsgemeinschaft, Fondation France Telecom, Conseil Regional Midi-Pyrenees, trice Surovell Haskells Fund for Child Mental Health Research of Copenhagen, Danish Natural Science Research Council (9802210) and National Institutes of Health (U19 HD35482, MO1 RR06022, K05 MH01196, K02 MH01389). AJ Bailey is the Cheryl and Reece Scott Professor of Psychiatry. AP Monaco is a Wellcome Trust principal research fellow. NR 62 TC 52 Z9 52 U1 2 U2 10 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 SEP PY 2010 VL 15 IS 9 BP 954 EP 968 DI 10.1038/mp.2009.34 PG 15 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 648EB UT WOS:000281672100010 PM 19401682 ER PT J AU Stern, ME Schaumburg, CS Dana, R Calonge, M Niederkorn, JY Pflugfelder, SC AF Stern, M. E. Schaumburg, C. S. Dana, R. Calonge, M. Niederkorn, J. Y. Pflugfelder, S. C. TI Autoimmunity at the ocular surface: pathogenesis and regulation SO MUCOSAL IMMUNOLOGY LA English DT Review ID PRIMARY SJOGRENS-SYNDROME; DRY-EYE DISEASE; STEVENS-JOHNSON-SYNDROME; TOXIC EPIDERMAL NECROLYSIS; CORNEAL EPITHELIAL-CELLS; ANTIGEN-PRESENTING CELLS; AUTOREACTIVE B-CELLS; VERSUS-HOST-DISEASE; DYSFUNCTIONAL TEAR SYNDROME; NONOBESE DIABETIC MICE AB A healthy ocular surface environment is essential to preserve visual function, and as such the eye has evolved a complex network of mechanisms to maintain homeostasis. Fundamental to the health of the ocular surface is the immune system, designed to respond rapidly to environmental and microbial insults, whereas maintaining tolerance to self-antigens and commensal microbes. To this end, activation of the innate and adaptive immune response is tightly regulated to limit bystander tissue damage. However, aberrant activation of the immune system can result in autoimmunity to self-antigens localized to the ocular surface and associated tissues. Environmental, microbial and endogenous stress, antigen localization, and genetic factors provide the triggers underlying the immunological events that shape the outcome of the diverse spectrum of autoimmune-based ocular surface disorders. C1 [Stern, M. E.; Schaumburg, C. S.] Allergan, Inflammat Res Program, Biol Sci, Irvine, CA USA. [Dana, R.] Harvard Univ, Sch Med, Dept Ophthalmol, Schepens Eye Res Inst, Boston, MA USA. [Dana, R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Calonge, M.] Univ Valladolid, IOBA, Valladolid, Spain. [Niederkorn, J. Y.] Univ Texas Dallas, SW Med Ctr, Dept Ophthalmol, Dallas, TX USA. [Pflugfelder, S. C.] Baylor Coll Med, Cullen Eye Inst, Ocular Surface Ctr, Houston, TX 77030 USA. RP Stern, ME (reprint author), Allergan, Inflammat Res Program, Biol Sci, Irvine, CA USA. EM stern_michael@allergan.com RI Calonge, Margarita/K-2839-2014 OI Calonge, Margarita/0000-0001-8178-4836 FU National Institutes of Health [NIH RO1 EY018090] FX This study has received funding from the National Institutes of Health (NIH RO1 EY018090). NR 200 TC 31 Z9 31 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1933-0219 J9 MUCOSAL IMMUNOL JI Mucosal Immunol. PD SEP PY 2010 VL 3 IS 5 BP 425 EP 442 DI 10.1038/mi.2010.26 PG 18 WC Immunology SC Immunology GA 641HM UT WOS:000281115400003 PM 20485329 ER PT J AU Mouquet, H Scheid, JF Zoller, MJ Krogsgaard, M Ott, RG Shukair, S Artyomov, MN Pietzsch, J Connors, M Pereyra, F Walker, BD Ho, DD Wilson, PC Seaman, MS Eisen, HN Chakraborty, AK Hope, TJ Ravetch, JV Wardemann, H Nussenzweig, MC AF Mouquet, Hugo Scheid, Johannes F. Zoller, Markus J. Krogsgaard, Michelle Ott, Rene G. Shukair, Shetha Artyomov, Maxim N. Pietzsch, John Connors, Mark Pereyra, Florencia Walker, Bruce D. Ho, David D. Wilson, Patrick C. Seaman, Michael S. Eisen, Herman N. Chakraborty, Arup K. Hope, Thomas J. Ravetch, Jeffrey V. Wardemann, Hedda Nussenzweig, Michel C. TI Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation SO NATURE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; MEMORY B-CELLS; NEUTRALIZING ANTIBODIES; ENVELOPE GLYCOPROTEIN; TYPE-1; AUTOREACTIVITY; INDIVIDUALS; MODULATION; GENERATION AB During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV) disfavours homotypic bivalent antibody binding(1-3). Here we show that during the human antibody response to HIV, somatic mutations that increase antibody affinity also increase breadth and neutralizing potency. Surprisingly, the responding naive and memory B cells produce polyreactive antibodies, which are capable of bivalent heteroligation between one high-affinity anti-HIV-gp140 combining site and a second low-affinity site on another molecular structure on HIV. Although cross-reactivity to self-antigens or polyreactivity is strongly selected against during B-cell development(4), it is a common serologic feature of certain infections in humans, including HIV, Epstein-Barr virus and hepatitis C virus. Seventy-five per cent of the 134 monoclonal anti-HIV-gp140 antibodies cloned from six patients(5) with high titres of neutralizing antibodies are polyreactive. Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV. C1 [Mouquet, Hugo; Scheid, Johannes F.; Pietzsch, John; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Scheid, Johannes F.] Charite, D-10117 Berlin, Germany. [Zoller, Markus J.; Wardemann, Hedda] Max Planck Inst Infect Biol, D-10117 Berlin, Germany. [Krogsgaard, Michelle] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Krogsgaard, Michelle] NYU, Sch Med, Inst Canc, New York, NY 10016 USA. [Ott, Rene G.; Ravetch, Jeffrey V.] Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10065 USA. [Shukair, Shetha; Hope, Thomas J.] Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Artyomov, Maxim N.; Eisen, Herman N.; Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Artyomov, Maxim N.; Eisen, Herman N.; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Artyomov, Maxim N.; Eisen, Herman N.; Chakraborty, Arup K.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Artyomov, Maxim N.; Eisen, Herman N.; Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Artyomov, Maxim N.; Eisen, Herman N.; Chakraborty, Arup K.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Pietzsch, John] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany. [Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Connors, Mark] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Pereyra, Florencia; Walker, Bruce D.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Pereyra, Florencia; Walker, Bruce D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ho, David D.] Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. [Wilson, Patrick C.] Univ Chicago, Dept Med, Rheumatol Sect, Chicago, IL 60637 USA. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussenzweig@rockefeller.edu RI Mouquet, Hugo/M-2750-2014 FU Rockefeller University; National Institutes of Health [NIH 1 PO1 AI081677, R01 AI047770]; International AIDS Vaccine Initiative; Bill and Melinda Gates Foundation; German Research Foundation [GRK1121] FX We thank J. R. Mascola and R. T. Wyatt for discussion and supplying gp140 and gp120 proteins. This research was supported by the Rockefeller University, the National Institutes of Health (NIH 1 PO1 AI081677), the International AIDS Vaccine Initiative and the Bill and Melinda Gates Foundation. T.J.H. was supported by the National Institutes of Health (R01 AI047770). M.J.Z. and H.W. were supported by the German Research Foundation (GRK1121). B.D.W. and M.C.N. are Howard Hughes Medical Institute investigators. NR 31 TC 203 Z9 204 U1 0 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 SEP PY 2010 VL 467 IS 7315 BP 591 EP U117 DI 10.1038/nature09385 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 655TT UT WOS:000282273100039 PM 20882016 ER PT J AU Schreiber, SL Shamji, AF Clemons, PA Hon, C Koehler, AN Munoz, B Palmer, M Stern, AM Wagner, BK Powers, S Lowe, SW Guo, XC Krasnitz, A Sawey, ET Sordella, R Stein, L Trotman, LC Califano, A Dalla-Favera, R Ferrando, A Iavarone, A Pasqualucci, L Silva, J Stockwell, BR Hahn, WC Chin, L DePinho, RA Boehm, JS Gopal, S Huang, A Root, DE Weir, BA Gerhard, DS Zenklusen, JC Roth, MG White, MA Minna, JD MacMillan, JB Posner, BA AF Schreiber, Stuart L. Shamji, Alykhan F. Clemons, Paul A. Hon, Cindy Koehler, Angela N. Munoz, Benito Palmer, Michelle Stern, Andrew M. Wagner, Bridget K. Powers, Scott Lowe, Scott W. Guo, Xuecui Krasnitz, Alex Sawey, Eric T. Sordella, Raffaella Stein, Lincoln Trotman, Lloyd C. Califano, Andrea Dalla-Favera, Riccardo Ferrando, Adolfo Iavarone, Antonio Pasqualucci, Laura Silva, Jose Stockwell, Brent R. Hahn, William C. Chin, Lynda DePinho, Ronald A. Boehm, Jesse S. Gopal, Shuba Huang, Alan Root, David E. Weir, Barbara A. Gerhard, Daniela S. Zenklusen, Jean Claude Roth, Michael G. White, Michael A. Minna, John D. MacMillan, John B. Posner, Bruce A. CA Canc Target Discovery Dev Network TI Towards patient-based cancer therapeutics SO NATURE BIOTECHNOLOGY LA English DT Article ID ONCOGENE ADDICTION; LIVER-CANCER; CELL-LINES; STEM-CELLS; IDENTIFICATION; GENOTYPE; THERAPY; MODELS; TUMORS C1 [Schreiber, Stuart L.; Shamji, Alykhan F.; Clemons, Paul A.; Hon, Cindy; Koehler, Angela N.; Munoz, Benito; Palmer, Michelle; Stern, Andrew M.; Wagner, Bridget K.; Canc Target Discovery Dev Network] Harvard & MIT, Broad Inst, Cambridge, MA USA. [Powers, Scott; Lowe, Scott W.; Guo, Xuecui; Krasnitz, Alex; Sawey, Eric T.; Sordella, Raffaella; Stein, Lincoln; Trotman, Lloyd C.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Califano, Andrea; Dalla-Favera, Riccardo; Ferrando, Adolfo; Iavarone, Antonio; Pasqualucci, Laura; Silva, Jose; Stockwell, Brent R.] Columbia Univ, New York, NY USA. [Hahn, William C.; Chin, Lynda; DePinho, Ronald A.; Boehm, Jesse S.; Gopal, Shuba; Huang, Alan; Root, David E.; Weir, Barbara A.] Dana Farber Canc Inst, Cambridge, MA USA. [Gerhard, Daniela S.; Zenklusen, Jean Claude] US Natl Canc Inst, Bethesda, MD USA. [Roth, Michael G.; White, Michael A.; Minna, John D.; MacMillan, John B.; Posner, Bruce A.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Schreiber, SL (reprint author), Harvard & MIT, Broad Inst, Cambridge, MA USA. EM stuart_schreiber@harvard.edu RI Califano, Andrea/F-7239-2012; OI Boehm, Jesse/0000-0002-6795-6336; Roth, Michael/0000-0002-9056-332X; MacMillan, John/0000-0003-1430-1077 NR 22 TC 42 Z9 42 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD SEP PY 2010 VL 28 IS 9 BP 904 EP 906 DI 10.1038/nbt0910-904 PG 3 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 648UF UT WOS:000281719100011 ER PT J AU Hamza, TH Zabetian, CP Tenesa, A Laederach, A Montimurro, J Yearout, D Kay, DM Doheny, KF Paschall, J Pugh, E Kusel, VI Collura, R Roberts, J Griffith, A Samii, A Scott, WK Nutt, J Factor, SA Payami, H AF Hamza, Taye H. Zabetian, Cyrus P. Tenesa, Albert Laederach, Alain Montimurro, Jennifer Yearout, Dora Kay, Denise M. Doheny, Kimberly F. Paschall, Justin Pugh, Elizabeth Kusel, Victoria I. Collura, Randall Roberts, John Griffith, Alida Samii, Ali Scott, William K. Nutt, John Factor, Stewart A. Payami, Haydeh TI Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUBSTANTIA-NIGRA; RISK-FACTORS; REACTIVE MICROGLIA; ALPHA-SYNUCLEIN; T-CELLS; POPULATION; PATHOGENESIS; METAANALYSIS; EXPRESSION AB Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC)(1-5). We confirmed associations with SNCA(2,6-8) and MAPT(3,7-9), replicated an association with GAK9 (using data from the NGRC and a previous study(9), P = 3.2 x 10(-9)) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 x 10(-8)), which replicated in two datasets (meta-analysis P = 1.9 x 10(-10)). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 x 10(-10)) and late-onset (P = 2.4 x 10(-8)) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ(10,11). The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia(12), and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk(4,13). The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development. C1 [Hamza, Taye H.; Laederach, Alain; Montimurro, Jennifer; Yearout, Dora; Kay, Denise M.; Kusel, Victoria I.; Collura, Randall; Payami, Haydeh] Wadsworth Ctr, New York State Dept Hlth, Albany, NY USA. [Zabetian, Cyrus P.; Yearout, Dora; Samii, Ali] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Zabetian, Cyrus P.; Yearout, Dora; Samii, Ali] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Tenesa, Albert] Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland. [Doheny, Kimberly F.; Pugh, Elizabeth] Johns Hopkins Univ, Sch Med, CIDR, Baltimore, MD USA. [Paschall, Justin] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Roberts, John] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Griffith, Alida] Evergreen Hosp Med Ctr, Booth Gardner Parkinsons Care Ctr, Washington, DC USA. [Scott, William K.] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL USA. [Scott, William K.] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA. [Nutt, John] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Factor, Stewart A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. RP Payami, H (reprint author), Wadsworth Ctr, New York State Dept Hlth, Albany, NY USA. EM hpayami@wadsworth.org OI Kay, Denise/0000-0002-9928-2698; Zabetian, Cyrus/0000-0002-7739-4306; Laederach, Alain/0000-0002-5088-9907 FU National Institute of Neurological Disorders and Stroke [R01NS36960]; Michael J. Fox Foundation for Parkinson's Disease Research; Department of Veterans Affairs [1I01BX000531]; National Institutes of Aging [P30AG08017]; National Institute of Mental Health [R21MH087336]; Office of Research and Development, Clinical Sciences Research and Development Service, Department of Veteran Affairs; US National Institutes of Health (NIH) at the National Library of Medicine; NIH [HHSN268200782096C, AG027944, NS039764] FX We would like to acknowledge the individuals with Parkinson's disease, their families and the healthy volunteers who participated in this study. We thank T. L. Edwards, J.M. Vance, E. R. Martin, J.L. Haines and M. A. Pericak-Vance for sharing their GWAS data with us; R. H. Myers, J.F. Gusella, T. Foroud and N. Pankratz for making their data public via dbGaP; and J. Degner for assistance with the eQTL data repository website at University of Chicago. We acknowledge M. Adams, M. Zilka and the staff of CIDR for excellent genotyping service, M. Palumbo, C. S. Carmack and the staff of the Computational Biology and Statistics Core of Wadsworth Center for computing support and C. Lambert and G. L. Peterson for developing the randomized plate layout. This project was supported by Award Number R01NS36960 from the National Institute of Neurological Disorders and Stroke. Additional support was provided by an Edmond J. Safra Global Genetic Consortium Grant from the Michael J. Fox Foundation for Parkinson's Disease Research, Merit Review Award from the Department of Veterans Affairs (1I01BX000531), National Institutes of Aging (P30AG08017), National Institute of Mental Health (R21MH087336), Office of Research and Development, Clinical Sciences Research and Development Service, Department of Veteran Affairs, The Intramural Research Program of the US National Institutes of Health (NIH) at the National Library of Medicine and the Close to the Cure Foundation. Genotyping services were provided by CIDR, which is fully funded through a federal contract from the NIH to Johns Hopkins University, contract number HHSN268200782096C. The work described in ref. 8, whose data were used for replication, was funded by NIH grants AG027944 and NS039764. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 35 TC 271 Z9 276 U1 4 U2 20 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 SEP PY 2010 VL 42 IS 9 BP 781 EP U75 DI 10.1038/ng.642 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 644OM UT WOS:000281388400015 PM 20711177 ER PT J AU Stephan, MT Moon, JJ Um, SH Bershteyn, A Irvine, DJ AF Stephan, Matthias T. Moon, James J. Um, Soong Ho Bershteyn, Anna Irvine, Darrell J. TI Therapeutic cell engineering with surface-conjugated synthetic nanoparticles SO NATURE MEDICINE LA English DT Article ID T-LYMPHOCYTES; STEM-CELLS; TRANSPLANTATION; ANTIGEN; IMPACT; CANCER; EXPANSION; TARGET; IL-15; TRIAL AB A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery. C1 [Stephan, Matthias T.; Moon, James J.; Um, Soong Ho; Bershteyn, Anna; Irvine, Darrell J.] MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. [Stephan, Matthias T.; Moon, James J.; Um, Soong Ho; Bershteyn, Anna; Irvine, Darrell J.] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. [Um, Soong Ho; Irvine, Darrell J.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Irvine, Darrell J.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Irvine, Darrell J.] Harvard Univ, Boston, MA 02115 USA. [Irvine, Darrell J.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Irvine, DJ (reprint author), MIT, Dept Mat Sci & Engn, Cambridge, MA 02139 USA. EM djirvine@mit.edu FU US National Institutes of Health [CA140476]; US National Science Foundation [DMR-02-13282]; US National Cancer Institute [P30-CA14051] FX This work was supported in part by the US National Institutes of Health (CA140476), the US National Science Foundation (Materials Research Science and Engineering Center award DMR-02-13282), Cancer Center Support (core) grant P30-CA14051 from the US National Cancer Institute and a gift to the Koch Institute by Curtis and Cathy Marble. D.J.I. is an investigator of the Howard Hughes Medical Institute. We thank M. Sadelain (Memorial Sloan-Kettering Cancer Center) for extG-luc and M. van den Brink (Memorial Sloan-Kettering Cancer Center) for F-luc-transgenic mice. NR 32 TC 163 Z9 165 U1 8 U2 117 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2010 VL 16 IS 9 BP 1035 EP U135 DI 10.1038/nm.2198 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 647MP UT WOS:000281622900034 PM 20711198 ER PT J AU Kotz, KT Xiao, W Miller-Graziano, C Qian, WJ Russom, A Warner, EA Moldawer, LL De, A Bankey, PE Petritis, BO Camp, DG Rosenbach, AE Goverman, J Fagan, SP Brownstein, BH Irimia, D Xu, WH Wilhelmy, J Mindrinos, MN Smith, RD Davis, RW Tompkins, RG Toner, M AF Kotz, Kenneth T. Xiao, Wenzong Miller-Graziano, Carol Qian, Wei-Jun Russom, Aman Warner, Elizabeth A. Moldawer, Lyle L. De, Asit Bankey, Paul E. Petritis, Brianne O. Camp, David G., II Rosenbach, Alan E. Goverman, Jeremy Fagan, Shawn P. Brownstein, Bernard H. Irimia, Daniel Xu, Weihong Wilhelmy, Julie Mindrinos, Michael N. Smith, Richard D. Davis, Ronald W. Tompkins, Ronald G. Toner, Mehmet CA Inflammation Host Response Injury TI Clinical microfluidics for neutrophil genomics and proteomics SO NATURE MEDICINE LA English DT Article ID CHROMATOGRAPHY-MASS SPECTROMETRY; COLONY-STIMULATING FACTOR; T-CELL; POLYMORPHONUCLEAR NEUTROPHILS; INFLAMMATORY STIMULI; EXPRESSION; LIPOPOLYSACCHARIDE; ACTIVATION; BLOOD; MACROPHAGES AB Neutrophils have key roles in modulating the immune response. We present a robust methodology for rapidly isolating neutrophils directly from whole blood with 'on-chip' processing for mRNA and protein isolation for genomics and proteomics. We validate this device with an ex vivo stimulation experiment and by comparison with standard bulk isolation methodologies. Last, we implement this tool as part of a near-patient blood processing system within a multi-center clinical study of the immune response to severe trauma and burn injury. The preliminary results from a small cohort of subjects in our study and healthy controls show a unique time-dependent gene expression pattern clearly demonstrating the ability of this tool to discriminate temporal transcriptional events of neutrophils within a clinical setting. C1 [Kotz, Kenneth T.; Xiao, Wenzong; Russom, Aman; Rosenbach, Alan E.; Goverman, Jeremy; Fagan, Shawn P.; Irimia, Daniel; Tompkins, Ronald G.; Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Shriners Hosp Children,Dept Surg, Boston, MA 02115 USA. [Xiao, Wenzong; Xu, Weihong; Wilhelmy, Julie; Mindrinos, Michael N.; Davis, Ronald W.] Stanford Genome Technol Ctr, Palo Alto, CA USA. [Miller-Graziano, Carol; De, Asit; Bankey, Paul E.] Univ Rochester, Sch Med, Dept Surg, Rochester, NY USA. [Qian, Wei-Jun; Petritis, Brianne O.; Camp, David G., II; Smith, Richard D.] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Qian, Wei-Jun; Petritis, Brianne O.; Camp, David G., II; Smith, Richard D.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Warner, Elizabeth A.; Moldawer, Lyle L.] Univ Florida, Coll Med, Dept Surg, Gainesville, FL USA. [Brownstein, Bernard H.] Washington Univ, Dept Radiat Oncol, St Louis, MO USA. RP Kotz, KT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Shriners Hosp Children,Dept Surg, Boston, MA 02115 USA. EM kkotz@partners.org; mtoner@hms.harvard.edu RI Qian, Weijun/C-6167-2011; Russom, Aman/B-1675-2012; Smith, Richard/J-3664-2012; Xu, Weihong/C-4175-2012; OI Smith, Richard/0000-0002-2381-2349; Irimia, Daniel/0000-0001-7347-2082; Russom, Aman/0000-0002-0242-358X FU US National Institutes of Health (NIH) [T32 GM-007035-32]; US NIH Inflammation FX We thank O. Hurtado, K. Eken, K. Richter and A. Gupta for microfabrication support. We thank C. Vanderburg for help with nucleic acid analysis and the use of the Harvard NeuroDiscovery Center Agilent Bioanalyzer 2100. We thank the University of Florida technical staff (A. Abouhamze, C. Tannahill and R. Ungaro) for managing clinical implementation of the microfluidic devices. K. T. K. was supported by a US National Institutes of Health (NIH) training grant T32 GM-007035-32. These studies were supported by the US NIH Inflammation and the Host Response to Injury Large Scale Collaborative Project, U54 GM-062119, BioMEMS Resource Center P41 EB-002503 and Proteomics Research Resource for Integrative Biology RR018522. The ex vivo stimulation studies and genomics protocol development were partially supported by US National Institutes of Health grants R01-GM-36214 and P01 HG000205, respectively. The proteomics work was performed in the Environmental Molecular Sciences Laboratory, a US Department of Energy Office of Biological and Environmental Research national scientific user facility on the Pacific Northwest National Laboratory (PNNL) campus. PNNL is multiprogram national laboratory operated by Battelle for the Department of Energy under contract number DE-AC05-76RLO 1830. NR 39 TC 78 Z9 79 U1 3 U2 45 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2010 VL 16 IS 9 BP 1042 EP U142 DI 10.1038/nm.2205 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 647MP UT WOS:000281622900035 PM 20802500 ER PT J AU Braun, P Tasan, M Cusick, M Hill, DE Vidal, M AF Braun, Pascal Tasan, Murat Cusick, Michael Hill, David E. Vidal, Marc TI Exhaustive benchmarking of the yeast two-hybrid system Reply SO NATURE METHODS LA English DT Letter ID NETWORK; MAP C1 [Braun, Pascal; Tasan, Murat; Cusick, Michael; Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Braun, Pascal; Tasan, Murat; Cusick, Michael; Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Braun, Pascal; Cusick, Michael; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Tasan, Murat] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. RP Braun, P (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. EM pascal_braun@dfci.harvard.edu; marc_vidal@dfci.harvard.edu RI Hill, David/B-6617-2011; Braun, Pascal/B-9669-2013 OI Braun, Pascal/0000-0003-2012-6746 NR 5 TC 2 Z9 2 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD SEP PY 2010 VL 7 IS 9 BP 668 EP 668 DI 10.1038/nmeth0910-668a PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 645CT UT WOS:000281429200005 ER PT J AU Giordano-Santini, R Milstein, S Svrzikapa, N Tu, D Johnsen, R Baillie, D Vidal, M Dupuy, D AF Giordano-Santini, Rosina Milstein, Stuart Svrzikapa, Nenad Tu, Domena Johnsen, Robert Baillie, David Vidal, Marc Dupuy, Denis TI An antibiotic selection marker for nematode transgenesis SO NATURE METHODS LA English DT Article ID CAENORHABDITIS-ELEGANS; C-ELEGANS; GENE-TRANSFER; TRANSFORMATION AB We have developed a nematode transformation vector carrying the bacterial neomycin resistance gene (NeoR) and shown that it could confer resistance to G-418 on both wild-type Caenorhabditis elegans and C. briggsae. This selection system allows hands-off maintenance and enrichment of transgenic worms carrying non-integrated transgenes on selective plates. We also show that this marker can be used for Mos1-mediated single-copy insertion in wild-type genetic backgrounds (MosSCISCISCI-biotic). C1 [Giordano-Santini, Rosina; Dupuy, Denis] Inst Europeen Chim & Biol, INSERM, U869, Pessac, France. [Milstein, Stuart; Svrzikapa, Nenad; Vidal, Marc] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Milstein, Stuart; Svrzikapa, Nenad; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Milstein, Stuart; Svrzikapa, Nenad; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Tu, Domena; Johnsen, Robert; Baillie, David] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada. RP Dupuy, D (reprint author), Inst Europeen Chim & Biol, INSERM, U869, Pessac, France. EM d.dupuy@iecb.u-bordeaux.fr RI Dupuy, Denis/M-7299-2014; OI Dupuy, Denis/0000-0002-4781-5595 NR 15 TC 32 Z9 33 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD SEP PY 2010 VL 7 IS 9 BP 721 EP U77 DI 10.1038/nmeth.1494 PG 5 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 645CT UT WOS:000281429200015 PM 20729841 ER PT J AU Sakadzic, S Roussakis, E Yaseen, MA Mandeville, ET Srinivasan, VJ Arai, K Ruvinskaya, S Devor, A Lo, EH Vinogradov, SA Boas, DA AF Sakadzic, Sava Roussakis, Emmanuel Yaseen, Mohammad A. Mandeville, Emiri T. Srinivasan, Vivek J. Arai, Ken Ruvinskaya, Svetlana Devor, Anna Lo, Eng H. Vinogradov, Sergei A. Boas, David A. TI Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue SO NATURE METHODS LA English DT Article ID IN-VIVO; PHOSPHORESCENCE; MICROSCOPY; BRAIN; TENSION; METABOLISM; CORTEX; ACCESSIBILITY; STIMULATION; TOMOGRAPHY AB Measurements of oxygen partial pressure (pO(2)) with high temporal and spatial resolution in three dimensions is crucial for understanding oxygen delivery and consumption in normal and diseased brain. Among existing pO(2) measurement methods, phosphorescence quenching is optimally suited for the task. However, previous attempts to couple phosphorescence with two-photon laser scanning microscopy have faced substantial difficulties because of extremely low two-photon absorption cross-sections of conventional phosphorescent probes. Here we report to our knowledge the first practical in vivo two-photon high-resolution pO(2) measurements in small rodents' cortical microvasculature and tissue, made possible by combining an optimized imaging system with a twophoton-enhanced phosphorescent nanoprobe. The method features a measurement depth of up to 250. m, sub-second temporal resolution and requires low probe concentration. The properties of the probe allowed for direct high-resolution measurement of cortical extravascular (tissue) pO(2), opening many possibilities for functional metabolic brain studies. C1 [Roussakis, Emmanuel; Vinogradov, Sergei A.] Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. [Sakadzic, Sava; Yaseen, Mohammad A.; Srinivasan, Vivek J.; Ruvinskaya, Svetlana; Devor, Anna; Boas, David A.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Photon Migrat Imaging Lab, Charlestown, MA USA. [Sakadzic, Sava; Yaseen, Mohammad A.; Mandeville, Emiri T.; Srinivasan, Vivek J.; Arai, Ken; Ruvinskaya, Svetlana; Devor, Anna; Lo, Eng H.; Boas, David A.] Harvard Univ, Sch Med, Charlestown, MA USA. [Mandeville, Emiri T.; Arai, Ken; Lo, Eng H.] Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Charlestown, MA USA. [Mandeville, Emiri T.; Arai, Ken; Lo, Eng H.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Devor, Anna] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Devor, Anna] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. RP Vinogradov, SA (reprint author), Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. EM vinograd@mail.med.upenn.edu; dboas@nmr.mgh.harvard.edu FU NHLBI NIH HHS [R01 HL081273, R01 HL081273-04, R01HL081273]; NIBIB NIH HHS [R01 EB000790, R01 EB000790-05, R01 EB007279, R01 EB007279-04, R01EB000790, R01EB007279]; NINDS NIH HHS [P01 NS055104-049001, K99 NS067050, K99 NS067050-01, K99NS067050, P01 NS055104, P01NS055104, P50 NS010828, P50 NS010828-320035, P50NS010828, R00 NS067050, R01 NS051188, R01 NS057198, R01 NS057476, R01 NS057476-04, R01NS057476] NR 34 TC 155 Z9 156 U1 3 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD SEP PY 2010 VL 7 IS 9 BP 755 EP U125 DI 10.1038/nmeth.1490 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 645CT UT WOS:000281429200022 PM 20693997 ER PT J AU Haun, JB Devaraj, NK Hilderbrand, SA Lee, H Weissleder, R AF Haun, Jered B. Devaraj, Neal K. Hilderbrand, Scott A. Lee, Hakho Weissleder, Ralph TI Bioorthogonal chemistry amplifies nanoparticle binding and enhances the sensitivity of cell detection SO NATURE NANOTECHNOLOGY LA English DT Article ID QUANTUM DOTS; CANCER-CELLS; TUMOR-CELLS; STREPTAVIDIN; THERAPEUTICS; DELIVERY; THERAPY; AVIDIN AB Nanoparticles have emerged as key materials for biomedical applications because of their unique and tunable physical properties, multivalent targeting capability, and high cargo capacity(1,2). Motivated by these properties and by current clinical needs, numerous diagnostic(3-10) and therapeutic(11-13) nanomaterials have recently emerged. Here we describe a novel nanoparticle targeting platform that uses a rapid, catalyst-free cycloaddition as the coupling mechanism. Antibodies against biomarkers of interest were modified with trans-cyclooctene and used as scaffolds to couple tetrazine-modified nanoparticles onto live cells. We show that the technique is fast, chemoselective, adaptable to metal nanomaterials, and scalable for biomedical use. This method also supports amplification of biomarker signals, making it superior to alternative targeting techniques including avidin/biotin. C1 [Haun, Jered B.; Devaraj, Neal K.; Hilderbrand, Scott A.; Lee, Hakho; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Haun, JB (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu RI Devaraj, Neal/B-4712-2014 FU NCI [P50CA86355, RO1 EB004626] FX The authors gratefully acknowledge N. Sergeyev for synthesizing CLIO and C. Wang for assistance with MALDI-TOF measurements. We especially thank G. Thurber, M. Pittet, F. Swirski and M. Nahrendorf for their many helpful suggestions. We also thank Y. Fisher-Jeffes for reviewing the manuscript. This work was funded in part by NCI grant P50CA86355 and RO1 EB004626. NR 30 TC 155 Z9 156 U1 8 U2 114 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1748-3387 J9 NAT NANOTECHNOL JI Nat. Nanotechnol. PD SEP PY 2010 VL 5 IS 9 BP 660 EP 665 DI 10.1038/NNANO.2010.148 PG 6 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA 647FO UT WOS:000281603400012 PM 20676091 ER PT J AU Silva, PS Cavallerano, JD Sun, JK Aiello, LM Aiello, LP AF Silva, Paolo S. Cavallerano, Jerry D. Sun, Jennifer K. Aiello, Lloyd M. Aiello, Lloyd Paul TI Effect of systemic medications on onset and progression of diabetic retinopathy SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; INTRAVITREAL BEVACIZUMAB AVASTIN; RANDOMIZED CLINICAL-TRIAL; BLOOD-GLUCOSE CONTROL; PLACEBO-CONTROLLED TRIALS; MACULAR EDEMA; FOLLOW-UP; CARDIOVASCULAR-DISEASE; MICROVASCULAR COMPLICATIONS; FOCAL/GRID PHOTOCOAGULATION AB Diabetic retinopathy remains a leading cause of visual loss worldwide. Patients with diabetes mellitus commonly have multiple comorbidities treated with a wide variety of medications. Systemic medications that target glycemic control and coexisting conditions may have beneficial or deleterious effects on the onset or progression of diabetic retinopathy. In addition, data is accumulating to suggest that the use of systemic therapy primarily to address ocular complications of diabetic retinopathy may be a promising therapeutic approach. This article reviews our current understanding of the ocular-specific effects of systemic medications commonly used by patients with diabetes mellitus, including those directed at control of hyperglycemia, dyslipidemia, hypertension, cardiac disease, anemia, inflammation and cancer. Current clinical evidence is strongest for the use of angiotensin-converting enzyme inhibitors and angiotensin-2 receptor blockers in preventing the onset or slowing the progression of early diabetic retinopathy. To a more limited extent, evidence of a benefit of fibrates for diabetic macular edema exists. Numerous other agents hold considerable promise or potential risk. Thus, these compounds must undergo further rigorous study to determine the actual clinical efficacy and adverse effects before definitive therapeutic care recommendations can be offered. C1 [Silva, Paolo S.; Cavallerano, Jerry D.; Sun, Jennifer K.; Aiello, Lloyd M.; Aiello, Lloyd Paul] Harvard Univ, Sch Med, Beetham Eye Inst, Joslin Diabet Ctr,Dept Ophthalmol, Boston, MA 02215 USA. RP Aiello, LP (reprint author), Harvard Univ, Sch Med, Beetham Eye Inst, Joslin Diabet Ctr,Dept Ophthalmol, 1 Joslin Pl, Boston, MA 02215 USA. EM lpaiello@joslin.harvard.ed NR 155 TC 19 Z9 19 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 EI 1759-5037 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD SEP PY 2010 VL 6 IS 9 BP 494 EP 507 DI 10.1038/nrendo.2010.122 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 641LH UT WOS:000281126900008 PM 20664533 ER PT J AU Muller, MR Rao, A AF Mueller, Martin R. Rao, Anjana TI NFAT, immunity and cancer: a transcription factor comes of age SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID REGULATORY T-CELLS; NUCLEAR-FACTOR; CYCLOSPORINE-A; KAPPA-B; FOXP3 EXPRESSION; GENE-EXPRESSION; MAST-CELLS; SELECTIVE-INHIBITION; SIGNALING PROTEINS; ANTIGEN RECEPTOR AB Nuclear factor of activated T cells (NFAT) was first identified more than two decades ago as a major stimulation-responsive DNA-binding factor and transcriptional regulator in T cells. It is now clear that NFAT proteins have important functions in other cells of the immune system and regulate numerous developmental programmes in vertebrates. Dysregulation of these programmes can lead to malignant growth and cancer. This Review focuses on recent advances in our understanding of the transcriptional functions of NFAT proteins in the immune system and provides new insights into their potential roles in cancer development. C1 [Mueller, Martin R.] Univ Tubingen, Dept Haematol Oncol & Immunol, Med Klin & Poliklin, D-72076 Tubingen, Germany. [Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Rao, Anjana] Childrens Hosp Boston, Immune Dis Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. [Rao, Anjana] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. RP Muller, MR (reprint author), Univ Tubingen, Dept Haematol Oncol & Immunol, Med Klin & Poliklin, Otfried Muller Str 10, D-72076 Tubingen, Germany. EM martin.mueller@med.uni-tuebingen.de FU Deutsche Krebshilfe; Cancer Research Institute; University of Tubingen; National Institutes of Health; Juvenile Diabetes Research Foundation FX This work was supported by grants from the Deutsche Krebshilfe, the Cancer Research Institute and the Fortune program of the University of Tubingen to M. R. M, and grants from the National Institutes of Health and the Juvenile Diabetes Research Foundation to A.R. NR 119 TC 191 Z9 195 U1 6 U2 31 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD SEP PY 2010 VL 10 IS 9 BP 645 EP 656 DI 10.1038/nri2818 PG 12 WC Immunology SC Immunology GA 643WG UT WOS:000281329900012 PM 20725108 ER PT J AU Kelly, PJ Lin, YB Yu, AYC Sher, DJ Hacker, FL Marcus, KJ Weiss, SE AF Kelly, P. J. Lin, Y. B. Yu, A. Y. C. Sher, D. J. Hacker, F. L. Marcus, K. J. Weiss, S. E. TI CASE SERIES OF FRAMELESS LINEAR ACCELERATOR-BASED STEREOTACTIC RADIOSURGERY TO THE POSTOPERATIVE RESECTION CAVITY FOR BRAIN METASTASIS: AN INITIAL REPORT OF OUTCOMES AND PATTERNS OF FAILURE SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 9th Meeting of European-Association-of-NeuroOncology CY SEP 16-19, 2010 CL Maastricht, NETHERLANDS SP European Assoc NeuroOncol C1 [Kelly, P. J.; Sher, D. J.; Hacker, F. L.; Marcus, K. J.; Weiss, S. E.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lin, Y. B.; Yu, A. Y. C.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD SEP PY 2010 VL 12 SU 3 BP 6 EP 6 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 642DU UT WOS:000281184800022 ER PT J AU Avni, B Grisariu, S Batchelor, TT van den Bent, MJ Bokstein, F Schiff, D Kuittinen, O Chamberlain, MC Roth, P Nemets, A Shalom, E Ben-Yehuda, D Siegal, T AF Avni, B. Grisariu, S. Batchelor, T. T. van den Bent, M. J. Bokstein, F. Schiff, D. Kuittinen, O. Chamberlain, M. C. Roth, P. Nemets, A. Shalom, E. Ben-Yehuda, D. Siegal, T. TI HAVE CLINICAL FEATURES AND TREATMENT OUTCOME OF 166 PATIENTS WITH NEUROLYMPHOMATOSIS (NL) CHANGED OVER A PERIOD OF 36 YEAR? ASSESSMENT OF A CONTEMPORARY INTERNATIONAL PRIMARY CNS LYMPHOMA COLLABORATIVE GROUP (IPCG) SERIES AND LITERATURE CASE REVIEW SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 9th Meeting of European-Association-of-NeuroOncology CY SEP 16-19, 2010 CL Maastricht, NETHERLANDS SP European Assoc NeuroOncol C1 [Avni, B.; Grisariu, S.; Shalom, E.; Ben-Yehuda, D.; Siegal, T.] Hadassah Hebrew Univ Med Ctr, Jerusalem, Israel. [Batchelor, T. T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [van den Bent, M. J.] Erasmus Univ, Med Ctr, Dr Daniel Den Hoed Canc Ctr, Rotterdam, Netherlands. [Bokstein, F.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. [Schiff, D.] Univ Virginia, Charlottesville, VA USA. [Kuittinen, O.] Oulu Univ Hosp, Oulu, Finland. [Chamberlain, M. C.] Univ Washington, Seattle, WA 98195 USA. [Roth, P.] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Nemets, A.] Barzilai Govt Hosp, Ashqelon, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD SEP PY 2010 VL 12 SU 3 BP 19 EP 19 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 642DU UT WOS:000281184800068 ER PT J AU Broekman, ML Maas, NSLN Skog, J Breakefield, XO Esteves, MS AF Broekman, M. L. Maas, N. S. L. N. Skog, J. Breakefield, X. O. Esteves, M. Sena TI REVERSAL OF EFFECT OF U87 DERIVED MICRO-VESICLES ON BIOLOGICAL PROCESSES OF GLIOBLASTOMA MULTIFORME SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 9th Meeting of European-Association-of-NeuroOncology CY SEP 16-19, 2010 CL Maastricht, NETHERLANDS SP European Assoc NeuroOncol C1 [Broekman, M. L.; Maas, N. S. L. N.] Univ Med Ctr Utrecht, Dept Neurosurg, Utrecht, Netherlands. [Broekman, M. L.] Erasmus MC, Dept Neurosurg, Neurooncol Lab, Rotterdam, Netherlands. [Maas, N. S. L. N.; Esteves, M. Sena] Univ Massachusetts, Sch Med, Dept Neurol & Gene Therapy, Worcester, MA USA. [Skog, J.; Breakefield, X. O.] Massachusetts Gen Hosp, Dept Neurol, Mol Neurogenet Unit, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD SEP PY 2010 VL 12 SU 3 BP 21 EP 21 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 642DU UT WOS:000281184800077 ER PT J AU Fulci, G Kleijn, A Buhrman, J Collins, S Lamfers, M Rabkin, S Martuza, R AF Fulci, G. Kleijn, A. Buhrman, J. Collins, S. Lamfers, M. Rabkin, S. Martuza, R. TI MODULATING THE IL-1 SIGNALING DURING GLIOMA ONCOLYTIC VIROTHERAPY SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 9th Meeting of European-Association-of-NeuroOncology CY SEP 16-19, 2010 CL Maastricht, NETHERLANDS SP European Assoc NeuroOncol C1 [Fulci, G.; Kleijn, A.; Buhrman, J.; Collins, S.; Rabkin, S.; Martuza, R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lamfers, M.] Erasmus MC, Rotterdam, Netherlands. RI rabkin, samuel/C-2443-2012 OI rabkin, samuel/0000-0003-2344-2795 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD SEP PY 2010 VL 12 SU 3 BP 29 EP 29 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 642DU UT WOS:000281184800107 ER PT J AU Kleijn, A Chen, JW Sun, PZ Buhrman, J Rabkin, SD Weissleder, R Martuza, RL Lamfers, ML Fulci, G AF Kleijn, A. Chen, J. W. Sun, P. Z. Buhrman, J. Rabkin, S. D. Weissleder, R. Martuza, R. L. Lamfers, M. L. Fulci, G. TI MAGNETIC RESONANCE IMAGING OF VIRAL SPREAD AND INTRATUMORAL INFLAMMATION DURING ONCOLYTIC VIROTHERAPY SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 9th Meeting of European-Association-of-NeuroOncology CY SEP 16-19, 2010 CL Maastricht, NETHERLANDS SP European Assoc NeuroOncol C1 [Kleijn, A.; Chen, J. W.; Sun, P. Z.; Buhrman, J.; Rabkin, S. D.; Weissleder, R.; Martuza, R. L.; Fulci, G.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA USA. [Kleijn, A.; Lamfers, M. L.] Erasmus MC, Rotterdam, Netherlands. RI rabkin, samuel/C-2443-2012 OI rabkin, samuel/0000-0003-2344-2795 NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD SEP PY 2010 VL 12 SU 3 BP 36 EP 36 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 642DU UT WOS:000281184800136 ER PT J AU Peyrl, A Heinrich, M Azizi, A Czech, T Reismuller, B Kieran, M Prayer, D Slavc, I AF Peyrl, A. Heinrich, M. Azizi, A. Czech, T. Reismueller, B. Kieran, M. Prayer, D. Slavc, I. TI MARKED REGRESSION OF CERVICAL PARAGANGLIOMA WITH ANTIANGIOGENIC METRONOMIC THERAPY SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 9th Meeting of European-Association-of-NeuroOncology CY SEP 16-19, 2010 CL Maastricht, NETHERLANDS SP European Assoc NeuroOncol C1 [Peyrl, A.; Heinrich, M.; Azizi, A.; Reismueller, B.; Slavc, I.] Med Univ Vienna, Dept Pediat, Vienna, Austria. [Czech, T.] Med Univ Vienna, Dept Neurosurg, Vienna, Austria. [Kieran, M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Prayer, D.] Med Univ Vienna, Dept Radiol, Vienna, Austria. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD SEP PY 2010 VL 12 SU 3 BP 54 EP 54 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 642DU UT WOS:000281184800205 ER PT J AU Bartzokis, G Lu, PH Tingus, K Mendez, MF Richard, A Peters, DG Oluwadara, B Barrall, KA Finn, JP Villablanca, P Thompson, PM Mintz, J AF Bartzokis, George Lu, Po H. Tingus, Kathleen Mendez, Mario F. Richard, Aurore Peters, Douglas G. Oluwadara, Bolanle Barrall, Katherine A. Finn, J. Paul Villablanca, Pablo Thompson, Paul M. Mintz, Jim TI Lifespan trajectory of myelin integrity and maximum motor speed SO NEUROBIOLOGY OF AGING LA English DT Article DE Age; Processing speed; Motor; White matter; Oligodendrocyte; Breakdown; Cognition; Dementia; Risk; Neurodegeneration; Alzheimer; Onset; Frontal lobe; Treatment; Prevention ID INDUCED INTRAMYELINIC EDEMA; DEMYELINATED NERVE-FIBERS; REITAN NEUROPSYCHOLOGICAL TESTS; MATTER STRUCTURAL INTEGRITY; PRIMATE CEREBRAL-CORTEX; WHITE-MATTER; COGNITIVE DECLINE; RHESUS-MONKEY; HUMAN BRAIN; ALZHEIMERS-DISEASE AB Objective Myelination of the human brain results in roughly quadratic trajectories of myelin content and integrity, reaching a maximum in mid-life and then declining in older age This trajectory is most evident in vulnerable later myelinating association regions such as frontal lobes and may be the biological substrate for similar trajectories of cognitive processing speed Speed of movement, such as maximal finger tapping speed (FTS), requires high-frequency action potential (AP) bursts and is associated with myelin integrity We tested the hypothesis that the age-related trajectory of FTS is related to brain myelin integrity Methods A sensitive in VIVO MRI biomarker of myelin integrity (calculated transverse relaxation rates (R(2))) of frontal lobe white matter (FLwm) was measured in a sample of very healthy males (N=72) between 23 and 80 years of age To assess specificity. R, of a contrasting early-myelinating region (splenium of the corpus callosum) was also measured Results FLwm R(2) and FTS measures were significantly correlated (r=45, p<0001) with no association noted in the early-myelinating region (splenium) Both FLwm R(2) and FTS had significantly quadratic lifespan trajectories that were virtually indistinguishable and both reached a peak at 39 years of age and declined with an accelerating trajectory thereafter Conclusions The results suggest that in this very healthy male sample, maximum motor speed requiring high-frequency AP burst may depend on brain myelin integrity To the extent that the FLwm changes assessed by R(2) contribute to an age-related reduction in AP burst frequency, it is possible that other brain functions dependent on AP bursts may also he affected Non-invasive measures of myelin integrity together with testing of basic measures of processing speed may aid in developing and targeting anti-aging treatments to mitigate age-related functional declines (C) 2008 Elsevier Inc All rights reserved C1 [Bartzokis, George; Richard, Aurore; Peters, Douglas G.; Oluwadara, Bolanle] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Bartzokis, George; Thompson, Paul M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Lab Neuroimaging,Div Brain Mapping, Los Angeles, CA 90095 USA. [Bartzokis, George; Mendez, Mario F.; Barrall, Katherine A.] Greater Los Angeles VA Healthcare Syst, Dept Psychiat, Los Angeles, CA 90073 USA. [Finn, J. Paul; Villablanca, Pablo] Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA 90095 USA. [Mintz, Jim] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. RP Bartzokis, G (reprint author), 300 UCLA Med Plaza,Suite 2200, Los Angeles, CA 90095 USA. RI Bartzokis, George/K-2409-2013 FU NIH [MH066029, AG027342, EB008281, P50 AG 16570, U54 RR021813]; RCS Alzheimer's Foundation; Sidell-Kagan Foundation; Department of Veterans Affairs FX This work was supported in part by NIH grants (MH066029; AG027342; EB008281, P50 AG 16570; U54 RR021813). the RCS Alzheimer's Foundation, Sidell-Kagan Foundation; and the Department of Veterans Affairs. NR 88 TC 82 Z9 83 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD SEP PY 2010 VL 31 IS 9 BP 1554 EP 1562 DI 10.1016/j.neurobiolaging.2008.08.015 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 632UO UT WOS:000280454700006 PM 18926601 ER PT J AU Viswanathan, A Godin, O Jouvent, E O'Sullivan, M Gschwendtner, A Peters, N Duering, M Guichard, JP Holtmannspotter, M Dufouil, C Pachai, C Bousser, MG Dichgans, M Chabriat, H AF Viswanathan, Anand Godin, Ophelia Jouvent, Eric O'Sullivan, Michael Gschwendtner, Andreas Peters, Nils Duering, Marco Guichard, Jean-Pierre Holtmannspoetter, Markus Dufouil, Carole Pachai, Chahin Bousser, Marie-Germaine Dichgans, Martin Chabriat, Hugues TI Impact of MRI markers in subcortical vascular dementia: A multi-modal analysis in CADASIL SO NEUROBIOLOGY OF AGING LA English DT Article DE CADASIL; Cerebral microhemorrhage; Lacunar infarction; Atrophy; White matter damage; Cognitive impairment; Disability ID WHITE-MATTER HYPERINTENSITIES; AUTOSOMAL-DOMINANT ARTERIOPATHY; DIFFUSION TENSOR MRI; STROKE RISK PROFILE; ISCHEMIC LEUKOARAIOSIS; CARDIOVASCULAR HEALTH; COGNITIVE PERFORMANCE; CEREBRAL MICROBLEEDS; DISEASE PROGRESSION; LACUNAR INFARCTS AB CADASIL is an arteriopathy caused by mutations of the Notch3 gene White matter hyperintensities (WMH). lacunar lesions (LL), cerebral microhemorrhages (CM). brain atrophy and tissue microstructural changes are detected on MRI Using an integrated multi-modal approach, we examined the relative impact of lesion burden and location of these MRI markers on cognitive impairment and disability Multi-modal imaging was performed on 147 patients from a two-center cohort study Volume of LL, WMH and number of CM was determined Whole brain mean apparent diffusion coefficient (mean-ADC) and brain parenchymal fraction (BPF) were measured In multivariate models accounting for lesion burden and location, volume of LL, mean-ADC, and BPF each had an independent influence on global cognitive function and BPF explained the largest portion of the variation in cognitive and disability scores (35-38%) Brain atrophy has the strongest independent Influence on clinical impairment in CA DASIL when all MRI markers in the disease are considered together The results suggest that the clinical impact of cerebral tissue loss plays a principal role in this genetic model of subcortical ischemic vascular dementia (C) 2008 Elsevier Inc All rights reserved C1 [Viswanathan, Anand; Godin, Ophelia; Jouvent, Eric; Bousser, Marie-Germaine; Chabriat, Hugues] CHU Lariboisiere, Dept Neurol, AP HP, Lariboisiere, France. [Viswanathan, Anand] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Viswanathan, Anand] Massachusetts Gen Hosp, Clin Trials Unit, Boston, MA 02114 USA. [Viswanathan, Anand] Harvard Univ, Sch Med, Boston, MA USA. [O'Sullivan, Michael; Gschwendtner, Andreas; Peters, Nils; Duering, Marco; Dichgans, Martin] Univ Munich, Klinikum Grosshadern, Dept Neurol, D-81377 Munich, Germany. [Guichard, Jean-Pierre] CHU Lariboisiere, AP HP, Dept Neuroradiol, Lariboisiere, France. [Holtmannspoetter, Markus] Univ Munich, Klinikum Grosshadern, Dept Neuroradiol, D-81377 Munich, Germany. [Godin, Ophelia; Dufouil, Carole] INSERM, Neuroepidemiol U708, F-75013 Paris, France. [Godin, Ophelia; Dufouil, Carole] Univ Paris 06, F-75005 Paris, France. [Pachai, Chahin] Bioimaging Technol SAS, Lyon, France. RP Chabriat, H (reprint author), Hop Lariboisiere, Serv Neurol, 2 Rue Ambroise Pare, F-75010 Paris, France. RI Dufouil, Carole/J-4968-2012; O'Sullivan, Michael/A-1796-2010; Jouvent, Eric/B-4320-2014; Chabriat, Hugues/G-5699-2010; OI Jouvent, Eric/0000-0001-7797-2236; Chabriat, Hugues/0000-0001-8436-6074; Duering, Marco/0000-0003-2302-3136 FU DRC/APHP [AOR 02-001]; Deutsche Forschungsgemeinschaft [SFB596/TPA4]; EISAI Medical Res Inc (Germany); Peel Medical Research Trust FX This work was supported by PHRC grant AOR 02-001 (DRC/APHP) and performed with the help of ARNEVA (Association de Recherche en Neurologic VAsculaire), Hopital Lariboisiere, France, the Deutsche Forschungsgemeinschaft (SFB596/TPA4), and a grant from EISAI Medical Res Inc (Germany) MO'S is an Alexander von Humboldt Fellow and was also supported by the Peel Medical Research Trust NR 43 TC 48 Z9 48 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD SEP PY 2010 VL 31 IS 9 BP 1629 EP 1636 DI 10.1016/j.neurobiolaging.2008.09.001 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 632UO UT WOS:000280454700014 PM 18926602 ER PT J AU Golfinopoulos, E Tourville, JA Guenther, FH AF Golfinopoulos, E. Tourville, J. A. Guenther, F. H. TI The integration of large-scale neural network modeling and functional brain imaging in speech motor control SO NEUROIMAGE LA English DT Article DE Computational model; Functional magnetic resonance imaging; Structural equation modeling; Speech production; DIVA model ID AUDITORY-FEEDBACK CONTROL; SENSORIMOTOR CORTEX; VERBAL FEEDBACK; TEMPORAL-LOBE; FMRI SIGNAL; LANGUAGE; AREA; REPRESENTATION; PREMOTOR; SYSTEM AB Speech production demands a number of integrated processing stages. The system must encode the speech motor programs that command movement trajectories of the articulators and monitor transient spatiotemporal variations in auditory and somatosensory feedback. Early models of this system proposed that independent neural regions perform specialized speech processes. As technology advanced, neuroimaging data revealed that the dynamic sensorimotor processes of speech require a distributed set of interacting neural regions. The DIVA (Directions into Velocities of Articulators) neurocomputational model elaborates on early theories, integrating existing data and contemporary ideologies, to provide a mechanistic account of acoustic, kinematic, and functional magnetic resonance imaging (fMRI) data on speech acquisition and production. This large-scale neural network model is composed of several interconnected components whose cell activities and synaptic weight strengths are governed by differential equations. Cells in the model are associated with neuroanatomical substrates and have been mapped to locations in Montreal Neurological Institute stereotactic space, providing a means to compare simulated and empirical fMRI data. The DIVA model also provides a computational and neurophysiological framework within which to interpret and organize research on speech acquisition and production in fluent and dysfluent child and adult speakers. The purpose of this review article is to demonstrate how the DIVA model is used to motivate and guide functional imaging studies. We describe how model predictions are evaluated using voxel-based, region-of-interest-based parametric analyses and inter-regional effective connectivity modeling of fMRI data. (C) 2009 Elsevier Inc. All rights reserved. C1 [Golfinopoulos, E.; Tourville, J. A.; Guenther, F. H.] Boston Univ, Dept Cognit & Neural Syst, Boston, MA 02115 USA. [Guenther, F. H.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Guenther, F. H.] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Guenther, F. 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 02115 USA. EM egolfino@cns.bu.edu FU National Institute on Deafness and other Communication Disorders [R01 DC02852]; CELEST, an NSF Science of Learning Center [NSF SBE-0354378]; 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 SBE-0354378). 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 Jon Brumberg for his patience and generous assistance and the entire Speechlab (past and present) for contributing ideas that continue to enhance the DIVA model. NR 99 TC 84 Z9 85 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 SEP PY 2010 VL 52 IS 3 BP 862 EP 874 DI 10.1016/j.neuroimage.2009.10.023 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 629FY UT WOS:000280181800012 PM 19837177 ER PT J AU Ziegler, DA Pritchett, DL Hosseini-Varnamkhasti, P Corkin, S Hamalainen, M Moore, CI Jones, SR AF Ziegler, David A. Pritchett, Dominique L. Hosseini-Varnamkhasti, Paymon Corkin, Suzanne Hamalainen, Matti Moore, Christopher I. Jones, Stephanie R. TI Transformations in oscillatory activity and evoked responses in primary somatosensory cortex in middle age: A combined computational neural modeling and MEG study SO NEUROIMAGE LA English DT Article ID MEDIAN NERVE-STIMULATION; SENSORIMOTOR CORTEX; MU-RHYTHM; QUANTITATIVE-ANALYSIS; SCALP TOPOGRAPHY; PHASE SYNCHRONY; HEALTHY-ADULTS; CENTRAL SULCUS; ALPHA-RHYTHMS; OLDER-ADULTS AB Oscillatory brain rhythms and evoked responses are widely believed to impact cognition, but relatively little is known about how these measures are affected by healthy aging. The present study used MEG to examine age-related changes in spontaneous oscillations and tactile evoked responses in primary somatosensory cortex (SI) in healthy young (YA) and middle-aged (MA) adults. To make specific predictions about neurophysiological changes that mediate age-related MEG changes, we applied a biophysically realistic model of SI that accurately reproduces SI MEG mu rhythms, containing alpha (7-14 Hz) and beta (15-30 Hz) components, and evoked responses. Analyses of MEG data revealed a significant increase in prestimulus mu power in SI, driven predominately by greater mu-beta dominance, and a larger and delayed M70 peak in the SI evoked response in MA. Previous analysis with our computational model showed that the SI mu rhythm could be reproduced with a stochastic sequence of rhythmic similar to 10 Hz feedforward (FF) input to the granular layers of SI (representative of lemniscal thalamic input) followed nearly simultaneously by similar to 10 Hz feedback (FB) input to the supragranular layers (representative of input from high order cortical or non-specific thalamic sources) (Jones et al., 2009). In the present study, the model further predicted that the rhythmic FF and FB inputs become stronger with age. Further, the FB input is predicted to arrive more synchronously to SI on each cycle of the 10 Hz input in MA. The simulated neurophysiological changes are sufficient to account for the age-related differences in both prestimulus mu rhythms and evoked responses. Thus, the model predicts that a single set of neurophysiological changes intimately links these age-related changes in neural dynamics. (C) 2010 Elsevier Inc. All rights reserved. C1 [Corkin, Suzanne; Hamalainen, Matti; Jones, Stephanie R.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ziegler, David A.; Pritchett, Dominique L.; Hosseini-Varnamkhasti, Paymon; Corkin, Suzanne; Moore, Christopher I.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Pritchett, Dominique L.; Moore, Christopher I.] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. RP Jones, SR (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM srjones@nmr.mgh.harvard.edu RI Hamalainen, Matti/C-8507-2013; OI Pritchett, Dominique/0000-0003-1187-1162 FU NIH [P41RR14075, K25MH072941, 1RO1-NS045130-01, T32 GM007484]; NSF [0316933]; Athinoula A. Martinos Center for Biomedical Imaging; McGovern Institute for Brain Research FX The authors wish to thank Michael Hines for excellent technical support in NEURON software code. This work was supported by NIH: P41RR14075, K25MH072941, 1RO1-NS045130-01, T32 GM007484, NSF: 0316933, the Athinoula A. Martinos Center for Biomedical Imaging, the McGovern Institute for Brain Research. NR 72 TC 17 Z9 17 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2010 VL 52 IS 3 BP 897 EP 912 DI 10.1016/j.neuroimage.2010.02.004 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 629FY UT WOS:000280181800015 PM 20149881 ER PT J AU Kay, DM Stevens, CF Hamza, TH Montimurro, JS Zabetian, CP Factor, SA Samii, A Griffith, A Roberts, JW Molho, ES Higgins, DS Gancher, S Moses, L Zareparsi, S Poorkaj, P Bird, T Nutt, J Schellenberg, GD Payami, H AF Kay, D. M. Stevens, C. F. Hamza, T. H. Montimurro, J. S. Zabetian, C. P. Factor, S. A. Samii, A. Griffith, A. Roberts, J. W. Molho, E. S. Higgins, D. S. Gancher, S. Moses, L. Zareparsi, S. Poorkaj, P. Bird, T. Nutt, J. Schellenberg, G. D. Payami, H. TI A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2 SO NEUROLOGY LA English DT Article ID ONSET PARKINSONS-DISEASE; RECESSIVE JUVENILE PARKINSONISM; DEPENDENT PROBE AMPLIFICATION; ALPHA-SYNUCLEIN; GENE; MUTATIONS; ASSOCIATION; HETEROZYGOSITY; SUSCEPTIBILITY; REARRANGEMENTS AB Objectives: To perform a comprehensive population genetic study of PARK2. PARK2 mutations are associated with juvenile parkinsonism, Alzheimer disease, cancer, leprosy, and diabetes mellitus, yet ironically, there has been no comprehensive study of PARK2 in control subjects; and to resolve controversial association of PARK2 heterozygous mutations with Parkinson disease (PD) in a well-powered study. Methods: We studied 1,686 control subjects (mean age 66.1 +/- 13.1 years) and 2,091 patients with PD (mean onset age 58.3 +/- 12.1 years). We tested for PARK2 deletions/multiplications/copy number variations (CNV) using semiquantitative PCR and multiplex ligation-dependent probe amplification, and validated the mutations by real-time quantitative PCR. Subjects were tested for point mutations previously. Association with PD was tested as PARK2 main effect, and in combination with known PD risk factors: SNCA, MAPT, APOE, smoking, and coffee intake. Results: A total of 0.95% of control subjects and 0.86% of patients carried a heterozygous CNV mutation. CNV mutations found in 16 control subjects were all in exons 1-4, sparing exons that encode functionally critical protein domains. Thirteen patients had 2 CNV mutations, 5 had 1 CNV and 1 point mutation, and 18 had 1 CNV mutation. Mutations found in patients spanned exons 2-9. In whites, having 1 CNV was not associated with increased risk (odds ratio 1.05, p = 0.89) or earlier onset of PD (64.7 +/- 8.6 heterozygous vs 58.5 +/- 11.8 normal). Conclusions: This comprehensive population genetic study in control subjects fills the void for a PARK2 reference dataset. There is no compelling evidence for association of heterozygous PARK2 mutations, by themselves or in combination with known risk factors, with PD. Neurology (R) 2010; 75: 1189-1194 C1 [Payami, H.] New York State Dept Hlth, Genom Inst, Wadsworth Ctr, Albany, NY 12201 USA. [Zabetian, C. P.; Samii, A.] VA Puget Sound Hlth Care Syst, Res Educ & Clin Ctr, Seattle, WA USA. [Factor, S. A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Factor, S. A.; Molho, E. S.; Higgins, D. S.] Albany Med Ctr, Parkinsons Dis & Movement Disorders Ctr, Albany, NY USA. [Griffith, A.] Evergreen Hosp, Med Ctr, Booth Gardner Parkinsons Care Ctr, Kirkland, WA USA. [Roberts, J. W.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Higgins, D. S.] Vet Affairs Med Ctr, Neurol Serv, Albany, NY USA. [Poorkaj, P.] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. [Poorkaj, P.] Univ Washington, Dept Behav Sci, Seattle, WA 98195 USA. [Zabetian, C. P.; Samii, A.; Bird, T.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Gancher, S.] Kaiser Permanente, Portland, OR USA. [Zareparsi, S.] W Virginia Univ, Dept Ophthalmol, Morgantown, WV 26506 USA. [Nutt, J.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Schellenberg, G. D.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Payami, H (reprint author), New York State Dept Hlth, Genom Inst, Wadsworth Ctr, POB 22002, Albany, NY 12201 USA. EM hpayami@wadsworth.org OI Kay, Denise/0000-0002-9928-2698 FU National Institutes of Health [NS R01-36960]; National Institutes of Neurologic Disease and Stroke (NINDS); Veterans Affairs Research Funds; Riley Family Chair in Parkinson's Disease; NIH National Institutes of Aging [AG 08017]; Swedish Medical Center; American Parkinson Disease Association; Portland Veterans Affairs Research Foundation; NIH (NINDS) [R01 NS065070-01 [PI], NINDS P50 NS062684-01 [PI Project 3], NINDSR01 NS036960-09, NINDS R01 NS057567-01, NIA R01 AG033398-01]; US Department of Veterans Affairs; Parkinson's Disease Foundation FX Supported by National Institutes of Health grant NS R01-36960 from the National Institutes of Neurologic Disease and Stroke (NINDS; H. P.); Veterans Affairs Research Funds (T. B., C. P. Z.); and the Riley Family Chair in Parkinson's Disease (E. S. M.). A subset of control subjects were acquired through the Indiana University National Cell Repository for Alzheimer's Disease, and NIH National Institutes of Aging grant AG 08017 (Jeffrey Kaye). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.; Dr. Kay, Dr. Stevens, Dr. Hamza, and J. S. Montimurro report no disclosures. Dr. Zabetian has received speaker honoraria from the Swedish Medical Center, the American Parkinson Disease Association, and the Portland Veterans Affairs Research Foundation; receives research support from the NIH (NINDS R01 NS065070-01 [PI], NINDS P50 NS062684-01 [PI Project 3], NINDSR01 NS036960-09 [coinvestigator], NINDS R01 NS057567-01 [coinvestigator], and NIA R01 AG033398-01 [coinvestigator]), the US Department of Veterans Affairs, the Parkinson's Disease Foundation, and the American Parkinson Disease Association. Dr. Factor serves as a Section Editor for Current Treatment Options in Neurology; receives royalties from the publication of Parkinson's Disease Diagnosis and Clinical Management (Demos, 2008) and Drug Induced Movement Disorders (Blackwell Futura, 2005); serves as a consultant for Allergan, Inc., UCB, and Lundbeck Inc.; receives research support from Teva Pharmaceutical Industries Ltd., Ipsen, UCB, and ScheringPlough Corp.; and has served as an expert witness on behalf of Boehringer Ingelheim. Dr. Samii has received funding for travel and speaker honoraria from Teva Pharmaceutical Industries Ltd., Boehringer Ingelheim, and Ipsen. Dr. Griffith has served on a scientific advisory board for and received speaker honoraria from Teva Pharmaceutical Industries Ltd.; and serves on speakers' bureaus for Teva Pharmaceutical Industries Ltd. and Novartis. Dr. Roberts has received speaker honoraria from Teva Pharmaceutical Industries Ltd. Dr. Molho has served on scientific advisory boards for Allergan, Inc., Ipsen, and Merz Pharmaceuticals, LLC; has served on speakers' bureaus for Allergan, Inc., Boehringer Ingelheim, and Teva Pharmaceutical Industries Ltd.; and receives research support from Teva Pharmaceutical Industries Ltd., IMPAX Laboratories, Inc., Allergan, Inc., the NIH [NINDS 1 UO1 NS50324-01A1] [site investigator]), and Molecular Biometrics, Inc. Dr. Higgins has served on speakers' bureaus for GlaxoSmithKline and Boehringer Ingelheim and has received research support from Acadia Pharmaceuticals and Schwarz Pharma. Dr. Gancher, L. Moses, and Dr. Zareparsi report no disclosures. Dr. Poorkaj has received research support from the NIH (NIA 5K01AG024329-02 [PI]) and the University of Washington. Dr. Bird serves on scientific advisory boards for the Association for Frontotemporal Dementia and CharcotMarie- Tooth Association; serves on the speakers' bureau for and has received funding for travel and a speaker honoraria from Athena Diagnostics, Inc.; serves on the editorial boards of Brain and Neurology Today; has received license fee payments from Athena Diagnostics, Inc. for patents re: Mutations In PKC ~ : are the cause for spinocerebellar ataxia, and Mutations associated with a human demyelinating neuropathy (Charcot-Marie-Tooth Disease Type 1C); receives royalties from the publication of Human Genetics: Principles and Approaches, 4th ed (SpringerVerlag GmbH Biomedical Sciences, 2010); and receives research support from the US Department of Veterans Affairs. Dr. Nutt has received funding for travel from Novartis and Teva Pharmaceutical Industries Ltd.; has received speaker honoraria from Novartis and Teva; has served as a consultant for XenoPort Inc., IMPAX Laboratories, Inc., Neurogen Inc., Synosia Therapeutics, NeuroDerm, Ltd.; , Merck, Lilly-Medtronics, Elan and Lundbeck; and has received research support from Schering-Plough Corp, the NIH (NINDS R01 NS 21062 [PI] and UL1-RR024140 [PI]), the Veterans Administration (PADRECC [Co-PI]), and the Nationl Parkinson Foundation. Dr. Schellenberg serves on a scientific advisory board and receives honoraria from the American Health Assistance Foundation; has served as a consultant for and received funding for travel from IntegraGen; serves on the editorial boards of the American Journal of Alzheimer's Disease and Other Dementias, Neurodegenerative Diseases, Current Alzheimer Research, and Pathology and Laboratory Medicine International; holds/ has filed patents re: Chromosome 14 and familial Alzheimer's disease genetic markers and assays, Chromosome 1 gene and gene products related to Alzheimer's disease, and Genetic basis of Alzheimer's disease and diagnosis and treatment thereof; and receives/ has received research support from the NIH (NIA R01 AG 11762 [PI], NIA R01 AG 21544 [PI], NHGRI ADD GRANT NUMBER [co-PI], NIA UO1AG032984 [PI], NIA RC2AG036528 [PI], and NIMH R01 MH089004 [PI]), the Autism Genome Project, Autism Speaks, the PSP Genetics Consortium, and CurePSP. Dr. Payami receives research support from the NIH (NINDS NS R01-36960 [PI]) and the New York Attorney General's Office. NR 32 TC 40 Z9 42 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP PY 2010 VL 75 IS 13 BP 1189 EP 1194 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 655CD UT WOS:000282219300015 PM 20876472 ER PT J AU Sonnen, JA Larson, EB Walker, RL Haneuse, S Crane, PK Gray, SL Breitner, JCS Montine, TJ AF Sonnen, J. A. Larson, E. B. Walker, R. L. Haneuse, S. Crane, P. K. Gray, S. L. Breitner, J. C. S. Montine, T. J. TI Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques SO NEUROLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; PARKINSONS-DISEASE; DEMENTIA; RISK; PATHOLOGY; ROFECOXIB; NEUROPATHOLOGY; METAANALYSIS AB Objectives: Observational and experimental studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer disease (AD); however, clinical trials and other observational studies, including the Adult Changes in Thought (ACT) study, show no protection or promotion of AD. The objective of this study is to determine the relationship between common dementia-associated pathologies and mid-to late-life NSAID exposure. Methods: We examined the association of mid-to late-life NSAID use with neuropathologic findings on 257 autopsies from ACT, a population-based study of brain aging and incident dementia. Cumulative standard daily doses (SDD) of nonselective NSAIDs were determined from >= 10 years of computerized pharmacy dispensing data. Analyses were adjusted for selection bias to broaden generalizability of results to 3,026 eligible participants in the ACT cohort. Seven pathologic indices were evaluated: intermediate or frequent score for neuritic plaques, Braak stages V or VI for neurofibrillary tangles, >2 cerebral microinfarcts, the presence of any neocortical Lewy bodies, any macroscopic infarcts, any amyloid angiopathy, and moderate or severe atherosclerosis. Results: Of the neuropathologic indices evaluated, only neuritic plaque score was significantly increased in participants with greater use of nonselective NSAIDs (p = 0.065), specifically in those with high levels of cumulative use: 1,000-2,000 SDD (adjusted relative risk [RR] 2.16, 95% confidence interval [CI] 1.02-4.25, compared to light/nonuse [ <60 SDD]) and >2,000 SDD (adjusted RR 2.37, 95% CI 1.24-4.67). Conclusions: Increased neuritic plaque accumulation may explain the association between heavy use of nonselective NSAIDs and increased risk of dementia among ACT participants. Neurology (R) 2010; 75: 1203-1210 C1 [Sonnen, J. A.; Montine, T. J.] Univ Washington, Dept Pathol, Seattle, WA 98104 USA. [Crane, P. K.] Univ Washington, Dept Med, Seattle, WA 98104 USA. [Gray, S. L.] Univ Washington, Dept Pharm, Seattle, WA 98104 USA. [Breitner, J. C. S.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98104 USA. [Larson, E. B.; Walker, R. L.; Haneuse, S.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Breitner, J. C. S.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Sonnen, JA (reprint author), Univ Washington, Dept Pathol, Seattle, WA 98104 USA. EM jsonnen@u.washington.edu RI Crane, Paul/C-8623-2014; Sonnen, 37382016/H-3738-2016; OI Sonnen, 37382016/0000-0001-9267-8705; Crane, Paul/0000-0003-4278-7465 FU NIH/NIA [AG05136, U01AG06781, AG02380, AG19349, AG06781, AG 06781 [PI], AG23801, AG000258]; Nancy and Buster Alvord Endowment; US Department of Veterans Affairs; NCI [AG05136, CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731] FX Supported by the NIH/NIA(AG05136, AG23801, AG000258, and U01AG06781), the Nancy and Buster Alvord Endowment, and the US Department of Veterans Affairs.; Dr. Sonnen serves as an Associate Editor of the Journal of Alzheimer's Disease; receives royalties from the publication of Molecular Pathology (Elsevier, 2009) and Essentials of Molecular Pathology (Elsevier, 2009); serves as a consultant for the Allen Brain Institute; and receives research support from the NIH/NIA (AG02380 [coinvestigator], AG05136 [coinvestigator], AG19349 [coinvestigator], and AG06781 [coinvestigator]). Dr. Larson served as Chair of the editorial board for the Journal of General Internal Medicine; receives publishing royalties from UpToDate, Inc.; and receives research support from the NIH (AG 06781 [PI]). Mr. Walker receives research support from the NIH (AG05136 [biostatistician], AG23801 [biostatistician], AG000258 [biostatistician], AG06781 [biostatistician], NCI CA63740 [biostatistician], NCI U01CA86076 [biostatistician], NCI U01CA86082 [biostatistician], NCI U01CA63736 [biostatistician], NCI U01CA70013 [biostatistician], NCI U01CA69976 [biostatistician], NCI U01CA63731 [biostatistician], and NCI U01CA70040 [biostatistician]). Dr. Haneuse serves as an Associate Editor for the Journal of Alzheimer's Disease and the International Society for Bayesian Analysis; and receives research support from the NIH (AG05136 [biostatistician], AG23801 [biostatistician], AG000258 [biostatistician], and AG06781 [biostatistician]), and the US Department of Veterans Affairs. Dr. Crane receives research support from the NIH (AG06781 [coinvestigator], AG024180 [coinvestigator], AG 029672-01 [PI], HG004610 [coinvestigator]; AG030618 [coinvestigator], AG010220 [coinvestigator], AR057954 [PI]. Dr. Gray serves on the editorial boards of the Journal of the American Geriatrics Society, Research in Gerontological Nursing, the American Journal of Geriatric Pharmacotherapy, and the Annals of Pharmacotherapy; and has received research support from the NIH (AG06781 [coinvestigator]). Dr. Breitner serves on scientific advisory boards for the N. Bud Grossman Center for Research in Memory and Care, the Florida ADRC (NIA and State of FL), and for the Chicago Health and Aging Project; serves on the editorial boards of Alzheimer's Disease and Associated Disorders, PLOS-One, Academics, Alzheimer's and Dementia, and the American Journal of Alzheimer's Disease; receives royalties from the publication of Fast Facts-Dementia, 2nd ed. (Health Press, 2009); and receives research support from the NIH (AG15477 [PI]) and from the Minnesota Medical Foundation. Dr. Montine serves on the editorial boards of the American Journal of Pathology, Brain Pathology, and the Journal of Alzheimer's Disease; and receives research support from the NIH (NS062684 [PI], AG32984 [co-PI], ES16754 [PI], ES007032 [PI], AG031892 [PI], AG023801 [PI], AG05136 [core leader], AG05136 [project leader], GM015431 [project leader], AG10880 [coinvestigator]) and from the Nancy and Buster Alvord Endowment. NR 34 TC 33 Z9 33 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP PY 2010 VL 75 IS 13 BP 1203 EP 1210 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 655CD UT WOS:000282219300017 PM 20811000 ER PT J AU Choi, JK Carreras, I Dedeoglu, A Jenkins, BG AF Choi, Ji-Kyung Carreras, Isabel Dedeoglu, Alpaslan Jenkins, Bruce G. TI Detection of increased scyllo-inositol in brain with magnetic resonance spectroscopy after dietary supplementation in Alzheimer's disease mouse models SO NEUROPHARMACOLOGY LA English DT Article DE Alzheimer's disease; Scyllo-inositol; Transgenic mouse; MRS; Magic angle spinning ID A-BETA; TRANSGENIC MICE; PLAQUES; IDENTIFICATION; MYOINOSITOL; METABOLISM; TRANSPORT; PROFILE; H-1; MRS AB There is evidence that inositol isomers may help protect against formation of toxic fibrils of All fragments in Alzheimer's disease mouse models. Scyllo-inositol is one of the more promising inositol isomers for the potential treatment of Alzheimer's disease (AD) and can be detected using MRS in human subjects. In this manuscript we demonstrate using MRS, in two different mouse models of AD (APP x PS1 and APP x PS1 x tau), that we could detect increased scyllo-inositol in the hippocampus and frontal cortex in mice fed water supplemented with 16.5 mg/L of scyllo-inositol equivalent to about 3.3 mg/kg/day. We used both brain extracts using solution MRS as well as intact brain tissue using high resolution magic angle spinning (HRMAS) to ensure that any membrane-associated scyllo-inositol would be detected. By brain extracts we detected a 3.0 fold increase in scyllo-inositol in the scyllo-fed AD mice compared to normal diet (p < 0.001). Using HRMAS we detected a 2.2-2.4-fold increase in scyllo-inositol (p < 0.001). Scyllo-inositol treatment was associated with an increase in glutamine in hippocampus. The concentrations of scyllo-inositol were higher in the hippocampus than in the frontal cortex. Mice have a smaller concentration of scyllo-inositol than humans (ca. 100 mu M vs. 500 mu M in humans). Given the ease with which scyllo-inositol can be measured in human MRS data with high signal to noise ratios, these data suggest that MRS will prove useful for evaluation of inositol treatment trials in AD subjects. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Choi, Ji-Kyung; Jenkins, Bruce G.] Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Choi, Ji-Kyung; Jenkins, Bruce G.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Carreras, Isabel; Dedeoglu, Alpaslan] VA Boston Healthcare Syst, Dept Vet Affairs, Boston, MA 02130 USA. [Carreras, Isabel; Dedeoglu, Alpaslan] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Choi, JK (reprint author), Massachusetts Gen Hosp, Dept Radiol, AA Martinos Ctr Biomed Imaging, 149-2301,13th St, Boston, MA 02114 USA. EM jchoi@nmr.mgh.harvard.edu OI Dedeoglu, Alpaslan/0000-0003-1156-0874 FU Department of Veteran Affairs; NIA [R01 AG031896]; NIH [P30 AG13846] FX This research is supported by grants from the Department of Veteran Affairs (Merit Award), NIA (R01 AG031896) to AD, NIH (P30 AG13846 Boston University ADC). There is no conflict of interest. The authors thank Lokman Hossain for animal husbandary. NR 24 TC 13 Z9 13 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP-OCT PY 2010 VL 59 IS 4-5 BP 353 EP 357 DI 10.1016/j.neuropharm.2010.03.011 PG 5 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 653EV UT WOS:000282072000014 PM 20399219 ER PT J AU Schmahmann, JD AF Schmahmann, Jeremy D. TI The Role of the Cerebellum in Cognition and Emotion: Personal Reflections Since 1982 on the Dysmetria of Thought Hypothesis, and Its Historical Evolution from Theory to Therapy SO NEUROPSYCHOLOGY REVIEW LA English DT Review DE Cerebrocerebellar system; Cerebellar cognitive affective syndrome; Ataxia; Behavior; Psychosis; Schizophrenia; Autism; History ID POSITRON-EMISSION-TOMOGRAPHY; POSTERIOR-FOSSA TUMORS; INFERIOR PARIETAL LOBULE; SUPERIOR TEMPORAL REGION; EXERCISE-BASED TREATMENT; DEEP BRAIN-STIMULATION; ATAXIA RATING-SCALE; RHESUS-MONKEY; BASIS PONTIS; CORTICOPONTINE PROJECTION AB The cognitive neuroscience of the cerebellum is now an established multidisciplinary field of investigation. This essay traces the historical evolution of this line of inquiry from an emerging field to its current status, with personal reflections over almost three decades on this journey of discovery. It pays tribute to early investigators who recognized the wider role of the cerebellum beyond motor control, traces the origins of new terms and concepts including the dysmetria of thought theory, the universal cerebellar transform, and the cerebellar cognitive affective syndrome, and places these developments within the broader context of the scientific efforts of a growing community of cerebellar cognitive neuroscientists. This account considers the converging evidence from theoretical, anatomical, physiological, clinical, and functional neuroimaging approaches that have resulted in the transition from recognizing the cerebellar incorporation into the distributed neural circuits subserving cognition and emotion, to a hopeful new era of treatment of neurocognitive and neuropsychiatric manifestations of cerebellar diseases, and to cerebellar-based interventions for psychiatric disorders. C1 [Schmahmann, Jeremy D.] Massachusetts Gen Hosp, Dept Neurol, Lab Neuroanat & Cerebellar Neurobiol, Boston, MA 02114 USA. [Schmahmann, Jeremy D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Schmahmann, JD (reprint author), Massachusetts Gen Hosp, Dept Neurol, Lab Neuroanat & Cerebellar Neurobiol, Suite 340,Charles River Plaza S,175 Cambridge St, Boston, MA 02114 USA. EM jschmahmann@partners.org FU NIH [R01 MH067980]; Sidney R. Baer Jr Foundation; MINDlink Foundation; Birmingham Foundation; Massachusetts General Hospital Executive Committee on Research FX Supported in part by NIH R01 MH067980, the Sidney R. Baer Jr Foundation, the MINDlink Foundation, the Birmingham Foundation, and the Massachusetts General Hospital Executive Committee on Research. The assistance of Jinny Sagorin, Jason MacMore and Laura Horton is gratefully acknowledged. NR 209 TC 194 Z9 196 U1 3 U2 36 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1040-7308 EI 1573-6660 J9 NEUROPSYCHOL REV JI Neuropsychol. Rev. PD SEP PY 2010 VL 20 IS 3 BP 236 EP 260 DI 10.1007/s11065-010-9142-x PG 25 WC Psychology, Clinical; Neurosciences SC Psychology; Neurosciences & Neurology GA 649SA UT WOS:000281792300003 PM 20821056 ER PT J AU Gruber, TJ Ogilvy, CS Hauck, EF Levy, EI Hopkins, LN Siddiqui, AH AF Gruber, Thomas J. Ogilvy, Christopher S. Hauck, Erik F. Levy, Elad I. Hopkins, L. Nelson Siddiqui, Adnan H. TI Endovascular Treatment of a Large Aneurysm Arising From a Basilar Trunk Fenestration Using the Waffle-Cone Technique SO NEUROSURGERY LA English DT Article DE Basilar artery aneurysm; Basilar artery fenestration; Intracranial stent; Stent-coiling; Waffle cone ID GUGLIELMI DETACHABLE COILS; INTRACRANIAL ANEURYSMS; ARTERY FENESTRATION; CLINICAL-EXPERIENCE; NEUROFORM STENT; RECONSTRUCTION; CIRCULATION AB OBJECTIVE: Endovascular treatment of large intracranial aneurysms arising from a fenestrated parent vessel may prove particularly difficult. We present a case of a large, broad-based aneurysm arising from a proximal basilar artery (BA) fenestration treated with the waffle-cone technique. Technical nuances and indications for this treatment option are reviewed. CLINICAL PRESENTATION: A 38-year-old man presented with headache, blurred vision, and dizziness. Angiography demonstrated an 11 x 14-mm BA aneurysm associated with the proximal portion of a BA fenestration. TECHNIQUE: A 28 x 4.5-mm Enterprise stent was placed from the right vertebral artery directly into the aneurysm. The stent tines were allowed to flare out in the aneurysm neck creating the "waffle cone." The aneurysm was then coiled with a series of Presidio coils. CONCLUSION: Use of the waffle-cone technique for stent placement resulted in nearly complete embolization of the aneurysm, retention of the entire coil mass in the dome, and preservation of flow through both vertebral arteries and both limbs of the fenestration. C1 [Gruber, Thomas J.; Ogilvy, Christopher S.; Hauck, Erik F.; Levy, Elad I.; Hopkins, L. Nelson; Siddiqui, Adnan H.] SUNY Buffalo, Dept Neurosurg, Toshiba Stroke Res Ctr, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. [Gruber, Thomas J.; Ogilvy, Christopher S.; Hauck, Erik F.; Levy, Elad I.; Hopkins, L. Nelson; Siddiqui, Adnan H.] Millard Fillmore Gates Hosp, Dept Neurosurg, Buffalo, NY 14209 USA. [Ogilvy, Christopher S.] Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. [Levy, Elad I.; Hopkins, L. Nelson; Siddiqui, Adnan H.] SUNY Buffalo, Dept Radiol, Toshiba Stroke Res Ctr, Sch Med & Biomed Sci, Buffalo, NY 14209 USA. RP Siddiqui, AH (reprint author), Univ Buffalo Neurosurg, Millard Fillmore Gates Hosp, 3 Gates Circle, Buffalo, NY 14209 USA. EM ASiddiqui@ubns.com FU Abbott (ACT 1 Choice); Boston Scientific (CABANA); Cordis (SAPPHIRE WW); ev3 (CREATE); Toshiba (for the Toshiba Stroke Research Center); University at Buffalo and the National Institutes of Health [NINDS 1R01NS064592-01A1]; Cordis; Micrus Endovascular FX Dr Hopkins receives research study grants from Abbott (ACT 1 Choice), Boston Scientific (CABANA), Cordis (SAPPHIRE WW), and ev3 (CREATE) and a research grant from Toshiba (for the Toshiba Stroke Research Center); has an ownership/financial interest in AccessClosure, Boston Scientific, Cordis, Micrus, and Valor Medical; serves on the Abbott Vascular Speakers' Bureau; receives honoraria from Bard, Boston Scientific, Cordis, and from the following for speaking at conferences-Complete Conference Management, Cleveland Clinic, and SCAT; receives royalties from Cordis (for the AngioGuard device), serves as a consultant to or on the advisory board for Abbott, AccessClosure, Bard, Boston Scientific, Cordis, Gore, Lumen Biomedical, Micrus, and Toshiba; and serves as the conference director for Nurcon Conferences/Strategic Medical Seminars LLC. Dr Levy receives research grant support (principal investigator: Stent-Assisted Recanalization in acute Ischemic Stroke, SARIS), other research support (devices), and honoraria from Boston Scientific and research support from Micrus Endovascular and ev3; has ownership interests in Intratech Medical Ltd. and Mynx/Access Closure; serves as a consultant on the board of Scientific Advisors to Codman & Shurtleff, Inc.; serves as a consultant per project and/or per hour for Micrus Endovascular, ev3, and TheraSyn Sensors, Inc.; and receives fees for carotid scent training from Abbott Vascular and ev3. Dr Levy receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr Siddiqui has received research grants from the University at Buffalo and the National Institutes of Health (co-principal investigator: NINDS 1R01NS064592-01A1, Hemodynamic induction of pathologic remodeling leading to intracranial aneurysms); is a consultant for Codman & Shurtleff, Inc., Concentric Medical, ev3, and Micrus Endovascular; belongs to Codman & Shurtleff, Inc. and Genentech speakers' bureaus; serves on an advisory board for Codman & Shurtleff, Inc.; and has received honoraria from Genentech, Neocure Group LLC, American Association of Neurological Surgeons' courses, an Emergency Medicine Conference, Abbott Vascular for training other neurointerventionists, and Codman & Shurtleff, Inc. for carotid scent training. Dr Siddiqui receives no consulting salary arrangements. All consulting is per project and/or per hour. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. NR 29 TC 11 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD SEP PY 2010 VL 67 IS 3 SU S BP 140 EP 144 DI 10.1227/01.NEU.0000382977.55504.6C PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 649KB UT WOS:000281766500033 PM 20679936 ER PT J AU Asaad, WF Walcott, BP Nahed, BV Ogilvy, CS AF Asaad, Wael F. Walcott, Brian P. Nahed, Brian V. Ogilvy, Christopher S. TI Operative management of brainstem cavernous malformations SO NEUROSURGICAL FOCUS LA English DT Article DE cavernous malformation; brainstem; review AB Brainstem cavernous malformations (CMs) are complex lesions associated with hemorrhage and neurological deficit. In this review, the authors describe the anatomical nuances relating to the operative techniques for these challenging lesions. The resection of brainstem CMs in properly selected patients has been demonstrated to reduce the risk of rehemorrhage and can be achieved relatively safely in experienced hands. (DOI: 10.3171/2010.6.FOCUS10134) C1 [Ogilvy, Christopher S.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA. RP Ogilvy, CS (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, 55 Fruit St,Wang Bldg 745, Boston, MA 02114 USA. EM cogilvy@partners.org RI Asaad, Wael/I-8485-2012 OI Asaad, Wael/0000-0003-4406-9096 NR 70 TC 10 Z9 12 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1092-0684 J9 NEUROSURG FOCUS JI Neurosurg. Focus PD SEP PY 2010 VL 29 IS 3 AR E10 DI 10.3171/2010.6.FOCUS10134 PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 646KU UT WOS:000281539800011 PM 20809751 ER PT J AU Chao, LL Rothlind, JC Cardenas, VA Meyerhoff, DJ Weiner, MW AF Chao, Linda L. Rothlind, Johannes C. Cardenas, Valerie A. Meyerhoff, Dieter J. Weiner, Michael W. TI Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans SO NEUROTOXICOLOGY LA English DT Article DE Cognitive functioning; Magnetic resonance imaging; Morphometric analysis; Brain; Central nervous system; Chemical warfare agents; Sarin; Cyclosarin; Gulf War veterans ID POSTTRAUMATIC-STRESS-DISORDER; ARMY VETERANS; MULTISYMPTOM ILLNESS; HIPPOCAMPAL VOLUME; NERVOUS-SYSTEM; SYMPTOMS; HEALTH; KHAMISIYAH; ATTACK AB Background: Potentially more than 100,000 US troops may have been exposed to the organophosphate chemical warfare agents sarin (GB) and cyclosarin (GF) when a munitions dump at Khamisiyah, Iraq was destroyed during the Gulf War (GW) in 1991. Although little is known about the long-term neurobehavioral or neurophysiological effects of low-dose exposure to GB/GF in humans, recent studies of GW veterans from the Devens Cohort suggest decrements in certain cognitive domains and atrophy in brain white matter occur individuals with higher estimated levels of presumed GB/GF exposure. The goal of the current study is to determine the generalizability of these findings in another cohort of GW veterans with suspected GB/GF exposure. Methods: Neurobehavioral and imaging data collected in a study on Gulf War Illness between 2002 and 2007 were used in this study. We focused on the data of 40 GW-deployed veterans categorized as having been exposed to GB/GF at Khamisiyah, Iraq and 40 matched controls. Magnetic resonance images (MRI) of the brain were analyzed using automated and semi-automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM), cerebrospinal fluid (CSF) and hippocampus. Results: GW veterans with suspected GB/GF exposure had reduced total GM and hippocampal volumes compared to their unexposed peers (p <= 0.01). Although there were no group differences in measures of cognitive function or total WM volume, there were significant, positive correlations between total WM volume and measures of executive function and visuospatial abilities in veterans with suspected GB/GF exposure. Conclusions: These findings suggest that low-level exposure to GB/GF can have deleterious effects on brain structure and brain function more than decade later. (C) 2010 Elsevier Inc. All rights reserved. C1 [Chao, Linda L.; Cardenas, Valerie A.; Meyerhoff, Dieter J.; Weiner, Michael W.] San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94121 USA. [Chao, Linda L.; Rothlind, Johannes C.; Weiner, Michael W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Chao, Linda L.; Cardenas, Valerie A.; Meyerhoff, Dieter J.; Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. RP Chao, LL (reprint author), San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, 4150 Clement St,114 M, San Francisco, CA 94121 USA. EM linda.chao@ucsf.edu FU Department of Defense [DAMD17-01-1-0764]; Department of Veteran's Affairs; National Institutes of Health National Center of Research Resources [P41 RR023953] FX The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or reflecting the views of the Army, Department of Defense, or Department of Veterans Affairs. Drs. Chao, Cardenas, Meyerhoff, and Weiner receive grant support from the Department of Defense and Dr. Weiner receives grant support from the Department of Veteran's Affairs.; This study was supported by Department of Defense grant DAMD17-01-1-0764, entitled 'Magnetic Resonance and Spectroscopy of the Human Brain in Gulf War Illness', 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 and partially by funding from the National Institutes of Health National Center of Research Resources (P41 RR023953). This material is the result of work supported with resources and the use of facilities at the San Francisco Veterans Affairs Medical Center. The authors express their thanks for the assistance and advice of Dr. Robert Haley, University of Texas Dallas TX, who provided questionnaires and software for syndrome analysis, and Col. Karl Friedl, US Army Medical Research and Materiel Command. The authors also acknowledge Derek Flenniken for managing the database, Jennifer Hlavin and her staff for subject recruitment and neuropsychological testing, Diana Truran Sacrey and her staff for scanning the subjects and processing the MRI data, Philip Insel for assistance with statistical analyses, Drs. Norbert Schuff, Susanne Mueller, and Ron Killiany for helpful comments, and Larry Sippos, Executive Officer to the Deputy Assistant Secretary of Defense for Force Health Protection and Readiness for providing information about the presence or absence of the research participants' units in the modeled hazard areas and the cumulative estimated GB/GF exposure levels. NR 44 TC 34 Z9 34 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD SEP PY 2010 VL 31 IS 5 BP 493 EP 501 DI 10.1016/j.neuro.2010.05.006 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 651PI UT WOS:000281939200011 PM 20580739 ER PT J AU Hansen, L Sasaki, A Zucker, B AF Hansen, Lissi Sasaki, Anna Zucker, Betsy TI End-Stage Liver Disease: Challenges and Practice Implications SO NURSING CLINICS OF NORTH AMERICA LA English DT Article DE End-stage liver disease; End of life; Palliative care; Pain ID HEPATIC-ENCEPHALOPATHY; TRANSPLANT CANDIDATES; HEPATORENAL-SYNDROME; PALLIATIVE CARE; UNITED-STATES; CIRRHOSIS; HEPATOTOXICITY; GUIDELINES; MANAGEMENT; INFECTION AB As the seventh leading cause of death among people aged 25 to 64 years, end-stage liver disease (ESLD) affects many Americans in the most productive years of their lives. Despite the increasing number of individuals who are dying of ESLD, little is documented about their end of life challenges as the disease progresses. The purpose of this article is to highlight specific challenges for people with ESLD, their families, and their implications for health care providers: ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, malnutrition, altered drug metabolism, renal insufficiency and hyponatremia, hepatocellular carcinoma, and pain. The authors also present a case study to illustrate disease progression and difficulties facing patients, family members, and providers. C1 [Hansen, Lissi] Oregon Hlth & Sci Univ, Sch Nursing, Portland, OR 97239 USA. [Zucker, Betsy] Portland VA Med Ctr, Liver Clin DHSM, Portland, OR 97239 USA. RP Hansen, L (reprint author), Oregon Hlth & Sci Univ, Sch Nursing, SN 65,3455 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM hansenli@ohsu.edu NR 64 TC 7 Z9 7 U1 2 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0029-6465 J9 NURS CLIN N AM JI Nurs. Clin. North Am. PD SEP PY 2010 VL 45 IS 3 BP 411 EP + DI 10.1016/j.cnur.2010.03.005 PG 17 WC Nursing SC Nursing GA 655IV UT WOS:000282244300009 PM 20804886 ER PT J AU Iqbal, N Vetter, ML Moore, RH Chittams, JL Dalton-Bakes, CV Dowd, M Williams-Smith, C Cardillo, S Wadden, TA AF Iqbal, Nayyar Vetter, Marion L. Moore, Renee H. Chittams, Jesse L. Dalton-Bakes, Cornelia V. Dowd, Monique Williams-Smith, Catherine Cardillo, Serena Wadden, Thomas A. TI Effects of a Low-intensity Intervention That Prescribed a Low-carbohydrate vs. a Low-fat Diet in Obese, Diabetic Participants SO OBESITY LA English DT Article ID RANDOMIZED-TRIAL; WEIGHT-LOSS; FOLLOW-UP; REDUCTION; PROTEIN; ADVICE; ADULTS AB Low-carbohydrate diets have been associated with significant reductions in weight and HbA(1c) in obese, diabetic participants who received high-intensity lifestyle modification for 6 or 12 months. This investigation sought to determine whether comparable results to those of short-term, intensive interventions could be achieved over a 24-month study period using a low-intensity intervention that approximates what is feasible in outpatient practice. A total of 144 obese, diabetic participants were randomly assigned to a low-carbohydrate diet (<30 g/day) or to a low-fat diet (<= 30% of calories from fat with a deficit of 500 kcal/day). Participants were provided weekly group nutrition education sessions for the first month, and monthly sessions thereafter through the end of 24 months. Weight, HbA(1c), glucose, and lipids were measured at baseline and 6, 12, and 24 months. Of the 144 enrolled participants, 68 returned for the month 24 assessment visit. Weights were retrieved from electronic medical records for an additional 57 participants (total, 125 participants) at month 24. All participants with a baseline measurement and at least one of the three other measurements were included in the mixed-model analyses (n = 138). The low-intensity intervention resulted in modest weight loss in both groups at month 24. At this time, participants in the low-carbohydrate group lost 1.5 kg, compared to 0.2 kg in the low-fat group (P = 0.147). Lipids, glycemic indexes, and dietary intake did not differ between groups at month 24 (or at months 6 or 12) C1 [Iqbal, Nayyar; Vetter, Marion L.; Dalton-Bakes, Cornelia V.; Cardillo, Serena] Hosp Univ Penn, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Iqbal, Nayyar; Vetter, Marion L.] Philadelphia Vet Affairs Med Ctr, Dept Med, Div Endocrinol, Philadelphia, PA USA. [Vetter, Marion L.; Moore, Renee H.; Wadden, Thomas A.] Univ Penn, Sch Med, Dept Psychiat, Ctr Weight & Eating Disorders, Philadelphia, PA 19104 USA. [Moore, Renee H.; Chittams, Jesse L.; Williams-Smith, Catherine] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Dowd, Monique] Springs Hosp, Dept Food & Nutr, Springfield, PA USA. RP Iqbal, N (reprint author), Hosp Univ Penn, Dept Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. EM nayyar.iqbal@uphs.upenn.edu FU VA Merit Review Entry Program FX This study is dedicated to the memory of Frederick F. Samaha, in recognition of his many contributions to this research. We gratefully acknowledge Rosa Kim, and Sara Ali, for assisting with study management and Jeffrey Lavenberg, for his technical assistance. Grant support: VA Merit Review Entry Program. NR 15 TC 31 Z9 32 U1 3 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD SEP PY 2010 VL 18 IS 9 BP 1733 EP 1738 DI 10.1038/oby.2009.460 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 646CE UT WOS:000281512400009 PM 20019677 ER PT J AU Utzschneider, KM Van de Lagemaat, A Faulenbach, MV Goedecke, JH Carr, DB Boyko, EJ Fujimoto, WY Kahn, SE AF Utzschneider, Kristina M. Van de Lagemaat, Anne Faulenbach, Mirjam V. Goedecke, Julia H. Carr, Darcy B. Boyko, Edward J. Fujimoto, Wilfred Y. Kahn, Steven E. TI Insulin Resistance is the Best Predictor of the Metabolic Syndrome in Subjects With a First-Degree Relative With Type 2 Diabetes SO OBESITY LA English DT Article ID BODY-MASS INDEX; CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; WAIST CIRCUMFERENCE; CARDIOMETABOLIC RISK; GLUCOSE-TOLERANCE; NORMAL-WEIGHT; OBESITY; MEN; DEFINITION AB Although obesity is associated with insulin resistance and the metabolic syndrome (MetS), some obese individuals are metabolically healthy. Conversely, some lean individuals are insulin resistant (IR) and at increased cardiometabolic risk. To determine the relative importance of insulin sensitivity, BMI and waist circumference (WC) in predicting MetS, we studied these two extreme groups in a high-risk population. One thousand seven hundred and sixty six subjects with a first-degree relative with type 2 diabetes were stratified by BMI and homeostasis model assessment of insulin resistance (HOMA(IR)) into groups. IR groups had higher triglycerides, fasting glucose, and more diabetes than their BMI-group insulin sensitive (IS) counterparts. Within both IS and IR groups, obesity was associated with higher HOMA(IR) and diastolic blood pressure (BP), but no difference in other metabolic variables. MetS (Adult Treatment Panel III (ATPIII)) prevalence was higher in IR groups (P < 0.001) and more subjects met each MetS criterion (P < 0.001). Within each BMI category, HOMA(IR) independently predicted MetS (P < 0.001) whereas WC did not. Within IS and IR groups, age and WC, but not BMI, were independent determinants of MetS (P < 0.001). WC was a less meaningful predictor of MetS at higher values of HOMA(IR). HOMA(IR) was a better predictor of MetS than WC or BMI (receiver operating characteristic (ROC) area under the curve 0.76 vs. 0.65 vs. 0.59, P < 0.001). In conclusion, insulin sensitivity rather than obesity is the major predictor of MetS and is better than WC at identifying obese individuals with a healthier metabolic profile. Further, as many lean individuals with a first-degree relative with type 2 diabetes are IR and metabolically unhealthy, they may all benefit from metabolic testing. C1 [Utzschneider, Kristina M.; Boyko, Edward J.] VA Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA USA. [Utzschneider, Kristina M.; Van de Lagemaat, Anne; Faulenbach, Mirjam V.; Kahn, Steven E.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Goedecke, Julia H.] Univ Cape Town, S African Med Res Council, Dept Human Biol, ZA-7925 Cape Town, South Africa. [Carr, Darcy B.] Univ Washington, Dept Obstet & Gynecol, Div Maternal Fetal Med, Seattle, WA 98195 USA. RP Utzschneider, KM (reprint author), VA Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA USA. EM kutzschn@u.washington.edu RI Goedecke, Julia/J-8628-2013; Goedecke, Julia/E-1820-2016; OI Goedecke, Julia/0000-0001-6795-4771; Goedecke, Julia/0000-0001-6795-4771; Kahn, Steven/0000-0001-7307-9002 FU Department of Veterans Affairs [DK-17047]; American Diabetes Association; Dutch Diabetes Research Foundation FX We thank Brian Fish for assistance with the database. This study was supported in part by the Department of Veterans Affairs and DK-17047. The GENNID Study was supported by the American Diabetes Association. A. V. was funded by the Dutch Diabetes Research Foundation. NR 31 TC 11 Z9 13 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD SEP PY 2010 VL 18 IS 9 BP 1781 EP 1787 DI 10.1038/oby.2010.77 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 646CE UT WOS:000281512400016 PM 20379148 ER PT J AU Halperin, F Patti, ME Goldfine, AB AF Halperin, Florencia Patti, Mary E. Goldfine, Allison B. TI Glucagon Treatment for Post-Gastric Bypass Hypoglycemia SO OBESITY LA English DT Article ID HYPERINSULINEMIC HYPOGLYCEMIA; NESIDIOBLASTOSIS; PANCREATECTOMY; SURGERY; GLUCOSE AB Hyperinsulinemic hypoglycemia is a recently described complication of Roux-en-Y gastric bypass (RYGB). We hypothesized that glucagon administration would help maintain normal postprandial plasma glucose concentrations by stimulating hepatic glucose output, and if so, represent a new therapeutic option for postbypass hypoglycemia. In this study, we compared the insulin and glycemic response to a mixed meal with and without concomitant glucagon infusion in a patient with severe recurrent hypoglycemia after RYGB. Although effective in transiently raising postprandial plasma glucose values, glucagon infusion was also associated with higher insulin concentrations, and failed to prevent symptomatic hypoglycemia. This case demonstrates that glucagon may have limited clinical utility in the treatment of post-RYGB hyperinsulinemic hypoglycemia. C1 [Halperin, Florencia; Patti, Mary E.; Goldfine, Allison B.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Halperin, Florencia; Goldfine, Allison B.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Halperin, Florencia; Patti, Mary E.; Goldfine, Allison B.] Harvard Univ, Sch Med, Boston, MA USA. RP Goldfine, AB (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM Allison.Goldfine@joslin.harvard.edu FU National Institutes of Health (Specialized Assay Core, Joslin Diabetes Center) [DERC P30DK-36836] FX This work was supported by National Institutes of Health grant DERC P30DK-36836 (Specialized Assay Core, Joslin Diabetes Center). NR 11 TC 14 Z9 14 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD SEP PY 2010 VL 18 IS 9 BP 1858 EP 1860 DI 10.1038/oby.2010.15 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 646CE UT WOS:000281512400027 PM 20168313 ER PT J AU Janakiraman, V Ecker, J Kaimal, AJ AF Janakiraman, Vanitha Ecker, Jeffrey Kaimal, Anjali J. TI Comparing the Second Stage in Induced and Spontaneous Labor SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat ID RANDOMIZED CONTROLLED-TRIAL; ELECTIVE INDUCTION; NEONATAL OUTCOMES; EXPECTANT MANAGEMENT; POSTTERM PREGNANCY; MULTIPAROUS WOMEN; PROGRESSION AB OBJECTIVE: To compare the duration and complications of the second stage of labor between women in induced and spontaneous labor. METHODS: This was a retrospective cohort study of women with singleton term gestations who reached full dilation at a single institution from 2001 through 2009. Second-stage duration, mode of delivery, and complication rates were compared between women in induced and spontaneous labor using survival analysis, univariable analysis, and multivariable analyses to control for potential confounders. RESULTS: We identified 14,727 women who reached the second stage; 3,139 (21.3%) were induced and 11,588 (78.7%) were in spontaneous labor. After adjusting for confounders (maternal age, body mass index, epidural use, gestational age, midwifery care, health center care, year of delivery), there was no difference in length of the second stage or risk of a prolonged second stage between women in induced and spontaneous labor. In both groups, risk of complications increased with duration of the second stage, including chorioamnionitis, postpartum hemorrhage, third-or fourth-degree laceration, operative vaginal delivery, and 5-minute Apgar score less than 7. Among nulliparas who reached full dilation, our data suggested an increased odds of cesarean (10.9% compared with 7.2%, adjusted odds ratio [OR] 1.32, 95% confidence interval [CI] 1.01-1.71) and postpartum hemorrhage (4.2% compared with 2.0%, adjusted OR 1.62, 95% CI 1.02-2.58) with induction. There was no differ-ence in mode of delivery or rates of complications among multiparas. CONCLUSION: Among women who reach full dilation, labor proceeds similarly regardless of induction status. Induced nulliparas may have an increased risk of hemorrhage and cesarean delivery. (Obstet Gynecol 2010;116:606-11) C1 [Janakiraman, Vanitha] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Maternal Fetal Med, Boston, MA 02114 USA. RP Janakiraman, V (reprint author), Massachusetts Gen Hosp, Dept Obstet & Gynecol, Div Maternal Fetal Med, 55 Fruit St, Boston, MA 02114 USA. EM vjanakiraman@partners.org NR 18 TC 6 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2010 VL 116 IS 3 BP 606 EP 611 DI 10.1097/AOG.0b013e3181eeb968 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 642AY UT WOS:000281176400008 PM 20733442 ER PT J AU Janakiraman, V Ecker, J AF Janakiraman, Vanitha Ecker, Jeffrey TI Quality in Obstetric Care: Measuring What Matters SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID HEALTH-CARE C1 Massachusetts Gen Hosp, Dept Maternal Fetal Med, Boston, MA 02114 USA. RP Janakiraman, V (reprint author), 55 Fruit St,Founders 4, Boston, MA 02114 USA. EM vjanakiraman@partners.org NR 17 TC 17 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2010 VL 116 IS 3 BP 728 EP 732 DI 10.1097/AOG.0b013e3181ea4d4f PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 642AY UT WOS:000281176400025 PM 20733459 ER PT J AU Wylie, BJ AF Wylie, Blair J. TI Comparison of Transverse and Vertical Skin Incision for Emergency Cesarean Delivery Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Wylie, Blair J.] Massachusetts Gen Hosp, Div Maternal Fetal Med, Boston, MA 02114 USA. RP Wylie, BJ (reprint author), Massachusetts Gen Hosp, Div Maternal Fetal Med, Boston, MA 02114 USA. 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 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD SEP PY 2010 VL 116 IS 3 BP 773 EP 773 DI 10.1097/AOG.0b013e3181f02af5 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 642AY UT WOS:000281176400034 ER PT J AU Whittaker, S Marais, R Zhu, AX AF Whittaker, S. Marais, R. Zhu, A. X. TI The role of signaling pathways in the development and treatment of hepatocellular carcinoma SO ONCOGENE LA English DT Review DE epidermal growth factor receptor; hepatocellular carcinoma; multikinase inhibitor; signaling; sorafenib; vascular endothelial growth factor ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; ACTIVATED PROTEIN-KINASES; MESSENGER-RNA EXPRESSION; C-MET PROTOONCOGENE; CELL LUNG-CANCER; PHASE-II TRIAL; FACTOR-RECEPTOR; PROGNOSTIC-SIGNIFICANCE; TUMOR-GROWTH AB Hepatocellular carcinoma (HCC) is a highly prevalent, treatment-resistant malignancy with a multifaceted molecular pathogenesis. Current evidence indicates that during hepatocarcinogenesis, two main pathogenic mechanisms prevail: (1) cirrhosis associated with hepatic regeneration after tissue damage caused by hepatitis infection, toxins (for example, alcohol or aflatoxin) or metabolic influences, and (2) mutations occurring in single or multiple oncogenes or tumor suppressor genes. Both mechanisms have been linked with alterations in several important cellular signaling pathways. These pathways are of interest from a therapeutic perspective, because targeting them may help to reverse, delay or prevent tumorigenesis. In this review, we explore some of the major pathways implicated in HCC. These include the RAF/MEK/ERK pathway, phosphatidylinositol-3 kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) pathway, WNT/beta-catenin pathway, insulin-like growth factor pathway, hepatocyte growth factor/c-MET pathway and growth factor-regulated angiogenic signaling. We focus on the role of these pathways in hepatocarcinogenesis, how they are altered, and the consequences of these abnormalities. In addition, we also review the latest preclinical and clinical data on the rationally designed targeted agents that are now being directed against these pathways, with early evidence of success. Oncogene (2010) 29, 4989-5005; doi:10.1038/onc.2010.236; published online 19 July 2010 C1 [Zhu, A. X.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Whittaker, S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Whittaker, S.] Broad Inst, Cambridge, MA USA. [Marais, R.] Inst Canc Res, London SW3 6JB, England. RP Zhu, AX (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Lawrence House,POB 232,55 Fruit St, Boston, MA 02114 USA. EM azhu@partners.org OI Marais, Richard/0000-0001-7484-4183 FU Bayer HealthCare Pharmaceuticals; Genentech, Inc. FX We would like to thank John D Zoidis, MD (Bayer HealthCare Pharmaceuticals, Montville, NJ, USA), and Anna Hunt and Catherine Crookes (GeoMed, Macclesfield, Cheshire, UK) for writing and editorial support, with funding from Bayer HealthCare Pharmaceuticals.; Steven Whittaker and Richard Marais have no competing financial interests in relation to this work. RichardMarais is on the editorial board of Oncogene. Andrew X Zhu has participated in advisory activities and has received research support from Bayer HealthCare Pharmaceuticals and Genentech, Inc. NR 165 TC 375 Z9 386 U1 14 U2 148 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP PY 2010 VL 29 IS 36 BP 4989 EP 5005 DI 10.1038/onc.2010.236 PG 17 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 647LN UT WOS:000281620100001 PM 20639898 ER PT J AU Weisberg, E Sattler, M Ray, A Griffin, JD AF Weisberg, E. Sattler, M. Ray, A. Griffin, J. D. TI Drug resistance in mutant FLT3-positive AML SO ONCOGENE LA English DT Review DE drug resistance; AML; FLT3; combination therapy; stroma ID ACUTE MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITOR; INTERNAL TANDEM DUPLICATION; ACUTE MYELOGENOUS LEUKEMIA; BONE-MARROW STROMA; HUMAN HEMATOLOGIC MALIGNANCIES; CONSTITUTIVELY ACTIVATED FLT3; ACQUIRED UNIPARENTAL DISOMY; SMALL-MOLECULE INHIBITORS; BCR-ABL AB Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance. Oncogene (2010) 29, 5120-5134; doi:10.1038/onc.2010.273; published online 12 July 2010 C1 [Weisberg, E.; Sattler, M.; Ray, A.; Griffin, J. D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol Hematol Neoplasia, Boston, MA 02115 USA. RP Weisberg, E (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM Ellen_Weisberg@dfci.harvard.edu FU National Institutes of Health [CA134660-02, CA36167, DK50654]; Leukemia and Lymphoma Society FX This work is supported in part by the National Institutes of Health Grants (CA134660-02, MS; and CA36167 and DK50654, JDG), and a Leukemia and Lymphoma Society SCOR grant (JDG). NR 164 TC 45 Z9 47 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD SEP PY 2010 VL 29 IS 37 BP 5120 EP 5134 DI 10.1038/onc.2010.273 PG 15 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 650QZ UT WOS:000281867200002 PM 20622902 ER PT J AU Chakrabarty, A Rexer, BN Wang, SE Cook, RS Engelman, JA Arteaga, CL AF Chakrabarty, A. Rexer, B. N. Wang, S. E. Cook, R. S. Engelman, J. A. Arteaga, C. L. TI H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3 SO ONCOGENE LA English DT Article DE PIK3CA mutations; HER2 overexpression; HER3; heregulin; breast cancer ID HUMAN BREAST-CANCER; TYROSINE KINASE INHIBITORS; GROWTH-FACTOR RECEPTOR; PIK3CA MUTATIONS; PHOSPHOINOSITIDE 3-KINASE; IN-VIVO; TRASTUZUMAB RESISTANCE; EPITHELIAL-CELLS; HIGH-FREQUENCY; PI3K PATHWAY AB Hyperactivation of phosphatidylinositol-3 kinase (PI3K) can occur as a result of somatic mutations in PIK3CA, the gene encoding the p110 alpha subunit of PI3K. The HER2 oncogene is amplified in 25% of all breast cancers and some of these tumors also harbor PIK3CA mutations. We examined mechanisms by which mutant PI3K can enhance transformation and confer resistance to HER2-directed therapies. We introduced the PI3K mutations E545K and H1047R in MCF10A human mammary epithelial cells that also overexpress HER2. Both mutants conferred a gain of function to MCF10A/HER2 cells. Expression of H1047R PI3K, but not E545K PI3K, markedly upregulated the HER3/HER4 ligand heregulin (HRG). HRG siRNA inhibited growth of H1047R but not E545K-expressing cells and synergized with the HER2 inhibitors trastuzumab and lapatinib. The PI3K inhibitor BEZ235 markedly inhibited HRG and pAKT levels and, in combination with lapatinib, completely inhibited growth of cells expressing H1047R PI3K. These observations suggest that PI3K mutants enhance HER2-mediated transformation by amplifying the ligand-induced signaling output of the ErbB network. This also counteracts the full effect of therapeutic inhibitors of HER2. These data also suggest that mammary tumors that contain both HER2 gene amplification and PIK3CA mutations should be treated with a combination of HER2 and PI3K inhibitors. Oncogene (2010) 29, 5193-5203; doi:10.1038/onc.2010.257; published online 28 June 2010 C1 [Chakrabarty, A.; Rexer, B. N.; Arteaga, C. L.] Vanderbilt Univ, Sch Med, Dept Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Wang, S. E.; Cook, R. S.; Arteaga, C. L.] Vanderbilt Univ, Sch Med, Dept Canc Biol, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Cook, R. S.; Arteaga, C. L.] Vanderbilt Univ, Sch Med, Breast Canc Res Program, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Engelman, J. A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Canc Ctr,Dept Med, Charlestown, MA USA. RP Arteaga, CL (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Vanderbilt Ingram Canc Ctr, 777 PRB,2220 Pierce Ave, Nashville, TN 37232 USA. EM carlos.arteaga@vanderbilt.edu FU ACS Clinical Research [CRP-07-234]; Breast Cancer Specialized Program of Research Excellence (SPORE) [P50 CA98131]; Vanderbilt-Ingram Comprehensive Cancer Center [P30 CA68485]; [R01 CA80195] FX We thank Dr H Shelton Earp III and Dr Carlos Garcia-Echeverria for providing the HER4 antibody and NVP-BEZ235, respectively. This work was supported by R01 CA80195 (CLA), ACS Clinical Research Professorship Grant CRP-07-234 (CLA), Breast Cancer Specialized Program of Research Excellence (SPORE) P50 CA98131 and Vanderbilt-Ingram Comprehensive Cancer Center Support Grant P30 CA68485. NR 52 TC 48 Z9 50 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP PY 2010 VL 29 IS 37 BP 5193 EP 5203 DI 10.1038/onc.2010.257 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 650QZ UT WOS:000281867200008 PM 20581867 ER PT J AU Jacobson, CA LaCasce, AS AF Jacobson, Caron A. LaCasce, Ann S. TI Lymphoma: Risk and Response After Solid Organ Transplant SO ONCOLOGY-NEW YORK LA English DT Article ID EPSTEIN-BARR-VIRUS; POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDERS; CYTOTOXIC T-LYMPHOCYTES; LIVER-TRANSPLANTATION; PROGNOSTIC-FACTORS; RENAL-TRANSPLANTATION; POSTRENAL TRANSPLANT; CLINICAL-TRIAL; ADULT PATIENTS; DISEASE AB Post-transplant lymphoproliferative disorder (PTLD) is a common and serious complication of solid organ transplantation. It is a heterogeneous collection of diagnoses with varied clinical courses and outcomes. The majority of PTLD is Epstein-Barr virus (EBV)-driven as a result of loss of immune control of EBV-positive B lymphocytes. Risk factors for the development of PTLD thus reflect loss or absence of EBV immunity; they include younger age and pre-transplant EBV naivety, as well as the degree and type of immune suppression, type of organ transplantation, and time from transplantation. Identifying patients at risk for PTLD and developing strategies to prevent PTLD is the subject of much research, and the use of antiviral medications and EBV vaccines has yielded intriguing, albeit preliminary, results. As we learn more about the prognostic factors affecting outcome and the pathogenesis of individual diseases, we are better able to tailor therapy to the individual. Further clinical investigation, including randomized controlled trials, will be important in reaching this goal. C1 [Jacobson, Caron A.; LaCasce, Ann S.] Dana Farber Canc Inst, Dept Med, Div Oncol, Boston, MA 02115 USA. RP LaCasce, AS (reprint author), Dana Farber Canc Inst, Dept Med, Div Oncol, 44 Binney St, Boston, MA 02115 USA. EM Ann_LaCasce@dfci.harvard.edu NR 70 TC 9 Z9 10 U1 0 U2 2 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD SEP PY 2010 VL 24 IS 10 BP 936 EP 944 PG 9 WC Oncology SC Oncology GA 800DW UT WOS:000293341000008 PM 21138175 ER PT J AU Oh, WY Vakoc, BJ Shishkov, M Tearney, GJ Bouma, BE AF Oh, Wang-Yuhl Vakoc, Benjamin J. Shishkov, Milen Tearney, Guillermo J. Bouma, Brett E. TI > 400 kHz repetition rate wavelength-swept laser and application to high-speed optical frequency domain imaging SO OPTICS LETTERS LA English DT Article ID COHERENCE TOMOGRAPHY; SEMICONDUCTOR-LASER; MODE-LOCKING; MICROSCOPY AB We demonstrate a high-speed wavelength-swept laser with a tuning range of 104 nm (1228-1332 nm) and a repetition rate of 403 kHz. The design of the laser utilizes a high-finesse polygon-based wavelength-scanning filter and a short-length unidirectional ring resonator. Optical frequency domain imaging of the human skin in vivo is presented using this laser, and the system shows sensitivity of higher than 98 dB with single-side ranging depth of 1.7 mm over 4 dB sensitivity roll-off. (C) 2010 Optical Society of America C1 [Oh, Wang-Yuhl; Vakoc, Benjamin J.; Shishkov, Milen; Tearney, Guillermo J.; Bouma, Brett E.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Oh, Wang-Yuhl; Vakoc, Benjamin J.; Shishkov, Milen; Tearney, Guillermo J.; Bouma, Brett E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Oh, WY (reprint author), Korea Adv Inst Sci & Technol, Dept Mech Engn, 335 Gwahangno, Taejon 305701, South Korea. EM woh1@kaist.ac.kr RI Oh, Wang-Yuhl/C-2055-2011 FU National Institutes of Health (NIH) [RO1 HL076398]; Terumo Corporation FX This research was supported in part by the National Institutes of Health (NIH) contract RO1 HL076398 and by the Terumo Corporation. NR 16 TC 63 Z9 64 U1 1 U2 17 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD SEP 1 PY 2010 VL 35 IS 17 BP 2919 EP 2921 PG 3 WC Optics SC Optics GA 646FI UT WOS:000281522700031 PM 20808369 ER PT J AU Morier, AM Minteer, J Tyszko, R McCann, R Clarke, V Browning, MF AF Morier, Albert M. Minteer, John Tyszko, Robert McCann, Rachel Clarke, Virginia Browning, Marsha F. TI Ocular manifestations of Fabry disease within in a single kindred SO OPTOMETRY-JOURNAL OF THE AMERICAN OPTOMETRIC ASSOCIATION LA English DT Article DE Fabry disease; Ocular manifestations; Optical coherence tomography; Corneal verticillata ID ALPHA-GALACTOSIDASE; CLINICAL-MANIFESTATIONS; OUTCOME SURVEY; CORNEAL THICKNESS; FEMALES; STORAGE; DIAGNOSIS; COHORT; REPLACEMENT; DEFICIENCY AB BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder that causes progressive complications within the kidneys, brain, and heart. Ocular manifestations of this disease are often present at a very young age, thereby facilitating early diagnosis, before the signs and symptoms of renal disease, stroke, or hypertrophic cardiomyopathy. Early diagnosis by the eye care provider may eventually reduce the morbidity and mortality of this disease through the institution of therapy before the development of sclerotic end organ damage. This study evaluated 23 Fabry-affected members of a single cohort for the presence of ocular signs of Fabry disease. METHODS: Twenty-three patients of a single family were seen on a single day. Patients were given comprehensive ophthalmic examinations and completed a health and lifestyle questionnaire. RESULTS: Eight hemizygous men (mean age, 32.3 years) and 15 heterozygous women (mean age, 26.9 years) from a single family of 43 known Fabry patients were evaluated. Corneal verticillata was present in all patients. Additional findings in the male patients included anterior capsule opacity (25% total) and Fabry cataract (12.5%). Thinning of the retinal nerve fiber layer was observed in one man whose medical history was significant for stroke. Conjunctival and/or retinal vessel tortuosity was present in the majority of patients (62.5% and 75% of hemizygotes, respectively; 40% and 13.3% heterozygotes, respectively). Additional findings in the women included anterior capsule opacity. The majority of patients (87.5% hemizygotes, 60% heterozygotes) felt Fabry disease had an impact on their quality of life. CONCLUSIONS: All evaluated patients who had Fabry disease had corneal verticillata, which generally does not affect vision and is readily recognizable by slit lamp examination. Greater than 60% showed conjunctival and/or retinal vessel tortuosity. The eye care provider can play a crucial role in the early recognition of ocular manifestations of Fabry disease and decrease both the time to accurate diagnosis and the delay in the institution of disease-modifying therapy. Optometry 2010;81:437-449 C1 [Morier, Albert M.] Albany Med Coll, Albany, NY 12208 USA. [Clarke, Virginia; Browning, Marsha F.] Massachusetts Gen Hosp, Lysosomal Dis Neurogenet Unit, Boston, MA 02114 USA. [Browning, Marsha F.] Harvard Univ, Sch Med, Boston, MA USA. RP Morier, AM (reprint author), 1426 Altamont Ave, Schenectady, NY 12303 USA. EM amorier1@nycap.rr.com FU NIH [U54]; FSIG FX The authors acknowledge Jim Riley, O.D. His quick diagnosis of the first patient led to the identification of Fabry disease in 44 family members (of whom 23 were evaluated in our study) so far, prolonging their lives and providing hope for the family's future. Albert Morier thanks John Minteer, O.D., Robert Tyszko, O.D., Rachel McCann, O.D., Stephanie Minteer, Sally Howe, and Donna Longo for giving up their time to help coordinate and assess the patients in this study. The authors acknowledge the pedigree research support of Katherine Sims, M.D. (Center for Human Genetic Research and Neurology Department, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts), and Danielle Metterville, M.S. (Genetic Counselor, Developmental Neurogenetics Clinic, Neurogenetics DNA and Biochemical Diagnostic Lab, Massachusetts General Hospital, Boston, Massachusetts), and thank Hans Ebels, M.D., Genzyme Corporation, for his editorial support. Finally, the authors thank the family, who could not have been more eager to help us learn more about this disease. Dr. Browning acknowledges NIH U54 and the foundation grant from FSIG and the patients who agreed to participate in this study. NR 41 TC 5 Z9 5 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 SEP PY 2010 VL 81 IS 9 BP 437 EP 449 DI 10.1016/j.optm.2010.02.011 PG 13 WC Ophthalmology SC Ophthalmology GA 800MH UT WOS:000293364500007 PM 20615758 ER PT J AU Pruitt, JA Ilsen, PF AF Pruitt, Joseph A. Ilsen, Pauline F. TI On the frontline: What an optometrist needs to know about myasthenia gravis SO OPTOMETRY-JOURNAL OF THE AMERICAN OPTOMETRIC ASSOCIATION LA English DT Article DE Myasthenia gravis; Ocular myasthenia; Myogenic ptosis; Ptosis crutch ID OCULAR MYASTHENIA; INTRAVENOUS IMMUNOGLOBULIN; ICE TEST; PTOSIS; BLEPHAROPTOSIS; THYMECTOMY; MANAGEMENT; THERAPY; THYMUS AB BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease that affects the voluntary skeletal muscles. It is characterized by transient weakness of the muscles that improves with rest. Muscle weakness involving the eyes can produce signs or symptoms of diplopia, blurred vision, ptosis, and ophthalmoplegia. Ptosis is defined as an abnormal eyelid "drooping" beyond the normal I to 2 mm of the upper limbus of the cornea. Hence, most patients with MG have ophthalmic manifestations. Among all patients with MG, up to half will have exclusively ocular symptoms. In these cases, the condition is referred to as ocular myasthenia. CASE REPORT: A 60-year-old man was referred from a neurology clinic for management of intermittent diplopia for greater than 1 year and intermittent bilateral ptosis for the prior year. He reported that he first noticed symptoms of MG at the age of 42, but did not receive the diagnosis until 1 year before his aforementioned neurology examination. He was prescribed spectacles with bilateral ptosis crutches. A diagnosis of severe seronegative MG was subsequently confirmed with neurologic examination and antibody testing. CONCLUSIONS: Because patients with undiagnosed myasthenia gravis may present initially with ocular signs or symptoms, it is important for the optometrist to be familiar with the condition and the simple "in-office" tests that can be performed to establish a tentative diagnosis and management plan. The optometrist can also participate in the management of ocular manifestations of myasthenia and should be familiar with the use of a ptosis crutch (in addition to prism spectacles or occlusion therapies if indicated) as a nonsurgical intervention for ptosis. Optometry 2010;81:454-460 C1 [Pruitt, Joseph A.] Minneapolis Vet Affairs Med Ctr, Minneapolis, MN 55417 USA. [Pruitt, Joseph A.] Univ Missouri, St Louis Coll Optometry, St Louis, MO 63121 USA. [Ilsen, Pauline F.] So Calif Coll Optometry, Fullerton, CA USA. [Ilsen, Pauline F.] W Los Angeles Vet Affairs Healthcare Ctr, Los Angeles, CA USA. RP Pruitt, JA (reprint author), Minneapolis Vet Affairs Med Ctr, 1 Vet Dr,100-77, Minneapolis, MN 55417 USA. EM Joseph.pruitt3@va.gov NR 54 TC 1 Z9 1 U1 0 U2 5 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 SEP PY 2010 VL 81 IS 9 BP 454 EP 460 DI 10.1016/j.optm.2009.09.023 PG 7 WC Ophthalmology SC Ophthalmology GA 800MH UT WOS:000293364500009 PM 20655284 ER PT J AU Ion, DI Stevenson, K Woo, SB Soiffer, R Antin, JH Treister, NS AF Ion, D. I. Stevenson, K. Woo, S. B. Soiffer, R. Antin, J. H. Treister, N. S. TI Characterization of oral involvement in acute-graft-versus-host disease SO ORAL DISEASES LA English DT Meeting Abstract C1 [Ion, D. I.; Woo, S. B.; Treister, N. S.] Brigham & Womens Hosp, Div Oral Med & Dent, Boston, MA 02115 USA. [Stevenson, K.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Soiffer, R.; Antin, J. H.] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD SEP PY 2010 VL 16 IS 6 BP 541 EP 542 PG 2 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 643HZ UT WOS:000281287500125 ER PT J AU Suri, P Katz, JN Rainville, J Kalichman, L Guermazi, A Hunter, DJ AF Suri, P. Katz, J. N. Rainville, J. Kalichman, L. Guermazi, A. Hunter, D. J. TI Vascular disease is associated with facet joint osteoarthritis SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE Osteoarthritis; Facet; Zygapophyseal; Vascular diseases; Calcification; Risk factors ID LOW-BACK-PAIN; ABDOMINAL AORTIC CALCIFICATION; DISC DEGENERATION; LUMBAR SPINE; VITAMIN-D; ZYGAPOPHYSIAL JOINT; COMPUTED-TOMOGRAPHY; CLINICAL-FEATURES; CORONARY-ARTERY; FRAMINGHAM AB Objective: Epidemiologic studies have demonstrated associations between vascular disease and spinal degeneration. We sought to examine whether vascular disease was associated with lumbar spine facet joint osteoarthritis (FJ OA) in a community-based population. Design: 441 participants from the Framingham Heart Study multi-detector computed tomography (MDCT) Study were included in this ancillary study. We used a quantitative summary measure of abdominal aortic calcification (ARC) from the parent study as a marker for vascular disease. RAC was categorized into tertiles of 'no' (reference), 'low', and 'high' calcification. FJ OR was evaluated on computerised tomography (CT) scans using a four-grade scale. For analytic purposes, FJ OR was dichotomized as moderate FJ OA of at least one joint from L2-S1 vs no moderate FJ OA. We examined the association of AAC and FJ OA using logistic regression before and after adjusting for age, sex and body mass index (BMI). Furthermore, we examined the independent effect of AAC on FJ OA after including the known cardiovascular risk factors; diabetes, hypertension, hypercholesterolemia, and smoking. Results: Low ARC (OR 3.84 [2.33-6.34]; P <= 0.0001) and high ARC (9.84 [5.29-18.3]; <= 0.0001) were strongly associated with FJ OA, compared with the reference group. After adjusting for age, sex, and BMI, the association with FJ OR was attenuated for both low ARC (1.81 [1.01-3.27]; P=0.05) and high ARC (2.63 [0.99-5.23]; P=0.05). BMI and age were independently and significantly associated with FJ OA. The addition of cardiovascular risk factors to the model did not substantially change parameter estimates for either AAC tertile. Conclusions: AACs were associated with FJ OA in this community-based population, when adjusting for epidemiologic factors associated with spinal degeneration, and cardiovascular risk factors. Potentially modifiable risk factors for facet degeneration unrelated to conventional biomechanical paradigms may exist. This study is limited by cross-sectional design; longitudinal studies are needed. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International, C1 [Suri, P.] New England Baptist Hosp, Div Res, Boston, MA 02130 USA. [Suri, P.; Rainville, J.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [Suri, P.] Spaulding Rehabil Hosp, Boston, MA USA. [Suri, P.] VA Boston Healthcare Syst, Boston, MA USA. [Katz, J. N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy,Dept Med, Boston, MA 02115 USA. [Katz, J. N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Orthoped Surg, Boston, MA 02115 USA. [Kalichman, L.] Ben Gurion Univ Negev, Dept Phys Therapy, IL-84105 Beer Sheva, Israel. [Guermazi, A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hunter, D. J.] Univ Sydney, No Clin Sch, Sydney, NSW 2006, Australia. RP Suri, P (reprint author), New England Baptist Hosp, Div Res, 125 Parker Hill Ave, Boston, MA 02130 USA. EM psuri@caregroup.harvard.edu RI Kalichman, Leonid/C-6266-2008; Hunter, David/A-4622-2010 OI Kalichman, Leonid/0000-0003-2987-4396; Hunter, David/0000-0003-3197-752X FU Rehabilitation Medicine Scientist Training Program (RMSTP); National Institutes of Health [K12 HD001097-12]; New England Baptist Hospital; NIH/NIAMS [K24 AR 02123, P60 AR 47782]; ARC; GE Healthcare FX Dr Suri is funded by the Rehabilitation Medicine Scientist Training Program (RMSTP), the National Institutes of Health (K12 HD001097-12), and a Research Funding Award from New England Baptist Hospital. Dr Katz is funded in part by NIH/NIAMS K24 AR 02123 and NIH/NIAMS P60 AR 47782. Dr Hunter is funded by an ARC Future Fellowship.; Grant: GE Healthcare NR 49 TC 8 Z9 8 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD SEP PY 2010 VL 18 IS 9 BP 1127 EP 1132 DI 10.1016/j.joca.2010.06.012 PG 6 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 657ZZ UT WOS:000282459500003 PM 20633684 ER PT J AU Goguen, LA Chapuy, CI Sher, DJ Israel, DA Blinder, RA Norris, CM Tishler, RB Haddad, RI Annino, DJ AF Goguen, Laura A. Chapuy, Claudia I. Sher, David J. Israel, David A. Blinder, Russell A. Norris, Charles M. Tishler, Roy B. Haddad, Robert I. Annino, Donald J. TI Utilizing computed tomography as a road map for designing selective and superselective neck dissection after chemoradiotherapy SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; NODE-POSITIVE HEAD; POSITRON-EMISSION-TOMOGRAPHY; DEFINITIVE RADIATION-THERAPY; UPPER AERODIGESTIVE TRACT; POSTRADIOTHERAPY NECK; CANCER; CHEMORADIATION; CHEMOTHERAPY; NEED AB OBJECTIVE: To determine whether computed tomography can distinguish low risk neck levels that can be omitted when neck dissection is undertaken after chemoradiotherapy. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care center. SUBJECTS AND METHODS: Head and neck squamous cell carcinoma patients undergoing neck dissection after chemoradiotherapy between January 1998 and June 2008. We compared computed tomography findings after chemoradiotherapy with neck dissection pathology results; used primary location and computed tomography findings to design selective or superselective neck dissection; and determined whether these surgeries would have contained all metastatic disease. RESULTS: A total of 104 patients were identified, providing 110 heminecks, 531 neck levels, and 3009 lymph nodes for analysis. Neck dissections were positive in 20 (19%) of 104 patients, corresponding to 20 hemineck dissections, 31 neck levels, and 53 lymph nodes. The negative predictive value for computed tomography was 95 percent. The negative predictive value for computed tomography per neck level was as follows: I, 100 percent; 11, 96 percent; 111, 96 percent; IV, 97 percent; and V. 96 percent. A selective neck dissection or a superselective neck dissection, guided by level specific computed tomography findings and limited to necks with post treatment partial response in one level, would have captured all disease in 52 (95%) of 55 and 51(93%) of 55 heminecks. CONCLUSION: Negative computed tomography accurately predicts pathologic complete response at neck dissection. Neck dissection can be avoided in these patients. Additionally, computed tomography reliably identifies low risk neck levels that do not require dissection, permitting selective neck dissection or superselective neck dissection in partial response patients with limited residual disease. (C) 2010 American Academy of Otolaryngology Head and Neck Surgery Foundation. All rights reserved. C1 [Goguen, Laura A.; Norris, Charles M.; Annino, Donald J.] Brigham & Womens Hosp, Dept Surg, Div Otolaryngol, Boston, MA 02115 USA. [Chapuy, Claudia I.; Haddad, Robert I.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Sher, David J.; Tishler, Roy B.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Israel, David A.; Blinder, Russell A.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. RP Goguen, LA (reprint author), Brigham & Womens Hosp, Dept Surg, Div Otolaryngol, 75 Francis St, Boston, MA 02115 USA. EM lgoguen@partners.org NR 29 TC 9 Z9 9 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD SEP PY 2010 VL 143 IS 3 BP 367 EP 374 DI 10.1016/j.otohns.2010.04.020 PG 8 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 643OX UT WOS:000281308400011 PM 20723773 ER PT J AU Liao, S Durand, ML Cunningham, MJ AF Liao, Selena Durand, Marlene L. Cunningham, Michael J. TI Sinogenic orbital and subperiosteal abscesses: Microbiology and methicillin-resistant Staphylococcus aureus incidence SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article ID PEDIATRIC NECK ABSCESSES; CHRONIC RHINOSINUSITIS; TISSUE INFECTIONS; ACUTE SINUSITIS; COMPLICATIONS; CELLULITIS AB OBJECTIVE: To assess the current bacteriology and the incidence of methicillin-resistant Staphylococcus aureus in orbital and subperiosteal abscesses of paranasal sinus disease origin. STUDY DESIGN: Case series with chart review. SETTING: An otolaryngology and ophthalmology specialty hospital. SUBJECTS AND METHODS: Fifty-three patients were treated between 1994 and 2008 for orbital or subperiosteal abscess and paranasal sinusitis, confirmed by imaging and surgical intervention; 46 had operative culture specimens and comprise the study cohort. RESULTS: The mean patient age was 28 years; one third were younger than 18. Nearly twice as many patients had subperiosteal (n = 30) as had orbital abscesses (n = 16). In 12 patients (26%), cultures were negative or grew only skin flora contaminants (coagulase-negative staphylococci, diphtheroids, and Propionibacterium acnes). Fifteen patients (33%) grew more than one pathogen. Streptococci were isolated in 17 of the 46 cases (37%), S. aureus in 13 (28.3%), gram-negative bacilli in eight (17.4%), and anaerobes in nine (19.6%). Methicillin-resistant S. aureus accounted for three (23.1%) of the S. aureus isolates and 6.5 percent of the total cases. CONCLUSION: Abscess cultures grew a mixture of bacteria, including gram-positive cocci, gram-negative bacilli, and anaerobes. Although streptococci were the most common genus of bacteria isolated, S. aureus was the single most common pathogen recovered and one fourth of these cases were methicillin-resistant S. aureus. Given the significant morbidity that may result from inadequate treatment, an antibiotic active against methicillin-resistant S. aureus should be included in the initial broad-spectrum antimicrobial treatment regimen of orbital and subperiosteal abscesses of sinusitis origin until culture results are available. (C) 2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation. All rights reserved. C1 [Liao, Selena] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Durand, Marlene L.] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Durand, Marlene L.] Massachusetts Eye & Ear Infirm, Infect Dis Serv, Boston, MA 02114 USA. [Cunningham, Michael J.] Harvard Univ, Dept Otolaryngol, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm,Med Sch, Boston, MA 02114 USA. RP Cunningham, MJ (reprint author), Harvard Univ, Dept Otolaryngol, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm,Med Sch, 243 Charles St, Boston, MA 02114 USA. EM michael_cunningham@meei.harvard.edu NR 15 TC 13 Z9 13 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD SEP PY 2010 VL 143 IS 3 BP 392 EP 396 DI 10.1016/j.otohns.2010.06.818 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 643OX UT WOS:000281308400015 PM 20723777 ER PT J AU Soler, ZM Sindwani, R Metson, R AF Soler, Zachary M. Sindwani, Raj Metson, Ralph TI Endoscopic sphenoid nasalization for the treatment of advanced sphenoid disease SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article ID SINUS; SURGERY C1 [Soler, Zachary M.; Metson, Ralph] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otolaryngol, Boston, MA USA. [Soler, Zachary M.; Metson, Ralph] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Sindwani, Raj] St Louis Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, St Louis, MO USA. RP Metson, R (reprint author), 0 Emerson Pl, Boston, MA 02114 USA. EM ralph_metson@meei.harvard.edu NR 5 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD SEP PY 2010 VL 143 IS 3 BP 456 EP 458 DI 10.1016/j.otohns.2010.05.032 PG 3 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 643OX UT WOS:000281308400026 PM 20723788 ER PT J AU Plotkin, SR Halpin, C McKenna, MJ Loeffler, JS Batchelor, TT Barker, FG AF Plotkin, Scott R. Halpin, Chris McKenna, Michael J. Loeffler, Jay S. Batchelor, Tracy T. Barker, Fred G., II TI Erlotinib for Progressive Vestibular Schwannoma in Neurofibromatosis 2 Patients SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Neurofibromatosis; Vestibular schwannoma; Acoustic neuroma; Erlotinib; Hearing ID GROWTH-FACTOR RECEPTOR; PHASE-II; ACOUSTIC NEUROMAS; LUNG-CANCER; RESPONSE CRITERIA; MALIGNANT GLIOMA; CLINICAL-TRIALS; TYPE-2; TEMOZOLOMIDE; MANAGEMENT AB Objective: In vitro treatment of Nf2-deficient cells with epidermal growth factor receptor (EGFR) inhibitors can reduce cellular proliferation. We sought to determine the activity of erlotinib for progressive vestibular schwannoma (VS) associated with neurofibromatosis 2 (NF2). Study Design: Retrospective case review. Setting: Tertiary referral center. Patients: Eleven NF2 patients with progressive VS who were poor candidates for standard therapy. Intervention: Erlotinib 150 mg daily. Main Outcome Measures: A radiographic response was defined as >= 20% decrease in tumor volume compared with baseline. A hearing response was defined as a statistically significant increase in word recognition score (WRS) compared with baseline; a minor hearing response was defined as a 10 dB improvement in pure-tone average with stable WRS. Results: Before treatment, the median and mean annual volumetric growth rate for 11 index VS were 26% and 46%, respectively. Among 10 evaluable patients, the median time-to-tumor progression was 9.2 months. Three patients with stable disease experienced maximum tumor shrinkage of 4%, 13%, and 14%. Nine patients underwent audiologic evaluations. One experienced a transient hearing response, 2 experienced minor hearing responses, 3 remained stable, and 2 developed progressive hearing loss. The median time-to-progressive hearing loss was 9.2 months and to either tumor growth or progressive hearing loss was 7.1 months. Adverse treatment effects included mild-to-moderate rash, diarrhea, and hair thinning, with 2 episodes of grade 3 toxicity. Conclusion: Erlotinib treatment was not associated with radiographic or hearing responses in NF2 patients with progressive VS. Because a subset of patients experienced prolonged stable disease, time-to-progression may be more appropriate than radiographic or hearing response for anti-EGFR agents in NF2-associated VS. C1 [Plotkin, Scott R.] Massachusetts Gen Hosp, Pappas Ctr Neurooncol, Dept Neurol, Boston, MA 02114 USA. [Plotkin, Scott R.; Batchelor, Tracy T.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Halpin, Chris] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. [McKenna, Michael J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Loeffler, Jay S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Barker, Fred G., II] Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. RP Plotkin, SR (reprint author), Massachusetts Gen Hosp, Pappas Ctr Neurooncol, Dept Neurol, Yawkey 9E,55 Fruit St, Boston, MA 02114 USA. EM splotkin@partners.org FU Harvard Medical School Center for Neurofibromatosis and Allied disorders; Department of Defense [NF050202] FX This study was supported by the Harvard Medical School Center for Neurofibromatosis and Allied disorders and Department of Defense grant NF050202 (to S. R. Plotkin). NR 41 TC 36 Z9 39 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2010 VL 31 IS 7 BP 1135 EP 1143 PG 9 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 647FM UT WOS:000281603200019 PM 20736812 ER PT J AU Benoit, MM Handzel, O McKenna, MJ Deschler, DG AF Benoit, Margo McKenna Handzel, Ophir McKenna, Michael J. Deschler, Daniel G. TI A 42-Year-Old Man With Facial Nerve Weakness and Multiple Recurrent Pleomorphic Adenoma SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Facial nerve; Parotid; Pleomorphic adenoma ID BENIGN PAROTID TUMOR; PARALYSIS; SCHWANNOMAS AB Objective: To describe a case and discuss the differential diagnosis of facial nerve paresis presenting years after resection of multiple recurrent parotid pleomorphic adenoma. Patients: Case report of a patient on immunosuppressive therapy with facial nerve weakness 3 years after last resection for multiple recurrent pleomorphic adenoma. Interventions: Computed tomography and magnetic resonance imaging followed by surgical exploration, resection, and reconstruction. Main Outcome Measures: Histopathologic diagnosis and treatment outcome. Results: Final diagnosis of recurrent pleomorphic adenoma causing compression of the facial nerve at the stylomastoid foramen. Conclusion: Facial nerve weakness caused by a benign salivary gland tumor is rare. Although alternate diagnoses must be considered, recurrent pleomorphic adenoma alone may impair facial function by impinging on the nerve in the stylomastoid foramen. C1 [Benoit, Margo McKenna; Handzel, Ophir; McKenna, Michael J.; Deschler, Daniel G.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. [Handzel, Ophir] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Otolaryngol Head & Neck Surg, IL-69978 Tel Aviv, Israel. RP Deschler, DG (reprint author), 243 Charles St, Boston, MA 02135 USA. EM Daniel_Deschler@meei.harvard.edu RI Handzel, Ophir/D-8236-2017 OI Handzel, Ophir/0000-0002-6905-3034 NR 13 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2010 VL 31 IS 7 BP 1157 EP 1159 PG 3 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 647FM UT WOS:000281603200022 PM 20657328 ER PT J AU Okun, MS Siderowf, A Nutt, JG O'Conner, GT Bloem, BR Olmstead, EM Guttman, M Simuni, T Cheng, E Cohen, EV Parashos, S Marsh, L Malaty, IA Giladi, N Schmidt, P Oberdorf, J AF Okun, Michael S. Siderowf, Andrew Nutt, John G. O'Conner, Gerald T. Bloem, Bastiaan R. Olmstead, Elaine M. Guttman, Mark Simuni, Tanya Cheng, Eric Cohen, Elaine V. Parashos, Sotirios Marsh, Laura Malaty, Irene A. Giladi, Nir Schmidt, Peter Oberdorf, Joyce TI Piloting the NPF data-driven quality improvement initiative SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE Parkinson's disease; Care; Treatment; Economic; Database ID PARKINSONS-DISEASE AB Objective: To pilot a data-driven quality care program in National Parkinson Foundation (NPF) Centers of Excellence. Background: Evidence from comparative effectiveness research (CER) can be used to guide decisions regarding health care and to improve quality and efficiency of care. We propose to develop the infrastructure required to conduct CER across an extensive network of NPF Centers of Excellence. Methods: We present the staged planning for a pilot study which will demonstrate the development and implementation of the infrastructure that will be needed for a large standardized patient-centered, clinical practice database for PD. This database will support CER and drive quality improvement studies. Results: We describe the infrastructure for the ongoing pilot feasibility testing in a subset of six NPF Centers of Excellence, and we discuss the impact that the data (available in 2010) could have in guiding PD management. Conclusion: This preliminary experience will facilitate the longitudinal tracking of therapies and of outcomes in PD clinical practice. Further, we are hopeful that the information will provide insight into PD that will extend beyond the clinical trials population (the population included in most available PD databases). This prospective standardized real-world multi-center clinical practice database will aim to identify positive health outcomes associated with treatment approaches, and to identify variations in clinical outcomes that may suggest improvements in best clinical practice patterns. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Okun, Michael S.; Malaty, Irene A.] Univ Florida, Dept Neurol, Natl Parkinson Fdn,Ctr Excellence, Movement Disorders Ctr,McKnight Brain Inst, Gainesville, FL 32611 USA. [Siderowf, Andrew] Univ Penn, Dept Neurol, Natl Parkinson Fdn,Ctr Excellence, Educ & Clin Ctr,NIH Udall Ctr,VA Parkinson Dis Re, Philadelphia, PA 19104 USA. [Nutt, John G.] Oregon Hlth & Sci Univ, VA Parkinson Dis Res, Natl Parkinson Fdn,Ctr Excellence, Educ & Clin Ctr, Portland Va, OR USA. [O'Conner, Gerald T.; Olmstead, Elaine M.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Bloem, Bastiaan R.] Radboud Univ Nijmegen, Med Ctr, Natl Parkinson Fdn,Ctr Excellence, Donders Inst Brain Cognit & Behav,Dept Neurol, Nijmegen, Netherlands. [Guttman, Mark] Univ Toronto, Dept Med, Div Neurol, Natl Parkinson Fdn,Ctr Excellence, Toronto, ON, Canada. [Simuni, Tanya] Northwestern Univ, Dept Neurol, Natl Parkinson Fdn,Ctr Excellence, Parkinsons Dis & Movement Disorders Ctr, Chicago, IL USA. [Cheng, Eric] VA Greater Los Angeles Healthcare Syst, VA Parkinsons Dis Res Educ & Clin Ctr, Los Angeles, CA USA. [Cohen, Elaine V.] NY Univ, New York Univ Pk, Natl Parkinson Fdn,Ctr Excellence, Dept Neurol, New York, NY USA. [Cohen, Elaine V.] NY Univ, Movement Disorder Ctr, New York, NY USA. [Parashos, Sotirios] Struthers Parkinsons Ctr, Natl Parkinson Fdn,Ctr Excellence, Minneapolis, MN USA. [Marsh, Laura] Menninger Dept Psychiat & Behav Sci, Houston, TX USA. [Giladi, Nir] Tel Aviv Univ, Sackler Sch Med, Tel Aviv Sourasky Med Ctr, Movement Disorders Unit,Natl Parkinson Fdn,Ctr Ex, IL-69978 Tel Aviv, Israel. [Schmidt, Peter; Oberdorf, Joyce] Natl Parkinson Fdn, Miami, FL USA. RP Okun, MS (reprint author), Univ Florida, Dept Neurol, Natl Parkinson Fdn,Ctr Excellence, Movement Disorders Ctr,McKnight Brain Inst, 100 S Newell Dr,Rm L3-101 3rd Floor Neurol, Gainesville, FL 32611 USA. EM okun@neurology.ufl.edu RI Bloem, Bastiaan/E-3812-2010; Bloem, B.R./H-8013-2014 OI Okun, Michael/0000-0002-6247-9358; FU National Parkinson Foundation FX Funding was provided for this project through the National Parkinson Foundation, and we thank Sharon Metz for organizational support. NR 12 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD SEP PY 2010 VL 16 IS 8 BP 517 EP 521 DI 10.1016/j.parkreldis.2010.06.005 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 665FE UT WOS:000283019800007 PM 20609611 ER PT J AU Kheir, JN Lawlor, MW Ahn, ES Lehmann, L Riviello, JJ Silvera, VM McManus, M Folkerth, RD AF Kheir, John N. Lawlor, Michael W. Ahn, Edward S. Lehmann, Leslie Riviello, James J. Silvera, V. Michelle McManus, Michael Folkerth, Rebecca D. TI Neuropathology of a Fatal Case of Posterior Reversible Encephalopathy Syndrome SO PEDIATRIC AND DEVELOPMENTAL PATHOLOGY LA English DT Article DE autopsy; complication; cyclosporine; hemorrhage; hypertension; leukoencephalopathy; PRES; RPLS; tacrolimus ID BONE-MARROW-TRANSPLANTATION; LEUKOENCEPHALOPATHY SYNDROME; HYPERTENSIVE ENCEPHALOPATHY; CYCLOSPORINE-A; INDUCED NEUROTOXICITY; HUMAN-BRAIN; ENDOTHELIN; RECEPTORS; CELLS AB The pathology of posterior reversible encephalopathy syndrome (PRES) is undefined, since it is rarely fatal and is biopsied in only exceptional circumstances. We describe rapidly progressive PRES following stem cell transplant for acute lymphoblastic leukemia. After development of altered mental status, this 8-year-old girl had T2 prolongation of the white matter in a posterior-dominant distribution, eventually developing cerebellar edema, hemorrhage, hydrocephalus, and herniation. Despite surgical and medical management, she died 36 hours later. At autopsy, the occipital and cerebellar white matter and focal occipital cortical gray matter showed a spectrum of microvascular changes, including dilated perivascular spaces containing proteinaceous exudates and macrophages, as well as fibrinoid necrosis and acute hemorrhage, in a distribution corresponding to the neuroimaging abnormalities and reminiscent of those seen in patients with acute hypertensive encephalopathy. Of note, similar microvascular changes were not seen in the kidney or other systemic sites. Thus, the findings indicate a brain-specific microvascular compromise as the substrate of PRES, at least in the rare instance of cases progressing to fatal outcome. C1 [Folkerth, Rebecca D.] Childrens Hosp Boston, Dept Pathol Neuropathol, Boston, MA 02115 USA. [Kheir, John N.; McManus, Michael] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Crit Care Med,Dept Anesthesiol Perioperat & P, Boston, MA USA. [Folkerth, Rebecca D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol Neurobiol, Boston, MA 02115 USA. [Lawlor, Michael W.] Harvard Univ, Sch Med, Dept Genet, Program Genom,Childrens Hosp Boston, Boston, MA USA. [Ahn, Edward S.] Johns Hopkins Univ Hosp, Div Pediat Neurosurg, Dept Neurosurg, Baltimore, MD 21287 USA. [Lehmann, Leslie] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Riviello, James J.] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Sect Neurol & Dev Neurosci, Houston, TX 77030 USA. [Silvera, V. Michelle] Harvard Univ, Sch Med, Dept Radiol, Div Neuroradiol,Childrens Hosp Boston, Boston, MA 02115 USA. RP Folkerth, RD (reprint author), Childrens Hosp Boston, Dept Pathol Neuropathol, Boston, MA 02115 USA. EM rfolkerth@partners.org NR 24 TC 10 Z9 13 U1 0 U2 1 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1093-5266 J9 PEDIATR DEVEL PATHOL JI Pediatr. Dev. Pathol. PD SEP-OCT PY 2010 VL 13 IS 5 BP 397 EP 403 DI 10.2350/09-04-0634-CR.1 PG 7 WC Pathology; Pediatrics SC Pathology; Pediatrics GA 692XW UT WOS:000285190200009 PM 20158377 ER PT J AU Beaty, O Berg, S Blaney, S Malogolowkin, M Krailo, M Knight, R Schaiquevich, P Stewart, C Chen, ZJ Nelson, M Voss, S Ivy, SP Adamson, PC AF Beaty, Orren, III Berg, Stacey Blaney, Susan Malogolowkin, Marcio Krailo, Mark Knight, Ronald Schaiquevich, Paula Stewart, Clinton Chen, Zhengjia Nelson, Marvin Voss, Stephan Ivy, S. Percy Adamson, Peter C. TI A Phase II Trial and Pharmacokinetic Study of Oxaliplatin in Children With Refractory Solid Tumors: A Children's Oncology Group Study SO PEDIATRIC BLOOD & CANCER LA English DT Article DE oxaliplatin; pediatric; pharmacokinetics; phase II study; refractory solid tumor ID METASTATIC COLORECTAL-CANCER; CARCINOMA CELL-LINES; ANTITUMOR-ACTIVITY; CARRIER LIGAND; FOLINIC ACID; FLUOROURACIL-LEUCOVORIN; PLATINUM RESISTANCE; CLINICAL-TRIAL; DNA-ADDUCTS; L-OHP AB Background. Platinating agents are used in the treatment of a spectrum of childhood cancers. Oxaliplatin, a third generation platinum compound, may provide less toxicity and be more effective. A phase 2 study was performed to estimate the response rate to single agent oxaliplatin in patients with refractory pediatric solid tumors, and to further describe the toxicities and pharmacokinetics of the drug in this population. Patients and Methods. Subjects, <= 21 years of age at original diagnosis, received oxaliplatin (130 mg/m(2)) intravenously every 21 days. Prior platinum exposure was acceptable. Histologies included: Ewing sarcoma/peripheral PNET, osteosarcoma, rhabdomyosarcoma, neuroblastoma, high and low grade astrocytoma, brain stem glioma, ependymoma, hepatoblastoma and selected rare tumors. A two-stage design, enrolling 10 + 10 subjects, was used for each disease stratum. Limited sampling pharmacokinetic studies were performed. Results. Of 124 eligible subjects (75 males), 113 were evaluable for response and 69 (62%) had received platinum previously. Only one objective response was observed, a partial response in a 6-year-old child with ependymoma. An additional 13 subjects with various other solid tumors had stable disease, receiving a median (range) of 13.5 (2-17) cycles. Five subjects completed 17 treatment cycles. Thrombocytopenia was the most common toxicity observed. The median (range) terminal half-life and clearance for ultrafiltrable platinum were 293 (187-662 hr) and 14.0 (1.9-24.9 Uhr/m(2)), respectively (n = 49). Conclusions. Although reasonably well tolerated, oxaliplatin administered as a single agent has limited activity in pediatric patients with relapsed or refractory solid tumors. Pediatr Blood Cancer. (C) 2010;55:440-445. 2010 Wiley-Liss, Inc. C1 [Beaty, Orren, III] Mission Hosp Inc, Zeis Childrens Canc Ctr, Asheville, NC 28803 USA. [Berg, Stacey; Blaney, Susan] Texas Childrens Canc Ctr, Houston, TX USA. [Malogolowkin, Marcio; Nelson, Marvin] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Krailo, Mark; Chen, Zhengjia] Childrens Oncol Grp, Arcadia, CA USA. [Knight, Ronald] Sanofi Aventis, Bridgewater, MA USA. [Schaiquevich, Paula; Stewart, Clinton] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Voss, Stephan] Dana Farber Canc Inst, Boston, MA 02115 USA. [Voss, Stephan] Childrens Hosp, Boston, MA 02115 USA. [Ivy, S. Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Beaty, O (reprint author), Mission Hosp Inc, Zeis Childrens Canc Ctr, Vanderbilt Pk Dr, Asheville, NC 28803 USA. EM orren.beaty@msj.org FU National Cancer Institute [U10 CA98543, U10CA98413]; Sanofi Aventis FX Grant sponsor: National Cancer Institute Grants; Grant numbers: U10 CA98543, U10CA98413; Grant sponsor: Sanofi Aventis. NR 40 TC 24 Z9 24 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2010 VL 55 IS 3 BP 440 EP 445 DI 10.1002/pbc.22544 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 632PV UT WOS:000280438600009 PM 20658614 ER PT J AU Wright, KD Qaddoumi, I Patay, Z Gajjar, A Wilson, MW Rodriguez-Galindo, C AF Wright, Karen D. Qaddoumi, Ibrahim Patay, Zoltan Gajjar, Amar Wilson, Matthew W. Rodriguez-Galindo, Carlos TI Successful Treatment of Early Detected Trilateral Retinoblastoma Using Standard Infant Brain Tumor Therapy SO PEDIATRIC BLOOD & CANCER LA English DT Article DE chemotherapy; pineal tumor; quadrilateral retinoblastoma; suprasellar tumor; trilateral retinoblastoma ID INTENSIVE CHEMOTHERAPY; CHILDREN; RESCUE AB Trilateral retinoblastoma is characterized by the presence of retinoblastoma with an intracranial tumor. The incidence is low and prognosis poor. Due to the paucity of information regarding successful treatment, we report the case of a 6 month old female referred for leukocoria and found to have an associated suprasellar tumor and pineal enhancement. The patient, treated with standard infant brain tumor therapy, remains alive without signs of active disease 35 months after diagnosis; no surgery or irradiation was used. Early diagnosis of trilateral retinoblastoma may facilitate the use of less intensive therapeutic approaches and result in excellent outcomes in these patients. Pediatr Blood Cancer. 2010;55:570-572. (C) 2010 Wiley-Liss, Inc. C1 [Wright, Karen D.] St Jude Childrens Hosp, Dept Oncol, Div Neurooncol, Memphis, TN 38105 USA. [Wright, Karen D.; Qaddoumi, Ibrahim; Gajjar, Amar] St Jude Childrens Hosp, Dept Neurooncol, Memphis, TN 38105 USA. [Patay, Zoltan] St Jude Childrens Hosp, Dept Radiol, Memphis, TN 38105 USA. [Wilson, Matthew W.] St Jude Childrens Hosp, Dept Surg, Memphis, TN 38105 USA. [Wilson, Matthew W.] Univ Tennessee, Dept Ophthalmol, Memphis, TN USA. [Wilson, Matthew W.] Univ Tennessee, Hamilton Eye Inst, Memphis, TN USA. [Rodriguez-Galindo, Carlos] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Rodriguez-Galindo, Carlos] Childrens Hosp Boston, Boston, MA USA. RP Wright, KD (reprint author), St Jude Childrens Hosp, Dept Oncol, Div Neurooncol, 262 Danny Thomas Pl,Mailstop 260, Memphis, TN 38105 USA. EM karen.wright@stjude.org FU National Institutes of Health [P30 CA21765]; Noyes Brain Tumor Foundation; Musicians Against Childhood Cancer (MACC); American Lebanese Syrian Associated Charities (ALSAC) FX Grant sponsor: National Institutes of Health; Grant number: P30 CA21765; Grant sponsor: Noyes Brain Tumor Foundation; Grant sponsor: Musicians Against Childhood Cancer (MACC); Grant sponsor: American Lebanese Syrian Associated Charities (ALSAC). NR 20 TC 6 Z9 7 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2010 VL 55 IS 3 BP 570 EP 572 DI 10.1002/pbc.22545 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 632PV UT WOS:000280438600032 PM 20658634 ER PT J AU Cheng, CE Irwin, B Mauriello, D Liang, L Pappert, A Kimball, AB AF Cheng, Carol E. Irwin, Blair Mauriello, Dana Liang, Laura Pappert, Amy Kimball, Alexandra B. TI Self-Reported Acne Severity, Treatment, and Belief Patterns across Multiple Racial and Ethnic Groups in Adolescent Students SO PEDIATRIC DERMATOLOGY LA English DT Article ID HIGH-SCHOOL-STUDENTS; VULGARIS; PREVALENCE; PERCEPTIONS; MAMMOGRAPHY; CARE AB Acne vulgaris is a common condition among adolescents regardless of age, gender, and race. We compare the frequency, severity, help-seeking behavior, treatment, and beliefs about acne among students based on race, ethnicity, gender, and age. Anonymous surveys were administered to 1,214 students aged 10-19 years of varied gender, race, and ethnicity in public middle and high schools in New Jersey. Results showed the frequency and severity of acne were high (76% and 65%, respectively) and more prevalent in white compared to non-white respondents (RR = 1.13, 95% CI = 1.04-1.24 and RR = 1.22, 95% CI = 1.09-1.37, respectively), and also in older compared to younger ages (RR = 1.24, 95% CI = 1.17-1.32 and RR = 1.43, 95% CI = 1.32-1.55, respectively). The majority of respondents (83%) reported never having seen a physician for their acne; however, those reporting acne of some severity were more likely to have seen a physician compared with those who did not report acne (21% vs. 8%, p < 0.001). Blacks who reported mild or moderate severity of acne were more likely to have seen a health professional compared to white respondents with same the acne severity (RR = 3.63, 95% CI = 2.06-6.37 and RR = 3.06, 95% CI = 2.02-4.65, respectively). Conversely, Hispanic respondents with mild or moderate acne were less likely to have seen a health professional compared to whites with the same acne severity (RR = 0.56, 95% CI = 0.35-0.89 and RR = 0.47, 95% CI = 0.26-0.86, respectively). Beliefs about external factors affecting acne also varied by race and ethnicity. In conclusion, the severity, frequency, and beliefs about acne all play a role in help-seeking behaviors, which vary to a significant extent by race and ethnicity. C1 [Cheng, Carol E.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Irwin, Blair; Pappert, Amy] UMDNJ, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Liang, Laura] UMDNJ, Sch Publ Hlth, New Brunswick, NJ USA. [Kimball, Alexandra B.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Kimball, AB (reprint author), Massachusetts Gen Hosp, 50 Staniford St,Suite 246, Boston, MA 02114 USA. EM harvardskinstudies@partners.org NR 25 TC 15 Z9 16 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-8046 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD SEP-OCT PY 2010 VL 27 IS 5 BP 446 EP 452 DI 10.1111/j.1525-1470.2010.01286.x PG 7 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA 654OW UT WOS:000282178800003 PM 20796234 ER PT J AU Cheng, C Kroshinsky, D AF Cheng, Carol Kroshinsky, Daniela TI Extensive Recalcitrant Warts Successfully Treated with Systemic 5-fluorouracil in an Immunocompromised Girl SO PEDIATRIC DERMATOLOGY LA English DT Letter ID CANCER C1 [Cheng, Carol; Kroshinsky, Daniela] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Cheng, C (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-8046 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD SEP-OCT PY 2010 VL 27 IS 5 BP 571 EP 571 PG 1 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA 654OW UT WOS:000282178800058 ER PT J AU Wesseling-Perry, K Tsai, E Ettenger, R Juppner, H Salusky, IB AF Wesseling-Perry, K. Tsai, E. Ettenger, R. Juppner, H. Salusky, I. B. TI FGF-23 Predicts Progression of Renal Dysfunction in Pediatric Transplant Recipients SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Wesseling-Perry, K.; Tsai, E.; Ettenger, R.; Salusky, I. B.] Univ Calif Los Angeles, Los Angeles, CA USA. [Juppner, H.] Mass Gen Hosp, Div Endocrine, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2010 VL 25 IS 9 MA 73 BP 1809 EP 1810 PG 2 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 630BU UT WOS:000280247200102 ER PT J AU Wesseling-Perry, K Pereira, RC Yadin, O Gales, B Juppner, H Salusky, IB AF Wesseling-Perry, K. Pereira, R. C. Yadin, O. Gales, B. Juppner, H. Salusky, I. B. TI Spectrum of ROD in Pediatric CKD SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Wesseling-Perry, K.; Pereira, R. C.; Yadin, O.; Gales, B.; Salusky, I. B.] Univ Calif Los Angeles, Los Angeles, CA USA. [Juppner, H.] Mass Gen Hosp, Endocrine Unit, Boston, MA USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2010 VL 25 IS 9 MA 554 BP 1905 EP 1906 PG 2 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 630BU UT WOS:000280247200583 ER PT J AU Wesseling-Perry, K Pereira, RC Gales, B Wang, H Elashoff, R Juppner, H Salusky, IB AF Wesseling-Perry, K. Pereira, R. C. Gales, B. Wang, H. Elashoff, R. Juppner, H. Salusky, I. B. TI FGF-23 Levels Predict Response to Treatment of Secondary Hyperparathyroidism SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Wesseling-Perry, K.; Pereira, R. C.; Gales, B.; Wang, H.; Elashoff, R.; Salusky, I. B.] Univ Calif Los Angeles, Los Angeles, CA USA. [Juppner, H.] Mass Gen Hosp, Div Endocrine, Boston, MA USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2010 VL 25 IS 9 MA 578 BP 1910 EP 1911 PG 2 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 630BU UT WOS:000280247200607 ER PT J AU Rozenfeld, J Tal, O Adler, L Efrati, E Stewart, A Carrithers, S Alper, S Zelikovic, I AF Rozenfeld, J. Tal, O. Adler, L. Efrati, E. Stewart, A. Carrithers, S. Alper, S. Zelikovic, I. TI The Pendrin Gene, PDS, Is Transcriptionally Regulated by the Intestinal Natriuretic Peptide Uroguanylin SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Rozenfeld, J.; Tal, O.; Adler, L.; Efrati, E.; Zelikovic, I.] Technion Israel Inst Technol, Rambam Med Ctr, Div Pediat Nephrol, Haifa, Israel. [Stewart, A.; Alper, S.] Beth Israel Deac Med Ctr, Ren Div, Boston, MA USA. [Stewart, A.; Alper, S.] Beth Israel Deac Med Ctr, Mol Vasc Med Div, Boston, MA USA. [Carrithers, S.] Sequela, Pewee Valley, KY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2010 VL 25 IS 9 MA 959 BP 1987 EP 1987 PG 1 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 630BU UT WOS:000280247200988 ER PT J AU Stengel, A Goebel, M Wang, LX Reeve, JR Tache, Y Lambrecht, NWG AF Stengel, Andreas Goebel, Miriam Wang, Lixin Reeve, Joseph R., Jr. Tache, Yvette Lambrecht, Nils W. G. TI Lipopolysaccharide differentially decreases plasma acyl and desacyl ghrelin levels in rats: Potential role of the circulating ghrelin-acylating enzyme GOAT SO PEPTIDES LA English DT Article DE Acyl ghrelin; Desacyl ghrelin; GOAT; LPS; RAPID method; Rat ID HELICOBACTER-PYLORI INFECTION; HORMONE SECRETAGOGUE RECEPTOR; BODY-MASS INDEX; FOOD-INTAKE; GASTRIC GHRELIN; SECRETION; STOMACH; PEPTIDE; CELLS; INSULIN AB Bacterial lipopolysaccharide (LPS) in rodents is an established model for studying innate immune responses to gram-negative bacteria and mimicking symptoms of infections including reduced food intake associated with decreased circulating total ghrelin levels. The ghrelin-acylating enzyme, ghrelin-O-acyltransferase (GOAT) involved in the formation of acyl ghrelin (AG) was recently identified. We investigated changes in circulating AG, desacyl ghrelin (DG) and GOAT induced by intraperitoneal LPS (100 mu g/kg) and associated changes in food intake. Plasma AG and total ghrelin were assessed by radioimmunoassay, GOAT protein by Western blot and mRNA by RT-OCR. DG was derived from total minus AG. Plasma AG and DG were decreased at 2,5 and 7 h (p < 0.01) post-injection compared to vehicle and recovered at 24 h. At 2 h there was a significantly greater decrease of AG (-53%) than DG (-28%) resulting in a decreased AG/DG ratio (1:5,p < 0.01), which thereafter returned to pre-injection values (1:3). This altered ratio was associated with a 38% decrease in plasma GOAT protein compared to vehicle (p < 0.001), whereas gastric GOAT protein was slightly increased by 10% (p < 0.05). GOAT mRNA expression was unchanged. Food intake was reduced by 58% measured during the 1.5-2 h period post-LPS injection. Decreased plasma AG and DG preceded the rise in rectal temperature and blood glucose that peaked at 7 h. These data indicate that LPS induces a long-lasting reduction of AG and DG levels that may have a bearing with the decrease in food intake. The faster drop in AG than DG within 2 h is associated with reduced circulating GOAT. Published by Elsevier Inc. C1 [Lambrecht, Nils W. G.] Vet Affairs Long Beach Healthcare Syst, Long Beach, CA 90822 USA. [Stengel, Andreas; Goebel, Miriam; Wang, Lixin; Reeve, Joseph R., Jr.; Tache, Yvette] Univ Calif Los Angeles, Dept Med, Div Digest Dis, CURE Digest Dis Res Ctr,Ctr Neurobiol Stress, Los Angeles, CA 90073 USA. [Stengel, Andreas; Goebel, Miriam; Wang, Lixin; Reeve, Joseph R., Jr.; Tache, Yvette] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. RP Lambrecht, NWG (reprint author), Vet Affairs Long Beach Healthcare Syst, 5901 E 7th St,Bldg 1,Rm 200M, Long Beach, CA 90822 USA. EM Nils.Lambrecht2@va.gov OI Lambrecht, Nils/0000-0002-1275-1384 FU Department of Veterans Affairs; VA Research Career Scientist Award; NIHDK [33061, DK-41301]; German Research Foundation [STE 1765/1-1, GO 1718/1-1] FX This work was supported by Department of Veterans Affairs Merit Awards (N.W.G.L. and Y.T.) and a VA Research Career Scientist Award (Y.T.), NIHDK 33061 (Y.T.), Center grant DK-41301 (Animal Core, Y.T. and Peptidomic, Radioimmunoassay and Proteomic Core, J.R.R., Jr.) and German Research Foundation grants STE 1765/1-1 (A.S.) and GO 1718/1-1 (M.G.). We are grateful to Mrs. Honghui Liang for her excellent technical support and we thank Ms. Eugenia Hu for reviewing the manuscript. NR 42 TC 26 Z9 26 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD SEP PY 2010 VL 31 IS 9 BP 1689 EP 1696 DI 10.1016/j.peptides.2010.06.015 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 644IL UT WOS:000281368400011 PM 20599577 ER PT J AU Arar, N Seo, J Abboud, HE Parchman, M Noel, P AF Arar, Nedal Seo, Joann Abboud, Hanna E. Parchman, Michael Noel, Polly TI Providers' behavioral beliefs regarding the delivery of genomic medicine at the Veterans Health Administration SO PERSONALIZED MEDICINE LA English DT Article DE behavioral intentions; genomic medicine; genomic services; theory of planned behavior; Veterans Health Administration ID PRIMARY-CARE PHYSICIANS; FAMILY-HISTORY; PLANNED BEHAVIOR; REASONED ACTION; GENETIC TESTS; PRACTITIONERS; PERSPECTIVES; INFORMATION; CHALLENGES; INTENTION AB To examine providers' behavioral intention toward the utilization of genomic services at the Veterans Health Administration (VHA; Washington, DC, USA) through the lens of the 'Theory of Planned Behavior'. The theory of planned behavior posits that individuals' behaviors (using genomic services) are driven by their behavioral intentions. Behavioral intentions is a function of: first, behavioral beliefs; second, normative beliefs, and third; control beliefs. Materials & methods: Semi-structured interviews were conducted with 20 providers working in different units at the South Texas Veterans Health Care System (STVHCS; TX USA). The interviews focused on assessing providers' behavioral beliefs, normative beliefs and control beliefs regarding the delivery of genomic medicine at the STVHCS. Interview materials were tape recorded, transcribed and the content was analyzed using qualitative methods. Results: All participating providers perceived genomic medicine to be an important area in medicine (behavioral beliefs). They agreed that the VHA has the necessary infrastructure to foster the delivery of genomic services. The majority of participants (n = 18; 90%) agreed that primary care providers will play a major role in delivering genomic services. Providers indicated that referents' (other providers) opinions about genomic services may affect their decisions about whether to utilize genomic services (normative beliefs). However, most providers (n = 17; 85%) raised concerns about the impact of using genomic services on the process of care (control beliefs). Participants indicated that additional training for providers and patients, and decision support will facilitate the delivery of genomic services (control beliefs). Providers also identified three external barriers: first, uncertainty about genomic findings; second, coordination of care between primary care, specialists and genetic services (system level barriers); and third ethical issues associated with genomic information and services. Conclusion: Our findings highlight several opportunities and challenges related to the delivery of genomic medicine at the VHA. The results suggest that strategies to address providers' concerns in the control beliefs domain may be necessary to enhance providers' utilization of genomic services in clinical practice. C1 [Arar, Nedal; Seo, Joann; Abboud, Hanna E.; Parchman, Michael; Noel, Polly] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Nephrol, Audie L Murphy Mem Vet Hosp, San Antonio, TX 78229 USA. RP Arar, N (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Nephrol, Audie L Murphy Mem Vet Hosp, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM ararn@uthscsa.edu OI Parchman, Michael/0000-0001-7129-2889 FU VHA-HSRD FX This work was supported by the VHA-HSR&D (PI: Nedal Arar). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 41 TC 4 Z9 4 U1 1 U2 6 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 J9 PERS MED JI Pers. Med. PD SEP PY 2010 VL 7 IS 5 BP 485 EP 494 DI 10.2217/PME.10.47 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 666HZ UT WOS:000283106800009 ER PT J AU Austad, K Brendel, DH Brendel, RW AF Austad, Kirsten Brendel, David H. Brendel, Rebecca W. TI FINANCIAL CONFLICTS OF INTEREST AND THE ETHICAL OBLIGATIONS OF MEDICAL SCHOOL FACULTY AND THE PROFESSION SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article ID PHARMACEUTICAL-INDUSTRY; HIDDEN CURRICULUM; CLINICAL CARE; PHYSICIANS; EDUCATION; DOCTORS; IMPACT AB Despite their potential benefits, relationships linking medical school faculty and the pharmaceutical and device industries may also challenge the professional value of primacy of patient welfare, a point highlighted in a recent Institute of Medicine report. Academic medical centers and professors have the added professional obligation to ensure the unbiased, evidence-based education of future doctors. This essay argues that faculty financial conflicts of interest may threaten this obligation by propagating the bias introduced by these relationships to students. This could occur directly through the process of curriculum determination and delivery, and also indirectly through the "hidden curriculum," which deserves particular attention, as its lessons may conflict with those professed in the formal curriculum. The essay concludes with guiding principles to consider when developing a conflict of interest policy at academic medical centers. C1 [Brendel, Rebecca W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Brendel, David H.] McLean Hosp, Belmont, MA USA. [Brendel, David H.; Brendel, Rebecca W.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. RP Brendel, RW (reprint author), Massachusetts Gen Hosp, 15 Parkman St,WAC 812, Boston, MA 02114 USA. EM Kirsten_Austad@hms.harvard.edu NR 29 TC 0 Z9 0 U1 0 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD FAL PY 2010 VL 53 IS 4 BP 534 EP 544 PG 11 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA 662HX UT WOS:000282799400005 PM 21037407 ER PT J AU Oyetayo, OO Rogers, CE Hofmann, PO AF Oyetayo, Ola O. Rogers, Carrie E. Hofmann, Prudence O. TI Dronedarone: A New Antiarrhythmic Agent SO PHARMACOTHERAPY LA English DT Review DE dronedarone; atrial fibrillation; atrial flutter; antiarrhythmics; amiodarone ID PERSISTENT ATRIAL-FIBRILLATION; AMIODARONE-LIKE AGENT; DE-POINTES ARRHYTHMIAS; RHYTHM-CONTROL; HEART-FAILURE; SINUS RHYTHM; COMPARATIVE EFFICACY; RANDOMIZED-TRIAL; SR-33589; MAINTENANCE AB Dronedarone is an antiarrhythmic agent recently approved by the United States Food and Drug Administration for the reduction of cardiovascular-related hospitalizations in patients with paroxysmal or persistent atrial fibrillation or atrial flutter The drug is a derivative of amiodarone and has been modified to reduce the organ toxicities frequently encountered with amiodarone. Dronedarone exerts its antiarrhythmic effects through multichannel blockade of the sodium, potassium, and calcium channels and also possesses antiadrenergic activity, thereby exhibiting pharmacologic effects of all four Vaughan Williams classes of antiarrhythmics The efficacy of dronedarone for the maintenance of sinus rhythm, ventricular rate control, and reduction in cardiovascular-related hospitalizations has been demonstrated in several randomized, placebo-controlled trials Although a high rate of gastrointestinal events (e g, nausea, vomiting, and diarrhea) has been associated with dronedarone, more serious adverse events such as thyroid, liver, or pulmonary toxicities have not been observed Because of a possible increase in mortality, dronedarone should be avoided in patients with New York Heart Association class IV or II-III heart failure with a recent decompensation Given the efficacy and safety data currently available, dronedarone represents a reasonable alternative for maintenance of sinus rhythm in appropriately selected patients C1 [Oyetayo, Ola O.; Rogers, Carrie E.; Hofmann, Prudence O.] Univ Texas Hlth Sci Ctr San Antonio, Pharmacotherapy Educ & Res Ctr, Sch Med, San Antonio, TX 78229 USA. [Oyetayo, Ola O.; Rogers, Carrie E.; Hofmann, Prudence O.] Univ Texas Austin, Coll Pharm, Austin, TX 78712 USA. [Rogers, Carrie E.; Hofmann, Prudence O.] Audie L Murphy Hosp, Dept Pharm, S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Oyetayo, OO (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Pharmacotherapy Educ & Res Ctr, Sch Med, 7703 Floyd Curl Dr,MC6220, San Antonio, TX 78229 USA. NR 52 TC 12 Z9 14 U1 0 U2 1 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD SEP PY 2010 VL 30 IS 9 BP 904 EP 915 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 648AL UT WOS:000281662200006 PM 20795846 ER PT J AU Klibanski, A Melmed, S Clemmons, DR Colao, A Cunningham, RS Molitch, ME Vinik, AI Adelman, DT Liebert, KJP AF Klibanski, Anne Melmed, Shlomo Clemmons, David R. Colao, Annamaria Cunningham, Regina S. Molitch, Mark E. Vinik, Aaron I. Adelman, Daphne T. Liebert, Karen J. P. TI The endocrine tumor summit 2008: appraising therapeutic approaches for acromegaly and carcinoid syndrome SO PITUITARY LA English DT Article DE Acromegaly; Carcinoid syndrome; Neuroendocrine tumor; NET; Somatostatin analogs; Somatostatin analogues; Lanreotide; Octreotide; Insulin-like growth factor-I; IGF-I; Growth hormone; GH ID GROWTH-FACTOR-I; QUALITY-OF-LIFE; PREOPERATIVE OCTREOTIDE TREATMENT; ADVANCED NEUROENDOCRINE TUMORS; SECRETING PITUITARY-ADENOMAS; SOMATOSTATIN ANALOG THERAPY; PRIMARY MEDICAL THERAPY; GLUCOSE-TOLERANCE TEST; LONG-ACTING RELEASE; FOLLOW-UP AB The Endocrine Tumor Summit convened in December 2008 to address 6 statements prepared by panel members that reflect important questions in the treatment of acromegaly and carcinoid syndrome. Data pertinent to each of the statements were identified through review of pertinent literature by one of the 9-member panel, enabling a critical evaluation of the statements and the evidence supporting or refuting them. Three statements addressed the validity of serum growth hormone (GH) and insulin-like growth factor-I (IGF-I) concentrations as indicators or predictors of disease in acromegaly. Statements regarding the effects of preoperative somatostatin analog use on pituitary surgical outcomes, their effects on hormone and symptom control in carcinoid syndrome, and the efficacy of extended dosing intervals were reviewed. Panel opinions, based on the level of available scientific evidence, were polled. Finally, their views were compared with those of surveyed community-based endocrinologists and neurosurgeons. C1 [Klibanski, Anne] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Melmed, Shlomo] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Clemmons, David R.] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. [Colao, Annamaria] Univ Naples Federico 2, Dept Mol & Clin Endocrinol & Oncol, I-80131 Naples, Italy. [Cunningham, Regina S.] Robert Wood Johnson Med Ctr, Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Molitch, Mark E.; Adelman, Daphne T.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Vinik, Aaron I.] Eastern Virginia Med Sch, Dept Internal Med, Norfolk, VA 23510 USA. [Liebert, Karen J. P.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. RP Klibanski, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM aklibanski@partners.org; Shlomo.melmed@cshs.org; endo@medicineexch.med.unc.edu; colao@unina.it; xlilrbcqtx@yahoo.com; molitch@northwestern.edu; VinikAI@evms.edu; d-adelman@northwestern.edu; kpulaski@partners.org FU Ipsen FX This activity is supported by an educational grant from Ipsen. NR 87 TC 5 Z9 5 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X J9 PITUITARY JI Pituitary PD SEP PY 2010 VL 13 IS 3 BP 266 EP 286 DI 10.1007/s11102-009-0210-2 PG 21 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 634EP UT WOS:000280562700012 PM 20012914 ER PT J AU Cantero, MR Cantiello, HF AF Cantero, Md R. Cantiello, H. F. TI LITHIUM INHIBITS CATION TRANSPORT IN THE TRP CHANNEL POLYCYSTIN-2 (TRPP2) SO PLACENTA LA English DT Meeting Abstract CT International-Federation-of-Placental-Associations Meeting 2010 CY OCT 19-22, 2010 CL Santiago, CHILE DE Polycystin-2; lithium; term human syncytiotrophoblast C1 [Cantero, Md R.; Cantiello, H. F.] Consejo Nacl Invest Cient & Tecn, Lab Canales Ion, RA-1033 Buenos Aires, DF, Argentina. [Cantiello, H. F.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP PY 2010 VL 31 IS 9 BP A130 EP A130 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 654CW UT WOS:000282147100288 ER PT J AU LaFramboise, T Dewal, N Wilkins, K Pe'er, I Freedman, ML AF LaFramboise, Thomas Dewal, Ninad Wilkins, Katherine Pe'er, Itsik Freedman, Matthew L. TI Allelic Selection of Amplicons in Glioblastoma Revealed by Combining Somatic and Germline Analysis SO PLOS GENETICS LA English DT Article ID MYELOPROLIFERATIVE NEOPLASMS; PHASE-II; SUSCEPTIBILITY; GENE; AMPLIFICATION; EXPRESSION; INHIBITORS; EVOLUTION; VARIANTS; PATHWAYS AB Cancer is a disease driven by a combination of inherited risk alleles coupled with the acquisition of somatic mutations, including amplification and deletion of genomic DNA. Potential relationships between the inherited and somatic aspects of the disease have only rarely been examined on a genome-wide level. Applying a novel integrative analysis of SNP and copy number measurements, we queried the tumor and normal-tissue genomes of 178 glioblastoma patients from the Cancer Genome Atlas project for preferentially amplified alleles, under the hypothesis that oncogenic germline variants will be selectively amplified in the tumor environment. Selected alleles are revealed by allelic imbalance in amplification across samples. This general approach is based on genetic principles and provides a method for identifying important tumor-related alleles. We find that SNP alleles that are most significantly overrepresented in amplicons tend to occur in genes involved with regulation of kinase and transferase activity, and many of these genes are known contributors to gliomagenesis. The analysis also implicates variants in synapse genes. By incorporating gene expression data, we demonstrate synergy between preferential allelic amplification and expression in DOCK4 and EGFR. Our results support the notion that combining germline and tumor genetic data can identify regions relevant to cancer biology. C1 [LaFramboise, Thomas; Wilkins, Katherine] Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. [LaFramboise, Thomas] Cleveland Clin Fdn, Lerner Res Inst, Genom Med Inst, Cleveland, OH USA. [Dewal, Ninad] Columbia Univ, Dept Biomed Informat, New York, NY USA. [Pe'er, Itsik] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. [Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Freedman, Matthew L.] Broad Inst Harvard, Med & Populat Genet Program, Cambridge, MA USA. [Freedman, Matthew L.] MIT, Cambridge, MA 02139 USA. RP LaFramboise, T (reprint author), Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. EM itsik@cs.columbia.edu; freedman@broadinstitute.org FU US National Institutes of Health [R01 R01 CA131341, U54 CA121852]; Howard Hughes Medical Institute FX This work was supported by grants from the US National Institutes of Health (R01 R01 CA131341 to TL and IP) and (U54 CA121852 to IP). MLF is a Howard Hughes Medical Institute Physician-Scientist Early Career Awardee. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 14 Z9 14 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2010 VL 6 IS 9 AR e1001086 DI 10.1371/journal.pgen.1001086 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 656VM UT WOS:000282369200056 PM 20824129 ER PT J AU Raychaudhuri, S Korn, JM McCarroll, SA Altshuler, D Sklar, P Purcell, S Daly, MJ AF Raychaudhuri, Soumya Korn, Joshua M. McCarroll, Steven A. Altshuler, David Sklar, Pamela Purcell, Shaun Daly, Mark J. CA Int Schizophrenia Consortium TI Accurately Assessing the Risk of Schizophrenia Conferred by Rare Copy-Number Variation Affecting Genes with Brain Function SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; INCREASE RISK; AUTISM; POPULATION; EXPRESSION; DELETIONS; PATHWAYS; DISORDER; DATABASE; TOOL AB Investigators have linked rare copy number variation (CNVs) to neuropsychiatric diseases, such as schizophrenia. One hypothesis is that CNV events cause disease by affecting genes with specific brain functions. Under these circumstances, we expect that CNV events in cases should impact brain-function genes more frequently than those events in controls. Previous publications have applied "pathway" analyses to genes within neuropsychiatric case CNVs to show enrichment for brain-functions. While such analyses have been suggestive, they often have not rigorously compared the rates of CNVs impacting genes with brain function in cases to controls, and therefore do not address important confounders such as the large size of brain genes and overall differences in rates and sizes of CNVs. To demonstrate the potential impact of confounders, we genotyped rare CNV events in 2,415 unaffected controls with Affymetrix 6.0; we then applied standard pathway analyses using four sets of brain-function genes and observed an apparently highly significant enrichment for each set. The enrichment is simply driven by the large size of brain-function genes. Instead, we propose a case-control statistical test, cnv-enrichment-test, to compare the rate of CNVs impacting specific gene sets in cases versus controls. With simulations, we demonstrate that cnv-enrichment-test is robust to case-control differences in CNV size, CNV rate, and systematic differences in gene size. Finally, we apply cnv-enrichment-test to rare CNV events published by the International Schizophrenia Consortium (ISC). This approach reveals nominal evidence of case-association in neuronal-activity and the learning gene sets, but not the other two examined gene sets. The neuronal-activity genes have been associated in a separate set of schizophrenia cases and controls; however, testing in independent samples is necessary to definitively confirm this association. Our method is implemented in the PLINK software package. C1 [Raychaudhuri, Soumya; Korn, Joshua M.; McCarroll, Steven A.; Altshuler, David; Daly, Mark J.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Raychaudhuri, Soumya; Korn, Joshua M.; Altshuler, David; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Raychaudhuri, Soumya] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Korn, Joshua M.] Harvard Univ, Grad Program Biophys, Cambridge, MA 02138 USA. [McCarroll, Steven A.; Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Sklar, Pamela] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Sklar, Pamela; Purcell, Shaun] Massachusetts Gen Hosp, Psychiat & Neurodeve Genet Unit, Boston, MA 02114 USA. [Sklar, Pamela; Purcell, Shaun] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA. RP Raychaudhuri, S (reprint author), Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. EM shaun@pngu.mgh.harvard.edu; mjdaly@chgr.mgh.harvard.edu RI Altshuler, David/A-4476-2009; macedo santos, antonio/M-5737-2013; Ruderfer, Douglas/M-5795-2016; McQuillin, Andrew/C-1623-2008; Morley, Christopher P/K-1907-2014; OI Altshuler, David/0000-0002-7250-4107; macedo santos, antonio/0000-0003-2180-2718; Ruderfer, Douglas/0000-0002-2365-386X; McQuillin, Andrew/0000-0003-1567-2240; Bergen, Sarah/0000-0002-5888-0034; Morley, Christopher P/0000-0003-0185-7148; lichtenstein, paul/0000-0003-3037-5287 FU National Institutes of Health (NIH) [AR055688, HG004171, DK62432, DK083756-1, DK64869]; NIH-NLBI [R01HL087676]; National Center for Research Resources FX For this work, SR is supported by a K08 National Institutes of Health (NIH) career development award (AR055688). MJD is supported by NIH grants through the U01 (HG004171, DK62432) and R01 (DK083756-1, DK64869) mechanisms. The MIGen study was funded by funding from the NIH-NLBI (R01HL087676) and a grant from the National Center for Research Resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 68 Z9 69 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2010 VL 6 IS 9 AR e1001097 DI 10.1371/journal.pgen.1001097 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 656VM UT WOS:000282369200037 PM 20838587 ER PT J AU Snow, JW Trowbridge, JJ Fujiwara, T Emambokus, NE Grass, JA Orkin, SH Bresnick, EH AF Snow, Jonathan W. Trowbridge, Jennifer J. Fujiwara, Tohru Emambokus, Nikla E. Grass, Jeffrey A. Orkin, Stuart H. Bresnick, Emery H. TI A Single cis Element Maintains Repression of the Key Developmental Regulator Gata2 SO PLOS GENETICS LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; ERYTHROID-DIFFERENTIATION; CHROMATIN OCCUPANCY; HEMATOPOIETIC-CELLS; H3K4 METHYLATION; FACTOR INTERPLAY; GENE-EXPRESSION; STEM-CELLS; ERYTHROPOIESIS; GENOME AB In development, lineage-restricted transcription factors simultaneously promote differentiation while repressing alternative fates. Molecular dissection of this process has been challenging as transcription factor loci are regulated by many transacting factors functioning through dispersed cis elements. It is not understood whether these elements function collectively to confer transcriptional regulation, or individually to control specific aspects of activation or repression, such as initiation versus maintenance. Here, we have analyzed cis element regulation of the critical hematopoietic factor Gata2, which is expressed in early precursors and repressed as GATA-1 levels rise during terminal differentiation. We engineered mice lacking a single cis element -1.8 kb upstream of the Gata2 transcriptional start site. Although Gata2 is normally repressed in late-stage erythroblasts, the -1.8 kb mutation unexpectedly resulted in reactivated Gata2 transcription, blocked differentiation, and an aberrant lineage-specific gene expression pattern. Our findings demonstrate that the -1.8 kb site selectively maintains repression, confers a specific histone modification pattern and expels RNA Polymerase II from the locus. These studies reveal how an individual cis element establishes a normal developmental program via regulating specific steps in the mechanism by which a critical transcription factor is repressed. C1 [Snow, Jonathan W.; Trowbridge, Jennifer J.; Emambokus, Nikla E.; Orkin, Stuart H.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Snow, Jonathan W.; Trowbridge, Jennifer J.; Emambokus, Nikla E.; Orkin, Stuart H.] Harvard Univ, Sch Med, Boston, MA USA. [Trowbridge, Jennifer J.; Orkin, Stuart H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Trowbridge, Jennifer J.; Orkin, Stuart H.] Harvard Stem Cell Inst, Boston, MA USA. [Fujiwara, Tohru; Grass, Jeffrey A.; Bresnick, Emery H.] Univ Wisconsin, Wisconsin Inst Med Res, Sch Med & Publ Hlth, Madison, WI USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Snow, JW (reprint author), Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. EM orkin@bloodgroup.tch.harvard.edu; ehbresni@wisc.edu RI cheng, yong/I-4270-2012 FU National Institutes of Health (NIH) [DK068634, HL32259]; National Cancer Institute [P30 CA014520] FX This work was funded by National Institutes of Health (NIH) grants DK068634 (EHB) and HL32259 (SHO) and by grant P30 CA014520 to the University of Wisconsin Paul Carbone Cancer Center from the National Cancer Institute. JWS and JJT are Fellows of the Leukemia & Lymphoma Society, and SHO 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 52 TC 22 Z9 22 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2010 VL 6 IS 9 AR e1001103 DI 10.1371/journal.pgen.1001103 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 656VM UT WOS:000282369200042 PM 20838598 ER PT J AU Yalcin, B Nicod, J Bhomra, A Davidson, S Cleak, J Farinelli, L Osteras, M Whitley, A Yuan, W Gan, XC Goodson, M Klenerman, P Satpathy, A Mathis, D Benoist, C Adams, DJ Mott, R Flint, J AF Yalcin, Binnaz Nicod, Jerome Bhomra, Amarjit Davidson, Stuart Cleak, James Farinelli, Laurent Osteras, Magne Whitley, Adam Yuan, Wei Gan, Xiangchao Goodson, Martin Klenerman, Paul Satpathy, Ansu Mathis, Diane Benoist, Christophe Adams, David J. Mott, Richard Flint, Jonathan TI Commercially Available Outbred Mice for Genome-Wide Association Studies SO PLOS GENETICS LA English DT Article ID QUANTITATIVE TRAIT LOCI; GENETIC-ANALYSIS; COLLABORATIVE CROSS; INBRED STRAINS; COMPLEX TRAITS; F-ST; MOUSE; STRATIFICATION; HAPLOTYPES; DISCOVERY AB Genome-wide association studies using commercially available outbred mice can detect genes involved in phenotypes of biomedical interest. Useful populations need high-frequency alleles to ensure high power to detect quantitative trait loci (QTLs), low linkage disequilibrium between markers to obtain accurate mapping resolution, and an absence of population structure to prevent false positive associations. We surveyed 66 colonies for inbreeding, genetic diversity, and linkage disequilibrium, and we demonstrate that some have haplotype blocks of less than 100 Kb, enabling gene-level mapping resolution. The same alleles contribute to variation in different colonies, so that when mapping progress stalls in one, another can be used in its stead. Colonies are genetically diverse: 45% of the total genetic variation is attributable to differences between colonies. However, quantitative differences in allele frequencies, rather than the existence of private alleles, are responsible for these population differences. The colonies derive from a limited pool of ancestral haplotypes resembling those found in inbred strains: over 95% of sequence variants segregating in outbred populations are found in inbred strains. Consequently it is possible to impute the sequence of any mouse from a dense SNP map combined with inbred strain sequence data, which opens up the possibility of cataloguing and testing all variants for association, a situation that has so far eluded studies in completely outbred populations. We demonstrate the colonies' potential by identifying a deletion in the promoter of H2-Ea as the molecular change that strongly contributes to setting the ratio of CD4+ and CD8+ lymphocytes. C1 [Yalcin, Binnaz; Nicod, Jerome; Bhomra, Amarjit; Davidson, Stuart; Cleak, James; Whitley, Adam; Yuan, Wei; Gan, Xiangchao; Goodson, Martin; Mott, Richard; Flint, Jonathan] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Farinelli, Laurent; Osteras, Magne] Fasteris, Plan Les Ouates, Switzerland. [Klenerman, Paul] Univ Oxford, Nuffield Dept Med, Oxford, England. [Satpathy, Ansu; Mathis, Diane; Benoist, Christophe] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Satpathy, Ansu; Mathis, Diane; Benoist, Christophe] Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. [Adams, David J.] Wellcome Trust Sanger Inst, Hinxton, Cambs, England. RP Yalcin, B (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM jf@well.ox.ac.uk RI Yalcin, Binnaz/P-5482-2016; OI Yalcin, Binnaz/0000-0002-1924-6807; Flint, Jonathan/0000-0002-9427-4429; Gan, Xiangchao/0000-0001-6398-5191 FU Wellcome Trust FX This work was funded by the Wellcome Trust. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 51 Z9 52 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2010 VL 6 IS 9 AR e1001085 DI 10.1371/journal.pgen.1001085 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 656VM UT WOS:000282369200055 PM 20838427 ER PT J AU Pinne, M Choy, HA Haake, DA AF Pinne, Marija Choy, Henry A. Haake, David A. TI The OmpL37 Surface-Exposed Protein Is Expressed by Pathogenic Leptospira during Infection and Binds Skin and Vascular Elastin SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID EXTRACELLULAR-MATRIX PROTEINS; OUTER-MEMBRANE PROTEINS; MONOCLONAL-ANTIBODIES; STAPHYLOCOCCUS-AUREUS; PULMONARY HEMORRHAGE; FIBRONECTIN; INTERROGANS; ADHESION; LAMININ; LIPL32 AB Pathogenic Leptospira spp. shed in the urine of reservoir hosts into freshwater can be transmitted to a susceptible host through skin abrasions or mucous membranes causing leptospirosis. The infection process involves the ability of leptospires to adhere to cell surface and extracellular matrix components, a crucial step for dissemination and colonization of host tissues. Therefore, the elucidation of novel mediators of host-pathogen interaction is important in the discovery of virulence factors involved in the pathogenesis of leptospirosis. In this study, we assess the functional roles of transmembrane outer membrane proteins OmpL36 (LIC13166), OmpL37 (LIC12263), and OmpL47 (LIC13050), which we recently identified on the leptospiral surface. We determine the capacity of these proteins to bind to host tissue components by enzyme-linked immunosorbent assay. OmpL37 binds elastin preferentially, exhibiting dose-dependent, saturating binding to human skin (K(d), 104 +/- 19 nM) and aortic elastin (K(d), 152 +/- 27 nM). It also binds fibrinogen (K(d), 244 +/- 15 nM), fibrinogen fragment D (K(d), 132 +/- 30 nM), plasma fibronectin (K(d), 359 +/- 68 nM), and murine laminin (K(d), 410 +/- 81 nM). The binding to human skin elastin by both recombinant OmpL37 and live Leptospira interrogans is specifically enhanced by rabbit antiserum for OmpL37, suggesting the involvement of OmpL37 in leptospiral binding to elastin and also the possibility that host-generated antibodies may promote rather than inhibit the adherence of leptospires to elastin-rich tissues. Further, we demonstrate that OmpL37 is recognized by acute and convalescent leptospirosis patient sera and also by Leptospira-infected hamster sera. Finally, OmpL37 protein is detected in pathogenic Leptospira serovars and not in saprophytic Leptospira. Thus, OmpL37 is a novel elastin-binding protein of pathogenic Leptospira that may be promoting attachment of Leptospira to host tissues. C1 [Pinne, Marija; Choy, Henry A.] Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. [Pinne, Marija; Choy, Henry A.; Haake, David A.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Haake, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA USA. [Haake, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Haake, David A.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. RP Pinne, M (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA. EM mpinne@ucla.edu FU National Institute of Allergy and Infectious Diseases [AI-34431]; VA Medical Research Funds FX This work was supported by Public Health Service grant AI-34431 (to D.A.H.) from the National Institute of Allergy and Infectious Diseases and by VA Medical Research Funds (to D.A.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 30 Z9 30 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2727 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD SEP PY 2010 VL 4 IS 9 AR e815 DI 10.1371/journal.pntd.0000815 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 655TB UT WOS:000282271300018 PM 20844573 ER PT J AU Benny, O Nakai, K Yoshimura, T Bazinet, L Akula, JD Nakao, S Hafezi-Moghadam, A Panigrahy, D Pakneshan, P D'Amato, RJ AF Benny, Ofra Nakai, Kei Yoshimura, Takeru Bazinet, Lauren Akula, James D. Nakao, Shintaro Hafezi-Moghadam, Ali Panigrahy, Dipak Pakneshan, Pouya D'Amato, Robert J. TI Broad Spectrum Antiangiogenic Treatment for Ocular Neovascular Diseases SO PLOS ONE LA English DT Article ID MACULAR DEGENERATION; CHOROIDAL NEOVASCULARIZATION; CYTOKINE EXPRESSION; ACTIVATION STEPS; PHOTOTRANSDUCTION; ANGIOGENESIS; RANIBIZUMAB; RETINOPATHY; RPE; ROD AB Pathological neovascularization is a hallmark of late stage neovascular (wet) age-related macular degeneration (AMD) and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV), while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF) exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD. Methods and Findings: Lodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH), Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2). Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1). The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG) assessing retinal and by histology. Conclusions: Lodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties make Lodamin especially beneficial for ophthalmic use. Our results support the concept that broad spectrum antiangiogenic drugs are promising agents for AMD treatment and prevention. C1 [Benny, Ofra; Nakai, Kei; Yoshimura, Takeru; Bazinet, Lauren; Panigrahy, Dipak; Pakneshan, Pouya; D'Amato, Robert J.] Harvard Univ, Sch Med, Childrens Hosp Boston, Vasc Biol Program, Boston, MA 02115 USA. [Benny, Ofra; Nakai, Kei; Yoshimura, Takeru; Bazinet, Lauren; Panigrahy, Dipak; Pakneshan, Pouya; D'Amato, Robert J.] Harvard Univ, Sch Med, Dept Surg, Childrens Hosp Boston, Boston, MA 02115 USA. [Benny, Ofra; Nakai, Kei; Yoshimura, Takeru; Bazinet, Lauren; Akula, James D.; Pakneshan, Pouya; D'Amato, Robert J.] Harvard Univ, Sch Med, Dept Ophthalmol, Childrens Hosp Boston, Boston, MA USA. [Nakao, Shintaro; Hafezi-Moghadam, Ali] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Benny, O (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Vasc Biol Program, Boston, MA 02115 USA. EM ofra.bennyratsaby@childrens.harvard.edu OI Hafezi-Moghadam, Ali/0000-0002-5336-0697 FU Departmental support fund FX Departmental support fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 12 Z9 12 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 1 PY 2010 VL 5 IS 9 AR e12515 DI 10.1371/journal.pone.0012515 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 645KT UT WOS:000281456100016 ER PT J AU Rolland, M Carlson, JM Manocheewa, S Swain, JV Lanxon-Cookson, E Deng, WJ Rousseau, CM Raugi, DN Learn, GH Maust, BS Coovadia, H Ndung'u, T Goulder, PJR Walker, BD Brander, C Heckerman, DE Mullins, JI AF Rolland, Morgane Carlson, Jonathan M. Manocheewa, Siriphan Swain, J. Victor Lanxon-Cookson, Erinn Deng, Wenjie Rousseau, Christine M. Raugi, Dana N. Learn, Gerald H. Maust, Brandon S. Coovadia, Hoosen Ndung'u, Thumbi Goulder, Philip J. R. Walker, Bruce D. Brander, Christian Heckerman, David E. Mullins, James I. TI Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-LYMPHOCYTE ESCAPE; PROTEASE INHIBITORS; ELITE CONTROLLERS; VIRAL LOAD; ASSOCIATIONS; MUTATIONS; POLYMORPHISMS; TRANSMISSION; INFECTION AB Background: Despite high potential for HIV-1 genetic variation, the emergence of some mutations is constrained by fitness costs, and may be associated with compensatory amino acid (AA) co-variation. To characterize the interplay between Cytotoxic T Lymphocyte (CTL)-mediated pressure and HIV-1 evolutionary pathways, we investigated AA co-variation in Gag sequences obtained from 449 South African individuals chronically infected with HIV-1 subtype C. Methodology/Principal Findings: Individuals with CTL responses biased toward Gag presented lower viral loads than individuals with under-represented Gag-specific CTL responses. Using methods that account for founder effects and HLA linkage disequilibrium, we identified 35 AA sites under Human Leukocyte Antigen (HLA)-restricted CTL selection pressure and 534 AA-to-AA interactions. Analysis of two-dimensional distances between co-varying residues revealed local stabilization mechanisms since 40% of associations involved neighboring residues. Key features of our co-variation analysis included sites with a high number of co-varying partners, such as HLA-associated sites, which had on average 55% more connections than other co-varying sites. Conclusions/Significance: Clusters of co-varying AA around HLA-associated sites (especially at typically conserved sites) suggested that cooperative interactions act to preserve the local structural stability and protein function when CTL escape mutations occur. These results expose HLA-imprinted HIV-1 polymorphisms and their interlinked mutational paths in Gag that are likely due to opposite selective pressures from host CTL-mediated responses and viral fitness constraints. C1 [Rolland, Morgane; Manocheewa, Siriphan; Swain, J. Victor; Lanxon-Cookson, Erinn; Deng, Wenjie; Rousseau, Christine M.; Raugi, Dana N.; Learn, Gerald H.; Maust, Brandon S.; Mullins, James I.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Mullins, James I.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Carlson, Jonathan M.; Heckerman, David E.] Microsoft Res, Redmond, WA USA. [Coovadia, Hoosen; Ndung'u, Thumbi; Goulder, Philip J. R.] Univ KwaZulu Natal, HIV Pathogenesis Program, Nelson Mandela Sch Med, Durban, South Africa. [Goulder, Philip J. R.] Univ Oxford, Dept Pediat, Nuffield Dept Med, Oxford, England. [Goulder, Philip J. R.; Walker, Bruce D.; Brander, Christian] Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. [Goulder, Philip J. R.; Walker, Bruce D.; Brander, Christian] Harvard Univ, Sch Med, Boston, MA USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Rolland, M (reprint author), Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. EM mrolland@u.washington.edu OI Brander, Christian/0000-0002-0548-5778; Ndung'u, Thumbi/0000-0003-2962-3992 FU Bill and Melinda Gates Foundation [43437]; amfAR Mathilde Krim Fellowship [107005-43-RFNT]; US Public Health Services [AI057005] FX This work was supported by grants from the Bill and Melinda Gates Foundation to JM [# 43437], an amfAR Mathilde Krim Fellowship to MR [# 107005-43-RFNT] and the US Public Health Services [AI057005], including to M. R. and the Computational Biology Core of the University of Washington Center for AIDS Research and STDs [AI27757]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 20 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 SEP 1 PY 2010 VL 5 IS 9 AR e12463 DI 10.1371/journal.pone.0012463 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 645KT UT WOS:000281456100003 ER PT J AU Cureton, DK Massol, RH Whelan, SPJ Kirchhausen, T AF Cureton, David K. Massol, Ramiro H. Whelan, Sean P. J. Kirchhausen, Tomas TI The Length of Vesicular Stomatitis Virus Particles Dictates a Need for Actin Assembly during Clathrin-Dependent Endocytosis SO PLOS PATHOGENS LA English DT Article ID COATED VESICLE FORMATION; ALDRICH-SYNDROME PROTEIN; EPIDERMAL-GROWTH-FACTOR; DEFECTIVE T PARTICLES; MEDIATED ENDOCYTOSIS; BINDING-PROTEIN; ENTRY; DYNAMIN; RECEPTOR; CELLS AB Microbial pathogens exploit the clathrin endocytic machinery to enter host cells. Vesicular stomatitis virus (VSV), an enveloped virus with bullet-shaped virions that measure 70x200 nm, enters cells by clathrin-dependent endocytosis. We showed previously that VSV particles exceed the capacity of typical clathrin-coated vesicles and instead enter through endocytic carriers that acquire a partial clathrin coat and require local actin filament assembly to complete vesicle budding and internalization. To understand why the actin system is required for VSV uptake, we compared the internalization mechanisms of VSV and its shorter (75 nm long) defective interfering particle, DI-T. By imaging the uptake of individual particles into live cells, we found that, as with parental virions, DI-T enters via the clathrin endocytic pathway. Unlike VSV, DI-T internalization occurs through complete clathrin-coated vesicles and does not require actin polymerization. Since VSV and DI-T particles display similar surface densities of the same attachment glycoprotein, we conclude that the physical properties of the particle dictate whether a virus-containing clathrin pit engages the actin system. We suggest that the elongated shape of a VSV particle prevents full enclosure by the clathrin coat and that stalling of coat assembly triggers recruitment of the actin machinery to finish the internalization process. Since some enveloped viruses have pleomorphic particle shapes and sizes, our work suggests that they may use altered modes of endocytic uptake. More generally, our findings show the importance of cargo geometry for specifying cellular entry modes, even when the receptor recognition properties of a ligand are maintained. C1 [Cureton, David K.; Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02163 USA. [Cureton, David K.; Kirchhausen, Tomas] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Massol, Ramiro H.] Childrens Hosp, Div Gastroenterol & Nutr, Boston, MA 02115 USA. [Whelan, Sean P. J.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Cureton, DK (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02163 USA. EM swhelan@hms.harvard.edu; kirchhausen@crystal.harvard.edu FU NIH [U54 AI057159, AI081842] FX This work was supported by NIH (http://www.nih.gov/) grants U54 AI057159 (New England Regional Center of Excellence in Biodefense and Emerging Infectious Disease (NERCE BEID)) to TK and AI081842 to SPJW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 66 Z9 68 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2010 VL 6 IS 9 AR e1001127 DI 10.1371/journal.ppat.1001127 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 656WY UT WOS:000282373000010 PM 20941355 ER PT J AU Persson, BD Schmitz, NB Santiago, C Zocher, G Larvie, M Scheu, U Casasnovas, JM Stehle, T AF Persson, B. David Schmitz, Nikolaus B. Santiago, Cesar Zocher, Georg Larvie, Mykol Scheu, Ulrike Casasnovas, Jose M. Stehle, Thilo TI Structure of the Extracellular Portion of CD46 Provides Insights into Its Interactions with Complement Proteins and Pathogens SO PLOS PATHOGENS LA English DT Article ID MEMBRANE COFACTOR PROTEIN; MEASLES-VIRUS RECEPTOR; CELLULAR PILUS RECEPTOR; SPECIES-B ADENOVIRUSES; MAXIMUM-LIKELIHOOD; LIGAND-BINDING; DOMAINS; SITES; MCP; EXPRESSION AB The human membrane cofactor protein (MCP, CD46) is a central component of the innate immune system. CD46 protects autologous cells from complement attack by binding to complement proteins C3b and C4b and serving as a cofactor for their cleavage. Recent data show that CD46 also plays a role in mediating acquired immune responses, and in triggering autophagy. In addition to these physiologic functions, a significant number of pathogens, including select adenoviruses, measles virus, human herpes virus 6 (HHV-6), Streptococci, and Neisseria, use CD46 as a cell attachment receptor. We have determined the crystal structure of the extracellular region of CD46 in complex with the human adenovirus type 11 fiber knob. Extracellular CD46 comprises four short consensus repeats (SCR1-SCR4) that form an elongated structure resembling a hockey stick, with a long shaft and a short blade. Domains SCR1, SCR2 and SCR3 are arranged in a nearly linear fashion. Unexpectedly, however, the structure reveals a profound bend between domains SCR3 and SCR4, which has implications for the interactions with ligands as well as the orientation of the protein at the cell surface. This bend can be attributed to an insertion of five hydrophobic residues in a SCR3 surface loop. Residues in this loop have been implicated in interactions with complement, indicating that the bend participates in binding to C3b and C4b. The structure provides an accurate framework for mapping all known ligand binding sites onto the surface of CD46, thereby advancing an understanding of how CD46 acts as a receptor for pathogens and physiologic ligands of the immune system. C1 [Persson, B. David; Schmitz, Nikolaus B.; Zocher, Georg; Scheu, Ulrike; Stehle, Thilo] Univ Tubingen, Tubingen, Germany. [Santiago, Cesar; Casasnovas, Jose M.] CSIC, Ctr Nacl Biotecnol, Madrid, Spain. [Larvie, Mykol] Massachusetts Gen Hosp, Lab Dev, Boston, MA 02114 USA. [Larvie, Mykol] Harvard Univ, Sch Med, Boston, MA USA. [Stehle, Thilo] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA. RP Persson, BD (reprint author), Novartis Inst BioMed Res Inc, Cambridge, MA USA. EM thilo.stehle@uni-tuebingen.de RI Casasnovas, Jose/L-6299-2014; Santiago, Cesar/K-4240-2014 OI Casasnovas, Jose/0000-0002-2873-6410; Santiago, Cesar/0000-0002-5149-1722 FU National Institutes of Health [R01-AI45716]; German Research Foundation [SFB-685]; MICINN [BFU2008-00971] FX This project has been supported by National Institutes of Health grant R01-AI45716 and German Research Foundation grant SFB-685 (to TS). JMC acknowledges support from MICINN (BFU2008-00971). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 30 Z9 31 U1 0 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD SEP PY 2010 VL 6 IS 9 AR e1001122 DI 10.1371/journal.ppat.1001122 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 656WY UT WOS:000282373000005 PM 20941397 ER PT J AU Wilens, TE Spencer, TJ AF Wilens, Timothy E. Spencer, Thomas J. TI Understanding Attention-Deficit/Hyperactivity Disorder From Childhood to Adulthood SO POSTGRADUATE MEDICINE LA English DT Article DE attention-deficit/hyperactivity disorder; attention-deficit disorder; comorbidity; treatment ID DEFICIT HYPERACTIVITY DISORDER; GUANFACINE EXTENDED-RELEASE; CLINICALLY REFERRED ADULTS; SUBSTANCE USE DISORDERS; DRUG-USE DISORDERS; ATOMOXETINE TREATMENT; MULTIMODAL-TREATMENT; CIGARETTE-SMOKING; PSYCHOSOCIAL TREATMENTS; STIMULANT TREATMENT AB Attention deficit/hyperactivity disorder (ADHD) is among the most common neurobehavioral disorders requiring treatment in children and adolescents. The disorder is often chronic, with prominent symptoms and impairment spanning into adulthood. It is often associated with co-occurring disorders, including disruptive, mood, anxiety, and substance abuse disorders. The diagnosis of ADHD is clinically established by review of symptoms and impairment. The biological underpinning of the disorder is supported by genetic, neuroimaging, neurochemistry, and neuropsychological data. All aspects of an individual's life need to be considered in the diagnosis and treatment of ADHD. Multimodal treatment includes educational, family, and individual support. Psychotherapy alone and in combination with medication is helpful for treating patients with ADHD and comorbid disorders. Pharmacotherapy, including stimulants, noradrenergic agents, alpha-agonists, and antidepressants, plays a fundamental role in the long-term management of ADHD. C1 [Wilens, Timothy E.] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Clin Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Wilens, Timothy E.; Spencer, Thomas J.] Harvard Univ, Sch Med, Boston, MA USA. RP Wilens, TE (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Clin Res Program Pediat Psychopharmacol, YAW 6A,55 Fruit St, Boston, MA 02114 USA. EM twilens@partners.org FU NIDA NIH HHS [K24 DA016264] NR 116 TC 34 Z9 36 U1 2 U2 17 PU JTE MULTIMEDIA PI BERWYN PA 1235 WESTLAKES DR, STE 220, BERWYN, PA 19312 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD SEP PY 2010 VL 122 IS 5 BP 97 EP 109 DI 10.3810/pgm.2010.09.2206 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 711UW UT WOS:000286617900012 PM 20861593 ER PT J AU Asch, DA Werner, RM AF Asch, David A. Werner, Rachel M. TI Paying for Performance in Population Health: Lessons From Health Care Settings SO PREVENTING CHRONIC DISEASE LA English DT Article AB The appeal of pay-for-performance in health care derives from the conceptual view that paying doctors and hospitals more to deliver better care will encourage them to deliver better care. What lessons can be learned from the successes and failures of pay-for-performance in health care settings that apply to pay-for-performance in population health? We argue that pay-for-performance requires conditions that are not easily met in population health settings. Pay-for-performance has focused on narrow clinical problems whose success depends on identifiable actors with the motivation and resources to change clinical processes or outcomes. In contrast, population health has broad goals, many antecedents, and no single, identifiable fiduciary (a person who holds assets in trust for a beneficiary). Nevertheless, with careful attention, conditions for successful pay-for-performance in population health might be met. C1 [Asch, David A.; Werner, Rachel M.] Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Equ Res & Promot, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Asch, DA (reprint author), Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Equ Res & Promot, Philadelphia Vet Affairs Med Ctr, 3641 Locust Walk, Philadelphia, PA 19104 USA. EM asch@wharton.upenn.edu FU Veterans Affairs Health Service; Robert Wood Johnson Foundation FX Rachel Werner is supported by a Veterans Affairs Health Services Research and Development Career Development Award. This manuscript was developed as part of the Mobilizing Action Toward Community Health (MATCH) project funded by the Robert Wood Johnson Foundation. NR 24 TC 1 Z9 1 U1 1 U2 3 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD SEP PY 2010 VL 7 IS 5 AR A98 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V20SD UT WOS:000208158800008 PM 20712946 ER PT J AU Curigliano, G Mayer, EL Burstein, HJ Winer, EP Goldhirsch, A AF Curigliano, Giuseppe Mayer, Erica L. Burstein, Harold J. Winer, Eric P. Goldhirsch, Aron TI Cardiac Toxicity From Systemic Cancer Therapy: A Comprehensive Review SO PROGRESS IN CARDIOVASCULAR DISEASES LA English DT Review ID METASTATIC BREAST-CANCER; ENDOTHELIAL GROWTH-FACTOR; ACUTE PROMYELOCYTIC LEUKEMIA; PHASE-III TRIAL; PACLITAXEL PLUS BEVACIZUMAB; TYROSINE KINASE INHIBITOR; RENAL-CELL CARCINOMA; ARSENIC TRIOXIDE; ANTHRACYCLINE CARDIOTOXICITY; RANDOMIZED-TRIAL AB Cardiovascular toxicity is a potential short- or long-term complication of anticancer therapy Exposure to chemotherapy medications, primarily the anthracycline class, can lead to potentially irreversible clinically significant cardiac dysfunction The advent of novel biologic agents, including monoclonal antibodies and tyrosine kinase inhibitors, has revolutionized the treatment of several types of malignancies Although targeted therapies are considered less toxic and better tolerated by patients compared with classic chemotherapy agents, rare serious complications have been observed, and longer-term follow-up is needed to determine the exact profile of related cardiac adverse effects Cardiac toxicity associated with cancer therapies can range from asymptomatic subclinical abnormalities, including electrocardiographic changes and temporary left ventricular ejection fraction decline, to life-threatening events such as congestive heart failure or acute coronary syndromes Assessment of the pit:valence, type, and severity of cardiac toxicity caused by various cancer treatments is a critical topic for patient management and specifically for new drug development Guidelines for monitoring cardiac adverse effects have been formulated, however, appropriate supportive evidence remains limited Given the rate of new drug development designed to fulfill unmet oncologic needs. efforts are needed to promote strategies for cardiac risk detection and management and to avoid unintended consequences potentially impeding development of. regulatory approval for, and patient access to novel therapies These advances require ongoing research to assess and manage the cardiovascular safety of patients treated with anticancer agents, as well as a well-organized collaboration between oncologists and cardiologists The aim of this review is to summarize potential cardiovascular toxicities for a range of cancer chemotherapeutics and to review general mechanisms of cardiovascular toxicity for each agent (Prog Cardiovasc Dis 2010,53.94-104) (C) 2010 Elsevier Inc All rights reserved C1 [Curigliano, Giuseppe; Goldhirsch, Aron] Ist Europeo Oncol, Dept Med, Div Med Oncol, I-20141 Milan, Italy. [Mayer, Erica L.; Burstein, Harold J.; Winer, Eric P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA 02115 USA. RP Curigliano, G (reprint author), Ist Europeo Oncol, Dept Med, Div Med Oncol, Via Ripamonti 435, I-20141 Milan, Italy. NR 108 TC 58 Z9 61 U1 0 U2 11 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-0620 J9 PROG CARDIOVASC DIS JI Prog. Cardiovasc. Dis. PD SEP-OCT PY 2010 VL 53 IS 2 BP 94 EP 104 DI 10.1016/j.pcad.2010.05.006 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 645TC UT WOS:000281488100004 PM 20728696 ER PT J AU Shannon, J O'Malley, J Mori, M Garzotto, M Palma, AJ King, IB AF Shannon, J. O'Malley, J. Mori, M. Garzotto, M. Palma, A. J. King, I. B. TI Erythrocyte fatty acids and prostate cancer risk: A comparison of methods SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article DE Fatty acids; Prostate cancer; Principal components analysis ID ALPHA-LINOLENIC ACID; GENE-TRANSCRIPTION; BREAST-CANCER; EXPRESSION; DISEASE; PHOSPHOLIPIDS; METAANALYSIS; HYPERPLASIA; METABOLISM; LIPIDOME AB The role of fatty acids (FA) in prostate carcinogenesis is unclear. Interest in the inter-relationship among different types of FA has resulted in new analytic approaches to FA and their role in cancer development. We evaluated the association between erythrocyte FA and prostate cancer in 127 prostate cancer patients and 183 screen negative controls. We present three approaches to the analyses of the FA and prostate cancer association; (1) individual or common groups of FA, (2) biologically meaningful FA ratios and (3) principal components analysis. Monounsaturated FA and the alpha-linolenic:eicosapentaenoic ratio were associated with reduced risk of prostate cancer. However, Factor 1, which was strongly correlated with some long chain saturated FA, was associated with an increased risk of prostate cancer. We provide an example of modeling FA and their inter-relationships on the risk of prostate cancer. Comparing three approaches suggests the importance of considering the impact of the entire fatty acid profile in disease prevention. Published by Elsevier Ltd. C1 [Shannon, J.; O'Malley, J.; Mori, M.; Garzotto, M.; Palma, A. J.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Shannon, J.; Garzotto, M.; Palma, A. J.] Portland VA Med Ctr, Portland, OR 97239 USA. [King, I. B.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98101 USA. RP Shannon, J (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM shannoja@ohsu.edu FU United States Public Health Service [5 M01 RR000334, 1 UL1 RR024120-01, K22CA94973]; Portland Veterans Affairs Medical Center FX Work Supported by: United States Public Health Service grants (5 M01 RR000334), (1 UL1 RR024120-01) and (K22CA94973) and was supported by the resources and facilities of the Portland Veterans Affairs Medical Center. Biostatistics support was provided through the Knight Cancer Institute Biostatistics Shared Resource (P30 CA069533-09) and the Oregon Clinical and Translational Research Institute (UL1 RR024140). NR 41 TC 14 Z9 14 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD SEP PY 2010 VL 83 IS 3 BP 161 EP 169 DI 10.1016/j.plefa.2010.06.003 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 657YL UT WOS:000282455200008 PM 20630734 ER PT J AU Dostalova, Z Liu, AP Zhou, XJ Farmer, SL Krenzel, ES Arevalo, E Desai, R Feinberg-Zadek, PL Davies, PA Yamodo, IH Forman, SA Miller, KW AF Dostalova, Zuzana Liu, Aiping Zhou, Xiaojuan Farmer, Sarah L. Krenzel, Eileen S. Arevalo, Enrique Desai, Rooma Feinberg-Zadek, Paula L. Davies, Paul A. Yamodo, Innocent H. Forman, Stuart A. Miller, Keith W. TI High-level expression and purification of Cys-loop ligand-gated ion channels in a tetracycline-inducible stable mammalian cell line: GABA(A) and serotonin receptors SO PROTEIN SCIENCE LA English DT Article DE GABA(A) alpha 1 beta 3 receptor; 5-HT3A receptor; inducible expression; mammalian cell lines; purification; functional reconstitution ID CRITICAL MICELLE CONCENTRATION; INTEGRAL MEMBRANE-PROTEINS; X-RAY-STRUCTURE; ACETYLCHOLINE-RECEPTOR; FUNCTIONAL RECONSTITUTION; 5-HT3 RECEPTOR; BINDING; OVEREXPRESSION; SURFACTANTS; RHODOPSIN AB The human neuronal Cys-loop ligand-gated ion channel superfamily of ion channels are important determinants of human behavior and the target of many drugs. It is essential for their structural characterization to achieve high-level expression in a functional state. The aim of this work was to establish stable mammalian cell lines that enable high-level heterologous production of pure receptors in a state that supports agonist-induced allosteric conformational changes. In a tetracycline-inducible stable human embryonic kidney cells (HEK293S) cell line, GABA(A) receptors containing alpha 1 and beta 3 subunits could be expressed with specific activities of 29-34 pmol/mg corresponding to 140-170 pmol/plate, the highest expression level reported so far. Comparable figures for serotonin (5-HT3A) receptors were 49-63 pmol/mg and 245-315 pmol/plate. The expression of 10 nmol of either receptor in suspension in a bioreactor required 0.3-3.0 L. Both receptor constructs had a FLAG epitope inserted at the N-terminus and could be purified in step after solubilization using ANTI-FLAG affinity chromatography with yields of 30-40%. Purified receptors were functional. Binding of the agonist [H-3]muscimol to the purified GABA(A)R was enhanced allosterically by the general anesthetic etomidate, and purified 5-hydroxytryptamine-3A receptor supported serotonin-stimulated cation flux when reconstituted into lipid vesicles. C1 [Dostalova, Zuzana; Liu, Aiping; Zhou, Xiaojuan; Farmer, Sarah L.; Krenzel, Eileen S.; Arevalo, Enrique; Desai, Rooma; Feinberg-Zadek, Paula L.; Davies, Paul A.; Yamodo, Innocent H.; Forman, Stuart A.; Miller, Keith W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Miller, Keith W.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Miller, KW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, 32 Fruit St, Boston, MA 02114 USA. EM k_miller@helix.mgh.harvard.edu OI Davies, Paul/0000-0002-3973-3143 FU National Institute of General Medical Sciences [GM 58448]; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital FX Grant sponsor: National Institute of General Medical Sciences; Grant number: GM 58448; Grant sponsor: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital. NR 48 TC 23 Z9 23 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD SEP PY 2010 VL 19 IS 9 BP 1728 EP 1738 DI 10.1002/pro.456 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 646SL UT WOS:000281563000012 PM 20662008 ER PT J AU Knouse, LE Safren, SA AF Knouse, Laura E. Safren, Steven A. TI Current Status of Cognitive Behavioral Therapy for Adult Attention-Deficit Hyperactivity Disorder SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Attention-deficit/hyperactivity disorder; Psychosocial treatment; Cognitive behavioral therapy; Adults; Treatment outcome ID ORIENTED GROUP REHABILITATION; PSYCHIATRIC COMORBIDITY; ADHD; PSYCHOTHERAPY; PREVALENCE; PROGRAM AB Attention-deficit/hyperactivity disorder (ADHD) is a valid and impairing psychological disorder that persists into adulthood in a majority of cases and is associated with chronic functional impairment and increased rates of comorbidity. Cognitive behavioral therapy (CBT) approaches for this disorder have emerged recently, and available evidence from open and randomized controlled trials suggests that these approaches are promising in producing significant symptom reduction. A conceptual model of how CBT may work for ADHD is reviewed along with existing efficacy studies. A preliminary comparison of effect sizes across intervention packages suggests that targeted learning and practice of specific behavioral compensatory strategies may be a critical active ingredient in CBT for adult ADHD. The article concludes with a discussion of future directions and critical questions that must be addressed in this area of clinical research. C1 [Knouse, Laura E.; Safren, Steven A.] Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, Boston, MA 02114 USA. [Knouse, Laura E.; Safren, Steven A.] Harvard Univ, Sch Med, Boston, MA USA. RP Knouse, LE (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Behav Med Serv, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM lknouse@partners.org FU NIMH NIH HHS [5R01MH69812, R01 MH069812, R01 MH069812-04] NR 34 TC 49 Z9 51 U1 2 U2 23 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD SEP PY 2010 VL 33 IS 3 BP 497 EP + DI 10.1016/j.psc.2010.04.001 PG 14 WC Psychiatry SC Psychiatry GA 644IE UT WOS:000281367600002 PM 20599129 ER PT J AU Cullen, SW Nath, SB Marcus, SC AF Cullen, Sara Wiesel Nath, Sara Bressi Marcus, Steven C. TI Toward Understanding Errors in Inpatient Psychiatry: A Qualitative Inquiry SO PSYCHIATRIC QUARTERLY LA English DT Article DE Medical error; Inpatient psychiatry; Patient safety; Error prevention ID ADVERSE EVENTS; HOSPITALIZED-PATIENTS; CARE AB While prior research has identified the impact, nature, and causes of medical error in general medical settings, little is known about errors in inpatient psychiatry. Understanding the broad range of errors that occur in inpatient psychiatry is a critical step toward improving systems of care for a vulnerable patient population. An explorative qualitative analysis of key informant interviews identified a preliminary typology of errors and the contextual factors that precipitate them in inpatient psychiatry. The types of errors and their contextual factors fall broadly within the rubric of categories identified in medicine and surgery. However, many of the specific errors and contextual factors manifest themselves differently and are shaped by the uniqueness of the inpatient psychiatric setting and patient population. Interventions geared toward improving systems of care for psychiatric patients should draw on best practices for safety in medicine and surgery, but also be complemented with new strategies specifically tailored to the inpatient psychiatric setting. C1 [Cullen, Sara Wiesel; Marcus, Steven C.] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. [Nath, Sara Bressi] Bryn Mawr Coll, Grad Sch Social Work & Social Res, Bryn Mawr, PA 19010 USA. [Marcus, Steven C.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Marcus, Steven C.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Marcus, SC (reprint author), Univ Penn, Sch Social Policy & Practice, 3701 Locust Walk, Philadelphia, PA 19104 USA. EM swiesel@sp2.upenn.edu; snath@brynmawr.edu; marcuss@sp2.upenn.edu NR 13 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-2720 J9 PSYCHIAT QUART JI Psychiatr. Q. PD SEP PY 2010 VL 81 IS 3 BP 197 EP 205 DI 10.1007/s11126-010-9129-z PG 9 WC Psychiatry SC Psychiatry GA 639YP UT WOS:000281013400002 PM 20204514 ER PT J AU Tanaka, A Koizumi, A Imai, H Hiramatsu, S Hiramoto, E de Gelder, B AF Tanaka, Akihiro Koizumi, Ai Imai, Hisato Hiramatsu, Saori Hiramoto, Eriko de Gelder, Beatrice TI I Feel Your Voice: Cultural Differences in the Multisensory Perception of Emotion SO PSYCHOLOGICAL SCIENCE LA English DT Article DE emotion; multisensory perception; cultural difference; audiovisual speech ID SPONTANEOUS ATTENTION; FACE; INTEGRATION; WORD AB Cultural differences in emotion perception have been reported mainly for facial expressions and to a lesser extent for vocal expressions. However, the way in which the perceiver combines auditory and visual cues may itself be subject to cultural variability. Our study investigated cultural differences between Japanese and Dutch participants in the multisensory perception of emotion. A face and a voice, expressing either congruent or incongruent emotions, were presented on each trial. Participants were instructed to judge the emotion expressed in one of the two sources. The effect of to-be-ignored voice information on facial judgments was larger in Japanese than in Dutch participants, whereas the effect of to-be-ignored face information on vocal judgments was smaller in Japanese than in Dutch participants. This result indicates that Japanese people are more attuned than Dutch people to vocal processing in the multisensory perception of emotion. Our findings provide the first evidence that multisensory integration of affective information is modulated by perceivers' cultural background. C1 [Tanaka, Akihiro] Waseda Inst Adv Study, Shinjuku Ku, Tokyo 1698050, Japan. [Tanaka, Akihiro; de Gelder, Beatrice] Tilburg Univ, Cognit & Affect Neurosci Lab, Tilburg, Netherlands. [Koizumi, Ai] Univ Tokyo, Dept Psychol, Tokyo 1138654, Japan. [Imai, Hisato; Hiramatsu, Saori; Hiramoto, Eriko] Tokyo Womans Christian Univ, Dept Psychol, Tokyo, Japan. [de Gelder, Beatrice] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [de Gelder, Beatrice] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Tanaka, A (reprint author), Waseda Inst Adv Study, Shinjuku Ku, 1-6-1 Nishi Waseda, Tokyo 1698050, Japan. EM akih.tanaka@gmail.com NR 19 TC 27 Z9 28 U1 1 U2 25 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD SEP PY 2010 VL 21 IS 9 BP 1259 EP 1262 DI 10.1177/0956797610380698 PG 4 WC Psychology, Multidisciplinary SC Psychology GA 696PU UT WOS:000285454700012 PM 20713633 ER PT J AU Choi, JK Mandeville, JB Chen, YI Grundt, P Sarkar, SK Newman, AH Jenkins, BG AF Choi, Ji-Kyung Mandeville, Joseph B. Chen, Y. Iris Grundt, Peter Sarkar, Susanta K. Newman, Amy H. Jenkins, Bruce G. TI Imaging brain regional and cortical laminar effects of selective D3 agonists and antagonists SO PSYCHOPHARMACOLOGY LA English DT Article DE Cortical layers; Dopamine D3 receptor; Hippocampus; Hypothalamus; Infralimbic cortex; Limbic circuitry; MRI; Nucleus accumbens; Subiculum ID DOPAMINE D-3 RECEPTOR; ABUSE THERAPEUTIC AGENTS; COCAINE-SEEKING; RAT-BRAIN; MRI; 7-OH-DPAT; PRIMATES; BINDING; CORTEX; LIGAND AB Dopamine D3 receptors (D3R) may be important therapeutic targets for both drug abuse and dyskinesias in Parkinson's disease; however, little is known about their functional circuitry. We wished to determine if D3R antagonists SB-277011 and PG-01037 and D3R-preferring agonist 7-OH-DPAT are D3R selective in vivo. We further wished to characterize the response to D3R drugs using whole brain imaging to identify novel D3R circuitry. We investigated D3R circuitry in rats using pharmacologic MRI and challenge with selective D3R antagonists and agonist at various doses to examine regional changes in cerebral blood volume (CBV). We compared regional activation patterns with D2R/D3R agonists, as well as with prior studies of mRNA expression and autoradiography. D3R antagonists induced positive CBV changes and D3R agonist negative CBV changes in brain regions including nucleus accumbens, infralimbic cortex, thalamus, interpeduncular region, hypothalamus, and hippocampus (strongest in subiculum). All D3R-preferring drugs showed markedly greater responses in nucleus accumbens than in caudate/putamen consistent with D3R selectivity and contrary to what was observed with D2R agonists. At high doses of D3R agonist, functional changes were differentiated across cortical laminae, with layer V-VI yielding positive CBV changes and layer IV yielding negative CBV changes. These results are not inconsistent with differential D1R and D3R innervation in these layers respectively showed previously using post-mortem techniques. MRI provides a new tool for testing the in vivo selectivity of novel D3R dopaminergic ligands where radiolabels may not be available. Further, the functional D3R circuitry strongly involves hypothalamus and subiculum as well as the limbic striatum. C1 [Choi, Ji-Kyung; Mandeville, Joseph B.; Chen, Y. Iris; Jenkins, Bruce G.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Choi, Ji-Kyung; Mandeville, Joseph B.; Chen, Y. Iris; Jenkins, Bruce G.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Grundt, Peter; Newman, Amy H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. [Sarkar, Susanta K.] GlaxoSmithKline Inc, Med Dev, Oncol R&D, Collegeville, PA 19426 USA. RP Jenkins, BG (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. EM bgj@nmr.mgh.harvard.edu FU NIH/NIDA [DA16187-06] FX This work was supported by NIH/NIDA DA16187-06. NR 47 TC 17 Z9 17 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2010 VL 212 IS 1 BP 59 EP 72 DI 10.1007/s00213-010-1924-6 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 638UQ UT WOS:000280922900006 PM 20628733 ER PT J AU Hitsman, B Shen, BJ Cohen, RA Morissette, SB Drobes, DJ Spring, B Schneider, K Evans, DE Gulliver, SB Kamholz, BW Price, LH Niaura, R AF Hitsman, Brian Shen, Biing-Jiun Cohen, Ronald A. Morissette, Sandra B. Drobes, David J. Spring, Bonnie Schneider, Kristin Evans, David E. Gulliver, Suzy B. Kamholz, Barbara W. Price, Lawrence H. Niaura, Raymond TI Measuring smoking-related preoccupation and compulsive drive: evaluation of the obsessive compulsive smoking scale SO PSYCHOPHARMACOLOGY LA English DT Article DE Tobacco use; Addiction; Smoking preoccupation; Compulsive smoking; Craving; Psychometrics; Obsessive compulsive smoking scale; College students; Adults ID DRINKING-SCALE; NICOTINE DEPENDENCE; WISCONSIN INVENTORY; TOBACCO DEPENDENCE; FAGERSTROM TEST; DRUG-USE; ADDICTION; VALIDITY; BEHAVIOR; SMOKERS AB Tobacco use for many people is compulsive in nature. Compelling theories of how smoking becomes compulsive exist but are largely based on extrapolation from neuroscience findings. Research on smokers is impeded, in part, by a lack of instruments that specifically measure compulsive smoking. This study evaluated the measurement structure and validity of the Obsessive Compulsive Smoking Scale (OCSS), a ten-item questionnaire designed to measure compulsive smoking. Participants were 239 daily smokers (a parts per thousand yen1 cigarette/day), including 142 students at a public university in Chicago and 97 veterans treated at the VA Boston Healthcare System. The OCSS and questionnaires measuring current and past smoking, cigarette craving, automatic smoking, and nicotine dependence were administered. Factor analysis with maximum likelihood extraction and oblique rotation revealed two correlated underlying factors, interpreted as "Preoccupation with Smoking" and "Compulsive Drive." The measurement structure was consistent across students and veterans, and confirmed in an independent sample of adults (n = 95). Veterans exhibited higher OCSS scores (full scale and subscales) than students. Across groups, higher OCSS scores were positively correlated with smoking intensity, craving, and nicotine dependence. OCSS full-scale and compulsive drive scores, but not smoking preoccupation scores, were inversely correlated with past month smoking reduction and minutes since last cigarette. The OCSS is a valid and reliable inventory for measuring the degree to which daily smokers are preoccupied with smoking and engage in compulsive tobacco use, and may be useful for advancing understanding of core smoking phenotypes or for tailoring cessation therapies. C1 [Hitsman, Brian; Spring, Bonnie] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Schneider, Kristin] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA USA. [Shen, Biing-Jiun] Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. [Cohen, Ronald A.; Price, Lawrence H.] Brown Univ, Warren Alpert Med Sch, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Kamholz, Barbara W.] VA Boston Healthcare Syst, Dept Psychol, Boston, MA USA. [Kamholz, Barbara W.] VA Boston Healthcare Syst, Dept Psychiat, Boston, MA USA. [Drobes, David J.; Evans, David E.] H Lee Moffitt Canc Ctr & Res Inst, Dept Oncol Sci, Tampa, FL USA. [Drobes, David J.] H Lee Moffitt Canc Ctr & Res Inst, Dept Psychol, Tampa, FL USA. [Drobes, David J.] Univ S Florida, Tampa, FL USA. [Niaura, Raymond] Schroeder Inst Tobacco Res, Washington, DC USA. [Niaura, Raymond] Policy Studies Amer Legacy Fdn, Washington, DC USA. [Morissette, Sandra B.; Gulliver, Suzy B.] Texas A&M Coll Med, Hlth Sci Ctr, Waco, TX USA. [Morissette, Sandra B.; Gulliver, Suzy B.] Cent Texas Vet Healthcare Syst, Waco, TX USA. [Kamholz, Barbara W.] Boston Univ, Boston, MA 02215 USA. RP Hitsman, B (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1400, Chicago, IL 60611 USA. EM b-hitsman@northwestern.edu FU Mentored Clinical Scientist Research Career Development Award [K08 DA017145]; Transdisciplinary Tobacco Use Research Center [P50 CA084719] FX This study was funded by a Mentored Clinical Scientist Research Career Development Award (K08 DA017145) to Dr. Brian Hitsman. Additional support was provided by a Transdisciplinary Tobacco Use Research Center Grant P50 CA084719 to Dr. Raymond Niaura and Mentored Patient-Oriented Research Career Development Awards to Dr. Sandra B. Morissette (K23 DA016376) and Dr. Barbara W. Kamholz (K23 DA016138).; Dr. Hitsman has consulted for Pinney Associates, subcontracted by GlaxoSmithKline, and Pfizer. Dr. Spring has consulted for Proteus. Dr. Price has received research contacts from Sepracor, UCB Pharma, and Pfizer, speaker's bureau honoraria from Jazz Pharmaceuticals, and has consulted for Gerson Lehrman, Wiley, and Springer. Dr. Niaura has consulted for Pfizer, Sanofi Aventis, GlaxoSmithKline, Novartis, and Orexigen Therapeutics. None of the other co-authors have competing interests to report. NR 37 TC 4 Z9 4 U1 4 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2010 VL 211 IS 4 BP 377 EP 387 DI 10.1007/s00213-010-1910-z PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 630AP UT WOS:000280243700002 PM 20582399 ER PT J AU Radant, AD Dobie, DJ Calkins, ME Olincy, A Braff, DL Cadenhead, KS Freedman, R Green, MF Greenwood, TA Gur, RE Gur, RC Light, GA Meichle, SP Millard, SP Mintz, J Nuechterlein, KH Schork, NJ Seidman, LJ Siever, LJ Silverman, JM Stone, WS Swerdlow, NR Tsuang, MT Turetsky, BI Tsuang, DW AF Radant, Allen D. Dobie, Dorcas J. Calkins, Monica E. Olincy, Ann Braff, David L. Cadenhead, Kristin S. Freedman, Robert Green, Michael F. Greenwood, Tiffany A. Gur, Raquel E. Gur, Ruben C. Light, Gregory A. Meichle, Sean P. Millard, Steve P. Mintz, Jim Nuechterlein, Keith H. Schork, Nicholas J. Seidman, Larry J. Siever, Larry J. Silverman, Jeremy M. Stone, William S. Swerdlow, Neal R. Tsuang, Ming T. Turetsky, Bruce I. Tsuang, Debby W. TI Antisaccade performance in schizophrenia patients, their first-degree biological relatives, and community comparison subjects: Data from the COGS study SO PSYCHOPHYSIOLOGY LA English DT Article DE Oculomotor; Endophenotype; Antisaccade; Schizophrenia; Family ID DORSOLATERAL PREFRONTAL CORTEX; SACCADIC EYE-MOVEMENTS; ADMIXTURE ANALYSIS; SMOOTH-PURSUIT; CORTICAL INHIBITION; ENDOPHENOTYPES; TASK; AGE; FAMILIES; DEFICITS AB The antisaccade task is a widely used technique to measure failure of inhibition, an important cause of cognitive and clinical abnormalities found in schizophrenia. Although antisaccade performance, which reflects the ability to inhibit prepotent responses, is a putative schizophrenia endophenotype, researchers have not consistently reported the expected differences between first-degree relatives and comparison groups. Schizophrenia participants (n=219) from the large Consortium on the Genetics of Schizophrenia (COGS) sample (n=1078) demonstrated significant deficits on an overlap version of the antisaccade task compared to their first-degree relatives (n=443) and community comparison subjects (CCS; n=416). Although mean antisaccade performance of first-degree relatives was intermediate between schizophrenia participants and CCS, a linear mixed-effects model adjusting for group, site, age, and gender found no significant performance differences between the first-degree relatives and CCS. However, admixture analyses showed that two components best explained the distributions in all three groups, suggesting two distinct doses of an etiological factor. Given the significant heritability of antisaccade performance, the effects of a genetic polymorphism is one possible explanation of our results. C1 [Radant, Allen D.; Dobie, Dorcas J.; Meichle, Sean P.; Millard, Steve P.; Tsuang, Debby W.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Radant, Allen D.; Dobie, Dorcas J.; Meichle, Sean P.; Millard, Steve P.; Tsuang, Debby W.] Mental Illness Res Educ & Clin Ctr, Dept Vet Affairs, Seattle, WA USA. [Calkins, Monica E.; Gur, Raquel E.; Gur, Ruben C.; Turetsky, Bruce I.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Olincy, Ann; Freedman, Robert] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Aurora, CO USA. [Braff, David L.; Cadenhead, Kristin S.; Greenwood, Tiffany A.; Light, Gregory A.; Schork, Nicholas J.; Swerdlow, Neal R.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Green, Michael F.; Nuechterlein, Keith H.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Mintz, Jim] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Seidman, Larry J.; Stone, William S.; Tsuang, Ming T.] Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr,Dept Psychiat, Publ Psychiat Div,Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Seidman, Larry J.; Stone, William S.; Tsuang, Ming T.] Harvard Inst Psychiat Epidemiol & Genet, Boston, MA USA. [Siever, Larry J.; Silverman, Jeremy M.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Siever, Larry J.] James J Peters VA Med Ctr, Dept Vet Affairs, Mental Illness Res Educ & Clin Ctr, VISN 3, Bronx, NY USA. RP Radant, AD (reprint author), VAPSHCS S-116 MHC,1660 S Columbian Way, Seattle, WA 98108 USA. EM aradant@u.washington.edu RI Greenwood, Tiffany/F-6356-2012; Tsuang, Debby/L-7234-2016 OI Greenwood, Tiffany/0000-0002-6080-6503; Tsuang, Debby/0000-0002-4716-1894 FU Office of Research and Development Medical Research Service (or) Health Services R&D Service, Department of Veterans Affairs; NIMH [R01 MH65571, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, R01 MH65558] FX This material is based upon work supported (or supported in part) by the Office of Research and Development Medical Research Service (or) Health Services R&D Service, Department of Veterans Affairs. This study was supported by NIMH grants R01 MH65571, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, and R01 MH65558. NR 68 TC 24 Z9 25 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD SEP PY 2010 VL 47 IS 5 BP 846 EP 856 DI 10.1111/j.1469-8986.2010.01004.x PG 11 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 635EO UT WOS:000280638600008 PM 20374545 ER PT J AU Morone, NE Weiner, DK Belnap, BH Karp, JF Mazumdar, S Houck, PR He, FY Rollman, BL AF Morone, Natalia E. Weiner, Debra K. Belnap, Bea Herbeck Karp, Jordan F. Mazumdar, Sati Houck, Patricia R. He, Fanyin Rollman, Bruce L. TI The Impact of Pain and Depression on Recovery After Coronary Artery Bypass Grafting SO PSYCHOSOMATIC MEDICINE LA English DT Article DE depression; pain; CABG; collaborative care ID POST-CABG DEPRESSION; COLLABORATIVE CARE; TREATMENT RESPONSE; SURGERY; PREDICTORS; SYMPTOMS; VALIDITY; ADULTS; SF-36; LIFE AB Objective: To describe the relationship between pain and depression on recovery after coronary artery bypass grafting (CABG). Methods: A secondary data analysis on 453 depressed and nondepressed post-CABG patients enrolled in a randomized, controlled, effectiveness trial of telephone-delivered collaborative care for depression. Outcome measures were collected from March 2004 to September 2007 and included pain, physical function, and mood symptoms. Results: Depressed patients (baseline Patient Health Questionnaire-9 score >= 10) versus those without depression reported significantly worse pain scores on the 36-Item Short Form Health Survey Bodily Pain Scale at baseline and up to 12 months post-CABG, p < .05. Among patients with depression, those who received collaborative care reported significantly better pain scores at each time point between 2 and 12 months post-CABG versus depressed patients randomized to the usual care control group, p < .05. Regardless of intervention status, depressed participants with at least moderate pain at baseline reported significantly lower functional status (measured by the Duke Activity Status Index) at 8 and 12 months versus depressed patients with none or mild pain, p < .05. Depressed patients with at least moderate pain at baseline were also significantly less likely to show improvement of depressive symptoms throughout the course of follow-up versus depressed patients with little or no pain, p < .05. These findings controlled for age, gender, education, race, comorbid conditions, and baseline pain diagnosis. Conclusions: Depression and pain seem to influence functional recovery post-CABG. The relationship between these two conditions and 12-month outcomes should be considered by clinicians when planning treatment. C1 [Morone, Natalia E.; Belnap, Bea Herbeck; Rollman, Bruce L.] Univ Pittsburgh, Div Gen Internal Med, Dept Med, Pittsburgh, PA 15260 USA. [Morone, Natalia E.; Karp, Jordan F.] Univ Pittsburgh, Clin & Translat Sci Inst, Pittsburgh, PA 15260 USA. [Weiner, Debra K.] Univ Pittsburgh, Div Geriatr Med, Dept Med, Pittsburgh, PA 15260 USA. [Weiner, Debra K.; Karp, Jordan F.; Mazumdar, Sati; Houck, Patricia R.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. [Weiner, Debra K.; Karp, Jordan F.] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA 15260 USA. [Mazumdar, Sati; He, Fanyin] Univ Pittsburgh, Dept Biostat, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. [Weiner, Debra K.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Morone, NE (reprint author), 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM moronene@upmc.edu FU National Institutes of Health (NIH) [R01 HL70000]; National Center for Research Resources (NCRR), NIH [KL2RR024154]; NIH Roadmap for Medical Research FX Supported by National Institutes of Health (NIH) Grant R01 HL70000 and by KL2RR024154 from the National Center for Research Resources (NCRR; a component of the NIH) and NIH Roadmap for Medical Research (to N.E.M. and J.F.K.). NR 23 TC 19 Z9 21 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP PY 2010 VL 72 IS 7 BP 620 EP 625 DI 10.1097/PSY.0b013e3181e6df90 PG 6 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 653IY UT WOS:000282084000004 PM 20562371 ER PT J AU Freudenreich, O Kontos, N Querques, J AF Freudenreich, Oliver Kontos, Nicholas Querques, John TI The Muddles of Medicine: A Practical, Clinical Addendum to the Biopsychosocial Model SO PSYCHOSOMATICS LA English DT Article ID CONSULTATION PSYCHIATRIST; GASLIGHT PHENOMENON; SCHIZOPHRENIA; CARE; NEUROPSYCHIATRY; PSYCHOTHERAPY; EXPERIENCE; CELECOXIB; PHYSICIAN; SYMPTOMS AB Background: The commonly-accepted "biopsychosocial model" does not always lend itself to the kind of pragmatic decisions that many clinical situations demand of physicians. Objective: The authors attempt to identify and close gaps in the biopsychosocial model that hinder its application in certain real-life clinical situations. Method: The authors review some of the current and historical literature on the development and application of the biopsychosocial model, and argue the shortcomings of this modality in various clinical situations. Results: The authors present three dicta to guide clinicians toward relevant areas of inquiry: 1) Think neuroanatomically; 2) Think existentially; and 3) Think "dirty;" that is, understand that patients and physicians sometimes work toward different goals. Discussion: These dicta form an addendum to the biopsychosocial model, identifying and filling three specific, commonly-encountered gaps in that paradigm, which, ironically, is usually considered all-inclusive. (Psychosomatics 2010; 51: 365-369) C1 MGH Div Psychiat & Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Psychiat Consultat Liaison Serv, Boston, MA USA. Cambridge Hlth Alliance, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Freudenreich, O (reprint author), Freedom Trail Clin, MGH Schizophrenia Program, 25 Staniford St,2nd Floor, Boston, MA 02114 USA. EM ofreudenreich@partners.org FU Harvard Medical School; Cephalon FX Dr. Kontos's work was supported by a fellowship grant from Harvard Medical School via The Eleanor and Miles Shore Fellowship Program for Scholars in Medicine. Dr. Freudenreich has received research grant support from Cephalon as well as honoraria from Primedia and Reed Medical Education. NR 49 TC 4 Z9 4 U1 2 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2010 VL 51 IS 5 BP 365 EP 369 PG 5 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 649AF UT WOS:000281736600001 PM 20833934 ER PT J AU Ali, S Miller, KK Freudenreich, O AF Ali, Shirin Miller, Karen Klahr Freudenreich, Oliver TI Management of Psychosis Associated With a Prolactinoma: Case Report and Review of the Literature SO PSYCHOSOMATICS LA English DT Review ID SECRETING PITUITARY-ADENOMA; INDUCED HYPERPROLACTINEMIA; SCHIZOPHRENIC-PATIENTS; ATYPICAL ANTIPSYCHOTICS; INCREASED PREVALENCE; ENDOCRINE DISEASE; CABERGOLINE; BROMOCRIPTINE; ARIPIPRAZOLE; PATIENT AB Background: Prolactinomas are the most common pituitary tumors; they are treated with dopamine agonists, which may cause psychotic symptoms as a side effect. Psychosis is treated with dopamine-receptor blockers that may result in elevated serum prolactin and symptomatic hyperprolactinemia. Objective: The authors will review a case of a patient with a prolactinoma as well as schizophrenia and illustrate the management of psychosis in this case. Method: The review describes the management of prolactinoma, symptoms of hyperprolactinemia, and long-term effects of hyperprolactinemia. Results: In the case presentation reviewed, the patient was finally discharged on risperidone long-acting injection and testosterone supplementation, with no growth of the adenoma after 3 years. Discussion: This review provides recommendations and treatment strategy for management of prolactinoma in a patient with schizophrenia. (Psychosomatics 2010; 51: 370-376) C1 McLean Hosp, Boston, MA USA. Neuroendocrine Unit, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. MGH, MGH Schizophrenia Program, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ali, S (reprint author), New York State Psychiat Inst & Hosp, 1051 Riverside Dr,Unit 5 S, New York, NY 10032 USA. EM alishir@pi.cpmc.columbia.edu FU NHLBI NIH HHS [K24 HL092902] NR 40 TC 12 Z9 12 U1 1 U2 5 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2010 VL 51 IS 5 BP 370 EP 376 PG 7 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 649AF UT WOS:000281736600002 PM 20833935 ER PT J AU Zimmerman, DJ Stern, TA AF Zimmerman, Daniel J. Stern, Theodore A. TI Offensive Language in the General Hospital SO PSYCHOSOMATICS LA English DT Review ID COPROLALIA AB Background: Offensive language (spoken by medical staff and by patients and their families) is often heard in the general hospital, but its manifestations and clinical implications have not been previously examined. Objective: The authors sought to facilitate an understanding of the effects and treatment of offensive utterances and their downstream consequences. Method: The authors present a sampling of clinical vignettes that illustrate a variety of examples of hospital-based events in which offensive language was used and discuss differential diagnoses and management strategies. Results: Swearing can also be used as a psychological tool in the service of helping. Swearing may provide a channel of catharsis for aggressive drives and affects that have been building in either the doctor or the patient. Discussion: Placing offensive behaviors, for example, use of profane language, in a biopsychosocial context can facilitate an understanding of the causes, effects, and treatment of these events. (Psychosomatics 2010; 51: 377-385) C1 [Zimmerman, Daniel J.; Stern, Theodore A.] Massachusetts Gen Hosp, Psychiat Consultat Serv, Dept Psychiat, Boston, MA 02114 USA. RP Zimmerman, DJ (reprint author), Bellevue Hosp Ctr, Dept Psychiat, 462 1st Ave, New York, NY 10016 USA. EM daniel.zimmerman@nyumc.org NR 17 TC 2 Z9 2 U1 0 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2010 VL 51 IS 5 BP 377 EP 385 PG 9 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 649AF UT WOS:000281736600003 PM 20833936 ER PT J AU Morasco, BJ Loftis, JM Indest, DW Ruimy, S Davison, JW Felker, B Hauser, P AF Morasco, Benjamin J. Loftis, Jennifer M. Indest, David W. Ruimy, Samantha Davison, John W. Felker, Bradford Hauser, Peter TI Prophylactic Antidepressant Treatment in Patients With Hepatitis C on Antiviral Therapy: A Double-Blind, Placebo-Controlled Trial SO PSYCHOSOMATICS LA English DT Article ID INTERFERON-INDUCED DEPRESSION; ALPHA-INDUCED DEPRESSION; SYMPTOMS; PREVENTION; PAROXETINE; MANAGEMENT; RIBAVIRIN AB Background: Approximately one-third of patients undergoing interferon-alpha (IFN-alpha) therapy for treatment of the hepatitis C virus (HCV) develop major depression, which decreases functioning and may lead to the reduction or discontinuation of treatment. Objective: The authors examined the efficacy of citalopram in preventing IFN-alpha-induced depression in HCV patients. Method: This was a randomized, controlled trial comparing citalopram with placebo in 39 HCV patients. Results: The rate of IFN-alpha-induced depression in the sample was 15.4% (6/39). Randomization to citalopram did not decrease the statistical likelihood of developing IFN-alpha-induced depression (10.5% for citalopram vs. 20.0% for placebo). Conclusion: Citalopram does not prevent depression onset; however, an empirically-supported treatment recommendation for IFN-alpha-induced depression includes monitoring depressive symptoms throughout antiviral therapy and initiating psychiatric treatment at the initial signs of depression. (Psychosomatics 2010; 51: 401-408) C1 [Morasco, Benjamin J.] Portland VA Med Ctr, Behav Hlth & Clin Neurosci Div, Portland, OR 97239 USA. Portland VA Med Ctr, NW Hepatitis Resource Ctr C, Portland, OR 97239 USA. OR Hlth & Sci Univ, Dept Psychiat, Portland, OR USA. OR Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR USA. Dept Vet Affairs, Publ Hlth Strateg Hlth Care Grp, Washington, DC USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. VISN 20 Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. OR Hlth & Sci Univ, Dept Internal Med, Portland, OR USA. RP Morasco, BJ (reprint author), Portland VA Med Ctr, Behav Hlth & Clin Neurosci Div, 3710 SW US Vet Hosp Rd R&D 99, Portland, OR 97239 USA. EM benjamin.morasco@va.gov FU Department of Veterans Affairs; National Institutes of Health [K23DA023467-01A1]; Janssen Pharmaceutica FX This material is based on work supported in part by the Office of Research Development, Clinical Sciences Research and Development Service, from the Department of Veterans Affairs. Dr. Morasco receives support from the National Institutes of Health (K23DA023467-01A1). The authors also appreciate collaboration from members of the Northwest Hepatitis C Resource Center.; Dr. Hauser has grant funding from Janssen Pharmaceutica and is currently on the speaker's bureau for AstraZeneca and Jazz Pharmaceutical. No other coauthor reports a potential conflict of interest. NR 23 TC 35 Z9 38 U1 0 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2010 VL 51 IS 5 BP 401 EP 408 PG 8 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 649AF UT WOS:000281736600006 PM 20833939 ER PT J AU Larsen, KA Kelly, SE Stern, TA Bode, RH Price, LL Hunter, DJ Gulczynski, D Bierbaum, BE Sweeney, GA Hoikala, KA Cotter, JJ Potter, AW AF Larsen, Kenneth A. Kelly, Susan E. Stern, Theodore A. Bode, Robert H., Jr. Price, Lori Lyn Hunter, David J. Gulczynski, Diane Bierbaum, Benjamin E. Sweeney, Gerard A. Hoikala, Karen A. Cotter, James J. Potter, Adam W. TI Administration of Olanzapine to Prevent Postoperative Delirium in Elderly Joint-Replacement Patients: A Randomized, Controlled Trial SO PSYCHOSOMATICS LA English DT Article ID CONFUSION ASSESSMENT METHOD; RISK-FACTORS; HALOPERIDOL PROPHYLAXIS; HIP FRACTURE; SURGERY; CARE; POPULATION; DONEPEZIL; COSTS AB Background: Delirium is a serious postoperative condition for which few pharmacologic prevention trials have been conducted. Objective: The authors tested the efficacy of perioperative olanzapine administration to prevent postoperative delirium in elderly patients after joint-replacement surgery. Method: The authors conducted a randomized, double-blind, placebo-controlled, prophylaxis trial at an orthopedic teaching hospital, enrolling 495 elderly patients age >= 65 years, who were undergoing elective knee-or hip-replacement surgery; 400 patients received either 5 mg of orally-disintegrating olanzapine or placebo just before and after surgery. The primary efficacy outcome was the incidence of (DSM-III-R) delirium. Results: The incidence of delirium was significantly lower in the olanzapine group than in the placebo group; this held true for both knee-and hip-replacement surgery. However, delirium lasted longer and was more severe in the olanzapine group. Advanced age, a high level of medical comorbidity, an abnormal albumin level, and having knee-replacement surgery were independent risk factors for postoperative delirium (Clinicaltrials.gov Identifier: NCT000699946). Conclusion: Administration of 10 mg of oral olanzapine perioperatively, versus placebo, was associated with a significantly lower incidence of delirium. These findings suggest that olanzapine prophylaxis of postoperative delirium may be an effective strategy. (Psychosomatics 2010; 51: 409-418) C1 New England Baptist Hosp, Dept Med, Boston, MA USA. New England Baptist Hosp, Dept Anesthesiol, Boston, MA USA. New England Baptist Hosp, Dept Res, Boston, MA USA. New England Baptist Hosp, Dept Orthoped, Boston, MA USA. New England Baptist Hosp, Dept Nursing, Boston, MA USA. New England Baptist Hosp, Dept Pharm, Boston, MA USA. New England Baptist Hosp, Dept Adm, Boston, MA USA. [Kelly, Susan E.] Beth Israel Deaconess Med Ctr, Dept Gastroenterol, Boston, MA 02215 USA. Tufts Med Ctr, Dept Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Stat Anal, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Kelly, SE (reprint author), Beth Israel Deaconess Med Ctr, Dept Gastroenterol, 110 Francis St,8th Floor, Boston, MA 02215 USA. EM skelly@bidmc.harvard.edu RI Hunter, David/A-4622-2010; Potter, Adam/D-9893-2014; OI Hunter, David/0000-0003-3197-752X; Potter, Adam/0000-0003-4980-8353 FU New England Baptist Hospital Research Department FX This study was made possible by a grant from the New England Baptist Hospital Research Department. The sponsor supplied the olanzapine and retained the study data; however, it had no other role in the study design; in the collection, analysis, and interpretation of the study; in the writing of the report; or in the decision to submit the paper for publication. NR 40 TC 73 Z9 77 U1 0 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2010 VL 51 IS 5 BP 409 EP 418 PG 10 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 649AF UT WOS:000281736600007 PM 20833940 ER PT J AU Beach, SR Wichman, CL Canterbury, RJ AF Beach, Scott R. Wichman, Christina L. Canterbury, R. J. TI Takotsubo Cardiomyopathy After Electroconvulsive Therapy SO PSYCHOSOMATICS LA English DT Article ID LEFT-VENTRICULAR DYSFUNCTION; APICAL BALLOONING SYNDROME; MYOCARDIAL-INFARCTION AB Background: Takotsubo cardiomyopathy is a novel acute cardiac syndrome characterized by transient regional systolic dysfunction of the left-ventricular apex and mid-ventricle, with hyperkinesis of the basal left ventricular segments, which has been associated with severe emotional or physical stress. Method: This is the second published case report of takotsubo cardiomyopathy occurring in the setting of electroconvulsive therapy (ECT). Results: The patient, a 52-year-old woman, experienced chest pain and discomfort shortly after ECT treatment. She was shown to have moderate left-ventricular dysfunction, with mid-cavity left-ventricular hypo-to akinesis, and hyperkinesis in the basilar region, consistent with a diagnosis of takotsubo cardiomyopathy. There was full resolution of her symptoms within 48 hours of the initial event. Discussion: This report highlights a previously undocumented complication of ECT and adds to the growing list of stressors responsible for cases of takotsubo cardiomyopathy. The prognosis is favorable, and recovery is generally complete, especially with early recognition of the syndrome and proper supportive treatment. (Psychosomatics 2010; 51: 432-436) C1 Univ Virginia, Dept Psychiat & Neurobehav Sci, Charlottesville, VA USA. Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA. RP Beach, SR (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Warren 605, Boston, MA 02114 USA. EM sbeach1@partners.org NR 10 TC 7 Z9 7 U1 0 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2010 VL 51 IS 5 BP 432 EP 436 PG 5 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 649AF UT WOS:000281736600010 PM 20833943 ER PT J AU Freudenreich, O AF Freudenreich, Oliver TI Medical Illness and Schizophrenia, 2nd edition SO PSYCHOSOMATICS LA English DT Book Review C1 [Freudenreich, Oliver] Massachusetts Gen Hosp, Episode & Early Psychosis Program 1, Boston, MA 02114 USA. RP Freudenreich, O (reprint author), Massachusetts Gen Hosp, Episode & Early Psychosis Program 1, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD SEP-OCT PY 2010 VL 51 IS 5 BP 451 EP 452 PG 2 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 649AF UT WOS:000281736600017 ER PT J AU Massin-Short, SB Grullon, MA Judge, CM Ruderman, KR Grullon, M Lora, V AF Massin-Short, Sarah B. Grullon, Minerva A. Judge, Christine M. Ruderman, Karen R. Grullon, Milagro Lora, Vilma TI A MOBILE MAMMOGRAPHY PILOT PROJECT TO INCREASE SCREENING AMONG LATINA WOMEN OF LOW SOCIOECONOMIC STATUS SO PUBLIC HEALTH REPORTS LA English DT Article ID OLDER WOMEN C1 [Massin-Short, Sarah B.; Judge, Christine M.] Harvard Univ, Sch Publ Hlth, Div Publ Hlth Practice, Boston, MA 02115 USA. [Lora, Vilma] YWCA Greater Lawrence, Womens Serv, Lawrence, MA USA. [Ruderman, Karen R.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Grullon, Milagro] City Lawrence Mayors Hlth Task Force, Community Hlth Strategies & Res, Lawrence, KS USA. RP Massin-Short, SB (reprint author), Harvard Univ, Sch Publ Hlth, Div Publ Hlth Practice, 677 Huntington Ave,Landmark Ctr,3rd Floor E, Boston, MA 02115 USA. EM sshort@hsph.harvard.edu FU National Cancer Institute (NCI) [5 U01 CA114644] FX This article was supported in part by MassCONECT, funded under grant #5 U01 CA114644 from the National Cancer Institute (NCI). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NCI's Center to Reduce Cancer Health Disparities. NR 9 TC 4 Z9 4 U1 0 U2 1 PU ASSOC SCHOOLS PUBLIC HEALTH PI WASHINGTON PA 1101 15TH ST NW, STE 910, WASHINGTON, DC 20005 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD SEP-OCT PY 2010 VL 125 IS 5 BP 765 EP 771 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 638MI UT WOS:000280898600020 PM 20873294 ER PT J AU UyBico, SJ Wu, CC Suh, RD Le, NH Brown, K Krishnam, MS AF UyBico, Stacy J. Wu, Carol C. Suh, Robert D. Le, Nanette H. Brown, Kathleen Krishnam, Mayil S. TI Lung Cancer Staging Essentials: The New TNM Staging System and Potential Imaging Pitfalls SO RADIOGRAPHICS LA English DT Article ID FORTHCOMING 7TH EDITION; POSITRON-EMISSION-TOMOGRAPHY; SMALL PULMONARY NODULES; GUIDELINES 2ND EDITION; BRONCHOGENIC-CARCINOMA; INTEGRATED PET/CT; PROJECT PROPOSALS; MALIGNANT-TUMORS; LYMPH-NODES; FDG-PET AB Lung cancer is the leading cause of cancer-related deaths worldwide, with a dismal 5-year survival rate of 15%. The TNM (tumor-node-metastasis) classification system for lung cancer is a vital guide for determining treatment and prognosis. Despite the importance of accuracy in lung cancer staging, however, correct staging remains a challenging task for many radiologists. The new 7th edition of the TNM classification system features a number of revisions, including subdivision of tumor categories on the basis of size, differentiation between local intrathoracic and distant metastatic disease, recategorization of malignant pleural or pericardial disease from stage III to stage IV, reclassification of separate tumor nodules in the same lung and lobe as the primary tumor from T4 to T3, and reclassification of separate tumor nodules in the same lung but not the same lobe as the primary tumor from M1 to T4. Radiologists must understand the details set forth in the TNM classification system and be familiar with the changes in the 7th edition, which attempts to better correlate disease with prognostic value and treatment strategy. By recognizing the relevant radiologic appearances of lung cancer, understanding the appropriateness of staging disease with the TNM classification system, and being familiar with potential imaging pitfalls, radiologists can make a significant contribution to treatment and outcome in patients with lung cancer. (C) RSNA, 2010 . radiographics.rsna.org C1 [UyBico, Stacy J.; Suh, Robert D.; Le, Nanette H.; Brown, Kathleen; Krishnam, Mayil S.] Univ Calif Los Angeles, Dept Radiol, Div Thorac Imaging, Ronald Reagan UCLA Med Ctr, Los Angeles, CA USA. [Wu, Carol C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Thorac Div,Dept Imaging, Boston, MA USA. RP Krishnam, MS (reprint author), Univ Calif Irvine, Div Diagnost Cardiovasc & Thorac Imaging, Dept Radiol Sci, Med Ctr, 101 City Dr S,Route 140, Orange, CA 92868 USA. EM mskrishn@uci.edu NR 52 TC 43 Z9 47 U1 0 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD SEP PY 2010 VL 30 IS 5 BP 1163 EP 1181 DI 10.1148/rg.305095166 PG 19 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 651YV UT WOS:000281966100002 PM 20833843 ER PT J AU Wieseler, KM Bhargava, P Kanal, KM Vaidya, S Stewart, BK Dighe, MK AF Wieseler, Karen M. Bhargava, Puneet Kanal, Kalpana M. Vaidya, Sandeep Stewart, Brent K. Dighe, Manjiri K. TI Imaging in Pregnant Patients: Examination Appropriateness SO RADIOGRAPHICS LA English DT Article ID ACUTE PULMONARY-EMBOLISM; AAPM/RSNA PHYSICS TUTORIAL; LOWER-QUADRANT PAIN; ACUTE APPENDICITIS; SUSPECTED APPENDICITIS; COMPUTED-TOMOGRAPHY; HELICAL CT; PERFUSION SCINTIGRAPHY; RADIATION-EXPOSURE; ABDOMINAL-PAIN AB A recurring source of contention between clinicians and radiologists continues to be examination appropriateness when imaging pregnant patients. With the multitude of references on potential radiation risks to the fetus, radiologists tend to be cautious and hesitant about exposing the fetus to radiation. This tendency is often interpreted by referring physicians as intrusion into and delay in the care of their patients. The risk burden of radiation exposure to the fetus has to be carefully weighed against the benefits of obtaining a critical diagnosis quickly and using a single tailored imaging study. In general, there is lower than expected awareness of radiation risks to the fetus from imaging pregnant patients. Modalities that do not use ionizing radiation, such as ultrasonography and magnetic resonance imaging, should be the preferred examinations for evaluating an acute condition in a pregnant patient. However, no examination should be withheld when an important clinical diagnosis is under consideration. Exposure to ionizing radiation may be unavoidable, but there is no evidence to suggest that the risk to the fetus after a single imaging study and an interventional procedure is significant. All efforts should be made to minimize the exposure, with consideration of the risk versus benefit for a given clinical scenario. (C) RSNA, 2010 . radiographics.rsna.org C1 [Wieseler, Karen M.; Bhargava, Puneet; Kanal, Kalpana M.; Vaidya, Sandeep; Stewart, Brent K.; Dighe, Manjiri K.] Univ Washington, Med Ctr, Dept Radiol, Seattle, WA 98195 USA. [Bhargava, Puneet] Vet Affairs Puget Sound Healthcare Syst, Dept Radiol, Seattle, WA USA. [Vaidya, Sandeep] Univ Washington, Harborview Med Ctr, Dept Radiol, Seattle, WA 98104 USA. RP Dighe, MK (reprint author), Univ Washington, Med Ctr, Dept Radiol, Box 357115,1959 NE Pacific St, Seattle, WA 98195 USA. EM dighe@u.washington.edu RI Bhargava, Puneet /F-1330-2011; OI Bhargava, Puneet/0000-0002-3849-9666 NR 62 TC 49 Z9 49 U1 0 U2 3 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD SEP PY 2010 VL 30 IS 5 BP 1215 EP 1229 DI 10.1148/rg.305105034 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 651YV UT WOS:000281966100005 PM 20833847 ER PT J AU Kopans, DB AF Kopans, Daniel B. TI The 2009 US Preventive Services Task Force (USPSTF) Guidelines are not Supported by Science: The Scientific Support for Mammography Screening SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE USPSTF guidelines; Mammography screening; Scientific support; Breast cancer screening ID BREAST-CANCER MORTALITY; RANDOMIZED CONTROLLED TRIAL; CARCINOMA IN-SITU; AGED 40-49 YEARS; DIFFERENT PERSPECTIVE; WOMEN YOUNGER; RISK; REDUCTION; DIAGNOSIS; BENEFITS AB Mammography screening is one of the major medical accomplishments of the past 40 years. In light of the downstream consequences of any screening test, it was critical that mammography screening be challenged. There have been many legitimate challenges, as well as many challenges that are not scientifically based but have gained credibility because of repetition. The latter have led to a great deal of confusion among women and their physicians. The aim of this review is to dispel many of the misunderstandings that have developed in the past 4 decades and, hopefully, reduce the confusion that has occurred. Mammography screening does not find all breast cancers and does not find all cancers early enough to result in a cure, but it is a major advance, and women should not be denied access to its benefits. C1 [Kopans, Daniel B.] Massachusetts Gen Hosp, Breast Imaging Div, Boston, MA 02114 USA. [Kopans, Daniel B.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Kopans, DB (reprint author), Massachusetts Gen Hosp, Breast Imaging Div, 15 Parkman St,Mailstop Level 2,Suite 219, Boston, MA 02114 USA. EM dkopans@partners.org NR 67 TC 18 Z9 18 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 0033-8389 EI 1557-8275 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD SEP PY 2010 VL 48 IS 5 BP 843 EP + DI 10.1016/j.rcl.2010.06.005 PG 16 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 673FC UT WOS:000283643500002 PM 20868889 ER PT J AU Birdwell, RL Mountford, CE Iglehart, JD AF Birdwell, Robyn L. Mountford, Carolyn E. Iglehart, J. Dirk TI Molecular Imaging of the Breast SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Breast cancer; Breast cancer screening; Molecular imaging; Magnetic resonance; Nuclear medicine ID PROTON-MAGNETIC-RESONANCE; GENE-EXPRESSION PATTERNS; FINE-NEEDLE BIOPSY; IN-VIVO; MR SPECTROSCOPY; H-1 MRS; CANCER; LESIONS; DIAGNOSIS; CHOLINE AB Contrast-enhanced magnetic resonance imaging (MRI), MR spectroscopy, and nuclear medicine sestamibi imaging using technetium-99m methoxyisobutyl isonitrile or positron emission tomography (PET) techniques provide information beyond that of structural imaging by displaying tumor neoangiogenesis, tumor metabolites, increased numbers of tumor cellular mitochondria, and hypermetabolic tumor cells. Much needs to be learned at the molecular level of normal cellular pathways either suppressed or enhanced by tumor-specific molecular changes. These discoveries will allow realization of true individualized patient tumor detection, treatment, and surveillance. C1 [Birdwell, Robyn L.] Brigham & Womens Hosp, Dept Radiol, Div Breast Imaging, Boston, MA 02129 USA. [Birdwell, Robyn L.; Mountford, Carolyn E.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Mountford, Carolyn E.] Brigham & Womens Hosp, Ctr Clin Spect, Dept Radiol, Boston, MA 02129 USA. [Iglehart, J. Dirk] Brigham & Womens Hosp, Dept Surg, Boston, MA 02129 USA. [Iglehart, J. Dirk] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Birdwell, RL (reprint author), Brigham & Womens Hosp, Dept Radiol, Div Breast Imaging, 75 Francis St, Boston, MA 02129 USA. EM rbirdwell@partners.org NR 60 TC 5 Z9 5 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0033-8389 EI 1557-8275 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD SEP PY 2010 VL 48 IS 5 BP 1075 EP + DI 10.1016/j.rcl.2010.07.017 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 673FC UT WOS:000283643500014 PM 20868901 ER PT J AU Pandharipande, PV Gervais, DA Hartman, RI Harisinghani, MG Feldman, AS Mueller, PR Gazelle, GS AF Pandharipande, Pari V. Gervais, Debra A. Hartman, Rebecca I. Harisinghani, Mukesh G. Feldman, Adam S. Mueller, Peter R. Gazelle, G. Scott TI Renal Mass Biopsy to Guide Treatment Decisions for Small Incidental Renal Tumors: A Cost-effectiveness Analysis SO RADIOLOGY LA English DT Article ID FINE-NEEDLE-ASPIRATION; NEPHRON-SPARING SURGERY; WILLINGNESS-TO-PAY; NORMAL CONTRALATERAL KIDNEY; OPEN PARTIAL NEPHRECTOMY; ADJUSTED LIFE YEAR; CELL CARCINOMA; NATURAL-HISTORY; PERCUTANEOUS BIOPSY; ACTIVE SURVEILLANCE AB Purpose: To evaluate the effectiveness, cost, and cost-effectiveness of using renal mass biopsy to guide treatment decisions for small incidentally detected renal tumors. Materials and Methods: A decision-analytic Markov model was developed to estimate life expectancy and lifetime costs for patients with small (<= 4-cm) renal tumors. Two strategies were compared: renal mass biopsy to triage patients to surgery or imaging surveillance and empiric nephron-sparing surgery. The model incorporated biopsy performance, the probability of track seeding with malignant cells, the prevalence and growth of benign and malignant tumors, treatment effectiveness and costs, and patient outcomes. An incremental cost-effectiveness analysis was performed to identify strategy preference under a willingness-to-pay threshold of $75 000 per quality-adjusted life-year (QALY). Effects of changes in key parameters on strategy preference were evaluated in sensitivity analysis. Results: Under base-case assumptions, the biopsy strategy yielded a minimally greater quality-adjusted life expectancy (4 days) than did empiric surgery at a lower lifetime cost ($3466), dominating surgery from a cost-effectiveness perspective. Over the majority of parameter ranges tested in one-way sensitivity analysis, the biopsy strategy dominated surgery or was cost-effective relative to surgery based on a $75 000-per-QALY willingness-to-pay threshold. In two-way sensitivity analysis, surgery yielded greater life expectancy when the prevalence of malignancy and propensity for biopsy-negative cancers to metastasize were both higher than expected or when the sensitivity and specificity of biopsy were both lower than expected. Conclusion: The use of biopsy to guide treatment decisions for small incidentally detected renal tumors is cost-effective and can prevent unnecessary surgery in many cases. (C) RSNA, 2010 C1 [Pandharipande, Pari V.; Gervais, Debra A.; Harisinghani, Mukesh G.; Mueller, Peter R.; Gazelle, G. Scott] Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent Radiol, Boston, MA 02114 USA. [Pandharipande, Pari V.; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Hartman, Rebecca I.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Pandharipande, PV (reprint author), Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM pari@mgh-ita.org FU National Cancer Institute [K07CA133097] FX This research was supported by the National Cancer Institute (grant K07CA133097). NR 76 TC 32 Z9 32 U1 2 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 SEP PY 2010 VL 256 IS 3 BP 836 EP 846 DI 10.1148/radiol.10092013 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 656LD UT WOS:000282335300018 PM 20720070 ER PT J AU Almandoz, JED Kelly, HR Schaefer, PW Lev, MH Gonzalez, RG Romero, JM AF Almandoz, Josser E. Delgado Kelly, Hillary R. Schaefer, Pamela W. Lev, Michael H. Gonzalez, R. Gilberto Romero, Javier M. TI Traumatic Dural Venous Sinus Thrombosis in High-Risk Acute Blunt Head Trauma Patients Response SO RADIOLOGY LA English DT Letter C1 [Almandoz, Josser E. Delgado; Kelly, Hillary R.; Schaefer, Pamela W.; Lev, Michael H.; Gonzalez, R. Gilberto; Romero, Javier M.] Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02114 USA. [Almandoz, Josser E. Delgado] Washington Univ, Sch Med, Div Neuroradiol, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. RP Almandoz, JED (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Boston, MA 02114 USA. EM delgadoj@mir.wustl.edu NR 1 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2010 VL 256 IS 3 BP 1015 EP 1015 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 656LD UT WOS:000282335300044 ER PT J AU Kuna, ST AF Kuna, Samuel T. TI Portable-Monitor Testing: An Alternative Strategy for Managing Patients With Obstructive Sleep Apnea SO RESPIRATORY CARE LA English DT Article; Proceedings Paper CT 56th International Respiratory Congress of the American-Association-for-Respiratory-Care CY DEC 06-09, 2010 CL Las Vegas, NV SP Amer Assoc Resp Care DE sleep; polysomnogram; continuous positive airway pressure; CPAP; comparative effectiveness research ID POSITIVE AIRWAY PRESSURE; SPLIT-NIGHT POLYSOMNOGRAPHY; MIDDLE-AGED MEN; CPAP TITRATION; DAYTIME SLEEPINESS; HEART HEALTH; PRACTICE PARAMETERS; TELEMONITORED POLYSOMNOGRAPHY; APNOEA/HYPOPNOEA SYNDROME; CARDIOVASCULAR OUTCOMES AB Portable-monitor testing is being used increasingly in ambulatory management pathways for the diagnosis and treatment of patients with obstructive sleep apnea. Wide varieties of portable monitors are commercially available and they range from single-channel recorders to units that record a full polysomnogram. Recent comparative effectiveness research studies have shown that clinical outcomes of patients with a high pretest probability for obstructive sleep apnea who receive ambulatory management using portable-monitor testing have similar functional outcomes and adherence to continuous positive airway pressure treatment, compared to patients managed with in-laboratory polysomnography. The cost-effectiveness of portable-monitor testing and its potential to improve patient access to diagnosis and treatment requires further investigation. C1 [Kuna, Samuel T.] Univ Penn, Sch Med, Div Pulm Allergy & Crit Care, Dept Med, Philadelphia, PA 19104 USA. [Kuna, Samuel T.] Philadelphia Vet Affairs Med Ctr, Pulm Crit Care & Sleep Sect, Philadelphia, PA USA. RP Kuna, ST (reprint author), Univ Penn, Sch Med, Div Pulm Allergy & Crit Care, Dept Med, 3624 Market St,Suite 205, Philadelphia, PA 19104 USA. EM skuna@mail.med.upenn.edu NR 123 TC 15 Z9 16 U1 0 U2 2 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD SEP PY 2010 VL 55 IS 9 SI SI BP 1196 EP 1215 PG 20 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 676AL UT WOS:000283882400006 PM 20800001 ER PT J AU Adams, SG Anzueto, A Briggs, DD Leimer, I Kesten, S AF Adams, Sandra G. Anzueto, Antonio Briggs, Dick D., Jr. Leimer, Inge Kesten, Steven TI Comment on tiotropium Response SO RESPIRATORY MEDICINE LA English DT Letter C1 [Adams, Sandra G.; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Adams, Sandra G.; Anzueto, Antonio] S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX 78229 USA. [Briggs, Dick D., Jr.] Univ Alabama, Birmingham, AL 35294 USA. [Leimer, Inge; Kesten, Steven] Boehringer Ingelheim GmbH & Co KG, Ingelheim, Germany. RP Adams, SG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, 7400 Merton Minter,111E, San Antonio, TX 78229 USA. EM ADAMSSG@UTHSCSA.EDU NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD SEP PY 2010 VL 104 IS 9 BP 1389 EP 1389 DI 10.1016/j.rmed.2010.04.019 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 640WJ UT WOS:000281084400024 ER PT J AU Boulle, A Clayden, P Cohen, K Cohen, T Conradie, F Dong, K Geffen, N Grimwood, A Hurtado, R Kenyon, C Lawn, S Maartens, G Meintjes, G Mendelson, M Murray, M Rangaka, M Sanne, I Spencer, D Taljaard, J Variava, E Venter, WDF Wilson, D AF Boulle, Andrew Clayden, Polly Cohen, Karen Cohen, Ted Conradie, Francesca Dong, Krista Geffen, Nathan Grimwood, Ashraf Hurtado, Rocio Kenyon, Christopher Lawn, Stephen Maartens, Gary Meintjes, Graeme Mendelson, Marc Murray, Megan Rangaka, Molebogeng Sanne, Ian Spencer, David Taljaard, Jantjie Variava, Ebrahim Venter, W. D. Francois Wilson, Douglas TI Prolonged deferral of antiretroviral therapy in the SAPIT trial: Did we need a clinical trial to tell us that this would increase mortality? SO SAMJ SOUTH AFRICAN MEDICAL JOURNAL LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PULMONARY TUBERCULOSIS; ADULTS; DRUGS; ERA; METAANALYSIS; SURVIVAL; IMPACT C1 [Cohen, Karen; Maartens, Gary] Univ Cape Town, Dept Med, Div Clin Pharmacol, ZA-7700 Rondebosch, South Africa. [Boulle, Andrew] Univ Cape Town, Sch Publ Hlth & Family Med, ZA-7700 Rondebosch, South Africa. [Cohen, Ted; Murray, Megan] Harvard Univ, Brigham & Womens Hosp, Div Global Hlth Equ, Sch Med, Cambridge, MA 02138 USA. [Cohen, Ted; Murray, Megan] Harvard Univ, Dept Epidemiol, Sch Publ Hlth, Cambridge, MA 02138 USA. [Conradie, Francesca] Univ Witwatersrand, Clin HIV Res Unit, Johannesburg, South Africa. [Hurtado, Rocio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Infect Dis, Cambridge, MA 02138 USA. [Lawn, Stephen] Univ Cape Town, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7700 Rondebosch, South Africa. [Lawn, Stephen] London Sch Hyg & Trop Med, Dept Infect & Trop Med, Clin Res Unit, London, England. [Mendelson, Marc] Univ Cape Town, Dept Med, Div Infect Dis & HIV Med, ZA-7700 Rondebosch, South Africa. [Sanne, Ian] Univ Witwatersrand, Dept Med, ZA-2050 Wits, South Africa. [Spencer, David] Edenvale, Toga Mol Lab, Johannesburg, South Africa. [Taljaard, Jantjie] Tygerberg Acad Hosp, Dept Med, Div Infect Dis, Tygerberg, South Africa. [Taljaard, Jantjie] Univ Stellenbosch, ZA-7600 Stellenbosch, South Africa. [Venter, W. D. Francois] Univ Witwatersrand, Reprod Hlth & HIV Res Unit, ZA-2050 Wits, South Africa. [Wilson, Douglas] Univ KwaZulu Natal, Durban, South Africa. RP Maartens, G (reprint author), Univ Cape Town, Dept Med, Div Clin Pharmacol, ZA-7700 Rondebosch, South Africa. EM gary.maartens@uct.ac.za RI Cohen, Ted/G-8101-2011; Maartens, Gary/F-3836-2014; Rangaka, Molebogeng/E-4116-2015; Cohen, Karen/D-4036-2017; OI Maartens, Gary/0000-0003-3080-6606; Cohen, Karen/0000-0002-1892-4207 NR 25 TC 8 Z9 8 U1 0 U2 1 PU SA MEDICAL ASSOC PI PRETORIA PA BLOCK F CASTLE WALK CORPORATE PARK, NOSSOB STREET, ERASMUSKLOOF EXT3, PRETORIA, 0002, SOUTH AFRICA SN 0256-9574 J9 SAMJ S AFR MED J JI SAMJ S. Afr. Med. J. PD SEP PY 2010 VL 100 IS 9 BP 566 EP + PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 658BP UT WOS:000282464000011 PM 20822639 ER PT J AU de Jong, JJ Hodiamont, PPG de Gelder, B AF de Jong, J. J. Hodiamont, P. P. G. de Gelder, B. TI Modality-specific attention and multisensory integration of emotions in schizophrenia: Reduced regulatory effects SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Emotion recognition; Multisensory integration; Selective attention; Modality-specific attention; Cognition; Schizophrenia ID FACIAL EXPRESSIONS; AUDIOVISUAL INTEGRATION; NEUROCOGNITIVE DEFICITS; FUNCTIONAL-SIGNIFICANCE; SELECTIVE ATTENTION; CROSSMODAL BINDING; SPEECH-PERCEPTION; SOCIAL COGNITION; HUMAN BRAIN; RECOGNITION AB Background: Deficits in emotion perception are a well-established phenomenon in schizophrenic patients and studies have typically used unimodal emotion tasks, presenting either emotional faces or emotional vocalizations. We introduced bimodal emotion conditions in two previous studies in order to study the process of multisensory integration of visible and audible emotion cues. We now build on our earlier work and address the regulatory effects of selective attention mechanisms on the ability to integrate emotion cues stemming from multisensory channels. Methods: We added a neutral secondary distractor condition to the original bimodal paradigm in order to investigate modality-specific selective attention mechanisms. We compared schizophrenic patients (n=50) to non-schizophrenic psychotic patients (n=46), as well as to healthy controls (n=50). A trained psychiatrist used the Schedules of Clinical Assessment in Neuropsychiatry (SCAN 2.1) to diagnose the patients. Results: As expected, in healthy controls, and to a lesser extent in non-schizophrenic psychotic patients, modality-specific attention attenuated multisensory integration of emotional faces and vocalizations. Conversely, in schizophrenic patients, auditory and visual distractor conditions yielded unaffected and even exaggerated multisensory integration. Conclusions: These results suggest that schizophrenics, as compared to healthy controls and non-schizophrenic psychotic patients, have modality-specific attention deficits when attempting to integrate information regarding emotions that stem from multichannel sources. Various explanations for our findings, as well as their possible consequences, are discussed. (C) 2010 Elsevier B.V. All rights reserved. C1 [de Gelder, B.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [de Gelder, B.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [de Jong, J. J.; de Gelder, B.] Tilburg Univ, Cognit Neurosci Lab, NL-5000 LE Tilburg, Netherlands. [de Jong, J. J.; Hodiamont, P. P. G.] GGz Breburg Grp, NL-5000 AT Tilburg, Netherlands. [Hodiamont, P. P. G.] Tilburg Univ, Dept Dev Clin & Cross Cultural Psychol, NL-5000 LE Tilburg, Netherlands. RP de Gelder, B (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Room 417,Bldg 36,1st St, Charlestown, MA 02129 USA. EM s.dejong@ggzbreburggroep.nl; p.hodiamont@uvt.nl; degelder@nmr.mgh.harvard.edu FU Dutch Science Foundation [100-002-015]; Human Frontier Science Program [HFSP-RGP0054/2004-C]; EC [FP6-NEST-2005-Path-IMP-043403] FX Research was funded by a ZonMw grant (Dutch Science Foundation; 100-002-015). Furthermore, the study was partly supported by Human Frontier Science Program HFSP-RGP0054/2004-C and EC-contract number FP6-NEST-2005-Path-IMP-043403. Neither ZonMw nor HFSP had a role in study design; in the collection, analysis and interpretation of data; in the writing the report; and in the decision to submit the paper for publication. NR 44 TC 24 Z9 24 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2010 VL 122 IS 1-3 BP 136 EP 143 DI 10.1016/j.schres.2010.04.010 PG 8 WC Psychiatry SC Psychiatry GA 709AH UT WOS:000286406900016 PM 20554159 ER PT J AU Kasckow, J Liu, N Haas, GL Phillips, MR AF Kasckow, John Liu, Nancy Haas, Gretchen L. Phillips, Michael R. TI Case-control study of the relationship of depressive symptoms to suicide in a community-based sample of individuals with schizophrenia in China SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Depression; Suicide; Schizophrenia; China; Psychological autopsy ID PSYCHOLOGICAL AUTOPSY; RISK-FACTORS; MENTAL-DISORDERS; RURAL-COMMUNITY; MAINLAND CHINA; PREVENTION; MORTALITY; TRIAL; MOOD AB Background: Suicide is the leading cause of premature death among people with schizophrenia. Most studies on suicide and schizophrenia report an associated depression history, but they are based on clinical samples from mostly western countries. Methods: We conducted a secondary analysis of 74 suicides (cases) and 24 accidental deaths (controls) among persons with schizophrenia identified in a national psychological autopsy study in mainland China using the Chinese version of the Structured Clinical Interview for DSM-IV. A 'depression symptom severity score' based on number, severity, and persistence of depressive symptoms 2 weeks before death was derived from psychiatric interviews with 2 informants; determination of a 'dysfunction due to depressive symptoms score' was based on informants' reports about effects of depressive symptoms on decedents' functioning in the month before death. In addition, the mean number of negative life events was determined along with the effect of the events on the decedent. Comparison of the measures made for cases and controls were made by univariate analysis followed by adjustments using the False Discovery Rate. Results: Compared to persons with schizophrenia who died by accident, those who died by suicide were more likely to have a recent DSM IV diagnosis of major depression, the symptom of depressed mood, thoughts of death and a prior suicide attempt. In addition, those who died by suicide were more likely to have a higher overall depression severity score and greater dysfunction due to depressive symptoms. Discussion: This community-based study of individuals with DSM-IV schizophrenia who died by suicide in a non-western culture extends findings from clinical studies in western cultures providing data on the importance of depressive symptoms as risk factors for suicide in schizophrenia in a low income rural setting. These findings underline the importance of routine screening for depressive symptoms among patients with schizophrenia. Published by Elsevier B.V. C1 [Kasckow, John; Haas, Gretchen L.] VA Pittsburgh Hlth Care Syst MIRECC, Pittsburgh, PA 15206 USA. [Kasckow, John; Haas, Gretchen L.] Behav Hlth Serv, Pittsburgh, PA 15206 USA. [Kasckow, John; Haas, Gretchen L.] Univ Pittsburgh, Western Psychiat Inst & Clin, Med Ctr, Pittsburgh, PA 15213 USA. [Liu, Nancy; Phillips, Michael R.] Beijing Hui Long Guan Hosp, WHO Collaborating Ctr Res & Training Suicide Prev, Beijing, Peoples R China. [Liu, Nancy] Univ Nebraska, Dept Psychol, Lincoln, NE 68588 USA. [Phillips, Michael R.] Columbia Univ, Dept Psychiat, New York, NY USA. [Phillips, Michael R.] Columbia Univ, Dept Epidemiol, New York, NY USA. RP Kasckow, J (reprint author), VA Pittsburgh Hlth Care Syst, Behav Hlth, 7180 Highland Dr, Pittsburgh, PA 15206 USA. EM kasckowjw@upmc.edu FU Ford Foundation; Befrienders International; University of Pittsburgh Medical Center FX This study was supported by institutional support from the University of Pittsburgh Medical Center as well as grants from the Ford Foundation, the Save the Children Fund, and Befrienders International. Participating institutions include 23 Disease Surveillance Points and four psychiatric centres (Department of Neuropsychiatry, Xijing Hospital, Xian, Shaanxi Province; Jingzhou City Psychiatric Hospital, Hubei Province; Shenyang Mental Health Centre, Liaoning Province; and Suzhou Guangji Hospital, Jiangsu Province).; This study is part of the 'Causes and Prevention of Accidental Deaths in China' project, which was supported by grants from the Ford Foundation, the Save the Children Fund, and Befrienders International. Participating institutions include 23 Disease Surveillance Points and four psychiatric centres (Department of Neuropsychiatry, Xijing Hospital, Xian, Shaanxi Province; Jingzhou City Psychiatric Hospital, Hubei Province; Shenyang Mental Health Centre, Liaoning Province; and Suzhou Guangji Hospital, Jiangsu Province). The authors thank all the institutions, investigators and respondents for their contribution to the research. NR 39 TC 9 Z9 10 U1 6 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2010 VL 122 IS 1-3 BP 226 EP 231 DI 10.1016/j.schres.2010.02.1056 PG 6 WC Psychiatry SC Psychiatry GA 709AH UT WOS:000286406900029 PM 20227247 ER PT J AU Messamore, E Hoffman, WF Yao, JK AF Messamore, Erik Hoffman, William F. Yao, Jeffrey K. TI Niacin sensitivity and the arachidonic acid pathway in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Niacin; Schizophrenia; RBC membrane; Arachidonic acid; Adrenic acid ID POLYUNSATURATED FATTY-ACID; SKIN FLUSH RESPONSE; NICOTINIC-ACID; HUMAN ERYTHROCYTES; ABSENT RESPONSE; RECEPTOR HM74A; CELL MEMBRANES; VASODILATION; PATCH AB Objective: Schizophrenia is associated with a blunted flush response to niacin. Since niacin-induced skin flushing is mediated by vasodilators derived from arachidonic acid (AA), we tested whether the blunted flush response to niacin is a marker of AA deficiency. Methods: Eight concentrations of methylnicotinate were applied to the forearms of 20 adults with schizophrenia and 20 controls. Laser Doppler measurement of blood flow responses was used to derive values for niacin sensitivity (defined as the concentration eliciting half-maximal response, i.e., EC(50) value) and efficacy (defined as the maximal evoked blood flow response). RBC membrane fatty acids were analyzed by gas chromatography. Results: Niacin sensitivity and efficacy were reduced in schizophrenia. In the control group, there was significant correlation between AA levels and niacin sensitivity as well as a trend toward correlation between AA levels and niacin efficacy. In contrast, neither sensitivity nor efficacy of niacin correlated with AA levels in schizophrenia. An expected correlation between the levels of AA and its elongation product (adrenic acid) was absent in schizophrenia. Adrenic acid levels correlated with niacin efficacy in schizophrenia. Conclusions: The schizophrenia-associated niacin response abnormality involves both diminished sensitivity and reduced efficacy. The lack of expected correlation between levels of AA and adrenic acid suggests homeostatic imbalance within the n-6 polyunsaturated fatty acid (PUFA) pathway in schizophrenia. Though AA levels were unrelated to measures of niacin response in schizophrenia, the correlation between adrenic acid and niacin efficacy in schizophrenia suggests relevance of the n-6 PUFA pathway to the blunted niacin response. Published by Elsevier B.V. C1 [Messamore, Erik; Hoffman, William F.] Portland VA Med Ctr, Behav Hlth & Clin Neurosci Div, Portland, OR 97239 USA. [Yao, Jeffrey K.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15206 USA. [Yao, Jeffrey K.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Yao, Jeffrey K.] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15213 USA. RP Messamore, E (reprint author), Portland VA Med Ctr, Div Mental Hlth, P35C,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM Erik.Messamore@va.gov FU NIMH [R03 MH070434, R01 MH58141]; VA FX Funding for this study was provided by: NIMH grant R03 MH070434 (to EM); NIMH grant R01 MH58141 (JKY); and a VA Senior Research Career Scientist Award (JKY). NR 42 TC 15 Z9 15 U1 3 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2010 VL 122 IS 1-3 BP 248 EP 256 DI 10.1016/j.schres.2010.03.025 PG 9 WC Psychiatry SC Psychiatry GA 709AH UT WOS:000286406900032 PM 20417059 ER PT J AU Nading, MA Balch, CM Sober, AJ AF Nading, Mary Alice Balch, Charles M. Sober, Arthur J. TI Implications of the 2009 American Joint Committee on Cancer Melanoma Staging and Classification on Dermatologists and Their Patients SO SEMINARS IN CUTANEOUS MEDICINE AND SURGERY LA English DT Article AB The Melanoma Staging and Classification system was recently revised by the American Joint Committee on Cancer (AJCC) and implemented effective January 2010 with changes reflecting new prognostic data gleaned by the significantly larger patient population studied for the 7th edition This newest analysis yields important long term outcome data as many of the patients were followed for nearly 2 decades Additions to edition 7 of the AJCC Melanoma Staging classification highlight several important prognostic factors particularly the addition of mitotic rate for classifying thin melanomas, the presence of microtumor burden in lymph nodes for stage III disease, and elevated lactate dehydrogenase levels in patients with distant metastatic disease Although the basic tumor nodes-metastases (ie TNM) cancer classification model remains unchanged in this newest edition, the current AJCC Melanoma Staging System has incorporated the latest prognostic data to accurately stratify patients into staging categories It is important for clinicians and dermatopathologists to familiarize themselves with these changes so that patients are suitably managed and referred to medical and surgical oncologists when appropriate Semin Cutan Med Surg 29 142 147 (C) 2010 Elsevier Inc All rights reserved C1 [Nading, Mary Alice; Sober, Arthur J.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Balch, Charles M.] Johns Hopkins Med Ctr, Dept Surg, Baltimore, MD USA. RP Sober, AJ (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 55 Fruit St,Bar 622, Boston, MA 02114 USA. NR 10 TC 5 Z9 5 U1 0 U2 1 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 SEP PY 2010 VL 29 IS 3 BP 142 EP 147 DI 10.1016/j.sder.2010.06.004 PG 6 WC Dermatology; Surgery SC Dermatology; Surgery GA 683ED UT WOS:000284453600002 PM 21051007 ER PT J AU Udayakumar, D Mahato, B Gabree, M Tsao, H AF Udayakumar, Durga Mahato, Bisundev Gabree, Michele Tsao, Hensin TI Genetic Determinants of Cutaneous Melanoma Predisposition SO SEMINARS IN CUTANEOUS MEDICINE AND SURGERY LA English DT Article ID POPULATION-BASED SAMPLE; CELL-CYCLE INHIBITION; SKIN-CANCER RISK; MALIGNANT-MELANOMA; FAMILIAL MELANOMA; PRONE FAMILIES; GERMLINE MUTATIONS; PANCREATIC-CANCER; TUMOR-SUPPRESSOR; CDKN2A MUTATIONS AB In the last 2 decades, advances in genomic technologies and molecular biology have accelerated the identification of multiple genetic loci that confer risk for cutaneous melanoma The risk alleles range from rarely occurring high risk variants with a strong familial predisposition to low risk to moderate risk variants with modest melanoma association Although the high risk alleles are limited to the CDKN2A and CDK4 loci the authors of recent genome wide association studies have uncovered a set of variants in pigmentation loci that contribute to low risk A biological validation of these new findings would provide greater understanding of the disease In this review we describe some of the important risk loci and their association to risk of developing cutaneous melanoma and also address the current clinical challenges in CDKN2A genetic testing Semin Cutan Med Surg 29 190 195 (C) 2010 Elsevier Inc All rights reserved C1 [Udayakumar, Durga; Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA. [Mahato, Bisundev; Tsao, Hensin] Harvard Univ, Sch Med, Boston, MA USA. [Gabree, Michele; Tsao, Hensin] Massachusetts Gen Hosp, Ctr Canc Risk Assessment, Boston, MA 02114 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Bartlett 622,48 Blossom St, Boston, MA 02114 USA. FU American Cancer Society [RSG MGO 112970]; National Institutes of Health [K24 CA149202 01, P50 CA 93683] FX This writing of this manuscript was supported by grants from the American Cancer Society (RSG MGO 112970 to H) and the National Institutes of Health (K24 CA149202 01 and P50 CA 93683 both to H T) NR 78 TC 15 Z9 15 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1085-5629 J9 SEMIN CUTAN MED SURG JI Semin. Cutan. Med. Surg. PD SEP PY 2010 VL 29 IS 3 BP 190 EP 195 DI 10.1016/j.sder.2010.06.002 PG 6 WC Dermatology; Surgery SC Dermatology; Surgery GA 683ED UT WOS:000284453600008 PM 21051013 ER PT J AU Puzanov, I Flaherty, KT AF Puzanov, Igor Flaherty, Keith T. TI Targeted Molecular Therapy in Melanoma SO SEMINARS IN CUTANEOUS MEDICINE AND SURGERY LA English DT Article ID CELL LUNG-CANCER; BRAF MUTATIONS; METASTATIC MELANOMA; MALIGNANT-MELANOMA; PHASE-II; SELECTIVE INHIBITOR; IMATINIB MESYLATE; ONCOGENIC BRAF; B-RAF; KINASE AB Immunotherapy and chemotherapy benefit few patients with metastatic melanoma, and even fewer experience durable survival benefit These poor results may come from treating all melanomas as though they are biologically homogeneous Recently, it has been shown that targeting specific activated tyrosine kinases (oncogenes) can have striking clinical benefits in patients with melanoma In 2002 a V600E mutation of the BRAF senne/threonine kinase was described as present in more than 50% of all melanomas The mutation appeared to confer a dependency by the melanoma cancer cell on activated signaling through mitogen activated protein kinase pathway The frequency and focality of this mutation (>95% of all BRAF mutations being at V600 position) suggested its importance in melanoma pathophysiology and potential as a target for therapy The recent results of a phase 1 study with PLX4032/RG7204, a small molecule RAF inhibitor, confirm this hypothesis Mucosal and acral lentiginous melanomas comprising 3% of all melanomas, frequently harbor activating mutations of c kit and drugs targeting this mutation seem to confer similar benefits for these types of tumors Here we provide an overview of the targeted therapy development in melanoma with emphasis on BRAF inhibition because of its prevalence and possibility of transforming the care of many melanoma patients Semin Cutan Med Surg 29 196 201 (C) 2010 Elsevier Inc All rights reserved C1 [Flaherty, Keith T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02115 USA. [Puzanov, Igor] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. RP Flaherty, KT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02115 USA. NR 52 TC 20 Z9 20 U1 0 U2 3 PU FRONTLINE MEDICAL COMMUNICATIONS PI THE WOODLANDS PA WRIGHTS MEDIA, 2407 TIMBERLOCH PLACE, SUITE B, THE WOODLANDS, TX 77386 USA SN 1085-5629 EI 1558-0768 J9 SEMIN CUTAN MED SURG JI Semin. Cutan. Med. Surg. PD SEP PY 2010 VL 29 IS 3 BP 196 EP 201 DI 10.1016/j.sder.2010.06.005 PG 6 WC Dermatology; Surgery SC Dermatology; Surgery GA 683ED UT WOS:000284453600009 PM 21051014 ER PT J AU O'Hare, AM Allon, M Kaufman, JS AF O'Hare, Ann M. Allon, Michael Kaufman, James S. TI Whether and When to Refer Patients for Predialysis AV Fistula Creation: Complex Decision Making in the Face of Uncertainty SO SEMINARS IN DIALYSIS LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; VASCULAR ACCESS SURGERY; ARTERIOVENOUS-FISTULAS; HEMODIALYSIS-PATIENTS; RENAL-FAILURE; UNITED-STATES; MORTALITY; DIALYSIS; OUTCOMES; AGE AB Patients who initiate chronic dialysis with a functional arteriovenous (AV) fistula survive longer and experience fewer complications after initiation of dialysis than those who require a catheter. However, more than 80% of patients in this country begin chronic dialysis with a catheter rather than a fistula, either because they do not have a permanent access or their permanent access is not ready for use. Increasing rates of predialysis AV fistula placement is thus considered a priority area for predialysis care in this country. However, achievement of a functional AV fistula by the time of dialysis initiation is not always an easy proposition. We here outline the limitations of currently recommended approaches toward timing of AV fistula placement. We also highlight the potential complexity of patient and clinician decision making in this area. Particularly in the presence of advanced age and a high burden of comorbidity and disability, it is often uncertain whether patients will need, want, or benefit from chronic dialysis. Adding to this uncertainty, it is often not known whether, when, and after how many revisions an AV fistula will be sufficiently mature to support dialysis. We argue that it is important to acknowledge the complexity of medical decision making in this area and the limitations of currently available prognostic tools to guide such decision making. We conclude that initiation of dialysis with a catheter is appropriate for patients in whom the perceived harms of preemptive fistula placement outweigh the expected benefit. C1 [O'Hare, Ann M.] VA Puget Sound Healthcare Syst, Seattle, WA 98109 USA. [O'Hare, Ann M.] Univ Washington, Seattle, WA 98195 USA. [Allon, Michael] Univ Alabama, Birmingham, AL USA. [Kaufman, James S.] VA Boston Healthcare Syst, Boston, MA USA. [Kaufman, James S.] Boston Univ, Boston, MA 02215 USA. RP O'Hare, AM (reprint author), VA Puget Sound Healthcare Syst, 1160 S Columbian Way,3J RDU, Seattle, WA 98109 USA. EM ann.ohare@va.gov FU NIDDK NIH HHS [K24 DK059818] NR 35 TC 18 Z9 18 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-0959 J9 SEMIN DIALYSIS JI Semin. Dial. PD SEP-OCT PY 2010 VL 23 IS 5 BP 452 EP 455 DI 10.1111/j.1525-139X.2010.00783.x PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 674EY UT WOS:000283718300002 PM 21039873 ER PT J AU Ouellette, HA Palmer, W Torriani, M Bredella, MA AF Ouellette, Hugue A. Palmer, William Torriani, Martin Bredella, Miriam A. TI Throwing Elbow in Adults SO SEMINARS IN MUSCULOSKELETAL RADIOLOGY LA English DT Article DE Elbow MRI; throwing injuries; ulnar collateral ligament ID ULNAR COLLATERAL LIGAMENT; POSTEROLATERAL ROTATORY INSTABILITY; OSTEOCHONDRITIS-DISSECANS; BASEBALL PLAYERS; MR ARTHROGRAPHY; VALGUS STABILITY; INJURY; RECONSTRUCTION; ATHLETE; EPICONDYLITIS AB Biomechanics are central in understanding the pathophysiology and magnetic resonance (MR) imaging of overhead throwing athlete injuries. Repetitive excessive valgus forces at the elbow result in characteristic injuries due to medial joint distraction, lateral joint compression, and rotatory forces at the olecranon. MR imaging is useful for assessment of the throwing elbow in adults. C1 [Ouellette, Hugue A.; Palmer, William; Torriani, Martin; Bredella, Miriam A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ouellette, HA (reprint author), Massachusetts Gen Hosp, Yawkey 6,55 Fruit St, Boston, MA 02114 USA. EM haouellette@partners.org NR 41 TC 1 Z9 1 U1 0 U2 7 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1089-7860 J9 SEMIN MUSCULOSKEL R JI Semin. Musculoskelet. Radiol. PD SEP PY 2010 VL 14 IS 4 BP 412 EP 418 DI 10.1055/s-0030-1263256 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 647OH UT WOS:000281627300004 PM 20827622 ER PT J AU Shah, AS Miller, JW AF Shah, Ankoor S. Miller, Joan W. TI Special Issue: Technological Advances Shaping the Future of Ophthalmology Foreward SO SEMINARS IN OPHTHALMOLOGY LA English DT Editorial Material C1 [Shah, Ankoor S.; Miller, Joan W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02163 USA. RP Shah, AS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02163 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 165 EP 165 DI 10.3109/08820538.2010.539489 PG 1 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600001 ER PT J AU Kumar, RL Cruzat, A Hamrah, P AF Kumar, Radhika L. Cruzat, Andrea Hamrah, Pedram TI Current State of In Vivo Confocal Microscopy in Management of Microbial Keratitis SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE acanthamoeba keratitis; cornea; fungal keratitis; in vivo confocal microscopy; infection ID ACANTHAMOEBA-KERATITIS; INFECTIOUS KERATITIS; DIAGNOSIS AB Purpose: The purpose of this study was to review the current literature on in vivo confocal microscopy of the cornea and to discuss the current clinical indications for its use in microbial keratitis. Methods: Review of select recent literature on in vivo confocal microscopy and atypical microbial keratitis. Results: Delayed diagnosis of Acanthamoeba and fungal keratitis is typical, resulting in significant vision loss. This is partially due to the low sensitivity and time delay of corneal cultures. In the hands of an experienced viewer, the confocal microscope has been found to have a sensitivity of up to 90% in the diagnosis of Acanthamoeba keratitis and close to 80% for fungal keratitis. Conclusion: In vivo confocal microscopy is emerging as a tool for rapid diagnoses in severe infectious keratitis with high sensitivity. In addition, it can be used to monitor treatment response, allowing guidance to clinicians for medical or surgical management. C1 [Kumar, Radhika L.; Cruzat, Andrea; Hamrah, Pedram] Harvard Univ, Ocular Surface Imaging Ctr, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv,Dept Ophthalmol,Med Sc, Boston, MA 02114 USA. RP Hamrah, P (reprint author), Harvard Univ, Ocular Surface Imaging Ctr, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv,Dept Ophthalmol,Med Sc, 243 Charles St, Boston, MA 02114 USA. EM pedram_hamrah@meei.harvard.edu OI Cruzat, Andrea/0000-0002-3724-7037 FU NEI NIH HHS [K12 EY016335, K08 EY020575-01, K08 EY020575] NR 18 TC 19 Z9 21 U1 1 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 166 EP 170 DI 10.3109/08820538.2010.518516 PG 5 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600002 PM 21090995 ER PT J AU Cruzat, A Pavan-Langston, D Hamrah, P AF Cruzat, Andrea Pavan-Langston, Deborah Hamrah, Pedram TI In Vivo Confocal Microscopy of Corneal Nerves: Analysis and Clinical Correlation SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE cornea; nerves; innervation; esthesiometry; sensation; confocal microscopy ID DRY EYE; SITU KERATOMILEUSIS; LONG-TERM; PHOTOREFRACTIVE KERATECTOMY; PENETRATING KERATOPLASTY; NONCONTACT ESTHESIOMETRY; DIABETES-MELLITUS; SJOGRENS-SYNDROME; SUBBASAL NERVES; LASER AB Corneal confocal microscopy is a growing technique for the study of the cornea at the cellular level, providing images comparable to ex vivo histochemical methods. In vivo confocal microscopy (IVCM) has an enormous potential, being a noninvasive procedure that images the living cornea, to study both its physiological and pathological states. Corneal nerves are of great interest to clinicians and scientists due to their important roles in regulating corneal sensation, epithelial integrity, proliferation, wound healing, and for their protective functions. IVCM enables the noninvasive examination of corneal nerves, allowing the study of nerve alterations in different ocular diseases, after corneal surgery, and in systemic diseases. To date, the correlation of sub-basal corneal nerves and their function has been studied in normal eyes, keratoconus, dry eye, contact lens wearers, and in neurotrophic keratopathy, among others. Further, the effect of corneal surgery on nerves has been studied, demonstrating the regenerative capacity of corneal nerves and the recovery of sensation. Moreover, IVCM has been applied in the diagnosis of peripheral diabetic neuropathy and the assessment of progression in this systemic disease. The purpose of this review is to describe the principles, applications, and clinical correlation of IVCM in the study of corneal nerves in different ocular and systemic diseases. C1 [Hamrah, Pedram] Harvard Univ, Ocular Surface Imaging Ctr, Massachusetts Eye & Ear Infirm,Dept Ophthalmol, Cornea & Refract Surg Serv,Cornea Serv,Med Sch, Boston, MA 02114 USA. RP Hamrah, P (reprint author), Harvard Univ, Ocular Surface Imaging Ctr, Massachusetts Eye & Ear Infirm,Dept Ophthalmol, Cornea & Refract Surg Serv,Cornea Serv,Med Sch, 243 Charles St, Boston, MA 02114 USA. EM pedram_hamrah@meei.harvard.edu OI Cruzat, Andrea/0000-0002-3724-7037 FU NEI NIH HHS [K08 EY020575, K08 EY020575-01] NR 67 TC 63 Z9 67 U1 0 U2 2 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 171 EP 177 DI 10.3109/08820538.2010.518133 PG 7 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600003 PM 21090996 ER PT J AU Mantopoulos, D Cruzat, A Hamrah, P AF Mantopoulos, Dimosthenis Cruzat, Andrea Hamrah, Pedram TI In Vivo Imaging of Corneal Inflammation: New Tools for Clinical Practice and Research SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE cornea; inflammation; in vivo imaging; confocal microscopy; OCT; multi-photon microscopy ID OPTICAL COHERENCE TOMOGRAPHY; CONFOCAL MICROSCOPY; ANTERIOR SEGMENT; BACTERIAL KERATITIS; PREDISPOSING FACTORS; MICROBIAL KERATITIS; MOORENS ULCER; CELLS; CONJUNCTIVA; RABBIT AB Purpose: Infectious and inflammatory corneal diseases are a major cause of blindness. To date, assessment of corneal inflammation, has only been possible by slit-lamp biomicroscopy. The purpose of this study is to review the current state of imaging technologies enabling in vivo imaging of inflammation in the cornea. Methods: Literature review of peer-reviewed articles on in vivo imaging modalities. Results: Current means of diagnosis and treatment follow-up for immune and infectious keratitis are limited to slit-lamp biomicroscopy. Several modalities are currently emerging, allowing for in vivo imaging of corneal inflammation, including in vivo confocal microscopy, anterior segment optical coherence tomography, and intravital multiphoton microscopy. Conclusion: Several in vivo imaging technologies are currently evolving, allowing for objective assessment of corneal inflammation and treatment response. C1 [Hamrah, Pedram] Harvard Univ, Ocular Surface Imaging Ctr, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv,Dept Ophthalmol,Med Sc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Cornea Serv,Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Hamrah, P (reprint author), Harvard Univ, Ocular Surface Imaging Ctr, Massachusetts Eye & Ear Infirm, Cornea & Refract Surg Serv,Dept Ophthalmol,Med Sc, 243 Charles St, Boston, MA 02114 USA. EM pedram_hamrah@meei.harvard.edu OI Cruzat, Andrea/0000-0002-3724-7037 FU NEI NIH HHS [K08 EY020575-01, K08 EY020575] NR 61 TC 17 Z9 17 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 178 EP 185 DI 10.3109/08820538.2010.518542 PG 8 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600004 PM 21090997 ER PT J AU Seyedahmadi, BJ Vavvas, D AF Seyedahmadi, Babak Jian Vavvas, Demetrios TI In Vivo High-Resolution Retinal Imaging Using Adaptive Optics SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE adaptive optics; retinal imaging ID SCANNING LASER OPHTHALMOSCOPY; HUMAN EYE AB Retinal imaging with conventional methods is only able to overcome the lowest order of aberration, defocus and astigmatism. The human eye is fraught with higher order of aberrations. Since we are forced to use the human optical system in retinal imaging, the images are degraded. In addition, all of these distortions are constantly changing due to head/eye movement and change in accommodation. Adaptive optics is a promising technology introduced in the field of ophthalmology to measure and compensate for these aberrations. High-resolution obtained by adaptive optics enables us to view and image the retinal photoreceptors, retina pigment epithelium, and identification of cone subclasses in vivo. In this review we will be discussing the basic technology of adaptive optics and hardware requirement in addition to clinical applications of such technology. C1 [Seyedahmadi, Babak Jian; Vavvas, Demetrios] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, Boston, MA 02114 USA. RP Seyedahmadi, BJ (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM Babak_Jian-Seyedahmadi@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 NR 26 TC 2 Z9 2 U1 1 U2 6 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 186 EP 191 DI 10.3109/08820538.2010.518483 PG 6 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600005 PM 21090998 ER PT J AU Al-Latayfeh, MM Sun, JK Aiello, LP AF Al-Latayfeh, M. M. Sun, J. K. Aiello, Lloyd P. TI Ocular Coherence Tomography and Diabetic Eye Disease SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE macular edema; diabetic retinopathy; retinal thickness; optical coherence tomography (OCT) ID MACULAR EDEMA; RETINAL THICKNESS; VISUAL-ACUITY; TIME-DOMAIN; RETINOPATHY; OCT; REPRODUCIBILITY; ANGIOGRAPHY; DIAGNOSIS; PATTERNS AB Optical Coherence Tomography (OCT) is a high-resolution, cross-sectional imaging technique that allows detailed assessment of retinal thickness and morphologic evaluation of the neurosensory retinal layers. OCT imaging has rapidly been integrated into diagnosis and management of diabetic macular edema (DME) in routine clinical practice and clinical trials. OCT findings correlate well with other evaluation techniques for DME. Although there is a moderate correlation between OCT measured retinal thickness and visual acuity, OCT cannot replace visual acuity because there is a high degree of variability. Recent improvements in OCT technology have led to widespread interest in the use of spectral domain OCT, which is faster and has higher resolution than time domain OCT. Future research in OCT imaging will likely result in improvements in image quality. The ability to combine OCT with other various diagnostic modalities will further improve the evaluation of DME in both clinical practice and trials. C1 [Al-Latayfeh, M. M.; Sun, J. K.; Aiello, Lloyd P.] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. RP Aiello, LP (reprint author), Joslin Diabet Ctr, Beetham Eye Inst, 1 Joslin Pl, Boston, MA 02215 USA. EM LloydPaul.Aiello@Joslin.Harvard.edu NR 32 TC 7 Z9 8 U1 0 U2 1 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 192 EP 197 DI 10.3109/08820538.2010.518107 PG 6 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600006 PM 21090999 ER PT J AU Heidary, G Rizzo, JF AF Heidary, Gena Rizzo, Joseph F., III TI Use of Optical Coherence Tomography to Evaluate Papilledema and Pseudopapilledema SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE idiopathic intracranial hypertension; pseudotumor cerebri; papilledema; optical coherence tomography ID NERVE-FIBER LAYER; IDIOPATHIC INTRACRANIAL HYPERTENSION; PSEUDOTUMOR CEREBRI; VISUAL-FIELD; MILD PAPILLEDEMA; STRATUS OCT; HEAD DRUSEN; AXONAL LOSS; DISC EDEMA; FOLLOW-UP AB Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, describes a condition of elevated intracranial pressure (ICP) that typically presents in obese women of childbearing age with symptoms and signs of posture-dependent headaches, pulsatile tinnitus, visual changes, and papilledema. Optical coherence tomography (OCT) has begun to be utilized as an adjunctive, quantitative tool in the evaluation of patients with IIH to help distinguish between true optic nerve head edema and pseudopapilledema, and to contribute to our understanding of the consequences of prolonged optic nerve edema. Although few longitudinal studies of patients with IIH have been published to date, it appears that there may be a correlation between retinal nerve fiber layer (RNFL) thickness and visual function. With the new spectral domain OCT, additional parameters of the optic nerve imaging, including volume and height measurements, might provide greater sensitivity of the response to treatment and the long-term visual outcome in patients with IIH. C1 [Heidary, Gena; Rizzo, Joseph F., III] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Neuroophthalmol Serv, Boston, MA 02114 USA. RP Heidary, G (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Neuroophthalmol Serv, 243 Charles St, Boston, MA 02114 USA. EM Gena_Heidary@childrens.harvard.edu OI Heidary, Gena/0000-0002-3557-0420 NR 47 TC 23 Z9 23 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 198 EP 205 DI 10.3109/08820538.2010.518462 PG 8 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600007 PM 21091000 ER PT J AU Choudhry, N Giani, A Miller, JW AF Choudhry, Netan Giani, Andrea Miller, Joan W. TI Fundus Autofluorescence in Geographic Atrophy: A Review SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE age-related macular degeneration; fundus autoflourescence; geographic atrophy; lipofuscin ID RETINAL-PIGMENT EPITHELIUM; AGE-RELATED MACULOPATHY; HUMAN RPE CELLS; MACULAR DEGENERATION; JUNCTIONAL ZONE; NATURAL-HISTORY; VISUAL-LOSS; LIPOFUSCIN; LASER; PROGRESSION AB Fundus autofluorescence is a noninvasive imaging technology that provides information on the distribution of lipofuscin within the retinal pigment epithelial cell monolayer. Progressive accumulation of lipofuscin within retinal pigment epithelial cells is involved in the pathogenesis of geographic atrophy in age-related macular degeneration. This review contains an introduction to fundus autofluorescence, review of currently available imaging methods, and discussion of the role of autofluorescence imaging in geographic atrophy progression. The recent classification of geographic atrophy phenotypes by the Fundus Autofluorescence in Age-related Macular Degeneration Study (FAM) and the association of phenotype and atrophy progression are also summarized. C1 [Choudhry, Netan; Giani, Andrea; Miller, Joan W.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02141 USA. RP Choudhry, N (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, 12th Floor,243 Charles St, Boston, MA 02141 USA. EM netan.choudhry@gmail.com NR 38 TC 12 Z9 13 U1 0 U2 1 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 206 EP 213 DI 10.3109/08820538.2010.518121 PG 8 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600008 PM 21091001 ER PT J AU Sanchez, CR Silva, PS Cavallerano, JD Aiello, LP Aiello, LM AF Sanchez, Cecilia R. Silva, Paolo S. Cavallerano, Jerry D. Aiello, Lloyd P. Aiello, Lloyd M. TI Ocular Telemedicine for Diabetic Retinopathy and the Joslin Vision Network SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE diabetes; diabetic retinopathy; teleophthalmology; telemedicine; retinal imaging ID OPHTHALMIC EXAMINATION; UNITED-STATES; EYE CARE; PROGRAM; PREVALENCE; DIAGNOSIS; MELLITUS; ADULTS; MODEL; RISK AB Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. The Joslin Vision Network Diabetes Eye Care Program (JVN) is a validated ocular telemedicine program developed at the Joslin Diabetes Center that has provided diabetes eye care to over 70,000 persons. The JVN allows accurate assessment of level of DR severity, detects the presence of nondiabetic eye disease, and allows determination of appropriate treatment recommendations. The JVN integrates eye care in a comprehensive diabetes program, extends access to evidence-based diabetes eye care, and offers alternative means of diabetes eye care in appropriate settings, ultimately preserving vision and preventing visual loss. C1 [Sanchez, Cecilia R.; Silva, Paolo S.; Cavallerano, Jerry D.; Aiello, Lloyd P.; Aiello, Lloyd M.] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. RP Aiello, LM (reprint author), Joslin Diabet Ctr, Beetham Eye Inst, 1 Joslin Pl, Boston, MA 02215 USA. EM LMAiello@joslin.harvard.edu NR 25 TC 9 Z9 9 U1 0 U2 0 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 218 EP 224 DI 10.3109/08820538.2010.518893 PG 7 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600010 PM 21091003 ER PT J AU He, M Cestari, D Cunnane, MB Rizzo, JF AF He, Ming Cestari, Dean Cunnane, Mary Beth Rizzo, Joseph F., III TI The Use of Diffusion MRI in Ischemic Optic Neuropathy and Optic Neuritis SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE MRI; diffusion MRI; optic neuritis; ischemic optic neuritis ID MULTIPLE-SCLEROSIS; WHITE-MATTER; FIBER TRACKING; SPINAL-CORD; NERVE; BRAIN; PATHOGENESIS; LESIONS; RISK; CORTICOSTEROIDS AB Ischemic optic neuropathy and optic neuritis are the most common causes of unilateral non-glaucomatous visual loss. While they have distinctive clinical features, they also share some overlapping profiles that make it difficult to clinically distinguish these two entities. MRI with gadolinium has been proven to be helpful to confirm the diagnosis of optic neuritis, but ischemic optic neuropathy remains a clinical diagnosis. Diffusion MRI, a newly advanced technique, has been used in studying the pathophysiology of optic neuritis, but its use in ischemic optic neuropathy is limited. Diffuse MRI may potentially be of help to diagnose ischemic optic neuropathy. C1 [Rizzo, Joseph F., III] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Neuroophthalmol Serv, Boston, MA 02114 USA. RP Rizzo, JF (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Neuroophthalmol Serv, 243 Charles St, Boston, MA 02114 USA. EM Joseph_Rizzo@meei.harvard.edu NR 71 TC 9 Z9 9 U1 0 U2 0 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 225 EP 232 DI 10.3109/08820538.2010.518450 PG 8 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600011 PM 21091004 ER PT J AU Tanhehco, T Jacobs, DS AF Tanhehco, Tasha Jacobs, Deborah S. TI Technological Advances Shaping Scleral Lenses: The Boston Ocular Surface Prosthesis in Patients with Glaucoma Tubes and Trabeculectomies SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE scleral lens ID CONTACT-LENS; PENETRATING KERATOPLASTY; GRAFT FAILURE; MANAGEMENT; DISEASE AB The Boston Ocular Surface Prosthesis (BOS-P) (Boston Foundation for Sight, Needham, MA) is a fluid-ventilated rigid gas-permeable scleral lens that is utilized for the treatment of irregular corneal astigmatism and severe ocular surface disease. Recent reports have highlighted the utility of the BOS-P as a therapeutic device in cases of persistent epithelial defects, corneal neovascularization, ocular graft versus host disease, and exposure keratopathy. Patients with significant cornea disease might also have glaucoma, and those who have undergone glaucoma surgery, which typically disrupts the limbus, present a challenge when fitting the BOS-P. This report describes five patients with a history of both corneal disease and glaucoma surgery who were successfully fitted with the BOS-P. C1 [Tanhehco, Tasha; Jacobs, Deborah S.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Jacobs, DS (reprint author), Boston Fdn Sight, Hillside Ave,Suite 205, Needham, MA 02494 USA. EM djacobs@bostonsight.org NR 20 TC 3 Z9 3 U1 0 U2 0 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 233 EP 238 DI 10.3109/08820538.2010.518873 PG 6 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600012 PM 21091005 ER PT J AU Traish, AS Chodosh, J AF Traish, Aisha S. Chodosh, James TI Expanding Application of the Boston Type I Keratoprosthesis Due to Advances in Design and Improved Post-operative Therapeutic Strategies SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE Boston keratoprosthesis; corneal blindness; corneal transplantation; keratoprosthesis ID ENDOPHTHALMITIS; MULTICENTER; PREVENTION; INFECTION; ANIRIDIA; GRAFTS AB Purpose: To evaluate how the advances in design of the Boston type I keratoprosthesis and in the treatment strategies to conquer the post operative complications have expanded the indications and application of this technology. Methods: A review and analysis of the keratoprosthesis literature specifically examining design modifications, treatment of post operative complications, and patient selection was performed. Results: Over the past two decades, many modifications to the design of the Boston type I keratoprosthesis and treatment of the patient in the post operative period have occurred. Also, the technology has been more widely accepted as a primary surgical option for patients with a poor preoperative prognosis for traditional penetrating keratoplasty. The outcomes of visual acuity, retention, and post-operative infection rates have all significantly improved since the technology has been modified and offers patients an alternative for visual rehabilitation. Conclusions: Thanks to advances in design and perioperative care, the boston type i keratoprosthesis can now be considered a viable option for surgical visual rehabilitation in many patients with corneal pathology, and in certain groups the primary surgical procedure of choice. C1 [Traish, Aisha S.; Chodosh, James] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02214 USA. RP Chodosh, J (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02214 USA. EM James_Chodosh@meei.harvard.edu NR 26 TC 26 Z9 26 U1 0 U2 2 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 239 EP 243 DI 10.3109/08820538.2010.518895 PG 5 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600013 PM 21091006 ER PT J AU Keating, A Pineda, R Colby, K AF Keating, Anne Pineda, Roberto, II Colby, Kathryn TI Corneal Cross Linking for Keratoconus SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE collagen cross-linking; keratoconus; riboflavin; ultraviolet light ID ULTRAVIOLET-A LIGHT; PROGRESSIVE KERATOCONUS; OCULAR RIGIDITY; COLLAGEN; RIBOFLAVIN AB Riboflavin-induced ultraviolet light (UV) cross linking has received a significant amount of attention in recent years. It is currently approved in Europe as a treatment for keratoconus and is also being used for other corneal disorders. The goal of this paper is to review in detail seminal papers and studies that have been done to support cross linking as a safe and effective treatment for patients with early stages of keratoconus. C1 [Keating, Anne; Pineda, Roberto, II; Colby, Kathryn] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Keating, A (reprint author), Massachusetts Eye & Ear Infirm, Cornea Dept, 243 Charles St, Boston, MA 02114 USA. EM keat0026@gmail.com NR 25 TC 13 Z9 13 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 249 EP 255 DI 10.3109/08820538.2010.518503 PG 7 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600015 PM 21091008 ER PT J AU Kullman, G Pineda, R AF Kullman, Ginny Pineda, Roberto, II TI Alternative Applications of the Femtosecond Laser in Ophthalmology SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE femtosecond laser-assisted anterior lamellar keratoplasty (FALK); FS laser-assisted keratoplasty (FLAK); FS laser-assisted posterior lamellar keratoplasty; femtosecond lenticule extraction (FLEx); INTACS; IntraLase-enabled keratoplasty (IEK) ID PENETRATING KERATOPLASTY; LAMELLAR KERATOPLASTY; CORNEAL BIOPSY; OUTCOMES; KERATOCONUS; PRESBYOPIA; EFFICACY; CREATION; SURGERY; PULSES AB Purpose: To provide an update of novel applications for the femtosecond (FS) laser in ophthalmology. Design: Perspective, literature review, case report, and commentary. Methods: Literature review. Results: The many advantages of etching flaps with the FS laser for laser in situ keratomileusis (LASIK) have been well established. Alternative applications of the FS have been approved and are now used in clinical practice. In refractive ophthalmology, the FS laser can be used for lenticule extraction to correct myopia and intrastromal biochemical manipulation to correct presbyopia. This laser can be used for preparing host and donor tissue for both full thickness and lamellar keratoplasty. Research is underway, exploring ways to employ the FS laser for different stages of cataract surgery. Cosmetic procedures with FS-assisted tattooing serve to correct leukoria. Conclusions: Advancements in technology have allowed measurable improvements in the surgical safety, efficiency, speed, and versatility of FS lasers in ophthalmology. C1 [Kullman, Ginny; Pineda, Roberto, II] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP Kullman, G (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM ginny_kullman@meei.harvard.edu NR 25 TC 18 Z9 20 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 256 EP 264 DI 10.3109/08820538.2010.518507 PG 9 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600016 PM 21091009 ER PT J AU Patel, S Pasquale, LR AF Patel, Shuchi Pasquale, Louis R. TI Glaucoma Drainage Devices: A Review of the Past, Present, and Future SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE Ahmed; Baerveldt; Krupin; Molteno ID RANDOMIZED CLINICAL-TRIAL; ADJUNCTIVE MITOMYCIN-C; DOUBLE-PLATE MOLTENO; AHMED GLAUCOMA; BAERVELDT IMPLANT; DIFFERENT BIOMATERIALS; COMPLICATED GLAUCOMAS; VALVE IMPLANTATION; TERM OUTCOMES; EXPERIENCE AB Glaucoma drainage devices are more frequently being used for glaucoma filtering surgeries, even those at low risk for failure with trabeculectomy. There are 4 major devices available: the Molteno, Baerveldt, Krupin, and Ahmed. The Molteno and Baerveldt are non-valved implants, while the Krupin and Ahmed are valved. The success rates of the different valves are about equal at approximately 70% with a mean intraocular pressure (IOP) lowering of at least 50% from the pre-operative IOP. Unfortunately, the failure rate is about 10% per year, leading to only 50% functional drainage devices at 5 years. Therefore, research on the biomaterials, shape, and technique of drainage implant surgery is being done in hopes of increasing long term success rates. C1 [Patel, Shuchi; Pasquale, Louis R.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Glaucoma Serv, Cambridge, MA 02138 USA. RP Patel, S (reprint author), Massachusetts Eye & Ear Infirm, Dept Glaucoma, Boston, MA 02114 USA. EM shuchibpatel@gmail.com NR 34 TC 24 Z9 29 U1 0 U2 6 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 265 EP 270 DI 10.3109/08820538.2010.518840 PG 6 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600017 PM 21091010 ER PT J AU Bahrani, HM Fazelat, AA Thomas, M Hirose, T Kroll, AJ Lou, PL Ryan, EA AF Bahrani, Hasan M. Fazelat, Ahad A. Thomas, Mathis Hirose, Tatsuo Kroll, Arnold J. Lou, Peter L. Ryan, Edward A. TI Endophthalmitis in the Era of Small Gauge Transconjunctival Sutureless Vitrectomy-Meta Analysis and Review of Literature SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE 20-gauge; 23-gauge; 25-gauge; pars plana vitrectomy endophthalmitis; transconjunctival sutureless vitrectomy endophthalmitis; small gauge vitrectomy ID PARS-PLANA VITRECTOMY; VITREOUS WICK SYNDROME; 25-GAUGE VITRECTOMY; 20-GAUGE VITRECTOMY; VITREORETINAL SURGERY; CATARACT-SURGERY; AFFER 25-GAUGE; WOUND CLOSURE; OUTCOMES; INCISION AB Purpose: The goal of this study was to review, evaluate, and perform a meta-analysis on the current literature that reports rates of postoperative endophthalmitis after small gauge transconjunctival sutureless vitrectomy (TSV) and compare it to 20-gauge pars plana vitrectomy (20G PPV). Methods: We performed an extensive review of the current literature. We included only large comparative institutional reviews. Meta-analysis of these reviews was performed. Results: We found six large retrospective comparative cases series on the 25-gauge (25G) TSV as compared to 20G PPV. The test for homogeneity for the meta-analysis indicates that the studies are not homogeneous and therefore the evidence is tentative. Conclusion: We cannot conclude that 25G TSV has a higher rate of postoperative endophthalmitis compared to the 20G PPV. Future retrospective or prospective trials need to take into consideration multiple factors. C1 [Bahrani, Hasan M.; Fazelat, Ahad A.; Hirose, Tatsuo; Kroll, Arnold J.; Lou, Peter L.; Ryan, Edward A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Thomas, Mathis] Harvard Univ, Program Quantitat Sci Med, Sch Publ Hlth, Dept Biostat, Boston, MA 02114 USA. RP Bahrani, HM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. EM hmbahrani@yahoo.com NR 45 TC 11 Z9 18 U1 0 U2 1 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 275 EP 282 DI 10.3109/08820538.2010.518109 PG 8 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600019 PM 21091012 ER PT J AU Lobo, AM Sobrin, L Papaliodis, GN AF Lobo, Ann-Marie Sobrin, Lucia Papaliodis, George N. TI Drug Delivery Options for the Treatment of Ocular Inflammation SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE corticosteroids; implant; intravitreal; macular edema; uveitis ID INTRAVITREAL TRIAMCINOLONE ACETONIDE; UVEITIC MACULAR EDEMA; NONINFECTIOUS POSTERIOR UVEITIS; CYTOMEGALOVIRUS RETINITIS; GANCICLOVIR IMPLANT; STERILE ENDOPHTHALMITIS; SYMPATHETIC OPHTHALMIA; INTRAOCULAR-PRESSURE; FOLLOW-UP; BEVACIZUMAB AB Treatments available for ocular inflammatory diseases and their associated complications have expanded significantly over the course of the last ten years. While corticosteroids are a mainstay of therapy for uveitis and macular edema, the methods of delivering corticosteroids have evolved. Intravitreal triamcinolone acetonide provides a local therapy for persistent cystoid macular edema (CME) and posterior uveitis. Other intravitreal therapies, such as bevacizumab and methotrexate, have also been used successfully in uveitic CME. Sustained release intravitreal implants, including the fluocinolone acetonide implant and the dexamethasone drug delivery system, offer an alternative therapy for chronic, recalcitrant posterior uveitis and CME. Their design was inspired by the ganciclovir implant, which prevented the progression of CMV retinitis in AIDS patients. Technological advances in drug delivery have supplied new treatments for patients with ocular inflammatory disease. C1 [Lobo, Ann-Marie] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Ocular Immunol Uveitis Serv, Boston, MA 02114 USA. RP Lobo, AM (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Ocular Immunol Uveitis Serv, Boston, MA 02114 USA. EM Ann-Marie_Lobo@meei.harvard.edu NR 37 TC 7 Z9 8 U1 2 U2 6 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 283 EP 288 DI 10.3109/08820538.2010.518522 PG 6 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600020 PM 21091013 ER PT J AU Walia, S Clermont, AC Gao, BB Aiello, LP Feener, EP AF Walia, Saloni Clermont, Allen C. Gao, Ben-Bo Aiello, Lloyd Paul Feener, Edward P. TI Vitreous Proteomics and Diabetic Retinopathy SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE diabetic retinopathy; mass spectrometry; vitreous; proteomics ID ENDOTHELIAL GROWTH-FACTOR; MASS-SPECTROMETRY; MACULAR EDEMA; RETINAL DISORDERS; FLUID; PROTEINS; BIOINFORMATICS; PATHOGENESIS AB Diabetic retinopathy is the major cause of acquired blindness in working-age adults. Studies of the vitreous proteome have provided insights into the etiology of diabetic retinopathy and suggested potential molecular targets for treatments. Further characterization of the protein changes associated with the progression of this disease may suggest additional therapeutic approaches as well as reveal novel factors that may be useful in predicting risk and functional outcomes of interventional therapies. This article provides an overview of the various techniques used for proteomic analysis of the vitreous and details results from various studies evaluating vitreous of diabetic patients using the proteomic approach. C1 [Walia, Saloni; Clermont, Allen C.; Gao, Ben-Bo; Aiello, Lloyd Paul; Feener, Edward P.] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Feener, EP (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM edward.feener@joslin.harvard.edu FU US National Institutes of Health [EY019029, DK 36836]; Massachusetts Lions Eye Research Fund FX This work was supported in part by the US National Institutes of Health (grants EY019029, DK 36836), and the Massachusetts Lions Eye Research Fund. NR 34 TC 12 Z9 13 U1 0 U2 0 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 289 EP 294 DI 10.3109/08820538.2010.518912 PG 6 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600021 PM 21091014 ER PT J AU Rheaume, MA Vavvas, D AF Rheaume, Marc-Andre Vavvas, Demetrios TI Pharmacologic Vitreolysis SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE pharmacology; vitreodynamics; vitreous ID POSTERIOR VITREOUS DETACHMENT; TISSUE-PLASMINOGEN ACTIVATOR; ENZYME-ASSISTED VITRECTOMY; ENDOGENOUS MATRIX METALLOPROTEINASE-2; PROLIFERATIVE DIABETIC-RETINOPATHY; OVINE HYALURONIDASE VITRASE(R); RETINAL VEIN OCCLUSION; INTRAVITREAL INJECTION; SUBTILISIN NAT; VITREORETINAL INTERFACE AB It is now well recognized that vitreous plays an important role in the pathogenesis of various retinal disorders. In many instances it can be addressed with pars plana vitrectomy, although this approach, like any surgery, has its limitations. The search for alternatives or adjunct to surgery has led to the development of pharmacologic vitreolysis. The use of intravitreal agents to alter the vitreous in order to reduce or eliminate its role in disease seems promising. The purpose of this article is to summarize the present knowledge on pharmacologic vitreolysis. A review of the different agents used and of ongoing trials will be presented. Also, current understanding of vitreous structure and its interaction with the retina will be discussed. C1 [Rheaume, Marc-Andre; Vavvas, Demetrios] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Retina Serv,Med Sch, Boston, MA 02114 USA. RP Rheaume, MA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Retina Serv,Med Sch, 243 Charles St, Boston, MA 02114 USA. EM marcandre80@hotmail.com OI Vavvas, Demetrios/0000-0002-8622-6478 NR 82 TC 12 Z9 13 U1 1 U2 9 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 295 EP 302 DI 10.3109/08820538.2010.518865 PG 8 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600022 PM 21091015 ER PT J AU Zhang, L Fay, A AF Zhang, Li Fay, Aaron TI Composite Implants in Oculoplastic Surgery SO SEMINARS IN OPHTHALMOLOGY LA English DT Article DE composite implant; hydrogel; polyethylene; polyglactin; silicone; titanium; Tarsys; Alphasphere; microphthalmos ID TISSUE EXPANSION; ORBITAL IMPLANT; CONJUNCTIVODACRYOCYSTORHINOSTOMY; ANOPHTHALMOS; TITANIUM; RABBITS; MEDPOR; DEFECT; TUBE AB Composite devices containing two or more different material components or phases are seen with increasing frequency in oculoplastic, orbital, and lacrimal surgery. These combinations aim to improve mechanical and biological properties such as expansion, malleability, and strength in ways that have not been achieved with solitary material designs. Herein we review a variety of these new generation implants, including distensible orbital tissue expanders, hydrophilic osmotic expanders, titanium and polyethylene rigid fixation devices, non-expandable hydrogels, laminated porcine intestine, and polyethylene-coated glass that likely herald a trend to more complex implantable devices in the future. C1 [Fay, Aaron] Massachusetts Eye & Ear Infirm, Ophthalm Plast & Reconstruct Surg Div, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Fay, A (reprint author), Massachusetts Eye & Ear Infirm, Ophthalm Plast & Reconstruct Surg Div, 243 Charles St, Boston, MA 02114 USA. EM aaron_fay@meei.harvard.edu NR 23 TC 1 Z9 1 U1 0 U2 0 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0882-0538 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 303 EP 308 DI 10.3109/08820538.2010.518919 PG 6 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600023 PM 21091016 ER PT J AU Turalba, AV Grosskreutz, C AF Turalba, Angela V. Grosskreutz, Cynthia TI A Review of Current Technology Used in Evaluating Visual Function in Glaucoma SO SEMINARS IN OPHTHALMOLOGY LA English DT Review DE perimetry; visual field; functional testing; glaucoma progression ID WAVELENGTH AUTOMATED PERIMETRY; FREQUENCY-DOUBLING-TECHNOLOGY; PASS RESOLUTION PERIMETRY; HUMPHREY FIELD ANALYZER; NORMAL-TENSION GLAUCOMA; OPEN-ANGLE GLAUCOMA; OCULAR HYPERTENSION; FULL-THRESHOLD; PATTERN ELECTRORETINOGRAM; STANDARD AB Glaucoma is a blinding disease associated with characteristic progressive optic nerve damage and visual field loss. Visual field testing in the form of automated perimetry is critical in the clinical diagnosis and monitoring of glaucoma. Functional tests can also be powerful research tools in clinical trials and in the field of neuroprotection. Standard automated perimetry (SAP) commonly used today, however, has its limitations. Early diagnosis of glaucoma based on functional measures can be challenging since it has been shown that retinal ganglion cell loss precedes defects detected on SAP. In addition, SAP is a subjective test prone to inter-test variability making the evaluation of disease progression problematic. Newer algorithms and functional tests are now being used and developed in an attempt to improve the accuracy in the detection of glaucoma and disease progression. C1 [Turalba, Angela V.; Grosskreutz, Cynthia] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP Turalba, AV (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charlest St, Boston, MA 02114 USA. EM Angela_Turalba@meei.harvard.edu NR 75 TC 10 Z9 10 U1 1 U2 12 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 0882-0538 EI 1744-5205 J9 SEMIN OPHTHALMOL JI Semin. Ophthalmol. PD SEP-NOV PY 2010 VL 25 IS 5-6 SI SI BP 309 EP 316 DI 10.3109/08820538.2010.518898 PG 8 WC Ophthalmology SC Ophthalmology GA 802HJ UT WOS:000293499600024 PM 21091017 ER PT J AU Joffe, H Massler, A Sharkey, KM AF Joffe, Hadine Massler, Anda Sharkey, Katherine M. TI Evaluation and Management of Sleep Disturbance during the Menopause Transition SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE Sleep; insomnia; menopause; apnea; PLMD; hot flash ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; ESTROGEN REPLACEMENT THERAPY; RESTLESS LEGS SYNDROME; COGNITIVE-BEHAVIORAL THERAPY; DATA-ANALYSIS SOFTWARE; MIDDLE-AGED WOMEN; CHRONIC PRIMARY INSOMNIA; CORE BODY-TEMPERATURE; SELF-REPORTED SLEEP AB Sleep disturbances in midlife women are common and have been associated with the menopause transition itself, symptoms of hot flashes, anxiety and depressive disorders, aging, primary sleep disorders (i.e., obstructive sleep apnea, periodic limb movement disorder), comorbid medical conditions and medications, as well as with psychosocial and behavioral factors. Because there are several common sources of sleep problems in midlife women, the cause of an individual woman's sleep disturbance may be multifactorial. Effective behavioral and pharmacological therapies are available to treat sleep disturbances of different etiologies. This review provides an overview of different types of sleep disturbance occurring in midlife women and presents data supporting the use of hormone therapy, hypnotic agents, and behavioral strategies to treat sleep problems in this population. The review aims to equip clinicians evaluating menopause-age women with the knowledge and evaluation tools to diagnose, engage sleep experts where appropriate, and treat sleep disturbance in this population. Sleep disorders in midlife women should be treated because substantial improvements in quality of life and health outcomes are achievable. C1 [Joffe, Hadine] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Ctr Womens Mental Hlth, Boston, MA 02114 USA. [Massler, Anda] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Sharkey, Katherine M.] Brown Univ, Dept Med, Warren Alpert Med Sch, Providence, RI 02912 USA. [Sharkey, Katherine M.] Brown Univ, Dept Psychiat & Human Behav, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Joffe, H (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Ctr Womens Mental Hlth, 185 Cambridge St,2nd Floor, Boston, MA 02114 USA. EM hjoffe@partners.org FU [1R01MH082922] FX This research was supported in part by 1R01MH082922 (HJ). The authors thank Elizabeth L. Lemon, M.A., and Stephanie Connors, B.A., for their administrative support. NR 146 TC 42 Z9 43 U1 1 U2 3 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD SEP PY 2010 VL 28 IS 5 BP 404 EP 421 DI 10.1055/s-0030-1262900 PG 18 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 645MS UT WOS:000281465000009 PM 20845239 ER PT J AU Hough, S AF Hough, Sigmund TI Sexuality and Disability: Being Mindful of the Moment SO SEXUALITY AND DISABILITY LA English DT Editorial Material C1 VA Boston Healthcare Syst, Spinal Cord Injury Serv SCI 128, W Roxbury, MA 02132 USA. RP Hough, S (reprint author), VA Boston Healthcare Syst, Spinal Cord Injury Serv SCI 128, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM Sigmund_Hough@hms.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0146-1044 J9 SEX DISABIL JI Sex. Disabil. PD SEP PY 2010 VL 28 IS 3 BP 145 EP 145 DI 10.1007/s11195-010-9171-7 PG 1 WC Rehabilitation SC Rehabilitation GA 634QV UT WOS:000280599000001 ER PT J AU DenBoer, JW Hough, S AF DenBoer, John W. Hough, Sigmund TI The Role of Clinical Neuropsychology in the Study of Sexuality and Disability SO SEXUALITY AND DISABILITY LA English DT Article DE Neuropsychology; Sexuality; Assessment; Gender; Sex; Disability ID SEX-DIFFERENCES; HOMOSEXUAL-MEN; CONCUSSION SYMPTOMS; COGNITIVE-ABILITIES; ORIENTATION; PERFORMANCE; GENDER; BRAIN; WOMEN AB Human sexuality is the way people experience themselves and each other as sexual beings. Clinical neuropsychology is an area of psychology that specializes in the diagnostic assessment and treatment of patients with brain injury or neurocognitive deficit. Specific neuropsychological correlates of sexuality have been researched in the past, including sex differences in cognitive abilities and sexual orientation. Although some consistent differences between sex and sexual orientation have been found, the majority of these differences appear to be due to an interaction of biological predisposition and sociological factors. Additionally, neuropathological correlates of sexual disorders have been found and future research into the neuropsychological correlates of sexual offenders (i.e., rapists, child molesters) is warranted. Although neuropsychology has been peripherally involved in research concerning human sexuality, there is a more prominent role for clinical neuropsychologists who are uniquely trained to provide assistance in the diagnosis and treatment of sexual deviance and sexual dysfunction/disability. C1 [DenBoer, John W.] Arizona Neurol Inst, Sun City, AZ USA. [Hough, Sigmund] VA Boston Healthcare Syst, W Roxbury, MA USA. [Hough, Sigmund] Harvard Univ, Sch Med, Boston, MA USA. [Hough, Sigmund] Boston Univ, Sch Med, Boston, MA 02118 USA. RP DenBoer, JW (reprint author), Arizona Neurol Inst, 10474 W Thunderbird Ave, Sun City, AZ USA. EM jwdenboer@yahoo.com NR 59 TC 0 Z9 0 U1 2 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0146-1044 J9 SEX DISABIL JI Sex. Disabil. PD SEP PY 2010 VL 28 IS 3 BP 147 EP 155 DI 10.1007/s11195-010-9163-7 PG 9 WC Rehabilitation SC Rehabilitation GA 634QV UT WOS:000280599000002 ER PT J AU Bougaki, M Searles, RJ Kida, K Yu, JD Buys, ES Ichinose, F AF Bougaki, Masahiko Searles, Robert J. Kida, Kotaro Yu, JiaDe Buys, Emmanuel S. Ichinose, Fumito TI NOS3 PROTECTS AGAINST SYSTEMIC INFLAMMATION AND MYOCARDIAL DYSFUNCTION IN MURINE POLYMICROBIAL SEPSIS SO SHOCK LA English DT Article DE Septic shock; inflammation; cardiomyocyte function; calcium handling; mitochondrial function ID NITRIC-OXIDE SYNTHASE; MITOCHONDRIAL PERMEABILITY TRANSITION; ASCENDENS STENT PERITONITIS; SEPTIC SHOCK; ANIMAL-MODELS; SARCOPLASMIC-RETICULUM; HEART-FAILURE; MICE; MECHANISMS; IMPAIRMENT AB NO has been implicated in the pathogenesis of septic shock. However, the role of NO synthase 3 (NOS3) during sepsis remains incompletely understood. Here, we examined the impact of NOS3 deficiency on systemic inflammation and myocardial dysfunction during peritonitis-induced polymicrobial sepsis. Severe polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) in wild-type (WT) and NOS3-deficient (NOS3KO) mice. NOS3KO mice exhibited shorter survival time than did WT mice after CASP. NOS3 deficiency worsened systemic inflammation assessed by the expression of inflammatory cytokines in the lung, liver, and heart. Colon ascendens stent peritonitis markedly increased the number of leukocyte infiltrating the liver and heart in NOS3KO but not in WT mice. The exaggerated systemic inflammation in septic NOS3KO mice was associated with more marked myocardial dysfunction than in WT mice 22 h after CASP. The detrimental effects of NOS3 deficiency on myocardial function after CASP seem to be caused by impaired Ca(2+) handling of cardiomyocytes. The impaired Ca(2+) handling of cardiomyocytes isolated from NOS3KO mice subjected to CASP was associated with depressed mitochondrial ATP production, a determinant of the Ca(2+) cycling capacity of sarcoplasmic reticulum Ca(2+)-ATPase. The NOS3 deficiency-induced impairment of the ability of mitochondria to produce ATP after CASP was at least in part attributable to reduction in mitochondrial respiratory chain complex I activity. These observations suggest that NOS3 protects against systemic inflammation and myocardial dysfunction after peritonitis-induced polymicrobial sepsis in mice. C1 Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA USA. RP Ichinose, F (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 149 13th St,3405, Charlestown, MA 02129 USA. EM fichinose@partners.org OI Yu, JiaDe/0000-0002-0874-3170 FU National Institutes of Health [HL71987, GM79360] FX This work was supported by the National Institutes of Health grants HL71987 and GM79360 to Dr Ichinose. NR 35 TC 16 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD SEP PY 2010 VL 34 IS 3 BP 281 EP 290 DI 10.1097/SHK.0b013e3181cdc327 PG 10 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 640GU UT WOS:000281038200011 PM 19997049 ER PT J AU Williams, B Woodby, L Drentea, P AF Williams, Beverley Woodby, Lesa Drentea, Patricia TI Ethical capital: 'What's a poor man got to leave?' SO SOCIOLOGY OF HEALTH & ILLNESS LA English DT Article DE dying; socioeconomic status; capital; legacy ID AFRICAN-AMERICAN; OLDER-ADULTS; LEGACY; DEATH; IMPACT; LIFE; PARTICIPATION; AWARENESS; ACCOUNTS; SELF AB For those of little or no means, leaving one's mark through financial assets, social connections, and human investment is difficult. Using secondary analysis of transcripts from face-to-face interviews with 33 terminally-ill patients from an outpatient clinic at a public hospital serving the disadvantaged in the southern United States, we examine the legacy participants wish to leave behind. As part of this process, participants assess life circumstances to try and generate a legacy allowing them to remain personally relevant to loved ones after death. For the low-SES terminally ill persons in this study, the desire to leave a material legacy and the means to do so are not congruous. In the absence of economic resources to bequeath loved ones, participants describe their desire to leave loved ones some form of ethical currency to facilitate interactions with others and protect them against social marginalisation. We call this concept ethical capital. We then argue ethical capital is a way for disadvantaged people to find dignity and to affirm their lives. C1 [Drentea, Patricia] Univ Alabama, Dept Sociol, Birmingham, AL 35294 USA. [Williams, Beverley; Woodby, Lesa] Birmingham VA Med Ctr, Dept Vet Affairs, Birmingham, AL USA. RP Drentea, P (reprint author), Univ Alabama, Dept Sociol, HHB 460,1530 3rd Ave S, Birmingham, AL 35294 USA. EM pdrentea@uab.edu NR 60 TC 3 Z9 3 U1 3 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0141-9889 J9 SOCIOL HEALTH ILL JI Sociol. Health Ill. PD SEP PY 2010 VL 32 IS 6 BP 880 EP 897 DI 10.1111/j.1467-9566.2010.01246.x PG 18 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical; Sociology SC Public, Environmental & Occupational Health; Biomedical Social Sciences; Sociology GA 655EC UT WOS:000282225800004 PM 20633241 ER PT J AU Frisbie, JH AF Frisbie, J. H. TI Physical therapy versus heparin for prevention of deep venous thrombosis SO SPINAL CORD LA English DT Letter C1 Harvard Univ, Sch Med, Res Serv, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Frisbie, JH (reprint author), Harvard Univ, Sch Med, Res Serv, VA Boston Healthcare Syst, Boston, MA 02115 USA. EM jfrisbie@comcast.net NR 3 TC 1 Z9 1 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 J9 SPINAL CORD JI Spinal Cord PD SEP PY 2010 VL 48 IS 9 BP 716 EP 716 DI 10.1038/sc.2010.3 PG 1 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 646XB UT WOS:000281577000012 PM 20125113 ER PT J AU Gaffey, JL Ghanayem, AJ Voronov, ML Havey, RM Carandang, G Abjornson, C Patwardhan, AG AF Gaffey, John L. Ghanayem, Alexander J. Voronov, Michael L. Havey, Robert M. Carandang, Gerard Abjornson, Celeste Patwardhan, Avinash G. TI Effect of Increasing Implant Height on Lumbar Spine Kinematics and Foraminal Size Using the ProDisc-L Prosthesis SO SPINE LA English DT Article DE lumbar spine; TDR; prosthesis height; range of motion; foramen; biomechanics ID TOTAL DISC REPLACEMENT; FOLLOW-UP; II PROSTHESIS; MOTION; OUTCOMES; FUSION; RANGE; ADJACENT; TRIAL AB Study Design. A biomechanical study using human lumbar spines. Objective. To test the hypotheses that with increasing implant height (1) the range of motion (ROM) of the implanted segment will decrease, (2) the segmental lordosis will increase, and (3) the size of the neural foramens will increase. Summary of Background Data. Little is known about the effects of the implant height on the segmental motion and foraminal size at the implanted level. Methods. Seven human lumbar spines (age, 54.4 +/- 11.4 years; L1-sacrum) were tested intact, and after discectomy at L4-L5 and sequential insertion of ProDisc-L implants (Synthes Spine, Paoli, PA) of increasing heights (10, 12, and 14 mm). The specimens were tested in flexion (8 Nm) and extension (+/- 6 Nm) with a 400 N follower preload as well as in lateral bending (+/- 6 Nm) and axial rotation (+/- 5 Nm) without preload. Three-dimensional motions were measured at L4-L5. Foraminal sizes at L4-L5 were measured in the specimen's neutral posture under a 400 N preload for the intact spine and after each implantation using finely graded cylindrical probes. Segmental lordosis was measured in the specimen's neutral posture under a 400 N preload by analyzing digital fluoroscopic images. Effects of implant height on the kinematics, foraminal size, and segmental lordosis were assessed using paired comparisons with Bonferroni correction. Results. Increasing implant height from 10 mm to 14 mm caused a significant decrease (P < 0.05) in segmental ROM by up to 37% +/- 21% in flexion/extension, 33% +/- 18% in lateral bending, and 29% +/- 28% in axial rotation. Increasing implant height also produced a significant increase in segmental lordosis (P < 0.05): from 9.7 degrees +/- 2.9 degrees at 10 mm, to 16.1 degrees +/- 5.1 degrees at 14 mm. The increase in foraminal size, while significant, was only 4.6% +/- 3.2% when comparing 10 mm to 14 mm implants. Conclusion. These results suggest that a smaller implant height should be selected to optimize the ROM of the implanted segment and maintain sagittal balance. C1 [Gaffey, John L.; Ghanayem, Alexander J.; Voronov, Michael L.; Havey, Robert M.; Patwardhan, Avinash G.] Loyola Univ, Med Ctr, Dept Orthopaed Surg & Rehabil, Maywood, IL 60153 USA. [Gaffey, John L.; Ghanayem, Alexander J.; Voronov, Michael L.; Havey, Robert M.; Carandang, Gerard; Patwardhan, Avinash G.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Abjornson, Celeste] Synthes Spine, Paoli, PA USA. RP Patwardhan, AG (reprint author), Loyola Univ, Med Ctr, Dept Orthopaed Surg & Rehabil, 2160 S 1st Ave, Maywood, IL 60153 USA. EM apatwar@lumc.edu FU Department of Veterans Affairs, WA, DC; Synthes Spine, Paoli, PA FX Supported by the Department of Veterans Affairs, WA, DC and Synthes Spine, Paoli, PA. NR 23 TC 10 Z9 10 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD SEP 1 PY 2010 VL 35 IS 19 BP 1777 EP 1782 DI 10.1097/BRS.0b013e3181ebaa4d PG 6 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 647YI UT WOS:000281656400006 PM 20700082 ER PT J AU Atlas, SJ AF Atlas, Steven J. TI Point of View Clinical Outcomes After Posterolateral Lumbar Fusion in Worker's Compensation Patients: A Case-Control Study SO SPINE LA English DT Editorial Material ID LOW-BACK-PAIN; SPONDYLOLISTHESIS; PREDICTORS; SURGERY C1 Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Atlas, SJ (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM satlas@partners.org NR 9 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD SEP 1 PY 2010 VL 35 IS 19 BP 1818 EP 1819 DI 10.1097/BRS.0b013e3181ccc7a6 PG 2 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 647YI UT WOS:000281656400013 ER PT J AU Vezeridis, PS Goel, DP Shah, AA Sung, SY Warner, JJP AF Vezeridis, Peter S. Goel, Danny P. Shah, Anup A. Sung, Seung-Yong Warner, Jon J. P. TI Postarthroscopic Arthrofibrosis of the Shoulder SO SPORTS MEDICINE AND ARTHROSCOPY REVIEW LA English DT Review DE shoulder joint; shoulder surgery; arthroscopy; stiffness; arthrofibrosis; capsular release ID ARTHROSCOPIC CAPSULAR RELEASE; ROTATOR CUFF TEARS; GLENOHUMERAL JOINT; CORACOHUMERAL LIGAMENT; ADHESIVE CAPSULITIS; EXTERNAL ROTATION; STIFF SHOULDER; BANKART REPAIR; ANTERIOR; CAPSULORRHAPHY AB Arthrofibrosis after shoulder surgery may be challenging to treat. Certain factors, including diabetes and history of keloid formation, predispose patients to the development of postoperative arthrofibrosis. Etiologies include rotator cuff repair, labral repair, capsulorrhaphy, shoulder arthroplasty, and proximal humerus fracture fixation. Systematic evaluation with thorough history and physical examination is essential to determine the proper treatment and to counsel patients on expectations for recovery. Nonoperative treatment focused on physical therapy is the first step in management. Manipulation under anesthesia may be an effective treatment for failure of physical therapy regimens in idiopathic adhesive capsulitis, however it is less successful in cases of postsurgical adhesions. In cases of postoperative stiffness, treatment options include arthroscopic and open capsular releases. Adequate postoperative pain control and adherence to a rigorous physical therapy regimen are integral to the success of surgical release. Surgical treatment is effective in the majority of patients with postsurgical arthrofibrosis. C1 [Vezeridis, Peter S.; Goel, Danny P.; Shah, Anup A.; Sung, Seung-Yong; Warner, Jon J. P.] Massachusetts Gen Hosp, Harvard Shoulder Serv, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Warner, JJP (reprint author), Massachusetts Gen Hosp, Harvard Shoulder Serv, Dept Orthopaed Surg, 55 Fruit St,YAW 3-3G, Boston, MA 02114 USA. EM jwarner@partners.org NR 47 TC 12 Z9 12 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-8592 J9 SPORTS MED ARTHROSC JI Sports Med. Arthrosc. Rev. PD SEP PY 2010 VL 18 IS 3 BP 198 EP 206 PG 9 WC Sport Sciences SC Sport Sciences GA 641GB UT WOS:000281111700010 PM 20711052 ER PT J AU Freter, R Osawa, M Nishikawa, SI AF Freter, Rasmus Osawa, Masatake Nishikawa, Shin-Ichi TI Adult Stem Cells Exhibit Global Suppression of RNA Polymerase II Serine-2 Phosphorylation SO STEM CELLS LA English DT Article DE Adult stem cells; Quiescence; mRNA transcription; Cyclin-dependent kinase 9 ID HAIR FOLLICLE BULGE; SELF-RENEWAL; HEAT-SHOCK; P-TEFB; TRANSCRIPTIONAL ELONGATION; GENE-EXPRESSION; SURFACE-MARKER; IN-VITRO; CDK9; KINASE AB Adult stem cells, which are characterized by their capacity for self-renewal and differentiation, participate in tissue homeostasis and response to injury. They are thought to enter a state of relative quiescence, known as reversible cell cycle arrest, but the underlying molecular mechanisms remain poorly characterized. Previous data from our laboratory has shown that housekeeping gene expression is downregulated in melanocyte stem cells (MelSCs), suggesting a global suppression of mRNA transcription. We now show, using antibodies against specific phosphorylated forms of RNA polymerase II (RNApII), that adult MelSCs do not undergo productive mRNA transcription elongation, while RNApII is activated and initialized, ready to synthesize mRNA upon stimulation, and that the RNApII kinase CDK9 is absent in adult MelSCs. Interestingly, other adult stem cells also, including keratinocyte, muscle, spermatogonia, and hematopoietic stem cells, showed a similar absence of RNApII phosphorylation. Although it is difficult to show the functional significance of this observation in vivo, CDK9 inhibition resulted in enhanced survival of cells that are deprived from survival factors. We conclude that the absence of productive mRNA transcription is an early, specific, and conserved characteristic of adult stem cells. Downregulation of mRNA transcription may lead to decreased rates of metabolism, and protection from cellular and genetic damage. Screening heterogeneous tissues, including tumors, for transcriptionally quiescent cells may result in the identification of cells with stem cell-like phenotypes. STEM CELLS 2010; 28: 1571-1580 C1 [Freter, Rasmus; Nishikawa, Shin-Ichi] Univ Oxford, Nuffield Dept Clin Med, Ludwig Inst Canc Res, Oxford OX1 2JD, England. [Osawa, Masatake] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr,Ctr Regenerat Med, Cambridge, MA 02138 USA. RP Freter, R (reprint author), Univ Oxford, Nuffield Dept Clin Med, Ludwig Inst Canc Res, Oxford OX1 2JD, England. EM rasmus.freter@ludwig.ox.ac.uk FU Monbukagakusho scholarship FX We thank Dr. Igor Samokhvalov for support with the generation of knock-in mice, Dr. Yoshiteru Sasaki for R26 IRES-eGFP targeting vector and support with western blotting, Dr. Lars Martin Jakt for helpful discussion, Douglas Sipp for critical reading of the manuscript, and the Laboratory for Animal Resources and Genetic Engineering at the RIKEN CDB for injection of ES cells and maintenance of mice. R.F. is supported by a Monbukagakusho scholarship. NR 57 TC 20 Z9 20 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD SEP PY 2010 VL 28 IS 9 BP 1571 EP 1580 DI 10.1002/stem.476 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 657YG UT WOS:000282454700014 PM 20641035 ER PT J AU Giles, MF Albers, GW Amarenco, P Arsava, MM Asimos, A Ay, H Calvet, D Coutts, S Cucchiara, BL Demchuk, AM Johnston, SC Kelly, PJ Kim, AS Labreuche, J Lavallee, PC Mas, JL Merwick, A Olivot, JM Purroy, F Rosamond, WD Sciolla, R Rothwell, PM AF Giles, Matthew F. Albers, Greg W. Amarenco, Pierre Arsava, Murat M. Asimos, Andrew Ay, Hakan Calvet, David Coutts, Shelagh Cucchiara, Brett L. Demchuk, Andrew M. Johnston, S. Claiborne Kelly, Peter J. Kim, Anthony S. Labreuche, Julien Lavallee, Philippa C. Mas, Jean-Louis Merwick, Aine Olivot, Jean Marc Purroy, Francisco Rosamond, Wayne D. Sciolla, Rossella Rothwell, Peter M. TI Addition of Brain Infarction to the ABCD(2) Score (ABCD(2)I) A Collaborative Analysis of Unpublished Data on 4574 Patients SO STROKE LA English DT Article DE ABCD(2) score; ABCD(2)I score; infarction; prediction; risk; TIA ID TRANSIENT ISCHEMIC ATTACK; EARLY STROKE RISK; TIA PATIENTS; METAANALYSIS; VALIDATION; PREDICT; LESIONS AB Background and Purpose-The ABCD system was developed to predict early stroke risk after transient ischemic attack. Incorporation of brain imaging findings has been suggested, but reports have used inconsistent methods and been underpowered. We therefore performed an international, multicenter collaborative study of the prognostic performance of the ABCD(2) score and brain infarction on imaging to determine the optimal weighting of infarction in the score (ABCD(2)I). Methods-Twelve centers provided unpublished data on ABCD(2) scores, presence of brain infarction on either diffusion-weighted imaging or CT, and follow-up in cohorts of patients with transient ischemic attack diagnosed by World Health Organization criteria. Optimal weighting of infarction in the ABCD(2)I score was determined using area under the receiver operating characteristic curve analyses and random effects meta-analysis. Results-Among 4574 patients with TIA, acute infarction was present in 884 (27.6%) of 3206 imaged with diffusion-weighted imaging and new or old infarction was present in 327 (23.9%) of 1368 imaged with CT. ABCD(2) score and presence of infarction on diffusion-weighted imaging or CT were both independently predictive of stroke (n=145) at 7 days (after adjustment for ABCD(2) score, OR for infarction=6.2, 95% CI=4.2 to 9.0, overall; 14.9, 7.4 to 30.2, for diffusion-weighted imaging; 4.2, 2.6 to 6.9, for CT; all P<0.001). Incorporation of infarction in the ABCD(2)I score improved predictive power with an optimal weighting of 3 points for infarction on CT or diffusion-weighted imaging. Pooled areas under the curve increased from 0.66 (0.53 to 0.78) for the ABCD(2) score to 0.78 (0.72 to 0.85) for the ABCD(2)I score. Conclusions-In secondary care, incorporation of brain infarction into the ABCD system (ABCD(2)I score) improves prediction of stroke in the acute phase after transient ischemic attack. (Stroke. 2010; 41:1907-1913.) C1 [Giles, Matthew F.] Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, Stroke Prevent Res Unit,NIHR Biomed Res Ctr, Oxford OX3 9DU, England. [Coutts, Shelagh; Demchuk, Andrew M.] Univ Calgary, Seaman Family Ctr, Dept Clin Neurosci, Calgary, AB, Canada. [Coutts, Shelagh; Demchuk, Andrew M.] Univ Calgary, Seaman Family Ctr, Dept Radiol, Calgary, AB, Canada. [Albers, Greg W.; Olivot, Jean Marc] Stanford Stroke Ctr, Dept Neurol & Neurol Sci, Stanford, CA USA. [Amarenco, Pierre; Labreuche, Julien; Lavallee, Philippa C.] Bichat Claude Bernard Univ Hosp, Dept Neurol, Paris, France. [Amarenco, Pierre; Labreuche, Julien; Lavallee, Philippa C.] Bichat Claude Bernard Univ Hosp, Stroke Ctr, Paris, France. [Purroy, Francisco] Univ Lleida, Dept Neurol, Lleida, Spain. [Calvet, David; Mas, Jean-Louis] Ctr Hosp St Anne, Dept Neurol, Paris, France. [Johnston, S. Claiborne; Kim, Anthony S.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Cucchiara, Brett L.] Univ Penn, Med Ctr, Dept Neurol, Philadelphia, PA 19104 USA. [Arsava, Murat M.; Ay, Hakan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Arsava, Murat M.; Ay, Hakan] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sciolla, Rossella] Univ Turin, Dept Neurol, Turin, Italy. [Kelly, Peter J.; Merwick, Aine] Mater Univ Hosp, Neurovasc Clin Sci Unit, Dublin, Ireland. [Asimos, Andrew] Carolinas Med Ctr, Dept Emergency Med, Charlotte, NC 28203 USA. [Rosamond, Wayne D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. RP Giles, MF (reprint author), Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, Stroke Prevent Res Unit,NIHR Biomed Res Ctr, Level 6,West Wing, Oxford OX3 9DU, England. EM matthew.giles@clneuro.ox.ac.uk RI Purroy, Francisco/D-4538-2009; Arsava, Ethem Murat/I-9197-2013; Merwick, Aine/L-9754-2013; Demchuk, Andrew/E-1103-2012 OI Arsava, Ethem Murat/0000-0002-6527-4139; Merwick, Aine/0000-0001-7533-0117; Demchuk, Andrew/0000-0002-4930-7789 FU National Institute for Health Research, Biomedical Research Centre, Oxford, UK FX M.F.G. receives funding from the National Institute for Health Research, Biomedical Research Centre, Oxford, UK. NR 26 TC 97 Z9 102 U1 5 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2010 VL 41 IS 9 BP 1907 EP 1913 DI 10.1161/STROKEAHA.110.578971 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 645YV UT WOS:000281503000011 PM 20634480 ER PT J AU Smith, EE Nandigam, KRN Chen, YW Jeng, J Salat, D Halpin, A Frosch, M Wendell, L Fazen, L Rosand, J Viswanathan, A Greenberg, SM AF Smith, Eric E. Nandigam, Kaveer R. N. Chen, Yu-Wei Jeng, Jed Salat, David Halpin, Amy Frosch, Matthew Wendell, Lauren Fazen, Louis Rosand, Jonathan Viswanathan, Anand Greenberg, Steven M. TI MRI Markers of Small Vessel Disease in Lobar and Deep Hemispheric Intracerebral Hemorrhage SO STROKE LA English DT Article DE cerebral amyloid angiopathy; intracerebral hemorrhage; leukoaraiosis; MRI; white matter disease ID CEREBRAL AMYLOID ANGIOPATHY; WHITE-MATTER LESIONS; ALZHEIMER-DISEASE; MICROBLEEDS; BRAIN; HYPERINTENSITIES; HYPERTENSION; VALIDATION; COGNITION; DEMENTIA AB Background and Purpose-MRI evidence of small vessel disease is common in intracerebral hemorrhage (ICH). We hypothesized that ICH caused by cerebral amyloid angiopathy (CAA) or hypertensive vasculopathy would have different distributions of MRI T2 white matter hyperintensity (WMH) and microbleeds. Methods-Data were analyzed from 133 consecutive patients with primary supratentorial ICH and adequate MRI sequences. CAA was diagnosed using the Boston criteria. WMH segmentation was performed using a validated semiautomated method. WMH and microbleeds were compared according to site of symptomatic hematoma origin (lobar versus deep) or by pattern of hemorrhages, including both hematomas and microbleeds, on MRI gradient recalled echo sequence (grouped as lobar only-probable CAA, lobar only-possible CAA, deep hemispheric only, or mixed lobar and deep hemorrhages). Results-Patients with lobar and deep hemispheric hematoma had similar median normalized WMH volumes (19.5 cm versus 19.9 cm(3), P=0.74) and prevalence of >= 1 microbleed (54% versus 52%, P=0.99). The supratentorial WMH distribution was similar according to hemorrhage location category; however, the prevalence of brain stem T2 hyperintensity was lower in lobar hematoma versus deep hematoma (54% versus 70%, P=0.004). Mixed ICH was common (23%). Patients with mixed ICH had large normalized WMH volumes and a posterior distribution of cortical hemorrhages similar to that seen in CAA. Conclusions-WMH distribution is largely similar between CAA-related and non-CAA-related ICH. Mixed lobar and deep hemorrhages are seen on MRI gradient recalled echo sequence in up to one fourth of patients; in these patients, both hypertension and CAA may be contributing to the burden of WMH. (Stroke. 2010; 41:1933-1938.) C1 [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Foothills Med Ctr, Calgary Stroke Program, Calgary, AB T2N 2T9, Canada. [Nandigam, Kaveer R. N.; Halpin, Amy; Wendell, Lauren; Fazen, Louis; Rosand, Jonathan; Viswanathan, Anand; Greenberg, Steven M.] Massachusetts Gen Hosp, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. [Frosch, Matthew] Massachusetts Gen Hosp, Dept Neurol, Dept Pathol, Boston, MA 02114 USA. [Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. Natl Taiwan Univ, Taipei, Taiwan. [Jeng, Jed; Salat, David] Martinos Ctr Biomed Imaging, Boston, MA USA. RP Smith, EE (reprint author), Univ Calgary, Dept Clin Neurosci, Foothills Med Ctr, Calgary Stroke Program, Room C1212,1403 29 St NW, Calgary, AB T2N 2T9, Canada. EM eesmith@ucalgary.org RI Smith, Eric/C-5443-2012 OI Smith, Eric/0000-0003-3956-1668 FU National Institute of Neurological Disorders and Stroke [K23NS046327, K24 NS056207]; National Institute on Aging [R01AG026484] FX This study was funded by grants from the National Institute of Neurological Disorders and Stroke (K23NS046327 and K24 NS056207) and the National Institute on Aging (R01AG026484). NR 23 TC 37 Z9 37 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2010 VL 41 IS 9 BP 1933 EP 1938 DI 10.1161/STROKEAHA.110.579078 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 645YV UT WOS:000281503000015 PM 20689084 ER PT J AU Qiu, JH Xu, JA Zheng, Y Wei, Y Zhu, XX Lo, EH Moskowitz, MA Sims, JR AF Qiu, Jianhua Xu, Jian Zheng, Yi Wei, Ying Zhu, Xiaoxia Lo, Eng H. Moskowitz, Michael A. Sims, John R. TI High-Mobility Group Box 1 Promotes Metalloproteinase-9 Upregulation Through Toll-Like Receptor 4 After Cerebral Ischemia SO STROKE LA English DT Article DE cerebral ischemia; matrix metalloproteinase; high-mobility group box 1 ID CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; EXPERIMENTAL STROKE; PROTEIN; CYTOKINE; HMGB1; MATRIX-METALLOPROTEINASE-9; NEUROINFLAMMATION; EXPRESSION; RESPONSES AB Background and Purpose-HMGB1 is a nuclear protein and an alarmin that signals cell damage in response to injury. It is believed that after release from injured cells, HMGB1 binds to its receptors to stimulate cross-talk among cells and to drive components of the inflammatory cascade. This study was intended to investigate the role of extracellular HMGB1 in ischemic stroke by examining the response of the zymogen matrix metalloproteinase-9 (MMP-9) to HMGB1 in vivo and in vitro. Methods-Toll-like receptor 2 (TLR2), TLR4, receptor for advanced glycation endproducts (RAGE), and MMP-9 expression was examined using quantitative RT-PCR in primary cultured neurons, astrocytes, and mouse brain after HMGB1 addition. MMP-9 expression/activity was examined using zymography. Middle cerebral artery occlusion was induced for 60 minutes using a filament model. Results-TLR4 is constitutively expressed in neurons, astrocytes, and mouse brain. HMGB1 addition to neuronal and glial cell cultures caused MMP-9 upregulation in a dose-and time-dependent manner. Lack of TLR4 function attenuated MMP-9 expression induced by HMGB1 in vitro. After striatal microinjection of HMGB1, MMP-9 was upregulated, and the response was independent of tumor necrosis factor-alpha. Interestingly, MMP-9 upregulation was reduced in TLR4 missense mutant mice after ischemia compared with wild-type controls, as was infarct volume. Conclusion-Our results suggest that HMGB1 triggers MMP-9 upregulation in neurons and astrocytes predominantly via TLR4 after cerebral ischemia. Hence, targeting HMGB1/TLRs signaling pathway may reduce the acute inflammatory response and reduce tissue damage in cerebral ischemia. (Stroke. 2010;41:2077-2082.) C1 [Qiu, Jianhua; Xu, Jian; Zheng, Yi; Wei, Ying; Zhu, Xiaoxia; Moskowitz, Michael A.; Sims, John R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol & Radiol, Charlestown, MA 02129 USA. [Xu, Jian] Huashan Hosp, Dept Neurosurg, Shanghai, Peoples R China. [Zhu, Xiaoxia] Huashan Hosp, Dept Rheumatol, Shanghai, Peoples R China. RP Qiu, JH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol & Radiol, 149 13th St,Room 6405, Charlestown, MA 02129 USA. EM jqiu@partners.org FU National Institutes of Health [R21NS056214, 5R01NS010828-33, R01NS48422, R01NS56458, R37NS37074, K08 NS049241]; Massachusetts General Hospital Neuroscience Center Core Facility [NIH P30-NS045776]; American Heart Association [N0335154]; Massachusetts General Hospital FX This work was supported by National Institutes of Health grants R21NS056214 (M.A.M.), 5R01NS010828-33 (M.A.M.), R01NS48422 (E.H.L.), R01NS56458 (E.H.L.), R37NS37074 (E.H.L.), and Massachusetts General Hospital Neuroscience Center Core Facility (NIH P30-NS045776). J.Q. was partly supported by American Heart Association grant N0335154 and Massachusetts General Hospital interim support fund. J.S. was supported by NIH grant K08 NS049241. NR 40 TC 94 Z9 103 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2010 VL 41 IS 9 BP 2077 EP 2082 DI 10.1161/STROKEAHA.110.590463 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 645YV UT WOS:000281503000039 PM 20671243 ER PT J AU Menon, BK Frankel, MR Liang, L LaBresh, KA Ellrodt, G Hernandez, AF Fonarow, GC Schwamm, LH Smith, EE AF Menon, Bijoy K. Frankel, Michael R. Liang, Li LaBresh, Kenneth A. Ellrodt, Gray Hernandez, Adrian F. Fonarow, Gregg C. Schwamm, Lee H. Smith, Eric E. CA Guidelines-Stroke Steering Comm TI Rapid Change in Prescribing Behavior in Hospitals Participating in Get With The Guidelines-Stroke After Release of the Management of Atherothrombosis With Clopidogrel in High-Risk Patients (MATCH) Clinical Trial Results SO STROKE LA English DT Article DE antiplatelet drugs; antithrombotics; health services research; ischemic stroke; quality of care ID TRANSIENT ISCHEMIC ATTACK; ANTIPLATELET THERAPY; ASPIRIN; TRENDS AB Background and Purpose-Physician prescribing patterns change slowly despite published randomized trials and consensus guidelines. We measure the effect of Management of Atherothrombosis With Clopidogrel in High-Risk Patients (MATCH) trial on discharge prescribing patterns for patients with stroke and those with transient ischemic attack in the Get With The Guidelines (GWTG)-Stroke Program. Methods-We analyzed discharge prescribing patterns of antithrombotic medications for patients admitted with ischemic stroke or transient ischemic attack at hospitals participating in GWTG-Stroke between October 2002 to January 2006. Clinical information by quarter was analyzed in relation to publication of the MATCH study. Frequency of discharge prescription of aspirin+clopidogrel post-MATCH publication was compared with the pre-MATCH period after adjusting for patient and hospital characteristics and clustering by hospital. Results-A total of 107 872 patients at 632 sites were eligible to receive antithrombotic therapy at discharge. Use of aspirin+clopidogrel therapy declined from 22.4% to 15.4% of patients after the publication of MATCH (adjusted OR 0.62, 95% CI 0.56 to 0.70, P<0.0001). Analysis by quarter revealed a rapid and sustained decrease in use of aspirin+clopidogrel therapy for the remainder of the study period. Conclusions-A rapid and sustained reduction in the frequency of aspirin+clopidogrel use in ischemic stroke and transient ischemic attack was observed after publication of the MATCH trial in the absence of MATCH-specific GWTG-Stroke initiatives and preceding an American Heart Association guideline update. (Stroke. 2010;41:2094-2097.) C1 [Menon, Bijoy K.; Smith, Eric E.] Univ Calgary, Calgary Stroke Program, Hotchkiss Brain Inst, Foothills Hosp, Calgary, AB T2N 2T9, Canada. [Frankel, Michael R.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Liang, Li; Hernandez, Adrian F.] Duke Clin Res Inst, Durham, NC USA. [LaBresh, Kenneth A.] Res Triangle Inst, Waltham, MA USA. [Ellrodt, Gray] Berkshire Med Ctr, Pittsfield, MA USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Stroke Serv, Boston, MA 02114 USA. RP Menon, BK (reprint author), Univ Calgary, Calgary Stroke Program, Hotchkiss Brain Inst, Foothills Hosp, C1212,1403 29 St NW, Calgary, AB T2N 2T9, Canada. EM bkmmenon@ucalgary.ca RI Smith, Eric/C-5443-2012; LaBresh, Kenneth/A-6995-2017; Hernandez, Adrian F./A-7818-2016 OI Smith, Eric/0000-0003-3956-1668; LaBresh, Kenneth/0000-0001-9040-1956; Schwamm, Lee/0000-0003-0592-9145; Hernandez, Adrian F./0000-0003-3387-9616 FU American Heart Association; American Stroke Association; Pfizer, Inc, New York, NY; Merck-Schering Plough Partnership (North Wales, Pa); National Institutes of Health; Agency for Healthcare Research and Quality; Johnson Johnson; Merck Co FX Get With the Guidelines-Stroke is funded by the American Heart Association and the American Stroke Association. The program is also supported in part by unrestricted educational grants to the American Heart Association by Pfizer, Inc, New York, NY, and the Merck-Schering Plough Partnership (North Wales, Pa), who did not participate in the design, analysis, manuscript preparation, or approval.; L.L. is a member of the Duke Clinical Research Institute, which serves as the American Heart Association (AHA) GWTG data coordinating center. K.A.L. receives research support from the National Institutes of Health (significant) and the Agency for Healthcare Research and Quality (significant). A.F.H. is a member of the Duke Clinical Research Institute, which serves as the AHA GWTG data coordinating center; receives research support from Johnson & Johnson and Merck & Co; serves on the speakers' bureau for Novartis; and receives honoraria from AstraZeneca and Medtronic. G.C.F. receives research support from the National Institutes of Health (significant); served as a consultant to Merck, Bristol Myers Squibb, and Sanofi-Aventis (all modest); received speaker honoraria from Pfizer, Merck, Bristol Myers Squibb, and Sanofi-Aventis (all significant); and is an employee of the University of California, which holds a patent on retriever devices for stroke (significant). L.H.S. serves as a consultant to the Massachusetts NR 9 TC 6 Z9 6 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 SEP PY 2010 VL 41 IS 9 BP 2094 EP 2097 DI 10.1161/STROKEAHA.110.584151 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 645YV UT WOS:000281503000043 PM 20634476 ER PT J AU Regenbogen, SE Bordeianou, L Hutter, MM Gawande, AA AF Regenbogen, Scott E. Bordeianou, Liliana Hutter, Matthew M. Gawande, Atul A. TI The intraoperative Surgical Apgar Score predicts postdischarge complications after colon and rectal resection SO SURGERY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-of-Colon-and-Rectal-Surgeons CY MAY 02-06, 2009 CL Hollywood, FL SP Amer Soc Colon & Rectal Surg ID QUALITY IMPROVEMENT PROGRAM; HOME-BASED INTERVENTION; HOSPITAL READMISSION; MYOCARDIAL-INFARCTION; INTESTINAL SURGERY; NONCARDIAC SURGERY; HEMODYNAMIC PREDICTORS; UNPLANNED READMISSIONS; COLORECTAL SURGERY; MORTALITY AB Background. We previously developed an intraoperative 10-point Surgical Apgar Score-based on blood loss, lowest heart rate, and lowest mean arterial pressure-to predict major complications after colorectal resection. However, because complications often arise after uncomplicated hospitalizations, we sought to evaluate whether this intraoperative metric would predict postdischarge complications after colectomy. Methods. We linked our institution's National Surgical Quality Improvement Program database with an Anesthesia Intraoperative Management System for all colorectal resections over 4 years. Using Chi-square trend tests and logistic regression, we evaluated the Surgical Apgar Score's prediction for major postoperative complications before and after discharge. Results. Among 795 colectomies, there were 230 (29%) major complications within 30 days; 45 (20%) after uncomplicated discharges. Surgical Apgar Scores predicted both inpatient complications and late postdischarge complications (both P < .0001). Late complications occurred from 0 to 27 (median, 11) days after discharge; the most common were surgical site infections (42%), sepsis (24%), and venous thromboembolism (16%). In pair-wise comparisons against average-scoring patients (Surgical Apgar Scores, 7-8), the relative risk of postdischarge complications trended lower, to 0.6 (95% confidence interval [CI], 0.2-1.7) for those with the best scores (9-10); and were significantly higher, at 2.6 (95% CI, 1.4-4.9) for scores 5-6, and 4.5 (95% CI, 1.8-11.0) for scores 0-4. Conclusion. The intraoperative Surgical Apgar Score remained a useful metric for predicting postcolectomy complications arising after uncomplicated discharges. Even late complications may thus be related to intraoperative condition and events. Surgeons could use this intraoperative metric to target low-scoring patients for intensive postdischarge surveillance and mitigation of postdischarge complications after colectomy. (Surgery 2010;148:559-66.) C1 [Regenbogen, Scott E.; Bordeianou, Liliana; Hutter, Matthew M.] 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. [Gawande, Atul A.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Gawande, Atul A.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. RP Regenbogen, SE (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,GRB 425, Boston, MA 02114 USA. EM sregenbogen@partners.org OI Gawande, Atul/0000-0002-1824-9176 FU AHRQ HHS [T32 HS000020, T32-HS000020]; NIDDK NIH HHS [L30 DK075553-01] NR 39 TC 26 Z9 27 U1 0 U2 5 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 SEP PY 2010 VL 148 IS 3 BP 559 EP 566 DI 10.1016/j.surg.2010.01.015 PG 8 WC Surgery SC Surgery GA 645PA UT WOS:000281473800010 PM 20227100 ER PT J AU Regenbogen, SE AF Regenbogen, Scott E. TI Weathering a "perfect storm" in surgical education SO SURGERY LA English DT Editorial Material ID GENERAL-SURGERY; RESIDENCY; WORK C1 [Regenbogen, Scott E.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Regenbogen, SE (reprint author), Lahey Clin Med Ctr, Dept Colon & Rectal Surg, 41 Mall Rd, Burlington, MA 01805 USA. EM scott.e.regenbogen@lahey.org NR 9 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD SEP PY 2010 VL 148 IS 3 BP 602 EP 604 DI 10.1016/j.surg.2010.06.013 PG 3 WC Surgery SC Surgery GA 645PA UT WOS:000281473800017 PM 20719255 ER PT J AU Meltzer, AJ AF Meltzer, Andrew J. TI Surgical residency, class of 2010: The kids are all right SO SURGERY LA English DT Editorial Material ID WORKWEEK C1 [Meltzer, Andrew J.] Massachusetts Gen Hosp, Surg Residency Program 2003 2010, Boston, MA USA. RP Meltzer, AJ (reprint author), New York Presbyterian Hosp, 1330 1st Ave, New York, NY 10021 USA. EM adrewjmeltzer@gmail.com NR 4 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD SEP PY 2010 VL 148 IS 3 BP 605 EP 606 DI 10.1016/j.surg.2010.06.014 PG 2 WC Surgery SC Surgery GA 645PA UT WOS:000281473800018 PM 20719256 ER PT J AU Tarabishy, AB Schulte, M Papaliodis, GN Hoffman, GS AF Tarabishy, Ahmad B. Schulte, Mark Papaliodis, George N. Hoffman, Gary S. TI Wegener's Granulomatosis: Clinical Manifestations, Differential Diagnosis, and Management of Ocular and Systemic Disease SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE Wegener's granulomatosis; vasculitis; ANCA; necrotizing granuloma; sinonasal disease; ocular manifestations of systemic disease ID PERIPHERAL ULCERATIVE KERATITIS; ANCA-ASSOCIATED VASCULITIS; ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; ISCHEMIC OPTIC NEUROPATHY; OF-THE-LITERATURE; NECROTIZING SCLERITIS; CILIARY BODY; IMMUNOSUPPRESSIVE THERAPY; METHOTREXATE-MAINTENANCE; INFLAMMATORY DISEASE AB Wegener's granulomatosis (WG) is a systemic inflammatory, disease whose histopathologic features often include necrosis, granuloma formation, and vasculitis of small-to-medium-sized vessels. WG involves many interrelated pathogenic pathways that are genetic, cell-mediated, neutrophil-mediated, humoral, and environmental. WG most commonly involves the upper respiratory tract, lungs, and kidneys, but has been reported to affect almost any organ. Ophthalmologic involvement is an important cause of morbidity in WC patients, occurring in approximately one-half of patients. The presence of unexplained orbital inflammatory disease, scleritis, peripheral ulcerative keratitis, cicatricial conjunctivitis, nasolacrimal duct stenosis, retinal vascular occlusion, or infrequently uveitis should raise the question of possible WG. A thorough clinical examination, laboratory testing, radiologic imaging, and histologic examination are essential to diagnosing WG and excluding potential mimics. Previously a uniformly fatal disease, treatment with cytotoxic and immunosuppressive agents has greatly improved survival. Treatment-related morbidity is a serious limitation of conventional therapies, leading to numerous ongoing studies of alternative agents. (Surv Ophthalmol 55:429-444, 2010. (C) 2010 Elsevier Inc. All rights reserved.) C1 [Hoffman, Gary S.] Cleveland Clin, Dept Rheumat & Immunol Dis, Cleveland, OH 44106 USA. [Tarabishy, Ahmad B.] Cleveland Clin, Cole Eye Inst, Cleveland, OH 44106 USA. [Schulte, Mark] Case Western Reserve Univ, Div Rheumatol, Cleveland, OH 44106 USA. [Papaliodis, George N.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Hoffman, GS (reprint author), Cleveland Clin, Dept Rheumat & Immunol Dis, 9500 Euclid Ave, Cleveland, OH 44106 USA. EM hoffmag@ccf.org FU Research to Prevent Blindness, New York, NY FX Publication of this article is supported by an unrestricted grant from Research to Prevent Blindness. New York, NY. NR 91 TC 43 Z9 46 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD SEP-OCT PY 2010 VL 55 IS 5 BP 429 EP 444 DI 10.1016/j.survophthal.2009.12.003 PG 16 WC Ophthalmology SC Ophthalmology GA 641AT UT WOS:000281096700002 PM 20638092 ER PT J AU Brastianos, PK Batchelor, TT AF Brastianos, Priscilla K. Batchelor, Tracy T. TI Vascular endothelial growth factor inhibitors in malignant gliomas SO TARGETED ONCOLOGY LA English DT Review DE Angiogenesis; Vascular endothelial growth factor; Malignant glioma; Glioblastoma ID TYROSINE KINASE INHIBITOR; HIGH-GRADE GLIOMAS; ANTI-ANGIOGENIC THERAPY; RENAL-CELL CARCINOMA; BRAIN-TUMOR GROWTH; FACTOR-RECEPTOR; IN-VIVO; GLIOBLASTOMA-MULTIFORME; INTERSTITIAL HYPERTENSION; HEPATOCELLULAR-CARCINOMA AB Glioblastomas are highly vascularized tumors. Treatment strategies targeting angiogenesis have demonstrated promising results in preclinical studies and clinical trials in patients with malignant gliomas. Anti-VEGF agents, either alone or in combination with chemotherapy, have been associated with reduction in vasogenic brain edema, and prolonged progression-free survival. Larger prospective clinical trials are needed to validate these results, and to assess the impact of these agents on overall survival. Unfortunately, antiangiogenic treatment inevitably fails in most patients. Further studies are needed to understand the molecular pathways that enable a tumor to evade antiangiogenic therapy. C1 [Brastianos, Priscilla K.; Batchelor, Tracy T.] Massachusetts Gen Hosp, Dept Neurol, Stephen E & Catherine Pappas Ctr Neurooncol, Div Hematol & Oncol,Canc Ctr, Boston, MA 02114 USA. [Brastianos, Priscilla K.] Dana Farber Brigham & Womens Canc Ctr, Dept Med Oncol, Boston, MA USA. [Batchelor, Tracy T.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Brastianos, PK (reprint author), Massachusetts Gen Hosp, Dept Neurol, Stephen E & Catherine Pappas Ctr Neurooncol, Div Hematol & Oncol,Canc Ctr, Boston, MA 02114 USA. EM pbrastianos@partners.org OI Brastianos, Priscilla/0000-0003-4470-8425 NR 85 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1776-2596 EI 1776-260X J9 TARGET ONCOL JI Target. Oncol. PD SEP PY 2010 VL 5 IS 3 BP 167 EP 174 DI 10.1007/s11523-010-0158-1 PG 8 WC Oncology SC Oncology GA 655EI UT WOS:000282227300003 PM 20821351 ER PT J AU Fenton, MS Marion, KM Salem, AK Hogen, R Naeim, F Hershman, JM AF Fenton, Mike S. Marion, Kenneth M. Salem, Andrew K. Hogen, Rachel Naeim, Faramarz Hershman, Jerome M. TI Sunitinib Inhibits MEK/ERK and SAPK/JNK Pathways and Increases Sodium/Iodide Symporter Expression in Papillary Thyroid Cancer SO THYROID LA English DT Article ID TYROSINE KINASE INHIBITOR; SODIUM-IODIDE SYMPORTER; UPSTREAM ENHANCER; GENE-EXPRESSION; CELL-LINES; CARCINOMA; ACTIVATION; GROWTH; TRANSCRIPTION; RECEPTOR AB Background: Sunitinib malate (Sutent (R), Pfizer, Inc.; SU11248) is a selective, multitargeted inhibitor of receptor tyrosine kinases and has been shown to inhibit receptors for VEGF, PDGF, KIT, FLT3, and RET. The objective of this study was to determine the effects of sunitinib on signal transduction pathways and on gene expression of iodide-metabolizing proteins in papillary cancer cells with the RET/PTC1 rearrangement. Methods: We investigated the effects of sunitinib on cell growth, signal transduction pathways, and thyroid-specific gene expression in papillary thyroid cancer (PTC) cell lines that had the RET/PTC1 rearrangement. Results: Sunitinib inhibited proliferation of RET/PTC1 subclones in a time-and dose-related manner. The mean 50% lethal concentration in the RET/PTC1 subclones was 1.81 mu M. Incubation of RET/PTC1 cells with 1 mu M sunitinib inhibited their migration potential and transformed their morphology. Sunitinib inhibited RET autophosphorylation at Y1062 and the activation of signal transducer and activator of transcription 3 by blocking Y705 phosphorylation. Sunitinib caused cell cycle arrest in the G0/G1 phase and dephosphorylation of retinoblastoma protein, but did not induce apoptosis. Western blot analysis of the p38, MEK/ERK, and SAPK/JNK mitogen-activated protein kinase signal transduction pathways showed that sunitinib blocked ERK 1/2 and JNK phosphorylation in the cytoplasm. Sunitinib treatment of RET/PTC1 cell lines, in combination, with forskolin induced expression of the sodium (Na)/iodide (I) symporter (NIS) and the transcription factors that bind the NIS upstream enhancer. Mechanistically, the inhibition of both MEK/ERK and SAPK/JNK cytoplasmic pathways individually and in combination caused an increase in NIS gene expression. Conclusion: Sunitinib appears to target the cytosolic MEK/ERK and SAPK/JNK pathways in the RET/PTC1 cell lines, suggesting that blocking these pathways is at least part of the mechanism by which sunitinib inhibits cell proliferation and causes stimulation of NIS gene expression in RET/PTC1 cells. C1 Univ Calif Los Angeles, Dept Med, Endocrinol & Diabet Div, Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Hershman, JM (reprint author), VA Med Ctr W Los Angeles, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jhershmn@ucla.edu FU Department of Veterans Affairs; Pfizer, Inc. FX The authors thank Dr. Gregory Brent and Dr. Takahiko Kogai for kindly providing the hNIS and hGAPDH primers and for enlightening discussions and review of the manuscript. The authors thank Dr. Masahiro Sugawara for providing material used in this work. The authors thank Matthew Rettig for helpful discussions. This work was supported by Merit Research Funds from the Department of Veterans Affairs to J.M.H. and a grant from Pfizer, Inc. NR 27 TC 20 Z9 24 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD SEP PY 2010 VL 20 IS 9 BP 965 EP 974 DI 10.1089/thy.2010.0008 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 648BW UT WOS:000281666400006 PM 20629553 ER PT J AU Kao, GS Sturtevant, OJ Hegarty, A Schott, D Ritz, J AF Kao, G. S. Sturtevant, O. J. Hegarty, A. Schott, D. Ritz, J. TI Higher Infusion Reactions in ABO Incompatible Allogeneic Hematopoietic Stem Cell Products with Low ABC volume Is Observed with Improved Reaction Reporting SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Kao, G. S.; Sturtevant, O. J.; Hegarty, A.; Schott, D.; Ritz, J.] Dana Farber Canc Inst, Cell Manipulat Core Facil, Boston, MA 02115 USA. EM grace_kao@dfci.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 218A EP 218A PG 1 WC Hematology SC Hematology GA 649JM UT WOS:000281764900559 ER PT J AU Shaz, B Szczepiorkowski, ZM Crawford, JM Black-Schaffer, WS Winters, JL AF Shaz, B. Szczepiorkowski, Z. M. Crawford, J. M. Black-Schaffer, W. S. Winters, J. L. TI Survey Results Regarding Implementation of the Transfusion Medicine Fellowship Match SO TRANSFUSION LA English DT Meeting Abstract CT AABB Annual Meeting 2010 CY OCT 09-12, 2010 CL Baltimore, MD SP AABB C1 [Shaz, B.] Emory, Dept Pathol & Lab Med, Atlanta, GA USA. [Szczepiorkowski, Z. M.] Dartmouth Hitchcock Med Ctr, Dept Pathol, Lebanon, NH 03766 USA. [Crawford, J. M.] N Shore Long Isl Jewish Hlth Syst, Dept Pathol & Lab Med, Hempstead, NY USA. [Crawford, J. M.] Hofstra Univ, Sch Med, Hempstead, NY 11550 USA. [Black-Schaffer, W. S.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Winters, J. L.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. EM bshaz@emory.edu RI Szczepiorkowski, Zbigniew/A-1359-2007; Winters, Jeffrey/A-2000-2013 OI Szczepiorkowski, Zbigniew/0000-0003-2357-9564; Winters, Jeffrey/0000-0001-8654-3732 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2010 VL 50 SU 2 BP 239A EP 240A PG 2 WC Hematology SC Hematology GA 649JM UT WOS:000281764900610 ER PT J AU Arrieta-Cruz, I Pavlides, C Pasinetti, GM AF Arrieta-Cruz, Isabel Pavlides, Constantine Pasinetti, Giulio Maria TI DEEP BRAIN STIMULATION IN MIDLINE THALAMIC REGION FACILITATES SYNAPTIC TRANSMISSION AND SHORT-TERM MEMORY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE SO TRANSLATIONAL NEUROSCIENCE LA English DT Article DE Alzheimer's disease; Deep brain stimulation; Hippocampus; LTP; Neuronal transmission Synaptic plasticity; Memory; TgCRND8 mice; Thalamus AB Based on evidence suggesting that deep brain stimulation (DBS) may promote certain cognitive processes, we have been interested in developing DBS as a means of mitigating memory and learning impairments in Alzheimer's disease (AD). In this study we used an animal model of AD (TgCRND8 mice) to determine the effects of high-frequency stimulation (HFS) on non-amyloidogenic alpha-secretase activity and DBS in short-term memory. We tested our hypothesis using hippocampal slices (in vitro studies) from TgCRND8 mice to evaluate whether HFS increases a-secretase activity (non-amyloidogenic pathway) in the CA1 region. In a second set of experiments, we performed in vivo studies to evaluate whether DBS in midline thalamic region re-establishes hippocampal dependent short-term memory in TgCRND8 mice. The results showed that application of HFS to isolated hippocampal slices significantly increased synaptic plasticity in the CA1 region and promoted a 2-fold increase of non-amyloidogenic a-secretase activity, in comparison to low frequency stimulated controls from TgCRND8 mice. In the in vivo studies, DBS treatment facilitated acquisition of object recognition memory in TgCRND8 mice, in comparison to their own baseline before treatment. These results provide evidence that DBS could enhance short-term memory in the CA1 region of hippocampus in a mouse model of AD. C1 [Arrieta-Cruz, Isabel; Pasinetti, Giulio Maria] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Pavlides, Constantine] Rockefeller Univ, New York, NY 10065 USA. [Pasinetti, Giulio Maria] James J Peters Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY 10468 USA. RP Arrieta-Cruz, I (reprint author), Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. EM giulio.pasinetti@mssm.edu FU NIA NIH HHS [U01 AG029310] NR 16 TC 7 Z9 7 U1 0 U2 9 PU VERSITA PI WARSAW PA SOLIPSKA 14A-1, 02-482 WARSAW, POLAND SN 2081-3856 J9 TRANSL NEUROSCI JI Transl. Neurosci. PD SEP PY 2010 VL 1 IS 3 BP 188 EP 194 DI 10.2478/v10134-010-0023-x PG 7 WC Neurosciences SC Neurosciences & Neurology GA V20PZ UT WOS:000208153200001 PM 23227306 ER PT J AU Uygun, K Tolboom, H Izamis, ML Uygun, B Sharma, N Yagi, H Soto-Gutierrez, A Hertl, M Berthiaume, F Yarmush, ML AF Uygun, K. Tolboom, H. Izamis, M. L. Uygun, B. Sharma, N. Yagi, H. Soto-Gutierrez, A. Hertl, M. Berthiaume, F. Yarmush, M. L. TI Diluted Blood Reperfusion as a Model for Transplantation of Ischemic Rat Livers: Alanine Aminotransferase Is a Direct Indicator of Viability SO TRANSPLANTATION PROCEEDINGS LA English DT Article ID MACHINE PERFUSION PRESERVATION; COLD-STORAGE; RECOVERY AB Donors after cardiac death present a significant pool of untapped organs for transplantation, and use of machine perfusion strategies has been an active focus area in experimental transplantation. However, despite 2 decades of research, a gold standard has yet to emerge for machine perfusion systems and protocols. Whole blood reperfusion has been used as a surrogate for organ transplantation, especially as a model for the short-term response posttransplantation, and for optimization of perfusion systems. Although it is known that there is a strong correlation between liver function in whole-blood reperfusion and survival, the exact nature of these correlations, and to what extent they can be considered as an indicator of viability for transplantation/recipient survival, remain unclear. In this work, we demonstrate that diluted whole-blood reperfusion can be used as a direct model for transplantation of ischemic rat liver grafts. Specifically, we show that recipient survival can be predicted based simply on the value of alanine aminotransferase during perfusion, providing quantitative criteria of viability for use in this animal model. These results indicate that in the rat model graft survival is highly correlated with hepatocellular damage. C1 [Yarmush, M. L.] Shriners Hosp Children, Boston, MA 02114 USA. [Uygun, K.; Tolboom, H.; Izamis, M. L.; Uygun, B.; Yagi, H.; Soto-Gutierrez, A.; Hertl, M.; Yarmush, M. L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA USA. [Uygun, K.; Tolboom, H.; Izamis, M. L.; Uygun, B.; Yagi, H.; Soto-Gutierrez, A.; Hertl, M.; Yarmush, M. L.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Sharma, N.; Berthiaume, F.; Yarmush, M. L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. RP Yarmush, ML (reprint author), Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org RI Uygun, Basak/I-1792-2012 OI Uygun, Basak/0000-0002-2600-7900 FU National Institutes of Health [R01DK59766, K99DK080942, K99DK083556]; Shriners Hospitals for Children, NSF [CBET-0853569]; Harvard University FX Supported by grants from the National Institutes of Health (R01DK59766, K99DK080942, K99DK083556), the Shriners Hospitals for Children, NSF (CBET-0853569), and the Harvard University William F. Milton Fund. NR 10 TC 7 Z9 7 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0041-1345 J9 TRANSPL P JI Transplant. Proc. PD SEP PY 2010 VL 42 IS 7 BP 2463 EP 2467 DI 10.1016/j.transproceed.2010.04.037 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 651QM UT WOS:000281942200009 PM 20832525 ER PT J AU Mukerji, S Windsor, AM Lee, DJ AF Mukerji, Sudeep Windsor, Alanna Marie Lee, Daniel J. TI Auditory Brainstem Circuits That Mediate the Middle Ear Muscle Reflex SO TRENDS IN AMPLIFICATION LA English DT Article DE acoustic reflex; middle ear muscle; pseudo-rabies virus; auditory prosthetic devices; middle ear ossicles AB The middle ear muscle (MEM) reflex is one of two major descending systems to the auditory periphery. There are two middle ear muscles (MEMs): the stapedius and the tensor tympani. In man, the stapedius contracts in response to intense low frequency acoustic stimuli, exerting forces perpendicular to the stapes superstructure, increasing middle ear impedance and attenuating the intensity of sound energy reaching the inner ear (cochlea). The tensor tympani is believed to contract in response to self-generated noise (chewing, swallowing) and nonauditory stimuli. The MEM reflex pathways begin with sound presented to the ear. Transduction of sound occurs in the cochlea, resulting in an action potential that is transmitted along the auditory nerve to the cochlear nucleus in the brainstem (the first relay station for all ascending sound information originating in the ear). Unknown interneurons in the ventral cochlear nucleus project either directly or indirectly to MEM motoneurons located elsewhere in the brainstem. Motoneurons provide efferent innervation to the MEMs. Although the ascending and descending limbs of these reflex pathways have been well characterized, the identity of the reflex interneurons is not known, as are the source of modulatory inputs to these pathways. The aim of this article is to (a) provide an overview of MEM reflex anatomy and physiology, (b) present new data on MEM reflex anatomy and physiology from our laboratory and others, and (c) describe the clinical implications of our research. C1 [Mukerji, Sudeep; Windsor, Alanna Marie; Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Mukerji, Sudeep; Windsor, Alanna Marie; Lee, Daniel J.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Lee, DJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM daniel_lee@meei.harvard.edu FU NIH-NIDCD [K08DC006285]; Norwegian State Funding Lending Agency FX The authors disclosed receipt of the following financial support for the research and/or authorship of this article:; This work is supported by NIH-NIDCD K08DC006285 and the Norwegian State Funding Lending Agency. NR 200 TC 22 Z9 22 U1 1 U2 11 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1084-7138 J9 TRENDS AMPLIF JI Trends Amplif. PD SEP PY 2010 VL 14 IS 3 BP 170 EP 191 DI 10.1177/1084713810381771 PG 22 GA V25ZV UT WOS:000208516800004 PM 20870664 ER PT J AU Eastham, JA Evans, CP Zietman, A AF Eastham, James A. Evans, Christopher P. Zietman, Anthony TI What is the optimal management of high risk, clinically localized prostate cancer? SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article; Proceedings Paper CT Annual Spring Meeting of the Society-of-Urologic-Oncology CY APR 25, 2009 CL Chicago, IL SP Soc Urol Oncol DE Prostate cancer; High-risk; Radical prostatectomy; Radiotherapy; Risk stratification ID RANDOMIZED CONTROLLED-TRIAL; ANDROGEN DEPRIVATION THERAPY; BEAM RADIATION-THERAPY; DOSE-ESCALATION TRIAL; PHASE-III TRIAL; RADICAL PROSTATECTOMY; BIOCHEMICAL RECURRENCE; CONFORMAL RADIOTHERAPY; HORMONAL-THERAPY; MORTALITY AB Objectives: To summarize the presentations and debate regarding the optimal treatment of localized high-risk prostate cancer as presented at the 2009 Spring Meeting of the Society of Urologic Oncology. Materials and methods: The debate was centered on presentations arguing for radical prostatectomy (RP) or radiotherapy as the optimal treatment for this condition. The meeting presentations are summarized by their respective presenters herein. Results: Dr. James Eastham presents the varied definitions for "high-risk" prostate cancer as strongly influencing which patients end up in this cohort. Based upon this, between 3% and 38% of patients with high-risk features could be defined as "high-risk". Despite that, these men do not have a uniformly poor prognosis after RP, and attention to surgical principles as outlined improve outcomes. Disease-specific survival at 12 years is excellent and up to one-half of these men may not need adjuvant or salvage therapies, depending on their specific disease characteristics. Adjuvant or salvage radiotherapies improve outcomes and are part of a sequential approach to treating these patients. Dr. Anthony Zietman presented radiotherapy as the gold-standard based upon large, randomized clinical trials of intermediate- and high-risk prostate cancer patients. Compared with androgen deprivation alone, the addition of radiotherapy provided a 12% cancer-specific survival advantage and 10% overall survival advantage. Dose escalation seems to confer further improvements in cancer control without significant escalation of toxicities, with more data forthcoming. Conclusions: There are no randomized trials comparing RP to radiotherapy for any risk category. In high-risk prostate cancer patients, both approaches have potential benefits and cumulative toxicities that must be matched to disease characteristics and patient expectations in selecting a treatment course. (C) 2010 Elsevier Inc. All rights reserved. C1 [Evans, Christopher P.] Univ Calif, Dept Urol, Sch Med, Sacramento, CA 95819 USA. [Eastham, James A.] Sidney Kimmel Ctr Prostate & Urol Canc, Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Zietman, Anthony] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Zietman, Anthony] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Evans, CP (reprint author), Univ Calif, Dept Urol, Sch Med, Sacramento, CA 95819 USA. EM christopher.evans@ucdmc.mcdavis.edu NR 57 TC 10 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD SEP-OCT PY 2010 VL 28 IS 5 BP 557 EP 567 DI 10.1016/j.urolonc.2009.12.012 PG 11 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 659BT UT WOS:000282542700019 PM 20816616 ER PT J AU Kane, CJ Im, R Amling, CL Presti, JC Aronson, WJ Terris, MK Freedland, SJ AF Kane, Christopher J. Im, Ronald Amling, Christopher L. Presti, Joseph C., Jr. Aronson, William J. Terris, Martha K. Freedland, Stephen J. CA SEARCH Database Study Grp TI Outcomes After Radical Prostatectomy Among Men Who Are Candidates for Active Surveillance: Results From the SEARCH Database SO UROLOGY LA English DT Article ID AGENT-ORANGE; CANCER; RISK; BIOPSY; PREDICTOR; RECURRENCE; MANAGEMENT; CARCINOMA; VETERANS; EXPOSURE AB OBJECTIVE We sought to evaluate outcomes after radical prostatectomy among men with low-risk prostate cancer who would be candidates for active surveillance. METHODS Using the Shared Equal Access Regional Cancer Hospital (SEARCH) database of men treated with radical prostatectomy at multiple equal-access medical centers between 1988 and 2007, 398 of 2062 men (19%) met our criteria for potential active surveillance: clinical stage T1c or T2a, prostate-specific antigen (PSA) < 10 ng/mL, Gleason sum <= 6, and no more than 1 or 2 positive cores on at least a sextant biopsy. We examined the risk of adverse pathology, biochemical progression, and PSA doubling time (PSADT) at the time of recurrence. We used a Cox proportional hazards model to determine the significant predictors of PSA progression. RESULTS Of the men with low-risk prostate cancer, 85% had organ-confined disease, only 2% had seminal vesicle invasion, and no patient had lymph node metastasis. The 5- and 10 year PSA-free survival rates were 81% (95% CI: 76-86%) and 66% (95% CI: 54-76%). On multivariate analysis, older age (P = .005), Agent Orange exposure (P = .02), and obesity (P = .03) were all significantly associated with biochemical failure. Mean and median PSADT among men who experienced recurrence were 37 and 20 months. Only 3 patients experienced recurrence with PSADT < 9 months. CONCLUSIONS Most men with low-risk prostate cancer treated with radical prostatectomy experience long-term PSA control. Those who did experience recurrence often did so with a long PSADT. Consistent with prior SEARCH database reports, older age, Agent Orange exposure, and obesity increased the risk of recurrence. UROLOGY 76: 695-702, 2010. (C) 2010 Elsevier Inc. All rights reserved. C1 Univ Calif San Diego, Div Urol, Dept Surg, San Diego, CA 92103 USA. Moores UCSD Canc Ctr, La Jolla, CA USA. Vet Affairs San Diego Med Ctr, Urol Sect, San Diego, CA USA. Univ Alabama, Dept Urol, Birmingham, AL USA. Stanford Univ, Sch Med, Dept Urol, Palo Alto, CA 94304 USA. Vet Affairs Palo Alto Hlth Care Syst, Urol Sect, Palo Alto, CA USA. Vet Affairs Greater Los Angeles Healthcare Syst, Urol Sect, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Dept Urol, Los Angeles, CA USA. Charlie Norwood Vet Affairs Med Ctr, Urol Sect, Augusta, GA USA. Med Coll Georgia, Urol Sect, Augusta, GA 30912 USA. Vet Affairs Med Ctr, Urol Sect, Durham, NC USA. Duke Univ, Sch Med, Dept Surg, Div Urol Surg, Durham, NC USA. Duke Univ, Sch Med, Dept Pathol, Durham, NC 27706 USA. Duke Univ, Sch Med, Duke Prostate Ctr, Durham, NC 27706 USA. RP Kane, CJ (reprint author), Univ Calif San Diego, Div Urol, Dept Surg, W Arbor Dr 8897, San Diego, CA 92103 USA. EM ckane@ucsd.edu OI Terris, Martha/0000-0002-3843-7270 FU Department of Veterans Affairs, National Institute of Health [R01CA100938]; National Institutes of Health Specialized Programs of Research Excellence [P50 CA92131-01A1] FX Supported by the Department of Veterans Affairs, National Institute of Health R01CA100938 (W.J.A.), National Institutes of Health Specialized Programs of Research Excellence Grant P50 CA92131-01A1 (W.J.A.), the Georgia Cancer Coalition (M. K. T.), the Department of Defense, Prostate Cancer Research Program, (S.J.F.), and the American Urological Association Foundation/Astellas Rising Star in Urology Award (S.J.F.). Views and opinions of, and endorsements by, the author(s) do not reflect those of the US Army or the Department of Defense. NR 30 TC 49 Z9 51 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD SEP PY 2010 VL 76 IS 3 BP 695 EP 700 DI 10.1016/j.urology.2009.12.073 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 649AD UT WOS:000281736300063 PM 20394969 ER PT J AU Farris, AB Lauwers, GY Deshpande, V AF Farris, Alton B., III Lauwers, Gregory Y. Deshpande, Vikram TI Autoimmune pancreatitis-related diabetes: quantitative analysis of endocrine islet cells and inflammatory infiltrate SO VIRCHOWS ARCHIV LA English DT Article DE Autoimmune pancreatitis; Diabetes; Immunohistochemistry; Morphometry; IgG4 ID FEATURES; MELLITUS; DISEASE; HUMANS; BIOPSY; MODEL AB In autoimmune pancreatitis (AIP), mechanism(s) of paradoxical glycemic control improvement (GCI) often occurring after pancreatic resection and steroid therapy are not fully elucidated. Using image quantitation, AIP cases (n = 10) with pre- and post-surgical glucose values were compared with chronic pancreatitis (CP) and normal pancreas (NP) regarding percent chromogranin immunohistochemistry (IHC) positivity as a surrogate marker of endocrine endowment; intra-islet T and B lymphocyte and plasma cell enumeration with CD3, CD20, and IgG4 IHC; and CD34 IHC islet vascularity quantitation. Postsurgical GCI, noted in 8/10 (80%) AIP cases, approached statistical significance (P = 0.07) compared to CP. Endocrine endowment reduction, noted by a lower percent of chromogranin + pancreatic parenchyma, was seen in AIP (4.54%) and CP (3.20%) compared to NP (7.95%); only the CP decrease was statistically significant (P = 0.02) since AIP often had ductular endocrine neogenesis. Regression suggested an inverse correlation between endocrine endowment and GCI in AIP (R = 0.62, P= 0.06). AIP islets were smaller and disrupted by inflammatory cell infiltration. Compared to CP, AIP islets had higher CD3 + and CD20 + cell densities. IgG4 + plasma cells were often present at a high density in AIP but typically preserved the islets. Intra-islet CD34 staining showed a lower average vascularity in AIP compared to NP (P= 0.05). This study reaffirms postsurgical GCI in AIP. Prominent intra-islet inflammation and decreased vascularity in AIP may contribute to diabetogenic effects. Endocrine cell neogenesis and relative islet preservation despite islet inflammatory infiltration may explain the paradoxical GCI in AIP. C1 [Farris, Alton B., III] Emory Univ Hosp, Dept Pathol, Atlanta, GA 30322 USA. [Farris, Alton B., III; Lauwers, Gregory Y.; Deshpande, Vikram] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. RP Farris, AB (reprint author), Emory Univ Hosp, Dept Pathol, 1364 Clifton Rd NE,Room H-188, Atlanta, GA 30322 USA. EM abfarri@emory.edu NR 37 TC 3 Z9 4 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD SEP PY 2010 VL 457 IS 3 BP 329 EP 336 DI 10.1007/s00428-010-0948-y PG 8 WC Pathology SC Pathology GA 657TB UT WOS:000282434100006 PM 20632032 ER PT J AU Walsh, MP Seto, J Tirado, D Chodosh, J Schnurr, D Seto, D Jones, MS AF Walsh, Michael P. Seto, Jason Tirado, Damaris Chodosh, James Schnurr, David Seto, Donald Jones, Morris S. TI Computational analysis of human adenovirus serotype 18 SO VIROLOGY LA English DT Article DE Human adenovirus; Molecular evolution; Species A; Oncogenesis ID EPIDEMIC KERATOCONJUNCTIVITIS; ENTERIC ADENOVIRUS-40; DNA-REPLICATION; GENOME TYPE; SEQUENCE; PROTEINS; INFANTS; GASTROENTERITIS; RECOMBINATION; LENGTH AB The genome of the sole remaining unsequenced member of species A, human adenovirus type 18 (HAdV-A18), has been sequenced and analyzed. Members of species A are implicated as gastrointestinal pathogens and were shown to be tumorigenic in rodents. These whole genome and in silico proteome data are important as references for reexamining and integrating earlier work and observations based on lower resolution techniques, such as restriction enzyme digestion patterns, particularly for hypotheses based on pre-genomics data. Additionally, the genome of HAdV-A18 will also serve as reference for current studies examining the molecular evolution and origins of human and simian adenoviruses, particularly genome recombination studies. Applications of this virus as a potential vector for gene delivery protocols may be practical as data accumulate on this and other adenovirus genomes. (C) 2010 Elsevier Inc. All rights reserved. C1 [Walsh, Michael P.; Seto, Jason; Seto, Donald] George Mason Univ, Dept Bioinformat & Computat Biol, Manassas, VA 20110 USA. [Tirado, Damaris; Jones, Morris S.] David Grant USAF Med Ctr, Clin Invest Facil, Travis, CA 94535 USA. [Chodosh, James] Harvard Univ, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Howe Lab,Med Sch, Boston, MA 02114 USA. [Schnurr, David] Calif Dept Publ Hlth, Viral & Rickettsial Dis Lab, Richmond, CA USA. RP Seto, D (reprint author), George Mason Univ, Dept Bioinformat & Computat Biol, 10900 Univ Blvd,MSN 5B3, Manassas, VA 20110 USA. EM mwalsh5@gmu.edu; jseto@gmu.edu; Damaris.Tirado@travis.af.mil; James_Chodosh@meei.harvard.edu; dseto@gmu.edu; Morris.Jones@travis.af.mil FU United States Air Force Surgeon General [FDG20040024E]; US Public Health Service NIH [EY013124, P30EY013104]; Massachusetts Lions Eye Research; USAF [FA442709P0262] FX The work reported herein was performed with the support of the United States Air Force Surgeon General, Clinical Investigation No. FDG20040024E. This was also supported in part by US Public Health Service NIH grants EY013124 and P30EY013104, Massachusetts Lions Eye Research Fund, and an unrestricted grant to the Department of Ophthalmology, Harvard Medical School from Research to Prevent Blindness. DS and MPW were also supported by a USAF contract, FA442709P0262. The views expressed in this material are those of the authors and do not reflect the official policy or position of the US Government, the Department of Defense, or the Department of the Air Force. NR 41 TC 6 Z9 7 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2010 VL 404 IS 2 BP 284 EP 292 DI 10.1016/j.virol.2010.05.013 PG 9 WC Virology SC Virology GA 629OP UT WOS:000280209800016 PM 20542532 ER PT J AU Johnson, DW Cobb, JP AF Johnson, Daniel W. Cobb, J. Perren TI Candida infection and colonization in critically ill surgical patients SO VIRULENCE LA English DT Editorial Material DE intensive care units; critical care; reanimation; sepsis; fungal; prophylaxis treatment; Candida; trauma ID METAANALYSIS; PROPHYLAXIS; TRAUMA C1 [Johnson, Daniel W.; Cobb, J. Perren] Massachusetts Gen Hosp, Crit Care Ctr, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Johnson, DW (reprint author), Massachusetts Gen Hosp, Crit Care Ctr, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM dwjohnson@partners.org; jpcobb@partners.org NR 4 TC 3 Z9 3 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD SEP-OCT PY 2010 VL 1 IS 5 BP 355 EP 356 DI 10.4161/viru.1.5.13254 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 789MY UT WOS:000292520800001 PM 21178469 ER PT J AU Kourkoumpetis, T Manolakaki, D Velmahos, GC Chang, YC Alam, HB De Moya, MM Sailhamer, EA Mylonakis, E AF Kourkoumpetis, Themistoklis Manolakaki, Dimitra Velmahos, George C. Chang, Yuchiao Alam, Hasan B. De Moya, Marc M. Sailhamer, Elizabeth A. Mylonakis, Eleftherios TI Candida infection and colonization among non-trauma emergency surgery patients SO VIRULENCE LA English DT Article DE candida; emergency surgery; risk factors; candidiasis; colonization; costs ID BLOOD-STREAM INFECTIONS; INTENSIVE-CARE-UNIT; INVASIVE FUNGAL-INFECTIONS; HIGH-RISK PATIENTS; ALBICANS CANDIDEMIA; EPIDEMIOLOGY; MULTICENTER; SURVEILLANCE; PROPHYLAXIS; FLUCONAZOLE AB Background: Candida is a significant pathogen among critically ill patients. However, candidiasis among non-trauma emergency surgery (NTES) patients has not been previously investigated. Herein we describe the incidence of both colonization and infection from Candida and risk factors for invasive disease in this population. Results: Of all 289 eligible patients, 63 (21.7%) fulfilled the criteria for Candida infection and 110 (38%) were included in the Candida colonization group. Interestingly, from the 63 patients with invasive candidiasis, 25 (39.7%) were infected by a non-albicans species. Upon multivariate analyses, ventilator-associated pneumonia (VAP) (Odds Ratio [OR]: 2.34; 95%, Confidence Interval [CI]: 1,213-4,533, p = 0.0112), bacteremia (OR: 4,778; 95% CI: 1,519-15,029, p = 0.0075) and surgical complications (OR: 3.903; 95% CI: 1,335-11,412, p = 0.0129) were independent risk factors for the development of Candida infection. Candida infection and colonization were both found to correlate with approximately $40,000-100,000 mean additional costs). Interestingly, candidemia was associated with 63% all-cause mortality. For all other forms of candidiasis, mortality was not significantly different among groups. Methods: For this retrospective single center study we included all NTES patients with ICU stay >= 4 days from May 1(st), 2002 to April 30(th), 2007. Patients were divided into 3 non-overlapping groups: (1) patients with Candida-infection, (2) patients with Candida colonization and (3) patients with negative Candida cultures. Groups were compared by univariate and multivariate analyses to identify significant risk factors for invasive candidiasis. Conclusion: We found that Candida infection is alarmingly high among NTES patients with prolonged intensive care unit (ICU) stay. Surgical complications and bacterial infections (VAP and bacteraemia) were significantly correlated with the development of candidiasis. Candidiasis reached a rate of 21.7/100 discharges, which is significantly higher than most established high-risk populations for candidiasis. Future studies should review the need for antifungal prophylaxis on this population. C1 [Manolakaki, Dimitra; Velmahos, George C.; Alam, Hasan B.; De Moya, Marc M.; Sailhamer, Elizabeth A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02115 USA. [Kourkoumpetis, Themistoklis; Mylonakis, Eleftherios] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. [Chang, Yuchiao] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Epidemiol Unit, Boston, MA USA. RP Velmahos, GC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02115 USA. EM gvelmahos@partners.org FU Astellas Pharma US, Inc. FX Research was supported by an unrestricted educational grant from Astellas Pharma US, Inc. NR 38 TC 21 Z9 24 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD SEP-OCT PY 2010 VL 1 IS 5 BP 359 EP 366 DI 10.4161/viru.1.5.12795 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 789MY UT WOS:000292520800003 PM 21178471 ER PT J AU Manolakaki, D Velmahos, GC Kourkoumpetis, T Chang, YC Alam, HB De Moya, MM Mylonakis, E AF Manolakaki, Dimitra Velmahos, George C. Kourkoumpetis, Themistoklis Chang, Yuchiao Alam, Hasan B. De Moya, Marc M. Mylonakis, Eleftherios TI Candida infection and colonization among trauma patients SO VIRULENCE LA English DT Article DE candidiasis; trauma; colonization; Candida; intensive care ID INTENSIVE-CARE-UNIT; BLOOD-STREAM INFECTIONS; RISK-FACTORS; SECULAR TRENDS; EPIDEMIOLOGY; MORTALITY; ALBICANS; STATES; FLORA AB Background: Data on Candida infection among critically ill trauma patients are limited and not recently updated. Here we study the epidemiology and economic impact of Candida and examine potential risk factors for Candida infection in this population. Results: 374 patients were included. Upon comparisons between groups, candidiasis patients received significantly more blood transfusions (p = 0.013), antibiotics (p = 0.005) and total parenteral nutrition (TPN) (p = 0.004), had a longer duration of mechanical ventilation (MV) (p = 0.008) and underwent more laparotomy procedures than Candida free patients (56.5% versus 16.4%; p < 0.001). Surgical complications (13% versus 1.4%; p = 0.013), injury of the upper (13% versus 0.9%; p = 0.007) and lower gastrointestinal tract (8.7% versus 0.9%; p = 0.048) and bacterial wound or intra-abdominal infections (17.4% versus 1.9%; p = 0.004) were also more common in candidiasis patients. Upon multivariate analysis, patients receiving TPN had 7-fold higher odds for developing candidiasis [Odds ratio (OR): 7.2; 95% Confidence interval (CI): 2.6-19.4; p = 0.0001]. Other predisposing factors included laparotomy (OR: 3.8, 95% CI: 1.5-9.9; p = 0.0057) and female gender (OR: 5.7; 95% CI: 2.1-15.6; p = 0.0007). Average total hospital charges were higher for patients with Candida infection compared to patients with Candida colonization or without a positive Candida culture. Methods: In this 5-year retrospective study, all severely injured patients with = 4 days of intensive care unit stay were included, with the primary outcome being Candida infection. We identified 3 distinct patient groups: (1) The Candida infection, (2) The Candida colonization and (3) the Candida-free group. All comparisons between groups with p values <= 0.2 from the univariate analysis were entered into stepwise logistic regression to identify independent risk factors for candidiasis. Conclusions: TPN, laparotomy and female gender independently predict the development of candidiasis among trauma patients. Severely injured women requiring laparotomy and TPN therapy should be carefully managed for the possibility of increased risk for candidiasis. C1 [Manolakaki, Dimitra; Velmahos, George C.; Alam, Hasan B.; De Moya, Marc M.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Kourkoumpetis, Themistoklis; Mylonakis, Eleftherios] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Chang, Yuchiao] Massachusetts Gen Hosp, Clin Epidemiol Unit, Boston, MA 02114 USA. [Chang, Yuchiao] Harvard Univ, Sch Med, Boston, MA USA. RP Velmahos, GC (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. EM gvelmahos@partners.org FU Astellas Pharma US, Inc. FX Research was supported by an unrestricted educational grant from Astellas Pharma US, Inc. NR 22 TC 17 Z9 17 U1 1 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD SEP-OCT PY 2010 VL 1 IS 5 BP 367 EP 375 DI 10.4161/viru.1.5.12796 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 789MY UT WOS:000292520800004 PM 21178472 ER PT J AU Jones, AS Lillie-Blanton, M Stone, VE Ip, EH Zhang, Q Wilson, TE Cohen, MH Golub, ET Hessol, NA AF Jones, Alison Snow Lillie-Blanton, Marsha Stone, Valerie E. Ip, Edward H. Zhang, Qiang Wilson, Tracey E. Cohen, Mardge H. Golub, Elizabeth T. Hessol, Nancy A. TI Multi-Dimensional Risk Factor Patterns Associated with Non-Use of Highly Active Antiretroviral Therapy among Human Immunodeficiency Virus-Infected Women SO WOMENS HEALTH ISSUES LA English DT Article ID HIV-SEROPOSITIVE WOMEN; UNITED-STATES; DRUG-USE; INTERAGENCY HIV; SUBSTANCE USE; ADHERENCE; SYMPTOMS; BEHAVIOR; PREDICTORS; SAMPLE AB Objectives: Relationships between non-use of highly active antiretroviral therapy (HAART), race/ethnicity, violence, drug use, and other risk factors are investigated using qualitative profiles of five risk factors (unprotected sex, multiple male partners, heavy drinking, crack, cocaine or heroin use, and exposure to physical violence) and association of the profiles and race/ethnicity with non-use of HAART over time. Methods: A hidden Markov model was used to summarize risk factor profiles and changes in profiles over time in a longitudinal sample of HIV-infected women enrolled in the Women's Interagency HIV Study with follow-up from 2002 to 2005 (n = 802). Results: Four risk factor profiles corresponding to four distinct latent states were identified from the five risk factors. Trajectory analysis indicated that states characterized by high probabilities of all risk factors or by low probabilities of all risk factors were both relatively stable over time. Being in the highest risk state did not significantly elevate the odds of HAART non-use (odds ratio [OR] 1.05; 95% confidence interval (CI], 0.6-1.8). However, being in a latent state characterized by elevated probabilities of heavy drinking and exposure to physical violence, along with slight elevations in three other risk factors, significantly increased odds of HAART non-use (OR, 1.4; 95% CI, 1.1-1.9). Conclusion: The research suggests that HAART use might be improved by interventions aimed at women who are heavy drinkers with recent exposure to physical violence and evidence of other risk factors. More research about the relationship between clustering and patterns of risk factors and use of HAART is needed. Copyright (C) 2010 by the Jacobs Institute of Women's Health. Published by Elsevier Inc. C1 [Jones, Alison Snow] Drexel Univ, Sch Publ Hlth, Dept Hlth Management & Policy, Philadelphia, PA 19102 USA. [Lillie-Blanton, Marsha] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Hlth Policy, Washington, DC USA. [Stone, Valerie E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Ip, Edward H.; Zhang, Qiang] Wake Forest Univ, Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Wilson, Tracey E.] Suny Downstate Med Ctr, Dept Community Hlth Sci, Brooklyn, NY 11203 USA. [Cohen, Mardge H.] Stroger Hosp, Dept Med, Chicago, IL USA. [Cohen, Mardge H.] Rush Univ, Chicago, IL 60612 USA. [Golub, Elizabeth T.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hessol, Nancy A.] Univ Calif San Francisco, Dept Clin Pharm, San Francisco, CA 94143 USA. [Hessol, Nancy A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. RP Jones, AS (reprint author), Drexel Univ, Sch Publ Hlth, Dept Hlth Management & Policy, 1505 Race St,MS 1035, Philadelphia, PA 19102 USA. EM Alison.S.Jones@drexel.edu FU NCRR NIH HHS [UL1 RR024131, UL1RR024131]; NIAID NIH HHS [U01 AI031834, U01 AI034989, U01 AI034993, U01 AI034994, U01 AI035004, U01 AI042590, UO1-AI-31834, UO1-AI-34989, UO1-AI-34993, UO1-AI-34994, UO1-AI-35004, UO1-AI-42590]; NICHD NIH HHS [U01 HD032632, UO1-HD-32632]; NIDA NIH HHS [R21 DA022971, R21 DA022971-01, R21 DA022971-02] NR 38 TC 9 Z9 9 U1 5 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1049-3867 J9 WOMEN HEALTH ISS JI Womens Health Iss. PD SEP-OCT PY 2010 VL 20 IS 5 BP 335 EP 342 DI 10.1016/j.whi.2010.03.005 PG 8 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 647AX UT WOS:000281588900007 PM 20579905 ER PT J AU Ramey, JD Villareal, VA Ng, C Ward, SC Xiong, JP Clubb, RT Bradley, KA AF Ramey, Jordan D. Villareal, Valerie A. Ng, Charles Ward, Sabrina C. Xiong, Jian-Ping Clubb, Robert T. Bradley, Kenneth A. TI Anthrax Toxin Receptor 1/Tumor Endothelial Marker 8: Mutation of Conserved Inserted Domain Residues Overrides Cytosolic Control of Protective Antigen Binding SO BIOCHEMISTRY LA English DT Article ID CAPILLARY MORPHOGENESIS PROTEIN-2; CD11B A-DOMAIN; I-DOMAIN; SECONDARY STRUCTURE; CRYSTAL-STRUCTURE; PORE FORMATION; LETHAL TOXIN; INTEGRIN REGULATION; CIRCULAR-DICHROISM; DISULFIDE BOND AB Anthrax toxin receptor I (ANTX RI)/tumor endothelial marker 8 (TEM 8) is one of two known proteinaceous cell surface anthrax toxin receptors. A metal ion dependent adhesion site (MIDAS) present in the integrin-like inserted (I) domain of ANTXRI mediates the binding of the anthrax toxin subunit, protective antigen (PA). Here we provide evidence that single point mutations in the 1 domain can override regulation of ANTX RI ligand-binding activity mediated by intracellular signals. A previously reported MIDAS mutant of ANTXRI (T118A) was found to retain normal metal ion binding and secondary structure but failed to bind PA, consistent with a locked inactive state. Conversely, mutation of a conserved I domain phenylalanine residue to a tryptophan (F205W) increased the proportion of cell-surface ANTX RI that bound PA, consistent with a locked active state. Interestingly, the K(D) and total amount of PA bound by the isolated ANTXRI I domain were not affected by the F205W mutation, indicating that ANTXRI is preferentially found in the active state in the absence of inside-out signaling. Circular dichroism (CD) spectroscopy and (1)H-(15)N heteronuclear single-quantum coherence (HSQC) nuclear magnetic resonance (NMR) revealed that structural changes between T118A, F205W, and WT I domains were minor despite a greater than 10(3)-fold difference in their abilities to bind toxin. Regulation of toxin binding has important implications for the design of toxin inhibitors and for the targeting of ANTXRI for antitumor therapies. C1 [Ramey, Jordan D.; Ng, Charles; Ward, Sabrina C.; Bradley, Kenneth A.] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. [Villareal, Valerie A.; Clubb, Robert T.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Ramey, Jordan D.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. [Xiong, Jian-Ping] Massachusetts Gen Hosp, Div Nephrol, Struct Biol Program, Charlestown, MA 02129 USA. [Xiong, Jian-Ping] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Bradley, KA (reprint author), Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. EM kbradley@microbio.ucla.edu FU UCLA DOE; UCLA Jonsson Comprehensive Cancer Center; UCLA AIDS Institute; NIH [CA-16042, AI-28697]; David Geffen School of Medicine at UCLA; National Institutes of Health (NIH) [A1057870, A152217, F31 GM075564] FX We acknowledge support of the UCLA DOE biochemistry instrumentation facility, UCLA Jonsson Comprehensive Cancer Center (JCCC), the UCLA AIDS Institute, and the flow cytometry, virology, mucosal immunology cores, which are supported by the NIH Awards CA-16042 and AI-28697 (UCLA-CFAR grant), the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA.; This work was funded by National Institutes of Health (NIH) Awards A1057870 to K.A.B. A152217 to R.T.C., and F31 GM075564 to V.A.V. NR 56 TC 3 Z9 3 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 31 PY 2010 VL 49 IS 34 BP 7403 EP 7410 DI 10.1021/bi100887w PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 640LL UT WOS:000281052600018 PM 20690680 ER PT J AU Rigotti, NA Pipe, AL Benowitz, NL Arteaga, C Garza, D Tonstad, S AF Rigotti, Nancy A. Pipe, Andrew L. Benowitz, Neal L. Arteaga, Carmen Garza, Dahlia Tonstad, Serena TI Response to Letter Regarding Article, "Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Cardiovascular Disease: A Randomized Trial" SO CIRCULATION LA English DT Letter ID SUSTAINED-RELEASE BUPROPION; RECEPTOR PARTIAL AGONIST; PLACEBO C1 [Rigotti, Nancy A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr,Gen Med Div,Dept Med, Boston, MA 02115 USA. [Pipe, Andrew L.] Univ Ottawa, Inst Heart, Ottawa, ON K1N 6N5, Canada. [Benowitz, Neal L.] Univ Calif San Francisco, Div Clin Pharmacol & Expt Therapeut, Dept Med & Biopharmaceut Sci, San Francisco, CA 94143 USA. [Arteaga, Carmen; Garza, Dahlia] Pfizer Inc, New York, NY USA. [Tonstad, Serena] Ullevaal Univ Hosp, Dept Prevent Cardiol, Oslo, Norway. RP Rigotti, NA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr,Gen Med Div,Dept Med, Boston, MA 02115 USA. NR 4 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 31 PY 2010 VL 122 IS 9 BP E446 EP E446 DI 10.1161/CIRCULATIONAHA.110.960856 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 645YU UT WOS:000281502900015 ER PT J AU Fein, AS Wang, YF Curtis, JP Masoudi, FA Varosy, PD Reynolds, MR AF Fein, Adam S. Wang, Yongfei Curtis, Jeptha P. Masoudi, Frederick A. Varosy, Paul D. Reynolds, Matthew R. CA Natl Cardiovasc Data Registry TI Prevalence and Predictors of Off-Label Use of Cardiac Resynchronization Therapy in Patients Enrolled in the National Cardiovascular Data Registry Implantable Cardiac-Defibrillator Registry SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiac resynchronization therapy; CRT; NCDR; ICD registry; overuse; guideline adherence; cardiac pacing utilization ID ATRIOVENTRICULAR JUNCTION ABLATION; LEFT-VENTRICULAR DYSFUNCTION; CHRONIC HEART-FAILURE; NARROW QRS COMPLEXES; CARDIOVERTER-DEFIBRILLATOR; DISEASE PROGRESSION; ATRIAL-FIBRILLATION; ASSOCIATION; TRIAL; COMPLICATIONS AB Objectives The purpose of the study was to define the extent and nature of cardiac resynchronization therapy (CRT) device usage outside consensus guidelines using national data. Background Recent literature has shown that the application of CRT in clinical practice frequently does not adhere to evidence-based consensus guidelines. Factors underlying these practices have not been fully explored. Methods From the National Cardiovascular Data Registry's Implantable Cardiac-Defibrillator Registry, we defined a cohort of 45,392 cardiac resynchronization therapy-defibrillator (CRT-D) implants between January 2006 and June 2008 with a primary prevention indication. We defined "off-label" implants as those in which the ejection fraction was >35%, the New York Heart Association functional class was below III, or the QRS interval duration was <120 ms in the absence of a documented need for ventricular pacing. The relationships between patient, implanting physician, and hospital characteristics with off-label use were explored with multivariable hierarchical logistic regression models. Results Overall, 23.7% of devices were placed without meeting all 3 implant criteria, most often due to New York Heart Association functional class below III (13.1% of implants) or QRS interval duration <120 ms (12.0%). Atrial fibrillation/flutter, previous percutaneous coronary intervention, and the performance of an electrophysiology study before implant were independently associated with increased odds of off-label use, whereas diabetes mellitus, increasing age, and female sex were associated with decreased odds. Physician training and insurance payer were weakly associated with the likelihood of off-label use. Conclusions Nearly 1 in 4 patients receiving CRT devices in the study time frame did not meet guideline-based indications. Given the evolving evidence base supporting the use of CRT, these practices require careful scrutiny. (J Am Coll Cardiol 2010;56:766-73) (C) 2010 by the American College of Cardiology Foundation C1 [Fein, Adam S.; Reynolds, Matthew R.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02217 USA. [Wang, Yongfei; Curtis, Jeptha P.] Yale Univ, Sch Med, New Haven, CT USA. [Masoudi, Frederick A.] Univ Colorado, Denver Hlth Med Ctr, Denver, CO 80202 USA. [Varosy, Paul D.] Univ Colorado, Denver Vet Affairs Med Ctr, Denver, CO 80202 USA. [Masoudi, Frederick A.] Kaiser Permanente Colorado Inst Hlth Res, Denver, CO USA. RP Reynolds, MR (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, 185 Pilgrim Rd, Boston, MA 02217 USA. EM mreynold@bidmc.harvard.edu FU NHLBI NIH HHS [K23 HL077171-05, K23 HL077171] NR 29 TC 21 Z9 22 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 31 PY 2010 VL 56 IS 10 BP 766 EP 773 DI 10.1016/j.jacc.2010.05.025 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 642JH UT WOS:000281207700004 PM 20797489 ER PT J AU Morrow, DA Scirica, BM AF Morrow, David A. Scirica, Benjamin M. TI Ranolazine Is Effective for Acute or Chronic Ischemic Dysfunction With Heart Failure Reply SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter ID 36 TRIAL; THROMBOLYSIS; ARRHYTHMIAS; OXIDATION C1 [Morrow, David A.; Scirica, Benjamin M.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. RP Morrow, DA (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM dmorrow@partners.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 31 PY 2010 VL 56 IS 10 BP 822 EP 823 DI 10.1016/j.jacc.2010.05.027 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 642JH UT WOS:000281207700014 ER PT J AU Meier, DS Balashov, KE Healy, B Weiner, HL Guttmann, CRG AF Meier, D. S. Balashov, K. E. Healy, B. Weiner, H. L. Guttmann, C. R. G. TI Seasonal prevalence of MS disease activity SO NEUROLOGY LA English DT Article ID MULTIPLE-SCLEROSIS EXACERBATIONS; LESIONS; FLUCTUATIONS; PROGRESSION; DISABILITY; TRIALS; REPAIR AB Objective: This observational cohort study investigated the seasonal prevalence of multiple sclerosis (MS) disease activity (likelihood and intensity), as reflected by new lesions from serial T2-weighted MRI, a sensitive marker of subclinical disease activity. Methods: Disease activity was assessed from the appearance of new T2 lesions on 939 separate brain MRI examinations in 44 untreated patients with MS. Likelihood functions for MS disease activity were derived, accounting for the temporal uncertainty of new lesion occurrence, individual levels of disease activity, and uneven examination intervals. Both likelihood and intensity of disease activity were compared with the time of year (season) and regional climate data (temperature, solar radiation, precipitation) and among relapsing and progressive disease phenotypes. Contrast-enhancing lesions and attack counts were also compared for seasonal effects. Results: Unlike contrast enhancement or attacks, new T2 activity revealed a likelihood 2-3 times higher in March-August than during the rest of the year, and correlated strongly with regional climate data, in particular solar radiation. In addition to the likelihood or prevalence, disease intensity was also elevated during the summer season. The elevated risk season appears to lessen for progressive MS and occur about 2 months earlier. Conclusion: This study documents evidence of a strong seasonal pattern in subclinical MS activity based on noncontrast brain MRI. The observed seasonality in MS disease activity has implications for trial design and therapy assessment. The observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity. Neurology (R) 2010;75:799-806 C1 [Meier, D. S.; Guttmann, C. R. G.] Brigham & Womens Hosp, Ctr Neurol Imaging, Boston, MA 02115 USA. [Balashov, K. E.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Healy, B.; Weiner, H. L.] Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. [Healy, B.; Weiner, H. L.] Massachusetts Gen Hosp, Partners Multiple Sclerosis Ctr, Boston, MA 02114 USA. RP Meier, DS (reprint author), Brigham & Womens Hosp, Ctr Neurol Imaging, 221 Longwood Ave,RF396, Boston, MA 02115 USA. EM meier@bwh.harvard.edu FU NIH [N01-NS-0-2397, R01 AG022092-01, R01 NS036524-05, R01 NS055083-01A1]; NCRR [P41 RR013218, UL1 RR025758-01, 2P41RR013218, 2U01AI063623-06]; Bayer Schering Pharma; NIH (NINDS) [K23NS052553, P01 NS 038037-06A2]; National Multiple Sclerosis Society; NIAID [R01 AI43458, R01 AG027437]; Teva Pharmaceutical Industries Ltd.; Maurice Pechet Foundation FX The study acquiring the MRI and clinical data (1991-1993) was supported by NIH contract N01-NS-0-2397.; Dr. Meier has received research support from the NIH (R01 AG022092-01 [coinvestigator] and NCRR P41 RR013218 [consultant]). Dr. Balashov has received research support from Bayer Schering Pharma, the NIH (NINDS K23NS052553, Balashov), and the National Multiple Sclerosis Society. Dr. Healy reports no disclosures. Dr. Weiner has served/serves on scientific advisory boards for and received speaker honoraria from Biogen Idec, Genentech, Inc., EMD Serono, Inc., and Teva Pharmaceutical Industries Ltd.; serves on the editorial boards of Clinical Immunology, Multiple Sclerosis, the Journal of Immunology, and the Journal of Autoimmunity; and receives research support from the NIH (NINDS P01 NS 038037-06A2 [Program Director], NIAID R01 AI43458 [PI], and R01 AG027437 [PI]) and the National Multiple Sclerosis Society. Dr. Guttmann has served on a scientific advisory board for Tibotec Therapeutics/Johnson & Johnson; holds patents re: Versatile stereotactic device, versatile stereotactic device and methods of use, and overlay of tinted images for visualizing change in serial radiologic images; and has received/ receives research support from Teva Pharmaceutical Industries Ltd., the NIH (R01 AG022092-01 [PI of subcontract], HRCA PO1AG004390 [PI of subcontract], NIH R01 NS036524-05 [PI of subcontract], R01 NS055083-01A1 [coinvestigator], NCRR UL1 RR025758-01 [coinvestigator], 2P41RR013218 Supplement [coinvestigator], 2U01AI063623-06 [coinvestigator], NCRR P41 RR013218[coinvestigator]), the Maurice Pechet Foundation, and the National Multiple Sclerosis Society. NR 23 TC 29 Z9 29 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 31 PY 2010 VL 75 IS 9 BP 799 EP 806 DI 10.1212/WNL.0b013e3181f0734c PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 648KF UT WOS:000281691800009 PM 20805526 ER PT J AU Conery, AR Sever, S Harlow, E AF Conery, Andrew R. Sever, Sanja Harlow, Ed TI Nucleoside diphosphate kinase Nm23-H1 regulates chromosomal stability by activating the GTPase dynamin during cytokinesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aneuploidy; RNAi screen; cell cycle; tetraploidy; p53 ID TETRAPLOIDY CHECKPOINT; MEDIATED ENDOCYTOSIS; SUPPRESSOR; CELLS; CENTROSOME; MECHANISM; INTERACTS; HOMOLOG; FAILURE; CANCER AB Chromosomal instability and the subsequent genetic mutations are considered to be critical factors in the development of the majority of solid tumors. Here, we describe how the nucleoside diphosphate kinase Nm23-H1, a protein with a known link to cancer progression, regulates a critical step during cytokinesis. Nm23-H1 acts to provide a local source of GTP for the GTPase dynamin. Loss of Nm23-H1 in diploid cells leads to cytokinetic furrow regression, followed by cytokinesis failure and generation of tetraploid cells. Loss of dynamin phenocopies loss of Nm23-H1, and ectopic overexpression of WT dynamin complements the loss of Nm23-H1. In the absence of p53 signaling, the tetraploid cells resulting from loss of Nm23-H1 continue cycling and develop classic hallmarks of tumor cells. We thus provide evidence that the loss of Nm23-H1, an event suspected to promote metastasis, may additionally function at an earlier stage of tumor development to drive the acquisition of chromosomal instability. C1 [Conery, Andrew R.; Harlow, Ed] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Sever, Sanja] Harvard Univ, Sch Med, Dept Med, Div Nephrol, Charlestown, MA 02129 USA. [Sever, Sanja] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Harlow, E (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM eharlow@hms.harvard.edu FU American Cancer Society [PF-07-030-01-CCG] FX We acknowledge J. Walter for insight into a potential connection with dynamin. We thank J. Sawyer for preparation of the kinase shRNA virus, J. Doench for construction of the lentiviral cDNA expression vector, and W. Endege for construction of the Flag-tagged lentiviral cDNA expression vector. We are also indebted to A. L. Conery and A. Rolfes for critical reading of the manuscript and members of the Harlow laboratory for helpful discussions. A. R. C. was supported by Postdoctoral Fellowship PF-07-030-01-CCG from the American Cancer Society. NR 40 TC 16 Z9 17 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 31 PY 2010 VL 107 IS 35 BP 15461 EP 15466 DI 10.1073/pnas.1010633107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 645NT UT WOS:000281468500032 PM 20713695 ER PT J AU Koh, HJ Toyoda, T Fujii, N Jung, MM Rathod, A Middelbeek, RJW Lessard, SJ Treebak, JT Tsuchihara, K Esumi, H Richter, EA Wojtaszewski, JFP Hirshman, MF Goodyear, LJ AF Koh, Ho-Jin Toyoda, Taro Fujii, Nobuharu Jung, Michelle M. Rathod, Amee Middelbeek, R. Jan-Willem Lessard, Sarah J. Treebak, Jonas T. Tsuchihara, Katsuya Esumi, Hiroyasu Richter, Erik A. Wojtaszewski, Jorgen F. P. Hirshman, Michael F. Goodyear, Laurie J. TI Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE LKB1; Akt Substrate of 160 kDa; TBC1D1; exercise ID ACTIVATED PROTEIN-KINASE; GLUT4 TRANSLOCATION; INSULIN SENSITIVITY; IN-VITRO; RAT; LKB1; METABOLISM; EXERCISE; PHOSPHORYLATION; IDENTIFICATION AB The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an insulin-independent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related protein kinases, significantly inhibited contraction-stimulated glucose transport. This finding, in conjunction with previous studies of ablated AMPK alpha 2 activity showing no effect on contraction-stimulated glucose transport, suggests that one or more AMPK-related protein kinases are important for this process. Muscle contraction increased sucrose nonfermenting AMPK-related kinase (SNARK) activity, an effect blunted in the muscle-specific LKB1 knockout mice. Expression of a mutant SNARK in mouse tibialis anterior muscle impaired contraction-stimulated, but not insulin-stimulated, glucose transport. Whole-body SNARK heterozygotic knockout mice also had impaired contraction-stimulated glucose transport in skeletal muscle, and knockdown of SNARK in C2C12 muscle cells impaired sorbitol-stimulated glucose transport. SNARK is activated by muscle contraction and is a unique mediator of contraction-stimulated glucose transport in skeletal muscle. C1 [Koh, Ho-Jin; Toyoda, Taro; Fujii, Nobuharu; Jung, Michelle M.; Rathod, Amee; Middelbeek, R. Jan-Willem; Lessard, Sarah J.; Hirshman, Michael F.; Goodyear, Laurie J.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Koh, Ho-Jin; Toyoda, Taro; Fujii, Nobuharu; Jung, Michelle M.; Rathod, Amee; Middelbeek, R. Jan-Willem; Lessard, Sarah J.; Hirshman, Michael F.; Goodyear, Laurie J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Treebak, Jonas T.; Richter, Erik A.; Wojtaszewski, Jorgen F. P.] Univ Copenhagen, Dept Exercise & Sport Sci, Copenhagen Muscle Res Ctr, Mol Physiol Grp, DK-2100 Copenhagen, Denmark. [Tsuchihara, Katsuya; Esumi, Hiroyasu] East Hosp, Natl Canc Ctr, Res Ctr Innovat Oncol, Canc Physiol Project, Chiba 2778577, Japan. RP Goodyear, LJ (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. EM laurie.goodyear@joslin.harvard.edu RI Fujii, Nobuharu/J-2724-2014; Wojtaszewski, Jorgen /P-6583-2014; Treebak, Jonas/B-4521-2017 OI Fujii, Nobuharu/0000-0002-0974-3033; Wojtaszewski, Jorgen /0000-0001-9785-6830; Treebak, Jonas/0000-0003-1488-7012 FU National Institutes of Health [AR45670, DK68626]; Joslin Diabetes and Endocrinology Research Center [DK36836]; Commission of the European Union [LSHM-CT-2004-005272]; Lundbeck Foundation; Novo Nordisk Foundation; Copenhagen Muscle Research Centre; Danish Medical Research Council; American Physiological Society; American Diabetes Association FX We thank Drs. R. A. DePinho and N. M. Bardeesy (Dana Farber Cancer Institute) for providing the floxed LKB1 mice, Dr. C. R. Kahn (Joslin Diabetes Center) for the MCK-Cre mice, Dr. J. Xie (Cell Signaling Technology, Danvers, MA) for generation of SNARK antibody, Yangfeng Lee for assistance with experiments, Julie A. Ripley for editorial contributions, and all other members of the Goodyear laboratory for critical discussions. This work was supported by National Institutes of Health Grants AR45670 and DK68626 (to L. J. G.), the Joslin Diabetes and Endocrinology Research Center Grant DK36836, Commission of the European Union Contract LSHM-CT-2004-005272 EXGENESIS, Lundbeck Foundation (to E.A.R.), and the Novo Nordisk Foundation, Copenhagen Muscle Research Centre, and the Danish Medical Research Council (J. F. P. W.). H. J. K. was supported by an American Physiological Society Fellowship in Physiological Genomics; T. T. was supported by a mentor-based fellowship awarded to L. J. G. from the American Diabetes Association; and S.J.L. was supported by an American Physiological Society Fellowship in Physiological Genomics. NR 43 TC 41 Z9 42 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 31 PY 2010 VL 107 IS 35 BP 15541 EP 15546 DI 10.1073/pnas.1008131107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 645NT UT WOS:000281468500046 PM 20713714 ER PT J AU McCarthy, JR AF McCarthy, Jason R. TI Multifunctional agents for concurrent imaging and therapy in cardiovascular disease SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Cardiovascular disease; Theranostic; Nanoparticle; Microparticle; Imaging; Therapy; Atherosclerosis; Thrombosis; Restenosis ID TISSUE-PLASMINOGEN ACTIVATOR; TARGETED FUMAGILLIN NANOPARTICLES; DEEP-VENOUS THROMBOSIS; MAGNETIC NANOPARTICLES; CONTRAST AGENT; PERFLUOROCARBON NANOPARTICLES; FLUORESCENCE MICROSCOPY; IN-VIVO; ATHEROSCLEROSIS; ANGIOGENESIS AB The development of agents for the simultaneous detection and treatment of disease has recently gained significant attention. These multifunctional theranostic agents posses a number of advantages over their monofunctional counterparts, as they potentially allow for the concomitant determination of agent localization, release, and efficacy. Whereas the development of these agents for use in cancers has received the majority of the attention, their use in cardiovascular disease is steadily increasing. As such, this review summarized some of the most poignant recent advances in the development of theranostic agents for the treatment of this class of diseases. (C) 2010 Elsevier B.V. All rights reserved. C1 [McCarthy, Jason R.] Harvard Univ, Ctr Syst Biol, Sch Med, Charlestown, MA 02129 USA. [McCarthy, Jason R.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [McCarthy, Jason R.] Harvard Univ, Ctr Mol Imaging Res, Sch Med, Charlestown, MA 02129 USA. RP McCarthy, JR (reprint author), Harvard Univ, Ctr Syst Biol, Sch Med, 149 13th St,Rm 6229, Charlestown, MA 02129 USA. EM jason_mccarthy@hms.harvard.edu FU NIH [R21HL093607, U01-HL080731] FX This work was supported in part by NIH grants R21HL093607 and U01-HL080731. NR 50 TC 35 Z9 37 U1 3 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD AUG 30 PY 2010 VL 62 IS 11 BP 1023 EP 1030 DI 10.1016/j.addr.2010.07.004 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 693LI UT WOS:000285225200003 PM 20654664 ER PT J AU Rai, P Mallidi, S Zheng, X Rahmanzadeh, R Mir, Y Elrington, S Khurshid, A Hasan, T AF Rai, Prakash Mallidi, Srivalleesha Zheng, Xiang Rahmanzadeh, Ramtin Mir, Youssef Elrington, Stefan Khurshid, Ahmat Hasan, Tayyaba TI Development and applications of photo-triggered theranostic agents SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Photodynamic therapy; Nanotechnology; Photothermal therapy; Cancer; Infections; Imaging; Diagnostics; Targeting; Multifunctional; Drug delivery ID PHOTOTHERMAL CANCER-THERAPY; GROWTH-FACTOR RECEPTOR; NEAR-INFRARED LIGHT; SENSITIVE PHOTODYNAMIC AGENTS; MODIFIED SILICA NANOPARTICLES; CONTROLLED DRUG-DELIVERY; HOLLOW GOLD NANOSPHERES; PHASE-II TRIAL; QUANTUM DOTS; MACULAR DEGENERATION AB Theranostics, the fusion of therapy and diagnostics for optimizing efficacy and safety of therapeutic regimes, is a growing field that is paving the way towards the goal of personalized medicine for the benefit of patients. The use of light as a remote-activation mechanism for drug delivery has received increased attention due to its advantages in highly specific spatial and temporal control of compound release. Photo-triggered theranostic constructs could facilitate an entirely new category of clinical solutions which permit early recognition of the disease by enhancing contrast in various imaging modalities followed by the tailored guidance of therapy. Finally, such theranostic agents could aid imaging modalities in monitoring response to therapy. This article reviews recent developments in the use of light-triggered theranostic agents for simultaneous imaging and photoactivation of therapeutic agents. Specifically, we discuss recent developments in the use of theranostic agents for photodynamic-, photothermal- or photo-triggered chemotherapy for several diseases. Published by Elsevier B.V. C1 [Rai, Prakash; Mallidi, Srivalleesha; Zheng, Xiang; Rahmanzadeh, Ramtin; Mir, Youssef; Elrington, Stefan; Khurshid, Ahmat; Hasan, Tayyaba] Harvard Univ, Wellman Ctr Photomed, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Hasan, Tayyaba] Harvard MIT, Boston, MA USA. [Khurshid, Ahmat] Pakistan Inst Engn & Appl Sci, Dept Phys & Appl Math, Islamabad, Pakistan. RP Hasan, T (reprint author), Harvard Univ, Wellman Ctr Photomed, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. EM thasan@partners.org RI Rahmanzadeh, Ramtin/L-7941-2016 FU National Institutes of Health [P01 CA084203, R44CA128364]; National Cancer Institute/National Institutes of Health [R01 CA119388, RC1 CA146337]; Department of Defense Air Force Office of Scientific Research [FA9550-04-1-0079]; Wellman Center for Photomedicine; Fonds quebecois de la recherche sur la nature et les technologies (FQRNT), Quebec, Canada; Higher Education Commission (HEC) of Pakistan FX We would like to thank Prof. Gang Zheng and his postdoctoral fellow Dr. Klara Stefflova for their help with making Fig. 2 of this manuscript. We would also like to thank Dr. Bryan Spring for his helpful suggestions. This work was supported by National Institutes of Health Grant Numbers P01 CA084203 and R44CA128364 National Cancer Institute/National Institutes of Health Grant Numbers R01 CA119388 and RC1 CA146337, the Department of Defense Air Force Office of Scientific Research FA9550-04-1-0079, and the Wellman Center for Photomedicine core funds. Y.M. acknowledges funding from Fonds quebecois de la recherche sur la nature et les technologies (FQRNT), Quebec, Canada. AK. would like to acknowledge funding from the Higher Education Commission (HEC) of Pakistan. NR 241 TC 214 Z9 218 U1 43 U2 237 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD AUG 30 PY 2010 VL 62 IS 11 BP 1094 EP 1124 DI 10.1016/j.addr.2010.09.002 PG 31 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 693LI UT WOS:000285225200008 PM 20858520 ER PT J AU Kleiner-Fisman, G Stern, MB Fisman, DN AF Kleiner-Fisman, Galit Stern, Matthew B. Fisman, David N. TI Health-Related Quality of Life in Parkinson disease: Correlation between Health Utilities Index III and Unified Parkinson's Disease Rating Scale (UPDRS) in US male veterans SO HEALTH AND QUALITY OF LIFE OUTCOMES LA English DT Article ID ECONOMIC-IMPACT; DISORDERS; DETERMINANTS; STIMULATION; POPULATION; PREDICTORS; SELECTION; SYMPTOMS; COMMON; TRIAL AB Objective: To apply a scaled, preference-based measure to the evaluation of health-related quality of life (HRQoL) in Parkinson's disease (PD); to evaluate the relationship between disease-specific rating scales and estimated HRQoL; and to identify predictors of diminished HRQoL. Background: Scaled, preference-based measures of HRQoL ("utilities") serve as indices of impact of disease, and can be used to generate quality-adjusted estimates of survival for health-economic evaluations. Evaluation of utilities for PD and their correlation with standard rating scales have been limited. Methods: Utilities were generated using the Health Utilities Index Mark III (HUI-III) on consecutive patients attending a PD Clinic between October 2003 and June 2006. Disease severity, medical, surgical (subthalamic nucleus deep brain stimulation (STN-DBS)), and demographic information were used as model covariates. Predictors of HUI-III utility scores were evaluated using the Wilxocon rank-sum test and linear regression models. Results: 68 men with a diagnosis of PD and a mean age of 74.0 (SD 7.4) were included in the data analysis. Mean HUI-III utility at first visit was 0.45 (SD 0.33). In multivariable models, UPDRS-II score (r(2) = 0.56, P < 0.001) was highly predictive of HRQoL. UPDRS-III was a weaker, but still significant, predictor of utility scores, even after adjustment for UPDRS-II (P = 0.01). Conclusions: Poor self-care in PD reflected by worsening UPDRS-II scores is strongly correlated with low generic HRQoL. HUI-III-based health utilities display convergent validity with the UPDRS-II. These findings highlight the importance of measures of independence as determinants of HRQoL in PD, and will facilitate the utilization of existing UPDRS data into economic analyses of PD therapies. C1 [Kleiner-Fisman, Galit] Baycrest Geriatr Hosp, Dept Neurol, Toronto, ON M6A 2E1, Canada. [Stern, Matthew B.] Philadelphia VA Med Ctr, Parkinson Dis Res Educ & Clin Ctr PADRECC, Philadelphia, PA 19104 USA. [Fisman, David N.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON M5T 3M7, Canada. RP Kleiner-Fisman, G (reprint author), Baycrest Geriatr Hosp, Dept Neurol, 3560 Bathurst St, Toronto, ON M6A 2E1, Canada. EM gkleinerfisman@yahoo.com NR 50 TC 7 Z9 8 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7525 J9 HEALTH QUAL LIFE OUT JI Health Qual. Life Outcomes PD AUG 30 PY 2010 VL 8 AR 91 DI 10.1186/1477-7525-8-91 PG 9 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 656CN UT WOS:000282303600001 PM 20799993 ER PT J AU Nishio, J Feuerer, M Wong, J Mathis, D Benoist, C AF Nishio, Junko Feuerer, Markus Wong, Jamie Mathis, Diane Benoist, Christophe TI Anti-CD3 therapy permits regulatory T cells to surmount T cell receptor-specified peripheral niche constraints SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NONOBESE DIABETIC MICE; MONOCLONAL-ANTIBODY; TGF-BETA; PANCREATIC-ISLETS; CD8+T CELLS; REG CELLS; NOD MICE; IN-VIVO; ANTIGEN; HOMEOSTASIS AB Treatment with anti-CD3 is a promising therapeutic approach for autoimmune diabetes, but its mechanism of action remains unclear. Foxp3(+) regulatory T (T reg) cells may be involved, but the evidence has been conflicting. We investigated this issue in mice derived from the NOD model, which were engineered so that T reg populations were perturbed, or could be manipulated by acute ablation or transfer. The data highlighted the involvement of Foxp3(+) cells in anti-CD3 action. Rather than a generic influence on all T reg cells, the therapeutic effect seemed to involve an similar to 50-60-fold expansion of previously constrained T reg cell populations; this expansion occurred not through conversion from Foxp3(-) conventional T (T conv) cells, but from a proliferative expansion. We found that T reg cells are normally constrained by TCR-specific niches in secondary lymphoid organs, and that intraclonal competition restrains their possibility for conversion and expansion in the spleen and lymph nodes, much as niche competition limits their selection in the thymus. The strong perturbations induced by anti-CD3 overcame these niche limitations, in a process dependent on receptors for interleukin-2 (IL-2) and IL-7. C1 [Nishio, Junko; Feuerer, Markus; Mathis, Diane; Benoist, Christophe] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Nishio, Junko; Feuerer, Markus; Wong, Jamie; Mathis, Diane; Benoist, Christophe] Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. [Feuerer, Markus] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Wong, Jamie] Alnylam Pharmaceut, Cambridge, MA 02142 USA. RP Benoist, C (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM cbdm@hms.harvard.edu FU National Institutes of Health [AI051530-07]; Juvenile Diabetes Research Foundation (JDRF) [4-2007-1057]; Young Chair; Joslin Diabetes Center's National Institutes of Diabetes and Digestive and Kidney Diseases; JDRF Center on Immunological Tolerance in Type-1 Diabetes at Harvard Medical School; Iacocca Foundation; German Research Foundation [FE 801/1-1]; Charles King Trust FX This work was supported by grants from the National Institutes of Health (AI051530-07) and the Juvenile Diabetes Research Foundation (JDRF; 4-2007-1057) and Young Chair funds to D. Mathis and C. Benoist; and by the core facilities of Joslin Diabetes Center's National Institutes of Diabetes and Digestive and Kidney Diseases funded Diabetes and Endocrinology Research Center and of the JDRF Center on Immunological Tolerance in Type-1 Diabetes at Harvard Medical School. J. Nishio was supported by an Iacocca Foundation fellowship; M. Feuerer was supported by postdoctoral fellowships from the German Research Foundation (Emmy-Noether Fellowship, FE 801/1-1) and the Charles King Trust. NR 52 TC 45 Z9 46 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 30 PY 2010 VL 207 IS 9 BP 1879 EP 1889 DI 10.1084/jem.20100205 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 660NQ UT WOS:000282650700009 PM 20679403 ER PT J AU Falet, H Pollitt, AY Begonja, AJ Weber, SE Duerschmied, D Wagner, DD Watson, SP Hartwig, JH AF Falet, Herve Pollitt, Alice Y. Begonja, Antonija Jurak Weber, Sarah E. Duerschmied, Daniel Wagner, Denisa D. Watson, Steve P. Hartwig, John H. TI A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID VON-WILLEBRAND-FACTOR; GLYCOPROTEIN-IB-ALPHA; FILAMIN-A BINDING; BERNARD-SOULIER-SYNDROME; PERIVENTRICULAR HETEROTOPIA; MEMBRANE SKELETON; GAMMA-CHAIN; CYTOPLASMIC DOMAIN; STRUCTURAL BASIS; ARP2/3 COMPLEX AB Filamin A (FlnA) cross-links actin filaments and connects the Von Willebrand factor receptor GPIb-IX-V to the underlying cytoskeleton in platelets. Because FlnA deficiency is embryonic lethal, mice lacking FlnA in platelets were generated by breeding FlnA(loxP/loxP) females with GATA1-Cre males. FlnA(loxP/y) GATA1-Cre males have a macrothrombocytopenia and increased tail bleeding times. FlnA-null platelets have decreased expression and altered surface distribution of GPIb. because they lack the normal cytoskeletal linkage of GPIb. to underlying actin filaments. This results in similar to 70% less platelet coverage on collagen-coated surfaces at shear rates of 1,500/s, compared with wild-type platelets. Unexpectedly, however, immunoreceptor tyrosine-based activation motif (ITAM)- and ITAM-like-mediated signals are severely compromised in FlnA-null platelets. FlnA-null platelets fail to spread and have decreased alpha-granule secretion, integrin alpha IIb beta 3 activation, and protein tyrosine phosphorylation, particularly that of the protein tyrosine kinase Syk and phospholipase C-gamma 2, in response to stimulation through the collagen receptor GPVI and the C-type lectin-like receptor 2. This signaling defect was traced to the loss of a novel FlnA-Syk interaction, as Syk binds to FlnA at immunoglobulin-like repeat 5. Our findings reveal that the interaction between FlnA and Syk regulates ITAM- and ITAM-like-containing receptor signaling and platelet function. C1 [Falet, Herve; Begonja, Antonija Jurak; Weber, Sarah E.; Hartwig, John H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Translat Med, Boston, MA 02115 USA. [Duerschmied, Daniel; Wagner, Denisa D.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Duerschmied, Daniel; Wagner, Denisa D.] Harvard Univ, Sch Med, Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA. [Falet, Herve; Begonja, Antonija Jurak; Weber, Sarah E.; Hartwig, John H.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Duerschmied, Daniel; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Pollitt, Alice Y.; Watson, Steve P.] Univ Birmingham, Coll Med & Dent Sci, Inst Biomed Res, Ctr Cardiovasc Sci, Birmingham B15 2TT, W Midlands, England. RP Falet, H (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Translat Med, Boston, MA 02115 USA. EM hfalet@rics.bwh.harvard.edu RI Watson, Stephen/Q-6292-2016; OI Watson, Stephen/0000-0002-7846-7423; Pollitt, Alice/0000-0001-8706-5154; Falet, Herve/0000-0003-0788-9204 FU National Institutes of Health [HL-056252, HL-056949, HL-059561]; British Heart Foundation (BHF) [PG/07/116] FX This work was supported by National Institutes of Health grants HL-056252 (J.H. Hartwig), HL-056949 (J.H. Hartwig and D.D. Wagner), and HL-059561 (J.H. Hartwig and H. Falet). A.Y. Pollitt was supported by the British Heart Foundation (BHF) project grant (PG/07/116). S.P. Watson holds a BHF Chair. NR 64 TC 52 Z9 56 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 30 PY 2010 VL 207 IS 9 BP 1967 EP 1979 DI 10.1084/jem.20100222 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 660NQ UT WOS:000282650700015 PM 20713593 ER PT J AU Brieu, N Beaumont, E Dubeau, S Cohen-Adad, J Lesage, F AF Brieu, Nicolas Beaumont, Eric Dubeau, Simon Cohen-Adad, Julien Lesage, Frederic TI Characterization of the hemodynamic response in the rat lumbar spinal cord using intrinsic optical imaging and laser speckle SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Intrinsic optical imaging; Laser speckle; Rat; Spinal cord; Blood flow; Blood oxygenation; Hemodynamic response function; Neurovascular coupling ID PERIPHERAL-NERVE STIMULATION; VOLUME-WEIGHTED FMRI; CEREBRAL-BLOOD-FLOW; FUNCTIONAL MRI; SOMATOSENSORY CORTEX; GRADIENT-ECHO; BOLD SIGNAL; HUMAN BRAIN; OXYGENATION; ACTIVATION AB Quantifying spinal cord functions is crucial for understanding neurophysiological mechanisms governing the intact and the injured spinal cord. Intrinsic optical imaging (IOI) and laser speckle provides measures of deoxyhemoglobin (HbR) and oxyhemoglobin (HbO(2)) concentrations, blood volume (BV) and blood flow (BF) at high spatial and temporal resolution. In this study we used IOI and laser speckle to characterize the hemodynamic response to neuronal activation in the lumbar spinal cord of anaesthetized rats (N = 9). We report consistent temporal variations of HbR, HbO(2), BV and BF located ipsilaterally at L3-L5. Responses were significantly higher when stimulation intensity was increased. Vascular changes extended several millimetres from the epicenter, supporting the venous drainage observed in functional magnetic resonance imaging studies. (C) 2010 Elsevier B.V. All rights reserved. C1 [Brieu, Nicolas; Beaumont, Eric; Dubeau, Simon; Lesage, Frederic] Ecole Polytech, Dept Genie Elect, Montreal, PQ H3C 3A7, Canada. [Cohen-Adad, Julien] Univ Montreal, Dept Physiol, GRSNC, Montreal, PQ H3C 3J7, Canada. [Cohen-Adad, Julien] Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Lesage, F (reprint author), Ecole Polytech, Dept Genie Elect, CP 6079,Succ Ctr Ville, Montreal, PQ H3C 3A7, Canada. EM frederic.lesage@polymtl.ca FU MITACS fellowship; Fondation pour la Recherche Medicale; NSERC FX Authors have no conflict of interest. N. Brieu was supported by a MITACS fellowship. J. Cohen-Adad was supported by the Fondation pour la Recherche Medicale. This work was supported by a NSERC discovery grant. NR 50 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 30 PY 2010 VL 191 IS 2 BP 151 EP 157 DI 10.1016/j.jneumeth.2010.06.012 PG 7 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 651KR UT WOS:000281927100001 PM 20600322 ER PT J AU Leak, RK Castro, SL Jaumotte, JD Smith, AD Zigmond, MJ AF Leak, Rehana K. Castro, Sandra L. Jaumotte, Juliann D. Smith, Amanda D. Zigmond, Michael J. TI Assaying multiple biochemical variables from the same tissue sample SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Sodium fluoride; Sonication; Dopamine; Parkinson's disease; Tyrosine hydroxylase; Dopamine Transporter; Phosphorylation; ERK1/2; Akt ID SUBSTANTIA-NIGRA; HUMAN BRAIN AB Experiments often involve multiple analyses, such as assays of neurotransmitters and proteins, and this can require different initial sample preparations. Typically, this is accomplished by using different animals or different tissue samples from the same animal. Either approach renders comparisons between assays more variable and greatly increases the effort and/or cost. Using tissue collected from rat striatum and molecules of special relevance to studies of Parkinson's disease, we show that tissue sonication in water prior to aliquoting into the appropriate concentrated solutions (e.g. HClO4 and lysis buffers) permits several types of measurements to be made from the same initial samples. Dopamine and its metabolite homovanillic acid, serotonin and its metabolite 5-hydroxyindoleacetic acid, tyrosine hydroxylase and its phosphorylation at Ser19 and Ser31, and the dopamine transporter were unaffected. However, phospho-Akt levels fell slightly and phospho-ERK1/2 tended to drop. We also present a simple technique to preserve phosphorylation state of proteins such as ERK1/2 by perfusing animals through the heart with a phosphatase inhibitor, NaF. Dopamine metabolite dihydroxyphenyl acetic acid (DOPAC) levels were raised with both techniques, however. The general principles reported here are likely to apply to other brain regions, facilitate multiple comparisons of variables, increase efficiency, and decrease costs. (C) 2010 Elsevier B.V. All rights reserved. C1 [Leak, Rehana K.] Duquesne Univ, Dept Pharmacol, Mylan Sch Pharm, Pittsburgh, PA 15282 USA. [Leak, Rehana K.; Castro, Sandra L.; Jaumotte, Juliann D.; Smith, Amanda D.; Zigmond, Michael J.] Univ Pittsburgh, Dept Neurol, Pittsburgh Inst Neurodegenerat Dis, Pittsburgh, PA 15260 USA. [Smith, Amanda D.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Leak, RK (reprint author), Duquesne Univ, Dept Pharmacol, Mylan Sch Pharm, Mellon Hall,Room 407-600 Forbes Ave, Pittsburgh, PA 15282 USA. EM leakr@duq.edu OI Leak, Rehana/0000-0003-2817-7417 FU NIH [P50 NS019608, R01 TW008040] FX This work was supported by NIH grants P50 NS019608 and R01 TW008040 to MJZ at the University of Pittsburgh and a startup award to RKL at Duquesne University. NR 10 TC 10 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 30 PY 2010 VL 191 IS 2 BP 234 EP 238 DI 10.1016/j.jneumeth.2010.06.023 PG 5 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 651KR UT WOS:000281927100012 PM 20600314 ER PT J AU Smith, JC Paulson, ES Cook, DB Verber, MD Tian, Q AF Smith, J. Carson Paulson, Eric S. Cook, Dane B. Verber, Matthew D. Tian, Qu TI Detecting changes in human cerebral blood flow after acute exercise using arterial spin labeling: Implications for fMRI SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Acute exercise; Physical activity; Cerebral blood flow; fMRI BOLD; Physiological monitoring; End-tidal CO2 ID DYNAMIC EXERCISE; ACTIVATION AB The use of arterial spin labeling to measure cerebral blood flow (CBF) after acute exercise has not been reported. The aims of this study were to examine: (1) the optimal inversion time to detect changes in CBF after acute exercise and (2) if acute exercise alters CBF in the motor cortex at rest or during finger-tapping. Subjects (n = 5) performed 30 min of moderate intensity exercise on an electronically braked cycle ergometer (perceived exertion 'somewhat hard'). Before and after exercise, relative CBF was measured using multiple inversion time (TI) pulsed arterial spin labeling (PASL). Two multiple TI runs were obtained at rest and during 4 Hz finger-tapping. Four inversion times (675, 975, 1275, and 1575 ms) were acquired per run, with 20 interleaved pairs of tag and control images per inversion time (320 s run). The results indicated that global CBF increased approximately 20% following exercise, with significant differences observed at an inversion time of 1575 ms (p < .05). Finger-tapping induced CBF in the motor cortex significantly increased from before to after exercise at TI = 1575 ms (p < .01). These findings suggest changes in human cerebral blood flow that result from acute moderate intensity exercise can be detected afterwards using PASL at 3T with an inversion time of 1575 ms. The effect of prior acute exercise to increase motor cortex CBF during the performance of a motor task suggests future use of indices of functional activation should account for exercise-induced changes in cardio-pulmonary physiology and CBF. (C) 2010 Elsevier B.V. All rights reserved. C1 [Smith, J. Carson; Tian, Qu] Univ Wisconsin, Dept Human Movement Sci, Milwaukee, WI 53201 USA. [Paulson, Eric S.] Med Coll Wisconsin, Dept Radiat Oncol, Milwaukee, WI 53226 USA. [Cook, Dane B.] Univ Wisconsin, Dept Kinesiol, Madison, WI 53706 USA. [Cook, Dane B.] William S Middleton Mem Vet Adm Med Ctr, Res Serv, Madison, WI 53706 USA. [Verber, Matthew D.] Med Coll Wisconsin, Clin & Translat Sci Inst, Milwaukee, WI 53226 USA. RP Smith, JC (reprint author), Univ Wisconsin, Dept Human Movement Sci, POB 413, Milwaukee, WI 53201 USA. EM jcarson@uwm.edu; epaulson@mcw.edu; dcook@education.wisc.edu; mverber@mcw.edu; qutian@uwm.edu RI Smith, J. Carson/G-6404-2013; OI Smith, J. Carson/0000-0001-6142-0920; Kennedy, Kristen/0000-0001-5373-9026 FU General Clinical Research Center at the Medical College of Wisconsin FX This work was supported by the General Clinical Research Center at the Medical College of Wisconsin. NR 15 TC 24 Z9 25 U1 2 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 30 PY 2010 VL 191 IS 2 BP 258 EP 262 DI 10.1016/j.jneumeth.2010.06.028 PG 5 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 651KR UT WOS:000281927100017 PM 20603148 ER PT J AU Yuan, J Peng, LL Bouma, BE Tearney, GJ AF Yuan, Jing Peng, Leilei Bouma, Brett E. Tearney, Guillermo J. TI Quantitative FRET measurement by high-speed fluorescence excitation and emission spectrometer SO OPTICS EXPRESS LA English DT Article ID RESONANCE ENERGY-TRANSFER; SINGLE-MOLECULE FLUORESCENCE; PROTEIN-PROTEIN INTERACTIONS; LIVING CELLS; IN-VIVO; IMAGING MICROSCOPY; DELAY-LINE; LIVE CELLS; SPECTROFLUOROMETER; DYNAMICS AB Forster resonance energy transfer (FRET) is an important method in studying biochemistry reactions. But quantifying FRET rapidly is difficult to do because of crosstalk between free donor, free acceptor and FRET fluorescent signals when only excitation or emission property of a FRET sample is measured. If FRET is studied with excitation-emission matrix (EEM) measurements, because the fluorescence intensity maxima of donor, acceptor, and FRET emissions occupy different regions within the EEM, FRET fluorescence can be easily separated out by linear unmixing. In this paper, we report a novel high-speed Fourier Fluorescence Excitation Emission spectrometer, which simultaneously measures three projections of EEM from a FRET sample, which are excitation, emission and excitation-emission cross-correlation spectra. We demonstrate that these three EEM projections can be measured and unmixed in approximately 1 ms to provide rapid quantitative FRET in the presence of free donors and acceptors. The system can be utilized to enable real-time biochemistry reaction studies. (C) 2010 Optical Society of America C1 [Yuan, Jing; Peng, Leilei; Bouma, Brett E.; Tearney, Guillermo J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Yuan, Jing; Peng, Leilei; Bouma, Brett E.; Tearney, Guillermo J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Yuan, Jing] Huazhong Univ Sci & Technol, Wuhan Natl Lab Optoelect, Britton Chance Ctr Biomed Photon, Wuhan 430074, Hubei, Peoples R China. RP Yuan, J (reprint author), Harvard Univ, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM gtearney@partners.org NR 44 TC 6 Z9 6 U1 6 U2 12 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD AUG 30 PY 2010 VL 18 IS 18 BP 18839 EP 18851 DI 10.1364/OE.18.018839 PG 13 WC Optics SC Optics GA 653PE UT WOS:000282107900036 PM 20940777 ER PT J AU Darmoise, A Teneberg, S Bouzonville, L Brady, RO Beck, M Kaufmann, SHE Winau, F AF Darmoise, Alexandre Teneberg, Susann Bouzonville, Lauriane Brady, Roscoe O. Beck, Michael Kaufmann, Stefan H. E. Winau, Florian TI Lysosomal alpha-Galactosidase Controls the Generation of Self Lipid Antigens for Natural Killer T Cells SO IMMUNITY LA English DT Article ID INVARIANT NKT CELLS; ENZYME REPLACEMENT; IMMUNE-RESPONSE; CD1D TETRAMERS; ACTIVATION; RECOGNITION; MICE; MATURATION; RECEPTORS; MOLECULES AB Natural Killer T (NKT) cells are lipid-reactive, CD1 drestricted T lymphocytes important in infection, cancer, and autoimmunity. In addition to foreign antigens, NKT cells react with endogenous self lipids. However, in the face of stimulating self antigen, it remains unclear how overstimulation of NKT cells is avoided. We hypothesized that constantly degraded endogenous antigen only accumulates upon inhibition of alpha-galactosidase A (alpha-Gal-A) in lysosomes. Here, we show that alpha-Gal-A deficiency caused vigorous activation of NKT cells. Moreover, microbes induced inhibition of alpha-Gal-A activity in antigen-presenting cells. This temporary enzyme block depended on Toll-like receptor (TLR) signaling and ultimately triggered lysosomal lipid accumulation. Thus, we present TLR-dependent negative regulation of alpha-Gal-A as a mechanistic link between pathogen recognition and self lipid antigen induction for NKT cells. C1 [Darmoise, Alexandre; Bouzonville, Lauriane; Winau, Florian] Harvard Univ, Sch Med, Dept Pathol,Immune Dis Inst, Childrens Hosp,Program Cellular & Mol Med, Boston, MA 02115 USA. [Teneberg, Susann] Univ Gothenburg, Dept Med Biochem & Cell Biol, Inst Biomed, S-40530 Gothenburg, Sweden. [Brady, Roscoe O.] NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. [Beck, Michael] Johannes Gutenberg Univ Mainz, Childrens Hosp, D-55131 Mainz, Germany. [Darmoise, Alexandre; Kaufmann, Stefan H. E.; Winau, Florian] Max Planck Inst Infect Biol, Dept Immunol, D-10117 Berlin, Germany. RP Winau, F (reprint author), Harvard Univ, Sch Med, Dept Pathol,Immune Dis Inst, Childrens Hosp,Program Cellular & Mol Med, Boston, MA 02115 USA. EM winau@idi.harvard.edu RI Kaufmann, Stefan HE/I-5454-2014 OI Kaufmann, Stefan HE/0000-0001-9866-8268 FU European Union Marie Curie Actions [MEST-CT-2005-020311]; German Science Foundation [SFB 421] FX We thank S. Weber for expert technical assistance. We are grateful to Dr. S. Porcelli for sharing mAb K253 with us. We thank Dr. A. d'Azzo for providing us with beta-Gal-deficient mice. We thank the NIH Tetramer Facility for CD1d-tetramers. This work was supported in part by the European Union Marie Curie Actions (MEST-CT-2005-020311 to A.D.) and the German Science Foundation (SFB 421 to S.H.E.K. and F.W.). NR 46 TC 64 Z9 64 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 27 PY 2010 VL 33 IS 2 BP 216 EP 228 DI 10.1016/j.immuni.2010.08.003 PG 13 WC Immunology SC Immunology GA 647XU UT WOS:000281654900011 PM 20727792 ER PT J AU Chou, RC Kim, ND Sadik, CD Seung, E Lan, YN Byrne, MH Haribabu, B Iwakura, Y Luster, AD AF Chou, Richard C. Kim, Nancy D. Sadik, Christian D. Seung, Edward Lan, Yinan Byrne, Michael H. Haribabu, Bodduluri Iwakura, Yoichiro Luster, Andrew D. TI Lipid-Cytokine-Chemokine Cascade Drives Neutrophil Recruitment in a Murine Model of Inflammatory Arthritis SO IMMUNITY LA English DT Article ID INFL AMMATORY ARTHRITIS; T-CELL TRAFFICKING; RHEUMATOID-ARTHRITIS; THERAPEUTIC TARGETS; MEDIATED ARTHRITIS; LEUKOTRIENE B-4; RECEPTOR BLT1; MAST-CELLS; MICE; DISEASE AB A large and diverse array of chemoattractants control leukocyte trafficking, but how these apparently redundant signals collaborate in vivo is still largely unknown. We previously demonstrated an absolute requirement for the lipid chemoattractant leukotriene B(4) (LTB(4)) and its receptor BLT1 for neutrophil recruitment into the joint in autoantibody-induced arthritis. We now demonstrate that BLT1 is required for neutrophils to deliver IL-1 into the joint to initiate arthritis. IL-1-expressing neutrophils amplify arthritis through the production of neutrophil-active chemokines from synovial tissue cells. CCR1 and CXCR2, two neutrophil chemokine receptors, operate nonredundantly to sequentially control the later phase of neutrophil recruitment into the joint and mediate all neutrophil chemokine activity in the model. Thus, we have uncovered a complex sequential relationship involving unique contributions from the lipid mediator LTB(4), the cytokine IL-1, and CCR1 and CXCR2 chemokine ligands that are all absolutely required for effective neutrophil recruitment into the joint. C1 [Chou, Richard C.; Kim, Nancy D.; Sadik, Christian D.; Seung, Edward; Lan, Yinan; Byrne, Michael H.; Luster, Andrew D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumat Allerg, Boston, MA 02114 USA. [Haribabu, Bodduluri] Univ Louisville Hlth Sci, James Graham Brown Canc Ctr, Tumor Immunobiol Program, Louisville, KY 40202 USA. [Iwakura, Yoichiro] Univ Tokyo, Inst Med Sci, Ctr Med Expt, Tokyo 1088639, Japan. RP Luster, AD (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumat Allerg, Boston, MA 02114 USA. EM aluster@mgh.harvard.edu RI Iwakura, Yoichiro/E-5457-2011; Sadik, Christian/E-8404-2012; OI Iwakura, Yoichiro/0000-0002-9934-5775; Bodduluri, Haribabu/0000-0002-8261-3294 FU National Institutes of Health [R01AI050892, K08 AR054094]; Abbott; Deutsche Forschungsgemeinschaft [Sa1960/1-1] FX Studies were supported by National Institutes of Health R01AI050892 (A.D.L.) and K08 AR054094 (N.D.K.), Abbott Scholar Award in Rheumatology Research (R.C.C.), and Deutsche Forschungsgemeinschaft Sa1960/1-1 (C.D.S.). NR 29 TC 138 Z9 143 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD AUG 27 PY 2010 VL 33 IS 2 BP 266 EP 278 DI 10.1016/j.immuni.2010.07.018 PG 13 WC Immunology SC Immunology GA 647XU UT WOS:000281654900015 PM 20727790 ER PT J AU Park, KH Kurokawa, K Zheng, L Jung, DJ Tateishi, K Jin, JO Ha, NC Kang, HJ Matsushita, M Kwak, JY Takahashi, K Lee, BL AF Park, Keun-Hwa Kurokawa, Kenji Zheng, Lili Jung, Dong-Jun Tateishi, Koichiro Jin, Jun-O Ha, Nam-Chul Kang, Hee Jung Matsushita, Misao Kwak, Jong-Young Takahashi, Kazue Lee, Bok Luel TI Human Serum Mannose-binding Lectin Senses Wall Teichoic Acid Glycopolymer of Staphylococcus aureus, Which Is Restricted in Infancy SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GRAM-POSITIVE BACTERIA; LIPOTEICHOIC ACID; SERINE-PROTEASE; COMPLEMENT ACTIVATION; INNATE IMMUNITY; ASSOCIATION; INFECTION; RESISTANCE; PATHWAY; GENE AB Innate immunity is the first line of host defense against invading pathogens, and it is recognized by a variety of pattern recognition molecules, including mannose-binding lectin (MBL). MBL binds to mannose and N-acetylglucosamine residues present on the glycopolymers of microorganisms. Human serum MBL functions as an opsonin and activates the lectin complement pathway. However, which glycopolymer of microorganism is recognized by MBL is still uncertain. Here, we show that wall teichoic acid of Staphylococcus aureus, a bacterial cell surface glycopolymer containing N-acetylglucosamine residue, is a functional ligand of MBL. Whereas serum MBL in adults did not bind to wall teichoic acid because of an inhibitory effect of anti-wall teichoic acid antibodies, MBL in infants who had not yet fully developed their adaptive immunity could bind to S. aureus wall teichoic acid and then induced complement C4 deposition. Our data explain the molecular reasons of why MBL-deficient infants are susceptible to S. aureus infection. C1 [Park, Keun-Hwa; Kurokawa, Kenji; Zheng, Lili; Jung, Dong-Jun; Ha, Nam-Chul; Lee, Bok Luel] Pusan Natl Univ, Coll Pharm, Natl Res Lab Def Prot, Pusan 609735, South Korea. [Tateishi, Koichiro; Matsushita, Misao] Tokai Univ, Dept Appl Biochem, Kanagawa 2591292, Japan. [Jin, Jun-O; Kwak, Jong-Young] Dong A Univ, Dept Biochem, Pusan 602714, South Korea. [Kang, Hee Jung] Hallym Univ, Coll Med, Dept Lab Med, Anyang Si 431070, South Korea. [Takahashi, Kazue] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Programs Dev Immunol, Boston, MA 02114 USA. RP Lee, BL (reprint author), Pusan Natl Univ, Coll Pharm, Natl Res Lab Def Prot, Pusan 609735, South Korea. EM brlee@pusan.ac.kr FU National Research Foundation of Korea [M10400000028-04J0000-02, 2009-032-2000, 2008-8057-6001, BK21] FX This work was supported by Programs M10400000028-04J0000-02, 2009-032-2000, 2008-8057-6001, and BK21 of the National Research Foundation of Korea. NR 47 TC 29 Z9 31 U1 2 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 27 PY 2010 VL 285 IS 35 BP 27167 EP 27175 DI 10.1074/jbc.M110.141309 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 641ZQ UT WOS:000281172700047 PM 20592033 ER PT J AU Kogai, T Liu, YY Richter, LL Mody, K Kagechika, H Brent, GA AF Kogai, Takahiko Liu, Yan-Yun Richter, Laura L. Mody, Kaizeen Kagechika, Hiroyuki Brent, Gregory A. TI Retinoic Acid Induces Expression of the Thyroid Hormone Transporter, Monocarboxylate Transporter 8 (Mct8) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EMBRYONIC STEM-CELLS; PLASMINOGEN-ACTIVATOR GENE; BREAST-CANCER CELLS; SODIUM/IODIDE SYMPORTER; INDUCED TRANSCRIPTION; RETINOBENZOIC ACIDS; BINDING PROTEINS; RECEPTOR-ALPHA; START SITES; DIFFERENTIATION AB Retinoic acid (RA) and thyroid hormone are critical for differentiation and organogenesis in the embryo. Mct8 (monocarboxylate transporter 8), expressed predominantly in the brain and placenta, mediates thyroid hormone uptake from the circulation and is required for normal neural development. RA induces differentiation of F9 mouse teratocarcinoma cells toward neurons as well as extraembryonal endoderm. We hypothesized that Mct8 is functionally expressed in F9 cells and induced by RA. All-trans-RA (tRA) and other RA receptor (RAR) agonists dramatically (>300-fold) induced Mct8. tRA treatment significantly increased uptake of triiodothyronine and thyroxine (4.1- and 4.3-fold, respectively), which was abolished by a selective Mct8 inhibitor, bromosulfophthalein. Sequence inspection of the Mct8 promoter region and 5'-rapid amplification of cDNA ends PCR analysis in F9 cells identified 11 transcription start sites and a proximal Sp1 site but no TATA box. tRA significantly enhanced Mct8 promoter activity through a consensus RA-responsive element located 6.6 kilobases upstream of the coding region. A chromatin immunoprecipitation assay demonstrated binding of RAR and retinoid X receptor to the RA response element. The promotion of thyroid hormone uptake through the transcriptional up-regulation of Mct8 by RAR is likely to be important for extraembryonic endoderm development and neural differentiation. This finding demonstrates cross-talk between RA signaling and thyroid hormone signaling in early development at the level of the thyroid hormone transporter. C1 [Kogai, Takahiko; Liu, Yan-Yun; Richter, Laura L.; Mody, Kaizeen; Brent, Gregory A.] Vet Affairs Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, Los Angeles, CA 90073 USA. [Kogai, Takahiko; Liu, Yan-Yun; Richter, Laura L.; Mody, Kaizeen; Brent, Gregory A.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Kogai, Takahiko; Liu, Yan-Yun; Richter, Laura L.; Mody, Kaizeen; Brent, Gregory A.] Univ Calif Los Angeles, Dept Physiol, David Geffen Sch Med, Los Angeles, CA 90073 USA. [Kagechika, Hiroyuki] Tokyo Med & Dent Univ, Inst Biomat & Bioengn, Tokyo 1010062, Japan. RP Kogai, T (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Mol Endocrinol Lab, Bldg 114,Rm 230,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM tkogai@ucla.edu; gbrent@ucla.edu FU Veterans Affairs; National Institutes of Health [RO1 CA089364] FX This work was supported, in whole or in part, by Veterans Affairs Merit Review Funds. This work was also supported by National Institutes of Health Grant RO1 CA089364 (to G. A. B.). NR 51 TC 13 Z9 13 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 27 PY 2010 VL 285 IS 35 BP 27279 EP 27288 DI 10.1074/jbc.M110.123158 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 641ZQ UT WOS:000281172700058 PM 20573951 ER PT J AU Qiang, L Banks, AS Accili, D AF Qiang, Li Banks, Alexander S. Accili, Domenico TI Uncoupling of Acetylation from Phosphorylation Regulates FoxO1 Function Independent of Its Subcellular Localization SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FORKHEAD TRANSCRIPTION FACTOR; BETA-CELL FUNCTION; FACTOR FKHR; SIGNALING PATHWAY; GENE-EXPRESSION; 14-3-3 BINDING; PROTEIN FOXO1; LIFE-SPAN; INSULIN; DIFFERENTIATION AB The activity of transcription factor FoxO1 is regulated by phosphorylation-dependent nuclear exclusion and deacetylation-dependent nuclear retention. It is unclear whether and how these two post-translational modifications affect each other. To answer this question, we expressed FoxO1 cDNAs with combined mutations of phosphorylation and acetylation sites in HEK-293 cells and analyzed their subcellular localization patterns. We show that mutations mimicking the acetylated state (KQ series) render FoxO1 more sensitive to Akt-mediated phosphorylation and nuclear exclusion and can reverse the constitutively nuclear localization of phosphorylation-defective FoxO1. Conversely, mutations mimicking the deacetylated state (KR series) promote FoxO1 nuclear retention. Oxidative stress and the Sirt1 activator resveratrol are thought to promote FoxO1 deacetylation and nuclear retention, thus increasing its activity. Accordingly, FoxO1 deacetylation was required for the effect of oxidative stress (induced by H(2)O(2)) to retain FoxO1 in the nucleus. H(2)O(2) also inhibited FoxO1 phosphorylation on Ser-253 and Thr-24, the key insulin-regulated sites, irrespective of its acetylation. In contrast, the effect of resveratrol was independent of FoxO1 acetylation and its phosphorylation on Ser-253 and Thr-24, suggesting that resveratrol acts on FoxO1 in a Sirt1- and Akt-independent manner. The dissociation of deacetylation from dephosphorylation in H(2)O(2)-treated cells indicates that the two modifications can occur independently of each other. It can be envisaged that FoxO1 exists in multiple nuclear forms with distinct activities depending on the balance of acetylation and phosphorylation. C1 [Qiang, Li; Accili, Domenico] Columbia Univ, Dept Med, New York, NY 10032 USA. [Banks, Alexander S.] Harvard Univ, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. RP Accili, D (reprint author), 1150 St Nicholas Ave,Rm 238, New York, NY 10032 USA. EM da230@columbia.edu RI Qiang, Li/C-9560-2012; Banks, Alexander/B-4832-2012 OI Banks, Alexander/0000-0003-1787-6925 FU National Institutes of Health, Columbia University Diabetes and Endocrinology Research Center [DK57539, DK63608] FX This work was supported by National Institutes of Health Grants DK57539 and DK63608 from the Columbia University Diabetes and Endocrinology Research Center. NR 39 TC 71 Z9 74 U1 0 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 AUG 27 PY 2010 VL 285 IS 35 BP 27396 EP 27401 DI 10.1074/jbc.M110.140228 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 641ZQ UT WOS:000281172700068 PM 20519497 ER PT J AU Christiansen, B Muguerza, NB Petersen, AM Kveiborg, B Madsen, CR Thomas, H Ihlemann, N Sorensen, JC Kober, L Sorensen, H Torp-Pedersen, C Dominguez, H AF Christiansen, Buris Muguerza, Natalia Bellostas Petersen, Atheline Major Kveiborg, Britt Madsen, Christian Rask Thomas, Hermann Ihlemann, Nikolaj Sorensen, Jens Christian Kober, Lars Sorensen, Hilmer Torp-Pedersen, Christian Dominguez, Helena TI Ingestion of Broccoli Sprouts Does Not Improve Endothelial Function in Humans with Hypertension SO PLOS ONE LA English DT Article ID OXIDATIVE STRESS; CARDIOVASCULAR INJURY; CANCER RISK; PART II; BRASSICA; METABOLISM; ISOTHIOCYANATES; POLYMORPHISMS; VASODILATION; DYSFUNCTION AB Ingestion of glucosinolates has previously been reported to improve endothelial function in spontaneously hypertensive rats, possibly because of an increase in NO availability in the endothelium due to an attenuation of oxidative stress; in our study we tried to see if this also would be the case in humans suffering from essential hypertension. Methods: 40 hypertensive individuals without diabetes and with normal levels of cholesterol were examined. The participants were randomized either to ingest 10 g dried broccoli sprouts, a natural donor of glucosinolates with high in vitro antioxidative potential, for a 4 week period or to continue their ordinary diet and act as controls. Blood pressure, endothelial function measured by flow mediated dilation (FMD) and blood samples were obtained from the participants every other week and the content of glucosinolates was measured before and after the study. Measurements were blinded to treatment allocation. Results: In the interventional group overall FMD increased from 4% to 5.8% in the interventional group whereas in the control group FMD was stable (4% at baseline and 3.9% at the end of the study). The change in FMD in the interventional group was mainly due to a marked change in FMD in two participants while the other participants did not have marked changes in FMD. The observed differences were not statistically significant. Likewise significant changes in blood pressure or blood samples were not detected between or within groups. Diastolic blood pressure stayed essentially unchanged in both groups, while the systolic blood pressure showed a small non significant decrease (9 mm Hg) in the interventional group from a value of 153 mm Hg at start. Conclusion: Daily ingestion of 10 g dried broccoli sprouts does not improve endothelial function in the presence of hypertension in humans. C1 [Christiansen, Buris] Copenhagen Univ Hosp, Herlev Hosp, Dept Oncol, Region Hovedstaden, Denmark. [Muguerza, Natalia Bellostas; Sorensen, Jens Christian; Sorensen, Hilmer] Univ Copenhagen, Fac Life Sci, Copenhagen, Denmark. [Petersen, Atheline Major] Odense Univ Hosp, Dept Endocrinol, Region Midt, Denmark. [Kveiborg, Britt] Sygehus Syd, Dept Med, Region Sjaelland, Denmark. [Madsen, Christian Rask; Thomas, Hermann] Joslin Diabet Ctr, Dept Vasc Biol & Complicat, Boston, MA 02215 USA. [Ihlemann, Nikolaj; Kober, Lars; Torp-Pedersen, Christian] Copenhagen Univ Hosp, Gentofte Hosp, Dept Cardiol, Region Hovedstaden, Denmark. [Dominguez, Helena] Copenhagen Univ Hosp, Herlev Hosp, Dept Cardiol, Region Hovedstaden, Denmark. RP Christiansen, B (reprint author), Copenhagen Univ Hosp, Herlev Hosp, Dept Oncol, Region Hovedstaden, Denmark. EM buris@dadlnet.dk RI Torp-Pedersen, Christian/E-5931-2013; OI DOMINGUEZ, HELENA/0000-0002-7089-2636 FU Danish Heart Association; Beckett foundation FX This study was supported by grants from the Danish Heart Association (hjerteforeningen.dk) and the Beckett foundation (www.beckett-fonden.dk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 7 Z9 7 U1 1 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 AUG 27 PY 2010 VL 5 IS 8 AR e12461 DI 10.1371/journal.pone.0012461 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643MT UT WOS:000281301500026 PM 20805984 ER PT J AU Shaffer, MH Huang, YP Corbo, E Wu, GF Velez, M Choi, JK Saotome, I Cannon, JL McClatchey, AI Sperling, AI Maltzman, JS Oliver, PM Bhandoola, A Laufer, TM Burkhardt, JK AF Shaffer, Meredith H. Huang, Yanping Corbo, Evann Wu, Gregory F. Velez, Marielena Choi, John K. Saotome, Ichiko Cannon, Judy L. McClatchey, Andrea I. Sperling, Anne I. Maltzman, Jonathan S. Oliver, Paula M. Bhandoola, Avinash Laufer, Terri M. Burkhardt, Janis K. TI Ezrin Is Highly Expressed in Early Thymocytes, but Dispensable for T Cell Development in Mice SO PLOS ONE LA English DT Article ID IMMUNOLOGICAL SYNAPSE; ERM PROTEINS; MOESIN; RADIXIN; CYTOSKELETON; LYMPHOCYTES; DEFECTS; CD43; MICROVILLI; KNOCKOUT AB Background: Ezrin/radixin/moesin (ERM) proteins are highly homologous proteins that function to link cargo molecules to the actin cytoskeleton. Ezrin and moesin are both expressed in mature lymphocytes, where they play overlapping roles in cell signaling and polarity, but their role in lymphoid development has not been explored. Methodology/Principal Findings: We characterized ERM protein expression in lymphoid tissues and analyzed the requirement for ezrin expression in lymphoid development. In wildtype mice, we found that most cells in the spleen and thymus express both ezrin and moesin, but little radixin. ERM protein expression in the thymus was differentially regulated, such that ezrin expression was highest in immature thymocytes and diminished during T cell development. In contrast, moesin expression was low in early thymocytes and upregulated during T cell development. Mice bearing a germline deletion of ezrin exhibited profound defects in the size and cellularity of the spleen and thymus, abnormal thymic architecture, diminished hematopoiesis, and increased proportions of granulocytic precursors. Further analysis using fetal liver chimeras and thymic transplants showed that ezrin expression is dispensable in hematopoietic and stromal lineages, and that most of the defects in lymphoid development in ezrin(-/-) mice likely arise as a consequence of nutritional stress. Conclusions/Significance: We conclude that despite high expression in lymphoid precursor cells, ezrin is dispensable for lymphoid development, most likely due to redundancy with moesin. C1 [Shaffer, Meredith H.; Huang, Yanping; Choi, John K.; Oliver, Paula M.; Burkhardt, Janis K.] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Shaffer, Meredith H.; Huang, Yanping; Choi, John K.; Oliver, Paula M.; Burkhardt, Janis K.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Shaffer, Meredith H.; Huang, Yanping; Velez, Marielena; Choi, John K.; Oliver, Paula M.; Bhandoola, Avinash; Burkhardt, Janis K.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Corbo, Evann; Maltzman, Jonathan S.; Laufer, Terri M.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Wu, Gregory F.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Saotome, Ichiko; McClatchey, Andrea I.] Massachusetts Gen Hosp, Ctr Canc, Dept Pathol, Charlestown, MA USA. [Saotome, Ichiko; McClatchey, Andrea I.] Harvard Univ, Sch Med, Charlestown, MA USA. [Cannon, Judy L.; Sperling, Anne I.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Shaffer, MH (reprint author), Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM jburkhar@mail.med.upenn.edu OI Cannon, Judy/0000-0003-0069-8106 FU National Institutes of Health (NIH) [R01 AI50098, P01 CA093615, T32-HD07516-09, T32-GM7229-29] FX This work was supported by National Institutes of Health (http://www.nih.gov) grants R01 AI50098 and P01 CA093615 (to J.K.B.) and by NIH training grants T32-HD07516-09 and T32-GM7229-29 (to M. H. S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 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 AUG 27 PY 2010 VL 5 IS 8 AR e12404 DI 10.1371/journal.pone.0012404 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643MT UT WOS:000281301500005 PM 20806059 ER PT J AU Harrison, SC Kirchhausen, T AF Harrison, Stephen C. Kirchhausen, Tomas TI STRUCTURAL BIOLOGY Conservation in vesicle coats SO NATURE LA English DT Editorial Material ID PROTEINS; COPII; CLATHRIN; COMPLEX; COATOMER; TRANSPORT; CAGE C1 [Harrison, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Harrison, Stephen C.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Kirchhausen, Tomas] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Harrison, SC (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM harrison@crystal.harvard.edu NR 15 TC 15 Z9 15 U1 3 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 26 PY 2010 VL 466 IS 7310 BP 1048 EP 1049 DI 10.1038/4661048a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 642IK UT WOS:000281203600024 PM 20739998 ER PT J AU Flaherty, KT Puzanov, I Kim, KB Ribas, A McArthur, GA Sosman, JA O'Dwyer, PJ Lee, RJ Grippo, JF Nolop, K Chapman, PB AF Flaherty, Keith T. Puzanov, Igor Kim, Kevin B. Ribas, Antoni McArthur, Grant A. Sosman, Jeffrey A. O'Dwyer, Peter J. Lee, Richard J. Grippo, Joseph F. Nolop, Keith Chapman, Paul B. TI Inhibition of Mutated, Activated BRAF in Metastatic Melanoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MISMATCH REPAIR DEFICIENCY; PAPILLARY CARCINOMAS; MALIGNANT-MELANOMA; TUMOR PROGRESSION; KRAS MUTATIONS; PHASE-III; CANCER; RAF; DACARBAZINE; SORAFENIB AB BACKGROUND The identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease. METHODS We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. RESULTS A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. CONCLUSIONS Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.) C1 [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Flaherty, Keith T.; O'Dwyer, Peter J.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Puzanov, Igor; Sosman, Jeffrey A.] Vanderbilt Univ, Nashville, TN USA. [Kim, Kevin B.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ribas, Antoni] Univ Calif Los Angeles, Los Angeles, CA USA. [McArthur, Grant A.] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Lee, Richard J.; Grippo, Joseph F.] Roche Pharmaceut, Nutley, NJ USA. [Nolop, Keith] Plexxikon, Berkeley, CA USA. [Chapman, Paul B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Flaherty, KT (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St,Yawkey 9E, Boston, MA 02114 USA. EM kflaherty@partners.org FU Plexxikon; Roche Pharmaceuticals FX Supported by Plexxikon and Roche Pharmaceuticals. NR 29 TC 1911 Z9 1946 U1 24 U2 153 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 26 PY 2010 VL 363 IS 9 BP 809 EP 819 DI 10.1056/NEJMoa1002011 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 642HG UT WOS:000281196600004 PM 20818844 ER PT J AU Pless, ML Kroshinsky, D LaRocque, RC Buchbinder, BR Duncan, LM AF Pless, Misha L. Kroshinsky, Daniela LaRocque, Regina C. Buchbinder, Bradley R. Duncan, Lyn M. TI Case 26-2010: A 54-Year-Old Man with Loss of Vision and a Rash SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACUTE RETINAL NECROSIS; OPTIC NEUROPATHY; HODGKINS-DISEASE; NERVE; MANIFESTATION; ASPERGILLUS; SECONDARY; PROPTOSIS; NEURITIS; ORBIT C1 [Pless, Misha L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Kroshinsky, Daniela] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Buchbinder, Bradley R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Duncan, Lyn M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [LaRocque, Regina C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Pless, Misha L.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Kroshinsky, Daniela] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [LaRocque, Regina C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Buchbinder, Bradley R.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Duncan, Lyn M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Pless, ML (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. FU Bayer; EMD Serono; Pfizer; Teva Neuroscience FX Dr. Pless reports receiving consulting fees from Bayer, EMD Serono, Pfizer, and Teva Neuroscience; gifts from EMD Serono, Pfizer, Teva, Bayer, and Novartis; grants from EMD Serono Clinical Trial; honoraria from EMD Serono, Pfizer, Teva, Bayer, and Novartis; and payment for development of educational presentations from EMD Serono, Bayer, Teva Neuroscience, and Pfizer. No other potential conflict of interest relevant to this article was reported. NR 27 TC 2 Z9 2 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 26 PY 2010 VL 363 IS 9 BP 865 EP 874 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 642HG UT WOS:000281196600011 PM 20818848 ER PT J AU Perrin, JM AF Perrin, James M. TI Treating Underinsurance SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HEALTH-CARE NEEDS; UNITED-STATES; CHILDREN; INSURANCE; FAMILIES; BURDEN C1 MassGen Hosp Children, MGH Ctr Child & Adolescent Hlth Policy, Boston, MA USA. RP Perrin, JM (reprint author), MassGen Hosp Children, MGH Ctr Child & Adolescent Hlth Policy, Boston, MA USA. NR 9 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 AUG 26 PY 2010 VL 363 IS 9 BP 881 EP 883 DI 10.1056/NEJMe1007674 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 642HG UT WOS:000281196600014 PM 20818850 ER PT J AU Dzik, W AF Dzik, Walter TI Cost Consciousness and Medical Education SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dzik, W (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM sdzik@partners.org 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 AUG 26 PY 2010 VL 363 IS 9 BP 889 EP 889 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 642HG UT WOS:000281196600020 PM 20799394 ER PT J AU Kong, J Tu, PC Zyloney, C Su, TP AF Kong, Jian Tu, Pei-chi Zyloney, Carolyn Su, Tung-ping TI Intrinsic functional connectivity of the periaqueductal gray, a resting fMRI study SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Periaqueductal gray; PAG; Pain; fMRI; Resting state; Functional connectivity ID DIABETIC NEUROPATHIC PAIN; MEDIAL PREFRONTAL CORTEX; ELECTRICAL-STIMULATION; PLACEBO ANALGESIA; NEURAL MECHANISMS; MAJOR DEPRESSION; HUMAN BRAIN; HPA AXIS; NETWORK; HUMANS AB The periaqueductal gray (PAG) is known to play a crucial role in pain modulation and has shown a strong interaction with anterior cingulate cortex in previous functional imaging studies. We investigated the intrinsic functional connectivity of PAG using resting fMRI data from 100 subjects. The results showed that PAG is functionally connected to ACC (rostral and pregenual ACC) and also rostral ventromedial medulla (RVM), forming a core ACC-PAG-RVM network for pain modulation even no pain stimulus is applied. The comparison between genders showed that for the contrast of female minus male, significant difference was observed at mid-cingulate cortex; for the contrast of male minus female, significant differences were observed at left medial orbital prefrontal cortex, and uncus; right insula/operculum and prefrontal cortex. We believe eluciation of this intrinsic PAG network duing the resting state will enhance our physiological and pathological understandings of the development and maintenance of chronic pain states. (C) 2010 Elsevier B.V. All rights reserved. C1 [Kong, Jian; Tu, Pei-chi; Zyloney, Carolyn] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Kong, Jian] MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. [Su, Tung-ping] Taipei Vet Gen Hosp, Dept Psychiat, Taipei, Taiwan. RP Kong, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Bldg 120,2nd St,Suite 101C, Charlestown, MA 02129 USA. EM kongj@nmr.mgh.harvard.edu FU NIH (NCCAM) [K01 AT003883, R21AT004497]; National Center for Research Resources (NCRR) [M01-RR-01066, UL1 RR025758-01, P41RR14075]; MIND Institute FX NIH (NCCAM) K01 AT003883 and R21AT004497 to JK. Brain Genomics Superstruct Project and the laboratory of Dr. Randy Buckner for functional MRI data. M01-RR-01066 and UL1 RR025758-01 for Clinical Research Center Biomedical Imaging Core from National Center for Research Resources (NCRR), P41RR14075 for Center for Functional Neuroimaging Technologies from NCRR and the MIND Institute. NR 61 TC 67 Z9 69 U1 2 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD AUG 25 PY 2010 VL 211 IS 2 BP 215 EP 219 DI 10.1016/j.bbr.2010.03.042 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 602VX UT WOS:000278168200011 PM 20347878 ER PT J AU Knoepp, SM Kuebler, DL Wilbur, DC AF Knoepp, Stewart M. Kuebler, Diane L. Wilbur, David C. TI Correlation Between Hybrid Capture II High-Risk Human Papillomavirus DNA Test Chemiluminescence Intensity From Cervical Samples With Follow-Up Histologic Results A Cytologic/Histologic Review of 367 Cases SO CANCER CYTOPATHOLOGY LA English DT Article DE cervical cytology; human papillomavirus (HPV) testing; SurePath; Hybrid Capture II ID ATYPICAL SQUAMOUS-CELLS; VIRAL LOAD; INTRAEPITHELIAL NEOPLASIA; UNDETERMINED SIGNIFICANCE; COST-EFFECTIVENESS; CANCER; WOMEN; HPV; CARCINOGENESIS; MANAGEMENT AB BACKGROUND: The Hybrid Capture II high-risk human papillomavirus (hrHPV) DNA test is a US Food and Drug Administration-approved nucleic acid hybridization assay using chemiluminescence for the semiquantitative detection of hrHPV in cervical samples. Patient samples and controls are used to calculate results as negative for hrHPV if <1.0, positive for hrHPV if >2.5, and "equivocal" if between 1.0 and 2.5. METHODS: The authors reported on the cervical histologic results of 209 patients demonstrating "equivocal" results for hrHPV from Sure Path (204 patients) or Thin Prep (5 patients) vials, and compared patients in this cohort with atypical squamous cells of undetermined significance (ASC-US) cytology on the index cervical Papanicolaou (Pap) test (Group 1: n = 148 patients) with a patient cohort demonstrating unequivocal positive hrHPV test results (Group 2; n = 148 patients). The chemiluminescence intensity of hrHPV tests from patients in Group 2 were correlated with the presence and severity of dysplasia on subsequent histologic results, and patients were thereby stratified for their subsequent risk of cervical intraepithelial neoplasia (CIN) types II/III. RESULTS: Approximately 97% of hrHPV tests demonstrating "equivocal" results were found to be positive at the time of retesting, and 15% of biopsied cases demonstrated CIN II or Ill. Results of follow-up histology after an ASC-US diagnosis, expressed as a percentage of the biopsied cohort, were: CIN II/III: 16.5% in Group 1 and 22.4% in Group 2; CIN 27% in Group 1 and 23.5% in Group 2; and negative: 56.5% in Group 1 and 54.1% in Group 2. Chemiluminescence intensity did not appear to be correlated with the severity of dysplasia. CONCLUSIONS: The percentage of high-grade CIN in the "equivocal" hrHPV cohort is highly significant and therefore the management of these patients should be similar to the unequivocally positive population. After an unequivocal positive hrHPV test, the hrHPV chemiluminescence intensity does not appear to further predict the rate of high-grade CIN. Cancer (Cancer Cytopathol) 2010;118:209-17. (C) 2010 American Cancer Society. C1 [Knoepp, Stewart M.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Kuebler, Diane L.; Wilbur, David C.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Knoepp, SM (reprint author), Univ Michigan, Dept Pathol, 2G332UH,1500 E Med Ctr Dr,SPC 5054, Ann Arbor, MI 48109 USA. EM sknoepp@umich.edu NR 29 TC 6 Z9 6 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD AUG 25 PY 2010 VL 118 IS 4 BP 209 EP 217 DI 10.1002/cncy.20093 PG 9 WC Oncology; Pathology SC Oncology; Pathology GA 639BC UT WOS:000280944800010 PM 20578088 ER PT J AU Leykum, LK Parchman, M Pugh, J Lawrence, V Noel, PH McDaniel, RR AF Leykum, Luci K. Parchman, Michael Pugh, Jacqueline Lawrence, Valerie Noel, Polly H. McDaniel, Reuben R., Jr. TI The importance of organizational characteristics for improving outcomes in patients with chronic disease: a systematic review of congestive heart failure SO IMPLEMENTATION SCIENCE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; HOME-BASED INTERVENTION; QUALITY-OF-LIFE; MANAGEMENT PROGRAM; PRIMARY-CARE; HEALTH-CARE; CHRONIC ILLNESS; OLDER PATIENTS; UNPLANNED READMISSIONS; MULTIDISCIPLINARY CARE AB Background: Despite applications of models of care and organizational or system-level interventions to improve patient outcomes for chronic disease, consistent improvements have not been achieved. This may reflect a mismatch between the interventions and the nature of the settings in which they are attempted. The application of complex adaptive systems (CAS) framework to understand clinical systems and inform efforts to improve them may lead to more successful interventions. We performed a systematic review of interventions to improve outcomes of patients with congestive heart failure (CHF) to examine whether interventions consistent with CAS are more likely to be effective. We then examine differences between interventions that are most effective for improving outcomes for patients with CHF versus previously published data for type 2 diabetes to explore the potential impact of the nature of the disease on the types of interventions that are more likely to be effective. Methods: We conducted a systematic review of the literature between 1998 and 2008 of organizational interventions to improve care of patients with CHF. Two independent reviewers independently assessed studies that met inclusion criteria to determine whether each reported intervention reflected one or more CAS characteristics. The effectiveness of interventions was rated as either 0 (no effect), 0.5 (mixed effect), or 1.0 (effective) based on the type, number, and significance of reported outcomes. Fisher's exact test was used to examine the association between CAS characteristics and intervention effectiveness. Specific CAS characteristics associated with intervention effectiveness for CHF were contrasted with previously published data for type 2 diabetes. Results and discussion: Forty-four studies describing 46 interventions met eligibility criteria. All interventions utilized at least one CAS characteristic, and 85% were either 'mixed effect' or 'effective' in terms of outcomes. The number of CAS characteristics present in each intervention was associated with effectiveness (p < 0.001), supporting the idea that interventions consistent with CAS are more likely to be effective. The individual CAS characteristics associated with CHF intervention effectiveness were learning, self-organization, and co-evolution, a finding different from our previously published analysis of interventions for diabetes. We suggest this difference may be related to the degree of uncertainty involved in caring for patients with diabetes versus CHF. Conclusion: These results suggest that for interventions to be effective, they must be consistent with the CAS nature of clinical systems. The difference in specific CAS characteristics associated with intervention effectiveness for CHF and diabetes suggests that interventions must also take into account attributes of the disease. C1 [Leykum, Luci K.; Pugh, Jacqueline; Lawrence, Valerie; Noel, Polly H.] Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Leykum, Luci K.; Parchman, Michael; Pugh, Jacqueline; Lawrence, Valerie; Noel, Polly H.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Parchman, Michael] Univ Texas Hlth Sci Ctr San Antonio, Dept Family & Community Med, San Antonio, TX 78229 USA. [McDaniel, Reuben R., Jr.] Univ Texas Austin, McCombs Sch Business, Austin, TX 78712 USA. RP Leykum, LK (reprint author), Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. EM leykum@uthscsa.edu OI Pugh, Jacqueline/0000-0003-4933-141X; Parchman, Michael/0000-0001-7129-2889 FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [01-091, REA 05-129] FX The research reported here was supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (TRX # 01-091 & REA 05-129). Investigator salary support is provided through this funding, and through the South Texas Veterans Health Care System. Dr. McDaniel receives support from the IC2 Institute of the University of Texas at Austin. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 72 TC 10 Z9 10 U1 2 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD AUG 25 PY 2010 VL 5 AR 66 DI 10.1186/1748-5908-5-66 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 656EN UT WOS:000282309100001 PM 20735859 ER PT J AU Safren, SA Sprich, S Mimiaga, MJ Surman, C Knouse, L Groves, M Otto, MW AF Safren, Steven A. Sprich, Susan Mimiaga, Matthew J. Surman, Craig Knouse, Laura Groves, Meghan Otto, Michael W. TI Cognitive Behavioral Therapy vs Relaxation With Educational Support for Medication-Treated Adults With ADHD and Persistent Symptoms A Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; DOUBLE-BLIND; ADOLESCENTS; PLACEBO AB Context Attention-deficit/hyperactivity disorder (ADHD) in adulthood is a prevalent, distressing, and impairing condition that is not fully treated by pharmacotherapy alone and lacks evidence-based psychosocial treatments. Objective To test cognitive behavioral therapy for ADHD in adults treated with medication but who still have clinically significant symptoms. Design, Setting, and Patients Randomized controlled trial assessing the efficacy of cognitive behavioral therapy for 86 symptomatic adults with ADHD who were already being treated with medication. The study was conducted at a US hospital between November 2004 and June 2008 (follow-up was conducted through July 2009). Of the 86 patients randomized, 79 completed treatment and 70 completed the follow-up assessments. Interventions Patients were randomized to 12 individual sessions of either cognitive behavioral therapy or relaxation with educational support (which is an attention-matched comparison). Main Outcome Measures The primary measures were ADHD symptoms rated by an assessor (ADHD rating scale and Clinical Global Impression scale) at baseline, post-treatment, and at 6- and 12-month follow-up. The assessor was blinded to treatment condition assignment. The secondary outcome measure was self-report of ADHD symptoms. Results Cognitive behavioral therapy achieved lower posttreatment scores on both the Clinical Global Impression scale (magnitude -0.0531; 95% confidence interval [CI], -1.01 to -0.05; P=.03) and the ADHD rating scale (magnitude -4.631; 95% CI, -8.30 to -0.963; P=.02) compared with relaxation with educational support. Throughout treatment, self-reported symptoms were also significantly more improved for cognitive behavioral therapy (beta=-0.41; 95% Cl, -0.64 to -0.17; P<001), and there were more treatment responders in cognitive behavioral therapy for both the Clinical Global Impression scale (53% vs 23%; odds ratio [OR], 3.80; 95% CI, 1.50 to 9.59; P=.01) and the ADHD rating scale (67% vs 33%; OR, 4.29; 95% Cl, 1.74 to 10.58; P=.002). Responders and partial responders in the cognitive behavioral therapy condition maintained their gains over 6 and 12 months. Conclusion Among adults with persistent ADHD symptoms treated with medication, the use of cognitive behavioral therapy compared with relaxation with educational support resulted in improved ADHD symptoms, which were maintained at 12 months. C1 [Safren, Steven A.; Sprich, Susan; Mimiaga, Matthew J.; Surman, Craig; Knouse, Laura; Groves, Meghan; Otto, Michael W.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Safren, Steven A.; Sprich, Susan; Mimiaga, Matthew J.; Surman, Craig; Knouse, Laura] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Otto, Michael W.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. RP Safren, SA (reprint author), Massachusetts Gen Hosp Behav Med, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM ssafren@partners.org FU Abbott; Alza; Cephalon; Eli Lilly; ElMinda the Hilda and Preston Davis Foundation; McNeil; Merck; New River; National Institutes of Health; Organon; Pfizer; Shire; Takeda; Jazz Pharmaceuticals; Organon (Schering-Plough); Sanofi-Aventis; National Institutes of Health [5R01MH69812] FX Drs Safren, Sprich, and Otto reported receiving royalty payments from Oxford University Press. Dr Surman reported receiving research support from Abbott, Alza, Cephalon, Eli Lilly, ElMinda the Hilda and Preston Davis Foundation, McNeil, Merck, New River, National Institutes of Health, Organon, Pfizer, Shire, and Takeda; being a speaker for Janssen-Ortho, McNeil, Novartis, Shire, and MGH Academy/Reed Medical Education (which receives funding from multiple pharmaceutical companies); and being a consultant or advisor for McNeil, Shire, and Takeda. Dr Knouse reported receiving consulting income from Eli Lilly. Dr Otto reported receiving consulting income from Jazz Pharmaceuticals, Organon (Schering-Plough), Pfizer, and Sanofi-Aventis; research support from Organon (Schering-Plough); and royalty payments for use of the SIGH-A from Lilly.; This study was funded by National Institutes of Health grant 5R01MH69812. NR 17 TC 123 Z9 125 U1 5 U2 32 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 25 PY 2010 VL 304 IS 8 BP 875 EP 880 DI 10.1001/jama.2010.1192 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 644OY UT WOS:000281389900025 PM 20736471 ER PT J AU Cornia, PB Hersh, AL Lipsky, BA Newman, TB Gonzales, R AF Cornia, Paul B. Hersh, Adam L. Lipsky, Benjamin A. Newman, Thomas B. Gonzales, Ralph TI Does This Coughing Adolescent or Adult Patient Have Pertussis? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CLINICAL-PRACTICE GUIDELINES; IMMUNIZATION PRACTICES ACIP; UNITED-STATES; EOSINOPHILIC BRONCHITIS; ADVISORY-COMMITTEE; PREVENTING TETANUS; PERSISTENT COUGH; EPIDEMIOLOGY; RECOMMENDATIONS; AZITHROMYCIN AB Context Pertussis is often overlooked as a cause of chronic cough, especially in adolescents and adults. Several symptoms are classically thought to be suggestive of pertussis, but the diagnostic value of each of them is uncertain. Objective To systematically review the evidence regarding the diagnostic value of 3 classically described symptoms of pertussis: paroxysmal cough, posttussive emesis, and inspiratory whoop. Data Sources, Study Selection, and Data Extraction We searched MEDLINE (January 1966 April 2010), EMBASE (January 1969 to April 2010), and the bibliographies of pertinent articles to identify relevant English-language studies. Articles were selected that included children older than 5 years, adolescents, or adults and confirmed the diagnosis of pertussis among patients with cough illness (of any duration) with an a priori defined accepted reference standard. Two authors independently extracted data from articles that met selection criteria and resolved any discrepancies by consensus. Data Synthesis Five prospective studies met inclusion criteria; 3 were used in the analysis. Presence of posttussive emesis (summary likelihood ratio [LR], 1.8; 95% confidence interval [Cl], 1.4-2.2) or inspiratory whoop (summary LR, 1.9; 95% Cl, 1.4-2.6) increases the likelihood of pertussis. Absence of paroxysmal cough (summary LR, 0.52; 95% Cl, 0.27-1.0) or posttussive emesis (summary LR, 0.58; 95% Cl, 0.44-0.77) reduced the likelihood. Absence of inspiratory whoop was less useful (summary LR, 0.78; 95% Cl, 0.66-0.93). No studies evaluated combinations of findings. Conclusions In a nonoutbreak setting, data to determine the diagnostic usefulness of symptoms classically associated with pertussis are limited and of relatively weak quality. The presence or absence of posttussive emesis or inspiratory whoop modestly change the likelihood of pertussis; therefore, clinicians must use their overall clinical impression to decide about additional testing or empirical treatment. JAMA. 2010;304(8):890-896 C1 [Gonzales, Ralph] Univ Calif San Francisco, Dept Med, Div Clin Epidemiol, San Francisco, CA 94118 USA. [Gonzales, Ralph] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94118 USA. [Hersh, Adam L.; Newman, Thomas B.] Univ Calif San Francisco, Div Gen Pediat, San Francisco, CA 94118 USA. [Hersh, Adam L.] Univ Calif San Francisco, Div Pediat Infect Dis, San Francisco, CA 94118 USA. [Cornia, Paul B.; Lipsky, Benjamin A.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Cornia, Paul B.; Lipsky, Benjamin A.] Vet Affairs Puget Sound Hlth Care Syst, Primary & Specialty Med Care Serv, Seattle, WA USA. RP Gonzales, R (reprint author), Univ Calif San Francisco, Dept Med, Div Clin Epidemiol, 3333 Calif St,Box 1211,Ste 430, San Francisco, CA 94118 USA. EM ralphg@medicine.ucsf.edu OI Lipsky, Benjamin A./0000-0001-9886-5114 NR 47 TC 45 Z9 48 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 25 PY 2010 VL 304 IS 8 BP 890 EP 896 DI 10.1001/jama.2010.1181 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 644OY UT WOS:000281389900027 PM 20736473 ER PT J AU Sinha, S Miller, L Subramanian, S McCarty, OJT Proctor, T Meza-Romero, R Huan, JY Burrows, GG Vandenbark, AA Offner, H AF Sinha, Sushmita Miller, Lisa Subramanian, Sandhya McCarty, Owen J. T. Proctor, Thomas Meza-Romero, Roberto Huan, Jianya Burrows, Gregory G. Vandenbark, Arthur A. Offner, Halina TI Binding of recombinant T cell receptor ligands (RTL) to antigen presenting cells prevents upregulation of CD11b and inhibits T cell activation and transfer of experimental autoimmune encephalomyelitis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE EAE; RTLs; Tolerance; APCs ID MULTIPLE-SCLEROSIS; CYTOKINE SWITCH; TRANSGENIC MICE; MYELIN; THERAPY; PEPTIDE; SEVERITY; MAC-1 AB Recombinant T cell ligands (RTLs) ameliorate experimental autoimmune encephalomyelitis (EAE) in an antigen-specific manner. We evaluated effects of RTL401 (I-A(s) alpha 1 beta 1 + PLP-139-151) on splenocytes from SJL/J mice with EAE to study RTL-T cell tolerance-inducing mechanisms. RTLs bound to B, macrophages and DCs, through RTL-MHC-alpha 1 beta 1 moiety. RTL binding reduced CD11b expression on splenic macrophages/DC, and RTL401-conditioned macrophages/DC, not B cells, inhibited T cell activation. Reduced ability of RU- incubated splenocytes to transfer EAE was likely mediated through macrophages/DC, since B cells were unnecessary for RTL treatment of EAE. These results demonstrate a novel pathway of T cell regulation by RTL-bound APCs. (C) 2010 Elsevier B.V. All rights reserved. C1 [Sinha, Sushmita; Miller, Lisa; Subramanian, Sandhya; Proctor, Thomas; Meza-Romero, Roberto; Vandenbark, Arthur A.; Offner, Halina] Portland VA Med Ctr, Portland, OR 97239 USA. [Sinha, Sushmita; Meza-Romero, Roberto; Huan, Jianya; Burrows, Gregory G.; Vandenbark, Arthur A.; Offner, Halina] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA. [McCarty, Owen J. T.] Oregon Hlth & Sci Univ, Dept Biomed Engn, Portland, OR 97239 USA. [Burrows, Gregory G.] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. [Vandenbark, Arthur A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. [Offner, Halina] Oregon Hlth & Sci Univ, Dept Anesthesiol & Perioperat Med, Portland, OR 97239 USA. [Proctor, Thomas; Meza-Romero, Roberto; Huan, Jianya; Burrows, Gregory G.; Vandenbark, Arthur A.; Offner, Halina] Oregon Hlth & Sci Univ, Tykeson MS Res Lab, Portland, OR 97239 USA. RP Offner, H (reprint author), Portland VA Med Ctr, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU National Multiple Sclerosis Society [FG1749-A-1, RG3794-A-4, RG3794-B-6]; NIH [NS47661, AI43960]; Biomedical Laboratory R&D Service, Department of Veterans Affairs; Artielle ImmunoTherapeutics, Inc. FX The authors wish to thank Ms. Eva Niehaus for assistance in preparing the manuscript. Dr. Sinha is a Postdoctoral Fellow of the National Multiple Sclerosis Society and this work was supported in part by the National Multiple Sclerosis Society Postdoctoral Fellowship FG1749-A-1, grants RG3794-A-4 and RG3794-B-6; NIH Grants NS47661 and AI43960; and the Biomedical Laboratory R&D Service, Department of Veterans Affairs.; Drs. Offner, Burrows, Vandenbark, and OHSU have a significant financial interest in Artielle ImmunoTherapeutics, Inc., a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by the OHSU and VAMC Conflict of Interest in Research Committees. NR 23 TC 15 Z9 15 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD AUG 25 PY 2010 VL 225 IS 1-2 BP 52 EP 61 DI 10.1016/j.jneuroim.2010.04.013 PG 10 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 651LA UT WOS:000281928000007 PM 20546940 ER PT J AU Goldwasser, J Cohen, PY Yang, E Balaguer, P Yarmush, ML Nahmias, Y AF Goldwasser, Jonathan Cohen, Pazit Y. Yang, Eric Balaguer, Patrick Yarmush, Martin L. Nahmias, Yaakov TI Transcriptional Regulation of Human and Rat Hepatic Lipid Metabolism by the Grapefruit Flavonoid Naringenin: Role of PPAR alpha, PPAR gamma and LXR alpha SO PLOS ONE LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTOR; FATTY-ACID OXIDATION; APOLIPOPROTEIN-B SECRETION; LIVER-X-RECEPTORS; HEPATOCYTE APO-B; NUCLEAR RECEPTORS; GENE-EXPRESSION; CROSS-TALK; CHOLESTEROL HOMEOSTASIS; NUTRITIONAL REGULATION AB Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity, and atherosclerosis. Therefore, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health. The grapefruit flavonoid naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia, as well as inhibit the production of HCV. Here, we demonstrate that naringenin regulates the activity of nuclear receptors PPARa, PPARc, and LXRa. We show it activates the ligand-binding domain of both PPARa and PPARc, while inhibiting LXRa in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRa, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARa co-activator, PGC1a. The flavonoid activates PPAR response element (PPRE) while suppressing LXRa response element (LXRE) in human hepatocytes, translating into the induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRa-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR. This effect results in the induction of a fasted-like state in primary rat hepatocytes in which fatty acid oxidation increases, while cholesterol and bile acid production decreases. Our findings explain the myriad effects of naringenin and support its continued clinical development. Of note, this is the first description of a non-toxic, naturally occurring LXRa inhibitor. C1 [Goldwasser, Jonathan; Yang, Eric; Yarmush, Martin L.; Nahmias, Yaakov] Shriners Burns Hosp, Ctr Engn Med, Boston, MA USA. [Goldwasser, Jonathan] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Cohen, Pazit Y.; Nahmias, Yaakov] Hebrew Univ Jerusalem, Selim & Rachel Benin Sch Engn, Jerusalem, Israel. [Yang, Eric; Yarmush, Martin L.; Nahmias, Yaakov] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Balaguer, Patrick] Univ Montpellier 1, INSERM, Montpellier, France. RP Goldwasser, J (reprint author), Shriners Burns Hosp, Ctr Engn Med, Boston, MA USA. EM ynahmias@cs.huji.ac.il RI Nahmias, Yaakov/H-4725-2013; Balaguer, Patrick/I-2973-2016 FU NIBIB NIH HHS [P41 EB-002503, P41 EB002503]; NIDDK NIH HHS [K01 DK080241, K01DK080241, P30 DK040561, P30 DK040561-15, P30-DK040561] NR 59 TC 67 Z9 73 U1 2 U2 27 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 AUG 25 PY 2010 VL 5 IS 8 AR e12399 DI 10.1371/journal.pone.0012399 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 642RO UT WOS:000281234700023 PM 20811644 ER PT J AU Matthews, LT Baeten, JM Celum, C Bangsberg, DR AF Matthews, Lynn T. Baeten, Jared M. Celum, Connie Bangsberg, David R. TI Periconception pre-exposure prophylaxis to prevent HIV transmission: benefits, risks, and challenges to implementation SO AIDS LA English DT Article DE antiretroviral prophylaxis; fertility; HIV; HIV prevention; HIV transmission; reproduction; serodiscordant couples ID RANDOMIZED CONTROLLED-TRIAL; SUB-SAHARAN AFRICA; SUCCESSFUL ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS-INFECTION; SEXUALLY-TRANSMITTED INFECTIONS; PLACEBO-CONTROLLED TRIAL; SOUTH-AFRICA; MALE CIRCUMCISION; DISCORDANT COUPLES; COST-EFFECTIVENESS AB HIV-serodiscordant couples face complicated choices between fulfilling reproductive desire and risking HIV transmission to their partners and children. Sexual HIV transmission can be dramatically reduced through artificial insemination and sperm washing; however, most couples cannot access these resources. We propose that periconception pre-exposure prophylaxis (PrEP) could offer an important, complementary therapy to harm reduction counseling programs that aim to decrease HIV transmission for couples who choose to conceive. In this paper, we describe the potential benefits of periconception PrEP and define critical points of clarification prior to implementation of PrEP as part of a reproductive health program. We consider sexual transmission risk, current risk reduction options, PrEP efficacy, cost, adherence, resistance, fetal toxicity, and impact of PrEP counseling on entry into health services. We address PrEP in the context of other periconception HIV-prevention strategies, including antiretroviral treatment of the HIV-infected partner. We conclude that, should PrEP prove safe and efficacious in ongoing trials, periconception PrEP may offer a useful approach to minimize risk of HIV transmission for individuals of reproductive age in HIV-endemic countries. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Matthews, Lynn T.] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. [Baeten, Jared M.; Celum, Connie] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Baeten, Jared M.; Celum, Connie] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ragon Inst,Ctr Global Hlth, Cambridge, MA 02138 USA. [Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. RP Matthews, LT (reprint author), Beth Israel Deaconess Med Ctr, Div Infect Dis, 110 Francis St,Lowry Med Off Bldg,Suite GB, Boston, MA 02215 USA. EM ltmatthe@bidmc.harvard.edu FU Mark and Lisa Schwartz Family Foundation; [MH K-24 87227] FX L. T. M. and D. R. B. received support from the Mark and Lisa Schwartz Family Foundation. D. R. B. received support from MH K-24 87227. NR 90 TC 52 Z9 52 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD AUG 24 PY 2010 VL 24 IS 13 BP 1975 EP 1982 DI 10.1097/QAD.0b013e32833bedeb PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 634BY UT WOS:000280555200001 PM 20679759 ER PT J AU Lo, J Abbara, S Rocha-Filho, JA Shturman, L Wei, J Grinspoon, SK AF Lo, Janet Abbara, Suhny Rocha-Filho, Jose A. Shturman, Leon Wei, Jeffrey Grinspoon, Steven K. TI Increased epicardial adipose tissue volume in HIV-infected men and relationships to body composition and metabolic parameters SO AIDS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INTIMA-MEDIA THICKNESS; HEART; RISK; FAT AB Epicardial fat accumulation may have important clinical consequences, yet little is known regarding this depot in HIV patients. We compared epicardial fat volume in 78 HIV-infected men and 32 HIV-negative controls. Epicardial fat volume was higher in HIV-infected patients than that in controls (P = 0.04). In HIV patients, epicardial fat volume was strongly associated with visceral adipose tissue area (rho = 0.76, P < 0.0001), fasting glucose (rho = 0.41, P = 0.001) and insulin (rho = 0.44, P = 0.0003). Relationships with glucose and insulin remained significant controlling for age, race, BMI, adiponectin, visceral adipose tissue and antiretroviral therapy. Epicardial fat may be an important fat depot in HIV-infected patients. C1 [Lo, Janet; Wei, Jeffrey; Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Abbara, Suhny; Rocha-Filho, Jose A.; Shturman, Leon] Massachusetts Gen Hosp, Div Cardiac Imaging, Boston, MA 02114 USA. [Abbara, Suhny; Rocha-Filho, Jose A.; Shturman, Leon] Harvard Univ, Sch Med, Boston, MA USA. RP Lo, J (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, 55 Fruit St,LON207, Boston, MA 02114 USA. EM jlo@partners.org FU Bristol Myers Squibb Inc.; NIH [K23 HL092792, K24 DK064545, T32 HL076136, M01 RR01066-25S1] FX We wish to thank the participants of this study and the Nursing and Bionutrition Staff of the MGH and MIT GCRC. Funding sources were Bristol Myers Squibb Inc., NIH K23 HL092792 (J.L.), K24 DK064545 (S.K.G.), T32 HL076136 (L.S.) and M01 RR01066-25S1. NR 14 TC 19 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD AUG 24 PY 2010 VL 24 IS 13 BP 2127 EP 2130 DI 10.1097/QAD.0b013e32833c055a PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 634BY UT WOS:000280555200020 PM 20588167 ER PT J AU Joseph, J AF Joseph, Jacob TI A Master of Versatility to the Heart's Rescue Mast Cells and Ischemic Preconditioning SO CIRCULATION LA English DT Editorial Material DE Editorials; mast cell; renin; angiotensin; ischemic preconditioning; arrhythmias ID BIOLOGY; RENIN C1 [Joseph, Jacob] VA Boston Healthcare Syst, Dept Med, Boston, MA USA. [Joseph, Jacob] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Joseph, Jacob] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Joseph, Jacob] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Joseph, J (reprint author), VA Boston Healthcare Syst, Cardiol Sect 111, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM jacob.joseph@va.gov NR 19 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 24 PY 2010 VL 122 IS 8 BP 761 EP 763 DI 10.1161/CIRCULATIONAHA.110.972422 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 642GN UT WOS:000281193100002 PM 20697024 ER PT J AU Mahoney, EM Wang, KJ Arnold, SV Cohen, DJ Proskorovsky, I Wiviott, S Antman, E Braunwald, E AF Mahoney, Elizabeth M. Wang, Kaijun Arnold, Suzanne V. Cohen, David J. Proskorovsky, Irina Wiviott, Stephen Antman, Elliott Braunwald, Eugene TI Response to Letter Regarding Article, "Cost-Effectiveness of Prasugrel Versus Clopidogrel in Patients With Acute Coronary Syndromes and Planned Percutaneous Coronary Intervention: Results From the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction TRITON-TIMI 38" SO CIRCULATION LA English DT Letter C1 [Mahoney, Elizabeth M.; Wang, Kaijun; Arnold, Suzanne V.; Cohen, David J.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Proskorovsky, Irina] United BioSource Corp, Dorval, PQ, Canada. [Wiviott, Stephen; Antman, Elliott; Braunwald, Eugene] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. RP Mahoney, EM (reprint author), St Lukes Mid Amer Heart Inst, Kansas City, MO USA. NR 3 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 24 PY 2010 VL 122 IS 8 BP E437 EP E437 DI 10.1161/CIRCULATIONAHA.110.951889 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 642GN UT WOS:000281193100018 ER PT J AU DeGutis, JM Van Vleet, TM AF DeGutis, Joseph M. Van Vleet, Thomas M. TI Tonic and phasic alertness training: a novel behavioral therapy to improve spatial and non-spatial attention in patients with hemispatial neglect SO FRONTIERS IN HUMAN NEUROSCIENCE LA English DT Article DE attention; visual; rehabilitation; neurological disorders; hemispatial neglect ID SUSTAINED ATTENTION; UNILATERAL NEGLECT; RIGHT-HEMISPHERE; VISUOSPATIAL NEGLECT; VISUAL-ATTENTION; LANDMARK TASK; BRAIN; FMRI; REHABILITATION; DISABILITY AB Hemispatial neglect is a debilitating disorder marked by a constellation of spatial and non-spatial attention deficits. Patients' alertness deficits have shown to interact with lateralized attention processes and correspondingly, improving tonic/general alertness as well as phasic/moment-to-moment alertness has shown to ameliorate spatial bias. However, improvements are often short-lived and inconsistent across tasks and patients. In an attempt to more effectively activate alertness mechanisms by exercising both tonic and phasic alertness, we employed a novel version of a continuous performance task (tonic and phasic alertness training, TAPAT). Using a between-subjects longitudinal design and employing sensitive outcome measures of spatial and non-spatial attention, we compared the effects of 9 days of TAPAT (36 min/day) in a group of patients with chronic neglect (N = 12) with a control group of chronic neglect patients (N = 12) who simply waited during the same training period. Compared to the control group, the group trained on TAPAT significantly improved on both spatial and non-spatial measures of attention with many patients failing to exhibit a lateralized attention bias at the end of training. TAPAT was effective for patients with a range of behavioral profiles and lesions, suggesting that its effectiveness may rely on distributed or lower-level attention mechanisms that are largely intact in patients with neglect. In a follow-up experiment, to determine if TAPAT is more effective in improving spatial attention than an active treatment that directly trains spatial attention, we trained three chronic neglect patients on both TAPAT and search training. In all three patients, TAPAT training was more effective in improving spatial attention than search training suggesting that, in chronic neglect, training alertness is a more effective treatment approach than directly training spatial attention. C1 [Van Vleet, Thomas M.] No Calif VA Healthcare Syst, Martinez, CA USA. [DeGutis, Joseph M.] Boston VA Healthcare Syst, Geriatr Res Educ Clin Ctr, Boston, MA USA. RP DeGutis, JM (reprint author), VA Boston Healthcare Syst 182JP, 150 S Huntington Ave, Boston, MA 02130 USA. EM degutis@wjh.harvard.edu FU VA Merit Grant [05-09-00371] FX We would like to acknowledge the efforts and dedication of the patients performing the testing and training, Albert Hoang-duc for his help in programming, data consolidation, and analysis, as well as Lynn Roberston, William Milberg, and Regina McGlinchey for fruitful discussions. This work was supported by VA Merit Grant # 05-09-00371. NR 61 TC 23 Z9 23 U1 2 U2 17 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5161 J9 FRONT HUM NEUROSCI JI Front. Hum. Neurosci. PD AUG 24 PY 2010 VL 4 AR 60 DI 10.3389/fnhum.2010.00060 PG 17 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 747FK UT WOS:000289305500001 ER PT J AU Biffi, A Halpin, A Towfighi, A Gilson, A Busl, K Rost, N Smith, EE Greenberg, MS Rosand, J Viswanathan, A AF Biffi, A. Halpin, A. Towfighi, A. Gilson, A. Busl, K. Rost, N. Smith, E. E. Greenberg, M. S. Rosand, J. Viswanathan, A. TI Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy SO NEUROLOGY LA English DT Article ID WHITE-MATTER LESIONS; ALZHEIMER-DISEASE; LOBAR HEMORRHAGE; ROTTERDAM-SCAN; RISK-FACTORS; MICROBLEEDS; WARFARIN; MRI; ASSOCIATION; PREVALENCE AB Objective: To identify and compare clinical and neuroimaging predictors of primary lobar intracerebral hemorrhage (ICH) recurrence, assessing their relative contributions to recurrent ICH. Methods: Subjects were consecutive survivors of primary ICH drawn from a single-center prospective cohort study. Baseline clinical, imaging, and laboratory data were collected. Survivors were followed prospectively for recurrent ICH and intercurrent aspirin and warfarin use, including duration of exposure. Cox proportional hazards models were used to identify predictors of recurrence stratified by ICH location, with aspirin and warfarin exposures as time-dependent variables adjusting for potential confounders. Results: A total of 104 primary lobar ICH survivors were enrolled. Recurrence of lobar ICH was associated with previous ICH before index event (hazard ratio [HR] 7.7, 95% confidence interval [CI] 1.4-15.7), number of lobar microbleeds (HR 2.93 with 2-4 microbleeds present, 95% CI 1.3-4.0; HR = 4.12 when >= 5 microbleeds present, 95% CI 1.6-9.3), and presence of CT-defined white matter hypodensity in the posterior region (HR 4.11, 95% CI 1.01-12.2). Although aspirin after ICH was not associated with lobar ICH recurrence in univariate analyses, in multivariate analyses adjusting for baseline clinical predictors, it independently increased the risk of ICH recurrence (HR 3.95, 95% CI 1.6-8.3, p = 0.021). Conclusions: Recurrence of lobar ICH is associated with previous microbleeds or macrobleeds and posterior CT white matter hypodensity, which may be markers of severity for underlying cerebral amyloid angiopathy. Use of an antiplatelet agent following lobar ICH may also increase recurrence risk. Neurology(R) 2010;75:693-698 C1 [Biffi, A.; Halpin, A.; Towfighi, A.; Gilson, A.; Busl, K.; Rost, N.; Smith, E. E.; Greenberg, M. S.; Rosand, J.; Viswanathan, A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Biffi, A.; Halpin, A.; Towfighi, A.; Gilson, A.; Busl, K.; Rost, N.; Smith, E. E.; Greenberg, M. S.; Rosand, J.; Viswanathan, A.] Massachusetts Gen Hosp, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. [Biffi, A.; Rost, N.; Rosand, J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Viswanathan, A (reprint author), Harvard Univ, Hemorrhag Stroke Res Program, Massachusetts Gen Hosp, Ctr Stroke Res,Med Sch, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM aviswanathan1@partners.org OI Smith, Eric/0000-0003-3956-1668 FU NIA NIH HHS [R01 AG026484, 5R01AG026484-04]; NINDS NIH HHS [5K23NS046327-05] NR 28 TC 103 Z9 108 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 24 PY 2010 VL 75 IS 8 BP 693 EP 698 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 642HH UT WOS:000281196700006 PM 20733144 ER PT J AU Sykiotis, GP Plummer, L Hughes, VA Au, M Durrani, S Nayak-Young, S Dwyer, AA Quinton, R Hall, JE Gusella, JF Seminara, SB Crowley, WF Pitteloud, N AF Sykiotis, Gerasimos P. Plummer, Lacey Hughes, Virginia A. Au, Margaret Durrani, Sadia Nayak-Young, Sadhana Dwyer, Andrew A. Quinton, Richard Hall, Janet E. Gusella, James F. Seminara, Stephanie B. Crowley, William F., Jr. Pitteloud, Nelly TI Oligogenic basis of isolated gonadotropin-releasing hormone deficiency SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE rare variant; idiopathic hypogonadotropic hypogonadism; Kallmann syndrome; digenic; FGFR1 ID IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; LINKED KALLMANN-SYNDROME; BARDET-BIEDL-SYNDROME; CLINICAL HETEROGENEITY; MISSENSE MUTATIONS; GNRH RECEPTOR; GENE; FIBROBLAST-GROWTH-FACTOR-RECEPTOR-1; PUBERTY; GPR54 AB Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases. C1 [Sykiotis, Gerasimos P.; Plummer, Lacey; Hughes, Virginia A.; Au, Margaret; Durrani, Sadia; Nayak-Young, Sadhana; Dwyer, Andrew A.; Hall, Janet E.; Seminara, Stephanie B.; Crowley, William F., Jr.; Pitteloud, Nelly] Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Dept Med, Boston, MA 02114 USA. [Sykiotis, Gerasimos P.; Plummer, Lacey; Hughes, Virginia A.; Au, Margaret; Durrani, Sadia; Nayak-Young, Sadhana; Dwyer, Andrew A.; Hall, Janet E.; Seminara, Stephanie B.; Crowley, William F., Jr.; Pitteloud, Nelly] Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Quinton, Richard] Royal Victoria Infirm, Dept Endocrinol, Newcastle Upon Tyne NE3 2NJ, Tyne & Wear, England. [Quinton, Richard] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England. [Gusella, James F.; Seminara, Stephanie B.; Crowley, William F., Jr.; Pitteloud, Nelly] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res,Dept Genet, Boston, MA 02114 USA. RP Pitteloud, N (reprint author), Massachusetts Gen Hosp, Harvard Reprod Endocrine Sci Ctr, Dept Med, Boston, MA 02114 USA. EM nelly.pitteloud@chuv.ch RI Dwyer, Andrew/D-8099-2012; PITTELOUD, Nelly/K-2709-2014; OI Dwyer, Andrew/0000-0002-7023-6794; Sykiotis, Gerasimos/0000-0002-9565-4941 FU National Institutes of Health [U54 HD028138, HD015788-23, HD056264, GM061354] FX This work was supported by National Institutes of Health Grants U54 HD028138, HD015788-23, HD056264, and GM061354. NR 62 TC 122 Z9 124 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 24 PY 2010 VL 107 IS 34 BP 15140 EP 15144 DI 10.1073/pnas.1009622107 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643PT UT WOS:000281311500038 PM 20696889 ER PT J AU Verzi, MP Hatzis, P Sulahian, R Philips, J Schuijers, J Shin, H Freed, E Lynch, JP Dang, DYT Brown, M Clevers, H Liu, XS Shivdasani, RA AF Verzi, Michael P. Hatzis, Pantelis Sulahian, Rita Philips, Juliet Schuijers, Jurian Shin, Hyunjin Freed, Ellen Lynch, John P. Dang, Duyen T. Brown, Myles Clevers, Hans Liu, X. Shirley Shivdasani, Ramesh A. TI TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE context specificity of signaling; genome-wide chromatin immunoprecipitation; signaling; Wnt signaling in intestine; tissue-specific gene regulation ID COLORECTAL-CANCER CELLS; MODEL-BASED ANALYSIS; GENE-EXPRESSION; TRANSGENIC MICE; HOMEOBOX; METAPLASIA; EPITHELIUM; PROMOTER; MOUSE; DIFFERENTIATION AB Surprisingly few pathways signal between cells, raising questions about mechanisms for tissue-specific responses. In particular, Wnt ligands signal in many mammalian tissues, including the intestinal epithelium, where constitutive signaling causes cancer. Genome-wide analysis of DNA cis-regulatory regions bound by the intestine-restricted transcription factor CDX2 in colonic cells uncovered highly significant overrepresentation of sequences that bind TCF4, a transcriptional effector of intestinal Wnt signaling. Chromatin immuno-precipitation confirmed TCF4 occupancy at most such sites and co-occupancy of CDX2 and TCF4 across short distances. A region spanning the single nucleotide polymorphism rs6983267, which lies within a MYC enhancer and confers colorectal cancer risk in humans, represented one of many co-occupied sites. Co-occupancy correlated with intestine-specific gene expression and CDX2 loss reduced TCF4 binding. These results implicate CDX2 in directing TCF4 binding in intestinal cells. Co-occupancy of regulatory regions by signal-effector and tissue-restricted transcription factors may represent a general mechanism for ubiquitous signaling pathways to achieve tissue-specific outcomes. C1 [Verzi, Michael P.; Sulahian, Rita; Philips, Juliet; Freed, Ellen; Brown, Myles; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Shin, Hyunjin; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Verzi, Michael P.; Sulahian, Rita; Brown, Myles; Shivdasani, Ramesh A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Verzi, Michael P.; Sulahian, Rita; Brown, Myles; Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hatzis, Pantelis; Schuijers, Jurian; Clevers, Hans] Netherlands Inst Dev Biol, NL-3508 AD Utrecht, Netherlands. [Hatzis, Pantelis; Schuijers, Jurian; Clevers, Hans] Hubrecht Inst, NL-3508 AD Utrecht, Netherlands. [Lynch, John P.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Dang, Duyen T.] Univ Michigan, Dept Med, Sch Med, Ann Arbor, MI 48109 USA. RP Shivdasani, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM ramesh_shivdasani@dfci.harvard.edu OI Schuijers, Jurian/0000-0003-2531-3516; Brown, Myles/0000-0002-8213-1658 FU Caring for Carcinoid Foundation; National Institutes of Health [RC2CA14822, T32DK07477]; Dana-Farber/Harvard Cancer Center [P50CA127003]; Crohn's and Colitis Foundation of America; Human Frontier Science Program FX We thank Clifford Meyer for computational support and sharing algorithms. This work was supported in part by the Caring for Carcinoid Foundation, National Institutes of Health Grant RC2CA14822 (to R. A. S.), and the Dana-Farber/Harvard Cancer Center SPORE Program in Gastrointestinal Cancers (P50CA127003). M. P. V. was supported by National Institutes of Health Training Grant T32DK07477 and a fellowship from the Crohn's and Colitis Foundation of America. P.H. was supported by a Human Frontier Science Program Long-Term Fellowship. NR 39 TC 47 Z9 49 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 24 PY 2010 VL 107 IS 34 BP 15157 EP 15162 DI 10.1073/pnas.1003822107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643PT UT WOS:000281311500041 PM 20696899 ER PT J AU Ghosh, S Koralov, SB Stevanovic, I Sundrud, MS Sasaki, Y Rajewsky, K Rao, A Muller, MR AF Ghosh, Srimoyee Koralov, Sergei B. Stevanovic, Irena Sundrud, Mark S. Sasaki, Yoshiteru Rajewsky, Klaus Rao, Anjana Mueller, Martin R. TI Hyperactivation of nuclear factor of activated T cells 1 (NFAT1) in T cells attenuates severity of murine autoimmune encephalomyelitis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autoimmunity; experimental autoimmune encephalomyelitis; IL-10; Treg ID LINEAGE DIFFERENTIATION; TRANSCRIPTION FACTOR; ROR-GAMMA; TGF-BETA; GENE; TOLERANCE; IL-10; INTERLEUKIN-10; CYCLOSPORINE; MECHANISMS AB Nuclear factor of activated T cells (NFAT) proteins are a group of Ca(2+)-regulated transcription factors residing in the cytoplasm of resting cells. Dephosphorylation by calcineurin results in nuclear translocation of NFAT and subsequent expression of target genes; rephosphorylation by kinases, including casein kinase 1 (CK1), restores NFAT to its latent state in the cytoplasm. We engineered a hyperactivable version of NFAT1 with increased affinity for calcineurin and decreased affinity for casein kinase 1. Mice expressing hyperactivable NFAT1 in their T-cell compartment exhibited a dramatically increased frequency of both IL-17- and IL-10-producing cells after differentiation under Th17 conditions-this was associated with direct binding of NFAT1 to distal regulatory regions of Il-17 and Il-10 gene loci in Th17 cells. Despite higher IL-17 production in culture, the mice were significantly less prone to myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis than controls, correlating with increased production of the immunomodulatory cytokine IL-10 and enhanced accumulation of regulatory T cells within the CNS. Thus, NFAT hyperactivation paradoxically leads to decreased susceptibility to experimental autoimmune encephalomyelitis, supporting previous observations linking defects in Ca(2+)/NFAT signaling to lymphopro-liferation and autoimmune disease. C1 [Ghosh, Srimoyee; Koralov, Sergei B.; Stevanovic, Irena; Sundrud, Mark S.; Sasaki, Yoshiteru; Rajewsky, Klaus; Rao, Anjana; Mueller, Martin R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ghosh, Srimoyee; Koralov, Sergei B.; Stevanovic, Irena; Sundrud, Mark S.; Sasaki, Yoshiteru; Rajewsky, Klaus; Rao, Anjana; Mueller, Martin R.] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Ghosh, Srimoyee; Koralov, Sergei B.; Stevanovic, Irena; Sundrud, Mark S.; Sasaki, Yoshiteru; Rajewsky, Klaus; Rao, Anjana; Mueller, Martin R.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Sasaki, Yoshiteru] RIKEN Ctr Dev Biol, Lab Stem Cell Biol, Kobe, Hyogo 6500047, Japan. [Mueller, Martin R.] Univ Tubingen, Med Klin & Poliklin, Dept Hematol Oncol & Immunol, D-72076 Tubingen, Germany. RP Rao, A (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM arao@idi.harvard.edu; Martin.Mueller@med.uni-tuebingen.de FU T32 Training Grant [5T32AI070085-03]; Deutsche Krebshilfe; Cancer Research Institute; National Institutes of Health [CA42471]; Juvenile Diabetes Research Foundation [16-2007-427, 17-2010-421] FX We thank Edward D. Lamperti and Curtis Gelinas for help with mouse colony maintenance and genotyping. This study was supported by T32 Training Grant 5T32AI070085-03 (to S. G.), a Deutsche Krebshilfe Postdoctoral Fellowship (to M.R.M.), an Irvington Institute Fellowship of the Cancer Research Institute (to M. R. M.), National Institutes of Health Grant CA42471 (to A. R.), and Juvenile Diabetes Research Foundation Grants 16-2007-427 and 17-2010-421 (to A. R.). NR 44 TC 20 Z9 24 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 24 PY 2010 VL 107 IS 34 BP 15169 EP 15174 DI 10.1073/pnas.1009193107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643PT UT WOS:000281311500043 PM 20696888 ER PT J AU Lu, XY Roberts, E Xia, FC Sanchez-Alavez, M Liu, TY Baldwin, R Wu, S Chang, J Wasterlain, CG Bartfai, T AF Lu, Xiaoying Roberts, Edward Xia, Fengcheng Sanchez-Alavez, Manuel Liu, Tianyu Baldwin, Roger Wu, Stephanie Chang, James Wasterlain, Claude G. Bartfai, Tamas TI GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE galanin; seizure; G protein-coupled receptor; status epilepticus ID GALANIN-LIKE IMMUNOREACTIVITY; CENTRAL-NERVOUS-SYSTEM; STATUS EPILEPTICUS; HIPPOCAMPAL GALANIN; KINDLING EPILEPTOGENESIS; ANTIEPILEPTIC DRUGS; MEDIATED EXPRESSION; ALZHEIMERS-DISEASE; RECEPTOR SUBTYPES; TYPE-2 RECEPTORS AB Galanin receptors type 1 (GalR1) and/or type 2 (GalR2) represent unique pharmacological targets for treatment of seizures and epilepsy. Previous studies have shown that the endogenous peptide ligand galanin exerts powerful anticonvulsant effect through activation of these two G protein-coupled receptors, which are highly expressed in the temporal lobe of rodent brain. Here we report the characterization of a putative GalR2-positive allosteric modulator CYM2503. CYM2503 potentiated the galanin-stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor, whereas it exhibited no detectable affinity for the (125)I galanin-binding site of GalR2 receptor, an effect consistent with that of a positive allosteric modulator. In the rat Li-pilocarpine status epilepticus model, CYM2503, injected intraperitoneally, increased the latency to first electrographic seizure and the latency to first stage 3 behavioral seizure, decreased the latency to the establishment of status epilepticus, and dramatically decreased the mortality. In a Li-pilocarpine seizure model in mice, CYM2503 increased the latency to first electrographic seizure and decreased the total time in seizure. CYM2503 also attenuated electroshock-induced seizures in mice. Thus, CYM2503 provides a starting point for the development of anticonvulsant therapy using the galanin R2 receptor as target. C1 [Lu, Xiaoying; Xia, Fengcheng; Sanchez-Alavez, Manuel; Wu, Stephanie; Chang, James; Bartfai, Tamas] Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. [Roberts, Edward; Liu, Tianyu] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. [Baldwin, Roger; Wasterlain, Claude G.] Vet Affairs Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. [Baldwin, Roger; Wasterlain, Claude G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90073 USA. RP Lu, XY (reprint author), Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. EM xiaoying@scripps.edu FU National Institute of Health [NS063560, R01MH074055] FX We thank Viktor Zhukov for technical assistance. The study was supported by National Institute of Health Grants NS063560 and R01MH074055 (to T. B.). The present study is Scripps Research Institute Manuscript 20798. NR 52 TC 22 Z9 22 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 24 PY 2010 VL 107 IS 34 BP 15229 EP 15234 DI 10.1073/pnas.1008986107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643PT UT WOS:000281311500053 PM 20660766 ER PT J AU Tian, PF Teng, IC May, LD Kurz, R Lu, K Scadeng, M Hillman, EMC De Crespigny, AJ D'Arceuil, HE Mandeville, JB Marota, JJA Rosen, BR Liu, TT Boas, DA Buxton, RB Dale, AM Devor, A AF Tian, Peifang Teng, Ivan C. May, Larry D. Kurz, Ronald Lu, Kun Scadeng, Miriam Hillman, Elizabeth M. C. De Crespigny, Alex J. D'Arceuil, Helen E. Mandeville, Joseph B. Marota, John J. A. Rosen, Bruce R. Liu, Thomas T. Boas, David A. Buxton, Richard B. Dale, Anders M. Devor, Anna TI Cortical depth-specific microvascular dilation underlies laminar differences in blood oxygenation level-dependent functional MRI signal SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE blood flow; cortical layer; hemodynamic; imaging; somatosensory ID CONDUCTED VASOMOTOR RESPONSES; STIMULUS-INDUCED CHANGES; RAT BARREL CORTEX; NEURONAL-ACTIVITY; SOMATOSENSORY CORTEX; SENSORY STIMULATION; NEURAL ACTIVITY; HEMODYNAMIC-RESPONSE; ELECTRICAL-ACTIVITY; TISSUE OXYGENATION AB Changes in neuronal activity are accompanied by the release of vasoactive mediators that cause microscopic dilation and constriction of the cerebral microvasculature and are manifested in macroscopic blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals. We used two-photon microscopy to measure the diameters of single arterioles and capillaries at different depths within the rat primary somatosensory cortex. These measurements were compared with cortical depth-resolved fMRI signal changes. Our microscopic results demonstrate a spatial gradient of dilation onset and peak times consistent with "upstream" propagation of vasodilation toward the cortical surface along the diving arterioles and "downstream" propagation into local capillary beds. The observed BOLD response exhibited the fastest onset in deep layers, and the "initial dip" was most pronounced in layer I. The present results indicate that both the onset of the BOLD response and the initial dip depend on cortical depth and can be explained, at least in part, by the spatial gradient of delays in microvascular dilation, the fastest response being in the deep layers and the most delayed response in the capillary bed of layer I. C1 [Tian, Peifang; Teng, Ivan C.; Dale, Anders M.; Devor, Anna] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [May, Larry D.; Kurz, Ronald; Lu, Kun; Scadeng, Miriam; Liu, Thomas T.; Buxton, Richard B.; Dale, Anders M.; Devor, Anna] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Hillman, Elizabeth M. C.; De Crespigny, Alex J.; D'Arceuil, Helen E.; Mandeville, Joseph B.; Marota, John J. A.; Rosen, Bruce R.; Boas, David A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Devor, A (reprint author), Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. EM adevor@ucsd.edu RI Dale, Anders/A-5180-2010; OI Hillman, Elizabeth M. C./0000-0001-5511-1451 FU National Institute of Neurological Disorders and Stroke [NS051188, NS-057198, NS057476]; National Institute of Biomedical Imaging and Bioengineering [EB00790, EB009118, EB2066] FX We gratefully acknowledge support from the National Institute of Neurological Disorders and Stroke (Grants NS051188 and NS-057198 to A. D. and NS057476 to D. A. B.) and the National Institute of Biomedical Imaging and Bioengineering (Grants EB00790 to A. M. D., EB009118 to A. D., and EB2066 to B. R. R.). NR 44 TC 102 Z9 104 U1 2 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 24 PY 2010 VL 107 IS 34 BP 15246 EP 15251 DI 10.1073/pnas.1006735107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643PT UT WOS:000281311500056 PM 20696904 ER PT J AU Tunis, SR Pearson, SD AF Tunis, Sean R. Pearson, Steven D. TI US moves to improve health decisions SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID CARE C1 [Tunis, Sean R.] Ctr Med Technol Policy, Baltimore, MD 21210 USA. [Pearson, Steven D.] Massachusetts Gen Hosp, Inst Clin & Econ Rev, Boston, MA USA. RP Tunis, SR (reprint author), Ctr Med Technol Policy, Baltimore, MD 21210 USA. EM sean.tunis@cmtpnet.org NR 13 TC 3 Z9 3 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BRIT MED J JI Br. Med. J. PD AUG 23 PY 2010 VL 341 AR c3615 DI 10.1136/bmj.c3615 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 645IF UT WOS:000281445800001 PM 20732966 ER PT J AU Cherra, SJ Kulich, SM Uechi, G Balasubramani, M Mountzouris, J Day, BW Chu, CT AF Cherra, Salvatore J., III Kulich, Scott M. Uechi, Guy Balasubramani, Manimalha Mountzouris, John Day, Billy W. Chu, Charleen T. TI Regulation of the autophagy protein LC3 by phosphorylation SO JOURNAL OF CELL BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; SIGNALING PATHWAYS; CRYSTAL-STRUCTURE; CELL-DEATH; KINASE; CAMP; DEGENERATION; INDUCTION; NEURODEGENERATION; LIGHT-CHAIN-3 AB Macroautophagy is a major catabolic pathway that impacts cell survival, differentiation, tumorigenesis, and neurodegeneration. Although bulk degradation sustains carbon sources during starvation, autophagy contributes to shrinkage of differentiated neuronal processes. Identification of autophagy-related genes has spurred rapid advances in understanding the recruitment of microtubule-associated protein 1 light chain 3 (LC3) in autophagy induction, although braking mechanisms remain less understood. Using mass spectrometry, we identified a direct protein kinase A (PKA) phosphorylation site on LC3 that regulates its participation in autophagy. Both metabolic (rapamycin) and pathological (MPP+) inducers of autophagy caused dephosphorylation of endogenous LC3. The pseudophosphorylated LC3 mutant showed reduced recruitment to autophagosomes, whereas the nonphosphorylatable mutant exhibited enhanced puncta formation. Finally, autophagy-dependent neurite shortening induced by expression of a Parkinson disease-associated G2019S mutation in leucine-rich repeat kinase 2 was inhibited by dibutyryl-cyclic adenosine monophosphate, cytoplasmic expression of the PKA catalytic subunit, or the LC3 phosphorylation mimic. These data demonstrate a role for phosphorylation in regulating LC3 activity. C1 [Cherra, Salvatore J., III; Kulich, Scott M.; Chu, Charleen T.] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA. [Day, Billy W.] Univ Pittsburgh, Sch Med, Dept Pharmaceut Sci & Chem, Pittsburgh, PA 15261 USA. [Chu, Charleen T.] Univ Pittsburgh, Sch Med, Ctr Neurosci, McGowan Inst Regenerat Med, Pittsburgh, PA 15261 USA. [Uechi, Guy; Balasubramani, Manimalha; Day, Billy W.] Univ Pittsburgh, Sch Med, Genom Lab, Pittsburgh, PA 15261 USA. [Uechi, Guy; Balasubramani, Manimalha; Day, Billy W.] Univ Pittsburgh, Sch Med, Prote Core Lab, Pittsburgh, PA 15261 USA. [Kulich, Scott M.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15213 USA. [Mountzouris, John] Abgent Inc, San Diego, CA 92121 USA. RP Chu, CT (reprint author), Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA. EM ctc4@pitt.edu RI Chu, Charleen/B-1601-2008 OI Chu, Charleen/0000-0002-5052-8271 FU National Institutes of Health [AG026389, DC009120, NS064728, NS065789, RR024153]; American Federation for Aging Research/Ellison Medical Foundation FX This work was supported in part by the National Institutes of Health (grants AG026389, DC009120, NS064728, NS065789, and RR024153). C.T. Chu is the recipient of an American Federation for Aging Research/Ellison Medical Foundation Julie Martin Mid-Career Award in Aging Research. J. Mountzouris is a former employee of Abgent, Inc. NR 28 TC 133 Z9 136 U1 2 U2 19 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD AUG 23 PY 2010 VL 190 IS 4 BP 533 EP 539 DI 10.1083/jcb.201002108 PG 7 WC Cell Biology SC Cell Biology GA 645RJ UT WOS:000281481800008 PM 20713600 ER PT J AU Liu, F Mih, JD Shea, BS Kho, AT Sharif, AS Tager, AM Tschumperlin, DJ AF Liu, Fei Mih, Justin D. Shea, Barry S. Kho, Alvin T. Sharif, Asma S. Tager, Andrew M. Tschumperlin, Daniel J. TI Feedback amplification of fibrosis through matrix stiffening and COX-2 suppression SO JOURNAL OF CELL BIOLOGY LA English DT Article ID IDIOPATHIC PULMONARY-FIBROSIS; GROWTH-FACTOR-BETA; PROSTAGLANDIN E-2 PRODUCTION; FIBROTIC LUNG FIBROBLASTS; SMOOTH MUSCLE ACTIN; EXTRACELLULAR-MATRIX; SUBSTRATE STIFFNESS; CYCLOOXYGENASE-2-DEFICIENT MICE; MYOFIBROBLAST DIFFERENTIATION; HISTONE ACETYLATION AB Tissue stiffening is a hallmark of fibrotic disorders but has traditionally been regarded as an outcome of fibrosis, not a contributing factor to pathogenesis. In this study, we show that fibrosis induced by bleomycin injury in the murine lung locally increases median tissue stiffness sixfold relative to normal lung parenchyma. Across this pathophysiological stiffness range, cultured lung fibroblasts transition from a surprisingly quiescent state to progressive increases in proliferation and matrix synthesis, accompanied by coordinated decreases in matrix proteolytic gene expression. Increasing matrix stiffness strongly suppresses fibroblast expression of COX-2 (cyclooxygenase-2) and synthesis of prostaglandin E(2) (PGE(2)), an autocrine inhibitor of fibrogenesis. Exogenous PGE(2) or an agonist of the prostanoid EP2 receptor completely counteracts the proliferative and matrix synthetic effects caused by increased stiffness. Together, these results demonstrate a dominant role for normal tissue compliance, acting in part through autocrine PGE(2), in maintaining fibroblast quiescence and reveal a feedback relationship between matrix stiffening, COX-2 suppression, and fibroblast activation that promotes and amplifies progressive fibrosis. C1 [Liu, Fei; Mih, Justin D.; Sharif, Asma S.; Tschumperlin, Daniel J.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Shea, Barry S.; Tager, Andrew M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Pulm & Crit Care Unit, Charlestown, MA 02129 USA. [Shea, Barry S.; Tager, Andrew M.] Harvard Univ, Div Rheumatol Allergy & Immunol, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Med Sch, Charlestown, MA 02129 USA. [Kho, Alvin T.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Kho, Alvin T.] Childrens Hosp Informat Program, Boston, MA 02115 USA. RP Tschumperlin, DJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. EM DTSCHUMP@hsph.harvard.edu FU National Institutes of Health [HL-092961, HL-088028, GM-073628]; Scleroderma Foundation; American Thoracic Society; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis/American Thoracic Society; Nirenberg Center for Advanced Lung Disease; National Science Foundation [ECS-0335765] FX This work was supported by National Institutes of Health grants HL-092961, HL-088028, GM-073628 and Scleroderma Foundation Established Investigator Grant to D.J. Tschumperlin; American Thoracic Society Fellows Career Development Award to B.S. Shea; and Pulmonary Fibrosis Foundation, Coalition for Pulmonary Fibrosis/American Thoracic Society, and Nirenberg Center for Advanced Lung Disease grants to A.M. Tager. This work was performed in part at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Infrastructure Network, which is supported by the National Science Foundation under NSF award ECS-0335765. CNS is part of the Faculty of Arts and Sciences at Harvard University. NR 74 TC 195 Z9 196 U1 2 U2 19 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD AUG 23 PY 2010 VL 190 IS 4 BP 693 EP 706 DI 10.1083/jcb.201004082 PG 14 WC Cell Biology SC Cell Biology GA 645RJ UT WOS:000281481800021 PM 20733059 ER PT J AU Kim, H Oh, S Sung, B Tian, YH Yang, LL Wang, SX Mao, JR AF Kim, Hyangin Oh, Saecheol Sung, Backil Tian, Yinghong Yang, Liling Wang, Shuxing Mao, Jianren TI Anti-morphine antibody contributes to the development of morphine tolerance in rats SO NEUROSCIENCE LETTERS LA English DT Article DE Morphine; Tolerance; Antibody; Fc receptor; 2.4G(2); Membrane current ID CENTRAL-NERVOUS-SYSTEM; FC-GAMMA RECEPTORS; SPINAL SUBARACHNOID SPACE; IMMUNE-COMPLEXES; INDUCTION; EXPRESSION; CLEARANCE; ADDICTS; BINDING; 2.4G2 AB Previous studies have shown that tolerance to the antinociceptive effect of morphine develops after a prolonged exposure, but its mechanisms remain unclear. In the present study, we examined whether anti-morphine antibody produced by chronic morphine exposure would contribute to the development of morphine antinociceptive tolerance in rats. Our results showed that anti-morphine antibody was present in rats rendered tolerance to antinociception after intrathecal morphine exposure for seven consecutive days. Superfusion of anti-morphine antibody onto spinal cord slice dose-dependently produced an inward excitatory current in spinal cord dorsal horn neurons using whole-cell patch-clamp recording, which surpassed morphine-induced outward inhibiting current. Co-administration of morphine with a monoclonal antibody (2.4G(2)) against Fc receptors for seven days significantly attenuated the production of anti-morphine antibody as well as the behavioral manifestation of morphine tolerance in same rats. These results indicate that anti-morphine antibody produced by morphine exposure may contribute to the development of morphine tolerance possibly through counteracting the inhibitory morphine effect on spinal cord dorsal horn neurons. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Kim, Hyangin; Oh, Saecheol; Sung, Backil; Tian, Yinghong; Yang, Liling; Wang, Shuxing; Mao, Jianren] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care,MGH Ctr Translat Pain, Boston, MA 02114 USA. RP Mao, JR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care,MGH Ctr Translat Pain, Boston, MA 02114 USA. EM jmao@partners.org FU US PHS [NS45681, DE 18214, DE18538] FX This work was supported in part by US PHS RO1 grants NS45681, DE 18214, and DE18538. NR 30 TC 2 Z9 2 U1 0 U2 7 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 AUG 23 PY 2010 VL 480 IS 3 BP 196 EP 200 DI 10.1016/j.neulet.2010.06.034 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 638VA UT WOS:000280924000007 PM 20561567 ER PT J AU Flynn, BP Bhole, AP Saeidi, N Liles, M DiMarzio, CA Ruberti, JW AF Flynn, Brendan P. Bhole, Amit P. Saeidi, Nima Liles, Melody DiMarzio, Charles A. Ruberti, Jeffrey W. TI Mechanical Strain Stabilizes Reconstituted Collagen Fibrils against Enzymatic Degradation by Mammalian Collagenase Matrix Metalloproteinase 8 (MMP-8) SO PLOS ONE LA English DT Article ID ARTICULAR-CARTILAGE; CONNECTIVE-TISSUE; IN-VITRO; DERMAL FIBROBLASTS; TENDON COLLAGEN; TENSILE STRAIN; STRESS; BONE; MECHANOTRANSDUCTION; EXPRESSION AB Background: Collagen, a triple-helical, self-organizing protein, is the predominant structural protein in mammals. It is found in bone, ligament, tendon, cartilage, intervertebral disc, skin, blood vessel, and cornea. We have recently postulated that fibrillar collagens (and their complementary enzymes) comprise the basis of a smart structural system which appears to support the retention of molecules in fibrils which are under tensile mechanical strain. The theory suggests that the mechanisms which drive the preferential accumulation of collagen in loaded tissue operate at the molecular level and are not solely cell-driven. The concept reduces control of matrix morphology to an interaction between molecules and the most relevant, physical, and persistent signal: mechanical strain. Methodology/Principal Findings: The investigation was carried out in an environmentally-controlled microbioreactor in which reconstituted type I collagen micronetworks were gently strained between micropipettes. The strained micronetworks were exposed to active matrix metalloproteinase 8 (MMP-8) and relative degradation rates for loaded and unloaded fibrils were tracked simultaneously using label-free differential interference contrast (DIC) imaging. It was found that applied tensile mechanical strain significantly increased degradation time of loaded fibrils compared to unloaded, paired controls. In many cases, strained fibrils were detectable long after unstrained fibrils were degraded. Conclusions/Significance: In this investigation we demonstrate for the first time that applied mechanical strain preferentially preserves collagen fibrils in the presence of a physiologically-important mammalian enzyme: MMP-8. These results have the potential to contribute to our understanding of many collagen matrix phenomena including development, adaptation, remodeling and disease. Additionally, tissue engineering could benefit from the ability to sculpt desired structures from physiologically compatible and mutable collagen. C1 [Flynn, Brendan P.; Bhole, Amit P.; Saeidi, Nima; Liles, Melody; DiMarzio, Charles A.; Ruberti, Jeffrey W.] Northeastern Univ, Boston, MA 02115 USA. [Saeidi, Nima] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn & Med, Boston, MA USA. [Liles, Melody] Cardiff Univ, Sch Optometry & Vis Sci, Cardiff, S Glam, Wales. RP Flynn, BP (reprint author), Northeastern Univ, Boston, MA 02115 USA. EM j.ruberti@neu.edu FU National Institutes of Health National Institute of Arthritis and Musculoskeletal Skin Dieseases (NIH NIAMS) [R21 AR053551-01] FX The research was funded by National Institutes of Health National Institute of Arthritis and Musculoskeletal Skin Dieseases (NIH NIAMS) R21 AR053551-01 (PI Jeff W. Ruberti). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 56 Z9 57 U1 4 U2 31 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 AUG 23 PY 2010 VL 5 IS 8 AR e12337 DI 10.1371/journal.pone.0012337 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 641TV UT WOS:000281153500018 PM 20808784 ER PT J AU Kimpel, J Braun, SE Qiu, G Wong, FE Conolle, M Schmitz, JE Brendel, C Humeau, LM Dropulic, B Rossi, JJ Berger, A von Laer, D Johnson, RP AF Kimpel, Janine Braun, Stephen E. Qiu, Gang Wong, Fay Eng Conolle, Michelle Schmitz, Joern E. Brendel, Christian Humeau, Laurent M. Dropulic, Boro Rossi, John J. Berger, Annemarie von Laer, Dorothee Johnson, R. Paul TI Survival of the Fittest: Positive Selection of CD4+T Cells Expressing a Membrane-Bound Fusion Inhibitor Following HIV-1 Infection SO PLOS ONE LA English DT Article ID MODIFIED T-CELLS; IMMUNODEFICIENCY-VIRUS; LENTIVIRAL VECTOR; GP41-DERIVED PEPTIDES; ANTIRETROVIRAL THERAPY; HEMATOPOIETIC-CELLS; GENE-EXPRESSION; LYMPHOCYTES; DELIVERY; CCR5 AB Although a variety of genetic strategies have been developed to inhibit HIV replication, few direct comparisons of the efficacy of these inhibitors have been carried out. Moreover, most studies have not examined whether genetic inhibitors are able to induce a survival advantage that results in an expansion of genetically-modified cells following HIV infection. We evaluated the efficacy of three leading genetic strategies to inhibit HIV replication: 1) an HIV-1 tat/rev-specific small hairpin (sh) RNA; 2) an RNA antisense gene specific for the HIV-1 envelope; and 3) a viral entry inhibitor, maC46. In stably transduced cell lines selected such that >95% of cells expressed the genetic inhibitor, the RNA antisense envelope and viral entry inhibitor maC46 provided the strongest inhibition of HIV-1 replication. However, when mixed populations of transduced and untransduced cells were challenged with HIV-1, the maC46 fusion inhibitor resulted in highly efficient positive selection of transduced cells, an effect that was evident even in mixed populations containing as few as 1% maC46-expressing cells. The selective advantage of the maC46 fusion inhibitor was also observed in HIV-1-infected cultures of primary T lymphocytes as well as in HIV-1-infected humanized mice. These results demonstrate robust inhibition of HIV replication with the fusion inhibitor maC46 and the antisense Env inhibitor, and importantly, a survival advantage of cells expressing the maC46 fusion inhibitor both in vitro and in vivo. Evaluation of the ability of genetic inhibitors of HIV-1 replication to confer a survival advantage on genetically-modified cells provides unique information not provided by standard techniques that may be important in the in vivo efficacy of these genes. C1 [Kimpel, Janine; Brendel, Christian; von Laer, Dorothee] Chemotherapeut Forschungsinst Georg Speyer Haus, Frankfurt, Germany. [Braun, Stephen E.; Qiu, Gang; Wong, Fay Eng; Conolle, Michelle; Johnson, R. Paul] Harvard Univ, Sch Med, Div Immunol, New England Primate Res Ctr, Southborough, MA 01772 USA. [Schmitz, Joern E.] Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Dept Med, Boston, MA 02215 USA. [Humeau, Laurent M.; Dropulic, Boro] VIRxSYS Corp, Gaithersburg, MD USA. [Rossi, John J.] Beckman Res Inst City Hope, Div Mol Biol, Duarte, CA USA. [Berger, Annemarie] JW Goethe Univ Hosp, Inst Med Virol, Frankfurt, Germany. [von Laer, Dorothee] Med Univ Innsbruck, Sekt Virol, Innsbruck, Austria. [Johnson, R. Paul] Massachusetts Gen Hosp, Ragon Inst MGH, Massachusetts Inst Technol & Harvard, Charlestown, MA USA. [Johnson, R. Paul] Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA USA. RP Kimpel, J (reprint author), Chemotherapeut Forschungsinst Georg Speyer Haus, Frankfurt, Germany. EM paul_johnson@hms.harvard.edu FU National Institute of Health (NIH) [R01 CA73473, RR00168]; Partners/Fenway/Shattuck Center for AIDS Research (CFAR); NIH [AI 42851]; Deutsche Forschungsgemeinschaft, DFG [GRK1172] FX These studies were supported by the National Institute of Health (NIH) Grants R01 CA73473, RR00168 and by a developmental award from the Partners/Fenway/Shattuck Center for AIDS Research (CFAR), an NIH-funded program (AI 42851). JK and CB were supported by a scholarship from the Deutsche Forschungsgemeinschaft, DFG, GRK1172. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 30 Z9 30 U1 1 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 AUG 23 PY 2010 VL 5 IS 8 AR e12357 DI 10.1371/journal.pone.0012357 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 641TV UT WOS:000281153500030 PM 20808813 ER PT J AU Atilla-Gokcumen, GE Sasse, S Eggert, U AF Atilla-Gokcumen, Gunes E. Sasse, Sofia Eggert, Ulrike TI Investigating the role of lipids in cytokinesis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 48-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700683 ER PT J AU Bhaumik, J Bardon, KM Weissleder, R McCarthy, JR AF Bhaumik, Jayeeta Bardon, Kevin M. Weissleder, Ralph McCarthy, Jason R. TI Sulfonamidophenyl porphyrinic macrocycles as thiol-activatable photosensitizers for biological applications SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Ctr Syst Biol, Charlestown, MA USA. Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA 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 AUG 22 PY 2010 VL 240 MA 153-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704701 ER PT J AU Devaraj, NK Haun, JB Weissleder, R AF Devaraj, Neal K. Haun, Jered B. Weissleder, Ralph TI Application of bioorthogonal tetrazine chemistry to nanoparticle based cell detection SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Devaraj, Neal K.; Haun, Jered B.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RI Devaraj, Neal/B-4712-2014 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 AUG 22 PY 2010 VL 240 MA 44-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164702013 ER PT J AU Devaraj, NK Hilderbrand, SA Weissleder, R AF Devaraj, Neal K. Hilderbrand, Scott A. Weissleder, Ralph TI Fluorogenic tetrazine cycloadditions for cellular imaging and detection SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Devaraj, Neal K.; Hilderbrand, Scott A.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RI Devaraj, Neal/B-4712-2014 NR 0 TC 0 Z9 0 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 186-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700586 ER PT J AU Erdem, SS Weissleder, R McCarthy, J AF Erdem, S. Sibel Weissleder, Ralph McCarthy, Jason TI Synthesis and conjugation of chlorins to iron oxide nanoparticles for diagnoses and treatment of atherosclerotic vascular disease SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. NR 0 TC 0 Z9 1 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 AUG 22 PY 2010 VL 240 MA 197-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704736 ER PT J AU Fu, J Muratoglu, OK AF Fu, Jun Muratoglu, Orhun K. TI Wear and oxidation resistant UHMWPE with improved mechanical properties for total joint implants SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Orthopaed Surg, Boston, MA USA. RI Fu, Jun/C-1648-2012 OI Fu, Jun/0000-0002-8723-1439 NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 230-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164706724 ER PT J AU Ghosh, B Thyagarajan, S Moore, A Vinogradov, SA AF Ghosh, Brahma Thyagarajan, Sujatha Moore, Anna Vinogradov, Sergei A. TI New family of sensors for detection of Zn in biological media SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Radiol, Mol Imaging Lab, AA Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 232-BIOL PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700628 ER PT J AU Hooker, JM AF Hooker, Jacob M. TI New uses of carbon-11 synthons: (CO2)-C-11, (H2CO)-C-11, and (HCN)-C-11 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Hooker, Jacob M.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Hooker, Jacob M.] Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Hooker, Jacob M.] Harvard Univ, Sch Med, Dept Radiol, Div Nucl Med & Mol Imaging,Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 44-NUCL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704531 ER PT J AU Jacques, V Dumas, S Greenfield, MT Sun, WC Troughton, JS Caravan, P AF Jacques, Vincent Dumas, Stephane Greenfield, Matthew T. Sun, Wei-Chuan Troughton, Jeffrey S. Caravan, Peter TI Structure-relaxivity relationships among macrocyclic gadolinium(III) complexes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. Harvard Univ, Sch Med, Dept Radiol, Charlestown, MA USA. Epix Pharmaceut, Lexington, MA 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 AUG 22 PY 2010 VL 240 MA 322-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164703423 ER PT J AU Jin, S Peterson, R AF Jin, Shan Peterson, Randall TI High-throughput screening of organophosphate antidotes in a zebrafish model SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Charlestown, MA USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 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 AUG 22 PY 2010 VL 240 MA 108-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164707238 ER PT J AU Karver, MR Panizzi, P Weissleder, R McCarthy, JR Hilderbrand, SA AF Karver, Mark R. Panizzi, Peter Weissleder, Ralph McCarthy, Jason R. Hilderbrand, Scott A. TI Biological oxidant-activated nanoagents for the detection and treatment of disease SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 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 AUG 22 PY 2010 VL 240 MA 183-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700584 ER PT J AU Kim, YW Kutchukian, PS Crenshaw, CM Stanton, SS Chang, A Verdine, GL AF Kim, Young-Woo Kutchukian, Peter S. Crenshaw, Charisse M. Stanton, Shaunna S. Chang, Andrew Verdine, Gregory L. TI Stitching a-helical peptides by tandem ring-closing metathesis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Dept Canc Biol, Program Canc & Chem Biol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 742-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164705329 ER PT J AU Kumar, M AF Kumar, Mohanraja TI Antigen targeted probe for imaging and delivery of siRNA to tumor cells SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Kumar, Mohanraja] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 178-BIOL PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700579 ER PT J AU Liu, JF Cuny, GD Yu, PB Xing, XC Bloch, KD Peterson, RT AF Liu, Ji-Feng Cuny, Gregory D. Yu, Paul B. Xing, Xuechao Bloch, Kenneth D. Peterson, Randall T. TI High-speed synthesis of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines applied to bone morphogenetic protein signaling inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Aberjona Labs Inc, Beverly, MA USA. Brigham & Womens Hosp, Lab Drug Discovery Neurodegenerat, Cambridge, MA USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 1100-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704660 ER PT J AU Liu, JF Cuny, GD Yu, PB Xing, XC Bloch, KD Peterson, RT AF Liu, Ji-Feng Cuny, Gregory D. Yu, Paul B. Xing, Xuechao Bloch, Kenneth D. Peterson, Randall T. TI High-speed synthesis of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines applied to bone morphogenetic protein signaling inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Aberjona Labs Inc, Beverly, MA USA. Brigham & Womens Hosp, Lab Drug Discovery Neurodegenerat, Cambridge, MA USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 153-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704057 ER PT J AU McCarthy, JR Sazonova, IY Weissleder, R Reed, GL Jaffer, FA AF McCarthy, Jason R. Sazonova, Irina Y. Weissleder, Ralph Reed, Guy L. Jaffer, Farouc A. TI Thrombus-targeted theranostic nanoagents for fibrinolysis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Charlestown, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. Med Coll Georgia, Dept Med, Augusta, GA 30912 USA. Univ Tennessee, Dept Med, Hlth Sci Ctr, Memphis, TN 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 AUG 22 PY 2010 VL 240 MA 240-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164701719 ER PT J AU Oral, E Muratoglu, OK AF Oral, Ebru Muratoglu, Orhun K. TI Highly impact resistant surface crosslinked UHMWPE for total joints SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Harris Orthopaed Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Orthopaed Surg, Boston, MA 02115 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 AUG 22 PY 2010 VL 240 MA 239-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164706731 ER PT J AU Qi, J Filippakopoulos, P Picaud, S Smith, W Keates, T Morse, E Philpott, M Shaw, K Fedorov, O West, N Heightman, T French, C Knapp, S Bradner, J AF Qi, Jun Filippakopoulos, Panagis Picaud, Sarah Smith, William Keates, Tracy Morse, Elizabeth Philpott, Martin Shaw, Katharin Fedorov, Oleg West, Nathan Heightman, Tom French, Christopher Knapp, Stefan Bradner, James TI Small-molecule bromodomain inhibitors for cancer therapy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Dana Farber Inst, Boston, MA USA. Univ Oxford, Struct Genom Consortium, Oxford, England. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RI Fedorov, Oleg/B-6412-2014 OI Fedorov, Oleg/0000-0001-9004-1815 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 180-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700582 ER PT J AU Ran, CZR Moore, A AF Ran, Chongzhao Ran Moore, Anna TI Imaging of amyloid beta species by using spectral unmixing with a "smart" fluorescence probe SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Ran, Chongzhao Ran; Moore, Anna] Harvard Univ, Sch Med, Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 513-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704414 ER PT J AU Roussakis, E Sinks, LE Sakadzic, S Boas, DA Vinogradov, SA AF Roussakis, Emmanuel Sinks, Louise E. Sakadzic, Sava Boas, David A. Vinogradov, Sergei A. TI Two-photon phosphorescent nanoprobes for in vivo microscopy of oxygen SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 198-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700597 ER PT J AU Thyagarajan, S Ghosh, B Cheprakov, AV Moore, A Vinogradov, SA AF Thyagarajan, Sujatha Ghosh, Brahma Cheprakov, Andrei V. Moore, Anna Vinogradov, Sergei A. TI Fluorescent sensors for Zn2+ based on (O)over-tilde-extended dipyrrins: Synthesis and spectroscopic characterization SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Penn, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. Moscow MV Lomonosov State Univ, Dept Chem, Moscow, Russia. RI Cheprakov, Andrey/D-7255-2015 OI Cheprakov, Andrey/0000-0001-9589-4104 NR 1 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 AUG 22 PY 2010 VL 240 MA 523-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164703612 ER PT J AU Uppal, R Caravan, P AF Uppal, Ritika Caravan, Peter TI Multimodal imaging probes for fibrin SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. Harvard Univ, Dept Radiol, Sch Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 138-NUCL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704495 ER PT J AU Wanamaker, S Meine, D Hao, T Hill, D Vidal, M Roecklein-Canfield, J AF Wanamaker, Shelly Meine, Danica Hao, Tong Hill, David Vidal, Marc Roecklein-Canfield, Jennifer TI Kaposi sarcoma virus: Virus-host protein interactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Simmons Coll, Boston, MA 02115 USA. Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. RI Hill, David/B-6617-2011 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 AUG 22 PY 2010 VL 240 MA 92-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700717 ER PT J AU Zhang, ZD Greenfield, M Kolodziej, A Caravan, P AF Zhang, Zhaoda Greenfield, Matt Kolodziej, Andrew Caravan, Peter TI Optimization of affinity and relaxity of peptide-based fibrin-targeted MRI contrast agents via N-terminal PNA modification SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. Epix Pharmaceut, Lexington, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 430-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164704332 ER PT J AU Zhou, Y Ollesch, J Wille, H Newburg, DS Costello, CE AF Zhou, Ying Ollesch, Julian Wille, Holger Newburg, David S. Costello, Catherine E. TI Method development for investigation of polar lipids in biological samples by reversed phase liquid chromatography coupled to mass spectrometry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2010 VL 240 MA 65-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V20UK UT WOS:000208164700480 ER PT J AU Viswanathan, AN AF Viswanathan, Akila N. TI Childhood cancer survivors: stillbirth and neonatal death SO LANCET LA English DT Editorial Material ID FEMALE SURVIVORS; PREGNANCY; FERTILITY; OUTCOMES C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Ctr, Boston, MA 02115 USA. RP Viswanathan, AN (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Ctr, Boston, MA 02115 USA. EM aviswanathan@lroc.harvard.edu NR 12 TC 3 Z9 3 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 AUG 21 PY 2010 VL 376 IS 9741 BP 570 EP 572 DI 10.1016/S0140-6736(10)61263-9 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 643PB UT WOS:000281309100006 PM 20728738 ER PT J AU Bonner, LM Simons, CE Parker, LE Yano, EM Kirchner, JE AF Bonner, Laura M. Simons, Carol E. Parker, Louise E. Yano, Elizabeth M. Kirchner, Joann E. TI 'To take care of the patients': Qualitative analysis of Veterans Health Administration personnel experiences with a clinical informatics system SO IMPLEMENTATION SCIENCE LA English DT Article ID UNINTENDED CONSEQUENCES; DEPRESSION CARE; TIME ALLOCATION; ORDER ENTRY; EXAM-ROOM; COMMUNICATION; IMPROVEMENT; REMINDERS; BARRIERS; RECORDS AB Background: The Veterans Health Administration (VA) has invested significant resources in designing and implementing a comprehensive electronic health record (EHR) that supports clinical priorities. EHRs in general have been difficult to implement, with unclear cost-effectiveness. We describe VA clinical personnel interactions with and evaluations of the EHR. Methods: As part of an evaluation of a quality improvement initiative, we interviewed 72 VA clinicians and managers using a semi-structured interview format. We conducted a qualitative analysis of interview transcripts, examining themes relating to participants' interactions with and evaluations of the VA EHR. Results: Participants described their perceptions of the positive and negative effects of the EHR on their clinical workflow. Although they appreciated the speed and ease of documentation that the EHR afforded, they were concerned about the time cost of using the technology and the technology's potential for detracting from interpersonal interactions. Conclusions: VA personnel value EHRs' contributions to supporting communication, education, and documentation. However, participants are concerned about EHRs' potential interference with other important aspects of healthcare, such as time for clinical care and interpersonal communication with patients and colleagues. We propose that initial implementation of an EHR is one step in an iterative process of ongoing quality improvement. C1 [Bonner, Laura M.; Simons, Carol E.] VA Puget Sound Healthcare Syst, Hlth Serv Res & Dev NW Ctr Excellence Outcomes Re, Seattle, WA USA. [Bonner, Laura M.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Parker, Louise E.] Independent Consultant, Cambridge, MA USA. [Parker, Louise E.] Hlth Serv Res & Dev Ctr Mental Healthcare & Outco, N Little Rock, AR USA. [Yano, Elizabeth M.] VA Greater Los Angeles Healthcare Syst, Hlth Serv Res & Dev Ctr Excellence Study Hlth Car, Sepulveda, CA USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Kirchner, Joann E.] Cent Arkansas Vet Healthcare Syst, VA S Cent Mental Illness Res Educ & Clin Ctr, N Little Rock, AR USA. [Kirchner, Joann E.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Kirchner, Joann E.] Cent Arkansas Vet Healthcare Syst, Hlth Serv Res & Dev Ctr Mental Healthcare & Outco, N Little Rock, AR USA. RP Bonner, LM (reprint author), VA Puget Sound Healthcare Syst, Hlth Serv Res & Dev NW Ctr Excellence Outcomes Re, Seattle, WA USA. EM Laura.bonner@va.gov FU VA; The VA Quality Enhancement Research Initiative [MNT-02-209] FX We gratefully acknowledge the contributions of Lisa V. Rubenstein, MD, MSPH, Mona J. Ritchie, MSW, Jacqueline Fickel, PhD, Penny White, BA, and the many study participants without whom this work would not have been possible. We thank Edmund Chaney, PhD, for helpful comments on an earlier version of the manuscript. This work was supported by the VA. The VA Quality Enhancement Research Initiative MNT-02-209 funded this study. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. NR 37 TC 8 Z9 8 U1 3 U2 11 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 AUG 20 PY 2010 VL 5 AR 63 DI 10.1186/1748-5908-5-63 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 656EL UT WOS:000282308900001 PM 20727182 ER PT J AU London, WB Frantz, CN Campbell, LA Seeger, RC Brumback, BA Cohn, SL Matthay, KK Castleberry, RP Diller, L AF London, Wendy B. Frantz, Christopher N. Campbell, Laura A. Seeger, Robert C. Brumback, Babette A. Cohn, Susan L. Matthay, Katherine K. Castleberry, Robert P. Diller, Lisa TI Phase II Randomized Comparison of Topotecan Plus Cyclophosphamide Versus Topotecan Alone in Children With Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MALIGNANT SOLID TUMORS; PEDIATRIC-PATIENTS; CONTINUOUS-INFUSION; TRIAL; WINDOW AB Purpose Single-agent topotecan (TOPO) and combination topotecan and cyclophosphamide (TOPO/CTX) were compared in a phase II randomized trial in relapsed/refractory neuroblastoma. Because responders often underwent further therapies, novel statistical methods were required to compare the long-term outcome of the two treatments. Patients and Methods Children with refractory/recurrent neuroblastoma (only one prior aggressive chemotherapy regimen) were randomly assigned to daily 5-day topotecan (2 mg/m(2)) or combination topotecan (0.75 mg/m(2)) and cyclophosphamide (250 mg/m(2)). A randomized two-stage group sequential design enrolled 119 eligible patients. Toxicity and response were estimated. Long-term outcome of protocol therapy was assessed using novel methods-causal inference-which allowed adjustment for the confounding effect of off-study therapies. Results Seven more responses were observed for TOPO/CTX (complete response [CR] plus partial response [PR], 18 [32%] of 57) than TOPO (CR + PR, 11 [19%] of 59; P = .081); toxicity was similar. At 3 years, progression-free survival (PFS) and overall survival (OS) were 4% +/- 2% and 15% +/- 4%, respectively. PFS was significantly better for TOPO/CTX (P = .029); there was no difference in OS. Older age at diagnosis and lack of MYCN amplification predicted increased OS (P < .05). Adjusting for randomized treatment effect and subsequent autologous stem-cell transplantation, there was no difference between TOPO and TOPO/CTX in terms of the proportion alive at 2 years. Conclusion TOPO/CTX was superior to TOPO in terms of PFS, but there was no OS difference. After adjustment for subsequent therapies, no difference was detected in the proportion alive at 2 years. Causal inference methods for assessing long-term outcomes of phase II therapies after subsequent treatment can elucidate effects of initial therapies. C1 [London, Wendy B.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Childrens Hosp Boston,Div Hematol Oncol, Boston, MA 02215 USA. Childrens Oncol Grp Stat & Data Ctr, Boston, MA USA. Alfred I DuPont Hosp Children, Wilmington, DE USA. Kaiser Permanente Med Grp, Oakland, CA USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Univ Calif San Francisco, Sch Med, San Francisco, CA USA. UCSF Childrens Hosp, San Francisco, CA USA. Univ Florida, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA. Univ Chicago, Chicago, IL 60637 USA. Univ Alabama Birmingham, Birmingham, AL USA. RP London, WB (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Childrens Hosp Boston,Div Hematol Oncol, 1 Autumn St,AU 022, Boston, MA 02215 USA. EM wendy@cog.ufl.edu OI Cohn, Susan/0000-0001-5749-7650 FU National Institutes of Health [U10 CA98413, U10 CA29139, U10 CA13539] FX Supported by Grant No. U10 CA98413 from the National Institutes of Health to the Children's Oncology Group, Grant No. U10 CA29139 to the Pediatric Oncology Group, and Grant No. U10 CA13539 to the Children's Cancer Group. NR 24 TC 37 Z9 40 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2010 VL 28 IS 24 BP 3808 EP 3815 DI 10.1200/JCO.2009.27.5016 PG 8 WC Oncology SC Oncology GA 641ME UT WOS:000281129700004 PM 20660830 ER PT J AU Gutierrez, A Dahlberg, SE Neuberg, DS Zhang, JH Grebliunaite, R Sanda, T Protopopov, A Tosello, V Kutok, J Larson, RS Borowitz, MJ Loh, ML Ferrando, AA Winter, SS Mullighan, CG Silverman, LB Chin, L Hunger, SP Sallan, SE Look, AT AF Gutierrez, Alejandro Dahlberg, Suzanne E. Neuberg, Donna S. Zhang, Jianhua Grebliunaite, Ruta Sanda, Takaomi Protopopov, Alexei Tosello, Valeria Kutok, Jeffery Larson, Richard S. Borowitz, Michael J. Loh, Mignon L. Ferrando, Adolfo A. Winter, Stuart S. Mullighan, Charles G. Silverman, Lewis B. Chin, Lynda Hunger, Stephen P. Sallan, Stephen E. Look, A. Thomas TI Absence of Biallelic TCR gamma Deletion Predicts Early Treatment Failure in Pediatric T-Cell Acute Lymphoblastic Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHILDRENS ONCOLOGY GROUP; PROGNOSTIC-FACTORS; INDUCTION FAILURE; SALVAGE THERAPY; EXPRESSION; DIFFERENTIATION; IDENTIFICATION; REARRANGEMENTS; CONSORTIUM; PRECURSOR AB Purpose To identify children with T-cell acute lymphoblastic leukemia (T-ALL) at high risk of induction chemotherapy failure by using DNA copy number analysis of leukemic cells collected at diagnosis. Patients and Methods Array comparative genomic hybridization (CGH) was performed on genomic DNA extracted from diagnostic lymphoblasts from 47 children with T-ALL treated on Children's Oncology Group Study P9404 or Dana-Farber Cancer Institute Protocol 00-01. These samples represented nine patients who did not achieve an initial complete remission, 13 who relapsed, and 25 who became long-term, event-free survivors. The findings were confirmed in an independent cohort of patients by quantitative DNA polymerase chain reaction (DNA-PCR), an assay that is well suited for clinical application. Results Analysis of the CGH findings in patients in whom induction chemotherapy failed compared with those in whom induction chemotherapy was successful identified the absence of biallelic TCR gamma locus deletion (ABD), a characteristic of early thymocyte precursors before V(D)J recombination, as the most robust predictor of induction failure (P < .001). This feature was also associated with markedly inferior event-free (P = .002) and overall survival (P < .001) rates: 25% versus 58% and 25% versus 72%, respectively. Using a rapid and inexpensive quantitative DNA-PCR assay, we validated ABD as a predictor of a poor response to induction chemotherapy in an independent series of patients. Conclusion Lymphoblasts from children with T-ALL should be evaluated at diagnosis for deletion within the TCR gamma locus. Patients lacking biallelic deletion, which confers a high probability of induction failure with contemporary therapy, should be assigned to alternative therapy in the context of a prospective clinical trial. C1 [Look, A. Thomas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Columbia Univ, Inst Canc Genet, New York, NY USA. Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. St Jude Childrens Hosp, Memphis, TN 38105 USA. Univ Colorado, Sch Med, Boulder, CO 80309 USA. Childrens Hosp, Aurora, CO USA. RP Look, AT (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM thomas_look@dfci.harvard.edu RI Ferrando, Adolfo /Q-7026-2016; OI Gutierrez, Alejandro/0000-0002-0249-9007 FU National Institutes of Health [NCI 5P01CA68484, NCI 1K08CA133103, NCI R01CA120196, R01CA129382, CA98543, CA114766, CA98413]; William Lawrence Foundation; Community Foundation of the National Capital Region; Children's Oncology Group FX Supported by National Institutes of Health Grants No. NCI 5P01CA68484 (S. E. S., L. B. S., A. T. L.), NCI 1K08CA133103 (A. G.), NCI R01CA120196, and R01CA129382 (A. A. F.), the William Lawrence Foundation (A. G., A. T. L.), the Wine Advocate Fund for Philanthropy of The Community Foundation of the National Capital Region (S. E. S.), Children's Oncology Group 9900 cell biology study, and Grants No. CA98543, CA114766, and CA98413 from the National Institutes of Health. A. G. is a scholar of the American Society of Hematology-Harold Amos Medical Faculty Development Program, V. T. is a Lady Tata Memorial Trust Research Fellow, A. A. F. is a Leukemia and Lymphoma Society Scholar, and S. P. H. is the Ergen Family Chair in Pediatric Cancer at The Children's Hospital, Aurora, CO. NR 33 TC 38 Z9 39 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2010 VL 28 IS 24 BP 3816 EP 3823 DI 10.1200/JCO.2010.28.3390 PG 8 WC Oncology SC Oncology GA 641ME UT WOS:000281129700005 PM 20644084 ER PT J AU Kerlikowske, K Cook, AJ Buist, DSM Cummings, SR Vachon, C Vacek, P Miglioretti, DL AF Kerlikowske, Karla Cook, Andrea J. Buist, Diana S. M. Cummings, Steve R. Vachon, Celine Vacek, Pamela Miglioretti, Diana L. TI Breast Cancer Risk by Breast Density, Menopause, and Postmenopausal Hormone Therapy Use SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MAMMOGRAPHIC DENSITY; PARENCHYMAL PATTERNS; REPLACEMENT THERAPY; UNITED-STATES; ASSOCIATION; WOMEN; AGE; PROGESTIN; ESTROGEN; SURVIVAL AB Purpose We determined whether the association between breast density and breast cancer risk and cancer severity differs according to menopausal status and postmenopausal hormone therapy (HT) use. Methods We collected data on 587,369 women who underwent 1,349,027 screening mammography examinations; 14,090 women were diagnosed with breast cancer. We calculated 5-year breast cancer risk from a survival model for subgroups of women classified by their Breast Imaging Reporting and Data System (BIRADS) breast density, age, menopausal status, and current HT use, assuming a body mass index of 25 kg/m(2). Odds of advanced (ie, IIb, III, IV) versus early (ie, I, IIa) stage invasive cancer was calculated according to BIRADS density. Results Breast cancer risk was low among women with low density (BIRADS-1): women age 55 to 59 years, 5-year risk was 0.8% (95% CI, 0.6 to 0.9%) for non-HT users and 0.9% (95% CI, 0.7% to 1.1%) for estrogen and estrogen plus progestin users. Breast cancer risk was high among women with very high density (BIRADS-4), particularly estrogen plus progestin users: women age 55 to 59 years, 5-year risk was 2.4% (95% CI, 2.0% to 2.8%) for non-HT users, 3.0% (95% CI, 2.6% to 3.5%) for estrogen users, and 4.2% (95% CI, 3.7% to 4.6%) for estrogen plus progestin users. Advanced-stage breast cancer risk was increased 1.7-fold for postmenopausal HT users who had very high density (BIRADS-4) compared to those with average density (BIRADS-2). Conclusion Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT, especially estrogen plus progestin. C1 [Kerlikowske, Karla] Univ Calif San Francisco, Gen Internal Med Sect, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94121 USA. Calif Pacific Med Ctr, San Francisco Coordinating Ctr, Res Inst, San Francisco, CA USA. Grp Hlth Cooperat Puget Sound, Biostat Unit, Grp Hlth Res Inst, Seattle, WA USA. Univ Washington, Seattle, WA 98195 USA. Mayo Clin, Coll Med, Rochester, MN USA. Univ Vermont, Coll Med, Burlington, VT USA. RP Kerlikowske, K (reprint author), Univ Calif San Francisco, Gen Internal Med Sect, San Francisco Vet Affairs Med Ctr, 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM Karla.Kerlikowske@ucsf.edu FU National Cancer Institute [P01 CA107584, U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040] FX Supported by Grant No. P01 CA107584 (K. K.) from the National Cancer Institute and the Breast Cancer Surveillance Consortium Co-Operative Agreement (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040) from the National Cancer Institute. The collection of cancer data used in this study was supported in part by several state public health departments and cancer registries throughout the United States. For a full description of these sources, please see: http://breastscreening.cancer.gov/work/acknowledgement. html. NR 38 TC 85 Z9 86 U1 0 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2010 VL 28 IS 24 BP 3830 EP 3837 DI 10.1200/JCO.2009.26.4770 PG 8 WC Oncology SC Oncology GA 641ME UT WOS:000281129700007 PM 20644098 ER PT J AU Housman, E Chang, P Lane, SW Blinder, R Galinsky, I Kesari, S Ho, VT Stone, RM Mullally, A AF Housman, Elizabeth Chang, Priscilla Lane, Steven W. Blinder, Russell Galinsky, Ilene Kesari, Santosh Ho, Vincent T. Stone, Richard M. Mullally, Ann TI CNS Relapse in Acute Promyeloctyic Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TRANS-RETINOIC ACID; STEM-CELL TRANSPLANTATION; ARSENIC TRIOXIDE; THERAPY; REMISSION; CHEMOTHERAPY; MULTICENTER; COMBINATION; PETHEMA; DISEASE C1 [Housman, Elizabeth] Boston Univ, Sch Med, Boston, MA 02118 USA. [Chang, Priscilla; Lane, Steven W.; Blinder, Russell] Brigham & Womens Hosp, Boston, MA 02115 USA. [Galinsky, Ilene; Kesari, Santosh; Ho, Vincent T.; Stone, Richard M.; Mullally, Ann] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Housman, E (reprint author), Boston Univ, Sch Med, Boston, MA 02118 USA. RI Lane, Steven/C-3215-2012; Kesari, Santosh/E-8461-2013 OI Lane, Steven/0000-0002-8050-6209; NR 20 TC 3 Z9 4 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2010 VL 28 IS 24 BP E409 EP E411 DI 10.1200/JCO.2009.27.1577 PG 3 WC Oncology SC Oncology GA 641ME UT WOS:000281129700017 PM 20530270 ER PT J AU Kantoff, PW Blumenstein, BA Gulley, JL Godfrey, WR AF Kantoff, Philip W. Blumenstein, Brent A. Gulley, James L. Godfrey, Wayne R. TI Poxviral-Based Prostate-Specific Antigen Vaccine in Prostate Cancer Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID SURVIVAL C1 [Kantoff, Philip W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Blumenstein, Brent A.] Trial Architecture Consulting, Washington, DC USA. [Gulley, James L.] NCI, Bethesda, MD 20892 USA. [Godfrey, Wayne R.] BN ImmunoTherapeut, Mountain View, CA USA. RP Kantoff, PW (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 3 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2010 VL 28 IS 24 BP E417 EP E417 DI 10.1200/JCO.2010.29.3472 PG 1 WC Oncology SC Oncology GA 641ME UT WOS:000281129700020 ER PT J AU Tawfeek, H Bedi, B Li, JY Adams, J Kobayashi, T Weitzmann, MN Kronenberg, HM Pacifici, R AF Tawfeek, Hesham Bedi, Brahmchetna Li, Jau-Yi Adams, Jonathan Kobayashi, Tatsuya Weitzmann, M. Neale Kronenberg, Henry M. Pacifici, Roberto TI Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss SO PLOS ONE LA English DT Article ID HORMONE-RELATED PROTEIN; MILD PRIMARY HYPERPARATHYROIDISM; HUMAN PARATHYROID-HORMONE; NECROSIS-FACTOR-ALPHA; ESTROGEN DEFICIENCY; TUBEROINFUNDIBULAR PEPTIDE; MECHANICAL-PROPERTIES; POSTMENOPAUSAL WOMEN; IFN-GAMMA; TNF-ALPHA AB Background: Hyperparathyroidism in humans and continuous parathyroid hormone (cPTH) treatment in mice cause bone loss by regulating the production of RANKL and OPG by stromal cells (SCs) and osteoblasts (OBs). Recently, it has been reported that T cells are required for cPTH to induce bone loss as the binding of the T cell costimulatory molecule CD40L to SC receptor CD40 augments SC sensitivity to cPTH. However it is unknown whether direct PTH stimulation of T cells is required for cPTH to induce bone loss, and whether T cells contribute to the bone catabolic activity of PTH with mechanisms other than induction of CD40 signaling in SCs. Methodology/Principal Findings: Here we show that silencing of PTH receptor 1 (PPR) in T cells blocks the bone loss and the osteoclastic expansion induced by cPTH, thus demonstrating that PPR signaling in T cells is central for PTH-induced reduction of bone mass. Mechanistic studies revealed that PTH activation of the T cell PPR stimulates T cell production of the osteoclastogenic cytokine tumor necrosis factor a (TNF). Attesting to the relevance of this effect, disruption of T cell TNF production prevents PTH-induced bone loss. We also show that a novel mechanism by which TNF mediates PTH induced osteoclast formation is upregulation of CD40 expression in SCs, which increases their RANKL/OPG production ratio. Conclusions/Significance: These findings demonstrate that PPR signaling in T cells plays an essential role in PTH induced bone loss by promoting T cell production of TNF. A previously unknown effect of TNF is to increase SC expression of CD40, which in turn increases SC osteoclastogenic activity by upregulating their RANKL/OPG production ratio. PPR-dependent stimulation of TNF production by T cells and the resulting TNF regulation of CD40 signaling in SCs are potential new therapeutic targets for the bone loss of hyperparathyroidism. C1 [Tawfeek, Hesham; Bedi, Brahmchetna; Li, Jau-Yi; Adams, Jonathan; Weitzmann, M. Neale; Pacifici, Roberto] Emory Univ, Dept Med, Div Endocrinol Metab & Lipids, Atlanta, GA 30322 USA. [Pacifici, Roberto] Emory Univ, Immunol & Mol Pathogenesis Program, Atlanta, GA 30322 USA. [Kobayashi, Tatsuya; Kronenberg, Henry M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Weitzmann, M. Neale] Atlanta VA Med Ctr, Decatur, GA USA. RP Tawfeek, H (reprint author), Emory Univ, Dept Med, Div Endocrinol Metab & Lipids, Atlanta, GA 30322 USA. EM roberto.pacifici@emory.edu FU National Institutes of Health [AR54625, AR49649, AR053607, AR056090, AR059364, DK007298, P30-AR46031]; Biomedical Laboratory Research & Development Service of the VA Office of Research and Development [5I01BX000105] FX This study was supported, in part, by grants from the National Institutes of Health (AR54625 and AR49649). NMW was supported in part by grants from the National Institutes of Health (AR053607, AR056090 and AR059364) and by a grant from the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (5I01BX000105). BB is supported by a training grant from the National Institutes of Health (DK007298). The authors are grateful to the University of Alabama at Birmingham, Center for Metabolic Bone Disease-Histomorphometry and Molecular Analysis Core Laboratory, NIH Grant P30-AR46031 for the histomorphometric analysis presented herein. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 30 Z9 30 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 AUG 20 PY 2010 VL 5 IS 8 AR e12290 DI 10.1371/journal.pone.0012290 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 640TW UT WOS:000281077000006 PM 20808842 ER PT J AU Kim, J Zhang, CZ Zhang, XH Springer, TA AF Kim, Jongseong Zhang, Cheng-Zhong Zhang, Xiaohui Springer, Timothy A. TI A mechanically stabilized receptor-ligand flex-bond important in the vasculature SO NATURE LA English DT Article ID VON-WILLEBRAND-FACTOR; IB-IX-V; LEUCINE-RICH REPEATS; FACTOR A1 DOMAIN; PLATELET-ADHESION; SINGLE-MOLECULE; CATCH BONDS; SHEAR; COMPLEX; FORCE AB Haemostasis in the arteriolar circulation mediated by von Willebrand factor (VWF) binding to platelets is an example of an adhesive interaction that must withstand strong hydrodynamic forces acting on cells. VWF is a concatenated, multifunctional protein that has binding sites for platelets as well as subendothelial collagen(1,2). Binding of the A1 domain in VWF to the glycoprotein Ib alpha subunit (GPIb alpha) on the surface of platelets mediates crosslinking of platelets to one another and the formation of a platelet plug for arterioles(3,4). The importance of VWF is illustrated by its mutation in von Willebrand disease, a bleeding diathesis(1). Here, we describe a novel mechanochemical specialization of the A1-GPIb alpha bond for force-resistance. We have developed a method that enables, for the first time, repeated measurements of the binding and unbinding of a receptor and ligand in a single molecule (ReaLiSM). We demonstrate two states of the receptor-ligand bond, that is, a flex-bond. One state is seen at low force; a second state begins to engage at 10 pN with a similar to 20-fold longer lifetime and greater force resistance. The lifetimes of the two states, how force exponentiates lifetime, and the kinetics of switching between the two states are all measured. For the first time, single-molecule measurements on this system are in agreement with bulk phase measurements. The results have important implications not only for how platelets bound to VWF are able to resist force to plug arterioles, but also how increased flow activates platelet plug formation. C1 [Kim, Jongseong; Zhang, Cheng-Zhong; Zhang, Xiaohui; Springer, Timothy A.] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Kim, Jongseong; Zhang, Cheng-Zhong; Zhang, Xiaohui; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Childrens Hosp, Immune Dis Inst, 3 Blackfan Circle, Boston, MA 02115 USA. EM springer@idi.harvard.edu RI Kim, Jongseong/M-9940-2014; Kim, Jongseong/I-6358-2013 OI Kim, Jongseong/0000-0001-9595-2765; Kim, Jongseong/0000-0002-9553-2258 FU NIH [HL-48675] FX Supported by NIH HL-48675 (TAS). The authors are indebted to S. B. Smith and C. Bustamante for help with laser tweezers construction and insightful discussion. We thank B. Coller, O. K. Dudko and C. Lu for reagents and insightful discussions, and J. Dill for software for data analysis. NR 31 TC 107 Z9 108 U1 3 U2 41 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 19 PY 2010 VL 466 IS 7309 BP 992 EP U123 DI 10.1038/nature09295 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 640ED UT WOS:000281030300038 PM 20725043 ER PT J AU Hodi, FS O'Day, SJ McDermott, DF Weber, RW Sosman, JA Haanen, JB Gonzalez, R Robert, C Schadendorf, D Hassel, JC Akerley, W van den Eertwegh, AJM Lutzky, J Lorigan, P Vaubel, JM Linette, GP Hogg, D Ottensmeier, CH Lebbe, C Peschel, C Quirt, I Clark, JI Wolchok, JD Weber, JS Tian, J Yellin, MJ Nichol, GM Hoos, A Urba, WJ AF Hodi, F. Stephen O'Day, Steven J. McDermott, David F. Weber, Robert W. Sosman, Jeffrey A. Haanen, John B. Gonzalez, Rene Robert, Caroline Schadendorf, Dirk Hassel, Jessica C. Akerley, Wallace van den Eertwegh, Alfons J. M. Lutzky, Jose Lorigan, Paul Vaubel, Julia M. Linette, Gerald P. Hogg, David Ottensmeier, Christian H. Lebbe, Celeste Peschel, Christian Quirt, Ian Clark, Joseph I. Wolchok, Jedd D. Weber, Jeffrey S. Tian, Jason Yellin, Michael J. Nichol, Geoffrey M. Hoos, Axel Urba, Walter J. TI Improved Survival with Ipilimumab in Patients with Metastatic Melanoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID T-LYMPHOCYTE ANTIGEN-4; STAGE-IV MELANOMA; MALIGNANT-MELANOMA; PROGNOSTIC-FACTORS; RESPONSE CRITERIA; CLINICAL-RESPONSE; TUMOR-REGRESSION; ADVERSE EVENTS; SOLID TUMORS; DOUBLE-BLIND AB BACKGROUND An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab - which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response - administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3: 1: 1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P = 0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P = 0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.) C1 [Hodi, F. Stephen] Dana Farber Canc Inst, Boston, MA 02115 USA. [McDermott, David F.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [O'Day, Steven J.] Angeles Clin & Res Inst, Los Angeles, CA USA. [Weber, Robert W.] St Marys Hosp, San Francisco, CA USA. [Sosman, Jeffrey A.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Haanen, John B.] Netherlands Canc Inst, Amsterdam, Netherlands. [van den Eertwegh, Alfons J. M.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Gonzalez, Rene] Univ Colorado, Ctr Canc, Aurora, CO USA. [Robert, Caroline] Inst Gustave Roussy, Villejuif, France. [Schadendorf, Dirk; Vaubel, Julia M.] Univ Hosp Essen, Essen, Germany. [Hassel, Jessica C.] Univ Mannheim, German Canc Res Ctr, Mannheim, Germany. [Peschel, Christian] Tech Univ Munich, Munich, Germany. [Akerley, Wallace] Huntsman Canc Inst, Salt Lake City, UT USA. [Lutzky, Jose] Mt Sinai Comprehens Canc Ctr, Miami, FL USA. [Lorigan, Paul] Christie Hosp NHS Trust, Manchester M20 4BX, Lancs, England. [Ottensmeier, Christian H.] Southampton Univ Hosp, Southampton, Hants, England. [Linette, Gerald P.] Washington Univ, Sch Med, St Louis, MO 63130 USA. [Hogg, David; Quirt, Ian] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Lebbe, Celeste] Hop St Louis, Paris, France. [Clark, Joseph I.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. [Wolchok, Jedd D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Weber, Jeffrey S.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Tian, Jason; Yellin, Michael J.; Nichol, Geoffrey M.] Medarex, Bloomsbury, NJ USA. [Hoos, Axel] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Urba, Walter J.] Earle A Chiles Res Inst, Portland, OR USA. RP Hodi, FS (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM stephen_hodi@dfci.harvard.edu RI Ottensmeier, Christian/E-8131-2012; Lorigan, Paul/J-6898-2015 OI Ottensmeier, Christian/0000-0003-3619-1657; Lorigan, Paul/0000-0002-8875-2164 FU Medarex; Bristol-Myers Squibb; Novartis; Genentech; Bristol-Myers Squibb-Medarex FX Supported by Medarex and Bristol-Myers Squibb.; Dr. Hodi reports receiving consulting fees from Bristol-Myers Squibb-Medarex, Novartis, and Genentech; Dr. O'Day, receiving consulting fees, grants, honoraria, and fees for participation in speakers' bureaus from Bristol-Myers Squibb; Dr. McDermott, receiving consulting fees from Bristol-Myers Squibb-Medarex; Dr. Gonzalez, receiving honoraria from Bristol-Myers Squibb; Dr. Schadendorf, serving on a board for and receiving consulting fees, fees for expert testimony, and fees for participation in speakers' bureaus from Bristol-Myers Squibb; Dr. Lutzky, receiving consulting fees and honoraria from Bristol-Myers Squibb; Dr. Lorigan, receiving consulting fees from Bristol-Myers Squibb; Dr. Hogg, serving on a board for Bristol-Myers Squibb (pending); Dr. Ottensmeier, receiving honoraria and grant funding from Bristol-Myers Squibb; Dr. Lebbe, serving on a board for Bristol-Myers Squibb; Dr. Wolchok, serving on a board for Bristol-Myers Squibb; Dr. J.S. Weber, receiving consulting fees from Bristol-Myers Squibb; Drs. Tian, Yellin, and Nichol being former employees of Medarex; Dr. Hoos being currently employed by Bristol-Myers Squibb with stock or stock options; and Dr. Urba, receiving consulting fees from Bristol-Myers Squibb-Medarex. No other potential conflicts of interest relevant to this article were reported. NR 39 TC 4458 Z9 4561 U1 71 U2 426 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 19 PY 2010 VL 363 IS 8 BP 711 EP 723 DI 10.1056/NEJMoa1003466 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 639TE UT WOS:000280996600005 PM 20525992 ER PT J AU Temel, JS Greer, JA Muzikansky, A Gallagher, ER Admane, S Jackson, VA Dahlin, CM Blinderman, CD Jacobsen, J Pirl, WF Billings, JA Lynch, TJ AF Temel, Jennifer S. Greer, Joseph A. Muzikansky, Alona Gallagher, Emily R. Admane, Sonal Jackson, Vicki A. Dahlin, Constance M. Blinderman, Craig D. Jacobsen, Juliet Pirl, William F. Billings, J. Andrew Lynch, Thomas J. TI Early Palliative Care for Patients with Metastatic Non-Small-Cell Lung Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID QUALITY-OF-LIFE; COOPERATIVE-ONCOLOGY-GROUP; RANDOMIZED CONTROLLED-TRIAL; FUNCTIONAL ASSESSMENT; ELDERLY-PATIENTS; SUPPORTIVE CARE; THERAPY-LUNG; DEPRESSION; SURVIVAL; CHEMOTHERAPY AB BACKGROUND Patients with metastatic non-small-cell lung cancer have a substantial symptom burden and may receive aggressive care at the end of life. We examined the effect of introducing palliative care early after diagnosis on patient-reported outcomes and end-of-life care among ambulatory patients with newly diagnosed disease. METHODS We randomly assigned patients with newly diagnosed metastatic non-small-cell lung cancer to receive either early palliative care integrated with standard oncologic care or standard oncologic care alone. Quality of life and mood were assessed at baseline and at 12 weeks with the use of the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale and the Hospital Anxiety and Depression Scale, respectively. The primary outcome was the change in the quality of life at 12 weeks. Data on end-of-life care were collected from electronic medical records. RESULTS Of the 151 patients who underwent randomization, 27 died by 12 weeks and 107 (86% of the remaining patients) completed assessments. Patients assigned to early palliative care had a better quality of life than did patients assigned to standard care (mean score on the FACT-L scale [in which scores range from 0 to 136, with higher scores indicating better quality of life], 98.0 vs. 91.5; P = 0.03). In addition, fewer patients in the palliative care group than in the standard care group had depressive symptoms (16% vs. 38%, P = 0.01). Despite the fact that fewer patients in the early palliative care group than in the standard care group received aggressive end-of-life care (33% vs. 54%, P = 0.05), median survival was longer among patients receiving early palliative care (11.6 months vs. 8.9 months, P = 0.02). CONCLUSIONS Among patients with metastatic non-small-cell lung cancer, early palliative care led to significant improvements in both quality of life and mood. As compared with patients receiving standard care, patients receiving early palliative care had less aggressive care at the end of life but longer survival. (Funded by an American Society of Clinical Oncology Career Development Award and philanthropic gifts; ClinicalTrials.gov number, NCT01038271.) C1 [Temel, Jennifer S.; Greer, Joseph A.; Muzikansky, Alona; Gallagher, Emily R.; Jackson, Vicki A.; Dahlin, Constance M.; Jacobsen, Juliet; Pirl, William F.; Billings, J. Andrew] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Admane, Sonal] SUNY Buffalo, Buffalo, NY 14260 USA. [Blinderman, Craig D.] Columbia Univ, Med Ctr, Dept Anesthesiol, New York, NY USA. [Lynch, Thomas J.] Yale Univ, New Haven, CT USA. RP Temel, JS (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 7B, Boston, MA 02114 USA. EM jtemel@partners.org FU American Society of Clinical Oncology; Joanne Hill Monahan Cancer Fund and Golf Fights Cancer; Roche; Boehringer Ingelheim; Merck; AstraZeneca; Bristol-Myers Squibb; Sanofi-Aventis FX Supported by an American Society of Clinical Oncology Career Development Award and philanthropic gifts from the Joanne Hill Monahan Cancer Fund and Golf Fights Cancer.; Dr. Temel reports receiving payment for developing continuing medical education (CME) programs from InforMEDical; and Dr. Lynch, serving on the board of Infinity Pharmaceuticals, receiving consulting fees from Roche, Boehringer Ingelheim, Merck, AstraZeneca, Bristol-Myers Squibb, and Sanofi-Aventis, royalties from Partners HealthCare, and payment for developing CME programs from InforMEDical. No other potential conflict of interest relevant to this article was reported. NR 39 TC 1751 Z9 1782 U1 25 U2 215 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 19 PY 2010 VL 363 IS 8 BP 733 EP 742 DI 10.1056/NEJMoa1000678 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 639TE UT WOS:000280996600007 PM 20818875 ER PT J AU Klempner, MS Talbot, EA Lee, SI Zaki, S Ferraro, MJ AF Klempner, Mark S. Talbot, Elizabeth A. Lee, Susanna I. Zaki, Sherif Ferraro, Mary Jane TI A Woman with Abdominal Pain and Shock Intestinal anthrax SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INFLAMMATORY RESPONSE SYNDROME; DANGER; SEPSIS; DAMPS C1 [Klempner, Mark S.] Boston Univ, Med Ctr, Natl Emerging Infect Dis Labs, Sch Med, Boston, MA 02118 USA. [Klempner, Mark S.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Lee, Susanna I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Ferraro, Mary Jane] Massachusetts Gen Hosp, Clin Microbiol Lab, Dept Pathol, Boston, MA 02114 USA. [Lee, Susanna I.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Ferraro, Mary Jane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Talbot, Elizabeth A.] Dartmouth Hitchcock Med Ctr, Dept Infect Dis & Int Hlth, Lebanon, NH 03766 USA. [Talbot, Elizabeth A.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Med, Hanover, NH 03756 USA. [Zaki, Sherif] Ctr Dis Control & Prevent, Infect Dis Pathol Branch, Atlanta, GA USA. RP Klempner, MS (reprint author), Boston Univ, Med Ctr, Natl Emerging Infect Dis Labs, Sch Med, Boston, MA 02118 USA. NR 14 TC 16 Z9 17 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 19 PY 2010 VL 363 IS 8 BP 766 EP 777 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 639TE UT WOS:000280996600012 PM 20818879 ER PT J AU Albayrak, A Otu, HH Sezerman, UO AF Albayrak, Aydin Otu, Hasan H. Sezerman, Ugur O. TI Clustering of protein families into functional subtypes using Relative Complexity Measure with reduced amino acid alphabets SO BMC BIOINFORMATICS LA English DT Article ID PHYLOGENETIC TREES; SEQUENCES; EVOLUTIONARY; ALIGNMENT; RESIDUES; DISTANCE; PROFILE AB Background: Phylogenetic analysis can be used to divide a protein family into subfamilies in the absence of experimental information. Most phylogenetic analysis methods utilize multiple alignment of sequences and are based on an evolutionary model. However, multiple alignment is not an automated procedure and requires human intervention to maintain alignment integrity and to produce phylogenies consistent with the functional splits in underlying sequences. To address this problem, we propose to use the alignment-free Relative Complexity Measure (RCM) combined with reduced amino acid alphabets to cluster protein families into functional subtypes purely on sequence criteria. Comparison with an alignment-based approach was also carried out to test the quality of the clustering. Results: We demonstrate the robustness of RCM with reduced alphabets in clustering of protein sequences into families in a simulated dataset and seven well-characterized protein datasets. On protein datasets, crotonases, mandelate racemases, nucleotidyl cyclases and glycoside hydrolase family 2 were clustered into subfamilies with 100% accuracy whereas acyl transferase domains, haloacid dehalogenases, and vicinal oxygen chelates could be assigned to subfamilies with 97.2%, 96.9% and 92.2% accuracies, respectively. Conclusions: The overall combination of methods in this paper is useful for clustering protein families into subtypes based on solely protein sequence information. The method is also flexible and computationally fast because it does not require multiple alignment of sequences. C1 [Albayrak, Aydin; Sezerman, Ugur O.] Sabanci Univ, Istanbul, Turkey. [Otu, Hasan H.] Harvard Univ, Sch Med, Dept Med, BIDMC Genom Ctr, Boston, MA 02115 USA. [Otu, Hasan H.] Istanbul Bilgi Univ, Dept Bioengn, TR-34060 Istanbul, Turkey. RP Sezerman, UO (reprint author), Sabanci Univ, Istanbul, Turkey. EM ugur@sabanciuniv.edu OI Otu, Hasan/0000-0002-9253-8152 FU Dubai Harvard Foundation for Medical Research FX The authors would like to thank Cem Meydan and Ozgur Gul for helpful discussions, Eric Peterson for supplying the perl script for the generation of substitution matrices. HHO is partially supported by a grant from The Dubai Harvard Foundation for Medical Research. NR 38 TC 10 Z9 10 U1 0 U2 3 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 AUG 18 PY 2010 VL 12 AR 428 DI 10.1186/1471-2105-11-428 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 803ZS UT WOS:000293622900001 PM 20718947 ER PT J AU Shargorodsky, J Curhan, SG Curhan, GC Eavey, R AF Shargorodsky, Josef Curhan, Sharon G. Curhan, Gary C. Eavey, Roland TI Change in Prevalence of Hearing Loss in US Adolescents SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; UNITED-STATES; NOISE EXPOSURE; CHILDREN 6; PERFORMANCE; IMPAIRMENT; AGE; EPIDEMIOLOGY; ADULTS AB Context Hearing loss is common and, in young persons, can compromise social development, communication skills, and educational achievement. Objective To examine the current prevalence of hearing loss in US adolescents and determine whether it has changed over time. Design Cross-sectional analyses of US representative demographic and audiometric data from the 1988 through 1994 and 2005 through 2006 time periods. Setting The Third National Health and Nutrition Examination Survey (NHANES Ill), 1988-1994, and NHANES 2005-2006. Participants NHANES III examined 2928 participants and NHANES 2005-2006 examined 1771 participants, aged 12 to 19 years. Main Outcome Measures We calculated the prevalence of hearing loss in participants aged 12 to 19 years after accounting for the complex survey design. Audiometrically determined hearing loss was categorized as either unilateral or bilateral for low frequency (0.5, 1, and 2 kHz) or high frequency (3, 4, 6, and 8 kHz), and as slight loss (>15 to <25 dB) or mild or greater loss (25 dB) according to hearing sensitivity in the worse ear. The prevalence of hearing loss from NHANES 2005-2006 was compared with the prevalence from NHANES III (1988-1994). We also examined the cross-sectional relations between several potential risk factors and hearing loss. Logistic regression was used to calculate multivariate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results The prevalence of any hearing loss increased significantly from 14.9% (95% CI, 13.0%-16.9%) in 1988-1994 to 19.5% (95% CI, 15.2%-23.8%) in 2005-2006 (P=.02). In 2005-2006, hearing loss was more commonly unilateral (prevalence, 14.0%; 95% CI, 10.4%-17.6%, vs 11.1%; 95% CI, 9.5%-12.8% in 1988-1994; P=.005) and involved the high frequencies (prevalence, 16.4%; 95% CI, 13.2%-19.7%, vs 12.8%; 95% CI, 11.1%-14.5% in 1988-1994; P=.02). Individuals from families below the federal poverty threshold (prevalence, 23.6%; 95% CI, 18.5%-28.7%) had significantly higher odds of hearing loss (multivariate adjusted OR, 1.60; 95% CI, 1.10-2.32) than those above the threshold (prevalence, 18.4%; 95% CI, 13.6%-23.2%). Conclusion The prevalence of hearing loss among a sample of US adolescents aged 12 to 19 years was greater in 2005-2006 compared with 1988-1994. JAMA. 2010;304(7):772-778 www.jama.com C1 [Shargorodsky, Josef; Curhan, Sharon G.; Curhan, Gary C.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Curhan, Gary C.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. [Shargorodsky, Josef] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Eavey, Roland] Vanderbilt Univ, Sch Med, Vanderbilt Bill Wilkerson Ctr Otolaryngol & Commu, Nashville, TN 37212 USA. [Curhan, Gary C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Shargorodsky, J (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM josef_shargorodsky@meei.harvard.edu FU Massachusetts Eye and Ear Infirmary Foundation; Vanderbilt University School of Medicine FX This work was supported by the Massachusetts Eye and Ear Infirmary Foundation and Vanderbilt University School of Medicine Development Funds. NR 26 TC 158 Z9 164 U1 8 U2 27 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 18 PY 2010 VL 304 IS 7 BP 772 EP 778 DI 10.1001/jama.2010.1124 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 639SB UT WOS:000280993700024 PM 20716740 ER PT J AU Knudsen, AB Lansdorp-Vogelaar, I Rutter, CM Savarino, JE van Ballegooijen, M Kuntz, KM Zauber, AG AF Knudsen, Amy B. Lansdorp-Vogelaar, Iris Rutter, Carolyn M. Savarino, James E. van Ballegooijen, Marjolein Kuntz, Karen M. Zauber, Ann G. TI Cost-Effectiveness of Computed Tomographic Colonography Screening for Colorectal Cancer in the Medicare Population SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SOCIETY-TASK-FORCE; CT COLONOGRAPHY; EXTRACOLONIC FINDINGS; VIRTUAL COLONOSCOPY; LARGE-INTESTINE; LARGE-BOWEL; FLEXIBLE SIGMOIDOSCOPY; ASYMPTOMATIC ADULTS; CONSENSUS UPDATE; AORTIC-ANEURYSM AB The Centers for Medicare and Medicaid Services (CMS) considered whether to reimburse computed tomographic colonography (CTC) for colorectal cancer screening of Medicare enrollees. To help inform its decision, we evaluated the reimbursement rate at which CTC screening could be cost-effective compared with the colorectal cancer screening tests that are currently reimbursed by CMS and are included in most colorectal cancer screening guidelines, namely annual fecal occult blood test (FOBT), flexible sigmoidoscopy every 5 years, flexible sigmoidoscopy every 5 years in conjunction with annual FOBT, and colonoscopy every 10 years. We used three independently developed microsimulation models to assess the health outcomes and costs associated with CTC screening and with currently reimbursed colorectal cancer screening tests among the average-risk Medicare population. We assumed that CTC was performed every 5 years (using test characteristics from either a Department of Defense CTC study or the National CTC Trial) and that individuals with findings of 6 mm or larger were referred to colonoscopy. We computed incremental cost-effectiveness ratios for the currently reimbursed screening tests and calculated the maximum cost per scan (ie, the threshold cost) for the CTC strategy to lie on the efficient frontier. Sensitivity analyses were performed on key parameters and assumptions. Assuming perfect adherence with all tests, the undiscounted number life-years gained from CTC screening ranged from 143 to 178 per 1000 65-year-olds, which was slightly less than the number of life-years gained from 10-yearly colonoscopy (152-185 per 1000 65-year-olds) and comparable to that from 5-yearly sigmoidoscopy with annual FOBT (149-177 per 1000 65-year-olds). If CTC screening was reimbursed at $488 per scan (slightly less than the reimbursement for a colonoscopy without polypectomy), it would be the most costly strategy. CTC screening could be cost-effective at $108-$205 per scan, depending on the microsimulation model used. Sensitivity analyses showed that if relative adherence to CTC screening was 25% higher than adherence to other tests, it could be cost-effective if reimbursed at $488 per scan. CTC could be a cost-effective option for colorectal cancer screening among Medicare enrollees if the reimbursement rate per scan is substantially less than that for colonoscopy or if a large proportion of otherwise unscreened persons were to undergo screening by CTC. C1 [Knudsen, Amy B.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Lansdorp-Vogelaar, Iris; van Ballegooijen, Marjolein] Univ Med Ctr Rotterdam, Dept Publ Hlth, Erasmus MC, Rotterdam, Netherlands. [Rutter, Carolyn M.] Biostat Unit, Seattle, WA USA. [Savarino, James E.] Grp Hlth Res Inst, Seattle, WA USA. [Kuntz, Karen M.] Univ Minnesota, Sch Publ Hlth, Div Hlth Policy & Management, Minneapolis, MN USA. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. RP Knudsen, AB (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM aknudsen@mgh-ita.org FU National Cancer Institute (NCI) [U01-CA-088204, U01-CA-097426, U01-CA-097427, U01-CA-115953] FX Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (HHSP233200800231A [Memorial Sloan-Kettering Cancer Center], HHSP233200800323A [Erasmus MC], HHSP233200800270A [University of Minnesota], and HHSP233200800234A [Group Health Cooperative]). The models used in the analysis were supported by awards from the National Cancer Institute (NCI) (U01-CA-088204, U01-CA-097426, U01-CA-097427, and U01-CA-115953). NR 67 TC 62 Z9 63 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 18 PY 2010 VL 102 IS 16 BP 1238 EP 1252 DI 10.1093/jnci/djq242 PG 15 WC Oncology SC Oncology GA 642DA UT WOS:000281182500008 PM 20664028 ER PT J AU Kanwal, F Schnitzler, MS Bacon, BR Hoang, TY Buchanan, PM Asch, SM AF Kanwal, Fasiha Schnitzler, Mark S. Bacon, Bruce R. Hoang, Tuyen Buchanan, Paula M. Asch, Steven M. TI Quality of Care in Patients With Chronic Hepatitis C Virus Infection A Cohort Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID UNITED-STATES; B VACCINATION; MISSED OPPORTUNITIES; ANTIVIRAL THERAPY; LIVER-DISEASE; VETERANS; PREDICTORS; RIBAVIRIN; IMPACT; MANAGEMENT AB Background: Medicare has proposed quality-of-care indicators for chronic hepatitis C virus (HCV) infection. The extent to which these standards are met in practice is largely unknown. Objective: To evaluate the quality of health care that patients with HCV receive and the factors associated with receipt of quality care. Design: Retrospective cohort study. Setting: Nationwide U. S. health insurance company research database. Participants: 10 385 patients with HCV enrolled in the database between 2003 and 2006. Patients were included if they were eligible for at least 1 quality indicator. Measurements: Quality of HCV care received by patients, as measured by 7 explicit quality indicators included in Medicare's 2009 Physician Quality Reporting Initiative. Results: Proportions of patients meeting quality indicators varied, ranging from 21.5% for vaccination to 79% for the HCV genotype testing indicator. Overall, 18.5% of patients (95% CI, 18% to 19%) received all recommended care. Older age and presence of comorbid conditions were associated with lower quality, whereas elevated liver enzyme levels, cirrhosis, and HIV infection were associated with higher quality. Patients who saw both generalists and specialists received the best care (odds ratio of receiving care for which a patient is eligible: specialists alone, 0.79 [CI, 0.66 to 0.95]; primary care physician alone, 0.44 [CI, 0.40 to 0.48]). Limitations: The study had an observational retrospective design, used a convenience sample, and had no information on patient ethnicity. It may be that the indicators or the reporting of the indicators of HCV care-and not the care itself-is suboptimum. Conclusion: Health care quality, based on Medicare criteria, is suboptimum for HCV. Care that included both specialists and generalists is associated with the best quality. Our results support the development of specialist and primary care collaboration to improve the quality of HCV care. C1 [Kanwal, Fasiha] John Cochran Vet Affairs Med Ctr, St Louis, MO 63106 USA. St Louis Univ, Sch Med, St Louis, MO 63110 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RAND Corp, Santa Monica, CA USA. RP Kanwal, F (reprint author), John Cochran Vet Affairs Med Ctr, 915 N Grand Blvd,111 JC GI, St Louis, MO 63106 USA. EM fasiha.kanwal@va.gov; schnitm@slu.edu; pbuchan1@slu.edu FU Saint Louis University Liver Center; Veterans Affairs Health Services Research and Development Service [IIR-07-111] FX Primary Funding Source: Saint Louis University Liver Center.; Grant Support: Dr. Kanwal is supported by Veterans Affairs Health Services Research and Development Service Investigator Initiated Research Award IIR-07-111. This study was supported by an intramural grant from the Saint Louis University Liver Center. NR 34 TC 42 Z9 42 U1 1 U2 1 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 AUG 17 PY 2010 VL 153 IS 4 BP 231 EP 239 DI 10.7326/0003-4819-153-4-201008170-00005 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 639KF UT WOS:000280973000003 PM 20713791 ER PT J AU Tobin, MJ Laghi, F Jubran, A AF Tobin, Martin J. Laghi, Franco Jubran, Amal TI Narrative Review: Ventilator-Induced Respiratory Muscle Weakness SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID INDUCED DIAPHRAGMATIC DYSFUNCTION; CONTROLLED MECHANICAL VENTILATION; RAT DIAPHRAGM; PRESSURE; CONTRACTILITY; STIMULATION; ATROPHY AB Clinicians have long been aware that substantial lung injury results when mechanical ventilation imposes too much stress on the pulmonary parenchyma. Evidence is accruing that substantial injury may also result when the ventilator imposes too little stress on the respiratory muscles. Through adjustment of ventilator settings and administration of pharmacotherapy, the respiratory muscles may be rendered almost (or completely) inactive. Research in animals has shown that diaphragmatic inactivity produces severe injury and atrophy of muscle fibers. Human data have recently revealed that 18 to 69 hours of complete diaphragmatic inactivity associated with mechanical ventilation decreased the cross-sectional areas of diaphragmatic fibers by half or more. The atrophic injury seems to result from increased oxidative stress leading to activation of protein-degradation pathways. Scientific understanding of ventilator-induced respiratory muscle injury has not reached the stage where meaningful controlled trials can be done, and thus, it is not possible to give concrete recommendations for patient management. In the meantime, clinicians are advised to select ventilator settings that avoid both excessive patient effort and excessive respiratory muscle rest. The contour of the airway pressure waveform on a ventilator screen provides the most practical indication of patient effort, and clinicians are advised to pay close attention to the waveform as they titrate ventilator settings. Research on ventilator-induced respiratory muscle injury is in its infancy and portends to be an exciting area to follow. C1 [Tobin, Martin J.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. Loyola Univ Chicago, Stritch Sch Med, Hines, IL USA. RP Tobin, MJ (reprint author), US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, 111 N 5th Ave & Roosevelt Rd, Hines, IL 60141 USA. EM mtobin2@lumc.edu FU Veterans Affairs Health Services Research and Development Service; National Institutes of Health [RO1 NR008782] FX Grant Support: By a Merit Review grant from the Veterans Affairs Health Services Research and Development Service and by a grant from the National Institutes of Health (RO1 NR008782). NR 36 TC 26 Z9 28 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 17 PY 2010 VL 153 IS 4 BP 240 EP 245 DI 10.7326/0003-4819-153-4-201008170-00006 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 639KF UT WOS:000280973000004 PM 20713792 ER PT J AU Sudore, RL Fried, TR AF Sudore, Rebecca L. Fried, Terri R. TI Redefining the "Planning" in Advance Care Planning: Preparing for End-of-Life Decision Making SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; SERIOUSLY ILL PATIENTS; HEALTH BEHAVIOR-CHANGE; SUSTAINING TREATMENT; PATIENT PREFERENCES; COMMUNICATION-SKILLS; PALLIATIVE CARE; FAMILY-MEMBERS; TRANSTHEORETICAL MODEL; HOSPITALIZED-PATIENTS AB The traditional objective of advance care planning has been to have patients make treatment decisions in advance so that clinicians can attempt to provide care consistent with their goals. The authors contend that the objective for advance care planning ought to be the preparation of patients and surrogates to participate with clinicians in making the best possible in-the-moment medical decisions. They provide practical steps for clinicians to help patients and surrogate decision makers achieve this objective in the outpatient setting. Preparation for in-the-moment decision making shifts the focus from having patients make premature decisions based on incomplete information to preparing them and their surrogates for the types of decisions and conflicts they may encounter when they do have to make in-the-moment decisions. Advance directives, although important, are just one piece of information to be used at the time of decision making. C1 [Sudore, Rebecca L.] Univ Calif San Francisco, Div Geriatr, Vet Affairs Med Ctr, San Francisco, CA 94121 USA. San Francisco VA Med Ctr, San Francisco, CA 94121 USA. Vet Affairs Connecticut Healthcare Syst, New Haven, CT USA. Yale Univ, Sch Med, New Haven, CT USA. RP Sudore, RL (reprint author), Univ Calif San Francisco, Div Geriatr, Vet Affairs Med Ctr, 4150 Clement St,Box 151R, San Francisco, CA 94121 USA. EM Rebecca.Sudore@ucsf.edu FU Veterans Affairs Career Development Award; Pfizer Fellowship in Clear Health Communication; National Institutes of Health [K24 AG028443] FX Grant Support: Dr. Sudore is supported by a Veterans Affairs Career Development Award and a Pfizer Fellowship in Clear Health Communication. Dr. Fried is supported by the National Institutes of Health (grant K24 AG028443). NR 92 TC 210 Z9 211 U1 8 U2 42 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 AUG 17 PY 2010 VL 153 IS 4 BP 256 EP 261 DI 10.7326/0003-4819-153-4-201008170-00008 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 639KF UT WOS:000280973000006 PM 20713793 ER PT J AU Inuzuka, H Tseng, A Gao, DM Zhai, B Zhang, Q Shaik, S Wan, LX Ang, XL Mock, C Yin, HQ Stommel, JM Gygi, S Lahav, G Asara, J Xiao, ZXJ Kaelin, WG Harper, JW Wei, WY AF Inuzuka, Hiroyuki Tseng, Alan Gao, Daming Zhai, Bo Zhang, Qing Shaik, Shavali Wan, Lixin Ang, Xiaolu L. Mock, Caroline Yin, Haoqiang Stommel, Jayne M. Gygi, Steven Lahav, Galit Asara, John Xiao, Zhi-Xiong Jim Kaelin, William G., Jr. Harper, J. Wade Wei, Wenyi TI Phosphorylation by Casein Kinase I Promotes the Turnover of the Mdm2 Oncoprotein via the SCF beta-TRCP Ubiquitin Ligase SO CANCER CELL LA English DT Article ID F-BOX PROTEINS; DNA-DAMAGE; CELL-CYCLE; DESTRUCTION MOTIF; TUMOR SUPPRESSION; P53 ACTIVATION; RING FINGER; DEGRADATION; CHECKPOINT; COMPLEX AB Mdm2 is the major negative regulator of the p53 pathway. Here, we report that Mdm2 is rapidly degraded after DNA damage and that phosphorylation of Mdm2 by casein kinase I (CKI) at multiple sites triggers its interaction with, and subsequent ubiquitination and destruction, by SCF beta-TRCP. Inactivation of either beta-TRCP or CKI results in accumulation of Mdm2 and decreased p53 activity, and resistance to apoptosis induced by DNA damaging agents. Moreover, SCF beta-TRCP-dependent Mdm2 turnover also contributes to the control of repeated p53 pulses in response to persistent DNA damage. Our results provide insight into the signaling pathways controlling Mdm2 destruction and further suggest that compromised regulation of Mdm2 results in attenuated p53 activity, thereby facilitating tumor progression. C1 [Inuzuka, Hiroyuki; Tseng, Alan; Gao, Daming; Shaik, Shavali; Wan, Lixin; Wei, Wenyi] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. [Asara, John] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA. [Mock, Caroline; Lahav, Galit] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Zhai, Bo; Gygi, Steven] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Zhang, Qing; Yin, Haoqiang; Stommel, Jayne M.; Kaelin, William G., Jr.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yin, Haoqiang; Xiao, Zhi-Xiong Jim] Boston Univ, Med Ctr, Dept Biochem, Boston, MA 02118 USA. RP Wei, WY (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. RI Wan, Lixin/F-2124-2011; OI Cambronne, Lulu/0000-0002-3547-448X FU Massachusetts Life Science Center; NIH [GM089763, GM054137, AG011085, 5R01CA076120-03]; Terri Brodeur Breast Cancer Foundation FX We thank A Toker, C Schorl, R Scully, A Lau, and S Glueck for critical reading of the manuscript, J DeCaprio, J Chen, A G Jochemsen, and W Hahn for providing reagents, and members of the Wei. Harper, Kaelin. and Xiao labs for useful discussions We also thank R Tomaino and X Yang for their kind help in the mass spectrometry analysis W W is a Leukemia and Lymphoma Society Special Fellow, Kimmel Scholar and V Scholar This work was supported in part by the Massachusetts Life Science Center New Investigator award (W W), and by NIH grants GM089763 to W W, GM054137 and AG011085 to J W H and 5R01CA076120-03 to W G K, X L A was supported by a predoctoral fellowship from NIH Q Z is supported by a postdoctoral fellowship from Terri Brodeur Breast Cancer Foundation NR 58 TC 99 Z9 100 U1 0 U2 7 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 AUG 17 PY 2010 VL 18 IS 2 BP 147 EP 159 DI 10.1016/j.ccr.2010.06.015 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 640LF UT WOS:000281052000008 PM 20708156 ER PT J AU Lu, CH Han, HD Mangala, LS Ali-Fehmi, R Newton, CS Ozbun, L Armaiz-Pena, GN Hu, W Stone, RL Munkarah, A Ravoori, MK Shahzad, MMK Lee, JW Mora, E Langley, RR Carroll, AR Matsuo, K Spannuth, WA Schmandt, R Jennings, NB Goodman, BW Jaffe, RB Nick, AM Kim, HS Guven, EO Chen, YH Li, LY Hsu, MC Coleman, RL Calin, GA Denkbas, EB Lim, JY Lee, JS Kundra, V Birrer, MJ Hung, MC Lopez-Berestein, G Sood, AK AF Lu, Chunhua Han, Hee Dong Mangala, Lingegowda S. Ali-Fehmi, Rouba Newton, Christopher S. Ozbun, Laurent Armaiz-Pena, Guillermo N. Hu, Wei Stone, Rebecca L. Munkarah, Adnan Ravoori, Murali K. Shahzad, Mian M. K. Lee, Jeong-Won Mora, Edna Langley, Robert R. Carroll, Amy R. Matsuo, Koji Spannuth, Whitney A. Schmandt, Rosemarie Jennings, Nicholas B. Goodman, Blake W. Jaffe, Robert B. Nick, Alpa M. Kim, Hye Sun Guven, Eylem Ozturk Chen, Ya-Huey Li, Long-Yuan Hsu, Ming-Chuan Coleman, Robert L. Calin, George A. Denkbas, Emir B. Lim, Jae Yun Lee, Ju-Seog Kundra, Vikas Birrer, Michael J. Hung, Mien-Chie Lopez-Berestein, Gabriel Sood, Anil K. TI Regulation of Tumor Angiogenesis by EZH2 SO CANCER CELL LA English DT Article ID NEGATIVE FEEDBACK REGULATOR; INTERFERING RNA DELIVERY; OVARIAN-CANCER; GROWTH-FACTOR; IN-VIVO; ANTIVASCULAR THERAPY; CHROMATIN-STRUCTURE; ENDOTHELIAL-CELLS; BREAST-CANCER; EXPRESSION AB Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibited angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth, which is further enhanced in combination with ezh2 silencing in tumor cells. Collectively, these data support the potential for targeting ezh2 as an important therapeutic approach. C1 [Lu, Chunhua; Han, Hee Dong; Mangala, Lingegowda S.; Armaiz-Pena, Guillermo N.; Hu, Wei; Stone, Rebecca L.; Shahzad, Mian M. K.; Lee, Jeong-Won; Mora, Edna; Carroll, Amy R.; Matsuo, Koji; Spannuth, Whitney A.; Schmandt, Rosemarie; Jennings, Nicholas B.; Goodman, Blake W.; Nick, Alpa M.; Kim, Hye Sun; Coleman, Robert L.; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Ravoori, Murali K.; Kundra, Vikas] Univ Texas MD Anderson Canc Ctr, Dept Expt Diagnost Imaging, Houston, TX 77030 USA. [Langley, Robert R.; Lopez-Berestein, Gabriel; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Hsu, Ming-Chuan; Hung, Mien-Chie] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. [Coleman, Robert L.; Calin, George A.; Lopez-Berestein, Gabriel; Sood, Anil K.] Univ Texas MD Anderson Canc Ctr, Ctr RNA & Noncoding RNA, Houston, TX 77030 USA. [Calin, George A.; Lopez-Berestein, Gabriel] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. [Lim, Jae Yun; Lee, Ju-Seog] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Ali-Fehmi, Rouba] Wayne State Univ, Sch Med, Karmanos Canc Inst, Dept Pathol, Detroit, MI 48201 USA. [Newton, Christopher S.; Ozbun, Laurent] NCI, Dept Cell & Canc Biol, Bethesda, MD 20892 USA. [Munkarah, Adnan] Henry Ford Hlth Syst, Womens Hlth Serv, Detroit, MI 48202 USA. [Shahzad, Mian M. K.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Lee, Jeong-Won] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Obstet & Gynecol, Seoul 135710, South Korea. [Mora, Edna] Univ Puerto Rico, Dept Surg, San Juan, PR 00935 USA. [Jaffe, Robert B.] Univ Calif San Francisco, Ctr Reprod Sci, San Francisco, CA 94143 USA. [Kim, Hye Sun] Kwandong Univ Coll Med, Cheil Gen Hosp, Dept Pathol, Seoul 100380, South Korea. [Kim, Hye Sun] Kwandong Univ Coll Med, Womens Healthcare Ctr, Seoul 100380, South Korea. [Guven, Eylem Ozturk] Hacettepe Univ, Nanotechnol & Nanomed Div, TR-06532 Ankara, Turkey. [Chen, Ya-Huey; Li, Long-Yuan; Hung, Mien-Chie] China Med Univ & Hosp, Ctr Mol Med, Taichung 40447, Taiwan. [Chen, Ya-Huey; Li, Long-Yuan; Hung, Mien-Chie] China Med Univ & Hosp, Grad Inst Canc Biol, Taichung 40447, Taiwan. [Li, Long-Yuan] Asia Univ, Dept Biotechnol, Taichung 41354, Taiwan. [Birrer, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Canc Ctr,Dept Med, Boston, MA 02114 USA. RP Sood, AK (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, 1515 Holcombe Blvd,Unit 950, Houston, TX 77030 USA. RI lee, jw/O-6237-2014; OI Armaiz-Pena, Guillermo N/0000-0002-9081-5339 FU NIH [CA 110793, 109298, P50 CA083639, P50 CA098258, CA128797, RC2GM092599]; Ovarian Cancer Research Fund, Inc; DOD [OC073399, W81XWH-10-1-0158, BC085265]; Zarrow Foundation; Marcus Foundation; Kim Medlin Fund; NCI-DHHS-NIH [T32 CA101642]; GCF/OCRF Ann Schreiber Ovarian Cancer Research; Meyer and Ida Gordon Foundation; NIH/NICHD [HD050128]; GCF-Molly Cade Ovarian Cancer Research; NSC [97-3111-B-039]; [NSC-96-3111-B] FX The authors thank Donna Reynolds, and Fang Wang for their technical expertise and helpful discussion We also thank Dr Vickie Williams for reviewing the manuscript Portions of this work were supported by the NIH (CA 110793, 109298, P50 CA083639, P50 CA098258, CA128797, RC2GM092599). the Ovarian Cancer Research Fund, Inc (Program Project Development Grant), the DOD (OC073399, W81XWH-10-1-0158, BC085265). NSC-96-3111-B, the Zarrow Foundation, the Marcus Foundation, the Kim Medlin Fund, and the Betty Anne Asche Murray Distinguished Professorship W A S A M N,A R C, and R S are supported by NCI-DHHS-NIH T32 Training Grant (T32 CA101642) K M is supported by the GCF/OCRF Ann Schreiber Ovarian Cancer Research grant and an award from the Meyer and Ida Gordon Foundation 2 M M K S is supported by the NIH/NICHD WRHR Grant (HD050128) and the GCF-Molly Cade Ovarian Cancer Research Grant M C H and L Y L are supported by the NSC 97-3111-B-039 NR 51 TC 163 Z9 178 U1 5 U2 39 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 AUG 17 PY 2010 VL 18 IS 2 BP 185 EP 197 DI 10.1016/j.ccr.2010.06.016 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 640LF UT WOS:000281052000011 PM 20708159 ER PT J AU Jefferson, AL Himali, JJ Beiser, AS Au, R Massaro, JM Seshadri, S Gona, P Salton, CJ DeCarli, C O'Donnell, CJ Benjamin, EJ Wolf, PA Manning, WJ AF Jefferson, Angela L. Himali, Jayandra J. Beiser, Alexa S. Au, Rhoda Massaro, Joseph M. Seshadri, Sudha Gona, Philimon Salton, Carol J. DeCarli, Charles O'Donnell, Christopher J. Benjamin, Emelia J. Wolf, Philip A. Manning, Warren J. TI Cardiac Index Is Associated With Brain Aging The Framingham Heart Study SO CIRCULATION LA English DT Article DE brain; cardiac output; epidemiology; imaging; neuropsychology; atrophy ID CARDIOVASCULAR MAGNETIC-RESONANCE; CHRONIC CEREBRAL HYPOPERFUSION; WHITE-MATTER LESIONS; STROKE RISK PROFILE; ALZHEIMERS-DISEASE; BLOOD-FLOW; COGNITIVE IMPAIRMENT; OFFSPRING COHORT; APOLIPOPROTEIN-E; FAILURE AB Background-Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Methods and Results-Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, or dementia (age, 61 +/- 9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent cardiovascular disease were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post hoc comparisons revealed that participants in the bottom cardiac index tertile (values <2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values >2.92). Conclusions-Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging. (Circulation. 2010;122:690-697.) C1 [Jefferson, Angela L.; Seshadri, Sudha] Boston Univ, Sch Med, Alzheimers Dis Ctr, Boston, MA 02118 USA. [Jefferson, Angela L.; Himali, Jayandra J.; Beiser, Alexa S.; Au, Rhoda; Seshadri, Sudha; Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Jefferson, Angela L.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Jefferson, Angela L.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Himali, Jayandra J.; Beiser, Alexa S.; Massaro, Joseph M.; Gona, Philimon] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Himali, Jayandra J.; Beiser, Alexa S.; Au, Rhoda; Massaro, Joseph M.; Seshadri, Sudha; Gona, Philimon; O'Donnell, Christopher J.; Benjamin, Emelia J.; Wolf, Philip A.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Salton, Carol J.; Manning, Warren J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Cardiovasc,Dept Med, Boston, MA 02215 USA. [Manning, Warren J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Radiol, Boston, MA 02215 USA. [DeCarli, Charles] Univ Calif Davis, Ctr Neurosci & Imaging, Dementia & Aging Lab, Dept Neurol, Davis, CA 95616 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol,Dept Med, Boston, MA 02215 USA. RP Jefferson, AL (reprint author), Boston Univ, Sch Med, Alzheimers Dis Ctr, 72 E Concord St,B 7800, Boston, MA 02118 USA. EM angelaj@bu.edu RI DeCarli, Charles/B-5541-2009; OI Massaro, Joseph/0000-0002-2682-4812; Seshadri, Sudha/0000-0001-6135-2622; Au, Rhoda/0000-0001-7742-4491; Benjamin, Emelia/0000-0003-4076-2336; Beiser, Alexa/0000-0001-8551-7778; /0000-0003-1391-9481 FU National Heart Lung Blood Institute [HC25195]; Paul B. Beeson Career Development Award [AG027480, AG030962]; Alzheimer's Association [IIRG-08-88733]; Boston University Alzheimer's Disease Core Center [P30-AG013846]; University of California at Davis Alzheimer's Disease Core Center [AG033193, AG031287, AG021028, AG010129, HL070279]; [AG08122]; [NS017950]; [AG033040]; [AG16495]; [AG028321]; [HL076784] FX This research was supported by the National Heart Lung Blood Institute's Framingham Heart Study HC25195; AG027480, AG030962, Paul B. Beeson Career Development Award in Aging Program, and Alzheimer's Association IIRG-08-88733 to Dr Jefferson; P30-AG013846 (Boston University Alzheimer's Disease Core Center); AG08122, NS017950, AG033040, and AG16495 to Dr Wolf; AG028321 and HL076784 to Dr Benjamin; AG033193 and AG031287 to Dr Seshadri; AG021028 to Dr DeCarli; AG010129 (University of California at Davis Alzheimer's Disease Core Center); and HL070279 to Dr Manning. NR 48 TC 80 Z9 83 U1 0 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 17 PY 2010 VL 122 IS 7 BP 690 EP 697 DI 10.1161/CIRCULATIONAHA.109.905091 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 639FS UT WOS:000280958300004 PM 20679552 ER PT J AU Maes, C Kobayashi, T Selig, MK Torrekens, S Roth, SI Mackem, S Carmeliet, G Kronenberg, HM AF Maes, Christa Kobayashi, Tatsuya Selig, Martin K. Torrekens, Sophie Roth, Sanford I. Mackem, Susan Carmeliet, Geert Kronenberg, Henry M. TI Osteoblast Precursors, but Not Mature Osteoblasts, Move into Developing and Fractured Bones along with Invading Blood Vessels SO DEVELOPMENTAL CELL LA English DT Article ID SITE-SPECIFIC RECOMBINATION; CARTILAGE DEVELOPMENT; SKELETAL DEVELOPMENT; DIFFERENTIATION; CELLS; CHONDROCYTES; GROWTH; MICE; EXPRESSION; HEDGEHOG AB During endochondral bone development, the first osteoblasts differentiate in the perichondrium surrounding avascular cartilaginous rudiments; the source of trabecular osteoblasts inside the later bone is, however, unknown. Here, we generated tamoxifen-inducible transgenic mice bred to Rosa26R-LacZ reporter mice to follow the fates of stage-selective subsets of osteoblast lineage cells. Pulse-chase studies showed that osterix-expressing osteoblast precursors, labeled in the perichondrium prior to vascular invasion of the cartilage, give rise to trabecular osteoblasts, osteocytes, and stromal cells inside the developing bone. Throughout the translocation, some precursors were found to intimately associate with invading blood vessels, in pericyte-like fashion. A similar coinvasion occurs during endochondral healing of bone fractures. In contrast, perichondrial mature osteoblasts did not exhibit perivascular localization and remained in the outer cortex of developing bones. These findings reveal the specific involvement of immature osteoblast precursors in the coupled vascular and osteogenic transformation essential to endochondral bone development and repair. C1 [Maes, Christa; Kobayashi, Tatsuya; Kronenberg, Henry M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Maes, Christa; Kobayashi, Tatsuya; Selig, Martin K.; Roth, Sanford I.; Kronenberg, Henry M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Maes, Christa; Torrekens, Sophie; Carmeliet, Geert] Katholieke Univ Leuven, Dept Expt Med & Endocrinol, B-3000 Louvain, Belgium. [Selig, Martin K.; Roth, Sanford I.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mackem, Susan] NCI, Canc & Dev Biol Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Kronenberg, HM (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM hkronenberg@partners.org FU NIH [DK056246]; FWO [G.0569.07, G.0500.08] FX We thank Abhishek Cole, Jennifer Paruch, Greg Nachtrab, and Ingrid Stock-mans for assistance with mouse breeding and genotyping. The Histology Core at the Endocrine Unit of Massachusetts General Hospital, Riet Van Looveren, and Karen Moermans (Legendo, K.U. Leuven) are acknowledged for excellent help with histology. For expert advice on ISH, FAGS analysis, confocal microscopy, and image analysis, we thank Przemko Tylzanowski (Rheumatology, K.U. Leuven), Aernout Luttun (CMVB, K.U. Leuven), Sebastian Munck (CME and VIB, K.U. Leuven), Nick Van Gastel, Maarten Depypere, and An Vanden Bosch (Legendo, K.U. Leuven). We thank Andy McMahon (Harvard) for generously providing the Osx-Cre:GFP mouse. We are also grateful to Joy Wu, Ernestina Schipani, and the members of the Endocrine Unit for helpful discussions. This work was supported by NIH grant DK056246 to H.M.K., FWO grants G.0569.07 and G.0500.08 to G.C., and a postdoctoral fellowship of the Fund for Scientific Research Flanders (FWO) to C.M. All authors declare no conflicts of interest. NR 28 TC 278 Z9 284 U1 1 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD AUG 17 PY 2010 VL 19 IS 2 BP 329 EP 344 DI 10.1016/j.devcel.2010.07.010 PG 16 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 640YK UT WOS:000281090000017 PM 20708594 ER PT J AU Dickerson, BC AF Dickerson, Bradford C. TI Primary progressive aphasia New insights paving the way toward clinical research tools SO NEUROLOGY LA English DT Editorial Material ID 3 VARIANTS C1 [Dickerson, Bradford C.] MGH Frontotemporal Dementia Unit, Charlestown, MA 02129 USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Alzheimers Dis Res Ctr, Frontotemporal Dementia Unit,Dept Neurol, Boston, MA USA. [Dickerson, Bradford C.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Alzheimers Dis Res Ctr, Frontotemporal Dementia Unit,Dept Psychiat, Boston, MA USA. [Dickerson, Bradford C.] Harvard Univ, Sch Med, Boston, MA USA. RP Dickerson, BC (reprint author), MGH Frontotemporal Dementia Unit, 149 13th St,Suite 2691, Charlestown, MA 02129 USA. EM bradd@nmr.mgh.harvard.edu FU NIA NIH HHS [R01 AG029411] NR 13 TC 0 Z9 0 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 AUG 17 PY 2010 VL 75 IS 7 BP 582 EP 583 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 640QO UT WOS:000281066700001 PM 20713946 ER PT J AU Healy, BC Liguori, M Tran, D Chitnis, T Glanz, B Wolfish, C Gauthier, S Buckle, G Houtchens, M Stazzone, L Khoury, S Hartzmann, R Fernandez-Vina, M Hafler, DA Weiner, HL Guttmann, CRG De Jager, PL AF Healy, B. C. Liguori, M. Tran, D. Chitnis, T. Glanz, B. Wolfish, C. Gauthier, S. Buckle, G. Houtchens, M. Stazzone, L. Khoury, S. Hartzmann, R. Fernandez-Vina, M. Hafler, D. A. Weiner, H. L. Guttmann, C. R. G. De Jager, P. L. TI HLA B*44 Protective effects in MS susceptibility and MRI outcome SO NEUROLOGY LA English DT Article ID MULTIPLE-SCLEROSIS SUSCEPTIBILITY; CLASS-I REGION; HLA-A; DISEASE SEVERITY; GENES; POPULATION; DISABILITY; RISK; HLA-DRB1-ASTERISK-1501; ASSOCIATION AB Objective: In addition to the main multiple sclerosis (MS) major histocompatibility complex (MHC) risk allele (HLA DRB1*1501), investigations of the MHC have implicated several class I MHC loci (HLA A, HLA B, and HLA C) as potential independent MS susceptibility loci. Here, we evaluate the role of 3 putative protective alleles in MS: HLA A*02, HLA B*44, and HLA C*05. Methods: Subjects include a clinic-based patient sample with a diagnosis of either MS or a clinically isolated syndrome (n = 532), compared to subjects in a bone marrow donor registry (n = 776). All subjects have 2-digit HLA data. Logistic regression was used to determine the independence of each allele's effect. We used linear regression and an additive model to test for correlation between an allele and MRI and clinical measures of disease course. Results: After accounting for the effect of HLA DRB1*1501, both HLA A*02 and HLA B*44 are validated as susceptibility alleles (p A*02 0.00039 and p B*44 0.00092) and remain significantly associated with MS susceptibility in the presence of the other allele. Although A*02 is not associated with MS outcome measures, HLA B*44 demonstrates association with a better radiologic outcome both in terms of brain parenchymal fraction and T2 hyperintense lesion volume (p = 0.03 for each outcome). Conclusion: The MHC class I alleles HLA A*02 and HLA B*44 independently reduce susceptibility to MS, but only HLA B*44 appears to influence disease course, preserving brain volume and reducing the burden of T2 hyperintense lesions in subjects with MS. Neurology (R) 2010; 75: 634-640 C1 [De Jager, P. L.] Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, Partners MS Ctr, Boston, MA 02115 USA. [Healy, B. C.; Chitnis, T.; Glanz, B.; Wolfish, C.; Gauthier, S.; Buckle, G.; Houtchens, M.; Stazzone, L.; Khoury, S.; Hafler, D. A.; Weiner, H. L.; Guttmann, C. R. G.; De Jager, P. L.] Harvard Univ, Sch Med, Boston, MA USA. [Healy, B. C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Healy, B. C.] Ctr Biostat, Boston, MA USA. [Liguori, M.; Guttmann, C. R. G.] Brigham & Womens Hosp, Ctr Neurol Imaging, Boston, MA 02115 USA. [Liguori, M.] CNR, Inst Neurol Sci, Mangone, Italy. [Tran, D.; Hafler, D. A.; De Jager, P. L.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Hartzmann, R.; Fernandez-Vina, M.] Georgetown Univ, USN, Med Res Ctr, CW Bill Young Dept,Def Marrow Program, Kensington, MA USA. [Fernandez-Vina, M.] Georgetown Univ, Dept Oncol, Washington, DC USA. [Hafler, D. A.] Yale Univ, Dept Neurol, Med Ctr, New Haven, CT USA. RP De Jager, PL (reprint author), Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, Partners MS Ctr, 77 Ave Louis Pasteur,NRB 168C, Boston, MA 02115 USA. EM pdejager@rics.bwh.harvard.edu RI Liguori, Maria/D-4390-2016; OI Liguori, Maria/0000-0003-4338-0392; khoury, samia/0000-0003-3198-6063 FU Merck Serono; NIH [NINDS K08 NS 047669-01, 5R01NS055083-03, R01 AI071448, R01 AI067472, R56 AI058680-05]; National Multiple Sclerosis Society; Biogen Idec FX Dr. Healy receives research support from Merck Serono. Dr. Liguori and D. Tran report no disclosures. Dr. Chitnis has served as a consultant for Biogen Idec, Teva Pharmaceutical Industries Ltd., and EMD Serono, Inc.; served on a speakers' bureau for EMD Serono, Inc.; and receives research support from the NIH (NINDS K08 NS 047669-01 [PI]) and the National Multiple Sclerosis Society. Dr. Glanz receives research support from Merck Serono, the NIH (NINDS 5R01NS055083-03 [coinvestigator]), and the National Multiple Sclerosis Society. C. Wolfish reports no disclosures. Dr. Gauthier has received funding for travel or speaker honoraria from Biogen Idec and EMD Serono, Inc.; and has received research support from EMD Serono, Inc. Dr. Buckle has served on scientific advisory boards for Acorda Therapeutics Inc., Biogen Idec, EMD Serono, Inc., Bayer Schering Pharma, Teva Pharmaceutical Industries Ltd., and Pfizer Inc.; and has served on speakers' bureaus for and received speaker honoraria from Biogen Idec, EMD Serono, Inc., Bayer Schering Pharma, Teva Pharmaceutical Industries Ltd., and Pfizer Inc. Dr. Houtchens has served on scientific advisory boards for and received speaker honoraria from EMD Serono, Inc., Biogen Idec, and Teva Pharmaceutical Industries Ltd. L. Stazzone has received funding for travel and speaker honoraria from EMD Serono, Inc. Dr. Khoury has served on scientific advisory boards for EpiVax and Repligen Corporation; serves as a Section Editor for Clinical Immunology; has received speaker honoraria from Repligen Corporation and EMD Serono, Inc.; has received research support from Biogen Idec, the NIH (R01 AI071448 [PI], R01 AI067472 [PI], and R56 AI058680-05 [PI]), the National Multiple Sclerosis Society, and the Fidelity Foundation; and her spouse receives research support from Genzyme Corporation. Dr. Hartzmann is an employee of the US Navy and has received intramural research funding from the Office of Naval Research and Naval Medical Research Center. Dr. Fernandez-Vina serves on editorial advisory boards for Immunogenetics and Human Immunology and serves as a consultant for the National Marrow Donor Program. Dr. Hafler serves on scientific advisory boards and as medico-legal consultant for, and has received speaker honoraria from, Allozyne, Inc., Eisai Inc., and Xceed Molecular Inc.; and receives research support from the NIH (NINDS R37 NS024247 [PI], NINDS POI NS038037, NINDS ROI NS049477, U19 AI0703S2 [PI], POI AI073748, and P01 AI045757) and the National Multiple Sclerosis Society. Dr. Weiner has served/serves on scientific advisory boards for and received speaker honoraria from Biogen Idec, Genentech, Inc., EMD Serono, Inc., and Teva Pharmaceutical Industries Ltd.; serves on the editorial boards of Clinical Immunology, Multiple Sclerosis, the Journal of Immunology, and the Journal of Autoimmunity; and receives research support from the NIH (NINDS P01 NS 038037-06A2 [Program Director], NIAID R01 AI43458 [PI], and R01 AG027437 [PI]), and the National Multiple Sclerosis Society. Dr. Guttmann has served on a scientific advisory board for Tibotec Therapeutics/ Johnson & Johnson; holds patents re: Versatile stereotactic device and methods of use and overlay of tinted images for visualizing change in serial radiologic images; and has received/ receives research support from Teva Pharmaceutical Industries Ltd.; , the NIH (R01 AG022092-01 [PI of subcontract], HRCA PO1AG004390 [PI of subcontract], NIH R01 NS036524-05 [PI of subcontract], R01 NS055083-01A1 [coinvestigator], NCRR UL1 RR025758-01 [coinvestigator], 2P41RR013218 Supplemnt [coinvestigator], 2U01AI063623-06 [coinvestigator], NCRR P41 RR013218 [coinvestigator]), the Maurice Pechet Foundation, and the National Multiple Sclerosis Society. Dr. De Jager has served on scientific advisory boards for Teva Pharmaceutical Industries Ltd. and Biogen Idec; serves on the editorial board of the Journal of Neuroimmunology; has received speaker honoraria from Biogen Idec and The Jackson Laboratory; has served as a consultant for Merck Serono; and receives research support from the NIH (ARRA RC2 AG036650 [PI], R01 NS067305 [PI], ARRA RC2 AG036547 [coinvestigator], ARRA RC2 GM093080 [coinvestigator], ARRA RC2 NS070340 [coinvestigator], and R01 AG036042 2008-R01 AG15819 [coinvestigator]), and the National Multiple Sclerosis Society. NR 35 TC 34 Z9 34 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 AUG 17 PY 2010 VL 75 IS 7 BP 634 EP 640 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 640QO UT WOS:000281066700010 PM 20713950 ER PT J AU Eugene, MC Kitei, D Silvers, D AF Eugene, Marie Carl Kitei, Daniel Silvers, David TI Clinical Reasoning: A 75-year-old woman with visual disturbances and unilateral ataxia SO NEUROLOGY LA English DT Editorial Material ID GLUTAMIC-ACID DECARBOXYLASE; CEREBELLAR-ATAXIA; ANTIBODIES; NYSTAGMUS; AUTOIMMUNITY; SPECTRUM C1 [Eugene, Marie Carl] Univ Connecticut, Hartford Hosp, Hartford, CT 06112 USA. [Kitei, Daniel] Harvards Brigham & Womens Hosp, Boston, MA USA. [Kitei, Daniel] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Eugene, MC (reprint author), Hartford Neurol, 85 Seymour St,Suite 800, Hartford, CT 06106 USA. EM mceugene@gmail.com NR 10 TC 0 Z9 0 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 AUG 17 PY 2010 VL 75 IS 7 BP E29 EP E33 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 640QO UT WOS:000281066700023 ER PT J AU Chen, X Xie, C Nishida, N Li, ZL Walz, T Springer, TA AF Chen, Xing Xie, Can Nishida, Noritaka Li, Zongli Walz, Thomas Springer, Timothy A. TI Requirement of open headpiece conformation for activation of leukocyte integrin alpha(X)beta(2) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID I-LIKE DOMAIN; ALPHA(L)BETA(2) HYBRID DOMAIN; EXTRACELLULAR SEGMENT; MONOCLONAL-ANTIBODIES; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; TERMINAL REGION; BETA(2) SUBUNIT; ALPHA-SUBUNITS; BETA-2 SUBUNIT AB Negative stain electron microscopy (EM) and adhesion assays show that alpha(X)beta(2) integrin activation requires headpiece opening as well as extension. An extension-inducing Fab to the beta(2) leg, in combination with representative activating and inhibitory Fabs, were examined for effect on the equilibrium between the open and closed headpiece conformations. The two activating Fabs stabilized the open headpiece conformation. Conversely, two different inhibitory Fabs stabilized the closed headpiece conformation. Adhesion assays revealed that alpha(X)beta(2) in the extended-open headpiece conformation had high affinity for ligand, whereas both the bent conformation and the extended-closed headpiece conformation represented the low affinity state. Intermediate integrin affinity appears to result not from a single conformational state, but from a mixture of equilibrating conformational states. C1 [Chen, Xing; Xie, Can; Nishida, Noritaka; Springer, Timothy A.] Harvard Univ, Sch Med, Immune Dis Inst, Childrens Hosp Boston, Boston, MA 02115 USA. [Chen, Xing; Xie, Can; Nishida, Noritaka; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Li, Zongli; Walz, Thomas] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Li, Zongli; Walz, Thomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, Childrens Hosp Boston, Boston, MA 02115 USA. EM springer@idi.harvard.edu FU National Institutes of Health [AI72765] FX This work was supported by National Institutes of Health Grant AI72765. X. C. is a Pfizer Fellow of Life Sciences Research Foundation. T. W. is an investigator in the Howard Hughes Medical Institute. NR 45 TC 53 Z9 53 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 17 PY 2010 VL 107 IS 33 BP 14727 EP 14732 DI 10.1073/pnas.1008663107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643IA UT WOS:000281287600039 PM 20679211 ER PT J AU Jin, HT Anderson, AC Tan, WG West, EE Ha, SJ Araki, K Freeman, GJ Kuchroo, VK Ahmed, R AF Jin, Hyun-Tak Anderson, Ana C. Tan, Wendy G. West, Erin E. Ha, Sang-Jun Araki, Koichi Freeman, Gordon J. Kuchroo, Vijay K. Ahmed, Rafi TI Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACTIVATION GENE-3 CD223; IN-VIVO; IMMUNITY; VIRUS; PERSISTENCE; POPULATION; EXPRESSION; CYTOLYSIS; TOLERANCE; BLOCKADE AB Inhibitory receptors play a crucial role in regulating CD8 T-cell function during chronic viral infection. T-cell Ig- and mucin-domain-containing molecule-3 (Tim-3) is well known to negatively regulate T-cell responses, but its role in CD8 T-cell exhaustion during chronic infection in vivo remains unclear. In this study, we document coregulation of CD8 T cell exhaustion by Tim-3 and PD-1 during chronic lymphocytic choriomeningitis virus infection. Whereas Tim-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high Tim-3 expression throughout chronic infection. The majority (approximately 65% to 80%) of lymphocytic choriomeningitis virus-specific CD8 T cells in lymphoid and nonlymphoid organs coexpressed Tim-3 and PD-1. This coexpression of Tim-3 and PD-1 was associated with more severe CD8 T-cell exhaustion in terms of proliferation and secretion of effector cytokines such as IFN-gamma, TNF-alpha, and IL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-10. Most importantly, combined blockade of Tim-3 and PD-1 pathways in vivo synergistically improved CD8 T cell responses and viral control in chronically infected mice. Taken together, our study defines a parameter for determining the severity of CD8 T cell dysfunction and for identifying virus-specific CD8 T cells that produce IL-10, and shows that targeting both PD-1 and Tim-3 is an effective immune strategy for treating chronic viral infections. C1 [Jin, Hyun-Tak; Tan, Wendy G.; West, Erin E.; Araki, Koichi; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Jin, Hyun-Tak; Tan, Wendy G.; West, Erin E.; Araki, Koichi; Ahmed, Rafi] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Anderson, Ana C.; Kuchroo, Vijay K.] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ha, Sang-Jun] Yonsei Univ, Dept Biochem, Coll Life Sci & Engn, Seoul 120749, South Korea. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. EM rahmed@emory.edu OI Ha, Sang-Jun/0000-0002-1192-6031 FU Gates Foundation Grand Challenge in Global Health; National Institutes of Health [AI054456, AI08080192, AI056299, AI73748, NS038037, NS045937, NS030843, NS054096]; Ministry for Health, Welfare and Family Affairs, Republic of Korea [A091204]; National Multiple Sclerosis Society; Juvenile Diabetes Research Foundation Center for Immunological Tolerance at Harvard University; Ragon Institute of Massachusetts Institute of Technology; Massachusetts General Hospital; Harvard University; National Institutes of Health FX We thank B. T. Konieczny and H. Wu for technical assistance and members of the R. A. laboratory for helpful discussion. This work was supported by grants from the Gates Foundation Grand Challenge in Global Health (R. A.); National Institutes of Health Grants AI054456, AI08080192, AI056299 (to G.J.F.), AI73748, NS038037, NS045937, NS030843 (to V. K. K.), and NS054096 (to A. C. A.); Korean Health Technology Research and Development Project A091204 from the Ministry for Health, Welfare and Family Affairs, Republic of Korea (to S.-J.H.); National Multiple Sclerosis Society (V. K. K.); Juvenile Diabetes Research Foundation Center for Immunological Tolerance at Harvard University (V. K. K.); and an Innovation Award from the Ragon Institute of Massachusetts Institute of Technology, Massachusetts General Hospital, and Harvard University (V. K. K.). V. K. K. is a recipient for the Javits Neuroscience Investigator Award from the National Institutes of Health. NR 27 TC 281 Z9 289 U1 2 U2 23 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 17 PY 2010 VL 107 IS 33 BP 14733 EP 14738 DI 10.1073/pnas.1009731107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643IA UT WOS:000281287600040 PM 20679213 ER PT J AU Biswas, A Liu, YJ Hao, LM Mizoguchi, A Salzman, NH Bevins, CL Kobayashi, KS AF Biswas, Amlan Liu, Yuen-Joyce Hao, Liming Mizoguchi, Atsushi Salzman, Nita H. Bevins, Charles L. Kobayashi, Koichi S. TI Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Crohn's disease; granuloma; Helicobacter hepaticus; innate immunity; Paneth cells ID ILEAL CROHNS-DISEASE; BOWEL-DISEASE; PANETH CELLS; FRAMESHIFT MUTATION; DEFENSIN EXPRESSION; EPITHELIAL-CELLS; PEYERS-PATCHES; NOD2 MUTATION; IMMUNITY; INNATE AB Mutations in the NOD2 gene are strong genetic risk factors for ileal Crohn's disease. However, the mechanism by which these mutations predispose to intestinal inflammation remains a subject of controversy. We report that Nod2-deficient mice inoculated with Helicobacter hepaticus, an opportunistic pathogenic bacterium, developed granulomatous inflammation of the ileum, characterized by an increased expression of Th1-related genes and inflammatory cytokines. The Peyer's patches and mesenteric lymph nodes were markedly enlarged with expansion of IFN-gamma-producing CD4 and CD8 T cells. Rip2-deficient mice exhibited a similar phenotype, suggesting that Nod2 function likely depends on the Rip2 kinase in this model. Transferring wild-type bone marrow cells into irradiated Nod2-deficient mice did not rescue the phenotype. However, restoring crypt antimicrobial function of Nod2-deficient mice by transgenic expression of alpha-defensin in Paneth cells rescued the Th1 inflammatory phenotype. Therefore, through the regulation of intestinal microbes, Nod2 function in nonhematopoietic cells of the small intestinal crypts is critical for protecting mice from a Th1-driven granulomatous inflammation in the ileum. The model may provide insight into Nod2 function relevant to inflammation of ileal Crohn's disease. C1 [Biswas, Amlan; Liu, Yuen-Joyce; Kobayashi, Koichi S.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Biswas, Amlan; Kobayashi, Koichi S.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Hao, Liming] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Mizoguchi, Atsushi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol Serv,Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Salzman, Nita H.] Med Coll Wisconsin, Dept Pediat, Div Gastroenterol, Milwaukee, WI 53226 USA. [Bevins, Charles L.] Univ Calif Davis, Sch Med, Dept Microbiol & Immunol, Davis, CA 95616 USA. RP Kobayashi, KS (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM koichi_kobayashi@dfci.harvard.edu OI Salzman, Nita/0000-0003-0939-6139 FU National Institutes of Health [R01DK074738, AI050843, AI032738, AI057757]; Crohn's and Colitis Foundation of America; Cancer Research Institute; Claudia Adams Barr Award FX We thank Tanja Petnicki-Ocwieja, Torsten Meissner, Kyoung-Hee Lee, Erika Reynoso, and Kutlu Elpek for helpful discussions; David Schubert, Norman Lautsch, and Amelia Chen for technical assistance; and Amy Li for critical reading. This work was supported by National Institutes of Health Grants R01DK074738 (to K. S. K.), AI050843, and AI032738 (to C. L. B.), AI057757 (to N.H.S.) and the Crohn's and Colitis Foundation of America (K. S. K.). K. S. K. is a recipient of the Investigator Award from the Cancer Research Institute and the Claudia Adams Barr Award. NR 47 TC 83 Z9 86 U1 2 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 17 PY 2010 VL 107 IS 33 BP 14739 EP 14744 DI 10.1073/pnas.1003363107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 643IA UT WOS:000281287600041 PM 20679225 ER PT J AU Cserti-Gazdewich, CM Dzik, WH Erdman, L Ssewanyana, I Dhabangi, A Musoke, C Kain, KC AF Cserti-Gazdewich, Christine M. Dzik, Walter H. Erdman, Laura Ssewanyana, Isaac Dhabangi, Aggrey Musoke, Charles Kain, Kevin C. TI Combined measurement of soluble and cellular ICAM-1 among children with Plasmodium falciparum malaria in Uganda SO MALARIA JOURNAL LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; HUMAN CEREBRAL MALARIA; ENDOTHELIAL ACTIVATION; GAMMA-INTERFERON; DISEASE SEVERITY; PLASMA-LEVELS; E-SELECTIN; EXPRESSION; INFECTION; BRAIN AB Background: Intercellular adhesion molecule-1 (ICAM-1) is a cytoadhesion molecule implicated in the pathogenesis of Plasmodium falciparum malaria. Elevated levels of soluble ICAM-1 (sICAM-1) have previously been reported with increased malaria disease severity. However, studies have not yet examined both sICAM-1 concentrations and monocyte ICAM-1 expression in the same cohort of patients. To better understand the relationship of soluble and cellular ICAM-1 measurements in malaria, both monocyte ICAM-1 expression and sICAM-1 concentration were measured in children with P. falciparum infection exhibiting a spectrum of clinical severity. Methods: Samples were analysed from 160 children, aged 0.5 to 10.8 years, with documented P. falciparum malaria in Kampala, Uganda. The patients belonged to one of three pre-study defined groups: uncomplicated malaria (UM), severe non-fatal malaria (SM-s), and fatal malaria (SM-f). Subset analysis was done on those with cerebral malaria (CM) or severe malaria anaemia (SMA). Monocyte ICAM-1 was measured by flow cytometry. sICAM-1 was measured by enzyme immunoassay. Results: Both sICAM-1 and monocyte cell-surface ICAM-1 followed a log-normal distribution. Median sICAM-1 concentrations increased with greater severity-of-illness: 279 ng/mL (UM), 462 ng/mL (SM-s), and 586 ng/mL (SM-f), p < 0.0001. sICAM-1 levels were not statistically different among children with CM compared to SMA. Monocyte ICAM-1 expression was significantly higher in cases of UM compared with SM-s or SM-f (p < 0.001) and was higher among the subset of patients with CM compared with SMA, p < 0.0014. The combination of sICAM-1 and cellular ICAM-1 identified distinct categories of patients (UM with low sICAM-1 and higher monocyte ICAM-1, CM with both sICAM-1 and monocyte ICAM-1 high, and SMA with sICAM-1 high but monocyte ICAM-1 low). Conclusion: In this cohort of children with P. falciparum malaria, sICAM-1 levels were associated with severity-of-illness. Patients with UM had higher monocyte ICAM-1 expression consistent with a role for monocyte ICAM-1 in immune clearance during non-severe malaria. Among the subsets of patients with either SMA or CM, monocyte ICAM-1 levels were higher in CM, consistent with the role of ICAM-1 as a marker of cytoadhesion. Categories of disease in pediatric malaria may exhibit specific combinations of soluble and cellular ICAM-1 expression. C1 [Cserti-Gazdewich, Christine M.] Univ Toronto, Univ Hlth Network, Dept Lab Med & Pathobiol, Toronto, ON, Canada. [Dzik, Walter H.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Erdman, Laura; Kain, Kevin C.] Univ Toronto, Univ Hlth Network, McLaughlin Rotman Ctr Global Hlth, Toronto, ON, Canada. [Ssewanyana, Isaac] Joint Clin Res Ctr, Kampala, Uganda. [Dhabangi, Aggrey; Musoke, Charles] Makerere Univ, Kampala, Uganda. RP Cserti-Gazdewich, CM (reprint author), Univ Toronto, Univ Hlth Network, Dept Lab Med & Pathobiol, Toronto, ON, Canada. EM christine.cserti@uhn.on.ca; sdzik@partners.org FU National Blood Foundation; International Society of Blood Transfusion Foundation; University of Toronto; CIHR [MT-13721]; Genome Canada through the Ontario Genomics Institute; CIHR Canada Research Chair FX Financial support: This work was supported in part by grants from the National Blood Foundation (CMC), the International Society of Blood Transfusion Foundation (CMC), a University of Toronto Dean's Fund grant (CMC), a CIHR MD/PhD training grant (LE), a CIHR Team Grant in Malaria (KCK), operating grant MT-13721 (KCK), Genome Canada through the Ontario Genomics Institute (KCK), and CIHR Canada Research Chair (KCK). Funding agencies had no role in study design, data collection, analysis or interpretation, the writing of the manuscript, or the decision to submit the work for publication. NR 32 TC 17 Z9 17 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD AUG 16 PY 2010 VL 9 AR 233 DI 10.1186/1475-2875-9-233 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 657MF UT WOS:000282416100001 PM 20712868 ER PT J AU Liu, DT Fan, XD Wang, Y Yang, ZL Zhuo, KM Song, ZH Wu, Y Li, CB Wang, JJ Xu, YF AF Liu, Dengtang Fan, Xiaoduo Wang, Yan Yang, Zhiliang Zhuo, Kaiming Song, Zhenhua Wu, Yan Li, Chunbo Wang, Jijun Xu, Yifeng TI Deficient inhibition of return in chronic but not first-episode patients with schizophrenia SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Inhibition of return (IOR); Orienting of attention; Schizophrenia ID EVENT-RELATED FMRI; FUNCTIONAL CONSEQUENCES; ATTENTIONAL ASYMMETRY; BLUNTED INHIBITION; LOBE DAMAGE; DISENGAGEMENT; MODEL; NEUROCOGNITION; ENDOPHENOTYPES; RELATIVES AB Background: Inhibition of return (IOR) has been tested in patients with schizophrenia with contradictory results. Some studies indicated that patients with schizophrenia have normal levels of IOR; however, other studies reported delayed or blunted IOR. Inconsistency in findings might be due to differences across studies in relevant aspects associated with disease, such as heterogeneity of the disorder, different medications, onset and severity of the illness. The present study was to explore different patterns of IOR in antipsychotic medication free first-episode schizophrenia and chronic schizophrenia. Methods: Forty two patients with first-episode schizophrenia, 44 patients with chronic schizophrenia, and 38 healthy controls were included in the study. All subjects went through a covert orienting of attention task with seven stimulus onset asynchrony (SOA) intervals (400 ms, 500 ms, 600 ms, 700 ms, 800 ms, 1200 ms and 1500 ms). Results: Compared with healthy controls, the magnitude and onset of IOR in first-episode patients with schizophrenia were intact. However, in patients with chronic schizophrenia, there was an attenuated cuing effect especially at SOA 700 ms; in addition, there was a robust IOR until at SOAs 800 ms or above. Moreover, the illness duration and the number of psychotic episodes were significantly correlated with the validity effect at SOAs 400 ms and 600 ms. Conclusion: Our study suggests that deficient IOR presents in chronic but not in first-episode patients with schizophrenia. IOR deficit in schizophrenia may begin during the course of illness and deteriorate over the course of illness. Our findings are consistent with the neurodegenerative model of schizophrenia. (C) 2010 Elsevier Inc. All rights reserved. C1 [Liu, Dengtang; Zhuo, Kaiming; Song, Zhenhua; Wu, Yan; Li, Chunbo; Wang, Jijun; Xu, Yifeng] Shanghai Jiao Tong Univ, Sch Med, Shanghai Mental Hlth Ctr, Dept Psychiat, Shanghai 200030, Peoples R China. [Liu, Dengtang; Wang, Yan; Yang, Zhiliang] E China Normal Univ, Dept Psychol, Shanghai 200062, Peoples R China. [Fan, Xiaoduo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Schizophrenia Program, Boston, MA 02114 USA. RP Xu, YF (reprint author), Shanghai Jiao Tong Univ, Sch Med, Shanghai Mental Hlth Ctr, Dept Psychiat, 600 Wan Ping Nan Rd, Shanghai 200030, Peoples R China. EM hyyyyb@gmail.com FU Science and Technology Commission of Shanghai Municipality [07ZR14093]; Health Bureau of Shanghai Municipality [024036]; Shanghai Medical Center for Mental Health [K042]; National Natural Science Foundations of China [30770773]; National Scientific and Technological 863 Program of China [2008AA02Z412] FX This work was supported by a grant 07ZR14093 from the Science and Technology Commission of Shanghai Municipality to Dr Liu, a grant 024036 from the Health Bureau of Shanghai Municipality to Dr Liu, a grant K042 from Shanghai Medical Center for Mental Health to Dr Xu. It was also supported by a grant 30770773 from National Natural Science Foundations of China and a grant 2008AA02Z412 from National Scientific and Technological 863 Program of China to Dr Wang. NR 63 TC 3 Z9 3 U1 3 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 AUG 16 PY 2010 VL 34 IS 6 BP 961 EP 967 DI 10.1016/j.pnpbp.2010.05.002 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 642EX UT WOS:000281187800023 PM 20460142 ER PT J AU Xu, MQ Xing, QH Li, S Zheng, YL Wu, SN Gao, R Yu, L Guo, TW Yang, YF Liu, JX Zhang, AP Zhao, XZ He, GA Zhou, JA Wang, L Xuan, JK Du, J Li, XW Feng, GY Lin, ZG Xu, YF St Clair, D Lin, ZC He, L AF Xu, Mingqing Xing, Qinghe Li, Sheng Zheng, Yonglan Wu, Shengnan Gao, Rui Yu, Lan Guo, Tingwei Yang, Yifeng Liu, Jixia Zhang, Aiping Zhao, Xinzhi He, Guang Zhou, Jian Wang, Lei Xuan, Jiekun Du, Jing Li, Xingwang Feng, Guoyin Lin, Zhiguang Xu, Yifeng St Clair, David Lin, Zhicheng He, Lin TI Pharacogenetic effects of dopamine transporter gene polymorphisms on response to chlorpromazine and clozapine and on extrapyramidal syndrome in schizophrenia SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE Antipsychotics; Association study; Chlorpromazine; Clozapine; Dopamine transporter; Extrapyramidal syndrome; Genetic polymorphism; Schizophrenia ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; RECEPTOR-BINDING PROFILES; THERAPEUTIC RESPONSE; TRANSCRIPTIONAL REGULATION; ATYPICAL ANTIPSYCHOTICS; LINKAGE DISEQUILIBRIUM; PARKINSONS-DISEASE; TARDIVE-DYSKINESIA; BIPOLAR DISORDER AB A number of studies have investigated the effectiveness of the dopamine transporter (SLC6A3) Gene as an antipsychotic target. However, the focus has mainly been on a 40-bp variable number of a tandem repeat (VNTR) in the 3'-region and results have been inconsistent. To fully evaluate SLC6A3 as a therapeutic antipshycotic target we investigated association of the gene with responses to chlorpromazine and clozapine and with chlorpromazine-induced extrapyramidal syndrome (EPS) in the Chinese schizophrenia population. Six polymorphisms across the whole region of this gene were analyzed, namely rs2652511 (T-844C) and rs2975226 (T-71A) in the 5'-regulatory region, rs2963238 (A1491C) in intron 1, a 30-bp VNTR in intron 8, rs27072 and the 40-bp VNTR in the 3'-region. We found that the polymorphic marker, rs2975226, showed significant association of allele and genotype frequencies with response to clozapine (allele-wise: adjusted p = 0.00404; genotype-wise: adjusted p = 0.024), and that patients with the T allele had a better response to the drug. The haplotype block constructed from the first three markers near the 5'-region showed significant association with response to clozapine (for haplotype T-T-A: p = 0.0085; for haplotype C-A-C: p = 0.0092). We did not identify any significant association of the six genetic variants or haplotypes with EPS after Bonferoni correction. Our findings suggest that the 5'-regulatory region of SLC6A3 plays an important role in response to clozapine and that its role in EPS needs to be replicated in a large-scale well designed study. (C) 2010 Published by Elsevier Inc. C1 [Xu, Mingqing; Li, Sheng; Zheng, Yonglan; Wu, Shengnan; Gao, Rui; Yu, Lan; Guo, Tingwei; Yang, Yifeng; Liu, Jixia; Zhang, Aiping; He, Guang; Zhou, Jian; Wang, Lei; Xuan, Jiekun; Du, Jing; Li, Xingwang; He, Lin] Shanghai Jiao Tong Univ, Bio X Ctr, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai 200030, Peoples R China. [Xu, Mingqing; Xing, Qinghe; Li, Sheng; Zheng, Yonglan; Wu, Shengnan; Gao, Rui; Yu, Lan; Guo, Tingwei; Yang, Yifeng; Liu, Jixia; Zhang, Aiping; Zhao, Xinzhi; He, Guang; Zhou, Jian; Wang, Lei; Xuan, Jiekun; Du, Jing; Li, Xingwang; He, Lin] Chinese Acad Sci, Inst Nutr Sci, Shanghai 200031, Peoples R China. [Xu, Mingqing] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Xu, Mingqing; Xu, Yifeng] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Xu, Mingqing; Lin, Zhicheng] Harvard Univ, Mailman Res Ctr, Massachusetts Gen Hosp, McLean Hosp,Sch Med, Belmont, MA 02478 USA. [Xing, Qinghe; He, Lin] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China. [Feng, Guoyin; Lin, Zhiguang] Shanghai Inst Mental Hlth, Shanghai 200030, Peoples R China. [St Clair, David] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. RP Xu, MQ (reprint author), Shanghai Jiao Tong Univ, Bio X Ctr, Key Lab Genet Dev & Neuropsychiat Disorders, Minist Educ, Shanghai 200030, Peoples R China. EM helin@bio-x.cn RI Yu, Lan/B-8770-2009; Zheng, Yonglan/C-4236-2011 FU Shanghai Municipal Commission of Science and Technology [09DJ1400601]; Shanghai Leading Academic Discipline Project [B205]; [2006AA02A407]; [2009AA022701]; [201003529600]; [2007CB914703]; [2007CB947300] FX This work was supported by grants (2006AA02A407, 2009AA022701, 201003529600, 2007CB914703, 2007CB947300), the Shanghai Municipal Commission of Science and Technology Program (09DJ1400601), and the Shanghai Leading Academic Discipline Project (B205). We are grateful to all the participants as well as to the psychiatrists and mental health workers who participated in this project. NR 56 TC 15 Z9 16 U1 5 U2 9 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 AUG 16 PY 2010 VL 34 IS 6 BP 1026 EP 1032 DI 10.1016/j.pnpbp.2010.05.017 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 642EX UT WOS:000281187800034 PM 20580759 ER PT J AU Singavarapu, R Buchinsky, N Cheon, DJ Orsulic, S AF Singavarapu, Rajasekhar Buchinsky, Natalie Cheon, Dong-Joo Orsulic, Sandra TI Whole ovary immunohistochemistry for monitoring cell proliferation and ovulatory wound repair in the mouse SO REPRODUCTIVE BIOLOGY AND ENDOCRINOLOGY LA English DT Article ID IN-SITU HYBRIDIZATION; SURFACE EPITHELIUM; MOUNT IMMUNOHISTOCHEMISTRY; CANCER; BIOLOGY; MICE AB Background: Ovarian surface epithelial cells are thought to be a precursor cell type for ovarian carcinoma. It has been proposed that an increased rate of ovarian surface epithelial cell proliferation during ovulatory wound repair contributes to the accumulation of genetic changes and cell transformation. The proliferation of ovarian surface epithelial cells during ovulatory wound repair has been studied primarily using immunohistochemical staining of paraffin-embedded ovary sections. However, such analyses require complex reconstruction from serially-cut ovary sections for the visualization and quantification of the cells on the ovarian surface. In order to directly visualize the proliferation and organization of the ovarian surface epithelial cells, we developed a technique for immunohistochemical staining of whole mouse ovaries. Using this method, we analyzed cell proliferation and morphologic changes in mouse ovarian surface epithelial cells during follicle growth and ovulatory wound repair. Methods: Three-week old FVB/N female mice were superovulated by sequential administration of pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG). Ten hours after hCG administration, mice were given 5-bromo-2-deoxyuridine (BrdU) and euthanized two hours after BrdU administration for ovary isolation. The levels of incorporated BrdU in the ovarian surface epithelial cells were measured by staining paraffin-embedded ovary sections and whole ovaries with the BrdU antibody. Re-epithelialization of the ovarian surface after ovulatory rupture was visualized by immunohistochemical staining with E-cadherin and Keratin 8 in paraffin-embedded ovary sections and whole ovaries. Results: We determined that active proliferation of ovarian epithelial surface cells primarily occurs during antral follicle formation and, to a lesser extent, in response to an ovulatory wound. We also demonstrated that ovarian surface epithelial cells exhibit a circular organization around the wound site Conclusion: Whole ovary immunohistochemistry enables efficient and comprehensive three-dimensional visualization of ovarian surface epithelial cells without the need for laborious reconstruction from immunohistochemically-stained serial ovary sections. C1 [Singavarapu, Rajasekhar; Buchinsky, Natalie; Orsulic, Sandra] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Singavarapu, Rajasekhar; Buchinsky, Natalie; Orsulic, Sandra] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Cheon, Dong-Joo; Orsulic, Sandra] Cedars Sinai Med Ctr, Womens Canc Res Inst, Samuel Oschin Comprehens Canc Inst, Los Angeles, CA 90048 USA. RP Orsulic, S (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM orsulics@cshs.org FU Women's Cancer Research Institute; Marsha Rivkin Center for Ovarian Cancer Research; American Cancer Society; DOD [W81XWH-04-1-0485] FX We thank Kristy Daniels for assistance in the preparation of the manuscript, Kader Yagiz from the Gene Therapeutics Research Institute for generating the dot plots, and Beth Karlan and members of the Women's Cancer Research Institute for their support. This work was funded by the Marsha Rivkin Center for Ovarian Cancer Research, the American Cancer Society Research Scholar Grant in Basic, Preclinical, Clinical and Epidemiology Research and the DOD W81XWH-04-1-0485 grant. NR 16 TC 7 Z9 8 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-7827 J9 REPROD BIOL ENDOCRIN JI Reprod. Biol. Endocrinol. PD AUG 16 PY 2010 VL 8 AR 98 DI 10.1186/1477-7827-8-98 PG 7 WC Endocrinology & Metabolism; Reproductive Biology SC Endocrinology & Metabolism; Reproductive Biology GA 659GZ UT WOS:000282556300002 PM 20712898 ER PT J AU Spiegel, BM Roberts, L Mody, R Harding, G Kothari-Talwar, S Kahrilas, PJ Camilleri, ML Dabbous, O Revicki, DA AF Spiegel, B. M. Roberts, L. Mody, R. Harding, G. Kothari-Talwar, S. Kahrilas, P. J. Camilleri, M. L. Dabbous, O. Revicki, D. A. TI The development and validation of a Nocturnal Gastro-oesophageal Reflux Disease Symptom Severity and Impact Questionnaire for adults SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID QUALITY-OF-LIFE; UPPER GASTROINTESTINAL DISORDERS; PATIENT-REPORTED OUTCOMES; CONTENT VALIDITY; NIGHTTIME GERD; HEALTH-STATUS; INDEX; RESPONSIVENESS AB Background Current questionnaires for assessing gastro-oesophageal reflux disease (GERD) symptoms are limited in their ability to capture nocturnal symptoms. Aim To develop and validate an instrument, the Nocturnal Gastro-oesophageal Reflux Disease Symptom Severity and Impact Questionnaire (N-GSSIQ), to assess severity and impact of nocturnal GERD symptoms. Methods Two focus groups and 16 cognitive debriefing interviews were conducted among GERD patients to identify key issues about nocturnal symptoms. A draft instrument was tested in 196 patients at 11 clinics in the US to evaluate psychometric properties. Exploratory factor and item response theory analyses were conducted to finalize items and subscales. Internal consistency reliability, reproducibility and construct validity were examined. Results Mean age was 45 (s.d. = 13.8) years; 76% were female and 68% were Caucasian. Patient-rated severity was mild-moderate for 69% of participants; 48% reported symptoms on two to three nights the past week. The final questionnaire includes 20 items and three subscales: Nocturnal GERD Symptoms, Morning Impact of Nocturnal GERD and Concern about Nocturnal GERD. The subscales demonstrated internal consistency reliability (Cronbach's alpha 0.84-0.94) and were significantly correlated with similar measures and disease severity (0.41-0.81; P < 0.0001). Conclusion The results support the reliability and validity of the N-GSSIQ as a measure of severity, morning impact and concern about nocturnal GERD. C1 [Spiegel, B. M.] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Roberts, L.; Harding, G.; Revicki, D. A.] United BioSource Corp, Bethesda, MD 20814 USA. [Mody, R.; Kothari-Talwar, S.; Dabbous, O.] Takeda Pharmaceut Int Inc, Deerfield, IL 60015 USA. [Kahrilas, P. J.] Northwestern Univ, Div Gastroenterol, Chicago, IL 60611 USA. [Camilleri, M. L.] Mayo Clin, Rochester, MN 55905 USA. RP Spiegel, BM (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 115,Rm 215, Los Angeles, CA 90073 USA. EM bspiegel@mednet.ucla.edu NR 29 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD AUG 15 PY 2010 VL 32 IS 4 BP 591 EP 602 DI 10.1111/j.1365-2036.2010.04385.x PG 12 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 625YF UT WOS:000279932100010 PM 20528826 ER PT J AU Khera, AV Wolfe, ML Cannon, CP Qin, J Rader, DJ AF Khera, Amit V. Wolfe, Megan L. Cannon, Christopher P. Qin, Jie Rader, Daniel J. TI On-Statin Cholesteryl Ester Transfer Protein Mass and Risk of Recurrent Coronary Events (from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 [PROVE IT-TIMI 22] Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HIGH-DENSITY-LIPOPROTEINS; ARTERY-DISEASE; CARDIOVASCULAR EVENTS; TORCETRAPIB; HYPERCHOLESTEROLEMIA; ATHEROSCLEROSIS; MEN; PROGRESSION AB Although cholesteryl ester transfer protein (CETP) plays an important role in human lipoprotein metabolism, its relation to coronary artery disease remains controversial. The present study evaluated the relation between on-statin CETP mass and recurrent coronary events. The plasma CETP mass, measured after 4 months of statin therapy, was quantified in 3,218 patients enrolled in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study. Of the 3,218 patients, 150 experienced the combined end point of recurrent myocardial infarction or death from coronary causes during a mean follow-up of 1.8 years. An increasing on-statin CETP mass was inversely related to the risk of coronary events in both unadjusted (hazard ratio [HR] per SD increase 0.77, 95% confidence interval 0.65 to 0.92, p = 0.005) and fully adjusted (HR per SD increase 0.81, 95% confidence interval 0.67 to 0.98, p = 0.027) analyses that included traditional cardiovascular risk factors. A similar trend was observed across increasing CETP mass quartiles (p trend = 0.07). A significant interaction between the CETP mass and on-treatment low-density lipoprotein (LDL) cholesterol was noted (p interaction = 0.007). A CETP mass greater than the median was associated with a decreased risk in patients with LDL cholesterol less than the median of 80 mg/dl (HR 0.52, 95% confidence interval 0.31 to 0.89, p = 0.02), but not in patients with LDL cholesterol greater than the median. In conclusion, an increasing on-statin CETP mass was inversely related to the coronary outcomes in this large clinical trial-based cohort, particularly among those with low LDL cholesterol levels. This finding is consistent with CETP facilitating reverse cholesterol transport in the setting of robust LDL clearance and might have important implications for efforts to optimally target patients with pharmacologic CETP inhibition. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:451-456) C1 [Khera, Amit V.; Wolfe, Megan L.; Rader, Daniel J.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Khera, Amit V.; Wolfe, Megan L.; Rader, Daniel J.] Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Cannon, Christopher P.; Qin, Jie] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. RP Rader, DJ (reprint author), Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. EM rader@mail.med.upenn.edu FU Howard Hughes Medical Institute Research Fellowship (Bethesda, Maryland); Accumetrics; San Diego; California; AstraZeneca; Wilmington; Delaware; Bristol-Meyers Squibb/Sanofi Partnership; GlaxoSmithKline; Philadelphia; Pennsylvania; Merck; White-house Station; New Jersey; Merck/Schering Plough; Bristol-Myers Squibb (New York, New York) FX This work, including the PROVE IT-TIMI 22 study and measurement of cholesteryl ester transfer protein mass, was funded largely by Bristol-Myers Squibb (New York, New York) and Sankyo Pharmaceuticals (Parsippany, New Jersey), which had no role in the analysis presented, manuscript preparation, or decision to submit for publication. Dr. Khera obtained support for this project from a Howard Hughes Medical Institute Research Fellowship (Bethesda, Maryland).; Dr. Cannon received research grant/support from Accumetrics, San Diego, California, AstraZeneca, Wilmington, Delaware, Bristol-Meyers Squibb/Sanofi Partnership, GlaxoSmithKline, Philadelphia, Pennsylvania, Merck, White-house Station, New Jersey, and Merck/Schering Plough and is a Clinical Advisor, with equity in Automedics Medical Systems, San Diego, California. Dr. Rader is a research grant recipient from Bristol-Myers Squibb (New York, New York) and GlaxoSmithKline and is a consultant/advisory member to AstraZeneca, Bristol-Myers Squibb, Johnson and Johnson, New Brunswick, New Jersey, Merck, and Schering Plough, Kenilworth, New Jersey, Lilly, Indianapolis, Indiana, and Novartis, Basel, Switzerland; and is on the speakers bureau for AstraZeneca, Merck, and Merck-Schering Plough. NR 27 TC 23 Z9 25 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2010 VL 106 IS 4 BP 451 EP 456 DI 10.1016/j.amjcard.2010.03.057 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 642AH UT WOS:000281174500001 PM 20691300 ER PT J AU Taylor, CM Humphries, KH Pu, A Ghali, W Gao, M Knudtson, M Hoffmann, U Carere, RG AF Taylor, Carolyn M. Humphries, Karin H. Pu, Aihua Ghali, William Gao, Min Knudtson, Merril Hoffmann, Udo Carere, Ronald G. TI A Proposed Clinical Model for Efficient Utilization of Invasive Coronary Angiography SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID SPIRAL COMPUTED-TOMOGRAPHY; DIAGNOSTIC-ACCURACY; HEART-DISEASE; RISK; LESIONS AB More than 1/4 of patients who undergo invasive coronary angiography are found to have no visible or nonobstructive (<50% stenosis) coronary artery disease (CAD). With the rapid evolution of noninvasive imaging for CAD diagnosis, avoiding invasive coronary angiography in patients unlikely to require coronary revascularization is desirable. We undertook to develop a clinical prediction tool to identify patients with a low likelihood of obstructive (>= 50% stenosis) CAD. The derivation cohort included 24,637 patients with a diagnosis of "stable angina" or "acute coronary syndrome" referred for first cardiac catheterization in the province of British Columbia, Canada. The model was validated using an external dataset from the province of Alberta and comprised 18,606 patients. Seven variables (female gender, age <50 years, atypical Canadian Cardiovascular Society angina class, absence of ST-segment change on electrocardiogram, lifelong nonsmoking, and absence of diabetes and hyperlipidemia) were associated with the angiographic finding of "no or nonobstructive CAD." The c-statistics for the derivation model were 0.76 and 0.74 using the validation dataset. In conclusion, this simple clinical prediction tool, applied to patients for whom determination of coronary anatomy was clinically indicated, identifies patients who have a low likelihood of obstructive CAD. The patient population identified by this tool may represent a population best suited to a noninvasive diagnostic strategy. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:457-462) C1 [Taylor, Carolyn M.; Humphries, Karin H.; Carere, Ronald G.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Taylor, Carolyn M.; Humphries, Karin H.; Carere, Ronald G.] St Pauls Hosp, Vancouver, BC V6Z 1Y6, Canada. [Taylor, Carolyn M.; Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA USA. [Taylor, Carolyn M.; Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Humphries, Karin H.; Pu, Aihua; Gao, Min] Prov Hlth Serv Author, Vancouver, BC, Canada. [Ghali, William; Knudtson, Merril] Foothills Prov Gen Hosp, Calgary, AB T2N 2T9, Canada. RP Taylor, CM (reprint author), Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. EM cmtaylor@providencehealth.bc.ca NR 17 TC 3 Z9 4 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 AUG 15 PY 2010 VL 106 IS 4 BP 457 EP 462 DI 10.1016/j.amjcard.2010.03.061 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 642AH UT WOS:000281174500002 PM 20691301 ER PT J AU Valera, EM Spencer, RMC Zeffiro, TA Makris, N Spencer, TJ Faraone, SV Biederman, J Seidman, LJ AF Valera, Eve M. Spencer, Rebecca M. C. Zeffiro, Thomas A. Makris, Nikos Spencer, Thomas J. Faraone, Stephen V. Biederman, Joseph Seidman, Larry J. TI Neural Substrates of Impaired Sensorimotor Timing in Adult Attention-Deficit/Hyperactivity Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE ADHD; basal ganglia; cerebellum; fMRI; frontal cortex; timing ID DEFICIT-HYPERACTIVITY-DISORDER; TIME PERCEPTION; TEMPORAL INFORMATION; BASAL GANGLIA; ALE METAANALYSIS; FUNCTIONAL MRI; MOTOR CONTROL; ADHD; CEREBELLUM; METHYLPHENIDATE AB Background: Timing abilities are critical to the successful management of everyday activities and personal safety, and timing abnormalities have been argued to be fundamental to impulsiveness, a core symptom of attention-deficit/hyperactivity disorder (ADHD). Despite substantial evidence of timing deficits in ADHD youth, only two studies have explicitly examined timing in ADHD adults and only at the suprasecond time scale. Also, the neural substrates of these deficits are largely unknown for both youth and adults with ADHD. The present study examined subsecond sensorimotor timing and its neural substrates in ADHD adults. Methods: Using functional magnetic resonance imaging, we examined paced and unpaced finger tapping in a sample of 20 unmedicated adults with ADHD and 19 control subjects comparable on age, sex, and estimated IQ. The blood oxygenation level-dependent contrast response was used to estimate task-related neural activity. Results: Behavioral data showed no between-group differences in mean tapping rates but greater within-subject variability in tap-to-tap intervals for ADHD adults relative to control subjects. Importantly, ADHD adults had greater clock rather than motor variability, consistent with a central timing locus for the atypical movements. The imaging results demonstrated that, relative to control subjects, ADHD adults showed less activity in a number of regions associated with sensorimotor timing, including prefrontal and precentral gyri, basal ganglia, cerebellum, inferior parietal lobule, superior temporal gyri, and insula. Conclusions: Our findings show that subsecond timing abnormalities in ADHD youth persist into adulthood and suggest that abnormalities in the temporal structure of behavior observed in ADHD adults result from atypical function of corticocerebellar and corticostriatal timing systems. C1 [Valera, Eve M.; Spencer, Thomas J.; Biederman, Joseph; Seidman, Larry J.] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Pediat Psychopharmacol, Charlestown, MA 02129 USA. [Valera, Eve M.; Spencer, Thomas J.; Biederman, Joseph; Seidman, Larry J.] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Adult Attent Deficit Hyperact, Charlestown, MA 02129 USA. [Valera, Eve M.] Massachusetts Gen Hosp, Dept Psychiat, Psychiat Neuroimaging Res Program, Charlestown, MA 02129 USA. [Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Massachusetts Mental Hlth Ctr,Publ Psychiat Div, Boston, MA 02215 USA. [Spencer, Rebecca M. C.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. [Zeffiro, Thomas A.] Massachusetts Gen Hosp, Neural Syst Grp, Charlestown, MA USA. [Makris, Nikos] Massachusetts Gen Hosp, Ctr Morphometr Anal, Dept Neurol, Boston, MA 02114 USA. [Makris, Nikos] Massachusetts Gen Hosp, Ctr Morphometr Anal, Dept Radiol, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Neurosci, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Physiol, Syracuse, NY USA. RP Valera, EM (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Pediat Psychopharmacol, Room 2660,149 13th St, Charlestown, MA 02129 USA. EM eve_valera@hms.harvard.edu OI Spencer, Rebecca/0000-0002-8674-2384; Faraone, Stephen/0000-0002-9217-3982 FU National Institutes of Health [MH 071535, MH 57934, MH 62152, MH 064019, AG29710]; National Alliance fir Research on Schizophrenia and Depression; Janssen and McNeil Pharmaceuticals; Research Council for Pediatric Psychopharmacology at the Massachusetts General Hospital; National Center for Research Resources [P41RR14075]; Commonwealth Research Center; Massachusetts Department of Mental Health; Alza; AstraZeneca; Bristol-Myers Squibb; Eli Lilly and Co.; Janssen Pharmaceuticals Inc.; McNeil; Merck; Organon; Otsuka; Shire; National Institute of Mental Health; National Institute of Child Health and Human Development; Fundacion Areces; Medice Pharmaceuticals; Spanish Child Psychiatry Association; Abbott; Celltech; Cephalon; Esai; Forest; Glaxo; Gliatech; Janssen; National Alliance for Research on Schizophrenia and Depression; National Institute of Drug Abuse; New River; Novartis; Noven; Neurosearch; Pfizer; Pharmacia; Prechter Foundation; Stanley Foundation; UCB Pharma Inc.; Wyeth; Shire Laboratories Inc.; GlaxoSmithKline; Janssen Pharmaceutical; McNeil Pharmaceutical; Novartis Pharmaceuticals; Ortho-McNeil FX This work was supported in part by Grants from the National Institutes of Health (MH 071535 to EMV, MH 57934 to SVF, MH 62152 to LIS, MH 064019 to TJS, AG29710 to RMCS); the National Alliance fir Research on Schizophrenia and Depression to JB; Research Grants from Janssen and McNeil Pharmaceuticals to JB; and the philanthropic support from the Research Council for Pediatric Psychopharmacology at the Massachusetts General Hospital, The National Center for Research Resources (P41RR14075), and the Commonwealth Research Center; Massachusetts Department of Mental Health to LJS. These funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.; We thank the individuals who served as research participants, as well as Denise Bond, Stacey Bilicki, Alysa Doyle, Ronna Fried, Brittany LeBlanc, Michael C. Monuteaux, and Timothy Wilens for their contributions to this work. Dr. Eve M. Valera has received travel support and honoraria from Shire Pharmaceuticals and the McNeil and Janssen divisions of Ortho-McNeil-Janssen Pharmaceuticals. Dr. Joseph Biederman is currently receiving research support from the following sources: Alza, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Co., Janssen Pharmaceuticals Inc., McNeil, Merck, Organon, Otsuka, Shire, National Institute of Mental Health, and National Institute of Child Health and Human Development. In 2009, Dr. Joseph Biederman received a speaker's fee from the following sources: Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association. In previous years, Dr. Joseph Biederman received research support, consultation fees, or speaker's fees for/from the following additional sources: Abbott, AstraZeneca, Celltech, Cephalon, Eli Lilly and Co., Esai, Forest, Glaxo, Gliatech, Janssen, McNeil, National Alliance for Research on Schizophrenia and Depression, National Institute of Drug Abuse, New River, Novartis, Noven, Neurosearch, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma Inc., and Wyeth. Dr. Thomas Spencer has received research support from, has been a speaker on a speaker bureau, or has been on an Advisory Board of the following sources: Shire Laboratories Inc., Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceutical, McNeil Pharmaceutical, Novartis Pharmaceuticals, Cephalon, Pfizer, and the National Institute of Mental Health. In the past year, Dr. Stephen Faraone has received consulting fees and has been on Advisory Boards for Eli Lilly, Ortho-McNeil, and Shire Development and has received research support from Eli Lilly, Pfizer, Shire, and the National Institutes of Health. In previous years, Dr. Faraone has received consulting fees, has been on Advisory Boards, or has been a speaker fir the following sources: Shire, McNeil, Janssen, Novartis, Pfizer, and Eli Lilly. In previous years, he has received research support from Eli Lilly, Shire, Pfizer, and the National Institutes of Health. Dr. Larry J. Seidman reports no financial disclosures or conflicts of interest for the past 2 years. He has been a speaker for Shire Pharmaceuticals and received an unrestricted educational grant from Janssen Pharmaceuticals in the past 5 years. All other authors report no biomedical financial interests or potential conflicts of interest. NR 78 TC 37 Z9 37 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2010 VL 68 IS 4 BP 359 EP 367 DI 10.1016/j.biopsych.2010.05.012 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 638MU UT WOS:000280899800008 PM 20619827 ER PT J AU Lee, AI Zuckerman, DS Van den Abbeele, AD Aquino, SL Crowley, D Toomey, C Lacasce, AS Feng, Y Neuberg, DS Hochberg, EP AF Lee, Alfred Ian Zuckerman, Dan S. Van den Abbeele, Annick D. Aquino, Suzanne L. Crowley, Diane Toomey, Christiana Lacasce, Ann S. Feng, Yang Neuberg, Donna S. Hochberg, Ephraim P. TI Surveillance Imaging of Hodgkin Lymphoma Patients in First Remission A Clinical and Economic Analysis SO CANCER LA English DT Article DE computed tomography scan; Hodgkin lymphoma; positron emission tomography scan; radiation exposure; remission; surveillance ID POSITRON-EMISSION-TOMOGRAPHY; ROUTINE FOLLOW-UP; FDG-PET; COMPUTED-TOMOGRAPHY; MALIGNANT-LYMPHOMA; RADIATION-EXPOSURE; RANDOMIZED-TRIAL; PROGNOSTIC VALUE; DISEASE; CHEMOTHERAPY AB BACKGROUND: The majority of patients with Hodgkin lymphoma (HL) achieve disease remission after primary therapy. To the best of the authors' knowledge, no consensus exists for postremission surveillance imaging. METHODS: Retrospectively analyzed were 192 adult patients with classic HL in first remission. Events were defined as recurrent HL or secondary malignancies. Primary outcome was positive predictive value (PPV) of surveillance positron emission tomography/computed tomography (PET/CT) and CT scans in event detection. Secondary outcomes were costs and radiation exposures of surveillance scans. RESULTS: Sixteen events (12 recurrent HL cases and 4 secondary malignancies) were detected during a median follow-up of 31 months. The PPV of surveillance PET/CT was 22.9% compared with 28.6% for CT (P = .73). Factors that were found to significantly improve the PPV of scans in detecting recurrent HL included PET and CT concordance, involvement of a prior disease site, or the occurrence of a radiographic abnormality within 12 months. There were too few events to determine whether event detection by PET/CT versus CT or the presence of symptoms at the time of event detection affected overall outcomes. The cost to detect a single event was approximately $100,000. Radiation exposure to detect a single event was 146.6 millisieverts per patient for each of 9 patients. CONCLUSIONS: For patients with HL in first disease remission, surveillance radiography appears to be expensive, with limited clinical impact. Surveillance CT is generally adequate. Cancer 2010;116:3835-42. (C) 2010 American Cancer Society. C1 [Crowley, Diane; Toomey, Christiana; Hochberg, Ephraim P.] Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. [Lee, Alfred Ian; Van den Abbeele, Annick D.; Lacasce, Ann S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zuckerman, Dan S.] St Lukes Mt State Tumor Inst, Boise, ID USA. [Aquino, Suzanne L.] Nighthawk Radiol, Coeur Dalene, ID USA. [Feng, Yang; Neuberg, Donna S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Hochberg, EP (reprint author), Massachusetts Gen Hosp, Dept Med Oncol, 55 Fruit St, Boston, MA 02114 USA. EM ehochberg@partners.org NR 37 TC 38 Z9 38 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2010 VL 116 IS 16 BP 3835 EP 3842 DI 10.1002/cncr.25240 PG 8 WC Oncology SC Oncology GA 635SR UT WOS:000280677100013 PM 20564135 ER PT J AU Cianfrocca, M Lee, S Von Roenn, J Tulpule, A Dezube, BJ Aboulafia, DM Ambinder, RF Lee, JY Krown, SE Sparano, JA AF Cianfrocca, Mary Lee, Sandra Von Roenn, Jamie Tulpule, Anil Dezube, Bruce J. Aboulafia, David M. Ambinder, Richard F. Lee, Jeannette Y. Krown, Susan E. Sparano, Joseph A. TI Randomized Trial of Paclitaxel Versus Pegylated Liposomal Doxorubicin for Advanced Human Immunodeficiency Virus-Associated Kaposi Sarcoma Evidence of Symptom Palliation From Chemotherapy SO CANCER LA English DT Article DE human immunodeficiency virus (HIV) infection; acquired immunodeficiency syndrome (AIDS); Kaposi sarcoma; paclitaxel; pegylated liposomal doxorubicin ID ACTIVE ANTIRETROVIRAL THERAPY; QUALITY-OF-LIFE; FUNCTIONAL ASSESSMENT; COMPLETE REGRESSION; AIDS; CANCER; VINCRISTINE; VALIDATION; INHIBITOR; BLEOMYCIN AB BACKGROUND: Paclitaxel and pegylated liposomal doxorubicin (PLD) are active cytotoxic agents for the treatment of human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS). A randomized trial comparing the efficacy and toxicity of paclitaxel and PLD was performed, and the effects of therapy on symptom palliation and quality of life were determined. METHODS: Patients with advanced HIV-associated KS were randomly assigned to receive paclitaxel at a dose of 100 mg/m(2) intravenously (iv) every 2 weeks or PLD at a dose of 20 mg/m(2) iv every 3 weeks. The KS Functional Assessment of HIV (FAH) quality of life instrument was used before and after every other treatment cycle. RESULTS: The study included 73 analyzable patients enrolled between 1998 and 2002, including 36 in the paclitaxel arm and 37 in the PLD arm; 73% of patients received highly active antiretroviral therapy (HAART) and 32% had an undetectable viral load (<400 copies/mL). Treatment was associated with significant improvements in pain (P=.024) and swelling (P < .001). Of the 36 patients who reported that pain interfered with their normal work or activities at baseline, 25 (69%) improved. Of the 41 patients who reported swelling at baseline, 38 (93%) improved. Comparing the paclitaxel and PLD arms revealed comparable response rates (56% vs 46%; P=.49), median progression-free survival (17.5 months vs 12.2 months; P=.66), and 2-year survival rates (79% vs 78%; P=.75), but somewhat more grade 3 to 5 toxicity for paclitaxel (84% vs 66%; P=.077). CONCLUSIONS: Treatment with either paclitaxel or PLD appears to produce significant improvements in pain and swelling in patients with advanced, symptomatic, HIV-associated KS treated in the HAART era. Cancer 2010;116:3969-77. (C) 2010 American Cancer Society. C1 [Cianfrocca, Mary; Von Roenn, Jamie] Northwestern Univ, Dept Med, Chicago, IL 60611 USA. [Lee, Sandra] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Tulpule, Anil] Univ So Calif, Dept Med, Los Angeles, CA USA. [Dezube, Bruce J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. [Aboulafia, David M.] Virginia Mason Med Ctr, Hematol Oncol Sect, Seattle, WA 98101 USA. [Ambinder, Richard F.] Johns Hopkins Univ, Dept Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Lee, Jeannette Y.] Univ Arkansas, Dept Biostat, Little Rock, AR 72204 USA. [Krown, Susan E.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Sparano, Joseph A.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. RP Cianfrocca, M (reprint author), Northwestern Univ, Dept Med, 676 N St Clair,Suite 850, Chicago, IL 60611 USA. EM m-cianfrocca@northwestern.edu FU Department of Health and Human Services; National Institutes of Health [CA23318, CA66636, CA21115, U01 CA121947] FX Supported in part by grants from the Department of Health and Human Services and the National Institutes of Health CA23318 to the Eastern Cooperative Oncology Group (ECOG) statistical center, CA66636 to the ECOG data management center, CA21115 to the ECOG coordinating center and chairman's office, and U01 CA121947 to the AIDS Malignancy Consortium. NR 32 TC 44 Z9 45 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2010 VL 116 IS 16 BP 3969 EP 3977 DI 10.1002/cncr.25362 PG 9 WC Oncology SC Oncology GA 635SR UT WOS:000280677100028 PM 20564162 ER PT J AU Davids, MS Steensma, DP AF Davids, Matthew S. Steensma, David P. TI The molecular pathogenesis of myelodysplastic syndromes SO CANCER BIOLOGY & THERAPY LA English DT Review DE myelodysplastic syndrome; pathogenesis; hematopoiesis; cytogenetic; genetic ID ACUTE MYELOID-LEUKEMIA; BONE-MARROW-CELLS; DIFFERENTIAL GENE-EXPRESSION; FAS-LIGAND; REFRACTORY-ANEMIA; SOMATIC MUTATIONS; HUMAN 5Q-SYNDROME; ARSENIC TRIOXIDE; POINT MUTATIONS; POOR-PROGNOSIS AB The myelodysplastic syndromes (MDS) are frequently associated with clonally restricted cytogenetic abnormalities, but until recently, the molecular pathobiology underlying this diverse group of neoplastic bone marrow disorders has been largely obscure. During the last 10 years, many investigative groups have applied the formidable power of new molecular biology techniques to hunt for recurrent genetic alterations in MDS primary cells. Several genetic abnormalities, including mutations in RUNX1 (AML1), TET2, ASXL1 and TP53, have been discovered in a substantial fraction of MDS cases; genes rearranged or mutated less commonly in MDS include IER3, ATRX, RAS and FLT3. Furthermore, haploinsufficiency and expression changes in RPS14, miR-145 and miR-146a, CDC25c, PP2A and SPARC in the absence of point mutations have also been implicated in MDS pathobiology. A major challenge will be to determine which of these mutations are causative "drivers" either in the development or progression of MDS, which might be therapeutically important because they predict response to treatment, and which are merely "passengers" along for the ride that alter phenotype but have no effect on the natural history of the disease. While the altered cellular biology of MDS is also increasingly well-understood, many mysteries remain. Abnormalities in iron regulation, microenvironment interactions, regulation of apoptosis and oxidative damage/DNA repair may all play an important pathobiological role. By gaining a deeper understanding of the mechanisms of these complex and heterogeneous diseases, we will hopefully improve our ability to treat our patients with MDS beyond the therapies with limited effectiveness that are available at present. C1 [Davids, Matthew S.; Steensma, David P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Hematol Malignancies, Boston, MA 02115 USA. RP Steensma, DP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Hematol Malignancies, 44 Binney St, Boston, MA 02115 USA. EM David_Steensma@dfci.harvard.edu OI Steensma, David/0000-0001-5130-9284 NR 102 TC 27 Z9 29 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG 15 PY 2010 VL 10 IS 4 BP 309 EP 319 DI 10.4161/cbt.10.4.12612 PG 11 WC Oncology SC Oncology GA 639WB UT WOS:000281005700001 PM 20592488 ER PT J AU Potash, J Anderson, KC AF Potash, Jesse Anderson, Kenneth C. TI What Can CCR Do for You? SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 [Potash, Jesse; Anderson, Kenneth C.] 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 2 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2010 VL 16 IS 16 BP 4069 EP 4070 DI 10.1158/1078-0432.CCR-10-1861 PG 2 WC Oncology SC Oncology GA 637PJ UT WOS:000280830300001 PM 20682715 ER PT J AU Vallet, S Smith, MR Raje, N AF Vallet, Sonia Smith, Matthew R. Raje, Noopur TI Novel Bone-Targeted Strategies in Oncology SO CLINICAL CANCER RESEARCH LA English DT Review ID REFRACTORY PROSTATE-CANCER; MULTIPLE-MYELOMA PATIENTS; CELL-ACTIVATING FACTOR; RANDOMIZED PHASE-II; DELTA T-CELLS; ZOLEDRONIC ACID; BREAST-CANCER; OSTEOCLAST FORMATION; TUMOR PROGRESSION; CONTROLLED-TRIAL AB Most patients with bone metastases experience skeletal complications, resulting in significant morbidity and increased risk of death. Although the use of bisphosphonates is a well-established form of supportive care treatment for bone metastasis, complications arising from long-term use require schedule optimization and a search for alternative strategies. Moreover, the scope of use of bone-targeted agents in oncology has widened to include therapy-induced bone loss and antitumor effects. Indeed, bone provides a permissive niche to tumor growth, and targeting the interactions within the bone microenvironment is a promising antitumor strategy. In addition, the pathogenesis of cancer-related bone disease has been partially unraveled with a focus on the anabolic bone compartment, and the rapid benchto- bedside translation has resulted in the identification of novel therapeutically amenable targets. This review focuses on studies optimizing bisphosphonate use and recent clinical data on denosumab in the treatment of bone disease. We also provide data on trials that have evaluated the antitumor effects of bisphosphonates and summarize the most recent discoveries on the role of the bone niche in cancer development, with insights into the preclinical rationale and clinical assessment of novel antiresorptive and anabolic bone-targeted agents. Clin Cancer Res; 16(16); 4084-93. (C) 2010 AACR. C1 [Vallet, Sonia; Smith, Matthew R.; Raje, Noopur] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol & Oncol,Dept Med,Canc Ctr, Boston, MA 02114 USA. RP Raje, N (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Hematol & Oncol,Dept Med,Canc Ctr, POB 216,55 Fruit St, Boston, MA 02114 USA. EM nraje@partners.org FU ASCO CDA; MMRF; LLS CDA; NIH [5K24CA121990-02] FX ASCO CDA, MMRF, LLS CDA, and NIH SPORE (N. Raje) and an NIH K24 Midcareer Investigator Award (5K24CA121990-02; M. Smith). NR 83 TC 24 Z9 27 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2010 VL 16 IS 16 BP 4084 EP 4093 DI 10.1158/1078-0432.CCR-10-0600 PG 10 WC Oncology SC Oncology GA 637PJ UT WOS:000280830300005 PM 20643782 ER PT J AU Parkin, B Ouillette, P Wang, Y Liu, Y Wright, W Roulston, D Purkayastha, A Dressel, A Karp, J Bockenstedt, P Al-Zoubi, A Talpaz, M Kujawski, L Liu, Y Shedden, K Shakhan, S Li, C Erba, H Malek, SN AF Parkin, Brian Ouillette, Peter Wang, Yin Liu, Yan Wright, Whitney Roulston, Diane Purkayastha, Anjali Dressel, Amanda Karp, Judith Bockenstedt, Paula Al-Zoubi, Ammar Talpaz, Moshe Kujawski, Lisa Liu, Yang Shedden, Kerby Shakhan, Sajid Li, Cheng Erba, Harry Malek, Sami N. TI NF1 Inactivation in Adult Acute Myelogenous Leukemia SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACQUIRED UNIPARENTAL DISOMY; COLONY-STIMULATING FACTOR; RAS SIGNALING PATHWAY; TUMOR-SUPPRESSOR; NEUROFIBROMATOSIS TYPE-1; COPY NUMBER; BONE-MARROW AB Purpose: This study was conducted to identify novel genes with importance to the biology of adult acute myelogenous leukemia (AML). Experimental Design: We analyzed DNA from highly purified AML blasts and paired buccal cells from 95 patients for recurrent genomic microdeletions using ultra-high density Affymetrix single nucleotide polymorphism 6.0 array-based genomic profiling. Results: Through fine mapping of microdeletions on 17q, we derived a minimal deleted region of similar to 0.9-Mb length that harbors 11 known genes; this region includes Neurofibromin 1 (NF1). Sequence analysis of all NF1 coding exons in the 11 AML cases with NF1 copy number changes identified acquired truncating frameshift mutations in two patients. These NF1 mutations were already present in the hematopoetic stem cell compartment. Subsequent expression analysis of NF1 mRNA in the entire AML cohort using fluorescence-activated cell sorting sorted blasts as a source of RNA identified six patients (one with a NF1 mutation) with absent NF1 expression. The NF1 null states were associated with increased Ras-bound GTP, and short hairpin RNA-mediated NF1 suppression in primary AML blasts with wild-type NF1 facilitated colony formation in methylcellulose. Primary AML blasts without functional NF1, unlike blasts with functional NF1, displayed sensitivity to rapamycin-induced apoptosis, thus identifying a dependence on mammalian target of rapamycin (mTOR) signaling for survival. Finally, colony formation in methylcellulose ex vivo of NF1 null CD34+/CD38- cells sorted from AML bone marrow samples was inhibited by low-dose rapamycin. Conclusions: NF1 null states are present in 7 of 95 (7%) of adult AML and delineate a disease subset that could be preferentially targeted by Ras or mammalian target of rapamycin-directed therapeutics. Clin Cancer Res; 16(16); 4135-47. (C) 2010 AACR. C1 [Parkin, Brian; Ouillette, Peter; Wright, Whitney; Dressel, Amanda; Bockenstedt, Paula; Al-Zoubi, Ammar; Talpaz, Moshe; Kujawski, Lisa; Shakhan, Sajid; Erba, Harry; Malek, Sami N.] Univ Michigan, Dept Internal Med, Div Hematol & Oncol, Ann Arbor, MI 48109 USA. [Shedden, Kerby] Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA. [Roulston, Diane; Purkayastha, Anjali; Malek, Sami N.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Wang, Yin; Liu, Yan; Liu, Yang] Univ Michigan, Dept Surg, Div Immunotherapy, Ann Arbor, MI 48109 USA. [Karp, Judith] Johns Hopkins Canc Ctr, Dept Oncol, Baltimore, MD USA. [Li, Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Li, Cheng] Harvard Univ, Sch Publ Hlth, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Li, Cheng] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Malek, SN (reprint author), Univ Michigan, Dept Internal Med, Div Hematol & Oncol, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM smalek@med.umich.edu FU NIH [1R01 CA136537-01]; Leukemia and Lymphoma Society of America; NIH through the University of Michigan's Cancer Center [5 P30 CA46592] FX NIH through 1R01 CA136537-01 (S.N. Malek) and the Translational Research Program of the Leukemia and Lymphoma Society of America (S.N. Malek). This research is supported (in part) by the NIH through the University of Michigan's Cancer Center Support Grant (5 P30 CA46592). NR 45 TC 30 Z9 30 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2010 VL 16 IS 16 BP 4135 EP 4147 DI 10.1158/1078-0432.CCR-09-2639 PG 13 WC Oncology SC Oncology GA 637PJ UT WOS:000280830300010 PM 20505189 ER PT J AU Walensky, RP Paltiel, AD Losina, E Morris, BL Scott, CA Rhode, ER Seage, GR Freedberg, KA AF Walensky, Rochelle P. Paltiel, A. David Losina, Elena Morris, Bethany L. Scott, Callie A. Rhode, Erin R. Seage, George R. Freedberg, Kenneth A. CA CEPAC Investigators TI Test and Treat DC: Forecasting the Impact of a Comprehensive HIV Strategy in Washington DC SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; UNITED-STATES; COST-EFFECTIVENESS; OPPORTUNISTIC INFECTIONS; VIRAL LOAD; PREVALENCE; DISEASE; TRANSMISSION; ADOLESCENTS; PREVENTION AB Background. The United States and international agencies have signaled their commitment to containing the human immunodeficiency virus (HIV) epidemic via early case identification and linkage to antiretroviral therapy (ART) immediately at diagnosis. We forecast outcomes of this approach if implemented in Washington DC. Methods. Using a mathematical model of HIV case detection and treatment, we evaluated combinations of HIV screening and ART initiation strategies. We define current practice as no regular screening program and ART at CD4 counts <= 350 cells/mL, and we define test and treat as annual screening and administration of ART at diagnosis. Outcomes include life expectancy of HIV-infected persons and changes in the population time with transmissible HIV RNA levels. Data, largely from Washington DC, include undiagnosed HIV prevalence of 0.6%, annual incidence of 0.13%, 31% rate of test offer, 60% rate of acceptance, and 50% linkage to care. Input parameters, including optimized ART efficacy, are varied in sensitivity analyses. Results. Projected life expectancies, from an initial mean age of 41 years, are 23.9, 25.0, and 25.6 years for current practice, test and treat, and test and treat with optimized ART, respectively. Compared with current practice, test and treat leads to a 14.7% reduction in time spent with transmissible HIV RNA level in the next 5 years; test and treat with optimized ART results in a 27.3% reduction. Conclusions. An expanded HIV test and treat program in Washington DC will increase life expectancy of HIV-infected patients but will have a modest impact on HIV transmission over the next 5 years and is unlikely to halt the HIV epidemic. C1 [Walensky, Rochelle P.; Morris, Bethany L.; Scott, Callie A.; Rhode, Erin R.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MA 02114 USA. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthopaed Surg, Boston, MA 02115 USA. [Walensky, Rochelle P.; Losina, Elena; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Harvard Univ Ctr AIDS Res, Boston, MA USA. [Seage, George R.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Paltiel, A. David] Yale Univ, Sch Med, New Haven, CT USA. RP Walensky, RP (reprint author), Massachusetts Gen Hosp, Div Gen Med, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM rwalensky@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X; Lipsitch, Marc/0000-0003-1504-9213 FU National Institute of Allergy and Infectious Diseases [R37 AI042006, K24 AI062476, P30 AI060354]; National Institute of Mental Health [R01 MH065869, R01 MH073445]; Doris Duke Charitable Foundation FX National Institute of Allergy and Infectious Diseases (R37 AI042006, K24 AI062476, and P30 AI060354), the National Institute of Mental Health (R01 MH065869 and R01 MH073445), and the Doris Duke Charitable Foundation (Clinical Scientist Development Award). NR 44 TC 70 Z9 70 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2010 VL 51 IS 4 BP 392 EP 400 DI 10.1086/655130 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 626WJ UT WOS:000279998300009 PM 20617921 ER PT J AU Li, JZ Tucker, JD Lobo, AM Marra, CM Davis, BT Papaliodis, GN Felsenstein, D Durand, ML Yawetz, S Robbins, GK AF Li, Jonathan Z. Tucker, Joseph D. Lobo, Ann-Marie Marra, Christina M. Davis, Benjamin T. Papaliodis, George N. Felsenstein, Donna Durand, Marlene L. Yawetz, Sigal Robbins, Gregory K. TI Ocular Syphilis among HIV-Infected Individuals SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; POSTERIOR UVEITIS; LOS-ANGELES; MANIFESTATIONS; NEUROSYPHILIS; EPIDEMIC; MEN AB We describe a human immunodeficiency virus (HIV)-infected individual with ocular manifestations of secondary syphilis. Twelve other cases of HIV-associated ocular syphilis are also presented. Six of 12 individuals had normal cerebrospinal fluid study results, and 3 patients required retreatment within 1.5 years. In patients with HIV infection, clinicians should be vigilant for ocular syphilis despite normal cerebrospinal fluid measures and for syphilis reinfection. C1 [Li, Jonathan Z.; Yawetz, Sigal] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Li, Jonathan Z.; Tucker, Joseph D.; Davis, Benjamin T.; Felsenstein, Donna; Durand, Marlene L.; Robbins, Gregory K.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Lobo, Ann-Marie; Papaliodis, George N.; Durand, Marlene L.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Robbins, Gregory K.] Massachusetts Gen Hosp, MIT, Ragon Inst, Charlestown, MA USA. [Robbins, Gregory K.] Harvard Univ, Charlestown, MA USA. [Marra, Christina M.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. RP Li, JZ (reprint author), Brigham & Womens Hosp, Div Infect Dis, 15 Francis St,PBB A4, Boston, MA 02115 USA. EM jli22@partners.org FU National Institutes of Health [T32 AI07387, NIH/NS34235, AI062435]; US NIH FX National Institutes of Health (T32 AI07387 to J.Z.L., NIH/NS34235 to C. M. M., and AI062435 to G. K. R.) and US NIH Fogarty International Clinical Fellowship (to J.D.T.). NR 21 TC 11 Z9 12 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2010 VL 51 IS 4 BP 468 EP 471 DI 10.1086/654797 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 626WJ UT WOS:000279998300018 PM 20604717 ER PT J AU Zhou, YL Cheunsuchon, P Nakayama, Y Lawlor, MW Zhong, Y Rice, KA Zhang, L Zhang, X Gordon, FE Lidov, HGW Bronson, RT Klibanski, A AF Zhou, Yunli Cheunsuchon, Pornsuk Nakayama, Yuki Lawlor, Michael W. Zhong, Ying Rice, Kimberley A. Zhang, Li Zhang, Xun Gordon, Francesca E. Lidov, Hart G. W. Bronson, Roderick T. Klibanski, Anne TI Activation of paternally expressed genes and perinatal death caused by deletion of the Gtl2 gene SO DEVELOPMENT LA English DT Article DE Gtl2; Meg3; Dlk1-Gtl2 locus; Genomic imprinting; Mouse; Methylation; Muscle development ID RETROTRANSPOSON-LIKE GENE; SKELETAL-MUSCLE; UNIPARENTAL DISOMY; IMPRINTED GENES; IODOTHYRONINE DEIODINASE; DLK1-GTL2 LOCUS; CHROMOSOME 12; STEM-CELLS; MOUSE; REGION AB The Dlk1-Gtl2 imprinting locus is located on mouse distal chromosome 12 and consists of multiple maternally expressed non-coding RNAs and several paternally expressed protein-coding genes. The imprinting of this locus plays a crucial role in embryonic development and postnatal growth. At least one cis-element, the intergenic differentially methylated region (IG-DMR) is required for expression of maternally expressed genes and repression of silenced paternally expressed genes. The mechanism by which the IG-DMR functions is largely unknown. However, it has been suggested that the unmethylated IG-DMR acts as a positive regulator activating expression of non-coding RNAs. Gtl2 is the first non-coding RNA gene downstream of the IG-DMR. Although its in vivo function in the mouse is largely unknown, its human ortholog MEG3 has been linked to tumor suppression in human tumor-derived cell lines. We generated a knockout mouse model, in which the first five exons and adjacent promoter region of the Gtl2 gene were deleted. Maternal deletion of Gtl2 resulted in perinatal death and skeletal muscle defects, indicating that Gtl2 plays an important role in embryonic development. The maternal deletion also completely abolished expression of downstream maternally expressed genes, activated expression of silenced paternally expressed genes and resulted in methylation of the IG-DMR. By contrast, the paternal inherited deletion did not have this effect. These data strongly indicate that activation of Gtl2 and its downstream maternal genes play an essential role in regulating Dlk1-Gtl2 imprinting, possibly by maintaining active status of the IG-DMR. C1 [Zhou, Yunli; Cheunsuchon, Pornsuk; Nakayama, Yuki; Zhong, Ying; Rice, Kimberley A.; Zhang, Xun; Gordon, Francesca E.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Zhou, Yunli; Cheunsuchon, Pornsuk; Nakayama, Yuki; Zhong, Ying; Rice, Kimberley A.; Zhang, Xun; Gordon, Francesca E.; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Lawlor, Michael W.; Lidov, Hart G. W.] Childrens Hosp, Div Genet & Program Genom, Boston, MA 02115 USA. [Lawlor, Michael W.; Zhang, Li; Lidov, Hart G. W.; Bronson, Roderick T.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Zhou, YL (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM yzhou2@partners.org RI Cheunsuchon, Pornsuk/O-7915-2015 OI Cheunsuchon, Pornsuk/0000-0001-8851-3553 FU National Institutes of Health [R01DK40947]; Guthart Family Foundation; Jarislowsky Foundation FX We thank Dr Hang Lee for his assistance with statistical analysis. This work was supported by grants from the National Institutes of Health (A. Klibanski, R01DK40947), the Guthart Family Foundation and the Jarislowsky Foundation. Deposited in PMC for release after 12 months. NR 39 TC 57 Z9 61 U1 0 U2 6 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 AUG 15 PY 2010 VL 137 IS 16 BP 2643 EP 2652 DI 10.1242/dev.045724 PG 10 WC Developmental Biology SC Developmental Biology GA 631IC UT WOS:000280339000004 PM 20610486 ER PT J AU Kee, Y D'Andrea, AD AF Kee, Younghoon D'Andrea, Alan D. TI Expanded roles of the Fanconi anemia pathway in preserving genomic stability SO GENES & DEVELOPMENT LA English DT Review DE Fanconi anemia; DNA repair; interstrand cross-link (ICL); homologous recombination (HR); nonhomologous end-joining (NHEJ); mitosis ID CROSS-LINK REPAIR; DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; HOMOLOGOUS RECOMBINATIONAL REPAIR; COMPLEMENTATION GROUP-M; FRAGILE-SITE STABILITY; CELL-CYCLE; MAMMALIAN-CELLS; CANCER SUSCEPTIBILITY; CORE COMPLEX AB Studying rare human genetic diseases often leads to a better understanding of normal cellular functions. Fanconi anemia ( FA), for example, has elucidated a novel DNA repair mechanism required for maintaining genomic stability and preventing cancer. The FA pathway, an essential tumor-suppressive pathway, is required for protecting the human genome from a specific type of DNA damage; namely, DNA interstrand cross-links (ICLs). In this review, we discuss the recent progress in the study of the FA pathway, such as the identification of new FANCM-binding partners and the identification of RAD51C and FAN1 (Fanconi-associated nuclease 1) as new FA pathway-related proteins. We also focus on the role of the FA pathway as a potential regulator of DNA repair choices in response to double-strand breaks, and its novel functions during the mitotic phase of the cell cycle. C1 [Kee, Younghoon; D'Andrea, Alan D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol & Pediat Oncol, Boston, MA 02115 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol & Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM alan_dandrea@dfci.harvard.edu FU Leukemia and Lymphoma Society; [R01DK43389]; [R01HL52725] FX We thank Simon Boulton for sharing data prior to publication. We thank Clark Chen, Dipanjan Chowdhury, Kalindi Parmar, and all of the members of the D'Andrea laboratory for critical reading of the manuscript. Y.K. is the recipient of the Leukemia and Lymphoma Society Career Development Fellowship. This work was supported by R01DK43389 and R01HL52725. NR 133 TC 189 Z9 194 U1 6 U2 20 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 AUG 15 PY 2010 VL 24 IS 16 BP 1680 EP 1694 DI 10.1101/gad.1955310 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 639JI UT WOS:000280970700002 PM 20713514 ER PT J AU Benhamouche, S Curto, M Saotome, I Gladden, AB Liu, CH Giovannini, M McClatchey, AI AF Benhamouche, Samira Curto, Marcello Saotome, Ichiko Gladden, Andrew B. Liu, Ching-Hui Giovannini, Marco McClatchey, Andrea I. TI Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver SO GENES & DEVELOPMENT LA English DT Article DE EGFR; Merlin; NF2; cholangiocellular carcinoma; hepatocellular carcinoma; liver progenitor ID NF2 TUMOR-SUPPRESSOR; GROWTH-FACTOR-ALPHA; HUMAN HEPATOCELLULAR-CARCINOMA; MEDIATES CONTACT INHIBITION; STEM-CELL NICHE; OVAL CELLS; TRANSGENIC MICE; ORGAN SIZE; RAT-LIVER; RENAL-CARCINOMA AB The molecular signals that control the maintenance and activation of liver stem/progenitor cells are poorly understood, and the role of liver progenitor cells in hepatic tumorigenesis is unclear. We report here that liver-specific deletion of the neurofibromatosis type 2 (Nf2) tumor suppressor gene in the developing or adult mouse specifically yields a dramatic, progressive expansion of progenitor cells throughout the liver without affecting differentiated hepatocytes. All surviving mice eventually developed both cholangiocellular and hepatocellular carcinoma, suggesting that Nf2(-/-) progenitors can be a cell of origin for these tumors. Despite the suggested link between Nf2 and the Hpo/Wts/Yki signaling pathway in Drosophila, and recent studies linking the corresponding Mst/Lats/Yap pathway to mammalian liver tumorigenesis, our molecular studies suggest that Merlin is not a major regulator of YAP in liver progenitors, and that the overproliferation of Nf2 (/) liver progenitors is instead driven by aberrant epidermal growth factor receptor (EGFR) activity. Indeed, pharmacologic inhibition of EGFR blocks the proliferation of Nf2(-/-) liver progenitors in vitro and in vivo, consistent with recent studies indicating that the Nf2-encoded protein Merlin can control the abundance and signaling of membrane receptors such as EGFR. Together, our findings uncover a critical role for Nf2/Merlin in controlling homeostasis of the liver stem cell niche. C1 [Benhamouche, Samira; Curto, Marcello; Saotome, Ichiko; Gladden, Andrew B.; Liu, Ching-Hui; McClatchey, Andrea I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res,Dept Pathol, Boston, MA 02129 USA. [Giovannini, Marco] Ctr Neural Tumor Res, House Ear Inst, Los Angeles, CA 90057 USA. RP McClatchey, AI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res,Dept Pathol, Boston, MA 02129 USA. EM mcclatch@helix.mgh.harvard.edu FU International Human Frontier Science Program Organization; Tucker-Gosnell Foundation; Department of Defense (DOD); National Institutes of Health (NIH); Children's Tumor Foundation (CTF) FX We gratefully acknowledge Othon Iliopoulos and all members of the McClatchey laboratory for helpful discussions and comments on the manuscript, Valentina Factor (NIH, Bethesda) for the A6 antibody, Lars Zender for the Yap shRNA expression vectors, Daniel Haber and Jianmin Zhang for the Lats expression vectors, and Anna Levitz and the Pathology Core Facility for histological support. This work was supported by The International Human Frontier Science Program Organization to S. B., and by grants from the Tucker-Gosnell Foundation, Department of Defense (DOD), National Institutes of Health (NIH), and the Children's Tumor Foundation (CTF) to A.I.M. NR 84 TC 113 Z9 116 U1 1 U2 20 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 AUG 15 PY 2010 VL 24 IS 16 BP 1718 EP 1730 DI 10.1101/gad.1938710 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 639JI UT WOS:000280970700005 PM 20675406 ER PT J AU Inda, MD Bonavia, R Mukasa, A Narita, Y Sah, DWY Vandenberg, S Brennan, C Johns, TG Bachoo, R Hadwiger, P Tan, P DePinho, RA Cavenee, W Furnari, F AF Inda, Maria-del-Mar Bonavia, Rudy Mukasa, Akitake Narita, Yoshitaka Sah, Dinah W. Y. Vandenberg, Scott Brennan, Cameron Johns, Terrance G. Bachoo, Robert Hadwiger, Philipp Tan, Pamela DePinho, Ronald A. Cavenee, Webster Furnari, Frank TI Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma SO GENES & DEVELOPMENT LA English DT Article DE Glioblastoma; EGFR; Delta EGFR; IL-6; LIF; gp130; tumor heterogeneity ID GROWTH-FACTOR-RECEPTOR; CONFERS ENHANCED TUMORIGENICITY; LEUKEMIA-INHIBITORY FACTOR; CELL SELF-RENEWAL; NEURAL STEM-CELL; IN-VITRO; TYROSINE PHOSPHORYLATION; GENE AMPLIFICATION; BRAIN-TUMORS; GLIOMA AB Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/Delta EGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the Delta EGFR lesion. We hypothesized that the minor Delta EGFR-expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by Delta EGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf(-/-) astrocytes that express Delta EGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically dissimilar cancer cells could provide novel points of therapeutic intervention. C1 [Inda, Maria-del-Mar; Bonavia, Rudy; Mukasa, Akitake; Narita, Yoshitaka; Cavenee, Webster; Furnari, Frank] Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. [Mukasa, Akitake] Univ Tokyo, Dept Neurosurg, Tokyo 1138655, Japan. [Narita, Yoshitaka] Natl Canc Ctr, Div Neurosurg, Tokyo 1040045, Japan. [Sah, Dinah W. Y.] Alnylam Pharmaceut Inc, Cambridge, MA 02142 USA. [Vandenberg, Scott] Univ Calif San Diego, Sch Med, Dept Pathol, La Jolla, CA 92093 USA. [Brennan, Cameron] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA. [Johns, Terrance G.] Monash Univ, Monash Inst Med Res, Clayton, Vic 3168, Australia. [Bachoo, Robert] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Hadwiger, Philipp; Tan, Pamela] Alnylam Europe AG, D-95326 Kulmbach, Germany. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci,Dept Med Oncol, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci,Dept Med, Boston, MA 02115 USA. [DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci,Dept Genet, Boston, MA 02115 USA. [Cavenee, Webster; Furnari, Frank] Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USA. RP Furnari, F (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. EM ffurnari@ucsd.edu RI Johns, Terrance/C-2441-2008; OI Johns, Terrance/0000-0002-8874-4543; Brennan, Cameron/0000-0003-4064-8891 FU Goldhirsh Foundation; NIH [P01-CA95616]; Gobierno de Navarra, Spain; American Brain Tumor Association; Federazione Italiana Ricerca Cancro; Robert A. and Renee E. Belfer Foundation; Associazione Italiana per la Ricerca sul Cancro FX We thank Dr. Keith Ligon for helpful discussions, Dr. Tim Fenton for technical assistance and advice, and Dr. Jayne Stommel and Alicia Pedraza for providing neurosphere cultures. This work was supported by an award from the Goldhirsh Foundation (to F. B. F.) and NIH Grant P01-CA95616 (to W. K. C., R. A. D., F. B. F., C. B.). W. K. C. is a fellow of the National Foundation for Cancer Research. M. M. I. thanks the Gobierno de Navarra, Spain, and the American Brain Tumor Association in Honor of Walter Terlik for the fellowships received. R. B. was supported by a fellowship from Federazione Italiana Ricerca Cancro. R. A. D. is supported by the Robert A. and Renee E. Belfer Foundation. NR 60 TC 217 Z9 225 U1 2 U2 13 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 AUG 15 PY 2010 VL 24 IS 16 BP 1731 EP 1745 DI 10.1101/gad.1890510 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 639JI UT WOS:000280970700006 PM 20713517 ER PT J AU Wilkin, TJ Su, ZH Krambrink, A Long, JM Greaves, W Gross, R Hughes, MD Flexner, C Skolnik, PR Coakley, E Godfrey, C Hirsch, M Kuritzkes, DR Gulick, RM AF Wilkin, Timothy J. Su, Zhaohui Krambrink, Amy Long, Jianmin Greaves, Wayne Gross, Robert Hughes, Michael D. Flexner, Charles Skolnik, Paul R. Coakley, Eoin Godfrey, Catherine Hirsch, Martin Kuritzkes, Daniel R. Gulick, Roy M. TI Three-Year Safety and Efficacy of Vicriviroc, a CCR5 Antagonist, in HIV-1-Infected Treatment-Experienced Patients SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE antiretroviral therapy; CCR5 antagonist; HIV-1; vicriviroc ID PLACEBO-CONTROLLED TRIAL; HIV-1 INFECTION; DOUBLE-BLIND; SUSCEPTIBILITY SCORES; TMC125 ETRAVIRINE; LARGE POPULATION; RESISTANT HIV-1; CORECEPTOR USE; GROUP A5211; IN-VIVO AB Background: Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity. Methods: Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10, or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14. Subjects experiencing virologic failure and subjects completing 48 weeks were offered open-label vicriviroc. Results: One hundred eighteen subjects were randomized. Virologic failure (<1 log(10) decline in HIV-1 RNA >= 16 weeks postrandomization) occurred by week 48 in 24 of 28 (86%), 12 of 30 (40%), 8 of 30 (27%), 10 of 30 (33%) of subjects randomized to placebo, 5, 10, and 15 mg, respectively. Overall, 113 subjects received vicriviroc at randomization or after virologic failure, and 52 (46%) achieved HIV-1 RNA <50 copies per milliliter within 24 weeks. Through 3 years, 49% of those achieving suppression did not experience confirmed viral rebound. Dual or mixed-tropic HIV-1 was detected in 33 (29%). Vicriviroc resistance (progressive decrease in maximal percentage inhibition on phenotypic testing) was detected in 6 subjects. Nine subjects discontinued vicriviroc due to adverse events. Conclusions: Vicriviroc seems safe and demonstrates sustained virologic suppression through 3 years of follow-up. Further trials of vicriviroc will establish its clinical utility for the treatment of HIV-1 infection. C1 [Wilkin, Timothy J.; Gulick, Roy M.] Weill Cornell Med Coll, Div Infect Dis, New York, NY USA. [Su, Zhaohui; Krambrink, Amy; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Long, Jianmin; Greaves, Wayne] Schering Plough Res Inst, Kenilworth, NJ USA. [Gross, Robert] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Gross, Robert] Univ Penn, Sch Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Flexner, Charles] Johns Hopkins Univ, Baltimore, MD USA. [Skolnik, Paul R.] Boston Univ, Med Ctr, Ctr HIV AIDS Care & Res, Boston, MA USA. [Coakley, Eoin] Monogram Biosci, San Francisco, CA USA. [Godfrey, Catherine] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Hirsch, Martin] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Kuritzkes, Daniel R.] Brigham & Womens Hosp, Sect Retroviral Therapeut, Boston, MA 02115 USA. [Kuritzkes, Daniel R.] Harvard Univ, Sch Med, Boston, MA USA. RP Wilkin, TJ (reprint author), 119 W 24th St Ground Floor, New York, NY 10011 USA. EM tiw2001@med.cornell.edu FU NCRR NIH HHS [M01 RR000046, M01 RR000052, M01 RR000096, M01 RR005280-08, M01- RR025780, M01-RR00046, M01-RR00052, M01-RR00096, M01-RR024160, RR024979, UL1 RR024160, UL1 RR024160-01, UL1 RR024979, UL1 RR024979-01, UL1 RR024996, UL1 RR024996-01, UL1 RR025780, UL1 RR025780-01, UL1-RR024996]; NIAID NIH HHS [U01 AI068636-01, AI- 69511, AI-25859, AI-27661, AI-32782, AI-34853, AI-46370, AI-68634, AI-69418, AI-69419, AI-69423, AI-69424, AI-69432, AI-69434, AI-69439, AI-69450, AI-69465, AI-69467, AI-69471, AI-69472, AI-69474, AI-69494, AI-69495, AI-69501, AI-69502, AI-69532, AI-69556, K23 AI055038, K23 AI055038-01, K23-AI-55038, K24 AI051966, K24 AI051966-01A1, K24-AI-51966, P30 AI045008, P30 AI045008-05, P30 AI050410, P30 AI050410-04, P30-AI-45008, P30-AI-50410, U01 AI025859, U01 AI025859-13, U01 AI027661, U01 AI027661-14, U01 AI032782, U01 AI032782-09, U01 AI034853, U01 AI034853-07, U01 AI046370, U01 AI046370-01, U01 AI068634, U01 AI068634-01, U01 AI068636, U01 AI069418, U01 AI069418-01, U01 AI069419, U01 AI069419-01, U01 AI069423, U01 AI069423-01, U01 AI069424, U01 AI069424-01, U01 AI069432, U01 AI069432-01, U01 AI069434, U01 AI069434-01, U01 AI069439, U01 AI069439-01, U01 AI069450, U01 AI069450-01, U01 AI069465, U01 AI069465-01, U01 AI069467, U01 AI069467-01, U01 AI069471, U01 AI069471-01, U01 AI069472, U01 AI069472-01, U01 AI069474, U01 AI069474-01, U01 AI069494, U01 AI069494-01, U01 AI069495, U01 AI069495-01, U01 AI069501, U01 AI069501-01, U01 AI069502, U01 AI069502-01, U01 AI069511-01, U01 AI069532, U01 AI069532-01, U01 AI069556, U01 AI069556-01, U01-AI-68636, UM1 AI068634, UM1 AI069418, UM1 AI069419, UM1 AI069423, UM1 AI069424, UM1 AI069432, UM1 AI069434, UM1 AI069439, UM1 AI069450, UM1 AI069465, UM1 AI069467, UM1 AI069471, UM1 AI069472, UM1 AI069474, UM1 AI069494, UM1 AI069495, UM1 AI069501, UM1 AI069502, UM1 AI069532, UM1 AI069556] NR 26 TC 15 Z9 17 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 AUG 15 PY 2010 VL 54 IS 5 BP 470 EP 476 DI 10.1097/QAI.0b013e3181e2cba0 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 628UU UT WOS:000280149000004 PM 20672447 ER PT J AU Li, WC Rukstalis, JM Nishimura, W Tchipashvili, V Habener, JF Sharma, A Bonner-Weir, S AF Li, Wan-Chun Rukstalis, J. Michael Nishimura, Wataru Tchipashvili, Vaja Habener, Joel F. Sharma, Arun Bonner-Weir, Susan TI Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats SO JOURNAL OF CELL SCIENCE LA English DT Article DE Regeneration; Pancreatic progenitors; Dedifferentiation ID BETA-CELLS; TRANSCRIPTION FACTOR; ISLET NEOGENESIS; ENDOCRINE-CELLS; 90-PERCENT PANCREATECTOMY; EMBRYONIC-DEVELOPMENT; EXPRESSION PATTERNS; LIVER-REGENERATION; GLUCOSE-TOLERANCE; TUBULAR COMPLEXES AB The adult pancreas has considerable capacity to regenerate in response to injury. We hypothesized that after partial pancreatectomy (Px) in adult rats, pancreatic-duct cells serve as a source of regeneration by undergoing a reproducible dedifferentiation and redifferentiation. We support this hypothesis by the detection of an early loss of the ductal differentiation marker Hnf6 in the mature ducts, followed by the transient appearance of areas composed of proliferating ductules, called foci of regeneration, which subsequently form new pancreatic lobes. In young foci, ductules express markers of the embryonic pancreatic epithelium -Pdx1, Tcf2 and Sox9 - suggesting that these cells act as progenitors of the regenerating pancreas. The endocrine-lineage-specific transcription factor Neurogenin3, which is found in the developing embryonic pancreas, was transiently detected in the foci. Islets in foci initially resemble embryonic islets in their lack of MafA expression and lower percentage of beta-cells, but with increasing maturation have increasing numbers of MafA(+) insulin(+) cells. Taken together, we provide a mechanism by which adult pancreatic duct cells recapitulate aspects of embryonic pancreas differentiation in response to injury, and contribute to regeneration of the pancreas. This mechanism of regeneration relies mainly on the plasticity of the differentiated cells within the pancreas. C1 [Li, Wan-Chun; Nishimura, Wataru; Tchipashvili, Vaja; Sharma, Arun; Bonner-Weir, Susan] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. [Rukstalis, J. Michael; Habener, Joel F.] Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. RP Bonner-Weir, S (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. EM susan.bonner-weir@joslin.harvard.edu OI Nishimura, Wataru/0000-0002-8068-1277 FU National Institutes of Health [R01 DK 66056, P30 DK36836]; Diabetes Research and Wellness Foundation; JDRF [3-2008-72]; NIH/NIDDK [K01 DK076791]; Mary K. Iacocca Fellowship; NICHD FX This study was supported by grants from the National Institutes of Health R01 DK 66056 (S.B.-W.), P30 DK36836 [Joslin Diabetes and Endocrinology Research Center (DERC) Advanced Microscopy Core] as well as the Diabetes Research and Wellness Foundation and an important group of private donors. W.-C. L. was supported by a JDRF postdoctoral fellowship (3-2008-72); J.M.R. by funds from the NIH/NIDDK (K01 DK076791); and W.N. by the Mary K. Iacocca Fellowship. Mouse monoclonal anti-ngn3 and anti-nkx6.1 antibodies (both generated by Ole D. Madsen) and mouse anti-nkx2.2 (generated by Thomas M. Jessell) were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biological Sciences, Iowa, IA 52242. We thank Christopher J. Cahill for superb technical support and Dr Loeken (Joslin Diabetes Center) for the use of fluorescent dissecting microscope. Deposited in PMC for release after 12 months. NR 78 TC 71 Z9 73 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG 15 PY 2010 VL 123 IS 16 BP 2792 EP 2802 DI 10.1242/jcs.065268 PG 11 WC Cell Biology SC Cell Biology GA 634YR UT WOS:000280622700012 PM 20663919 ER PT J AU Saito, TI Li, HW Sykes, M AF Saito, Toshiki I. Li, Hao Wei Sykes, Megan TI Invariant NKT Cells Are Required for Antitumor Responses Induced by Host-Versus-Graft Responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECIPIENT LEUKOCYTE INFUSIONS; CD8(+) T-CELLS; DENDRITIC CELLS; IN-VIVO; ALPHA-GALACTOSYLCERAMIDE; IFN-GAMMA; CUTTING EDGE; CROSS-TALK; DISEASE; INDUCTION AB Based on clinical observations, we have previously shown in a murine model that recipient leukocyte infusion (RLI) induces a host-versus-graft reaction in mixed bone marrow chimeras and that rejection of donor cells leads to a specific antitumor response against recipient malignancies. This response is dependent on T cells and IFN-gamma. We investigated the role of NKT cells (NKTs) in this phenomenon. Depletion of recipient NK1.1(+) cells led to loss of an anti-tumor effect induced by RLI in mixed bone marrow chimeras. In recipients specifically lacking host invariant NKT cells (iNKTs), RLI did not induce an antitumor effect, indicating a critical role for recipient iNKTs. Conversely, specific activation of iNKTs enhanced the anti-tumor effect induced by RLI. Following RLI, recipient iNKTs, NK cells, dendritic cells (DCs), and CD8 T cells were activated. CD8 T cells were the major producers of IFN-gamma. Lack of recipient iNKTs resulted in failure of activation of NK cells and DCs by RLI. Our studies demonstrate a central role for iNKTs in promoting RLI-induced anti-tumor effects and suggest that this pathway involved promotion of the activation of recipient NK cells and DCs. The Journal of Immunology, 2010, 185: 2099-2105. C1 [Saito, Toshiki I.; Li, Hao Wei; Sykes, Megan] Harvard Univ, Bone Marrow Transplantat Sect, Transplantat Biol Res Ctr, Massachusetts Gen Hosp,Med Sch, Boston, MA 02129 USA. RP Sykes, M (reprint author), Columbia Univ, Med Ctr, Columbia Ctr Translat Immunol, 622 W 168th St,PH17 111, New York, NY 10032 USA. EM megan.sykes@columbia.edu FU National Institutes of Health [RO1 CA079989-07, PO1 CA111519]; Multiple Myeloma Research Foundation FX This work was supported by National Institutes of Health Grants RO1 CA079989-07 and PO1 CA111519. T. I. S. was supported by a Multiple Myeloma Research Foundation 2007 Fellow Award. NR 29 TC 11 Z9 13 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2010 VL 185 IS 4 BP 2099 EP 2105 DI 10.4049/jimmunol.0901985 PG 7 WC Immunology SC Immunology GA 635NH UT WOS:000280661900016 PM 20631307 ER PT J AU Baker, DA Barth, J Chang, R Obeid, LM Gilkeson, GS AF Baker, DeAnna A. Barth, Jeremy Chang, Raymond Obeid, Lina M. Gilkeson, Gary S. TI Genetic Sphingosine Kinase 1 Deficiency Significantly Decreases Synovial Inflammation and Joint Erosions in Murine TNF-alpha-Induced Arthritis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; RHEUMATOID-ARTHRITIS; BIOACTIVE SPHINGOLIPIDS; 1-PHOSPHATE RECEPTORS; EXPRESSION; SPHINGOSINE-1-PHOSPHATE; DISEASE; ROLES; MODULATION; INDUCTION AB Sphingosine kinase 1 (SphK1) is an enzyme that converts sphingosine to bioactive sphingosine-1-phosphate. Recent in vitro data suggest a potential role of SphK1 in TNF-alpha-mediated inflammation. Our aims in this study were to determine the in vivo significance of SphK1 in TNF-alpha-mediated chronic inflammation and to define which pathogenic mechanisms induced by TNF-alpha are SphK1 dependent. To pursue these aims, we studied the effect of SphK1 deficiency in an in vivo model of TNF-alpha-induced chronic inflammatory arthritis. Transgenic hTNF-alpha mice, which develop spontaneous inflammatory erosive arthritis beginning at 14-16 wk, were crossed with SphK1 null mice (SphK1(-/-)), on the C57BL6 genetic background. Beginning at 4 mo of age, hTNF/SphK1(-/-) mice had significantly less severe clinically evident paw swelling and deformity, less synovial and periarticular inflammation, and markedly decreased bone erosions as measured quantitatively through micro-CT images. Mechanistically, the mice lacking SphK1 had less articular cyclooxygenase 2 protein and fewer synovial Th17 cells than did hTNF/SphK1(+/+) littermates. Microarray analysis and real-time RT-PCR of the ankle synovial tissue demonstrated that hTNF/SphK1(-/-) mice had increased transcript levels of suppressor of cytokine signaling 3 compared with hTNF/SphK1(+/+) mice, likely also contributing to the decreased inflammation in the SphK1-deficient mice. Finally, significantly fewer mature osteoclasts were detected in the ankle joints of hTNF/SphK1(-/-) mice compared with hTNF/SphK1(+/+) mice. These data indicate that SphK1 plays a key role in hTNF-alpha-induced inflammatory arthritis via impacting synovial inflammation and osteoclast number. The Journal of Immunology, 2010, 185: 2570-2579. C1 [Gilkeson, Gary S.] Med Univ S Carolina, Div Rheumatol, Dept Med, Charleston, SC 29425 USA. [Baker, DeAnna A.] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Barth, Jeremy] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Chang, Raymond] Med Univ S Carolina, Small Anim Imaging Core Facil, Dept Radiol & Radiol Sci, Charleston, SC 29425 USA. [Obeid, Lina M.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Obeid, Lina M.; Gilkeson, Gary S.] Ralph H Johnson Vet Affairs Med Ctr, Dept Vet Affairs, Charleston, SC 29401 USA. RP Gilkeson, GS (reprint author), Med Univ S Carolina, Div Rheumatol, Dept Med, 114 Doughty St,STB 425, Charleston, SC 29425 USA. EM gilkeson@musc.edu FU American College of Rheumatology Research; Education Foundation's Within Our Reach: Finding a Cure for Arthritis Campaign; U.S. National Institutes of Health [R01GM062887, 1F31AR057307-01] FX This work was supported by the American College of Rheumatology Research and the Education Foundation's Within Our Reach: Finding a Cure for Arthritis Campaign and U. S. National Institutes of Health Grants R01GM062887 and 1F31AR057307-01. NR 40 TC 42 Z9 43 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2010 VL 185 IS 4 BP 2570 EP 2579 DI 10.4049/jimmunol.1000644 PG 10 WC Immunology SC Immunology GA 635NH UT WOS:000280661900065 PM 20644167 ER PT J AU Asztalos, BF Mujawar, Z Morrow, MP Grant, A Pushkarsky, T Wanke, C Shannon, R Geyer, M Kirchhoff, F Sviridov, D Fitzgerald, ML Bukrinsky, M Mansfield, KG AF Asztalos, Bela F. Mujawar, Zahedi Morrow, Matthew P. Grant, Angela Pushkarsky, Tatiana Wanke, Christine Shannon, Richard Geyer, Matthias Kirchhoff, Frank Sviridov, Dmitri Fitzgerald, Michael L. Bukrinsky, Michael Mansfield, Keith G. TI Circulating Nef Induces Dyslipidemia in Simian Immunodeficiency Virus-Infected Macaques by Suppressing Cholesterol Efflux SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; CASSETTE TRANSPORTER A1; CELL-SURFACE EXPRESSION; DIETARY-FAT SATURATION; CD4 DOWN-REGULATION; HIV-INFECTION; HDL SUBPOPULATIONS; ANTIRETROVIRAL THERAPY; PROTEASE INHIBITORS; CARDIOVASCULAR RISK AB Human immunodeficiency virus (HIV) infection and subsequent antiretroviral therapy have been associated with an increased incidence of dyslipidemia and cardiovascular disease and has been shown to suppress cholesterol efflux from virus-infected macrophages by inducing Nef-dependent down-regulation of adenosine triphosphate-binding cassette transporter A1 (ABCA1). Here, the simian immunodeficiency virus (SIV)-infected macaque model was used to examine the consequences and mechanisms involved. SIV infection drove a significant remodeling of high-density lipoprotein profiles, suggesting that systemic inhibition of the ABCA1-dependent reverse cholesterol transport pathway occurred. The ABCA1 cholesterol transporter was significantly down-regulated in the livers of the SIV-infected macaques, and the viral protein Nef could be detected in the livers as well as in the plasma of infected animals. Extracellular myristoylated HIV Nef inhibited cholesterol efflux from macrophages and hepatocytes. Moreover, serum samples from SIV-infected macaques also suppressed cholesterol efflux in a Nef-dependent fashion. These results indicate that SIV infection is a significant contributor to primary dyslipidemia, likely through the ability of Nef to suppress ABCA1-dependent reverse cholesterol transport. C1 [Morrow, Matthew P.; Grant, Angela; Pushkarsky, Tatiana; Bukrinsky, Michael] George Washington Univ, Dept Microbiol & Trop Med, Washington, DC 20037 USA. [Shannon, Richard] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Geyer, Matthias] Max Planck Inst Mol Physiol, D-44139 Dortmund, Germany. [Kirchhoff, Frank] Univ Ulm, Inst Virol, Ulm, Germany. [Sviridov, Dmitri] Baker IDI Heart & Diabet Inst, Melbourne, Vic, Australia. [Asztalos, Bela F.] Tufts Univ, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Lipid Metab Lab, Boston, MA 02111 USA. [Wanke, Christine] Tufts Univ, Sch Med, Dept Publ Hlth & Family Med, Boston, MA 02111 USA. [Mujawar, Zahedi; Fitzgerald, Michael L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lipid Metab Unit,Ctr Computat & Integrat Biol, Boston, MA USA. [Mansfield, Keith G.] Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA. RP Bukrinsky, M (reprint author), George Washington Univ, Dept Microbiol & Trop Med, 2300 Eye St NW, Washington, DC 20037 USA. EM mtmmib@gwumc.edu; keith_mansfield@hms.harvard.edu RI Sviridov, Dmitri/E-7943-2010; Bukrinsky, Jens/D-7151-2013 OI Bukrinsky, Jens/0000-0002-4993-6366 FU American Heart Association; Deutsche Forschungsgemeinschaft; National Institutes of Health [RR00168, HL075836, DK55510, HL074136, HL093818]; National Health and Medical Research Council of Australia [526615, 317810]; US Department of Agriculture [53-3K06-5-10] FX Financial support: This work was supported by the American Heart Association (grant to M.B.), the Deutsche Forschungsgemeinschaft (grant to F.K.), the National Institutes of Health (grants RR00168, HL075836, and DK55510 to K.G.M. and R.S., grant HL074136 to M.L.F., and grant HL093818 to D.S. and M.B.), the National Health and Medical Research Council of Australia (grant 526615 to D.S. and M.B. and grant 317810 to D.S.), and the US Department of Agriculture (contract 53-3K06-5-10 to B.F.A.). Z.M. was supported by predoctoral and postdoctoral fellowships from the American Heart Association. NR 50 TC 28 Z9 28 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 AUG 15 PY 2010 VL 202 IS 4 BP 614 EP 623 DI 10.1086/654817 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 625HR UT WOS:000279886600014 PM 20617930 ER PT J AU Lin, TA Kwak, YH Sammy, F He, P Thundivalappil, S Sun, GJ Chao, W Warren, HS AF Lin, Tian Kwak, Young Ho Sammy, Fatima He, Ping Thundivalappil, Sujatha Sun, Guangjie Chao, Wei Warren, H. Shaw TI Synergistic Inflammation Is Induced by Blood Degradation Products with Microbial Toll-Like Receptor Agonists and Is Blocked by Hemopexin SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CROSS-LINKED HEMOGLOBIN; DENDRITIC CELLS; BACTERIAL-ENDOTOXIN; ESCHERICHIA-COLI; INNATE IMMUNITY; NITRIC-OXIDE; HEME; SEPSIS; TOLL-LIKE-RECEPTOR-4; LIPOPOLYSACCHARIDE AB Detection of microbial components by immune cells via Toll-like receptors (TLRs) with subsequent induction of inflammation is essential for host defense. However, an overactive immune response can cause tissue damage and sepsis. The endogenous molecule hemoglobin and its derivative heme are often released into tissue compartments where there is infection in the presence of degrading blood. We found that hemoglobin synergizes with multiple TLR agonists to induce high levels of tumor necrosis factor and interleukin-6 from macrophages and that this synergy is independent of TLR4 and MyD88. In contrast, heme synergized with some but not all TLR agonists studied. Furthermore, the synergy of both hemoglobin and heme with lipopolysaccharide was suppressed by hemopexin, a plasma heme-binding protein. These studies suggest that hemoglobin and heme may substantially contribute to microbe-induced inflammation when bacterial or viral infection coexists with blood degradation and that hemopexin may play a role in controlling inflammation in such settings. C1 [Lin, Tian; Kwak, Young Ho; Sammy, Fatima; He, Ping; Thundivalappil, Sujatha; Sun, Guangjie; Warren, H. Shaw] Massachusetts Gen Hosp, Infect Dis Unit, Boston, MA 02114 USA. [Chao, Wei] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Warren, HS (reprint author), Massachusetts Gen Hosp E, Infect Dis Unit, 149 13th St,5th Fl, Charlestown, MA 02129 USA. EM swarren1@partners.org RI Kwak, Young Ho/J-5373-2012; OI Kwak, Young Ho/0000-0003-2062-7575 FU National Institutes of Health [AI059010, GM59694]; Shriners Hospital for Crippled Children [8720] FX Financial support: National Institutes of Health (grants AI059010 and GM59694) and the Shriners Hospital for Crippled Children (grant 8720). NR 48 TC 40 Z9 42 U1 0 U2 3 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 AUG 15 PY 2010 VL 202 IS 4 BP 624 EP 632 DI 10.1086/654929 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 625HR UT WOS:000279886600015 PM 20617898 ER PT J AU Kozora, E West, SG Maier, SF Filley, CM Arciniegas, DB Brown, M Miller, D Grimm, A Zhang, LN AF Kozora, Elizabeth West, Sterling G. Maier, Steven F. Filley, Christopher M. Arciniegas, David B. Brown, Mark Miller, David Grimm, Alex Zhang, Lening TI Antibodies against N-methyl-D-aspartate receptors in patients with systemic lupus erythematosus without major neuropsychiatric syndromes SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE SLE; Neuropsychology; Auto-antibodies; NMDA ID COGNITIVE IMPAIRMENT; GLUTAMATE-RECEPTOR; CEREBROSPINAL-FLUID; NEUROPSYCHOLOGIC DYSFUNCTION; NMDA RECEPTORS; PREVALENCE; AUTOANTIBODIES; DISEASE; SERUM; MANIFESTATIONS AB Purpose: Approximately 14-54% of patients with systemic lupus erythematosus without a history of major neuropsychiatric syndromes (nonNPSLE) have cognitive deficits. Elevated N-methyl-D-aspartate (NMDA) receptor antibodies (anti-NR2) have been reported in 35% of patients with SLE, but few studies have utilized controls or a composite memory index. We hypothesized that serum anti-NR2 would be elevated in nonNPSLE compared to healthy controls, and that elevated anti-NR2 would be associated with memory dysfunction and depression. Methods: Subjects included 43 nonNPSLE patients with a mean age of 36.5 (SD = 9.0) and mean education level of 14.7 years (SD = 2.5). Twenty-seven healthy control subjects with similar demographic characteristics were also enrolled in this study. A global Cognitive Impairment Index (CII) and a Memory Impairment Index (MII) were calculated using impaired test scores from the ACR-SLE neuropsychological battery. Serum samples were analyzed using a standard ELISA for anti-NR2. Results: Elevations of serum anti-NR2 were found in 14.0% of the nonNPSLE and 7.4% of the controls (p = 0.47). There was no relationship between elevated anti-NR2 status and higher CII or performance on the MII. No relationship between levels of depressive symptoms and anti-NR2 was found. Conclusions: The frequency of elevated anti-NR2 was low (14.0%) in this sample of SLE patients and not significantly different from controls. A relationship was not found between the presence of anti-NR2 in serum and global cognitive or memory indices, or with depression. Results suggest that serum anti-NR2 is not likely related to mild cognitive dysfunction in SLE patients without a prior history of NPSLE. (C) 2010 Elsevier B.V. All rights reserved. C1 [Kozora, Elizabeth] Natl Jewish Hlth, ABPP CN, Denver, CO 80206 USA. [Kozora, Elizabeth; West, Sterling G.; Filley, Christopher M.; Arciniegas, David B.; Brown, Mark; Miller, David; Grimm, Alex; Zhang, Lening] Univ Colorado Hosp, Aurora, CO USA. [Maier, Steven F.] Univ Colorado, Boulder, CO 80309 USA. [Filley, Christopher M.] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Kozora, E (reprint author), Natl Jewish Hlth, ABPP CN, 1400 Jackson St,B106, Denver, CO 80206 USA. EM Kozorae@njhealth.org FU National Institute of Musculoskeletal and Skin Diseases [RO1 AR049152-02]; National Center for Research Resources [UL1 RR025780] FX This study was supported by the National Institute of Musculoskeletal and Skin Diseases (grant RO1 AR049152-02) and supported in part by grants from the Clinical Translational Scientific Award from the National Center for Research Resources (UL1 RR025780). NR 48 TC 23 Z9 25 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD AUG 15 PY 2010 VL 295 IS 1-2 BP 87 EP 91 DI 10.1016/j.jns.2010.04.016 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 628LA UT WOS:000280120000017 PM 20546792 ER PT J AU Gardener, H Gao, XA Chen, HL Schwarzschild, MA Spiegelman, D Ascherio, A AF Gardener, Hannah Gao, Xiang Chen, Honglei Schwarzschild, Michael A. Spiegelman, Donna Ascherio, Alberto TI Prenatal and Early Life Factors and Risk of Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE birth weight; epidemiology; functional laterality; maternal exposure; Parkinson's disease ID HAND PREFERENCE; LEFT-HANDEDNESS; MATERNAL AGE; BIRTH-WEIGHT; DIGIT RATIO; WOMEN; CHILDREN; PERFORMANCE; ORIGINS; DIETHYLSTILBESTROL AB Few studies have investigated the relation between early life factors and risk of Parkinson's disease (PD), although a potential role of exposures during pregnancy and childhood has been hypothesized. The study population comprised participants in two prospective cohorts: the Nurses' Health Study (121,701 female nurses followed up from 1976-2002) and the Health Professionals Follow-up Study (51,529 male health professionals followed up from 1986-2002). PD risk was examined in relation to season of birth, birthweight, parental age at birth, preterm birth, multiple birth, ever having been breast-fed, and handedness. We identified 659 incident PD cases. No significant relation with PD was observed for birthweight, paternal age, preterm birth, multiple birth, and having been breast-fed. A modest nonsignificant association was suggested for season of birth (30% higher risk of PD associated with spring versus winter birth) and for older maternal age at birth (75% increased risk among those with mothers aged 30 years and older versus younger than 20 years). Left-handedness was associated with a 62% increased risk of PD in women but not in men. Further investigation of the relation between prenatal, perinatal, or neonatal factors and PD in other study populations is suggested. (C) 2010 Movement Disorder Society C1 [Gardener, Hannah; Spiegelman, Donna; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Chen, Honglei] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Spiegelman, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. [Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Gardener, H (reprint author), Univ Miami, Dept Neurol, Miller Sch Med, POB 016960 M-877, Miami, FL 33101 USA. EM hgardener@med.miami.edu OI Chen, Honglei/0000-0003-3446-7779 FU National Research Service [T32 MH17119]; NIH/NINDS; NIH; Department of Defense; American Parkinson Disease Association; Parkinson's Disease Foundation; Health Resources and Services Administration; NIH/NCI; NIH/NIEHS; National Multiple Sclerosis Society FX We thank Dr. Steve Buka and Dr. Janet Rich-Edwards for their help and guidance in reviewing the results and manuscript. We also thank Alvin Wing and Ellis O'Reilly for reviewing the statistical programs. This work was supported by a National Research Service Award grant from the Training Program in Psychiatric Epidemiology and Biostatistics (T32 MH17119).; Dr. Gardener: support from the NIH/NINDS. Dr. Gao: serves on the Monitoring Committee of the Parkinson Study Group and support from NIH/NINDS. Dr. Chen: support from the Intramural research program of the NIH. Dr. Schwarzschild: support from the NIH/NINDS and the Department of Defense and the American Parkinson Disease Association, Parkinson's Disease Foundation, and the Michael J Fox Foundation. Dr. Spiegelman: support from Health Resources and Services Administration, NIH/NCI, and NIH/NIEHS. Dr. Ascherio: personal compensation for speaking activities from Merck-Serono and research funding from the the Department of Defense, Autism Speaks, the National Multiple Sclerosis Society, and the Michael J. Fox Foundation. NR 50 TC 13 Z9 14 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2010 VL 25 IS 11 BP 1560 EP 1567 DI 10.1002/mds.23339 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 644BW UT WOS:000281346400005 PM 20740569 ER PT J AU Rao, HY Mamikonyan, E Detre, JA Siderowf, AD Stern, MB Potenza, MN Weintraub, D AF Rao, Hengyi Mamikonyan, Eugenia Detre, John A. Siderowf, Andrew D. Stern, Matthew B. Potenza, Marc N. Weintraub, Daniel TI Decreased Ventral Striatal Activity with Impulse Control Disorders in Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE functional magnetic resonance imaging; Parkinson's disease; impulse control disorder ID RISK-TASK BART; DOPAMINE AGONIST USE; DECISION-MAKING; PATHOLOGICAL GAMBLERS; COGNITIVE IMPAIRMENT; COMPULSIVE BEHAVIORS; REWARD; BRAIN; FMRI; NEUROBIOLOGY AB A range of impulse control disorders (ICDs) are reported to occur in Parkinson's disease (PD). However, alterations in brain activity at rest and during risk taking occurring with ICDs in PD are not well understood. We used both arterial spin labeling perfusion functional magnetic resonance imaging (fMRI) to directly quantify resting cerebral blood flow (CBF) and blood oxygenation level dependent (BOLD) fMRI to measure neural responses to risk taking during performance on the Balloon Analogue Risk Task (BART). Eighteen PD patients, either with a diagnosis of one or more ICDs (N = 9) or no lifetime ICD history (N = 9), participated. BOLD fMRI data demonstrated that PD patients without an ICD activate the mesocorticolimbic pathway during risk taking. Compared with non-ICD patients. ICD patients demonstrated significantly diminished BOLD activity in the right ventral striatum during risk taking and significantly reduced resting CBF in the right ventral striatum. ICDs in PD are associated with reduced right ventral striatal activity at rest and diminished striatal activation during risk taking, suggesting that a common neural mechanism may underlie ICDs in individuals with PD and those without PD. Thus, treatments for ICDs in non-PD patients warrant consideration in PD patients with ICDs. (C) 2010 Movement Disorder Society C1 [Rao, Hengyi; Detre, John A.; Siderowf, Andrew D.; Stern, Matthew B.; Weintraub, Daniel] Univ Penn, Ctr Funct Neuroimaging, Dept Neurol & Radiol, Philadelphia, PA 19104 USA. [Rao, Hengyi; Mamikonyan, Eugenia; Weintraub, Daniel] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Rao, Hengyi] S China Normal Univ, Ctr Funct Brain Imaging, Guangzhou, Guangdong, Peoples R China. [Rao, Hengyi] S China Normal Univ, Ctr Studies Psychol Applicat, Guangzhou, Guangdong, Peoples R China. [Stern, Matthew B.; Weintraub, Daniel] Philadelphia VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA USA. [Stern, Matthew B.; Weintraub, Daniel] Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. [Potenza, Marc N.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Potenza, Marc N.] Yale Univ, Ctr Child Study, Sch Med, New Haven, CT 06520 USA. RP Weintraub, D (reprint author), 3615 Chestnut St,330, Philadelphia, PA 19104 USA. EM daniel.weintraub@uphs.upenn.edu RI Rao, Hengyi/A-7064-2009 OI Rao, Hengyi/0000-0003-2735-2500 FU Center for Functional Neuroimaging at the University of Pennsylvania; NSF [BCS-0224007]; NTH [P30 NS045839, K23 MH067894, R01 DA019039, R01 AA017539] FX This research was supported by a Project Development (ProDev) Grant from the Center for Functional Neuroimaging at the University of Pennsylvania, the NSF grant BCS-0224007, the NTH Grants P30 NS045839, K23 MH067894, R01 DA019039, and R01 AA017539, VA VISNI MIRECC, Sun Yat-Sen University 985 Project, and a Center of Excellence in Gambling Research grant from the National Center for Responsible Gaming and its affiliated Institute for Research on Gambling Disorders. The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of any of the funding agencies. NR 53 TC 60 Z9 62 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2010 VL 25 IS 11 BP 1660 EP 1669 DI 10.1002/mds.23147 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 644BW UT WOS:000281346400019 PM 20589879 ER PT J AU Kaplan, E Naeser, MA Martin, PI Ho, M Wang, YY Baker, E Pascual-Leone, A AF Kaplan, Elina Naeser, Margaret A. Martin, Paula I. Ho, Michael Wang, Yunyan Baker, Errol Pascual-Leone, Alvaro TI Horizontal portion of arcuate fasciculus fibers track to pars opercularis, not pars triangularis, in right and left hemispheres: A DTI study SO NEUROIMAGE LA English DT Article DE Aphasia; Arcuate fasciculus; Broca's area; Pars triangularis; Pars opercularis; Diffusion tensor imaging; Ventral premotor cortex ID INFERIOR PREFRONTAL CORTEX; PROBABILISTIC DIFFUSION TRACTOGRAPHY; TRANSCRANIAL MAGNETIC STIMULATION; ANISOTROPIC WATER DIFFUSION; HUMAN BRAIN; BROCAS AREA; LANGUAGE PATHWAYS; SPEECH PRODUCTION; CORTICAL ORGANIZATION; APHASIA PATIENT AB The arcuate fasciculus (AF) is a white matter pathway traditionally considered to connect left Broca's area with posterior language zones. We utilized diffusion tensor imaging (DTI) in eight healthy subjects (5 M) to track pathways in the horizontal mid-portion of the AF (hAF) to subregions of Broca's area - pars triangularis (PTr) and pars opercularis (POp); and to ventral premotor cortex (vPMC) in the right and left hemispheres (RH, LH). These pathways have previously been studied in the LH, but not in the RH. Only 1/8 subjects showed fiber tracts between PTr and hAF in the RH (also, only 1/8 in the LH). In contrast to PTr, 5/8 subjects showed fiber tracts between POp and hAF in the RH (8/8 in the LH). Fiber tracts for vPMC were similar to those of POp, where 7/8 subjects showed fiber tracts between vPMC and hAF in the RH (8/8 in the LH). Our designated hAF could have included some of the superior longitudinal fasciculus (SLF) III, because it is difficult to separate the two fiber bundles. The SLF III has been previously reported to connect supramarginal gyrus with POp and vPMC in the LH. Thus, although the present DTI study showed almost no pathways between PTr and hAF in the RH (and in the LH), robust pathways were observed between POp and/or vPMC with hAF in the RH (and in LH). These results replicate previous studies for the LH, but are new, for the RH. They could contribute to better understanding of recovery in aphasia. Published by Elsevier Inc. C1 [Kaplan, Elina; Naeser, Margaret A.; Martin, Paula I.; Ho, Michael; Wang, Yunyan; Baker, Errol] Boston Univ, Sch Med, Dept Neurol, Harold Goodglass Boston Univ Aphasia Res Ctr, Boston, MA 02215 USA. [Pascual-Leone, Alvaro] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Cambridge, MA 02138 USA. [Pascual-Leone, Alvaro] Inst Univ Neurorehabil Guttmann UAB, Badalona 08916, Spain. RP Naeser, MA (reprint author), VA Boston Healthcare Syst, Aphasia Res Ctr 12 A, JP, 150 So Huntington Ave, Boston, MA 02130 USA. EM mnaeser@bu.edu FU Medical Research Service, Department of Veterans Affairs, Washington, D.C.; National Institute on Deafness and Other Communication Disorders (NIDCD), Bethesda, MD [RO1 DC05672]; NIH; Harvard-Thorndike General Clinical Research Center [NCRR MO1 RR01032]; NIDCD [P30 DC05207] FX This work was supported by a grant from the Medical Research Service, Department of Veterans Affairs, Washington, D.C. (to M.A.N.); and NIH grant RO1 DC05672 from the National Institute on Deafness and Other Communication Disorders (NIDCD), Bethesda, MD, (to M.A.N.); and a K24 NIH award (RRO18875, to A.P.-L) and the Harvard-Thorndike General Clinical Research Center (NCRR MO1 RR01032); and a P30 DC05207 NIDCD grant to the Harold Goodglass BU Aphasia Research Center. NR 74 TC 30 Z9 33 U1 3 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 AUG 15 PY 2010 VL 52 IS 2 BP 436 EP 444 DI 10.1016/j.neuroimage.2010.04.247 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 615TK UT WOS:000279160200004 PM 20438853 ER PT J AU Bailey, JN Goenjian, AK Noble, EP Walling, DP Ritchie, T Goenjian, HA AF Bailey, Julia N. Goenjian, Armen K. Noble, Ernest P. Walling, David P. Ritchie, Terry Goenjian, Haig A. TI PTSD and dopaminergic genes, DRD2 and DAT, in multigenerational families exposed to the Spitak earthquake SO PSYCHIATRY RESEARCH LA English DT Article DE Heritability; DRD2; DAT; PTSD; B category symptoms ID POSTTRAUMATIC-STRESS-DISORDER; TRAIT LINKAGE ANALYSIS; DEPRESSIVE REACTIONS; ALLELIC ASSOCIATION; RECEPTOR GENE; TRAUMA EXPOSURE; TWIN; ADOLESCENTS; SYMPTOMS; POLYMORPHISM AB The objective of this study was to assess the generality of the association of DRD2 and DAT genes and Post-Traumatic Stress Disorder (PTSD) diagnosis/symptom severity. Two hundred ethnic Armenians from 12 multigenerational families exposed to the catastrophic 1988 Spitak earthquake were studied. Common polymorphisms A1/A2 alleles of the DRD2 and '9' repeat allele of DAT gene were genotyped. Heritability, association and linkage were assessed using variance component genetic analyses. After adjusting for the covariates, the heritabilities of PTSD diagnosis and B and C category symptoms were: 0.37, 0.75 and 0.39 respectively. Category D symptoms were not heritable. Neither the DRD2 nor the DAT polymorphisms explained the variation seen in PTSD diagnosis, total PTSD symptom severity, and categories B and C symptom severities. These findings contradict prior reports of positive associations between both DRD2 and DAT, and PTSD. Published by Elsevier Ireland Ltd. C1 [Bailey, Julia N.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Epidemiol, Los Angeles, CA 90095 USA. [Goenjian, Armen K.; Noble, Ernest P.; Ritchie, Terry] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90095 USA. [Bailey, Julia N.] VA GLAHS Epilepsy Ctr Excellence, Epilepsy Genet Genom Labs, Comprehens Epilepsy Program, Los Angeles, CA USA. [Goenjian, Armen K.; Walling, David P.; Goenjian, Haig A.] Collaborat Neurosci Network, Garden Grove, CA USA. RP Bailey, JN (reprint author), VA GLAHSWest Los Angeles, Comprehens Epilepsy Program, Epilepsy Genet Genom Labs, W Los Angeles VA Med Ctr, Room 3405 127B,Bldg 500,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jbailey@mednet.ucla.edu NR 29 TC 21 Z9 24 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 15 PY 2010 VL 178 IS 3 BP 507 EP 510 DI 10.1016/j.psychres.2010.04.043 PG 4 WC Psychiatry SC Psychiatry GA 642CQ UT WOS:000281181400010 PM 20554017 ER PT J AU Thomas, JJ Delinsky, SS St Germain, SA Weigel, TJ Tangren, CM Levendusky, PG Becker, AE AF Thomas, Jennifer J. Delinsky, Sherrie S. St Germain, Sarah A. Weigel, Thomas J. Tangren, Christopher M. Levendusky, Philip G. Becker, Anne E. TI How do eating disorder specialist clinicians apply DSM-IV diagnostic criteria in routine clinical practice? Implications for enhancing clinical utility in DSM-5 SO PSYCHIATRY RESEARCH LA English DT Article DE Diagnostic reliability; Structured interview; Subtype; Anorexia nervosa; Bulimia nervosa; Eating disorder not otherwise specified; Amenorrhea ID ANOREXIA-NERVOSA; BULIMIA-NERVOSA; ADOLESCENTS; RECOVERY; VALIDITY; PREDICTORS; AGREEMENT; SYMPTOMS AB The clinical utility of the DSM-IV eating disorder (ED) diagnostic criteria among practicing clinicians has not been formally evaluated, despite the considerable diagnostic challenges these disorders present. This study evaluated inter-rater reliability between research and clinical diagnoses, identified discrepantly rated diagnostic criteria, and evaluated ED subtype use in a naturalistic treatment setting. Seventy-six adolescent and young adult female patients consecutively admitted to a residential ED program were evaluated independently by clinicians (unstructured clinical interview) and research assessors (Structured Clinical Interview for DSM-IV). Clinicians and research assessors conferred concordant ED diagnoses in 80.3% of cases (kappa=0.70), thus highlighting the clinical utility of the extant DSM-IV diagnostic scheme in this specialty ED treatment setting. All but two discordant cases included a diagnosis of ED not otherwise specified (EDNOS). Clinicians applied ED subtypes in just 20.4% of eligible cases, and were significantly more likely to apply subtypes to major depressive disorder. Although clinical and research interviews yielded substantial reliability, EDNOS had the lowest reliability among the ED diagnoses. Moreover, infrequent subtype application on this specialty unit raises questions about the clinical utility of DSM-IV anorexia nervosa and bulimia nervosa subtypes, even in the context of clinically useful overarching categories. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Thomas, Jennifer J.; Tangren, Christopher M.; Becker, Anne E.] Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Thomas, Jennifer J.; Delinsky, Sherrie S.; St Germain, Sarah A.; Weigel, Thomas J.; Levendusky, Philip G.] McLean Hosp, Klarman Eating Disorders Ctr, Belmont, MA 02178 USA. [Thomas, Jennifer J.; Delinsky, Sherrie S.; Weigel, Thomas J.; Tangren, Christopher M.; Levendusky, Philip G.; Becker, Anne E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [St Germain, Sarah A.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Becker, Anne E.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. RP Thomas, JJ (reprint author), Massachusetts Gen Hosp, Eating Disorders Clin & Res Program, WAC 816D,15 Parkman St, Boston, MA 02114 USA. EM jjthomas@partners.org FU Klarman Family Foundation; Harvard Medical School FX The investigators would like to thank the Klarman Family Foundation, Mr. and Mrs. Samuel Martini, and Harvard Medical School's Livingston Fellowship for funding this research. NR 32 TC 10 Z9 10 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 15 PY 2010 VL 178 IS 3 BP 511 EP 517 DI 10.1016/j.psychres.2010.05.021 PG 7 WC Psychiatry SC Psychiatry GA 642CQ UT WOS:000281181400011 PM 20591498 ER PT J AU Yang, C Hornicek, FJ Wood, KB Schwab, JH Choy, E Mankin, H Duan, ZF AF Yang, Cao Hornicek, Francis J. Wood, Kirkham B. Schwab, Joseph H. Choy, Edwin Mankin, Henry Duan, Zhenfeng TI Blockage of Stat3 With CDDO-Me Inhibits Tumor Cell Growth in Chordoma SO SPINE LA English DT Article DE chordoma; Src; Stat3; CDDO-Me; chemotherapy ID SIGNALING INDUCES APOPTOSIS; RESISTANT OVARIAN-CANCER; TERM-FOLLOW-UP; CONSTITUTIVE ACTIVATION; CARCINOMA CELLS; FACTOR RECEPTOR; CONFERS RESISTANCE; TYROSINE KINASES; METHYL-ESTER; MOBILE SPINE AB Study Design. An experimental study to investigate the activation of Src/Stat3 pathways in chordomas and blockage of this pathway as a potential strategy for chordoma treatment. Objective. To investigate the activation of Src/Stat3 pathway in chordomas cells and to determine the efficiency of inhibiting this pathway by 2-cyano-3,12-dioxooleana- 1,9 (11)-dien-28-oic acid-methyl ester (CDDO-Me) as a potential chemotherapeutic agent for chordoma treatment. Summary of Background Data. The advent of molecularly targeted therapies has raised interest for their use in the treatment of chordomas. Unfortunately, the current understanding of molecular markers in chordomas is limited. Constitutive activation of Stat3 is a common finding in a wide spectrum of human cancers. The function of Stat3 pathway in chordomas has not been elucidated. Methods. The expression of key components of the Src/Stat3 signaling cascade was evaluated by Western blot in chordoma tissues and chordoma cell lines. The effects of CDDO-Me on chordoma cell growth were evaluated in these chordoma cell lines by MTT assay. The expression of key components of the Src/Stat3 signaling cascade and poly (ADP-ribose) polymerase cleavage in these CDDO-Me treated cells were analyzed by Western blot and immunofluorescence. Furthermore, the synergistic effect of CDDO-Me on cisplatin and doxorubicin-induced cytotoxicity was evaluated by MTT. Finally, chordoma cells were grown in a 3-dimensional (3D) culture and treated with CDDO-Me. Results. The key components of the Src/Stat3 signaling cascade, including Stat3, pStat3, Src, pSrc, Bcl-xL, and Myeloid Cell Leukemia-1, were all highly expressed in chordomas. Expression of the key components of the Src/Stat3 signaling cascade was inhibited in chordoma cells after treatment with CDDO-Me. The growth of chordoma cells was inhibited and apoptosis associated poly (ADP-ribose) polymerase cleavage was detected after treatment with CDDO-Me. Additionally, CDDO-Me has a synergistic effect on cisplatin or doxorubicin-induced chordoma cell death (P < 0.001). Finally, expression of pSrc and pStat3 and chordoma cell growth was inhibited by treatment of CDDO-Me using 3D culture. Conclusion. The Src/Stat3 signaling pathway was activated in chordomas. Blockage of Src/Stat3 pathway by CDDO-Me is a potential strategy for chordoma treatment and may be focus for future research. C1 [Yang, Cao; Hornicek, Francis J.; Wood, Kirkham B.; Schwab, Joseph H.; Mankin, Henry; Duan, Zhenfeng] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Yang, Cao; Hornicek, Francis J.; Schwab, Joseph H.; Choy, Edwin; Mankin, Henry; Duan, Zhenfeng] Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Yang, Cao; Hornicek, Francis J.; Schwab, Joseph H.; Choy, Edwin; Mankin, Henry; Duan, Zhenfeng] Harvard Univ, Sch Med, Boston, MA USA. [Yang, Cao] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Orthopaed Surg, Wuhan 430074, Peoples R China. [Choy, Edwin] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, 70 Blosson St,GRJ 1115, Boston, MA 02114 USA. EM zduan@partners.org OI Choy, Edwin/0000-0001-9896-8084 FU Stephan L. Harris Fund; Sarcoma Foundation of America; National Cancer Institute; NIH [R01-CA119617]; Gattegno and Wechsler funds FX Supported by the Stephan L. Harris Fund, Sarcoma Foundation of America (to Z. D.), National Cancer Institute, NIH (Nanotechnology Platform Partnership), R01-CA119617 (to Z. D.), and Gattegno and Wechsler funds. NR 49 TC 17 Z9 20 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD AUG 15 PY 2010 VL 35 IS 18 BP 1668 EP 1675 DI 10.1097/BRS.0b013e3181c2d2b4 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 643EF UT WOS:000281277700002 PM 20386502 ER PT J AU Clegg, LX Hankey, BF Tiwari, R Feuer, EJ Edwards, BK AF Clegg, Limin X. Hankey, Benjamin F. Tiwari, Ram Feuer, Eric J. Edwards, Brenda K. TI Comment on 'Estimating average annual per cent change in trend analysis' Reply SO STATISTICS IN MEDICINE LA English DT Letter C1 [Clegg, Limin X.] US Dept Vet Affairs, Washington, DC 20001 USA. [Tiwari, Ram] US FDA, Silver Spring, MD 20993 USA. [Feuer, Eric J.; Edwards, Brenda K.] NCI, Bethesda, MD 20892 USA. RP Clegg, LX (reprint author), US Dept Vet Affairs, 801 1 St NW,Room 1018, Washington, DC 20001 USA. EM ram.tiwari@fda.hhs.gov; edwardsb@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 15 PY 2010 VL 29 IS 18 BP 1961 EP 1961 DI 10.1002/sim.3983 PG 1 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 640XR UT WOS:000281088000010 ER PT J AU Cannon, CP AF Cannon, Christopher P. TI Online Cardiology's move online-and onto my iPad SO LANCET LA English DT Editorial Material C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp,Cardiovasc Div, Boston, MA 02115 USA. RP Cannon, CP (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, TIMI Study Grp,Cardiovasc Div, Boston, MA 02115 USA. EM cpcannon@partners.org NR 0 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 0140-6736 J9 LANCET JI Lancet PD AUG 14 PY 2010 VL 376 IS 9740 BP 505 EP 506 DI 10.1016/S0140-6736(10)61238-X PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 643BE UT WOS:000281266800014 ER PT J AU Lee, PT Henderson, M Patel, V AF Lee, Patrick T. Henderson, Michael Patel, Vikram TI A UN summit on global mental health SO LANCET LA English DT Letter C1 [Lee, Patrick T.] Massachusetts Gen Hosp, Boston, MA 02130 USA. [Lee, Patrick T.] Harvard Univ, Sch Med, Boston, MA 02130 USA. [Henderson, Michael] Harvard Univ, Boston, MA USA. [Patel, Vikram] London Sch Hyg & Trop Med, Ctr Global Mental Hlth, London WC1, England. RP Lee, PT (reprint author), Massachusetts Gen Hosp, Boston, MA 02130 USA. EM drpatricktlee@gmail.com NR 5 TC 11 Z9 11 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 AUG 14 PY 2010 VL 376 IS 9740 BP 516 EP 516 DI 10.1016/S0140-6736(10)61254-8 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 643BE UT WOS:000281266800029 PM 20709232 ER PT J AU Topol, EJ Bousser, MG Fox, KAA Creager, MA Despres, JP Easton, JD Hamm, CW Montalescot, G Steg, PG Pearson, TA Cohen, E Gaudin, C Job, B Murphy, JH Bhatt, DL AF Topol, Eric J. Bousser, Marie-Germaine Fox, Keith A. A. Creager, Mark A. Despres, Jean-Pierre Easton, J. Donald Hamm, Christian W. Montalescot, Gilles Steg, P. Gabriel Pearson, Thomas A. Cohen, Eric Gaudin, Christophe Job, Bernard Murphy, Judith H. Bhatt, Deepak L. CA CRESCENDO Investigators TI Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial SO LANCET LA English DT Article ID CANNABINOID-1 RECEPTOR BLOCKER; RISK-FACTORS; OVERWEIGHT PATIENTS; ASSOCIATION; CLOPIDOGREL; VARIANTS; OBESITY; DISEASE; WEIGHT AB Background Blockade of the endocannabinoid receptor reduces obesity and improves metabolic abnormalities such as triglycerides, HDL cholesterol, and fasting blood glucose. We assessed whether rimonabant would improve major vascular event-free survival. Methods This double-blind, placebo-controlled trial was undertaken in 974 hospitals in 42 countries. 18 695 patients with previously manifest or increased risk of vascular disease were randomly assigned to receive either rimonabant 20 mg (n=9381) or matching placebo (n=9314). Randomisation was stratified by centre, implemented with an independent interactive voice response system, and all study personnel and participants were masked to group assignment. The primary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke, as determined via central adjudication. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00263042. Findings At a mean follow-up of 13.8, months (95% CI 13.6-14.0), the trial was prematurely discontinued because of concerns by health regulatory authorities in three countries about suicide in individuals receiving rimonabant. All randomised participants were analysed. At the close of the trial (Nov 6, 2008), the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 364 (3.9%) patients assigned to rimonabant and 375 (4.0%) assigned to placebo (hazard ratio 0.97, 95% CI 0.84-1.12, p=0.68). With rimonabant, gastrointestinal (3038 [33%] vs 2084 [22%]), neuropsychiatric (3028 [32%] vs 1989 [21%]), and serious psychiatric side-effects (232 [2.5%] vs 120 [1.3%]) were significantly increased compared with placebo. Four patients in the rimonabant group and one in the placebo group committed suicide. Interpretation The premature termination of this trial has important lessons for drug development. A drug that was being marketed for weight loss, but being tested for improving cardiovascular outcomes, induced a level of serious neuropsychiatric effects that was deemed unacceptable by regulatory authorities, and both the drug and the trial were abruptly terminated. C1 [Topol, Eric J.] Scripps Translat Sci Inst, La Jolla, CA 92037 USA. [Bousser, Marie-Germaine] Hop Lariboisiere, F-75475 Paris, France. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Creager, Mark A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Creager, Mark A.] Harvard Univ, Boston, MA 02115 USA. [Despres, Jean-Pierre] Inst Univ Cardiol & Pneumol Quebec, Ctr Rech, Quebec City, PQ, Canada. [Easton, J. Donald] Rhode Isl Hosp, Providence, RI USA. [Easton, J. Donald] Brown Univ, Providence, RI 02912 USA. [Hamm, Christian W.] Max Planck Inst Physiol & Clin Res, Kerckhoff Klin, D-6350 Bad Nauheim, Germany. [Montalescot, Gilles] CHU Pitie Salpetriere, Paris, France. [Steg, P. Gabriel] Univ Paris 07, INSERM, U698, Paris, France. [Steg, P. Gabriel] Hop Bichat Claude Bernard, AP HP, F-75877 Paris, France. [Pearson, Thomas A.] Univ Rochester, Rochester, NY USA. [Cohen, Eric] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Gaudin, Christophe; Job, Bernard; Murphy, Judith H.] Sanofi Aventis, Paris, France. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. RP Topol, EJ (reprint author), Scripps Translat Sci Inst, 3344 N Torrey Pines Court, La Jolla, CA 92037 USA. EM etopol@scripps.edu RI Zateyshchikov, Dmitry/D-6575-2012; Chen, Christopher/E-7023-2013; Urina, Miguel/H-2605-2016; Chazova, Irina/B-8688-2017 OI viana baptista, miguel/0000-0001-6166-2073; Zateyshchikov, Dmitry/0000-0001-7065-2045; Urina, Miguel/0000-0001-6003-4622; Chazova, Irina/0000-0002-9822-4357 FU Sanofi-Aventis; Servier; AstraZeneca; Boehringer-Ingelheim; Bristol-Myers Squibb; GlaxoSmithKline; Menarini; Medtronic; Nycomed; Pierre Fabre; Medicines Company; Astellas; Bayer; Daiichi-Sankyo; MSD; Otsuka; Eisai; Ethicon; Heartscape; Eli Lilly Canada; Torrent Pharmaceuticals; Teratechnologies; Abbott Laboratories; Merck; Pfizer; Solvay Pharma; Novartis; Guerbet Medical; Boston Scientific; Cordis; Sago; Centocor; Fondation de France; INSERM; Federation Francaise de Cardiologie; Societe Francaise de Cardiologie; ITC Edison; Schering-Plough; Portola; Merck Sharpe St Dohme; Accumetrics; Scripps Translational Science institute [NIH UL1 RR025774] FX All authors disclose relationships with the sponsor of the study, Sanofi-Aventis, such that all authors have received research finding support and either consulting or honoraria fees with the exception of CG, BJ, and JHM who are employees of Sanofi-Aventis. PGS reports receiving research grants from Sanofi-Avenfis and Servier, speaking fees for AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Menarini, Medtronic, Nycomed, Pierre Fabre, Sanofi-Aventis, Service and The Medicines Company; consulting fees from Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Medtronic, MSD, Otsuka, Sanofi-Aventis, Servier, and The Medicines Company; and being a stockholder with Aterovax. DLB specifically reports receiving research grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and The Medicines Company. J-PD reports receiving research funding from Eli Lilly Canada and Sanofi-Aventis; consulting fees from Torrent Pharmaceuticals and Teratechnologies; and speaker fees from Abbott Laboratories, AstraZereca, Merck, Pfizer, Solvay Pharma, GlaxoSmithKline, and Novartis. GM reports receiving research grants from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Sago, Centocor, Fondation de France, INSERM, Federation Francaise de Cardiologie, Societe Francaise de Cardiologie. ITC Edison, and Pfizer; consulting fees from Sanofi-Aventis, Eli Lilly, Bristol-Myers Squibb, The Medicines Company, Schering-Plough, Portola, Novartis, Menarini, Eisai, Daiichi, Bayer, and Boehringer Ingelheim; and lecture fees from Sanofi-Aventis, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe St Dohme, Cordis, GlaxoSinithKline, Schering-Plough, Accumetrics, AstraZeneca, Daiichi, and Menarini. TAP reports receiving speaking fees for Bayer and consulting fees for Bayer and Sanofi-Aventis. MG reports receiving grants from Sanofi-Aventis and Service CH reports receiving speaking and advisory fees from Sanofi-Aventis. Bristol-Myers Squibb, AstraZeneca, The Medicines Company, GlaxoSmithKline, Daiichi-Sankyo, Irak, and MSD.; This trial was funded by Sanofi-Aventis. EJT is supported in part by the Scripps Translational Science institute Clinical Translational Science Award (NIH UL1 RR025774). The authors thank all the patients who participated in the CRESCENDO trial and the study site research coordinators. NR 15 TC 97 Z9 98 U1 2 U2 27 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 AUG 14 PY 2010 VL 376 IS 9740 BP 517 EP 523 DI 10.1016/S0140-6736(10)60935-X PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 643BE UT WOS:000281266800030 PM 20709233 ER PT J AU Kaufman, L Potla, U Coleman, S Dikiy, S Hata, Y Kurihara, H He, JC D'Agati, VD Klotman, PE AF Kaufman, Lewis Potla, Uma Coleman, Sarah Dikiy, Stanislav Hata, Yutaka Kurihara, Hidetake He, John C. D'Agati, Vivette D. Klotman, Paul E. TI Up-regulation of the Homophilic Adhesion Molecule Sidekick-1 in Podocytes Contributes to Glomerulosclerosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; HIV-ASSOCIATED NEPHROPATHY; GLOMERULAR SLIT DIAPHRAGM; TIGHT JUNCTION PROTEIN; CELL-ADHESION; NEPHROTIC SYNDROME; GUANYLATE KINASE; RENAL-DISEASE; MAGI-1; MICE AB Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease worldwide. Although the mechanisms underlying this important disease are poorly understood, the glomerular podocyte clearly plays a central role in disease pathogenesis. In the current work, we demonstrate that the homophilic adhesion molecule sidekick-1 (sdk-1) is up-regulated in podocytes in FSGS both in rodent models and in human kidney biopsy samples. Transgenic mice that have podocyte-specific overexpression of sdk-1 develop gradually progressive heavy proteinuria and severe FSGS. We also show that sdk-1 associates with the slit diaphragm linker protein MAGI-1, which is already known to interact with several critical podocyte proteins including synaptopodin, alpha-actinin-4, nephrin, JAM4, and beta-catenin. This interaction is mediated through a direct interaction between the carboxyl terminus of sdk-1 and specific PDZ domains of MAGI-1. In vitro expression of sdk-1 enables a dramatic recruitment of MAGI-1 to the cell membrane. Furthermore, a truncated version of sdk-1 that is unable to bind to MAGI-1 does not induce podocyte dysfunction when overexpressed. We conclude that the up-regulation of sdk-1 in podocytes is an important pathogenic factor in FSGS and that the mechanism involves disruption of the actin cytoskeleton possibly via alterations in MAGI-1 function. C1 [Kaufman, Lewis; Klotman, Paul E.] Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA. [Kaufman, Lewis; He, John C.] James J Peters Vet Affairs Med Ctr, Div Nephrol, Bronx, NY 10468 USA. [Hata, Yutaka] Tokyo Med & Dent Univ, Grad Sch Med, Dept Med Biochem, Tokyo 1138519, Japan. [Kurihara, Hidetake] Juntendo Univ, Sch Med, Dept Anat, Tokyo 1138421, Japan. [D'Agati, Vivette D.] Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. RP Kaufman, L (reprint author), Mt Sinai Sch Med, Div Nephrol, 1 Gustave L Levy Pl,Box 1243, New York, NY 10029 USA. EM lewis.kaufman@mssm.edu OI Dikiy, Stanislav/0000-0002-8287-6561 FU National Institutes of Health [K08 DK070530, R01 DK084006, P01 DK056492] FX This work was supported, in whole or in part, by National Institutes of Health Grants K08 DK070530 (to L. K.) R01 DK084006 (to L. K.) and P01 DK056492 (to P. E. K.). NR 39 TC 16 Z9 16 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 13 PY 2010 VL 285 IS 33 BP 25677 EP 25685 DI 10.1074/jbc.M110.133959 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 635UN UT WOS:000280682400061 PM 20562105 ER PT J AU Burton, DR Weiss, RA AF Burton, Dennis R. Weiss, Robin A. TI A Boost for HIV Vaccine Design SO SCIENCE LA English DT Editorial Material ID ANTIBODIES; GP120; BROAD C1 [Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Burton, Dennis R.] MIT & Harvard, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Weiss, Robin A.] UCL, Div Infect & Immun, London W1T 4JF, England. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. EM burton@scripps.edu; r.weiss@ucl.ac.uk NR 14 TC 47 Z9 49 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 13 PY 2010 VL 329 IS 5993 BP 770 EP 773 DI 10.1126/science.1194693 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637ID UT WOS:000280809900026 PM 20705840 ER PT J AU Zhou, TQ Georgiev, I Wu, XL Yang, ZY Dai, KF Finzi, A Kwon, YD Scheid, JF Shi, W Xu, L Yang, YP Zhu, JA Nussenzweig, MC Sodroski, J Shapiro, L Nabel, GJ Mascola, JR Kwong, PD AF Zhou, Tongqing Georgiev, Ivelin Wu, Xueling Yang, Zhi-Yong Dai, Kaifan Finzi, Andres Kwon, Young Do Scheid, Johannes F. Shi, Wei Xu, Ling Yang, Yongping Zhu, Jiang Nussenzweig, Michel C. Sodroski, Joseph Shapiro, Lawrence Nabel, Gary J. Mascola, John R. Kwong, Peter D. TI Structural Basis for Broad and Potent Neutralization of HIV-1 by Antibody VRC01 SO SCIENCE LA English DT Article ID GP120 ENVELOPE GLYCOPROTEIN; RECEPTOR; SITE; EPITOPE; SURFACE; INDIVIDUALS; ATTACHMENT; MATURATION; HYPOTHESIS; VACCINES AB During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. We determined the crystal structure of VRC01 in complex with a human immunodeficiency virus HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies. C1 [Zhou, Tongqing; Georgiev, Ivelin; Wu, Xueling; Yang, Zhi-Yong; Dai, Kaifan; Kwon, Young Do; Shi, Wei; Xu, Ling; Yang, Yongping; Zhu, Jiang; Shapiro, Lawrence; Nabel, Gary J.; Mascola, John R.; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Finzi, Andres; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Dept Pathol,Div AIDS, Boston, MA 02115 USA. [Scheid, Johannes F.; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Scheid, Johannes F.; Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Shapiro, Lawrence] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Kwon, Young Do/A-6957-2010; Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU NIH; International AIDS Vaccine Initiative's Neutralizing Antibody Consortium; U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-Eng-38] FX T.Z., I.G., Z.Y., J.S., L.S., G.J.N., J.R.M., and P.D.K. designed the research; T.Z., I.G., X.W., Z.Y., K.D.A.F., W.S., L.X., Y.Y., and J.Z. performed the research; X.W., Y.K., J.F.S., M.C.N., and J.R.M. contributed new reagents or reference data; T.Z., I.G., X.W., J.S., L.S., G.J.N., J.R.M., and P.D.K. analyzed the data; and T.Z., I.G., J.S., L.S., G.J.N., J.R.M., and P.D.K. wrote the paper, on which all authors commented. We thank I.A. Wilson and members of the Structural Biology Section and Structural Bioinformatics Core, Vaccine Research Center, for discussions and comments on the manuscript; the staff of sector 22 for assistance with data collection; and J. Stuckey for assistance with figures. Support for this work was provided by the Intramural Research Program of NIH and by grants from NIH and from the International AIDS Vaccine Initiative's Neutralizing Antibody Consortium. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract W-31-109-Eng-38. Coordinates and structure factors for the VRC01-gp120 complex have been deposited with the PDB under accession code 3NGB. NR 38 TC 532 Z9 545 U1 11 U2 98 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 13 PY 2010 VL 329 IS 5993 BP 811 EP 817 DI 10.1126/science.1192819 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637ID UT WOS:000280809900043 PM 20616231 ER PT J AU Lukina, E Watman, N Arreguin, EA Banikazemi, M Dragosky, M Iastrebner, M Rosenbaum, H Phillips, M Pastores, GM Rosenthal, DI Kaper, M Singh, T Puga, AC Bonate, PL Peterschmitt, MJ AF Lukina, Elena Watman, Nora Arreguin, Elsa Avila Banikazemi, Maryam Dragosky, Marta Iastrebner, Marcelo Rosenbaum, Hanna Phillips, Mici Pastores, Gregory M. Rosenthal, Daniel I. Kaper, Mathilde Singh, Tejdip Puga, Ana Cristina Bonate, Peter L. Peterschmitt, M. Judith TI A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1 SO BLOOD LA English DT Article ID ENZYME REPLACEMENT THERAPY; GLUCOSYLCERAMIDE SYNTHASE; GLUCOCEREBROSIDASE; DISORDER AB Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia. The composite primary efficacy end point required improvement after 52 weeks in at least 2 of these 3 disease manifestations and was met by 77% (95% confidence interval [CI] = 58%-89%) of all patients and 91% (95% CI = 72%-98%) of the 22 patients completing 52 weeks. Statistically significant improvements occurred in mean hemoglobin level (1.62 g/dL; 95% CI = 1.05-2.18 g/dL), platelet count (40.3%; 95% CI = 23.7-57.0 g/dL), spleen volume (-38.5%; 95% CI = -43.5%--33.5%), liver volume (-17.0%; 95% CI = -21.6%-12.3%), and lumbar spine bone mineral density (0.31 Z-score; 95% CI = 0.09-0.53). Elevated biomarkers (chitotriosidase; chemokine CCL18; angiotensin-converting enzyme; tartrate-resistant acid phosphatase) decreased by 35% to 50%. Plasma glucosylceramide and ganglioside GM3 normalized. Eliglustat tartrate was well tolerated: 7 mild, transient adverse events in 6 patients were considered treatment-related. Individual pharmacokinetics varied; mean time to maximal observed concentration was 2.3 hours and mean half-life was 6.8 hours. Eliglustat tartrate appears to be a promising oral treatment for GD1. C1 [Kaper, Mathilde; Singh, Tejdip; Puga, Ana Cristina; Bonate, Peter L.; Peterschmitt, M. Judith] Genzyme Corp, Cambridge, MA 02142 USA. [Lukina, Elena] Russian Acad Med Sci, Hematol Res Ctr, Moscow, Russia. [Watman, Nora] Hosp Ramos Mejia, Buenos Aires, DF, Argentina. [Arreguin, Elsa Avila] Hosp Especialidades Ctr Med La Raza, Inst Mexicano Seguro Social, Mexico City, DF, Mexico. [Banikazemi, Maryam; Pastores, Gregory M.] NYU, New York, NY 10003 USA. [Dragosky, Marta; Iastrebner, Marcelo] Inst Argentino Diagnost & Tratamiento, Buenos Aires, DF, Argentina. [Rosenbaum, Hanna] Rambam Med Ctr, Haifa, Israel. [Phillips, Mici] Shaare Zedek Med Ctr, Jerusalem, Israel. [Rosenthal, Daniel I.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Peterschmitt, MJ (reprint author), Genzyme Corp, 500 Kendall St, Cambridge, MA 02142 USA. EM judith.peterschmitt@genzyme.com FU Genzyme Corporation; Amicus; Actelion; Biomarin; Shire HGT; Protalix FX This work was supported by Genzyme Corporation (E. L., N.W., E. A. A., M. B., M. D., M. I., H. R., M. P., G. M. P., and D. I. R.).; M.J.P., M. K., A. C. P., and T. S. are employees and stockholders of Genzyme Corporation; P. L. B. is a former employee of Genzyme Corporation; E. L. and M. B. received honoraria for travel and speaking from Genzyme Corporation; G. M. P. is the recipient of research grants from Amicus, Actelion, Biomarin, Genzyme Corporation, Shire HGT, and Protalix; D. I. R. was contracted by Genzyme Corporation to review bone images. The remaining authors declare no competing financial interests. NR 22 TC 108 Z9 112 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 12 PY 2010 VL 116 IS 6 BP 893 EP 899 DI 10.1182/blood-2010-03-273151 PG 7 WC Hematology SC Hematology GA 638GO UT WOS:000280881700010 PM 20439622 ER PT J AU Hirose, K Inukai, T Kikuchi, J Furukawa, Y Ikawa, T Kawamoto, H Oram, SH Gottgens, B Kiyokawa, N Miyagawa, Y Okita, H Akahane, K Zhang, XC Kuroda, I Honna, H Kagami, K Goi, K Kurosawa, H Look, AT Matsui, H Inaba, T Sugita, K AF Hirose, Kinuko Inukai, Takeshi Kikuchi, Jiro Furukawa, Yusuke Ikawa, Tomokatsu Kawamoto, Hiroshi Oram, S. Helen Goettgens, Berthold Kiyokawa, Nobutaka Miyagawa, Yoshitaka Okita, Hajime Akahane, Koshi Zhang, Xiaochun Kuroda, Itaru Honna, Hiroko Kagami, Keiko Goi, Kumiko Kurosawa, Hidemitsu Look, A. Thomas Matsui, Hirotaka Inaba, Toshiya Sugita, Kanji TI Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19) SO BLOOD LA English DT Article ID ACUTE-LYMPHOBLASTIC-LEUKEMIA; T-CELL LEUKEMIA; APOPTOSIS-INDUCING LIGAND; LIM-PROTEIN LMO2; TRANSGENIC MICE; DNA-BINDING; GENE-THERAPY; CHROMOSOMAL TRANSLOCATIONS; TRANSACTIVATION DOMAINS; EXPRESSION AB LMO2, a critical transcription regulator of hematopoiesis, is involved in human T-cell leukemia. The binding site of proline and acidic amino acid-rich protein (PAR) transcription factors in the promoter of the LMO2 gene plays a central role in hematopoietic-specific expression. E2A-HLF fusion derived from t(17;19) in B-precursor acute lymphoblastic leukemia (ALL) has the transactivation domain of E2A and the basic region/leucine zipper domain of HLF, which is a PAR transcription factor, raising the possibility that E2A-HLF aberrantly induces LMO2 expression. We here demonstrate that cell lines and a primary sample of t(17;19)-ALL expressed LMO2 at significantly higher levels than other B-precursor ALLs did. Transfection of E2A-HLF into a non-t(17;19) B-precursor ALL cell line induced LMO2 gene expression that was dependent on the DNA-binding and transactivation activities of E2A-HLF. The PAR site in the LMO2 gene promoter was critical for E2A-HLF-induced LMO2 expression. Gene silencing of LMO2 in a t(17;19)-ALL cell line by short hairpin RNA-induced apoptotic cell death. These observations indicated that E2A-HLF promotes cell survival of t(17;19)-ALL cells by aberrantly up-regulating LMO2 expression. LMO2 could be a target for a new therapeutic modality for extremely chemo-resistant t(17;19)-ALL. (Blood. 2010;116(6):962-970) C1 [Inukai, Takeshi] Univ Yamanashi, Dept Pediat, Sch Med, Chuo Ku, Yamanashi 4093898, Japan. [Kikuchi, Jiro; Furukawa, Yusuke] Jichi Med Sch, Ctr Mol Med, Shimotsuke, Tochigi, Japan. [Ikawa, Tomokatsu; Kawamoto, Hiroshi] RIKEN, Res Ctr Allergy & Immunol, Lab Lymphocyte Dev, Yokohama, Kanagawa, Japan. [Oram, S. Helen; Goettgens, Berthold] Univ Cambridge, Dept Haematol, Cambridge Inst Med Res, Cambridge, England. [Kiyokawa, Nobutaka; Miyagawa, Yoshitaka; Okita, Hajime] Natl Res Inst Child Hlth & Dev, Tokyo, Japan. [Kurosawa, Hidemitsu] Dokkyo Med Sch, Dept Pediat, Mibu, Tochigi, Japan. [Look, A. Thomas] Dana Farber Canc Inst, Boston, MA 02115 USA. [Matsui, Hirotaka; Inaba, Toshiya] Hiroshima Univ, Res Inst Radiat Biol & Med, Hiroshima, Japan. RP Inukai, T (reprint author), Univ Yamanashi, Dept Pediat, Sch Med, Chuo Ku, 1110 Shimokato, Yamanashi 4093898, Japan. EM tinukai@yamanashi.ac.jp OI Gottgens, Berthold/0000-0001-6302-5705 FU Medical Research Council [G0800784]; National Centre for the Replacement, Refinement and Reduction of Animals in Research [G0900729/1] NR 45 TC 19 Z9 19 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 AUG 12 PY 2010 VL 116 IS 6 BP 962 EP 970 DI 10.1182/blood-2009-09-244673 PG 9 WC Hematology SC Hematology GA 638GO UT WOS:000280881700018 PM 20519628 ER PT J AU Choi, HG Ren, PD Adrian, F Sun, FX Lee, HS Wang, X Ding, QA Zhang, GB Xie, YP Zhang, JM Liu, Y Tuntland, T Warmuth, M Manley, PW Mestan, J Gray, NS Sim, T AF Choi, Hwan Geun Ren, Pingda Adrian, Francisco Sun, Fangxian Lee, Hyun Soo Wang, Xia Ding, Qiang Zhang, Guobao Xie, Yongping Zhang, Jianming Liu, Yi Tuntland, Tove Warmuth, Markus Manley, Paul W. Mestan, Juergen Gray, Nathanael S. Sim, Taebo TI A Type-II Kinase Inhibitor Capable of Inhibiting the T315I "Gatekeeper" Mutant of Bcr-Abl SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; TYROSINE KINASE; AURORA KINASES; IN-VITRO; IMATINIB RESISTANCE; C-SRC; POTENT; CELLS; TARGET; GROWTH AB The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I "gatekeeper" mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, E255K, E255V, F317L, and M35I T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors. C1 [Choi, Hwan Geun; Zhang, Jianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Choi, Hwan Geun; Zhang, Jianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ren, Pingda; Adrian, Francisco; Sun, Fangxian; Lee, Hyun Soo; Wang, Xia; Ding, Qiang; Zhang, Guobao; Xie, Yongping; Liu, Yi; Tuntland, Tove; Warmuth, Markus; Sim, Taebo] Novartis Res Fdn, Dept Chem, Genom Inst, San Diego, CA 92121 USA. [Manley, Paul W.; Mestan, Juergen] Novartis Inst Biomed Res, CH-4056 Basel, Switzerland. [Choi, Hwan Geun; Sim, Taebo] Korea Inst Sci & Technol, Life Sci Res Div, Seoul 136791, South Korea. RP Gray, NS (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 250 Longwood Ave,Seeley G Mudd Bldg 628A, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu; tbsim@kist.re.kr FU NCI NIH HHS [R01 CA130876] NR 37 TC 41 Z9 41 U1 0 U2 6 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 AUG 12 PY 2010 VL 53 IS 15 BP 5439 EP 5448 DI 10.1021/jm901808w PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 633RV UT WOS:000280523300005 PM 20604564 ER PT J AU Mendez-Ferrer, S Michurina, TV Ferraro, F Mazloom, AR MacArthur, BD Lira, SA Scadden, DT Ma'ayan, A Enikolopov, GN Frenette, PS AF Mendez-Ferrer, Simon Michurina, Tatyana V. Ferraro, Francesca Mazloom, Amin R. MacArthur, Ben D. Lira, Sergio A. Scadden, David T. Ma'ayan, Avi Enikolopov, Grigori N. Frenette, Paul S. TI Mesenchymal and haematopoietic stem cells form a unique bone marrow niche SO NATURE LA English DT Article ID PROGENITOR CELLS; SELF-RENEWAL; NEURAL CREST; DIFFERENTIATION; OSTEOBLAST; EXPRESSION; RECEPTOR; MICROENVIRONMENT; OSTEOPONTIN; COOPERATION AB The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta 3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs. C1 [Mendez-Ferrer, Simon; Lira, Sergio A.; Frenette, Paul S.] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Mendez-Ferrer, Simon; Frenette, Paul S.] Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY 10029 USA. [Michurina, Tatyana V.; Enikolopov, Grigori N.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Ferraro, Francesca; Scadden, David T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. [Mazloom, Amin R.; MacArthur, Ben D.; Ma'ayan, Avi] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA. [Frenette, Paul S.] Yeshiva Univ Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 USA. RP Frenette, PS (reprint author), Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. EM simon.mendez-ferrer@cnic.es; paul.frenette@einstein.yu.edu RI Frenette, Paul/J-8272-2012; OI MacArthur, Ben/0000-0002-5396-9750; Enikolopov, Grigori/0000-0001-8178-8917; Mendez-Ferrer, Simon/0000-0002-9805-9988 FU National Institutes of Health [DK056638, HL69438, HL097819]; Department of Defence [PC060271]; National Institute of Mental Health; Ira Hazan Fund; American Society of Hematology FX We thank M. Garcia-Fernandez, Y. Kunisaki, C. Scheiermann, J. Isern, E. Nistal-Villan and D. Lucas for help with some experiments; M. Kiel and S. Morrison for advice about immunohistological analysis of HSCs; C. Lin for help with intravital microscopy imaging; G. Fishell for the gift of Nes-creERT2 and RCE:loxP transgenic mice; J. Ahmed, W. Kao and J. Godbold for help with immunofluorescence and statistical analyses; S. Lymperi for advice about LT-CIC; L. Silberstein, G. Khitrov and W. Zhang for help with microarray experiments; M. Grisotto for help with cell sorting; and L. Shang, A. J. Peired and C. Prophete for help with animals. This work was supported by the National Institutes of Health (R01 grants DK056638, HL69438, HL097819) and the Department of Defence (Idea Development Award PC060271) to P. S. F. and by the National Institute of Mental Health and Ira Hazan Fund to G.N.E. S.M.-F. is the recipient of a Scholar Award by the American Society of Hematology. P. S. F. is an Established Investigator of the American Heart Association. NR 43 TC 1170 Z9 1221 U1 24 U2 177 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 12 PY 2010 VL 466 IS 7308 BP 829 EP U59 DI 10.1038/nature09262 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636TT UT WOS:000280766100028 PM 20703299 ER PT J AU Campbell, EG Zinner, DE AF Campbell, Eric G. Zinner, Darren E. TI Disclosing Industry Relationships - Toward an Improved Federal Research Policy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Zinner, Darren E.] Brandeis Univ, Heller Sch Social Policy & Management, Waltham, MA USA. RP Campbell, EG (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. NR 4 TC 16 Z9 16 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 12 PY 2010 VL 363 IS 7 BP 604 EP 606 DI 10.1056/NEJMp1006973 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 636TN UT WOS:000280764600002 PM 20647185 ER PT J AU Ng, AK Abramson, JS Digumarthy, SR Reingold, JS Stone, JR AF Ng, Andrea K. Abramson, Jeremy S. Digumarthy, Subba R. Reingold, Jason S. Stone, James R. TI A Woman with a History of Hodgkin's Lymphoma and Sudden Onset of Dyspnea and Shock SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article; Proceedings Paper CT Lymphoma Conference CY APR 30, 2010 CL Massachusetts Gen Hosp, Boston, MA HO Massachusetts Gen Hosp ID INVOLVED-FIELD RADIOTHERAPY; 2ND MALIGNANT NEOPLASMS; INDUCED HEART-DISEASE; RADIATION-THERAPY; CHILDHOOD-CANCER; STAGE-II; ABVD CHEMOTHERAPY; ONCOLOGY-GROUP; LUNG-CANCER; SURVIVORS C1 [Ng, Andrea K.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Ng, Andrea K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Abramson, Jeremy S.] Massachusetts Gen Hosp, Dept Med, Div Med Oncol, Boston, MA 02114 USA. [Reingold, Jason S.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Digumarthy, Subba R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ng, Andrea K.] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Abramson, Jeremy S.; Reingold, Jason S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Digumarthy, Subba R.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA USA. [Stone, James R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA USA. RP Ng, AK (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. NR 37 TC 3 Z9 3 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 12 PY 2010 VL 363 IS 7 BP 664 EP 675 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 636TN UT WOS:000280764600011 PM 20818858 ER PT J AU Yan, H Venkatesan, K Beaver, JE Klitgord, N Yildirim, MA Hao, T Hill, DE Cusick, ME Perrimon, N Roth, FP Vidal, M AF Yan, Han Venkatesan, Kavitha Beaver, John E. Klitgord, Niels Yildirim, Muhammed A. Hao, Tong Hill, David E. Cusick, Michael E. Perrimon, Norbert Roth, Frederick P. Vidal, Marc TI A Genome-Wide Gene Function Prediction Resource for Drosophila melanogaster SO PLOS ONE LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; SACCHAROMYCES-CEREVISIAE; INTERACTOME NETWORK; INTERACTION MAP; C-ELEGANS; STRESS-RESPONSE; EXPRESSION; IDENTIFICATION; MICROARRAY; CELLS AB Predicting gene functions by integrating large-scale biological data remains a challenge for systems biology. Here we present a resource for Drosophila melanogaster gene function predictions. We trained function-specific classifiers to optimize the influence of different biological datasets for each functional category. Our model predicted GO terms and KEGG pathway memberships for Drosophila melanogaster genes with high accuracy, as affirmed by cross-validation, supporting literature evidence, and large-scale RNAi screens. The resulting resource of prioritized associations between Drosophila genes and their potential functions offers a guide for experimental investigations. C1 [Yan, Han; Venkatesan, Kavitha; Klitgord, Niels; Yildirim, Muhammed A.; Hao, Tong; Hill, David E.; Cusick, Michael E.; Roth, Frederick P.; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, CCSB, Boston, MA 02115 USA. [Yan, Han; Venkatesan, Kavitha; Klitgord, Niels; Yildirim, Muhammed A.; Hao, Tong; Hill, David E.; Cusick, Michael E.; Perrimon, Norbert; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Perrimon, Norbert] Howard Hughes Med Inst, Boston, MA 02115 USA. [Yildirim, Muhammed A.] Harvard Univ, Div Engn & Appl Sci, Appl Phys Program, Grad Sch Arts & Sci, Cambridge, MA 02138 USA. [Beaver, John E.; Roth, Frederick P.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Yan, H (reprint author), Dana Farber Canc Inst, Dept Canc Biol, CCSB, Boston, MA 02115 USA. EM frederick_roth@hms.harvard.edu; marc_vidal@dfci.harvard.edu RI Klitgord, Niels/B-5121-2009; Hill, David/B-6617-2011; Roth, Frederick/H-6308-2011; Yildirim, Muhammed/J-3695-2014; OI Yildirim, Muhammed/0000-0003-2826-1766; Roth, Frederick/0000-0002-6628-649X FU National Institutes of Health (NIH) [HG001715, HG004233, HG003224]; Canadian Institute for Advanced Research; Harvard University FX This work was supported by grants from the National Institutes of Health (NIH; HG001715, HG004233 and HG003224; http://www.nih.gov/), the Canadian Institute for Advanced Research (http://www2.cifar.ca/), and the Presidential Scholarship from Harvard University (http://www.harvard.edu/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 7 Z9 7 U1 1 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 AUG 12 PY 2010 VL 5 IS 8 AR e12139 DI 10.1371/journal.pone.0012139 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637ZU UT WOS:000280859700024 PM 20711346 ER PT J AU Valenza, M Leoni, V Karasinska, JM Petricca, L Fan, JJ Carroll, J Pouladi, MA Fossale, E Nguyen, HP Riess, O MacDonald, M Wellington, C DiDonato, S Hayden, M Cattaneo, E AF Valenza, Marta Leoni, Valerio Karasinska, Joanna M. Petricca, Lara Fan, Jianjia Carroll, Jeffrey Pouladi, Mahmoud A. Fossale, Elisa Nguyen, Huu Phuc Riess, Olaf MacDonald, Marcy Wellington, Cheryl DiDonato, Stefano Hayden, Michael Cattaneo, Elena TI Cholesterol Defect Is Marked across Multiple Rodent Models of Huntington's Disease and Is Manifest in Astrocytes SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MUTANT HUNTINGTIN; BIOSYNTHESIS PATHWAY; BRAIN CHOLESTEROL; MOUSE MODEL; DYSFUNCTION; REPEAT; MICE AB Brain cholesterol, which is synthesized locally, is a major component of myelin and cell membranes and participates in neuronal functions, such as membrane trafficking, signal transduction, neurotransmitter release, and synaptogenesis. Here we show that brain cholesterol biosynthesis is reduced in multiple transgenic and knock-in Huntington's disease (HD) rodent models, arguably dependent on deficits in mutant astrocytes. Mice carrying a progressively increased number of CAG repeats show a more evident reduction in cholesterol biosynthesis. In postnatal life, the cholesterol-dependent activities of neurons mainly rely on the transport of cholesterol from astrocytes on ApoE-containing particles. Our data show that mRNA levels of cholesterol biosynthesis and efflux genes are severely reduced in primary HD astrocytes, along with impaired cellular production and secretion of ApoE. Consistently, in CSF of HD mice, ApoE is mostly associated with smaller lipoproteins, indicating reduced cholesterol transport on ApoE-containing lipoproteins circulating in the HD brain. These findings indicate that cholesterol defect is robustly marked in HD animals, implying that strategies aimed at selectively modulating brain cholesterol metabolism might be of therapeutic significance. C1 [Valenza, Marta; Petricca, Lara; Cattaneo, Elena] Univ Milan, Dept Pharmacol Sci, I-20133 Milan, Italy. [Valenza, Marta; Petricca, Lara; Cattaneo, Elena] Univ Milan, Ctr Stem Cell Res, I-20133 Milan, Italy. [Leoni, Valerio; DiDonato, Stefano] Ist Nazl Neurol Carlo Besta, Unit Genet Neurodegenerat & Metab Dis, I-20133 Milan, Italy. [Karasinska, Joanna M.; Carroll, Jeffrey; Pouladi, Mahmoud A.; Hayden, Michael] Univ British Columbia, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada. [Fan, Jianjia; Wellington, Cheryl] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 2B5, Canada. [Fossale, Elisa; MacDonald, Marcy] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Nguyen, Huu Phuc; Riess, Olaf] Univ Tubingen, Dept Med Genet, D-72016 Tubingen, Germany. RP Cattaneo, E (reprint author), Univ Milan, Dept Pharmacol Sci, Via Balzaretti 9, I-20133 Milan, Italy. EM elena.cattaneo@unimi.it RI Di Donato, Stefano/B-9717-2012; Nguyen, Huu Phuc/F-5390-2015; Pouladi, Mahmoud/B-8743-2016; Hayden, Michael/D-8581-2011; OI Nguyen, Huu Phuc/0000-0001-6139-788X; Pouladi, Mahmoud/0000-0002-9030-0976; Hayden, Michael/0000-0001-5159-1419; Carroll, Jeffrey/0000-0003-1711-8868; VALENZA, MARTA/0000-0002-7048-9257; CATTANEO, ELENA/0000-0002-0755-4917 FU CHDI Foundation (United States) [LHSB-CT-2006-037349]; European Union; Telethon [GGP02215]; Huntington's Disease Society of America Coalition for the Cure (United States); National Institutes of Health [NS32765]; Fondazione Cariplo (Italy) FX This work was supported by CHDI Foundation (United States), STEM-HD (LHSB-CT-2006-037349, Sixth Framework Program, European Union), and Telethon (#GGP02215) to E. C.; Huntington's Disease Society of America Coalition for the Cure (United States) to E. C., M. M., and M. H.; a National Institutes of Health grant (NS32765) to M. M.; and Fondazione Cariplo (Italy) to M. V. and M. H. E. C., M. M., and M. H. are members of the HDSA Coalition for the Cure "Huntingtin Function" Team. We thank Veronica Hirsch-Reinshagen for insightful comments and suggestions related to ApoE secretion in astrocytes and CHDI members for their continuous encouragement to investigate cholesterol dysfunction in HD. We are also very grateful to N. Bissada, L. Liu, Y. Xie (Robert), and P. Ruddle for their technical support during the time during which M. V. visited M.H.'s laboratory. Finally, we also thank the families of the patients with Huntington's disease for their continuous support. NR 25 TC 54 Z9 57 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 AUG 11 PY 2010 VL 30 IS 32 BP 10844 EP 10850 DI 10.1523/JNEUROSCI.0917-10.2010 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 637DL UT WOS:000280795900024 PM 20702713 ER PT J AU Martinez, D Heudebert, G Seas, C Henostroza, G Rodriguez, M Zamudio, C Centor, RM Herrera, C Gotuzzo, E Estrada, C AF Martinez, Dalila Heudebert, Gustavo Seas, Carlos Henostroza, German Rodriguez, Martin Zamudio, Carlos Centor, Robert M. Herrera, Cesar Gotuzzo, Eduardo Estrada, Carlos TI Clinical Prediction Rule for Stratifying Risk of Pulmonary Multidrug-Resistant Tuberculosis SO PLOS ONE LA English DT Article ID METHODOLOGICAL STANDARDS; CONFIDENCE-INTERVALS; TREATMENT FAILURE; MDR-TB; DIAGNOSIS; VALIDATION; CALIFORNIA; INPATIENTS; COUNTRIES; RUSSIA AB Background: Multidrug-resistant tuberculosis (MDR-TB), resistance to at least isoniazid and rifampin, is a worldwide problem. Objective: To develop a clinical prediction rule to stratify risk for MDR-TB among patients with pulmonary tuberculosis. Methods: Derivation and internal validation of the rule among adult patients prospectively recruited from 37 health centers (Peru), either a) presenting with a positive acid-fast bacillus smear, or b) had failed therapy or had a relapse within the first 12 months. Results: Among 964 patients, 82 had MDR-TB (prevalence, 8.5%). Variables included were MDR-TB contact within the family, previous tuberculosis, cavitary radiologic pattern, and abnormal lung exam. The area under the receiver-operating curve (AUROC) was 0.76. Selecting a cut-off score of one or greater resulted in a sensitivity of 72.6%, specificity of 62.8%, likelihood ratio (LR) positive of 1.95, and LR negative of 0.44. Similarly, selecting a cut-off score of two or greater resulted in a sensitivity of 60.8%, specificity of 87.5%, LR positive of 4.85, and LR negative of 0.45. Finally, selecting a cut-off score of three or greater resulted in a sensitivity of 45.1%, specificity of 95.3%, LR positive of 9.56, and LR negative of 0.58. Conclusion: A simple clinical prediction rule at presentation can stratify risk for MDR-TB. If further validated, the rule could be used for management decisions in resource-limited areas. C1 [Martinez, Dalila; Seas, Carlos; Zamudio, Carlos; Gotuzzo, Eduardo] Univ Peruana Cayetano Heredia, Inst Trop Med Alexander von Humboldt, Lima, Peru. [Heudebert, Gustavo; Centor, Robert M.; Estrada, Carlos] Univ Alabama, Div Gen Internal Med, Birmingham, AL USA. [Heudebert, Gustavo; Centor, Robert M.; Estrada, Carlos] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Herrera, Cesar] Minist Hlth, Peruvian TB Program, Lima, Peru. [Henostroza, German; Rodriguez, Martin] Univ Alabama, Div Infect Dis, Birmingham, AL USA. RP Martinez, D (reprint author), Univ Peruana Cayetano Heredia, Inst Trop Med Alexander von Humboldt, Lima, Peru. EM cestrada@uab.edu FU NIH [1U2RTW007368-01A1] FX Funding and Support: Peru ICOHRTA Network for AIDS/TB Research Training (NIH Grant 1U2RTW007368-01A1- Fogarty International Center, Dr Gotuzzo, Lima Peru) for funding the training of Dr. Martinez at the School of Public Health at University of Alabama at Birmingham (UAB). http://projectreporter. nih.gov/project_info_description.cfm?aid=7239089&icde=4053480. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 8 Z9 8 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 AUG 11 PY 2010 VL 5 IS 8 AR e12082 DI 10.1371/journal.pone.0012082 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637WJ UT WOS:000280849100020 PM 20711459 ER PT J AU Dou, X Menkari, C Shanmugasundararaj, S Miller, KW Charness, ME AF Dou, X. Menkari, C. Shanmugasundararaj, S. Miller, K. W. Charness, M. E. TI CHARACTERIZATION OF AN ALCOHOL BINDING SITE ON THE L1 NEURAL CELL ADHESION MOLECULE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Dou, X.; Menkari, C.; Shanmugasundararaj, S.; Miller, K. W.; Charness, M. E.] Harvard Univ, Sch Med, VA Boston Healthcare Syst, VA Boston Healthcare Syst 011, W Roxbury, MA 02132 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 30A EP 30A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600067 ER PT J AU Rasmussen, DD Raskind, MA Walker, BM Koob, GF Froehlich, JC Simpson, TL Saxon, AJ AF Rasmussen, D. D. Raskind, M. A. Walker, B. M. Koob, G. F. Froehlich, J. C. Simpson, T. L. Saxon, A. J. TI TRANSLATIONAL APPROACH TO DEVELOPMENT OF NORADRENERGIC AGENTS FOR TREATMENT OF ALCOHOL DEPENDENCE SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, VA Med Ctr, Seattle, WA 98108 USA. RI koob, george/P-8791-2016 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 64A EP 64A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600201 ER PT J AU Ooteman, W Naassila, M Koeter, MWJ Verheul, R Schippers, GM Houchi, H Daoust, M van den Brink, W AF Ooteman, W. Naassila, M. Koeter, M. W. J. Verheul, R. Schippers, G. M. Houchi, H. Daoust, M. van den Brink, W. TI PREDICTING THE EFFECT OF NALTREXONE AND ACAMPROSATE ON CUE-INDUCED CRAVING IN ALCOHOL-DEPENDENT PATIENTS USING GENETIC INDICATORS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Ooteman, W.; Naassila, M.; Koeter, M. W. J.; Verheul, R.; Schippers, G. M.; Houchi, H.; Daoust, M.; van den Brink, W.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94121 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 70A EP 70A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600226 ER PT J AU Bradley, KA Lapham, GT Williams, EC Achtmeyer, C Thomas, R Hawkins, E Saitz, R Kivlahan, D AF Bradley, K. A. Lapham, G. T. Williams, E. C. Achtmeyer, C. Thomas, R. Hawkins, E. Saitz, R. Kivlahan, D. TI EFFECTS OF THE PROPORTION SCREENING POSITIVE ON A PERFORMANCE MEASURE FOR BRIEF ALCOHOL INTERVENTION SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Bradley, K. A.; Lapham, G. T.; Williams, E. C.; Achtmeyer, C.; Thomas, R.; Hawkins, E.; Saitz, R.; Kivlahan, D.] VA Puget Sound Hlth Care Syst, Seattle, WA 98146 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 82A EP 82A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600272 ER PT J AU Williams, EC Bradley, KA Harris, AHS AF Williams, E. C. Bradley, K. A. Harris, A. H. S. TI ASSOCIATION BETWEEN ALCOHOL SCREENING SCORES AND MORTALITY AMONG BLACK, HISPANIC, AND WHITE MALE VETERANS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 VA Puget Sound, NW Ctr Excellence Hlth Serv Res & Dev, Seattle, WA 98101 USA. VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk, CA 94025 USA. Stanford Univ, Sch Med, Menlo Pk, CA 94025 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 120A EP 120A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600418 ER PT J AU Williams, EC Lapham, GT Johnson, ML Bradley, KA AF Williams, E. C. Lapham, G. T. Johnson, M. L. Bradley, K. A. TI STRATEGIES TO IMPLEMENT ALCOHOL SCREENING AND BRIEF INTERVENTION: A STRUCTURED LITERATURE REVIEW SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Williams, E. C.; Lapham, G. T.; Johnson, M. L.; Bradley, K. A.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA 98101 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 120A EP 120A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600417 ER PT J AU Durazzo, TC Fryer, S Vertinski, M Gazdzinski, S Mon, A Meyerhoff, DJ AF Durazzo, T. C. Fryer, S. Vertinski, M. Gazdzinski, S. Mon, A. Meyerhoff, D. J. TI MEASURES OF LEARNING, MEMORY AND PROCESSING SPEED ACCURATELY PREDICT SMOKING STATUS IN TREATMENT SEEKING ALCOHOL DEPENDENT INDIVIDUALS SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT World Congress on International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 13-16, 2010 CL Paris, FRANCE SP Int Soc Biomed Res Alcoholism, Soc Francaise Alcoolog C1 [Durazzo, T. C.; Fryer, S.; Vertinski, M.; Gazdzinski, S.; Mon, A.; Meyerhoff, D. J.] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94121 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG 10 PY 2010 VL 34 IS 8 SU S BP 136A EP 136A PG 1 WC Substance Abuse SC Substance Abuse GA 630DN UT WOS:000280252600481 ER PT J AU Dang-Vu, TT McKinney, SM Buxton, OM Solet, JM Ellenbogen, JM AF Dang-Vu, Thien Thanh McKinney, Scott M. Buxton, Orfeu M. Solet, Jo M. Ellenbogen, Jeffrey M. TI Spontaneous brain rhythms predict sleep stability in the face of noise SO CURRENT BIOLOGY LA English DT Letter ID SPINDLES; INSOMNIA C1 [Dang-Vu, Thien Thanh; Buxton, Orfeu M.; Solet, Jo M.; Ellenbogen, Jeffrey M.] Harvard Univ, Sch Med, Div Sleep Med, Boston, MA 02115 USA. [Dang-Vu, Thien Thanh; McKinney, Scott M.; Ellenbogen, Jeffrey M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Dang-Vu, Thien Thanh] Univ Liege, Cyclotron Res Ctr, B-4000 Liege, Belgium. [Buxton, Orfeu M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Solet, Jo M.] Cambridge Hlth Alliance, Dept Psychiat, Cambridge, MA 02139 USA. RP Dang-Vu, TT (reprint author), Harvard Univ, Sch Med, Div Sleep Med, Boston, MA 02115 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 NR 10 TC 72 Z9 73 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 10 PY 2010 VL 20 IS 15 BP R626 EP R627 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 638MV UT WOS:000280899900010 PM 20692606 ER PT J AU Burstein, HJ Prestrud, AA Seidenfeld, J Anderson, H Buchholz, TA Davidson, NE Gelmon, KE Giordano, SH Hudis, CA Malin, J Mamounas, EP Rowden, D Solky, AJ Sowers, MR Stearns, V Winer, EP Somerfield, MR Griggs, JJ AF Burstein, Harold J. Prestrud, Ann Alexis Seidenfeld, Jerome Anderson, Holly Buchholz, Thomas A. Davidson, Nancy E. Gelmon, Karen E. Giordano, Sharon H. Hudis, Clifford A. Malin, Jennifer Mamounas, Eleftherios P. Rowden, Diana Solky, Alexander J. Sowers, MaryFran R. Stearns, Vered Winer, Eric P. Somerfield, Mark R. Griggs, Jennifer J. TI American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID QUALITY-OF-LIFE; PLACEBO-CONTROLLED TRIAL; BONE-MINERAL DENSITY; PLUS ZOLEDRONIC ACID; TO-TREAT ANALYSIS; BIG 1-98 TRIAL; POSTMENOPAUSAL WOMEN; AROMATASE INHIBITORS; RANDOMIZED-TRIAL; TECHNOLOGY-ASSESSMENT AB Purpose To develop evidence-based guidelines, based on a systematic review, for endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. Methods A literature search identified relevant randomized trials. Databases searched included MEDLINE, PREMEDLINE, the Cochrane Collaboration Library, and those for the Annual Meetings of the American Society of Clinical Oncology (ASCO) and the San Antonio Breast Cancer Symposium (SABCS). The primary outcomes of interest were disease-free survival, overall survival, and time to contralateral breast cancer. Secondary outcomes included adverse events and quality of life. An expert panel reviewed the literature, especially 12 major trials, and developed updated recommendations. Results An adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initial endocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AI after 5 years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with 5 years of tamoxifen alone. Data suggest that including an AI as primary monotherapy or as sequential treatment after 2 to 3 years of tamoxifen yields similar outcomes. Tamoxifen and AIs differ in their adverse effect profiles, and these differences may inform treatment preferences. Conclusion The Update Committee recommends that postmenopausal women with hormone receptor-positive breast cancer consider incorporating AI therapy at some point during adjuvant treatment, either as up-front therapy or as sequential treatment after tamoxifen. The optimal timing and duration of endocrine treatment remain unresolved. The Update Committee supports careful consideration of adverse effect profiles and patient preferences in deciding whether and when to incorporate AI therapy. J Clin Oncol 28: 3784-3796. (C) 2010 by American Society of Clinical Oncology C1 [Burstein, Harold J.] Dana Farber Canc Inst, Boston, MA 02115 USA. Amer Soc Clin Oncol, Alexandria, VA 22314 USA. Breast Canc Coalit Rochester, Rochester, MN USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Susan G Komen Cure, Dallas, TX USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Greater Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. Aultman Hlth Fdn, Canton, OH USA. Johns Hopkins Sch Med, Baltimore, MD USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Burstein, HJ (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. FU Vered Stearns; Novartis; Pfizer FX Research Funding: Vered Stearns, Novartis, Pfizer Expert Testimony NR 115 TC 370 Z9 376 U1 1 U2 30 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2010 VL 28 IS 23 BP 3784 EP 3796 DI 10.1200/JCO.2009.26.3756 PG 13 WC Oncology SC Oncology GA 641LX UT WOS:000281129000017 PM 20625130 ER PT J AU Cleary, JM Sadow, PM Randolph, GW Palmer, EL Lynch, TP Nikiforov, YE Wirth, LJ AF Cleary, James M. Sadow, Peter M. Randolph, Gregory W. Palmer, Edwin L. Lynch, Thomas P. Nikiforov, Yuri E. Wirth, Lori J. TI Neoadjuvant Treatment of Unresectable Medullary Thyroid Cancer With Sunitinib SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID RET PROTOONCOGENE; CARCINOMA; PREDISPOSITION; MUTATIONS C1 [Cleary, James M.; Sadow, Peter M.; Randolph, Gregory W.; Palmer, Edwin L.; Lynch, Thomas P.; Wirth, Lori J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Cleary, James M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Randolph, Gregory W.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. [Lynch, Thomas P.] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT USA. [Nikiforov, Yuri E.] Univ Pittsburgh, Dept Pathol & Lab Med, Pittsburgh, PA USA. RP Cleary, JM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. FU NCI NIH HHS [T32 CA009172] NR 16 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2010 VL 28 IS 23 BP E390 EP E392 DI 10.1200/JCO.2009.27.4225 PG 3 WC Oncology SC Oncology GA 641LX UT WOS:000281129000020 PM 20567012 ER PT J AU Levine, RA Nattel, S AF Levine, Robert A. Nattel, Stanley TI Looking Into the Left Atrial Crystal Ball A Ray of Hope for Patients With Organic Mitral Regurgitation SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE mitral regurgitation; left atrial size; atrial fibrillation; mitral valve surgery; left atrial remodeling ID LEFT-VENTRICULAR FUNCTION; CONGESTIVE-HEART-FAILURE; PHYSIOLOGICAL DETERMINANTS; DIASTOLIC DYSFUNCTION; NATRIURETIC PEPTIDE; SURGICAL-CORRECTION; CANINE MODEL; SIZE; FIBRILLATION; DISEASE C1 [Levine, Robert A.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Dept Med, Boston, MA 02114 USA. [Levine, Robert A.] Harvard Univ, Sch Med, Boston, MA USA. [Nattel, Stanley] Montreal Heart Inst, Dept Med, Montreal, PQ H1T 1C8, Canada. [Nattel, Stanley] Univ Montreal, Montreal, PQ, Canada. RP Levine, RA (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Dept Med, 55 Fruit St,Yawkey 5068, Boston, MA 02114 USA. EM rlevine@partners.org FU Canadian Institutes of Health Research [MGP 6957]; NHLBI NIH HHS [K24 HL067434-09, K24 HL67434, R01 HL072265-05A2, K24 HL067434, R01 HL072265, R01 HL72265] NR 46 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 10 PY 2010 VL 56 IS 7 BP 579 EP 581 DI 10.1016/j.jacc.2009.11.103 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 634TT UT WOS:000280609200007 PM 20688213 ER PT J AU Noguchi, Y Nishikata, N Shikata, N Kimura, Y Aleman, JO Young, JD Koyama, N Kelleher, JK Takahashi, M Stephanopoulos, G AF Noguchi, Yasushi Nishikata, Natsumi Shikata, Nahoko Kimura, Yoshiko Aleman, Jose O. Young, Jamey D. Koyama, Naoto Kelleher, Joanne K. Takahashi, Michio Stephanopoulos, Gregory TI Ketogenic Essential Amino Acids Modulate Lipid Synthetic Pathways and Prevent Hepatic Steatosis in Mice SO PLOS ONE LA English DT Article ID INDUCED INSULIN-RESISTANCE; ACTIVATED PROTEIN-KINASE; REGULATES FOOD-INTAKE; FATTY LIVER-DISEASE; UNCOUPLING PROTEIN-3; ENERGY-EXPENDITURE; IMPROVES GLUCOSE; DE-NOVO; MUSCLE; RAT AB Background: Although dietary ketogenic essential amino acid (KAA) content modifies accumulation of hepatic lipids, the molecular interactions between KAAs and lipid metabolism are yet to be fully elucidated. Methodology/Principal Findings: We designed a diet with a high ratio (E/N) of essential amino acids (EAAs) to non-EAAs by partially replacing dietary protein with 5 major free KAAs (Leu, Ile, Val, Lys and Thr) without altering carbohydrate and fat content. This high-KAA diet was assessed for its preventive effects on diet-induced hepatic steatosis and whole-animal insulin resistance. C57B6 mice were fed with a high-fat diet, and hyperinsulinemic ob/ob mice were fed with a high-fat or high-sucrose diet. The high-KAA diet improved hepatic steatosis with decreased de novo lipogensis (DNL) fluxes as well as reduced expressions of lipogenic genes. In C57B6 mice, the high-KAA diet lowered postprandial insulin secretion and improved glucose tolerance, in association with restored expression of muscle insulin signaling proteins repressed by the high-fat diet. Lipotoxic metabolites and their synthetic fluxes were also evaluated with reference to insulin resistance. The high-KAA diet lowered muscle and liver ceramides, both by reducing dietary lipid incorporation into muscular ceramides and preventing incorporation of DNL-derived fatty acids into hepatic ceramides. Conclusion: Our results indicate that dietary KAA intake improves hepatic steatosis and insulin resistance by modulating lipid synthetic pathways. C1 [Noguchi, Yasushi; Aleman, Jose O.; Young, Jamey D.; Kelleher, Joanne K.; Stephanopoulos, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Kelleher, Joanne K.] Massachusetts Gen Hosp, Shriners Burn Hosp, Boston, MA 02114 USA. [Noguchi, Yasushi; Nishikata, Natsumi; Shikata, Nahoko; Kimura, Yoshiko; Koyama, Naoto; Takahashi, Michio] Ajinomoto Co Inc, Res Inst Hlth Fundamentals, Kanagawa, Japan. RP Noguchi, Y (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM gregstep@mit.edu RI Young, Jamey/A-5857-2012 FU National Institutes of Health (NIH) Bioengineering Research Partnership [DK58533]; NIH Metabolomics Roadmap Initiative [DK070291]; NIH [DK072856] FX This work was supported by the National Institutes of Health (NIH) Bioengineering Research Partnership Grant DK58533 and NIH Metabolomics Roadmap Initiative DK070291. J.D.Y. was supported by NIH grant DK072856. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 26 Z9 27 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 AUG 10 PY 2010 VL 5 IS 8 AR e12057 DI 10.1371/journal.pone.0012057 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637IW UT WOS:000280811900015 PM 20706589 ER PT J AU Bird, GH Madani, N Perry, AF Princiotto, AM Supko, JG He, XY Gavathiotis, E Sodroski, JG Walensky, LD AF Bird, Gregory H. Madani, Navid Perry, Alisa F. Princiotto, Amy M. Supko, Jeffrey G. He, Xiaoying Gavathiotis, Evripidis Sodroski, Joseph G. Walensky, Loren D. TI Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fusion inhibitor; HIV-1; protease resistance; stapled peptide; alpha-helix ID IMMUNODEFICIENCY-VIRUS TYPE-1; RING-CLOSING METATHESIS; HIV-1 FUSION INHIBITOR; ENVELOPE GLYCOPROTEIN; HELICAL PEPTIDES; STRUCTURAL CHARACTERIZATION; CRYSTAL-STRUCTURE; MEMBRANE-FUSION; ALPHA-HELICES; BH3 HELIX AB The pharmacologic utility of lengthy peptides can be hindered by loss of bioactive structure and rapid proteolysis, which limits bioavailability. For example, enfuvirtide (Fuzeon, T20, DP178), a 36-amino acid peptide that inhibits human immunodeficiency virus type 1 (HIV-1) infection by effectively targeting the viral fusion apparatus, has been relegated to a salvage treatment option mostly due to poor in vivo stability and lack of oral bioavailability. To overcome the proteolytic shortcomings of long peptides as therapeutics, we examined the biophysical, biological, and pharmacologic impact of inserting all-hydrocarbon staples into an HIV-1 fusion inhibitor. We find that peptide double-stapling confers striking protease resistance that translates into markedly improved pharmacokinetic properties, including oral absorption. We determined that the hydrocarbon staples create a proteolytic shield by combining reinforcement of overall alpha-helical structure, which slows the kinetics of proteolysis, with complete blockade of peptide cleavage at constrained sites in the immediate vicinity of the staple. Importantly, double-stapling also optimizes the antiviral activity of HIV-1 fusion peptides and the antiproteolytic feature extends to other therapeutic peptide templates, such as the diabetes drug exenatide (Byetta). Thus, hydrocarbon double-stapling may unlock the therapeutic potential of natural bioactive polypeptides by transforming them into structurally fortified agents with enhanced bioavailability. C1 [Bird, Gregory H.; Perry, Alisa F.; Gavathiotis, Evripidis; Walensky, Loren D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Bird, Gregory H.; Perry, Alisa F.; Gavathiotis, Evripidis; Walensky, Loren D.] Harvard Univ, Childrens Hosp Boston, Sch Med, Boston, MA 02115 USA. [Bird, Gregory H.; Perry, Alisa F.; Gavathiotis, Evripidis; Walensky, Loren D.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. [Madani, Navid; Princiotto, Amy M.; Sodroski, Joseph G.] Harvard Univ, Dept Canc Immunol & AIDS, Sch Med, Dana Farber Canc Inst,Div AIDS, Boston, MA 02115 USA. [Madani, Navid] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Supko, Jeffrey G.; He, Xiaoying] Massachusetts Gen Hosp, Clin Pharmacol Lab, Dept Med, Boston, MA 02114 USA. [Sodroski, Joseph G.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM Loren_Walensky@dfci.harvard.edu FU National Institutes of Health [5F32 AI077371]; Harvard Catalyst; Melinda Gates Foundation FX We thank E. Smith for editorial and graphics assistance, and J. Fisher and J. Quijada for technical support in conducting the mouse pharmacokinetic studies. This work was supported by National Institutes of Health Grant 5F32 AI077371 (G.H.B.) and a Harvard Catalyst pilot grant and a Bill and Melinda Gates Foundation Grand Challenges Exploration award (L.D.W.). NR 36 TC 101 Z9 103 U1 5 U2 50 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 10 PY 2010 VL 107 IS 32 BP 14093 EP 14098 DI 10.1073/pnas.1002713107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636UD UT WOS:000280767700024 PM 20660316 ER PT J AU Lipinski, MM Zheng, B Lu, T Yan, ZY Py, BF Ng, A Xavier, RJ Li, C Yankner, BA Scherzer, CR Yuan, JY AF Lipinski, Marta M. Zheng, Bin Lu, Tao Yan, Zhenyu Py, Benedicte F. Ng, Aylwin Xavier, Ramnik J. Li, Cheng Yankner, Bruce A. Scherzer, Clemens R. Yuan, Junying TI Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE reactive oxygen species; type III PI3 kinase; neurodegeneration; signaling; transcriptional regulation ID AMYLOID-BETA; A-BETA; MITOCHONDRIAL DYSFUNCTION; REDUCED EXPRESSION; BASAL AUTOPHAGY; PROTEIN; MICE; ACCUMULATION; INHIBITION; TOXICITY AB Dysregulation of autophagy, a cellular catabolic mechanism essential for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy dysfunction are still not clear. Based on the results of a genome-wide screen, we show that reactive oxygen species (ROS) serve as common mediators upstream of the activation of the type III PI3 kinase, which is critical for the initiation of autophagy. Furthermore, ROS play an essential function in the induction of the type III PI3 kinase and autophagy in response to amyloid beta peptide, the main pathogenic mediator of Alzheimer's disease (AD). However, lysosomal blockage also caused by A beta is independent of ROS. In addition, we demonstrate that autophagy is transcriptionally down-regulated during normal aging in the human brain. Strikingly, in contrast to normal aging, we observe transcriptional up-regulation of autophagy in the brains of AD patients, suggesting that there might be a compensatory regulation of autophagy. Interestingly, we show that an AD drug and an AD drug candidate have inhibitory effects on autophagy, raising the possibility that decreasing input into the lysosomal system may help to reduce cellular stress in AD. Finally, we provide a list of candidate drug targets that can be used to safely modulate levels of autophagy without causing cell death. C1 [Lipinski, Marta M.; Py, Benedicte F.; Yuan, Junying] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Zheng, Bin; Scherzer, Clemens R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Cambridge, MA 02139 USA. [Lu, Tao; Yankner, Bruce A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Yan, Zhenyu; Li, Cheng] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Yuan, JY (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. EM junying_yuan@hms.harvard.edu RI Zheng, Bin/A-6832-2011; Py, Benedicte/M-6129-2014; OI Lipinski, Marta/0000-0002-7537-9014 FU National Institutes of Health [R37 AG012859, PO1 AG027916, AI062773, DK043351, R01 NS064155, R21 NS060227, P01 NS058793]; RJG Foundation; Crohn's and Colitis Foundation of America FX We thank the members of the Yuan laboratory and Institute of Chemistry and Cell Biology (ICCB)-Longwood for help during this work. This work was supported in part by National Institutes of Health Grants R37 AG012859 (to J.Y.), PO1 AG027916 (to B.A.Y. and J.Y.), AI062773 and DK043351 (to R.J.X.), as well as R01 NS064155, R21 NS060227, P01 NS058793, and an RJG Foundation grant (to C.R.S.). A.N. is supported by the Crohn's and Colitis Foundation of America. NR 28 TC 178 Z9 191 U1 2 U2 26 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 10 PY 2010 VL 107 IS 32 BP 14164 EP 14169 DI 10.1073/pnas.1009485107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636UD UT WOS:000280767700036 PM 20660724 ER PT J AU Guo, SQ Lu, J Schlanger, R Zhang, H Wang, JY Fox, MC Purton, LE Fleming, HH Cobb, B Merkenschlager, M Golub, TR Scadden, DT AF Guo, Shangqin Lu, Jun Schlanger, Rita Zhang, Hao Wang, Judy Y. Fox, Michelle C. Purton, Louise E. Fleming, Heather H. Cobb, Bradley Merkenschlager, Matthias Golub, Todd R. Scadden, David T. TI MicroRNA miR-125a controls hematopoietic stem cell number SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IN-VIVO; DICER; DIFFERENTIATION; LEUKEMIA; PROGENITORS; APOPTOSIS; OVEREXPRESSION; PROLIFERATION; DISTINCT; TISSUES AB MicroRNAs influence hematopoietic differentiation, but little is known about their effects on the stem cell state. Here, we report that the microRNA processing enzyme Dicer is essential for stem cell persistence in vivo and a specific microRNA, miR-125a, controls the size of the stem cell population by regulating hematopoietic stem/progenitor cell (HSPC) apoptosis. Conditional deletion of Dicer revealed an absolute dependence for the multipotent HSPC population in a cell-autonomous manner, with increased HSPC apoptosis in mutant animals. An evolutionarily conserved microRNA cluster containing miR-99b, let-7e, and miR-125a was preferentially expressed in long-term hematopoietic stem cells. MicroRNA miR-125a alone was capable of increasing the number of hematopoietic stem cells in vivo by more than 8-fold. This result was accomplished through a differentiation stage-specific reduction of apoptosis in immature hematopoietic progenitors, possibly through targeting multiple proapoptotic genes. Bak1 was directly down-regulated by miR-125a and expression of a 3'UTR-less Bak1 blocked miR-125a-induced hematopoietic expansion in vivo. These data demonstrate cell-state-specific regulation by microRNA and identify a unique microRNA functioning to regulate the stem cell pool size. C1 [Guo, Shangqin; Schlanger, Rita; Fox, Michelle C.; Purton, Louise E.; Fleming, Heather H.; Scadden, David T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. [Guo, Shangqin; Schlanger, Rita; Fox, Michelle C.; Purton, Louise E.; Fleming, Heather H.; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Guo, Shangqin; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Lu, Jun; Zhang, Hao; Wang, Judy Y.; Golub, Todd R.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Lu, Jun; Zhang, Hao; Wang, Judy Y.; Golub, Todd R.] Harvard Univ, Cambridge, MA 02142 USA. [Lu, Jun] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Golub, Todd R.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Cobb, Bradley; Merkenschlager, Matthias] Univ London Imperial Coll Sci Technol & Med, Ctr Clin Sci, Med Res Ctr, Lymphocyte Dev Grp, London W12 0NN, England. [Guo, Shangqin; Lu, Jun; Golub, Todd R.] Yale Univ, Yale Stem Cell Ctr, Dept Genet, New Haven, CT 06520 USA. RP Scadden, DT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. EM dscadden@mgh.harvard.edu RI Xie, Huangming/B-2260-2012; OI Merkenschlager, Matthias/0000-0003-2889-3288 FU Howard Hughes Medical Institute; Medical Research Council [MC_U120027516] NR 38 TC 162 Z9 168 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 10 PY 2010 VL 107 IS 32 BP 14229 EP 14234 DI 10.1073/pnas.0913574107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636UD UT WOS:000280767700047 PM 20616003 ER PT J AU Burrows, AE Smogorzewska, A Elledge, SJ AF Burrows, Anna E. Smogorzewska, Agata Elledge, Stephen J. TI Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; PBAF; SWI/SNF; p21 ID NASOPHARYNGEAL CARCINOMA-CELLS; ONCOGENE-INDUCED SENESCENCE; TRANSCRIPTIONAL REGULATION; HUMAN FIBROBLASTS; BREAST-CANCER; EXPRESSION; CHROMATIN; GENE; COMPLEX; LINES AB A variety of tumor-suppressor mechanisms exist to promote genome integrity and organismal survival. One such mechanism is cellular senescence. In response to replicative aging, DNA damage, and oncogenic stimuli, the p53 and Rb pathways are activated to prevent the proliferation of damaged cells by inducing senescence or apoptosis. We have performed a loss-of-function genetic screen in primary human cells to identify components of the senescence machinery. Here we describe BRD7 and BAF180 as unique regulators of replicative senescence in human cells. Both regulate p53 transcriptional activity toward a subset of its target genes required for replicative and oncogenic stress senescence induction, and BRD7 physically interacts with p53. BRD7 is a deletion target in human cancer, suggesting that loss of BRD7 may provide an additional mechanism to antagonize p53 function in cancer cells. C1 [Burrows, Anna E.; Smogorzewska, Agata; Elledge, Stephen J.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Burrows, Anna E.; Smogorzewska, Agata; Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Burrows, Anna E.; Smogorzewska, Agata; Elledge, Stephen J.] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Smogorzewska, Agata] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Smogorzewska, Agata] Rockefeller Univ, Lab Genome Maintenance, New York, NY 10065 USA. RP Elledge, SJ (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu RI Smogorzewska, Agata/B-8891-2011 FU National Institutes of Health and Department of Defense; Pathology Department at the Massachusetts General Hospital [T32CA09216]; Burroughs Wellcome Fund FX We thank Ji Luo for helpful discussions of the manuscript, members of the Elledge laboratory for advice and reagents, and Bert Vogelstein (Johns Hopkins Medical School, Baltimore), Scott Lowe (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY), and Guang Hu (National Institute of Environmental Health Sciences, Research Triangle Park, NC) for reagents. This work was supported by grants from National Institutes of Health and Department of Defense (to S.J.E.) A.S. was supported by the Pathology Department at the Massachusetts General Hospital (T32CA09216) and by the Burroughs Wellcome Fund Career Award for Medical Scientists, and is an Irma T. Hirschl scholar. S.J.E. is an investigator with The Howard Hughes Medical Institute. NR 29 TC 83 Z9 87 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 10 PY 2010 VL 107 IS 32 BP 14280 EP 14285 DI 10.1073/pnas.1009559107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636UD UT WOS:000280767700056 PM 20660729 ER PT J AU Mitsdoerffer, M Lee, Y Jager, A Kim, HJ Korn, T Kolls, JK Cantor, H Bettelli, E Kuchroo, VK AF Mitsdoerffer, Meike Lee, Youjin Jaeger, Anneli Kim, Hye-Jung Korn, Thomas Kolls, Jay K. Cantor, Harvey Bettelli, Estelle Kuchroo, Vijay K. TI Proinflammatory T helper type 17 cells are effective B-cell helpers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE germinal center; IL-17; immunoglobulin; isotype class switching; T helper cell ID IN-VIVO; IL-21; DIFFERENTIATION; GENERATION; RESPONSES; PLASTICITY; RECEPTOR; LINEAGE; IL-17; TH1 AB T helper type 17 (TH17) cells are highly proinflammatory effector T cells that are characterized by the production of high amounts of IL-17A, IL-17F, IL-21, and IL-22. Furthermore, TH17 cells have been associated with a number of autoimmune diseases. However, it is not clear whether TH17 cells can also serve as effective helper cells. Here we show that TH17 cells can function as B-cell helpers in that they not only induce a strong proliferative response of B cells in vitro but also trigger antibody production with class switch recombination in vivo. Transfer of TH17 cells into WT or T-cell receptor a-deficient mice, which lack endogenous T cells, induces a pronounced antibody response with preferential isotype class switching to IgG1, IgG2a, IgG2b, and IgG3, as well as the formation of germinal centers. Conversely, blockade of IL-17 signaling results in a significant reduction in both number and size of germinal centers. Whereas IL-21 is known to help B cells, IL-17 on its own drives B cells to undergo preferential isotype class switching to IgG2a and IgG3 subtypes. These observations provide insights into the unappreciated role of TH17 cells and their signature cytokines in mediating B-cell differentiation and class switch recombination. C1 [Kim, Hye-Jung; Cantor, Harvey] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mitsdoerffer, Meike; Lee, Youjin; Jaeger, Anneli; Kuchroo, Vijay K.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Korn, Thomas] Tech Univ Munich, Dept Neurol, D-81675 Munich, Germany. [Kolls, Jay K.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA 70112 USA. [Bettelli, Estelle] Benaroya Res Inst, Seattle, WA 98101 USA. RP Cantor, H (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM harvey_cantor@dfci.harvard.edu; ebettelli@benaroyaresearch.org; vkuchroo@rics.bwh.harvard.edu OI Korn, Thomas/0000-0002-3633-0955 FU National Institutes of Health [P01AI045757, P01NS038037, R37NS030843, R01NS035685, P01AI056299, RO1NS059996-01A1]; National Multiple Sclerosis Society [RG2571, TA3014A1/1]; Deutsche Forschungsgemeinschaft [Mi 1221/1-1, KO 2964/2-1] FX We thank T. Koeglsperger for technical assistance with the confocal microscope and D. Kozoriz for cell sorting. This work was supported by National Institutes of Health Grants P01AI045757, P01NS038037, R37NS030843, R01NS035685, P01AI056299 (to V. K. K.) and RO1NS059996-01A1 (to E. B.) and National Multiple Sclerosis Society Grants RG2571 (to V. K. K.) and TA3014A1/1 (to E. B.). V. K. K. is a recipient of the Javits Neuroscience Investigator Award from the National Institutes of Health. M.M. (Mi 1221/1-1) and T.K. (KO 2964/2-1) were supported by the Deutsche Forschungsgemeinschaft. NR 36 TC 199 Z9 203 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 10 PY 2010 VL 107 IS 32 BP 14292 EP 14297 DI 10.1073/pnas.1009234107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636UD UT WOS:000280767700058 PM 20660725 ER PT J AU Kurz, FT Aon, MA O'Rourke, B Armoundas, AA AF Kurz, Felix T. Aon, Miguel A. O'Rourke, Brian Armoundas, Antonis A. TI Spatio-temporal oscillations of individual mitochondria in cardiac myocytes reveal modulation of synchronized mitochondrial clusters SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE wavelets; frequency; amplitude; mitochondrial oscillator; mitochondrial coupling ID COUPLED OSCILLATORS; HEART-CELLS; NETWORK; ORGANIZATION; DYNAMICS; POPULATIONS; CRITICALITY; KURAMOTO; RELEASE; RHYTHMS AB Mitochondrial networks in cardiac myocytes under oxidative stress show collective (cluster) behavior through synchronization of their inner membrane potentials (Delta Psi(m)). However, it is unclear whether the oscillation frequency and coupling strength between individual mitochondria affect the size of the cluster and vice versa. We used the wavelet transform and developed advanced signal processing tools that allowed us to capture individual mitochondrial Delta Psi(m) oscillations in cardiac myocytes and examine their dynamic spatio-temporal properties. Heterogeneous frequency behavior prompted us to sort mitochondria according to their frequencies. Signal analysis of the mitochondrial network showed an inverse relationship between cluster size and cluster frequency as well as between cluster amplitude and cluster size. High cross-correlation coefficients between neighboring mitochondria clustered longitudinally along the myocyte striations, indicated anisotropic communication between mitochondria. Isochronal mapping of the onset of myocyte-wide Delta Psi(m) depolarization further exemplified heterogeneous Delta Psi(m) among mitochondria. Taken together, the results suggest that frequency and amplitude modulation of clusters of synchronized mitochondria arises by means of strong changes in local coupling between neighboring mitochondria. C1 [Kurz, Felix T.; Armoundas, Antonis A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Kurz, Felix T.] Charite, Campus Virchow Klinikum, Med Klin MS Kardiol, D-13353 Berlin, Germany. [Aon, Miguel A.; O'Rourke, Brian] Johns Hopkins Univ, Inst Mol Cardiobiol, Dept Med, Baltimore, MD 21205 USA. RP Armoundas, AA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. EM aarmoundas@partners.org RI Aon, Miguel/A-6564-2008 OI Aon, Miguel/0000-0002-4355-5431 FU American Heart Association [0635127N]; National Institutes of Health [R37-HL54598]; Cardiovascular Research Society; Boehringer Ingelheim Fonds FX The work was supported by an American Heart Association Scientist Development Grant 0635127N, by National Institutes of Health Grant R37-HL54598, by the Cardiovascular Research Society, and by a fellowship from the Boehringer Ingelheim Fonds. NR 42 TC 43 Z9 43 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 10 PY 2010 VL 107 IS 32 BP 14315 EP 14320 DI 10.1073/pnas.1007562107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 636UD UT WOS:000280767700062 PM 20656937 ER PT J AU Shi, M Zabetian, CP Hancock, AM Ginghina, C Hong, Z Yearout, D Chung, KA Quinn, JF Peskind, ER Galasko, D Jankovic, J Leverenz, JB Zhang, J AF Shi, Min Zabetian, Cyrus P. Hancock, Aneeka M. Ginghina, Carmen Hong, Zhen Yearout, Dora Chung, Kathryn A. Quinn, Joseph F. Peskind, Elaine R. Galasko, Douglas Jankovic, Joseph Leverenz, James B. Zhang, Jing TI Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson's disease SO NEUROSCIENCE LETTERS LA English DT Article DE Biomarker; DJ-1; alpha-Synuclein; Plasma; Parkinson's disease; Alzheimer's disease ID CEREBROSPINAL-FLUID; HUMAN PLASMA; BIOMARKERS; MARKER; ELISA AB DJ-1 and alpha-synuclein are leading biomarkers for Parkinson's disease diagnosis and/or monitoring disease progression. A few recent investigations have determined DJ-1 and alpha-synuclein levels in plasma or serum, a more convenient sample source than cerebrospinal fluid; but the results were variable or even contradictory. Besides limitations in detection technology and limited number of cases in some studies, inadequate control of several important confounders likely has contributed to these inconsistent results. In this study, the relative contribution of each blood component to blood DJ-1 and alpha-synuclein was evaluated, followed by quantification of plasma levels of both markers in a larger cohort of patients/subjects (similar to 300 cases) whose cerebrospinal fluid DJ-1 and alpha-synuclein levels have been determined recently. The results demonstrated that the DJ-1 and alpha-synuclein in blood resided predominantly in red blood cells (>95%), followed by platelets (1-4%), white blood cells and plasma (<= 1%), indicating that variations in hemolysis and/or platelet contamination could have a significant effect on plasma/serum DJ-1 and alpha-synuclein levels. Nonetheless, after adjusting for the age, although there was a trend of decrease in DJ-1 and alpha-synuclein in patients with Parkinson's or Alzheimer's disease compared with healthy controls, no statistical difference was observed in this cohort between any groups, even when the extent of hemolysis and platelet contamination were controlled for. Additionally, no correlation between DJ-1 or alpha-synuclein and Parkinson's disease severity was identified. In conclusion, unlike in cerebrospinal fluid, total DJ-1 or alpha-synuclein in plasma alone is not useful as biomarkers for Parkinson's disease diagnosis or progression/severity. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Shi, Min; Hancock, Aneeka M.; Ginghina, Carmen; Hong, Zhen; Zhang, Jing] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98104 USA. [Zabetian, Cyrus P.; Yearout, Dora] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Zabetian, Cyrus P.; Yearout, Dora; Leverenz, James B.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA 98104 USA. [Chung, Kathryn A.; Quinn, Joseph F.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Peskind, Elaine R.; Leverenz, James B.] Vet Affairs Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Peskind, Elaine R.; Leverenz, James B.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98104 USA. [Galasko, Douglas] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Jankovic, Joseph] Baylor Coll Med, Parkinsons Dis Ctr, Houston, TX 77030 USA. [Zhang, Jing] Baylor Coll Med, Movement Disorders Clin, Houston, TX 77030 USA. RP Zhang, J (reprint author), Univ Washington, Sch Med, Dept Pathol, Box 359635,325 9th Ave, Seattle, WA 98104 USA. EM zhangj@uw.edu RI Shi, Min/G-6165-2012; OI Shi, Min/0000-0002-6901-2558; Zabetian, Cyrus/0000-0002-7739-4306 FU National Institutes of Health [ES004696, NS057567, AG025327, AG033398, NS060252, NS062684, AG005136, AG008017]; Michael J. Fox Foundation FX This research was supported by the National Institutes of Health grants (ES004696, NS057567, AG025327, AG033398, NS060252, NS062684, AG005136 and AG008017) as well as grants from the Michael J. Fox Foundation. We thank Mr. Joshua Bradner and Travis Cook for their assistance on sample preparation and assays, and Mr. Thomas Quinn for manuscript preparation. We also deeply appreciate those who have donated their blood for our studies. NR 20 TC 60 Z9 63 U1 2 U2 11 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 AUG 9 PY 2010 VL 480 IS 1 BP 78 EP 82 DI 10.1016/j.neulet.2010.06.009 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 633AJ UT WOS:000280471400018 PM 20540987 ER PT J AU Ismail-Beigi, F Craven, T Banerji, MA Basile, J Calles, J Cohen, RM Cuddihy, R Cushman, WC Genuth, S Grimm, RH Hamilton, BP Hoogwerf, B Karl, D Katz, L Krikorian, A O'Connor, P Pop-Busui, R Schubart, U Simmons, D Taylor, H Thomas, A Weiss, D Hramiak, I AF Ismail-Beigi, Faramarz Craven, Timothy Banerji, Mary Ann Basile, Jan Calles, Jorge Cohen, Robert M. Cuddihy, Robert Cushman, William C. Genuth, Saul Grimm, Richard H., Jr. Hamilton, Bruce P. Hoogwerf, Byron Karl, Diane Katz, Lois Krikorian, Armand O'Connor, Patrick Pop-Busui, Rodica Schubart, Ulrich Simmons, Debra Taylor, Harris Thomas, Abraham Weiss, Daniel Hramiak, Irene CA ACCORD Trial Grp TI Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial SO LANCET LA English DT Article ID URINARY ALBUMIN EXCRETION; BLOOD-GLUCOSE CONTROL; CLINICAL-TRIALS; RISK-FACTORS; COMPLICATIONS; UKPDS; PROGRESSION; MELLITUS; MICROALBUMINURIA; HYPERTENSION AB Background Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes. Methods ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA(1c). concentrations (>7.5%), and cardiovascular disease (or >= 2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A(1c) [HbA(1c)] of <6.0%) or standard (7.0-7.9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291.7 mu mol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov, number NCT00000620. Findings 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1.00, 95% CI 0.88-1.14; p=1.00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0.96, 0.89-1.02; p=0.19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 [HR 0.95,95% CI 0.85-1.07, p=0.44]; and second 1956 of 5119 vs 2046 of 5115, respectively [0.95, 0.89-1.01, p=0.12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy (p<0.05). Interpretation Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia. C1 [Ismail-Beigi, Faramarz] Case Western Reserve Univ, Dept Med, Div Clin & Mol Endocrinol, Cleveland, OH 44106 USA. [Craven, Timothy] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Banerji, Mary Ann] Suny Downstate Med Ctr, New York, NY USA. [Basile, Jan] Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. [Calles, Jorge] Wake Forest Univ, Baptist Med Ctr, Winston Salem, NC 27109 USA. [Cohen, Robert M.] Univ Cincinnati, Cincinnati, OH USA. [Cohen, Robert M.] Cincinnati Vet Affairs Med Ctr, Cincinnati, OH USA. [Cuddihy, Robert] Int Diabet Ctr Pk Nicollet, Minneapolis, MN USA. [Cuddihy, Robert] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Cushman, William C.] Memphis Vet Affairs Med Ctr, Memphis, TN USA. [Grimm, Richard H., Jr.] Berman Ctr Outcomes & Clin Res, Minneapolis, MN USA. [Hamilton, Bruce P.] VA Med Ctr, Baltimore, MD USA. [Hamilton, Bruce P.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Hoogwerf, Byron] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Karl, Diane] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Katz, Lois] NYU, Sch Med, VA New York Harbor Healthcare Syst, New York, NY 10003 USA. [O'Connor, Patrick] HealthPartners Res Fdn, Minneapolis, MN USA. [Pop-Busui, Rodica] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Schubart, Ulrich] Albert Einstein Coll Med, Jacobi Med Ctr, Bronx, NY 10467 USA. [Simmons, Debra] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. Henry Ford Hosp, Detroit, MI 48202 USA. [Weiss, Daniel] Your Diabet Endocrine Nutr Grp, Mentor, OH USA. [Hramiak, Irene] St Josephs Hlth Care, London, ON, Canada. RP Ismail-Beigi, F (reprint author), Case Western Reserve Univ, Dept Med, Div Clin & Mol Endocrinol, 10900 Euclid Ave, Cleveland, OH 44106 USA. EM faramarz.ismail-beigi@case.edu RI Friedewald, William/C-8034-2011; Bryan, R. Nick/P-1661-2014; OI Thomas, Abraham/0000-0002-3941-1195 FU National Heart, Lung, and Blood Institute [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, IAA-Y1-HC-1010]; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, National Institute on Aging; National Institutes of Health, National Eye Institute; Centers for Disease Control and Prevention; General Clinical Research Centers; Novartis; Boehringer Ingelheim; Roche; Sanofi-Aventis; BMS; Takeda; Eli Lilly; Merck; US National Institutes of Health; Roche Diabetes; Novo Nordisk; Cequr; Bayer; Eli Lily; Abbott; Amylin; Dalichi-Sankyo; Edwards Lifesciences; Dexcom; Johnson and Johnson/Lifescan; Mannkind; Medtronic; Quotient Diagnostics; ResMed; King Pharmaceuticals; Lawson Research Institute; Bristol-Myers Squibb; Hofmann-La Roche; Merck Frosst; Pfizer; Eisai; Inekrin; Oresigen FX The ACCORD Trial was supported by grants (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035, and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by other components of the National Institutes of Health, including the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; and by General Clinical Research Centers. The following companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Takeda Pharmaceuticals.; MAB has received consulting fees from Novartis, Boehringer Ingelheim, Roche, and Sanofi-Aventis; board membership fees from Novartis and BMS; grants from Roche, Boehringer Ingleheim, Takeda, Novartis, and Eli Lilly; honoraria from Merck and Sanofi-Aventis; and travel expenses from the US National Institutes of Health, Merck, Sanofi-Aventis, Roche and Boehringer Ingelheim. JC has received grants from Merck and honoraria and travel expenses from Sanofi-Aventis and Merck. RMC has received grants from the US National Institutes of Health and holds stock in Abbott Laboratories. RC has received grant and travel support from the US National Institutes of Health; board membership fees from Roche Diabetes; consultancy fees from Novo Nordisk, Cequr, Bayer, Eli Lily, Abbott; grant support from Amylin, Abbott, Bayer, Dalichi-Sankyo, Edwards Lifesciences, Elil Lily, Dexcom, Johnson and Johnson/Lifescan, Mannkind, Medtronic, Merck, NovoNordisk, Quotient Diagnostics, ResMed, Roche, Sanofi-Aventis, and Takeda; honoraria from Novo Nordisk and Roche; and payment for development of educational presentations from Eli Lilly, Johnson and Johnson/Lifescan, Merck, Novartis, Sanofi-Aventis. WCC has received consulting fees from Novartis, Sanofi-Aventis, Takeda, Bristol-Myers Squibb, King Pharmaceuticals, and Daiichi-Sankyo, and grant funding from Novartis and GlaxoSmithKline and NHLBI. RHG has received Data and Safety Monitoring Boards funding for Pfizer. BH has received travel support from NHLBI. BH has received full-time employment salary with stock benefits from Eli Lilly. IH has received consulting fees from GlaxoSmithKline; grants from Lawson Research Institute, Bristol-Myers Squibb, Eli Lilly, Hofmann-La Roche, Merck Frosst, Novo Nordisk, Pfizer, Sanofi-Aventis, and Abbott; honoraria from Boehringer Ingelheim, Eli Lilly, Bristol Myers Squibb, Merck Frosst, GlaxoSmithKline, Medtronic, Novo Nordisk, and Sanofi-Aventis; payment for development of educational programs from Bristol-Myers Squibb, AstraZeneca, and Merck Frosst; and travel support from Merck Frosst and Sanofi-Aventis. Fl-B has received travel support from NHLBI. DK has received grants from Amylin and Sanofi-Aventis, and honoraria from Amylin, Sanofi-Aventis, and Novo Nordisk, and travel support from NHLBI. LK has received grants from Novartis and Abbott; honoraria from Novartis; and travel support from Narrows Research Foundation. PO'C has received grant and travel support from NHLBI. RP-B has received consulting fees from Pfizer; grants from Amylin; and honoraria from GlaxoSmithKline and Pfizer. US has received grant and travel support from NHLBI. AT has received consulting fees from Novo Nordisk and Takeda; grants from Eli Lily, Amylin, Roche, and Abbot; and travel support from Novo Nordisk, Takeda, and NHLBI. DW reports grants from Amylin, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Eli Lily, Inekrin, Mannkind, Novo Nordisk, Oresigen, Sanofi-Aventis, Takeda; honoraria from Amylin, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lily, GlaxoSmithKline, Merk, Novo Nordisk, Sanofi-Aventis, and Takeda; and payment for development of educational materials from Daiichi Sankyo. All other authors declare that they have no conflicts of interest. NR 32 TC 394 Z9 408 U1 3 U2 36 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 AUG 7 PY 2010 VL 376 IS 9739 BP 419 EP 430 DI 10.1016/S0140-6736(10)60576-4 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 639YK UT WOS:000281012900027 PM 20594588 ER PT J AU Szostak, J AF Szostak, Jack TI Out of a harsh and hostile earth SO NEW SCIENTIST LA English DT Editorial Material C1 [Szostak, Jack] Harvard Univ, Sch Med, Dept Genet, Cambridge, MA 02138 USA. [Szostak, Jack] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Szostak, J (reprint author), Harvard Univ, Sch Med, Dept Genet, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU REED BUSINESS INFORMATION LTD PI SUTTON PA QUADRANT HOUSE THE QUADRANT, SUTTON SM2 5AS, SURREY, ENGLAND SN 0262-4079 J9 NEW SCI JI New Sci. PD AUG 7 PY 2010 VL 207 IS 2772 BP 26 EP 27 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 635RB UT WOS:000280672700029 ER PT J AU Aristophanous, M Rottmann, J Park, SJ Nishioka, S Shirato, H Berbeco, RI AF Aristophanous, Michalis Rottmann, Joerg Park, Sang-June Nishioka, Seiko Shirato, Hiroki Berbeco, Ross I. TI Image-guided adaptive gating of lung cancer radiotherapy: a computer simulation study SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID STEREOTACTIC BODY RADIOTHERAPY; EXTERNAL RESPIRATORY SURROGATES; GATED RADIOTHERAPY; RADIATION-THERAPY; TUMOR POSITION; MOTION; TRACKING; FEASIBILITY; INTRAFRACTION; DELIVERY AB The purpose of this study is to investigate the effect that image-guided adaptation of the gating window during treatment could have on the residual tumor motion, by simulating different gated radiotherapy techniques. There are three separate components of this simulation: (1) the 'Hokkaido Data', which are previously measured 3D data of lung tumor motion tracks and the corresponding 1D respiratory signals obtained during the entire ungated radiotherapy treatments of eight patients, (2) the respiratory gating protocol at our institution and the imaging performed under that protocol and (3) the actual simulation in which the Hokkaido Data are used to select tumor position information that could have been collected based on the imaging performed under our gating protocol. We simulated treatments with a fixed gating window and a gating window that is updated during treatment. The patient data were divided into different fractions, each with continuous acquisitions longer than 2 min. In accordance to the imaging performed under our gating protocol, we assume that we have tumor position information for the first 15 s of treatment, obtained from kV fluoroscopy, and for the rest of the fractions the tumor position is only available during the beam-on time from MV imaging. The gating window was set according to the information obtained from the first 15 s such that the residual motion was less than 3 mm. For the fixed gating window technique the gate remained the same for the entire treatment, while for the adaptive technique the range of the tumor motion during beam-on time was measured and used to adapt the gating window to keep the residual motion below 3 mm. The algorithm used to adapt the gating window is described. The residual tumor motion inside the gating window was reduced on average by 24% for the patients with regular breathing patterns and the difference was statistically significant (p-value = 0.01). The magnitude of the residual tumor motion depended on the regularity of the breathing pattern suggesting that image-guided adaptive gating should be combined with breath coaching. The adaptive gating window technique was able to track the exhale position of the breathing cycle quite successfully. Out of a total of 53 fractions the duty cycle was greater than 20% for 42 fractions for the fixed gating window technique and for 39 fractions for the adaptive gating window technique. The results of this study suggest that real-time updating of the gating window can result in reliably low residual tumor motion and therefore can facilitate safe margin reduction. C1 [Aristophanous, Michalis; Rottmann, Joerg; Park, Sang-June; Berbeco, Ross I.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Aristophanous, Michalis; Rottmann, Joerg; Park, Sang-June; Berbeco, Ross I.] Harvard Univ, Sch Med, Boston, MA USA. [Nishioka, Seiko] NTT Hosp, Dept Radiol, Sapporo, Hokkaido, Japan. [Shirato, Hiroki] Hokkaido Univ, Sch Med, Dept Radiat Med, Sapporo, Hokkaido 060, Japan. RP Aristophanous, M (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM maristophanous@lroc.harvard.edu RI Shirato, Hiroki/A-7068-2010 NR 35 TC 9 Z9 9 U1 1 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD AUG 7 PY 2010 VL 55 IS 15 BP 4321 EP 4333 DI 10.1088/0031-9155/55/15/009 PG 13 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 628JI UT WOS:000280115200009 PM 20647609 ER PT J AU Lane, AA Scadden, DT AF Lane, Andrew A. Scadden, David T. TI Stem Cells and DNA Damage: Persist or Perish? SO CELL LA English DT Editorial Material C1 [Lane, Andrew A.; Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Ctr Regenerat Med, Boston, MA 02114 USA. [Lane, Andrew A.; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Boston, MA 02114 USA. RP Lane, AA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Ctr Regenerat Med, Boston, MA 02114 USA. EM aalane@partners.org; dscadden@mgh.harvard.edu NR 6 TC 17 Z9 17 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 6 PY 2010 VL 142 IS 3 BP 360 EP 362 DI 10.1016/j.cell.2010.07.030 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 634TS UT WOS:000280609100011 PM 20691895 ER PT J AU Seita, J Rossi, DJ Weissman, IL AF Seita, Jun Rossi, Derrick J. Weissman, Irving L. TI Differential DNA Damage Response in Stem and Progenitor Cells SO CELL STEM CELL LA English DT Editorial Material ID RESISTANCE; BCL-2; MOUSE C1 [Seita, Jun; Weissman, Irving L.] Stanford Univ, Stanford Inst Stem Cell Biol & Regenerat Med, Sch Med, Stanford, CA 94305 USA. [Rossi, Derrick J.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Rossi, Derrick J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Rossi, Derrick J.] Immune Dis Inst, Boston, MA 02115 USA. [Rossi, Derrick J.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. RP Seita, J (reprint author), Stanford Univ, Stanford Inst Stem Cell Biol & Regenerat Med, Sch Med, Stanford, CA 94305 USA. EM jseita@stanford.edu OI Seita, Jun/0000-0002-3008-3615 NR 10 TC 23 Z9 23 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD AUG 6 PY 2010 VL 7 IS 2 BP 145 EP 147 DI 10.1016/j.stem.2010.07.006 PG 3 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 641EK UT WOS:000281107400006 PM 20682442 ER PT J AU Kokovay, E Goderie, S Wang, Y Lotz, S Lin, G Sun, Y Roysam, B Shen, Q Temple, S AF Kokovay, Erzsebet Goderie, Susan Wang, Yue Lotz, Steve Lin, Gang Sun, Yu Roysam, Badrinath Shen, Qin Temple, Sally TI Adult SVZ Lineage Cells Home to and Leave the Vascular Niche via Differential Responses to SDF1/CXCR4 Signaling SO CELL STEM CELL LA English DT Article ID NEURAL STEM-CELLS; POSTNATAL SUBVENTRICULAR ZONE; CHEMOKINE RECEPTOR CXCR4; PROGENITOR CELLS; NEUROBLAST MIGRATION; NEURONAL MIGRATION; MAMMALIAN BRAIN; NEUROGENESIS; STROKE; PRECURSORS AB Neural progenitor cells (NPCs) in the adult subventricular zone (SVZ) are associated with ependymal and vasculature niches, which regulate stem cell self-renewal and differentiation. Activated Type B stem cells and their progeny, the transit-amplifying type C cells, which express EGFR, are most highly associated with vascular cells, indicating that this niche supports lineage progression. Here, we show that proliferative SVZ progenitor cells home to endothelial cells in a stromal-derived factor 1 (SDF1)- and CXC chemokine receptor 4 (CXCR4)-dependent manner. We show that SDF1 strongly upregulates EGFR and alpha 6 integrin in activated type B and type C cells, enhancing their activated state and their ability to bind laminin in the vascular niche. SDF1 increases the motility of type A neuroblasts, which migrate from the SVZ toward the olfactory bulb. Thus, differential responses to SDF1 can regulate progenitor cell occupancy of and exit from the adult SVZ vascular niche. C1 [Kokovay, Erzsebet; Goderie, Susan; Wang, Yue; Lotz, Steve; Shen, Qin; Temple, Sally] New York Neural Stem Cell Inst, Rensselaer, NY 12144 USA. [Kokovay, Erzsebet; Shen, Qin; Temple, Sally] Albany Med Coll, Ctr Neuropharmacol & Neurosci, Albany, NY 12208 USA. [Lin, Gang; Roysam, Badrinath] Rensselaer Polytech Inst, Rensselaer, NY 12180 USA. [Sun, Yu] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Temple, S (reprint author), New York Neural Stem Cell Inst, Rensselaer, NY 12144 USA. EM sallytemple@nynsci.org FU NIH [R01NS051531]; Regenerative Research Foundation; NIDA [5T32DA007307] FX We thank Chris Fasano and Tim Phoenix for assistance in generating lentiviral shRNA contructs and Patty Lederman for invaluable technical support. This project was supported by NIH grant R01NS051531 and the Regenerative Research Foundation, and E.K. was supported in part by NIDA grant 5T32DA007307. NR 53 TC 162 Z9 168 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD AUG 6 PY 2010 VL 7 IS 2 BP 163 EP 173 DI 10.1016/j.stem.2010.05.019 PG 11 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 641EK UT WOS:000281107400009 PM 20682445 ER PT J AU Michelow, IC Dong, MD Mungall, BA Yantosca, LM Lear, C Ji, X Karpel, M Rootes, CL Brudner, M Houen, G Eisen, DP Kinane, TB Takahashi, K Stahl, GL Olinger, GG Spear, GT Ezekowitz, RAB Schmidt, EV AF Michelow, Ian C. Dong, Mingdong Mungall, Bruce A. Yantosca, L. Michael Lear, Calli Ji, Xin Karpel, Marshall Rootes, Christina L. Brudner, Matthew Houen, Gunnar Eisen, Damon P. Kinane, T. Bernard Takahashi, Kazue Stahl, Gregory L. Olinger, Gene G. Spear, Gregory T. Ezekowitz, R. Alan B. Schmidt, Emmett V. TI A Novel L-ficolin/Mannose-binding Lectin Chimeric Molecule with Enhanced Activity against Ebola Virus SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PATTERN-RECOGNITION MOLECULE; CELL-SURFACE CALRETICULIN; SERINE PROTEASES; OPSONIC ACTIVITY; DEFICIENT MICE; HUMAN PLASMA; L-FICOLIN; PROTEIN; COMPLEMENT; SITE AB Ebola viruses constitute a newly emerging public threat because they cause rapidly fatal hemorrhagic fevers for which no treatment exists, and they can be manipulated as bioweapons. We targeted conserved N-glycosylated carbohydrate ligands on viral envelope surfaces using novel immune therapies. Mannose-binding lectin (MBL) and L-ficolin (L-FCN) were selected because they function as opsonins and activate complement. Given that MBL has a complex quaternary structure unsuitable for large scale cost-effective production, we sought to develop a less complex chimeric fusion protein with similar ligand recognition and enhanced effector functions. We tested recombinant human MBL and three L-FCN/MBL variants that contained the MBL carbohydrate recognition domain and varying lengths of the L-FCN collagenous domain. Non-reduced chimeric proteins formed predominantly nona-and dodecameric oligomers, whereas recombinant human MBL formed octadecameric and larger oligomers. Surface plasmon resonance revealed that L-FCN/MBL76 had the highest binding affinities for N-acetylglucosamine-bovine serum albumin and mannan. The same chimeric protein displayed superior complement C4 cleavage and binding to calreticulin (cC1qR), a putative receptor for MBL. L-FCN/MBL76 reduced infection by wild type Ebola virus Zaire significantly greater than the other molecules. Tapping mode atomic force microscopy revealed that L-FCN/MBL76 was significantly less tall than the other molecules despite similar polypeptide lengths. We propose that alterations in the quaternary structure of L-FCN/MBL76 resulted in greater flexibility in the collagenous or neck region. Similarly, a more pliable molecule might enhance cooperativity between the carbohydrate recognition domains and their cognate ligands, complement activation, and calreticulin binding dynamics. L-FCN/MBL chimeric proteins should be considered as potential novel therapeutics. C1 [Michelow, Ian C.; Brudner, Matthew; Kinane, T. Bernard; Takahashi, Kazue] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp,Program Dev Immunol, Boston, MA 02114 USA. [Dong, Mingdong] Univ Aarhus, Interdisciplinary Nanosci Ctr iNANO, DK-8000 Aarhus, Denmark. [Mungall, Bruce A.; Rootes, Christina L.] Commonwealth Sci & Ind Res Org Livestock Ind, Australian Anim Hlth Lab, Geelong, Vic 3220, Australia. [Lear, Calli; Olinger, Gene G.] USA, Med Res Inst Infect Dis, Div Virol, Frederick, MD 21702 USA. [Ji, Xin; Spear, Gregory T.] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. [Houen, Gunnar] Statens Serum Inst, Dept Clin Biochem & Immunol, DK-2300 Copenhagen, Denmark. [Eisen, Damon P.] Royal Melbourne Hosp, Victorian Infect Dis Serv, Parkville, Vic 3050, Australia. [Stahl, Gregory L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Michelow, IC (reprint author), Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp,Program Dev Immunol, 55 Fruit St,GRJ 1402, Boston, MA 02114 USA. EM imichelow@partners.org RI Dong, Mingdong/B-3341-2010; OI Dong, Mingdong/0000-0002-2025-2171; Olinger, Gene/0000-0001-7338-0292; Houen, Gunnar/0000-0002-5948-4156 FU National Institutes of Health [U01 AI070330, R01 HL52886, R01 HL56086, R21 HL092469, P50 DE016191]; United States Department of Defense, Defense Threat Reduction Agency [4.10006, 4.10007] FX This work was supported, in whole or in part, by National Institutes of Health Grants U01 AI070330 (to E. V. S.) and R01 HL52886, R01 HL56086, R21 HL092469, and P50 DE016191 (to G. L. S.). This work was also supported by United States Department of Defense, Defense Threat Reduction Agency Biological Therapeutics Program Grants 4.10006 and 4.10007 (to G. G. O.). NR 47 TC 33 Z9 35 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 6 PY 2010 VL 285 IS 32 BP 24729 EP 24739 DI 10.1074/jbc.M110.106260 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 633YB UT WOS:000280542100045 PM 20516066 ER PT J AU Murthy, S Ryan, A He, C Mallampalli, RK Carter, AB AF Murthy, Shubha Ryan, Alan He, Chao Mallampalli, Rama K. Carter, A. Brent TI Rac1-mediated Mitochondrial H2O2 Generation Regulates MMP-9 Gene Expression in Macrophages via Inhibition of SP-1 and AP-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; NF-KAPPA-B; MATRIX METALLOPROTEINASES; TNF-ALPHA; TRANSCRIPTIONAL ACTIVATION; SP1 PHOSPHORYLATION; SIGNAL-TRANSDUCTION; TISSUE INHIBITOR; BINDING-PROTEIN; IV COLLAGENASE AB Aberrant matrix deposition is a hallmark of pulmonary fibrosis and is characterized by an imbalance between matrix deposition and degradation. We have previously shown that mice harboring a conditional deletion of the GTP-binding protein, Rac1, in macrophages are protected from asbestos-induced pulmonary fibrosis. To investigate the contribution of aberrant matrix degradation, we addressed the role of Rac1 in regulating expression of macrophage-specific MMP-9 (matrix metalloproteinase-9). We found that MMP-9 gene transcription was significantly greater in Rac1 null macrophages. Deletion and mutational analysis of the MMP-9 promoter revealed that both SP-1 and AP-1 are essential for MMP-9 transcription. Overexpression of constitutive active Rac1 (V12) revealed that H2O2 was derived from the mitochondria. Rac1-induced H2O2 generation down-regulated MMP-9 gene transcription, whereas catalase overexpression in WT cells enhanced MMP-9 expression. SP-1 interacted directly with both c-Jun and c-Fos, and H2O2 decreased this binding, suggesting that SP-1 and AP-1 function cooperatively to regulate MMP-9 transcription. Rac1-mediated H2O2 inhibited the ERK MAPK, which was essential for activation of SP-1 and AP-1. ERK activation and MMP-9 expression were recovered by overexpressing catalase or transfecting siRNA for the mitochondrial iron-sulfur protein, Rieske. These observations were recapitulated in vivo. MMP-9 mRNA was higher in alveolar macrophages isolated from Rac1 null mice and wild type mice given catalase. Rac1 regulates MMP-9 transcription via mitochondrial H2O2 generation, providing a potential mechanism by which Rac1 null mice fail to develop pulmonary fibrosis. C1 [Murthy, Shubha; Ryan, Alan; Carter, A. Brent] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [He, Chao; Carter, A. Brent] Univ Iowa, Carver Coll Med, Dept Free Rad & Radiat Biol, Iowa City, IA 52242 USA. [Carter, A. Brent] Univ Iowa, Coll Publ Hlth, Dept Human Toxicol, Iowa City, IA 52242 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. RP Carter, AB (reprint author), Univ Iowa, Carver Coll Med, Dept Internal Med, C33 GH, Iowa City, IA 52242 USA. FU National Institutes of Health [HL068135, HL081784, HL097376, ES015981, ES014871]; Department of Veterans Affairs, Office of Research and Development FX This work was supported, in whole or in part, by National Institutes of Health Grants HL068135, HL081784, and HL097376 (to R. K. M.) and ES015981 and ES014871 (to A. B. C.). This work was also supported by a grant from the Department of Veterans Affairs, Office of Research and Development (to R. K. M.). NR 57 TC 27 Z9 29 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 6 PY 2010 VL 285 IS 32 BP 25062 EP 25073 DI 10.1074/jbc.M109.099655 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 633YB UT WOS:000280542100079 PM 20529870 ER PT J AU Drain, PK Barry, M AF Drain, Paul K. Barry, Michele TI Cuban Health Care: Benefits Without Costs Response SO SCIENCE LA English DT Letter C1 [Drain, Paul K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barry, Michele] Stanford Univ, Sch Med, Palo Alto, CA 94305 USA. RP Drain, PK (reprint author), Massachusetts Gen Hosp, 55 Fruit St,GRJ-504, Boston, MA 02114 USA. EM pkdrain@gmail.com NR 6 TC 0 Z9 1 U1 1 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 6 PY 2010 VL 329 IS 5992 BP 628 EP 628 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 634RV UT WOS:000280602700015 ER PT J AU Richardson, PG Weller, E Lonial, S Jakubowiak, AJ Jagannath, S Raje, NS Avigan, DE Xie, WL Ghobrial, IM Schlossman, RL Mazumder, A Munshi, NC Vesole, DH Joyce, R Kaufman, JL Doss, D Warren, DL Lunde, LE Kaster, S DeLaney, C Hideshima, T Mitsiades, CS Knight, R Esseltine, DL Anderson, KC AF Richardson, Paul G. Weller, Edie Lonial, Sagar Jakubowiak, Andrzej J. Jagannath, Sundar Raje, Noopur S. Avigan, David E. Xie, Wanling Ghobrial, Irene M. Schlossman, Robert L. Mazumder, Amitabha Munshi, Nikhil C. Vesole, David H. Joyce, Robin Kaufman, Jonathan L. Doss, Deborah Warren, Diane L. Lunde, Laura E. Kaster, Sarah DeLaney, Carol Hideshima, Teru Mitsiades, Constantine S. Knight, Robert Esseltine, Dixie-Lee Anderson, Kenneth C. TI Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; INDUCTION TREATMENT PRIOR; PLUS DEXAMETHASONE; PERIPHERAL NEUROPATHY; IMPROVED SURVIVAL; COMPLETE RESPONSE; THALIDOMIDE; PROGRESSION; MELPHALAN; EFFICACY AB This phase 1/2 study is the first prospective evaluation of lenalidomide-bortezomib-dexamethasone in front-line myeloma. Patients (N = 66) received 3-week cycles (n = 8) of bortezomib 1.0 or 1.3 mg/m(2) (days 1, 4, 8, 11), lenalidomide 15 to 25 mg (days 1-14), and dexamethasone 40 or 20 mg (days 1, 2, 4, 5, 8, 9, 11, 12). Responding patients proceeded to maintenance or transplantation. Phase 2 dosing was determined to be bortezomib 1.3 mg/m2, lenalidomide 25 mg, and dexamethasone 20 mg. Most common toxicities included sensory neuropathy (80%) and fatigue (64%), with only 27%/2% and 32%/3% grade 2/3, respectively. In addition, 32% reported neuropathic pain (11%/3%, grade 2/3). Grade 3/4 hematologic toxicities included lymphopenia (14%), neutropenia (9%), and thrombocytopenia (6%). Thrombosis was rare (6% overall), and no treatment-related mortality was observed. Rate of partial response was 100% in both the phase 2 population and overall, with 74% and 67% each achieving very good partial response or better. Twenty-eight patients (42%) proceeded to undergo transplantation. With median follow-up of 21 months, estimated 18-month progression-free and overall survival for the combination treatment with/without transplantation were 75% and 97%, respectively. Lenalidomide-bortezomib-dexamethasone demonstrates favorable tolerability and is highly effective in the treatment of newly diagnosed myeloma. This study is registered at http://clinicaltrials.gov as NCT00378105. (Blood. 2010; 116(5): 679-686) C1 [Richardson, Paul G.; Weller, Edie; Xie, Wanling; Ghobrial, Irene M.; Schlossman, Robert L.; Munshi, Nikhil C.; Doss, Deborah; Warren, Diane L.; Lunde, Laura E.; Hideshima, Teru; Mitsiades, Constantine S.; Anderson, Kenneth C.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lonial, Sagar; Kaufman, Jonathan L.] Emory Winship Canc Inst, Atlanta, GA USA. [Jakubowiak, Andrzej J.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Jagannath, Sundar; Mazumder, Amitabha; Vesole, David H.] St Vincents Comprehens Canc Ctr, New York, NY USA. [Raje, Noopur S.; Kaster, Sarah] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Avigan, David E.; Joyce, Robin; DeLaney, Carol] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Knight, Robert] Celgene Inc, Summit, NJ USA. [Esseltine, Dixie-Lee] Millennium Pharmaceut Inc, Cambridge, MA USA. RP Richardson, PG (reprint author), Dana Farber Canc Inst, 44 Binney St,Dana 1B02, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu FU Millennium Pharmaceuticals; Celgene; Bristol-Myers Squibb; AstraZeneca; Novartis FX Conflict-of-interest disclosure: P.G.R.: advisory boards for Millennium Pharmaceuticals, Celgene, and Johnson & Johnson group companies. S.L.: consultancy/advisory committee for and research funding from Millennium Pharmaceuticals, Celgene, Bristol-Myers Squibb, and Novartis. A.J.J.: consultancy/member of speakers' bureau/advisory committee for and received honoraria from Millennium Pharmaceuticals, Celgene, Exelixis, Bristol-Myers Squibb, and Centocor OrthoBiotech. S.J.: honoraria from Millennium Pharmaceuticals, Celgene, and Merck. N.S.R.: consultancy for Celgene, Novartis, and Amgen; member of speakers' bureau for, and honoraria from, Celgene, Millennium Pharmaceuticals, and Novartis; and research funding from AstraZeneca. D.E.A.: consultancy for and honoraria from Millennium Pharma-ceuticals. I.M.G.: consultancy, member of speaker bureaus for, and honoraria from Millennium Pharmaceuticals, Celgene, and Novartis, and research funding from Millennium Pharmaceuticals. R.L.S.: consultancy for Celgene and honoraria from Celgene and Millennium Pharmaceuticals. A.M.: member of speakers' bureau/advisory committee for and honoraria from Millennium Pharmaceuticals and Celgene and research funding from Millennium Pharmaceuticals. N.C.M.: consultancy for and honoraria from Millennium Pharmaceuticals, Celgene, and Novartis. D.H.V.: member of speakers' bureau/advisory committee for Celgene and Millennium Pharmaceuticals. J.L.K.: consultancy for and honoraria and research funding from Millennium Pharmaceuticals and Celgene. D.D.: member of speakers' bureau/advisory committee for and honoraria from Millennium Pharmaceuticals. T.H.: consultancy for Biotest AG. C.S.M.: consultancy for and honoraria from Millennium Pharmaceuticals, Novartis, Pharmion, and Centocor. R.K.: employee of and equity ownership in Celgene. D.-L. E.: employee of Millennium Pharmaceuticals and equity ownership in Millennium/Takeda and Johnson & Johnson. K.C.A.: consultancy for and research funding from Millennium Pharmaceuticals, Celgene, and Novartis. NR 47 TC 400 Z9 411 U1 5 U2 30 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 5 PY 2010 VL 116 IS 5 BP 679 EP 686 DI 10.1182/blood-2010-02-268862 PG 8 WC Hematology SC Hematology GA 634PX UT WOS:000280596500006 PM 20385792 ER PT J AU Bunn, HF Nathan, DG Dover, GJ Hebbel, RP Platt, OS Rosse, WF Ware, RE AF Bunn, H. Franklin Nathan, David G. Dover, George J. Hebbel, Robert P. Platt, Orah S. Rosse, Wendell F. Ware, Russell E. TI Pulmonary hypertension and nitric oxide depletion in sickle cell disease SO BLOOD LA English DT Article ID REGURGITANT JET VELOCITY; PLASMA HEMOGLOBIN; LUNG-DISEASE; RISK-FACTORS; HEMOLYSIS; ANEMIA; HYDROXYUREA; CHILDREN; PRIAPISM; DEATH AB During the past decade a large body of experimental and clinical studies has focused on the hypothesis that nitric oxide (NO) depletion by plasma hemoglobin in the microcirculation plays a central role in the pathogenesis of many manifestations of sickle cell disease (SCD), particularly pulmonary hypertension. We have carefully examined those studies and believe that the conclusions drawn from them are not adequately supported by the data. We agree that NO depletion may well play a role in the pathophysiology of other hemolytic states such as paroxysmal nocturnal hemoglobinuria, in which plasma hemoglobin concentrations are often at least an order of magnitude greater than in SCD. Accordingly, we conclude that clinical trials in SCD designed to increase the bioavailability of NO or association studies in which SCD clinical manifestations are related to plasma hemoglobin via its surrogates should be viewed with caution. (Blood. 2010; 116(5): 687-692) C1 [Bunn, H. Franklin] Harvard Univ, Sch Med, Dept Med, Div Hematol, Boston, MA USA. [Nathan, David G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Dover, George J.] Johns Hopkins Sch Med, Dept Pediat, Baltimore, MD USA. [Hebbel, Robert P.] Univ Minnesota, Sch Med, Dept Med, Div Hematol Oncol Transplantat, Minneapolis, MN 55455 USA. [Platt, Orah S.] Harvard Univ, Childrens Hosp, Sch Med, Div Lab Med, Boston, MA 02115 USA. [Rosse, Wendell F.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Ware, Russell E.] St Jude Childrens Hosp, Dept Hematol, Memphis, TN 38105 USA. RP Bunn, HF (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM hfbunn@rics.bwh.harvard.edu NR 62 TC 110 Z9 116 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 AUG 5 PY 2010 VL 116 IS 5 BP 687 EP 692 DI 10.1182/blood-2010-02-268193 PG 6 WC Hematology SC Hematology GA 634PX UT WOS:000280596500007 PM 20395414 ER PT J AU Teslovich, TM Musunuru, K Smith, AV Edmondson, AC Stylianou, IM Koseki, M Pirruccello, JP Ripatti, S Chasman, DI Willer, CJ Johansen, CT Fouchier, SW Isaacs, A Peloso, GM Barbalic, M Ricketts, SL Bis, JC Aulchenko, YS Thorleifsson, G Feitosa, MF Chambers, J Orho-Melander, M Melander, O Johnson, T Li, XH Guo, XQ Li, MY Cho, YS Go, MJ Kim, YJ Lee, JY Park, T Kim, K Sim, X Ong, RTH Croteau-Chonka, DC Lange, LA Smith, JD Song, K Zhao, JH Yuan, X Luan, JA Lamina, C Ziegler, A Zhang, W Zee, RYL Wright, AF Witteman, JCM Wilson, JF Willemsen, G Wichmann, HE Whitfield, JB Waterworth, DM Wareham, NJ Waeber, G Vollenweider, P Voight, BF Vitart, V Uitterlinden, AG Uda, M Tuomilehto, J Thompson, JR Tanaka, T Surakka, I Stringham, HM Spector, TD Soranzo, N Smit, JH Sinisalo, J Silander, K Sijbrands, EJG Scuteri, A Scott, J Schlessinger, D Sanna, S Salomaa, V Saharinen, J Sabatti, C Ruokonen, A Rudan, I Rose, LM Roberts, R Rieder, M Psaty, BM Pramstaller, PP Pichler, I Perola, M Penninx, BWJH Pedersen, NL Pattaro, C Parker, AN Pare, G Oostra, BA O'Donnell, CJ Nieminen, MS Nickerson, DA Montgomery, GW Meitinger, T McPherson, R McCarthy, MI McArdle, W Masson, D Martin, NG Marroni, F Mangino, M Magnusson, PKE Lucas, G Luben, R Loos, RJF Lokki, ML Lettre, G Langenberg, C Launer, LJ Lakatta, EG Laaksonen, R Kyvik, KO Kronenberg, F Konig, IR Khaw, KT Kaprio, J Kaplan, LM Johansson, A Jarvelin, MR Janssens, ACJW Ingelsson, E Igi, W Hovingh, GK Hottenga, JJ Hofman, A Hicks, AA Hengstenberg, C Heid, IM Hayward, C Havulinna, AS Hastie, ND Harris, TB Haritunians, T Hall, AS Gyllensten, U Guiducci, C Groop, LC Gonzalez, E Gieger, C Freimer, NB Ferrucci, L Erdmann, J Elliott, P Ejebe, KG Doering, A Dominiczak, AF Demissie, S Deloukas, P de Geus, EJC de Faire, U Crawford, G Collins, FS Chen, YDI Caulfield, MJ Campbell, H Burtt, NP Bonnycastle, LL Boomsma, DI Boekholdt, SM Bergman, RN Barroso, I Bandinelli, S Ballantyne, CM Assimes, TL Quertermous, T Altshuler, D Seielstad, M Wong, TY Tai, ES Feranil, AB Kuzawa, CW Adair, LS Taylor, HA Borecki, IB Gabriel, SB Wilson, JG Holm, H Thorsteinsdottir, U Gudnason, V Krauss, RM Mohlke, KL Ordovas, JM Munroe, PB Kooner, JS Tall, AR Hegele, RA Kastelein, JJP Schadt, EE Rotter, JI Boerwinkle, E Strachan, DP Mooser, V Stefansson, K Reilly, MP Samani, NJ Schunkert, H Cupples, LA Sandhu, MS Ridker, PM Rader, DJ van Duijn, CM Peltonen, L Abecasis, GR Boehnke, M Kathiresan, S AF Teslovich, Tanya M. Musunuru, Kiran Smith, Albert V. Edmondson, Andrew C. Stylianou, Ioannis M. Koseki, Masahiro Pirruccello, James P. Ripatti, Samuli Chasman, Daniel I. Willer, Cristen J. Johansen, Christopher T. Fouchier, Sigrid W. Isaacs, Aaron Peloso, Gina M. Barbalic, Maja Ricketts, Sally L. Bis, Joshua C. Aulchenko, Yurii S. Thorleifsson, Gudmar Feitosa, Mary F. Chambers, John Orho-Melander, Marju Melander, Olle Johnson, Toby Li, Xiaohui Guo, Xiuqing Li, Mingyao Cho, Yoon Shin Go, Min Jin Kim, Young Jin Lee, Jong-Young Park, Taesung Kim, Kyunga Sim, Xueling Ong, Rick Twee-Hee Croteau-Chonka, Damien C. Lange, Leslie A. Smith, Joshua D. Song, Kijoung Zhao, Jing Hua Yuan, Xin Luan, Jian'an Lamina, Claudia Ziegler, Andreas Zhang, Weihua Zee, Robert Y. L. Wright, Alan F. Witteman, Jacqueline C. M. Wilson, James F. Willemsen, Gonneke Wichmann, H. -Erich Whitfield, John B. Waterworth, Dawn M. Wareham, Nicholas J. Waeber, Gerard Vollenweider, Peter Voight, Benjamin F. Vitart, Veronique Uitterlinden, Andre G. Uda, Manuela Tuomilehto, Jaakko Thompson, John R. Tanaka, Toshiko Surakka, Ida Stringham, Heather M. Spector, Tim D. Soranzo, Nicole Smit, Johannes H. Sinisalo, Juha Silander, Kaisa Sijbrands, Eric J. G. Scuteri, Angelo Scott, James Schlessinger, David Sanna, Serena Salomaa, Veikko Saharinen, Juha Sabatti, Chiara Ruokonen, Aimo Rudan, Igor Rose, Lynda M. Roberts, Robert Rieder, Mark Psaty, Bruce M. Pramstaller, Peter P. Pichler, Irene Perola, Markus Penninx, Brenda W. J. H. Pedersen, Nancy L. Pattaro, Cristian Parker, Alex N. Pare, Guillaume Oostra, Ben A. O'Donnell, Christopher J. Nieminen, Markku S. Nickerson, Deborah A. Montgomery, Grant W. Meitinger, Thomas McPherson, Ruth McCarthy, Mark I. McArdle, Wendy Masson, David Martin, Nicholas G. Marroni, Fabio Mangino, Massimo Magnusson, Patrik K. E. Lucas, Gavin Luben, Robert Loos, Ruth J. F. Lokki, Marja-Liisa Lettre, Guillaume Langenberg, Claudia Launer, Lenore J. Lakatta, Edward G. Laaksonen, Reijo Kyvik, Kirsten O. Kronenberg, Florian Koenig, Inke R. Khaw, Kay-Tee Kaprio, Jaakko Kaplan, Lee M. Johansson, Asa Jarvelin, Marjo-Riitta Janssens, A. Cecile J. W. Ingelsson, Erik Igi, Wilmar Hovingh, G. Kees Hottenga, Jouke-Jan Hofman, Albert Hicks, Andrew A. Hengstenberg, Christian Heid, Iris M. Hayward, Caroline Havulinna, Aki S. Hastie, Nicholas D. Harris, Tamara B. Haritunians, Talin Hall, Alistair S. Gyllensten, Ulf Guiducci, Candace Groop, Leif C. Gonzalez, Elena Gieger, Christian Freimer, Nelson B. Ferrucci, Luigi Erdmann, Jeanette Elliott, Paul Ejebe, Kenechi G. Doering, Angela Dominiczak, Anna F. Demissie, Serkalem Deloukas, Panagiotis de Geus, Eco J. C. de Faire, Ulf Crawford, Gabriel Collins, Francis S. Chen, Yii-der I. Caulfield, Mark J. Campbell, Harry Burtt, Noel P. Bonnycastle, Lori L. Boomsma, Dorret I. Boekholdt, S. Matthijs Bergman, Richard N. Barroso, Ines Bandinelli, Stefania Ballantyne, Christie M. Assimes, Themistocles L. Quertermous, Thomas Altshuler, David Seielstad, Mark Wong, Tien Y. Tai, E-Shyong Feranil, Alan B. Kuzawa, Christopher W. Adair, Linda S. Taylor, Herman A., Jr. Borecki, Ingrid B. Gabriel, Stacey B. Wilson, James G. Holm, Hilma Thorsteinsdottir, Unnur Gudnason, Vilmundur Krauss, Ronald M. Mohlke, Karen L. Ordovas, Jose M. Munroe, Patricia B. Kooner, Jaspal S. Tall, Alan R. Hegele, Robert A. Kastelein, John J. P. Schadt, Eric E. Rotter, Jerome I. Boerwinkle, Eric Strachan, David P. Mooser, Vincent Stefansson, Kari Reilly, Muredach P. Samani, Nilesh J. Schunkert, Heribert Cupples, L. Adrienne Sandhu, Manjinder S. Ridker, Paul M. Rader, Daniel J. van Duijn, Cornelia M. Peltonen, Leena Abecasis, Goncalo R. Boehnke, Michael Kathiresan, Sekar TI Biological, clinical and population relevance of 95 loci for blood lipids SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; DISEASE; RISK; TRAITS; TRIGLYCERIDES; CHOLESTEROL; HUMANS AB Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD. C1 [Musunuru, Kiran; Pirruccello, James P.; Voight, Benjamin F.; Bandinelli, Stefania; Altshuler, David; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Teslovich, Tanya M.; Willer, Cristen J.; Stringham, Heather M.; Bergman, Richard N.; Abecasis, Goncalo R.; Boehnke, Michael] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Musunuru, Kiran; Ballantyne, Christie M.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Musunuru, Kiran; Pirruccello, James P.; Voight, Benjamin F.; Guiducci, Candace; Gonzalez, Elena; Ejebe, Kenechi G.; Crawford, Gabriel; Burtt, Noel P.; Altshuler, David; Wong, Tien Y.; Gabriel, Stacey B.; Kathiresan, Sekar] Broad Inst, Cambridge, MA 02142 USA. [Musunuru, Kiran; Chasman, Daniel I.; Zee, Robert Y. L.; O'Donnell, Christopher J.; Assimes, Themistocles L.; Quertermous, Thomas; Altshuler, David; Ridker, Paul M.; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Musunuru, Kiran; Pirruccello, James P.; Tai, E-Shyong] Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. [Smith, Albert V.; Feranil, Alan B.; Gudnason, Vilmundur] Iceland Heart Assoc, Heart Prevent Clin & Res Inst, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Kuzawa, Christopher W.; Thorsteinsdottir, Unnur; Gudnason, Vilmundur; Stefansson, Kari] Univ Iceland, IS-101 Reykjavik, Iceland. [Edmondson, Andrew C.; Li, Mingyao; Adair, Linda S.; Reilly, Muredach P.; Rader, Daniel J.] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Edmondson, Andrew C.; Stylianou, Ioannis M.; Li, Mingyao; Reilly, Muredach P.; Rader, Daniel J.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Koseki, Masahiro; Masson, David; Tall, Alan R.] Columbia Univ, Dept Med, Div Mol Med, New York, NY 10032 USA. [Ripatti, Samuli; Surakka, Ida; Silander, Kaisa; Saharinen, Juha; Perola, Markus; Kaprio, Jaakko] Univ Helsinki, FIMM, FI-00014 Helsinki, Finland. [Ripatti, Samuli; Surakka, Ida; Silander, Kaisa; Perola, Markus; Kaprio, Jaakko] Natl Inst Hlth & Welf, FI-00251 Helsinki, Finland. [Chasman, Daniel I.; Zee, Robert Y. L.; Rose, Lynda M.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Johansen, Christopher T.; Hegele, Robert A.] Univ Western Ontario, Robarts Res Inst, London, ON N6A 5K8, Canada. [Fouchier, Sigrid W.; Hovingh, G. Kees; Kastelein, John J. P.] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Isaacs, Aaron; Aulchenko, Yurii S.; Witteman, Jacqueline C. M.; Uitterlinden, Andre G.; Sijbrands, Eric J. G.; Janssens, A. Cecile J. W.; Hofman, Albert; van Duijn, Cornelia M.] Erasmus Univ, Med Ctr, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Peloso, Gina M.; Demissie, Serkalem; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Peloso, Gina M.; O'Donnell, Christopher J.; Demissie, Serkalem; Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Barbalic, Maja; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA. [Ricketts, Sally L.; Luben, Robert; Khaw, Kay-Tee; Sandhu, Manjinder S.] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Bis, Joshua C.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA. [Bis, Joshua C.] Univ Washington, Dept Med, Seattle, WA 98101 USA. [Thorleifsson, Gudmar; Holm, Hilma; Thorsteinsdottir, Unnur; Stefansson, Kari] DeCODE, IS-101 Reykjavik, Iceland. [Feitosa, Mary F.; Borecki, Ingrid B.] Washington Univ, Sch Med, Div Stat Genom, Ctr Genome Sci, St Louis, MO 63108 USA. [Chambers, John; Zhang, Weihua] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England. [Orho-Melander, Marju; Melander, Olle; Groop, Leif C.] Lund Univ, Dept Clin Sci, SE-20502 Malmo, Sweden. [Johnson, Toby; Caulfield, Mark J.] Queen Mary Univ London, Clin Pharmacol & Barts & London Genome Ctr, William Harvey Res Inst, Barts & London Sch Med, London EC1M 6BQ, England. [Li, Xiaohui; Guo, Xiuqing; Haritunians, Talin; Chen, Yii-der I.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Cho, Yoon Shin; Go, Min Jin; Kim, Young Jin; Lee, Jong-Young] Natl Inst Hlth, Ctr Genome Sci, Seoul 122701, South Korea. [Park, Taesung] Seoul Natl Univ, Coll Nat Sci, Interdisciplinary Program Bioinformat, Seoul 151742, South Korea. [Park, Taesung] Seoul Natl Univ, Coll Nat Sci, Dept Stat, Seoul 151742, South Korea. [Kim, Kyunga] Sookmyung Womens Univ, Dept Stat, Seoul 140742, South Korea. [Sim, Xueling] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117597, Singapore. [Croteau-Chonka, Damien C.; Lange, Leslie A.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Ong, Rick Twee-Hee; Seielstad, Mark] Genome Inst Singapore, Singapore 138672, Singapore. [Smith, Joshua D.; Rieder, Mark; Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Song, Kijoung; Yuan, Xin; Waterworth, Dawn M.; Mooser, Vincent] GlaxoSmithKline R&D, Div Genet, King Of Prussia, PA 19406 USA. [Zhao, Jing Hua; Luan, Jian'an; Wareham, Nicholas J.; Loos, Ruth J. F.; Langenberg, Claudia; Sandhu, Manjinder S.] Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England. [Lamina, Claudia; Kronenberg, Florian] Innsbruck Med Univ, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, A-6020 Innsbruck, Austria. [Ziegler, Andreas; Koenig, Inke R.] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23562 Lubeck, Germany. [Wright, Alan F.; Vitart, Veronique; Hayward, Caroline; Hastie, Nicholas D.] Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Witteman, Jacqueline C. M.; Uitterlinden, Andre G.; Hofman, Albert; van Duijn, Cornelia M.] NGI, NCHA, NL-2300 RC Leiden, Netherlands. [Witteman, Jacqueline C. M.; Uitterlinden, Andre G.; Hofman, Albert; van Duijn, Cornelia M.] CMSB, NL-2300 RC Leiden, Netherlands. [Wilson, James F.; Rudan, Igor; Campbell, Harry] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland. [Willemsen, Gonneke; Hottenga, Jouke-Jan; de Geus, Eco J. C.; Boomsma, Dorret I.] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands. [Wichmann, H. -Erich; Heid, Iris M.; Gieger, Christian; Doering, Angela] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, D-85764 Neuherberg, Germany. [Whitfield, John B.; Montgomery, Grant W.; Martin, Nicholas G.] PO Royal Brisbane Hosp, Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld 4029, Australia. [Waeber, Gerard; Vollenweider, Peter] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Uitterlinden, Andre G.; Sijbrands, Eric J. G.] Erasmus Univ, Med Ctr, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Uda, Manuela; Sanna, Serena] Cittadella Univ Monserrato, CNR, INN, I-09042 Cagliari, Italy. [Tuomilehto, Jaakko; Salomaa, Veikko; Havulinna, Aki S.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. [Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester LE1 6TP, Leics, England. [Tanaka, Toshiko] NIA, Clin Res Branch, NIH, Baltimore, MD 21225 USA. [Tanaka, Toshiko] Medstar Res Inst, Baltimore, MD 21218 USA. [Spector, Tim D.; Soranzo, Nicole; Mangino, Massimo] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Soranzo, Nicole; Deloukas, Panagiotis; Barroso, Ines; Sandhu, Manjinder S.] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Smit, Johannes H.; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam, Med Ctr, EMGO Inst, Dept Psychiat, NL-1007 MB Amsterdam, Netherlands. [Sinisalo, Juha; Nieminen, Markku S.] HUCH, Dept Med, Div Cardiol, FI-00029 Helsinki, Finland. [Scuteri, Angelo] IRCCS, INRCA, Unita Operat Geriatria, I-00189 Rome, Italy. [Scott, James; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London W12 0NN, England. [Schlessinger, David; Lakatta, Edward G.] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Sabatti, Chiara] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Ruokonen, Aimo] Univ Oulu, Dept Clin Chem, FI-90220 Oulu, Finland. [Tanaka, Toshiko] Univ Ottawa, John & Jennifer Ruddy Canadian Cardiovasc Gen Ctr, Ottawa, ON K1Y 4W7, Canada. [Psaty, Bruce M.] Univ Washington, Dept Med, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98101 USA. [Pramstaller, Peter P.; Pichler, Irene; Pattaro, Cristian; Hicks, Andrew A.] Univ Lubeck, European Acad Bozen Bolzano EURAC, Inst Med Genet, Lubeck, Germany. [Pedersen, Nancy L.; Magnusson, Patrik K. E.; Ingelsson, Erik] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Parker, Alex N.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Pare, Guillaume] McMaster Univ, Genet & Mol Epidemiol Lab, Hamilton, ON L8N 3Z5, Canada. [Oostra, Ben A.] Erasmus Univ, Med Ctr, Dept Clin Genet, NL-3000 CA Rotterdam, Netherlands. [Meitinger, Thomas] Deutsch Forsch Zentrum Umwelt & Gesundheit, Helmholtz Zentrum Munchen, Inst Humangenet, D-85764 Neuherberg, Germany. [Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-81675 Munich, Germany. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [McCarthy, Mark I.] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Med, Oxford OX3 7LJ, England. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [McArdle, Wendy] Univ Bristol, Avon Longitudinal Study Parents & Children, Bristol BS8 2BN, Avon, England. [Marroni, Fabio] Inst Appl Genom, I-33100 Udine, Italy. [Lucas, Gavin] Inst Municipal Invest Med, E-08003 Barcelona, Spain. [Lokki, Marja-Liisa] Univ Helsinki, Haartman Inst, Transplantat Lab, FI-00014 Helsinki, Finland. [Lettre, Guillaume] Univ Montreal, Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Laaksonen, Reijo] Tampere Univ Hosp, Ctr Sci, FI-33521 Tampere, Finland. [Kyvik, Kirsten O.] Univ So Denmark, Inst Reg Hlth Res, DK-5000 Odense, Denmark. [Kyvik, Kirsten O.] Univ So Denmark, Danish Twin Registry, Inst Publ Hlth, DK-5000 Odense, Denmark. [Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Fac Med, FI-00014 Helsinki, Finland. [Kaplan, Lee M.] Massachusetts Gen Hosp, Weight Ctr, Boston, MA 02114 USA. [Johansson, Asa; Igi, Wilmar; Gyllensten, Ulf] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, SE-75185 Uppsala, Sweden. [Jarvelin, Marjo-Riitta; Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England. [Jarvelin, Marjo-Riitta] Univ Oulu, Dept Publ Hlth Sci & Gen Practice, FI-90220 Oulu, Finland. [Hengstenberg, Christian] Univ Regensburg, Klin & Poliklin Innere Med 2, D-93053 Regensburg, Germany. [Heid, Iris M.] Univ Regensburg, Med Ctr, Dept Epidemiol & Prevent Med, D-93053 Regensburg, Germany. [Havulinna, Aki S.] Aalto Univ, Sch Sci & Technol, Dept Biomed Engn & Computat Sci, FI-00076 Aalto, Finland. [Hall, Alistair S.] Univ Leeds, Fac Med & Hlth, LIGHT Res Inst, Leeds LS2 9JT, W Yorkshire, England. [Groop, Leif C.] Helsinki Univ Hosp, Dept Med, FI-00029 Helsinki, Finland. [Freimer, Nelson B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat,Ctr Neurobehav Genet, Jane & Terry Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, NIH, Baltimore, MD 21225 USA. [Erdmann, Jeanette; Schunkert, Heribert] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Elliott, Paul] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, London W2 1PG, England. [Dominiczak, Anna F.] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [de Faire, Ulf] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, SE-17177 Stockholm, Sweden. [Collins, Francis S.; Bonnycastle, Lori L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Boekholdt, S. Matthijs] 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. [Bergman, Richard N.] Univ So Calif, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [Bandinelli, Stefania] ASF, Geriatr Unit, I-50125 Florence, Italy. [Ballantyne, Christie M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Assimes, Themistocles L.; Quertermous, Thomas] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 168751, Singapore. [Tai, E-Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117597, Singapore. [Tai, E-Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Epidemiol, Singapore 117597, Singapore. [Tai, E-Shyong] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Publ Hlth, Singapore 117597, Singapore. [Feranil, Alan B.] Univ San Carlos, Off Populat Studies Fdn, Cebu 6000, Philippines. [Kuzawa, Christopher W.] Northwestern Univ, Dept Anthropol, Evanston, IL 60208 USA. [Adair, Linda S.] Univ N Carolina, Carolina Populat Ctr, Dept Nutr, Chapel Hill, NC 27516 USA. [Taylor, Herman A., Jr.; Wilson, James G.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39126 USA. [Krauss, Ronald M.] Childrens Hosp, Oakland Res Inst, Oakland, CA 94609 USA. [Ordovas, Jose M.] Ctr Nacl Invest Cardiovasc, Dept Cardiovasc Epidemiol & Populat Genet, Madrid 28029, Spain. [Ordovas, Jose M.] Tufts Univ, Nutr & Genom Lab, Jean Mayer US Dept Agr, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Munroe, Patricia B.] Queen Mary Univ London, Clin Pharmacol & Barts & London Genome Ctr, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England. [Schadt, Eric E.] Sage Bionetworks, Seattle, WA 98109 USA. [Strachan, David P.] St Georges Univ London, Div Community Hlth Sci, London SW17 0RE, England. [Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, NIHR Biomed Res Unit Cardiovasc Dis, Glenfield Hosp, Leicester LE3 9QP, Leics, England. RP Kathiresan, S (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM skathiresan@partners.org RI Erdmann, Jeanette/P-7513-2014; Ejebe, Kenechi/I-9238-2016; Smith, Albert/K-5150-2015; Kyvik, Kirsten /K-5680-2016; mangino, massimo/F-5134-2011; Hayward, Caroline/M-8818-2016; Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Magnusson, Patrik/C-4458-2017; Feitosa, Mary/K-8044-2012; Hicks, Andrew/E-9518-2017; Aulchenko, Yurii/M-8270-2013; Laaksonen, Reijo/D-6323-2014; Boekholdt, Matthijs/G-7562-2014; Pramstaller, Peter/C-2357-2008; Fouchier, Sigrid/A-8310-2011; Gudnason, Vilmundur/K-6885-2015; Ripatti, Samuli/H-9446-2014; Wilson, James F/A-5704-2009; de Geus, Eco/M-9318-2015; Montgomery, Grant/B-7148-2008; Meitinger, Thomas/O-1318-2015; Hegele, Robert/G-3301-2011; Rudan, Igor/I-1467-2012; Johansson, Asa/G-5270-2011; Deloukas, Panos/B-2922-2013; Colaus, PsyColaus/K-6607-2013; Abecasis, Goncalo/B-7840-2010; Altshuler, David/A-4476-2009; Kronenberg, Florian/B-1736-2008; Voight, Benjamin/F-1775-2011; Stylianou, Ioannis/C-6061-2012; Lucas, Gavin/D-4346-2012; Spector, Tim/F-6533-2012; Lamina, Claudia/F-7608-2010 OI Kaprio, Jaakko/0000-0002-3716-2455; Tai, E Shyong/0000-0003-2929-8966; Martin, Nicholas/0000-0003-4069-8020; Erdmann, Jeanette/0000-0002-4486-6231; Luben, Robert/0000-0002-5088-6343; Gieger, Christian/0000-0001-6986-9554; Ziegler, Andreas/0000-0002-8386-5397; Janssens, A Cecile/0000-0002-6153-4976; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Ordovas, Jose/0000-0002-7581-5680; Soranzo, Nicole/0000-0003-1095-3852; Willer, Cristen/0000-0001-5645-4966; Seielstad, Mark/0000-0001-5783-1401; Sijbrands, Eric/0000-0001-8857-7389; sanna, serena/0000-0002-3768-1749; Johnson, Toby/0000-0002-5998-3270; Abecasis, Goncalo/0000-0003-1509-1825; Ejebe, Kenechi/0000-0002-6090-8657; Smith, Albert/0000-0003-1942-5845; Kyvik, Kirsten /0000-0003-2981-0245; mangino, massimo/0000-0002-2167-7470; Hayward, Caroline/0000-0002-9405-9550; Feitosa, Mary/0000-0002-0933-2410; Hicks, Andrew/0000-0001-6320-0411; Pichler, Irene/0000-0001-8251-0757; Cupples, L. Adrienne/0000-0003-0273-7965; Marroni, Fabio/0000-0002-1556-5907; Aulchenko, Yurii/0000-0002-7899-1575; Gudnason, Vilmundur/0000-0001-5696-0084; Ripatti, Samuli/0000-0002-0504-1202; Wilson, James F/0000-0001-5751-9178; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Rudan, Igor/0000-0001-6993-6884; Johansson, Asa/0000-0002-2915-4498; Deloukas, Panos/0000-0001-9251-070X; Altshuler, David/0000-0002-7250-4107; Kronenberg, Florian/0000-0003-2229-1120; FU British Heart Foundation [PG/02/128, PG/08/094, PG/08/094/26019, RG/07/005/23633, SP/08/005/25115]; CCR NIH HHS [RC1 HL099634-02]; Chief Scientist Office [CZB/4/710]; FIC NIH HHS [TW05596]; Intramural NIH HHS; Medical Research Council [G0000934, G0401527, G0601966, G0700931, G0701863, G0801056, G0801566, G9521010, G9521010D, MC_QA137934, MC_U106179471, MC_U106188470, MC_U127561128]; NCI NIH HHS [CA 047988]; NCRR NIH HHS [M01-RR00425, RR20649, U54 RR020278, UL1RR025005]; NHGRI NIH HHS [1Z01 HG000024, N01-HG-65403, T32 HG00040, U01HG004402]; NHLBI NIH HHS [N01-HC-75150, 5R01HL087679-02, 5R01HL08770003, 5R01HL08821502, HL 04381, HL 080467, HL-54776, HL085144, K99 HL098364, K99 HL098364-01, K99HL094535, N01 HC-15103, N01 HC-55222, N01-HC-25195, N01-HC-35129, N01-HC-45133, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N02-HL-6-4278, R01 HL087647, R01 HL087676, R01 HL089650, R01HL086694, R01HL087641, R01HL087652, R01HL59367, RC1 HL099634, RC1 HL099634-02, RC1 HL099793, RC2 HL101864,, RC2 HL102419, T32HL007208, U01 HL069757, U01 HL080295]; NIA NIH HHS [N01-AG-12100]; NICHD NIH HHS [R24 HD050924]; NIDDK NIH HHS [5R01DK06833603, 5R01DK07568102, DK062370, DK063491, DK072193, DK078150, DK56350, R01 DK072193, R01 DK078150, U01 DK062370, U01 DK062418]; NIEHS NIH HHS [ES10126]; NIGMS NIH HHS [T32 GM007092]; PHS HHS [HHSN268200625226C]; Wellcome Trust [068545/Z/02, 076113/B/04/Z, 077016/Z/05/Z, 079895] NR 20 TC 1524 Z9 1557 U1 24 U2 218 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 5 PY 2010 VL 466 IS 7307 BP 707 EP 713 DI 10.1038/nature09270 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 634EN UT WOS:000280562500029 PM 20686565 ER PT J AU Musunuru, K Strong, A Frank-Kamenetsky, M Lee, NE Ahfeldt, T Sachs, KV Li, XY Li, H Kuperwasser, N Ruda, VM Pirruccello, JP Muchmore, B Prokunina-Olsson, L Hall, JL Schadt, EE Morales, CR Lund-Katz, S Phillips, MC Wong, J Cantley, W Racie, T Ejebe, KG Orho-Melander, M Melander, O Koteliansky, V Fitzgerald, K Krauss, RM Cowan, CA Kathiresan, S Rader, DJ AF Musunuru, Kiran Strong, Alanna Frank-Kamenetsky, Maria Lee, Noemi E. Ahfeldt, Tim Sachs, Katherine V. Li, Xiaoyu Li, Hui Kuperwasser, Nicolas Ruda, Vera M. Pirruccello, James P. Muchmore, Brian Prokunina-Olsson, Ludmila Hall, Jennifer L. Schadt, Eric E. Morales, Carlos R. Lund-Katz, Sissel Phillips, Michael C. Wong, Jamie Cantley, William Racie, Timothy Ejebe, Kenechi G. Orho-Melander, Marju Melander, Olle Koteliansky, Victor Fitzgerald, Kevin Krauss, Ronald M. Cowan, Chad A. Kathiresan, Sekar Rader, Daniel J. TI From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus SO NATURE LA English DT Article ID DENSITY-LIPOPROTEIN CHOLESTEROL; GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; PROTEIN; GENE; SORTILIN; TRANSCRIPTION; POPULATION; TRANSPORT; DESIGN AB Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes. C1 [Strong, Alanna; Sachs, Katherine V.; Li, Xiaoyu; Li, Hui; Rader, Daniel J.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Strong, Alanna; Sachs, Katherine V.; Li, Xiaoyu; Li, Hui; Rader, Daniel J.] Univ Penn, Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA. [Strong, Alanna; Sachs, Katherine V.; Li, Xiaoyu; Li, Hui; Rader, Daniel J.] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Musunuru, Kiran; Lee, Noemi E.; Ahfeldt, Tim; Kuperwasser, Nicolas; Ruda, Vera M.; Pirruccello, James P.; Ejebe, Kenechi G.; Cowan, Chad A.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Musunuru, Kiran; Lee, Noemi E.; Ahfeldt, Tim; Kuperwasser, Nicolas; Ruda, Vera M.; Pirruccello, James P.; Ejebe, Kenechi G.; Cowan, Chad A.; Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Musunuru, Kiran; Lee, Noemi E.; Kuperwasser, Nicolas; Ruda, Vera M.; Pirruccello, James P.; Ejebe, Kenechi G.; Cowan, Chad A.; Kathiresan, Sekar] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Musunuru, Kiran; Pirruccello, James P.; Hall, Jennifer L.; Ejebe, Kenechi G.; Cowan, Chad A.; Kathiresan, Sekar] Broad Inst, Cambridge, MA 02142 USA. [Musunuru, Kiran] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 21287 USA. [Frank-Kamenetsky, Maria; Wong, Jamie; Cantley, William; Racie, Timothy; Koteliansky, Victor; Fitzgerald, Kevin] Alnylam Pharmaceut Inc, Cambridge, MA 02142 USA. [Ahfeldt, Tim] Univ Med Ctr Hamburg Eppendorf, Dept Biochem & Mol Biol Mol Cell Biol 2, D-20246 Hamburg, Germany. [Muchmore, Brian; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hall, Jennifer L.] Univ Minnesota, Program Cardiovasc Translat Genom, Lillehei Heart Inst, Minneapolis, MN 55455 USA. [Schadt, Eric E.] Sage Bionetworks, Seattle, WA 98109 USA. [Morales, Carlos R.] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ H3A 2B2, Canada. [Lund-Katz, Sissel; Phillips, Michael C.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Orho-Melander, Marju; Melander, Olle] Lund Univ, Skania Univ Hosp, Dept Clin Sci, SE-20502 Malmo, Sweden. [Krauss, Ronald M.] Childrens Hosp, Oakland Res Inst, Oakland, CA 94609 USA. RP Rader, DJ (reprint author), Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. EM skathiresan@partners.org; rader@mail.med.upenn.edu RI Morales, Carlos/H-1055-2011; Ejebe, Kenechi/I-9238-2016; Ahfeldt, Tim/E-2935-2017; OI Ejebe, Kenechi/0000-0002-6090-8657; Prokunina-Olsson, Ludmila/0000-0002-9622-2091 FU United States National Institutes of Health (NIH); NIH [K99-HL098364, U01-HL069757, RC2-HL101864, P01-HL059407]; Harvard Stem Cell Institute; Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH; Swedish Medical Research Council; Heart-Lung Foundation; Pahlsson Foundation; Quest Diagnostics, Inc.; Bristol-Myers Squibb FX We thank D. Altshuler, E. Fisher and J. Maraganore for advice and guidance, and A. Akinc, J. Billheimer, R. Brown, R. Camahort, D. Cromley, E. Eduoard, I. Fuki, C. Geaney, G. Hinkle, I. Kohaar, S. Kuchimanchi, W. Lagor, F. Lau, D. Lum, M. Maier, D. Marchadier, R. Meyers, J. Millar, S. Milstein, D. Nguyen, D. Perez, D. Peters, V. Redon, A. Rigamonti, R. Schinzel, M.-S. Sun, S.-A. Toh, A. Wilson and K. Wojnoonski for assistance and suggestions. We acknowledge the National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program for providing support for viral vector production as well as the Vector Core laboratory of the University of Pennsylvania for producing the vectors. We acknowledge the members of the NHLBI Candidate Gene Association Resource (CARe) lipids working group for the contribution of association data in African Americans. This work was supported in part by a T32 grant in Cell and Molecular Training for Cardiovascular Biology from the United States National Institutes of Health (NIH), K99-HL098364 from the NIH, and the Clinician Scientist Program of the Harvard Stem Cell Institute (K. M.); a Medical Scientist Training Program grant from the NIH (A. S.); the intramural research program of the Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH (L.P.-O.); the Swedish Medical Research Council, Heart-Lung Foundation, and Pahlsson Foundation (M.O.-M., O.M.); U01-HL069757 from the NIH and research support from Quest Diagnostics, Inc. (R. M. K.); RC2-HL101864 from the NIH (S. K.); and P01-HL059407 and RC2-HL101864 from the NIH and a "Freedom to Discover'' Unrestricted Cardiovascular Research Grant from Bristol-Myers Squibb (D.J.R.). NR 35 TC 431 Z9 443 U1 3 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 5 PY 2010 VL 466 IS 7307 BP 714 EP U2 DI 10.1038/nature09266 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 634EN UT WOS:000280562500030 PM 20686566 ER PT J AU Ahn, YY Bagrow, JP Lehmann, S AF Ahn, Yong-Yeol Bagrow, James P. Lehmann, Sune TI Link communities reveal multiscale complexity in networks SO NATURE LA English DT Article ID HIERARCHICAL ORGANIZATION; METABOLIC NETWORKS AB Networks have become a key approach to understanding systems of interacting objects, unifying the study of diverse phenomena including biological organisms and human society(1-3). One crucial step when studying the structure and dynamics of networks is to identify communities(4,5): groups of related nodes that correspond to functional subunits such as protein complexes(6,7) or social spheres(8-10). Communities in networks often overlap(9,10) such that nodes simultaneously belong to several groups. Meanwhile, many networks are known to possess hierarchical organization, where communities are recursively grouped into a hierarchical structure(11-13). However, the fact that many real networks have communities with pervasive overlap, where each and every node belongs to more than one group, has the consequence that a global hierarchy of nodes cannot capture the relationships between overlapping groups. Here we reinvent communities as groups of links rather than nodes and show that this unorthodox approach successfully reconciles the antagonistic organizing principles of overlapping communities and hierarchy. In contrast to the existing literature, which has entirely focused on grouping nodes, link communities naturally incorporate overlap while revealing hierarchical organization. We find relevant link communities in many networks, including major biological networks such as protein-protein interaction(6,7,14) and metabolic networks(11,15,16), and show that a large social network(10,17,18) contains hierarchically organized community structures spanning inner-city to regional scales while maintaining pervasive overlap. Our results imply that link communities are fundamental building blocks that reveal overlap and hierarchical organization in networks to be two aspects of the same phenomenon. C1 [Lehmann, Sune] Harvard Univ, Inst Quantitat Social Sci, Cambridge, MA 02138 USA. [Ahn, Yong-Yeol; Bagrow, James P.] Northeastern Univ, Dept Phys, Ctr Complex Network Res, Boston, MA 02115 USA. [Ahn, Yong-Yeol; Bagrow, James P.] Harvard Univ, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02215 USA. [Lehmann, Sune] Northeastern Univ, Coll Comp & Informat Sci, Boston, MA 02115 USA. RP Lehmann, S (reprint author), Harvard Univ, Inst Quantitat Social Sci, Cambridge, MA 02138 USA. EM sune.lehmann@gmail.com OI Ahn, Yong-Yeol/0000-0002-4352-4301; Lehmann, Sune/0000-0001-6099-2345 FU James S. McDonnell Foundation; NSF-DDDAS [CNS-0540348]; NSF-ITR [DMR-0426737]; US ONR [N00014-07-C]; NIH [U01 A1070499-01, 111620-2]; DTRA [BRBAA07-J-2-0035]; US ARL [W911NF-09-2-0053]; NKTH NAP [KCKHA005]; Danish Natural Science Research Council; [NSF-IIS-0513650] FX The authors thank A.-L. Barabasi, S. Ahnert, J. Park, D.-S. Lee, P.-J. Kim, N. Blumm, D. Wang, M. A. Yildirim and H. Yu. The authors acknowledge the Center for Complex Network Research, supported by the James S. McDonnell Foundation 21st Century Initiative in Studying Complex Systems; the NSF-DDDAS (CNS-0540348), NSF-ITR (DMR-0426737) and NSF-IIS-0513650 programmes; US ONR Award N00014-07-C; the NIH (U01 A1070499-01/Sub #:111620-2); the DTRA (BRBAA07-J-2-0035); the NS-CTA sponsored by US ARL (W911NF-09-2-0053); and NKTH NAP (KCKHA005). S. L. acknowledges support from the Danish Natural Science Research Council. NR 30 TC 507 Z9 590 U1 13 U2 139 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 5 PY 2010 VL 466 IS 7307 BP 761 EP U11 DI 10.1038/nature09182 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 634EN UT WOS:000280562500040 PM 20562860 ER PT J AU Cicardi, M Banerji, A Bracho, F Malbran, A Rosenkranz, B Riedl, M Bork, K Lumry, W Aberer, W Bier, H Bas, M Greve, J Hoffmann, TK Farkas, H Reshef, A Ritchie, B Yang, W Grabbe, J Kivity, S Kreuz, W Levy, RJ Luger, T Obtulowicz, K Schmid-Grendelmeier, P Bull, C Sitkauskiene, B Smith, WB Toubi, E Werner, S Anne, S Bjorkander, J Bouillet, L Cillari, E Hurewitz, D Jacobson, KW Katelaris, CH Maurer, M Merk, H Bernstein, JA Feighery, C Floccard, B Gleich, G Hebert, J Kaatz, M Keith, P Kirkpatrick, CH Langton, D Martin, L Pichler, C Resnick, D Wombolt, D Romero, DSF Zanichelli, A Arcoleo, F Knolle, J Kravec, I Dong, L Zimmermann, J Rosen, K Fan, WT AF Cicardi, M. Banerji, A. Bracho, F. Malbran, A. Rosenkranz, B. Riedl, M. Bork, K. Lumry, W. Aberer, W. Bier, H. Bas, M. Greve, J. Hoffmann, T. K. Farkas, H. Reshef, A. Ritchie, B. Yang, W. Grabbe, J. Kivity, S. Kreuz, W. Levy, R. J. Luger, T. Obtulowicz, K. Schmid-Grendelmeier, P. Bull, C. Sitkauskiene, B. Smith, W. B. Toubi, E. Werner, S. Anne, S. Bjorkander, J. Bouillet, L. Cillari, E. Hurewitz, D. Jacobson, K. W. Katelaris, C. H. Maurer, M. Merk, H. Bernstein, J. A. Feighery, C. Floccard, B. Gleich, G. Hebert, J. Kaatz, M. Keith, P. Kirkpatrick, C. H. Langton, D. Martin, L. Pichler, C. Resnick, D. Wombolt, D. Fernandez Romero, D. S. Zanichelli, A. Arcoleo, F. Knolle, J. Kravec, I. Dong, L. Zimmermann, J. Rosen, K. Fan, W. -T. TI Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID C1 INHIBITOR CONCENTRATE; ANGIONEUROTIC EDEMA; LARYNGEAL EDEMA; TRANEXAMIC ACID AB BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.) C1 [Banerji, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Banerji, A.] Harvard Univ, Sch Med, Boston, MA USA. [Cicardi, M.; Zanichelli, A.] Univ Milan, Milan, Italy. [Bracho, F.] Georgetown Univ Hosp, Lombardi Canc Ctr, Washington, DC 20007 USA. [Malbran, A.; Fernandez Romero, D. S.] Hosp Britan Buenos Aires, Buenos Aires, DF, Argentina. [Bork, K.] Johannes Gutenberg Univ Mainz, Mainz, Germany. [Bier, H.; Bas, M.] Tech Univ Munich, Munich, Germany. [Greve, J.; Hoffmann, T. K.] Univ Dusseldorf, Dusseldorf, Germany. [Grabbe, J.] Univ Hosp Lubeck, Lubeck, Germany. [Kreuz, W.] Goethe Univ Frankfurt, Frankfurt, Germany. [Luger, T.] Univ Hosp Munster, Munster, Germany. [Maurer, M.] Charite, D-13353 Berlin, Germany. [Merk, H.] Univ Hosp Rhein Westfal Tech Hsch Aachen, Aachen, Germany. [Kaatz, M.] Univ Jena, Jena, Germany. [Riedl, M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Lumry, W.] Asthma Allergy Res Associates Res Ctr, Dallas, TX USA. [Aberer, W.] Med Univ Graz, Graz, Austria. [Farkas, H.] Semmelweis Univ, H-1085 Budapest, Hungary. [Reshef, A.] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Kivity, S.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel. [Toubi, E.] Bnai Zion Med Ctr, Haifa, Israel. [Ritchie, B.] Univ Alberta, Edmonton, AB, Canada. [Yang, W.] Allergy & Asthma Res Ctr, Ottawa, ON, Canada. [Hebert, J.] Ctr Rech Appl Allergie Quebec, Quebec City, PQ, Canada. [Keith, P.] McMaster Univ, Hamilton Hlth Sci Ctr, Hamilton, ON, Canada. [Levy, R. J.] Family Allergy & Asthma Ctr, Atlanta, GA USA. [Obtulowicz, K.] Szpital Uniwersytecki Krakowie, Krakow, Poland. [Schmid-Grendelmeier, P.; Bull, C.] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Pichler, C.] Insel Spital BE Bern, Bern, Switzerland. [Sitkauskiene, B.] Kaunas Univ Med, Kaunas, Lithuania. [Smith, W. B.] Royal Adelaide Hosp, Adelaide, SA 5000, Australia. [Katelaris, C. H.] Westmead Hosp, Sydney, NSW, Australia. [Langton, D.] Frankston Hosp, Frankston, Vic, Australia. [Werner, S.] Univ Lund Hosp, S-22185 Lund, Sweden. [Bjorkander, J.] Sahlgrens Univ Hosp, Gothenburg, Sweden. [Anne, S.] Asthma Allergy & Immunol Ctr, Flint, MI USA. [Bouillet, L.] CHU Grenoble, F-38043 Grenoble, France. [Floccard, B.] Hop Edouard Herriot, Lyon, France. [Martin, L.] Ctr Hosp Reg Orleans, Orleans, France. [Cillari, E.; Arcoleo, F.] Azienda Osped V Cervello, Palermo, Italy. [Hurewitz, D.] Allergy Clin Tulsa, Tulsa, OK USA. [Jacobson, K. W.] Allergy & Asthma Res Grp, Eugene, OR USA. [Bernstein, J. A.] Univ Cincinnati, Cincinnati, OH USA. [Feighery, C.] St James Hosp, Dublin, Ireland. [Gleich, G.] Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. [Kirkpatrick, C. H.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Resnick, D.] Columbia Univ, Med Ctr, New York, NY USA. [Wombolt, D.] Clin Res Associates Tidewater, Norfolk, VA USA. RP Banerji, A (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Cox 201, Boston, MA 02114 USA. EM abanerji@partners.com RI Martin, Ludovic/K-2674-2015; cicardi, marco/K-9219-2016; OI cicardi, marco/0000-0003-1251-225X; Smith, William/0000-0002-4610-998X FU Jerini [FAST-1]; National Institutes of Health [M01 RR-00051] FX Supported by Jerini and, for the FAST-1 trial only, in part by a grant from the National Institutes of Health (M01 RR-00051). NR 20 TC 241 Z9 244 U1 1 U2 19 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 5 PY 2010 VL 363 IS 6 BP 532 EP 541 DI 10.1056/NEJMoa0906393 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 634BB UT WOS:000280552700007 PM 20818888 ER PT J AU Bhargava, P Maki, JH AF Bhargava, Puneet Maki, Jeffrey H. TI "Cotton Wool" Appearance of Paget's Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Bhargava, Puneet; Maki, Jeffrey H.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. RP Bhargava, P (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. EM bhargp@u.washington.edu OI Bhargava, Puneet/0000-0002-3849-9666 NR 0 TC 1 Z9 1 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 AUG 5 PY 2010 VL 363 IS 6 BP E9 EP E9 DI 10.1056/NEJMicm0912945 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 634BB UT WOS:000280552700012 PM 20836245 ER PT J AU Wilting, RH Yanover, E Heideman, MR Jacobs, H Horner, J van der Torre, J DePinho, RA Dannenberg, JH AF Wilting, Roel H. Yanover, Eva Heideman, Marinus R. Jacobs, Heinz Horner, James van der Torre, Jaco DePinho, Ronald A. Dannenberg, Jan-Hermen TI Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis SO EMBO JOURNAL LA English DT Article DE Hdac1; Hdac2; haematopoiesis; p21(Cip); senescence ID HISTONE DEACETYLASE INHIBITORS; SENESCENCE-LIKE STATE; TRANSCRIPTIONAL NETWORKS; TUMOR SUPPRESSION; MICE; GROWTH; REQUIREMENT; PROGRESSION; CHROMATIN; COMPLEX AB Histone deacetylases (HDACs) counterbalance acetylation of lysine residues, a protein modification involved in numerous biological processes. Here, Hdac1 and Hdac2 conditional knock-out alleles were used to study the function of class I Hdac1 and Hdac2 in cell cycle progression and haematopoietic differentiation. Combined deletion of Hdac1 and Hdac2, or inactivation of their deacetylase activity in primary or oncogenic-transformed fibroblasts, results in a senescence-like G(1) cell cycle arrest, accompanied by up-regulation of the cyclin-dependent kinase inhibitor p21(Cip). Notably, concomitant genetic inactivation of p53 or p21(Cip) indicates that Hdac1 and Hdac2 regulate p53-p21(Cip)-independent pathways critical for maintaining cell cycle progression. In vivo, we show that Hdac1 and Hdac2 are not essential for liver homeostasis. In contrast, total levels of Hdac1 and Hdac2 in the haematopoietic system are critical for erythrocyte-megakaryocyte differentiation. Dual inactivation of Hdac1 and Hdac2 results in apoptosis of megakaryocytes and thrombocytopenia. Together, these data indicate that Hdac1 and Hdac2 have overlapping functions in cell cycle regulation and haematopoiesis. In addition, this work provides insights into mechanism-based toxicities observed in patients treated with HDAC inhibitors. The EMBO Journal (2010) 29, 2586-2597. doi:10.1038/emboj.2010.136; Published online 22 June 2010 C1 [Wilting, Roel H.; Yanover, Eva; van der Torre, Jaco; Dannenberg, Jan-Hermen] Netherlands Canc Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands. [Heideman, Marinus R.; Jacobs, Heinz] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. [Horner, James; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Med Oncol, Boston, MA 02115 USA. [Horner, James; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Med, Boston, MA 02115 USA. [Horner, James; DePinho, Ronald A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Genet, Boston, MA 02115 USA. [Horner, James; DePinho, Ronald A.] Harvard Univ, Sch Med, Boston, MA USA. RP Dannenberg, JH (reprint author), Netherlands Canc Inst, Div Mol Genet, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM j.dannenberg@nki.nl OI Jacobs, Heinz/0000-0001-6227-9850 FU NWO [NWO-VIDI 864.07.008, NWO-VIDI 917.56.328]; Dutch Cancer Society [KWF-2007-3978] FX We thank Thomas Rosahl and Merck & Co. Genetically Engineered Models Center of Excellence for providing the unpublished Hdac1 cKO mice designed and produced in collaboration with Xavier Warot, Marie-Christine Birling and Guillaume Pavlovic at the Institut Clinique Souris, Strasbourg, France. We thank Victoria Richon, Chantale Guy, Judy Fleming and Andreas Bloecher at Merck and Co. for discussions on this project. We thank Paul Krimpenfort and Anton Berns for generously providing p21-/- and Cdkn2a cKO mice. We thank Ton Schrauwers, Corine van Langen, Auke Zwerver, Cor Spaan and Dienke Jonkers for animal care. We thank Hein te Riele and Floris Foijer for providing p21Cip shRNA constructs, Hilda de Vries for p53 reagents and Rene Bernards for p53 shRNA constructs. We are grateful to Martin van der Valk for histology review. We thank Kenneth Scott for providing the pQXCIP-DEST retroviral vector. We thank Hein te Riele and Paul Krimpenfort for critical reading of the paper. This work was supported by grants from the NWO to J-HD (NWO-VIDI 864.07.008) and HJ (NWO-VIDI 917.56.328) and the Dutch Cancer Society (KWF-2007-3978). NR 51 TC 84 Z9 84 U1 1 U2 11 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 AUG 4 PY 2010 VL 29 IS 15 BP 2586 EP 2597 DI 10.1038/emboj.2010.136 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 635MD UT WOS:000280658900012 PM 20571512 ER PT J AU Strumbos, JG Brown, MR Kronengold, J Polley, DB Kaczmarek, LK AF Strumbos, John G. Brown, Maile R. Kronengold, Jack Polley, Daniel B. Kaczmarek, Leonard K. TI Fragile X Mental Retardation Protein Is Required for Rapid Experience-Dependent Regulation of the Potassium Channel Kv3.1b SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AUDITORY BRAIN-STEM; RAT MEDIAL NUCLEUS; TRAPEZOID BODY; MESSENGER-RNAS; SUBCELLULAR-LOCALIZATION; BC1 RNA; NEURONS; TRANSLATION; EXPRESSION; STIMULI AB Fragile X mental retardation protein (FMRP) is an RNA-binding protein that regulates synaptic plasticity by repressing translation of specific mRNAs. We found that FMRP binds mRNA encoding the voltage-gated potassium channel Kv3.1b in brainstem synaptosomes. To explore the regulation of Kv3.1b by FMRP, we investigated Kv3.1b immunoreactivity and potassium currents in the auditory brainstem sound localization circuit of male mice. The unique features of this circuit allowed us to control neuronal activity in vivo by exposing animals to high-frequency, amplitude-modulated stimuli, which elicit predictable and stereotyped patterns of input to the anterior ventral cochlear nucleus (AVCN) and medial nucleus of the trapezoid body (MNTB). In wild-type (WT) animals, Kv3.1b is expressed along a tonotopic gradient in the MNTB, with highest levels in neurons at the medial, high-frequency end. At baseline, Fmr1(-/-) mice, which lack FMRP, displayed dramatically flattened tonotopicity in Kv3.1b immunoreactivity and K(+) currents relative to WT controls. Moreover, after 30 min of acoustic stimulation, levels of Kv3.1b immunoreactivity were significantly elevated in both the MNTB and AVCN of WT, but not Fmr1(-/-), mice. These results suggest that FMRP is necessary for maintenance of the gradient in Kv3.1b protein levels across the tonotopic axis of the MNTB, and are consistent with a role for FMRP as a repressor of protein translation. Using numerical simulations, we demonstrate that Kv3.1b tonotopicity may be required for accurate encoding of stimulus features such as modulation rate, and that disruption of this gradient, as occurs in Fmr1(-/-) animals, degrades processing of this information. C1 [Strumbos, John G.; Brown, Maile R.; Kronengold, Jack; Kaczmarek, Leonard K.] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06511 USA. [Polley, Daniel B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RP Kaczmarek, LK (reprint author), Yale Univ, Sch Med, Dept Pharmacol, 333 Cedar St,SHM Room B-309, New Haven, CT 06511 USA. EM leonard.kaczmarek@yale.edu OI Polley, Daniel/0000-0002-5120-2409 FU FRAXA Research Foundation; National Institutes of Health [DC001919, DC009488] FX This work was supported by a FRAXA Research Foundation grant (to L. K. K.) as well as National Institutes of Health Grants DC001919 (to L. K. K.) and DC009488 (to D. B. P.). We thank Kenton Hokanson for technical assistance with Western blots. NR 56 TC 47 Z9 48 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 4 PY 2010 VL 30 IS 31 BP 10263 EP 10271 DI 10.1523/JNEUROSCI.1125-10.2010 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 637BP UT WOS:000280789600002 PM 20685971 ER PT J AU Annunziata, CM Birrer, MJ AF Annunziata, Christina M. Birrer, Michael J. TI CD157 in Ovarian Carcinoma: How Does It Help Us? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material C1 [Annunziata, Christina M.; Birrer, Michael J.] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA. [Annunziata, Christina M.] Natl Canc Inst, Med Oncol Branch, Bethesda, MD USA. RP Birrer, MJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Med, 55 Fruit St, Boston, MA 02114 USA. EM mbirrer@partners.org RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 NR 5 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 4 PY 2010 VL 102 IS 15 BP 1004 EP 1005 DI 10.1093/jnci/djq269 PG 2 WC Oncology SC Oncology GA 636CL UT WOS:000280705500002 ER PT J AU Scirica, BM Braunwald, E Belardinelli, L Hedgepeth, CM Spinar, J Wang, W Qin, J Karwatowska-Prokopczuk, E Verheugt, FWA Morrow, DA AF Scirica, Benjamin M. Braunwald, Eugene Belardinelli, Luiz Hedgepeth, Chester M. Spinar, Jindrich Wang, Whedy Qin, Jie Karwatowska-Prokopczuk, Ewa Verheugt, Freek W. A. Morrow, David A. TI Relationship Between Nonsustained Ventricular Tachycardia After Non-ST-Elevation Acute Coronary Syndrome and Sudden Cardiac Death Observations From the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) Randomized Controlled Trial SO CIRCULATION LA English DT Article DE acute coronary syndrome; antiarrhythmic drugs; death sudden; electrocardiography; ventricular tachycardia ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; SEGMENT-ELEVATION; ANTIANGINAL AGENT; PROGNOSTIC VALUE; HEART-FAILURE; FOLLOW-UP; ARRHYTHMIAS; ERA; PREVALENCE; RISK AB Background-Most studies examining the relationship between ventricular tachycardia (VT) after acute coronary syndrome and sudden cardiac death (SCD) were performed before widespread use of reperfusion, revascularization, or contemporary medical therapy and were limited to ST-elevation myocardial infarction. The incidence and prognostic implications of VT in patients with non-ST-elevation acute coronary syndrome receiving contemporary care have not been examined. Methods and Results-The Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non-ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG recording was performed for the first 7 days after randomization and evaluated in a blinded core laboratory. SCD (n = 121) was assessed over a median follow-up of 1 year. A total of 6345 patients (97%) had continuous ECG recordings evaluable for analysis. Compared with patients with no VT (n = 2764), there was no increased risk of SCD in patients with only ventricular triplets (n = 1978, 31.2%) (1.4% versus 1.2%); however, the risk of SCD was significantly greater in patients with VT lasting 4 to 7 beats (n = 1172, 18.5%) (SCD, 2.9%; adjusted hazard ratio, 2.3; P < 0.001) and in patients with VT lasting at least 8 beats (n = 431, 6.8%) (SCD, 4.3%; adjusted hazard ratio, 2.8; P = 0.001). This effect was independent of baseline characteristics and ejection fraction. VT occurring within the first 48 hours after admission was not associated with SCD. Conclusion-Nonsustained VT is common after admission for non-ST-elevation acute coronary syndrome, and even short episodes of VT lasting 4 to 7 beats are independently associated with the risk of SCD over the subsequent year. C1 [Scirica, Benjamin M.; Braunwald, Eugene; Hedgepeth, Chester M.; Qin, Jie; Morrow, David A.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, Boston, MA 02115 USA. [Scirica, Benjamin M.; Braunwald, Eugene; Hedgepeth, Chester M.; Qin, Jie; Morrow, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Belardinelli, Luiz; Wang, Whedy; Karwatowska-Prokopczuk, Ewa] Gilead Sci Inc, Palo Alto, CA USA. [Spinar, Jindrich] Univ Hosp Brno, Brno, Czech Republic. [Verheugt, Freek W. A.] Onze Lieve Vrouw Hosp, Amsterdam, Netherlands. RP Scirica, BM (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM bscirica@partners.org RI Verheugt, F.W.A./H-8105-2014 FU CV Therapeutics (now Gilead Science Inc); Michael Lerner Foundation; Bayer AG; Roche; Eli Lilly; Boehringer Ingelheim; Ministry of Education of the Czech Republic FX MERLIN-TIMI 36 was supported by CV Therapeutics (now Gilead Science Inc).; Dr Scirica reports having receiving honoraria for educational presentations from CV Therapeutics (now Gilead Sciences), Novartis, Merck, Schering-Plough, sanofi-aventis, Lilly, and Daiichi-Sankyo and has served as a consultant for AstraZeneca, Novartis, Cogentus, Gilead Sciences, and Shionegi. He is the recipient of unrestricted research grant from the Michael Lerner Foundation. Dr Braunwald has received honoraria for educational presentations and consulting from CV Therapeutics. Dr Verheugt reports having received educational and research grants from Bayer AG, Roche, Eli Lilly, and Boehringer Ingelheim and honoraria for consultancies from Pharmacia Upjohn, Eli Lilly, Merck, and Bayer (the Netherlands). Drs Belardinelli, Karwatowska-Prokopczuk, and Wang are employees of and hold stocks/options in CV Therapeutics (now Gilead Sciences). Dr Hedgepeth reports having received honoraria from Johnson and Johnson. Dr Spinar reports having received grants from the Ministry of Education of the Czech Republic. Dr Morrow reports receiving honoraria for educational presentations from CV Therapeutics and sanofi-aventis, serving as a consultant for GlaxoSmithKline and sanofi-aventis, and being on an advisory board for Genentech. J. Qin reports no conflicts. NR 29 TC 47 Z9 50 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 3 PY 2010 VL 122 IS 5 BP 455 EP U36 DI 10.1161/CIRCULATIONAHA.110.937136 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 634EA UT WOS:000280561100004 PM 20644019 ER PT J AU Shroyer, ALW Collins, JF Grover, FL AF Shroyer, A. Laurie W. Collins, Joseph F. Grover, Frederick L. TI Evaluating Clinical Applicability The STICH Trial's Findings SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material ID SURGICAL VENTRICULAR RECONSTRUCTION; HEART-FAILURE; EPIDEMIOLOGY; RELIABILITY; SURGERY C1 [Shroyer, A. Laurie W.] SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. [Shroyer, A. Laurie W.] Northport VA Med Ctr, Northport, NY USA. [Collins, Joseph F.] Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. [Grover, Frederick L.] Eastern Colorado Hlth Care Syst, Denver VA Med Ctr, Denver, CO USA. [Grover, Frederick L.] Univ Colorado Denver, Sch Med, Aurora, CO USA. RP Shroyer, ALW (reprint author), SUNY Stony Brook, Sch Med, T19-020A,100 Nicholls Rd, Stony Brook, NY 11794 USA. EM annielaurie.shroyer@stonybrook.edu RI Shroyer, Annie Laurie/B-8836-2016 OI Shroyer, Annie Laurie/0000-0001-6461-0623 NR 11 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 3 PY 2010 VL 56 IS 6 BP 508 EP 509 DI 10.1016/j.jacc.2010.03.052 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 631TZ UT WOS:000280373400009 PM 20670762 ER PT J AU Weintraub, D Mavandadi, S Mamikonyan, E Siderowf, AD Duda, JE Hurtig, HI Colcher, A Horn, SS Nazem, S Ten Have, TR Stern, MB AF Weintraub, D. Mavandadi, S. Mamikonyan, E. Siderowf, A. D. Duda, J. E. Hurtig, H. I. Colcher, A. Horn, S. S. Nazem, S. Ten Have, T. R. Stern, M. B. TI Atomoxetine for depression and other neuropsychiatric symptoms in Parkinson disease SO NEUROLOGY LA English DT Article ID PROVISIONAL DIAGNOSTIC-CRITERIA; LOCUS-COERULEUS; EXECUTIVE DYSFUNCTION; DAYTIME SLEEPINESS; CONTROLLED-TRIAL; DOUBLE-BLIND; OPEN-LABEL; ANTIDEPRESSANTS; NOREPINEPHRINE; PERFORMANCE AB Objectives: Depression and antidepressant use, especially selective serotonin reuptake inhibitors (SSRIs), are common in Parkinson disease (PD). The objective of this clinical trial was to assess the efficacy of atomoxetine, a selective norepinephrine reuptake inhibitor (SNRI), for the treatment of clinically significant depressive symptoms and common comorbid neuropsychiatric symptoms in PD. Methods: A total of 55 subjects with PD and an Inventory of Depressive Symptomatology-Clinician (IDS-C) score >= 22 were randomized to 8 weeks of atomoxetine or placebo treatment (target dosage = 80 mg/day). Depression response (> 50% decrease in IDS-C score or Clinical Global Impression-Improvement [CGI-I] score of 1 or 2) was assessed using intention-to-treat modeling procedures. Secondary outcomes included global cognition, daytime sleepiness, anxiety, apathy, and motor function. Results: There were no between-groups differences in a priori-defined response rates. Using a more liberal response criterion of > 40% decrease in IDS score from baseline, there was a trend (p = 0.08) favoring atomoxetine. Patients receiving atomoxetine experienced significantly greater improvement in global cognition (p = 0.003) and daytime sleepiness (p = 0.001), and atomoxetine was well-tolerated. Conclusions: Atomoxetine treatment was not efficacious for the treatment of clinically significant depressive symptoms in PD, but was associated with improvement in global cognitive performance and daytime sleepiness. Larger studies of SNRIs in PD for disorders of mood, cognition, and wakefulness are appropriate. Classification of evidence: This interventional study provides Class II evidence that atomoxetine (target dosage = 80 mg/day) is not efficacious in improving clinically significant depression in PD. Neurology (R) 2010;75:448-455 C1 [Weintraub, D.; Mavandadi, S.; Mamikonyan, E.; Nazem, S.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Weintraub, D.; Duda, J. E.; Stern, M. B.] Philadelphia VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA USA. [Weintraub, D.; Mavandadi, S.] Philadelphia VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Philadelphia, PA USA. [Siderowf, A. D.; Duda, J. E.; Hurtig, H. I.; Colcher, A.; Horn, S. S.; Stern, M. B.] Univ Penn, Dept Neurol, Penn Hosp, Parkinsons Dis & Movement Disorders Ctr, Philadelphia, PA 19104 USA. [Ten Have, T. R.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Weintraub, D (reprint author), 3615 Chestnut St,330, Philadelphia, PA 19104 USA. EM daniel.weintraub@uphs.upenn.edu FU NIH NIMH [067894]; Avid Radiopharmaceuticals, Inc.; Boehringer Ingelheim; NIH [NIMH K23 MH067894, NINDS P50 NS053488-01, NIA RO1AG031348, NINDS R01NS065087]; Michael J. Fox Foundation for Parkinson's Research; Institute for Neurodegenerative Disorders; U.S. Department of Veterans Affairs; Samueli Institute; Johnson; Teva Pharmaceutical Industries Ltd.; Bayer Schering Pharma; Kyowa Hakko Kirin Pharma, Inc.; PRA International; Novartis; GlaxoSmithKline; Amarin Corporation; St Jude Medical; Prestwick Pharmaceutical, Inc.; HP Therapeutics Foundation, Inc.; Cephalon, Inc. FX Supported by the NIH NIMH 067894 (D.W.).; Dr. Weintraub has served on a scientific advisory board for Boehringer Ingelheim; serves on the editorial board of Movement Disorders; has received speaker honoraria from Boehringer Ingelheim, ACADIA Pharmaceuticals, Novartis, Osmotica Pharmaceutical Corp., BrainCells Inc., Merck Serono, sanofi-aventis, and Pfizer Inc; and has received/receives research support from Avid Radiopharmaceuticals, Inc., Boehringer Ingelheim, NIH (NIMH K23 MH067894 [PI], NINDS P50 NS053488-01 [Co-Investigator], NIA RO1AG031348 [Site PI], and NINDS R01NS065087 [Co-Investigator]), and from the Michael J. Fox Foundation for Parkinson's Research. Dr. Mavandadi and Ms. Mamikon-yan report no disclosures. Dr. Siderowf serves on a scientific advisory board for and has received speaker honoraria from Teva Pharmaceutical Industries Ltd.; serves as a consultant for Supernus Pharmaceuticals, Inc.; and receives research support from Avid Radiopharmaceuticals, Inc., the NIH (NINDS U10 NS044451-023 [Site PI], NINDS P50 NS053488-01 [Co-Core Leader and Project Leader], NINDS R43NS0636071 [Site PI], and NINDS R01NS065087 [Co-Investigator]), and from the Institute for Neurodegenerative Disorders. Dr. Duda serves on a grant review panel for the Michael J. Fox Foundation for Parkinson's Research; receives research support from the U.S. Department of Veterans Affairs (Merit Award [PI]), the Michael J. Fox Foundation, and the Samueli Institute; and holds stock in C. R. Bard, Inc., Celgene, Clarient, Inc., and Johnson& Johnson. Dr. Hurtig serves on a grant review panel for the Michael J. Fox Foundation for Parkinson's Research; serves on the editorial board of Parkinsonism and Related Disorders; receives publishing royalties from UpToDate, Inc.; has received speaker honoraria from Teva Pharmaceutical Industries Ltd.; receives research support from Teva Pharmaceutical Industries Ltd., Boehringer Ingelheim, Bayer Schering Pharma, Kyowa Hakko Kirin Pharma, Inc., PRA International, Novartis, GlaxoSmithKline, Avid Radiopharmaceuticals, Inc., St Jude Medical, Amarin Corporation, Prestwick Pharmaceutical, Inc., HP Therapeutics Foundation, Inc., Cephalon, Inc., NIH (NINDS P50 NS053488-01 [Core Leader and PI] and NINDS U10 NS044451-023 [Site PI]); and holds stock in Teva Pharmaceutical Industries Ltd. Dr. Colcher has received speaker honoraria from Lundbeck Inc. and Teva Pharmaceutical Industries Ltd. Dr. Horn has received speaker honoraria from Teva Pharmaceutical Industries Ltd. Ms. Nazem reports no disclosures. Dr. Ten Have serves on a scientific advisory board for the NIH; served as a consultant for Abbott and Avid Radiopharmaceuticals, Inc.; and receives research support from the NIH (R01-MH078016 [PI], R01-HL073932 [Co-Investigator], R01-MH067498 [PI], U01HL087072 [Co-Investigator], U49-CE001093 [Co-Investigator], R01HD053270 [Co-Investigator], R01-MH079736 [Co-Investigator], R01-HL086830 [Co-Investigator], P30-AG031043 [Co-Investigator], R01-AA016187 [Co-Investigator], R01-MH083717 [Co-Investigator], R01CA132656 [Co-Investigator], R01-AT004921 [Co-Investigator], R34MH085906 [Co-Investigator], NHBLI R01-HL096651 [Co-Investigator], R01-HD061061 [Co-Investigator], R01-MH082799 [Co-Investigator], R01-DA027204 [Co-Investigator], R01-CE001615 [Co-Investigator], RC1HL099612 [Co-Investigator], RC1-AA019092 [Co-Investigator], and R34MH085880 [Co-Investigator]). Dr. Stern has served on scientific advisory boards for Boehringer Ingelheim, Teva Pharmaceutical Industries Ltd., Ipsen, Schering-Plough Corp.; , Novartis, and Adamas Pharmaceuticals; has received funding for travel or speaker honorariafrom Novartis, Boehringer Ingelheim, and Teva Pharmaceutical Industries Ltd.; receives royalties from the publication of Surgical Management of Parkinson's Disease (Taylor and Francis Group, 2004); has served as a consultant for Teva Pharmaceutical Industries Ltd., Boehringer Ingelheim, Novartis, Ipsen, Schering-Plough Corp., and Adamas Pharmaceuticals; receives research support from the Institute for Neurodegenerative Disorders; and holds stock options in Adamas Pharmaceuticals. NR 38 TC 94 Z9 98 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 3 PY 2010 VL 75 IS 5 BP 448 EP 455 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 634FN UT WOS:000280565600013 PM 20679638 ER PT J AU Cohen, AB Rizzo, JF AF Cohen, Adam B. Rizzo, Joseph F., III TI Teaching NeuroImages: Central retinal artery occlusion with cilioretinal artery sparing in giant cell arteritis SO NEUROLOGY LA English DT Editorial Material C1 [Cohen, Adam B.] Harvard Univ, Dept Neurol, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Cohen, Adam B.] Harvard Univ, Dept Radiol, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Rizzo, Joseph F., III] Harvard Univ, Dept Neuroophthalmol, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. RP Cohen, AB (reprint author), Harvard Univ, Dept Neurol, Sch Med, Brigham & Womens Hosp, 45 Francis St, Boston, MA 02115 USA. EM abcohen@partners.org 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 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 3 PY 2010 VL 75 IS 5 BP E21 EP E22 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 634FN UT WOS:000280565600024 PM 20679629 ER PT J AU Meissner, TB Li, A Biswas, A Lee, KH Liu, YJ Bayir, E Iliopoulos, D van den Elsen, PJ Kobayashi, KS AF Meissner, Torsten B. Li, Amy Biswas, Amlan Lee, Kyoung-Hee Liu, Yuen-Joyce Bayir, Erkan Iliopoulos, Dimitrios van den Elsen, Peter J. Kobayashi, Koichi S. TI NLR family member NLRC5 is a transcriptional regulator of MHC class I genes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antigen presentation; class II transactivator; IFN-gamma ID COMPLEX CLASS-II; BARE LYMPHOCYTE SYNDROME; TRANSACTIVATOR CIITA; MICE LACKING; IFN-GAMMA; ANTIGEN PRESENTATION; EXPRESSION; BINDING; PROMOTERS; PATHWAY AB MHC class I plays a critical role in the immune defense against viruses and tumors by presenting antigens to CD8 T cells. An NLR protein, class II transactivator (CIITA), is a key regulator of MHC class II gene expression that associates and cooperates with transcription factors in the MHC class II promoter. Although CIITA also transactivates MHC class I gene promoters, loss of CIITA in humans and mice results in the severe reduction of only MHC class II expression, suggesting that additional mechanisms regulate the expression of MHC class I. Here, we identify another member of the NLR protein family, NLRC5, as a transcriptional regulator of MHC class I genes. Similar to CIITA, NLRC5 is an IFN-gamma-inducible nuclear protein, and the expression of NLRC5 resulted in enhanced MHC class I expression in lymphoid as well as epithelial cell lines. Using chromatin immunoprecipitation and reporter gene assays, we show that NLRC5 associates with and activates the promoters of MHC class I genes. Furthermore, we show that the IFN-gamma-induced up-regulation of MHC class I requires NLRC5, because knockdown of NLRC5 specifically impaired the expression of MHC class I. In addition to MHC class I genes, NLRC5 also induced the expression of beta 2-microglobulin, transporter associated with antigen processing, and large multifunctional protease, which are essential for MHC class I antigen presentation. Our results suggest that NLRC5 is a transcriptional regulator, orchestrating the concerted expression of critical components in the MHC class I pathway. C1 [Meissner, Torsten B.; Li, Amy; Biswas, Amlan; Lee, Kyoung-Hee; Liu, Yuen-Joyce; Bayir, Erkan; Kobayashi, Koichi S.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Meissner, Torsten B.; Biswas, Amlan; Lee, Kyoung-Hee; Kobayashi, Koichi S.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Iliopoulos, Dimitrios] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [van den Elsen, Peter J.] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2333 ZA Leiden, Netherlands. [van den Elsen, Peter J.] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1081 HV Amsterdam, Netherlands. RP Kobayashi, KS (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM Koichi_Kobayashi@dfci.harvard.edu OI Van den Elsen, Peter/0000-0002-5196-0082 FU National Institutes of Health; Crohn's and Colitis Foundation of America; European Molecular Biology Organization (EMBO); Cancer Research Institute; Claudia Adams Barr Award FX We thank Peter Cresswell (Yale University, New Haven, CT), Martin Hemler (DFCI, Boston, MA), Marja van Eggermond (Leiden University, Leiden, The Netherlands) and Cheong-Hee Chang (University of Michigan, Ann Arbor, MI) for providing reagents, Kai Wucherpfennig and Diane Mathis for critically reading the manuscript, Carl Novina, Shannon Turley, and Harvey Cantor for helpful discussions, Bettina Franz, Etienne Gagnon, and Maja Janas for technical advice, and Norman Lautsch, Amelia Chen, and Andrea Dearth for general assistance. This work was supported by grants from the National Institutes of Health and the Crohn's and Colitis Foundation of America (K. S. K.). T. B. M. is a recipient of the European Molecular Biology Organization (EMBO) Long-Term Fellowship, and K. S. K. is a recipient of the Investigator Award from the Cancer Research Institute and the Claudia Adams Barr Award. The authors have no conflicting financial interests. NR 43 TC 116 Z9 120 U1 2 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 3 PY 2010 VL 107 IS 31 BP 13794 EP 13799 DI 10.1073/pnas.1008684107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 634SP UT WOS:000280605900045 PM 20639463 ER PT J AU Doores, KJ Bonomelli, C Harvey, DJ Vasiljevic, S Dwek, RA Burton, DR Crispin, M Scanlan, CN AF Doores, Katie J. Bonomelli, Camille Harvey, David J. Vasiljevic, Snezana Dwek, Raymond A. Burton, Dennis R. Crispin, Max Scanlan, Christopher N. TI Envelope glycans of immunodeficiency virions are almost entirely oligomannose antigens SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV; 2G12; gp120; glycosylation; vaccine ID MASS-SPECTROMETRIC CHARACTERIZATION; TYPE-1 ANTIBODY 2G12; VIRUS TYPE-1; DC-SIGN; N-GLYCANS; NEUTRALIZING ANTIBODIES; LINKED OLIGOSACCHARIDES; GLYCOPROTEIN GP120; VACCINE DESIGN; HIV-1 GP120 AB The envelope spike of HIV is one of the most highly N-glycosylated structures found in nature. However, despite extensive research revealing essential functional roles in infection and immune evasion, the chemical structures of the glycans on the native viral envelope glycoprotein gp120-as opposed to recombinantly generated gp120-have not been described. Here, we report on the identity of the N-linked glycans from primary isolates of HIV-1 (clades A, B, and C) and from the simian immunodeficiency virus. MS analysis reveals a remarkably simple and highly conserved virus-specific glycan profile almost entirely devoid of medial Golgi-mediated processing. In stark contrast to recombinant gp120, which shows extensive exposure to cellular glycosylation enzymes (>70% complex type glycans), the native envelope shows barely detectable processing beyond the biosynthetic intermediate Man(5)GlcNAc(2) (<2% complex type glycans). This oligomannose (Man(5-9)GlcNAc(2)) profile is conserved across primary isolates and geographically divergent clades but is not reflected in the current generation of gp120 antigens used for vaccine trials. In the context of vaccine design, we also note that Man alpha 1 -> 2Man-terminating glycans (Man(6-9)GlcNAc(2)) of the type recognized by the broadly neutralizing anti-HIV antibody 2G12 are 3-fold more abundant on the native envelope than on the recombinant monomer and are also found on isolates not neutralized by 2G12. The Man alpha 1 -> 2Man residues of gp120 therefore provide a vaccine target that is physically larger and antigenically more conserved than the 2G12 epitope itself. This study revises and extends our understanding of the glycan shield of HIV with implications for AIDS vaccine design. C1 [Doores, Katie J.; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbiol Sci, La Jolla, CA 92037 USA. [Doores, Katie J.; Burton, Dennis R.] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA. [Doores, Katie J.; Burton, Dennis R.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Doores, Katie J.; Burton, Dennis R.] Harvard Univ, Boston, MA 02114 USA. [Bonomelli, Camille; Harvey, David J.; Vasiljevic, Snezana; Dwek, Raymond A.; Crispin, Max; Scanlan, Christopher N.] Univ Oxford, Dept Biochem, Oxford Glycobiol Inst, Oxford OX1 3QU, England. RP Doores, KJ (reprint author), Scripps Res Inst, Dept Immunol & Microbiol Sci, La Jolla, CA 92037 USA. EM chris.scanlan@bioch.ox.ac.uk RI Harvey, David/A-5579-2013; OI Doores, Katie/0000-0002-5507-1725 FU International AIDS Vaccine Initiative; Oxford Glycobiology Endowment; National Institute of Allergy and Infectious Diseases [AI33292]; Ragon Institute FX We thank Michael Huber, Pascal Poignard, Mark Wormald, and Nicole Zitzmann for helpful discussions. This work was supported by the International AIDS Vaccine Initiative, the Oxford Glycobiology Endowment, National Institute of Allergy and Infectious Diseases Grant AI33292 (to D.R. B.), and the Ragon Institute. We acknowledge an equipment grant from the International AIDS Vaccine Initiative to purchase the Shimazu AXIMA TOF2 MALDI TOF/TOF mass spectrometer. NR 50 TC 152 Z9 153 U1 1 U2 24 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 3 PY 2010 VL 107 IS 31 BP 13800 EP 13805 DI 10.1073/pnas.1006498107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 634SP UT WOS:000280605900046 PM 20643940 ER PT J AU Li, HL He, CW Feng, JH Zhang, Y Tang, QZ Bian, ZY Bai, X Zhou, H Jiang, H Heximer, SP Qin, M Huang, H Liu, PP Huang, CX AF Li, Hongliang He, Chengwei Feng, Jinhua Zhang, Yan Tang, Qizhu Bian, Zhouyan Bai, Xue Zhou, Heng Jiang, Hong Heximer, Scott P. Qin, Mu Huang, He Liu, Peter. P. Huang, Congxin TI Regulator of G protein signaling 5 protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ERK1/2; RGS5; MEK1/2; signal transduction ID BLOOD-PRESSURE; RGS5; OVEREXPRESSION; EXPRESSION; PATHWAYS; MICE AB The development of cardiac hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response that may eventually lead to ventricular dilation and heart failure. Regulator of G protein signaling 5 (Rgs5) is a negative regulator of G protein-mediated signaling by inactivating G alpha(q) and G alpha(i), which mediate actions of most known vaso-constrictors. Previous studies have demonstrated that Rgs5 expresses among various cell types within mature heart and showed high levels of Rgs5 mRNA in monkey and human heart tissue by Northern blot analysis. However, the critical role of Rgs5 on cardiac remodeling remains unclear. To specifically determine the role of Rgs5 in pathological cardiac remodeling, we used transgenic mice with cardiac-specific overexpression of human Rgs5 gene and Rgs5(-/-) mice. Our results demonstrated that the transgenic mice were resistant to cardiac hypertrophy and fibrosis through inhibition of MEK-ERK1/2 signaling, whereas the Rgs5(-/-) mice displayed the opposite phenotype in response to pressure overload. These studies indicate that Rgs5 protein is a crucial component of the signaling pathway involved in cardiac remodeling and heart failure. C1 [Li, Hongliang; Feng, Jinhua; Zhang, Yan; Tang, Qizhu; Bian, Zhouyan; Bai, Xue; Zhou, Heng; Jiang, Hong; Qin, Mu; Huang, He; Huang, Congxin] Wuhan Univ, Renmin Hosp, Dept Cardiol, Wuhan 430060, Peoples R China. [Li, Hongliang; Feng, Jinhua; Zhang, Yan; Tang, Qizhu; Bian, Zhouyan; Bai, Xue; Zhou, Heng; Jiang, Hong; Qin, Mu; Huang, He; Huang, Congxin] Wuhan Univ, Cardiovasc Res Inst, Wuhan 430060, Peoples R China. [He, Chengwei] Harvard Univ, Sch Med, Boston, MA 02114 USA. [He, Chengwei] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Heximer, Scott P.] Univ Toronto, Dept Physiol, Toronto, ON M5S 3J9, Canada. [Liu, Peter. P.] Univ Toronto, Univ Hlth Network, Heart & Stroke Richard Lewar Ctr Excellence, Div Cardiol, Toronto, ON M5S 3E2, Canada. RP Li, HL (reprint author), Wuhan Univ, Renmin Hosp, Dept Cardiol, Wuhan 430060, Peoples R China. EM lihl@whu.edu.cn; cxhuang@whu.edu.cn FU National Natural Science Foundation of China [30900524, 30972954, 30770733] FX This research was supported by National Natural Science Foundation of China Grants 30900524, 30972954, and 30770733. NR 20 TC 71 Z9 72 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 AUG 3 PY 2010 VL 107 IS 31 BP 13818 EP 13823 DI 10.1073/pnas.1008397107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 634SP UT WOS:000280605900049 PM 20643937 ER PT J AU Paranjape, AS Kuranov, R Baranov, S Ma, LL Villard, JW Wang, TY Sokolov, KV Feldman, MD Johnston, KP Milner, TE AF Paranjape, Amit S. Kuranov, Roman Baranov, Stepan Ma, Li Leo Villard, Joseph W. Wang, Tianyi Sokolov, Konstantin V. Feldman, Marc D. Johnston, Keith P. Milner, Thomas E. TI Depth resolved photothermal OCT detection of macrophages in tissue using nanorose SO BIOMEDICAL OPTICS EXPRESS LA English DT Article AB Application of photothermal Optical Coherence Tomography (OCT) to detect macrophages in ex vivo rabbit arteries which have engulfed nanoclusters of gold coated iron oxide (nanorose) is reported. Nanorose engulfed by macrophages associated with atherosclerotic lesions in rabbit arteries absorb incident laser (800nm) energy and cause optical pathlength (OP) variation which is measured using photothermal OCT. OP variation in polydimethyl siloxane tissue phantoms containing varying concentrations of nanorose match values predicted from nanoparticle and material properties. Measurement of OP variation in rabbit arteries in response to laser excitation provides an estimate of nanorose concentration in atherosclerotic lesions of 2.5x10(9) particles/ml. OP variation in atherosclerotic lesions containing macrophages taking up nanorose has a different magnitude and profile from that observed in control thoracic aorta without macrophages and is consistent with macrophage presence as identified with RAM-11 histology staining. Our results suggest that tissue regions with macrophages taking up nanorose can be detected using photothermal OCT. (C) 2010 Optical Society of America C1 [Paranjape, Amit S.; Baranov, Stepan; Wang, Tianyi; Sokolov, Konstantin V.; Milner, Thomas E.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Ma, Li Leo; Johnston, Keith P.] Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA. [Kuranov, Roman; Villard, Joseph W.; Feldman, Marc D.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Feldman, Marc D.] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Paranjape, AS (reprint author), Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. EM stepan@baranov.su RI Baranov, Stepan/G-5272-2010; OI Baranov, Stepan/0000-0002-1450-327X; Ma, Li/0000-0002-0959-5616; Sokolov, Konstantin/0000-0002-0198-2005 FU Veterans Administration; National Institutes of Health [R01EY016462-04] FX The authors gratefully acknowledge the Veterans Administration and the National Institutes of Health (R01EY016462-04) for financial support to this research. NR 35 TC 22 Z9 22 U1 2 U2 9 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD AUG 2 PY 2010 VL 1 IS 1 BP 2 EP 16 PG 15 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA V21LC UT WOS:000208208100001 PM 21258441 ER EF