FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kuntz, NL Chabas, D Weinstock-Guttman, B Chitnis, T Yeh, EA Krupp, L Ness, J Rodriguez, M Waubant, E AF Kuntz, Nancy L. Chabas, Dorothee Weinstock-Guttman, Bianca Chitnis, Tanuja Yeh, E. Ann Krupp, Lauren Ness, Jayne Rodriguez, Moses Waubant, Emmanuelle CA Network US Pediat Multiple Scleros TI Treatment of multiple sclerosis in children and adolescents SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE disease modifying therapy; glatiramer acetate; interferon beta; intravenous immune globulin; intravenous methylprednisolone; multiple sclerosis; pediatric; plasma exchange; relapsing; remitting multiple sclerosis ID ACUTE DISSEMINATED ENCEPHALOMYELITIS; PLACEBO-CONTROLLED TRIAL; DOSE INTRAVENOUS METHYLPREDNISOLONE; BLOOD MONONUCLEAR-CELLS; CENTRAL-NERVOUS-SYSTEM; DOUBLE-BLIND; INTERFERON-BETA; FOLLOW-UP; GLATIRAMER ACETATE; RANDOMIZED-TRIAL AB Areas covered in this review: Literature published over the past two decades relating to pharmacologic treatment of multiple sclerosis (MS) in adults and children is reviewed, with emphasis on current publications. What the reader will gain: This article reviews available research and clinical experience regarding treatment of acute episodes of CNS demyelination in children and adolescents, strategies for introduction and modification of disease-modifying therapies depending on disease course, and use of medication for symptomatic improvement in quality of life. Take home message: Pharmacotherapy for MS has been studied in adults but to a significantly lesser extent in children or adolescents. However, children and adolescents have different biology than adults in terms of drug metabolism, immune mechanisms and incomplete maturity of CNS myelin. Effectiveness as well as long-term safety needs to be studied in children and adolescents. C1 [Kuntz, Nancy L.; Rodriguez, Moses] Mayo Coll Med, Mayo Pediat MS Clin, Rochester, MN 55905 USA. [Chabas, Dorothee; Waubant, Emmanuelle] Univ Calif San Francisco, Reg Pediat MS Ctr, San Francisco, CA 94143 USA. [Weinstock-Guttman, Bianca; Yeh, E. Ann] SUNY Buffalo, Pediat MS Ctr, Jacobs Neurol Inst, Buffalo, NY 14260 USA. [Chitnis, Tanuja] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners Pediat MS Ctr, Boston, MA USA. [Krupp, Lauren] SUNY Stony Brook, Natl Pediat MS Ctr, Stony Brook, NY 11794 USA. [Ness, Jayne] Univ Alabama, Ctr Pediat Onset Demyelinating Dis, Birmingham, AL USA. RP Kuntz, NL (reprint author), Mayo Coll Med, Mayo Pediat MS Clin, 200 1st St SW, Rochester, MN 55905 USA. EM kuntz.nancy@mayo.edu OI Rodriguez, Moses/0000-0001-6328-6497 FU National Multiple Sclerosis society,; Spinal Muscular Atrophy Foundation; Cooperative International Neuromuscular Research Group; Nancy Davis foundation; Biogen; Serono; Teva; cyberonics; NIH [NINDS KO8 NS 047669-01, NIDDK DK51413 [PI], KO8NS43220 [PI]]; Acorda; Genentech FX NL Kuntz has received honoraria for lectures not funded by industry. Travel expenses for educational activities sponsored by Baxter have been received as well as research support from the National Multiple Sclerosis society, Spinal Muscular Atrophy Foundation and the Cooperative International Neuromuscular Research Group. D Chabas has received honoraria from Teva, EMD Sorono and Pfizer. D Chabas has received license fee payment and may accrue revenue on office of technology licensing Stanford docket (501085) and also receives support from the National Multiple Sclerosis society and the Nancy Davis foundation. B WeinstockGuttman serves on the speaker's bureau for Biogen, Teva and EMD Serono. She also receives research support from Biogen, Serono, Teva, cyberonics and the National Multiple Sclerosis Society. T Chitnis has received travel expenses and/or honoraria for lectures or educational activities not funded by industry. She has served/serves as a consultant to Biogen, Serono, Teva and Bayer Schering Pharma. She serves on the speakers bureau for EMD serono, Wyeth and Zymogenetics and receives research support from the NIH (NINDS KO8 NS 047669-01) the National Multiple Sclerosis society and the Nancy Davis foundation. L Krupp has received personal compensation for activities with Bayer Healthcare, Biogen, Teva, EMD Serono and GSK. Royalty payments have been received from Demos Med. Publishing, Eli Lilly, Medimmune, Vertex, Wyeth and Zymogenetics. L Krupp also has received research support from Acorda and Biogen. J Ness serves as a consultant to Merck Serono, receives research support from the NIH (NIDDK DK51413 [PI]) and the National Multiple Sclerosis; and her spouse receives research support from the NIH (KO8NS43220 [PI]). M Rodriguez has received travel expenses and honorarium for features or educational activities not funded by industry. He is serves on scientific editorial boards for the NIH/NINDS and Fast Forward, LLC and serves on the editorial advisory boards of Annals of Neurology, Brain Pathology, Journal of Neurovirology and VerusMed. E Waubant has received personal compensation for activities with Actelion, Biogen, Millennium and Teva. He has received research support from Genentech. NR 154 TC 17 Z9 18 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD MAR PY 2010 VL 11 IS 4 BP 505 EP 520 DI 10.1517/14656560903527218 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 560ES UT WOS:000274885400003 PM 20163265 ER PT J AU Sonpavde, G Palapattu, GS AF Sonpavde, Guru Palapattu, Ganesh S. TI Neoadjuvant therapy preceding prostatectomy for prostate cancer: rationale and current trials SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Review DE androgen-deprivation therapy; biologic agents; chemotherapy; neoadjuvant therapy; prostate cancer ID PHASE-II TRIAL; RANDOMIZED CONTROLLED-TRIAL; RADICAL PROSTATECTOMY; HIGH-RISK; HORMONAL-THERAPY; BREAST-CANCER; CHEMOHORMONAL THERAPY; ADJUVANT RADIOTHERAPY; ANDROGEN DEPRIVATION; RADIATION-THERAPY AB Neoadjuvant therapy improves outcomes for a number of malignancies and provides intermediate pathologic outcomes, which correlate with long-term outcomes. Neoadjuvant androgen-deprivation therapy, alone or with docetaxel chemotherapy, preceding prostatectomy for localized prostate cancer is feasible and demonstrates pathologic activity, but evidence for improved long-term outcomes is lacking. Data in support of the further exploration of neoadjuvant therapy for localized prostate cancer preceding prostatectomy are reviewed. Ongoing randomized trials are elucidating the impact of neoadjuvant androgen deprivation combined with docetaxel chemotherapy on pathologic and long-term outcomes. The correlation of pathologic and biologic outcomes with long-term outcomes in this setting is unknown. The neoadjuvant therapy approach followed by prostatectomy is feasible with a wide array of agents and provides a paradigm for evaluating the activity, and mechanism of action and resistance to new treatments. This promising modality may aid the rapid development of novel therapeutic agents. A multidisciplinary approach involving oncologists, urologists and pathologists is critical to the success of this model. C1 [Sonpavde, Guru] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Sonpavde, Guru] Sect Med Oncol, Dept Med, Webster, TX 77598 USA. [Palapattu, Ganesh S.] Methodist Hosp, Dept Urol, Houston, TX 77030 USA. RP Sonpavde, G (reprint author), 501 Med Ctr Blvd, Webster, TX 77598 USA. EM guru.sonpavde@usoncology.com; gpalapattu@tmhs.org FU BMS; Pfizer; Novartis; Astrazeneca; Cytogen FX Guru Sonpavde is a member of the speakers' bureau for Sanofi-Aventis, Wyeth, Pfizer and Novartis. He has received research support from BMS, Pfizer, Novartis, Astrazeneca and Cytogen. Guru Sonpavde is also on the advisory board for Celgene, Pfizer, Halozyme, Novartis and BMS. 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 75 TC 4 Z9 4 U1 0 U2 0 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7140 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD MAR PY 2010 VL 10 IS 3 BP 439 EP 450 DI 10.1586/ERA.10.17 PG 12 WC Oncology SC Oncology GA 571VO UT WOS:000275784200020 PM 20214524 ER PT J AU Paganetti, H Kooy, H AF Paganetti, Harald Kooy, Hanne TI Proton radiation in the management of localized cancer SO EXPERT REVIEW OF MEDICAL DEVICES LA English DT Review DE cancer; proton beam delivery; proton therapy; radiation therapy ID INTENSITY-MODULATED PHOTON; X-RAY; THERAPY; BEAM; RADIOTHERAPY; RANGE; PATIENT AB Proton radiation therapy has been available for decades. However, until recently it was only applied to a small number of patients at approximately 20 centers worldwide. increased clinical experience with protons, as well as extensive research in the physics, biology and clinical aspects of proton therapy, have recently led to a huge interest in proton therapy among radiation oncologists. in addition, the cost for facilities is expected to decrease. Many proton therapy facilities are currently being built and planned worldwide. It is expected that the number of patients treated with protons will increase substantially in the near future. This article summarizes the rationale for (proton) radiation therapy and addresses the promises and challenges of proton-beam therapy in the management of localized cancer. C1 [Paganetti, Harald; Kooy, Hanne] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Paganetti, Harald; Kooy, Hanne] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Paganetti, H (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM h.paganetti@partners.org NR 29 TC 8 Z9 8 U1 0 U2 4 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1743-4440 J9 EXPERT REV MED DEVIC JI Expert Rev. Med. Devices PD MAR PY 2010 VL 7 IS 2 BP 275 EP 285 DI 10.1586/ERD.10.2 PG 11 WC Engineering, Biomedical SC Engineering GA 571VK UT WOS:000275783800017 PM 20214431 ER PT J AU Salmon, AB Richardson, A Perez, VI AF Salmon, Adam B. Richardson, Arlan Perez, Viviana I. TI Update on the oxidative stress theory of aging: Does oxidative stress play a role in aging or healthy aging? SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE Oxidative stress; Aging; Disease; Life span; Health span; Free radicals ID EXTRACELLULAR-SUPEROXIDE-DISMUTASE; AMES DWARF MICE; METHIONINE-SULFOXIDE-REDUCTASE; NAKED MOLE-RAT; FREE-RADICAL PRODUCTION; LONGEST-LIVING RODENT; GLUTATHIONE-PEROXIDASE PROTECTS; AMYOTROPHIC-LATERAL-SCLEROSIS; ADULT DROSOPHILA-MELANOGASTER; TRANSGENIC MOUSE MODEL AB The oxidative stress theory of aging predicts that manipulations that alter oxidative stress/damage will alter aging. The gold standard for determining whether aging is altered is life span, i.e., does altering oxidative stress/damage change life span? Mice with genetic manipulations in their antioxidant defense system designed to directly address this prediction have, with few exceptions, shown no change in life span. However, when these transgenic/knockout mice are tested using models that develop various types of age-related pathology, they show alterations in progression and/or severity of pathology as predicted by the oxidative stress theory: increased oxidative stress accelerates pathology and reduced oxidative stress retards pathology. These contradictory observations might mean that (a) oxidative stress plays a very limited, if any, role in aging but a major role in health span and/or (b) the role that oxidative stress plays in aging depends on environment. In environments with minimal stress, as expected under optimal husbandry, oxidative damage plays little role in aging. However, under chronic stress, including pathological phenotypes that diminish optimal health, oxidative stress/damage plays a major role in aging. Under these conditions, enhanced antioxidant defenses exert an "antiaging" action, leading to changes in life span, age-related pathology, and physiological function as predicted by the oxidative stress theory of aging. (C) 2009 Elsevier Inc. All rights reserved. C1 [Salmon, Adam B.; Richardson, Arlan; Perez, Viviana I.] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Richardson, Arlan; Perez, Viviana I.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Richardson, Arlan] S Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. RP Salmon, AB (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. EM salmona@uthscsa.edu FU NIH [T32AG021890-05, R01AG015908, R01AG023843, P01AG19316, P01AG020591, R37AG026557]; American Federation for Aging Research Senior Postdoctoral; Department of Veterans Affairs; San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging FX This work was supported by NIH Training Grant T32AG021890-05; NIH Grants R01AG015908, R01AG023843, P01AG19316, P01AG020591, and R37AG026557; an American Federation for Aging Research Senior Postdoctoral Grant; the Department of Veterans Affairs (Merit Grants and a Research Enhancement Award Program); and the San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging. NR 218 TC 170 Z9 175 U1 1 U2 78 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 EI 1873-4596 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAR 1 PY 2010 VL 48 IS 5 BP 642 EP 655 DI 10.1016/j.freeradbiomed.2009.12.015 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 555IN UT WOS:000274503100002 PM 20036736 ER PT J AU Uppal, R Caravan, P AF Uppal, Ritika Caravan, Peter TI Targeted probes for cardiovascular MRI SO FUTURE MEDICINAL CHEMISTRY LA English DT Review ID ULTRASMALL SUPERPARAMAGNETIC PARTICLES; PARAMAGNETIC CONTRAST AGENT; ACUTE CORONARY SYNDROMES; MESENCHYMAL STEM-CELLS; IN-VIVO DETECTION; IRON-OXIDE; ATHEROSCLEROTIC PLAQUES; MATRIX METALLOPROTEINASES; MAGNETIC NANOPARTICLES; MYOCARDIAL-INFARCTION AB Molecular MRI plays an important role in studying molecular and cellular processes associated with heart disease. Targeted probes that recognize important biomarkers of atherosclerosis, apoptosis, necrosis, angiogenesis, thrombosis and inflammation have been developed. This review discusses the properties of chemically different contrast agents including iron oxide nanoparticles, gadolinium-based nanoparticles or micelles, discrete peptide conjugates and activatable probes. Numerous examples of contrast agents based on these approaches have been used in preclinical MRI of cardiovascular diseases. Clinical applications are still under investigation for some selected agents with highly promising initial results. Molecular MRI shows great potential for the detection and characterization of a wide range of cardiovascular diseases, as well as for monitoring response to therapy. C1 [Caravan, Peter] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Caravan, P (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu FU National Institute for Biomedical Imaging and Bioengineering [R21EB009738, R01EB009062]; Siemens Medical Solutions FX Ritika Uppal and Peter Caravan acknowledge research support from the National Institute for Biomedical Imaging and Bioengineering, awards R21EB009738 and R01EB009062 to Peter Caravan and from Siemens Medical Solutions. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. NR 95 TC 22 Z9 25 U1 3 U2 21 PU FUTURE SCI LTD PI LONDON PA UNITED HOUSE, 2 ALBERT PL, LONDON, N3 1QB, ENGLAND SN 1756-8919 J9 FUTURE MED CHEM JI Future Med. Chem. PD MAR PY 2010 VL 2 IS 3 SI SI BP 451 EP 470 DI 10.4155/FMC.09.154 PG 20 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 576GI UT WOS:000276132000017 PM 20539821 ER PT J AU MacLaughlin, DT Donahoe, PK AF MacLaughlin, David T. Donahoe, Patricia K. TI Mullerian Inhibiting Substance/anti-Mullerian hormone: a potential therapeutic agent for human ovarian and other cancers SO FUTURE ONCOLOGY LA English DT Review DE anti-Mullerian hormone; Mullerian Inhibiting Substance; ovarian cancer ID NF-KAPPA-B; REPRODUCTIVE TECHNOLOGY CYCLES; NUCLEAR RECEPTOR SF-1; GRANULOSA-CELL TUMORS; II RECEPTOR; IN-VIVO; DUCT REGRESSION; BREAST-CANCER; FETAL TESTIS; GENE-EXPRESSION AB According to the 2008 American Cancer Society statistics, cancer remains the second leading cause of death in American today. Early detection, innovative surgery, new drugs and increased public education regarding avoidable risk factors, such as smoking, have had significant impact on the incidence and survival rates of many cancers, while overall death rates from all cancers have declined a modest 5% over the past 50 years. Ovarian cancer statistics, however, have not been as encouraging. Despite recent advances in the management of this disease, 5-year survival has not improved, and the search continues for rationally designed new treatments. Mullerian Inhibiting Substance is a strong candidate because it addresses many of the deficiencies of existing treatments. Namely, Mullerian Inhibiting Substance has little demonstrated toxicity, it complements the activity of known anticancer drugs, it is highly specific against cancers expressing its receptor and it inhibits the proliferation of drug-resistant tumors, C1 [MacLaughlin, David T.; Donahoe, Patricia K.] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. RP MacLaughlin, DT (reprint author), Massachusetts Gen Hosp, Pediat Surg Res Labs, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM maclaugh@helix.mgh.harvard.edu; pdonahoe@partners.org FU NCI NIH HHS [R01 CA017393] NR 122 TC 14 Z9 15 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 J9 FUTURE ONCOL JI Future Oncol. PD MAR PY 2010 VL 6 IS 3 BP 391 EP 405 DI 10.2217/FON.09.172 PG 15 WC Oncology SC Oncology GA 571NQ UT WOS:000275759700012 PM 20222796 ER PT J AU Mahindra, A Cirstea, D Raje, N AF Mahindra, Anuj Cirstea, Diana Raje, Noopur TI Novel therapeutic targets for multiple myeloma SO FUTURE ONCOLOGY LA English DT Review DE aurora kinase inhibitor; cyclin-dependent kinase inhibitor; histone deacetylase inhibitor; HSP90 inhibitor; mTOR inhibitor; myeloma; novel agent; pomalidomide ID LENALIDOMIDE PLUS DEXAMETHASONE; HISTONE DEACETYLASE INHIBITOR; NEWLY-DIAGNOSED MYELOMA; SUBEROYLANILIDE HYDROXAMIC ACID; ACTIVE PROTEASOME INHIBITOR; DEPENDENT KINASE INHIBITOR; CELL-ACTIVATING FACTOR; IN-VIVO; COMBINATION THERAPY; ANTITUMOR-ACTIVITY AB The past decade has witnessed a dramatic improvement in the therapeutic options in multiple myeloma (MM), Several novel biologically targeted agents are in clinical use and have resulted in improved outcomes, However, the disease remains incurable, underscoring the need for continued efforts towards understanding MM biology, better risk stratification and exploitation of novel therapeutic approaches. Novel agents that target tumor and stromal compartments can be categorized as those that target protein dynamics (e.g., heat shock protein 90 and the ubiquitin-proteasome system), intracellular signaling kinases (e,g,, JAK/STAT, PI3k/Akt/mTOR and MAPK pathways), cell cycle molecular machinery (e.g., cyclin-dependent kinase inhibitor and Aurora kinase inhibitors), membrane-bound receptors (e.g,, IGF-1, VEGF and CD40), epigenetic modulators (e.g., DNA methyltransferase and histone deacetylase), tumor vasculature and microenvironment (e.g., angiogenesis and integrins) and agents modulating anti-MM immune responses, This article focuses on a series of new therapeutic targets that have shown promising preclinical results and early evidence of anti-MM activity in clinical studies, either alone or in combination with other conventional or novel anti-MM treatments. C1 [Mahindra, Anuj; Raje, Noopur] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cirstea, Diana; Raje, Noopur] Harvard Univ, Sch Med, Leebow Inst Myeloma Therapeut, Boston, MA USA. [Cirstea, Diana; Raje, Noopur] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Dis Ctr, Boston, MA 02115 USA. RP Mahindra, A (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM amahindra@partners.org FU ASCO CDA; MMRF; LLS CDA FX This work has received the following grant support: ASCO CDA, MMRF, LLS CDA (NR). 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 96 TC 17 Z9 17 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD MAR PY 2010 VL 6 IS 3 BP 407 EP 418 DI 10.2217/FON.10.2 PG 12 WC Oncology SC Oncology GA 571NQ UT WOS:000275759700013 PM 20222797 ER PT J AU Strobel, O Rosow, DE Rakhlin, EY Lauwers, GY Trainor, AG Alsina, J Fernandez-Del Castillo, C Warshaw, AL Thayer, SP AF Strobel, Oliver Rosow, David E. Rakhlin, Elena Y. Lauwers, Gregory Y. Trainor, Amanda G. Alsina, Janivette Fernandez-Del Castillo, Carlos Warshaw, Andrew L. Thayer, Sarah P. TI Pancreatic Duct Glands Are Distinct Ductal Compartments That React to Chronic Injury and Mediate Shh-Induced Metaplasia SO GASTROENTEROLOGY LA English DT Article DE Pancreatic Duct Glands; Sonic Hedgehog; PanIN; GI Metaplasia ID CANCER STEM-CELLS; INTRAEPITHELIAL NEOPLASIA; SONIC HEDGEHOG; EPITHELIAL-CELLS; ADULT MICE; REGENERATION; EXPRESSION; DIFFERENTIATION; INDUCTION; TRACT AB BACKGROUND & AIMS: Pancreatic intraepithelial neoplasia (PanIN) are pancreatic cancer precursor lesions of unclear origin and significance. PanIN aberrantly express sonic hedgehog (Shh), an initiator of pancreatic cancer, and gastrointestinal mucins. A majority of PanIN are thought to arise from ducts. We identified a novel ductal compartment that is gathered in gland-like outpouches (pancreatic duct glands [PDG]) of major ducts and characterized its role in injury and metaplasia. METHODS: The ductal system was analyzed in normal pancreata and chronic pancreatitis in humans and mice. Anatomy was assessed by serial hematoxylin and eosin sections and scanning electron microscopy of corrosion casts. Expression of mucins and developmental genes and proliferation were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. Effects of Shh on ductal cells were investigated by exposure to Shh in vitro and transgenic misexpression in vivo. RESULTS: Three-dimensional analysis revealed blind-ending outpouches of ducts in murine and human pancreata. These PDG are morphologically and molecularly distinct from normal ducts; even in normal pancreata they display PanIN and metaplastic features, such as expression of Shh and gastric mucins. They express other developmental genes, such as Pdx-1 and Hes-1. In injury, Shh is up-regulated along with gastric mucins. Expansion of the PDG compartment results in a mucinous metaplasia. Shh promotes this transformation in vitro and in vivo. CONCLUSIONS: PDG are distinct gland-like mucinous compartments with a distinct molecular signature. In response to injury, PDG undergo an Shh-mediated mucinous gastrointestinal metaplasia with PanIN-like features. PDG may provide a link between Shh, mucinous metaplasia, and neoplasia. C1 [Strobel, Oliver; Rosow, David E.; Rakhlin, Elena Y.; Trainor, Amanda G.; Alsina, Janivette; Fernandez-Del Castillo, Carlos; Warshaw, Andrew L.; Thayer, Sarah P.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Strobel, Oliver] Univ Heidelberg, Dept Gen Surg, Heidelberg, Germany. RP Thayer, SP (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St,WACC 460, Boston, MA 02114 USA. EM sthayer@partners.org FU German Research Foundation [STR 690/1-1]; Surgery Foundation Heidelberg; Karin Grunebaum Cancer Research Foundation; Lustgarten Foundation for Pancreatic Cancer Research [RFP05-008]; National Institutes of Health [K08DK71329, P50CA127003, P01CA117969] FX This work was supported by grants from the German Research Foundation (STR 690/1-1) and the Surgery Foundation Heidelberg (Lautenschlager Scholarship) (O.S.), the Karin Grunebaum Cancer Research Foundation (D. E. R.), the Lustgarten Foundation for Pancreatic Cancer Research (RFP05-008), and the National Institutes of Health (K08DK71329, P50CA127003, and P01CA117969) (S. P. T.). NR 38 TC 65 Z9 67 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2010 VL 138 IS 3 BP 1166 EP 1177 DI 10.1053/j.gastro.2009.12.005 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 563EF UT WOS:000275109900046 PM 20026066 ER PT J AU Kaplan, LM AF Kaplan, Lee M. TI Pharmacologic Therapies for Obesity SO GASTROENTEROLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Obesity treatment; Pharmacology treatments obesity; Weight loss medication ID WEIGHT-LOSS; LIFE-STYLE; FENFLURAMINE-PHENTERMINE; OVERWEIGHT PATIENT; CONTROLLED-TRIAL; DRUG-TREATMENT; PHARMACOTHERAPY; METAANALYSIS; TOPIRAMATE; NALTREXONE AB This article examines the transitions in pharmacological therapy for obesity. It reviews the current options approved by the Food and Drug Administration and several drugs approved for other indications that can be used to treat obesity as well. Because weight regulation is complex and redundant systems protect against perceived starvation, optimal treatment of obesity in individual patients will likely require different combinations of behavioral, nutritional, pharmacologic, endoscopic, and surgical therapies. C1 [Kaplan, Lee M.] Massachusetts Gen Hosp, MGH Weight Ctr, Boston, MA 02114 USA. [Kaplan, Lee M.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Kaplan, LM (reprint author), Massachusetts Gen Hosp, MGH Weight Ctr, 50 Staniford St,4th Floor, Boston, MA 02114 USA. EM LMKaplan@partners.org FU NIDDK NIH HHS [DK088661, DK046200]; NLM NIH HHS [LM008748] NR 39 TC 42 Z9 44 U1 4 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8553 J9 GASTROENTEROL CLIN N JI Gastroenterol. Clin. North Am. PD MAR PY 2010 VL 39 IS 1 BP 69 EP + DI 10.1016/j.gtc.2010.01.001 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 577FF UT WOS:000276207000008 PM 20202580 ER PT J AU Cotton, PB Eisen, GM Aabakken, L Baron, TH Hutter, MM Jacobson, BC Mergener, K Nemcek, A Petersen, BT Petrini, JL Pike, IM Rabeneck, L Romagnuolo, J Vargo, JJ AF Cotton, Peter B. Eisen, Glenn M. Aabakken, Lars Baron, Todd H. Hutter, Matt M. Jacobson, Brian C. Mergener, Klaus Nemcek, Albert, Jr. Petersen, Bret T. Petrini, John L. Pike, Irving M. Rabeneck, Linda Romagnuolo, Joseph Vargo, John J. TI A lexicon for endoscopic adverse events: report of an ASGE workshop SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID COMPLICATIONS 30 DAYS; GASTROINTESTINAL-ENDOSCOPY; OUTPATIENT COLONOSCOPY; AMERICAN-SOCIETY; RISK-FACTORS; OUTCOMES; ERCP; SPHINCTEROTOMY; EXPERIENCE; MORTALITY C1 [Cotton, Peter B.] Med Univ S Carolina, Ctr Digest Dis, Charleston, SC 29425 USA. [Romagnuolo, Joseph] Med Univ S Carolina, Dept Gastroenterol & Hepatol, Charleston, SC 29425 USA. [Eisen, Glenn M.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Aabakken, Lars] Univ Hosp, Rikshosp, Oslo, Norway. [Baron, Todd H.; Petersen, Bret T.] Mayo Clin, Div Gastroenterol, Rochester, MN USA. [Baron, Todd H.; Petersen, Bret T.] Mayo Clin, Div Hepatol, Rochester, MN USA. [Hutter, Matt M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jacobson, Brian C.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Mergener, Klaus] Digest Hlth Specialists, Tacoma, WA USA. [Nemcek, Albert, Jr.] NW Mem Hosp, Chicago, IL 60611 USA. [Petrini, John L.] Sansum Clin, Santa Barbara, CA USA. [Pike, Irving M.] Gastrointestinal & Liver Specialists Tidewater PL, Virginia Beach, VA USA. [Rabeneck, Linda] Univ Toronto, Toronto, ON, Canada. [Vargo, John J.] Cleveland Clin Fdn, Inst Digest Dis, Dept Gastroenterol & Hepatol, Sect Adv Endoscopy, Cleveland, OH 44195 USA. RP Cotton, PB (reprint author), Med Univ S Carolina, Ctr Digest Dis, 25 Courtenay Dr,ART 7100A,MSC 290, Charleston, SC 29425 USA. OI Jacobson, Brian/0000-0001-7064-2357; Vargo, John/0000-0001-7638-5283 NR 38 TC 286 Z9 287 U1 1 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD MAR PY 2010 VL 71 IS 3 BP 446 EP 454 DI 10.1016/j.gie.2009.10.027 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 573GV UT WOS:000275897900002 PM 20189503 ER PT J AU Young, BA Von Korff, M Heckbert, SR Ludman, EJ Rutter, C Lin, EHB Ciechanowski, PS Oliver, M Williams, L Himmelfarb, J Katon, WJ AF Young, Bessie A. Von Korff, Michael Heckbert, Susan R. Ludman, Evette J. Rutter, Carolyn Lin, Elizabeth H. B. Ciechanowski, Paul S. Oliver, Malia Williams, Lisa Himmelfarb, Jonathan Katon, Wayne J. TI Association of major depression and mortality in Stage 5 diabetic chronic kidney disease SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Depression; Diabetes; Mortality; Chronic kidney disease; ESRD ID GLOMERULAR-FILTRATION-RATE; RENAL-DISEASE; HEMODIALYSIS-PATIENTS; DIALYSIS PATIENTS; UNITED-STATES; PSYCHOLOGICAL-FACTORS; SERUM CREATININE; PRIMARY-CARE; SELF-CARE; RISK AB Objectives: Depression is the most common psychiatric disorder in patients with chronic kidney disease (CKD). We sought to determine the association of major depression with mortality among diabetic patients with late stage CKD. Method: The Pathways Study is a longitudinal, prospective cohort study initiated to determine the impact of depression on outcomes among primary care diabetic patients. Subjects were followed from 2001 until 2007 for a mean duration of 4.4 years. Major depression, identified by the Patient Health Questionnaire-9, was the primary exposure of interest. Stage 5 CKD was determined by dialysis codes and estimated glomerular filtration rate (<15 ml/min). An adjusted Cox proportional hazards multivariable model was used to determine the association of baseline major depression with mortality. Results: Of the 4128 enrolled subjects, 110 were identified with stage 5 CKD at baseline. Of those, 34 (22.1%) had major depression. Over a period of 5 years, major depression was associated with 2.95-fold greater risk of death (95% CI=1.24-7.02) compared to those with no or few depressive symptoms. Conclusion: Major depression at baseline was associated with a 2.95-fold greater risk of mortality among stage 5 CKD diabetic patients. Given the high mortality risk, further testing of targeted depression interventions should be considered in this population. Published by Elsevier Inc. C1 [Young, Bessie A.] Vet Affairs Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA 98101 USA. [Young, Bessie A.; Himmelfarb, Jonathan] Univ Washington, Div Nephrol, Kidney Res Inst, Seattle, WA 98195 USA. [Young, Bessie A.; Williams, Lisa] Vet Affairs Puget Sound Hlth Care Syst, Primary & Specialty Care, Seattle, WA USA. [Von Korff, Michael; Ludman, Evette J.; Rutter, Carolyn; Lin, Elizabeth H. B.; Oliver, Malia] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA USA. [Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heckbert, Susan R.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Ciechanowski, Paul S.; Katon, Wayne J.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Young, BA (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA 98101 USA. EM youngb@u.washington.edu FU NIDDK NIH HHS [R01 DK079745] NR 42 TC 33 Z9 33 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD MAR-APR PY 2010 VL 32 IS 2 BP 119 EP 124 DI 10.1016/j.genhosppsych.2009.11.018 PG 6 WC Psychiatry SC Psychiatry GA 578KX UT WOS:000276293500001 PM 20302984 ER PT J AU Mamtani, M Anaya, JM He, W Ahuja, SK AF Mamtani, M. Anaya, J-M He, W. Ahuja, S. K. TI Association of copy number variation in the FCGR3B gene with risk of autoimmune diseases SO GENES AND IMMUNITY LA English DT Article DE copy number variation (CNV); FCGR3B; CCL3L1; systemic lupus erythematosus; Sjogren's syndrome ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; CONTAINING SEGMENTAL DUPLICATIONS; SJOGRENS-SYNDROME; IMMUNE-COMPLEXES; HUMAN GENOME; SUSCEPTIBILITY; CCL3L1; POLYMORPHISMS; GLOMERULONEPHRITIS; CLASSIFICATION AB Copy number variation (CNV) in the human genome is an important determinant of susceptibility to autoimmune diseases. Many autoimmune diseases share similar clinical and pathogenic features. Thus, CNVs of genes involved in immunity may serve as shared determinants of multiple autoimmune diseases. Here, we determined the association between CNV in the gene encoding FCGR3B with the risk of developing autoimmune diseases and whether the observed associations are modified by the CNV in CCL3L1 (CC chemokine ligand 3-like 1), a gene encoding a potent chemokine. In a cross-sectional study of 774 subjects, we estimated FCGR3B and CCL3L1 gene copy number in 146, 158 and 61 subjects with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and primary Sjogren's syndrome (SS), respectively, and 409 healthy controls. The median gene dose of FCGR3B in the study population was two. FCGR3B copy number < or >2 was associated with an increased risk of SLE and primary SS but not RA. This association was mostly evident in subjects who also had two copies of CCL3L1. Thus, our data suggest that epistatic interactions between CNV of FCGR3B and CCL3L1, two immune response genes, may influence phenotypically related autoimmune diseases. Genes and Immunity (2010) 11, 155-160; doi:10.1038/gene.2009.71; published online 10 September 2009 C1 [Mamtani, M.; He, W.; Ahuja, S. K.] Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, Vet Adm Ctr AIDS & HIV Infect 1, San Antonio, TX 78229 USA. [Mamtani, M.; He, W.; Ahuja, S. K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Anaya, J-M] Univ Nacl Rosario, Sch Med, Ctr Autoimmune Dis Res CREA, Corp Invest Biol, Medellin, Colombia. [Ahuja, S. K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Ahuja, S. K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. RP Ahuja, SK (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med Microbiol & Immunol, 7703 Floyd Curl Dr,Room 5-009R DTL, San Antonio, TX 78229 USA. EM ahujas@uthscsa.edu RI Anaya, Juan-Manuel/J-1960-2016; OI Anaya, Juan-Manuel/0000-0002-6444-1249; Universidad del Rosario, Biblioteca/0000-0003-3491-9392 FU Voelcker Fund Scholar Award; Max and Minnie Tomerlin Voelcker Fund; Elizabeth Glaser Scientist Award; Burroughs Wellcome Clinical Scientist Award in Translational Research; Doris Duke Distinguished Clinical Scientist Award; Rosario University, Bogota, Colombia FX We thank Robert A Clark and George Crawford for their institutional support; Jill King and Adriana Benavides for their help with the bioinformatics for designing the primers and probe. We thank the reviewers of this study for their critical review that greatly helped in improving our paper. This work was supported by the Voelcker Fund Scholar Award to Dr Sunil Ahuja from the Max and Minnie Tomerlin Voelcker Fund. SKA is also a recipient of the Elizabeth Glaser Scientist Award, the Burroughs Wellcome Clinical Scientist Award in Translational Research and the Doris Duke Distinguished Clinical Scientist Award. This work was also supported in part by the Rosario University, Bogota, Colombia. NR 40 TC 47 Z9 50 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD MAR PY 2010 VL 11 IS 2 BP 155 EP 160 DI 10.1038/gene.2009.71 PG 6 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 563XF UT WOS:000275169900006 PM 19741716 ER PT J AU Svenson, JL Chike-Harris, K Amria, MY Nowling, TK AF Svenson, J. L. Chike-Harris, K. Amria, M. Y. Nowling, T. K. TI The mouse and human Fli1 genes are similarly regulated by Ets factors in T cells SO GENES AND IMMUNITY LA English DT Article DE Fli1; Ets; gene expression; transcription factors; lymphocytes; lupus ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; MURINE LEUKEMIA-VIRUS; TRANSCRIPTION FACTORS; ENDOTHELIAL-CELLS; RENAL-DISEASE; EXPRESSION; FAMILY; PROMOTER; MEMBER; ERYTHROLEUKEMIA AB Fli1 is a member of the Ets family of transcription factors and is preferentially expressed in hematopoietic cell lineages. Its expression level is linked to the pathogenesis of lupus. In this study, we identified mechanisms involved in the transcriptional regulation of the mouse and human Fli1 promoters. We show that the Fli1 promoter is upregulated by Ets factors Ets1, Ets2, Fli1 and Elf1 either alone or in combination with GATA factors, but is inhibited by Tel. In vitro binding studies show that Elf1, Tel and Fli1 in T cells bind the three Ets-binding sites in the murine Fli1 proximal promoter. We identified transcription factor-binding sites in the human Fli1 promoter region that function in T cells in a similar manner to those in the mouse promoter. Furthermore, we show similar binding of Ets factors to the endogenous mouse and human Fli1 promoters in T cells and knocking down Ets1 results in an upregulation of Fli1 expression. Together, these results suggest that the human and mouse genes are regulated similarly and that Ets1 may be important in preventing the overexpression of Fli1 in T cells. This report lays the groundwork for identifying targets for manipulating Fli1 expression as a possible therapeutic approach. Genes and Immunity (2010) 11, 161- 172; doi: 10.1038/gene.2009.73; published online 15 October 2009 C1 [Svenson, J. L.; Chike-Harris, K.; Amria, M. Y.; Nowling, T. K.] Med Univ S Carolina, Childrens Res Inst, Dept Med, Div Rheumatol, Charleston, SC 29425 USA. [Nowling, T. K.] Ralph H Johnson VAMC, Res Serv, Charleston, SC USA. RP Nowling, TK (reprint author), Med Univ S Carolina, Childrens Res Inst, Dept Med, Div Rheumatol, MSC 637,CSB,Ste 912,96 Jonathon Lucas St, Charleston, SC 29425 USA. EM nowling@musc.edu FU NIH [DK072306, AR053376] FX This work was supported by NIH grants DK072306 and AR053376. The authors thank Dr Angie Rizzino, Dr Dennis Watson and Dr Maria Trojanowska for their kind gifts of Ets and GATA expression vectors. A special thanks also goes to Dr Gary Gilkeson for critical reading of the paper and providing valuable comments. NR 29 TC 16 Z9 16 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 J9 GENES IMMUN JI Genes Immun. PD MAR PY 2010 VL 11 IS 2 BP 161 EP 172 DI 10.1038/gene.2009.73 PG 12 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 563XF UT WOS:000275169900007 PM 19829305 ER PT J AU Sumegi, J Streblow, R Frayer, RW Dal Cin, P Rosenberg, A Meloni-Ehrig, A Bridge, JA AF Sumegi, Janos Streblow, Renae Frayer, Robert W. Dal Cin, Paola Rosenberg, Andrew Meloni-Ehrig, Aurelia Bridge, Julia A. TI Recurrent t(2;2) and t(2;8) Translocations in Rhabdomyosarcoma Without the Canonical PAX-FOXO1 Fuse PAX3 to Members of the Nuclear Receptor Transcriptional Coactivator Family SO GENES CHROMOSOMES & CANCER LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ALVEOLAR RHABDOMYOSARCOMA; EMBRYONAL RHABDOMYOSARCOMA; HISTONE ACETYLTRANSFERASE; ESTROGEN-RECEPTOR; INTERGROUP RHABDOMYOSARCOMA; PROTEIN METHYLTRANSFERASE; FUSION; GENE; TIF2 AB The fusion oncoproteins PAX3-FOXO1 [t(2;13)(q35;q14)] and PAX7-FOXO1 [t(1;13)(p36;q14)] typify alveolar rhabdomyosarcoma (ARMS); however, 20-30% of cases lack these specific translocations. In this study, cytogenetic and/or molecular characterization to include FISH, reverse transcription polymerase chain reaction (RT-PCR), and sequencing analyses of five rhabdomyosarcomas [four ARMS and one embryonal rhabdomyosarcoma (ERMS)] with novel, recurrent t(2;2)(p23;q35) or t(2;8)(q35;q13) revealed that these noncanonical translocations fuse PAX3 to NCOA1 or NCOA2, respectively. The PAX3-NCOA1 and PAX3-NCOA2 transcripts encode chimeric proteins composed of the paired-box and homeodomain DNA-binding domains of PAX3, and the CID domain, the Q-rich region, and the activation domain 2 (AD2) domain of NCOA1 or NCOA2. To investigate the biological function of these recurrent variant translocations, the coding regions of PAX3-NCOA1 and PAX3-NCOA2 cDNA constructs were introduced into expression vectors with tetracycline-regulated expression. Both fusion proteins showed transforming activity in the soft-agar assay. Deletion of the AD2 portion of the PAX3-NCOA fusion proteins reduced the transforming activity of each chimeric protein. Similarly, but with greater impact, CID domain deletion fully abrogated the transforming activity of the chimeric protein. These studies (1) expand our knowledge of PAX3 variant translocations in RMS with identification of a novel PAX3-NCOA2 fusion, (2) show that both PAX3-NCOA I and PAX3-NCOA2 represent recurrent RMS rearrangements, (3) confirm the transforming activity of both translocation events and demonstrate the essentiality of intact AD2 and CID domains for optimal transforming activity, and (4) provide alternative approaches (FISH and RT-PCR) for detecting PAX-NCOA fusions in nondividing cells of RMS. The latter could potentially be used as aids in diagnostically challenging cases. (C) 2009 Wiley-Liss, Inc. C1 [Streblow, Renae; Bridge, Julia A.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. [Sumegi, Janos; Frayer, Robert W.] Univ Cincinnati, Fac Med, Cincinnati Childrens Hosp, Div Hematol Oncol,Med Ctr, Cincinnati, OH USA. [Dal Cin, Paola] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Rosenberg, Andrew] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Meloni-Ehrig, Aurelia] Quest Diagnost Nichols Inst, Dept Cytogenet, Chantilly, VA USA. [Bridge, Julia A.] Univ Nebraska Med Ctr, Meyer Munroe Inst, Dept Pediat, Omaha, NE 68198 USA. [Bridge, Julia A.] Univ Nebraska Med Ctr, Dept Orthopaed Surg, Omaha, NE 68198 USA. RP Bridge, JA (reprint author), Univ Nebraska Med Ctr, Dept Pathol & Microbiol, 983135 Nebraska Med Ctr, Omaha, NE 68198 USA. EM jbridge@unmc.edu FU NIH [U-10-CA98543-01RO1-CA89461]; UNMC Eppley Pediatric Cancer; American Cancer Society; La Fondation des Gouverneurs de l'Espoir FX Supported by: NIH, Grant number: U-10-CA98543-01RO1-CA89461: UNMC Eppley Pediatric Cancer Award, The Ohio division of the American Cancer Society, and the La Fondation des Gouverneurs de l'Espoir. NR 47 TC 52 Z9 58 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAR PY 2010 VL 49 IS 3 BP 224 EP 236 DI 10.1002/gcc.20731 PG 13 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 547ZT UT WOS:000273929200003 PM 19953635 ER PT J AU Klusmann, JH Li, Z Bohmer, K Maroz, A Koch, ML Emmrich, S Godinho, FJ Orkin, SH Reinhardt, D AF Klusmann, Jan-Henning Li, Zhe Boehmer, Katarina Maroz, Aliaksandra Koch, Mia Lee Emmrich, Stephan Godinho, Frank J. Orkin, Stuart H. Reinhardt, Dirk TI miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia SO GENES & DEVELOPMENT LA English DT Article DE Down syndrome; chromosome 21; leukemia; miRNA ID DOWN-SYNDROME; CELL-DIFFERENTIATION; EXPRESSION PROFILES; MICRORNA TARGETS; GENE-EXPRESSION; BREAST-CANCER; GATA1; PROLIFERATION; ONCOGENE; DICER AB Children with trisomy 21/Down syndrome (DS) are at high risk to develop acute megakaryoblastic leukemia (DS-AMKL) and the related transient leukemia (DS-TL). The factors on human chromosome 21 (Hsa21) that confer this predisposing effect, especially in synergy with consistently mutated transcription factor GATA1 (GATA1s), remain poorly understood. Here, we investigated the role of Hsa21-encoded miR-125b-2, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of miR-125b-2 in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). miR-125b-2 overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid differentiation. The proproliferative effect of miR-125b-2 on MEPs accentuated the Gata1s mutation, whereas growth of DS-AMKL/TL cells was impaired upon miR-125b repression, suggesting synergism during leukemic transformation in GATA1s-mutated DS-AMKL/TL. Integrative transcriptome analysis of hematopoietic cells upon modulation of miR-125b expression levels uncovered a set of miR-125b target genes, including DICER1 and ST18 as direct targets. Gene Set Enrichment Analysis revealed that this target gene set is down-regulated in DS-AMKL patients highly expressing miR-125b. Thus, we propose miR-125b-2 as a positive regulator of megakaryopoiesis and an oncomiR involved in the pathogenesis of trisomy 21-associated megakaryoblastic leukemia. C1 [Klusmann, Jan-Henning; Li, Zhe; Godinho, Frank J.; Orkin, Stuart H.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Klusmann, Jan-Henning; Boehmer, Katarina; Maroz, Aliaksandra; Koch, Mia Lee; Emmrich, Stephan; Reinhardt, Dirk] Hannover Med Sch, Dept Pediat Hematol Oncol, D-30625 Hannover, Germany. [Li, Zhe; Orkin, Stuart H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Li, Zhe; Orkin, Stuart H.] Harvard Stem Cell Inst, Boston, MA 02115 USA. [Li, Zhe] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA. [Godinho, Frank J.; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. EM Stuart_Orkin@dfci.harvard.edu RI Reinhardt, Dirk/D-3939-2011; Xie, Huangming/B-2260-2012; Klusmann, Jan-Henning/M-9655-2015 OI Reinhardt, Dirk/0000-0003-4313-9056; Klusmann, Jan-Henning/0000-0002-1070-0727 FU German National Academic Foundation [RE2580/2-1]; Madelein Schickedanz Foundation; NIH FX We thank M. Hamblen for general laboratory support, M. Ballmaier for cell sorting, Thanaseelan Pushpanathan and M. Wackerhahn for technical assistance, A. Schambach and C. Baum for providing plasmids and assistance with lentiviral transduction, and N. von Neuhoff for providing support and assistance with protein analyses. Z.L. was a Fellow of the Leukemia and Lymphoma Society and was supported by the K99 Pathway-to-Independence award from NCI. This work was supported by a grant to D. R. and J.-H. K. from the German National Academic Foundation (RE2580/2-1) and the Madelein Schickedanz Foundation, and to S.H.O. from the NIH. S. H. O. is an Investigator of the Howard Hughes Medical Institute. NR 50 TC 108 Z9 117 U1 2 U2 9 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAR 1 PY 2010 VL 24 IS 5 BP 478 EP 490 DI 10.1101/gad.1856210 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 562MO UT WOS:000275055900007 PM 20194440 ER PT J AU Perrin, JM Knapp, AA Browning, MF Comeau, AM Green, NS Lipstein, EA Metterville, DR Prosser, L Queally, D Kemper, AR AF Perrin, James M. Knapp, Alixandra A. Browning, Marsha F. Comeau, Anne Marie Green, Nancy S. Lipstein, Ellen A. Metterville, Danielle R. Prosser, Lisa Queally, Denise Kemper, Alex R. TI An evidence development process for newborn screening SO GENETICS IN MEDICINE LA English DT Review ID TASK-FORCE C1 [Perrin, James M.; Knapp, Alixandra A.; Lipstein, Ellen A.; Metterville, Danielle R.] MassGen Hosp Children, Ctr Child & Adolescent Hlth Policy, Boston, MA USA. [Perrin, James M.; Browning, Marsha F.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Browning, Marsha F.] MassGen Hosp Children, Ctr Human Genet Res, Boston, MA USA. [Comeau, Anne Marie] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA USA. [Comeau, Anne Marie] Univ Massachusetts, Sch Med, New England Newborn Screening Program, Worcester, MA USA. [Green, Nancy S.] Columbia Univ, Dept Pediat, New York, NY 10027 USA. [Prosser, Lisa] Univ Michigan Hlth Syst, Dept Pediat, Child Hlth Evaluat & Res Unit, Ann Arbor, MI USA. [Queally, Denise] New England Connect PKU & Allied Disorders, Woburn, MA USA. [Kemper, Alex R.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Kemper, Alex R.] Duke Univ, Duke Clin Res Inst, Durham, NC 27706 USA. RP Perrin, JM (reprint author), MGH Ctr Child & Adolescent Hlth Policy, 50 Staniford St,901, Boston, MA 02114 USA. EM jperrin@partners.org OI Green, Nancy/0000-0002-9877-1561 FU Center for Child and Adolescent Health Policy [HHSP23320045014XI]; Maternal and Child Health Bureau (MCHB); Health Resources and Services Administration (HRSA); U.S. Department of Health and Human Services (DHHS); [SC-07-028] FX This review was made possible by subcontract number SC-07-028 to Massachusetts General Hospital, Center for Child and Adolescent Health Policy under prime contract number HHSP23320045014XI to Altarum Institute, from the Maternal and Child Health Bureau (MCHB) (Title V, Social Security Act), Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services (DHHS). NR 15 TC 18 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD MAR PY 2010 VL 12 IS 3 BP 131 EP 134 DI 10.1097/GIM.0b013e3181d28eb1 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 574VU UT WOS:000276023100001 PM 20154629 ER PT J AU Tang, KS Suh, SW Alano, CC Shao, ZJ Hunt, WT Swanson, RA Anderson, CM AF Tang, Kim San Suh, Sang Won Alano, Conrad C. Shao, Zongjun Hunt, Waylon T. Swanson, Raymond A. Anderson, Christopher M. TI Astrocytic Poly(ADP-ribose) Polymerase-1 Activation Leads to Bioenergetic Depletion and Inhibition of Glutamate Uptake Capacity SO GLIA LA English DT Article DE DNA damage; excitotoxicity; NAD(+); ATP depletion; astrocyte-neuron communication ID DNA STRAND BREAKS; BRAIN-INJURY; CELL-DEATH; CEREBRAL-ISCHEMIA; NEURONAL DEATH; ENERGY-METABOLISM; TRANSPORTER GLT-1; NAD(+) DEPLETION; GENE DISRUPTION; FOCAL ISCHEMIA AB Poly(ADP-ribose) polymerase-1 (PARP-1) is a ubiquitous nuclear enzyme involved in genomic stability. Excessive oxidative DNA strand breaks lead to PARP-1-induced depletion of cellular NAD(+), glycolytic rate, ATP levels, and eventual cell death. Glutamate neurotransmission is tightly controlled by ATP-dependent astrocytic glutamate transporters, and thus we hypothesized that astrocytic PARP-1 activation by DNA damage leads to bioenergetic depletion and compromised glutamate uptake. PARP-1 activation by the DNA alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), caused a significant reduction of cultured cortical astrocyte survival (EC(50) = 78.2 +/- 2.7 mu M). HPLC revealed MNNG-induced time-dependent reductions in NAD(+) (98%, 4 h), ATP (71%, 4 h), ADP (63%, 4 h), and AMP (66%, 4 h). The maximal [(3)H]glutamate uptake rate (V(max)) also declined in a manner that corresponded temporally with ATP depletion, falling from 19.3 +/- 2.8 in control cells to 2.1 +/- 0.8 nmol/min/mg protein 4 h post-MNNG. Both bioenergetic depletion and loss of glutamate uptake capacity were attenuated by genetic deletion of PARP-1, directly indicating PARP-1 involvement, and by adding exogenous NAD+ (10 mM). In mixed neurons/astrocyte cultures, MNNG neurotoxicity was partially mediated by extracellular glutamate and was reduced by co-culture with PARP-1(-/-) astrocytes, suggesting that impairment of astrocytic glutamate uptake by PARP-1 can raise glutamate levels sufficiently to have receptor-mediated effects at neighboring neurons. Taken together, these experiments showed that PARP-1 activation leads to depletion of the total adenine nucleotide pool in astrocytes and severe reduction in neuroprotective glutamate uptake capacity. (C) 2009 Wiley-Liss, Inc. C1 [Tang, Kim San; Shao, Zongjun; Hunt, Waylon T.; Anderson, Christopher M.] St Boniface Gen Hosp, Res Ctr, Div Neurodegenerat Disorders, Winnipeg, MB R2H 2A6, Canada. [Tang, Kim San; Shao, Zongjun; Hunt, Waylon T.; Anderson, Christopher M.] Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada. [Suh, Sang Won] Hallym Univ, Coll Med, Dept Physiol, Chunchon, South Korea. [Suh, Sang Won; Alano, Conrad C.; Swanson, Raymond A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Suh, Sang Won; Alano, Conrad C.; Swanson, Raymond A.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Anderson, CM (reprint author), St Boniface Gen Hosp, Res Ctr, Div Neurodegenerat Disorders, 351 Tache Ave,R4046, Winnipeg, MB R2H 2A6, Canada. EM canderson@sbrc.ca RI Anderson, Chris/J-7081-2014; OI Swanson, Raymond/0000-0002-3664-5359; Anderson, Christopher/0000-0003-0678-3002 FU Canadian Institutes of Health Research [MOP68829]; Heart and Stroke Foundation; Canadian Stroke Network; AstraZeneca FX Grant sponsor: Canadian Institutes of Health Research; Grant number: MOP68829. K.S.T. received a Focus on Stroke Research Fellowship from the CIHR, Heart and Stroke Foundation, Canadian Stroke Network, and AstraZeneca. C.M.A. received salary support from the Heart and Stroke Foundation of Canada. NR 65 TC 11 Z9 13 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-1491 J9 GLIA JI Glia PD MAR PY 2010 VL 58 IS 4 BP 446 EP 457 DI 10.1002/glia.20936 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 550YZ UT WOS:000274172500007 PM 19795500 ER PT J AU Hoff, G Dominitz, JA AF Hoff, Geir Dominitz, Jason A. TI Contrasting US and European approaches to colorectal cancer screening: which is best? SO GUT LA English DT Article ID FECAL-OCCULT-BLOOD; RANDOMIZED CONTROLLED-TRIAL; AVERAGE-RISK POPULATION; BASE-LINE FINDINGS; UNITED-STATES; FLEXIBLE SIGMOIDOSCOPY; ASYMPTOMATIC ADULTS; COLONOSCOPIC POLYPECTOMY; ADENOMA DETECTION; AMERICAN-COLLEGE AB In the recent 1-2 decades, we have seen a considerable development in colorectal cancer (CRC) screening modalities and programme implementation, but major challenges remain. While CRC is still the second leading cause of cancer death in both the USA and Europe, there are limited data on the efficacy and effectiveness of all screening modalities except for the faecal occult blood test (FOBT). Newer screening tests, such as faecal immunochemical tests, molecular markers and CT colonography are being introduced and variably adopted, though overall rates of screening are suboptimal. Professional societies and governmental bodies have endorsed screening, though recommended approaches are quite variable, which may help to explain the great variation in screening practices. Unfortunately, quality assurance programmes are underutilised. Comparing the USA and Europe there may be more variation in CRC screening recommendation and practice within each continent than between them, but there seems to be a stronger emphasis on programmatic screening in Europe, facilitating quality assurance. The much debated need for randomised trials as new screening modalities emerge could be more easily handled if running screening programmes are regarded as natural platforms for testing out and evaluating presumed improvements in the service-including new emerging screening modalities. C1 [Hoff, Geir] Telemark Hosp, Dept Med, NO-3710 Skien, Norway. [Dominitz, Jason A.] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Dominitz, Jason A.] Univ Washington, Dept Med, Div Gastroenterol, Seattle, WA USA. RP Hoff, G (reprint author), Telemark Hosp, Dept Med, NO-3710 Skien, Norway. EM hofg@online.no OI Dominitz, Jason/0000-0002-8070-7086 FU VA Puget Sound Health Care System; Department of Veterans Affairs; American Society for Gastrointestinal Endoscopy Career Development Award FX This material is based upon work supported by the VA Puget Sound Health Care System, Department of Veterans Affairs. JAD is supported by an American Society for Gastrointestinal Endoscopy Career Development Award. 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 87 TC 37 Z9 39 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0017-5749 J9 GUT JI Gut PD MAR PY 2010 VL 59 IS 3 BP 407 EP 414 DI 10.1136/gut.2009.192948 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 564XQ UT WOS:000275252400027 PM 20207645 ER PT J AU Duska, LR Garrett, L Henretta, M Ferriss, JS Lee, L Horowitz, N AF Duska, Linda R. Garrett, Leslie Henretta, Melissa Ferriss, J. Stuart Lee, Lisa Horowitz, Neil TI When 'never-events' occur despite adherence to clinical guidelines: The case of venous thromboembolism in clear cell cancer of the ovary compared with other epithelial histologic subtypes SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Ovarian cancer; Clear cell; Venous thromboembolism; Endometriosis ID CARCINOMA; PROGNOSIS AB Objective. To determine the incidence of clinically significant venous thromboembolism (VTE) in women diagnosed with clear cell carcinoma of the ovary (CCC-O) interpreted in the context of Centers for Medicare and Medicaid Services (CMS) 'never-events.' Methods. Using the institutional pathology Tumor Registry at the Massachusetts General Hospital (MGH), all women diagnosed with a CCC-O from 1994 to 2004 were identified. Controls with epithelial ovarian cancer of other histologies were matched for stage, age and year of diagnosis. Medical records were abstracted and pathology reviewed. All patients had surgical staging and/or cytoreductive surgery by a Gynecologic Oncologist at the MGH. All patients received appropriate peri- and post-operative prophylaxis with subcutaneous heparin and/or sequential compression devices. WE was diagnosed with standard imaging techniques when clinical suspicion arose. Results. Fifty-eight (58) women were diagnosed with CCC-O during the Study period, 43 of whom had complete data available for analysis. Patients with Stage I or 11 disease Comprised 70% of the patients. The mean age of the cohort was 55 and the mean weight 7 1 kg. Eighty-six (86) age, stage, and year of diagnosis matched controls were selected. The majority of controls had serous tumors (47%) with the remainder being endometrioid (33%), mucinous (14%), transitional cell (2%), sarcoma (2%) and mixed (2%). CCC-0 was often seen it) association with endometriosis 70% compared with 22% of controls (p<0.0001). Overall, 18 of 43 CCC-O patients (42%) had VTE while only 19 of 86 control patients (22%) had VTE (p = 0.024, OR = 2.5 Cl 1.1504-5.60). The Fate of VFE was not influenced by weight OF smoking In the CCC-O patients, seventeen percent (17%) of VTE was diagnosed at presentation while 50% was diagnosed postoperatively and 33% at the time of disease recurrence or progression. overall, including cases and controls, late stage disease was more likely associated with VFE (18 of 39, 46%) vs. early stage disease (19 of 90, 21%). p = 0.004. Conclusions. Women with CCC-0 have a 2.5-times greater risk of disease related VTE than women with other histologies of epithelial ovarian cancer despite adherence to prophylactic guidelines. Given the high rate of VTE postoperatively as well as with disease recurrence, one should consider indefinite therapeutic anticoagulation in women with CCC-O. The case of CCC-O is one example of the impracticality of payment denial for 'never-events,' as VTE arises despite best efforts at prevention. (C) 2009 Elsevier Inc. Ail rights reserved. C1 [Duska, Linda R.; Henretta, Melissa; Ferriss, J. Stuart] Univ Virginia Hlth Syst, Div Gynecol Oncol, Charlottesville, VA 22903 USA. [Garrett, Leslie] Massachusetts Gen Hosp, Div Gynecol Oncol, Boston, MA 02114 USA. [Lee, Lisa] Santa Clara Valley Med Ctr, Dept Obstet & Gynecol, San Jose, CA 95128 USA. [Horowitz, Neil] Brigham & Womens Hosp, Div Gynecol Oncol, Boston, MA 02115 USA. RP Duska, LR (reprint author), Univ Virginia Hlth Syst, Div Gynecol Oncol, POB 800712, Charlottesville, VA 22903 USA. EM lduska@virginia.edu OI Ferriss, James/0000-0002-2053-8604 NR 13 TC 45 Z9 45 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 BP 374 EP 377 DI 10.1016/j,ygyno.2009.10.069 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 566HF UT WOS:000275360000018 PM 19922988 ER PT J AU Boruta, D Growdon, W McCann, C Garrett, L Therrien, V Del Carmen, M Goodman, A Schorge, J AF Boruta, D. Growdon, W. McCann, C. Garrett, L. Therrien, V. Del Carmen, M. Goodman, A. Schorge, J. TI Systematic pelvic and paraaortic lymphadenectomy in early-stage endometrial cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Boruta, D.; Growdon, W.; McCann, C.; Garrett, L.; Therrien, V.; Del Carmen, M.; Goodman, A.; Schorge, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 222 BP S88 EP S89 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000216 ER PT J AU Boruta, D Growdon, W McCann, C Garrett, L Therrien, V Del Carmen, M Goodman, A Schorge, J AF Boruta, D. Growdon, W. McCann, C. Garrett, L. Therrien, V. Del Carmen, M. Goodman, A. Schorge, J. TI Evolution of surgical management of early-stage endometrial cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Boruta, D.; Growdon, W.; McCann, C.; Garrett, L.; Therrien, V.; Del Carmen, M.; Goodman, A.; Schorge, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 193 BP S77 EP S78 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000187 ER PT J AU Boruta, D Growdon, W McCann, C Garrett, L Therrien, V Del Carmen, M Goodman, A Schorge, J AF Boruta, D. Growdon, W. McCann, C. Garrett, L. Therrien, V. Del Carmen, M. Goodman, A. Schorge, J. TI Influence of hospital setting and gynecologic oncologist involvement on surgical management of early-stage endometrial cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Boruta, D.; Growdon, W.; McCann, C.; Garrett, L.; Therrien, V.; Del Carmen, M.; Goodman, A.; Schorge, J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 191 BP S77 EP S77 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000185 ER PT J AU Campos, S Penson, R Berlin, S Matulonis, U Horowitz, N AF Campos, S. Penson, R. Berlin, S. Matulonis, U. Horowitz, N. TI A phase II trial of sunitinib in recurrent and refractory ovarian, fallopian tube, and peritoneal carcinoma SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Campos, S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Penson, R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Berlin, S.; Matulonis, U.; Horowitz, N.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 306 BP S119 EP S120 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000297 ER PT J AU Del Carmen, M Lowery, C Micha, J Small, L Street, D Lantz, K Londhe, A AF Del Carmen, M. Lowery, C. Micha, J. Small, L. Street, D. Lantz, K. Londhe, A. TI A single-arm study of carboplatin and pegylated liposomal doxorubicin plus bevacizumab in subjects with platinum-sensitive recurrent ovarian, fallopian tube and primary peritoneal cancers: An interim safety analysis SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Del Carmen, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lowery, C.; Lantz, K.; Londhe, A.] Centocor Ortho Biotech Serv LLC, Horsham, PA USA. [Micha, J.] St Josephs Hosp, Laguna Beach, CA USA. [Small, L.] Maine Med Ctr, Cape Elizabeth, ME USA. [Street, D.] Canc Care Associates, Tulsa, OK USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 318 BP S124 EP S125 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000308 ER PT J AU Esselen, K Growdon, W Schorge, J Boruta, D Goodman, A AF Esselen, K. Growdon, W. Schorge, J. Boruta, D. Goodman, A. TI Defining prognostic variables in recurrent endometrioid endometrial cancer: A 15-year, single-institution review SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Esselen, K.; Growdon, W.; Schorge, J.; Boruta, D.; Goodman, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 218 BP S87 EP S87 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000212 ER PT J AU Ferriss, J Brix, B Tambouret, R DeSimone, C Stoler, M Modesitt, S AF Ferriss, J. Brix, B. Tambouret, R. DeSimone, C. Stoler, M. Modesitt, S. TI Extent of cervical involvement in endometrial cancer predicts survival SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Ferriss, J.; Brix, B.; Stoler, M.; Modesitt, S.] Univ Virginia, Charlottesville, VA USA. [Tambouret, R.] Massachusetts Gen Hosp, Cambridge, MA USA. [DeSimone, C.] Univ Kentucky, Med Ctr, Lucille P Markey Canc Ctr, Lexington, KY 40536 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 208 BP S83 EP S83 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000202 ER PT J AU Ghosh, S Nevadunsky, N Horowitz, N Abrahm, J Berkowitz, R AF Ghosh, S. Nevadunsky, N. Horowitz, N. Abrahm, J. Berkowitz, R. TI Identification of palliative care needs for gynecology oncology patients SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Ghosh, S.; Nevadunsky, N.; Horowitz, N.; Abrahm, J.; Berkowitz, R.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. NR 0 TC 1 Z9 1 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 368 BP S142 EP S142 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000356 ER PT J AU Ghosh, S Baron, E Nevadunsky, N Goldstein, D Horowitz, N Berkowitz, R AF Ghosh, S. Baron, E. Nevadunsky, N. Goldstein, D. Horowitz, N. Berkowitz, R. TI The use of EMA-CO in high-risk gestational trophoblastic neoplasia: The New England Trophoblastic Disease Center experience SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Ghosh, S.; Baron, E.; Nevadunsky, N.; Goldstein, D.; Horowitz, N.; Berkowitz, R.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 230 BP S91 EP S92 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000224 ER PT J AU Growdon, W Drapkin, R Engler, D Gupta, S Nitta, M Sergent, P Orsulic, S Rueda, B Mohapatra, G AF Growdon, W. Drapkin, R. Engler, D. Gupta, S. Nitta, M. Sergent, P. Orsulic, S. Rueda, B. Mohapatra, G. TI Array comparative genomic hybridization identifies genomic markers associated with platinum resistance in human papillary serous ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Growdon, W.; Drapkin, R.; Nitta, M.; Sergent, P.; Rueda, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Engler, D.; Mohapatra, G.] Brigham & Young Univ Hosp, Provo, UT USA. [Gupta, S.] MIT, Cambridge, MA 02139 USA. [Orsulic, S.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RI Drapkin, Ronny/E-9944-2016 OI Drapkin, Ronny/0000-0002-6912-6977 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 421 BP S162 EP S162 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000408 ER PT J AU Growdon, W Rauh-Hain, J Garrett, L McCann, C Schorge, J Boruta, D Goodman, A Rueda, B Horowitz, N Del Carmen, M AF Growdon, W. Rauh-Hain, J. Garrett, L. McCann, C. Schorge, J. Boruta, D. Goodman, A. Rueda, B. Horowitz, N. Del Carmen, M. TI Surgical staging of serous tumors of the uterus associated with improved survival SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Growdon, W.; Rauh-Hain, J.; Garrett, L.; McCann, C.; Schorge, J.; Boruta, D.; Goodman, A.; Rueda, B.; Horowitz, N.; Del Carmen, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 206 BP S82 EP S83 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000200 ER PT J AU Horowitz, N Olawaiye, A Growdon, W Borger, D Dizon, D Brard, L Matulonis, U MacNeill, K Roche, M Krasner, C AF Horowitz, N. Olawaiye, A. Growdon, W. Borger, D. Dizon, D. Brard, L. Matulonis, U. MacNeill, K. Roche, M. Krasner, C. TI Phase II trial of erlotinib (Tarceva) in women with squamous cell carcinoma of the vulva SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Horowitz, N.; Matulonis, U.; MacNeill, K.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Olawaiye, A.] Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. [Growdon, W.; Borger, D.; Roche, M.; Krasner, C.] Massachusetts Gen Hosp, Boston, MA USA. [Dizon, D.] Brown Univ, Sch Med, Providence, RI 02912 USA. [Brard, L.] Brown Univ, Sch Med, Women & Infants Hosp Rhode Isl, Providence, RI 02912 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 31 BP S14 EP S14 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000028 ER PT J AU McCann, C Growdon, W Curley, M Proctor, J Ferguson, J Sheikh, H Borger, D Foster, R MacDougall, J Rueda, B AF McCann, C. Growdon, W. Curley, M. Proctor, J. Ferguson, J. Sheikh, H. Borger, D. Foster, R. MacDougall, J. Rueda, B. TI Hedgehog pathway inhibition impedes ovarian cancer xenograft growth in the adjuvant and maintenance setting SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [McCann, C.; Growdon, W.; Curley, M.; Borger, D.; Foster, R.; Rueda, B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Proctor, J.; Ferguson, J.; Sheikh, H.; MacDougall, J.] Infin Pharmaceut, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 394 BP S152 EP S152 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000382 ER PT J AU Mok, S Birrer, M Donninger, H Hao, K Ozbun, L Samini, G Vathepadiekal, V Berkowitz, R Bonome, T Wong, K AF Mok, S. Birrer, M. Donninger, H. Hao, K. Ozbun, L. Samini, G. Vathepadiekal, V. Berkowitz, R. Bonome, T. Wong, K. TI A gene signature predictive for outcome in advanced ovarian cancer identifies a novel survival factor: Microfibril-associated glycoprotein 2 SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Mok, S.; Wong, K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Birrer, M.; Vathepadiekal, V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Donninger, H.; Ozbun, L.; Samini, G.; Bonome, T.] NCI, Bethesda, MD 20892 USA. [Hao, K.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Berkowitz, R.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 426 BP S164 EP S164 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000413 ER PT J AU Ng, S Huang, K Zhou, Y Hasselblatt, K Yang, J Felmate, C Muto, M Auersperg, N Crum, C Berkowitz, R AF Ng, S. Huang, K. Zhou, Y. Hasselblatt, K. Yang, J. Felmate, C. Muto, M. Auersperg, N. Crum, C. Berkowitz, R. TI A microRNA hypothesis for the precursor lesions of ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Ng, S.; Huang, K.; Zhou, Y.; Hasselblatt, K.; Yang, J.; Felmate, C.; Muto, M.; Crum, C.; Berkowitz, R.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Auersperg, N.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 287 BP S113 EP S113 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000279 ER PT J AU Olawaiye, A Rauh-Hain, J Bristow, R Santillan, A AF Olawaiye, A. Rauh-Hain, J. Bristow, R. Santillan, A. TI Sentinel lymph node dissection versus groin lymph node dissection versus groin radiation in carcinoma of the vulva: A cost-effectiveness analysis SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Olawaiye, A.] Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. [Rauh-Hain, J.] Massachusetts Gen Hosp, Cambridge, MA USA. [Bristow, R.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Santillan, A.] Texas Tech Univ, El Paso, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 236 BP S93 EP S94 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000230 ER PT J AU Rauh-Hain, J Growdon, W McCann, C Schorge, J Rueda, B Goodman, A Horowitz, N Del Carmen, M AF Rauh-Hain, J. Growdon, W. McCann, C. Schorge, J. Rueda, B. Goodman, A. Horowitz, N. Del Carmen, M. TI Optimal cytoreduction associated with improved survival in patients with advanced-stage serous cancers of the uterus SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Rauh-Hain, J.; Growdon, W.; McCann, C.; Schorge, J.; Rueda, B.; Goodman, A.; Del Carmen, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Horowitz, N.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 213 BP S85 EP S85 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000207 ER PT J AU Rodriguez, N Yang, J Zhou, Y Hasselblatt, K Welch, W Berkowitz, R Ng, S AF Rodriguez, N. Yang, J. Zhou, Y. Hasselblatt, K. Welch, W. Berkowitz, R. Ng, S. TI Functional characterization of the tumor antigen casein kinase I-epsilon in ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Rodriguez, N.; Yang, J.; Zhou, Y.; Hasselblatt, K.; Welch, W.; Berkowitz, R.; Ng, S.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 410 BP S157 EP S158 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000397 ER PT J AU Schorge, J McCann, C Growdon, W Boruta, D Del Carmen, M Goodman, A AF Schorge, J. McCann, C. Growdon, W. Boruta, D. Del Carmen, M. Goodman, A. TI Primary debulking surgery for advanced ovarian cancer: Is it the past, present, or future? SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Schorge, J.; McCann, C.; Growdon, W.; Boruta, D.; Del Carmen, M.; Goodman, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 333 BP S130 EP S130 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000322 ER PT J AU Spencer, R Wright, A Nilsson, M Prigerson, H Chalas, E Pearl, M Villella, J AF Spencer, R. Wright, A. Nilsson, M. Prigerson, H. Chalas, E. Pearl, M. Villella, J. TI Gynecologic oncologists' preferences for end-of-life care: Communication, palliation or aggressive care in patients with advanced ovarian cancer? SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Spencer, R.; Wright, A.; Nilsson, M.; Prigerson, H.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Chalas, E.; Villella, J.] Winthrop Univ Hosp, Mineola, NY 11501 USA. [Pearl, M.] Suny Downstate Med Ctr, St James, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 134 BP S53 EP S54 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000128 ER PT J AU Thompson, M Albitar, L Ghosh, S Wong, K Welch, W Birrer, M Mok, S AF Thompson, M. Albitar, L. Ghosh, S. Wong, K. Welch, W. Birrer, M. Mok, S. TI Identification of secretory stromal gene signature of the ovarian tumor microenvironment and implications for ovarian cancer progression SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Thompson, M.; Wong, K.; Mok, S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Albitar, L.; Ghosh, S.; Welch, W.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Birrer, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 330 BP S129 EP S129 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000319 ER PT J AU Viswanathan, A Mirabeau-Beale, K Russell, A Britz-Cunningham, S AF Viswanathan, A. Mirabeau-Beale, K. Russell, A. Britz-Cunningham, S. TI Analysis of the role of PET in the management of patients with vulvar carcinoma SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Viswanathan, A.; Britz-Cunningham, S.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Mirabeau-Beale, K.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Russell, A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 147 BP S58 EP S59 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000141 ER PT J AU Wong, K Tsang, Y Zu, Z Mok, S Deavers, M Birrer, M Wolf, J Lu, K Gershenson, D AF Wong, K. Tsang, Y. Zu, Z. Mok, S. Deavers, M. Birrer, M. Wolf, J. Lu, K. Gershenson, D. TI Insulin growth factor 1 pathway is a potential therapeutic target for low-grade ovarian serous carcinomas SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Wong, K.; Tsang, Y.; Zu, Z.; Mok, S.; Deavers, M.; Wolf, J.; Lu, K.; Gershenson, D.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Birrer, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 290 BP S113 EP S114 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000281 ER PT J AU Yeung, T Ghosh, S Wong, K Gutierrez-Hartmann, A Kwong, J Welch, W Gershenson, D Birrer, M Mok, S AF Yeung, T. Ghosh, S. Wong, K. Gutierrez-Hartmann, A. Kwong, J. Welch, W. Gershenson, D. Birrer, M. Mok, S. TI Differential nuclear Elf-3 expression in high-grade serous ovarian cancer is associated with patient survival SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Yeung, T.; Wong, K.; Gershenson, D.; Mok, S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Ghosh, S.; Welch, W.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Gutierrez-Hartmann, A.] Univ Colorado, Denver, CO 80202 USA. [Kwong, J.] Chinese Univ Hong Kong, Shatin, Hong Kong, Peoples R China. [Birrer, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Gutierrez-Hartmann, Arthur/F-1295-2011; Kwong, Joseph/H-2368-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 40 BP S17 EP S18 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000037 ER PT J AU Zaid, T Thompson, M Wong, K Yeung, T Yeung, Z Yates, M Birrer, M Mok, S AF Zaid, T. Thompson, M. Wong, K. Yeung, T. Yeung, Z. Yates, M. Birrer, M. Mok, S. TI Identification of FGFR4 in the chromosome 5q31-35 prognostic amplicon as the mediator for FGF1 signaling in high-grade serous ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Zaid, T.; Thompson, M.; Wong, K.; Yeung, T.; Yeung, Z.; Yates, M.; Mok, S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Birrer, M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 320 BP S125 EP S125 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000310 ER PT J AU Koreth, J Antin, JH AF Koreth, John Antin, Joseph H. TI Iron overload in hematologic malignancies and outcome of allogeneic hematopoietic stem cell transplantation SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Editorial Material ID BONE-MARROW-TRANSPLANTATION; LONG-TERM SURVIVORS; RISK-FACTOR; SERUM FERRITIN; MYELODYSPLASTIC SYNDROMES; INVASIVE ASPERGILLOSIS; LIVER DYSFUNCTION; INFERIOR SURVIVAL; THALASSEMIA; RECIPIENTS C1 [Koreth, John; Antin, Joseph H.] Dana Farber Canc Inst, Div Hematol Malignancies, Stem Cell Transplant Program, Boston, MA 02115 USA. RP Koreth, J (reprint author), Dana Farber Canc Inst, Div Hematol Malignancies, Stem Cell Transplant Program, Boston, MA 02115 USA. EM john_koreth@dfci.harvard.edu FU NCI NIH HHS [CA142106, P01 CA142106] NR 27 TC 15 Z9 15 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD MAR PY 2010 VL 95 IS 3 BP 364 EP 366 DI 10.3324/haematol.2009.017244 PG 3 WC Hematology SC Hematology GA 578KK UT WOS:000276292100006 PM 20207843 ER PT J AU Hunter, ZR Manning, RJ Hanzis, C Ciccarelli, BT Loakimidis, L Patterson, CJ Lewicki, MC Tseng, H Gong, P Liu, X Zhou, YS Yang, G Sun, J Xu, L Sheehy, P Morra, M Treon, SP AF Hunter, Zachary R. Manning, Robert J. Hanzis, Christine Ciccarelli, Bryan T. Loakimidis, Leukothea Patterson, Christopher J. Lewicki, Megan C. Tseng, Hsuiyi Gong, Ping Liu, Xia Zhou, Yangsheng Yang, Guang Sun, Jenny Xu, Lian Sheehy, Patricia Morra, Massimo Treon, Steven P. TI IgA and IgG hypogammaglobulinemia in Waldenstrom's macroglobulinemia SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE hypogammaglobulinemia; Waldenstrom's macroglobulinemia; serum IgM levels ID URACIL-DNA GLYCOSYLASE; COMMON VARIABLE IMMUNODEFICIENCY; CHRONIC LYMPHOCYTIC-LEUKEMIA; INTERNATIONAL WORKSHOP; RECOMMENDATIONS; CLASSIFICATION; DEFICIENCY; LYMPHOMA; MICE; TACI AB Background Hypogammaglobulinemia is common in Waldenstrom's macroglobulinemia. The etiology of this finding remains unclear, but it has been speculated to be based on tumor-induced suppression of the 'uninvolved' immunoglobulin production Design and Methods We evaluated the incidence of IgA and IgG hypogammaglobulinemia in 207 untreated patients with Waldenstrom's macroglobulinemia and investigated the associated clinicopathological findings and impact of therapy. We also sequenced eight genes (AICDA, BTK, CD40, CD154, NEMO, TACI, SH2D1A, UNC) implicated in immunoglobulin deficiency in 19 Waldenstrom's macroglobulinemia patients with IgA and/or IgG hypogammaglobulinemia. Results At baseline 63.3%, 58.0% and 49.3% of the 207 patients had abnormally low serum levels of IgA, IgG, or both. No association between IgA and IgG hypogammaglobulinemia and disease burden, serum IgM levels, beta(2)-microglobulin, International Prognostic Scoring System score, or incidence of recurrent infections was observed, although the presence of adenopathy and/or splenomegaly was associated with a lower incidence of hypogammaglobulinemia. Lower IgA and IgG levels were associated with disease progression in patients managed with a 'watch and wait' strategy. IgA and/or IgG levels remained abnormally low despite response to treatment, including complete remissions. A missense mutation in the highly conserved catalytic site of UNG was observed in a patient with hypogammaglobulinemia, warranting further study of this pathway in Waldenstrom's macroglobulinemia. Conclusions IgA and IgG hypogammaglobulinemia is common in Waldenstrom's macroglobulinemia and persists despite therapeutic intervention and response. IgA and IgG hypogammaglobulinemia does not predict the risk of recurrent infections in patients with Waldenstrom's macroglobulinemia, although lower levels of serum IgA and IgG are associated with disease progression in Waldenstrom's macroglobulinemia patients being managed with a 'watch and wait' strategy. C1 [Hunter, Zachary R.; Manning, Robert J.; Hanzis, Christine; Ciccarelli, Bryan T.; Loakimidis, Leukothea; Patterson, Christopher J.; Lewicki, Megan C.; Tseng, Hsuiyi; Gong, Ping; Liu, Xia; Zhou, Yangsheng; Yang, Guang; Sun, Jenny; Xu, Lian; Sheehy, Patricia; Treon, Steven P.] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Zhou, Yangsheng; Yang, Guang; Sun, Jenny; Xu, Lian; Treon, Steven P.] Harvard Med Sch, Boston, MA USA. [Morra, Massimo] Correlagen Diagnost Inc, Waltham, MA USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M547,44 Binney St, Boston, MA 02115 USA. EM steven_treon@dfci.har-vard.edu RI Hunter, Zachary/H-3018-2013 OI Hunter, Zachary/0000-0002-1689-1691 FU International Waldenstrom's Macroglobulinemia Foundation; Bing Fund for Waldenstrom's Macroglobulinemia; Bailey Family Fund for Waldenstrom's Research; Linda and Edward Nelson Fund for Waldenstrom's Macroglobulinemia; Bauman Family Trust FX Funding: this study was supported by the International Waldenstrom's Macroglobulinemia Foundation, and the Bing Fund for Waldenstrom's Macroglobulinemia, the Bailey Family Fund for Waldenstrom's Research, the Linda and Edward Nelson Fund for Waldenstrom's Macroglobulinemia, and a gift from the Bauman Family Trust. NR 23 TC 17 Z9 18 U1 0 U2 1 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD MAR PY 2010 VL 95 IS 3 BP 470 EP 475 DI 10.3324/haemato1.2009.010348 PG 6 WC Hematology SC Hematology GA 578KK UT WOS:000276292100020 PM 19903677 ER PT J AU Cartreine, JA Ahern, DK Locke, SE AF Cartreine, James A. Ahern, David K. Locke, Steven E. TI A Roadmap to Computer-Based Psychotherapy in the United States SO HARVARD REVIEW OF PSYCHIATRY LA English DT Article DE cognitive-behavioral therapy; computer-assisted psychotherapy; computer-based treatment; distance therapy; self-guided treatment; telehealth; telemedicine; technology in behavioral health; technology in psychiatry ID COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; VIRTUAL-REALITY EXPOSURE; MENTAL-HEALTH TREATMENT; ANXIETY DISORDERS; PRIMARY-CARE; EATING-DISORDER; INTERNET; DEPRESSION; INTERVENTION AB Computers can be used to deliver self-guided interventions and to provide access to live therapists at remote locations. These treatment modalities could help overcome barriers to treatment, including cost, availability of therapists, logistics of scheduling and traveling to appointments, stigma, and lack of therapist training in evidence-based treatments (EBTs). EBTs could be delivered at any time in any place to individuals who might otherwise not have access to them, improving public mental health across the United States. In order to fully exploit the opportunities to use computers for mental health care delivery, however, advances need to be made in four domains: (1) research, (2) training, (3) policy, and (4) industry. This article discusses specific challenges (and some possible solutions) to implementing computer-based distance therapy and self-guided treatments in the United States. It lays out both a roadmap and, in each of the four domains, the milestones that need to be met to reach the goal of making EBTs for behavioral health problems available to all Americans.= 2 psychotropics) increased in 2009 (affective or schizoaffective disorders > schizophrenia). Total psychotropics/patient (3.1-3.2) remained stable but mood-stabilizers/patient increased markedly and antipsychotics/patient decreased somewhat in 2009. Antipsychotic-choice (2009) ranked: quetiapine, aripiprazole, risperidone, and others; mood-stabilizers ranked: lamotrigine, valproate, lithium, and others (1/4 off-label). In 2009, final total antipsychotic doses (mg/day) increased by 97%, and mood-stabilizers by 75%. Adverse-effect rates fell by half. Factors differing independently for 2009 versus 2004 ranked: (a) more CGI improvement, (b) more mood-stabilizers/patient, (c) lower admission CGI scores, and (c) higher total antipsychotic dose. Comment Combinations and doses of antipsychotic and mood-stabilizing drugs for inpatients increased markedly (2004 vs. 2009) without consistent correspondence of agents/person and doses, without apparent increase in major adverse effects, and with possibly superior clinical improvement. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Centorrino, Franca; Baldessarini, Ross J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Centorrino, Franca; Baldessarini, Ross J.] Massachusetts Gen Hosp, Int Consortium Bipolar & Psychot Disorders Res, McLean Div, Boston, MA 02114 USA. [Ventriglio, Antonio] Univ Foggia, Dept Psychiat, Riunite Hosp, Sch Med, Foggia, Italy. [Vincenti, Alessio; Talamo, Alessandra] Univ Roma La Sapienza, Dept Neurosci Mental Hlth & Sensory Funct NESMOS, Sch Med 2, Rome, Italy. [Vincenti, Alessio; Talamo, Alessandra] SantAndrea Hosp, Psychiat Unit, Rome, Italy. RP Baldessarini, RJ (reprint author), McLean Hosp, Mailman Res Ctr 312, 115 Mill St, Belmont, MA 02478 USA. EM rjb@mclean.org OI Talamo, Alessandra/0000-0001-7321-9247; Ventriglio, Antonio/0000-0002-3934-7007 FU Universities of Foggia; Bruce J. Anderson Foundation; McLean Private Donors Psychopharmacology Research Fund FX This work was supported in part by research fellowships from the Universities of Foggia (Dr Ventriglio) and of Rome (Dr Vincenti), and by a grant from the Bruce J. Anderson Foundation and the McLean Private Donors Psychopharmacology Research Fund (Dr Baldessarini). NR 35 TC 23 Z9 23 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0885-6222 J9 HUM PSYCHOPHARM CLIN JI Hum. Psychopharmacol.-Clin. Exp. PD MAR PY 2010 VL 25 IS 2 BP 179 EP 186 DI 10.1002/hup.1095 PG 8 WC Clinical Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry; Psychology GA 575OZ UT WOS:000276078100012 PM 20196186 ER PT J AU Pang, CY Hu, W Hu, BQ Shi, Y Vanderburg, CR Rogers, JT Huang, XD AF Pang, Chao-Yang Hu, Wei Hu, Ben-Qiong Shi, Ying Vanderburg, Charles R. Rogers, Jack T. Huang, Xudong TI A Special Local Clustering Algorithm for Identifying the Genes Associated With Alzheimer's Disease SO IEEE TRANSACTIONS ON NANOBIOSCIENCE LA English DT Article DE Algorithm; Alzheimer's disease (AD); compact class; local clustering (LC) feature; special local clustering (SLC) ID VECTOR QUANTIZATION AB Clustering is the grouping of similar objects into a class. Local clustering feature refers to the phenomenon whereby one group of data is separated from another, and the data from these different groups are clustered locally. A compact class is defined as one cluster in which all similar elements cluster tightly within the cluster. Herein, the essence of the local clustering feature, revealed by mathematical manipulation, results in a novel clustering algorithm termed as the special local clustering (SLC) algorithm that was used to process gene microarray data related to Alzheimer's disease (AD). SLC algorithm was able to group together genes with similar expression patterns and identify significantly varied gene expression values as isolated points. If a gene belongs to a compact class in control data and appears as an isolated point in incipient, moderate and/or severe AD gene microarray data, this gene is possibly associated with AD. Application of a clustering algorithm in disease-associated gene identification such as in AD is rarely reported. C1 [Huang, Xudong] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol,Div Nucl Med & Mol Imaging,Conjugate, Boston, MA 02115 USA. [Pang, Chao-Yang] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol,Conjugate & Med Chem Lab,Biomed Infor, Boston, MA 02115 USA. [Pang, Chao-Yang] Sichuan Normal Univ, Coll Math & Software Sci, Key Software Lab, Chengdu 610066, Peoples R China. [Hu, Ben-Qiong] Chengdu Univ Technol, Coll Informat Management, Chengdu 610059, Peoples R China. [Vanderburg, Charles R.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Vanderburg, Charles R.] Massachusetts Gen Hosp, Harvard NeuroDiscovery Ctr, Boston, MA 02114 USA. [Vanderburg, Charles R.; Rogers, Jack T.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Rogers, Jack T.] Massachusetts Gen Hosp, Dept Psychiat, Neurochem Lab, Boston, MA 02114 USA. RP Huang, XD (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol,Div Nucl Med & Mol Imaging,Conjugate, Boston, MA 02115 USA. EM cpang@bwh.harvard.edu; cyp_900@hotmail.com; bqh@msn.com; yshi@rics.bwh.harvard.edu; crvanderburg@partners.org; jtrogers@partners.org; xhuang3@partners.org FU National Institute of Health/National Institute on Aging [5R21AG028850]; Alzheimer's Association [IIRG07-60397]; Radiology Department, Brigham and Women's Hospital, Boston, MA FX This work was supported by National Institute of Health/National Institute on Aging under Grant 5R21AG028850 and Alzheimer's Association under Grant IIRG07-60397, and by the Radiology Department, Brigham and Women's Hospital, Boston, MA. Asterisk indicates corresponding author. NR 21 TC 8 Z9 8 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1536-1241 J9 IEEE T NANOBIOSCI JI IEEE Trans. Nanobiosci. PD MAR PY 2010 VL 9 IS 1 BP 44 EP 50 DI 10.1109/TNB.2009.2037745 PG 7 WC Biochemical Research Methods; Nanoscience & Nanotechnology SC Biochemistry & Molecular Biology; Science & Technology - Other Topics GA 575UL UT WOS:000276094400006 PM 20089478 ER PT J AU Christian, M Cermak, T Zhang, F Hummel, A Doyle, E Schmidt, C Baller, J Joung, J Bogdanove, A Voytas, D AF Christian, Michelle Cermak, Tomas Zhang Feng Hummel, Aaron Doyle, Erin Schmidt, Clarice Baller, Joshua Joung, J. Bogdanove, Adam Voytas, Daniel TI Fusions of TAL Effectors to the FokI Endonuclease Confer Site Specificity in DNA Cleavage SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Meeting Abstract C1 [Christian, Michelle; Cermak, Tomas; Zhang Feng; Baller, Joshua; Voytas, Daniel] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Christian, Michelle; Cermak, Tomas; Zhang Feng; Baller, Joshua; Voytas, Daniel] Univ Minnesota, Ctr Genome Engn, Minneapolis, MN 55455 USA. [Hummel, Aaron; Doyle, Erin; Schmidt, Clarice; Bogdanove, Adam] Iowa State Univ, Dept Plant Pathol, Ames, IA 50011 USA. [Joung, J.] Massachusetts Gen Hosp, Dept Mol Pathol, Charlestown, MA 02129 USA. [Hummel, Aaron] Iowa State Univ, Ames, IA 50010 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-2690 J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD SPR PY 2010 VL 46 SU S BP S205 EP S206 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 695JX UT WOS:000285367500463 ER PT J AU Sonnenberg, A AF Sonnenberg, Amnon TI Age Distribution of IBD Hospitalization SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE birth cohort; environmental risk factors; epidemiology of inflammatory bowel disease; hospital statistics; age effects; time trends ID INFLAMMATORY-BOWEL-DISEASE; CROHNS-DISEASE; ULCERATIVE-COLITIS; UNITED-STATES; TIME TRENDS; EPIDEMIOLOGY; PREVALENCE; MORTALITY; POPULATION; COUNTY AB Background and Aims: The ages of patients with Crohn's disease (CD) and ulcerative colitis (UC) are characterized by a bimodal distribution. The present study used hospital statistics to compare the age distribution of inflammatory bowel disease (IBD) among different countries. Methods: Hospital statistics from the period 1994 to 2007 were obtained through special requests to the national statistical offices of 9 European countries. Hospitalization was expressed as age- and sex-specific rates per 10,000 living people. Results: Hospitalization rates of different countries varied between 1.2 and 4.3 discharges per 10,000 for CD and between 0.7 and 4.7 discharges per 10.000 for UC. Countries with high CD rates were associated with similarly high UC rates (r = 0.955, P < 0.0001). In all countries alike, the age-distribution of CD hospitalization was characterized by a large peak in younger patients followed by a small peak in older patients. UC hospitalization was characterized by a small peak in younger patients followed by a large peak in older patients. Conclusions: The bimodal age distribution of IBD hospitalization can be explained in terms of varying exposure to 2 separate environmental risk factors that affected consecutive age groups differently over the course of the 20th century. C1 [Sonnenberg, Amnon] Portland VA Med Ctr, Portland, OR 97239 USA. [Sonnenberg, Amnon] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Sonnenberg, A (reprint author), Portland VA Med Ctr, P3-GI,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu NR 22 TC 20 Z9 22 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR PY 2010 VL 16 IS 3 BP 452 EP 457 DI 10.1002/ibd.21058 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 576GX UT WOS:000276133600016 PM 19714765 ER PT J AU Sonnenberg, A AF Sonnenberg, Amnon TI Similar Geographic Variations of Mortality and Hospitalization Associated with IBD and Clostridium difficile Colitis SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE environmental risk factors; epidemiology of IBD; geographic variation; hospital statistics; mortality from IBD ID INFLAMMATORY-BOWEL-DISEASE; UNITED-STATES; INFECTIONS; COHORT; IMPACT; STOOL AB Background: Superinfection with Clostridium difficile can aggravate the symptoms of preexisting inflammatory bowel disease (IBD). The study served to assess whether the geographic variation of IBD within the United States might be influenced by C. difficile infection. Methods: Hospitalization data of the Healthcare Cost and Utilization Project (HCUP) from 2001-2006 and mortality data from 1979-2005 of the US were analyzed by individual states. Hospitalization and mortality associated with Crohn's disease (CD), ulcerative colitis (UC), and C. difficile colitis were correlated with each other, using weighted least square linear regression with the population size of individual states as weight. Results: Among the hospitalization rates, there were strong correlations between both types of IBD, as well as each type of IBD with C. difficile colitis. Similarly, among the mortality rates there were strong correlations between both types of IBD, as well as each type of IBD with C. difficile colitis. Lastly, each type of hospitalization rate was also strongly correlated with each type of mortality rate. In general, hospitalization and mortality associated with IBD tended to be frequent in many of the northern states and infrequent in the Southwest and several southern states. Conclusions: The similarity in the geographic distribution of the 3 diseases could indicate the influence of C. difficile colitis in shaping the geographic patterns of IBD. It could also indicate that shared environmental risk factors influence the occurrence of IBD, as well as C. difficile colitis. C1 [Sonnenberg, Amnon] Portland VA Med Ctr, Portland, OR 97239 USA. [Sonnenberg, Amnon] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Sonnenberg, A (reprint author), Portland VA Med Ctr, P3-GI,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu NR 19 TC 12 Z9 12 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR PY 2010 VL 16 IS 3 BP 487 EP 493 DI 10.1002/ibd.21054 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 576GX UT WOS:000276133600022 PM 19637331 ER PT J AU Bordeianou, L Dursun, A AF Bordeianou, Liliana Dursun, Abdulmetin TI Current Thinking on Recurrence: Does Anastomotic Surgical Technique Affect Recurrence Rates in Crohn's Patients? SO INFLAMMATORY BOWEL DISEASES LA English DT Editorial Material ID TO-END ANASTOMOSIS; ILEOCOLONIC RESECTION; DISEASE; VS. C1 [Bordeianou, Liliana; Dursun, Abdulmetin] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Bordeianou, L (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. NR 9 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD MAR PY 2010 VL 16 IS 3 BP 539 EP 540 DI 10.1002/ibd.21100 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 576GX UT WOS:000276133600030 PM 19760782 ER PT J AU Polsky, D Marcus, SC Werner, RM AF Polsky, Daniel Marcus, Steven C. Werner, Rachel M. TI Malpractice Premiums and the Supply of Obstetricians SO INQUIRY-THE JOURNAL OF HEALTH CARE ORGANIZATION PROVISION AND FINANCING LA English DT Article ID INSURANCE; CRISIS; LIABILITY; CARE; REFORMS; CAPS AB Using longitudinal data on practicing obstetricians from 1998 to 2004 derived from Pennsylvania, Florida, and New York hospital discharge data, this study finds that rising malpractice premiums are associated with an increased rate of exit and a reduced rate of entry for obstetricians. In Pennsylvania and Florida, where premiums rose by an average of 20% per year for four years, the combined effect of more exits and fewer entries was associated with a decline in obstetrical labor supply of 80 physicians, or 5.3% of the supply of obstetricians. C1 [Polsky, Daniel; Werner, Rachel M.] Univ Penn, Div Gen Internal Med, Sch Med, Philadelphia, PA 19104 USA. [Polsky, Daniel] Univ Penn, Wharton Sch, Philadelphia, PA 19104 USA. [Marcus, Steven C.] Univ Penn, Sch Social Policy & Practice, Philadelphia, PA 19104 USA. [Werner, Rachel M.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Polsky, D (reprint author), Univ Penn, Div Gen Internal Med, Sch Med, Blockley Hall,Rm 1204,423 Guardian Dr, Philadelphia, PA 19104 USA. EM polsky@mail.med.upenn.edu NR 27 TC 5 Z9 5 U1 1 U2 1 PU BLUE CROSS BLUE SHIELD ASSOC PI ROCHESTER PA 150 EAST MAIN ST, ROCHESTER, NY 14647 USA SN 0046-9580 J9 INQUIRY-J HEALTH CAR JI Inquiry-J. Health Care Organ. Provis. Financ. PD SPR PY 2010 VL 47 IS 1 BP 48 EP 61 DI 10.5034/inquiryjrnl_47.01.48 PG 14 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 595VA UT WOS:000277640300005 PM 20464954 ER PT J AU Einstein, DR Del Pin, F Jiao, XM Kuprat, AP Carson, JP Kunzelman, KS Cochran, RP Guccione, JM Ratcliffe, MB AF Einstein, Daniel R. Del Pin, Facundo Jiao, Xiangmin Kuprat, Andrew P. Carson, James P. Kunzelman, Karyn S. Cochran, Richard P. Guccione, Julius M. Ratcliffe, Mark B. TI Fluid-structure interactions of the mitral valve and left heart: Comprehensive strategies, past, present and future SO INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING LA English DT Article DE biofluid-structure interactions; ischemic mitral regurgitation; imaging-based finite element models ID FINITE-ELEMENT-METHOD; LEFT-VENTRICULAR WALL; IN-VITRO QUANTIFICATION; AORTIC-VALVE; PAPILLARY-MUSCLE; SHEAR-STRESS; ENDOTHELIAL-CELLS; COMPUTATIONAL ANALYSIS; MYOCARDIAL-INFARCTION; INCOMPRESSIBLE FLOWS AB The remodeling that occurs after a posterolateral myocardial infarction can alter mitral valve function by creating conformational abnormalities in the mitral annulus and in the posteromedial papillary muscle, leading to mitral regurgitation (MR). It is generally assumed that this remodeling is caused by a volume load and is mediated by an increase in diastolic wall stress. Thus, MR can be both the cause and effect of an abnormal cardiac stress environment. Computational modeling of ischemic MR and its surgical correction is attractive because it enables an examination of whether a given intervention addresses the correction of regurgitation (fluid-flow) at the cost of abnormal tissue stress. This is significant because the negative effects of an increased wall stress due to the intervention will only be evident over time. However, a meaningful fluid structure interaction (FSI) model of the left heart is not trivial; it requires a careful characterization of the in vivo cardiac geometry, the tissue parameterization through inverse analysis, a robust coupled solver that handles collapsing Lagrangian interfaces, the automatic grid-generation algorithms that are capable of accurately discretizing the cardiac geometry, the innovations in image analysis, the competent and efficient constitutive models and an understanding of the spatial organization of tissue microstructure. In this paper, we profile our work toward a comprehensive FSI model of the left heart by reviewing our early work, presenting our current work and laying out our future work in four broad categories: data collection, geometry, FSI and validation. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Einstein, Daniel R.; Kuprat, Andrew P.; Carson, James P.] Pacific NW Natl Lab, Richland, WA 99352 USA. [Del Pin, Facundo] Livermore Software Technol Corp, Livermore, CA USA. [Jiao, Xiangmin] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. [Kunzelman, Karyn S.] Univ Maine, Dept Mech Engn, Orono, ME 04469 USA. [Cochran, Richard P.] Cent Maine Heart & Vasc Inst, Lewiston, ME USA. [Guccione, Julius M.; Ratcliffe, Mark B.] San Francisco VA Med Ctr, Dept Surg, San Francisco, CA USA. RP Einstein, DR (reprint author), Pacific NW Natl Lab, Richland, WA 99352 USA. EM daniel.einstein@pnl.gov OI Kuprat, Andrew/0000-0003-4159-918X; Jiao, Xiangmin/0000-0002-7111-9813 FU National Heart and Blood Institute [5R01HL077921-03, 1R01HL084431-01A1, 1RO1-HL073598-01A] FX Contract/grant sponsor: National Heart and Blood Institute; contract/grant numbers: 5R01HL077921-03, 1R01HL084431-01A1, 1RO1-HL073598-01A NR 120 TC 34 Z9 35 U1 2 U2 15 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 2040-7939 J9 INT J NUMER METH BIO JI Int. J. Numer. Meth. Biomed. PD MAR-APR PY 2010 VL 26 IS 3-4 SI SI BP 348 EP 380 DI 10.1002/cnm.1280 PG 33 WC Engineering, Biomedical; Mathematical & Computational Biology; Mathematics, Interdisciplinary Applications SC Engineering; Mathematical & Computational Biology; Mathematics GA 586HR UT WOS:000276897700007 PM 20454531 ER PT J AU Cruess, DG Localio, AR Platt, AB Brensinger, CM Christie, JD Gross, R Parker, CS Price, M Metlay, JP Cohen, A Newcomb, CW Strom, BL Kimmel, SE AF Cruess, Dean G. Localio, A. Russell Platt, Alec B. Brensinger, Colleen M. Christie, Jason D. Gross, Robert Parker, Catherine S. Price, Maureen Metlay, Joshua P. Cohen, Abigail Newcomb, Craig W. Strom, Brian L. Kimmel, Stephen E. TI Patient Attitudinal and Behavioral Factors Associated with Warfarin Non-adherence at Outpatient Anticoagulation Clinics SO INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE Warfarin adherence; Patient factors; MBMD; MEMS ID ACTIVE ANTIRETROVIRAL THERAPY; NONRHEUMATIC ATRIAL-FIBRILLATION; HIV-POSITIVE MEN; RISK-FACTORS; PSYCHOSOCIAL FACTORS; IN-RANGE; ANTIHYPERTENSIVE THERAPY; BLEEDING COMPLICATIONS; ANTITHROMBOTIC THERAPY; MEDICATION ADHERENCE AB Warfarin is an anticoagulant effective in preventing stroke, but it has a narrow therapeutic range requiring optimal adherence to achieve the most favorable effects. The goal of this study was to examine specific patient factors that might help explain warfarin non-adherence at outpatient anticoagulation clinics. In a prospective cohort study of 156 adults, we utilized logistic regression analyses to examine the relationship between the five Treatment Prognostics scales from the Millon Behavioral Medicine Diagnostic (MBMD), as well as three additional MBMD scales (Depression, Future Pessimism, and Social Isolation), and daily warfarin non-adherence assessed using electronic medication event monitoring systems caps over a median of 139 days. Four of the five Treatment Prognostic scales and greater social isolation were associated with warfarin non-adherence. When controlling for pertinent demographic and medical variables, the Information Discomfort scale remained significantly associated with warfarin non-adherence over time. Although several factors were related to warfarin non-adherence, patients reporting a lack of receptivity to details regarding their medical illness seemed most at risk for warfarin non-adherence. This information might aid in the development of interventions to enhance warfarin adherence and perhaps reduce adverse medical events. C1 [Cruess, Dean G.] Univ Connecticut, Dept Psychol, Storrs, CT 06269 USA. [Platt, Alec B.; Christie, Jason D.; Gross, Robert; Metlay, Joshua P.; Strom, Brian L.; Kimmel, Stephen E.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Localio, A. Russell; Platt, Alec B.; Brensinger, Colleen M.; Christie, Jason D.; Gross, Robert; Parker, Catherine S.; Price, Maureen; Metlay, Joshua P.; Cohen, Abigail; Newcomb, Craig W.; Strom, Brian L.; Kimmel, Stephen E.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Localio, A. Russell; Platt, Alec B.; Brensinger, Colleen M.; Christie, Jason D.; Gross, Robert; Parker, Catherine S.; Price, Maureen; Metlay, Joshua P.; Cohen, Abigail; Newcomb, Craig W.; Strom, Brian L.; Kimmel, Stephen E.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Metlay, Joshua P.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Cruess, DG (reprint author), Univ Connecticut, Dept Psychol, 406 Babbidge Rd,Unit 1020, Storrs, CT 06269 USA. EM Dean.Cruess@uconn.edu RI Cohen, Abigail/K-9180-2013 OI Cohen, Abigail/0000-0002-7425-7218 FU AHRQ HHS [P01 HS011530, P01-HS11530]; NHLBI NIH HHS [K24 HL070936, K24HL070936, R01 HL066176, R01 HL066176-01, R01-HL66176, T32 HL007891] NR 58 TC 24 Z9 24 U1 1 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1070-5503 J9 INT J BEHAV MED JI Int. J. Behav. Med. PD MAR PY 2010 VL 17 IS 1 BP 33 EP 42 DI 10.1007/s12529-009-9052-6 PG 10 WC Psychology, Clinical SC Psychology GA 552LV UT WOS:000274293100004 PM 19579066 ER PT J AU Bordeianou, L Kunitake, H Shellito, P Hodin, R AF Bordeianou, Liliana Kunitake, Hiroko Shellito, Paul Hodin, Richard TI Preoperative infliximab treatment in patients with ulcerative and indeterminate colitis does not increase rate of conversion to emergent and multistep abdominal surgery SO INTERNATIONAL JOURNAL OF COLORECTAL DISEASE LA English DT Article DE Infliximab; Subtotal colectomy; Surgical complications; Ulcerative colitis ID SHORT-TERM COMPLICATIONS; CROHNS-DISEASE; HOSPITALIZATIONS; COMORBIDITY; OPERATION AB A recent study has raised concerns that infliximab treatment, by postpoing surgery for ulcerative and indeterminate colitis patients, may result in a greater need for high-risk emergent or multistep surgical procedures (subtotal colectomies). Our aim was to assess whether infliximab exposure affects rates of subotal colectomy in a large cohort of patients. We evaluated 171 consecutive patients with ulcerative or indeterminate colitis who had a total proctocolectomy or a subtotal colectomy between 1993 and 2006 for symptoms of unremitting disease. Forty-four patients (25.7%) received infliximab prior to surgery. We compared the surgical procedures employed on these 44 patients to the surgical procedures employed on the 127 non-infliximab patients, using Fisher's exact or Student's t test. Infliximab exposure did not appear to affect the rate of emergent surgery (4.5% vs 4.4%, p = 0.98), rate of subtotal colectomy (19.2% vs. 18.0%, p = 0.99), or rate of ileoanal J pouch reconstruction (53.8% vs. 62%, p = 0.98). Nor did it affect intraoperative findings of perforation, toxic megacolon, and active disease. The infliximab and non-infliximab cohorts were similar in age, Charlson Comorbidity Index, concomitant steroid use, and albumin levels, although infliximab patients had higher rates of concomitant exposure to 6-mercaptopurine (34.1% vs 16.6%, p = 0.02) and azathioprine (40.9% vs 22.6%, p = 0.02). Infliximab does not appear to increase rates of emergent surgery or multistep procedures in patients undergoing treatment for ulcerative or indeterminative colitis at our institution. C1 [Bordeianou, Liliana; Kunitake, Hiroko; Shellito, Paul; Hodin, Richard] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Bordeianou, Liliana; Kunitake, Hiroko; Shellito, Paul; Hodin, Richard] Harvard Univ, Sch Med, MGH Crohns & Colitis Ctr, Boston, MA USA. RP Bordeianou, L (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St,ACC 460, Boston, MA 02114 USA. EM lbordeianou@partners.org NR 12 TC 18 Z9 19 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-1958 J9 INT J COLORECTAL DIS JI Int. J. Colorectal Dis. PD MAR PY 2010 VL 25 IS 3 BP 401 EP 404 DI 10.1007/s00384-009-0800-5 PG 4 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 550EA UT WOS:000274109900014 PM 19798508 ER PT J AU Becker, AE Thomas, JJ Bainivualiku, A Richards, L Navara, K Roberts, AL Gilman, SE Striegel-Moore, RH AF Becker, Anne E. Thomas, Jennifer J. Bainivualiku, Asenaca Richards, Lauren Navara, Kesaia Roberts, Andrea L. Gilman, Stephen E. Striegel-Moore, Ruth H. CA HEALTHY Fiji Study Grp TI Validity and Reliability of a Fijian Translation and Adaptation of the Eating Disorder Examination Questionnaire SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE eating disorder; EDE-Q; validity; cross-cultural; Fiji ID SELF-REPORT QUESTIONNAIRE; ADOLESCENT GIRLS; TELEVISION; YOUNG AB Objective: Assessment of disordered eating has uncertain validity across culturally diverse populations This study evaluated Eating Disorder Examination Questionnaire (EDE-Q) performance in an ethnic Fijian study population Method: The EDE-Q was translated, adapted, and administered to school-going Fijian adolescent females (N = 523) A subsample (n = 81) completed it again within similar to 1 week we assessed feasibility, internal consistency, and test-retest reliability, evaluation constrict validity through factor analysis and correlation with similar constructs, and examined the marginal Utility of an additional question on traditional purgative Use Results: Internal consistency reliability was adequate for the global scale and subscales (Cronbach's alpha = 0 66-0 91). retest reliability was adequate for both the languages (range of ICCs, 0 50-0 79, and of kappas, 0 46-0 81, excluding purging Items) Construct. validity was supported by significant correlations with measures of similar constructs Factor analysis confirms multiple dimensions of eating disorder symptoms but suggests possible culture-specific variation in this population The majority of respondents endorsing traditional purgative Use (58%) did riot endorse conventional EDE-Q items assessing purging Discussion: The EDE-Q is a valid measure of eating disorder pathology for ethnic Fijian adolescent females and measures a Unitary Underlying construct (C) 2009 by Wiley Periodicals, Inc C1 [Becker, Anne E.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA 02115 USA. [Becker, Anne E.; Thomas, Jennifer J.] Massachusetts Gen Hosp, Dept Psychiat, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Thomas, Jennifer J.] McLean Hosp, Klarman Eating Disorders Ctr, Belmont, MA 02178 USA. [Bainivualiku, Asenaca] Univ Victoria, Dept Child & Youth Care, Vancouver, BC, Canada. [Richards, Lauren] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Roberts, Andrea L.; Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Striegel-Moore, Ruth H.] Wesleyan Univ, Dept Psychol, Middletown, CT USA. RP Becker, AE (reprint author), Harvard Univ, Sch Med, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. RI Gilman, Stephen/E-7632-2010 OI Gilman, Stephen/0000-0002-8331-6419 FU Harvard University; [K23 MH068575] FX Supported by K23 MH068575 and a Harvard University Research Enabling Grant NR 22 TC 23 Z9 23 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0276-3478 J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD MAR PY 2010 VL 43 IS 2 BP 171 EP 178 PG 8 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA 562CD UT WOS:000275025900008 PM 19308995 ER PT J AU Becker, AE Thomas, JJ Bainivualiku, A Richards, L Navara, K Roberts, AL Gilman, SE Striegel-Moore, RH AF Becker, Anne E. Thomas, Jennifer J. Bainivualiku, Asenaca Richards, Lauren Navara, Kesaia Roberts, Andrea L. Gilman, Stephen E. Striegel-Moore, Ruth H. CA HEALTHY Fiji Study Grp TI Adaptation and Evaluation of the Clinical Impairment Assessment to Assess Disordered Eating Related Distress in an Adolescent Female Ethnic Fijian Population SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE eating disorder; Clinical Impairment Assessment; distress; cross-cultural; Fiji ID QUALITY-OF-LIFE; MENTAL-HEALTH; TELEVISION AB Objective: Measurement of disease-related Impairment and distress is central to diagnostic, therapeutic. and health policy considerations for eating disorders across diverse populations This study evaluates psychometric properties of a translated and adapted version of the Clinical Impairment Assessment (CIA) in an ethnic Fijian population Method: The adapted CIA was administered to ethnic Fijian adolescent schoolgirls (N = 215) We calculated Cronbach's alpha to assess the Internal consistency, examined the association between indicators of eating disorder symptom severity and the CIA to assess construct and criterion validity, and compared the strength of relation between the CIA and measures of disordered eating versus with measures of generalized distress Results: The Fijian version of the CIA is feasible to administer as art Investigator-based interview it has excellent Internal consistency (alpha = 0 93) Both construct and criterion validity were supported by the data, and regression models indicated that the CIA predicts eating disorder severity, even when controlling for generalized distress and psychopathology Discussion: The adapted CIA has excellent psychometric properties In this Fijian study population Findings suggest that the CIA can be successfully adapted for use in a non-Western study population and that at least Some associated distress and Impairment transcends cultural differences (C) 2009 by Wiley Periodicals. Inc C1 [Becker, Anne E.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA 02115 USA. [Becker, Anne E.; Thomas, Jennifer J.] Massachusetts Gen Hosp, Dept Psychiat, Eating Disorders Clin & Res Program, Boston, MA 02114 USA. [Thomas, Jennifer J.] McLean Hosp, Klarman Eating Disorders Ctr, Belmont, MA 02178 USA. [Bainivualiku, Asenaca] Univ Victoria, Vancouver, BC, Canada. [Richards, Lauren] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Roberts, Andrea L.; Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Striegel-Moore, Ruth H.] Wesleyan Univ, Dept Psychol, Middletown, CT USA. RP Becker, AE (reprint author), Harvard Univ, Sch Med, Dept Global Hlth & Social Med, 641 Huntington Ave, Boston, MA 02115 USA. RI Gilman, Stephen/E-7632-2010; OI Gilman, Stephen/0000-0002-8331-6419; Roberts, Andrea/0000-0001-5023-4399; weissman, ruth/0000-0001-6121-4641 FU NIMH [K23 MH068575]; Harvard University FX Supported by K23 MH068575 from the NIMH and by a Harvard University Research Enabling Grant NR 25 TC 15 Z9 15 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0276-3478 J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD MAR PY 2010 VL 43 IS 2 BP 179 EP 186 DI 10.1002/eat.20665 PG 8 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA 562CD UT WOS:000275025900009 PM 19308992 ER PT J AU Wadleigh, M Tefferi, A AF Wadleigh, Martha Tefferi, Ayalew TI Classification and diagnosis of myeloproliferative neoplasms according to the 2008 World Health Organization criteria SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE JAK2V617F; Myeloproliferative neoplasms; WHO criteria ID CHRONIC MYELOMONOCYTIC LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; TYROSINE KINASE MUTATION; JAK2 V617F MUTATION; POLYCYTHEMIA-VERA; ESSENTIAL THROMBOCYTHEMIA; ACTIVATING MUTATION; MYELOID METAPLASIA; JAK2(V617F) MUTATION; CELL LINEAGES AB The myeloproliferative neoplasms (MPNs) were first recognized by William Dameshek in 1951. The classic MPNs were polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and chronic myelogenous leukemia. They were originally grouped together based on their shared phenotype of myeloproliferation. Since then, important discoveries have been made, identifying a central role of protein tyrosine kinases in the pathogenesis of these disorders. As such, the 2008 WHO diagnostic classification for myeloproliferative neoplasms has incorporated molecular markers with histologic, clinical and laboratory information into the diagnostic algorithms for the MPNs. Important changes include (1) the change of nomenclature of myeloproliferative disorder to myeloproliferative neoplasm emphasizing the clonal nature of these disorders; (2) the classification of mast cell disease as an MPN; (3) the reorganization of the eosinophilic disorders into a molecularly defined category of PDGFRA, PDGFRB and FGFR1-associated myeloid and lymphoid neoplasms with eosinophilia and chronic eosinophilic leukemia, not otherwise specified; and (4) refinement of the diagnostic criteria for PV, ET and PMF incorporating recently described molecular markers, JAK2V617F, JAK2 exon 12 mutations and MPL mutations. This review focuses upon the important changes of the 2008 WHO diagnostic criteria for MPNs. C1 [Tefferi, Ayalew] Mayo Clin, Dept Med, Div Hematol, Rochester, MN 55905 USA. [Wadleigh, Martha] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Tefferi, A (reprint author), Mayo Clin, Dept Med, Div Hematol, 200 1st St SW, Rochester, MN 55905 USA. EM Martha_Wadleigh@DFCI.harvard.edu; Tefferi.ayalew@mayo.edu NR 50 TC 54 Z9 61 U1 1 U2 3 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD MAR PY 2010 VL 91 IS 2 BP 174 EP 179 DI 10.1007/s12185-010-0529-5 PG 6 WC Hematology SC Hematology GA 580OX UT WOS:000276459900006 PM 20191332 ER PT J AU LaRocque, R Rao, S Lawton, T Tsibris, A Schoenfeld, D Barry, A Yanni, E Marano, N Gallagher, N Marano, C Brunette, G Ryan, E AF LaRocque, R. Rao, S. Lawton, T. Tsibris, A. Schoenfeld, D. Barry, A. Yanni, E. Marano, N. Gallagher, N. Marano, C. Brunette, G. Ryan, E. TI Use and sources of medical information among departing international travelers to low and middle income countries at Logan International Airport-Boston, MA, 2009 SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [LaRocque, R.; Rao, S.; Lawton, T.; Tsibris, A.; Schoenfeld, D.; Ryan, E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Barry, A.] Boston Publ Hlth Commiss, Boston, MA USA. [Yanni, E.; Marano, N.; Gallagher, N.; Marano, C.; Brunette, G.] Ctr Dis Control & Prevent, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD MAR PY 2010 VL 14 SU 1 BP E132 EP E132 DI 10.1016/j.ijid.2010.02.1777 PG 1 WC Infectious Diseases SC Infectious Diseases GA 578MQ UT WOS:000276298200298 ER PT J AU LaRocque, R Rao, S Yanni, E Marano, N Gallagher, N Marano, C Brunette, G Lee, J Ansdell, V Schwartz, BS Knouse, M Cahill, J Hagmann, S Vinetz, J Hoffman, R Alvarez, S Goad, J Franco-Paredes, C Kozarsky, P Schoenfeld, D Ryan, E AF LaRocque, R. Rao, S. Yanni, E. Marano, N. Gallagher, N. Marano, C. Brunette, G. Lee, J. Ansdell, V. Schwartz, B. S. Knouse, M. Cahill, J. Hagmann, S. Vinetz, J. Hoffman, R. Alvarez, S. Goad, J. Franco-Paredes, C. Kozarsky, P. Schoenfeld, D. Ryan, E. TI Demographics, medical conditions, and use of immunizations and chemoprophylaxis among international travelers within the Global TravEpiNet US National Clinic Network SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [LaRocque, R.; Rao, S.; Schoenfeld, D.; Ryan, E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Yanni, E.; Marano, N.; Gallagher, N.; Marano, C.; Brunette, G.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Lee, J.] NW Mem Hosp, Travel & Immunizat Ctr, Chicago, IL 60611 USA. [Ansdell, V.] Kaiser Permanente Honolulu Travel Med Clin, Honolulu, HI USA. [Schwartz, B. S.] Univ Calif San Francisco, Travel Med & Immunizat Ctr, San Francisco, CA 94143 USA. [Knouse, M.] Lehigh Valley Med Ctr, Allenton, PA USA. [Cahill, J.] Travel & Immunizat Ctr, New York, NY USA. [Hagmann, S.] Bronx Lebanon Hosp Ctr, Neighborhod Clin Travel Hlth, Bronx, NY 10456 USA. [Vinetz, J.] Univ Calif, San Diego Travel Clin, La Jolla, CA USA. [Hoffman, R.] Univ Calif Los Angeles, Travel & Trop Med Clin, Los Angeles, CA USA. [Alvarez, S.] Mayo Clin, Jacksonville, FL 32224 USA. [Goad, J.] USC Int Travel Med Clin, Los Angeles, CA USA. [Franco-Paredes, C.; Kozarsky, P.] Emory TravelWell, Atlanta, GA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD MAR PY 2010 VL 14 SU 1 BP E131 EP E132 DI 10.1016/j.ijid.2010.02.1776 PG 2 WC Infectious Diseases SC Infectious Diseases GA 578MQ UT WOS:000276298200297 ER PT J AU Manoff, S McFetride, R Liss, C Marchese, R Rabb, J Rueda, A Musher, D AF Manoff, S. McFetride, R. Liss, C. Marchese, R. Rabb, J. Rueda, A. Musher, D. TI Antibody persistence 10 years after 1st and 2nd doses of 23-valent pneumococcal polysaccharide vaccine (PN23), and immunogenicity and safety of 2nd and 3rd doses in older adults SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [Manoff, S.; McFetride, R.; Liss, C.; Marchese, R.] Merck, N Wales, PA USA. [Rabb, J.] PPD Vaccines & Biol, Wayne, PA USA. [Rueda, A.; Musher, D.] Baylor Coll Med, Houston, TX 77030 USA. [Rueda, A.; Musher, D.] VA Med Ctr, Houston, TX USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD MAR PY 2010 VL 14 SU 1 BP E454 EP E454 DI 10.1016/j.ijid.2010.02.627 PG 1 WC Infectious Diseases SC Infectious Diseases GA 578MQ UT WOS:000276298201587 ER PT J AU Maturo, S Hartnick, C AF Maturo, Stephen Hartnick, Christopher TI Initial experience using propranolol as the sole treatment for infantile airway hemangiomas SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Article DE Pediatric; Airway; Hemangioma; Propranolol ID INFANCY AB The objective of this study is to describe the initial use of propranolol as the sole treatment for focal infantile airway hemangiomas, and to report on available literature describing the use of propranolol for airway lesions. This retrospective case series was carried out at a tertiary pediatric medical center We obtained the following results: two children demonstrated significant response to oral propranolol therapy and avoided not only invasive Surgical procedures, but also long-term administration of oral corticosteroids This is the first report of treating infantile airway hemangiomas with only propranolol without additional surgical intervention or corticosteroid use. Review of literature reveals initial case series with similar, successful results using propranolol as an adjuvant treatment along with other medications and Surgical interventions We conclude that the initial use of propranolol as the sole treatment for infantile airway hemangioma is promising. Literature review reveals that propranolol as the sole treatment for most head and neck hemangiomas shows significant promise based on early case reports Further studies are needed to determine the long-term effectiveness. dosing strategies. and side effect profile of propranolol treatment for hemangiomas (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Maturo, Stephen; Hartnick, Christopher] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Maturo, S (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 11 TC 36 Z9 42 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-5876 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD MAR PY 2010 VL 74 IS 3 BP 323 EP 325 DI 10.1016/j.ijporl.2009.12.008 PG 3 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA 569QF UT WOS:000275612400019 PM 20071038 ER PT J AU Malament, KA Socransky, SS AF Malament, Kenneth A. Socransky, Sigmund S. TI Survival of Dicor Glass-Ceramic Dental Restorations Over 20 Years: Part IV. The Effects of Combinations of Variables SO INTERNATIONAL JOURNAL OF PROSTHODONTICS LA English DT Article ID TOOTH; CROWNS AB Purpose: Previous studies have shown the relationship of individual clinical variables to the survival of Dicor (Corning Glass Works) restorations. The purpose of the present investigation was to examine the effect of combinations of these variables on the intraoral survival of Dicor restorations. Materials and Methods: Dicor glass-ceramic restorations (n = 1,444) were placed in 417 adult patients. Failure was defined as a restoration that required remake because of material fracture. The survival of restorations with different combinations of variables that were each individually associated with survival was described using Kaplan-Meier survivor functions. The statistical significance of differences in survival between different combinations of specific predictor variables was examined using the proportional hazards model. Results: Kaplan-Meier survival analysis indicated that significantly worse survival rates were found for restorations that included combinations of molar teeth, a dentin core, and a glass-ionomer luting agent; molar teeth, a dentin core, and a resin luting agent; and single-rooted teeth, a dentin core, and a glass-ionomer luting agent than for any other combinations tested. The Cox proportional hazards model described a hazard ratio of 3.37 (95% confidence interval [CI]: 2.23 to 5.08) for molar teeth (versus single-rooted teeth), 2.65 (95% CI: 1.44 to 4.87) for dentin core (versus gold core), 2.35 (95% CI: 1.58 to 3.51) for men (versus women), and 1.72 (95% CI: 1.13 to 2.60) for glass-ionomer luting agent (versus resin) after adjusting for the other variables in the model. Conclusion: Factors beyond individual restoration design impact the survival of Dicor glass-ceramic. These include sex, tooth position, and restorations luted to gold core foundation bases. Int J Prosthodont 2010;23:134-140. C1 [Malament, Kenneth A.] Tufts Univ, Sch Dent Med, Boston, MA 02111 USA. [Socransky, Sigmund S.] Forsyth Inst, Dept Periodontol, Boston, MA USA. RP Malament, KA (reprint author), 50 Staniford St, Boston, MA 02114 USA. EM ken.malament@verizon.net NR 9 TC 14 Z9 14 U1 0 U2 6 PU QUINTESSENCE PUBLISHING CO INC PI HANOVER PARK PA 4350 CHANDLER DRIVE, HANOVER PARK, IL 60133 USA SN 0893-2174 J9 INT J PROSTHODONT JI Int. J. Prosthodont. PD MAR-APR PY 2010 VL 23 IS 2 BP 134 EP 140 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 583NC UT WOS:000276682400009 PM 20305851 ER PT J AU Bourgier, C Marsiglia, H Taghian, A AF Bourgier, Celine Marsiglia, Hugo Taghian, Alphonse TI A MIXED-MODALITY 3D-CONFORMAL ACCELERATED PARTIAL BREAST IRRADIATION TECHNIQUE USING OPPOSED MINI-TANGENT PHOTON FIELDS AND EN FACE ELECTRONS TO MINIMIZE THE LUNG EXPOSURE TO RADIATION: IN REGARD TO JAIN ET AL. (INT J RADIAT ONCOL BIOL PHYS 2009;75:82-88) SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Letter C1 [Bourgier, Celine; Marsiglia, Hugo] Inst Gustave Roussy, Dept Radiat Therapy, Breast Unit, Villejuif, France. [Marsiglia, Hugo] Univ Florence, Florence, Italy. [Taghian, Alphonse] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Bourgier, C (reprint author), Inst Gustave Roussy, Dept Radiat Therapy, Breast Unit, Villejuif, France. NR 3 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 1 PY 2010 VL 76 IS 3 BP 956 EP 957 DI 10.1016/j.ijrobp.2009.10.026 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 562RT UT WOS:000275072200041 PM 20159367 ER PT J AU Richardson, LK Amstadter, AB Kilpatrick, DG Gaboury, MT Tran, TL Trung, LT Tam, NT Tuan, T Buoi, LT Ha, TT Thach, TD Acierno, R AF Richardson, Lisa K. Amstadter, Ananda B. Kilpatrick, Dean G. Gaboury, Mario T. Trinh Luong Tran Lam Tu Trung Nguyen Thanh Tam Tran Tuan La Thi Buoi Tran Thu Ha Tran Duc Thach Acierno, Ron TI ESTIMATING MENTAL DISTRESS IN VIETNAM: THE USE OF THE SRQ-20 SO INTERNATIONAL JOURNAL OF SOCIAL PSYCHIATRY LA English DT Article DE community estimate; mental distress; mental health; Self Reporting Questionnaire 20; SRQ-20; Vietnam ID COMORBIDITY SURVEY REPLICATION; DSM-IV DISORDERS; HEALTH; PREVALENCE; COUNTRIES AB Background: Community-based estimates of psychopathology prevalence in developing countries such as Vietnam, are needed to reduce presumed significant burden of poor mental health. Aims: This study derived population-based prevalence estimates of mental distress, as measured by the SRQ-20, in a community sample of 4,981 adults living in Vietnam. This study also examined correlates of mental distress based on SRQ-20 caseness indications. Risk and protective factors were identified in terms of their unique contribution to caseness. Results: Using a cut-off of 7/8, 19.2% of the sample was considered to be a probable case (n = 954), with females endorsing more items than males. Marital status and employment status were not associated with mental health distress. Higher wealth, endorsing religious affiliation, and self-reports of good health were associated with lower SRQ-20 scores. Age and being female were associated with higher SRQ-20 scores. Conclusions: A single item was as adequate a measure of wealth as multi-item rating scales. Our estimate of mental distress using the SRQ-20 is much greater than that of other studies, and in contrast to western prevalence studies, age was not a protective factor in this study. The SRQ-20 is a brief, cost-effective and reasonably valid measure of both community and individual mental distress. C1 [Amstadter, Ananda B.; Kilpatrick, Dean G.; Acierno, Ron] Med Univ S Carolina, Charleston, SC 29425 USA. [Acierno, Ron] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Tran Tuan; La Thi Buoi; Tran Thu Ha; Tran Duc Thach] Res & Training Ctr Community Dev, Hanoi, Vietnam. [Nguyen Thanh Tam] Vietnam Vet Amer Fdn, Washington, DC USA. [Lam Tu Trung] Da Nang Mental Hlth Hosp, Da Nang, Vietnam. [Trinh Luong Tran] Hlth Dept Da Nang City, Da Nang, Vietnam. [Gaboury, Mario T.] Univ New Haven, Dept Criminal Justice, West Haven, CT USA. [Gaboury, Mario T.] Univ New Haven, Oskar Schindler Humanities Fdn, West Haven, CT USA. [Richardson, Lisa K.] Murdoch Univ, Perth, WA, Australia. RP Acierno, R (reprint author), Med Univ S Carolina, Charleston, SC 29425 USA. EM acierno@musc.edu RI Tran, Thach/H-7734-2014 OI Tran, Thach/0000-0002-4686-8601 NR 17 TC 10 Z9 10 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0020-7640 J9 INT J SOC PSYCHIATR JI Int. J. Soc. Psychiatr. PD MAR PY 2010 VL 56 IS 2 BP 133 EP 142 DI 10.1177/0020764008099554 PG 10 WC Psychiatry SC Psychiatry GA 564QU UT WOS:000275232000003 PM 20207676 ER PT J AU Wilkosz, PA Seltman, HJ Devlin, B Weamer, EA Lopez, OL DeKosky, ST Sweet, RA AF Wilkosz, Patricia A. Seltman, Howard J. Devlin, Bernie Weamer, Elise A. Lopez, Oscar L. DeKosky, Steven T. Sweet, Robert A. TI Trajectories of cognitive decline in Alzheimer's disease SO INTERNATIONAL PSYCHOGERIATRICS LA English DT Article DE late-onset Alzheimer disease (LOAD); psychosis; cognitive neuropsychology in dementia; assessment of cognitive disorders/dementia; APOE epsilon 4 ID EPSILON-4 ALLELE; DEMENTIA; RISK; PSYCHOSIS; CONSORTIUM; CLINICIAN; DIAGNOSIS; MODELS; ONSET; AGE AB Background: Late-onset Alzheimer disease (LOAD) is a clinically heterogeneous complex disease defined by progressively disabling cognitive impairment. Psychotic symptoms which affect approximately one-half of LOAD subjects have been associated with more rapid cognitive decline. However, the variety of cognitive trajectories in LOAD, and their correlates, have not been well defined. We therefore used latent class modeling to characterize trajectories of cognitive and behavioral decline in a cohort of AD subjects. Methods: 201 Caucasian subjects with possible or probable Alzheimer's disease (AD) were evaluated for cognitive and psychotic symptoms at regular intervals for up to 13.5 years. Cognitive symptoms were evaluated serially with the Mini-mental State Examination (MMSE), and psychotic symptoms were rated using the CERAD behavioral rating scale (CBRS). Analyses undertaken were latent class mixture models of quadratic trajectories including a random intercept with initial MMSE score, age, gender, education, and APOE epsilon 4 count modeled as concomitant variables. In a secondary analysis, psychosis status was also included. Results: AD subjects showed six trajectories with significantly different courses and rates of cognitive decline. The concomitant variables included in the best latent class trajectory model were initial MMSE and age. Greater burden of psychotic symptoms increased the probability of following a trajectory of more rapid cognitive decline in all age and initial MMSE groups. APOE epsilon 4 was not associated with any trajectory Conclusion: Trajectory modeling of longitudinal cognitive and behavioral data may provide enhanced resolution of phenotypic variation in AD. C1 [Wilkosz, Patricia A.; Devlin, Bernie; Weamer, Elise A.; Lopez, Oscar L.; DeKosky, Steven T.; Sweet, Robert A.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Weamer, Elise A.; Lopez, Oscar L.; DeKosky, Steven T.; Sweet, Robert A.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. [Seltman, Howard J.] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. [Sweet, Robert A.] VA Pittsburgh Healthcare Syst, VISN MIRECC 4, Pittsburgh, PA USA. RP Sweet, RA (reprint author), Univ Pittsburgh, Dept Psychiat, Biomed Sci Tower,Rm W-1645,3811 OHara St, Pittsburgh, PA 15213 USA. EM sweetra@upmc.edu OI Seltman, Howard/0000-0002-7543-3578 FU National Institute of Aging [AG027224, AG005133] FX This study was supported in part by research grants AG027224 and AG005133 from the National Institute of Aging. The authors wish to thank Mr. James Emanuel for formatting the manuscript and the staff of the Alzheimer Disease Research and Clinic at the University of Pittsburgh. We also wish to thank the two anonymous reviewers for many helpful suggestions. NR 34 TC 46 Z9 47 U1 2 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1041-6102 J9 INT PSYCHOGERIATR JI Int. Psychogeriatr. PD MAR PY 2010 VL 22 IS 2 BP 281 EP 290 DI 10.1017/S1041610209991001 PG 10 WC Psychology, Clinical; Geriatrics & Gerontology; Gerontology; Psychiatry; Psychology SC Psychology; Geriatrics & Gerontology; Psychiatry GA 563LF UT WOS:000275132800013 PM 19781112 ER PT J AU Trichonas, G Manola, A Morizane, Y Thanos, A Koufomichali, X Papakostas, TD Montezuma, S Young, L Miller, JW Gragoudas, E Vavvas, D AF Trichonas, George Manola, Akrivi Morizane, Yuki Thanos, Aristomenis Koufomichali, Xanthi Papakostas, Thanos D. Montezuma, Sandra Young, Lucy Miller, Joan W. Gragoudas, Evangelos Vavvas, Demetrios TI A Novel Nonradioactive Method to Evaluate Vascular Barrier Breakdown and Leakage SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; BLOOD-RETINAL BARRIER; DIABETIC-RETINOPATHY; PERMEABILITY; RATS; QUANTITATION; CLEARANCE; ENDOTOXIN; BLUE AB PURPOSE. To identify a novel, sensitive, nonradioactive leakage assay that can be used in the assessment of retinal vascular permeability in rats and mice. METHODS. Breakdown of the vascular barrier was induced by vascular endothelial growth factor (VEGF), lipopolysaccharide (LPS), or diabetes. Biotinylated bovine serum albumin (bBSA) was administered as a tracer. After perfusion with lactated Ringer's solution, extravasated bBSA was detected with immunoprecipitation and Western blot analysis or sandwich ELISA. The results were then normalized against the final bBSA plasma concentration, the circulation time, and the protein concentration of the tissue. RESULTS. Six hours after VEGF injection, BRB breakdown was quantified in the injected eye and was 2.5-fold higher than in the contralateral phosphate-buffered saline (PBS)-injected eye (n = 6 rats, P < 0.01). Intravitreal LPS injection induced severe inflammation in the directly injected eye and moderate inflammation in the contralateral untreated eye. Leakage was six- and threefold higher, respectively, compared with that in the untreated control animals (n = 5 rats, P < 0.01). Nine-month diabetic rats had a threefold increase in vascular leakage compared with age-matched control animals (n = 6 retinas, P < 0.05). Twenty-four hours after intraperitoneal administration of LPS in mice, the animals showed increased vascular leakage in all tissue organs examined (retina, 1.7-fold; brain, 1.5-fold; and kidney, 1.3-fold). CONCLUSIONS. bBSA can serve as an effective alternative to the current methods used for quantitating vascular leakage and especially the blood-retinal barrier breakdown. It is reasonably easy to perform, low in cost, and adaptable to experiments in mice. (Invest Ophthalmol Vis Sci. 2010;51:1677-1682) DOI: 10.1167/iovs.09-4193 C1 [Trichonas, George; Manola, Akrivi; Morizane, Yuki; Thanos, Aristomenis; Koufomichali, Xanthi; Papakostas, Thanos D.; Montezuma, Sandra; Young, Lucy; Miller, Joan W.; Gragoudas, Evangelos; Vavvas, Demetrios] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Retina Serv,Angiogenesis Lab, Boston, MA USA. RP Vavvas, D (reprint author), Harvard Massachusetts Eye & Ear Infirm, 325 Cambridge St,3rd Floor, Boston, MA 02114 USA. EM demetrios_vavvas@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 FU Boston area Diabetes and Endocrinology Research Center; Fight for Sight; Research to Prevent Blindness; Lions Onassis Foundation; Bacardi Fund FX Supported by the Boston area Diabetes and Endocrinology Research Center, Fight for Sight, Research to Prevent Blindness, the Lions Onassis Foundation, and the Bacardi Fund. NR 25 TC 9 Z9 10 U1 0 U2 8 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR PY 2010 VL 51 IS 3 BP 1677 EP 1682 DI 10.1167/iovs.09-4193 PG 6 WC Ophthalmology SC Ophthalmology GA 563VW UT WOS:000275164300061 PM 19875655 ER PT J AU Falutz, J Potvin, D Mamputu, JC Assaad, H Zoltowska, M Michaud, SE Berger, D Somero, M Moyle, G Brown, S Martorell, C Turner, R Grinspoon, S AF Falutz, Julian Potvin, Diane Mamputu, Jean-Claude Assaad, Hani Zoltowska, Monika Michaud, Sophie-Elise Berger, Daniel Somero, Michael Moyle, Graeme Brown, Stephen Martorell, Claudia Turner, Ralph Grinspoon, Steven TI Effects of Tesamorelin, a Growth Hormone-Releasing Factor, in HIV-Infected Patients With Abdominal Fat Accumulation: A Randomized Placebo-Controlled Trial With a Safety Extension SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE body image; growth hormone; growth hormone releasing hormone; visceral fat ID VISCERAL ADIPOSE-TISSUE; RISK-FACTORS; BODY-COMPOSITION; LIPODYSTROPHY; MEN; DISEASE; ASSOCIATION; METFORMIN; THERAPY AB Background: HIV-infected patients receiving antiretroviral therapy often demonstrate excess visceral fat. A growth hormone-releasing factor, tesamorelin, may selectively reduce visceral fat in this population. We investigated the effects of tesamorelin (GHRH(1-44)) in HIV-infected patients with central fat accumulation. Methods: A 12-month study of 404 HIV-infected patients with excess abdominal fat in the context of antiretroviral therapy was conducted between January 2007 and October 2008. The study consisted of 2 sequential phases. In the primary efficacy phase (months 0-6), patients were randomly assigned to receive tesamorelin [2 mg subcutaneous (SC) every day] or placebo in a 2:1 ratio. In the extension phase (months 6-12), patients receiving tesamorelin were rerandomized to continue on tesamorelin (2 mg SC every day) or switch to placebo. Patients initially randomized to placebo switched to tesamorelin. Patients and investigators were blinded to treatment assignment throughout the study. The primary endpoint was visceral adipose tissue (VAT). Secondary endpoints included body image, IGF-I, safety measures, including glucose, and other body composition measures. Results: VAT decreased by -10.9% (-21 cm(2)) in the tesamorelin group vs. -0.6% (-1 cm(2)) in the placebo group in the 6-month efficacy phase, P < 0.0001. Trunk fat (P < 0.001), waist circumference (P = 0.02), and waist-hip-ratio (P = 0.001) improved, with no change in limb or abdominal SC fat. Insulin-like growth factor-1 increased (P < 0.001), but no change in glucose parameters was observed. Patient rating of belly appearance distress (P = 0.02) and physician rating of belly profile (P = 0.02) were significantly improved in the tesamorelin vs. placebo-treated groups. The drug was well tolerated. VATwas reduced by approximately 18% (P < 0.001) in patients continuing tesamorelin for 12 months. The initial improvements over 6 months in VAT were rapidly lost in those switching from tesamorelin to placebo. Conclusions: Tesamorelin reduces visceral fat by approximately 18% and improves body image distress in HIV-infected patients with central fat accumulation. These changes are achieved without significant side effects or perturbation of glucose. C1 [Potvin, Diane; Mamputu, Jean-Claude; Assaad, Hani; Zoltowska, Monika; Michaud, Sophie-Elise; Grinspoon, Steven] Mass Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Potvin, Diane; Mamputu, Jean-Claude; Assaad, Hani; Zoltowska, Monika; Michaud, Sophie-Elise; Grinspoon, Steven] Harvard Univ, Sch Med, Boston, MA USA. [Falutz, Julian] Montreal Gen Hosp, Dept Med, Montreal, PQ, Canada. [Falutz, Julian] McGill Univ, Sch Med, Montreal, PQ H3A 2T5, Canada. [Potvin, Diane; Mamputu, Jean-Claude; Assaad, Hani; Zoltowska, Monika; Michaud, Sophie-Elise; Grinspoon, Steven] Theratechnol Inc, Montreal, CA USA. [Berger, Daniel] Northstar HealthCare, Chicago, IL USA. [Moyle, Graeme] Chelsea & Westminster Hosp, St Stephens Ctr, London, England. [Martorell, Claudia] Res Inst, Springfield, MA USA. [Turner, Ralph] Phase V Technol, Wellesley Hills, MA USA. RP Grinspoon, S (reprint author), Mass Gen Hosp, Program Nutr Metab, LON 207, Boston, MA 02114 USA. EM sgrinspoon@partners.org OI Mamputu, Jean-Claude/0000-0001-8493-959X NR 30 TC 31 Z9 32 U1 0 U2 3 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 MAR 1 PY 2010 VL 53 IS 3 BP 311 EP 322 DI 10.1097/QAI.0b013e3181cbdaff PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 565VX UT WOS:000275324500005 PM 20101189 ER PT J AU Wilson, IB Laws, MB Safren, SA Lee, Y Lu, MY Coady, W Skolnik, PR Rogers, WH AF Wilson, Ira B. Laws, Michael Barton Safren, Steven A. Lee, Yoojin Lu, Minyi Coady, William Skolnik, Paul R. Rogers, William H. TI Provider-Focused Intervention Increases Adherence-Related Dialogue but Does Not Improve Antiretroviral Therapy Adherence in Persons With HIV SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE communication; electronic monitoring; HIV infections/drug therapy; patient compliance; physician-patient relations; randomized controlled trial ID INTERPERSONAL-COMMUNICATION SKILLS; RANDOMIZED CLINICAL-TRIAL; SELF-REPORTED ADHERENCE; PRIMARY-CARE PHYSICIANS; DRUG-RESISTANCE; VIROLOGICAL FAILURE; INTERVIEWING SKILLS; PROSPECTIVE COHORT; VIRAL LOAD; MEDICATION AB Background: Physicians' limited knowledge of patients' antiretroviral adherence may reduce their ability to perform effective adherence counseling. Methods: We conducted a randomized, cross-over study of an intervention to improve physicians' knowledge of patients' antiretroviral adherence. The intervention was a report given to the physician before a routine office visit that included data on Medication Event Monitoring System and self-reported data on antiretroviral adherence, patients' beliefs about antiretroviral therapy, reasons for missed doses, alcohol and drug use, and depression. We audio recorded 1 intervention and 1 control visit for each patient to analyze differences in adherence-related dialogue. Results: One hundred fifty-six patients were randomized, and 106 completed all 5 study visits. Paired audio recorded visits were available for 58 patients. Using a linear regression model that adjusted for site and baseline Medication Event Monitoring System adherence, adherence after intervention visits did not differ significantly from control visits (2.0% higher, P = 0.31, 95% confidence interval: -1.95% to 5.9%). There was a trend toward more total adherence-related utterances (median of 76 vs. 49.5, P = 0.07) and a significant increase in utterances about the current regimen (median of 51.5 vs. 32.5, P = 0.0002) in intervention compared with control visits. However, less than 10% of adherence-related utterances were classified as "problem solving'' in content, and one third of physicians' problem-solving utterances were directive in nature. Conclusions: Receipt of a detailed report before clinic visits containing data about adherence and other factors did not improve patients' antiretroviral adherence. Analyses of patient-provider dialogue suggests that providers who care for persons with HIV may benefit from training in adherence counseling techniques. C1 [Wilson, Ira B.; Laws, Michael Barton; Lee, Yoojin; Lu, Minyi; Coady, William; Rogers, William H.] Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA 02111 USA. [Laws, Michael Barton] Tufts Univ, Sch Med, Dept Family Med & Publ Hlth, Medford, MA 02155 USA. [Safren, Steven A.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Safren, Steven A.] Fenway Community Hlth, Boston, MA USA. [Skolnik, Paul R.] Boston Univ, Med Ctr, Ctr HIV AIDS Care & Res, Boston, MA USA. RP Wilson, IB (reprint author), Tufts Med Ctr, Inst Clin Res & Hlth Policy Studies, Box 345,800 Washington St, Boston, MA 02111 USA. EM iwilson@tuftsmedicalcenter.org RI Wilson, Ira/F-9190-2016 OI Wilson, Ira/0000-0002-0246-738X FU National Institute on Drug Abuse [R01DA015679, R21MH073420]; National Institute for Mental Health [R21MH073420]; Lifespan/Tufts/Brown Centers for AIDS Research [P30AI042853]; National Center for Research Resources [K24 RR020300] FX Supported by grants from the National Institute on Drug Abuse (R01DA015679, R21MH073420), the National Institute for Mental Health (R21MH073420), the Lifespan/Tufts/Brown Centers for AIDS Research (P30AI042853), and the National Center for Research Resources (K24 RR020300). NR 55 TC 22 Z9 22 U1 3 U2 10 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 MAR 1 PY 2010 VL 53 IS 3 BP 338 EP 347 DI 10.1097/QAI.0b013e3181c7a245 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 565VX UT WOS:000275324500008 PM 20048680 ER PT J AU Geng, EH Bangsberg, DR Musinguzi, N Emenyonu, N Bwana, MB Yiannoutsos, CT Glidden, DV Deeks, SG Martin, JN AF Geng, Elvin H. Bangsberg, David R. Musinguzi, Nicolas Emenyonu, Nneka Bwana, Mwebesa Bosco Yiannoutsos, Constantin T. Glidden, David V. Deeks, Steven G. Martin, Jeffrey N. TI Understanding Reasons for and Outcomes of Patients Lost to Follow-Up in Antiretroviral Therapy Programs in Africa Through a Sampling-Based Approach SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE Africa; antiretroviral scale-up; losses to follow-up; monitoring and evaluation; sampling studies ID SUB-SAHARAN AFRICA; RESOURCE-LIMITED SETTINGS; HIV-INFECTED PATIENTS; SCALE-UP; INCOME COUNTRIES; MORTALITY; SURVIVAL; EXPERIENCE; ADHERENCE; MALAWI AB Objectives: Losses to follow-up after initiation of antiretroviral therapy (ART) are common in Africa and are a considerable obstacle to understanding the effectiveness of nascent treatment programs. We sought to characterize, through a sampling-based approach, reasons for and outcomes of patients who become lost to follow-up. Design: Cohort study. Methods: We searched for and interviewed a representative sample of lost patients or close informants in the community to determine reasons for and outcomes among lost patients. Results: Three thousand six hundred twenty-eight HIV-infected adults initiated ART between January 1, 2004 and September 30, 2007 in Mbarara, Uganda. Eight hundred twenty-nine became lost to follow-up (cumulative incidence at 1, 2, and 3 years of 16%, 30%, and 39%). We sought a representative sample of 128 lost patients in the community and ascertained vital status in 111 (87%). Top reasons for loss included lack of transportation or money and work/child care responsibilities. Among the 111 lost patients who had their vital status ascertained through tracking, 32 deaths occurred (cumulative 1-year incidence 36%); mortality was highest shortly after the last clinic visit. Lower pre-ART CD4(+) T-cell count, older age, low blood pressure, and a central nervous system syndrome at the last clinic visit predicted deaths. Of patients directly interviewed, 83% were in care at another clinic and 71% were still using ART. Conclusions: Sociostructural factors are the primary reasons for loss to follow-up. Outcomes among the lost are heterogeneous: both deaths and transfers to other clinics were common. Tracking a sample of lost patients is an efficient means for programs to understand site-specific reasons for and outcomes among patients lost to follow-up. C1 [Geng, Elvin H.; Deeks, Steven G.; Martin, Jeffrey N.] Univ Calif San Francisco, Dept Med, Div HIV AIDS, San Francisco Gen Hosp, San Francisco, CA 94110 USA. [Glidden, David V.; Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ragon Inst,Ctr Global Hlth, Boston, MA USA. [Emenyonu, Nneka] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Initiat Global Hlth,Dept Med, Boston, MA USA. [Musinguzi, Nicolas; Bwana, Mwebesa Bosco] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Yiannoutsos, Constantin T.] Indiana Univ, Dept Med, Div Biostat, Indianapolis, IN USA. RP Geng, EH (reprint author), Univ Calif San Francisco, Dept Med, Div HIV AIDS, San Francisco Gen Hosp, 995 Potrero Ave,Bldg 80, San Francisco, CA 94110 USA. EM genge@php.ucsf.edu FU National Institutes of Health [U01 AI069911, T32 AI06530, P30 AI027763, R01 MH054907]; East Africa International Epidemiologic Databases to Evaluate AIDS Consortium; United States President's Emergency Plan for AIDS Relief; Antiretroviral Treatment in Lower Income Countries Collaboration FX Supported by grants U01 AI069911, T32 AI06530, P30 AI027763, and R01 MH054907 from the National Institutes of Health, the East Africa International Epidemiologic Databases to Evaluate AIDS Consortium, the United States President's Emergency Plan for AIDS Relief, and the Antiretroviral Treatment in Lower Income Countries Collaboration. NR 25 TC 112 Z9 113 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAR 1 PY 2010 VL 53 IS 3 BP 405 EP 411 DI 10.1097/QAI.0b013e3181b843f0 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 565VX UT WOS:000275324500016 PM 19745753 ER PT J AU Williams, EC Peytremann-Bridevaux, I Fan, VS Bryson, CL Blough, DK Kivlahan, DR Bradley, KA AF Williams, Emily C. Peytremann-Bridevaux, Isabelle Fan, Vincent S. Bryson, Chris L. Blough, David K. Kivlahan, Daniel R. Bradley, Katharine A. TI The Association Between Alcohol Screening Scores and Health Status in Male Veterans SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE alcohol screening; alcohol misuse; self-reported health status; health-related quality of life ID QUALITY-OF-LIFE; PRIMARY-CARE PATIENTS; POSTTRAUMATIC-STRESS-DISORDER; ALL-CAUSE MORTALITY; SUBJECTIVE HEALTH; OLDER-ADULTS; CONSUMPTION PATTERNS; MENTAL-HEALTH; AUDIT-C; DRINKING AB Objectives: Alcohol use is associated with self-reported health status. However, little is known about the concurrent association between alcohol screening scores and patient perception of health. We evaluated this association in a sample of primarily older male veterans. Methods: This secondary, cross-sectional analysis included male general medicine outpatients from 7 VA medical centers who returned mailed questionnaires. Screening scores from the Alcohol Use Disorders Identification Test Consumption (AUDIT-C) questionnaire were divided into 6 categories (0, 1-3, 4-5, 6-7, 8-9, and 10-12). Outcomes included scores on the 8 subscales and 2 component scores of the 36-item Short Form Health Survey (SF-36). Unadjusted and adjusted linear regression models were fit to characterize the association between AUDIT-C categories and SF-36 scores. Models were adjusted for demographic characteristics, smoking, and site-both alone and in combination with 14 self-reported comorbid conditions. Results: Male respondents (n = 24,531; mean age = 63.6 years) represented 69% of those surveyed with the SF-36. After adjustment, a quadratic (inverted U-shaped) relationship was demonstrated between AUDIT-C categories and all SF-36 scores such that patients with AUDIT-C scores 4-5 or 6-7 reported the highest health status, and patients with AUDIT-C scores 0, 8-9, and >= 10 reported the lowest health status. Conclusions: Across all measures of health status, patients with the most severe alcohol misuse had significantly poorer health status than those who screened positive for alcohol misuse at mild or moderate levels of severity. The relatively good health status reported by patients with mild-moderate alcohol misuse might interfere with clinicians' acceptance and adoption of guidelines recommending that they counsel these patients about their drinking. C1 [Williams, Emily C.; Fan, Vincent S.; Bryson, Chris L.; Kivlahan, Daniel R.; Bradley, Katharine A.] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA 98101 USA. [Fan, Vincent S.; Bryson, Chris L.; Bradley, Katharine A.] VA Puget Sound Hlth Care Syst, Primary & Specialty Med Care Serv, Seattle, WA 98101 USA. [Williams, Emily C.; Kivlahan, Daniel R.; Bradley, Katharine A.] VA Puget Sound Hlth Care Syst, Ctr Excellence Subst Abuse Treatment & Educ, Seattle, WA 98101 USA. [Bryson, Chris L.; Bradley, Katharine A.] Univ Washington, Dept Med, Seattle, WA USA. [Kivlahan, Daniel R.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Fan, Vincent S.] Univ Washington, Dept Pulm & Crit Care, Seattle, WA 98195 USA. [Williams, Emily C.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Blough, David K.] Univ Washington, Dept Pharm, Seattle, WA 98195 USA. [Peytremann-Bridevaux, Isabelle] Univ Lausanne, Inst Social & Prevent Med, Lausanne, Switzerland. Ctr Hosp Vaudois, Lausanne, Switzerland. RP Williams, EC (reprint author), VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM emily.williams3@va.gov FU VA HSRD IIR [IAC 05-206-1]; VA Career Development Awards [RCD 02-170-2, RCD 03-177]; VA HSRD [SDR96-002, IIR99-376] FX Supported by VA HSR&D IIR Grant IAC 05-206-1, VA Career Development Awards RCD 02-170-2 (to V. S. F.) and RCD 03-177 (to C. L. B.) and the VA Ambulatory Care Quality Improvement Project (ACQUIP) was funded by VA HSR&D Grants SDR96-002 and IIR99-376. NR 74 TC 23 Z9 23 U1 3 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-0620 J9 J ADDICT MED JI J. Addict. Med. PD MAR PY 2010 VL 4 IS 1 BP 27 EP 37 DI 10.1097/ADM.0b013e3181a196b5 PG 11 WC Substance Abuse SC Substance Abuse GA 642OR UT WOS:000281226000004 PM 21769021 ER PT J AU Goldman, M Suh, JJ Lynch, KG Szucs, R Ross, J Xie, H O'Brien, CP Oslin, DW AF Goldman, Marina Suh, Jesse J. Lynch, Kevin G. Szucs, Regina Ross, Jennifer Xie, Hu O'Brien, Charles P. Oslin, David W. TI Identifying Risk Factors for Marijuana Use Among Veterans Affairs Patients SO JOURNAL OF ADDICTION MEDICINE LA English DT Article DE veterans; cannabis; screening; primary care ID HEAVY CANNABIS USERS; PRIMARY-CARE; SUBSTANCE USE; COST-EFFECTIVENESS; CELL CARCINOMA; UNITED-STATES; USE DISORDERS; TOBACCO; SMOKING; HEALTH AB Objectives: Cannabis is the most widely used drug in the United States, and its use carries negative health consequences; however, universal screening for cannabis use is cumbersome. If data commonly collected in the primary care setting (eg, use of alcohol, smoking status, and depression symptoms) could predict cannabis use, then providers can implement targeted marijuana screening in high-risk groups. Methods: We reviewed Behavioral Health Laboratory data collected between 2003 and 2006 from 5512 patients referred by Veterans Affairs primary care clinics for potential mental health needs. Logistic regression was used to determine the predictors of past year marijuana use. Results: A total of 11.5% of the sample reported using marijuana in the past year. Age, gender, other drug use, presence of alcohol use disorders, smoking status, depressive disorders, posttraumatic stress disorder, anxiety disorders, and psychotic symptoms, individually, were associated with the patients' use of marijuana during the past year. When controlling for age, race, and gender in a logistic regression analyses, only other drug use, alcohol use disorder, and smoking status were linked to past year marijuana use. Patients were 5.4 (95% confidence interval [CI] 4.3-6.7) times more likely to have used marijuana during the past year if they used another illicit drug during the past year. Those with alcohol use disorder diagnosis or current smokers were 2.3 (95% CI 1.9-2.8) and 1.5 times (95% CI 1.3-1.7), respectively, more likely to have used marijuana during the past year. Receiver operating characteristic curve (area under curve = 0.79) represents good sensitivity and specificity of the model, correctly classifying 88.4% of the past year marijuana users. Conclusion: Identifying patients at high risk for cannabis use may facilitate targeted screening and provision of interventions in primary care. Patients who screen positive for cigarette use, alcohol abuse or dependence, or have evidence of other illicit drug use could be considered for cannabis screening. C1 [Goldman, Marina; Suh, Jesse J.; Szucs, Regina; Xie, Hu; O'Brien, Charles P.; Oslin, David W.] Univ Penn, Dept Psychiat, Sch Med, Philadelphia, PA 19104 USA. [Suh, Jesse J.; Ross, Jennifer; O'Brien, Charles P.; Oslin, David W.] Vet Affairs Med Ctr VAMC Philadelphia, Philadelphia, PA USA. VISN 4 Mental Illness Res Educ & Clin Ctr MIRECC, Philadelphia, PA USA. RP Goldman, M (reprint author), Univ Penn, Dept Psychiat, Sch Med, 3900 Chestnut St, Philadelphia, PA 19104 USA. EM Goldman_M@mail.TRC.Upenn.edu FU Philadelphia Veterans Affairs Medical Center; VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC); National Institute on Drug Abuse [T32-DA-07241] FX Supported, in part, by grants from the Philadelphia Veterans Affairs Medical Center and VISN 4 Mental Illness Research, Education and Clinical Center (MIRECC), and the National Institute on Drug Abuse (T32-DA-07241). NR 42 TC 5 Z9 5 U1 7 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-0620 J9 J ADDICT MED JI J. Addict. Med. PD MAR PY 2010 VL 4 IS 1 BP 47 EP 51 DI 10.1097/ADM.0b013e3181b18782 PG 5 WC Substance Abuse SC Substance Abuse GA 642OR UT WOS:000281226000006 PM 21625378 ER PT J AU Venios, K Kelly, JF AF Venios, Kiki Kelly, John F. TI The Rise, Risks, and Realities of Methamphetamine use among Women: Implications for Research, Prevention and Treatment SO JOURNAL OF ADDICTIONS NURSING LA English DT Article DE Methamphetamine; Sexual Risks; Violence; HIV/AIDS; Women ID CRYSTAL METHAMPHETAMINE; GENDER-DIFFERENCES; INJECTION RISK; SEXUAL RISK; DRUG-USERS; ABUSERS; ASSOCIATION; IMPAIRMENT; CALIFORNIA; BEHAVIORS AB Methamphetamine (meth) is a highly addictive psychostimulant which activates the brain's reward pathway like no other substance. It is associated with risky sexual practices, HIV/AIDS, antisocial behavior, and violence. For the first time, women are presenting for treatment with a primary methamphetamine use disorder at higher rates than men. Yet, current treatment and prevention initiatives may not be sufficiently sensitive to the unique risks associated with women's use of meth. This article describes the history and rise of methamphetamine and outlines the qualities of meth that contribute to its unique social and environmental impact. Specific attention is devoted to women's experiences with meth focusing on sexual practices, HIV/AIDS, antisocial and violent behavior. Implications for treatment, prevention and research are discussed.Aim. This paper is a report of the continued psychometric evaluation of the Trust in Nurses Scale. Background. Qualitative analyses indicate that trust in nurses is critically important to adult patients. Instruments that distinctively measure this concept are lacking. A middle-range theory of patient-centred nursing care provided the theoretical basis for the Trust in Nurses Scale. Content validity was assessed by an expert panel and patient interviews. Construct validity and reliability were found acceptable using multi-trait/multi-item analysis techniques. These findings were previously reported. Methods. Construct validity and reliability of the Trust in Nurses Scale was assessed in 2007 using data collected during 2004-2005 from 187 hospitalized patients in a haematology-oncology setting. Trust in nurses (the latent factor) was operationalized by five items (manifest variables) using confirmatory factor analyses. Fit statistics included comparative fit index, Tucker-Lewis Index, root mean square error of approximation and the standardized root mean square residual. Internal consistency reliability was assessed using coefficient alpha. Findings. Both a five-item and a four-item version demonstrate acceptable psychometric properties. The five-item version met three fit statistics criteria. Fifty-nine per cent of the variance was explained. A four-item version met all fit statistics criteria. Sixty-six per cent of the variance was explained. Acceptable internal consistency reliability was found for both versions. Conclusion. Previous psychometric testing of the Trust in Nurses Scale provided evidence of the instrument's reliability, content validity and construct validity. The presented analyses further support construct validity. Thus, cumulative findings indicate that the instrument measures with a few items the underlying concept of trust. C1 [Radwin, Laurel E.] Massachusetts Gen Hosp, Inst Patient Care, Boston, MA 02114 USA. [Cabral, Howard J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. RP Radwin, LE (reprint author), Massachusetts Gen Hosp, Inst Patient Care, Boston, MA 02114 USA. EM lradwin@partners.org OI Cabral, Howard/0000-0002-1185-8331 FU Agency for Health Care Research and Quality (AHRQ) [HS K08 11625] FX This project was funded by an Agency for Health Care Research and Quality (AHRQ) Mentored Clinical Scientist Award to Dr Radwin (HS K08 11625). NR 15 TC 15 Z9 16 U1 1 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0309-2402 J9 J ADV NURS JI J. Adv. Nurs. PD MAR PY 2010 VL 66 IS 3 BP 683 EP 689 DI 10.1111/j.1365-2648.2009.05168.x PG 7 WC Nursing SC Nursing GA 554BU UT WOS:000274411300022 PM 20423403 ER PT J AU Skoner, D Gentile, D Bush, R Fasano, MB McLaughlin, A Esch, RE AF Skoner, David Gentile, Deborah Bush, Robert Fasano, Mary Beth McLaughlin, Anne Esch, Robert E. TI Sublingual immunotherapy in patients with allergic rhinoconjunctivitis caused by ragweed pollen SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Allergic rhinoconjunctivitis; maximum tolerable dose; medication score; subcutaneous immunotherapy; sublingual immunotherapy; symptom score ID CLINICAL-TRIALS; PEDIATRIC-PATIENTS; RHINITIS; EFFICACY; GRASS; ASTHMA; METAANALYSIS; RESPONSES; CHILDREN; FUTURE AB Background: Specific allergen immunotherapy is most often delivered subcutaneously, but sublingual immunotherapy may confer greater benefit in terms of tolerability and safety, accessibility, and improved antigen delivery. Objective: This randomized, double-blind, placebo-controlled trial was conducted to identify a safe and effective maintenance dose range of sublingual standardized glycerinated short ragweed pollen extract in adults with ragweed-induced rhinoconjunctivitis. Methods: In May 2006, a total of 115 patients with ragweed-induced rhinoconjunctivitis were randomly allocated to placebo (n = 40), medium-dose extract (4.8 mu g Amb a 1/d; n = 39), or high-dose extract (48 mu g Amb a 1/d; n = 36). In a 1-day (rush) dose-escalation regimen, ragweed pollen extract was administered sublingually in incremental doses until maximum tolerable or scheduled dose was reached and then maintained during the ragweed pollen season. Patient diaries were used to monitor nasal and ocular symptoms and medication. The primary endpoint was symptom score. Results: Both active treatment groups achieved a 15% reduction in total rhinoconjunctivitis symptom scores compared with placebo during the entire ragweed pollen season, but the difference was not statistically significant (P > .10) However, in an analysis of covariance correcting for preseasonal symptoms, both mean daily symptom scores (0.19 +/- 1.16 vs 1.00 +/- 2.30) and medication scores (0.0003 +/- 1.64 vs 0.63 +/- 1.06) for the entire pollen season were significantly reduced in the high-dose versus placebo groups, respectively (P <= .05). Ragweed-specific IgG, IgG(4), and IgA antibodies were increased after treatment in the medium- and high-dose groups and not the placebo group. Frequency of adverse events was similar between, the placebo and treatment groups, but oral-mucosal adverse events occurred more often with treatment. Conclusion: Standardized glycerinated short ragweed pollen extract administered sublingually at maintenance doses of 4.8 to 48 mu g Amb a 1/d was safe and can induce favorable clinical and immunologic changes in ragweed-sensitive subjects. However, additional trials are needed to establish efficacy. (J Allergy Clin Immunol 2010;125:660-6.) C1 [Skoner, David; Gentile, Deborah] Drexel Univ, Coll Med, Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Bush, Robert] Univ Wisconsin, Sch Med & Publ Hlth, William S Middleton Mem Vet Adm Hosp, Madison, WI 53706 USA. [Fasano, Mary Beth] Univ Iowa, Hosp & Clin, Iowa City, IA 52242 USA. [McLaughlin, Anne] Welborn Clin Res Ctr, Evansville, IN USA. [Esch, Robert E.] Greer Labs Inc, Lenoir, NC USA. RP Skoner, D (reprint author), Drexel Univ, Coll Med, Allegheny Gen Hosp, 320 EN Ave, Pittsburgh, PA 15212 USA. EM dskoner@wpahs.org FU Greer Laboratories, Inc; Novartis Pharmaceuticals Corp; Schering Plough; Greer Laboratories; NIH; Lev Pharmaceuticals; Merck; Pharming; GlaxoSmithKline; Map Pharmaceuticals FX Editorial support was funded by Greer Laboratories, Inc.; Disclosure of potential conflict of interest: D. Skoner is on the speakers' bureau for AstraZeneca, GlaxoSmithKline, Merck. Inc, and Novartis Pharmaceutical Corp; receives research support from Novartis Pharmaceuticals Corp, and Schering Plough; and is a consultant for Merck, Inc. D. Gentile receives research support from Greer Laboratories. R. Bush invests in TEVA Pharmaceuticals and receives research support from the NIH and Greer Laboratories. M. B. Fasano receives research support from Greer Laboratories, Lev Pharmaceuticals, and CSL-Behring and is on the Board of Directors for ABAI. A. McLaughlin receives research support from Greer, Lev Pharmaceuticals, Merck, Pharming, GlaxoSmithKline, Novartis, and Map Pharmaceuticals and receives speakers' honoraria from Merck, Schering. GlaxoSmithKline, AstraZeneca, and Sanofi-Aventis. R. E. Esch is employed by Greer Laboratories. NR 35 TC 49 Z9 49 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2010 VL 125 IS 3 BP 660 EP 666 DI 10.1016/j.jaci.2009.12.931 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 573BK UT WOS:000275883200023 PM 20153030 ER PT J AU Wang, J Lin, J Bardina, L Goldis, M Nowak-Wegrzyn, A Shreffler, WG Sampson, HA AF Wang, Julie Lin, Jing Bardina, Ludmilla Goldis, Marina Nowak-Wegrzyn, Anna Shreffler, Wayne G. Sampson, Hugh A. TI Correlation of IgE/IgG4 milk epitopes and affinity of milk-specific IgE antibodies with different phenotypes of clinical milk allergy SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Milk allergy; peptide microarray; IgE epitope; IgE affinity; IgG4 epitope ID BINDING EPITOPES; MICROARRAY IMMUNOASSAY; PEANUT EPITOPES; COWS; SEVERITY; IDENTIFICATION; ASSOCIATION; PERSISTENT; TOLERANCE; CHILDREN AB Background: Results from large-scale epitope mapping with a peptide microarray have been shown to correlate with clinical features of milk allergy. Objectives: We sought to assess IgE and IgG4 epitope diversity and IgE affinity in different clinical phenotypes of milk allergy and identify informative epitopes that might be predictive of clinical outcomes of milk allergy. Methods: Forty-one subjects were recruited from a larger study on the effects of ingesting heat-denatured milk proteins in subjects with milk allergy. Using food challenges, subjects were characterized as being clinically reactive to all forms of milk (n = 17), being tolerant to heated milk (HM) products (n = 16), or having outgrown their milk allergy (n = 8). Eleven healthy volunteers without milk allergy served as control subjects. A peptide microarray was performed by using the previously published protocol. Results: Subjects with milk allergy had increased epitope diversity compared with those who outgrew their allergy. HM-tolerant subjects had IgE-binding patterns similar to those who had outgrown their allergy, but IgG4-binding patterns that were more similar to those of the allergic group. Binding to higher numbers of IgE peptides was associated with more severe allergic reactions during challenge. There was no association between IgG4 peptides and clinical features of milk allergy. Using a competitive peptide microarray assay, allergic patients demonstrated a combination of high- and low-affinity IgE binding, whereas HM-tolerant subjects and those who had outgrown their milk allergy had primarily low-affinity binding. Conclusions: Greater IgE epitope diversity and higher affinity, as determined by using the peptide microarray, were associated with clinical phenotypes and severity of milk allergy. (J Allergy Clin Immunol 2010;125:695-702.) C1 [Wang, Julie; Lin, Jing; Bardina, Ludmilla; Goldis, Marina; Nowak-Wegrzyn, Anna; Sampson, Hugh A.] Mt Sinai Sch Med, New York, NY 10029 USA. [Shreffler, Wayne G.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Shreffler, Wayne G.] Massachusetts Gen Hosp, Food Allergy Res Program, Boston, MA 02114 USA. RP Wang, J (reprint author), Mt Sinai Sch Med, Box 1198, New York, NY 10029 USA. EM julie.wang@mssm.edu RI Lin, Jing/C-8877-2010 FU National Institute of Allergy and Infectious Diseases (NIAID) [AI-44236]; National Institutes of Health (NIH)/NIAID [AI083883, AI 059318]; Food Allergy and Anaphylaxis Network; Food Allergy Initiative FX Supported in part by a grant from the National Institute of Allergy and Infectious Diseases (NIAID; AI-44236). J.W. is funded in part by a grant from the National Institutes of Health (NIH)/NIAID (AI083883). A.N.-W is supported in part by NIH/NIAID grant AI 059318.; Disclosure of potential conflict of interest: J. Wang is a consultant for Quest Diagnostics. A. Nowak-Wegrzyn is a member of Schering-Plough's Data Safety Monitoring Board. W. G. Shreffler has received research support from the Food Allergy and Anaphylaxis Network. H. A. Sampson is a consultant for Allertein Pharmaceuticals, LLC, and holds shares in that company; has received research support from the Food Allergy Initiative and the National Institutes of Health/National Institute of Allergy and Infectious Diseases; is a consultant and scientific advisor for the Food Allergy Initiative; and is 45% of Herbal Springs, LLC. The rest of the authors have declared that they have no conflict of interest. NR 20 TC 82 Z9 83 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2010 VL 125 IS 3 BP 695 EP 702 DI 10.1016/j.jaci.2009.12.017 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 573BK UT WOS:000275883200028 PM 20226304 ER PT J AU Roth, MY Lin, K Amory, JK Matsumoto, AM Anawalt, BD Snyder, CN Kalhorn, TF Bremner, WJ Page, ST AF Roth, M. Y. Lin, K. Amory, J. K. Matsumoto, A. M. Anawalt, B. D. Snyder, C. N. Kalhorn, T. F. Bremner, W. J. Page, S. T. TI Serum LH Correlates Highly With Intratesticular Steroid Levels in Normal Men SO JOURNAL OF ANDROLOGY LA English DT Article DE Contraception; hormone; infertility; testis ID HUMAN TESTIS; TESTOSTERONE CONCENTRATIONS; ANDROGEN MICROENVIRONMENT; GONADOTROPIN SUPPRESSION; MASS-SPECTROMETRY; SPERMATOGENESIS; FINASTERIDE; DIHYDROTESTOSTERONE; MAINTENANCE; DUTASTERIDE AB Sex steroids are essential for spermatogenesis; however, normal intratesticular concentrations of these hormones in man have not been extensively studied. To improve our understanding of intratesticular hormone concentrations, we performed bilateral testicular aspirations in a group of normal men, determined sex steroid concentrations within each testis, and compared these levels to serum hormone concentrations. Ten healthy human subjects aged 20-49 underwent bilateral testicular aspirations. Intratesticular hormone concentrations of testosterone, dihydrotestosterone (DHT), and estradiol were measured using liquid chromatography tandem mass spectrometry. Intratesticular testosterone concentrations ranged from 119 to 1251 ng/mL, with a mean of 635 +/- 368 ng/mL. Intratesticular estradiol ranged from 0.41 to 3.9 ng/mL, with a mean of 2.4 +/- 1.3 ng/mL. Intratesticular DHT ranged from 1.1 to 7.9 ng/mL, with a mean of 3.5 +/- 3.2 ng/mL. Intratesticular testosterone and estradiol concentrations correlated highly with serum luteinizing hormone (LH; r = 0.87 and r = 0.70 respectively, P < .01). Intratesticular testosterone correlated highly with serum testosterone. Moreover, a significant correlation between the right and left testes was observed for testosterone (r = 0.82, P = .003), but not for estradiol or DHT. Intratesticular hormone concentrations can be safely assessed by testicular aspiration. Intratesticular testosterone and estradiol correlate highly with serum LH concentrations, and variation in serum LH accounts for most of the variation in intratesticular testosterone among men. In addition, intratesticular testosterone is highly correlated between testes in a given individual. Direct measurement of intratesticular testosterone will improve our understanding of the relationship between intratesticular sex steroids and spermatogenesis, and may have implications for the development of male hormonal contraception. C1 [Roth, M. Y.; Lin, K.; Amory, J. K.; Matsumoto, A. M.; Anawalt, B. D.; Bremner, W. J.; Page, S. T.] Univ Washington, Dept Internal Med, Seattle, WA 98195 USA. [Roth, M. Y.; Amory, J. K.; Matsumoto, A. M.; Anawalt, B. D.; Snyder, C. N.; Bremner, W. J.; Page, S. T.] Univ Washington, Ctr Res Reprod & Contracept, Seattle, WA 98195 USA. [Lin, K.] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Kalhorn, T. F.] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. [Matsumoto, A. M.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. RP Roth, MY (reprint author), Univ Washington, Dept Internal Med, 1959 NE Pacific St,Box 357138, Seattle, WA 98195 USA. EM mylang@u.washington.edu FU National Institute of Child Health and Human Development [U54-HD-12629, U54 HD-42454, K23 HD45386]; Training in Reproductive Biology [5 T32 HD007453]; Department of Veterans Affairs; National Institute of Aging, a Division of the National Institute of Health [K23 AG027238] FX Supported by the National Institute of Child Health and Human Development through cooperative agreements U54-HD-12629 and U54 HD-42454 as part of the specialized Cooperative Centers Program in Reproductive Research and the Cooperative Contraceptive Research Centers Program. M.Y.R. is supported by Training in Reproductive Biology grant 5 T32 HD007453. A.M.M. is supported by the Department of Veterans Affairs. J.K.A. is supported, in part, by the National Institute of Child Health and Human Development, through grant K23 HD45386. S.T.P. is supported by the National Institute of Aging, a Division of the National Institute of Health, by grant K23 AG027238. NR 28 TC 18 Z9 18 U1 0 U2 3 PU AMER SOC ANDROLOGY, INC PI LAWRENCE PA C/O ALLEN PRESS, INC PO BOX 368, LAWRENCE, KS 66044 USA SN 0196-3635 EI 1939-4640 J9 J ANDROL JI J. Androl. PD MAR-APR PY 2010 VL 31 IS 2 BP 138 EP 145 DI 10.2164/jandrol.109.008391 PG 8 WC Andrology SC Endocrinology & Metabolism GA 573NH UT WOS:000275920100007 PM 19779211 ER PT J AU Matsumoto, AM AF Matsumoto, Alvin M. TI Testosterone and the Aging Male SO JOURNAL OF ANDROLOGY LA English DT Meeting Abstract CT 35th Annual Meeting of the American-Society-of-Andrology CY APR 10-13, 2010 CL Houston, TX SP Amer Soc Androl C1 [Matsumoto, Alvin M.] Univ Washington, VA Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA 98195 USA. [Matsumoto, Alvin M.] Univ Washington, Dept Med, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC ANDROLOGY, INC PI LAWRENCE PA C/O ALLEN PRESS, INC PO BOX 368, LAWRENCE, KS 66044 USA SN 0196-3635 J9 J ANDROL JI J. Androl. PD MAR-APR PY 2010 SU S BP 26 EP 26 PG 1 WC Andrology SC Endocrinology & Metabolism GA 573NK UT WOS:000275920400018 ER PT J AU Storch, EA Larson, MJ Muroff, J Caporino, N Geller, D Reid, JM Morgan, J Jordan, P Murphy, TK AF Storch, Eric A. Larson, Michael J. Muroff, Jordana Caporino, Nicole Geller, Daniel Reid, Jeannette M. Morgan, Jessica Jordan, Patrice Murphy, Tanya K. TI Predictors of functional impairment in pediatric obsessive-compulsive disorder SO JOURNAL OF ANXIETY DISORDERS LA English DT Article DE Obsessive-compulsive disorder; Children; Impairment; Disability; Treatment; Anxiety ID QUALITY-OF-LIFE; COGNITIVE-BEHAVIORAL THERAPY; FAMILY ACCOMMODATION; SYMPTOM DIMENSIONS; ANXIETY DISORDERS; BROWN ASSESSMENT; CONTROLLED-TRIAL; BELIEFS SCALE; COMORBIDITY; IMPACT AB The current study examined factors associated with obsessive-compulsive disorder (OCD) related functional impairment among 99 youth with OCD. A trained evaluator administered the Children's Yale-Brown Obsessive-Compulsive Scale, items assessing family accommodation, and a version of the Brown Assessment of Beliefs Scale that was modified for children. Youth completed the Child Obsessive-Compulsive Impact Scale-Child Version, Obsessive-Compulsive Inventory-Child Version, Multidimensional Anxiety Scale for Children, and Children's Depression Inventory-Short Form. The child's parent completed the Child Obsessive-Compulsive Impact Scale-Parent Version. Results indicated that OCD symptom severity, depressive symptoms, and family accommodation were directly related to impairment, while insight was inversely related to functional impairment. Insight, family accommodation, and depressive symptoms predicted parent- and/or child-rated functional impairment above and beyond OCD symptom severity. Among symptom dimensions, contamination/cleaning and aggressive/checking symptoms were the only dimensions significantly associated with impairment. Assessment and treatment implications are discussed; specifically, we highlight how the variables of interest may impact clinical presentation and treatment course. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Storch, Eric A.; Reid, Jeannette M.; Morgan, Jessica; Jordan, Patrice; Murphy, Tanya K.] Univ S Florida, Dept Pediat, St Petersburg, FL 33701 USA. [Storch, Eric A.; Murphy, Tanya K.] Univ S Florida, Dept Psychiat, St Petersburg, FL 33701 USA. [Storch, Eric A.; Caporino, Nicole] Univ S Florida, Dept Psychol, St Petersburg, FL 33701 USA. [Larson, Michael J.] Brigham Young Univ, Dept Psychol, Provo, UT 84602 USA. [Muroff, Jordana] Boston Univ, Sch Social Work, Boston, MA 02215 USA. [Geller, Daniel] Massachusetts Gen Hosp, Dept Pediat Psychopharmacol, Boston, MA 02114 USA. RP Storch, EA (reprint author), Univ S Florida, Dept Pediat, 800 6th St S,4th Floor, St Petersburg, FL 33701 USA. EM estorch@health.usf.edu RI Larson, Michael/C-8543-2012; Storch, Eric/I-4935-2012 OI Larson, Michael/0000-0002-8199-8065; NR 55 TC 58 Z9 60 U1 4 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD MAR PY 2010 VL 24 IS 2 BP 275 EP 283 DI 10.1016/j.janxdis.2009.12.004 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 555HE UT WOS:000274498900015 PM 20056376 ER PT J AU Safren, SA Sprich, SE Cooper-Vince, C Knouse, LE Lerner, JA AF Safren, Steven A. Sprich, Susan E. Cooper-Vince, Christine Knouse, Laura E. Lerner, Jonathan A. TI Life Impairments in Adults With Medication-Treated ADHD SO JOURNAL OF ATTENTION DISORDERS LA English DT Article DE adults; life impairments; life satisfaction; quality of life ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; COGNITIVE-BEHAVIORAL THERAPY; STRUCTURED INTERVIEW GUIDE; RATING-SCALE; DEPRESSION; PHARMACOTHERAPY; METAANALYSIS; COMORBIDITY; CHILDREN AB Objective: In developing psychosocial approaches to augment outcomes for medication-treated adults with ADHD, it is important to understand what types of life-impairments are most affected by continued ADHD symptoms that occur despite medication treatment. This may assist in delineating targets for interventions, as well as assessments of functional outcomes that are sensitive to change in this population. Method: The sample consists of 105 adults with ADHD presenting for entry into clinical trials of CBT for residual ADHD. Life impairments are rated by a clinician using the LIFE-RIFT, which has subscales for work impairment, interpersonal impairment, life-satisfaction, and recreation, ADHD symptoms using the ADHD Rating Scale, overall ADHD severity using the clinical global impression, and associated distress using the Hamilton Depression and Anxiety Rating Scales. Results: The most problematic impairments are in the domain of work, followed by interpersonal. Generally, the subscales of the LIFE-RIFT are associated, at the bivariate level, with all 4 symptom indices. Work and interpersonal impairments are uniquely associated with overall severity of ADHD symptoms using both the CGI and the ADHD Rating Scale. However interpersonal and life-satisfaction impairments are uniquely associated with depression, and life-satisfaction is uniquely associated with anxiety. Conclusion: In medication-treated adults with ADHD, work and interpersonal impairments appear to be the most problematic areas of life-impairment, which are uniquely associated with ADHD severity. Life-satisfaction appears to be uniquely associated with distress as defined by anxiety and depression symptoms, with interpersonal impairments also playing a role. Psychosocial treatments for medication treated adults should target work and interpersonal domains and should include skills for managing associated distress. (J. of Att. Dis. 2010; 13(5) 524-531) C1 [Safren, Steven A.; Sprich, Susan E.] Massachusetts Gen Hosp, Cognit Behav Therapy Program, Boston, MA 02114 USA. [Knouse, Laura E.; Lerner, Jonathan A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Behav Med Serv, Cambridge, MA 02138 USA. RP Safren, SA (reprint author), Massachusetts Gen Hosp, Cognit Behav Therapy Program, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM ssafren@partners.org FU NIMH NIH HHS [R03 MH060940, R01 MH069812] NR 45 TC 24 Z9 26 U1 3 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0547 J9 J ATTEN DISORD JI J. Atten. Disord. PD MAR PY 2010 VL 13 IS 5 BP 524 EP 531 DI 10.1177/1087054709332460 PG 8 WC Psychology, Developmental; Psychiatry SC Psychology; Psychiatry GA 583PR UT WOS:000276691300011 PM 19395647 ER PT J AU Hodge, SM Makris, N Kennedy, DN Caviness, VS Howard, J McGrath, L Steele, S Frazier, JA Tager-Flusberg, H Harris, GJ AF Hodge, Steven M. Makris, Nikos Kennedy, David N. Caviness, Verne S., Jr. Howard, James McGrath, Lauren Steele, Shelly Frazier, Jean A. Tager-Flusberg, Helen Harris, Gordon J. TI Cerebellum, Language, and Cognition in Autism and Specific Language Impairment SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Review DE Autism; Specific language impairment; Cerebellum; Broca's area; Asymmetry ID PERVASIVE DEVELOPMENTAL DISORDERS; POSTERIOR-FOSSA TUMORS; LEFT-RIGHT ASYMMETRY; CEREBRAL-BLOOD-FLOW; INFANTILE-AUTISM; CHILDHOOD AUTISM; VERBAL FLUENCY; NEUROPSYCHOLOGICAL CONSEQUENCES; CEREBROCEREBELLAR SYSTEM; ASSOCIATION CORTEX AB We performed cerebellum segmentation and parcellation on magnetic resonance images from right-handed boys, aged 6-13 years, including 22 boys with autism [16 with language impairment (ALI)], 9 boys with Specific Language Impairment (SLI), and 11 normal controls. Language-impaired groups had reversed asymmetry relative to unimpaired groups in posterior-lateral cerebellar lobule VIIIA (right side larger in unimpaired groups, left side larger in ALI and SLI), contralateral to previous findings in inferior frontal cortex language areas. Lobule VIIA Crus I was smaller in SLI than in ALI. Vermis volume, particularly anterior I-V, was decreased in language-impaired groups. Language performance test scores correlated with lobule VIIIA asymmetry and with anterior vermis volume. These findings suggest ALI and SLI subjects show abnormalities in neurodevelopment of fronto-corticocerebellar circuits that manage motor control and the processing of language, cognition, working memory, and attention. C1 [Hodge, Steven M.; Harris, Gordon J.] Massachusetts Gen Hosp, Radiol Comp Aided Diagnost Lab, Boston, MA 02114 USA. [Hodge, Steven M.; Makris, Nikos; Kennedy, David N.; Caviness, Verne S., Jr.; Howard, James] Massachusetts Gen Hosp, Ctr Morphometr Anal, Boston, MA 02114 USA. [McGrath, Lauren; Steele, Shelly; Tager-Flusberg, Helen] Boston Univ, Sch Med, Cognit Neurosci Lab, Boston, MA 02118 USA. [Frazier, Jean A.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Frazier, Jean A.] Ctr Child & Adolescent Dev, Dept Psychiat, Cambridge, MA USA. RP Harris, GJ (reprint author), Massachusetts Gen Hosp, Radiol Comp Aided Diagnost Lab, 25 New Chardon St,Suite 400C, Boston, MA 02114 USA. EM gjharris@partners.org OI McGrath, Lauren/0000-0001-6928-9656 FU NIDCD NIH HHS [P01 DC003610, U19 DC003610, U19/PO1 DC 03610]; NIMH NIH HHS [K08 MH001573, K08 MH01573] NR 138 TC 45 Z9 48 U1 7 U2 23 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD MAR PY 2010 VL 40 IS 3 BP 300 EP 316 DI 10.1007/s10803-009-0872-7 PG 17 WC Psychology, Developmental SC Psychology GA 553XZ UT WOS:000274401400004 PM 19924522 ER PT J AU Gruber, JD Paliwal, A Krishnaswamy, V Ghadyani, H Jermyn, M O'Hara, JA Davis, SC Kerley-Hamilton, JS Shworak, NW Maytin, EV Hasan, T Pogue, BW AF Gruber, Josiah D. Paliwal, Akshat Krishnaswamy, Venkataramanan Ghadyani, Hamid Jermyn, Michael O'Hara, Julie A. Davis, Scott C. Kerley-Hamilton, Joanna S. Shworak, Nicholas W. Maytin, Edward V. Hasan, Tayyaba Pogue, Brian W. TI System development for high frequency ultrasound-guided fluorescence quantification of skin layers SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE tomography; ultrasound-coupled fluorescence; protoporphyrin IX; skin tumors ID PROTOPORPHYRIN-IX ACCUMULATION; PHOTODYNAMIC THERAPY; OPTICAL TOMOGRAPHY; IN-VIVO; PHOTOSENSITIZER; LOCALIZATION; HEMOGLOBIN; ACID AB A high frequency ultrasound-coupled fluorescence tomography system, primarily designed for imaging of protoporphyrin IX production in skin tumors in vivo, is demonstrated for the first time. The design couples fiber-based spectral sampling of the protoporphyrin IX fluorescence emission with high frequency ultrasound imaging, allowing thin-layer fluorescence intensities to be quantified. The system measurements are obtained by serial illumination of four linear source locations, with parallel detection at each of five interspersed detection locations, providing 20 overlapping measures of subsurface fluorescence from both superficial and deep locations in the ultrasound field. Tissue layers are defined from the segmented ultrasound images and diffusion theory used to estimate the fluorescence in these layers. The system calibration is presented with simulation and phantom validation of the system in multilayer regions. Pilot in-vivo data are also presented, showing recovery of subcutaneous tumor tissue values of protoporphyrin IX in a subcutaneous U251 tumor, which has less fluorescence than the skin. (C) 2010 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3374040] C1 [Gruber, Josiah D.; Krishnaswamy, Venkataramanan; Ghadyani, Hamid; Jermyn, Michael; O'Hara, Julie A.; Davis, Scott C.; Pogue, Brian W.] Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. [Maytin, Edward V.; Hasan, Tayyaba] Harvard Univ, Wellman Ctr Photomed, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Paliwal, Akshat; Maytin, Edward V.] Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44195 USA. [Kerley-Hamilton, Joanna S.; Shworak, Nicholas W.] Dartmouth Med Sch, Dept Med, Lebanon, NH 03756 USA. RP Pogue, BW (reprint author), Dartmouth Coll, Thayer Sch Engn, Hanover, NH 03755 USA. EM brian.w.pogue@dartmouth.edu FU NIH [P01CA84203] FX The authors are extremely grateful to Subhadra Srinivasan, Hamid Dehghani, and Keith Paulsen for productive discussions about the algorithm development. This work has been funded by NIH Program Project P01CA84203. NR 14 TC 19 Z9 19 U1 0 U2 1 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD MAR-APR PY 2010 VL 15 IS 2 AR 026028 DI 10.1117/1.3374040 PG 5 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 606YO UT WOS:000278465300059 PM 20459273 ER PT J AU Park, J Mroz, P Hamblin, MR Yaroslavsky, AN AF Park, Jesung Mroz, Pawel Hamblin, Michael R. Yaroslavsky, Anna N. TI Dye-enhanced multimodal confocal microscopy for noninvasive detection of skin cancers in mouse models SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE skin cancer; reflectance; fluorescence; confocal microscopy; contrast agents ID BASAL-CELL CARCINOMA; METHYLENE-BLUE; MELANOMA; TUMORS; RADIOTHERAPY AB Skin cancer is the most common form of human cancer. Its early diagnosis and timely treatment is of paramount importance for dermatology and surgical oncology. In this study, we evaluate the use of reflectance and fluorescence confocal microscopy for detecting skin cancers in an in-vivo trial with B16F10 melanoma and SCCVII squamous cell carcinoma in mice. For the experiments, the mice are anesthetized, then the tumors are infiltrated with aqueous solution of methylene blue and imaged. Reflectance images are acquired at 658 nm. Fluorescence is excited at 658 nm and registered in the range between 690 and 710 nm. After imaging, the mice are sacrificed. The tumors are excised and processed for hematoxylin and eosin histopathology, which is compared to the optical images. The results of the study indicate that in-vivo reflectance images provide valuable information on vascularization of the tumor, whereas the fluorescence images mimic the structural features seen in histopathology. Simultaneous dye-enhanced reflectance and fluorescence confocal microscopy shows promise for the detection, demarcation, and noninvasive monitoring of skin cancer development. (C) 2010 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3394301] C1 [Park, Jesung; Mroz, Pawel; Hamblin, Michael R.; Yaroslavsky, Anna N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Yaroslavsky, Anna N.] Univ Massachusetts, Dept Phys & Appl Phys, Lowell, MA 01854 USA. RP Yaroslavsky, AN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, 55 Fruit St,BAR314B, Boston, MA 02114 USA. EM Anna_Yaroslavsky@uml.edu OI Hamblin, Michael/0000-0001-6431-4605 FU NIH [5R21CA124986] FX We gratefully acknowledge Mei Wu and Thomas Flotte for help with interpretation of histopathology, Rox Anderson for the support of this project, William Meng, Elena Salomatina, and Jenny Zhao for help with processing histopathology. This project was funded in part by the NIH (5R21CA124986). NR 17 TC 8 Z9 8 U1 0 U2 4 PU SPIE-SOC PHOTOPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD MAR-APR PY 2010 VL 15 IS 2 AR 026023 DI 10.1117/1.3394301 PG 5 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 606YO UT WOS:000278465300054 PM 20459268 ER PT J AU Susa, M Choy, E Yang, C Schwab, J Mankin, H Hornicek, F Duan, ZF AF Susa, Michiro Choy, Edwin Yang, Cao Schwab, Joseph Mankin, Henry Hornicek, Francis Duan, Zhenfeng TI Multidrug Resistance Reversal Agent, NSC77037, Identified with a Cell-Based Screening Assay SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE cell-based screening; NSC77037/tetrandrine; drug resistance; PGP ID P-GLYCOPROTEIN; DRUG-RESISTANCE; PACLITAXEL RESISTANCE; OVARIAN-CANCER; IN-VITRO; TETRANDRINE; INHIBITOR; CARCINOMA; CHEMOTHERAPY; POTENT AB The development of multidrug resistance (MDR) remains a significant obstacle in treating cancer patients with chemotherapy. to identify small-molecule compounds that can reverse MDR, the authors used a cell-based screening assay with an MDR ovarian cancer cell line. incubating MDR cells with a sublethal concentration of paclitaxel in combination with each of 2000 small-molecule compounds from the national cancer institute diversity set library, they identified NSC77037. the cytotoxic activity of NSC77037 and the duration of its effect were evaluated in vitro using a panel of cancer cell lines expressing permeability glycoprotein (PGP), multiple drug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP). the mechanism of its effects was further analyzed by assessing the retention of calcein and PGP- atpase activity. the relative potency of MDR reversal by NSC77037 was significantly higher than that of frequently used MDR reversal agents such as verapamil and cyclosporine a. NSC77037 reversed PGP without reversing MRP or BCRP-mediated MDR. NSC77037, at a concentration of > 10 mu M, moderately inhibited the proliferation of both sensitive and resistant cell lines, but the inhibitory effect of NSC77037 was not altered by coincubation with the PGP inhibitor verapamil, suggesting that NSC77037 itself is not a substrate of PGP. NSC77037 directly inhibited the function of PGP in a dose-dependent manner, but it did not alter the protein expression level of PGP. the use of NSC77037 to restore sensitivity to chemotherapy or to prevent resistance could be a potential treatment strategy for cancer patients. (Journal of Biomolecular Screening 2010: 287-296) C1 [Susa, Michiro; Yang, Cao; Schwab, Joseph; Mankin, Henry; Hornicek, Francis; Duan, Zhenfeng] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. [Choy, Edwin] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, 55 Fruit St Jackson 1115, Boston, MA 02114 USA. EM duanz@helix.mgh.harvard.edu RI Susa, Michiro/L-2291-2013; OI Choy, Edwin/0000-0001-9896-8084 FU Gattegno and Wechsler funds; Ovarian Cancer Research Foundation (OCRF); Sarcoma Foundation of America; National Cancer Institute, NIH [R01-CA119617]; Jennifer Hunter Yates Foundation FX this project was supported in part by a grant from the Gattegno and Wechsler funds. Dr. Duan is supported in part through a grant from Ovarian Cancer Research Foundation (OCRF), Sarcoma Foundation of America, and the National Cancer Institute, NIH (Nanotechnology platform partnership), R01-CA119617. Dr. Choy is supported by the Jennifer Hunter Yates Foundation. NR 38 TC 14 Z9 18 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD MAR PY 2010 VL 15 IS 3 BP 287 EP 296 DI 10.1177/1087057109359422 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 565KU UT WOS:000275292000006 PM 20150589 ER PT J AU Jupiter, JB Marent-Huber, M AF Jupiter, Jesse B. Marent-Huber, M. CA LCP Study Grp TI Operative Management of Distal Radial Fractures with 2.4-Millimeter Locking Plates: A Multicenter Prospective Case Series SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID FIXATION AB BACKGROUND: In the past decade, there has been a trend toward open reduction and internal fixation of unstable distal radial fractures. There are now more than thirty different implant designs specific for the fixation of distal radial fractures. A multicenter prospective study of a case series was conducted to determine the efficacy of the operative management of distal radial fractures stabilized with 2.4-mm locking plates. METHODS: One hundred and fifty patients were entered into the study over a two-year period. The mean age of these patients was fifty-one years, and the cohort included eighty-eight women and sixty-two men. Eighty-six patients sustained a low-energy injury. Seventy-one percent of the fractures in the series were intra-articular and were Type C according to the Muller-AO Comprehensive Classification. The follow-up evaluations, which were conducted at six weeks, six months, one year, and two years, included assessments of pain, motion, grip strength, and standard radiographs. Gartland and Werley scores were recorded at six months and one and two years, and Disabilities of the Arm, Shoulder and Hand (DASH) scores were recorded at one and two years. RESULTS: One hundred and twenty-five patients (83%) had a complete follow-up at six months; 121 (81%), at one year; and 117 (78%), at two years. Significant improvements in motion, grip strength, and patient satisfaction were observed between six months and one year, but further improvements were not seen at the two-year follow-up examination. The mean DASH score changed from a preinjury baseline of 2 points to 8 points at one year and 7 points at two years (p < 0.0001). The mean Gartland and Werley score improved significantly from 4 points at six months to 2 points at two years. Of the 102 intra-articular fractures examined in the immediate postoperative period, twenty had a step-off of <= 2 mm and seven had a step-off of >2 mm. Of the seventy-one intra-articular fractures seen at two years, sixty-one had no step-off, five had a step-off of <= 2 mm, and five had a step-off of >2 mm. Twenty-seven percent of the patients showed an increase of at least one grade in radiographic signs of arthritis at two years. There were twenty-eight complications, twenty of which were considered minor. Tendon inflammation occurred in nine patients. There were two tendon ruptures, one of which was due to a prominent dorsal screw tip placed through a volar plate and one of which was due to a prominent volar plate. Loss of reduction occurred in two patients, and screw loosening occurred in two patients. CONCLUSIONS: Internal fixation of displaced distal radial fractures with implants featuring locking screw fixation can result in good-to-excel lent outcomes with a limited number of complications. C1 [Jupiter, Jesse B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. AO Clin Invest & Documentat, Dubendorf, Switzerland. RP Jupiter, JB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 2100 Yawkey Bldg,55 Fruit St, Boston, MA 02114 USA. EM jjupiter1@partners.org; marta.marent@aofoundation.org FU AO Foundation FX In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants of less than $10,000 from the AO Foundation. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. NR 6 TC 13 Z9 14 U1 0 U2 1 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD MAR PY 2010 VL 92A SU 1 BP 96 EP 106 DI 10.2106/JBJS.I.01340 PN 1 PG 11 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 564KV UT WOS:000275214000009 PM 20194348 ER PT J AU Kwon, YM Glyn-Jones, S Simpson, DJ Kamali, A McLardy-Smith, P Gill, HS Murray, DW AF Kwon, Y. -M. Glyn-Jones, S. Simpson, D. J. Kamali, A. McLardy-Smith, P. Gill, H. S. Murray, D. W. TI Analysis of wear of retrieved metal-on-metal hip resurfacing implants revised due to pseudotumours SO JOURNAL OF BONE AND JOINT SURGERY-BRITISH VOLUME LA English DT Article ID ELASTOHYDRODYNAMIC LUBRICATION ANALYSIS; ARTHROPLASTY; PROSTHESES; COMPONENT; GROIN AB The presence of pseudotumours, which are soft-tissue masses relating to the hip, after metal-on-metal hip resurfacing arthroplasty has been associated with elevated levels of metal ions in serum, suggesting that pseudotumours occur when there is increased wear. We aimed to quantify the wear in vivo of implants revised for pseudotumours (eight) and of a control group of implants (22) revised for other reasons of failure. We found that the implant group with pseudotumours had a significantly higher rate of median linear wear of the femoral component at 8.1 mu m/year (2.75 to 25.4) than the 1.79 mu m/year (0.82 to 4.15; p = 0.002) of the non-pseudotumour group. For the acetabular component a significantly higher rate of median linear wear of 7.36 mu m/year (1.61 to 24.9) was observed in the pseudotumour group compared with 1.28 mu m/year (0.81 to 3.33, p = 0.001) in the other group. Wear of the acetabular component in the pseudotumour group always involved the edge of the implant, indicating that edge-loading had occurred. Our findings are the first direct evidence that pseudotumour is associated with increased wear at the metal-on-metal articulation. Furthermore, edge-loading with the loss of fluid-film lubrication may be an important mechanism of generation of wear in patients with a pseudotumour. C1 [Kwon, Y. -M.; Glyn-Jones, S.; Simpson, D. J.; Kamali, A.; McLardy-Smith, P.; Gill, H. S.; Murray, D. W.] Nuffield Orthopaed Ctr, Oxford OX3 7LD, England. RP Kwon, YM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. EM kwan.young-min@mgh.harvard.edu RI Murray, David/D-7117-2011; Gill, Richie/A-9808-2011 OI Gill, Richie/0000-0002-7740-2062 NR 27 TC 120 Z9 121 U1 0 U2 14 PU BRITISH EDITORIAL SOC BONE JOINT SURGERY PI LONDON PA 22 BUCKINGHAM STREET, LONDON WC2N 6ET, ENGLAND SN 0301-620X J9 J BONE JOINT SURG BR JI J. Bone Joint Surg.-Br. Vol. PD MAR PY 2010 VL 92B IS 3 BP 356 EP 361 DI 10.1302/0301-620X.92B3.23281 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 561UW UT WOS:000275006000006 PM 20190305 ER PT J AU Dylewski, ML Prelack, K Keaney, T Sheridan, RL AF Dylewski, Maggie L. Prelack, Kathy Keaney, Timothy Sheridan, Robert L. TI Asymptomatic Hyperamylasemia and Hyperlipasemia in Pediatric Patients With Toxic Epidermal Necrolysis SO JOURNAL OF BURN CARE & RESEARCH LA English DT Article ID ELEVATED SERUM AMYLASE; NUTRITIONAL SUPPORT; PANCREATIC LIPASE AB Although pancreatitis is rare in pediatric burn patients, elevated pancreatic enzymes have been recently observed among toxic epidermal necrolysis (TEN) patients. This clinical phenomenon has implications particularly for the nutritional management of patients involved. The objective of this study was to assess the frequency of sustained, elevated amylase, and lipase enzymes among children with TEN or Stevens Johnson Syndrome (SJS) and to evaluate the utilization of enteral nutrition support in this population. Medical records of 24 patients admitted to our hospital between January 1994 and October 2008 with TEN or SJS were retrospectively reviewed. Only patients with >= 4 consecutive measures for both amylase and lipase were included in this study (n = 10). Serial laboratory values were collected during the first 30 days of disease. Four patients (40%) had elevated amylase and lipase values, whereas six patients had values within normal limits. Patients with elevated pancreatic enzymes were significantly younger in age (4.7 +/- 1.7 years) than patients without elevated enzymes (11 +/- 5.9 years) and also had a higher incidence of sepsis. All other characteristics were similar between the groups. Enteral nutrition support was initiated within 4 days of admission in all 10 patients and did not correlate with elevated enzymes. Our findings suggest that hyperlipasemia and hyperamylasemia can occur in the pediatric population with TEN or SJS. Although the sample size in this study makes it difficult to determine the cause, sepsis may have been a contributing factor. In the absence of symptomatic pancreatitis, patients with TEN can safely meet nutritional goals orally or with standard enteral nutrition support. (J Burn Care Res 2010;31:292-296) C1 [Dylewski, Maggie L.; Prelack, Kathy; Keaney, Timothy; Sheridan, Robert L.] Shriners Hosp Children, Dept Nutr Serv, Boston, MA 02114 USA. [Dylewski, Maggie L.; Prelack, Kathy; Keaney, Timothy; Sheridan, Robert L.] Shriners Hosp Children, Dept Surg, Boston, MA 02114 USA. [Sheridan, Robert L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Dylewski, ML (reprint author), Shriners Hosp Children, Dept Nutr Serv, 51 Blossom St, Boston, MA 02114 USA. NR 19 TC 4 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1559-047X J9 J BURN CARE RES JI J. Burn Care Res. PD MAR-APR PY 2010 VL 31 IS 2 BP 292 EP 296 DI 10.1097/BCR.0b013e3181d0f448 PG 5 WC Emergency Medicine; Dermatology; Surgery SC Emergency Medicine; Dermatology; Surgery GA 564DL UT WOS:000275193400010 PM 20182382 ER PT J AU Obler, D Wu, BL Lip, V Estrella, E Keck, S Haggan, C Semigran, M Smoot, LB AF Obler, Dita Wu, Bai-Lin Lip, Va Estrella, Elicia Keck, Sally Haggan, Coral Semigran, Marc Smoot, Leslie B. TI Familial Dilated Cardiomyopathy Secondary to Dystrophin Splice Site Mutation SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE Family history; genetics; myocarditis; CPK ID MUSCULAR-DYSTROPHY; SKELETAL-MUSCLE; GENE; HEART; PREVALENCE; EXPRESSION; DUCHENNE AB Background: Idiopathic dilated cardiomyopathy (DCM) encompasses a heterogeneous group of disorders, posing significant diagnostic challenges. Genetic etiologies underlie an important subset of DCM, including 20 genes and 5 X-linked disorders to date. We report a family with a rare dystrophin gene alteration, identified after evaluation of asymptomatic children whose extended family history included cardiomyopathy, premature cardiac death, or cardiac transplantation. Methods and Results: Record review, clinical evaluations, and DNA samples were obtained from members of a 5-generation pedigree with early onset DCM. Five of 6 affected males experienced death or cardiac transplant in their second or third decades. No affected individuals had skeletal muscle weakness before acute cardiac decompensation. Dystrophin gene analysis of an affected family member revealed sequence alteration at the conserved 5' splice site of exon I of the muscle-specific isoform of dystrophin (IVS1 +1 G>T) and co-segregated with cardiac disease in this family. Conclusions: Young males presenting with apparent isolated cardiomyopathy or acute myocarditis may harbor dystrophin mutations without overt skeletal muscle pathology. The etiology of familial risk was not evident in this pedigree before retrospective cardiovascular genetics assessment, highlighting ongoing diagnostic challenges and limitations of standardized screening panels (which do not include dystrophin) in patients with "idiopathic" DCM. (J Cardiac Fail 2010;16:194-199) C1 [Obler, Dita] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Keck, Sally; Haggan, Coral; Semigran, Marc] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Obler, D (reprint author), Childrens Hosp, Dept Cardiol, 300 Longwood Ave, Boston, MA 02115 USA. EM dita.obler.cgc@gmail.com FU Cardiology Foundation at Children's Hospital, Boston FX Supported in part by the Cardiology Foundation at Children's Hospital, Boston. NR 26 TC 4 Z9 5 U1 0 U2 2 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD MAR PY 2010 VL 16 IS 3 BP 194 EP 199 DI 10.1016/j.cardfail.2009.11.009 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 595AC UT WOS:000277582100003 PM 20206892 ER PT J AU Shah, RV Desai, AS Givertz, MM AF Shah, Ravi V. Desai, Akshay S. Givertz, Michael M. TI The Effect of Renin-Angiotensin System Inhibitors on Mortality and Heart Failure Hospitalization in Patients With Heart Failure and Preserved Ejection Fraction: A Systematic Review and Meta-Analysis SO JOURNAL OF CARDIAC FAILURE LA English DT Review DE Heart failure; meta-analysis; drugs; renin-angiotensin system ID RANDOMIZED-TRIAL; HYPERTENSION; FIBROSIS; ALDOSTERONE; CANDESARTAN; DYSFUNCTION; IRBESARTAN; ENALAPRIL; PROGNOSIS; BLOCKADE AB Background: Although renin-angiotensin system (RAS) inhibitors have little demonstrable effect on mortality in patients with heart failure and preserved ejection fraction (HF-PEF), some trials have suggested a benefit with regard to reduction in HF hospitalization. Methods and Results: Here, we systematically review and evaluate prospective clinical studies of RAS inhibitors enrolling patients with HF-PEF including the 3 major trials of RAS inhibition (Candesartan in Patients with Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction [CHARM-Preserved], Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction [I-PRESERVE], and Perindopril in Elderly People with Chronic Heart Failure [PEP-CHF]). We also conducted a pooled analysis of 8021 patients in the 3 major randomized trials of RAS inhibition in HF-PEF (CHARM-Preserved, I-PRESERVE, and PEP-CHF) in fixed-effect models, finding no clear benefit with regard to all-cause mortality (odds ratio [OR] 1.03, 95% confidence interval [CI], 0.92-1.15; P = .62), or HF hospitalization (OR 0.90, 95% Cl 0.80-1.02; P = .09). Conclusions: Although RAS inhibition may be valuable in the management of comorbidities related to HF-PEF RAS inhibition in HF-PEF is not associated with consistent reduction in HF hospitalization or mortality in this emerging cohort. (J Cardiac Fail 2010;16:260-267) C1 [Desai, Akshay S.; Givertz, Michael M.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Shah, Ravi V.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Shah, Ravi V.; Desai, Akshay S.; Givertz, Michael M.] Harvard Univ, Sch Med, Boston, MA USA. RP Givertz, MM (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM mgivertz@partners.org FU National Institutes of Health, National Heart, Lung and Blood Institute Heart Failure Clinical Research Network [U01 HL084904] FX R.V.S. has received fellowship support from the National Institutes of Health, National Heart, Lung and Blood Institute Heart Failure Clinical Research Network (U01 HL084904). NR 23 TC 46 Z9 50 U1 0 U2 1 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD MAR PY 2010 VL 16 IS 3 BP 260 EP 267 DI 10.1016/j.cardfail.2009.11.007 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 595AC UT WOS:000277582100013 PM 20206902 ER PT J AU Rocha-Filho, JA Shturman, LD Okada, DR Abbara, S Mamuya, W AF Rocha-Filho, Jose A. Shturman, Leonid D. Okada, David R. Abbara, Suhny Mamuya, Wilfred TI Intravenous leiomyoma extending into the right ventricle SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article DE Cardiac; Computed tomography; Inferior vena cava; Leiomyoma AB We present a case of a retroperitoneal leiomyoma invading the inferior vena cava and extending to the right ventricle. The tumor was visualized with electrocardiographic-gated dual-source computed tomography, showing a low-density, lobulated mass invading the inferior vena cava and prolapsing through the tricuspid valve during diastole. Cardiac computed tomography is useful in assessing the extension and hemodynamic effect of intracardiac masses. (C) 2010 Society of Cardiovascular Computed Tomography. All rights reserved. C1 [Rocha-Filho, Jose A.; Shturman, Leonid D.; Okada, David R.; Abbara, Suhny; Mamuya, Wilfred] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mamuya, Wilfred] Lown Cardiovasc Ctr, Brookline, MA USA. RP Mamuya, W (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 5800, Boston, MA 02114 USA. EM wmamuya@partners.org NR 3 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 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD MAR-APR PY 2010 VL 4 IS 2 BP 136 EP 138 DI 10.1016/j.jcct.2009.12.006 PG 3 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA V26BO UT WOS:000208521300011 PM 20430345 ER PT J AU Natale, A Raviele, A Al-Ahmad, A Alfieri, O Aliot, E Almendral, J Breithardt, G Brugada, J Calkins, H Callans, D Cappato, R Camm, JA Della Bella, P Guiraudon, GM Haissaguerre, M Hindricks, G Ho, SY Kuck, KH Marchlinski, F Packer, DL Prystowsky, EN Reddy, VY Ruskin, JN Scanavacca, M Shivkumar, K Soejima, K Stevenson, WJ Themistoclakis, S Verma, A Wilber, D AF Natale, Andrea Raviele, Antonio Al-Ahmad, Amin Alfieri, Ottavio Aliot, Etienne Almendral, Jesus Breithardt, Guenter Brugada, Josep Calkins, Hugh Callans, David Cappato, Riccardo Camm, John A. Della Bella, Paolo Guiraudon, Gerard M. Haissaguerre, Michel Hindricks, Gerhard Ho, Siew Yen Kuck, Karl H. Marchlinski, Francis Packer, Douglas L. Prystowsky, Eric N. Reddy, Vivek Y. Ruskin, Jeremy N. Scanavacca, Mauricio Shivkumar, Kalyanam Soejima, Kyoko Stevenson, William J. Themistoclakis, Sakis Verma, Atul Wilber, David CA Venice Chart TI Venice Chart International Consensus Document on Ventricular Tachycardia/Ventricular Fibrillation Ablation SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE catheter ablation; guidelines; heart failure; ventricular fibrillation; ventricular tachycardia ID RADIOFREQUENCY CATHETER ABLATION; OUTFLOW TRACT TACHYCARDIA; IMPLANTABLE-CARDIOVERTER-DEFIBRILLATORS; CORONARY-ARTERY-DISEASE; LEFT-BUNDLE-BRANCH; LONG-TERM SUCCESS; CARDIOVASCULAR MAGNETIC-RESONANCE; ANTIARRHYTHMIC-DRUG-THERAPY; STRUCTURAL HEART-DISEASE; PHRENIC-NERVE INJURY AB (J Cardiovasc Electrophysiol, Vol. 21, pp. 339-379, March 2010). C1 [Raviele, Antonio] Osped Angelo, Cardiovasc Dept, Arrhythmia Ctr, Mestre Venice, Italy. [Natale, Andrea] St Davids Med Ctr, Texas Cardiac Arrhythmia Inst, Austin, TX USA. [Al-Ahmad, Amin] Stanford Univ, Cardiac Arrhythmia Serv, Sch Med, Stanford, CA 94305 USA. [Alfieri, Ottavio] Univ Milan, Osped San Raffaele, Dept Cardiac Surg, I-20127 Milan, Italy. [Aliot, Etienne] Hop Brabois, Dept Cardiovasc Dis, CHU Nancy, Vandoeuvre Les Nancy, France. [Almendral, Jesus] Hosp Gen Gregorio Maranon, Div Cardiol, Madrid, Spain. [Breithardt, Guenter] Univ Hosp Munster, Dept Cardiol & Angiol, Munster, Germany. [Brugada, Josep] Univ Barcelona, Thorax Inst Cardiol, Hosp Clin, Barcelona, Spain. [Calkins, Hugh] Johns Hopkins Univ Hosp, Dept Cardiol, Baltimore, MD 21287 USA. [Callans, David] Hosp Univ Penn, Dept Med, Sect Cardiovasc Dis, Philadelphia, PA 19104 USA. [Cappato, Riccardo] Policlin San Donato, Dept Electrophysiol, San Donato Milanese, Italy. [Camm, John A.] St George Hosp, Sch Med, London, England. [Della Bella, Paolo] Ctr Cardiol Monzino, Div Cardiol, Milan, Italy. [Guiraudon, Gerard M.] Univ Western Ontario, London, ON, Canada. [Haissaguerre, Michel] Hop Cardiol Haut Leveque, Bordeaux, France. [Hindricks, Gerhard] Univ Leipzig, Ctr Heart, Dept Cardiol, Leipzig, Germany. [Ho, Siew Yen] Royal Brompton Hosp, Cardiac Morphol Unit, London SW3 6LY, England. [Ho, Siew Yen] Univ London Imperial Coll Sci Technol & Med, London, England. [Kuck, Karl H.] Asklepios Klin St Georg, Dept Cardiol, Hamburg, Germany. [Marchlinski, Francis] Univ Penn, Dept Med, Sect Cardiovasc Dis, Philadelphia, PA 19104 USA. [Packer, Douglas L.] Mayo Clin Fdn, Cardiac Translat & Electrophysiol Lab, Rochester, NY USA. [Prystowsky, Eric N.] Care Grp, Indianapolis, IN USA. [Reddy, Vivek Y.] Univ Miami, Miller Sch Med, Cardiac Arrhythmia Serv, Miami, FL 33136 USA. [Ruskin, Jeremy N.] Massachusetts Gen Hosp, Arrhythmia Serv, Boston, MA 02114 USA. [Scanavacca, Mauricio] Univ Sao Paulo, Sch Med, Inst Heart, Sao Paulo, Brazil. [Shivkumar, Kalyanam] Univ Calif Los Angeles, David Geffen Sch Med, Cardiac Arrhythmia Ctr, Los Angeles, CA 90095 USA. [Soejima, Kyoko] Univ Miami Hosp, Div Cardiovasc, Miami, FL USA. [Stevenson, William J.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Verma, Atul] Southlake Reg Hlth Ctr, Toronto, ON, Canada. [Wilber, David] Loyola Univ, Med Ctr, Dept Cardiol, Chicago, IL 60611 USA. RP Raviele, A (reprint author), Osped Angelo, Cardiovasc Dept, Arrhythmia Ctr, Mestre Venice, Italy. EM araviele@tin.it RI Scanavacca, Mauricio Ibrahim/F-7693-2012; Guiraudon, Gerard/B-7811-2015; OI Scanavacca, Mauricio Ibrahim/0000-0001-7327-2275; Guiraudon, Gerard/0000-0002-7418-2500; Sanchez-Quintana, Damian/0000-0002-6714-5322 FU Biosense Webster, Johnson & Johnson Company FX This document was made possible by an Educational Grant of Biosense Webster, a Johnson & Johnson Company. NR 368 TC 35 Z9 36 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-3873 EI 1540-8167 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD MAR PY 2010 VL 21 IS 3 BP 339 EP 379 DI 10.1111/j.1540-8167.2009.01686.x PG 41 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 559GX UT WOS:000274812700022 PM 20082650 ER PT J AU Kirschen, DG Laby, DM Kirschen, MP Applegate, R Thibos, LN AF Kirschen, David G. Laby, Daniel M. Kirschen, Matthew P. Applegate, Raymond Thibos, Larry N. TI Optical aberrations in professional baseball players SO JOURNAL OF CATARACT AND REFRACTIVE SURGERY LA English DT Article ID PREDICT VISUAL PERFORMANCE; IMAGE QUALITY; EYES; METRICS; ACUITY; ERROR AB PURPOSE: To determine the presence, type, and size of optical higher-order aberrations (HOAs) in professional athletes with superior visual acuity and to compare them with those in an age-matched population of nonathletes. SETTING: Vero Beach and Fort Myers, Florida, USA. METHODS: Players from 2 professional baseball teams were studied. Each player's optical aberrations were measured with a naturally dilated 4.0 mm pupil using a Z-Wave aberrometer and a LADAR Wave aberrometer. RESULTS: One hundred sixty-two players (316 eyes) were evaluated. The HOAs were less than 0.026 mu m in all cases. Spherical aberration C(4,0) was the largest aberration with both aberrometers. There were small but statistically significant differences between the aberrometers in mean values for trefoil C(3,3) and C(3,-3) and secondary astigmatism C(4,2). Although statistically significant, the differences were clinically insignificant, being similar at approximately 0.031 diopter (D) of spherical power. A statistically significant difference was found between the professional baseball players and the control population in trefoil C(3,-3). These differences were clinically insignificant, similar to 0.071 D of spherical power. CONCLUSIONS: Professional baseball players have small higher-order optical aberrations when tested with naturally dilated pupils. No clinically significant differences were found between the 2 aberrometers. Statistically significant differences in trefoil were found between the players and the control population; however, the difference was clinically insignificant. It seems as though the visual system of professional baseball players is limited by lower-order aberrations and that the smaller HOAs do not enhance visual function over that in a control population. C1 [Kirschen, David G.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Kirschen, David G.] So Calif Coll Optometry, Fullerton, CA USA. [Kirschen, Matthew P.] Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. [Laby, Daniel M.] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Applegate, Raymond] Univ Houston, Coll Optometry, Houston, TX USA. [Thibos, Larry N.] Indiana Univ, Sch Optometry, Bloomington, IN USA. RP Kirschen, DG (reprint author), 428 S Brea Blvd, Brea, CA 92821 USA. EM davidkirschen@mac.com NR 20 TC 2 Z9 2 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0886-3350 J9 J CATARACT REFR SURG JI J. Cataract. Refract. Surg. PD MAR PY 2010 VL 36 IS 3 BP 396 EP 401 DI 10.1016/j.jcrs.2009.09.032 PG 6 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 592VZ UT WOS:000277411000006 PM 20202535 ER PT J AU Monuteaux, MC Mick, E Faraone, SV Biederman, J AF Monuteaux, Michael C. Mick, Eric Faraone, Stephen V. Biederman, Joseph TI The influence of sex on the course and psychiatric correlates of ADHD from childhood to adolescence: A longitudinal study SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE ADHD; growth curve; sex; longitudinal; structural equation model ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; PROSPECTIVE FOLLOW-UP; DSM-III-R; GENDER; GIRLS; BOYS; BRAIN; PREVALENCE; FEMALE AB Background: Little is known about the influence of sex on the course of attention-deficit/hyperactivity disorder (ADHD) and its comorbid psychiatric conditions. The purpose of this study was to examine the effect of sex on the course and psychiatric correlates of ADHD from childhood into adolescence. Methods: Two identically designed, longitudinal, case-control family studies of male and female probands with and without ADHD and their siblings were combined. All subjects were blindly assessed with structured diagnostic interviews. Among subjects with a lifetime history of ADHD (n = 471, mean age 11.5 +/- 4.3 years at baseline), we used linear growth curve models to estimate the effect of time on the change in ADHD symptoms, and whether this effect differed by sex. We also we examined the effect of sex on the association between ADHD and the longitudinal progression of comorbid psychopathology using structural equation models. Results: We found no evidence that sex moderated the effect of age on ADHD symptoms; in both genders, age exhibited a similar effect on the decline of ADHD symptoms. However, the female sample demonstrated greater stability in comorbid psychopathology from childhood into adolescence. Furthermore, we found that the stability of comorbid psychopathology in females remained significant after accounting for the correlation between adolescent psychopathology and adolescent ADHD. In males, childhood and adolescent comorbid psychopathology were no longer correlated when adolescent ADHD was taken into account. Conclusions: Our findings indicate that while the course of ADHD across childhood and adolescence did not differ between males and females, patterns of psychiatric comorbidity were conditional on sex. Future studies should explicitly test how sex modifies the associations between ADHD and risk factors and ADHD and associated functional outcomes. C1 [Monuteaux, Michael C.; Mick, Eric; Biederman, Joseph] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Dept Psychiat, Clin & Res Program Pediat Psychiat, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, SUNY Genet Res Program, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Monuteaux, Michael C.; Mick, Eric; Biederman, Joseph] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Dept Psychiat, Clin & Res Program Adult ADHD, Boston, MA 02114 USA. RP Monuteaux, MC (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Dept Psychiat, Clin & Res Program Pediat Psychiat, 55 Fruit St,Warren 705, Boston, MA 02114 USA. EM mmonuteaux@partners.org OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU USPHS (NICHD) [5RO1 HD-36317-07] FX This work was supported, in part, by a grant from USPHS (NICHD), grant 5RO1 HD-36317-07 (JB) and a grant from USPHS (NICHD), 5RO1 HD-36317-07 (JB). NR 35 TC 21 Z9 22 U1 3 U2 19 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD MAR PY 2010 VL 51 IS 3 BP 233 EP 241 DI 10.1111/j.1469-7610.2009.02152.x PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 551BS UT WOS:000274181300003 PM 19769586 ER PT J AU Valassi, E Klibanski, A Biller, BMK AF Valassi, Elena Klibanski, Anne Biller, Beverly M. K. TI Potential Cardiac Valve Effects of Dopamine Agonists in Hyperprolactinemia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID VALVULAR HEART-DISEASE; TERM CABERGOLINE THERAPY; PARKINSONS-DISEASE; LONG-TERM; BROMOCRIPTINE TREATMENT; DOPPLER-ECHOCARDIOGRAPHY; TRICUSPID REGURGITATION; PLEUROPULMONARY DISEASE; INCREASED PREVALENCE; DOSE CABERGOLINE AB Context: An association has been demonstrated between valvular heart disease and dopamine agonist use in patients treated for Parkinson's disease. Following these reports, concern has been raised among endocrinologists about the safety of long-term treatment with dopamine agonists in hyperprolactinemic patients. The article will summarize all currently published research regarding the possible risk of valvulopathy in hyperprolactinemic patients on dopamine agonists and provide guidance based on current findings. Evidence Acquisition: The major source of data acquisition included PubMed search strategies. PubMed was searched for publications containing the terms "valve," " valvular," or "valvulopathy," and one of the terms "dopamine agonists," "cabergoline," "bromocriptine," "pergolide," "prolactin," "prolactinoma," or "hyperprolactinemia." All publications from 1950 to August, 2008, were screened for use in this review. Evidence Synthesis: The majority of studies showed no risk of valvular regurgitation associated with cabergoline. However, an increased risk of mild to moderate regurgitation, usually at the tricuspid valve, was reported in a few studies. Only one study suggested a relationship with the mean cumulative dose of cabergoline. Conclusions: Although most reports do not show an association between use of dopamine agonists and valvulopathy, caution must be exercised, especially in patients requiring long-term, high-dose medication regimens. Clinicians should recommend the lowest possible doses of dopamine agonists and address the question of echocardiographic monitoring on an individual basis. (J Clin Endocrinol Metab 95: 1025-1033, 2010) C1 [Biller, Beverly M. K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Neuroendocrine Clin Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Biller, BMK (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Neuroendocrine Clin Ctr, Bulfinch 457B, Boston, MA 02114 USA. EM bbiller@partners.org NR 45 TC 58 Z9 60 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2010 VL 95 IS 3 BP 1025 EP 1033 DI 10.1210/jc.2009-2095 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 564FA UT WOS:000275197500006 PM 20130078 ER PT J AU Halban, PA German, MS Kahn, SE Weir, GC AF Halban, Philippe A. German, Michael S. Kahn, Steven E. Weir, Gordon C. TI Current Status of Islet Cell Replacement and Regeneration Therapy SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID EMBRYONIC STEM-CELLS; PANCREATIC BETA-CELLS; TYPE-2 DIABETES-MELLITUS; NORMAL GLUCOSE-TOLERANCE; INSULIN-PRODUCING CELLS; IN-VIVO; EXTRACELLULAR-MATRIX; DEFINITIVE ENDODERM; SIGNALING PATHWAYS; ENDOCRINE PANCREAS AB Context: B cell mass and function are decreased to varying degrees in both type 1 and type 2 diabetes. In the future, islet cell replacement or regeneration therapy may thus offer therapeutic benefit to people with diabetes, but there are major challenges to be overcome. Evidence Acquisition: A review of published peer-reviewed medical literature on beta-cell development and regeneration was performed. Only publications considered most relevant were selected for citation, with particular attention to the period 2000-2009 and the inclusion of earlier landmark studies. Evidence Synthesis: Islet cell regenerative therapy could be achieved by in situ regeneration or implantation of cells previously derived in vitro. Both approaches are being explored, and their ultimate success will depend on the ability to recapitulate key events in the normal development of the endocrine pancreas to derive fully differentiated islet cells that are functionally normal. There is also debate as to whether beta-cells alone will assure adequate metabolic control or whether it will be necessary to regenerate islets with their various cell types and unique integrated function. Any approach must account for the potential dangers of regenerative therapy. Conclusions: Islet cell regenerative therapy may one day offer an improved treatment of diabetes and potentially a cure. However, the various approaches are at an early stage of preclinical development and should not be offered to patients until shown to be safe as well as more efficacious than existing therapy. (J Clin Endocrinol Metab 95: 1034-1043, 2010) C1 [Halban, Philippe A.] Univ Geneva, Univ Med Ctr, Dept Genet Med & Dev, CH-1211 Geneva 4, Switzerland. [German, Michael S.] Univ Calif San Francisco, Hormone Res Inst, Ctr Diabet, San Francisco, CA 94143 USA. [Kahn, Steven E.] Vet Affairs Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. Univ Washington, Seattle, WA 98195 USA. [Weir, Gordon C.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02115 USA. RP Halban, PA (reprint author), Univ Geneva, Univ Med Ctr, Dept Genet Med & Dev, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland. EM philippe.halban@unige.ch OI Kahn, Steven/0000-0001-7307-9002 FU Swiss National Science Foundation [3200B0-101902]; Juvenile Diabetes Research Foundation [7-2005-1158, 16-2007-429]; Department of Veterans Affairs; National Institutes of Health [DK66056]; Diabetes Research and Wellness Foundation; Larry L. Hillblom Foundation [2007/1B] FX This work was supported in part by Grant 3200B0-101902 from the Swiss National Science Foundation and Grant 7-2005-1158 from the Juvenile Diabetes Research Foundation (to P. A. H.); a grant from the Department of Veterans Affairs (to S. E. K.); Grant DK66056 from the National Institutes of Health and the Diabetes Research and Wellness Foundation (to G. C. W.); Grant 2007/1B from the Larry L. Hillblom Foundation; and Grant 16-2007-429 from the Juvenile Diabetes Research Foundation (to M.S.G.). NR 105 TC 48 Z9 52 U1 0 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2010 VL 95 IS 3 BP 1034 EP 1043 DI 10.1210/jc.2009-1819 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 564FA UT WOS:000275197500007 PM 20061422 ER PT J AU Russell, M Mendes, N Miller, KK Rosen, CJ Lee, H Klibanski, A Misra, M AF Russell, Melissa Mendes, Nara Miller, Karen K. Rosen, Clifford J. Lee, Hang Klibanski, Anne Misra, Madhusmita TI Visceral Fat Is a Negative Predictor of Bone Density Measures in Obese Adolescent Girls SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MINERAL DENSITY; INSULIN-RESISTANCE; METABOLIC SYNDROME; GROWTH-HORMONE; POSTMENOPAUSAL WOMEN; ANOREXIA-NERVOSA; BODY-COMPOSITION; ADIPOSE-TISSUE; ADIPONECTIN; LEPTIN AB Context: Regional fat is increasingly recognized as a determinant of bone mineral density (BMD), an association that may be mediated by adipokines, such as adiponectin and leptin, and inflammatory fat products. Chronic inflammation is deleterious to bone, and visceral adipose tissue (VAT) predicts inflammatory markers such as soluble intercellular adhesion molecule-1 and E-selectin, whereas sc adipose tissue (SAT) and VAT predict IL-6 in adolescents. Objective: Our objective was to determine associations of regional fat mass and adipokines with BMD. We hypothesized that girls with greater VAT relative to SAT would have lower bone density mediated by inflammatory cytokines, adiponectin, and leptin. Design: This was a cross-sectional study. Setting: The study was conducted at a clinical research center. Subjects: Subjects included 30 girls (15 obese, 15 normal weight) 12-18 yr old, matched for maturity (bone age), race, and ethnicity. Outcome Measures: We assessed regional fat (SAT, VAT) using magnetic resonance imaging, total fat, and BMD using dual-energy x-ray absorptiometry. Fasting leptin, adiponectin, IL-6, soluble intercellular adhesion molecule-1, and E-selectin were obtained. Results: Mean body mass index SD score was 3.7 +/- 1.5 in obese subjects and 0.1 +/- 0.4 kg/m(2) in controls. VAT was a negative predictor of spine BMD and bone mineral apparent density, whole-body BMD and bone mineral content/height in obese girls and whole-body BMD and bone mineral content/height for the group as a whole after controlling for SAT, as was the ratio of VAT to SAT. In a regression model that included VAT/SAT, adipokines, and cytokines, E-selectin and adiponectin were negative predictors of BMD and leptin a positive predictor. Conclusion: VAT is an independent inverse determinant of bone density in obesity. This association may be mediated by adipokines and a chronic inflammatory state. (J Clin Endocrinol Metab 95: 1247-1255, 2010) C1 [Russell, Melissa; Mendes, Nara; Miller, Karen K.; Klibanski, Anne; Misra, Madhusmita] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Russell, Melissa; Misra, Madhusmita] Harvard Univ, Sch Med, Pediat Endocrine Unit, Mass Gen Hosp Children, Boston, MA 02114 USA. [Lee, Hang] Harvard Catalyst, Biostat Core, Boston, MA 02114 USA. [Rosen, Clifford J.] Maine Med Ctr, Res Inst, Scarborough, ME 04074 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM mmisra@partners.org FU National Institutes of Health [5P30DK4620-15, M01-RR-01066] FX This work was supported by grants National Institutes of Health Grants 5P30DK4620-15 and M01-RR-01066. NR 33 TC 93 Z9 99 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2010 VL 95 IS 3 BP 1247 EP 1255 DI 10.1210/jc.2009-1475 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 564FA UT WOS:000275197500032 PM 20080853 ER PT J AU Ladenson, PW McCarren, M Morkin, E Edson, RG Shih, MC Warren, SR Barnhill, JG Churby, L Thai, H O'Brien, T Anand, I Warner, A Hattler, B Dunlap, M Erikson, J Goldman, S AF Ladenson, P. W. McCarren, M. Morkin, E. Edson, R. G. Shih, Mei-Chiung Warren, S. R. Barnhill, J. G. Churby, L. Thai, H. O'Brien, T. Anand, I. Warner, A. Hattler, B. Dunlap, M. Erikson, J. Goldman, S. TI Effects of the Thyromimetic Agent Diiodothyropropionic Acid on Body Weight, Body Mass Index, and Serum Lipoproteins: A Pilot Prospective, Randomized, Controlled Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID THYROID-HORMONE; HEART-FAILURE; HYPERTHYROIDISM; CHOLESTEROL; HYPOTHYROIDISM AB Context: Widespread thyroid hormone actions offer the possibility of developing selective thyromimetic analogs with salutary metabolic properties. Consequently, effects of diiodothyropropionic acid (DITPA) on body weight, serum lipoproteins, and bone metabolism markers were studied in a prospective, controlled, double-blind 24-wk trial, which was primarily designed to assess treatment of stable chronic heart failure. Design: Eighty-six patients (aged 66 +/- 11 yr, mean +/- SD) were randomized (1: 2) to placebo or an escalating DITPA dose (90 to 180, 270, and 360 mg/d)over 8 wk until serum TSH was less than 0.02 mU/liter. Patients were studied at 2, 4, 6, 8, 16, and 24 wk and after 4 wk off study drug. Only 21 DITPA-treated and 27 placebo patients completed the full 24 wk of therapy. Results: DITPA therapy lowered serum TSH levels and, to a lesser extent, serum T(3) and T(4), but there were no differences in clinical manifestations of thyrotoxicosis or hypothyroidism. Serum total and low density lipoprotein cholesterol levels both decreased on DITPA; there was a transient decrease in triglycerides and no change in high-density lipoprotein cholesterol. DITPA therapy was associated with significant reduction in body weight, 12.5 lb at 24 wk. Increases in serum osteocalcin, N-telopeptide, and deoxypyridinoline levels were consistent with increased bone turnover on DITPA. Conclusion: This investigation of DITPA actions demonstrated its efficacy in reducing body weight and lowering total and low-density lipoprotein cholesterol levels. However, DITPA's adverse effects at doses used resulted in a high dropout rate and potentially dangerous skeletal actions were observed. (J Clin Endocrinol Metab 95: 1349-1354, 2010) C1 [Ladenson, P. W.] Johns Hopkins Med Inst, Baltimore, MD 21287 USA. [McCarren, M.] Hines Vet Affairs Pharm Benefits Management, Hines, IL 60141 USA. [Morkin, E.; Thai, H.; Goldman, S.] Univ Arizona, Hlth Sci Ctr, Phoenix, AZ 85004 USA. [Edson, R. G.; Shih, Mei-Chiung; Churby, L.] Vet Affairs Palo Alto Hlth Care Syst, Vet Affairs Cooperat Studies Program, Coordinating Ctr, Palo Alto, CA 94304 USA. Clin Res Pharm Coordinating Ctr, Vet Affairs Cooperat Studies Program, Albuquerque, NM 87131 USA. [Warren, S. R.; Barnhill, J. G.] Univ New Mexico, Albuquerque, NM 87131 USA. Charleston Vet Affairs Med Ctr, Charleston, SC 29403 USA. [O'Brien, T.] Med Univ S Carolina, Charleston, SC 29403 USA. [Dunlap, M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. Cleveland Vet Affairs Med Ctr, Cleveland, OH 44106 USA. [Hattler, B.] Univ Colorado, Denver, CO 80262 USA. Denver Vet Affairs Med Ctr, Denver, CO 80262 USA. [Anand, I.] Univ Minnesota, Minneapolis, MN 55455 USA. Minneapolis Vet Affairs Med Ctr, Minneapolis, MN 55455 USA. [Erikson, J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. San Antonio Vet Affairs Med Ctr, San Antonio, TX 78229 USA. [Thai, H.; Goldman, S.] So Arizona Vet Affairs Hlth Care Syst, Tucson, AZ 85723 USA. [Shih, Mei-Chiung] Stanford Univ, Stanford, CA 94305 USA. [Warner, A.] Univ Calif Los Angeles, Los Angeles, CA 90095 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. RP Ladenson, PW (reprint author), Johns Hopkins Univ, Dept Endocrinol & Metab, 1830 E Monument St,Suite 333, Baltimore, MD 21287 USA. EM ladenson@jhmi.edu FU Department of Veterans Affairs Office of Research and Development FX This work was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development. NR 19 TC 27 Z9 29 U1 1 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2010 VL 95 IS 3 BP 1349 EP 1354 DI 10.1210/jc.2009-1209 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 564FA UT WOS:000275197500045 PM 20080837 ER PT J AU Karel, MJ Gurrera, RJ Hicken, B Moye, J AF Karel, Michele J. Gurrera, Ronald J. Hicken, Bret Moye, Jennifer TI Reasoning in the Capacity to Make Medical Decisions: The Consideration of Values SO JOURNAL OF CLINICAL ETHICS LA English DT Article ID LIFE-SUSTAINING TREATMENT; OLDER-ADULTS; ALZHEIMERS-DISEASE; INFORMED-CONSENT; COMPETENCE; PREFERENCES; CARE; JUDGMENTS; DEMENTIA; HEALTH AB Purpose To examine the contribution of "values-based reasoning" in evaluating older adults' capacity to make medical decisions. Design and Methods Older men with schizophrenia (n=20) or dementia (n=20), and a primary care comparison group (n=19), completed cognitive and psychiatric screening and an interview to determine their capacity to make medical decisions, which included a component on values. All of the participants were receiving treatment at Veterans Administration (VA) outpatient clinics. Results Participants varied widely in the activities and relationships they most valued, the extent to which religious beliefs would influence healthcare decisions, and in ratings of the importance of preserving quality versus length of life. Most participants preferred shared decision making with doctor, family, or both. Individuals with schizophrenia or dementia performed worse than a primary care comparison group in reasoning measured by the ability to list risks and benefits and compare choices. Individuals with dementia performed comparably to the primary care group in reasoning measured by the ability to justify choices in terms of valued abilities or activities, whereas individuals with schizophrenia performed relatively worse compared to the other two groups. Compared to primary care patients, participants with schizophrenia and with dementia were impaired on the ability to explain treatment choices in terms of valued relationships. Conclusion Medical decision making may be influenced by strongly held values and beliefs, emotions, and long life experience. To date, these issues have not been explicitly included in structured evaluations of medical decision-making capacity. This study demonstrated that it is possible to inquire of and elicit a range of healthcare related values and preferences from older adults with dementia or schizophrenia, and individuals with mild to moderate dementia may be able to discuss healthcare options in relation to their values. However, how best to incorporate a values assessment into a structured capacity evaluation deserves further research attention. C1 [Karel, Michele J.; Gurrera, Ronald J.; Moye, Jennifer] VA Boston Healthcare Syst, Mental Hlth Serv, Boston, MA USA. [Karel, Michele J.; Gurrera, Ronald J.; Moye, Jennifer] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Hicken, Bret] VA Salt Lake City Hlth Care Syst, VA Rural Hlth Resource Ctr Western Reg, Salt Lake City, UT USA. RP Karel, MJ (reprint author), VA Boston Healthcare Syst, Mental Hlth Serv, Boston, MA USA. EM Michele.Karel@va.gov RI Moye, Jennifer/F-2240-2017 OI Moye, Jennifer/0000-0002-3434-347X FU NIA NIH HHS [P60 AG08814, P30 AG028717, P30 AG028717-02] NR 69 TC 13 Z9 13 U1 0 U2 8 PU UNIV PUBLISHING GROUP PI HAGERSTOWN PA 138 W WASHINGTON ST, STE 403-405, HAGERSTOWN, MD 21740 USA SN 1046-7890 J9 J CLIN ETHIC JI J. Clin. Ethics PD SPR PY 2010 VL 21 IS 1 BP 58 EP 71 PG 14 WC Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Biomedical Social Sciences GA 797XS UT WOS:000293164000009 PM 20465077 ER PT J AU Percival, JM Anderson, KNE Huang, P Adams, ME Froehner, SC AF Percival, Justin M. Anderson, Kendra N. E. Huang, Paul Adams, Marvin E. Froehner, Stanley C. TI Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NITRIC-OXIDE SYNTHASE; DUCHENNE MUSCULAR-DYSTROPHY; DEFICIENT; NNOS; COMPLEX; MU; PATHOPHYSIOLOGY; MICROTUBULES; ORGANIZATION; PERFORMANCE AB Signaling via the neuronal NOS (nNOS) splice variant nNOS mu is essential for skeletal muscle health and is commonly reduced in neuromuscular disease. nNOS mu is thought to be the predominant source of NO in skeletal muscle. Here we demonstrate the existence of what we believe to be a novel signaling pathway, mediated by the nNOS splice variant nNOS beta, localized at the Golgi complex in mouse skeletal muscle cells. In contrast to muscles lacking nNOS mu alone, muscles missing both nNOS mu and nNOS beta were severely myopathic, exhibiting structural defects in the microtubule cytoskeleton, Golgi complex, and mitochondria. Skeletal muscles lacking both nNOS mu and nNOS beta were smaller in mass, intrinsically weak, highly susceptible to fatigue, and exhibited marked postexercise weakness. Our data indicate that nNOS beta is a critical regulator of the structural and functional integrity of skeletal muscle and demonstrate the existence of 2 functionally distinct nNOS micro-domains in skeletal muscle, created by the differential targeting of nNOS mu to the sarcolemma and nNOS beta to the Golgi. We have previously shown that sarcolemmal nNOS mu matches the blood supply to the metabolic demands of active muscle. We now demonstrate that nNOS beta simultaneously modulates the ability of skeletal muscle to maintain force production during and after exercise. We conclude therefore that nNOS splice variants are critical regulators of skeletal muscle exercise performance. C1 [Percival, Justin M.; Anderson, Kendra N. E.; Adams, Marvin E.; Froehner, Stanley C.] Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. [Huang, Paul] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Percival, JM (reprint author), Univ Washington, Dept Physiol & Biophys, Box 357290, Seattle, WA 98195 USA. EM justinp2@u.washington.edu FU Muscular Dystrophy Association; NIH; National Institute of Neurological Disorders and Stroke FX We thank Greg Martin of the Keck Imaging Center at the University of Washington for microscopy assistance, the Hauschka laboratory for assistance with myosin immunohistochemistry, and Stephanie Lara and Steve MacFarlane for assistance with electron microscopy. We thank Kimberley Craven, Michael Puljung, and members of the Froehner laboratory for manuscript editing and advice. This work was supported by grants from the Muscular Dystrophy Association (to J.M. Percival), NIH (to S.C. Froehner), and National Institute of Neurological Disorders and Stroke (to P.L. Huang). NR 39 TC 56 Z9 57 U1 0 U2 2 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAR PY 2010 VL 120 IS 3 BP 816 EP 826 DI 10.1172/JCI40736 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 565ET UT WOS:000275272700019 PM 20124730 ER PT J AU Walsh, MP Seto, J Jones, MS Chodosh, J Xu, WB Seto, D AF Walsh, Michael P. Seto, Jason Jones, Morris S. Chodosh, James Xu, Wenbo Seto, Donald TI Computational Analysis Identifies Human Adenovirus Type 55 as a Re-Emergent Acute Respiratory Disease Pathogen SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID EPIDEMIC KERATOCONJUNCTIVITIS; MILITARY RECRUITS; RECOMBINATION; ALIGNMENT; OUTBREAK; SEROTYPE; ILLNESS; CAMP AB Novel human adenoviruses (HAdVs) arise from genome recombination. Analysis of HAdV type 55 from an outbreak in China shows a hexon recombination between HAdV-B11 and HAdV-B14, resulting in a genome that is 97.4% HAdV-B14. Sporadic appearances as a re-emergent pathogen and misidentification as "HAdV-B11a" are due to this partial hexon. C1 [Walsh, Michael P.; Seto, Jason; Seto, Donald] George Mason Univ, Dept Bioinformat & Computat Biol, Manassas, VA 20110 USA. [Jones, Morris S.] David Grant USAF Med Ctr, Clin Invest Facil, Travis, CA 94535 USA. [Chodosh, James] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Howe Lab, Boston, MA 02114 USA. [Xu, Wenbo] Chinese Ctr Dis Control & Prevent, Natl Inst Viral Dis Control & Prevent, State Key Lab Mol Virol & Genet Engn, Beijing 100050, Peoples R China. RP Seto, D (reprint author), George Mason Univ, Dept Bioinformat & Computat Biol, 10900 Univ Blvd,MSN 5B3, Manassas, VA 20110 USA. EM dseto@gmu.edu FU U.S. Public Health Service NIH [EY013124, P30EY013104]; Massachusetts Lions Eye Research Fund, Inc.; Department of Ophthalmology, Harvard Medical School; Research to Prevent Blindness, Inc.; United States Air Force Surgeon General, Clinical Investigation [FDG20040024E] FX This work was supported in part by U.S. Public Health Service NIH grants EY013124 (D. S., M. P. W., M.S.J., and J.C.) and P30EY013104 (J.C.). J.C. is also supported by funding from the Massachusetts Lions Eye Research Fund, Inc., and an unrestricted grant to the Department of Ophthalmology, Harvard Medical School, from Research to Prevent Blindness, Inc. M.S.J. is supported by the United States Air Force Surgeon General, Clinical Investigation no. FDG20040024E. NR 23 TC 90 Z9 103 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD MAR PY 2010 VL 48 IS 3 BP 991 EP 993 DI 10.1128/JCM.01694-09 PG 3 WC Microbiology SC Microbiology GA 561RL UT WOS:000274996200054 PM 20042633 ER PT J AU Lee, DK Nahrendorf, M Schellingerhout, D Kim, DE AF Lee, Dong Kun Nahrendorf, Matthias Schellingerhout, Dawid Kim, Dong-Eog TI Will Molecular Optical Imaging Have Clinically Important Roles in Stroke Management, and How? SO JOURNAL OF CLINICAL NEUROLOGY LA English DT Review DE molecular imaging; stroke; optical imaging ID TISSUE-PLASMINOGEN ACTIVATOR; ACUTE ISCHEMIC-STROKE; CEREBRAL-ARTERY INFARCTION; CAROTID-ARTERY; IN-VIVO; REAL-TIME; HEMORRHAGIC TRANSFORMATION; ATHEROSCLEROTIC LESIONS; CARDIOVASCULAR-DISEASE; NONINVASIVE DETECTION AB Molecular imaging is a novel technology to visualize biological processes at the cellular and molecular levels, which is reshaping both biomedical research and clinical practice. By providing molecular information to supplement and augment conventional anatomy-based imaging, molecular imaging is expected to allow 1) the earlier detection of diseases, 2) precise evaluation of disease stages, and 3) both diagnostic and therapeutic monitoring of disease progression in a quantitative manner. In this brief review, we present our view on the prospects of molecular optical imaging in the field of stroke practice, focusing on the imaging vulnerability of atherosclerotic plaques, thrombolytic resistance, real-time cerebral perfusion, and penumbra. J Clin Neurol 2010;6:10-18 C1 [Lee, Dong Kun; Kim, Dong-Eog] Dongguk Univ, Ilsan Hosp, Mol Imaging & Neurovasc Res Lab, Dept Neurol, Goyang 410773, South Korea. [Nahrendorf, Matthias] Harvard Univ, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Sch Med,Dept Radiol, Charlestown, MA USA. [Schellingerhout, Dawid] Univ Texas MD Anderson Canc Ctr, Dept Radiol, Houston, TX 77030 USA. RP Kim, DE (reprint author), Dongguk Univ, Ilsan Hosp, Mol Imaging & Neurovasc Res Lab, Dept Neurol, 814 Siksa Dong, Goyang 410773, South Korea. EM kdongeog@duih.org FU Korean Ministry for Health, Welfare and Family Affairs [A084274] FX This work was supported by a grant (A084274 to Dr. Dong-Eog Kim) from the Korean Ministry for Health, Welfare and Family Affairs. NR 88 TC 7 Z9 7 U1 0 U2 2 PU KOREAN NEUROLOGICAL ASSOC PI SEOUL PA 1111 DAEIL BLD, 43 INSA-DONG, JONGNO-GU, SEOUL, 110-741, SOUTH KOREA SN 1738-6586 J9 J CLIN NEUROL JI J. Clin. Neurol. PD MAR PY 2010 VL 6 IS 1 BP 10 EP 18 DI 10.3988/jcn.2010.6.1.10 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 575SR UT WOS:000276088800002 PM 20386638 ER PT J AU Kantoff, PW Schuetz, TJ Blumenstein, BA Glode, LM Bilhartz, DL Wyand, M Manson, K Panicali, DL Laus, R Schlom, J Dahut, WL Arlen, PM Gulley, JL Godfrey, WR AF Kantoff, Philip W. Schuetz, Thomas J. Blumenstein, Brent A. Glode, L. Michael Bilhartz, David L. Wyand, Michael Manson, Kelledy Panicali, Dennis L. Laus, Reiner Schlom, Jeffrey Dahut, William L. Arlen, Philip M. Gulley, James L. Godfrey, Wayne R. TI Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; COSTIMULATORY MOLECULES; CLINICAL-TRIALS; ANTIGEN; THERAPY; VACCINES AB Purpose Therapeutic prostate-specific antigen (PSA)-targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study. Patients and Methods In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections. Results Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061. Conclusion PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study. J Clin Oncol 28:1099-1105. (C) 2010 by American Society of Clinical Oncology C1 [Godfrey, Wayne R.] BN Immunotherapeut, Mountain View, CA 94043 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Therion Biol, Cambridge, MA USA. Trial Architecture Consulting, Washington, DC USA. Univ Colorado, Aurora, CO USA. Urol Associates, Nashville, TN USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Godfrey, WR (reprint author), BN Immunotherapeut, 2425 Garcia Ave, Mountain View, CA 94043 USA. EM wayne.godfrey@bn-it.com RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU National Cancer Institute; Center for Cancer Research; National Institutes of Health; Laboratory of Tumor Immunology and Biology FX Supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. Additional support was provided by the Laboratory of Tumor Immunology and Biology, via the National Cancer Institute, which had a Collaborative Research and Development Agreement with Therion Biologics and currently has one with BN ImmunoTherapeutics. NR 22 TC 491 Z9 502 U1 3 U2 37 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2010 VL 28 IS 7 BP 1099 EP 1105 DI 10.1200/JCO.2009.25.0597 PG 7 WC Oncology SC Oncology GA 560HG UT WOS:000274892500006 PM 20100959 ER PT J AU Zietman, AL Bae, K Slater, JD Shipley, WU Efstathiou, JA Coen, JJ Bush, DA Lunt, M Spiegel, DY Skowronski, R Jabola, BR Rossi, CJ AF Zietman, Anthony L. Bae, Kyounghwa Slater, Jerry D. Shipley, William U. Efstathiou, Jason A. Coen, John J. Bush, David A. Lunt, Margie Spiegel, Daphna Y. Skowronski, Rafi Jabola, B. Rodney Rossi, Carl J. TI Randomized Trial Comparing Conventional-Dose With High-Dose Conformal Radiation Therapy in Early-Stage Adenocarcinoma of the Prostate: Long-Term Results From Proton Radiation Oncology Group/American College of Radiology 95-09 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID EXTERNAL-BEAM RADIOTHERAPY; ESCALATION TRIAL; COMPETING RISK; CANCER; IRRADIATION; CARCINOMA; SEQUELAE; PHOTONS; MEN AB Purpose To test the hypothesis that increasing radiation dose delivered to men with early-stage prostate cancer improves clinical outcomes. Patients and Methods Men with T1b-T2b prostate cancer and prostate-specific antigen <= 15 ng/mL were randomly assigned to a total dose of either 70.2 Gray equivalents (GyE; conventional) or 79.2 GyE (high). No patient received androgen suppression therapy with radiation. Local failure (LF), biochemical failure (BF), and overall survival (OS) were outcomes. Results A total of 393 men were randomly assigned, and median follow-up was 8.9 years. Men receiving high-dose radiation therapy were significantly less likely to have LF, with a hazard ratio of 0.57. The 10-year American Society for Therapeutic Radiology and Oncology BF rates were 32.4% for conventional-dose and 16.7% for high-dose radiation therapy (P < .0001). This difference held when only those with low-risk disease (n = 227; 58% of total) were examined: 28.2% for conventional and 7.1% for high dose (P < .0001). There was a strong trend in the same direction for the intermediate-risk patients (n = 144; 37% of total; 42.1% v 30.4%, P = .06). Eleven percent of patients subsequently required androgen deprivation for recurrence after conventional dose compared with 6% after high dose (P = .047). There remains no difference in OS rates between the treatment arms (78.4% v 83.4%; P = .41). Two percent of patients in both arms experienced late grade >= 3 genitourinary toxicity, and 1% of patients in the high-dose arm experienced late grade >= 3 GI toxicity. Conclusion This randomized controlled trial shows superior long-term cancer control for men with localized prostate cancer receiving high-dose versus conventional-dose radiation. This was achieved without an increase in grade >= 3 late urinary or rectal morbidity. J Clin Oncol 28: 1106-1111. (C) 2010 by American Society of Clinical Oncology C1 Loma Linda Univ, Med Ctr, Loma Linda, CA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. Amer Coll Radiol, Radiat Therapy Oncol Grp, Philadelphia, PA USA. RP Zietman, AL (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Cox 3, Boston, MA 02114 USA. EM azietman@partners.org OI Bush, David/0000-0003-0552-5861 FU Radiation Therapy Oncology Group [U10 CA21661]; Community Clinical Oncology Program [U10 CA37422]; National Cancer Institute [P01 CA21239] FX Supported by Radiation Therapy Oncology Group Grant No. U10 CA21661, and Community Clinical Oncology Program Grant No. U10 CA37422 and by Grant No. P01 CA21239 from the National Cancer Institute. NR 25 TC 297 Z9 302 U1 0 U2 16 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2010 VL 28 IS 7 BP 1106 EP 1111 DI 10.1200/JCO.2009.25.8475 PG 6 WC Oncology SC Oncology GA 560HG UT WOS:000274892500007 PM 20124169 ER PT J AU Cooperberg, MR Broering, JM Carroll, PR AF Cooperberg, Matthew R. Broering, Jeanette M. Carroll, Peter R. TI Time Trends and Local Variation in Primary Treatment of Localized Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; UNITED-STATES; RADICAL PROSTATECTOMY; MANAGEMENT; INTERVENTION; THERAPY; CAPSURE; MEN AB Purpose In the absence of high-level evidence or clinical guidelines supporting any given active treatment approach over another for localized prostate cancer, clinician and patient preferences may lead to substantial variation in treatment use. Methods Data were analyzed from 36 clinical sites that contributed data to the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. Distribution of primary treatment use was measured over time. Prostate cancer risk was assessed using the D'Amico risk groups and the Cancer of the Prostate Risk Assessment (CAPRA) score. Descriptive analyses were performed, and a hierarchical model was constructed that controlled for year of diagnosis, cancer risk variables, and other patient factors to estimate the proportion of variation in primary treatment selection explicable by practice site. Results Among 11,892 men analyzed, 6.8% elected surveillance, 49.9% prostatectomy, 11.6% external-beam radiation, 13.3% brachytherapy, 4.0% cryoablation, and 14.4% androgen deprivation monotherapy. Prostate cancer risk drives treatment selection, but the data suggest both overtreatment of low-risk disease and undertreatment of high-risk disease. The former trend appears to be improving over time, while the latter is worsening. Treatment varies with age, comorbidity, and socioeconomic status. However, treatment patterns vary markedly across clinical sites, and this variation is not explained by case-mix variability or known patient factors. Practice site explains a proportion of this variation ranging from 13% for androgen deprivation monotherapy to 74% for cryoablation. Conclusion Substantial variation exists in management of localized prostate cancer that is not explained by measurable factors. A critical need exists for high-quality comparative effectiveness research in localized prostate cancer to help guide treatment decision making. J Clin Oncol 28: 1117-1123. (C) 2010 by American Society of Clinical Oncology C1 [Cooperberg, Matthew R.] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. RP Cooperberg, MR (reprint author), Univ Calif San Francisco, Dept Urol, Box 1695,1600 Divisadero St,A 607, San Francisco, CA 94143 USA. EM mcooperberg@urology.ucsf.edu FU Department of Urology, University of California, San Francisco; National Institutes of Health/National Cancer Institute, University of California, San Francisco [P50CA89520] FX Support for CaPSURE is provided in part by Abbott Labs, Abbott Park, IL; by the Department of Urology, University of California, San Francisco; and by Special Program of Research Excellence (SPORE) Grant No. P50CA89520 from the National Institutes of Health/National Cancer Institute, University of California, San Francisco. NR 25 TC 455 Z9 466 U1 1 U2 19 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2010 VL 28 IS 7 BP 1117 EP 1123 DI 10.1200/JCO.2009.26.0133 PG 7 WC Oncology SC Oncology GA 560HG UT WOS:000274892500009 PM 20124165 ER PT J AU Blackwell, KL Burstein, HJ Storniolo, AM Rugo, H Sledge, G Koehler, M Ellis, C Casey, M Vukelja, S Bischoff, J Baselga, J O'Shaughnessy, J AF Blackwell, Kimberly L. Burstein, Harold J. Storniolo, Anna Maria Rugo, Hope Sledge, George Koehler, Maria Ellis, Catherine Casey, Michelle Vukelja, Svetislava Bischoff, Joachim Baselga, Jose O'Shaughnessy, Joyce TI Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory Metastatic Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-II; 1ST-LINE TREATMENT; KINASE INHIBITOR; POOLED ANALYSIS; SINGLE-AGENT; SAFETY; THERAPY; EFFICACY; CHEMOTHERAPY; MONOTHERAPY AB Purpose Preclinical studies in ErbB2-positive cell lines demonstrated a synergistic interaction between lapatinib and trastuzumab, suggesting that dual blockade is more effective than a single agent alone. EGF104900 compared the activity of lapatinib alone or in combination with trastuzumab in patients with ErbB2-positive, trastuzumab-refractory metastatic breast cancer (MBC). Patients and Methods Patients with ErbB2-positive MBC who experienced progression on prior trastuzumab-containing regimens were randomly assigned to receive either lapatinib alone or in combination with trastuzumab. The primary end point was progression-free survival (PFS). Secondary efficacy end points included overall response rate (ORR), clinical benefit rate (CBR; complete response, partial response, and stable disease for >= 24 weeks), and overall survival (OS). Results In the intent-to-treat population (N = 296) who received a median of three prior trastuzumab-containing regimens, the combination of lapatinib with trastuzumab was superior to lapatinib alone for PFS (hazard ratio [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008) and CBR (24.7% in the combination arm v 12.4% in the monotherapy arm; P = .01). A trend for improved OS in the combination arm was observed (HR = 0.75; 95% CI, 0.53 to 1.07; P = .106). There was no difference in ORR (10.3% in the combination arm v 6.9% in the monotherapy arm; P = .46). The most frequent adverse events were diarrhea, rash, nausea, and fatigue; diarrhea was higher in the combination arm (P = .03). The incidence of symptomatic and asymptomatic cardiac events was low (combination therapy = 2% and 3.4%; monotherapy = 0.7% and 1.4%, respectively). Conclusion Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC. J Clin Oncol 28: 1124-1130. (C) 2010 by American Society of Clinical Oncology C1 [Blackwell, Kimberly L.] Duke Univ, Med Ctr, Durham, NC 27701 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Indiana Univ Melvin, Indianapolis, IN USA. Bren Simon Canc Ctr, Indianapolis, IN USA. Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. GlaxoSmithKline Inc, Med Dev Ctr Oncol, Collegeville, PA USA. Texas Oncol PA, US Oncol, Tyler, TX USA. US Oncol, Texas Oncol PA, Baylor Sammons Canc Ctr, Dallas, TX USA. Otto Von Guericke Univ, Magdeburg, Germany. Vall Hebron Univ Hosp, Barcelona, Spain. RP Blackwell, KL (reprint author), Duke Univ, Med Ctr, Durham, NC 27701 USA. EM black034@mc.duke.edu FU GlaxoSmithKline FX Supported by GlaxoSmithKline. NR 27 TC 420 Z9 440 U1 2 U2 25 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2010 VL 28 IS 7 BP 1124 EP 1130 DI 10.1200/JCO.2008.21.4437 PG 7 WC Oncology SC Oncology GA 560HG UT WOS:000274892500010 PM 20124187 ER PT J AU Silver, DP Richardson, AL Eklund, AC Wang, ZC Szallasi, Z Li, Q Juul, N Leong, CO Calogrias, D Buraimoh, A Fatima, A Gelman, RS Ryan, PD Tung, NM De Nicolo, A Ganesan, S Miron, A Colin, C Sgroi, DC Ellisen, LW Winer, EP Garber, JE AF Silver, Daniel P. Richardson, Andrea L. Eklund, Aron C. Wang, Zhigang C. Szallasi, Zoltan Li, Qiyuan Juul, Nicolai Leong, Chee-Onn Calogrias, Diana Buraimoh, Ayodele Fatima, Aquila Gelman, Rebecca S. Ryan, Paula D. Tung, Nadine M. De Nicolo, Arcangela Ganesan, Shridar Miron, Alexander Colin, Christian Sgroi, Dennis C. Ellisen, Leif W. Winer, Eric P. Garber, Judy E. TI Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ESTROGEN-RECEPTOR STATUS; SQUAMOUS-CELL CARCINOMA; BASAL-LIKE; PREOPERATIVE CHEMOTHERAPY; EXPRESSION PROFILES; BRCA1 MUTATIONS; P53 MUTATIONS; SURVIVAL; TUMORS; CHEMOSENSITIVITY AB Purpose Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. Patients and Methods Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m(2) every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations; 18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). Conclusion Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response. J Clin Oncol 28: 1145-1153. (C) 2010 by American Society of Clinical Oncology C1 [Garber, Judy E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Hosp, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. BioCtr Tech Univ Denmark, Ctr Biol Sequence Anal, Lyngby, Denmark. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. RP Garber, JE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Smith 209,1 Jimmy Fund Way, Boston, MA 02115 USA. EM judy_garber@dfci.harvard.edu OI Szallasi, Zoltan/0000-0001-5395-7509; Eklund, Aron Charles/0000-0003-0861-1001 FU National Cancer Institute Program of Research Excellence (SPORE) [CA089393]; National Institutes of Health [R21LM008823-01A1]; Breast Cancer Research Foundation; Sidney Kimmel Foundation; Avon supplement to the Dana-Farber/Harvard Cancer Center FX Supported by Grants No. CA089393 from the National Cancer Institute Program of Research Excellence (SPORE) in Breast Cancer at the DanaFarber/Harvard Cancer Center and No. R21LM008823-01A1 from the National Institutes of Health, and by the Breast Cancer Research Foundation, Sidney Kimmel Foundation, Avon supplement to the Dana-Farber/Harvard Cancer Center support grant, and Susan G. Komen for the Cure. NR 49 TC 392 Z9 423 U1 5 U2 45 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2010 VL 28 IS 7 BP 1145 EP 1153 DI 10.1200/JCO.2009.22.4725 PG 9 WC Oncology SC Oncology GA 560HG UT WOS:000274892500013 PM 20100965 ER PT J AU Gunturu, KS Meehan, KR Mackenzie, TA Crocenzi, TS McDermott, D Usherwood, EJ Margolin, KA Crosby, NA Atkins, MB Turk, MJ Ahonen, C Fuse, S Clark, JI Fisher, JL Noelle, RJ Ernstoff, MS AF Gunturu, Krishna S. Meehan, Kenneth R. Mackenzie, Todd A. Crocenzi, Todd S. McDermott, David Usherwood, Edward J. Margolin, Kim A. Crosby, Nancy A. Atkins, Michael B. Turk, Mary Jo Ahonen, Cory Fuse, Shinichiro Clark, Joseph I. Fisher, Jan L. Noelle, Randolph J. Ernstoff, Marc S. TI Cytokine Working Group Study of Lymphodepleting Chemotherapy, Interleukin-2, and Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Metastatic Melanoma: Clinical Outcomes and Peripheral-Blood Cell Recovery SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ANTIGEN-4 MONOCLONAL-ANTIBODY; PHASE-I TRIAL; T-CELLS; HOMEOSTATIC PROLIFERATION; AUTOIMMUNITY; REGRESSION; RESPONSES; BLOCKADE AB Purpose Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. Patients and Methods This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 mu g/m(2)/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Results The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8' cells was observed in one of four HLA-A2-positive patients. Conclusion Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone. C1 [Ernstoff, Marc S.] Dartmouth Hitchcock Med Ctr, Hematol Oncol Sect, Immunotherapy Grp Med Oncol, Lebanon, NH 03756 USA. Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Med,Dept Microbiol & Immunol, Hanover, NH 03756 USA. Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Immunotherapy Program, Hanover, NH 03756 USA. Loyola Univ, Stritch Sch Med, Cardinal Bernardin Canc Ctr Hines, Chicago, IL 60611 USA. Beth Israel Deaconess Med Ctr, Dana Farber Harvard Canc Ctr, Boston, MA 02215 USA. City Hope Natl Med Ctr, Duarte, CA USA. Earle A Chiles Canc Res Ctr, Portland, OR USA. RP Ernstoff, MS (reprint author), Dartmouth Hitchcock Med Ctr, Hematol Oncol Sect, Immunotherapy Grp Med Oncol, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM marc.s.ernstoff@hitchcock.org FU National Cancer Institute [R21CA112761]; Chiron; Berlex FX Supported in part by National Cancer Institute Grant No. R21CA112761, Chiron, and Berlex. NR 20 TC 10 Z9 10 U1 1 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 MAR 1 PY 2010 VL 28 IS 7 BP 1196 EP 1202 DI 10.1200/JCO.2009.24.8153 PG 7 WC Oncology SC Oncology GA 560HG UT WOS:000274892500020 PM 20124177 ER PT J AU Mack, JW Weeks, JC Wright, AA Block, SD Prigerson, HG AF Mack, Jennifer W. Weeks, Jane C. Wright, Alexi A. Block, Susan D. Prigerson, Holly G. TI End-of-Life Discussions, Goal Attainment, and Distress at the End of Life: Predictors and Outcomes of Receipt of Care Consistent With Preferences SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SERIOUSLY ILL PATIENTS; SUSTAINING TREATMENT; CANCER CARE; CARDIOPULMONARY-RESUSCITATION; TERMINAL ILLNESS; MENTAL-HEALTH; OLDER PERSONS; AGGRESSIVENESS; SURVIVAL; QUALITY AB Purpose Physicians have an ethical obligation to honor patients' values for care, including at the end of life (EOL). We sought to evaluate factors that help patients to receive care consistent with their preferences. Methods This was a longitudinal multi-institutional cohort study. We measured baseline preferences for life-extending versus symptom-directed care and actual EOL care received in 325 patients with advanced cancer. We also measured associated sociodemographic, health, and communication characteristics, including EOL discussions between patients and physicians. Results Preferences were assessed a median of 125 days before death. Overall, 68% of patients (220 of 325 patients) received EOL care consistent with baseline preferences. The proportion was slightly higher among patients who recognized they were terminally ill (74%, 90 of 121 patients; P = .05). Patients who recognized their terminal illness were more likely to prefer symptom-directed care (83%, 100 of 121 patients; v 66%, 127 of 191 patients; P = .003). However, some patients who were aware they were terminally ill wished to receive life-extending care (17%, 21 of 121 patients). Patients who reported having discussed their wishes for EOL care with a physician (39%, 125 of 322 patients) were more likely to receive care that was consistent with their preferences, both in the full sample (odds ratio [OR] = 2.26; P < .0001) and among patients who were aware they were terminally ill (OR = 3.94; P = .0005). Among patients who received no life-extending measures, physical distress was lower (mean score, 3.1 v 4.1; P = .03) among patients for whom such care was consistent with preferences. Conclusion Patients with cancer are more likely to receive EOL care that is consistent with their preferences when they have had the opportunity to discuss their wishes for EOL care with a physician. C1 [Mack, Jennifer W.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. Dana Farber Canc Inst, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. RP Mack, JW (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St 454, Boston, MA 02115 USA. EM jennifer_mack@dfci.harvard.edu FU NCI NIH HHS [CA106370, R01 CA106370]; NIMH NIH HHS [MH63892, R01 MH063892] NR 28 TC 185 Z9 185 U1 3 U2 25 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2010 VL 28 IS 7 BP 1203 EP 1208 DI 10.1200/JCO.2009.25.4672 PG 6 WC Oncology SC Oncology GA 560HG UT WOS:000274892500021 PM 20124172 ER PT J AU Makhija, S Amler, LC Glenn, D Ueland, FR Gold, MA Dizon, DS Paton, V Lin, CY Januario, T Ng, K Strauss, A Kelsey, S Sliwkowski, MX Matulonis, U AF Makhija, Sharmila Amler, Lukas C. Glenn, Dana Ueland, Frederick R. Gold, Michael A. Dizon, Don S. Paton, Virginia Lin, Chin-Yu Januario, Thomas Ng, Kimmie Strauss, Andreas Kelsey, Stephen Sliwkowski, Mark X. Matulonis, Ursula TI Clinical Activity of Gemcitabine Plus Pertuzumab in Platinum-Resistant Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PHASE-II; DIMERIZATION INHIBITOR; MONOCLONAL-ANTIBODY; REFRACTORY OVARIAN; SIGNALING PATHWAY; BREAST-CANCER; SOLID TUMORS; KINASE; HER2; RECURRENT AB Purpose Pertuzumab is a humanized monoclonal antibody that inhibits human epidermal growth factor receptor 2 (HER2) heterodimerization and has single-agent activity in recurrent epithelial ovarian cancer. The primary objective of this phase II study was to characterize the safety and estimate progression-free survival (PFS) of pertuzumab with gemcitabine in patients with platinum-resistant ovarian cancer. Patients and Methods Patients with advanced, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who had received a maximum of one prior treatment for recurrent cancer were randomly assigned to gemcitabine plus either pertuzumab or placebo. Collection of archival tissue was mandatory to permit exploration of biomarkers that would predict benefit from pertuzumab in this setting. Results One hundred thirty patients (65 per arm) were treated. Baseline characteristics were similar between arms. The adjusted hazard ratio (HR) for PFS was 0.66 (95% CI, 0.43 to 1.03; P = .07) in favor of gemcitabine = pertuzumab. The objective response rate was 13.8% in patients who received gemcitabine = pertuzumab compared with 4.6% in patients who received gemcitabine = placebo. In patients whose tumors had low HER3 mRNA expression (< median, n = 61), an increased treatment benefit was observed in the gemcitabine = pertuzumab arm compared with the gemcitabine alone arm (PFS HR = 0.32; 95% CI, 0.17 to 0.59; P = .0002). Grade 3 to 4 neutropenia, diarrhea, and back pain were increased in patients treated with gemcitabine + pertuzumab. Symptomatic congestive heart failure was reported in one patient in the gemcitabine + pertuzumab arm. Conclusion Pertuzumab may add activity to gemcitabine for the treatment of platinum-resistant ovarian cancer. Low HER3 mRNA expression may predict pertuzumab clinical benefit and be a valuable prognostic marker. C1 Emory Univ, Dept Gynecol Oncol, Atlanta, GA 30322 USA. Genentech Inc, San Francisco, CA 94080 USA. Sharp Rees Stealy Med Grp, San Diego, CA USA. Univ Kentucky, Lucille P Markey Canc Ctr, Lexington, KY USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Brown Univ, Women & Infants Hosp, Warren Alpert Med Sch, Providence, RI USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Roche Diagnost, Penzberg, Germany. RP Makhija, S (reprint author), Emory Univ, Sch Med, Dept Gynecol & Obstet, Woodruff Mem Res Bldg,1639 Pierce Dr 4305, Atlanta, GA 30322 USA. EM drmakhija@yahoo.com FU Genentech, South San Francisco, CA FX Supported by Genentech, South San Francisco, CA. NR 26 TC 84 Z9 85 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 MAR 1 PY 2010 VL 28 IS 7 BP 1215 EP 1223 DI 10.1200/JCO.2009.22.3354 PG 9 WC Oncology SC Oncology GA 560HG UT WOS:000274892500023 PM 19901115 ER PT J AU Ogino, S Meyerhardt, JA Fuchs, CS AF Ogino, Shuji Meyerhardt, Jeffrey A. Fuchs, Charles S. TI Prognostic Significance of 18q Loss of Heterzygosity in Microsatellite-Stable Colorectal Cancer Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID COLON-CANCER; INSTABILITY; EXPRESSION; SURVIVAL; MARKERS; COHORT C1 [Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Ogino, S (reprint author), Harvard Univ, Sch Med, Boston, MA USA. NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2010 VL 28 IS 7 BP E120 EP E120 DI 10.1200/JCO.2009.27.1007 PG 1 WC Oncology SC Oncology GA 560HG UT WOS:000274892500036 ER PT J AU Perlis, RH Ostacher, MJ Miklowitz, DJ Hay, A Nierenberg, AA Thase, ME Sachs, GS AF Perlis, Roy H. Ostacher, Michael J. Miklowitz, David J. Hay, Aleena Nierenberg, Andrew A. Thase, Michael E. Sachs, Gary S. TI Clinical Features Associated With Poor Pharmacologic Adherence in Bipolar Disorder: Results From the STEP-BD Study SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; TREATMENT ENHANCEMENT PROGRAM; MEDICATION ADHERENCE; INCREASE ADHERENCE; LITHIUM TREATMENT; I-DISORDER; DSM-IV; RISK; INDIVIDUALS; VALIDATION AB Background: Poor medication adherence is common among bipolar patients. Method: We examined prospective data from 2 cohorts of individuals from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (1999-2005) with bipolar disorder. Clinical and sociodemographic features associated with missing at least 25% of doses of at least 1 medication were assessed using logistic regression, and a risk stratification model was developed and validated. Results: Of 3,640 subjects with 48,287 follow-up visits, 871 (24%) reported nonadherence on 20% or more study visits. Clinical features significantly associated (P<.05) with poor adherence included rapid cycling, suicide attempts, earlier onset of illness, and current anxiety or alcohol use disorder. Nonadherence during the first 3 months of follow-up was associated with less improvement in functioning at 12-month follow-up (P<.03). A risk stratification model using clinical predictors accurately classified 80.6% of visits in an independent validation cohort. Conclusion: Risk for poor medication adherence can be estimated and may be useful in targeting interventions. J Clin Psychiatry 2010;71(3):296-303 (C) Copyright 2010 Physicians Postgraduate Press, Inc. C1 [Perlis, Roy H.; Ostacher, Michael J.; Hay, Aleena; Nierenberg, Andrew A.; Sachs, Gary S.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Perlis, Roy H.; Ostacher, Michael J.; Hay, Aleena; Nierenberg, Andrew A.; Sachs, Gary S.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Perlis, Roy H.; Ostacher, Michael J.; Hay, Aleena; Nierenberg, Andrew A.; Sachs, Gary S.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Miklowitz, David J.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Thase, Michael E.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. RP Perlis, RH (reprint author), Massachusetts Gen Hosp, Bipolar Clin & Res Program, 50 Staniford St,5th Floor, Boston, MA 02114 USA. EM rperlis@partners.org OI Ostacher, Michael/0000-0003-0353-7535 FU Eli Lilly; Elan/Eisai; AstraZeneca; Bristol-Myers Squibb; Pfizer; Proteus Biomedical; GlaxoSmithKline; Concordant Rater Systems; Alcoholism; Alcohol Abuse; Massachusetts General Psychiatry Academy (MGHPA); Janssen Pharmaceuticals; Cyberonics; MedAvante; Transcept; Supernus; Shire; Forest; Cederroth; Stanley Foundation; Broad Institute; Pam Labs; NARSAD Young Investigator Award; Sydney L. Baer Foundation Award; Bowman Family Foundation Award; NIMH, National Institutes of Health [N01MH80001] FX Bipolar Clinical and Research Program and Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston (Drs Perlis, Ostacher, Nierenberg, and Sachs and Ms Hay); Department of Psychology, University of Colorado, Boulder (Dr Miklowitz); and Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia (Dr Thase). Potential conflicts of interest: Dr Perlis has received research support from Eli Lilly and Elan/Eisai; advisory/consulting fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Pfizer, and Proteus Biomedical; and speaking fees or honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Pfizer and has equity holdings and patents for Concordant Rater Systems, LLC. Dr Ostacher reports receiving research support from the National Institute on Alcohol Abuse and Alcoholism and Pfizer; advisory/consulting fees from Pfizer and Concordant Rater Systems; speaker's fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Pfizer, and Massachusetts General Psychiatry Academy (MGHPA) (MGHPA talks were supported through Independent Medical Education grants from the following pharmaceutical companies in 2008: AstraZeneca, Eli Lilly, and Janssen Pharmaceuticals). Dr Thase has served as an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Organon, Schering-Plough, Sepracor, Shire, Supernus, Transcept, and Wyeth; has served on the speakers' bureaus of AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, Organon, Sanofi-Aventis, and Wyeth; has provided expert testimony for Jones Day (Wyeth litigation) and Phillips Lytle (GlaxoSmithKline litigation); is a shareholder with MedAvante; and receives income from royalties and/or patents with American Psychiatric Publishing, Guilford Publications, Herald House, and WW Norton; his wife is the senior medical director for Advogent (formerly Cardinal Health). Dr Sachs has received research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Memory Pharmaceuticals, the National Institute of Mental Health (NIMH), Novartis, Pfizer, Repligen, Shire, and Wyeth; has served on the speaker bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Memory Pharmaceuticals, Novartis, Otsuka, Pfizer, Sanofi-Aventis, Takeda, and Wyeth; has served as an advisory board member or consultant for Abbott, AstraZeneca, Bristol-Myers Squibb, Cephalon, CNS Response, Elan Pharmaceuticals, Eli Lilly, GlaxoSmithKline, Janssen, Memory Pharmaceuticals, Merck, Novartis, Organon, Pfizer, Repligen, Sanofi-Aventis, Shire, Sigma-Tau, Solvay, and Wyeth; and his spouse is a shareholder with Concordant Rater Systems.; Dr Nierenberg has served in the past 3 years as a consultant/advisor to Abbott, Appliance Computing, BrainCells, Bristol-Myers Squibb, Eli Lilly, EpiQ, GHenaissance, Forest, GlaxoSmithKline, Innapharma, Janssen, Jazz, Merck, Novartis, Pam Labs, Pfizer, PGX Health, Schering-Plough, Sepracor, Shire, Somerset, Takeda, and Targacept; has received research/grant support from Bristol-Myers Squibb, Cederroth, Cyberonics, Eli Lilly, Forest, GlaxoSmith Kline, Janssen, Lichtwer Pharma, Medtronics, NARSAD, NIMH, Pfizer, Stanley Foundation through Broad Institute, Ortho-McNeil-Janssen, Pfizer, Pam Labs, Shire, and Wyeth-Ayerst; and has received honoraria from Bristol-Myers Squibb, Cyberonics, Eli Lilly, Forest, GlaxoSmithKlin, the MGH Psychiatry Academy (MGHPA activities in 2008 and 2009 were supported through Independent Medical Education grants from AstraZeneca, Eli Lilly, and Janssen), and Wyeth-Ayerst; earns fees for editorial functions for CNS Spectrums through MBL Publishing and Psychiatric Annals through Slack, honoraria as a CME Executive Director for The Journal of Clinical Psychiatry through Physicians Postgraduate Press, and royalties from Cambridge University Press and Belvoir Publishing; owns stock options in Appliance Computing and Brain Cells; and, through MGH, owns copyrights to the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery Asberg Depression Scale exclusively licensed to the MGH Clinical Trials Network and Institute. Dr Miklowitz and Ms Hay have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article.; The study was supported by a NARSAD Young Investigator Award (R. H. P.); a Sydney L. Baer Foundation Award (R. H. P.); and a Bowman Family Foundation Award (R. H. P.). The STEP-BD project was funded in whole or in part with federal funds from the NIMH, National Institutes of Health, under contract N01MH80001 to Gary S. Sachs, MD (Principal Investigator [PI]), Michael E. Thase, MD (Co-PI), and Mark S. Bauer, MD (Co-PI). NR 48 TC 48 Z9 50 U1 3 U2 11 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAR PY 2010 VL 71 IS 3 BP 296 EP 303 DI 10.4088/JCP.09m05514yel PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 578DK UT WOS:000276273500011 PM 20331931 ER PT J AU Raman, SS Leary, C Bluemke, DA Amendola, M Sahani, D McTavish, JD Brody, J Outwater, E Mitchell, D Sheafor, DH Fidler, J Francis, IR Semelka, RC Shamsi, K Gschwend, S Feldman, DR Breuer, J AF Raman, Steven S. Leary, Christopher Bluemke, David A. Amendola, Marco Sahani, Dushyant McTavish, Jeffrey D. Brody, Jeffrey Outwater, Eric Mitchell, Donald Sheafor, Douglas H. Fidler, Jeff Francis, Isaac R. Semelka, Richard C. Shamsi, Kohkan Gschwend, Simone Feldman, David R. Breuer, Josy CA US EOB Study Grp TI Improved Characterization of Focal Liver Lesions With Liver-Specific Gadoxetic Acid Disodium-Enhanced Magnetic Resonance Imaging: A Multicenter Phase 3 Clinical Trial SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE liver lesion; magnetic resonance; computed tomography; contrast agent; Gd-EOB-DTPA ID GD-EOB-DTPA; CONTRAST AGENT; HEPATOCELLULAR-CARCINOMA; HEPATIC METASTASES; EFFICACY; SAFETY; MRI; CT; HEMANGIOMAS; FERUMOXIDES AB Objectives: To evaluate the safety of gadoxetic acid disodium (Gd-EOB-DTPA) magnetic resonance imaging (MRI) and its efficacy in characterizing liver lesions. Methods: Lesion characterization and classification using combined (unenhanced and Gd-EOB-DTPA-enhanced) MRI were compared with those using unenhanced MRI and contrast-enhanced spiral computed tomography (CT) using on-site clinical and off-site blinded evaluations for patients with focal liver lesions. Results: Gadoxetic acid disodium was well tolerated in this study. For the clinical evaluation, more lesions were correctly characterized using combined (unenhanced and Gd-EOB-DTPA-enhanced) MRI than using unenhanced MRI and spiral CT (96% vs 84% and 85%, respectively; P <= 0.0008). For the blinded evaluation, more lesions were correctly characterized using combined MRI compared with using unenhanced MRI (61%-76% vs 48%-65%, respectively; P <= 0.0012 for 2/3 readers); when compared with spiral CT, a similar proportion of lesions were correctly characterized. Conclusions: Gadoxetic acid disodium-enhanced MRI is of clinical benefit relative to unenhanced MRI and spiral CT for a radiological diagnosis of liver lesions. C1 [Raman, Steven S.] Univ Calif Los Angeles, Dept Radiol Sci, Los Angeles, CA 90095 USA. [Bluemke, David A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Leary, Christopher] Hartford Hosp, Hartford, CT 06115 USA. [Amendola, Marco] MRI Ctr, Miami, FL USA. [Sahani, Dushyant] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [McTavish, Jeffrey D.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Brody, Jeffrey] Rhode Isl Hosp, Dept Diagnost Imaging, Providence, RI USA. [Outwater, Eric] Univ Arizona, Hlth Sci Ctr, Dept Radiol, Tucson, AZ USA. [Mitchell, Donald] Thomas Jefferson Univ Hosp, Dept Radiol, Philadelphia, PA 19107 USA. [Sheafor, Douglas H.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Fidler, Jeff] Mayo Clin, Dept Radiol, Rochester, MN USA. [Francis, Isaac R.] Univ Michigan Hosp, Dept Radiol, Ann Arbor, MI 48109 USA. [Semelka, Richard C.] Univ N Carolina, Sch Med, Dept Radiol, Chapel Hill, NC 27514 USA. [Shamsi, Kohkan; Feldman, David R.] Bayer HealthCare Pharmaceut, Wayne, NJ USA. [Gschwend, Simone; Breuer, Josy] Bayer Schering Pharma AG, Berlin, Germany. RP Raman, SS (reprint author), Univ Calif Los Angeles, Dept Radiol Sci, 10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM sraman@mednet.ucla.edu OI Bluemke, David/0000-0002-8323-8086 FU Bayer Schering Pharma AG, Berlin, Germany FX Funding of this study and its editorial support were received from and sponsored by Bayer Schering Pharma AG, Berlin, Germany. NR 29 TC 39 Z9 42 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD MAR-APR PY 2010 VL 34 IS 2 BP 163 EP 172 DI 10.1097/RCT.0b013e3181c89d87 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 581BS UT WOS:000276496600001 PM 20351497 ER PT J AU Prakash, P Kalra, MK Digumarthy, SR Shepard, JAO AF Prakash, Priyanka Kalra, Mannudeep K. Digumarthy, Subba R. Shepard, Jo-Anne O. TI Alterations of Anatomic Relationships on Chest Computed Tomography as a Function of Arm Position SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE shoulder position; arm position; chest CT ID CT AB Purpose: To determine the effects of arm position on the appearance of structures in the upper chest as seen on computed tomography (CT), such as clavicular angle, course of axillary vessels, pectoralis major muscle, and bicipital groove. Materials and Methods: The study consisted of 52 chest CT examinations (32 from men and 20 from women; mean [SD] age, 64 [20] years) performed with 1 or both arms at or above the shoulder (n = 44 arms) or by the side of the body ( n = 60 arms). Three chest radiologists assessed randomized CT examinations for specific anatomical structures including orientation of the bicipital groove of the humerus, appearance of the pectoralis major muscle, and the course of the axillary vessels. Orientation of the clavicle and the scapula were assessed by measuring their angles with the mid-sagittal plane. Data were analyzed using the Student t test. Results: There was a significant difference in the mean angle of the clavicles with the mid-sagittal plane in arms at or above the shoulder level (41.3 +/- 11.7 degrees) compared with arms-by-side position (54.8 +/- 14.7 degrees; P < 0.0001), but no significant difference was found in scapular angles (P = 0.4). All 3 radiologists found anteriorly directed bicipital groove, flat pectoralis major, and straight course of the axillary vessels from the chest to the axilla when arms were by the side. With arms at or above the level of the shoulder, however, the bicipital groove was directed posteromedially, the pectoralis major was buckled, and the axillary vessels had an angulated course. Conclusion: The bicipital groove, the pectoralis muscles, the axillary vessels, or the angle of the clavicle with the mid-sagittal plane on transverse CT images can help predict the position of the arms in patients undergoing chest CT. C1 [Kalra, Mannudeep K.] Massachusetts Gen Hosp, Dept Radiol, Div Thorac Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kalra, MK (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Thorac Radiol, 25 New Chardon St, Boston, MA 02114 USA. EM mkalra@partners.org NR 4 TC 0 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD MAR-APR PY 2010 VL 34 IS 2 BP 285 EP 289 DI 10.1097/RCT.0b013e3181bc05c0 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 581BS UT WOS:000276496600026 PM 20351522 ER PT J AU DeMambro, VE Kawai, M Clemens, TL Fulzele, K Maynard, JA de Evsikova, CM Johnson, KR Canalis, E Beamer, WG Rosen, CJ Donahue, LR AF DeMambro, Victoria E. Kawai, Masanobu Clemens, Thomas L. Fulzele, Keertik Maynard, Jane A. de Evsikova, Caralina Marin Johnson, Kenneth R. Canalis, Ernesto Beamer, Wesley G. Rosen, Clifford J. Donahue, Leah Rae TI A novel spontaneous mutation of Irs1 in mice results in hyperinsulinemia, reduced growth, low bone mass and impaired adipogenesis SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID INSULIN-RECEPTOR SUBSTRATE-1; DIFFERENT GENETIC BACKGROUNDS; DEPENDENT DIABETES-MELLITUS; FACTOR-I GENE; POSTNATAL-GROWTH; TRANSGENIC MICE; INNER-EAR; IGF-I; HORMONE-RECEPTOR; BODY-COMPOSITION AB A spontaneous mouse mutant, designated 'small' (sml), was recognized by reduced body size suggesting a defect in the IGF1/GH axis. The mutation was mapped to the chromosome 1 region containing Irs1, a viable candidate gene whose sequence revealed a single nucleotide deletion resulting in a premature stop codon. Despite normal mRNA levels in mutant and control littermate livers, western blot analysis revealed no detectable protein in mutant liver lysates. When compared with the control littermates, Irs1(sml)/Irs1(sml) (Irs1(sml/sml)) mice were small, lean, hearing impaired; had 20% less serum IGF1; were hyperinsulinemic; and were mildly insulin resistant. Irs1(sml/sml) mice had low bone mineral density, reduced trabecular and cortical thicknesses, and low bone formation rates, while osteoblast and osteoclast numbers were increased in the females but not different in the males compared with the Irs1(+/+) controls. In vitro, Irs1(sml/sml) bone marrow stromal cell cultures showed decreased alkaline phosphatase-positive colony forming units (pre-osteoblasts; CFU-AP+) and normal numbers of tartrate-resistant acid phosphatase-positive osteoclasts. Irs1(sml/sml) stromal cells treated with IGF1 exhibited a 50% decrease in AKT phosphorylation, indicative of defective downstream signaling. Similarities between engineered knockouts and the spontaneous mutation of Irs1(sml) were identified as well as significant differences with respect to heterozygosity and gender. In sum, we have identified a spontaneous mutation in the Irs1 gene associated with a major skeletal phenotype. Changes in the heterozygous Irs1(+/sml) mice raise the possibility that similar mutations in humans are associated with short stature or osteoporosis. Journal of Endocrinology (2010) 204, 241-253 C1 [DeMambro, Victoria E.; Maynard, Jane A.; de Evsikova, Caralina Marin; Johnson, Kenneth R.; Beamer, Wesley G.; Donahue, Leah Rae] Jackson Lab, Bar Harbor, ME 04609 USA. [Kawai, Masanobu; Rosen, Clifford J.] Res Inst, Med Ctr, Scarborough, ME 04074 USA. [Clemens, Thomas L.] Johns Hopkins Univ, Baltimore, MD 21287 USA. [Fulzele, Keertik] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Canalis, Ernesto] St Francis Hosp & Med Ctr, Dept Res, Hartford, CT 06105 USA. RP DeMambro, VE (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM victoria.demambro@yahoo.com RI Marin de Evsikova, Caralina/G-8189-2012 FU National Institute of Heath [RR01183, ARMYLRD, DK042424, DK073267, AR46544, AR043618] FX This work was supported by the National Institute of Heath (grants: RR01183, ARMYLRD, DK042424, DK073267, AR46544, and AR043618). NR 63 TC 15 Z9 15 U1 0 U2 2 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 EI 1479-6805 J9 J ENDOCRINOL JI J. Endocrinol. PD MAR PY 2010 VL 204 IS 3 BP 241 EP 253 DI 10.1677/JOE-09-0328 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 568ND UT WOS:000275528200003 PM 20032200 ER PT J AU Chen, DCR Pahilan, ME Orlander, JD AF Chen, Daniel C. R. Pahilan, M. Elaine Orlander, Jay D. TI Comparing a Self-Administered Measure of Empathy with Observed Behavior Among Medical Students SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE empathy; JSPE; OSCE ID ENABLEMENT; DECLINE; DOCTOR; SCHOOL AB PURPOSE: Studies show that measures of physician and medical students' empathy decline with clinical training. Presently, there are limited data relating self-reported measures to observed behavior. This study explores a self-reported measure and observed empathy in medical students. METHOD: Students in the Class of 2009, at a university-based medical school, were surveyed at the end of their 2nd and 3rd year. Students completed the Jefferson Scale of Physician Empathy-Student Version (JSPE-S), a self-administered scale, and were evaluated for demonstrated empathic behavior during Objective Structured Clinical Examinations (OSCEs). RESULTS: 97.6% and 98.1% of eligible students participated in their 2nd and 3rd year, respectively. The overall correlation between the JSPE-S and OSCE empathy scores was 0.22, p < 0.0001. Students had higher self-reported JSPE-S scores in their 2nd year compared to their 3rd year (118.63 vs. 116.08, p < 0.0001), but had lower observed empathy scores (3.96 vs. 4.15, p < 0.0001). CONCLUSIONS: Empathy measured by a self-administered scale decreased, whereas observed empathy increased among medical students with more medical training. C1 [Chen, Daniel C. R.; Orlander, Jay D.] Boston Univ, Sch Med, Evans Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Pahilan, M. Elaine] Boston Univ, Sch Med, Off Med Educ, Boston, MA 02118 USA. [Orlander, Jay D.] VA Boston Healthcare Syst, Med Serv, Boston, MA USA. RP Chen, DCR (reprint author), Boston Univ, Sch Med, Evans Dept Med, Gen Internal Med Sect, 801 Massachusetts Ave,2nd Floor, Boston, MA 02118 USA. EM daniel.chen@bmc.org OI Chen, Daniel/0000-0001-6672-6814; Orlander, Jay/0000-0003-0204-8449 NR 20 TC 16 Z9 21 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAR PY 2010 VL 25 IS 3 BP 200 EP 202 DI 10.1007/s11606-009-1193-4 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 574SS UT WOS:000276014300006 PM 20013070 ER PT J AU Souer, JS Ring, D Matschke, S Audige, L Maren-Hubert, M Jupiter, J AF Souer, J. Sebastiaan Ring, David Matschke, Stefan Audige, Laurent Maren-Hubert, Marta Jupiter, Jesse TI Comparison of Functional Outcome After Volar Plate Fixation With 2.4-mm Titanium Versus 3.5-mm Stainless-Steel Plate for Extra-Articular Fracture of Distal Radius SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Distal radius fracture; open reduction and internal fixation; plate and screws; outcome ID INTERNAL-FIXATION; COMPLICATIONS; BIOMECHANICS; COMPRESSION; REDUCTION; DESIGN; ADULTS AB Purpose Open reduction and locked volar plate and screw fixation is a popular treatment method for extra-articular distal radius fractures with dorsal metaphyseal comminution. In this study, we compared the use of a titanium 2.4-mm precontoured plate with that of a stainless-steel oblique 3.5-mm T-shaped plate to test the null hypothesis that there would be no difference in wrist function or upper extremity specific health status in the internal fixation of AO-type A3.2 distal radius fractures. Methods We retrospectively analyzed 24 patients treated with a 2.4-mm titanium plate and 38 patients treated with a 3.5-mm stainless-steel plate for an extra-articular and dorsally angulated distal radius fracture, from data gathered in a prospective cohort study of plate and screw fixation of distal radius fractures. The 2 cohorts were analyzed for differences in motion, grip strength, pain. Gartland and Werley score, Disabilities of the Arm, Shoulder, and Hand score, and Short Form-36 score at 6, 12, and 24 months of follow-up. Group differences and their change over time were determined using regression analysis and the likelihood ratio test. Results There were no significant differences in wrist function and arm-specific health status between patients treated with a 2.4-mm plate and those treated with a 3.5-mm plate at 6, 12, or 24 months of follow-up. However, we observed a trend toward greater wrist flexion at 1 year (66 degrees vs 55 degrees; p=.07) and greater flexion extension arc (137 degrees vs 123 degrees; p=.08) and pronation supination arc (172 degrees vs 160 degrees; p=.07) at 24 months after surgery in patients treated with a 2.4-mm plate. Conclusions Patients with a dorsally angulated extra-articular distal radius facture can expect similar results when treated with either a precontoured 2.4-mm titanium plate or a 3.5-mm stainless-steel T-shaped plate. (J Hand Surg 2010;35A:398-405. (C) 2010 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand.) C1 [Ring, David] Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Yawkey Ctr 2100 2C, Boston, MA 02114 USA. BG Unfallklin, Ludwigshafen, Germany. [Maren-Hubert, Marta] AO Clin Invest & Documentat, Dubendorf, Switzerland. RP Ring, D (reprint author), Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Yawkey Ctr 2100 2C, 55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org RI AOCID, AO Foundation/R-6455-2016 FU Arbeitsgemeinschaft fur Osteosynthesefragen Center for Investigation and Documentation; Small Bone Innovations; Smith and Nephew; Wright Medical; Acumed; Tornier FX The study was supported by the Arbeitsgemeinschaft fur Osteosynthesefragen Center for Investigation and Documentation. D.R. received unrestricted research grants from Small Bone Innovations, Smith and Nephew, Wright Medical, Acumed, and Tornier. D.R. received royalties from Hand Innovation and is a paid consultant for Smith and Nephew, Wright Medical, Acumed, and Tornier. NR 24 TC 12 Z9 15 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD MAR PY 2010 VL 35A IS 3 BP 398 EP 405 DI 10.1016/j.jhsa.2009.11.023 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 588SB UT WOS:000277092800006 PM 20138716 ER PT J AU Guitton, TG van der Werf, HJ Ring, D AF Guitton, Thierry G. van der Werf, Huub J. Ring, David TI Quantitative Measurements of the Volume and Surface Area of the Radial Head SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Computed tomography; morphology; predict; quantitative; radial head ID MORPHOMETRIC PARAMETERS; SEX DETERMINATION; PROSTHESIS; MORPHOLOGY; DESIGN; NECK; BONE; ARM AB Purpose We investigated the hypothesis that a quantitative 3-dimensional computed tomography (Q3DCT) modeling technique based on anatomical and demographic data that can measure size, shape, and proximal articular surface area can be used to develop formulas that could predict the volume and proximal surface area of the intact radial head in patients with fractures of the radial head. Methods We used a consecutive series of 50 computed tomography scans with a slice thickness of 1.25 mm or less obtained in patients with fracture of the distal humerus, but no injury to the radial head, to create 3-dimensional models. The volume and proximal articular surface area of the radial head were measured, and predictive formulas based on anatomical measurements and gender were calculated using multiple linear regression. Results There were significant correlations between total radial head volume and proximal radial head articular surface area for height, weight, radial head diameter, radial neck diameter, coronoid diameter, and gender. Multiple linear regression modeling resulted in formulas that could account for 89% of the variation in radial head volume and 75% of the variation in proximal articular surface area. Conclusions The volume and proximal articular surface area of the radial head can be estimated based on anatomical measurements and gender. This may lead to better estimates of lost fragments when it is not possible to directly model the fractured radial head and computed tomography scan of the opposite limb is not available. (J Hand Surg 2010:35A:457-463. (C) 2010 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand.) C1 [Ring, David] Harvard Univ, Yawkey Ctr, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv,Med Sch, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Yawkey Ctr, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv,Med Sch, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org OI Guitton, Thierry/0000-0002-2599-1985 FU Acumed LLC; Biomet; Small Bone Innovations; Smith Nephew; Tornier; Wright Medical Technology Inc. FX D.R. received support from Acumed LLC, Biomet, Small Bone Innovations, Smith & Nephew, Tornier, and Wright Medical Technology Inc. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. NR 22 TC 15 Z9 16 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 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD MAR PY 2010 VL 35A IS 3 BP 457 EP 463 DI 10.1016/j.jhsa.2009.11.021 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 588SB UT WOS:000277092800016 PM 20133087 ER PT J AU Guitton, TG Ring, D AF Guitton, Thierry G. Ring, David TI Nonsurgically Treated Terrible Triad Injuries of the Elbow: Report of Four Cases SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Dislocations; elbow; nonsurgical; terrible triad ID RADIAL HEAD; FRACTURES; DISLOCATIONS AB This case series describes 4 patients with terrible triad injury of the elbow (dislocation with fractures of the radial head and coronoid) who were treated nonsurgically. Following nonsurgical treatment in this select group of patients, the elbow was well aligned, and the patients regained good elbow function. Three of these 4 patients had good results. One patient had surgery for residual stiffness, ulnar neuropathy, and a radial head deformity. We conclude that, in selected terrible triad cases, when the elbow is well aligned and the radial head and coronoid fractures are relatively small and minimally displaced after closed reduction and there is no mechanical block to motion, patients might regain good elbow function without surgery. (J Hand Surg 2010;35A:464-467.(C) 2010 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand.) C1 [Ring, David] Harvard Univ, Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv,Med Sch, Boston, MA 02114 USA. RP Ring, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Yawkey Ctr, Orthopaed Hand & Upper Extrem Serv,Med Sch, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org OI Guitton, Thierry/0000-0002-2599-1985 FU Small Bone Innovations; Wright Medical; Stichting Anna Fonds; Stichting Wetenschappelijk Ondernek Orthopaedisch Chirurgie; VSB Fonds; Smith and Nephew; Acumed; Tornier FX Funding was received from Small Bone Innovations (DR.), Wright Medical (DR.), Stichting Anna Fonds (T.G.G.),Stichting Wetenschappelijk Ondernek Orthopaedisch Chirurgie (T.G.G.), VSB Fonds (T.G.G.), Smith and Nephew (D.R.), Acumed (DA.), and Tornier (DA.). NR 13 TC 6 Z9 13 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 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD MAR PY 2010 VL 35A IS 3 BP 464 EP 467 DI 10.1016/j.jhsa.2009.12.015 PG 4 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 588SB UT WOS:000277092800017 PM 20193862 ER PT J AU Ring, D AF Ring, David TI More Experiments SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkee Ctr, Boston, MA 02114 USA. RP Ring, D (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Yawkee Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD MAR PY 2010 VL 35A IS 3 BP 473 EP 473 DI 10.1016/j.jhsa.2009.12.030 PG 1 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 588SB UT WOS:000277092800019 PM 20193864 ER PT J AU Lindenhovius, A Ring, D AF Lindenhovius, Anneluuk Ring, David TI Two-Dimensional Versus Three-Dimensional Computed Tomography Reply SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Letter C1 [Lindenhovius, Anneluuk; Ring, David] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Lindenhovius, A (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD MAR PY 2010 VL 35A IS 3 BP 513 EP 514 DI 10.1016/j.jhsa.2009.11.024 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 588SB UT WOS:000277092800031 ER PT J AU Corrigan, JD Selassie, AW Orman, JA AF Corrigan, John D. Selassie, Anbesaw W. Orman, Jean A. (Langlois) TI The Epidemiology of Traumatic Brain Injury SO JOURNAL OF HEAD TRAUMA REHABILITATION LA English DT Article DE craniocerebral trauma; epidemiology; traumatic brain injury ID TBI IDENTIFICATION METHOD; LONG-TERM DISABILITY; BIRTH COHORT; HEAD-INJURY; UNITED-STATES; PSYCHIATRIC-SYMPTOMS; NORTHERN FINLAND; SUBSTANCE-ABUSE; HOMELESS MEN; YOUNG-ADULTS AB Objective: To describe the most recent estimates of the incidence and prevalence of traumatic brain injury (TBI) and review current issues related to measurement and use of these data. Design: State of the science literature for the United States and abroad was analyzed and issues were identified for (1) incidence of TBI, (2) prevalence of lifetime history of TBI, and (3) incidence and prevalence of disability associated with TBI. Results: The most recent estimates indicate that each year 235 000 Americans are hospitalized for nonfatal TBI, 1.1 million are treated in emergency departments, and 50 000 die. The northern Finland birth cohort found that 3.8% of the population had experienced at least 1 hospitalization due to TBI by 35 years of age. The Christchurch New Zealand birth cohort found that by 25 years of age 31.6% of the population had experienced at least 1 TBI, requiring medical attention (hospitalization, emergency department, or physician office). An estimated 43.3% of Americans have residual disability 1 year after injury. The most recent estimate of the prevalence of US civilian residents living with disability following hospitalization with TBI is 3.2 million. Conclusion: Estimates of the incidence and prevalence of TBI are based on varying sources of data, methods of calculation, and assumptions. Informed users should be cognizant of the limitations of these estimates when determining their applicability. C1 [Corrigan, John D.] Ohio State Univ, Dept Phys Med & Rehabil, Columbus, OH 43210 USA. [Selassie, Anbesaw W.] Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29425 USA. [Orman, Jean A. (Langlois)] Res & Dev Serv, US Dept Vet Affairs, Washington, DC USA. RP Corrigan, JD (reprint author), Ohio State Univ, Dept Phys Med & Rehabil, 480 Med Ctr Dr, Columbus, OH 43210 USA. EM corrigan.1@osu.edu RI Corrigan, John/E-2921-2011 FU Department of Education, National Institute on Disability and Rehabilitation Research [H133A070029] FX The contents of this article were developed under the grant from the Department of Education, National Institute on Disability and Rehabilitation Research (grant H133A070029 [Corrigan]). NR 51 TC 261 Z9 272 U1 7 U2 51 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-9701 J9 J HEAD TRAUMA REHAB JI J. Head Trauma Rehabil. PD MAR-APR PY 2010 VL 25 IS 2 BP 72 EP 80 DI 10.1097/HTR.0b013e3181ccc8b4 PG 9 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 578EJ UT WOS:000276276000002 PM 20234226 ER PT J AU Ayotte, BJ Margrett, JA Hicks-Patrick, J AF Ayotte, Brian J. Margrett, Jennifer A. Hicks-Patrick, Julie TI Physical Activity in Middle-aged and Young-old Adults The Roles of Self-efficacy, Barriers, Outcome Expectancies, Self-regulatory Behaviors and Social Support SO JOURNAL OF HEALTH PSYCHOLOGY LA English DT Article DE middle age; physical activity; social cognitive theory; young-old adults ID HEALTH-PROMOTION; COGNITIVE THEORY; EXERCISE; INTERVENTIONS; DETERMINANTS; REHABILITATION; PARTICIPANTS; EXPECTATIONS; MAINTENANCE; MODELS AB This study tests the associations of self-efficacy, outcome expectancies, perceived barriers, self-regulatory behaviors and social support with physical activity. Data from 116 married community-dwelling middle-aged and young-old couples (M = 58.86 years, SD = 7.16, range = 50 to 75) were collected via mail-in survey. The model indicated that self-efficacy was directly and indirectly related to physical activity through outcome expectancies, perceived barriers and self-regulatory behaviors. The results clarify the associations among the social cognitive constructs and physical activity, and suggest that interventions targeting multiple social cognitive constructs could increase the activity levels of middle-aged and young-old adults. C1 [Ayotte, Brian J.] VA Boston Healthcare Syst, Boston, MA USA. [Margrett, Jennifer A.] Iowa State Univ, Ames, IA USA. [Hicks-Patrick, Julie] W Virginia Univ, Life Span Dev Psychol Program, Morgantown, WV 26506 USA. RP Ayotte, BJ (reprint author), VA Med Ctr 152, Ctr Hlth Serv Res Primary Care, 508 Fulton St, Durham, NC 27705 USA. EM brian.ayotte@va.gov OI Su, Yan/0000-0001-9602-7969; Margrett, Jennifer/0000-0003-0628-5660 NR 43 TC 46 Z9 46 U1 6 U2 37 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1359-1053 J9 J HEALTH PSYCHOL JI J. Health Psychol. PD MAR PY 2010 VL 15 IS 2 BP 173 EP 185 DI 10.1177/1359105309342283 PG 13 WC Psychology, Clinical SC Psychology GA 564RG UT WOS:000275233400002 PM 20207661 ER PT J AU LeGuern, C Akiyama, Y Germana, S Tanaka, K Fernandez, L Iwamoto, Y Houser, S Benichou, G AF LeGuern, Christian Akiyama, Yoshinobu Germana, Sharon Tanaka, Katsunori Fernandez, Luis Iwamoto, Yoshiko Houser, Stuart Benichou, Gilles TI Intracellular MHC Class II Controls Regulatory Tolerance to Allogeneic Transplants SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; TRANSGENIC SKIN-GRAFTS; BONE-MARROW-CELLS; T-CELLS; IMMUNE-RESPONSE; GENETIC-CONTROL; NEGATIVE SELECTION; RETROVIRUS VECTOR; CHRONIC REJECTION; EFFECTOR FUNCTION AB MHC class II (MHCII) genes have been implicated in the regulation of T lymphocyte responses. However, the mechanism of MHCII-driven regulation remains unknown. Matching for MHCII between donors and recipients of allografts favors regulatory T cell tolerance to transplants and provides a unique opportunity to study this regulation. In this study, we investigated MHCII regulation using transfer of donor MHCII genes in recipients of cardiac allografts. Transfer of MHCII IA(b) genes in the bone marrow of CBA mice (H-2(k)) prior to the grafting of IA(b+) fully allogeneic C57BL/6 (B6, H-2(b)) heart transplants resulted in donor-specific tolerance associated with long-term survival of 136, but not third-party, allografts without sustained immunosuppression. Strikingly, the majority of accepted heart transplants (>170 d) were devoid of allograft vasculopathy. Further studies indicated that intracellular IA(b) initiated the tolerogenic process, which was mediated by regulatory T cells (Tregs) that polarized antigraft responses to Th2 cytokine producers. This mechanism seems to be unique to MHCII genes, because previous MHC class I gene-based therapies failed to produce Tregs. These results demonstrate the key role of MHCII in the induction of Tregs. They also underscore a potential mechanism of specific inactivation of T cells in this model; when activated by IA(b+) grafts, IA(b)-specific Tregs repress the entire alloresponse to C57BL/6 transplants (including MHC I and minor Ags), thus mediating T cell tolerance. The Journal of Immunology, 2010, 184: 2394-2400. C1 [LeGuern, Christian; Germana, Sharon; Fernandez, Luis] Harvard Univ, Mol Biol Lab, Transplantat Biol Res Ctr, Massachusetts Gen Hosp,Sch Med, Boston, MA 02129 USA. [Akiyama, Yoshinobu; Tanaka, Katsunori; Iwamoto, Yoshiko; Benichou, Gilles] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Dept Surg, Cellular & Mol Immunol Lab,Transplant Unit, Boston, MA 02129 USA. [Houser, Stuart] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02129 USA. RP LeGuern, C (reprint author), Harvard Univ, Mol Biol Lab, Transplantat Biol Res Ctr, Massachusetts Gen Hosp,Sch Med, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. EM christian.leguern@tbrc.mgh.harvard.edu FU National Institutes of Health [R01EY13310, R01AI063408]; American Society of Transplantation FX This work was supported by National Institutes of Health Grants R01EY13310 (to G.B.) and R01AI063408 (to C.L.). Y.A. was the recipient of a Sangstat fellowship from the American Society of Transplantation. NR 47 TC 13 Z9 13 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 MAR 1 PY 2010 VL 184 IS 5 BP 2394 EP 2400 DI 10.4049/jimmunol.0803664 PG 7 WC Immunology SC Immunology GA 558TG UT WOS:000274768900022 PM 20100928 ER PT J AU Paredes, R Lalama, CM Ribaudo, HJ Schackman, BR Shikuma, C Giguel, F Meyer, WA Johnson, VA Fiscus, SA D'Aquila, RT Gulick, RM Kuritzkes, DR AF Paredes, Roger Lalama, Christina M. Ribaudo, Heather J. Schackman, Bruce R. Shikuma, Cecilia Giguel, Francoise Meyer, William A., III Johnson, Victoria A. Fiscus, Susan A. D'Aquila, Richard T. Gulick, Roy M. Kuritzkes, Daniel R. CA ACTG TI Pre-existing Minority Drug-Resistant HIV-1 Variants, Adherence, and Risk of Antiretroviral Treatment Failure SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE INHIBITORS; EFAVIRENZ-CONTAINING REGIMENS; SOCIETY-USA PANEL; VIROLOGICAL FAILURE; 2008 RECOMMENDATIONS; PROTEASE INHIBITORS; INFECTED PATIENTS; RANDOMIZED-TRIAL; CLINICAL-TRIALS AB Background. The clinical relevance of detecting minority drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is uncertain. Methods. To determine the effect of pre-existing minority nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistant variants on the risk of virologic failure, we reanalyzed a case-cohort substudy of efavirenz recipients in AIDS Clinical Trials Group protocol A5095. Minority K103N or Y181C populations were determined by allele-specific polymerase chain reaction in subjects without NNRTI resistance by population sequencing. Weighted Cox proportional hazards models adjusted for recent treatment adherence estimated the relative risk of virologic failure in the presence of NNRTI-resistant minority variants. Results. The evaluable case-cohort sample included 195 subjects from the randomly selected subcohort (51 with virologic failure, 144 without virologic failure), plus 127 of the remaining subjects who experienced virologic failure. Presence of minority K103N or Y181C mutations, or both, was detected in 8 (4.4%), 54 (29.5%), and 11 (6%), respectively, of 183 evaluable subjects in the random subcohort. Detection of minority Y181C mutants was associated with an increased risk of virologic failure in the setting of recent treatment adherence (hazard ratio, 3.45 [95% confidence interval, 1.90-6.26]) but not in nonadherent subjects (hazard ratio, 1.39 [95% confidence interval, 0.58-3.29]). Of note, 70% of subjects with minority Y181C variants achieved long-term viral suppression. Conclusions. In adherent patients, pre-existing minority Y181C mutants more than tripled the risk of virologic failure of first-line efavirenz-based antiretroviral therapy. C1 [Paredes, Roger; Giguel, Francoise; Kuritzkes, Daniel R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Lalama, Christina M.; Ribaudo, Heather J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Paredes, Roger] Univ Autonoma Barcelona, Hosp Univ Germans Trias & Pujol, Fdn IrsiCaixa & Lluita SIDA, Badalona, Catalonia, Spain. [Schackman, Bruce R.; Gulick, Roy M.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Shikuma, Cecilia] Univ Hawaii, Honolulu, HI 96822 USA. [Meyer, William A., III] Quest Diagnost, Baltimore, MD USA. [Johnson, Victoria A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Johnson, Victoria A.] Univ Alabama, Sch Med, Birmingham, AL USA. [Fiscus, Susan A.] Univ N Carolina, Chapel Hill, NC USA. [D'Aquila, Richard T.] Vanderbilt Univ, Nashville, TN USA. RP Kuritzkes, DR (reprint author), Brigham & Womens Hosp, Sect Retroviral Therapeut, 65 Landsdowne St,Rm 449, Cambridge, MA 02139 USA. EM dkuritzkes@partners.org FU NCRR NIH HHS [RR024996, UL1 RR024996, UL1 RR024996-01]; NIAID NIH HHS [AI060354, AI069452, AI069472, AI38858, AI50410, K24 AI051966, K24 AI051966-07, P30 AI027767, P30 AI027767-099003, U01 AI038858, U01 AI038858-05, U01 AI068636-04S1, U01 AI069452, U01 AI069452-01, U01 AI069472, UM1 AI068636, UM1 AI069419, P30 AI050410, AI027767, AI051966, AI06836, AI068636, AI069419, P30 AI050410-099003, P30 AI060354, P30 AI060354-019003, U01 AI068636, U01 AI069419, U01 AI069419-03, UM1 AI069452, UM1 AI069472, U01 AI069472-01] NR 35 TC 114 Z9 115 U1 0 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 1 PY 2010 VL 201 IS 5 BP 662 EP 671 DI 10.1086/650543 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 552MW UT WOS:000274296600007 PM 20102271 ER PT J AU Sherman, KE Rouster, SD Stanford, S Blackard, JT Shire, N Koziel, M Peters, M Chung, RT AF Sherman, Kenneth E. Rouster, Susan D. Stanford, Sandra Blackard, Jason T. Shire, Norah Koziel, Margaret Peters, Marion Chung, Raymond T. CA AIDS Clinical Trials Grp 5071 Stud TI Hepatitis C Virus (HCV) Quasispecies Complexity and Selection in HCV/HIV-Coinfected Subjects Treated with Interferon-Based Regimens SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ALPHA-2A PLUS RIBAVIRIN; HIV-INFECTED PATIENTS; STAGE LIVER-DISEASE; COMBINATION THERAPY; VARIABILITY; MORTALITY; EVOLUTION; PREDICT AB Background. Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) has emerged as a major cause of morbidity and mortality due to liver disease. Interferon-based therapy response rates have been disappointingly low. Baseline HCV complexity and the relationship between complexity and viral kinetic parameters has not been well described in HCV/HIV-coinfected subjects. Methods. A subset of patients enrolled in the AIDS Clinical Trials Group 5071 trial underwent sampling to evaluate viral kinetics and changes in HCV complexity. Early kinetic parameters, baseline complexity, and treatment outcomes-including rapid viral response (RVR), early viral response (EVR), and sustained viral response (SVR) were evaluated. HCV-monoinfected subjects were matched to HCV/HIV-coinfected subjects. Results. Baseline complexity was determined in 108 HCV/HIV-coinfected subjects and in 13 HCV-monoinfected control subjects. Quasispecies complexity was a mean of 2.24 bands for HCV/HIV-coinfected subjects and a mean of 1.90 bands for HCV-monoinfected subjects (P = .14). Lower baseline complexity was associated with EVR (P = .04) and approached statistical significance for SVR. In patients who underwent viral kinetic modeling, a decrease in complexity was associated with RVR (P = .03) and was independent of the correlation between first-phase viral decline efficiency and RVR. Conclusion. Baseline HCV complexity is an independent predictor of EVR in HCV/HIV-coinfected subjects. A decrease in complexity occurs by 4 weeks after the initiation of interferon-based therapy and is associated with RVR. These findings may enhance the predictive modeling of treatment outcome in HCV/HIV-coinfected patients. C1 [Sherman, Kenneth E.] Univ Cincinnati, Coll Med, Div Digest Dis, Cincinnati, OH 45267 USA. [Shire, Norah] Merck & Co Inc, Infect Dis Epidemiol, N Wales, PA USA. [Koziel, Margaret] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Chung, Raymond T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Peters, Marion] Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. RP Sherman, KE (reprint author), Univ Cincinnati, Coll Med, Div Digest Dis, 231 Albert Sabin Way, Cincinnati, OH 45267 USA. EM Kenneth.sherman@uc.edu FU National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group [AI25897, AI068636, U01 AI38858]; National Institute of Diabetes and Digestive and Kidney Diseases [K24 DK070528] FX Financial support: National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group (grants AI25897, AI068636, and U01 AI38858); National Institute of Diabetes and Digestive and Kidney Diseases (award K24 DK070528 to K. E. S.). Roche Laboratories provided study drug and hepatitis C virus RNA monitoring kits. NR 24 TC 14 Z9 14 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 1 PY 2010 VL 201 IS 5 BP 712 EP 719 DI 10.1086/650490 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 552MW UT WOS:000274296600012 PM 20105080 ER PT J AU Spentzou, A Bergin, P Gill, D Cheeseman, H Ashraf, A Kaltsidis, H Cashin-Cox, M Anjarwalla, I Steel, A Higgs, C Pozniak, A Piechocka-Trocha, A Wong, J Anzala, O Karita, E Dally, L Gotch, F Walker, B Gilmour, J Hayes, P AF Spentzou, Aggeliki Bergin, Philip Gill, Dilbinder Cheeseman, Hannah Ashraf, Ambreen Kaltsidis, Harry Cashin-Cox, Michelle Anjarwalla, Insiyah Steel, Alan Higgs, Christopher Pozniak, Anton Piechocka-Trocha, Alicja Wong, Johnson Anzala, Omu Karita, Etienne Dally, Len Gotch, Frances Walker, Bruce Gilmour, Jill Hayes, Peter TI Viral Inhibition Assay: A CD8 T Cell Neutralization Assay for Use in Clinical Trials of HIV-1 Vaccine Candidates SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; IMMUNOGENICITY EVALUATION; UNINFECTED INDIVIDUALS; LYMPHOCYTE ACTIVITY; PHASE-1 SAFETY; INFECTED CELLS; REPLICATION; RESPONSES; IMMUNITY; ESCAPE AB We have characterized an assay measuring CD8 T cell-mediated inhibition of human immunodeficiency virus (HIV) type 1 replication, demonstrating specificity and reproducibility and employing a panel of primary HIV-1 isolates. The assay uses relatively simple autologous cell culture and enzyme-linked immunosorbent assay, avoids generation of T cell clones, and can be performed with <2 million peripheral blood mononuclear cells. Efficient CD8 T cell-mediated cross-clade inhibition of HIV-1 replication in vitro was demonstrated in antiretroviral therapy-naive HIV-1-infected subjects with controlled viral replication in vivo but not in viremic subjects. An HIV-1 vaccine candidate, consisting of DNA and recombinant adenovirus 5 vectors tested in a phase I clinical trial, induced CD8 T cells that efficiently inhibited HIV-1 in a HLA-I-dependent manner. Assessment of direct antiviral T cell function by this assay provides additional information to guide vaccine design and the prioritizing of candidates for further clinical trials. C1 [Spentzou, Aggeliki; Bergin, Philip; Gill, Dilbinder; Cheeseman, Hannah; Ashraf, Ambreen; Kaltsidis, Harry; Cashin-Cox, Michelle; Anjarwalla, Insiyah; Gotch, Frances; Gilmour, Jill; Hayes, Peter] Univ London Imperial Coll Sci Technol & Med, Human Immunol Lab, Int AIDS Vaccine Initiat, London, England. [Steel, Alan; Higgs, Christopher; Pozniak, Anton] Chelsea & Westminster Hosp, London, England. [Piechocka-Trocha, Alicja; Walker, Bruce] MIT & Harvard, Ragon Inst MGH, Boston, MA USA. [Wong, Johnson] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dally, Len] EMMES Corp, Rockville, MD USA. [Anzala, Omu] Univ Nairobi, Kenya AIDS Vaccine Initiat, Nairobi, Kenya. [Karita, Etienne] Projet San Francisco, Kigali, Rwanda. RP Hayes, P (reprint author), St Stephens Ctr, Int AIDS Vaccine Initiat Labs, 5th Floor,369 Fulham Rd, London SW10 9NH, England. EM p.hayes@imperial.ac.uk OI Bergin, Philip/0000-0001-5522-8350; Cashin-Cox, Michelle/0000-0002-7501-9203 FU International AIDS Vaccine Initiative; United States Agency FX Financial support: International AIDS Vaccine Initiative and its donors, including the United States Agency for International Development. NR 41 TC 43 Z9 43 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 1 PY 2010 VL 201 IS 5 BP 720 EP 729 DI 10.1086/650492 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 552MW UT WOS:000274296600013 PM 20132004 ER PT J AU Ogilvy, CS Yang, XY Natarajan, SK Hauck, EF Sun, LN Lewis-Mason, L Hopkins, LN Siddiqui, AH Levy, EI AF Ogilvy, Christopher S. Yang, Xinyu Natarajan, Sabareesh K. Hauck, Erik F. Sun, Luona Lewis-Mason, Laura Hopkins, L. Nelson Siddiqui, Adnan H. Levy, Elad I. TI Restenosis Rates following Vertebral Artery Origin Stenting: Does Stem Type Make a Difference? SO JOURNAL OF INVASIVE CARDIOLOGY LA English DT Article DE sirolimus- and paclitaxel-eluting stents; endovascular treatment; extracranial atherosclerotic disease; vertebral artery origin stenosis; restenosis ID DRUG-ELUTING STENTS; NATIVE CORONARY-ARTERY; BARE METAL STENTS; OF-THE-LITERATURE; RANDOMIZED-TRIAL; TRANSLUMINAL ANGIOPLASTY; SINGLE-CENTER; CASE SERIES; STENOSIS; DISEASE AB Objectives. To compare our experience with sirolimus- and paclitaxel-eluting scents (drug. eluting scents [DES]) and non-drug-eluting stems (NDES) for treatment of vertebral artery (VA) origin stenosis and review the literature. Methods. A retrospective review of our prospectivey collected database was performed. Clinical and radiologic follow up was obtained by reviewing office records and radiology. Data collected included demographics: comorbidities presenting symptoms, stenosis severity, contralateral VA stenosis and/or carotid stenosis, type of stent used, angioplasty before or after stenting, post-treatment residual stenosis, clinical and radiological follow up and retreatment. Patients with symptomatic > 60% stenosis or asymptomatic > 70% stenosis and/or a hypoplastic or oc-duded contralateral VA or significant carotid occlusion were chosen for revascularization. Results. Thirty-five patients treated with NDES and 15 treated with DES for management of VA origin stenosis were identified. C1 [Ogilvy, Christopher S.; Yang, Xinyu] Massachusetts Gen Hosp, Neurovasc Serv, Boston, MA 02114 USA. [Ogilvy, Christopher S.; Natarajan, Sabareesh K.; Hauck, Erik F.; Sun, Luona; Lewis-Mason, Laura; Hopkins, L. Nelson; Siddiqui, Adnan H.; Levy, Elad I.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Neurosurg, Buffalo, NY 14260 USA. [Ogilvy, Christopher S.; Natarajan, Sabareesh K.; Hauck, Erik F.; Sun, Luona; Lewis-Mason, Laura; Hopkins, L. Nelson; Siddiqui, Adnan H.; Levy, Elad I.] SUNY Buffalo, Sch Med & Biomed Sci, Toshiba Stroke Res Ctr, Buffalo, NY 14260 USA. [Sun, Luona; Hopkins, L. Nelson; Siddiqui, Adnan H.; Levy, Elad I.] SUNY Buffalo, Sch Med & Biomed Sci, Dept Radiol, Buffalo, NY 14260 USA. [Yang, Xinyu] Tianjin Med Univ, Gen Hosp, Dept Neurosurg, Tianjin, Peoples R China. RP Ogilvy, CS (reprint author), Wang 745,55 Fruit St, Boston, MA 02114 USA. EM cogilvy@partners.org FU Abbott [ACT 1 Choice]; Boston Scientific (CABANA); Cordis (SAPPHIRE WW); ev3 (CREATE); Toshiba (for the Toshiba Stroke Research Center); AccessClosure; Boston Scientific; Micrus; Stent-Assisted Recanalization in acute Ischemic Stroke, (SARIS); Endovascular; Intratech Medical Ltd.; Mynx/Access Closure; University at Buffalo; National Institutes of Health (NINDS) [1 R0 I NS064592-01A1] 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, and Micrus; 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 SCAI; 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 Nureon 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 Neurovascular/Cordis Corporation; serves as a consultant per project and/or per hour for Micrus Endovascular, ev3, and TheraSyn Sensors, Inc.; and receives fees for carotid stent training front Abbott vascular and ev3. Dr. Levy receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr. Ogilvy serves as a consultant to Mizuho America, Dr. Siddiqui has received research grants from the University at Buffalo and from the National Institutes of Health (NINDS 1 R0 I NS064592-01A1, Hemodynamic induction of pathologic remodeling leading to intracranial aneurysms); is a consultant to Codman Neurovascular/Cordis Corporation, Concentric Medical, ev3, and Micrus Endovascular; serves on speakers' bureaus for Codman Neurovascular/Cordis Corporation and Genentech; and has received honoraria from Genentech, Neocure Group LLC, American Association of Neurological Surgeons' course, and an Emergency Medicine Conference and from Codinan Neurovascular/Cordis Corporation for training other neurointerventionists. Dr. Siddiqui receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr. Hauck, Ms. Lewis-Mason, Dr. Natarajan, Ms. Sun, and Dr. Yang have no financial relationships to disclose. NR 47 TC 25 Z9 31 U1 0 U2 1 PU H M P COMMUNICATIONS PI MALVERN PA 83 GENERAL WARREN BLVD, STE 100, MALVERN, PA 19355 USA SN 1042-3931 J9 J INVASIVE CARDIOL JI J. Invasive Cardiol. PD MAR PY 2010 VL 22 IS 3 BP 119 EP 124 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 687VZ UT WOS:000284807600008 PM 20197579 ER PT J AU Nam, EC Lewis, R Nakajima, HH Merchant, SN Levine, RA AF Nam, E-C Lewis, R. Nakajima, H. H. Merchant, S. N. Levine, R. A. TI Head rotation evoked tinnitus due to superior semicircular canal dehiscence SO JOURNAL OF LARYNGOLOGY AND OTOLOGY LA English DT Article DE Tinnitus; Semicircular Canal; Positional Vertigo AB Introduction: Superior semicircular canal dehiscence affects the auditory and vestibular systems due to a partial defect in the canal's bony wall. In most cases, sound- and pressure-induced vertigo are present, and are sometimes accompanied by pulse-synchronous tinnitus. Case presentation: We describe a 50-year-old man with superior semicircular canal dehiscence whose only complaints were head rotation induced tinnitus and autophony. Head rotation in the plane of the right semicircular canal with an angular velocity exceeding 600 degrees/second repeatedly induced a 'cricket' sound in the patient's right ear. High resolution temporal bone computed tomography changes, and an elevated umbo velocity, supported the diagnosis of superior semicircular canal dehiscence. Conclusion: In addition to pulse-synchronous or continuous tinnitus, head rotation induced tinnitus can be the only presenting symptom of superior semicircular canal dehiscence without vestibular complaints. We suggest that, in our patient, the bony defect of the superior semicircular canal ('third window') might have enhanced the flow of inner ear fluid, possibly producing tinnitus. C1 [Nam, E-C; Nakajima, H. H.; Merchant, S. N.; Levine, R. A.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Dept Otolaryngol, Boston, MA 02114 USA. [Nam, E-C] Kangwon Natl Univ, Sch Med, Dept Otolaryngol, Chunchon, South Korea. [Lewis, R.; Nakajima, H. H.; Merchant, S. N.; Levine, R. A.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Levine, R. A.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Levine, R. A.] Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. RP Levine, RA (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM Robert_Levine@MEEI.harvard.edu FU NIDCD NIH HHS [R01 DC004798, R01 DC004798-08] NR 5 TC 5 Z9 7 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0022-2151 J9 J LARYNGOL OTOL JI J. Laryngol. Otol. PD MAR PY 2010 VL 124 IS 3 BP 333 EP 335 DI 10.1017/S0022215109991241 PG 3 WC Otorhinolaryngology SC Otorhinolaryngology GA 569IF UT WOS:000275589100018 PM 19785926 ER PT J AU Divers, J Sale, MM Lu, LY Chen, WM Lok, KH Spruill, IJ Fernandes, JK Langefeld, CD Garvey, WT AF Divers, Jasmin Sale, Michele M. Lu, Lingyi Chen, Wei-Min Lok, Kerry H. Spruill, Ida J. Fernandes, Jyotika K. Langefeld, Carl D. Garvey, W. Timothy TI The genetic architecture of lipoprotein subclasses in Gullah-speaking African American families enriched for type 2 diabetes: The Sea Islands Genetic African American Registry (Project SuGAR) SO JOURNAL OF LIPID RESEARCH LA English DT Article DE linkage analysis; lipids; lipoproteins; heritability; genetic correlation ID CORONARY-ARTERY-DISEASE; GENOME-WIDE ASSOCIATION; NUCLEAR-MAGNETIC-RESONANCE; TRAIT LINKAGE ANALYSIS; ISCHEMIC-HEART-DISEASE; CARDIOVASCULAR-DISEASE; PARTICLE-SIZE; INSULIN-RESISTANCE; HDL CHOLESTEROL; MYOCARDIAL-INFARCTION AB We sought to partition the genetic and environmental influences on lipoprotein subclasses and identify genomic regions that may harbor genetic variants that influence serum lipoprotein levels in a sample of Gullah-speaking African-Americans. We genotyped 5,974 SNPs in 979 subjects from 418 pedigrees and used the variance component approach to compute heritability estimates, genetic and environmental correlations, and linkage analyses for selected lipoprotein subclasses. The highest heritability estimate was observed for large VLDL particle concentration (0.56 +/- 0.14). Mean LDL particle size and small LDL particle concentration (-0.94) had the strongest genetic correlation estimate. The highest logarithm of odds (LOD) score detected (3.0) was on chromosome 6p24 for small LDL particle concentration. The strongest signal, obtained with the reduced sample of diabetic individuals only, was observed on chromosome 20p13 for small LDL particle concentration. The highest bivariate linkage signal (LOD 2.4) was observed on chromosome 6p24 for mean LDL particle size and small LDL particle concentration.jlr Our results suggest a significant genetic contribution to multiple lipoprotein subclasses studied in this sample and that novel loci on chromosomes 6, 10, 16, and 20 may harbor genes contributing to small, atherogenic LDL particle concentration and large, triglyceride-rich VLDL particle concentration.-Divers, J., M. M. Sale, L. Lu, W-M. Chen, K. H. Lok, I. J. Spruill, J. K. Fernandes, C. D. Langefeld, and W. T. Garvey. The genetic architecture of lipoprotein subclasses in Gullah-speaking African American families enriched for type 2 diabetes: The Sea Islands Genetic African American Registry (Project SuGAR). J. Lipid Res. 2010. 51: 586-597. C1 [Divers, Jasmin; Lu, Lingyi; Langefeld, Carl D.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27106 USA. [Divers, Jasmin; Langefeld, Carl D.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC USA. [Sale, Michele M.; Chen, Wei-Min] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Sale, Michele M.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Sale, Michele M.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. [Chen, Wei-Min] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Lok, Kerry H.; Garvey, W. Timothy] Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. [Spruill, Ida J.; Fernandes, Jyotika K.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Garvey, W. Timothy] Birmingham VA Med Ctr, Birmingham, AL USA. RP Divers, J (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC 27106 USA. EM jdivers@wfubmc.edu FU W.M. Keck Foundation, Los Angeles; General Clinical Research Center at the Medical University of South Carolina [M01 RR-1070]; UAB [P30 DK-56336, P60 DK079626]; Wake Forest Health Sciences Center for Public Health Genomics; National Institutes of Health [DK47461, DK038765, DK66358, N01-HG-65403]; South Carolina Center of Biomedical Excellence (CO-BRE) for Oral Health [P20 RR17696]; American Diabetes Association FX Project SuGAR could not have been accomplished without a grant from the W.M. Keck Foundation, Los Angeles CA. We acknowledge the support of the General Clinical Research Center at the Medical University of South Carolina (M01 RR-1070), the Genetics Core Facility of the UAB Clinical Nutrition Research Unit (P30 DK-56336), and the UAB Diabetes Research and Training Center (P60 DK079626). The work was supported by the Wake Forest Health Sciences Center for Public Health Genomics (J.D. and C.D.L), research grants from the National Institutes of Health including DK47461 and DK038765 (W.T.G.), DK66358 (M.M.S.), the South Carolina Center of Biomedical Excellence (CO-BRE) for Oral Health P20 RR17696, and from the American Diabetes Association in the form of a GENNID Study Center grant (W.T.G.) and Career Development Award (M.M.S.). Center for Inherited Disease Research is funded through a federal contract from the National Institutes of Health to Johns Hopkins University, contract number N01-HG-65403. 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 79 TC 3 Z9 3 U1 1 U2 2 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 MAR PY 2010 VL 51 IS 3 BP 586 EP 597 DI 10.1194/jlr.M001842 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 555LW UT WOS:000274513300015 PM 19783527 ER PT J AU Mitha, AP Ahmad, MS Cohen, SJ Lieberman, JS Udengaard, MR Slocum, AH Coumans, JVCE AF Mitha, Alim P. Ahmad, Mohamed S. Cohen, Sarah J. Lieberman, Janet S. Udengaard, Martin R. Slocum, Alexander H. Coumans, Jean-Valery C. E. TI A Modified Footplate for the Kerrison Rongeur SO JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME LA English DT Article DE Intraoperative complication; laminectomy; spinal stenosis; spine surgery; surgical instruments ID UNINTENDED INCIDENTAL DUROTOMY; LUMBAR SPINE SURGERY; DURAL TEARS; MANAGEMENT AB Use of the Kerrison rongeur for bone removal in spinal surgery is associated with dural tears and cerebrospinal fluid (CSF) leaks. We report a modification of the Kerrison rongeur footplate designed to reduce the risk of dural tears. A novel footplate was designed by incorporating the following parameters: (1) tapering the footplate to deflect soft tissue downward during positioning of the rongeur underneath the bone, and (2) making the footplate longer and wider than the cutting element to prevent soft tissue from entering into the cutting surface. Stereolithography models of the modified footplate were made and tested in a cadaver A stainless steel modified footplate was then incorporated into an existing Kerrison rongeur as a working prototype, and tested in 20 laminectomy cases to clinically validate its design. The modified footplate prevented soft tissue from entering the cutting surface of the Kerrison rongeur in the manner intended by its design. No dural tears or CSF leaks were encountered in any instance. Potential soft tissue compression caused by an increase in footplate dimensions was not a significant issue in the rongeur size tested. This modification, however might not be practical in rongeurs larger than 3 mm. The risk of dural tears and cerebrospinal fluid leaks in spinal surgery may be reduced by this footplate modification of the Kerrison rongeur Soft tissue compression may limit the incorporation of this modification to rongeurs of 3 aim or smaller The promising results warrant further tests with a wider range of sizes. [DOI: 10.1115/1.4000594] C1 [Mitha, Alim P.; Coumans, Jean-Valery C. E.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Mitha, Alim P.; Ahmad, Mohamed S.; Cohen, Sarah J.; Lieberman, Janet S.; Udengaard, Martin R.; Slocum, Alexander H.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Coumans, JVCE (reprint author), Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. EM jcoumans@partners.org FU U.S. Army Medical Acquisition Activity (USAMRAA) [DAMD 17-02-2-0006]; Center for Integration of Medicine and Innovative Technology FX The authors would like to thank the other individuals who contributed to design reviews of this work during its development in MIT course 2.75 Precision Machine Design. We are also grateful to Massachusetts General Hospital for access to their facilities and excellent staff. The Center for Integration of Medicine and Innovative Technology (www.cimit.org) has supported this project with funding provided from the U.S. Army Medical Acquisition Activity (USAMRAA) under cooperative agreement No. DAMD 17-02-2-0006. The content of this information does not necessarily reflect the position or policy of the Government, and no official endorsement should be inferred. NR 16 TC 0 Z9 0 U1 0 U2 1 PU ASME-AMER SOC MECHANICAL ENG PI NEW YORK PA THREE PARK AVE, NEW YORK, NY 10016-5990 USA SN 1932-6181 J9 J MED DEVICES JI J. Med. Devices PD MAR PY 2010 VL 4 IS 1 AR 014502 DI 10.1115/1.4000594 PG 4 WC Engineering, Biomedical SC Engineering GA 674RC UT WOS:000283764000006 ER PT J AU Scherrer-Crosbie, M Kurtz, B AF Scherrer-Crosbie, Marielle Kurtz, Baptiste TI Ventricular remodeling and function: Insights using murine echocardiography SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Review DE Echocardiography; Heart failure; Mice; Ventricular remodeling; Nitric oxide; Myocardial perfusion; Ventricular function ID CHRONIC PRESSURE-OVERLOAD; MYOCARDIAL CONTRAST ECHOCARDIOGRAPHY; ULTRASONIC TISSUE CHARACTERIZATION; NITRIC-OXIDE; EXTRACELLULAR-MATRIX; TARGETED DELETION; DILATED CARDIOMYOPATHY; HEART-FAILURE; MOUSE MODEL; INTEGRATED BACKSCATTER AB Extracellular matrix disturbances play an important role in the development of ventricular remodeling and failure. Genetically modified mice with abnormalities in the synthesis and degradation of extracellular matrix have been generated, in particular mice with deletion or overexpression of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). Echocardiography is ideally suited to serially evaluate left ventricular (LV) size and function, thus defining the progression of LV remodeling and failure. This Review describes the echocardiographic parameters that may provide insights into the development of ventricular remodeling and heart failure. The application of echocardiography to study LV remodeling and function after myocardial infarction and LV pressure-overload in wild-type mice and mice deficient or overexpressing MMPs or TIMPs is then detailed. Finally, using the example of mice deficient in nitric oxide synthase 3, a cautionary example is given illustrating discrepancies between the cardiac echocardiographic phenotype and modifications of the extracellular matrix. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Div Cardiol, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Scherrer-Crosbie, M (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Div Cardiol, Dept Med, 55 Fruit St, Boston, MA 02114 USA. EM marielle@crosbie.com FU NCRR NIH HHS [S10 RR022586, S10 RR022586-01A1] NR 71 TC 15 Z9 16 U1 0 U2 3 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 MAR PY 2010 VL 48 IS 3 SI SI BP 512 EP 517 DI 10.1016/j.yjmcc.2009.07.004 PG 6 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 560SI UT WOS:000274922300013 PM 19615377 ER PT J AU McCurdy, S Baicu, CF Heymans, S Bradshaw, AD AF McCurdy, Sarah Baicu, Catalin F. Heymans, Stephane Bradshaw, Amy D. TI Cardiac extracellular matrix remodeling: Fibrillar collagens and Secreted Protein Acidic and Rich in Cysteine (SPARC) SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Review DE BM-40; Osteonectin; SPARC; Extracellular matrix; Remodeling; Review ID DIASTOLIC HEART-FAILURE; MYOCARDIAL-INFARCTION; PRESSURE-OVERLOAD; GENE-EXPRESSION; MATRICELLULAR PROTEINS; PULMONARY-FIBROSIS; LEFT-VENTRICLE; NULL MOUSE; RAT-HEART; HYPERTROPHY AB The cardiac interstitium is a unique and adaptable extracellular matrix (ECM) that provides a milieu in which myocytes, fibroblasts, and endothelial cells communicate and function. The composition of the ECM in the heart includes structural proteins such as fibrillar collagens and matricellular proteins that modulate cell: ECM interaction. Secreted Protein Acidic and Rich in Cysteine (SPARC), a collagen-binding matricellular protein, serves a key role in collagen assembly into the ECM. Recent results demonstrated increased cardiac rupture, dysfunction and mortality in SPARC-null mice in response to myocardial infarction that was associated with a decreased capacity to generate organized, mature collagen fibers. In response to pressure overload induced-hypertrophy, the decrease in insoluble collagen incorporation in the left ventricle of SPARC-null hearts was coincident with diminished ventricular stiffness in comparison to WT mice with pressure overload. This review will focus on the role of SPARC in the regulation of interstitial collagen during cardiac remodeling following myocardial infarction and pressure overload with a discussion of potential cellular mechanisms that control SPARC-dependent collagen assembly in the heart. (C) 2009 Elsevier Ltd. All rights reserved. C1 [McCurdy, Sarah] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Cardiol, San Antonio, TX 78229 USA. [Heymans, Stephane] Univ Maastricht, Heart Failure Res Ctr, Cardiovasc Res Inst Maastricht, Maastricht, Netherlands. [Baicu, Catalin F.; Bradshaw, Amy D.] Ralph H Johnson Vet Adm, Charleston, SC USA. [Bradshaw, Amy D.] Med Univ S Carolina, Gazes Cardiac Res Inst, Div Cardiol, Dept Med, Charleston, SC 29425 USA. RP Bradshaw, AD (reprint author), Med Univ S Carolina, Gazes Cardiac Res Inst, Div Cardiol, Dept Med, 114 Doughty St, Charleston, SC 29425 USA. EM bradshad@musc.edu FU American Physiological Society (SM); Netherlands Heart Foundation [200513082, 200713036, 200813011]; European Union [EST 2005-020706-2]; Dutch Scientific Organisation (NWO); Veteran's Administration; NIDCR, NIH [P20RR017696] FX This work was supported by an Undergraduate Student Summer Research Fellowship from the American Physiological Society (SM), Netherlands Heart Foundation (200513082, 200713036, 200813011), Ingenious Hypercare NoE from the European Union (EST 2005-020706-2), a VIDI grant of the Dutch Scientific Organisation (NWO) to (SH), and a Merit Award from the Veteran's Administration (ADB), and P20RR017696 from the NIDCR, NIH (CFB, ADB). NR 51 TC 44 Z9 48 U1 0 U2 7 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 MAR PY 2010 VL 48 IS 3 SI SI BP 544 EP 549 DI 10.1016/j.yjmcc.2009.06.018 PG 6 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 560SI UT WOS:000274922300018 PM 19577572 ER PT J AU Irahara, N Nosho, K Baba, Y Shima, K Lindeman, NI Hazra, A Schernhammer, ES Hunter, DJ Fuchs, CS Ogino, S AF Irahara, Natsumi Nosho, Katsuhiko Baba, Yoshifumi Shima, Kaori Lindeman, Neal I. Hazra, Aditi Schernhammer, Eva S. Hunter, David J. Fuchs, Charles S. Ogino, Shuji TI Precision of Pyrosequencing Assay to Measure LINE-1 Methylation in Colon Cancer, Normal Colonic Mucosa, and Peripheral Blood Cells SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID GENE PROMOTER METHYLATION; TUMOR-SUPPRESSOR GENE; DNA METHYLATION; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; MUTATION DETECTION; HYPOMETHYLATION; PHENOTYPE; LEVEL; MICE AB Genome-wide DNA hypomethylation plays an important role in epigenomic and genomic instability and colorectal carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of global DNA methylation level. In addition, LINE-1 hypomethylation in blood cells has been associated with colorectal adenoma risk, and LINE-1 hypomethylation in colorectal cancer is related with prognosis and linearly predicts shorter patient survival. However, no study has comprehensively evaluated the precision of sodium bisulfite conversion and PCR-pyrosequencing to measure LINE-1 methylation. Using 10 paraffin-embedded colon cancers, 5 matched normal colon mucosa, and 5 unrelated peripheral blood buffy coat leukocyte specimens, we enriched tumor DNA by macrodissection and laser capture microdissection. LINE-1 methylation was calculated as an average of 100 * C/(C + T) at 4 CpG sites after bisulfite-PCR-pyrosequencing. The LINE-1 methylation value in colon cancers varied, ranging approximately from 30 to 80. To measure assay precision, we performed bisulfite conversion on seven different DNA specimen aliquots and repeated PCR-pyrosequencing seven times. Run-to-run (between-run) SD ranged from 1.3 to 4.4 (median, 3.0) in macrodissected colon cancers; 1.1 to 10.5 (median, 3.8) in laser capture microdissection specimens; 1.3 to 2.5 (median, 1.9) in normal colon; and 1.5 to 3.4 (median, 1.9) in leukocyte DNA. In conclusion, bisulfite conversion and PCR-pyrosequencing assay can measure LINE-1 methylation in macrodissected colon cancer, normal colon, and blood DNA, and may be useful in clinical and C1 [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med,Ctr Mol Oncol Pathol,Dept Med Oncol, Boston, MA 02115 USA. [Irahara, Natsumi; Nosho, Katsuhiko; Baba, Yoshifumi; Shima, Kaori; Fuchs, Charles S.; Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Lindeman, Neal I.; Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Hazra, Aditi; Schernhammer, Eva S.; Hunter, David J.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hazra, Aditi; Schernhammer, Eva S.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Schernhammer, Eva S.] Ludwig Boltzmann Inst Appl Canc Res, Vienna, Austria. RP Ogino, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med,Ctr Mol Oncol Pathol,Dept Med Oncol, 44 Binney St,Room JF-215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU U.S. National Institute of Health [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826] FX Supported by the U.S. National Institute of Health (grant P01 CA87969 to S. Hankinson, P01 CA55075 to W. Willett, P50 CA127003 to C.S.F.. K07 CA122826 to S.O.); the Bennett Family Rind: and the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. K.N. was supported by a fellowship grant from the Japan Society for Promotion of Science. NR 51 TC 85 Z9 88 U1 0 U2 6 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 MAR PY 2010 VL 12 IS 2 BP 177 EP 183 DI 10.2353/jmoldx.2010.090106 PG 7 WC Pathology SC Pathology GA 583RQ UT WOS:000276697300007 PM 20093385 ER PT J AU Bruguera, CM Hirsch, JA AF Bruguera, Carolyn M. Hirsch, Joshua A. TI Letting the sunshine in: shining a new light on physician-industry relationships SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article AB The pending federal healthcare reform legislation includes Physician Payment Sunshine provisions that would mandate public disclosure of virtually all payments by industry to US physicians on government websites. The requirements reflect a growing trend toward public disclosure of payments following high-profile government investigations of allegedly improper payments and undisclosed conflicts of interests. The pending law world require broad disclosure and will affect most physicians. Industry and physicians groups have offered qualified support to the legislation. C1 [Bruguera, Carolyn M.] Micrus Endovasc Corp, San Jose, CA 95131 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bruguera, CM (reprint author), Micrus Endovasc Corp, 821 Fox Lane, San Jose, CA 95131 USA. EM cbruguera@micruscorp.com NR 11 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 MAR PY 2010 VL 2 IS 1 BP 80 EP 82 DI 10.1136/jnis.2010.002196 PG 3 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 601YJ UT WOS:000278103800018 PM 21990565 ER PT J AU Gomez, MA Hirsch, JA Stingley, P Byers, E Sheridan, RM AF Gomez, Max A., II Hirsch, Joshua A. Stingley, Preston Byers, Ernest Sheridan, Robert M. TI Applying the Lean management philosophy to NeuroInterventional radiology SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID PRODUCTION SYSTEM C1 [Gomez, Max A., II; Hirsch, Joshua A.; Stingley, Preston; Byers, Ernest; Sheridan, Robert M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Gomez, MA (reprint author), Massachusetts Gen Hosp, 175 Cambridge St,Suite 200, Boston, MA 02114 USA. EM mgomezii@partners.org NR 14 TC 4 Z9 4 U1 1 U2 5 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 MAR PY 2010 VL 2 IS 1 BP 83 EP 86 DI 10.1136/jnis.2009.002162 PG 4 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 601YJ UT WOS:000278103800019 PM 21990566 ER PT J AU McNamara, P Holtgraves, T Durso, R Harris, E AF McNamara, Patrick Holtgraves, Thomas Durso, Raymon Harris, Erica TI Social cognition of indirect speech: Evidence from Parkinson's disease SO JOURNAL OF NEUROLINGUISTICS LA English DT Article DE Evolution of cooperation; Reputation; Indirect speech; Politeness conventions; Face-saving; Parkinson's disease ID ALTRUISTIC PUNISHMENT; INDIRECT REPLIES; LANGUAGE AB We examined potential neurocognitive mechanisms of indirect speech ill Support of face management in 28 patients with Parkinson's disease (PD) and 32 elderly controls with chronic disease. In Experiment 1, we demonstrated automatic activation of indirect meanings Of particularized implicatures in controls but not in PD patients. Failure to automatically engage comprehension of indirect meanings of indirect speech acts in PD patients was correlated with a measure of prefrontal dysfunction. In Experiment 2, we showed that while PD patients and controls offered similar interpretations of indirect. speech acts, PD participants were overly confident in their interpretations and unaware of errors of interpretation. Efficient reputational adjustment mechanisms apparently require intact striatal-prefrontal networks. (C) 2009 Elsevier Ltd. All rights reserved. C1 [McNamara, Patrick; Durso, Raymon; Harris, Erica] Boston VA Healthcare Syst, Dept Neurol 127, Boston, MA 02130 USA. [McNamara, Patrick; Durso, Raymon; Harris, Erica] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Holtgraves, Thomas] Ball State Univ, Dept Psychol Sci, Muncie, IN 47306 USA. RP McNamara, P (reprint author), Boston VA Healthcare Syst, Dept Neurol 127, 150 S Huntington Ave, Boston, MA 02130 USA. EM mcnamar@bu.edu FU NIDCD [5R01DC007956-03]; Office of Research and Development; Medical Research Service; Department of Veterans Affairs FX This project was supported by a grant from NIDCD Grant no. 5R01DC007956-03 and is based upon work supported, in part, by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. NR 19 TC 5 Z9 5 U1 1 U2 11 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 MAR PY 2010 VL 23 IS 2 BP 162 EP 171 DI 10.1016/j.jneuroling.2009.12.003 PG 10 WC Linguistics; Neurosciences; Psychology, Experimental SC Linguistics; Neurosciences & Neurology; Psychology GA 563KK UT WOS:000275130500005 PM 20161657 ER PT J AU Agam, Y Huang, J Sekuler, R AF Agam, Yigal Huang, Jie Sekuler, Robert TI Neural Correlates of Sequence Encoding in Visuomotor Learning SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID EVENT-RELATED POTENTIALS; WORKING-MEMORY; SELECTIVE ATTENTION; INDIVIDUAL-DIFFERENCES; NEUROIMAGING EVIDENCE; SERIAL-RECALL; REPETITION; BRAIN; MODEL; SUPPRESSION AB Agam Y, Huang J, Sekuler R. Neural correlates of sequence encoding in visuomotor learning. J Neurophysiol 103: 1418-1424, 2010. First published January 13, 2010; doi:10.1152/jn.00662.2009. To examine the neural basis of sequence learning, a fundamental but poorly understood human ability, we recorded event-related potentials (ERPs) while subjects viewed and memorized randomly directed sequences of motions for later imitation. Previously, we found that the amplitude of ERPs elicited by successive motion segments decreased as a function of each segment's serial position. This happened when subjects were required to remember the sequence, but not when they were performing a perceptual task. Here, to study the functional significance of this amplitude gradient in sequence learning, we presented each sequence several times in succession and examined changes in ERP amplitude as subjects learned the sequence through repeated observation and imitation. Behaviorally, with each repetition subjects grew more accurate in reproducing what they had seen. At the same time, ERPs grew smaller with each successive presentation, replicating and extending previous demonstrations of repetition suppression. Importantly, a comparison of ERPs to segments occupying different serial positions within a sequence revealed a decreasing amplitude gradient that grew steeper with sequence repetition. This sharpening of the amplitude gradient may reflect an explicit encoding process that relies on a magnitude code for serial order. C1 [Agam, Yigal] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Huang, Jie; Sekuler, Robert] Brandeis Univ, Volen Ctr Complex Syst, Waltham, MA USA. RP Agam, Y (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, 149 13th St,Room 2611, Charlestown, MA 02129 USA. EM yigal@nmr.mgh.harvard.edu FU National Science Foundation-sponsored Science of Learning Center/Center of Excellence for Learning in Education, Science, and Technology [SBE-0354378]; National Institute of Mental Health [MH-068404] FX This work was supported in part by National Science Foundation-sponsored Science of Learning Center/Center of Excellence for Learning in Education, Science, and Technology Grant SBE-0354378 and National Institute of Mental Health Grant MH-068404. NR 40 TC 8 Z9 8 U1 2 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD MAR PY 2010 VL 103 IS 3 BP 1418 EP 1424 DI 10.1152/jn.00662.2009 PG 7 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 570EY UT WOS:000275656200025 PM 20071631 ER PT J AU Ottowitz, WE Deckersbach, T Savage, CR Lindquist, MA Dougherty, DD AF Ottowitz, William E. Deckersbach, Thilo Savage, Cary R. Lindquist, Martin A. Dougherty, Darin D. TI Neural Correlates of Strategic Processes Underlying Episodic Memory in Women with Major Depression: A O-15-PET Study SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; ANTERIOR CINGULATE ACTIVATION; INFERIOR PREFRONTAL CORTEX; VERBAL-LEARNING TEST; DECLARATIVE MEMORY; GERIATRIC DEPRESSION; ALZHEIMERS-DISEASE; GENDER-DIFFERENCES; SEX-DIFFERENCES; FUNCTIONAL MRI AB To evaluate the functional integrity of brain regions underlying strategic mnemonic processing in patients with major depressive disorder, the authors administered a modified version of the California Verbal Learning Test to depressed patients during presentation of lists of unrelated words and, conversely, during presentation of lists of related words with and without orientation regarding the relatedness of the words (eight healthy females, IQ = 122, and eight depressed females, IQ = 107). Brain function evaluated across all three conditions showed that patients with major depressive disorder revealed activation of the right anterior cingulate cortex, left ventrolateral prefrontal cortex, both hippocampi, and the left orbitofrontal cortex. Further analysis showed that patients with major depressive disorder had greater activation of the right anterior cingulate cortex during semantic organization and the right ventrolateral prefrontal cortex during strategy initiation. (The Journal of Neuropsychiatry and Clinical Neurosciences 2010; 22: 218-230) C1 [Ottowitz, William E.] Columbia Univ, Grad Sch Arts & Sci, Dept Stat, New York, NY 10027 USA. [Deckersbach, Thilo; Dougherty, Darin D.] Massachusetts Gen Hosp, Div Psychiat Neurosci Res & Neurotherapeut, Charlestown, MA USA. [Savage, Cary R.] Univ Kansas, Med Ctr, Hoglund Brain Imaging Ctr, Kansas City, KS 66103 USA. RP Ottowitz, WE (reprint author), Columbia Univ, Grad Sch Arts & Sci, Dept Stat, Rm 1005,MC 4690,1255 Amsterdam, New York, NY 10027 USA. EM weo2101@columbia.edu FU NARSAD FX This study was completed at the Psychiatric Neuroscience Program of Massachusetts General Hospital, Charlestown, Massachusetts. This study was supported by a NARSAD young investigator award to William Ottowitz, M.D. NR 56 TC 0 Z9 0 U1 4 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD SPR PY 2010 VL 22 IS 2 BP 218 EP 230 PG 13 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 595ZY UT WOS:000277654200010 PM 20463116 ER PT J AU Arai, K Lo, EH AF Arai, Ken Lo, Eng H. TI Astrocytes Protect Oligodendrocyte Precursor Cells via MEK/ERK and PI3K/Akt Signaling SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE astrocyte; oligodendrocyte precursor cell; cell-cell interaction; white matter; stroke ID CEREBRAL ENDOTHELIAL-CELLS; BLOOD-BRAIN-BARRIER; PROJECTION NEURONS; NEUROVASCULAR UNIT; NERVOUS SYSTEMS; ADULT BRAIN; SURVIVAL; DEATH; PROLIFERATION; NEUROGENESIS AB Accumulating evidence suggest that trophic coupling among different cell types in the brain is required to maintain normal CNS function. Here we show that astrocytes secrete soluble factors that can be oligodendrocyte-supportive. Oligodendrocyte precursor cells (OPCs) and astrocytes were prepared from neonatal rat brain and cultured separately. We conducted cell culture medium-transfer experiments to examine whether astrocytes secrete OPC-protective factors. Conditioned media from astrocytes protected OPCs against H(2)O(2)-induced oxidative stress, starvation, and oxygen-glucose deprivation. This protective effect may be mediated in part via ERK and Akt signaling pathways. Astrocyte-conditioned media upregulated the phosphorylation levels of ERK and Akt in OPC cultures. Blockade of ERK or Akt signaling with U0126 or LY294002 cancelled the OPC-protective effects of astrocyte-conditioned media. Taken together, these data suggest that astrocytes are an important source for oligodendrocyte-supportive factors. Coupling between these two major glial components in brain may be vital for sustaining white matter homeostasis. (C) 2009 Wiley-Liss, Inc. C1 Massachusetts Gen Hosp, Dept Radiol, Neuroprotect Res Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Neuroprotect Res Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Arai, K (reprint author), Neuroprotect Res Lab, MGH E 149-2401, Charlestown, MA 02129 USA. FU Deane Foundation; American Heart Association; NIH FX Contract grant sponsor The Deane Foundation. Contract grant sponsor The American Heart Association. Contract grant sponsor NIH NR 44 TC 37 Z9 37 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAR PY 2010 VL 88 IS 4 BP 758 EP 763 DI 10.1002/jnr.22256 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 550YY UT WOS:000274172400006 PM 19830833 ER PT J AU Salinas, TJ Desa, VP Katsnelson, A Miloro, M AF Salinas, Thomas J. Desa, Valmont P. Katsnelson, Alexander Miloro, Michael TI Clinical Evaluation of Implants in Radiated Fibula Flaps SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID OSSEOINTEGRATED IMPLANTS; CANCER-PATIENTS; ENDOSSEOUS IMPLANTS; RECONSTRUCTION; PATIENT; BONE; REHABILITATION; EFFICACY; TISSUE; JAW AB Purpose: The success of osseointegrated implants in the radiated fibula flap used for mandibular reconstruction is variable, and there are few long-term data available in the literature. The purpose of this study is to evaluate implant success in radiated fibula flaps and the native mandible after ablative tumor surgery. Materials and Methods: The medical records of 44 patients who underwent resection and reconstruction of the mandible from 1994 to 2006 were reviewed retrospectively. A total of 206 implants were placed; 144 were placed in a fibula flap, and 92 were placed in the native mandible. Before implant placement, 22 patients (50%) received adjuvant tumoricidal doses of radiation therapy (>6,000 cGy). All patients who received radiation received a standard regimen of 20 preoperative and 10 postoperative hyperbaric oxygen treatments. The follow-up period ranged from 4 to 108 months (mean, 41.1 months). Comparisons were made between groups regarding long-term implant success based on several variables. Results: Implants were considered to be successful if there was no radiographic evidence of peri-implant bone loss and if they were clinically osseointegrated. Of 206 implants, 31 failed, with an overall success rate of 85%. The success rate of implants placed in fibula flaps was 82.4%, and the success rate in native mandibles was 88%. Most of the failures in the fibula (90%) occurred within the first 6 months after implant placement, whereas most of the failures in the mandible occurred after 6 months. The cumulative survival rate was 91.9%, and there was no difference in survival between implants placed in the fibula versus the native mandible or depending on whether the patient received radiation therapy. Conclusion: Acceptable long-term implant success rates may be achieved in the radiated mandible with vascularized fibula flap reconstruction. (C) 2010 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 68:524-529, 2010 C1 [Miloro, Michael] Univ Illinois, Coll Dent, Dept Oral & Maxillofacial Surg, Chicago, IL 60612 USA. [Salinas, Thomas J.] Mayo Clin, Dept Prosthodont, Rochester, MN USA. [Katsnelson, Alexander] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Miloro, M (reprint author), Univ Illinois, Coll Dent, Dept Oral & Maxillofacial Surg, 801 S Paulina St MC 835, Chicago, IL 60612 USA. EM mmiloro@uic.edu NR 30 TC 19 Z9 20 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD MAR PY 2010 VL 68 IS 3 BP 524 EP 529 DI 10.1016/j.joms.2009.09.104 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 617KY UT WOS:000279280800006 PM 20171471 ER PT J AU Susarla, SM Sharaf, BA Faquin, W Hasserjian, RP McDermott, N Lahey, E AF Susarla, Srinivas M. Sharaf, Basel A. Faquin, William Hasserjian, Robert P. McDermott, Nancy Lahey, Edward TI Extranodal Natural Killer T-Cell Lymphoma, Nasal Type, With Minimal Osseous Involvement: Report of a Case and Literature Review SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Review ID NON-HODGKINS-LYMPHOMA; NK/T-CELL; IMMUNOPHENOTYPE C1 [Susarla, Srinivas M.; Sharaf, Basel A.; McDermott, Nancy] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Susarla, Srinivas M.; Faquin, William; Hasserjian, Robert P.] Harvard Univ, Sch Med, Boston, MA USA. [Sharaf, Basel A.] Montefiore Med Ctr, New York, NY USA. [Lahey, Edward] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Susarla, SM (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, 55 Fruit St,Warren 1201, Boston, MA 02114 USA. EM smsusarla@gmail.com OI Susarla, Srinivas/0000-0003-0155-8260 NR 26 TC 3 Z9 3 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD MAR PY 2010 VL 68 IS 3 BP 674 EP 681 DI 10.1016/j.joms.2009.07.035 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 617KY UT WOS:000279280800032 PM 19959270 ER PT J AU Varadarajan, KM Gill, TJ Freiberg, AA Rubash, HE Li, GA AF Varadarajan, Kartik M. Gill, Thomas J. Freiberg, Andrew A. Rubash, Harry E. Li, Guoan TI Patellar Tendon Orientation and Patellar Tracking in Male and Female Knees SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE patellar tendon orientation; patellar tracking; sex difference; knee kinematics; trochlear groove geometry ID PATELLOFEMORAL CONTACT PRESSURES; SIMULATED MUSCLE LOADS; IN-VIVO; GENDER-DIFFERENCES; TROCHLEAR GROOVE; KINEMATICS; JOINT; RECONSTRUCTION; ARTHROPLASTY; DIMORPHISM AB Knowledge of patellofemoral joint biomechanics is important for understanding set-related dimorphism in patellofemoral pathologies and advancement of related treatments. We evaluated the hypotheses that sex differences exist in patellar tendon (PT) orientation and patellar tracking during weight-bearing knee flexion and that they relate to differences in tibiofemoral rotation. The PT orientation and patellar trucking were measured in healthy subjects (18 male, 13 female) during weight-hearing knee flexion, using magnetic resonance and dual fluoroscopic Imaging. These data were analyzed for sex differences and correlation with previously reported tibiofemoral rotation data. The result indicated a significant effect of sex on PT orientation particularly at low flexion angles. In females the PT was oriented more anteriorly. In the sagittal plane more medially in the coronal plane, and showed greater external tilt in the transverse plane of the tibia (p < 0 05). Significant correlations between tibiofemoral rotation and PT orientation (p < 0 01). Indicated that sex differences in coronal and transverse plane orientation of the PT relate to differences in tibiofemoral rotation. Patellar tracking did not show significant sex differences or correlation to tibiofemoral rotation. Further studies are warranted to determine implications for patellofemoral pathologies and treatments like total knee arthroplasty. (C) 2009 Orthopaedic Research Society Published by Wiley Periodicals, Inc J Orthop Res 28 322-328, 2010 C1 [Varadarajan, Kartik M.; Gill, Thomas J.; Freiberg, Andrew A.; Rubash, Harry E.; Li, Guoan] Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA. [Varadarajan, Kartik M.; Gill, Thomas J.; Freiberg, Andrew A.; Rubash, Harry E.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA USA. [Varadarajan, Kartik M.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, 55 Fruit St,GRI 1215, Boston, MA 02114 USA. FU NIH [R01-AR052408, R21-AR05107] FX This study was made possible through grants received from the NIH (R01-AR052408. R21-AR05107). We thank Kyung Wook Nha, Louis E DeFrate, Jefferey Bingham, Ramprasad Papannagari, and Samuel Van de Velde for their technical assistance NR 30 TC 7 Z9 7 U1 0 U2 6 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 MAR PY 2010 VL 28 IS 3 BP 322 EP 328 DI 10.1002/jor.20977 PG 7 WC Orthopedics SC Orthopedics GA 560SF UT WOS:000274921900007 PM 19777466 ER PT J AU Alici, Y Smith, D Lu, HL Bailey, A Shreve, S Rosenfeld, K Ritchie, C Casarett, DJ AF Alici, Yesne Smith, Dawn Lu, Hien L. Bailey, Amos Shreve, Scott Rosenfeld, Kenneth Ritchie, Christine Casarett, David J. TI Families' Perceptions of Veterans' Distress Due to Post-Traumatic Stress Disorder-Related Symptoms at the End of Life SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE End of life; post-traumatic stress disorder; families' perceptions of the quality of care ID PRIMARY-CARE; VIETNAM VETERANS; NATIONAL SAMPLE; QUALITY MEASURE; PREVALENCE; CANCER; PTSD; SETTINGS; DELIRIUM AB Objectives. To define the frequency of post-traumatic stress disorder (PTSD)related symptoms among veterans who are near the end of life and to describe the impact that these symptoms have on patients and their families. Methods. Patients had received inpatient or outpatient care from a participating VA facility in the last month of life, and one family member per patient was selected using predefined eligibility criteria. Family members then completed a telephone survey, The Family Assessment of Treatment at End-of-Life, which assessed their perceptions of the quality of the care that the patients and they themselves received during the patients' last month of life. Results. Seventeen percent of padents (89 of 524) were reported to have had PTSD-related symptoms in the last month of life. PTSD-related symptoms caused discomfort less often than pain did (mean frequency score 1.79 vs. 1.93; Wilcoxon sign rank test, P < 0.001) but more often than dyspnea did (mean severity score 1.79 vs. 1.73; Wilcoxon sign rank test, P < 0.001). Family members of patients with PTSD-related symptoms reported less satisfaction overall with the care the patient received (mean score 48 vs. 62; rank sum test, P < 0.001). Patients who received a palliative care consult (n = 49) had lower ratings of discomfort attributed to PTSD-related symptoms (mean 1.55 vs. 2.07; rank sum test, P = 0.007). Conclusion. PTSD-related symptoms may be common and severe among veterans near the end of life and may have a negative effect on families' perceptions of the quality of care that the veteran received. J Pain Symptom Manage 2010;39:507-514. (C) 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. C1 [Alici, Yesne] Cent Reg Hosp, Geriatr Serv Unit, Butner, NC 27509 USA. [Smith, Dawn; Casarett, David J.] Philadelphia VA Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Lu, Hien L.; Casarett, David J.] Univ Penn, Div Geriatr Med, Philadelphia, PA 19104 USA. [Bailey, Amos; Ritchie, Christine] Birmingham VA Med Ctr, Birmingham, AL USA. [Shreve, Scott] Lebanon VA Med Ctr, Lebanon, PA USA. [Rosenfeld, Kenneth] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. RP Alici, Y (reprint author), Cent Reg Hosp, Geriatr Serv Unit, Butner, NC 27509 USA. EM yesne.alici@dhhs.nc.gov FU Department of Veterans Affairs; Presidential Early Career Award for Scientists and Engineers FX This work was supported by a Health Services Research and Development Merit Award from the Department of Veterans Affairs (Dr Casarett) and by a Presidential Early Career Award for Scientists and Engineers (Dr. Casarett). The views expressed here are those of the authors and do not necessarily reflect those of the Department of Veterans Affairs or the Department of Health and Human Services. NR 38 TC 6 Z9 6 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD MAR PY 2010 VL 39 IS 3 BP 507 EP 514 DI 10.1016/j.jpainsymman.2009.07.011 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 582EI UT WOS:000276578500004 PM 20083372 ER PT J AU Bekelman, DB Parry, C Curlin, FA Yamashita, TE Fairclough, DL Wamboldt, FS AF Bekelman, David B. Parry, Carla Curlin, Farr A. Yamashita, Traci E. Fairclough, Diane L. Wamboldt, Frederick S. TI A Comparison of Two Spirituality Instruments and Their Relationship With Depression and Quality of Life in Chronic Heart Failure SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Spirituality; quality of life; depression; questionnaires; measurement; heart failure ID COMPLICATED GRIEF; HEALTH-STATUS; RELIGIOUS SERVICES; TERMINALLY-ILL; MORTALITY; DISTINCT; ATTENDANCE; SYMPTOMS; SCALE; QUESTIONNAIRE AB Spirituality is a multifaceted construct related to health outcomes that remains ill defined and difficult to measure. Spirituality in patients with advanced chronic illnesses, such Os chronic heart failure, has received limited attention. We compared two widely used spirituality instruments, the Functional Assessment of Chronic Illness Therapy Spiritual Well-Being (FACIT-Sp) and the Ironson-Woods Spirituality/Religiousness Index (IW), to better understand what duo) measure in 60 outpatients with chronic heart failure. We examined lion) these instruments related to each other and to measures of depression and quality of life using correlations and principal component analyses. The FACIT-Sp measured aspects of spirituality related to feelings of peace and coping, whereas the IW measured beliefs, coping, and relational aspects of spirituality. Only the FACIT-Sp Meaning/Peace subscale consistently correlated with depression (r = -0.50, P < 0.0001) and quality of life (r 0.41, P = 0.001). Three items from the depression measure loaded onto the same factor as the FACIT-Sp Meaning/Peace subscale (r = 0.43, -0.43, and 0.71), whereas the remaining 12 items formed a separate factor (Cronbach's alpha = 0.82) when combined with the spirituality instruments in a principal component analysis. The results demonstrate several clinically useful constructs of spirituality in patients with heart failure and suggest that psychological and spiritual well-being, despite some overlap, remain distinct phenomena. J Pain Symptom Manage 2010;39:515-526. (C) 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. C1 [Bekelman, David B.] Denver VA Med Ctr, Denver, CO 80220 USA. [Curlin, Farr A.] Univ Chicago, MacLean Ctr Clin Med Eth, Gen Internal Med Sect, Chicago, IL 60637 USA. [Fairclough, Diane L.] Colorado Sch Publ Hlth, Dept Biostat & Informat, Aurora, CO USA. [Bekelman, David B.; Wamboldt, Frederick S.] Natl Jewish Hlth, Div Psychosocial Med, Denver, CO USA. [Bekelman, David B.; Yamashita, Traci E.] Univ Colorado Denver, Sch Med, Div Gen Internal Med, Aurora, CO USA. [Parry, Carla] Univ Colorado Denver, Sch Med, Div Hlth Care Policy & Res, Aurora, CO USA. [Fairclough, Diane L.] Univ Colorado Denver, Sch Med, Colorado Hlth Outcomes Program, Aurora, CO USA. [Wamboldt, Frederick S.] Univ Colorado Denver, Sch Med, Dept Psychiat, Aurora, CO USA. RP Bekelman, DB (reprint author), Denver VA Med Ctr, Res 151,1055 Clermont St, Denver, CO 80220 USA. EM david.bekelman@ucdenver.edu FU Johns Hopkins Center for Complementary and Alternative Medicine; National Center for Complementary and Alternative Medicine, National Institutes of Health; University of Colorado Denver Hartford/Jahnigen Center of Excellence in Geriatric Medicine FX This study was funded by the Johns Hopkins Center for Complementary and Alternative Medicine; the National Center for Complementary and Alternative Medicine, National Institutes of Health; and the University of Colorado Denver Hartford/Jahnigen Center of Excellence in Geriatric Medicine. The views in this article are those of the authors and do not necessarily reflect the views of the Department of Veterans Affairs. NR 36 TC 16 Z9 17 U1 1 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD MAR PY 2010 VL 39 IS 3 BP 515 EP 526 DI 10.1016/j.jpainsymman.2009.08.005 PG 12 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 582EI UT WOS:000276578500005 PM 20303028 ER PT J AU Wagner, GJ Riopelle, D Steckart, J Lorenz, KA Rosenfeld, KE AF Wagner, Glenn J. Riopelle, Deborah Steckart, Jillisa Lorenz, Karl A. Rosenfeld, Kenneth E. TI Provider Communication and Patient Understanding of Life-Limiting Illness and Their Relationship to Patient Communication of Treatment Preferences SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Physician-patient communication; prognosis; advance care planning; patient autonomy; medical decision making ID SERIOUSLY ILL PATIENTS; DECISION-MAKING; ADVANCE DIRECTIVES; CANCER-PATIENTS; HOSPITALIZED-PATIENTS; STATUS QUESTIONNAIRE; CONTROLLED TRIAL; MEDICAL-CARE; LUNG-CANCER; END AB Medical decision making in the context of serious illness ideally involves a patient who understands his or her condition and prognosis and can effectively formulate and communicate his or her care preferences. To understand the relationships among these care processes, we analyzed baseline into-view data from veterans enrolled in a randomized controlled trial of a palliative care intervention. Participants were 400 inpatient veterans admitted with a physician-estimated risk of one-year mortality more than, 25 %; 260 (65 %) had cancer as the primary diagnosis. Patients who believed that they had a illness (89% sample) reported that their provider had communicated this to them more frequently than those who did not share that belief (78% vs. 22%, P < 0.001). Over half (53%) of the participants reported discussing their cam preferences with their providers and 66% reported such discussions with their family; 35% had a living will. In multivariate analysis, greater functional impairment was associated with patients having discussed their care preferences with providers (P < 0.05), whereas patient understanding of prognosis (P < 0.05), better quality of life (P < 0.01), and not being African American (P < 0.05) were associated with patients having discussed their care preferences with family higher education (P < 0.001), and not being African American (P < 0.01) were associated with having a living will. Patients with poor understanding of prognosis are less likely to discuss care preferences with family members, suggesting the importance of provider communication with patients regarding prognosis. Because functional decline may prompt physicians to discuss prognosis with patients, patients with relatively preserved function may particularly need such communication. J Pain Symptom Manage 2010;39:527-534. (C) 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. C1 [Wagner, Glenn J.] RAND Corp, Santa Monica, CA 90407 USA. [Riopelle, Deborah; Steckart, Jillisa; Lorenz, Karl A.; Rosenfeld, Kenneth E.] Vet Adm Greater Los Angeles Healthcare Ctr, Los Angeles, CA USA. RP Wagner, GJ (reprint author), RAND Corp, 1776 Main St, Santa Monica, CA 90407 USA. EM gwagner@rand.org FU VA Center for the Study of Healthcare Provider Behavior; VA HSRD [IIR 02-294] FX Support for this study was provided by the VA Center for the Study of Healthcare Provider Behavior, and funding was provided by VA HSR&D grant IIR 02-294 (Principal Investigator, Dr. Rosenfeld). NR 38 TC 18 Z9 20 U1 5 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD MAR PY 2010 VL 39 IS 3 BP 527 EP 534 DI 10.1016/j.jpainsymman.2009.07.012 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 582EI UT WOS:000276578500006 PM 20171827 ER PT J AU Dahlin, C AF Dahlin, Constance TI Ethical Issues in Home Health Care SO JOURNAL OF PALLIATIVE CARE LA English DT Book Review C1 [Dahlin, Constance] Massachusetts Gen Hosp, Palliat Care Serv, Boston, MA 02114 USA. RP Dahlin, C (reprint author), Massachusetts Gen Hosp, Palliat Care Serv, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU CENTRE RECHERCHE INSTITUT UNIV GERIATRIE MONTREAL PI MONTREAL PA 4565 CHEMIN QUEEN MARY, MONTREAL, QUEBEC H3W 1W5, CANADA SN 0825-8597 J9 J PALLIAT CARE JI J. Palliative Care PD SPR PY 2010 VL 26 IS 1 BP 71 EP 71 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 802BB UT WOS:000293483200019 ER PT J AU Casarett, D Pickard, A Fishman, JM Alexander, SC Arnold, RM Pollak, KI Tulsky, JA AF Casarett, David Pickard, Amy Fishman, Jessica M. Alexander, Stewart C. Arnold, Robert M. Pollak, Kathryn I. Tulsky, James A. TI Can Metaphors and Analogies Improve Communication with Seriously Ill Patients? SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID OF-LIFE CARE; CONTROLLED-TRIAL; PULMONARY-DISEASE; ADVANCED CANCER; FAMILY-MEMBERS; END; CONSULTATION; DISCUSSIONS; EFFICACY; MEDICINE AB Objective: It is not known how often physicians use metaphors and analogies, or whether they improve patients' perceptions of their physicians' ability to communicate effectively. Therefore, the objective of this study was to determine whether the use of metaphors and analogies in difficult conversations is associated with better patient ratings of their physicians' communication skills. Design: Cross-sectional observational study of audio-recorded conversations between patients and physicians. Setting: Three outpatient oncology practices. Patients: Ninety-four patients with advanced cancer and 52 physicians. Intervention: None. Main outcome measures: Conversations were reviewed and coded for the presence of metaphors and analogies. Patients also completed a 6-item rating of their physician's ability to communicate. Results: In a sample of 101 conversations, coders identified 193 metaphors and 75 analogies. Metaphors appeared in approximately twice as many conversations as analogies did (65/101, 64% versus 31/101, 31%; sign test p<0.001). Conversations also contained more metaphors than analogies (mean 1.6, range 0-11 versus mean 0.6, range 0-5; sign rank test p<0.001). Physicians who used more metaphors elicited better patient ratings of communication (rho = 0.27; p = 0.006), as did physicians who used more analogies (Spearman rho = 0.34; p<0.001). Conclusions: The use of metaphors and analogies may enhance physicians' ability to communicate. C1 [Casarett, David] Univ Penn, Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Pickard, Amy] Univ Penn, Div Geriatr Med, Philadelphia, PA 19104 USA. [Fishman, Jessica M.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Tulsky, James A.] Duke Univ, Med Ctr, Ctr Palliat Care, Durham, NC USA. [Arnold, Robert M.] Univ Pittsburgh, Sch Med, Sect Palliat Care & Med Eth, Pittsburgh, PA USA. [Pollak, Kathryn I.] Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Duke Dept Family & Community Med, Durham, NC 27710 USA. [Tulsky, James A.] Durham Vet Affairs Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC USA. RP Casarett, D (reprint author), 3615 Chestnut St, Philadelphia, PA 19104 USA. EM Casarett@mail.med.upenn.edu FU Greenwall Foundation; National Cancer Institute [R01-CA100387-01] FX This work was funded by grants from the Greenwall Foundation (Casarett) and from the National Cancer Institute (R01-CA100387-01) (Tulsky). NR 30 TC 24 Z9 24 U1 2 U2 13 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 MAR PY 2010 VL 13 IS 3 BP 255 EP 260 DI 10.1089/jpm.2009.0221 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 559SH UT WOS:000274846700008 PM 19922170 ER PT J AU Billings, ME Engelberg, R Curtis, JR Block, S Sullivan, AM AF Billings, Martha E. Engelberg, Ruth Curtis, J. Randall Block, Susan Sullivan, Amy M. TI Determinants of Medical Students' Perceived Preparation To Perform End-of-Life Care, Quality of End-of-Life Care Education, and Attitudes Toward End-of-Life Care SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID PALLIATIVE CARE; HIDDEN CURRICULUM; CLINICAL YEARS; UNITED-STATES; SCHOOL; COMMUNICATION; PERCEPTIONS; EXPERIENCES; CLERKSHIP; KNOWLEDGE AB Background: Medical students' learning about end-of-life care can be categorized into three learning modalities: formal curriculum, taught in lectures; informal curriculum, conveyed through clinical experiences; and "hidden curriculum," inferred from behaviors and implicit in medical culture. In this study, we evaluated associations between survey items assessing these learning modalities and students' perceptions of their preparation, quality of education, and attitudes toward end-of-life care. Methods: Data were collected from a national survey of fourth-year medical students (n = 1455) at 62 medical schools in 2001. Linear regression analyses were performed to assess associations between formal, informal and hidden end-of-life care curricula and students' perceived preparedness to provide end-of-life care, quality of end-of-life care education and attitudes toward end-of-life, controlling for students' demographics and clustered by school. Results: Students reporting more exposure to formal and informal curricula felt more prepared and rated their end-of-life care education higher. Students with more exposure to a hidden curriculum that devalued end-of-life care perceived their preparation as poorer and had poorer attitudes toward end-of-life care. Minority students had slightly more negative attitudes but no differences in perceived end-of-life care preparation. Conclusions: Medical students' sense of preparedness for end-of-life care and perceptions of educational quality are greater with more coursework and bedside teaching. By contrast, the hidden curriculum conveying negative messages may impair learning. Our findings suggest that implicit messages as well as intentional teaching have a significant impact on students' professional development. This has implications for designing interventions to train physicians to provide outstanding end-of-life care. C1 [Billings, Martha E.; Engelberg, Ruth; Curtis, J. Randall] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98104 USA. [Block, Susan] Dana Farber Canc Inst, Div Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Sullivan, Amy M.] Virginia Commonwealth Univ, Dept Social & Behav Hlth, Richmond, VA USA. RP Billings, ME (reprint author), Univ Washington, Div Pulm & Crit Care Med, 325 Ninth Ave,Box 359762, Seattle, WA 98104 USA. EM mebillin@u.washington.edu FU National Institutes of Health [HL07287] FX This research was performed with the financial support of National Institutes of Health Training Grant HL07287. NR 37 TC 42 Z9 47 U1 1 U2 23 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 MAR PY 2010 VL 13 IS 3 BP 319 EP 326 DI 10.1089/jpm.2009.0293 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 559SH UT WOS:000274846700018 PM 20178433 ER PT J AU Canullo, L Quaranta, A Teles, RP AF Canullo, Luigi Quaranta, Alessandro Teles, Ricardo P. TI The Microbiota Associated With Implants Restored With Platform Switching: A Preliminary Report SO JOURNAL OF PERIODONTOLOGY LA English DT Article DE Bone resorption; dental implants; digoxigenin; DNA probes; microbiology ID OSSEOINTEGRATED DENTAL IMPLANTS; RANDOMIZED-CONTROLLED-TRIAL; CRESTAL BONE CHANGES; TITANIUM IMPLANTS; ABUTMENT INTERFACE; BACTERIAL-COLONIZATION; HISTOMETRIC EVALUATION; EDENTULOUS PATIENTS; SUBMERGED IMPLANTS; INTERNAL SURFACES AB Background: It was demonstrated that implants restored according to a platform-switching concept presented less crestal bone loss than implants restored with standard protocols. The aim of this study is to examine differences between the composition of the pen-implant microbiotas associated with implants restored with the platform-switching approach and implants restored with a standard internal connection protocol. Methods: A total of 48 implants were examined in 18 subjects: 33 implants were restored with platform switching, and 15 implants were restored using the traditional approach. Thirty-six months after prosthetic loading, subgingival plaque samples were taken from the mesio- and disto-buccal aspects of each implant and from one tooth adjacent to one of the implants in each subject. The levels of 40 subgingival species were measured using checkerboard DNA-DNA hybridization. Microbiologic parameters were averaged within each subject and across subjects in each clinical group (platform switching versus control) and site category (implants versus teeth) separately. The significance of differences between clinical groups and site categories was determined using the Mann-Whitney test and the Wilcoxon test, respectively. Results: There were no statistically significant differences between groups for any of the species. The platform-switching group showed a small trend for lower levels of early colonizer members of the Actinomyces, purple and yellow complexes, Campylobacter species, Tannerella forsythia (previously T. forsythensis), and Porphyromonas gingivalis. Teeth and implants presented similar microbial profiles. Conclusion: The results of the study suggest that the difference in bone crest resorption between implants restored with platform switching compared to traditionally restored implants is not associated with differences in the pen-implant microbiota. J Periodontol 2010;81:403-411. C1 [Canullo, Luigi] Univ Bonn, Dept Orthodont, D-5300 Bonn, Germany. [Quaranta, Alessandro] Univ Roma La Sapienza, Dept Prosthodont, Rome, Italy. [Teles, Ricardo P.] Forsyth Inst, Dept Periodontol, Boston, MA USA. RP Canullo, L (reprint author), Via Nizza 46, I-00198 Rome, Italy. EM luigicanullo@yahoo.com NR 37 TC 20 Z9 22 U1 1 U2 4 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 MAR PY 2010 VL 81 IS 3 BP 403 EP 411 DI 10.1902/jop.2009.090498 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 665FL UT WOS:000283020500013 PM 20192867 ER PT J AU Putcha, P Danzer, KM Kranich, LR Scott, A Silinski, M Mabbett, S Hicks, CD Veal, JM Steed, PM Hyman, BT McLean, PJ AF Putcha, Preeti Danzer, Karin M. Kranich, Lisa R. Scott, Anisa Silinski, Melanie Mabbett, Sarah Hicks, Carol D. Veal, James M. Steed, Paul M. Hyman, Bradley T. McLean, Pamela J. TI Brain-Permeable Small-Molecule Inhibitors of Hsp90 Prevent alpha-Synuclein Oligomer Formation and Rescue alpha-Synuclein-Induced Toxicity SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PARKINSONS-DISEASE; GAUSSIA LUCIFERASE; FIBRIL FORMATION; GELDANAMYCIN; AGGREGATION; DEGRADATION; MUTATION; PROTEIN; HSP70; CHIP AB Aggregation of alpha-synuclein (alpha syn) is a hallmark of sporadic and familial Parkinson's disease (PD) and dementia with Lewy bodies. Lewy bodies contain alpha syn and several heat shock proteins (Hsp), a family of molecular chaperones up-regulated by the cell under stress. We have previously shown that direct expression of Hsp70 and pharmacological up-regulation of Hsp70 by geldanamycin, an Hsp90 inhibitor, are protective against alpha syn-induced toxicity and prevent aggregation in culture. Here, we use a novel protein complementation assay to screen a series of small-molecule Hsp90 inhibitors for their ability to prevent alpha syn oligomerization and rescue toxicity. By use of this assay, we found that several compounds prevented alpha syn oligomerization as measured by decreased luciferase activity, led to a reduction in high-molecular-mass oligomeric alpha syn, and protected against alpha syn cytotoxicity. A lead compound, SNX-0723 (2-fluoro-6-[(3S)-tetrahydrofuran-3-ylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl) benzamide) was determined to have an EC(50) for inhibition of alpha syn oligomerization of approximately 48 nM and was able to rescue alpha syn-induced toxicity. In vivo assessment of SNX-0723 showed significant brain concentrations along with induction of brain Hsp70. With a low EC(50), brain permeability, and oral availability, these novel inhibitors represent an exciting new therapeutic strategy for PD. C1 [Putcha, Preeti; Danzer, Karin M.; Kranich, Lisa R.; Hyman, Bradley T.; McLean, Pamela J.] Massachusetts Gen Hosp East, Dept Neurol, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Scott, Anisa; Silinski, Melanie; Mabbett, Sarah; Veal, James M.; Steed, Paul M.] Serenex Inc, Durham, NC USA. [Hicks, Carol D.] Pfizer Inc, Groton, CT 06340 USA. RP McLean, PJ (reprint author), Massachusetts Gen Hosp East, Dept Neurol, MassGen Inst Neurodegenerat Dis, 114 16th St, Charlestown, MA 02129 USA. EM pmclean@partners.org FU National Institutes of Health [NS038372]; Michael J. Fox Foundation FX This work was supported by the National Institutes of Health [Grant NS038372]; and the Michael J. Fox Foundation. NR 40 TC 63 Z9 64 U1 1 U2 20 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR PY 2010 VL 332 IS 3 BP 849 EP 857 DI 10.1124/jpet.109.158436 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 559DF UT WOS:000274800200018 PM 19934398 ER PT J AU Tarazi, FI Moran-Gates, T Wong, EHF Henry, B Shahid, M AF Tarazi, F. I. Moran-Gates, T. Wong, E. H. F. Henry, B. Shahid, M. TI Asenapine induces differential regional effects on serotonin receptor subtypes SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE asenapine; caudate putamen; frontal cortex; hippocampus; serotonin receptor ID RAT-BRAIN; ANTIPSYCHOTIC-DRUGS; PREFRONTAL CORTEX; CELLULAR-LOCALIZATION; 5-HT1A RECEPTORS; MESSENGER-RNA; SCHIZOPHRENIA; RISPERIDONE; BINDING; DOPAMINE AB Asenapine, a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder, has high affinity for a wide range of receptors, including the serotonergic receptors 5-HT(1A), 5-HT(1B), 5-HT(2A), 5-HT(2B), 5-HT(2C), 5-HT(5A), 5-HT(6) and 5-HT(7). We examined the long-term effects in rat brain of multiple doses of asenapine on representative serotonin receptor subtypes: 5-HT(1A), 5-HT(2A) and 5-HT(2C). Rats were given asenapine (0.03, 0.1 or 0.3 mg/kg) subcutaneously twice daily or vehicle for 4 weeks. Brain sections were collected from the medial prefrontal cortex (mPFC), dorsolateral frontal cortex (DFC), caudate putamen, nucleus accumbens, hippocampal CA(1) and CA(3) regions, and entorhinal cortex and processed for in-vitro receptor autoradiography. Asenapine 0.1 and 0.3 mg/kg significantly increased 5-HT(1)A binding in mPFC (by 24% and 33%, respectively), DFC (27%, 31%) and hippocampal C(A1) region (23%, 25%) (all P < 0.05). All three asenapine doses (0.03, 0.1 and 0.3 mg/ kg) significantly decreased 5-HT(2A) binding by a similar degree in mPFC (40%, 44%, 47%, respectively) and DFC (45%, 51%, 52%) (all P < 0.05), but did not alter 5-HT(2A) binding in the other brain regions studied. In contrast to the effects on 5-HT(1A) and 5-HT(2A) receptors, asenapine did not alter 5-HT(2C) binding in any brain region examined at the doses tested. Our results indicate that repeated administration of asenapine produces regional-specific effects on 5-HT(1A) and 5-HT(2A) receptors in rat forebrain regions, which may contribute to the distinctive psychopharmacologic profile of asenapine. C1 [Tarazi, F. I.; Moran-Gates, T.] Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Belmont, MA USA. [Tarazi, F. I.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Tarazi, F. I.] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. [Wong, E. H. F.] Pfizer Global R&D, Ann Arbor, MI USA. [Henry, B.; Shahid, M.] Schering Plough Corp, Newhouse, Lanark, Scotland. RP Tarazi, FI (reprint author), Harvard Univ, Sch Med, McLean Hosp, Lab Psychiat Neurosci, 115 Mill St, Belmont, MA 02478 USA. EM ftarazi@hms.harvard.edu FU Schering-Plough Corporation [HD-052752]; Pfizer Inc; Organon International Inc FX Supported by HD-052752, Schering-Plough Corporation and Pfizer Inc. Editorial support was provided by Karen Zimmermann and was funded by Organon International Inc. and Pfizer Inc. NR 51 TC 21 Z9 23 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD MAR PY 2010 VL 24 IS 3 BP 341 EP 348 DI 10.1177/0269881108095704 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 564QL UT WOS:000275230900006 PM 18719049 ER PT J AU Conners, W Rhoden, EL Morgentaler, A AF Conners, William Rhoden, Ernani Luis Morgentaler, Abraham TI SYMPTOMATIC IMPROVEMENT IN LIBIDO AND LIKELIHOOD OF COMPLETING 12 MONTHS OF TESTOSTERONE THERAPY SO JOURNAL OF SEXUAL MEDICINE LA English DT Meeting Abstract C1 [Conners, William; Morgentaler, Abraham] Mens Hlth Boston Beth Israel Deaconess Med Ctr, Boston, MA USA. [Rhoden, Ernani Luis] Univ Fed Ciencias Saude Porto Alegre, Porto Alegre, RS, Brazil. 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 1743-6095 J9 J SEX MED JI J. Sex. Med. PD MAR PY 2010 VL 7 SU 1 BP 13 EP 13 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 568XC UT WOS:000275558300027 ER PT J AU Conners, W Mousseau, G Flinn, K Morgentaler, A AF Conners, William Mousseau, Gary Flinn, Kevin Morgentaler, Abraham TI TESTOSTERONE PELLET THERAPY AFTER PROSTATE CANCER SO JOURNAL OF SEXUAL MEDICINE LA English DT Meeting Abstract C1 [Conners, William; Mousseau, Gary; Flinn, Kevin; Morgentaler, Abraham] Mens Hlth Boston Beth Israel Deaconess Med Ctr, Boston, MA 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 1743-6095 J9 J SEX MED JI J. Sex. Med. PD MAR PY 2010 VL 7 SU 1 BP 14 EP 14 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 568XC UT WOS:000275558300031 ER PT J AU Prasad, MM Prasad, SM Hevelone, ND Gu, XM Weinberg, AC Lipsitz, SR Palapattu, GS Hu, JC AF Prasad, Michaella M. Prasad, Sandip M. Hevelone, Nathanael D. Gu, Xiangmei Weinberg, Aaron C. Lipsitz, Stuart R. Palapattu, Ganesh S. Hu, Jim C. TI Utilization of Pharmacotherapy for Erectile Dysfunction Following Treatment for Prostate Cancer SO JOURNAL OF SEXUAL MEDICINE LA English DT Review DE Erectile Dysfunction; Prostate Cancer; Pharmacotherapy; PDE5 Inhibitors ID SPARING RADICAL PROSTATECTOMY; PLACEBO-CONTROLLED TRIAL; BASE-LINE POTENCY; QUALITY-OF-LIFE; SILDENAFIL CITRATE; RETROPUBIC PROSTATECTOMY; SEXUAL FUNCTION; DOUBLE-BLIND; PRESCRIPTION DRUGS; 2009 UPDATE AB Introduction. Pharmacotherapies improve sexual function following treatments for localized prostate cancer; however, patterns of care remain unknown. Aim. To ascertain post-treatment utilization of pharmacotherapies for erectile dysfunction (ED) using a population-based approach. Methods. We identified 38,958 men who underwent definitive treatment for localized prostate cancer during 2003-2006 from the MarketScan Medstat data. Main Outcome Measures. We compared the use of ED pharmacotherapy at baseline (up to 3 months prior) and up to 30 months following radical prostatectomy (RP) or radiotherapy (RT) for localized prostate cancer by utilizing National Drug Classification codes for phosphodiesterase-5 inhibitors (PDE5I), intracavernosal injectable therapies (IT), urethral suppositories and vacuum erection devices (VED). In adjusted analyses, we controlled for the effect of age, comorbidity, type of treatment, health plan and use of adjuvant hormone therapy on the use of pharmacotherapies. Results. Men undergoing RP vs. RT were younger with less co-morbid conditions. Utilization of PDE5I was up to three times greater for men undergoing RP vs. RT, 25.6% vs. 8.8%, (P < 0.0001) in the first post-treatment year, and usage of these agents was greatest for men undergoing minimally-invasive RP procedures. A higher percentage of men also used IT, suppositories and VED after RP vs. RT (P < 0.001). However, more men in the RT group received adjuvant hormonal therapy (39.53% vs. 5.25% for RP, P < 0.01). In adjusted analyses, men undergoing RP vs. RT were more than two times likely (OR 2.1, 95% CI 1.98, 2.26) to use PDE5I post-treatment while men on adjuvant hormonal therapy were less likely to use PDE5I (OR 0.74, 95% CI 0.70-0.79, P < 0.0001). Conclusion. Men undergoing RP vs. RT, particularly minimally-invasive RP, are more likely to employ IT, suppositories, VED, and PDE5I pharmacotherapy post-treatment. Prasad MM, Prasad SM, Hevlone ND, Gu X, Weinberg AC, Lipsitz SR, Palapattu GS, and Hu JC. Utilization of pharmacotherapy for erectile dysfunction following treatment for prostate cancer. J Sex Med 2010;7:1062-1073. C1 [Prasad, Michaella M.; Prasad, Sandip M.; Hu, Jim C.] Brigham & Womens Hosp, Div Urol Surg, Boston, MA 02115 USA. [Hevelone, Nathanael D.; Gu, Xiangmei; Weinberg, Aaron C.; Lipsitz, Stuart R.; Hu, Jim C.] Brigham & Womens Hosp, Ctr Surg & Publ Hlth, Boston, MA 02115 USA. [Palapattu, Ganesh S.] Methodist Hosp, Dept Urol, Houston, TX 77030 USA. [Hu, Jim C.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. RP Hu, JC (reprint author), Brigham & Womens Hosp, Div Urol, ASBII-3,45 Francis ST, Boston, MA 02115 USA. EM jhu2@partners.org OI Hevelone, Nathanael/0000-0003-4740-2085; weinberg, aaron/0000-0002-0957-5703 FU Lance Armstrong Young Investigator Award FX This study was funded by a Lance Armstrong Young Investigator Award conferred to Dr. Jim Hu. NR 47 TC 12 Z9 12 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1743-6095 J9 J SEX MED JI J. Sex. Med. PD MAR PY 2010 VL 7 IS 3 BP 1062 EP 1073 DI 10.1111/j.1743-6109.2009.01644.x PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 563BF UT WOS:000275099700004 PM 20059662 ER PT J AU Hopkins, LN Roubin, GS Chakhtoura, EY Gray, WA Ferguson, RD Katzen, BT Rosenfield, K Goldstein, J Cutlip, DE Morrish, W Lal, BK Sheffet, AJ Tom, M Hughes, S Voeks, J Kathir, K Meschia, JF Hobson, RW Brott, TG AF Hopkins, L. Nelson Roubin, Gary S. Chakhtoura, Elie Y. Gray, William A. Ferguson, Robert D. Katzen, Barry T. Rosenfield, Kenneth Goldstein, Jonathan Cutlip, Donald E. Morrish, William Lal, Brajesh K. Sheffet, Alice J. Tom, MeeLee Hughes, Susan Voeks, Jenifer Kathir, Krishna Meschia, James F. Hobson, Robert W., II Brott, Thomas G. TI The Carotid Revascularization Endarterectomy versus Stenting Trial: Credentialing of Interventionalists and Final Results of Lead-in Phase SO JOURNAL OF STROKE & CEREBROVASCULAR DISEASES LA English DT Article DE Carotid stenosis; carotid stenting; interventional credentialing; revascularization; stent AB The success of carotid artery stenting in preventing stroke requires a low risk of peri-procedural stroke and death. A comprehensive training and credentialing process was prerequisite to the randomized Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) to assemble a competent team of interventionalists with low periprocedural event rates. Interventionalists submitted cases to a multidisciplinary Interventional Management Committee. This committee evaluated 427 applicants. Of these, 238 (56%) were selected to participate in the training program and the lead-in phase, 73 (17%) who had clinical registry experience and satisfactory results with the devices used in CREST were exempt from training and were approved for the randomized phase, and 116 (27%) did not qualify for training. At 30 days in the lead-in study, stroke, myocardial infarction, or death occurred in 6.1% of symptomatic subjects and 4.8% of asymptomatic subjects. Stroke or death occurred in 5.8% of symptomatic subjects and 3.8% of asymptomatic subjects. Outcomes were better for younger subjects and varied by operator training. Based on experience, training, and lead-in results, the Interventional Management Committee selected 224 interventionalists to participate in the randomized phase of CREST. We believe that the credentialing and training of interventionalists participating in CREST have been the most rigorous reported to date for any randomized trial evaluating endovascular treatments. The study identified competent operators, which ensured that the randomized trial results fairly contrasted outcomes between endarterectomy and stenting. C1 [Meschia, James F.; Brott, Thomas G.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Hopkins, L. Nelson] SUNY Buffalo, Dept Neurosurg, Millard Fillmore Hosp, Buffalo, NY 14260 USA. [Roubin, Gary S.; Kathir, Krishna] Lenox Hill Hosp, Dept Intervent Cardiol, New York, NY 10021 USA. [Chakhtoura, Elie Y.; Goldstein, Jonathan] St Michaels Hosp, Div Cardiol, Newark, NJ USA. [Gray, William A.] New York Presbyterian Hosp Columbia, Dept Internal Med, New York, NY USA. [Ferguson, Robert D.] Metrohlth Med Ctr, Dept Radiol, Cleveland, OH USA. [Katzen, Barry T.] Baptist Cardiac & Vasc Inst, Miami, FL USA. [Rosenfield, Kenneth] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Cutlip, Donald E.] Harvard Clin Res Inst, Boston, MA USA. [Morrish, William] Foothills Prov Gen Hosp, Dept Diagnost Imaging, Calgary, AB T2N 2T9, Canada. [Lal, Brajesh K.; Sheffet, Alice J.; Tom, MeeLee; Hughes, Susan; Hobson, Robert W., II] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Voeks, Jenifer] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. RP Brott, TG (reprint author), Mayo Clin, Dept Neurol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM brott.thomas@mayo.edu FU National Institutes of Health, National Institute of Neurological Disorders of Stroke [RO1-NS38384] FX Supported by National Institutes of Health, National Institute of Neurological Disorders of Stroke Grant RO1-NS38384. Industry support was provided by Abbott Vascular Solutions (formerly Guidant Endovascular Solutions). NR 24 TC 87 Z9 90 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1052-3057 J9 J STROKE CEREBROVASC JI J. Stroke Cerebrovasc. Dis. PD MAR PY 2010 VL 19 IS 2 BP 153 EP 162 DI 10.1016/j.jstrokecerebrovasdis.2010.01.001 PG 10 WC Neurosciences; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA V22OC UT WOS:000208283500010 PM 20189092 ER PT J AU Durazzo, TC Pathak, V Gazdzinski, S Mon, A Meyerhoff, DJ AF Durazzo, Timothy C. Pathak, Varsha Gazdzinski, Stefan Mon, Anderson Meyerhoff, Dieter J. TI Metabolite Levels in the Brain Reward Pathway Discriminate Those Who Remain Abstinent From Those Who Resume Hazardous Alcohol Consumption After Treatment for Alcohol Dependence SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID MAGNETIC-RESONANCE SPECTROSCOPY; FRONTAL-SUBCORTICAL CIRCUITS; DSM-IV ALCOHOL; NATIONAL EPIDEMIOLOGIC SURVEY; PROTON MR SPECTROSCOPY; USE DISORDERS; UNITED-STATES; POSTTREATMENT ALCOHOLICS; CIGARETTE-SMOKING; FAMILY-HISTORY AB Objective: This study compared baseline metabolite levels in components of the brain reward system among individuals who remained abstinent and those who resumed hazardous alcohol consumption after treatment for alcohol dependence. Method: Fifty-one treatment-seeking alcohol-dependent individuals (abstinent for approximately 7 days [SD = 3]) and 26 light-drinking nonsmoking controls completed 1.5-T proton magnetic resonance spectroscopic imaging, yielding regional concentrations of N-acetylaspartate, choline-containing compounds, creatinc-containing compounds, and myoinositol. Metabolite levels were obtained in the following component of the brain reward system: dorsolateral prefrontal cortex, anterior cingulate cortex, insula, superior corona radiata, and cerebellar vermis. Alcohol-dependent participants were followed over a 12-month period after baseline study (i.e., at 7 days of abstinence [SD = 3]) and were classified as abstainers (no alcohol consumption; n = 18) and resumers (any alcohol consumption; n = 33) at follow-up. Baseline metabolite levels in abstainers and resumers and light-drinking nonsmoking controls were compared in the above regions of interest. Results: Resumers demonstrated significantly lower baseline N-acetylaspartate concentrations than light-drinking nonsmoking controls and abstainers in all regions of interest. Resumers also exhibited lower creatine-containing-compound concentrations than abstainers in the dorsolateral prefrontal cortex, superior corona radiata, and cerebellar vermis. Abstainers did not differ from light-drinking nonsmoking controls on baseline metabolite concentrations in any region of interest. Conclusions: The significantly decreased N-acetylaspartate and creatine-containing-compound concentrations in resumers suggest compromised neuronal integrity and abnormalities in cellular bioenergetics in major neocortical components and white-matter interconnectivity of the brain reward pathway. The lack of metabolite differences between abstainers and light-drinking nonsmoking controls suggests premorbid factors potentially contributed to the baseline brain metabolite abnormalities observed in resumers. (J Stud. Alcohol Drugs, 71, 278-289, 2010) C1 [Durazzo, Timothy C.; Pathak, Varsha; Mon, Anderson; Meyerhoff, Dieter J.] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA. [Durazzo, Timothy C.; Pathak, Varsha; Gazdzinski, Stefan; Mon, Anderson; Meyerhoff, Dieter J.] San Francisco Vet Adm Med Ctr, Ctr Imaging Neurodegenerat Dis 114M, San Francisco, CA 94121 USA. RP Durazzo, TC (reprint author), San Francisco Vet Adm Med Ctr, Ctr Imaging Neurodegenerat Dis 114M, 4150 Clement St, San Francisco, CA 94121 USA. EM timothy.durazzo@ucsf.edu FU National Institute on Alcohol Abuse and Alcoholism [AA10788]; National Institute on Drug Abuse [DA24136] FX This research was supported by National Institute on Alcohol Abuse and Alcoholism grant AA10788 awarded to Dieter J. Meyerhoff and National Institute on Drug Abuse grant DA24136 awarded to Timothy C. Durazzo, and with resources and the use of facilities at the San Francisco Veterans Administration Medical Center, San Francisco, CA. NR 87 TC 19 Z9 21 U1 2 U2 4 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 MAR PY 2010 VL 71 IS 2 BP 278 EP 289 PG 12 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 578FJ UT WOS:000276278700015 PM 20230726 ER PT J AU Li, YQ Liu, BL Dillon, ST Fukudome, EY Kheirbek, T Sailhamer, EA Velmahos, G deMoya, M Libermann, TA Alam, HB AF Li, Yongqing Liu, Baoling Dillon, Simon T. Fukudome, Eugene Y. Kheirbek, Tareq Sailhamer, Elizabeth A. Velmahos, George deMoya, Marc Libermann, Towia A. Alam, Hasan B. TI Identification of a Novel Potential Biomarker in a Model of Hemorrhagic Shock and Valproic Acid Treatment SO JOURNAL OF SURGICAL RESEARCH LA English DT Article; Proceedings Paper CT 4th Annual-Academic-Surgical-Congress CY FEB 03-06, 2009 CL Ft Myers, FL SP Assoc Acad Surg, Soc Univ Surg DE hemorrhagic shock; biomarker; claudin-3; valproic acid; survival ID BLOOD-BRAIN-BARRIER; LOCALIZATION; DISCOVERY; EXPRESSION; PROTEOMICS; CLAUDIN-3; MARKERS; SELDI; CELLS AB Background. The initial management of a polytrauma patient requires evaluation for potential hemorrhage and ongoing monitoring to assess the efficacy of treatment and avoid complications related to massive blood loss. Certain serum protein levels may be altered in response to hemorrhagic shock, and may serve as useful biomarkers to guide diagnosis, prognosis, and therapeutics in traumatic hemorrhagic shock (HS). Treatment with valproic acid (VPA) has been shown to up-regulate various survival pathways and improve outcome. Here we determine whether these changes would result in altered serum biomarkers. Methods. Wistar-Kyoto rats underwent hemorrhagic shock (60% blood loss) followed by treatment with or without VPA (300 mg/kg). Using surface enhanced laser desorption-time of flight mass spectrometry (SELDI or SELDI-TOF MS) technology, we screened serum samples obtained from five rats at different time points (baseline, post-hemorrhagic shock, and post-VPA treatment) in a lethal model of hemorrhagic shock (HS). Additionally, we used isobaric tag labeling for relative quantitation (iTRAQ) to identify potential biomarkers in the serum. Western blots were performed to validate iTRAQ-identified biomarker from independent serum samples, and to analyze protein biomarker levels in the intestine during hemorrhagic shock and treatment. Results. HS and treatment with VPA affected serum levels of many proteins. One such protein with a mass spectrum around 22.7 kDa was detected in all five rats. The same serum samples subjected to iTRAQ resulted in our identification of claudin-3, a 23 kDa tight junction protein. HS elevated serum claudin-3 protein levels, which was reversed by VPA treatment in a pattern similar to the SELDI-TOF MS studies. Further validation with independent serum and intestine samples from individual rats by Western blots confirmed that HS increased the protein level of claudin-3 in serum and decreased its level in the intestine. Treatment with VPA reversed the hemorrhagic shock-induced alteration in claudin-3 to sham levels. Conclusions. HS causes an acute rise in serum clandin-3 protein levels and a concurrent decrease in intestinal claudin-3 protein expression. VPA treatment attenuates these alterations and stabilizes intestinal claudin-3 levels. Our results demonstrate for the first time that claudin-3 is a potential biomarker in HS and treatment. (C) 2010 Elsevier Inc. All rights reserved. C1 [Li, Yongqing; Liu, Baoling; Fukudome, Eugene Y.; Kheirbek, Tareq; Sailhamer, Elizabeth A.; Velmahos, George; deMoya, Marc; Alam, Hasan B.] Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Dillon, Simon T.; Libermann, Towia A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Alam, HB (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM hbalam@partners.org RI Libermann, Towia/F-9866-2010; OI Libermann, Towia/0000-0002-4006-8179 NR 18 TC 15 Z9 18 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 MAR PY 2010 VL 159 IS 1 BP 474 EP 481 DI 10.1016/j.jss.2009.04.011 PG 8 WC Surgery SC Surgery GA 601NJ UT WOS:000278066600006 PM 19765733 ER PT J AU Slama, MCC Ravicz, ME Rosowski, JJ AF Slama, Michael C. C. Ravicz, Michael E. Rosowski, John J. TI Middle ear function and cochlear input impedance in chinchilla SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID SOUND-PRESSURE MEASUREMENTS; SUPERIOR CANAL DEHISCENCE; HUMAN TEMPORAL BONES; MONGOLIAN GERBIL; STAPES VELOCITY; CADAVER EARS; INNER-EAR; TRANSMISSION; CAT; MODEL AB Simultaneous measurements of middle ear-conducted sound pressure in the cochlear vestibule P(V) and stapes velocity V(S) have been performed in only a few individuals from a few mammalian species. In this paper, simultaneous measurements of P(V) and V(S) in six chinchillas are reported, enabling computation of the middle ear pressure gain G(ME) (ratio of P(V) to the sound pressure in the ear canal P(TM)), the stapes velocity transfer function SVTF (ratio of the product of V(S) and area of the stapes footplate A(FP) to P(TM)), and, for the first time, the cochlear input impedance Z(C) (ratio of P(V) to the product of V(S) and A(FP)) in individuals. vertical bar G(ME)vertical bar ranged from 25 to 35 dB over 125 Hz-8 kHz; the average group delay between 200 Hz and 10 kHz was about 52 mu s. SVTF was comparable to that of previous studies. Z(C) was resistive from the lowest frequencies up to at least 10 kHz, with a magnitude on the order of 10(11) acoustic ohms. P(V), V(S), and the acoustic power entering the cochlea were good predictors of the shape of the audiogram at frequencies between 125 Hz and 2 kHz. (C) 2010 Acoustical Society of America. [DOI: 10.1121/1.3279830] C1 [Slama, Michael C. C.] MIT, Speech & Hearing Biosci & Technol Program, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Ravicz, Michael E.; Rosowski, John J.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RP Slama, MCC (reprint author), MIT, Speech & Hearing Biosci & Technol Program, Harvard Mit Div Hlth Sci & Technol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. FU National Institute on Deafness and other Communication Disorders (NIDCD) [RO1-DC00194, T32-DC00038] FX We thank Elizabeth Olson, Wei Dong, and Heidi Nakajima, for their assistance in making the fiber-optic pressure sensors and their advice in using them in our experiments. We also thank Melissa Wood for her mastery of chinchilla surgery and her help with the experiments. We would also like to express our appreciation to the staff of the Microsystems Technology Laboratories at MIT and, in particular, to Kurt Broderick. This work was supported by Grant Nos. RO1-DC00194 and T32-DC00038 from the National Institute on Deafness and other Communication Disorders (NIDCD). NR 52 TC 15 Z9 15 U1 2 U2 10 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD MAR PY 2010 VL 127 IS 3 BP 1397 EP 1410 DI 10.1121/1.3279830 PN 1 PG 14 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 573TO UT WOS:000275938000032 PM 20329840 ER PT J AU Eddy, KT Le Grange, D Crosby, RD Hoste, RR Doyle, AC Smyth, A Herzog, DB AF Eddy, Kamryn T. Le Grange, Daniel Crosby, Ross D. Hoste, Renee Rienecke Doyle, Angela Celio Smyth, Angela Herzog, David B. TI Diagnostic Classification of Eating Disorders in Children and Adolescents: How Does DSM-IV-TR Compare to Empirically-Derived Categories? SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article; Proceedings Paper CT Annual Conference of the Eating-Disorders-Research-Society CY SEP, 2009 CL Brooklyn, NY SP Eating Disorders Res Soc DE Eating disorders; Diagnosis; Classification; Latent profile analysis ID LATENT CLASS ANALYSIS; OTHERWISE SPECIFIED EDNOS; BULIMIA-NERVOSA; PROFILE ANALYSIS; MODEL-SELECTION; PSYCHOPATHOLOGY; PHENOTYPES; SYMPTOMS; TYPOLOGY; TAXOMETRICS AB Objective: The purpose of this study was to empirically derive eating disorder phenotypes in a clinical sample of children and adolescents using latent profile analysis (LPA), and to compare these latent profile (LP) groups to the DSM-IV-TR eating disorder categories. Method: Eating disorder symptom data collected from 401 youth (aged 7 through 19 years; mean 15.14 +/- 2.35 years) seeking eating disorder treatment were included in LPA; general linear models were used to compare LP groups to DSM-IV-TR eating disorder categories on pretreatment and outcome indices. Results: Three LP groups were identified: LP1 (n = 144), characterized by binge eating and purging ("Binge/purge"); LP2 (n = 126), characterized by excessive exercise and extreme eating disorder cognitions ("Exercise-extreme cognitions"); and LP3 (n = 131), characterized by minimal eating disorder behaviors and cognitions ("Minimal behaviors/cognitions"). Identified LPs imperfectly resembled DSM-IV-TR eating disorders. LP1 resembled bulimia nervosa; LP2 and LP3 broadly resembled anorexia nervosa with a relaxed weight criterion, differentiated by excessive exercise and severity of eating disorder cognitions. The LP groups were more differentiated than the DSM-IV-TR categories across pretreatment eating disorder and general psychopathology indices, as well as weight change at follow-up. Neither LP nor DSM-IV-TR categories predicted change in binge/purge behaviors. Validation analyses suggest these empirically derived groups improve upon the current DSM-IV-TR categories. Conclusions: In children and adolescents, revisions for DSM-V should consider recognition of patients with minimal cognitive eating disorder symptoms. J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(3):277-287. C1 [Eddy, Kamryn T.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Eddy, Kamryn T.; Herzog, David B.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Le Grange, Daniel; Hoste, Renee Rienecke; Doyle, Angela Celio; Smyth, Angela] Univ Chicago, Chicago, IL 60637 USA. RP Eddy, KT (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 2 Longfellow Pl,Suite 200, Boston, MA 02114 USA. EM keddy@partners.org RI Le Grange, Daniel/A-2649-2011; OI Crosby, Ross/0000-0001-9131-1629 FU NIDDK NIH HHS [P30 DK040561-14, P30 DK040561]; NIMH NIH HHS [F32MH084396), F32 MH084396, R13 MH081447, F32 MH084396-01A1] NR 42 TC 21 Z9 21 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD MAR PY 2010 VL 49 IS 3 BP 277 EP 287 DI 10.1016/j.jaac.2009.10.012 PG 11 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 561ZA UT WOS:000275017400010 PM 20410717 ER PT J AU Magro, CM Crowson, AN Mihm, MC Gupta, K Walker, MJ Solomon, G AF Magro, Cynthia M. Crowson, A. Neil Mihm, Martin C., Jr. Gupta, Kapil Walker, Michael J. Solomon, Garron TI The dermal-based borderline melanocytic tumor: A categorical approach SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID LYMPH-NODE BIOPSY; PIGMENTED EPITHELIOID MELANOCYTOMA; DEEP PENETRATING NEVUS; IN-SITU HYBRIDIZATION; MALIGNANT-MELANOMA; SPITZ TUMORS; LESIONS; DIAGNOSIS; FEATURES; MANAGEMENT AB Background: The borderline melanocytic tumor (BMT) is a morphologically and biologically indeterminate melanocytic proliferation manifesting worrisome architectural features and cytologic atypia exceeding that encountered in melanocytic nevi yet insufficient to warrant designation as melanoma. The criteria that define the BMT are not well defined nor is the concept widely recognized. Objective: The purpose of this study is to provide a practical framework for the approach to the dermal BMT. Methods: Thirty-two patients with BMTs extending into the reticular dermis and at: a depth of 0.75 nun or more underwent local excision and sentinel lymph node biopsy between 2000 and 2006. Four categories of BMT were recognized: (1) nevoid BMT (BNM); (2) the atypical Spitz tumor (AST); (3) pigmented epithelioid melanocytoma (PEM); and (4) BMT arising in a deep penetrating nevus (B-DPN). Results: Four patients were in the BNM category (male/female ratio [M:F] = 1:3; mean age = 27 years, range = 15-36), 14 in the AST category (M:F = 7:7; mean age = 20.9, range = 3-58), 7 in the PENT category (M:F = 4:3; mean age = 23.5; range = 3-39), and 7 in the B-DPN category (M:F = 5:2; mean age = 22.3, range = 14-36). The percentages of patients with positive sentinel nodes in each category were 25% (1/4), 35% (5/14); 14% (1/7), and 57% (4/7), respectively. The average time of follow-Up was approximately 4.2 years. One patient, a 36-year-old man, died of disease, while the others are alive and well. In the one death attributable to widespread metastatic disease, the lesion was initially interpreted as a deep penetrating nevus; however, retrospective review revealed features compatible with a B-DPN: the review was prompted by a recurrence that was morphologically compatible with a Clark level V malignant melanoma, reflecting clinical and morphologic progression. Limitations: The mean follow-Up Was less than 5 years. Molecular studies to further explore the biologic commonality with melanoma were not performed. Conclusion: The dermal variant of BMT is a tumor of younger adults and children that can be associated with lymph node disease and a potential for morphologic and biologic progression when inadequately treated. (J Air Acad Dermatol 2010;62:469-79.) C1 [Magro, Cynthia M.] Cornell Univ, Dept Pathol, Weill Med Coll, New York, NY 10021 USA. [Solomon, Garron] Strata Pathol Serv Inc, Lexington, MA USA. [Crowson, A. Neil] Univ Oklahoma, Reg Med Lab, St Johns Med Ctr, Tulsa, OK USA. [Mihm, Martin C., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Gupta, Kapil] Dermatol Grp Carolinas, Concord, NC USA. [Walker, Michael J.] Ohio State Univ, Columbus, OH 43210 USA. RP Magro, CM (reprint author), Cornell Univ, Dept Pathol, Weill Med Coll, 1300 York Ave,F-309, New York, NY 10021 USA. EM cym2003@med.cornell.edu NR 34 TC 25 Z9 25 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2010 VL 62 IS 3 BP 469 EP 479 DI 10.1016/j.jaad.2009.06.042 PG 11 WC Dermatology SC Dermatology GA 573AJ UT WOS:000275880500015 PM 20159313 ER PT J AU Kimball, A Pariser, D Kricorian, G Gelfand, J AF Kimball, Alexa Pariser, David Kricorian, Gregory Gelfand, Joel TI Safety update from OBSERVE-5, a long-term safety surveillance registry of etanercept therapy for psoriasis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Academy-of-Dermatology CY MAR 05-09, 2010 CL Miami, FL SP Amer Acad Dermatol C1 [Kimball, Alexa] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kimball, Alexa] Brigham & Womens Hosp, Boston, MA 02115 USA. [Pariser, David] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Pariser, David] Virginia Clin Res, Norfolk, VA USA. [Kricorian, Gregory] Amgen Inc, Thousand Oaks, CA USA. [Gelfand, Joel] Univ Penn Hlth Syst, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2010 VL 62 IS 3 SU S BP AB129 EP AB129 PG 1 WC Dermatology SC Dermatology GA 573AL UT WOS:000275880700504 ER PT J AU Landeck, L Gonzalez, E Neumann, K Baden, L Schalock, P AF Landeck, Lilla Gonzalez, Ernesto Neumann, Konrad Baden, Lynn Schalock, Peter TI Common allergens in periorbital dermatitis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Academy-of-Dermatology CY MAR 05-09, 2010 CL Miami, FL SP Amer Acad Dermatol C1 [Landeck, Lilla; Gonzalez, Ernesto; Schalock, Peter] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Neumann, Konrad] Charite, Dept Biometry & Clin Epidemiol, D-13353 Berlin, Germany. [Baden, Lynn] Newton Ctr, Ctr Dermatol Aesthet Med, Newton, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2010 VL 62 IS 3 SU S BP AB49 EP AB49 PG 1 WC Dermatology SC Dermatology GA 573AL UT WOS:000275880700185 ER PT J AU Lima, XT Kimball, AB Abuabara, K AF Lima, Xinaida T. Kimball, Alexandra B. Abuabara, Katrina TI Pregnancy outcomes in psoriasis: A retrospective analysis SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Academy-of-Dermatology CY MAR 05-09, 2010 CL Miami, FL SP Amer Acad Dermatol C1 [Lima, Xinaida T.; Kimball, Alexandra B.; Abuabara, Katrina] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2010 VL 62 IS 3 SU S BP AB125 EP AB125 PG 1 WC Dermatology SC Dermatology GA 573AL UT WOS:000275880700486 ER PT J AU Pena-Robichaux, V Watson, AJ Kvedar, JC AF Pena-Robichaux, Venessa Watson, Alice J. Kvedar, Joseph C. TI Text messages as a reminder aid and educational tool in adolescents and adults with atopic dermatitis: A pilot study SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Meeting Abstract CT 68th Annual Meeting of the American-Academy-of-Dermatology CY MAR 05-09, 2010 CL Miami, FL SP Amer Acad Dermatol C1 [Pena-Robichaux, Venessa; Watson, Alice J.; Kvedar, Joseph C.] Harvard Univ, Sch Med, Dept Dermatol,Massachusetts Gen Hosp, Partners Ctr Connected Hlth, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD MAR PY 2010 VL 62 IS 3 SU S BP AB10 EP AB10 PG 1 WC Dermatology SC Dermatology GA 573AL UT WOS:000275880700038 ER PT J AU Lichtman, DM Bindra, RR Boyer, MI Putnam, MD Ring, D Slutsky, DJ Taras, JS Watters, WC Goldberg, MJ Keith, M Turkelson, CM Wies, JL Haralson, RH Boyer, KM Hitchcock, K Raymond, L AF Lichtman, David M. Bindra, Randipsingh R. Boyer, Martin I. Putnam, Matthew D. Ring, David Slutsky, David J. Taras, John S. Watters, William C., III Goldberg, Michael. J. Keith, Michael Turkelson, Charles M. Wies, Janet L. Haralson, Robert H., III Boyer, Kevin M. Hitchcock, Kristin Raymond, Laura TI Treatment of Distal Radius Fractures SO JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS LA English DT Article ID BRIDGING EXTERNAL FIXATION; REDISPLACED UNSTABLE FRACTURES; REDISLOCATED COLLES FRACTURE; PROSPECTIVE RANDOMIZED-TRIAL; WRIST FRACTURES; NORIAN SRS; INTRAARTICULAR FRACTURES; BONE-CEMENT; ARTHROSCOPIC REDUCTION; POSTMENOPAUSAL WOMEN AB The clinical practice guideline is based on a systematic review of published studies on the treatment of distal radius fractures in adults. None of the 29 recommendations made by the work group was graded as strong; most are graded as inconclusive or consensus; seven are graded as weak. The remaining five moderate-strength recommendations include surgical fixation, rather than cast fixation, for fractures with postreduction radial shortening >3 mm, dorsal tilt >10 degrees, or intra-articular displacement or step-off >2 mm; use of rigid immobilization rather than removable splints for nonsurgical treatment; making a postreduction true lateral radiograph of the carpus to assess dorsal radial ulnar joint alignment; beginning early wrist motion following stable fixation; and recommending adjuvant treatment with vitamin C to prevent disproportionate pain. C1 [Lichtman, David M.] Univ N Texas Hlth Sci Ctr, Dept Orthopaed Surg, Ft Worth, TX 76107 USA. [Lichtman, David M.] John Peter Smith Hosp, Dept Orthopaed Surg, Ft Worth, TX 76104 USA. [Bindra, Randipsingh R.] Loyola Univ, Med Ctr, Dept Orthopaed Surg, Maywood, IL 60153 USA. [Boyer, Martin I.] Washington Univ, Sch Med, Affiliated Hosp, Dept Orthoped Surg, St Louis, MO USA. [Putnam, Matthew D.] Univ Minnesota, Dept Orthopaed Surg, Minneapolis, MN 55455 USA. [Slutsky, David J.] Slutsky Hand & Wrist Inst, Torrance, CA USA. [Ring, David] Massachusetts Gen Hosp, Hand & Upper Extrem Serv, Boston, MA 02114 USA. [Taras, John S.] Philadelphia & S Jersey Hand Ctr, Philadelphia, PA USA. [Watters, William C., III] Bone & Joint Clin Houston, Houston, TX USA. [Goldberg, Michael. J.] Seattle Childrens Hosp, Dept Orthopaed, Skeletal Dysplasia Clin, Seattle, WA USA. [Keith, Michael] Metrohlth Med Ctr, Cleveland, OH USA. [Haralson, Robert H., III] Amer Acad Orthopaed Surg, Dept Med Affairs, Rosemont, IL USA. [Turkelson, Charles M.; Wies, Janet L.; Boyer, Kevin M.; Hitchcock, Kristin; Raymond, Laura] Amer Acad Orthopaed Surg, Dept Res & Sci Affairs, Rosemont, IL USA. RP Lichtman, DM (reprint author), Univ N Texas Hlth Sci Ctr, Dept Orthopaed Surg, Ft Worth, TX 76107 USA. OI Putnam, Matthew/0000-0002-3968-5233 NR 71 TC 54 Z9 57 U1 2 U2 7 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 MAR PY 2010 VL 18 IS 3 BP 180 EP 189 PG 10 WC Orthopedics SC Orthopedics GA 563ZT UT WOS:000275180800007 PM 20190108 ER PT J AU Thrall, JH AF Thrall, James H. TI Health Care Legislation: A Cautionary Tale of Unintended Consequences SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Thrall, JH (reprint author), Massachusetts Gen Hosp, Dept Radiol, 32 Fruit St,Room 216, Boston, MA 02114 USA. EM jthrall@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1546-1440 J9 J AM COLL RADIOL JI J. Am. Coll. Radiol. PD MAR PY 2010 VL 7 IS 3 BP 165 EP 166 DI 10.1016/j.jacr.2010.01.022 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V23SM UT WOS:000208362500001 PM 20193916 ER PT J AU Iyer, VR Hahn, PF Blaszkowsky, LS Thayer, SP Halpern, EF Harisinghani, MG AF Iyer, Veena R. Hahn, Peter F. Blaszkowsky, Lawrence S. Thayer, Sarah P. Halpern, Elkan F. Harisinghani, Mukesh G. TI Added Value of Selected Images Embedded Into Radiology Reports to Referring Clinicians SO JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY LA English DT Article DE Radiology reporting; radiology practice; communication; digital images AB Purpose: The aim of this study was to evaluate the added utility of embedding images for findings described in radiology text reports to referring clinicians. Methods: Thirty-five cases referred for abdominal CT scans in 2007 and 2008 were included. Referring physicians were asked to view text-only reports, followed by the same reports with pertinent images embedded. For each pair of reports, a questionnaire was administered. A 5-point, Likert-type scale was used to assess if the clinical query was satisfactorily answered by the text-only report. A "yes-or-no" question was used to assess whether the report with images answered the clinical query better; a positive answer to this question generated "yes-or-no" queries to examine whether the report with images helped in making a more confident decision on management, whether it reduced time spent in forming the plan, and whether it altered management. The questionnaire asked whether a radiologist would be contacted with queries on reading the text-only report and the report with images. Results: In 32 of 35 cases, the text-only reports satisfactorily answered the clinical queries. In these 32 cases, the reports with attached images helped in making more confident management decisions and reduced time in planning management. Attached images altered management in 2 cases. Radiologists would have been consulted for clarifications in 21 and 10 cases on reading the text-only reports and the reports with embedded images, respectively. Conclusions: Providing relevant images with reports saves time, increases physicians' confidence in deciding treatment plans, and can alter management. C1 [Iyer, Veena R.; Hahn, Peter F.; Harisinghani, Mukesh G.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med, Boston, MA 02114 USA. [Blaszkowsky, Lawrence S.] Harvard Univ, Massachusetts Gen Hosp, Dept Med Oncol, Sch Med, Boston, MA 02114 USA. [Thayer, Sarah P.] Harvard Univ, Massachusetts Gen Hosp, Dept Surg, Sch Med, Boston, MA 02114 USA. [Halpern, Elkan F.] Harvard Univ, Massachusetts Gen Hosp, Inst Technol Assessment, Sch Med, Boston, MA 02114 USA. RP Iyer, VR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med, 55 Fruit St,White 270, Boston, MA 02114 USA. EM viyer@partners.org FU NCI NIH HHS [P50 CA127003-04, P01 CA117969-03, P01 CA117969, P50 CA127003, P50 CA127003-05, P01 CA117969-04, P01 CA117969-04S1, P50 CA127003-03]; NIAID NIH HHS [P01 AI054904-04, P01 AI054904]; NIDDK NIH HHS [K08 DK071329-05, K08 DK071329-04, K08 DK071329] NR 18 TC 15 Z9 15 U1 0 U2 3 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 MAR PY 2010 VL 7 IS 3 BP 205 EP 210 DI 10.1016/j.jacr.2009.10.014 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V23SM UT WOS:000208362500011 PM 20193926 ER PT J AU Yueh, B Collins, MP Souza, PE Boyko, EJ Loovis, CF Heagerty, PJ Liu, CF Hedrick, SC AF Yueh, Bevan Collins, Margaret P. Souza, Pamela E. Boyko, Edward J. Loovis, Carl F. Heagerty, Patrick J. Liu, Chuan-Fen Hedrick, Susan C. TI Long-Term Effectiveness of Screening for Hearing Loss: The Screening for Auditory Impairment-Which Hearing Assessment Test (SAI-WHAT) Randomized Trial SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE screening; hearing loss; hearing aids; randomized clinical trial ID QUALITY-OF-LIFE; ELDERLY PEOPLE; OLDER-ADULTS; PRIMARY-CARE; TASK-FORCE; HEALTH; AMPLIFICATION; VALIDATION; HANDICAP; AIDS AB OBJECTIVES To evaluate the effect of hearing screening on long-term hearing outcomes in a general population of older veterans. DESIGN Hearing loss in the elderly is underdetected and undertreated. Routine hearing screening has been proposed, but it is not clear whether screening identifies patients who are sufficiently motivated to adhere to treatment. A four-arm randomized clinical trial was conducted to compare three screening strategies with no screening in 2,305 older veterans seeking general medical care. SETTING Veterans Affairs Puget Sound Health Care System. INTERVENTIONS The screening strategies were a tone-emitting otoscope, a widely used questionnaire about hearing handicap, and a combination of both tools. MEASUREMENTS Hearing aid use 1 year after screening. RESULTS Of participants who underwent screening with the tone-emitting otoscope, questionnaire, and combined testing, 18.6%, 59.2%, and 63.6%, respectively, screened positive for hearing loss (P <.01 for test of equality across three arms). Patients proceeded to formal audiology evaluation 14.7%, 23.0%, and 26.6% of the time in the same screening arms, compared with 10.8% in the control arm (P <.01 for test of equality across four arms). Hearing aid use 1 year after screening was 6.3%, 4.1%, and 7.4% in the same arms, compared with 3.3% in the control arm (P <.01). Hearing aid users experienced significant improvements in hearing-related function and communication ability. CONCLUSION In older veterans, screening for hearing loss led to significantly more hearing aid use. Screening with the tone-emitting otoscope was more efficient. The results are most applicable to older populations with few cost barriers to hearing aids. C1 [Yueh, Bevan] Univ Minnesota, Dept Otolaryngol Head & Neck Surg, Minneapolis, MN 55455 USA. [Collins, Margaret P.; Boyko, Edward J.] Hlth Serv Res, Seattle, WA USA. [Collins, Margaret P.; Boyko, Edward J.] Dev Serv, Seattle, WA USA. [Collins, Margaret P.; Loovis, Carl F.] Rehabil Care Serv, Seattle, WA USA. [Boyko, Edward J.; Heagerty, Patrick J.] Vet Affairs Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA USA. [Souza, Pamela E.] Univ Washington, Dept Speech & Hearing Sci, Seattle, WA 98195 USA. [Boyko, Edward J.] Univ Washington, Dept Internal Med, Seattle, WA 98195 USA. [Heagerty, Patrick J.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. RP Yueh, B (reprint author), Univ Minnesota, Dept Otolaryngol Head & Neck Surg, MMC396,420 Delaware St SE, Minneapolis, MN 55455 USA. EM byueh@umn.edu OI Yueh, Bevan/0000-0003-1380-1053 FU Health Services Research and Development Service of the Veterans Health Administration [99-377]; Department of Veterans Affairs; Veterans Health Administration; Health Services Research and Development Service [CD-98318] FX This work was supported by a grant from the Health Services Research and Development Service of the Veterans Health Administration (IIR 99-377). Dr. Yueh was also supported by a career development award from the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (CD-98318). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. NR 46 TC 36 Z9 37 U1 1 U2 8 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 MAR PY 2010 VL 58 IS 3 BP 427 EP 434 DI 10.1111/j.1532-5415.2010.02738.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 568JS UT WOS:000275519200002 PM 20398111 ER PT J AU Pugh, MJV VanCott, AC Steinman, MA Mortensen, EM Amuan, ME Wang, CP Knoefe, JE Berlowitz, DR AF Pugh, Mary Jo V. VanCott, Anne C. Steinman, Michael A. Mortensen, Eric M. Amuan, Megan E. Wang, Chen-Pin Knoefe, Janice E. Berlowitz, Dan R. TI Choice of Initial Antiepileptic Drug for Older Veterans: Possible Pharmacokinetic Drug Interactions with Existing Medications SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE drug-drug interaction; epilepsy; geriatrics; antiepileptic drugs ID ONSET GERIATRIC EPILEPSY; ELDERLY VETERANS; ALZHEIMERS-DISEASE; SEIZURE DISORDERS; INAPPROPRIATE; CARBAMAZEPINE; POPULATION; PHENYTOIN; STROKE; HYPERTENSION AB OBJECTIVES To identify clinically meaningful potential drug-drug interactions (PDIs) with antiepileptic drugs (AEDs), the AEDs and co-administered drugs commonly associated with AED-PDIs, and characteristics of patients with high likelihood of AED-PDI exposure. DESIGN Five-year retrospective cohort study of veterans with new-onset epilepsy. SETTING National Veterans Affairs and Medicare databases. PARTICIPANTS Veterans aged 66 and older with a new diagnosis of epilepsy between October 1, 1999, and September 30, 2004 (N=9,682). MEASUREMENTS AED-PDI was restricted to clinically meaningful PDIs identified using prior literature review. AED-PDIs were identified using participants' date of initial AED prescription and overlapping concomitant medications. Logistic regression analysis identified factors associated with AED-PDI, including demographic characteristics, chronic disease states, and diagnostic setting. RESULTS AED-PDI exposure was found in 45.5% (4,406/9,682); phenytoin, a drug with many PDIs, was the most commonly prescribed AED. Cardiovascular drugs, lipid-lowering medications, and psychotropic agents were the most commonly co-administered AED-PDI medications. Individuals with AED-PDI exposure were more likely to have hypertension (odds ratio (OR)=1.46, 99% confidence interval (CI)=1.24-1.82) and hypercholesterolemia (OR=1.40, 99% CI=1.24-1.57) than those without and to be diagnosed in an emergency or primary care setting than a neurology setting (emergency: OR=1.30, 99% CI=1.08-1.58; primary care: OR=1.29 99% CI=1.12-1.49). CONCLUSION Exposure to AED-PDI was substantial but less common in patients with epilepsy diagnosed in a neurology setting. Because potential outcomes associated with AED-PDI include stroke and myocardial infarction in a population already at high risk, clinicians should closely monitor blood pressure, coagulation, and lipid measures to minimize adverse effects of AED-PDIs. Interventions to reduce AED-PDIs may improve patient outcomes. C1 [Pugh, Mary Jo V.; Mortensen, Eric M.; Wang, Chen-Pin] S Texas Hlth Care Syst, VERDICT REAP, San Antonio, TX 78229 USA. [Pugh, Mary Jo V.; Wang, Chen-Pin] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Mortensen, Eric M.] Univ Texas Hlth Sci Ctr San Antonio, Div Gen Internal Med, Dept Med, San Antonio, TX 78229 USA. [VanCott, Anne C.] Vet Affairs Pittsburgh Healthcare Syst, Div Neurol, Pittsburgh, PA USA. [VanCott, Anne C.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. [Steinman, Michael A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Steinman, Michael A.; Knoefe, Janice E.] Univ Calif San Francisco, Dept Geriatr, San Francisco, CA 94143 USA. [Amuan, Megan E.; Berlowitz, Dan R.] Bedford Vet Affairs Hosp, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Knoefe, Janice E.] New Mexico Vet Healthcare Syst, Geriatr Extended Care Sect, Albuquerque, NM USA. [Knoefe, Janice E.] Univ New Mexico, Dept Med, Div Gerontol, Albuquerque, NM 87131 USA. Univ New Mexico, Dept Neurol, Albuquerque, NM 87131 USA. [Berlowitz, Dan R.] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Pugh, MJV (reprint author), S Texas Hlth Care Syst, Audie L Murphy Div VERDICT 11C6, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM pughm@uthscsa.edu OI Pugh, Mary Jo/0000-0003-4196-7763; Mortensen, Eric/0000-0002-3880-5563 FU Department of Veterans Affairs, Health Services Research and Development Service [IIR-02-274]; Epilepsy Foundation; VA Health Services Research and Development Service (HSRD) [MRP-05-145]; VA HSR& D Career Development Transition Award [01-013]; National Institute on Aging Paul Beeson Career Development Award [1K23AG030999]; South Texas Veterans Healthcare System/Audie L. Murphy Division; VERDICT research program FX This study was funded by the Department of Veterans Affairs, Health Services Research and Development Service (IIR-02-274, Dr. Pugh PI) and the Epilepsy Foundation (Dr. Pugh PI). Dr. Copeland received funding from VA Health Services Research and Development Service (HSR&D) Merit Review Entry Program Award (MRP-05-145). Dr. Steinman was supported by a VA HSR& D Career Development Transition Award (01-013) and a National Institute on Aging Paul Beeson Career Development Award (1K23AG030999). The authors also acknowledge and appreciate support from the South Texas Veterans Healthcare System/Audie L. Murphy Division and the VERDICT research program. The views expressed in this article are those of the authors and do not necessarily represent the views of the VA. We also acknowledge contributions of other members of the TIGER research team: Joyce Cramer BA, Jeffrey Tabares BA, Francesca Cunningham PharmD, Omotola Hope MD, Nancy Kressin PhD, Barbara Bokhour PhD, Mark Glickman, PhD, Richard Lewis, MSA. NR 39 TC 15 Z9 15 U1 1 U2 1 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 MAR PY 2010 VL 58 IS 3 BP 465 EP 471 DI 10.1111/j.1532-5415.2010.02732.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 568JS UT WOS:000275519200007 PM 20398114 ER PT J AU Covinsky, KE Yaffe, K Lindquist, K Cherkasova, E Yelin, E Blazer, DG AF Covinsky, Kenneth E. Yaffe, Kristine Lindquist, Karla Cherkasova, Elena Yelin, Edward Blazer, Dan G. TI Depressive Symptoms in Middle Age and the Development of Later-Life Functional Limitations: The Long-Term Effect of Depressive Symptoms SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE depression; functional status; outcomes; aging; disability ID LIVING OLDER PERSONS; PHYSICAL-DISABILITY; MENTAL-DISORDERS; PROGNOSTIC INDEX; FUTURE-RESEARCH; ADULTS; DECLINE; HEALTH; VALIDATION; MORTALITY AB OBJECTIVES To determine whether middle-aged persons with depressive symptoms are at higher risk for developing activity of daily living (ADL) and mobility limitations as they advance into older age than those without. DESIGN Prospective cohort study. SETTING The Health and Retirement Study (HRS), a nationally representative sample of people aged 50 to 61. PARTICIPANTS Seven thousand two hundred seven community living participants in the 1992 wave of the HRS. MEASUREMENTS Depressive symptoms were measured using the 11-item Center for Epidemiologic Studies Depression Scale (CES-D 11), with scores of 9 or more (out of 33) classified as significant depressive symptoms. Difficulty with five ADLs and basic mobility tasks (walking several blocks or up one flight of stairs) was measured every 2 years through 2006. The primary outcome was persistent difficulty with ADLs or mobility, defined as difficulty in two consecutive waves. RESULTS Eight hundred eighty-seven (12%) subjects scored 9 or higher on the CES-D 11 and were classified as having significant depressive symptoms. Over 12 years of follow-up, subjects with depressive symptoms were more likely to reach the primary outcome measure of persistent difficulty with mobility or difficulty with ADL function (45% vs 23%, Cox hazard ratio (HR)=2.33, 95% confidence interval (CI)=2.06-2.63). After adjusting for age, sex, measures of socioeconomic status, comorbid conditions, high body mass index, smoking, exercise, difficulty jogging 1 mile, and difficulty climbing several flights of stairs, the risk was attenuated but still statistically significant (Cox HR=1.44, 95% CI=1.25-1.66). CONCLUSION Depressive symptoms independently predict the development of persistent limitations in ADLs and mobility as middle-aged persons advance into later life. Middle-aged persons with depressive symptoms may be at greater risk for losing their functional independence as they age. C1 [Covinsky, Kenneth E.; Lindquist, Karla; Cherkasova, Elena; Yelin, Edward] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA. [Covinsky, Kenneth E.; Lindquist, Karla; Cherkasova, Elena] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94121 USA. [Yelin, Edward] Univ Calif San Francisco, Div Rheumatol, San Francisco, CA 94121 USA. [Yelin, Edward] Univ Calif San Francisco, Inst Hlth Policy Studies, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. [Covinsky, Kenneth E.; Yaffe, Kristine; Lindquist, Karla; Cherkasova, Elena] San Francisco VA Med Ctr, San Francisco, CA USA. [Blazer, Dan G.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. RP Covinsky, KE (reprint author), Univ Calif San Francisco, San Francisco VA Med Ctr 181G, 4150 Clement, San Francisco, CA 94121 USA. EM ken.covinsky@ucsf.edu FU National Institute on Aging (NIA) [R01AG028481, K24AG029812] FX Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Kristine Yaffe served on the Women's Health Initiative Observational Study Monitoring Board. Supported by Grants R01AG028481 and K24AG029812 from the National Institute on Aging (NIA). The HRS is funded by the NIA. NR 30 TC 31 Z9 32 U1 3 U2 3 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 MAR PY 2010 VL 58 IS 3 BP 551 EP 556 DI 10.1111/j.1532-5415.2010.02723.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 568JS UT WOS:000275519200020 PM 20163486 ER PT J AU Gerber, JB Bloom, PA Ross, JS AF Gerber, Jaime B. Bloom, Patricia A. Ross, Joseph S. TI THE PHYSICAL ACTIVITY CONTRACT-TAILORED TO PROMOTE PHYSICAL ACTIVITY IN A GERIATRIC OUTPATIENT SETTING: A PILOT STUDY SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Letter ID CONTROLLED-TRIAL; PRIMARY-CARE C1 [Gerber, Jaime B.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Bloom, Patricia A.; Ross, Joseph S.] Mt Sinai Sch Med, Dept Geriatr & Palliat Med, New York, NY USA. [Ross, Joseph S.] James J Peters Vet Adm Med Ctr, Hlth Serv Res & Dev Res Enhancement Award Program, Bronx, NY USA. [Ross, Joseph S.] James J Peters Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. RP Gerber, JB (reprint author), Univ Washington, Dept Med, Seattle, WA 98195 USA. FU NIA NIH HHS [K08 AG032886, K08 AG032886-02] NR 10 TC 1 Z9 1 U1 0 U2 1 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 MAR PY 2010 VL 58 IS 3 BP 604 EP 606 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 568JS UT WOS:000275519200030 PM 20398129 ER PT J AU Murphy, SN Weber, G Mendis, M Gainer, V Chueh, HC Churchill, S Kohane, I AF Murphy, Shawn N. Weber, Griffin Mendis, Michael Gainer, Vivian Chueh, Henry C. Churchill, Susanne Kohane, Isaac TI Serving the enterprise and beyond with informatics for integrating biology and the bedside (i2b2) SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID ELECTRONIC MEDICAL-RECORD; CLINICAL-RESEARCH; DATABASE AB Informatics for Integrating Biology and the Bedside (i2b2) is one of seven projects sponsored by the NIH Roadmap National Centers for Biomedical Computing (http://www. ncbcs.org). Its mission is to provide clinical investigators with the tools necessary to integrate medical record and clinical research data in the genomics age, a software suite to construct and integrate the modern clinical research chart. i2b2 software may be used by an enterprise's research community to find sets of interesting patients from electronic patient medical record data, while preserving patient privacy through a query tool interface. Project-specific mini-databases ("data marts") can be created from these sets to make highly detailed data available on these specific patients to the investigators on the i2b2 platform, as reviewed and restricted by the Institutional Review Board. The current version of this software has been released into the public domain and is available at the URL: http://www.i2b2.org/software. C1 [Murphy, Shawn N.; Chueh, Henry C.] Massachusetts Gen Hosp, Comp Sci Lab, Boston, MA 02114 USA. [Weber, Griffin] Harvard Univ, Sch Med, Boston, MA USA. [Murphy, Shawn N.; Mendis, Michael; Gainer, Vivian; Churchill, Susanne] Partners HealthCare Syst Inc, Informat Syst, Wellesley, MA USA. [Kohane, Isaac] Childrens Hosp, Boston, MA 02115 USA. [Kohane, Isaac] Brigham & Womens Hosp, Boston, MA 02115 USA. [Weber, Griffin] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. RP Murphy, SN (reprint author), Partners HealthCare Syst Inc, Constitut Ctr 1, Informat Syst, Charlestown, MA 02129 USA. EM murphy.shawn@mgh.harvard.edu RI Kohane, Isaac Kohane/K-3716-2012; OI Kohane, Isaac Kohane/0000-0003-2192-5160; Weber, Griffin/0000-0002-2597-881X FU NIH [U54LM008748] FX This work was funded by the National Institutes of Health through the NIH Roadmap for Medical Research, Grant U54LM008748. Other funders: NIH. NR 22 TC 206 Z9 207 U1 2 U2 38 PU HANLEY & BELFUS-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAR PY 2010 VL 17 IS 2 BP 124 EP 130 DI 10.1136/jamia.2009.000893 PG 7 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 567ZH UT WOS:000275488100002 PM 20190053 ER PT J AU Gradman, AH Basile, JN Carter, BL Bakris, GL AF Gradman, Alan H. Basile, Jan N. Carter, Barry L. Bakris, George L. CA Hypertension Writing Grp TI Combination therapy in hypertension SO JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION LA English DT Article DE Hypertension; combination therapy; drug therapy; angiotensin converting enzyme inhibitor; angiotensin receptor blocker; beta blockers diuretic; calcium channel blocker ID BLOOD-PRESSURE CONTROL; LOW-DOSE HYDROCHLOROTHIAZIDE; FELODIPINE EXTENDED-RELEASE; CONVERTING-ENZYME-INHIBITOR; HIGH CARDIOVASCULAR RISK; CALCIUM-CHANNEL BLOCKER; DOUBLE-BLIND; RANDOMIZED-TRIAL; ANTIHYPERTENSIVE TREATMENT; SYSTEMIC HYPERTENSION AB The goal of antihypertensive therapy is to abolish the risks associated with blood pressure (BP) elevation without adversely affecting quality of life. Drug selection is based on efficacy in lowering BP and in reducing cardiovascular (CV) end points including stroke, myocardial infarction, and heart failure. Although the choice of initial drug therapy exerts some effect on long-term outcomes, it is evident that BP reduction per se is the primary determinant of CV risk reduction. Available data suggest that at least 75% of patients will require combination therapy to achieve contemporary BP targets, and increasing emphasis is being placed on the practical tasks involved in consistently achieving and maintaining goal BP in clinical practice. It is within this context that the American Society of Hypertension presents this Position Paper on Combination Therapy for Hypertension. It will address the scientific basis of combination therapy, present the pharmacologic rationale for choosing specific drug combinations, and review patient selection criteria for initial and secondary use. The advantages and disadvantages of single pill (fixed) drug combinations, and the implications of recent clinical trials involving specific combination strategies will also be discussed. J Am Soc Hypertens 2010;4(2):90-98. (C) 2010 American Society of Hypertension. All rights reserved. C1 [Gradman, Alan H.] Western Penn Hosp, Dept Med, Pittsburgh, PA 15224 USA. [Gradman, Alan H.] Temple Univ, Sch Med, Philadelphia, PA 19122 USA. [Basile, Jan N.] Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. [Carter, Barry L.] Univ Iowa, Roy J & Lucille A Carver Coll Med, Iowa City, IA USA. [Bakris, George L.] Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA. RP Gradman, AH (reprint author), Western Penn Hosp, Dept Med, 4800 Friendship Ave, Pittsburgh, PA 15224 USA. EM gradmanmd@aol.com FU Novartis; NHLBI; NIH; Juvenile Diabetes Research Foundation (JDRF); GlaxoSmithKline; Forest Laboratories; CVRx; VA HSRD FX Dr. Gradman has served as a consultant for Novartis, Forest Laboratories, Daiich-Sankyo, NicOx, Merck; and speakers' bureau for Novartis, Merck, Forest Laboratories. and Daiichi-Sankyo. He has received grant/search support from Novartis. Dr. Basile has served as a consultant for Daiichi-Sankyo, Forest Laboratories, Novartis, Takeda; and speakers's bureau for Daiichi-Sankyo, Forest Laboratories, and Novartis. He has received grant/research support from the NHLBI. Dr. Carter has received grant/research support from the NIH, VA HSR&D. Dr. Bakris has served as a consultant for GlaxoSmithKline, Merck, Novartis, Boehringer-Ingelheim, Takeda, Abbott, Walgreen's, Bristol-Myers Squibb/Sanofi, Gilead, Forest Laboratories; and speakers' bureau for Forest Laboratories and Novartis. He has received grant/research support from the Juvenile Diabetes Research Foundation (JDRF), GlaxoSmithKline, Forest Laboratories and CVRx. NR 65 TC 61 Z9 68 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-1711 J9 J AM SOC HYPERTENS JI J. Am. Soc. Hypertens. PD MAR-APR PY 2010 VL 4 IS 2 SI SI BP 90 EP 98 DI 10.1016/j.jash.2010.03.001 PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 592RN UT WOS:000277397300007 PM 20400053 ER PT J AU Garrett, MR Pezzolesi, MG Korstanje, R AF Garrett, Michael R. Pezzolesi, Marcus G. Korstanje, Ron TI Integrating Human and Rodent Data to Identify the Genetic Factors Involved in Chronic Kidney Disease SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Review ID GENOME-WIDE ASSOCIATION; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; URINARY ALBUMIN EXCRETION; QUANTITATIVE TRAIT LOCI; SYSTEMIC-LUPUS-ERYTHEMATOSUS; DOUBLE CONGENIC RATS; STAGE RENAL-DISEASE; DIABETIC-NEPHROPATHY; AFRICAN-AMERICANS; NEPHROTIC SYNDROME AB The increasing numbers of patients with chronic kidney disease combined with no satisfying interventions for preventing or curing the disease emphasize the need to better understand the genes involved in the initiation and progression of complex renal diseases, their interactions with other host genes, and the environment. Linkage and association studies in human, rat, and mouse have been successful in identifying genetic loci for various disease-related phenotypes but have thus far not been very successful identifying underlying genes. The purpose of this review is to summarize the progress in human, rat, and mouse genetic studies to show the concordance between the loci among the different species. The collective utilization of human and nonhuman mammalian datasets and resources can lead to a more rapid narrowing of disease loci and the subsequent identification of candidate genes. In addition, genes identified through these methods can be further characterized and investigated for interactions using animal models, which is not possible in humans. C1 [Korstanje, Ron] Jackson Lab, Bar Harbor, ME 04609 USA. [Garrett, Michael R.] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Garrett, Michael R.] Med Coll Wisconsin, Kidney Dis Ctr, Milwaukee, WI 53226 USA. [Pezzolesi, Marcus G.] Harvard Univ, Sch Med, Boston, MA USA. [Pezzolesi, Marcus G.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. RP Korstanje, R (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM ron.korstanje@jax.org FU National Institutes of Health (NIH)/National Heart Lung and Blood Institute [HL094446]; NIH [DK77532, T32 DK007260-32, DK069381] FX M.R.G. is supported by National Institutes of Health (NIH)/National Heart Lung and Blood Institute grant HL094446 and funds from Advancing Healthier Wisconsin; M.G.P. is supported by NIH grants DK77532 and T32 DK007260-32; and R.K. is supported by NIH grant DK069381. We thank Joanne Currer for writing assitance and Jesse Hammer for prepration of the figures. NR 60 TC 18 Z9 19 U1 0 U2 0 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 MAR PY 2010 VL 21 IS 3 BP 398 EP 405 DI 10.1681/ASN.2009080881 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 564WS UT WOS:000275249700008 PM 20133484 ER PT J AU Schroppel, B Kruger, B Walsh, L Yeung, M Harris, S Garrison, K Himmelfarb, J Lerner, SM Bromberg, JS Zhang, PL Bonventre, JV Wang, Z Farris, AB Colvin, RB Murphy, BT Vella, JP AF Schroppel, Bernd Krueger, Bernd Walsh, Liron Yeung, Melissa Harris, Shay Garrison, Krista Himmelfarb, Jonathan Lerner, Susan M. Bromberg, Jonathan S. Zhang, Ping L. Bonventre, Joseph V. Wang, Zhu Farris, Alton B. Colvin, Robert B. Murphy, Barbara T. Vella, John P. TI Tubular Expression of KIM-1 Does not Predict Delayed Function After Transplantation SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID KIDNEY INJURY MOLECULE-1; GRAFT FUNCTION; RENAL-TRANSPLANTATION; URINARY BIOMARKERS; DONOR KIDNEYS; BRAIN-DEATH; RECIPIENTS; RECEPTOR; DISEASE; EXCRETION AB Injured epithelial cells of the proximal tubule upregulate the glycoprotein kidney injury molecule 1 (KIM-1), suggesting its potential as a biomarker of incipient kidney allograft injury. It is unknown whether KIM-1 expression changes in kidney allografts with delayed graft function (DGF), which often follows ischemia-reperfusion injury. Here, we prospectively measured KIM-1 RNA and protein expression in preperfusion biopsies of 30 living- and 85 deceased-donor kidneys and correlated the results with histologic and clinical outcomes after transplantation. We detected KIM-1 expression in 62% of deceased-donor kidneys and only 13% of living-donor kidneys (P < 0.0001). The level of KIM-1 expression before reperfusion correlated inversely with renal function at the time of procurement and correlated directly with the degree of interstitial fibrosis. Surprising, however, we did not detect a significant correlation between KIM-1 staining intensity and the occurrence of DGF. Our findings are consistent with a role for KIM-1 as an early indicator of tubular injury but do not support tissue KIM-1 measurement before transplantation to identify kidneys at risk for DGF. C1 [Schroppel, Bernd; Krueger, Bernd; Walsh, Liron; Murphy, Barbara T.] Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA. [Schroppel, Bernd; Lerner, Susan M.; Bromberg, Jonathan S.; Murphy, Barbara T.] Mt Sinai Sch Med, Inst Transplantat, New York, NY 10029 USA. [Krueger, Bernd] Klinikum Ruhr Univ Bochum, Marienhosp Herne, Med Klin 1, D-4690 Herne, Germany. [Yeung, Melissa; Harris, Shay; Garrison, Krista; Himmelfarb, Jonathan; Vella, John P.] Maine Med Ctr, Portland, ME 04102 USA. [Zhang, Ping L.] William Beaumont Hosp, Dept Anat Pathol, Royal Oak, MI 48073 USA. [Yeung, Melissa; Bonventre, Joseph V.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Renal Div, Boston, MA 02115 USA. [Wang, Zhu] Yale Sch Med, Nephrol Sect, New Haven, CT USA. [Wang, Zhu] Yale Sch Med, Clin Epidemiol Res Ctr, New Haven, CT USA. [Wang, Zhu] VAMC, New Haven, CT USA. [Farris, Alton B.; Colvin, Robert B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Schroppel, B (reprint author), Mt Sinai Sch Med, Div Nephrol, 1 Gustave L Levy Pl,Box 1243, New York, NY 10029 USA. EM bernd.schroppel@mssm.edu RI Kruger, Bernd/F-5781-2011 FU Satellite Healthcare research; National Institutes of Health research [UOI AI070107-01] FX This work is supported by Satellite Healthcare research grant (B.S,) and National Institutes of Health research grant to B.M. (UOI AI070107-01) NR 35 TC 34 Z9 35 U1 0 U2 4 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 MAR PY 2010 VL 21 IS 3 BP 536 EP 542 DI 10.1681/ASN.2009040390 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 564WS UT WOS:000275249700023 PM 20019169 ER PT J AU Butler, PM McNamara, P Durso, R AF Butler, Paul M. McNamara, Patrick Durso, Raymon TI Deficits in the automatic activation of religious concepts in patients with Parkinson's disease SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Semantic memory; Neurodegenerative disorders; Religion; Gain/decay hypothesis; Frontal lobes; Dopamine ID EXPERIENCE; DYSFUNCTION; MECHANISMS; EPILEPSY; SCALES; BELIEF; MIND AB Religion is central to the lives of billions of people worldwide. To probe processing dynamics of religious cognition and its potential brain correlates, we used a novel priming procedure to assess the integrity of religious and control semantic networks in patients with Parkinson's disease (PD) and controls. Priming for control, but not religious, concepts was intact in PD patients. Patients with left-onset (right-forebrain disease) evidenced severe impairment activating religious concepts. We next modeled the priming performance with modified cable equations. These analyses suggested that deficient performance of PD patients on activation of religious concepts was due to a change in the time constants governing gain and rate of decay of activation in these semantic networks. These modeling results are consistent with dopaminergic dysfunction in right-sided striatal-prefrontal networks. We conclude that right striatal-prefrontal dopaminergic networks support activation of complex religious concepts but not equally complex and related control concepts. (JINS, 2010, 16, 252-261.) C1 [Butler, Paul M.; McNamara, Patrick; Durso, Raymon] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Butler, Paul M.; McNamara, Patrick; Durso, Raymon] VA Boston Healthcare Syst, Dept Neurol, Boston, MA USA. RP Butler, PM (reprint author), Boston Univ, Sch Med, Dept Neurol, 72 E Concord St,Robinson Bldg,5th Floor,Room 528, Boston, MA 02118 USA. EM pmbutler@bu.edu FU Office of Research Development, Medical Research Service, Department of Veterans Affairs; National Institute of Deafness and other Communication Disorders (NIDCD) [5ROIDC007956-03] FX The authors report no conflicts of interest. This is based on work supported by the Office of Research Development, Medical Research Service, Department of Veterans Affairs and the National Institute of Deafness and other Communication Disorders (NIDCD) Grant No. 5ROIDC007956-03. NR 43 TC 12 Z9 12 U1 1 U2 4 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 MAR PY 2010 VL 16 IS 2 BP 252 EP 261 DI 10.1017/S1355617709991202 PG 10 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 562DZ UT WOS:000275030900005 PM 19958570 ER PT J AU Zelenetz, AD Abramson, JS Advani, RH Andreadis, CB Byrd, JC Czuczman, MS Fayad, L Forero, A Glenn, MJ Gockerman, JP Gordon, LI Harris, NL Hoppe, RT Horwitz, SM Kaminski, MS Kim, YH LaCasce, AS Mughal, TI Nademanee, A Porcu, P Press, O Prosnitz, L Reddy, N Smith, MR Sokol, L Swinnen, L Vose, JM Wierda, WG Yahalom, J Yunus, F AF Zelenetz, Andrew D. Abramson, Jeremy S. Advani, Ranjana H. Andreadis, C. Babis Byrd, John C. Czuczman, Myron S. Fayad, Luis Forero, Andres Glenn, Martha J. Gockerman, Jon P. Gordon, Leo I. Harris, Nancy Lee Hoppe, Richard T. Horwitz, Steven M. Kaminski, Mark S. Kim, Youn H. LaCasce, Ann S. Mughal, Tariq I. Nademanee, Auyporn Porcu, Pierluigi Press, Oliver Prosnitz, Leonard Reddy, Nashitha Smith, Mitchell R. Sokol, Lubomir Swinnen, Lode Vose, Julie M. Wierda, William G. Yahalom, Joachim Yunus, Furhan CA NCCN TI Non-Hodgkin's Lymphomas SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review DE NCCN Clinical Practice Guidelines; non-Hodgkin's lymphoma; chronic lymphocytic leukemia; follicular lymphoma; diffuse large B-cell lymphoma; mantle cell lymphoma; peripheral T-cell lymphoma; cutaneous T-cell lymphoma; mycosis fungoides; Sezary syndrome; marginal zone lymphoma; mucosa-associated lymphoid tissue lymphoma; diagnosis; treatment; hematopathology; immunohistochemistry; treatment guidelines; staging evaluation; lymphoma pathology ID B-CELL LYMPHOMA; ACTIVE ANTIRETROVIRAL THERAPY; ACUTE LYMPHOBLASTIC-LEUKEMIA; FINE-NEEDLE-ASPIRATION; CHRONIC LYMPHOCYTIC-LEUKEMIA; PHASE-II TRIAL; DISTINCT CLINICOPATHOLOGICAL ENTITY; IMMUNE THROMBOCYTOPENIC PURPURA; RECOMBINANT URATE OXIDASE; AIDS-RELATED MALIGNANCIES C1 [Zelenetz, Andrew D.; Horwitz, Steven M.; Yahalom, Joachim] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Abramson, Jeremy S.; Harris, Nancy Lee] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Advani, Ranjana H.; Hoppe, Richard T.; Kim, Youn H.] Stanford Comprehens Canc Ctr, Stanford, CA USA. [Andreadis, C. Babis] UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA. [Byrd, John C.; Porcu, Pierluigi] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Fayad, Luis; Wierda, William G.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Forero, Andres] Univ Alabama, Ctr Comprehens Canc, Birmingham, AL USA. [Glenn, Martha J.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Gockerman, Jon P.; Prosnitz, Leonard] Duke Comprehens Canc Ctr, Durham, NC USA. [Gordon, Leo I.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Kaminski, Mark S.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [LaCasce, Ann S.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Mughal, Tariq I.; Yunus, Furhan] Univ Tennessee, Inst Canc, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Press, Oliver] Seattle Canc Care Alliance, Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Sokol, Lubomir] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Vose, Julie M.] Nebraska Med Ctr, UNMC Eppley Canc Ctr, Omaha, NE USA. RP Zelenetz, AD (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. NR 142 TC 99 Z9 112 U1 0 U2 12 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PINE DR, SUDBURY, MA 01776 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD MAR PY 2010 VL 8 IS 3 BP 288 EP 334 PG 47 WC Oncology SC Oncology GA 566DI UT WOS:000275349900005 PM 20202462 ER PT J AU Drake, BF Shelton, RC Gilligan, T Allen, JD AF Drake, Bettina F. Shelton, Rachel C. Gilligan, Timothy Allen, Jennifer D. TI A Church-Based Intervention to Promote Informed Decision Making for Prostate Cancer Screening Among African American Men SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE prostate cancer; screening; racial disparities; African Americans ID RANDOMIZED CONTROLLED-TRIAL; EDUCATIONAL INTERVENTIONS; INFORMATION; KNOWLEDGE; HISTORY AB Objectives: This feasibility study developed and pilot tested an intervention to: (1) increase knowledge about prostate cancer screening; and (2) promote self-efficacy to participate in the informed decision-making process. Setting.: African American men are a priority audience for prostate cancer screening interventions to promote informed decision making, and faith-based settings have been shown to be an effective venue to reach this population. Therefore we used predominantly African American churches to develop and test our intervention. Participants: Participants (N = 73) were recruited, and the intervention was administered by an African American health educator. Intervention: We developed and pretested a prostate cancer screening informed decision-making intervention based on the Ottawa Decision Support Framework and the health belief model. The intervention included a tool called the "road map," which depicts the potential consequences of a decision to undergo or forgo screening. A quasiexperimental design was used to test the intervention. Main Outcome Measures: The main outcome measures were change in knowledge and self-efficacy post intervention. Results: Prostate cancer knowledge (p<.0001) and self-efficacy (p=.025) significantly increased. Conclusions: A church-based intervention delivered by an African American health educator is a promising strategy for promoting informed decision making among African American men. C1 [Drake, Bettina F.] Washington Univ, Dept Surg, Sch Med, St Louis, MO 63110 USA. [Shelton, Rachel C.] Mt Sinai Sch Med, Dept Oncol Sci, New York, NY USA. [Gilligan, Timothy] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. [Allen, Jennifer D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med,Ctr Community Based Res & Cantor Ctr, Boston, MA 02115 USA. RP Drake, BF (reprint author), Washington Univ, Dept Surg, Sch Med, 660 S Euclid,Campus,Box 8100, St Louis, MO 63110 USA. EM drakeb@wudosis.wustl.edu RI Allen, Jennifer/M-2113-2015; OI Gilligan, Timothy/0000-0003-2308-9303; Drake, Bettina/0000-0001-9340-5848 FU National Cancer Institute [5-U0ICA86274-05] FX This study was funded by National Cancer Institute grant 5-U0ICA86274-05. NR 38 TC 33 Z9 33 U1 3 U2 8 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 MAR PY 2010 VL 102 IS 3 BP 164 EP 171 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 574CV UT WOS:000275967000001 PM 20355345 ER PT J AU Kressin, NR Manze, M Russell, SL Katz, RV Claudio, C Green, BL Wang, MQ AF Kressin, Nancy R. Manze, Meredith Russell, Stefanie L. Katz, Ralph V. Claudio, Cristina Green, B. Lee Wang, Min Qi TI Self-Reported Willingness to Have Cancer Screening and the Effects of Sociodemographic Factors SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE cancer screening; knowledge, attitudes, and beliefs; minority health ID AFRICAN-AMERICAN WOMEN; BREAST-CANCER; COLORECTAL-CANCER; PROSTATE-CANCER; HISPANIC WOMEN; UNITED-STATES; ETHNIC-GROUPS; ANGLO WOMEN; HEALTH; ATTITUDES AB Background: The relative effects of race/ethnicity and other sociodemographic factors, compared to those of attitudes and beliefs on willingness to have cancer screening, are not well understood. Methods: We conducted telephone interviews with 1148 adults (31% African American, 27% Puerto Rican American, 43% white) from 3 cities in mainland United States and Puerto Rico. Respondents reported their sociodemographic characteristics, attitudes about barriers and facilitators of cancer screening, and willingness to have cancer screening under 4 scenarios: when done in the community vs one's doctor's office, and whether or not one had symptoms. Results: Racial/ethnic minority status, age, and lower income were frequently associated with increased willingness to have cancer screening, even after including attitudes and beliefs about screening. Having screening nearby was important for community screening, and anticipation of embarrassment from screening for when there were no cancer symptoms. Associations varied across 4 screening scenarios, with the fewest predictors for screening by one's doctor when there were symptoms. Conclusions: Sociodemographic characteristics not only were related to willingness to have cancer screenings in almost all cases, but were generally much stronger factors than attitudinal barriers and facilitators. Cancer screening campaigns should affect attitudinal change where possible, but should also recognize that targeting screening to specific population groups may be necessary. C1 [Kressin, Nancy R.; Manze, Meredith] Boston Univ, Sch Med, Hlth Care Dispar Res Program, Gen Internal Med Sect, Boston, MA 02118 USA. [Kressin, Nancy R.] VA Boston Healthcare Syst, Jamaica Plain, MA USA. [Kressin, Nancy R.] VAMC, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Kressin, Nancy R.; Katz, Ralph V.] NYU, Coll Dent, Dept Epidemiol & Hlth Promot, New York, NY USA. [Claudio, Cristina] Univ Puerto Rico, Sch Dent, Community Dent Sect, San Juan, PR 00936 USA. [Green, B. Lee] H Lee Moffitt Canc Ctr & Res Inst, Off Inst Divers & Hlth Outcomes & Behav, Tampa, FL USA. [Wang, Min Qi] Univ Maryland, Dept Publ & Community Hlth, College Pk, MD 20742 USA. RP Kressin, NR (reprint author), Boston Univ, Sch Med, Hlth Care Dispar Res Program, Gen Internal Med Sect, 801 Massachusetts Ave,2090, Boston, MA 02118 USA. EM nkressin@bu.edu FU VA Health Services Research and Development Service; [U54 DE 14257] FX This study was supported by U54 DE 14257, and a VA Research Career Scientist award from the VA Health Services Research and Development Service to Dr Kressin. NR 41 TC 5 Z9 5 U1 1 U2 6 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 MAR PY 2010 VL 102 IS 3 BP 219 EP 227 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 574CV UT WOS:000275967000007 PM 20355351 ER PT J AU Toole, JM Ikonomidis, JS Szeto, WY Zellner, JL Mulcahy, J Deardorff, RL Spinale, FG AF Toole, John M. Ikonomidis, John S. Szeto, Wilson Y. Zellner, James L. Mulcahy, John Deardorff, Rachael L. Spinale, Francis G. TI Selective endothelin-1 receptor type A inhibition in subjects undergoing cardiac surgery with preexisting left ventricular dysfunction: Influence on early postoperative hemodynamics SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID PULMONARY ARTERIAL-HYPERTENSION; BYPASS GRAFT-SURGERY; CARDIOPULMONARY BYPASS; HEART-FAILURE; CARDIOVASCULAR-DISEASE; IN-VIVO; PATHOPHYSIOLOGY; ANTAGONISM; SYSTEM; SITAXSENTAN AB Objective: A robust release of endothelin-1 with subsequent endothelin-A subtype receptor activation occurs in patients after cardiac surgery requiring cardiopulmonary bypass. Increased endothelin-A subtype receptor activation has been identified in patients with poor left ventricular function (reduced ejection fraction). Accordingly, this study tested the hypothesis that a selective endothelin-A subtype receptor antagonist administered perioperatively would favorably affect post-cardiopulmonary bypass hemodynamic profiles in patients with a preexisting poor left ventricular ejection fraction. Methods: Patients (n = 29; 66 +/- 2 years) with a reduced left ventricular ejection fraction (37% +/- 2%) were prospectively randomized in a blinded fashion, at the time of elective coronary revascularization or valve replacement requiring cardiopulmonary bypass, to infusion of the highly selective and potent endothelin-A subtype receptor antagonist sitaxsentan at 1 or 2 mg/kg (intravenous bolus; n 9, 10 respectively) or vehicle (saline; n 10). Infusion of the endothelin-A subtype receptor antagonist/vehicle was performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass. Endothelin and hemodynamic measurements were performed at baseline, at separation from cardiopulmonary bypass (time 0), and at 0.5, 6, 12, and 24 hours after cardiopulmonary bypass. Results: Baseline plasma endothelin (4.0 +/- 0.3 fmol/mL) was identical across all 3 groups, but when compared with preoperative values, baseline values obtained from age-matched subjects with a normal left ventricular ejection fraction (n 37; left ventricular ejection fraction>50%) were significantly increased (2.9 +/- 0.2 fmol/mL, P<.05). Baseline systemic (1358 +/- 83 dynes/sec/cm(-5)) and pulmonary (180 +/- 23 dynes/sec/cm(-5)) vascular resistance were equivalent in all 3 groups. As a function of time 0, systemic vascular resistance changed in an equivalent fashion in the post-cardiopulmonary bypass period, but a significant endothelin-A subtype receptor antagonist effect was observed for pulmonary vascular resistance (analysis of variance; P<.05). For example, at 24 hours post-cardiopulmonary bypass, pulmonary vascular resistance increased by 40 dynes/sec/cm(-5) in the vehicle group but directionally decreased by more than 40 dynes/sec/cm(-5) in the 2 mg/kg endothelin-A subtype receptor antagonist group (P<.05). Total adverse events were equivalently distributed across the endothelin-A subtype receptor antagonist/placebo groups. Conclusion: These unique findings demonstrated that infusion of an endothelin-A subtype receptor antagonist in high-risk patients undergoing cardiac surgery was not associated with significant hemodynamic compromise. Moreover, the endothelin-A subtype receptor antagonist favorably affected pulmonary vascular resistance in the early postoperative period. Thus, the endothelin-A subtype receptor serves as a potential pharmacologic target for improving outcomes after cardiac surgery in patients with compromised left ventricular function. (J Thorac Cardiovasc Surg 2010;139:646-54) C1 [Toole, John M.; Ikonomidis, John S.; Mulcahy, John; Deardorff, Rachael L.; Spinale, Francis G.] Med Univ S Carolina, Charleston, SC 29425 USA. [Toole, John M.; Ikonomidis, John S.; Mulcahy, John; Deardorff, Rachael L.; Spinale, Francis G.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Szeto, Wilson Y.] Univ Penn, Philadelphia, PA 19104 USA. [Zellner, James L.] Univ Tennessee, Chattanooga, TN USA. RP Spinale, FG (reprint author), Strom Thurmond Res Ctr, 114 Doughty St,Suite 625, Charleston, SC 29425 USA. EM wilburnm@musc.edu FU Encysive Pharmaceuticals; National Institutes of Health [HL87134]; Veterans' Affairs Health Administration FX This study was supported by an unrestricted research grant from Encysive Pharmaceuticals, which was acquired by Pfizer Inc in June 2008, National Institutes of Health grant HL87134, and a Merit Award from the Veterans' Affairs Health Administration. NR 37 TC 4 Z9 4 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 MAR PY 2010 VL 139 IS 3 BP 646 EP 654 DI 10.1016/j.jtcvs.2009.11.046 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 558IS UT WOS:000274735400018 PM 20074751 ER PT J AU Gottlieb, D Kunal, T Emani, S Aikawa, E Brown, DW Powell, AJ Nedder, A Engelmayr, GC Melero-Martin, JM Sacks, MS Mayer, JE AF Gottlieb, Danielle Kunal, Tandon Emani, Sitaram Aikawa, Elena Brown, David W. Powell, Andrew J. Nedder, Arthur Engelmayr, George C., Jr. Melero-Martin, Juan M. Sacks, Michael S. Mayer, John E., Jr. TI In vivo monitoring of function of autologous engineered pulmonary valve SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID MESENCHYMAL STEM-CELLS; BONE-MARROW; HEART-VALVE AB Objectives: Clinical translation of tissue-engineered heart valves requires valve competency and lack of stenosis in the short and long term. Early studies of engineered valves showed promise, although lacked complete definition of valve function. Building on prior experiments, we sought to define the in vivo changes in structure and function of autologous engineered pulmonary valved conduits. Methods: Mesenchymal stem cells were isolated from neonatal sheep bone marrow and seeded onto a bioresorbable scaffold. After 4 weeks of culture, valved conduits were implanted. Valve function, cusp, and conduit dimensions were evaluated at implantation (echocardiography), at the experimental midpoint (magnetic resonance imaging), and at explant, at 1 day, and 1, 6, 12, or 20 weeks postoperatively (direct measurement, echocardiography). Histologic evaluation was performed. Results: Nineteen animals underwent autologous tissue-engineered valved conduit replacement. At implantation, valved conduit function was excellent; maximum transvalvular pressure gradient by Doppler echocardiography was 17 mm Hg; most valved conduits showed trivial pulmonary regurgitation. At 6 postoperative weeks, valve cusps appeared less mobile; pulmonary regurgitation was mild to moderate. At 12 weeks or more, valved conduit cusps were increasingly attenuated and regurgitant. Valved conduit diameter remained unchanged over 20 weeks. Dimensional measurements by magnetic resonance imaging correlated with direct measurement at explant. Conclusions: We demonstrate autologous engineered tissue valved conduits that function well at implantation, with subsequent monitoring of dimensions and function in real time by magnetic resonance imaging. In vivo valves undergo structural and functional remodeling without stenosis, but with worsening pulmonary regurgitation after 6 weeks. Insights into mechanisms of in vivo remodeling are valuable for future iterations of engineered heart valves. (J Thorac Cardiovasc Surg 2010; 139: 723-31) C1 [Gottlieb, Danielle; Kunal, Tandon; Emani, Sitaram; Brown, David W.; Powell, Andrew J.; Nedder, Arthur; Melero-Martin, Juan M.; Mayer, John E., Jr.] Childrens Hosp, Boston, MA 02115 USA. [Gottlieb, Danielle; Aikawa, Elena] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Gottlieb, Danielle; Aikawa, Elena] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Engelmayr, George C., Jr.] MIT, Boston, MA USA. [Sacks, Michael S.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. RP Mayer, JE (reprint author), Childrens Hosp, Bader 273, Boston, MA 02115 USA. EM john.mayer@cardio.chboston.org RI Sacks, Michael/F-3703-2011; Engelmayr, George/I-4368-2012 FU National Institutes of Health [RO1 HL089750, R01 HL089750]; American Heart Association FX Funding provided by National Institutes of Health grant RO1 HL089750 (to M. S. S., J.E.M., D. G.), American Heart Association Postdoctoral Fellowship Award (to D. G), and National Institutes of Health grant R01 HL089750 (to J.E.M., D. G.). NR 20 TC 61 Z9 61 U1 0 U2 10 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 MAR PY 2010 VL 139 IS 3 BP 723 EP 731 DI 10.1016/j.jtcvs.2009.11.006 PG 9 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 558IS UT WOS:000274735400030 PM 20176213 ER PT J AU Tournoij, E Weber, GJ Akkerman, JWN de Groot, PG Zon, LI Moll, FL Schulte-Merker, S AF Tournoij, E. Weber, G. J. Akkerman, J. W. N. de Groot, P. G. Zon, L. I. Moll, F. L. Schulte-Merker, S. TI Mlck1a is expressed in zebrafish thrombocytes and is an essential component of thrombus formation SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE gene expression; mlck; Platelet; thrombosis; zebrafish ID LIGHT-CHAIN KINASE; PLATELET SHAPE CHANGE; SMOOTH-MUSCLE MYOSIN; INTEGRIN ALPHA(IIB)BETA(3); PROTEIN-KINASE; RHO-KINASE; PHOSPHORYLATION; CYTOSKELETON; COLLAGEN; BINDING AB Background: We have used the advantages of the zebrafish model system to demonstrate which of the vertebrate Myosin Light Chain Kinase (MLCK) genes is expressed in thrombocytes and important for thrombus formation. Methods and Results: Here we report that Mlck1a is an essential component of thrombus formation. Phylogenetic data revealed four zebrafish orthologous for three human MLCK genes. To investigate expression of the zebrafish mlck genes in thrombocytes we compared GFP-tagged platelets with other cells by microarray analysis, and showed that mlck1a expression was 4.5-fold enriched in platelets. Furthermore, mlck1a mRNA and mRNA for the platelet-specific cd41 co-localized in thrombi. Expression of other mlck subtypes was lower in GFP-tagged platelets (mlck1b; 0.77-fold enriched) and absent in thrombi (mlck1b, -2, -3). To investigate the role of Mlck1a in thrombus formation, we knocked down mlck1a using two morpholinos. This resulted in impaired morphology changes of platelets adhering on fibrinogen. In a thrombosis model, in which thrombocytes adhere to the vessel wall damaged by laser irradiation, thrombus formation was slowed down in mlck1a-deficient embryos. Conclusion: We conclude that Mlck1a is the subtype of MLCK that contributes to platelet shape change and thrombus formation. C1 [Tournoij, E.; Schulte-Merker, S.] KNAW, Hubrecht Inst, NL-3584 CT Utrecht, Netherlands. [Tournoij, E.; Schulte-Merker, S.] UMC Utrecht, NL-3584 CT Utrecht, Netherlands. [Tournoij, E.; Moll, F. L.] Univ Med Ctr Utrecht, Dept Vasc Surg, Utrecht, Netherlands. [Weber, G. J.; Zon, L. I.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Weber, G. J.; Zon, L. I.] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Weber, G. J.; Zon, L. I.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Weber, G. J.; Zon, L. I.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Akkerman, J. W. N.; de Groot, P. G.] Univ Med Ctr Utrecht, Dept Clin Chem & Haematol, Lab Thrombosis & Haemostasis, Utrecht, Netherlands. RP Schulte-Merker, S (reprint author), KNAW, Hubrecht Inst, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands. EM s.schulte@hubrecht.eu FU 'Friends of the Hubrecht Foundation' FX The authors thank J. Bussmann for assistance in bioinformatics, J. Korving for histological assistance, R. Handin (Boston, MA) for making the Tg(cd41:GFP) available for our research, J. Bakkers for access to the laser set-up and T. Kidd for discussions. E. Tournoij was funded by the 'Friends of the Hubrecht Foundation'. NR 41 TC 4 Z9 5 U1 2 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD MAR PY 2010 VL 8 IS 3 BP 588 EP 595 DI 10.1111/j.1538-7836.2009.03721.x PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 554RW UT WOS:000274453100022 PM 20002541 ER PT J AU Alam, HB AF Alam, Hasan B. TI Evaluation of Novel Vanilloid-Based Hemostatic Agents in Rats EDITORIAL COMMENT SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Editorial Material ID HEMORRHAGE; SWINE; MODEL; DRESSINGS; INJURY C1 Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. RP Alam, HB (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5282 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD MAR PY 2010 VL 68 IS 3 BP 680 EP 681 PG 2 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 567ZY UT WOS:000275491200039 ER PT J AU Bromley, B Shipp, TD Benacerraf, BR AF Bromley, Bryann Shipp, Thomas D. Benacerraf, Beryl R. TI Structural Anomalies in Early Embryonic Death A 3-Dimensional Pictorial Essay SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE embryonic death; malformation; 3-dimensional sonography ID SAC SIZE; MISCARRIAGE; TRIMESTER AB Objective. The purpose of this pictorial essay was to determine whether 3-dimensional (3D) surface rendering of a dead first-trimester embryo can provide any information for the loss. Methods. Three-dimensional surface rendering was performed on a collection of dead first-trimester embryos with crown-rump lengths between 12 and 27 mm. These were compared with 2-dimensional (2D) images of the same embryos and with 2D images and 3D surface renderings of normally developing embryos. Results. Surface rendering of dead embryos showed a variety of abnormalities in the contour and limb formation. Conclusions. The use of 3D sonography may provide insight into the etiology of first-trimester embryonic death. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. RP Bromley, B (reprint author), Diagnost Ultrasound Associates PC, 333 Longwood Ave,Suite 400, Boston, MA 02115 USA. EM bbsono@aol.com NR 14 TC 4 Z9 4 U1 0 U2 0 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 MAR PY 2010 VL 29 IS 3 BP 445 EP 453 PG 9 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 570NV UT WOS:000275685900012 PM 20194939 ER PT J AU De Jesus, M Puleo, E Shelton, RC McNeill, LH Emmons, KM AF De Jesus, Maria Puleo, Elaine Shelton, Rachel C. McNeill, Lorna H. Emmons, Karen M. TI Factors Associated with Colorectal Cancer Screening among a Low-Income, Multiethnic, Highly Insured Population: Does Provider's Understanding of the Patient's Social Context Matter? SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Article DE Urban low-income population; Colorectal cancer; Social context; Provider's recommendation for CRC screening ID UNITED-STATES; OLDER WOMEN; PREDICTORS; DISPARITIES; ADHERENCE; PATTERNS; BEHAVIOR; URBAN AB The primary aim of this paper was to explore whether provider's understanding of patient's social context is associated with screening uptake, independent of provider's recommendation. Baseline data were collected in 2004-2005 from a cluster randomized control trial in 12 low-income housing sites. Participants included 695 low-income, multiethnic adults aged 50 years and over who were primarily insured (97%). Provider's recommendation was significantly associated with current adherence to colorectal cancer (CRC) screening. Provider's understanding of patient's social context, as operationalized by how well participants felt that their provider knew (a) their responsibilities at work, home, or school; (b) their worries about health; and (c) them as a person and their values and beliefs, was also significantly associated with current adherence to screening, independent of provider's recommendation. Participants who reported that their provider knew them well on two or three items were significantly more likely to be current with CRC screening compared to those who reported their provider knew them well on only one or none of the items (odds ratio = 1.56; 95% confidence interval = 1.06, 2.29). Our findings indicate that provider's understanding of patient's social context, independent of provider's recommendation for CRC screening, contributed to adherence to CRC screening in this low-income, multiethnic population. C1 [De Jesus, Maria; Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [De Jesus, Maria; Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Puleo, Elaine] Univ Massachusetts, Div Biostat & Epidemiol, Dept Publ Hlth, Amherst, MA 01003 USA. [Shelton, Rachel C.] Mt Sinai Sch Med, Div Canc Prevent & Control, Dept Oncol Sci, New York, NY USA. [McNeill, Lorna H.] Univ Texas MD Anderson Canc Ctr, Dept Hlth Dispar Res, Houston, TX 77030 USA. RP De Jesus, M (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St,LW 703, Boston, MA 02115 USA. EM Maria_Dejesus@dfci.harvard.edu FU National Cancer Institute [5R01CA098864-02, 1K22CA126992-01, K05 CA124415]; Dana-Farber Cancer Institute FX This research was supported by grants 5R01CA098864-02, 1K22CA126992-01, and K05 CA124415 from the National Cancer Institute and support to the Dana-Farber Cancer Institute by Liberty Mutual, National Grid, the Patterson Fellowship, and the Yerby Fellowship Program. NR 25 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1099-3460 J9 J URBAN HEALTH JI J. Urban Health PD MAR PY 2010 VL 87 IS 2 BP 236 EP 243 DI 10.1007/s11524-009-9420-1 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 575JA UT WOS:000276062100007 PM 20043214 ER PT J AU McDougal, WS AF McDougal, W. Scott TI Performance of the Chronic Kidney Disease-Epidemiology Study Equations for Estimating Glomerular Filtration Rate Before and After Nephrectomy EDITORIAL COMMENT SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP McDougal, WS (reprint author), Massachusetts Gen Hosp, Dept Urol, 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 MAR PY 2010 VL 183 IS 3 BP 902 EP 902 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 558NJ UT WOS:000274750100017 PM 20083277 ER PT J AU Nguyen, PL AF Nguyen, Paul L. TI Definition of Biochemical Recurrence After Radical Prostatectomy Does Not Substantially Impact Prognostic Factor Estimates EDITORIAL COMMENT SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp, 44 Binney St, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAR PY 2010 VL 183 IS 3 BP 989 EP 989 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 558NJ UT WOS:000274750100054 PM 20083273 ER PT J AU Cambria, RP AF Cambria, Richard P. TI R. Clement Darling Jr, MD, and the evolution of vascular surgery SO JOURNAL OF VASCULAR SURGERY LA English DT Editorial Material ID ABDOMINAL AORTIC-ANEURYSMS; TRANS-LUMINAL ANGIOPLASTY; CORONARY-ARTERY DISEASE; PULSE VOLUME RECORDER; VEIN BYPASS GRAFTS; DURABILITY; EXPERIENCE; REPAIR C1 [Cambria, Richard P.] Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. [Cambria, Richard P.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Cambria, RP (reprint author), Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, 15 Parkman St WAC 410, Boston, MA 02114 USA. EM rcambria@partners.org NR 33 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD MAR PY 2010 VL 51 IS 3 BP 747 EP 755 DI 10.1016/j.jvs.2009.10.112 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 571GB UT WOS:000275738600034 PM 20206816 ER PT J AU Lim, CS Qiao, X Mam, V Xia, Y Rafetto, JD Paleolog, E Davies, AH Khalil, RA AF Lim, C. S. Qiao, X. Mam, V. Xia, Y. Rafetto, J. D. Paleolog, E. Davies, A. H. Khalil, R. A. TI Prolonged Mechanical Stretch is Associated with Upregulation of Hypoxia-inducible Factors and Reduced Contraction in Rat Inferior Vena Cava SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 22nd Annual Meeting of the American-Venous-Forum CY FEB 10-13, 2010 CL Amelia Isl, FL SP Amer Venous Forum C1 [Lim, C. S.; Paleolog, E.; Davies, A. H.] Univ London Imperial Coll Sci Technol & Med, London, England. [Qiao, X.; Mam, V.; Xia, Y.; Khalil, R. A.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Rafetto, J. D.] VA Boston HCS, W Roxbury, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD MAR PY 2010 VL 51 IS 3 BP 791 EP 791 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 571GB UT WOS:000275738600055 ER PT J AU Corey, KE Mendez-Navarro, J Gorospe, EC Zheng, H Chung, RT AF Corey, K. E. Mendez-Navarro, J. Gorospe, E. C. Zheng, H. Chung, R. T. TI Early treatment improves outcomes in acute hepatitis C virus infection: a meta-analysis SO JOURNAL OF VIRAL HEPATITIS LA English DT Article DE acute hepatitis C; meta-analysis; spontaneous clearance; sustained virologic response ID PEGYLATED INTERFERON-ALPHA; RANDOMIZED CONTROLLED-TRIAL; VIRAL CLEARANCE; UNITED-STATES; DRUG-USERS; THERAPY; MONOTHERAPY; OUTBREAK AB Acute hepatitis C virus infection is associated with high rates of spontaneous clearance and variable rates of treatment-induced clearance. The benefit of early treatment versus awaiting spontaneous clearance is unknown, as is the optimal timing of treatment.We performed a MEDLINE and EMBASE search for the time period 1950 to October 2008. All English language abstracts using the search terms acute hepatitis C, hepatitis C and acute and hepatitis C and acute disease or acute infection were reviewed. Bibliographies were reviewed.Twenty-two studies including 1075 patients met the inclusion criteria. The sustained virologic response (SVR) rate for treated patients was 78%, significantly higher than 55.1% in untreated patients (OR = 3.08, 95% CI: 1.8-4.8 P value < 0.0001). Mean time from diagnosis to spontaneous clearance was 9.7 weeks (SD 6.5). SVR rates varied inversely with time from acute HCV diagnosis. SVR rates for treatment within 12 weeks was 82.5% (95% CI: 75.6-89.3), significantly better than the clearance rates in untreated patients (P < 0.001). Response rates fell to 66.9% for treatment between 12 and 24 weeks, and decreased further to 62.5% for treatment beyond 24 weeks. Rates of viral clearance in treated patients with acute hepatitis C virus infection were significantly higher than that in untreated patients. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis. Based on these findings, we would advocate a 12 week period of observation for spontaneous clearance before treatment initiation. If no clearance has occurred by 12 weeks, treatment should be initiated. C1 [Corey, K. E.; Mendez-Navarro, J.; Gorospe, E. C.; Chung, R. T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Corey, K. E.; Zheng, H.; Chung, R. T.] Harvard Univ, Sch Med, Boston, MA USA. [Mendez-Navarro, J.] Hosp Especialidades CMN Siglo XXI, IMSS, Mexico City, DF, Mexico. [Zheng, H.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Warren 1007,55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org FU Bristol-Myer-Squibb; Roche Laboratories; Schering-Plough; NIH [AI69939, DK78772] FX KEC has received research support from Bristol-Myer-Squibb Virology Fellowship.; RTC has received research support from Roche Laboratories and Schering-Plough. RTC is supported by NIH AI69939 and DK78772. NR 28 TC 45 Z9 48 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1352-0504 J9 J VIRAL HEPATITIS JI J. Viral Hepatitis PD MAR PY 2010 VL 17 IS 3 BP 201 EP 207 DI 10.1111/j.1365-2893.2009.01167.x PG 7 WC Gastroenterology & Hepatology; Infectious Diseases; Virology SC Gastroenterology & Hepatology; Infectious Diseases; Virology GA 545ID UT WOS:000273724800007 PM 19674285 ER PT J AU Subramanya, S Kim, SS Abraham, S Yao, JH Kumar, M Kumar, P Haridas, V Lee, SK Shultz, LD Greiner, D Manjunath, N Shankar, P AF Subramanya, Sandesh Kim, Sang-Soo Abraham, Sojan Yao, Jiahong Kumar, Mukesh Kumar, Priti Haridas, Viraga Lee, Sang-Kyung Shultz, Leonard D. Greiner, Dale Manjunath, N. Shankar, Premlata TI Targeted Delivery of Small Interfering RNA to Human Dendritic Cells To Suppress Dengue Virus Infection and Associated Proinflammatory Cytokine Production SO JOURNAL OF VIROLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; MONOCYTE-DERIVED MACROPHAGES; COLONY-STIMULATING FACTOR; TNF-ALPHA; GENE-EXPRESSION; IN-VIVO; DISEASE PATHOGENESIS; HEMORRHAGIC-FEVER; SIRNA DELIVERY; MOUSE MODEL AB Dengue is a common arthropod-borne flaviviral infection in the tropics, for which there is no vaccine or specific antiviral drug. The infection is often associated with serious complications such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), in which both viral and host factors have been implicated. RNA interference (RNAi) is a potent antiviral strategy and a potential therapeutic option for dengue if a feasible strategy can be developed for delivery of small interfering RNA (siRNA) to dendritic cells (DCs) and macrophages, the major in vivo targets of the virus and also the source of proinflammatory cytokines. Here we show that a dendritic cell-targeting 12-mer peptide (DC3) fused to nona-D-arginine (9dR) residues (DC3-9dR) delivers siRNA and knocks down endogenous gene expression in heterogenous DC subsets, (monocyte-derived DCs [MDDCs], CD34(+) hematopoietic stem cell [HSC])-derived Langerhans DCs, and peripheral blood DCs). Moreover, DC3-9dR-mediated delivery of siRNA targeting a highly conserved sequence in the dengue virus envelope gene (siFvE(D)) effectively suppressed dengue virus replication in MDDCs and macrophages. In addition, DC-specific delivery of siRNA targeting the acute-phase cytokine tumor necrosis factor alpha (TNF-alpha), which plays a major role in dengue pathogenesis, either alone or in combination with an antiviral siRNA, significantly reduced virus-induced production of the cytokine in MDDCs. Finally to validate the strategy in vivo, we tested the ability of the peptide to target human DCs in the NOD/SCID/IL-2R gamma(-/-) mouse model engrafted with human CD34(+) hematopoietic stem cells (HuHSC mice). Treatment of mice by intravenous (i.v.) injection of DC3-9dR-complexed siRNA targeting TNF-alpha effectively suppressed poly(I:C)-induced TNF-alpha production by DCs. Thus, DC3-9dR can deliver siRNA to DCs both in vitro and in vivo, and this delivery approach holds promise as a therapeutic strategy to simultaneously suppress virus replication and curb virus-induced detrimental host immune responses in dengue infection. C1 [Subramanya, Sandesh; Kim, Sang-Soo; Abraham, Sojan; Manjunath, N.; Shankar, Premlata] Texas Tech Univ, Hlth Sci Ctr, Paul L Foster Sch Med, Dept Biomed Sci,Ctr Excellence Infect Dis, El Paso, TX 79905 USA. [Subramanya, Sandesh; Kim, Sang-Soo; Yao, Jiahong; Kumar, Mukesh; Haridas, Viraga; Manjunath, N.; Shankar, Premlata] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Kumar, Mukesh] Albert Einstein Coll Med, Dept Med Hepatol, Bronx, NY 10461 USA. [Kumar, Priti] Yale Univ, Sch Med, Infect Dis Sect, Dept Internal Med, New Haven, CT 06520 USA. [Lee, Sang-Kyung] Hanyang Univ, Dept Bioengn, Seoul 133791, South Korea. [Lee, Sang-Kyung] Hanyang Univ, Hanyang Fus Mat Program, Seoul 133791, South Korea. [Shultz, Leonard D.] Jackson Lab, Bar Harbor, ME 04609 USA. [Greiner, Dale] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. RP Shankar, P (reprint author), Texas Tech Univ, Hlth Sci Ctr, Paul L Foster Sch Med, Dept Biomed Sci,Ctr Excellence Infect Dis, 5001 El Paso Dr, El Paso, TX 79905 USA. EM Premlata.shankar@ttuhsc.edu RI Kumar, Priti/C-5699-2009 FU NIH [AI071882, AI056900, AI075419] FX The first two authors contributed equally to this study. This work was supported by NIH grants AI071882 (P. S.), AI056900 (P. S. and N. M.), and AI075419 (N. M.). NR 59 TC 50 Z9 56 U1 1 U2 10 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 MAR PY 2010 VL 84 IS 5 BP 2490 EP 2501 DI 10.1128/JVI.02105-08 PG 12 WC Virology SC Virology GA 552YD UT WOS:000274330300027 PM 20015996 ER PT J AU Goodman, JH Tyer-Viola, L AF Goodman, Janice H. Tyer-Viola, Lynda TI Detection, Treatment, and Referral of Perinatal Depression and Anxiety by Obstetrical Providers SO JOURNAL OF WOMENS HEALTH LA English DT Article ID PATIENT HEALTH QUESTIONNAIRE; DIAGNOSING MENTAL-DISORDERS; ANTENATAL RISK-FACTORS; POSTPARTUM DEPRESSION; POSTNATAL DEPRESSION; PREGNANT-WOMEN; PRIMARY-CARE; INTERPERSONAL PSYCHOTHERAPY; PSYCHIATRIC-DISORDERS; INFANT DEVELOPMENT AB Aims: This study aimed to assess the rates of detection, treatment, and referral of maternal depression and anxiety by obstetrical providers during pregnancy and at 6 weeks postpartum. Methods: A convenience sample of women receiving obstetrical care at a large urban teaching hospital (n=491) was screened for depression and anxiety during the third trimester of pregnancy and again at 6 weeks postpartum using the Edinburgh Postnatal Depression Scale and the anxiety portions of the Patient Health Questionnaire. Participants were also asked if they thought they needed help for depression, anxiety, or stress at the two time points. Obstetrical providers were blind to screening results. Two months postdelivery, each woman's obstetrical electronic medical record (EMR) was reviewed for documentation of psychiatric symptoms, diagnoses, psychiatric treatment, and mental health referrals at the two time points. Data were analyzed using descriptive statistics. Results: Twenty-three percent of participants screened positive for an anxiety disorder or high levels of depressive symptoms or both prenatally, and 17% screened positive at 6 weeks postpartum. The majority of women who screened positive were not identified by their providers during pregnancy or postpartum. Only 15% of positively screened participants had evidence of any mental health treatment in their EMR during pregnancy, with equally low rates of referral to mental health or social services. In the postpartum period, only 25% of positively screened postpartum women received treatment, and an additional 2.5% were referred. A low proportion of women who reported they felt a need for help with depression, anxiety, or stress prenatally or postpartum received treatment or referral. Conclusions: These findings indicate that detection, treatment, and referral of perinatal depression by obstetrical providers are seriously lacking and need to be addressed. C1 Massachusetts Gen Hosp, MGH Inst Hlth Profess, Boston, MA 02114 USA. Massachusetts Gen Hosp, Yvonne L Munn Ctr Nursing Res, Boston, MA 02114 USA. RP Goodman, JH (reprint author), 36 1st Ave, Boston, MA 02129 USA. EM jgoodman@mghihp.edu FU Freedom from Fear Foundation; MGH Institute of Health Professions Faculty Research Fellowship FX This study was supported by a Sharon Davies Memorial Research Award from the Freedom from Fear Foundation (J.H.G.) and from an MGH Institute of Health Professions Faculty Research Fellowship (J.H.G.). We would like to acknowledge the following MGH Institute of Health Professions graduate nursing students who assisted with data collection: Jessica Gould, Alison Bates, Maeve Dargush, Isis Lucia, Neena Philip, Kerry Decker, Tricia Keogh, and Anita Pandofe-Ruchman. NR 87 TC 62 Z9 63 U1 2 U2 16 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2010 VL 19 IS 3 BP 477 EP 490 DI 10.1089/jwh.2008.1352 PG 14 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 574IS UT WOS:000275983200014 PM 20156110 ER PT J AU Isaac, C Griffin, L Carnes, M AF Isaac, Carol Griffin, Lindsay Carnes, Molly TI A Qualitative Study of Faculty Members' Views of Women Chairs SO JOURNAL OF WOMENS HEALTH LA English DT Article ID REQUISITE MANAGEMENT CHARACTERISTICS; SEX-ROLE STEREOTYPES; ACADEMIC MEDICINE; FEMALE LEADERS; GENDER STEREOTYPES; DOUBLE STANDARDS; METAANALYSIS; PHYSICIANS; PROMOTION; SUCCESS AB Background: Concurrent with the evolving role of the department chair in academic medicine is the entry of women physicians into chair positions. Because implicit biases that stereotypically masculine behaviors are required for effective leadership remain strong, examining faculty members' perceptions of their chair's leadership in medical school departments with women chairs can provide insight into the views of women leaders in academic medicine and the complex ways in which gender may impact these chairs' leadership style and actions. Methods: We conducted semistructured interviews with 13 male and 15 female faculty members representing all faculty tracks in three clinical departments chaired by women. Inductive, qualitative analysis of the subsequent text allowed themes to emerge across interviews. Results: Four themes emerged regarding departmental leadership. One dealt with the leadership of the previous chair. The other three described the current chair's characteristics (tough, direct, and transparent), her use of communal actions to help support and mentor her faculty, and her ability to build power through consensus. Because all three chairs were early in their tenure, a wait and see attitude was frequently expressed. Faculty generally viewed having a woman chair as an indication of positive change, with potential individual and institutional advantages. Conclusions: This exploratory study suggests that the culture of academic medicine has moved beyond questioning women physicians' competence to lead once they are in top organizational leadership positions. The findings are also consonant with experimental research indicating that women leaders are most successful when they pair stereotypic male (agentic) behaviors with stereotypic female (communal) behaviors. All three chairs exhibited features of a transformational leadership style and characteristics deemed essential for effective leadership in academic medicine. C1 [Isaac, Carol; Carnes, Molly] Univ Wisconsin, Ctr Womens Hlth Res, Madison, WI 53715 USA. [Isaac, Carol; Griffin, Lindsay; Carnes, Molly] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI 53715 USA. [Carnes, Molly] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Carnes, M (reprint author), Univ Wisconsin, Ctr Womens Hlth Res, 700 Regent St,Suite 301, Madison, WI 53715 USA. EM mlcarnes@wisc.edu FU School of Medicine and Public Health's; National Institute on Aging [T-32 AG 00265] FX L.G. was supported by the School of Medicine and Public Health's 2008 Shapiro Summer Research Program. Dr. Isaac was supported by grant No. T-32 AG 00265 from the National Institute on Aging. Dr. Carnes is employed part time by the William S. Middleton Memorial Veterans Hospital. NR 71 TC 11 Z9 11 U1 2 U2 12 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD MAR PY 2010 VL 19 IS 3 BP 533 EP 546 DI 10.1089/jwh.2009.1506 PG 14 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 574IS UT WOS:000275983200020 PM 20156081 ER PT J AU Weston, AL Weinstein, AM Barton, C Yaffe, K AF Weston, Andrea L. Weinstein, Andrea M. Barton, Cynthia Yaffe, Kristine TI Potentially Inappropriate Medication Use in Older Adults With Mild Cognitive Impairment SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Mild cognitive impairment; Potentially inappropriate medication; Epidemiology ID CHOLINESTERASE-INHIBITORS; ANTICHOLINERGIC DRUGS; ALZHEIMERS-DISEASE; PRESCRIBED DRUGS; DEMENTIA AB Background. Patients with mild cognitive impairment (MCI) may be especially vulnerable to the side effects of potentially inappropriate medications (PIMs), especially those that impair cognition. Methods. We conducted a cross-sectional study to determine the prevalence of PIM use among 689 patients with MCI. We used the 2003 Beers Criteria for cognitive impairment to identify PIMs. We then determined if certain patients were more likely to use PIMs. Results. There were 143 (20.8%) patients with MCI taking a PIM: 108 (15.7%) patients were taking one PIM and 35 (5.1%) patients were taking two or more PIMs. The most common PIMs were anticholinergics (35.7%) and benzodiazepines (31.5%). Patients were more likely to be taking PIMs if they were women and were taking a greater number of medications and less likely if they had a history of myocardial infarction. Conclusions. Patients with MCI are frequently taking PIMs that may negatively affect cognition. Future research is needed to assess whether cognitive impairment symptoms are improved if PIM use is reduced. C1 [Weston, Andrea L.; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. [Weston, Andrea L.; Weinstein, Andrea M.; Barton, Cynthia; Yaffe, Kristine] San Francisco VA Med Ctr, Dept Geriatr Psychiat, San Francisco, CA USA. [Weinstein, Andrea M.] No Calif Inst Res & Educ, San Francisco, CA USA. [Barton, Cynthia; Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. RP Weston, AL (reprint author), Univ Calif San Francisco, Dept Psychiat, Box 116H,4150 Clement St, San Francisco, CA 94121 USA. EM andrea.weston@ucsf.edu FU Mental Illness Research, Education, and Clinical Center at the Department of Veterans Affairs; California Department of Public Health ARCCs [99-86138]; National Institute of Aging [1K24AG031155-01] FX This work was supported by the Mental Illness Research, Education, and Clinical Center at the Department of Veterans Affairs: The California Department of Public Health ARCCs Grant (99-86138); and National Institute of Aging Grant (1K24AG031155-01 to K.Y.). NR 25 TC 20 Z9 20 U1 0 U2 2 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2010 VL 65 IS 3 BP 318 EP 321 DI 10.1093/gerona/glp158 PG 4 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 567CV UT WOS:000275420800017 PM 19843646 ER PT J AU Jung, YY Gruenewald, TL Seeman, TE Sarkisian, CA AF Jung, Yunkyung Gruenewald, Tara L. Seeman, Teresa E. Sarkisian, Catherine A. TI Productive Activities and Development of Frailty in Older Adults SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article DE Productive activities; Volunteering; Frailty ID MACARTHUR; HEALTH; WOMEN AB Objective. Our aim was to examine whether engagement in productive activities, including volunteering, paid work, and childcare, protects older adults against the development of geriatric frailty. Methods. Data from the first (1988) and second (1991) waves of the MacArthur Study of Successful Aging, a prospective cohort study of high-functioning older adults aged 70-79 years (n = 1,072), was used to examine the hypothesis that engagement in productive activities is associated with lower levels of frailty 3 years later. Results. Engagement in productive activities at baseline was associated with a lower cumulative odds of frailty 3 years later in unadjusted models (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.58-0.96) but not after adjusting for age, disability, and cognitive function (adjusted OR = 0.78, 95% CI = 0.60-1.01). Examination of productive activity domains showed that volunteering (but neither paid work nor childcare) was associated with a lower cumulative odds of frailty after adjusting for age, disability, and cognitive function. This relationship diminished and was no longer statistically significant after adjusting for personal mastery and religious service attendance. Discussion. Though high-functioning older adults who participate in productive activities are less likely to become frail, after adjusting for age, disability, and cognitive function, only volunteering is associated with a lower cumulative odds of frailty. C1 [Sarkisian, Catherine A.] VA Greater Los Angeles Healthcare Syst, Geriatr Res Educ Clin Ctr, Los Angeles, CA 90073 USA. [Gruenewald, Tara L.; Seeman, Teresa E.; Sarkisian, Catherine A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Geriatr, Los Angeles, CA 90095 USA. [Jung, Yunkyung] Univ Calif Los Angeles, Sch Publ Affairs, Dept Social Welf, Los Angeles, CA 90095 USA. RP Sarkisian, CA (reprint author), VA Greater Los Angeles Healthcare Syst, Geriatr Res Educ Clin Ctr, Bldg 220,Room 315 11G,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM csarkisian@mednet.ucla.edu FU National Institute on Aging [1 R21 AG025764-02, K01-AG028582]; Catherine T. MacArthur Foundation FX National Institute on Aging ("Testing the Validity of a Construct of Geriatric Frailty" and 1 R21 AG025764-02 to C. A. S. and K01-AG028582 to T. L. G.); John D. and Catherine T. MacArthur Foundation (the MacArthur Research network on Successful Aging and the macArthur Research network on SES and Health grants). NR 26 TC 26 Z9 27 U1 6 U2 8 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5014 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD MAR PY 2010 VL 65 IS 2 BP 256 EP 261 DI 10.1093/geronb/gbq005 PG 6 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 558WT UT WOS:000274780100013 PM 20018794 ER PT J AU Dalkara, T Nozari, A Moskowitz, MA AF Dalkara, Turgay Nozari, Ala Moskowitz, Michael A. TI Migraine aura pathophysiology: the role of blood vessels and microembolisation SO LANCET NEUROLOGY LA English DT Article ID PATENT FORAMEN OVALE; CORTICAL SPREADING DEPRESSION; TO-LEFT SHUNTS; ISCHEMIC-STROKE; IN-VIVO; ATHEROSCLEROSIS RISK; PARADOXICAL EMBOLISM; INCREASED PREVALENCE; RAYNAUDS-PHENOMENON; PROSPECTIVE COHORT AB Migraine attacks with auras are sometimes associated with underlying hereditary or acquired cerebrovascular disorders. A unifying pathophysiological explanation linking migraine to these conditions has been difficult to identify. On the basis of genetic and epidemiological evidence, we suggest that changes in blood vessels, hypoperfusion disorders, and microembolisation can cause neurovascular dysfunction and evoke cortical spreading depression, an event that is widely thought to underlie aura symptoms. In fact, recent experimental data have indicated that focal, mild, and transient ischaemia can trigger cortical spreading depression without an enduring tissue signature. Although migraine with aura has many causes (eg, neuronal network excitability), it seems that migraine and stroke might both be triggered by hypoperfusion and could therefore exist on a continuum of vascular complications in a subset of patients who have these hereditary or acquired comorbid vascular conditions. C1 [Dalkara, Turgay; Moskowitz, Michael A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab,Dept Radiol, Charlestown, MA 02129 USA. [Nozari, Ala] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Charlestown, MA 02129 USA. [Dalkara, Turgay] Hacettepe Univ, Fac Med, Dept Neurol, TR-06100 Ankara, Turkey. RP Moskowitz, MA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab,Dept Radiol, 149 13th St,Room 6403, Charlestown, MA 02129 USA. EM moskowitz@helix.mgh.harvard.edu FU National Institute of Neurological Disorders and Stroke [NS35611] FX Some of the studies cited in this paper were supported by a National Institute of Neurological Disorders and Stroke grant NS35611 (MAM). NR 86 TC 73 Z9 76 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD MAR PY 2010 VL 9 IS 3 BP 309 EP 317 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 565BL UT WOS:000275263400014 PM 20170844 ER PT J AU Weiss, SE Kelly, PJ AF Weiss, Stephanie E. Kelly, Paul J. TI Neurocognitive function after WBRT plus SRS or SRS alone SO LANCET ONCOLOGY LA English DT Editorial Material ID WHOLE-BRAIN RADIATION C1 [Weiss, Stephanie E.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Weiss, Stephanie E.; Kelly, Paul J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Weiss, SE (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM sweiss@lroc.harvard.edu NR 3 TC 6 Z9 7 U1 0 U2 0 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 MAR PY 2010 VL 11 IS 3 BP 220 EP 221 PG 2 WC Oncology SC Oncology GA 568MA UT WOS:000275525300009 PM 20202605 ER PT J AU Richer, SL Yelken, K Cunningham, MJ Randolph, GW Franco, RA AF Richer, Sara L. Yelken, Kursat Cunningham, Michael J. Randolph, Gregory W. Franco, Ramon A., Jr. TI Hypopharyngeal Pharyngoplasty for the Management of Piriform Fossa Sinus SO LARYNGOSCOPE LA English DT Article DE Piriform sinus; pharyngoplasty; branchial anomaly ID BRANCHIAL CLEFT SINUS; ENDOSCOPIC CAUTERIZATION; ANOMALIES; 3RD; FISTULA C1 [Richer, Sara L.; Yelken, Kursat; Cunningham, Michael J.; Randolph, Gregory W.; Franco, Ramon A., Jr.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. RP Richer, SL (reprint author), St Vincents Hosp, Dept Surg, 2800 Main St, Bridgeport, CT 06606 USA. EM sara.richer@stvincents.org NR 14 TC 0 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD MAR PY 2010 VL 120 IS 3 BP 500 EP 503 DI 10.1002/lary.20786 PG 4 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 564OI UT WOS:000275224200012 PM 20131369 ER PT J AU DeAngelo, DJ Attar, EC AF DeAngelo, Daniel J. Attar, Eyal C. TI Use of dasatinib and nilotinib in imatinib-resistant chronic myeloid leukemia: translating preclinical findings to clinical practice SO LEUKEMIA & LYMPHOMA LA English DT Review DE Imatinib; dasatinib; nilotinib; chronic myeloid leukemia ID CHRONIC MYELOGENOUS LEUKEMIA; TYROSINE KINASE INHIBITOR; BCR-ABL MUTATIONS; SRC-FAMILY KINASES; PATIENTS RECEIVING IMATINIB; HEMATOPOIETIC STEM-CELLS; GIMEMA WORKING PARTY; LONG-TERM OUTCOMES; CHRONIC-PHASE; DOMAIN MUTATIONS AB The BCR-ABL inhibitor imatinib revolutionized the treatment of chronic myeloid leukemia (CML). However, resistance and intolerance to imatinib have emerged as substantial clinical issues. The mechanisms underlying resistance are multifactorial and may include mutations in the kinase domain of BCR-ABL, increased production of BCR-ABL, or activation of BCR-ABL-independent pathways. Two second-line BCR-ABL inhibitors are now approved for treatment of patients with resistance or intolerance to imatinib. Dasatinib is a dual BCR-ABL/Src-family kinase (SFK) inhibitor approved for patients with imatinib-resistant and -intolerant CML in any phase and Ph+ ALL. Nilotinib, an analogue of imatinib, is approved for the treatment of imatinib-resistant or -intolerant patients with chronic or accelerated phase CML. Both agents have shown significant clinical activity in patients with imatinib-resistant or -intolerant CML, and their approval represents a major advancement in the treatment options available. Choosing the most appropriate treatment after imatinib failure may be critical in attaining the best possible long-term prognosis. The presence of certain disease characteristics (e.g. specific BCR-ABL mutations) or patient comorbidities may facilitate more effective treatment. In this review, we discuss mechanisms of imatinib resistance and preclinical and clinical data with dasatinib and nilotinib which may have potential use for guiding second-line treatment decisions.3,500 small molecules to selectively impair growth and viability of human fibroblasts in media containing either galactose or glucose as the sole sugar source. We identify several clinically used drugs never linked to energy metabolism, including the antiemetic meclizine, which attenuates mitochondrial respiration through a mechanism distinct from that of canonical inhibitors. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion injury in murine models. Nutrient-sensitized screening may provide a useful framework for understanding gene function and drug action within the context of energy metabolism. C1 [Gohil, Vishal M.; Sheth, Sunil A.; Nilsson, Roland; Perocchi, Fabiana; Chen, William; Mootha, Vamsi K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Gohil, Vishal M.; Sheth, Sunil A.; Nilsson, Roland; Perocchi, Fabiana; Chen, William; Clish, Clary B.; Mootha, Vamsi K.] MIT, Broad Inst, Cambridge, MA 02139 USA. [Gohil, Vishal M.; Sheth, Sunil A.; Nilsson, Roland; Perocchi, Fabiana; Chen, William; Clish, Clary B.; Mootha, Vamsi K.] Harvard Univ, Cambridge, MA 02138 USA. [Gohil, Vishal M.; Sheth, Sunil A.; Nilsson, Roland; Perocchi, Fabiana; Chen, William; Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Wojtovich, Andrew P.; Brookes, Paul S.] Univ Rochester, Med Ctr, Dept Anesthesiol, Rochester, NY 14642 USA. [Wojtovich, Andrew P.; Brookes, Paul S.] Univ Rochester, Med Ctr, Dept Pharmacol & Physiol, Rochester, NY 14642 USA. [Lee, Jeong Hyun; Ayata, Cenk] Massachusetts Gen Hosp, Dept Radiol, Stroke & Neurovasc Regulat Lab, Charlestown, MA USA. RP Mootha, VK (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM vamsi@hms.harvard.edu RI Lee, Jeong Hyun/G-1676-2013 OI Lee, Jeong Hyun/0000-0003-0504-0119 FU United Mitochondrial Disease Foundation; Howard Hughes Medical Institute; National Institutes of Health [RO1 HL-071158]; Deane Institute for Integrative Research in Stroke and Atrial Fibrillation; American Heart Association [0815770D]; Burroughs Wellcome Fund; Center for Integration of Medical and Innovative Technology; American Diabetes Association/Smith Family Foundation FX We thank E. Shoubridge for the MCH58 cell line; M. MacDonald for immortalized striatal cells; R. Xavier for the HRE luciferase construct; S. Norton, B. Wagner and the Broad Chemical Screening Platform for assistance in compound arraying; J. Evans of the Whitehead Institute/MIT BioImaging Center for assistance with high-throughput microscopy; C. Belcher-Timme for technical assistance; T. Kitami for assistance with mitochondrial imaging; M. Mehta for assistance reviewing drug toxicity data; S. Calvo, A. Chess, R. Gould, E. Lander, A. Ting, S. Vafai and members of Mootha lab for valuable discussions and comments. This work was supported by fellowships or grants from the United Mitochondrial Disease Foundation (V. M. G.); Howard Hughes Medical Institute (S. A. S. and V. K. M.); National Institutes of Health (RO1 HL-071158 to P. S. B.); Deane Institute for Integrative Research in Stroke and Atrial Fibrillation (C. A.); American Heart Association (#0815770D to A. P. W.); the Burroughs Wellcome Fund (V. K. M.); the Center for Integration of Medical and Innovative Technology (V. K. M.); and the American Diabetes Association/Smith Family Foundation (V. K. M.). NR 48 TC 102 Z9 102 U1 3 U2 29 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 MAR PY 2010 VL 28 IS 3 BP 249 EP U100 DI 10.1038/nbt.1606 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 565JT UT WOS:000275288300023 PM 20160716 ER PT J AU Atfi, A Baron, R AF Atfi, Azeddine Baron, Roland TI PTH battles TGF-beta in bone SO NATURE CELL BIOLOGY LA English DT Editorial Material ID PARATHYROID-HORMONE; RECEPTOR AB Bone remodelling in vertebrates is coordinately regulated by the opposing effects of parathyroid hormone (PTH) and transforming growth factor-beta (TGF-beta). PTH couples the processes of bone resorption and formation by enforcing simultaneous internalization of TGF-beta type II receptor (T beta RII) and PTH type 1 receptor (PTH1R), which attenuates both TGF-beta and PTH signalling in vivo. C1 [Atfi, Azeddine] Hop St Antoine, NSERM, UMRS 938, F-75571 Paris, France. [Atfi, Azeddine; Baron, Roland] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Baron, Roland] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Endocrine Unit, Boston, MA 02115 USA. RP Atfi, A (reprint author), Hop St Antoine, NSERM, UMRS 938, 184 Rue Faubourg St Antoine, F-75571 Paris, France. EM azeddine.atfi@inserm.fr NR 15 TC 9 Z9 10 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD MAR PY 2010 VL 12 IS 3 BP 205 EP 207 PG 4 WC Cell Biology SC Cell Biology GA 562MD UT WOS:000275054200004 PM 20190828 ER PT J AU Kokel, D Bryan, J Laggner, C White, R Cheung, CYJ Mateus, R Healey, D Kim, S Werdich, AA Haggarty, SJ MacRae, CA Shoichet, B Peterson, RT AF Kokel, David Bryan, Jennifer Laggner, Christian White, Rick Cheung, Chung Yan J. Mateus, Rita Healey, David Kim, Sonia Werdich, Andreas A. Haggarty, Stephen J. MacRae, Calum A. Shoichet, Brian Peterson, Randall T. TI Rapid behavior-based identification of neuroactive small molecules in the zebrafish SO NATURE CHEMICAL BIOLOGY LA English DT Article ID ZINC-FINGER NUCLEASES; MONOAMINE OXIDASES; CHEMICAL GENETICS; DISCOVERY AB Neuroactive small molecules are indispensable tools for treating mental illnesses and dissecting nervous system function. However, it has been difficult to discover novel neuroactive drugs. Here, we describe a high-throughput, behavior-based approach to neuroactive small molecule discovery in the zebrafish. We used automated screening assays to evaluate thousands of chemical compounds and found that diverse classes of neuroactive molecules caused distinct patterns of behavior. These 'behavioral barcodes' can be used to rapidly identify new psychotropic chemicals and to predict their molecular targets. For example, we identified new acetylcholinesterase and monoamine oxidase inhibitors using phenotypic comparisons and computational techniques. By combining high-throughput screening technologies with behavioral phenotyping in vivo, behavior-based chemical screens can accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior. C1 [Kokel, David; Cheung, Chung Yan J.; Mateus, Rita; Healey, David; Kim, Sonia; Werdich, Andreas A.; MacRae, Calum A.; Peterson, Randall T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. [Kokel, David; Cheung, Chung Yan J.; Mateus, Rita; Healey, David; Kim, Sonia; Werdich, Andreas A.; MacRae, Calum A.; Peterson, Randall T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol,Dept Med, Charlestown, MA USA. [Kokel, David; Cheung, Chung Yan J.; Mateus, Rita; Healey, David; Kim, Sonia; Haggarty, Stephen J.; Peterson, Randall T.] Broad Inst, Cambridge, MA USA. [Bryan, Jennifer; White, Rick] Univ British Columbia, Dept Stat, Vancouver, BC V6T 1W5, Canada. [Bryan, Jennifer] Univ British Columbia, Michael Smith Labs, Vancouver, BC V5Z 1M9, Canada. [Laggner, Christian; Shoichet, Brian] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Haggarty, Stephen J.] Stanley Ctr Psychiat Res, Cambridge, MA USA. RP Kokel, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. EM dkokel@cvrc.mgh.harvard.edu; peterson@cvrc.mgh.harvard.edu OI Bryan, Jennifer/0000-0002-6983-2759; kokel, david/0000-0002-1981-1511; Haggarty, Stephen J./0000-0002-7872-168X FU US National Institutes of Health [HL07208, NS063733, MH085205, MH086867, GM71896]; National Sciences and Engineering Council of Canada; Canadian Institutes of Health Research; Max Kade Foundation; Stanley Medical Research Institute FX We thank E. Scolnick, M. Granato, J. Dowling, D. Milan, C. Felts, J. Rihel, A. Schier and members of our research groups for encouragement and advice. This work was supported by US National Institutes of Health training grant HL07208 (D. K.) and grants NS063733 (R. T. P.), MH085205 (R. T. P.), MH086867 (R. T. P.) and GM71896 (B. K. S. and J. Irwin), the National Sciences and Engineering Council of Canada (J. B.), the Canadian Institutes of Health Research (J. B.), the Max Kade Foundation (C. L.) and the Stanley Medical Research Institute (S. J. H.). NR 20 TC 224 Z9 226 U1 3 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD MAR PY 2010 VL 6 IS 3 BP 231 EP 237 DI 10.1038/NCHEMBIO.307 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 556CK UT WOS:000274565100016 PM 20081854 ER PT J AU Bradner, JE West, N Grachan, ML Greenberg, EF Haggarty, SJ Warnow, T Mazitschek, R AF Bradner, James E. West, Nathan Grachan, Melissa L. Greenberg, Edward F. Haggarty, Stephen J. Warnow, Tandy Mazitschek, Ralph TI Chemical phylogenetics of histone deacetylases SO NATURE CHEMICAL BIOLOGY LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; ZINC-BINDING; CATALYTIC-ACTIVITY; INHIBITORS; MAFFT; IDENTIFICATION; COMPLEXES; LARGAZOLE; DOMAIN; HDAC7 AB The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of class I and II histone deacetylases (HDACs) as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as nonselective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of, to our knowledge, the first nonselective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents. C1 [Bradner, James E.; West, Nathan; Greenberg, Edward F.; Haggarty, Stephen J.; Mazitschek, Ralph] Broad Inst Harvard & Massachusetts Inst Technol, Chem Biol Program, Cambridge, MA USA. [Bradner, James E.; West, Nathan; Greenberg, Edward F.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bradner, James E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Grachan, Melissa L.; Mazitschek, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA USA. [Haggarty, Stephen J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Warnow, Tandy] Univ Texas Austin, Dept Comp Sci, Austin, TX 78712 USA. [Mazitschek, Ralph] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Bradner, JE (reprint author), Broad Inst Harvard & Massachusetts Inst Technol, Chem Biol Program, Cambridge, MA USA. EM james_bradner@dfci.harvard.edu; rmazitschek@mgh.harvard.edu RI Mazitschek, Ralph/E-3741-2013; OI Mazitschek, Ralph/0000-0002-1105-689X; Haggarty, Stephen J./0000-0002-7872-168X FU US National Cancer Institute [1K08CA128972]; American Society of Hematology; Multiple Myeloma Research Foundation; Burroughs-Wellcome Foundation; US National Institutes of Health [T32CA079443, 1R01DA028301-01, P01CA078048]; US National Science Foundation [0733029, ITR 0331453]; US National Cancer Institute's Initiative for Chemical Genetics [N01-CO-12400] FX We thank S. Schreiber and the Broad Chemical Biology Program for research space and support. We thank J. Clardy, T. Mitchison, R. Weissleder, O. Wiest, R. Williams (Colorado State University), T. Lewis (Broad Institute) and R. Maglathlin (Broad Institute) for support, thoughtful discussions and access to key instrumentation and reagents. We thank A. Stamatakis for helpful discussions on phylogenetics. We thank C. Johnson, G. Beletsky and S. Jonston for analytical support. This work was supported by grants from the US National Cancer Institute (1K08CA128972; J. E. B.), the American Society of Hematology (J. E. B.), the Multiple Myeloma Research Foundation (J. E. B.), the Burroughs-Wellcome Foundation (J. E. B.), the US National Institutes of Health (T32CA079443 to M. L. G., 1R01DA028301-01 to S. J. H. and P01CA078048 to R. M.), and the US National Science Foundation (DEB 0733029 and ITR 0331453 to T. W.). The project has been funded in part with funds from the US National Cancer Institute's Initiative for Chemical Genetics (contract number N01-CO-12400). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US government. NR 31 TC 326 Z9 332 U1 5 U2 56 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD MAR PY 2010 VL 6 IS 3 BP 238 EP 243 DI 10.1038/NCHEMBIO.313 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 556CK UT WOS:000274565100017 PM 20139990 ER PT J AU Girirajan, S Rosenfeld, JA Cooper, GM Antonacci, F Siswara, P Itsara, A Vives, L Walsh, T McCarthy, SE Baker, C Mefford, HC Kidd, JM Browning, SR Browning, BL Dickel, DE Levy, DL Ballif, BC Platky, K Farber, DM Gowans, GC Wetherbee, JJ Asamoah, A Weaver, DD Mark, PR Dickerson, J Garg, BP Ellingwood, SA Smith, R Banks, VC Smith, W McDonald, MT Hoo, JJ French, BN Hudson, C Johnson, JP Ozmore, JR Moeschler, JB Surti, U Escobar, LF El-Khechen, D Gorski, JL Kussmann, J Salbert, B Lacassie, Y Biser, A McDonald-McGinn, DM Zackai, EH Deardorff, MA Shaikh, TH Haan, E Friend, KL Fichera, M Romano, C Gecz, J DeLisi, LE Sebat, J King, MC Shaffer, LG Eichler, EE AF Girirajan, Santhosh Rosenfeld, Jill A. Cooper, Gregory M. Antonacci, Francesca Siswara, Priscillia Itsara, Andy Vives, Laura Walsh, Tom McCarthy, Shane E. Baker, Carl Mefford, Heather C. Kidd, Jeffrey M. Browning, Sharon R. Browning, Brian L. Dickel, Diane E. Levy, Deborah L. Ballif, Blake C. Platky, Kathryn Farber, Darren M. Gowans, Gordon C. Wetherbee, Jessica J. Asamoah, Alexander Weaver, David D. Mark, Paul R. Dickerson, Jennifer Garg, Bhuwan P. Ellingwood, Sara A. Smith, Rosemarie Banks, Valerie C. Smith, Wendy McDonald, Marie T. Hoo, Joe J. French, Beatrice N. Hudson, Cindy Johnson, John P. Ozmore, Jillian R. Moeschler, John B. Surti, Urvashi Escobar, Luis F. El-Khechen, Dima Gorski, Jerome L. Kussmann, Jennifer Salbert, Bonnie Lacassie, Yves Biser, Alisha McDonald-McGinn, Donna M. Zackai, Elaine H. Deardorff, Matthew A. Shaikh, Tamim H. Haan, Eric Friend, Kathryn L. Fichera, Marco Romano, Corrado Gecz, Jozef DeLisi, Lynn E. Sebat, Jonathan King, Mary-Claire Shaffer, Lisa G. Eichler, Evan E. TI A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; COPY NUMBER VARIATIONS; COMORBID SCHIZOPHRENIA; CHROMOSOMAL IMBALANCE; LEARNING-DISABILITY; MENTAL-RETARDATION; DELETION SYNDROME; INCREASE RISK; COSTA-RICA; ARRAY CGH AB We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease. C1 [Girirajan, Santhosh; Cooper, Gregory M.; Antonacci, Francesca; Siswara, Priscillia; Itsara, Andy; Vives, Laura; Baker, Carl; Mefford, Heather C.; Kidd, Jeffrey M.; Dickel, Diane E.; King, Mary-Claire; Eichler, Evan E.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Rosenfeld, Jill A.; Ballif, Blake C.; Shaffer, Lisa G.] Signature Genom Labs, Spokane, WA USA. [Walsh, Tom; King, Mary-Claire] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [McCarthy, Shane E.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Browning, Sharon R.; Browning, Brian L.] Univ Auckland, Dept Stat, Fac Sci, Auckland 1, New Zealand. [Levy, Deborah L.] McLean Hosp, Psychol Res Lab, Belmont, MA 02178 USA. [Levy, Deborah L.; DeLisi, Lynn E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Platky, Kathryn; Gowans, Gordon C.; Wetherbee, Jessica J.; Asamoah, Alexander] Univ Louisville, Dept Pediat, Weisskopf Child Evaluat Ctr, Louisville, KY 40292 USA. [Farber, Darren M.] Univ Louisville, Sch Med, Dept Neurol, Div Child Neurol, Louisville, KY 40292 USA. [Weaver, David D.; Mark, Paul R.] Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Dickerson, Jennifer; Garg, Bhuwan P.] Indiana Univ, Sch Med, Dept Neurol, Div Pediat Neurol, Indianapolis, IN 46202 USA. [Ellingwood, Sara A.; Smith, Rosemarie; Banks, Valerie C.; Smith, Wendy] Maine Med Ctr, Div Genet, Portland, ME 04102 USA. [McDonald, Marie T.] Duke Univ, Med Ctr, Div Med Genet, Durham, NC USA. [Hoo, Joe J.; French, Beatrice N.] Univ Toledo, Coll Med, Dept Pediat, Toledo, OH 43606 USA. [Hoo, Joe J.; French, Beatrice N.] NW Ohio Reg Genet Ctr, Toledo, OH USA. [Hudson, Cindy; Johnson, John P.] Shodair Childrens Hosp, Helena, MT USA. [Ozmore, Jillian R.; Moeschler, John B.] Dartmouth Hitchcock Med Ctr, Div Clin Genet, Lebanon, NH 03766 USA. [Surti, Urvashi] Univ Pittsburgh, Magee Womens Hosp, Med Ctr, Pittsburgh, PA 15213 USA. [Escobar, Luis F.; El-Khechen, Dima] St Vincent Childrens Hosp, Med Genet & Neurodev Ctr, Indianapolis, IN USA. [Gorski, Jerome L.; Kussmann, Jennifer] Univ Missouri, Div Med Genet, Columbia, MO USA. [Salbert, Bonnie] Geisinger Med Ctr, Danville, PA 17822 USA. [Lacassie, Yves] Louisiana State Univ, Hlth Sci Ctr, Div Genet, Dept Pediat, New Orleans, LA USA. [Lacassie, Yves] Childrens Hosp, New Orleans, LA USA. [Biser, Alisha; McDonald-McGinn, Donna M.; Zackai, Elaine H.; Deardorff, Matthew A.; Shaikh, Tamim H.] Univ Penn, Dept Pediat & Genet, Philadelphia, PA 19104 USA. [Biser, Alisha; McDonald-McGinn, Donna M.; Zackai, Elaine H.; Deardorff, Matthew A.; Shaikh, Tamim H.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Haan, Eric] S Australian Pathol Womens & Childrens Hosp, S Australian Clin Genet Serv, Adelaide, SA, Australia. [Haan, Eric; Gecz, Jozef] Univ Adelaide, Dept Paediat, Adelaide, SA, Australia. [Fichera, Marco; Romano, Corrado] Oasi Inst Res & Care Mental Retardat & Brain Ag, Troina, Italy. [DeLisi, Lynn E.] VA Boston Healthcare Syst, Brockton, MA USA. [Sebat, Jonathan] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Sebat, Jonathan] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Eichler, EE (reprint author), Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. EM eee@gs.washington.edu RI Browning, Sharon/B-1530-2008; Browning, Brian/A-1178-2010; Cooper, Gregory/D-6914-2011; Romano, Corrado/B-9695-2008; Antonacci, Francesca/F-5457-2013; Fichera, Marco/K-9220-2016; OI Browning, Sharon/0000-0001-7251-9715; Browning, Brian/0000-0001-6454-6633; Cooper, Gregory/0000-0001-5509-9923; Romano, Corrado/0000-0003-1049-0683; Antonacci, Francesca/0000-0002-5833-6186; Fichera, Marco/0000-0002-8225-6880; Sebat, Jonathan/0000-0002-9087-526X; Walsh, Tom/0000-0002-8875-0310; Kidd, Jeffrey/0000-0002-9631-1465; Dickel, Diane/0000-0001-5497-6824; Gecz, Jozef/0000-0002-7884-6861 FU National Institute on Aging, National Heart, Lung, and Blood Institute, National Institutes of Health; Department of Health and Human Services; NIH [HD065285]; Simons Foundation [SFARI 137578]; NARSAD Award; Merck, Jane Coffin Childs Memorial Fund FX We thank the subjects and their families for participating in this study. We thank M. Whyte for providing cardiological evaluation (for case SG07). We thank A. Singleton, L. Ferrucci and R. Krauss for sharing the control CNV data generated with support from the Intramural Research Program of the National Institute on Aging, National Heart, Lung, and Blood Institute (PARC project), and the National Institutes of Health, Department of Health and Human Services. For the schizophrenia study, genotyping of samples was also provided through the genetic association information network (GAIN). Samples and associated phenotype data for the genome-wide association of schizophrenia study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator: P. V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, Illinois, USA). We also thank J. Smith for SNP genotyping; T. Louie for bioinformatics support; C. Campbell, L. Perez-Jurado, G. Kirov, M. K. Rudd and C. Lese-Martin for useful discussions; and T. Brown, P. Sudmant and J. Kitzman for critical review of the manuscript. This work was supported by NIH grant HD065285 (E. E. E.), a grant from the Simons Foundation (SFARI 137578 to E. E. E.) and a NARSAD Award (M.-C. K.). G. M. C. is supported by a Merck, Jane Coffin Childs Memorial Fund post-doctoral fellowship. E. E. E. is an investigator of the Howard Hughes Medical Institute. NR 46 TC 303 Z9 307 U1 2 U2 17 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 MAR PY 2010 VL 42 IS 3 BP 203 EP U24 DI 10.1038/ng.534 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 560OQ UT WOS:000274912400007 PM 20154674 ER PT J AU Petersen, GM Amundadottir, L Fuchs, CS Kraft, P Stolzenberg-Solomon, RZ Jacobs, KB Arslan, AA Bueno-de-Mesquita, HB Gallinger, S Gross, M Helzlsouer, K Holly, EA Jacobs, EJ Klein, AP LaCroix, A Li, DH Mandelson, MT Olson, SH Risch, HA Zheng, W Albanes, D Bamlet, WR Berg, CD Boutron-Ruault, MC Buring, JE Bracci, PM Canzian, F Clipp, S Cotterchio, M de Andrade, M Duell, EJ Gaziano, JM Giovannucci, EL Goggins, M Hallmans, G Hankinson, SE Hassan, M Howard, B Hunter, DJ Hutchinson, A Jenab, M Kaaks, R Kooperberg, C Krogh, V Kurtz, RC Lynch, SM McWilliams, RR Mendelsohn, JB Michaud, DS Parikh, H Patel, AV Peeters, PHM Rajkovic, A Riboli, E Rodriguez, L Seminara, D Shu, XO Thomas, G Tjonneland, A Tobias, GS Trichopoulos, D Van Den Eeden, SK Virtamo, J Wactawski-Wende, J Wang, ZM Wolpin, BM Yu, H Yu, K Zeleniuch-Jacquotte, A Fraumeni, JF Hoover, RN Hartge, P Chanock, SJ AF Petersen, Gloria M. Amundadottir, Laufey Fuchs, Charles S. Kraft, Peter Stolzenberg-Solomon, Rachael Z. Jacobs, Kevin B. Arslan, Alan A. Bueno-de-Mesquita, H. Bas Gallinger, Steven Gross, Myron Helzlsouer, Kathy Holly, Elizabeth A. Jacobs, Eric J. Klein, Alison P. LaCroix, Andrea Li, Donghui Mandelson, Margaret T. Olson, Sara H. Risch, Harvey A. Zheng, Wei Albanes, Demetrius Bamlet, William R. Berg, Christine D. Boutron-Ruault, Marie-Christine Buring, Julie E. Bracci, Paige M. Canzian, Federico Clipp, Sandra Cotterchio, Michelle de Andrade, Mariza Duell, Eric J. Gaziano, J. Michael Giovannucci, Edward L. Goggins, Michael Hallmans, Goran Hankinson, Susan E. Hassan, Manal Howard, Barbara Hunter, David J. Hutchinson, Amy Jenab, Mazda Kaaks, Rudolf Kooperberg, Charles Krogh, Vittorio Kurtz, Robert C. Lynch, Shannon M. McWilliams, Robert R. Mendelsohn, Julie B. Michaud, Dominique S. Parikh, Hemang Patel, Alpa V. Peeters, Petra H. M. Rajkovic, Aleksandar Riboli, Elio Rodriguez, Laudina Seminara, Daniela Shu, Xiao-Ou Thomas, Gilles Tjonneland, Anne Tobias, Geoffrey S. Trichopoulos, Dimitrios Van Den Eeden, Stephen K. Virtamo, Jarmo Wactawski-Wende, Jean Wang, Zhaoming Wolpin, Brian M. Yu, Herbert Yu, Kai Zeleniuch-Jacquotte, Anne Fraumeni, Joseph F., Jr. Hoover, Robert N. Hartge, Patricia Chanock, Stephen J. TI A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33 SO NATURE GENETICS LA English DT Article ID BASE-LINE CHARACTERISTICS; RECOMBINATION HOTSPOTS; WOMENS HEALTH; BREAST-CANCER; RISK; GENE; VARIANTS; TELOMERASE; CELLS; LUNG AB We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies. C1 [Amundadottir, Laufey; Parikh, Hemang; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Petersen, Gloria M.; Bamlet, William R.; de Andrade, Mariza; McWilliams, Robert R.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Fuchs, Charles S.; Wolpin, Brian M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.; Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. [Giovannucci, Edward L.; Hankinson, Susan E.; Hunter, David J.; Michaud, Dominique S.; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Jacobs, Kevin B.; Hutchinson, Amy; Wang, Zhaoming] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21701 USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD USA. [Arslan, Alan A.] NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Dept Environm Med, New York, NY USA. [Arslan, Alan A.; Zeleniuch-Jacquotte, Anne] NYU, Inst Canc, New York, NY USA. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, RIVM, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Gallinger, Steven] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Gross, Myron] Univ Minnesota, Dept Lab Med & Pathol, Sch Med, Minneapolis, MN 55455 USA. [Helzlsouer, Kathy] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Holly, Elizabeth A.; Bracci, Paige M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Jacobs, Eric J.; Patel, Alpa V.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Klein, Alison P.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Klein, Alison P.] Johns Hopkins Med Inst, Sol Goldman Pancreat Res Ctr, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [LaCroix, Andrea; Mandelson, Margaret T.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Li, Donghui; Hassan, Manal] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Mandelson, Margaret T.] Grp Hlth Ctr Hlth Studies, Seattle, WA USA. [Olson, Sara H.] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Risch, Harvey A.; Yu, Herbert] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Zheng, Wei; Shu, Xiao-Ou] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Berg, Christine D.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Boutron-Ruault, Marie-Christine] Univ Paris Sud, INSERM, Inst Gustave Roussy, Villejuif, France. [Buring, Julie E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.] Brigham & Womens Hosp, Dept Med, Dept Aging, Boston, MA 02115 USA. [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Canzian, Federico] German Canc Res Ctr, Heidelberg, Germany. [Clipp, Sandra] George W Comstock Ctr Publ Hlth Res & Prevent, Johns Hopkins Bloomberg Sch Publ Hlth, Hagerstown, MD USA. [Cotterchio, Michelle] Univ Toronto, Canc Care Ontario & Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Duell, Eric J.] Catalan Inst Oncol, Barcelona, Spain. [Gaziano, J. Michael] Brigham & Womens Hosp, Phys Hlth Study, Div Aging, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Phys Hlth Study, Div Cardiovasc Dis, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Brigham & Womens Hosp, Phys Hlth Study, Div Prevent Med, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] Vet Affairs Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Goggins, Michael] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Howard, Barbara] Georgetown Univ, MedStar Res Inst, Hyattsville, MD USA. [Krogh, Vittorio] Fdn IRCCS, Ist Nazl Tumoridi Milano, Nutr Epidemiol Unit, Milan, Italy. [Kurtz, Robert C.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Lynch, Shannon M.; Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Michaud, Dominique S.; Peeters, Petra H. M.; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Div Epidemiol Publ Hlth & Primary Care, London, England. [Peeters, Petra H. M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Rajkovic, Aleksandar] Univ Pittsburgh, Dept Obstet Gynecol & Reprod Biol, Pittsburgh, PA USA. [Rodriguez, Laudina] Hlth & Hlth Care Serv Council, Publ Hlth & Participat Directorate, Asturias, Spain. [Thomas, Gilles] Ctr Leon Berard, INSERM, F-69373 Lyon, France. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Trichopoulos, Dimitrios] Acad Athens, Bur Epidemiol Res, Athens, Greece. [Van Den Eeden, Stephen K.] Kaiser Permanente, Div Res, Oakland, CA USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Chanock, SJ (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov RI Boutron Ruault, Marie-Christine/G-3705-2013; Gallinger, Steven/E-4575-2013; Boutron, Marie-Christine/K-8168-2013; Michaud, Dominique/I-5231-2014; Albanes, Demetrius/B-9749-2015; Boutron-Ruault, Marie-Christine/H-3936-2014; Krogh, Vittorio/K-2628-2016; Amundadottir, Laufey/L-7656-2016; Tobias, Geoffrey/M-4135-2016; OI Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303; Krogh, Vittorio/0000-0003-0122-8624; Amundadottir, Laufey/0000-0003-1859-8971; Tobias, Geoffrey/0000-0002-2878-8253; Duell, Eric J/0000-0001-5256-0163 FU Intramural NIH HHS [ZIA CP010193-03]; NCI NIH HHS [P50 CA062924-140011, K07 CA140790, P50 CA062924, P50 CA062924-130011, P50 CA062924-150011, P50 CA062924-160011, P50 CA102701, R01 CA082729, R01 CA097193, R01 CA124908, R37 CA070867] NR 63 TC 274 Z9 278 U1 0 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 MAR PY 2010 VL 42 IS 3 BP 224 EP U29 DI 10.1038/ng.522 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 560OQ UT WOS:000274912400010 PM 20101243 ER PT J AU Qin, YJ Yao, L King, EE Buddavarapu, K Lenci, RE Chocron, ES Lechleiter, JD Sass, M Aronin, N Schiavi, F Boaretto, F Opocher, G Toledo, RA Toledo, SPA Stiles, C Aguiar, RCT Dahia, PLM AF Qin, Yuejuan Yao, Li King, Elizabeth E. Buddavarapu, Kalyan Lenci, Romina E. Chocron, E. Sandra Lechleiter, James D. Sass, Meghan Aronin, Neil Schiavi, Francesca Boaretto, Francesca Opocher, Giuseppe Toledo, Rodrigo A. Toledo, Sergio P. A. Stiles, Charles Aguiar, Ricardo C. T. Dahia, Patricia L. M. TI Germline mutations in TMEM127 confer susceptibility to pheochromocytoma SO NATURE GENETICS LA English DT Article ID TUMOR-SUPPRESSOR; CELL-GROWTH; MTOR; COMPLEX; SIGNALS; RAPTOR; PHOSPHORYLATION; PARAGANGLIOMA; MALIGNANCIES; APOPTOSIS AB Pheochromocytomas, which are catecholamine-secreting tumors of neural crest origin, are frequently hereditary(1). However, the molecular basis of the majority of these tumors is unknown(2). We identified the transmembrane-encoding gene TMEM127 on chromosome 2q11 as a new pheochromocytoma susceptibility gene. In a cohort of 103 samples, we detected truncating germline TMEM127 mutations in approximately 30% of familial tumors and about 3% of sporadic-appearing pheochromocytomas without a known genetic cause. The wild-type allele was consistently deleted in tumor DNA, suggesting a classic mechanism of tumor suppressor gene inactivation. Pheochromocytomas with mutations in TMEM127 are transcriptionally related to tumors bearing NF1 mutations and, similarly, show hyperphosphorylation of mammalian target of rapamycin (mTOR) effector proteins. Accordingly, in vitro gain-of-function and loss-of-function analyses indicate that TMEM127 is a negative regulator of mTOR. TMEM127 dynamically associates with the endomembrane system and colocalizes with perinuclear (activated) mTOR, suggesting a subcompartmental-specific effect. Our studies identify TMEM127 as a tumor suppressor gene and validate the power of hereditary tumors to elucidate cancer pathogenesis. C1 [Qin, Yuejuan; Yao, Li; King, Elizabeth E.; Buddavarapu, Kalyan; Lenci, Romina E.; Aguiar, Ricardo C. T.; Dahia, Patricia L. M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Chocron, E. Sandra; Lechleiter, James D.; Dahia, Patricia L. M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Sass, Meghan] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Schiavi, Francesca; Boaretto, Francesca; Opocher, Giuseppe] Veneto Inst Oncol, Padua, Italy. [Toledo, Rodrigo A.; Toledo, Sergio P. A.] Univ Sao Paulo, Sch Med, Sao Paulo, Brazil. [Stiles, Charles] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Aguiar, Ricardo C. T.; Dahia, Patricia L. M.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. RP Dahia, PLM (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. EM dahia@uthscsa.edu RI Qin, Yuejuan/F-6801-2010; Opocher, Giuseppe/F-3950-2014; Toledo, Rodrigo/N-4078-2013; boaretto, francesca/K-9811-2016 OI Opocher, Giuseppe/0000-0002-9845-9623; Toledo, Rodrigo/0000-0003-3070-6795; schiavi, francesca/0000-0001-8529-4455; boaretto, francesca/0000-0003-2015-929X FU Voelcker Foundation Young Investigator Award; Cancer Therapy and Research Center (CTRC) at the University of Texas Health Science Center at San Antonio (UTHSCSA); NIH [P30 CA54174]; Voelcker Fund; US National Institutes of Health (NIH)National Cancer Institute [P30 CA54174]; NIH-National Institute on Aging (NIA) [P30 AG013319, P01AG19316] FX We thank S. Jiang for technical assistance, V. Frohlich and J. Wewer for help with optical imaging, J. Blenis for kindly providing the 293E cell line, W. Kaelin Jr. for his comments and suggestions, and M. Jech, C. Colin, N. V. Nguyen, M. Pujana, M. Vidal, D. Hill, J. Bruder and the Familial Pheochromocytoma Consortium members for their contribution to earlier phases of this project. We also thank the subjects and families that participated in the study for their cooperation. P. L. M. D. is a Kimmel Foundation Scholar and a recipient of a Voelcker Foundation Young Investigator Award and is supported by the Cancer Therapy and Research Center (CTRC) at the University of Texas Health Science Center at San Antonio (UTHSCSA) (NIH-P30 CA54174). R. C. T. A. is supported by the Voelcker Fund. Immunofluorescence images were generated in the Core Optical Imaging Facility which is supported by UTHSCSA, US National Institutes of Health (NIH)National Cancer Institute P30 CA54174 (CTRC), NIH-National Institute on Aging (NIA) P30 AG013319 (Nathan Shock Center) and NIH-NIA P01AG19316. NR 29 TC 184 Z9 190 U1 0 U2 4 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 MAR PY 2010 VL 42 IS 3 BP 229 EP U31 DI 10.1038/ng.533 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 560OQ UT WOS:000274912400011 PM 20154675 ER PT J AU Van Deerlin, VM Sleiman, PMA Martinez-Lage, M Chen-Plotkin, A Wang, LS Graff-Radford, NR Dickson, DW Rademakers, R Boeve, BF Grossman, M Arnold, SE Mann, DMA Pickering-Brown, SM Seelaar, H Heutink, P van Swieten, JC Murrell, JR Ghetti, B Spina, S Grafman, J Hodges, J Spillantini, MG Gilman, S Lieberman, AP Kaye, JA Woltjer, RL Bigio, EH Mesulam, M al-Sarraj, S Troakes, C Rosenberg, RN White, CL Ferrer, I Llado, A Neumann, M Kretzschmar, HA Hulette, CM Welsh-Bohmer, KA Miller, BL Alzualde, A de Munain, AL McKee, AC Gearing, M Levey, AI Lah, JJ Hardy, J Rohrer, JD Lashley, T Mackenzie, IRA Feldman, HH Hamilton, RL Dekosky, ST van der Zee, J Kumar-Singh, S Van Broeckhoven, C Mayeux, R Vonsattel, JPG Troncoso, JC Kril, JJ Kwok, JBJ Halliday, GM Bird, TD Ince, PG Shaw, PJ Cairns, NJ Morris, JC McLean, CA DeCarli, C Ellis, WG Freeman, SH Frosch, MP Growdon, JH Perl, DP Sano, M Bennett, DA Schneider, JA Beach, TG Reiman, EM Woodruff, BK Cummings, J Vinters, HV Miller, CA Chui, HC Alafuzoff, I Hartikainen, P Seilhean, D Galasko, D Masliah, E Cotman, CW Tunon, MT Martinez, MCC Munoz, DG Carroll, SL Marson, D Riederer, PF Bogdanovic, N Schellenberg, GD Hakonarson, H Trojanowski, JQ Lee, VMY AF Van Deerlin, Vivianna M. Sleiman, Patrick M. A. Martinez-Lage, Maria Chen-Plotkin, Alice Wang, Li-San Graff-Radford, Neill R. Dickson, Dennis W. Rademakers, Rosa Boeve, Bradley F. Grossman, Murray Arnold, Steven E. Mann, David M. A. Pickering-Brown, Stuart M. Seelaar, Harro Heutink, Peter van Swieten, John C. Murrell, Jill R. Ghetti, Bernardino Spina, Salvatore Grafman, Jordan Hodges, John Spillantini, Maria Grazia Gilman, Sid Lieberman, Andrew P. Kaye, Jeffrey A. Woltjer, Randall L. Bigio, Eileen H. Mesulam, Marsel al-Sarraj, Safa Troakes, Claire Rosenberg, Roger N. White, Charles L., III Ferrer, Isidro Llado, Albert Neumann, Manuela Kretzschmar, Hans A. Hulette, Christine Marie Welsh-Bohmer, Kathleen A. Miller, Bruce L. Alzualde, Ainhoa Lopez de Munain, Adolfo McKee, Ann C. Gearing, Marla Levey, Allan I. Lah, James J. Hardy, John Rohrer, Jonathan D. Lashley, Tammaryn Mackenzie, Ian R. A. Feldman, Howard H. Hamilton, Ronald L. Dekosky, Steven T. van der Zee, Julie Kumar-Singh, Samir Van Broeckhoven, Christine Mayeux, Richard Vonsattel, Jean Paul G. Troncoso, Juan C. Kril, Jillian J. Kwok, John B. J. Halliday, Glenda M. Bird, Thomas D. Ince, Paul G. Shaw, Pamela J. Cairns, Nigel J. Morris, John C. McLean, Catriona Ann DeCarli, Charles Ellis, William G. Freeman, Stefanie H. Frosch, Matthew P. Growdon, John H. Perl, Daniel P. Sano, Mary Bennett, David A. Schneider, Julie A. Beach, Thomas G. Reiman, Eric M. Woodruff, Bryan K. Cummings, Jeffrey Vinters, Harry V. Miller, Carol A. Chui, Helena C. Alafuzoff, Irina Hartikainen, Paivi Seilhean, Danielle Galasko, Douglas Masliah, Eliezer Cotman, Carl W. Tunon, M. Teresa Martinez, M. Cristina Caballero Munoz, David G. Carroll, Steven L. Marson, Daniel Riederer, Peter F. Bogdanovic, Nenad Schellenberg, Gerard D. Hakonarson, Hakon Trojanowski, John Q. Lee, Virginia M-Y TI Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP43 inclusions SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; GLOBAL GENE-EXPRESSION; GENOTYPE DATA; DEMENTIA; PROGRANULIN; MUTATIONS; CONSENSUS; DISEASE; ONSET; FAMILIES AB Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP) 1. FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism. C1 [Van Deerlin, Vivianna M.; Martinez-Lage, Maria; Chen-Plotkin, Alice; Wang, Li-San; Schellenberg, Gerard D.; Trojanowski, John Q.; Lee, Virginia M-Y] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Hakonarson, Hakon] Univ Penn, Childrens Hosp Philadelphia, Ctr Appl Genom, Div Human Genet,Sch Med, Philadelphia, PA 19104 USA. [Martinez-Lage, Maria] Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain. [Chen-Plotkin, Alice; Grossman, Murray; Arnold, Steven E.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Graff-Radford, Neill R.] Mayo Coll Med, Dept Neurol, Jacksonville, FL USA. [Dickson, Dennis W.; Rademakers, Rosa] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Boeve, Bradley F.] Mayo Clin, Dept Neurol, Rochester, MN USA. [Arnold, Steven E.] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Arnold, Steven E.] Univ Penn, Sch Med, Penn Memory Ctr, Philadelphia, PA 19104 USA. [Mann, David M. A.; Pickering-Brown, Stuart M.] Univ Manchester, Sch Community Based Med, Manchester, Lancs, England. [Seelaar, Harro; van Swieten, John C.] Erasmus MC, Rotterdam, Netherlands. [Heutink, Peter] Vrije Univ Amsterdam, Med Ctr, Sect Med Genom, Dept Clin Genet, Amsterdam, Netherlands. [Murrell, Jill R.; Ghetti, Bernardino; Spina, Salvatore] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA. [Murrell, Jill R.; Ghetti, Bernardino; Spina, Salvatore] Indiana Univ Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN USA. [Spina, Salvatore] Univ Siena, Dept Neurol Neurosurg & Behav Sci, I-53100 Siena, Italy. [Grafman, Jordan] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, Bethesda, MD USA. [Spillantini, Maria Grazia] Univ Cambridge, Cambridge Ctr Brain Repair, Dept Clin Neurosci, Cambridge, England. [Gilman, Sid] Univ Michigan, Dept Neurol, Ann Arbor, MI USA. [Lieberman, Andrew P.] Univ Michigan, Dept Pathol, Ann Arbor, MI USA. [Kaye, Jeffrey A.] Oregon Hlth & Sci Univ, Dept Neurol & Biomed Engn, Portland, OR 97201 USA. [Woltjer, Randall L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. [Bigio, Eileen H.] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. [Bigio, Eileen H.; Mesulam, Marsel] Northwestern Univ, Feinberg Sch Med, Cognit Neurol & Alzheimer Dis Ctr, Chicago, IL 60611 USA. [al-Sarraj, Safa] Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England. [Troakes, Claire] Kings Coll Hosp London, MRC, London Neurodegenerat Dis Brain Bank, Inst Psychiat, London, England. [Rosenberg, Roger N.] Univ Texas SW Med Ctr Dallas, Rush Alzheimers Dis Ctr, Dallas, TX 75390 USA. [White, Charles L., III] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Ferrer, Isidro] Hosp Univ Bellvitge, Inst Neuropatol, Inst Invest Biomed Bellvitge IDIBELL, Barcelona, Spain. [Llado, Albert] Hosp Clin Barcelona, Alzheimers Dis & Cognit Disorders Unit, Serv Neurol, Inst Clin Neurociencies, Barcelona, Spain. [Neumann, Manuela] Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland. [Kretzschmar, Hans A.] Univ Munich, Ctr Neuropathol & Prion Res, Munich, Germany. [Hulette, Christine Marie] Duke Univ, Dept Pathol, Hlth Sci Ctr, Durham, NC 27706 USA. [Welsh-Bohmer, Kathleen A.] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [Welsh-Bohmer, Kathleen A.] Duke Univ, Med Ctr, Bryan Alzheimers Dis Res Ctr, Durham, NC 27710 USA. [Miller, Bruce L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Alzualde, Ainhoa] Hosp Donostia, Neurogenet Unit, Inst Biodonostia, San Sebastian, Spain. [Lopez de Munain, Adolfo] Hosp Donostia, Serv Neurol, San Sebastian, Spain. [McKee, Ann C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [McKee, Ann C.] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. [McKee, Ann C.] Ctr Geriatr Res Educ & Clin, Bedford Vet Adm Med Ctr, Bedford, MA USA. [Gearing, Marla] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Gearing, Marla; Levey, Allan I.] Emory Univ, Sch Med, Alzheimers Dis Res Ctr, Atlanta, GA 30322 USA. [Gearing, Marla; Levey, Allan I.] Emory Univ, Sch Med, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA. [Levey, Allan I.; Lah, James J.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Hardy, John] UCL, Inst Neurol, Reta Lila Labs, London, England. [Hardy, John; Lashley, Tammaryn] UCL, Inst Neurol, Dept Mol Neurosci, London, England. [Rohrer, Jonathan D.] UCL, Inst Neurol, Dementia Res Ctr, London, England. [Lashley, Tammaryn] UCL, Inst Neurol, Queen Sq Brain Bank Neurol Disorders, London, England. [Mackenzie, Ian R. A.] Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. [Mackenzie, Ian R. A.; Feldman, Howard H.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Feldman, Howard H.] Vancouver Gen Hosp, Div Neurol, Vancouver, BC, Canada. [Feldman, Howard H.] Bristol Myers Squibb Co, Neurosci, Wallingford, CT 06492 USA. [Hamilton, Ronald L.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Dekosky, Steven T.] Univ Virginia, Sch Med, Dept Neurol, Charlottesville, VA 22908 USA. [van der Zee, Julie; Kumar-Singh, Samir; Van Broeckhoven, Christine] VIB, Neurodegenerat Brain Dis Grp, Dept Mol Genet, Antwerp, Belgium. [van der Zee, Julie; Kumar-Singh, Samir; Van Broeckhoven, Christine] Univ Antwerp, Inst Born Bunge, B-2020 Antwerp, Belgium. [Mayeux, Richard; Vonsattel, Jean Paul G.] Columbia Univ, Taub Inst Res Alzheimers Dis, New York, NY USA. [Vonsattel, Jean Paul G.] Columbia Univ, New York Brain Bank, New York, NY USA. [Vonsattel, Jean Paul G.] Columbia Univ, Dept Pathol, New York, NY USA. [Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Kril, Jillian J.] Univ Sydney, Discipline Med, Sydney, NSW 2006, Australia. [Kril, Jillian J.] Univ Sydney, Discipline Pathol, Sydney, NSW 2006, Australia. [Kwok, John B. J.; Halliday, Glenda M.] Univ New S Wales, Prince Wales Med Res Inst, Sydney, NSW, Australia. [Bird, Thomas D.] Vet Affairs Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. [Bird, Thomas D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Ince, Paul G.; Shaw, Pamela J.] Univ Sheffield, Dept Neurosci, Sheffield, S Yorkshire, England. [Cairns, Nigel J.; Morris, John C.] Washington Univ, Sch Med, Alzheimers Dis Res Ctr, St Louis, MO USA. [Cairns, Nigel J.; Morris, John C.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO USA. [McLean, Catriona Ann] Alfred Hosp, Dept Anat Pathol, Melbourne, Vic, Australia. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Alzheimers Dis Ctr, Imaging Dementia & Aging Lab,Ctr Neurosci, Sacramento, CA 95817 USA. [Ellis, William G.] Univ Calif Davis, Dept Pathol, Sacramento, CA 95817 USA. [Freeman, Stefanie H.; Frosch, Matthew P.] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA. [Freeman, Stefanie H.; Frosch, Matthew P.; Growdon, John H.] Harvard Univ, Sch Med, Boston, MA USA. [Growdon, John H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Perl, Daniel P.] Mt Sinai Sch Med, Dept Pathol, New York, NY USA. [Sano, Mary] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Sano, Mary] James J Peters Vet Affairs Med Ctr, New York, NY USA. [Bennett, David A.; Schneider, Julie A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Beach, Thomas G.] Sun Hlth Res Inst, Sun City, AZ USA. [Reiman, Eric M.] Univ Arizona, Banner Alzheimers Inst, Translat Genom Res Inst, Phoenix, AZ USA. [Reiman, Eric M.] Arizona Alzheimers Consortium, Phoenix, AZ USA. [Woodruff, Bryan K.] Mayo Clin, Scottsdale, AZ USA. [Cummings, Jeffrey] Univ Calif Los Angeles, David Geffen Sch Med, Mary S Easton Ctr Alzheimers Dis Res, Los Angeles, CA 90095 USA. [Vinters, Harry V.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Vinters, Harry V.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Miller, Carol A.; Chui, Helena C.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Alafuzoff, Irina] Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. [Alafuzoff, Irina] Univ Kuopio, Dept Clin Med, FIN-70211 Kuopio, Finland. [Hartikainen, Paivi] Univ Kuopio, Dept Neurol, FIN-70211 Kuopio, Finland. [Seilhean, Danielle] Univ Paris 06, Paris, France. [Seilhean, Danielle] AP HP, Paris, France. [Galasko, Douglas; Masliah, Eliezer] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Masliah, Eliezer] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. [Cotman, Carl W.] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. [Tunon, M. Teresa] Hosp Navarra Pathol Dept, Navarra, Spain. [Tunon, M. Teresa; Martinez, M. Cristina Caballero] Brain Bank Navarra, Navarra, Spain. [Martinez, M. Cristina Caballero] Navarra Hlth Serv Osasunbidea, Biomed Res Ctr, Navarra, Spain. [Munoz, David G.] Univ Toronto, St Michaels Hosp, Dept Lab Med & Pathobiol, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Carroll, Steven L.] Univ Alabama, Dept Pathol, Tuscaloosa, AL 35487 USA. [Marson, Daniel] Univ Alabama, Dept Neurol, Tuscaloosa, AL 35487 USA. [Marson, Daniel] Univ Alabama, Alzheimers Dis Res Ctr, Tuscaloosa, AL 35487 USA. [Riederer, Peter F.] Univ Wurzburg, Clin & Policlin Psychiat Psychosomat & Psychother, Wurzburg, Germany. [Bogdanovic, Nenad] Karolinska Univ Hosp, Dept Geriatr Med, Stockholm, Sweden. [Hakonarson, Hakon] Univ Penn, Sch Med, Childrens Hosp Philadelphia, Div Pulm Med,Dept Pediat, Philadelphia, PA 19104 USA. RP Van Deerlin, VM (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. EM vivianna@mail.med.upenn.edu; trojanow@mail.med.upenn.edu RI Shaw, Pamela/A-7620-2010; Pickering-Brown, Stuart/D-4008-2009; Lashley, Tammaryn/D-2583-2009; Shaw, Pamela/E-6193-2010; Ince, Paul/A-5064-2009; Morris, John/A-1686-2012; Neumann, Manuela/F-6558-2011; Hardy, John/C-2451-2009; Kumar-Singh, Samir/G-6280-2012; Arnold, Steven/J-7546-2012; Halliday, Glenda/E-8555-2011; Troakes, Claire/K-4346-2015; Tunon, Teresa/B-2525-2017; OI Rohrer, Jonathan/0000-0002-6155-8417; Dickson, Dennis W/0000-0001-7189-7917; Kaye, Jeffrey/0000-0002-9971-3478; Grafman, Jordan H./0000-0001-8645-4457; Kwok, John/0000-0001-9574-6195; Munoz, David/0000-0003-0957-6244; Martinez-Lage, Maria/0000-0002-5859-7562; Feldman, Howard/0000-0002-9258-4538; Kril, Jillian/0000-0001-9407-8674; Pickering-Brown, Stuart/0000-0003-1561-6054; Ince, Paul/0000-0001-6677-8753; Kumar-Singh, Samir/0000-0001-9466-6732; Halliday, Glenda/0000-0003-0422-8398; Tunon, Teresa/0000-0001-6589-1084; Carroll, Steven/0000-0001-6714-4373 FU National Health and Medical Research Council of Australia; Biobank at the Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium; French clinical and genetic research network FX This project was enabled by the contributions and efforts of many individuals in several supportive capacities. Most importantly, we extend our appreciation to the study subjects and families who made this research possible. Extensive technical assistance was provided by R. Greene, T. Unger and C. Kim and study coordination was provided by E. McCarty Wood. The following individuals contributed through sample ascertainment, epidemiology, coordination, and/or clinical evaluation of cases: S. Weintraub, N. Johnson, C. Shaw, V. Haroutunian, R. C. Petersen, D. S. Knopman, K. A. Josephs, D. Neary, J. Snowden, J. Heidebrink, N. Barbas, R. Re e, J. R. Burke, K. Hayden, J. Browndyke, P. Gaskell, M. Szymanski, J. D. Glass, M. Rossor, F. Moreno, B. Indakoetxea, M. Barandiaran, S. Engelborghs, P. P. De Deyn, W. S. Brooks, T. Chow, V. Meininger, L. Lacomblez and E. Gruenblatt. The following individuals contributed through pathological characterization and evaluation of cases: D. Clark, A. King, I. Bodi, D. Purohit, L. Kwong, J. E. Parisi, W. Kamphorst, I. Ruiz, T. Revesz, J.-J. Martin, R. Highley and C. Duyckaerts. The following individuals contributed through general technical assistance and/or genetic studies: J. Kirby, E. Moore, M. Baker, R. Crook, S. Rollinson, N. Halliwell, S. Usher, R. M. Richardson, M. Mishra, C. Foong, J. Ervin, K. Price Bryan, J. Ervin, C. Kubilus, A. Gorostidi, M. Cruts, I. Gijselinck, H. McCann, P. R. Schofield, G. Forster, K. Firch, J. Pomaician, I. Leber, V. Sazdovitch and I. Volkmann. We also thank the Brain Bank of University of Barcelona, Hospital Clinic, Clinic for Alzheimer's Disease and Related Disorders University of British Columbia, Australian Brain Donor Programs supported by the National Health and Medical Research Council of Australia, Biobank at the Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium and the French clinical and genetic research network on FTD/FTD-motor neuron disease (MND). Many grant funding agencies provided financial support for this study, including the US National Institutes of Health (NIH) (grant numbers AG10124, AG17586, AG16574, AG03949, AG17586, NS44266, AG15116, NS53488, AG10124, AG010133, AG08671, NS044233, NS15655, AG008017, AG13854, AG12300, AG028377, AG 019724, AG13846, AG025688, AG05133, AG08702, AG05146, AG005136, AG005681, AG03991, AG010129, AG05134, NS038372, AG02219, AG05138, AG10161, AG19610, AG19610, AG16570, AG16570, AG05142, AG005131, AG5131, AG18440, AG16582, AG16573, AG033101 and NIH Intramural Program). Additional funds were provided by Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program, the Pacific Alzheimer's disease Research Foundation (PARF) grant #C06-01, the Alzheimer's Research Trust, Alzheimer's Society, Medical Research Council (Programme Grant and Returning Scientist Award), Stichting Dioraphte (07010500), Hersenstichting (15F07.2.34), Prinses Beatrix Fonds (0060204), Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, the McCune Foundation, Instituto Carlos III, Federal Ministry of Education and Research (01GI0505), SAIOTEK Program (Basque Government), Department of Innovation, Diputacion Foral de Gipuzkoa (DFG 0876/08), ILUNDAIN Fundazioa, Centro de Investigaciones Biomedicas en Red en Enfermededades Neurodegenerativas (CIBERNED), Wellcome Trust, Canadian Institutes of Health Research (75480), Fund for Scientific Research Flanders (FWOV), Alzheimer Research (SAO/FRMA), Interuniversity Attraction Poles (IAP) P6/43 network of the Belgian Science Policy Office (BELSPO), J.v.d.; Z receves a postdoctoral fellowship from the FWOV, the Joseph Iseman Fund, the Louis and Rachel Rudin Foundation, National Health and Medical Research Council of Australia, Veteran's Affairs Research Funds, Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011 and 05901 to the Arizona Parkinson's Disease Consortium), the Prescott Family Initiative of the Michael J. Fox Foundation for Parkinson's Research, the Daljits and Elaine Sarkara Chair in Diagnostic Medicine, BrainNet Europe II, Ministerio de Ciencia y Tecnologia, Ref Saud y Farmacia 2001-4888, Burroghs Wellcome Fund Career Award for Medical Scientists and Fundacion 'La Caxia'. NR 29 TC 193 Z9 194 U1 5 U2 25 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 MAR PY 2010 VL 42 IS 3 BP 234 EP U34 DI 10.1038/ng.536 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 560OQ UT WOS:000274912400012 PM 20154673 ER PT J AU Ellinor, PT Lunetta, KL Glazer, NL Pfeufer, A Alonso, A Chung, MK Sinner, MF de Bakker, PIW Mueller, M Lubitz, SA Fox, E Darbar, D Smith, NL Smith, JD Schnabel, RB Soliman, EZ Rice, KM Van Wagoner, DR Beckmann, BM van Noord, C Wang, K Ehret, GB Rotter, JI Hazen, SL Steinbeck, G Smith, AV Launer, LJ Harris, TB Makino, S Nelis, M Milan, DJ Perz, S Esko, T Kottgen, A Moebus, S Newton-Cheh, C Li, M Moehlenkamp, S Wang, TJ Kao, WHL Vasan, RS Nothen, MM MacRae, CA Stricker, BHC Hofman, A Uitterlinden, AG Levy, D Boerwinkle, E Metspalu, A Topol, EJ Chakravarti, A Gudnason, V Psaty, BM Roden, DM Meitinger, T Wichmann, HE Witteman, JCM Barnard, J Arking, DE Benjamin, EJ Heckbert, SR Kaab, S AF Ellinor, Patrick T. Lunetta, Kathryn L. Glazer, Nicole L. Pfeufer, Arne Alonso, Alvaro Chung, Mina K. Sinner, Moritz F. de Bakker, Paul I. W. Mueller, Martina Lubitz, Steven A. Fox, Ervin Darbar, Dawood Smith, Nicholas L. Smith, Jonathan D. Schnabel, Renate B. Soliman, Elsayed Z. Rice, Kenneth M. Van Wagoner, David R. Beckmann, Britt-M van Noord, Charlotte Wang, Ke Ehret, Georg B. Rotter, Jerome I. Hazen, Stanley L. Steinbeck, Gerhard Smith, Albert V. Launer, Lenore J. Harris, Tamara B. Makino, Seiko Nelis, Mari Milan, David J. Perz, Siegfried Esko, Tonu Koettgen, Anna Moebus, Susanne Newton-Cheh, Christopher Li, Man Moehlenkamp, Stefan Wang, Thomas J. Kao, W. H. Linda Vasan, Ramachandran S. Noethen, Markus M. MacRae, Calum A. Stricker, Bruno H. Ch Hofman, Albert Uitterlinden, Andre G. Levy, Daniel Boerwinkle, Eric Metspalu, Andres Topol, Eric J. Chakravarti, Aravinda Gudnason, Vilmundur Psaty, Bruce M. Roden, Dan M. Meitinger, Thomas Wichmann, H-Erich Witteman, Jacqueline C. M. Barnard, John Arking, Dan E. Benjamin, Emelia J. Heckbert, Susan R. Kaeaeb, Stefan TI Common variants in KCNN3 are associated with lone atrial fibrillation SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; CA2+-ACTIVATED K+ CHANNEL; SMALL-CONDUCTANCE; FAMILIAL AGGREGATION; FUNCTIONAL ROLES; CHROMOSOME 4Q25; BLOOD-PRESSURE; HEART-DISEASE; RISK; EXPRESSION AB Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization. C1 [Ellinor, Patrick T.; Lubitz, Steven A.; Makino, Seiko; Milan, David J.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Ellinor, Patrick T.; Milan, David J.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Ellinor, Patrick T.; Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Lunetta, Kathryn L.; Wang, Ke] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Lunetta, Kathryn L.; Schnabel, Renate B.; Wang, Thomas J.; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Glazer, Nicole L.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Pfeufer, Arne; Meitinger, Thomas] Tech Univ Munich, Klinikum Rechts Isar, Inst Human Genet, D-8000 Munich, Germany. [Pfeufer, Arne; Meitinger, Thomas] Deutsch Forschungszentrum Gesundheit & Umwelt, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Chung, Mina K.; Van Wagoner, David R.; Hazen, Stanley L.] Cleveland Clin, Dept Cardiovasc Med, Inst Heart & Vasc, Lerner Res Inst, Cleveland, OH 44106 USA. [Sinner, Moritz F.; Mueller, Martina; Beckmann, Britt-M; Steinbeck, Gerhard; Kaeaeb, Stefan] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [de Bakker, Paul I. W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Genet, Boston, MA 02115 USA. [de Bakker, Paul I. W.; Newton-Cheh, Christopher] Harvard & Massachusetts Inst Technol, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Mueller, Martina; Wichmann, H-Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Mueller, Martina; Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Lubitz, Steven A.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Fox, Ervin] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. [Darbar, Dawood] Vanderbilt Univ, Sch Med, Div Cardiovasc Med, Nashville, TN 37212 USA. [Smith, Nicholas L.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] Dept Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Smith, Jonathan D.] Cleveland Clin, Dept Cell Biol, Lerner Res Inst, Cleveland, OH 44106 USA. [Soliman, Elsayed Z.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr EPICARE, Winston Salem, NC USA. [Rice, Kenneth M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [van Noord, Charlotte; Stricker, Bruno H. Ch; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Noord, Charlotte] Dutch Med Evaluat Board, The Hague, Netherlands. [van Noord, Charlotte; Stricker, Bruno H. Ch; Hofman, Albert; Uitterlinden, Andre G.; Witteman, Jacqueline C. M.] Netherlands Consortium Healthy Aging, Leiden, Netherlands. [Ehret, Georg B.; Chakravarti, Aravinda; Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Smith, Albert V.; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Nelis, Mari; Esko, Tonu; Metspalu, Andres] Estonian Bioctr, Genotyping Core Facil, Tartu, Estonia. [Nelis, Mari; Esko, Tonu; Metspalu, Andres] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia. [Perz, Siegfried] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Biol & Med Imaging, Neuherberg, Germany. [Esko, Tonu; Metspalu, Andres] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia. [Koettgen, Anna; Li, Man; Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Moebus, Susanne] Univ Duisburg Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany. [Newton-Cheh, Christopher; Wang, Thomas J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Moehlenkamp, Stefan] Univ Duisburg Essen, W German Heart Ctr Essen, Dept Cardiol, Essen, Germany. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Dept Med, Boston, MA 02118 USA. [Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Noethen, Markus M.] Life & Brain Ctr Bonn, Dept Genom, Bonn, Germany. [MacRae, Calum A.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Stricker, Bruno H. Ch; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Stricker, Bruno H. Ch] Inspectorate Hlth Care, The Hague, Netherlands. [Stricker, Bruno H. Ch] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Topol, Eric J.] Scripps Res Inst, Scripps Translat Sci Inst, La Jolla, CA 92037 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth, Res Inst, Seattle, WA USA. [Roden, Dan M.] Vanderbilt Univ, Sch Med, Div Clin Pharmacol, Nashville, TN 37212 USA. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Barnard, John] Cleveland Clin, Dept Quantitat Hlth Sci, Lerner Res Inst, Cleveland, OH 44106 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Cardiol & Prevent Med Div,Evans Dept Med, Boston, MA 02118 USA. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM pellinor@partners.org; stefan.kaab@med.uni-muenchen.de RI Smith, Albert/K-5150-2015; Darbar, Dawood/C-9079-2015; Gudnason, Vilmundur/K-6885-2015; Meitinger, Thomas/O-1318-2015; Van Wagoner, David/C-6783-2008; Alonso, Alvaro/A-4917-2010; Soliman, Elsayed/D-8124-2011; EHRET, Georg/A-9532-2009; Kottgen, Anna/D-2920-2012; Kaab, Stefan/H-3915-2012; Rice, Kenneth/A-4150-2013; Pfeufer, Arne/B-6634-2013; de Bakker, Paul/B-8730-2009; Schnabel, Renate/F-6527-2014 OI Smith, Albert/0000-0003-1942-5845; Lunetta, Kathryn/0000-0002-9268-810X; Esko, Tonu/0000-0003-1982-6569; Topol, Eric/0000-0002-1478-4729; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Nothen, Markus/0000-0002-8770-2464; Darbar, Dawood/0000-0002-4103-5977; Gudnason, Vilmundur/0000-0001-5696-0084; Van Wagoner, David/0000-0001-8250-9828; Alonso, Alvaro/0000-0002-2225-8323; Soliman, Elsayed/0000-0001-5632-8150; EHRET, Georg/0000-0002-5730-0675; Rice, Kenneth/0000-0001-5779-4495; de Bakker, Paul/0000-0001-7735-7858; FU CCR NIH HHS [RC1 HL101056-01]; NCRR NIH HHS [CTSA 1UL-RR024989, M01 RR000069, M01 RR000069-43, M01RR00069, RR025774, UL1 RR024989, UL1 RR024989-03, UL1 RR025005, UL1 RR025005-01, UL1 RR025005-025914, UL1 RR025774, UL1 RR025774-01, UL1RR025005]; NHGRI NIH HHS [U01 HG004402, U01 HG004402-01, U01HG004402]; NHLBI NIH HHS [HL076784, N01 HC-55222, N01 HC015103, N01 HC025195, N01 HC035129, N01 HC045133, N01 HC055015, N01 HC055016, N01 HC055018, N01 HC055019, N01 HC055020, N01 HC055021, N01 HC055022, N01 HC055222, N01 HC075150, N01 HC085079, N01 HC085080, N01 HC085081, N01 HC085082, N01 HC085083, N01 HC085084, N01 HC085085, N01 HC085086, N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-75150, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85086, N02 HL64278, N02-HL-6-4278, P01 HL 076491, P01 HL076491, P01 HL076491-01, P50 HL077107, P50 HL077107-03, R01 HL059367, R01 HL059367-02, R01 HL068986, R01 HL068986-05A2, R01 HL076784, R01 HL076784-01, R01 HL086694, R01 HL086694-01A1, R01 HL087641, R01 HL087641-01, R01 HL087652, R01 HL087652-01, R01 HL090620, R01 HL090620-01A1, R01 HL092217, R01 HL092217-01A2, R01 HL092577, R01 HL092577-01A1, R01 HL104156, R01HL086694, R01HL087641, R01HL092217, R01HL092577, R01HL59367, RC1 HL101056, RC1 HL101056-01, RC1HL101056, T32 HL007575, T32 HL007575-25, U01 HL065962, U01 HL065962-01A1, U01 HL065962-09, U01 HL080295, U01 HL080295-01, U01HL65962, U10 HL054512-05, U10HL054512]; NIA NIH HHS [1R01AG028321, N01 AG012100, N01-AG-12100, R01 AG028321, R01 AG028321-01]; NIDA NIH HHS [1R21DA027021, R21 DA026982, R21 DA027021, R21 DA027021-01]; NIDDK NIH HHS [DK063491, P30 DK063491, P30 DK063491-02, P30 DK063491-07, R01 DK033651]; PHS HHS [HHSN268200625226C] NR 33 TC 229 Z9 236 U1 2 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 MAR PY 2010 VL 42 IS 3 BP 240 EP U36 DI 10.1038/ng.537 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 560OQ UT WOS:000274912400013 PM 20173747 ER PT J AU Shen, J Gilmore, EC Marshall, CA Haddadin, M Reynolds, JJ Eyaid, W Bodell, A Barry, B Gleason, D Allen, K Ganesh, VS Chang, BS Grix, A Hill, RS Topcu, M Caldecott, KW Barkovich, AJ Walsh, CA AF Shen, Jun Gilmore, Edward C. Marshall, Christine A. Haddadin, Mary Reynolds, John J. Eyaid, Wafaa Bodell, Adria Barry, Brenda Gleason, Danielle Allen, Kathryn Ganesh, Vijay S. Chang, Bernard S. Grix, Arthur Hill, R. Sean Topcu, Meral Caldecott, Keith W. Barkovich, A. James Walsh, Christopher A. TI Mutations in PNKP cause microcephaly, seizures and defects in DNA repair SO NATURE GENETICS LA English DT Article ID STRAND BREAK REPAIR; HUMAN POLYNUCLEOTIDE KINASE; LIGASE IV; HAPLOTYPE RECONSTRUCTION; SPINOCEREBELLAR ATAXIA; MICE; DAMAGE; XRCC1; IMMUNODEFICIENCY; 3'-PHOSPHATASE AB Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration(1). We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways. C1 [Shen, Jun; Marshall, Christine A.; Bodell, Adria; Barry, Brenda; Allen, Kathryn; Ganesh, Vijay S.; Chang, Bernard S.; Walsh, Christopher A.] Beth Israel Deaconess Med Ctr, Dept Neurol, Howard Hughes Med Inst, Boston, MA 02215 USA. [Shen, Jun; Marshall, Christine A.; Bodell, Adria; Barry, Brenda; Allen, Kathryn; Ganesh, Vijay S.; Chang, Bernard S.; Walsh, Christopher A.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Gilmore, Edward C.; Gleason, Danielle; Hill, R. Sean; Walsh, Christopher A.] Childrens Hosp Boston, Div Genet, Boston, MA USA. [Gilmore, Edward C.; Gleason, Danielle; Hill, R. Sean; Walsh, Christopher A.] Childrens Hosp Boston, Manton Ctr Orphan Dis Res, Dept Med, Boston, MA USA. [Gilmore, Edward C.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp,Div Child Neurol, Boston, MA 02115 USA. [Haddadin, Mary] Al Bashir Hosp, Minist Hlth, Dept Pathol, Cytogenet Lab, Amman, Jordan. [Reynolds, John J.; Caldecott, Keith W.] Univ Sussex, Genome Damage & Stabil Ctr, Brighton, E Sussex, England. [Eyaid, Wafaa] King Fahad Natl Guard Hosp, Dept Pediat, King Abdul Aziz Med City, Saudi Arabia. [Grix, Arthur] Kaiser Permanente, Point W Med Off, Dept Med Genet, Sacramento, CA USA. [Topcu, Meral] Hacettepe Univ, Fac Med, Ihsan Dogramaci Childrens Hosp, Dept Pediat,Sect Pediat Neurol, Ankara, Turkey. [Barkovich, A. James] Univ Calif San Francisco, Dept Radiol, Dept Neurol, San Francisco, CA 94143 USA. [Barkovich, A. James] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Walsh, Christopher A.] MIT, Broad Inst, Cambridge, MA 02139 USA. [Walsh, Christopher A.] Harvard Univ, Cambridge, MA 02138 USA. RP Walsh, CA (reprint author), Beth Israel Deaconess Med Ctr, Dept Neurol, Howard Hughes Med Inst, Boston, MA 02215 USA. EM Christopher.Walsh@childrens.harvard.edu FU Victoria and Stuart Quan Fellowship; US National Institute of Neurological Disorders and Stroke [5K08NS059673-02, NSR01-35129]; Fogarty International Center [R21 NS061772]; Manton Center for Orphan Disease Research; Simons Foundation; Dubai Harvard Foundation for Medical Research; K12 Child Health Research Center [1 K12 HD052896-01A1]; Child Neurology Foundation; UK Medical Research Council [G0400959]; US National Institutes of Health [HHSN268200782096C, N01-HG-65403]; Intellectual and Developmental Disabilities Research Centers [P30 HD18655]; [G0600776] FX J.S. was supported by the Victoria and Stuart Quan Fellowship. Research was supported by grants from the US National Institute of Neurological Disorders and Stroke to E. C. G. (5K08NS059673-02) and to C. A. W. (NSR01-35129), the Fogarty International Center (R21 NS061772), the Manton Center for Orphan Disease Research, the Simons Foundation and by Dubai Harvard Foundation for Medical Research. E. C. G. was also supported by a K12 Child Health Research Center award to Children's Hospital Boston (1 K12 HD052896-01A1) and a Research in Training Award from the Child Neurology Foundation. J.J.R. and K. W. C. are supported by the UK Medical Research Council (G0600776 & G0400959). C. A. W. is an Investigator of the Howard Hughes Medical Institute. We thank S. Lindsay and S. Lisgo from the Medical Research Council-Wellcome Trust Human Developmental Biology Resource (HDBR), Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK, for performing human in situ hybridizations. We are grateful for genotyping services provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the US National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C and NIH N01-HG-65403. Genotyping at Children's Hospital Boston is supported by the Intellectual and Developmental Disabilities Research Centers (CHB MRDDRC, P30 HD18655). NR 28 TC 110 Z9 115 U1 0 U2 12 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 MAR PY 2010 VL 42 IS 3 BP 245 EP U38 DI 10.1038/ng.526 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 560OQ UT WOS:000274912400014 PM 20118933 ER PT J AU Garrison, BS Rossi, DJ AF Garrison, Brian S. Rossi, Derrick J. TI Controlling stem cell fate one substrate at a time SO NATURE IMMUNOLOGY LA English DT Editorial Material ID UBIQUITIN LIGASE; C-MYC; SELF-RENEWAL; DIFFERENTIATION; FBXW7; FBW7 AB Hematopoietic stem cell self-renewal is tightly regulated. Regulation of the stability of c-Myc protein contributes to this control of hematopoietic stem cell quiescence and repopulation. C1 [Garrison, Brian S.; Rossi, Derrick J.] Childrens Hosp Boston, Harvard Stem Cell Inst, Immune Dis Inst, Program Cellular & Mol Med, Boston, MA USA. [Garrison, Brian S.; Rossi, Derrick J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Garrison, BS (reprint author), Childrens Hosp Boston, Harvard Stem Cell Inst, Immune Dis Inst, Program Cellular & Mol Med, Boston, MA USA. EM rossi@di.harvard.edu NR 13 TC 3 Z9 3 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2010 VL 11 IS 3 BP 193 EP 194 DI 10.1038/ni0310-193 PG 2 WC Immunology SC Immunology GA 556QI UT WOS:000274605800006 PM 20157300 ER PT J AU Min, J Zaslavsky, A Fedele, G McLaughlin, SK Reczek, EE De Raedt, T Guney, I Strochlic, DE MacConaill, LE Beroukhim, R Bronson, RT Ryeom, S Hahn, WC Loda, M Cichowski, K AF Min, Junxia Zaslavsky, Alexander Fedele, Giuseppe McLaughlin, Sara K. Reczek, Elizabeth E. De Raedt, Thomas Guney, Isil Strochlic, David E. MacConaill, Laura E. Beroukhim, Rameen Bronson, Roderick T. Ryeom, Sandra Hahn, William C. Loda, Massimo Cichowski, Karen TI An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappa B SO NATURE MEDICINE LA English DT Article ID ABERRANT PROMOTER METHYLATION; PROTEIN HDAB2IP GENE; PROGRESSION; EZH2; ADENOCARCINOMA; MUTATIONS; INACTIVATION; MECHANISMS; SIGNATURE; PATHWAYS AB Metastasis is responsible for the majority of prostate cancer-related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene-tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-kappa B (NF-kappa B). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-kappa B through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N-methyltransferase EZH2 activates Ras and NF-kappa B and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis. C1 [Min, Junxia; McLaughlin, Sara K.; Reczek, Elizabeth E.; De Raedt, Thomas; Cichowski, Karen] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Min, Junxia; Fedele, Giuseppe; McLaughlin, Sara K.; Reczek, Elizabeth E.; De Raedt, Thomas; Guney, Isil; Strochlic, David E.; Beroukhim, Rameen; Bronson, Roderick T.; Hahn, William C.; Loda, Massimo; Cichowski, Karen] Harvard Univ, Sch Med, Boston, MA USA. [Zaslavsky, Alexander; Ryeom, Sandra] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Dept Canc Biol, Philadelphia, PA 19104 USA. [Fedele, Giuseppe; Guney, Isil; Strochlic, David E.; Beroukhim, Rameen; Hahn, William C.; Loda, Massimo] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [MacConaill, Laura E.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Beroukhim, Rameen] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Beroukhim, Rameen; Hahn, William C.; Loda, Massimo] Broad Inst Harvard, Cambridge, MA USA. [Beroukhim, Rameen; Hahn, William C.] MIT, Cambridge, MA 02139 USA. [Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Loda, Massimo] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Cichowski, Karen] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA USA. RP Cichowski, K (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. EM kcichowski@rics.bwh.harvard.edu RI Min, Junxia/E-7622-2016 OI Min, Junxia/0000-0001-8099-6327 FU US Department of Defense [PC074048]; Ludwig Center at Dana-Farber/Harvard Cancer Center FX The PMMP-luc-neo retroviral luciferase construct was generously provided by A. L. Kung and M. Chheda (Dana-Farber Cancer Institute (DFCI)). pRL-TK was a gift from J. Boehm (Broad Institute). We thank D. Barbie (DFCI), J. Boehm for NF-kappa B target primers and R. Chen (DFCI) for I kappa B alpha SR and G. Evan for helpful discussions. This grant was supported by in part by the US Department of Defense (PC074048) and the Ludwig Center at Dana-Farber/Harvard Cancer Center. NR 51 TC 199 Z9 222 U1 2 U2 19 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 MAR PY 2010 VL 16 IS 3 BP 286 EP U82 DI 10.1038/nm.2100 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 565KA UT WOS:000275289500033 PM 20154697 ER PT J AU Yadav, VK Balaji, S Suresh, PS Liu, XS Lu, X Li, ZS Guo, XE Mann, JJ Balapure, AK Gershon, MD Medhamurthy, R Vidal, M Karsenty, G Ducy, P AF Yadav, Vijay K. Balaji, Santhanam Suresh, Padmanaban S. Liu, X. Sherry Lu, Xin Li, Zhishan Guo, X. Edward Mann, J. John Balapure, Anil K. Gershon, Michael D. Medhamurthy, Rudraiah Vidal, Marc Karsenty, Gerard Ducy, Patricia TI Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis SO NATURE MEDICINE LA English DT Article ID TRYPTOPHAN-HYDROXYLASE INHIBITORS; PARATHYROID-HORMONE; DISORDERS; SYSTEM; MICE; MASS AB Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation(1). As gut-derived serotonin (GDS) inhibits bone formation(2), we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis. C1 [Yadav, Vijay K.; Karsenty, Gerard] Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10027 USA. [Balaji, Santhanam; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Balaji, Santhanam; Vidal, Marc] Ctr Canc Syst Biol, Boston, MA USA. [Balaji, Santhanam; Vidal, Marc] Dana Farber Canc Inst, Boston, MA 02115 USA. [Suresh, Padmanaban S.; Medhamurthy, Rudraiah] Indian Inst Sci, Dept Mol Reprod Dev & Genet, Bangalore 560012, Karnataka, India. [Liu, X. Sherry; Lu, Xin; Guo, X. Edward] Columbia Univ, Dept Biomed Engn, New York, NY USA. [Li, Zhishan; Gershon, Michael D.; Ducy, Patricia] Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA. [Mann, J. John] Columbia Univ, Dept Psychiat, New York, NY USA. [Balapure, Anil K.] Cent Drug Res Inst, Tissue & Cell Culture Unit, Lucknow 226001, Uttar Pradesh, India. RP Karsenty, G (reprint author), Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY 10027 USA. EM gk2172@columbia.edu; pd2193@columbia.edu RI yadav, VIJAY /Q-2540-2016; OI yadav, VIJAY /0000-0003-2345-2846; Liu, Xiaowei/0000-0001-7247-2232 FU US National Institutes of Health; International Bone and Mineral Society FX We thank M.-T. Rached, Y.-Y. Huang, N. Suda and G. Ren for help in experiments and D. Landry (Organic Chemistry, Columbia University) for providing LP533401 for the initial stages of these experiments. Special thanks go to S. Kousteni and J. Martin for helpful suggestions. This work was supported by grants from the US National Institutes of Health (V.K.Y., G. K. and P. D.) and a Gideon and Sevgi Rodan fellowship from International Bone and Mineral Society (V.K.Y.). NR 25 TC 127 Z9 135 U1 0 U2 26 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 MAR PY 2010 VL 16 IS 3 BP 308 EP U103 DI 10.1038/nm.2098 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 565KA UT WOS:000275289500036 PM 20139991 ER PT J AU Barouch, DH O'Brien, KL Simmons, NL King, SL Abbink, P Maxfield, LF Sun, YH La Porte, A Riggs, AM Lynch, DM Clark, SL Backus, K Perry, JR Seaman, MS Carville, A Mansfield, KG Szinger, JJ Fischer, W Muldoon, M Korber, B AF Barouch, Dan H. O'Brien, Kara L. Simmons, Nathaniel L. King, Sharon L. Abbink, Peter Maxfield, Lori F. Sun, Ying-Hua La Porte, Annalena Riggs, Ambryice M. Lynch, Diana M. Clark, Sarah L. Backus, Katherine Perry, James R. Seaman, Michael S. Carville, Angela Mansfield, Keith G. Szinger, James J. Fischer, Will Muldoon, Mark Korber, Bette TI Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys SO NATURE MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNOGENICITY; REPLICATION; VARIANTS; VECTORS; STEP AB The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development(1,2). Antigens derived from natural HIV-1 sequences have elicited only a limited breadth of cellular immune responses in nonhuman primate studies and clinical trials to date. Polyvalent 'mosaic' antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity(3). Here we show that mosaic HIV-1 Gag, Pol and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors markedly augmented both the breadth and depth without compromising the magnitude of antigen-specific T lymphocyte responses as compared with consensus or natural sequence HIV-1 antigens in rhesus monkeys. Polyvalent mosaic antigens therefore represent a promising strategy to expand cellular immunologic vaccine coverage for genetically diverse pathogens such as HIV-1. C1 [Barouch, Dan H.; O'Brien, Kara L.; Simmons, Nathaniel L.; King, Sharon L.; Abbink, Peter; Maxfield, Lori F.; Sun, Ying-Hua; La Porte, Annalena; Riggs, Ambryice M.; Lynch, Diana M.; Clark, Sarah L.; Backus, Katherine; Perry, James R.; Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Div Vaccine Res, Boston, MA 02215 USA. [Barouch, Dan H.] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. [Barouch, Dan H.] Harvard Univ, Boston, MA 02115 USA. [Carville, Angela; Mansfield, Keith G.] New England Reg Primate Res Ctr, Southborough, MA 01772 USA. [Szinger, James J.; Fischer, Will; Korber, Bette] Los Alamos Natl Lab, Los Alamos, NM USA. [Muldoon, Mark] Univ Manchester, Sch Math, Manchester, Lancs, England. [Muldoon, Mark; Korber, Bette] Santa Fe Inst, Santa Fe, NM 87501 USA. RP Barouch, DH (reprint author), Beth Israel Deaconess Med Ctr, Div Vaccine Res, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu RI Muldoon, Mark/C-7505-2009; Fischer, Will/B-1323-2013; OI Fischer, Will/0000-0003-4579-4062; Muldoon, Mark/0000-0002-5004-7195; Korber, Bette/0000-0002-2026-5757 FU US National Institutes of Health (NIH) AIDS Research and Reference Reagent Program; NIH [AI058727, AI066305, AI066924, AI078526, AI084794, RR000168, AI067854, AI061734]; Los Alamos National Laboratory FX We thank B. Haynes, N. Letvin, P. Swanson, F. Stephens, B. Hahn, J. McElrath, J. Goudsmit, M. Pau, N. Michael, M. Marovich and M. Pensiero for generous advice and assistance. We obtained peptides from the US National Institutes of Health (NIH) AIDS Research and Reference Reagent Program. We acknowledge support from NIH grants AI058727 (D. H. B.), AI066305 (D. H. B.), AI066924 (D. H. B.), AI078526 (D. H. B.), AI084794 (D. H. B.), RR000168, AI067854 (B. K.), AI061734 (B. K.) and directed research funding from Los Alamos National Laboratory (B. K.). NR 20 TC 180 Z9 185 U1 1 U2 7 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 MAR PY 2010 VL 16 IS 3 BP 319 EP U116 DI 10.1038/nm.2089 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 565KA UT WOS:000275289500038 PM 20173752 ER PT J AU Blackburn, JS Langenau, DM AF Blackburn, Jessica S. Langenau, David M. TI aMAZe-ing tools for mosaic analysis in zebrafish SO NATURE METHODS LA English DT Editorial Material ID TRANSGENIC ZEBRAFISH; EXPRESSION AB Mosaic analysis in zebrafish (MAZe) allows lineage tracing and analysis of mosaic animals. C1 [Blackburn, Jessica S.] Massachusetts Gen Hosp, Dept Mol Pathol, Massachusetts Gen Canc Ctr, Boston, MA 02114 USA. Harvard Stem Cell Inst, Boston, MA USA. RP Blackburn, JS (reprint author), Massachusetts Gen Hosp, Dept Mol Pathol, Massachusetts Gen Canc Ctr, Boston, MA 02114 USA. EM dlangenau@partners.org FU NIAMS NIH HHS [K01 AR055619-03, K01 AR055619-03S1, K01 AR055619] NR 8 TC 7 Z9 7 U1 2 U2 4 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 MAR PY 2010 VL 7 IS 3 BP 188 EP 190 DI 10.1038/nmeth0310-188 PG 4 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 562NI UT WOS:000275058200015 PM 20195251 ER PT J AU Cosker, KE Segal, RA AF Cosker, Katharina E. Segal, Rosalind A. TI The longer U(T)R, the further you go SO NATURE NEUROSCIENCE LA English DT Editorial Material ID MESSENGER-RNA LOCALIZATION; LOCAL TRANSLATION; HIPPOCAMPAL-NEURONS; AXONS; TRANSPORT C1 [Cosker, Katharina E.; Segal, Rosalind A.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Cosker, Katharina E.; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Cosker, Katharina E.; Segal, Rosalind A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Cosker, KE (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. EM rosalind_segal@dfci.harvard.edu NR 15 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAR PY 2010 VL 13 IS 3 BP 273 EP 275 DI 10.1038/nn0310-273 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 559WW UT WOS:000274860100003 PM 20177416 ER PT J AU Efstathiou, JA Shipley, WU Zietman, AL Smith, MR AF Efstathiou, Jason A. Shipley, William U. Zietman, Anthony L. Smith, Matthew R. TI HORMONAL THERAPIES ADT for prostate cancer: true love or heartbreak? SO NATURE REVIEWS CLINICAL ONCOLOGY LA English DT Editorial Material ID ANDROGEN DEPRIVATION THERAPY; CARDIOVASCULAR MORTALITY; DISEASE; IMPACT; MEN C1 [Efstathiou, Jason A.; Shipley, William U.; Zietman, Anthony L.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Smith, Matthew R.] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. RP Efstathiou, JA (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM jefstathiou@partners.org FU NCI NIH HHS [K24 CA121990, K24 CA121990-03, K24 CA121990-05, K24 CA121990-04] NR 10 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 1759-4774 J9 NAT REV CLIN ONCOL JI Nat. Rev. Clin. Oncol. PD MAR PY 2010 VL 7 IS 3 BP 130 EP 132 DI 10.1038/nrclinonc.2010.12 PG 4 WC Oncology SC Oncology GA 562LX UT WOS:000275053500005 PM 20190794 ER PT J AU Aguayo-Mazzucato, C Bonner-Weir, S AF Aguayo-Mazzucato, Cristina Bonner-Weir, Susan TI Stem cell therapy for type 1 diabetes mellitus SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Review ID INSULIN-PRODUCING CELLS; PANCREATIC-DUCT CELLS; ISLET-LIKE CLUSTERS; HUMAN CORD-BLOOD; GLUCAGON-LIKE PEPTIDE-1; INTER-ALPHA-INHIBITOR; ADULT-MOUSE PANCREAS; HUMAN UMBILICAL-CORD; BETA-CELLS; IN-VITRO AB The use of stem cells in regenerative medicine holds great promise for the cure of many diseases, including type 1 diabetes mellitus (T1DM). Any potential stem-cell-based cure for T1DM should address the need for beta-cell replacement, as well as control of the autoimmune response to cells which express insulin. The ex vivo generation of beta cells suitable for transplantation to reconstitute a functional beta-cell mass has used pluripotent cells from diverse sources, as well as organ-specific facultative progenitor cells from the liver and the pancreas. The most effective protocols to date have produced cells that express insulin and have molecular characteristics that closely resemble bona fide insulin-secreting cells; however, these cells are often unresponsive to glucose, a characteristic that should be addressed in future protocols. The use of mesenchymal stromal cells or umbilical cord blood to modulate the immune response is already in clinical trials; however, definitive results are still pending. This Review focuses on current strategies to obtain cells which express insulin from different progenitor sources and highlights the main pathways and genes involved, as well as the different approaches for the modulation of the immune response in patients with T1DM. C1 [Aguayo-Mazzucato, Cristina; Bonner-Weir, Susan] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. RP Bonner-Weir, S (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM susan.bonner-weir@joslin.harvard.edu OI Bonner-Weir, Susan/0000-0003-4682-0656 NR 145 TC 83 Z9 94 U1 4 U2 32 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD MAR PY 2010 VL 6 IS 3 BP 139 EP 148 DI 10.1038/nrendo.2009.274 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 558WK UT WOS:000274779100007 PM 20173775 ER PT J AU Lee, DH Pan, YF Kanner, S Sung, P Borowiec, JA Chowdhury, D AF Lee, Dong-Hyun Pan, Yunfeng Kanner, Shlomo Sung, Patrick Borowiec, James A. Chowdhury, Dipanjan TI A PP4 phosphatase complex dephosphorylates RPA2 to facilitate DNA repair via homologous recombination SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID REPLICATION PROTEIN-A; STRAND BREAK REPAIR; DAMAGE CHECKPOINT; HUMAN-CELLS; PHOSPHORYLATION; ATR; HYPERPHOSPHORYLATION; BINDING; KINASE; STRESS AB Double-stranded DNA breaks (DSBs) induce a phosphorylation-mediated signaling cascade, but the role of phosphatases in this pathway remains unclear. Here we show that human protein phosphatase 4 (PP4) dephosphorylates replication protein A (RPA) subunit RPA2, regulating its role in the DSB response. PP4R2, a regulatory subunit of PP4, mediates the DNA damage-dependent association between RPA2 and the PP4C catalytic subunit. PP4 efficiently dephosphorylates phospho-RPA2 in vitro, and silencing PP4R2 in cells alters the kinetics and pattern of RPA2 phosphorylation. Depletion of PP4R2 impedes homologous recombination (HR) via inefficient loading of the essential HR factor RAD51, causing an extended G2-M checkpoint and hypersensitivity to DNA damage. Cells expressing phosphomimetic RPA2 mutants have a comparable phenotype, suggesting that PP4-mediated dephosphorylation of RPA2 is necessary for an efficient DNA-damage response. These observations provide new insight into the role and regulation of RPA phosphorylation in HR-mediated repair. C1 [Lee, Dong-Hyun; Pan, Yunfeng; Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lee, Dong-Hyun; Pan, Yunfeng; Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [Kanner, Shlomo; Borowiec, James A.] NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. [Kanner, Shlomo; Borowiec, James A.] NYU, Sch Med, New York Univ Canc Inst, New York, NY 10016 USA. [Sung, Patrick] Yale Univ, Sch Med, Dept Mol Biophys & Biochem, New Haven, CT 06510 USA. RP Chowdhury, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM dipanjan_chowdhury@dfci.harvard.edu OI Borowiec, James/0000-0003-4117-0826 FU Joint Center for Radiation Therapy; Barr Award; US National Institutes of Health [GM083185]; Breast Cancer Alliance FX We thank M. Michael and members of the Chowdhury and Borowiec laboratories for useful discussions. This work was supported by the Joint Center for Radiation Therapy and a Barr Award (D. C.), US National Institutes of Health grant GM083185 and an Exceptional Project Award Grant from the Breast Cancer Alliance (J. A. B.). NR 46 TC 58 Z9 66 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAR PY 2010 VL 17 IS 3 BP 365 EP U138 DI 10.1038/nsmb.1769 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 564AK UT WOS:000275182700018 PM 20154705 ER PT J AU Ix, JH Shlipak, MG Wassel, CL Whooley, MA AF Ix, Joachim H. Shlipak, Michael G. Wassel, Christina L. Whooley, Mary A. TI Fibroblast growth factor-23 and early decrements in kidney function: the Heart and Soul Study SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE albuminuria; chronic; fibroblast growth factor-23; kidney disease; osteodystrophy ID CYSTATIN-C; CARDIOVASCULAR MORTALITY; ELDERLY PERSONS; DISEASE; FIBROBLAST-GROWTH-FACTOR-23; COMMUNITY; CALCIUM; RISK; ASSOCIATION; PHOSPHORUS AB Methods. In 792 outpatients with stable cardiovascular disease (CVD) and normal kidney function to moderate CKD, we evaluate the associations of estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) with plasma FGF-23 concentrations. Results. Compared to participants with eGFR >= 90 ml/min/1.73m(2), mean FGF-23 concentrations were 7.8 RU/ml higher (4.3-11.5, P = 0.01) in those with eGFR 60-89 ml/min/1.73m(2) in models adjusted for age, sex, race, ACR, blood pressure, diabetes and body mass index. More advanced decrements in eGFR were associated with much higher FGF-23 concentrations. In spline analysis, the slope of change in FGF-23 concentration was evident at eGFR < 90 ml/min/1.73m(2). Compared to participants with ACR < 30 mg/g, mean FGF-23 concentrations were 18.4 RU/ml higher (9.3-29.2, P < 0.001) in those with ACR 30-299 mg/g in models adjusted for identical covariates plus eGFR and much higher in individuals with ACR >= 300 mg/g. Spline analysis demonstrated a linear relationship of ACR with FGF-23, independent of eGFR, even among persons with ACR < 30 mg/g. Conclusion. Modest decrements in eGFR or elevations in albuminuria are each independently associated with higher FGF-23 concentrations in outpatients with stable CVD. C1 [Ix, Joachim H.] Univ Calif San Diego, Dept Med, Div Nephrol, San Diego, CA 92103 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA USA. [Ix, Joachim H.; Wassel, Christina L.] Univ Calif San Diego, Dept Family & Prevent Med, Div Prevent Med, San Diego, CA 92103 USA. [Shlipak, Michael G.; Whooley, Mary A.] San Francisco VA Med Ctr, Gen Med Sect, San Francisco, CA USA. [Shlipak, Michael G.; Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Shlipak, Michael G.; Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Ix, JH (reprint author), Univ Calif San Diego, Dept Med, Div Nephrol, San Diego, CA 92103 USA. EM joeix@ucsd.edu FU American Heart Association; Department of Veterans Epidemiology Merit Review Program; Department of Veterans Affairs Health Services Research and Development service; National Heart Lung and Blood Institute [R01 HL079235]; American Federation for Aging Research; Robert Wood Johnson Foundation; Ischemia Research and Education Foundation FX The authors thank Ms. Clydene Nee for review and assistance with the manuscript. This study was supported by an American Heart Association Fellow to Faculty Transition Award (JHI). The Heart and Soul Study was supported by the Department of Veterans Epidemiology Merit Review Program; the Department of Veterans Affairs Health Services Research and Development service; the National Heart Lung and Blood Institute (R01 HL079235); the American Federation for Aging Research ( Paul Beeson Scholars Program); the Robert Wood Johnson Foundation ( Generalist Physician Faculty Scholars Program); and the Ischemia Research and Education Foundation. NR 18 TC 68 Z9 72 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD MAR PY 2010 VL 25 IS 3 BP 993 EP 997 DI 10.1093/ndt/gfp699 PG 5 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 561OQ UT WOS:000274987800054 PM 20037168 ER PT J AU Chao, LL Mueller, SG Buckley, ST Peek, K Raptentsetseng, S Elman, J Yaffe, K Miller, BL Kramer, JH Madison, C Mungas, D Schuff, N Weiner, MW AF Chao, L. L. Mueller, S. G. Buckley, S. T. Peek, K. Raptentsetseng, S. Elman, J. Yaffe, K. Miller, B. L. Kramer, J. H. Madison, C. Mungas, D. Schuff, N. Weiner, M. W. TI Evidence of neurodegeneration in brains of older adults who do not yet fulfill MCI criteria SO NEUROBIOLOGY OF AGING LA English DT Article DE Aging; MCI; AD; Structural MRI; MRS ID MILD COGNITIVE IMPAIRMENT; VOXEL-BASED MORPHOMETRY; MAGNETIC-RESONANCE SPECTROSCOPY; GRAY-MATTER LOSS; ALZHEIMERS-DISEASE; ENTORHINAL CORTEX; HIPPOCAMPAL ATROPHY; EXECUTIVE FUNCTION; CEREBRAL-CORTEX; ELDERLY-PEOPLE AB We sought to determine whether there are structural and metabolic changes in the brains of older adults with cognitive complaints yet who do not meet MCI criteria (i.e., preMCI). We compared the volumes of regional lobar gray matter (GM) and medial temporal lobe structures, including the hippocampus, entorhinal cortex (ERC), fusiform and parahippocampal gyri, and metabolite ratios from the posterior cingulate in individuals who had a Clinical Demetia Rating (CDR) of 0.5, but who did not meet MCI criteria (preMCI, N = 17), patients with mild cognitive impairment (MCI, N = 13), and cognitively normal controls (N = 18). Controls had more ERC, fusiform, and frontal gray matter volume than preMCI and MCI subjects and greater parahippocampal volume and more posterior cingulate N-acetylaspartate (NAA)/myoinosotil (mI) than MCI. There were no significant differences between MCI and preMCI subjects on any of these measures. These findings suggest there are neurodegenerative changes in the brains of older adults who have cognitive complaints severe enough to qualify for CDR = 0.5 yet show no deficits on formal neuropsychological testing. The results further support the hypothesis that detection of individuals with very mild forms of Alzheimer's disease (AD) may be facilitated by use of the CDR, which emphasizes changes in cognition over time within individuals rather than comparison with group norms. (C) 2008 Elsevier Inc. All rights reserved. C1 [Chao, L. L.; Mueller, S. G.; Buckley, S. T.; Peek, K.; Raptentsetseng, S.; Elman, J.; Schuff, N.; Weiner, M. W.] San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA 94121 USA. [Chao, L. L.; Mueller, S. G.; Schuff, N.; Weiner, M. W.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Chao, L. L.; Yaffe, K.; Weiner, M. W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, K.; Miller, B. L.; Kramer, J. H.; Weiner, M. W.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Madison, C.] Calif Pacific Med Ctr, San Francisco, CA 94120 USA. [Mungas, D.] Univ Calif Davis, Dept Neurol, Davis, CA 95817 USA. RP Chao, LL (reprint author), San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, 4150 Clement St,114M, San Francisco, CA 94121 USA. EM linda.chao@ucsf.edu RI Mungas, Dan/E-6810-2011; OI Elman, Jeffrey/0000-0002-8072-2294 FU National Institute on Aging [AG10897]; San Francisco Veterans Affairs Medical Center FX National Institute on Aging (Grant AG10897), Jennifer Hlavin, Kari Haws, Prediction of Cognitive Decline volunteers, and the San Francisco Veterans Affairs Medical Center. NR 82 TC 19 Z9 19 U1 0 U2 5 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 MAR PY 2010 VL 31 IS 3 BP 368 EP 377 DI 10.1016/j.neurobiolaging.2008.05.004 PG 10 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 584NP UT WOS:000276759600002 PM 18550226 ER PT J AU Loftis, JM Huckans, M Morasco, BJ AF Loftis, Jennifer M. Huckans, Marilyn Morasco, Benjamin J. TI Neuroimmune mechanisms of cytokine-induced depression: Current theories and novel treatment strategies SO NEUROBIOLOGY OF DISEASE LA English DT Review DE Depression; Cytokines; Inflammation; Antidepressants; Animal models; Sickness behavior; Biomarkers ID TUMOR-NECROSIS-FACTOR; INTERFERON-INDUCED DEPRESSION; LONG-TERM POTENTIATION; CENTRAL-NERVOUS-SYSTEM; CHRONIC HEPATITIS-C; RAT DENTATE GYRUS; INTERLEUKIN-1-INDUCED SICKNESS BEHAVIOR; PRO-INFLAMMATORY CYTOKINES; IRRITABLE-BOWEL-SYNDROME; MAJOR DEPRESSION AB The relationships between immune and neural function are an increasingly important area of study for neuropsychiatric disorders, in particular depression. This is exemplified by the growing number of publications on cytokines and depression during the last 10 years, as compared to earlier decades. This review summarizes the current theories and novel treatment strategies for depression, with a focus on cytokine-induced depression. Neuroimmune mechanisms are now viewed as central to the development of depressive symptoms and emerging evidence is beginning to identify the neural circuits involved in cytokine-induced depression. The current diagnostic categories for depression, as defined by the Diagnostic and Statistical Manual of Mental Disorders, however, are not etiologically or biologically derived, and it has been proposed that "depression", likely reflects multiple pathogeneses leading to varying symptom constellations. As we move toward a better biological understanding of depression-related symptom constellations or syndromes, the term "depression" may prove inadequately broad, and an integration of interdisciplinary literatures will increase in importance. Future research should aim to characterize these depression-related symptom constellations or syndromes better with the goal of optimizing treatment strategies. (C) Published by Elsevier Inc. C1 [Loftis, Jennifer M.; Huckans, Marilyn; Morasco, Benjamin J.] Portland VA Med Ctr, Behav Hlth & Clin Neurosci Div, Res & Dev Serv, Portland, OR 97239 USA. [Loftis, Jennifer M.; Huckans, Marilyn; Morasco, Benjamin J.] Portland VA Med Ctr, NW Hepatitis Resource Ctr C, Portland, OR 97239 USA. [Loftis, Jennifer M.; Huckans, Marilyn; Morasco, Benjamin J.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. [Loftis, Jennifer M.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. RP Loftis, JM (reprint author), Portland VA Med Ctr, Behav Hlth & Clin Neurosci Div, Res & Dev Serv, 3710 SW US Vet Hosp Rd,R&D 99, Portland, OR 97239 USA. EM loftisj@ohsu.edu FU NIDA NIH HHS [K23 DA023467, K23 DA023467-02] NR 180 TC 94 Z9 103 U1 3 U2 28 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD MAR PY 2010 VL 37 IS 3 SI SI BP 519 EP 533 DI 10.1016/j.nbd.2009.11.015 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 560PH UT WOS:000274914100005 PM 19944762 ER PT J AU Shen, HX Hu, XM Liu, C Wang, SP Zhang, WT Gao, H Steder, RA Gao, YQ Chen, J AF Shen, Hongxia Hu, Xiaoming Liu, Can Wang, Suping Zhang, Wenting Gao, Hui Steder, R. Anne Gao, Yanqin Chen, Jun TI Ethyl pyruvate protects against hypoxic-ischemic brain injury via anti-cell death and anti-inflammatory mechanisms SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Neonatal hypoxia-ischemia; Neuroprotection; Cell death; Inflammation; Microglia; Calpain; Calcium; NF-kappa B ID APOPTOSIS-INDUCING FACTOR; OXYGEN-GLUCOSE DEPRIVATION; WIDE THERAPEUTIC WINDOW; FOCAL CEREBRAL-ISCHEMIA; NEONATAL-RAT; OXIDATIVE STRESS; PERMEABILITY TRANSITION; INFLAMMATORY MEDIATORS; ACTIVATED MICROGLIA; REPERFUSION INJURY AB Ethyl pyruvate (EP) is protective in experimental models of many illnesses. This study investigates whether EP can protect against neonatal hypoxic-ischemic (H-I) brain injury. Pre-treatment with EP significantly reduced brain damage at 7 days post-H-I, with 50 mg/kg EP achieving over 50% recovery in tissue loss compared to vehicle-treated animals. Delayed treatment with EP until 30 min after H-I was still neuroprotective. EP-afforded brain protection, together with neurological function improvement, was observed up to 2 months after HA We further demonstrated an inhibitory effect of EP on cell death, both in an in vivo model of H-I and in in vitro neuronal cultures subjected to OGD, by reducing calpain activation and calcium dysregulation. Moreover, EP exerted an anti-inflammatory effect in microglia by inhibiting NF-kappa B activation and subsequent release of inflammatory mediators. Taken together, our results suggest that EP confers potent neuroprotection against neonatal H-I brain injury via its anti-cell death and antiinflammatory actions. EP is a potential novel therapeutic agent for neonatal H-I brain injury. (C) Published by Elsevier Inc. C1 [Hu, Xiaoming; Wang, Suping; Steder, R. Anne; Gao, Yanqin; Chen, Jun] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. [Shen, Hongxia; Liu, Can; Zhang, Wenting; Gao, Hui; Gao, Yanqin; Chen, Jun] Fudan Univ, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. [Shen, Hongxia; Liu, Can; Zhang, Wenting; Gao, Hui; Gao, Yanqin; Chen, Jun] Fudan Univ, Inst Brain Sci, Shanghai 200032, Peoples R China. [Hu, Xiaoming; Wang, Suping; Steder, R. Anne; Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15260 USA. RP Chen, J (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, S-507,Biomed Sci Tower, Pittsburgh, PA 15213 USA. EM yqgao@shmu.edu.cn; chenj2@upmc.edu RI Gao, Yanqin/I-6790-2016 OI Gao, Yanqin/0000-0002-4915-9819 FU NIH/NINDS [NS36736, NS43802, NS45048]; Chinese Natural Science Foundation [30470592, 30670642, J0730860] FX H.S. and X.H. contributed equally to this manuscript. This project was supported by NIH/NINDS grants NS36736, NS43802, and NS45048 (to J.C.). Y.G. was supported by the Chinese Natural Science Foundation (grants 30470592, 30670642 and J0730860). C.L. was supported by the Chinese Natural Science Foundation (grant J0730860). We thank Carol Culver for excellent editorial assistance. NR 76 TC 43 Z9 48 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD MAR PY 2010 VL 37 IS 3 SI SI BP 711 EP 722 DI 10.1016/j.nbd.2009.12.010 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 560PH UT WOS:000274914100024 PM 20026271 ER PT J AU Eutamene, H Bradesi, S Larauche, M Theodorou, V Beaufrand, C Ohning, G Fioramonti, J Cohen, M Bryant, AP Kurtz, C Currie, MG Mayer, EA Bueno, L AF Eutamene, H. Bradesi, S. Larauche, M. Theodorou, V. Beaufrand, C. Ohning, G. Fioramonti, J. Cohen, M. Bryant, A. P. Kurtz, C. Currie, M. G. Mayer, E. A. Bueno, L. TI Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE guanylate cyclase C; irritable bowel syndrome; linaclotide; visceral pain ID IRRITABLE-BOWEL-SYNDROME; CORTICOTROPIN-RELEASING-FACTOR; HEAT-STABLE ENTEROTOXIN; DEPENDENT PROTEIN-KINASE; ESCHERICHIA-COLI; CHRONIC CONSTIPATION; COLORECTAL DISTENSION; RECTAL DISTENSION; SMALL-INTESTINE; MAST-CELLS AB Background Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C). Methods Orally administered linaclotide was evaluated in non-inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory model in Wistar rats and GC-C null mice. Key Results In TNBS-induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC-C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice. Conclusions & Inferences These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C. C1 [Eutamene, H.; Theodorou, V.; Beaufrand, C.; Fioramonti, J.; Bueno, L.] INRA, UMR, Purpan Neurogastroenterol & Nutr Unit, F-31931 Toulouse 9, France. [Bradesi, S.; Larauche, M.; Mayer, E. A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Ctr Neurobiol Stress, Los Angeles, CA 90095 USA. [Ohning, G.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Cohen, M.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Bryant, A. P.; Kurtz, C.; Currie, M. G.] Ironwood Pharmaceut, Cambridge, MA USA. RP Bueno, L (reprint author), INRA, UMR 1054, Neurogastroenterol & Nutr Unit, EI Purpan, 180 Chemin Tournefeuille,BP3, F-31931 Toulouse 9, France. EM lbueno@toulouse.inra.fr OI Larauche, Muriel/0000-0003-3320-3675; Cohen, Mitchell/0000-0002-4412-350X FU Ironwood Pharmaceuticals FX The authors acknowledge V. Tondereau for her expert technical assistance, the INRA institute for all experimental facilities and Ironwood Pharmaceuticals for their financial support to the laboratories of Dr Bueno and Dr Mayer for performing these studies. NR 47 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 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD MAR PY 2010 VL 22 IS 3 DI 10.1111/j.1365-2982.2009.01385.x PG 11 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 553AG UT WOS:000274336200011 ER PT J AU Kokkotou, E Conboy, LA Ziogas, DC Quilty, MT Kelley, JM Davis, RB Lembo, AJ Kaptchuk, TJ AF Kokkotou, E. Conboy, L. A. Ziogas, D. C. Quilty, M. T. Kelley, J. M. Davis, R. B. Lembo, A. J. Kaptchuk, T. J. TI Serum correlates of the placebo effect in irritable bowel syndrome SO NEUROGASTROENTEROLOGY AND MOTILITY LA English DT Article DE biomarkers; irritable bowel syndrome; placebo effect; randomized controlled trials; serum ID RANDOMIZED CONTROLLED-TRIAL; FUNCTIONAL GASTROINTESTINAL DISORDERS; GENE POLYMORPHISMS; CLINICAL-TRIALS; CROHNS-DISEASE; MECHANISMS; IMMUNE; PAIN; RESPONSES; AXIS AB Background In diseases defined primarily by the subjective nature of patient self-report, placebo effects can overwhelm the capacity of randomized controlled trials to detect medication-placebo differences. Moreover, it is unclear whether such placebo effects represent genuine psychobiological phenomena or just shifts in selective attention. Knowledge of predictors of the placebo response could improve the design of clinical trials and the delivery of personalized medical care. Methods In patients with irritable bowel syndrome (IBS), a subset of our previous study that were randomized to placebo treatment (sham acupuncture) or no-treatment group (waitlist), we tested an enriched panel of 10 serum biomarkers at the enrolment and the 3rd week of intervention, using a multiplex electrochemiluminescent immunoassay. Key Results More pronounced changes overtime in serum levels of osteoprotegerin (OPG) have been found in patients who received placebo treatment compared with the waitlist group (P = 0.039). Moreover, serum levels of OPG at baseline were found to be higher (P = 0.0167) in patients who subsequently achieved adequate relief (AR) of their IBS symptoms, independently of their treatment group. Besides, serum levels of TNF-related weak inducer of apoptosis (TWEAK) at baseline were also higher (P = 0.0144) in patients who reported AR and in particular in those who received the placebo treatment. Conclusions & Inferences These two measurable biological parameters associated with placebo, namely serum OPG and TWEAK, provide a proof of principle for discovering putative molecular signatures of placebo response in IBS and perhaps in other illnesses with patient self-reported outcomes. C1 [Kokkotou, E.; Ziogas, D. C.; Davis, R. B.; Lembo, A. J.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Conboy, L. A.; Quilty, M. T.; Kaptchuk, T. J.] Harvard Univ, Sch Med, Osher Res Ctr, Boston, MA 02215 USA. [Kelley, J. M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02215 USA. [Kelley, J. M.] Endicott Coll, Beverly, MA USA. RP Kokkotou, E (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dana 501,330 Brookline Ave, Boston, MA 02215 USA. EM ekokkoto@bidmc.harvard.edu FU National Center for Complementary and Alternative Medicine (NCCAM), NIH [R01AT004662, K24 AT004095] FX This research was made possible by grants R01AT004662 and K24 AT004095 from the National Center for Complementary and Alternative Medicine (NCCAM), NIH. The contents of this report are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. NR 61 TC 12 Z9 12 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1350-1925 J9 NEUROGASTROENT MOTIL JI Neurogastroenterol. Motil. PD MAR PY 2010 VL 22 IS 3 DI 10.1111/j.1365-2982.2009.01440.x PG 9 WC Gastroenterology & Hepatology; Clinical Neurology; Neurosciences SC Gastroenterology & Hepatology; Neurosciences & Neurology GA 553AG UT WOS:000274336200008 PM 20028464 ER PT J AU Tanaka, N Hamalainen, M Ahlfors, SP Liu, HS Madsen, JR Bourgeois, BF Lee, JW Dworetzky, BA Belliveau, JW Stufflebeam, SM AF Tanaka, Naoaki Hamalainen, Matti Ahlfors, Seppo P. Liu, Hesheng Madsen, Joseph R. Bourgeois, Blaise F. Lee, Jong Woo Dworetzky, Barbara A. Belliveau, John W. Stufflebeam, Steven M. TI Propagation of epileptic spikes reconstructed from spatiotemporal magnetoencephalographic and electroencephalographic source analysis SO NEUROIMAGE LA English DT Article DE Epilepsy; Magnetoencephalography; Electroencephalography; Propagation; Spatiotemporal source analysis; Minimum norm estimate ID TEMPORAL-LOBE EPILEPSY; SURFACE-BASED ANALYSIS; TO-NOISE-RATIOS; SOURCE LOCALIZATION; PRESURGICAL EVALUATION; INTERICTAL DISCHARGES; DIPOLE LOCALIZATION; CONDUCTOR MODEL; HEAD MODELS; EEG AB The purpose of this study is to assess the accuracy of spatiotemporal source analysis of magnetoencephalography (MEG) and scalp electroencephalography (EEG) for representing the propagation of frontotemporal spikes in patients with partial epilepsy. This study focuses on frontotemporal spikes, which are typically characterized by a preceding anterior temporal peak followed by an ipsilateral inferior frontal peak. Ten patients with frontotemporal spikes on MEG/EEG were studied. We analyzed the propagation of temporal to frontal epileptic spikes on both MEG and EEG independently by using a cortically constrained minimum norm estimate (MNE). Spatiotemporal source distribution of each spike was obtained on the cortical surface derived from the patient's MRI. All patients underwent an extraoperative intracranial EEG (IEEG) recording covering temporal and frontal lobes after presurgical evaluation. We extracted source waveforms of MEG and EEG from the source distribution of interictal spikes at the sites corresponding to the location of intracranial electrodes. The time differences of the ipsilateral temporal and frontal peaks as obtained by MEG, EEG and IEEG were statistically compared in each patient. In all patients, MEG and IEEG showed similar time differences between temporal and frontal peaks. The time differences of EEG spikes were significantly smaller than those of IEEG in nine of ten patients. Spatiotemporal analysis of MEG spikes models the time course of frontotemporal spikes as observed on IEEG more adequately than EEG in our patients. Spatiotemporal source analysis may be useful for planning epilepsy surgery, by predicting the pattern of IEEG spikes. (C) 2009 Elsevier Inc. All rights reserved. C1 [Tanaka, Naoaki; Hamalainen, Matti; Ahlfors, Seppo P.; Liu, Hesheng; Belliveau, John W.; Stufflebeam, Steven M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Madsen, Joseph R.] Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Bourgeois, Blaise F.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Lee, Jong Woo; Dworetzky, Barbara A.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Hamalainen, Matti; Ahlfors, Seppo P.; Belliveau, John W.; Stufflebeam, Steven M.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Tanaka, N (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM naoro@nmr.mgh.harvard.edu RI Hamalainen, Matti/C-8507-2013; Ahlfors, Seppo/P-3644-2016; OI Dworetzky, Barbara/0000-0002-3364-2347; Liu, Hesheng/0000-0002-7233-1509 FU NCRR NIH HHS [P41 RR014075, P41 RR014075-07]; NINDS NIH HHS [R01 NS037462, R01 NS037462-07] NR 44 TC 21 Z9 21 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2010 VL 50 IS 1 BP 217 EP 222 DI 10.1016/j.neuroimage.2009.12.033 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 559GC UT WOS:000274810100021 PM 20006721 ER PT J AU Salameh, J AF Salameh, Johnny TI A 62-Year-Old Woman With Cerebral Artery Air Embolism During Commercial Air Travel SO NEUROLOGIST LA English DT Article DE air embolism; lung bulla; ischemic stroke AB Objective: Air embolism to the cerebral artery circulation is a rare complication previously associated with surgery, scuba-diving, induced abortion, angiography, and pneumothorax. However, air embolism secondary to a ruptured air bulla during commercial air travel has rarely been reported. Methods: We report a patient who became unconsciousness 30 minutes after her plane took off. Results: The patient was found to have an acute brain infarct in a watershed distribution secondary to multiple, bilateral, intraparenchymal air bubbles. Further investigation revealed a large lung bulla with an air-fluid level. Conclusion: Air embolism was due to rupture of the lung bulla into the pulmonary venous outflow. Whether the rupture was spontaneous or due to a stretch injury from a change of air pressure resulting in pulmonary barotrauma occurring during commercial air travel is uncertain. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Salameh, J (reprint author), Massachusetts Gen Hosp, Dept Neurol, 165 Cambridge St,Suite 820, Boston, MA 02114 USA. EM johnnysalameh@hotmail.com NR 3 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1074-7931 J9 NEUROLOGIST JI Neurologist PD MAR PY 2010 VL 16 IS 2 BP 136 EP 137 DI 10.1097/NRL.0b013e3181cf8695 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 567ZU UT WOS:000275490500015 PM 20220454 ER PT J AU Sperling, RA Dickerson, BC Pihlajamaki, M Vannini, P LaViolette, PS Vitolo, OV Hedden, T Becker, JA Rentz, DM Selkoe, DJ Johnson, KA AF Sperling, Reisa A. Dickerson, Bradford C. Pihlajamaki, Maija Vannini, Patrizia LaViolette, Peter S. Vitolo, Ottavio V. Hedden, Trey Becker, J. Alex Rentz, Dorene M. Selkoe, Dennis J. Johnson, Keith A. TI Functional Alterations in Memory Networks in Early Alzheimer's Disease SO NEUROMOLECULAR MEDICINE LA English DT Review DE Functional magnetic resonance imaging; Amyloid; PiB; Alzheimer's disease; Aging; Hippocampus; Default network ID MILD COGNITIVE IMPAIRMENT; PITTSBURGH COMPOUND-B; CEREBROSPINAL-FLUID A-BETA(42); POSITRON-EMISSION-TOMOGRAPHY; APOLIPOPROTEIN-E EPSILON-4; TEMPORAL-LOBE ACTIVATION; PROTEIN TRANSGENIC MICE; TEST-RETEST RELIABILITY; RESTING-STATE NETWORKS; AMYLOID-BETA PLAQUES AB The hallmark clinical symptom of early Alzheimer's disease (AD) is episodic memory impairment. Recent functional imaging studies suggest that memory function is subserved by a set of distributed networks, which include both the medial temporal lobe (MTL) system and the set of cortical regions collectively referred to as the default network. Specific regions of the default network, in particular, the posteromedial cortices, including the precuneus and posterior cingulate, are selectively vulnerable to early amyloid deposition in AD. These regions are also thought to play a key role in both memory encoding and retrieval, and are strongly functionally connected to the MTL. Multiple functional magnetic resonance imaging (fMRI) studies during memory tasks have revealed alterations in these networks in patients with clinical AD. Similar functional abnormalities have been detected in subjects at-risk for AD, including those with genetic risk and older individuals with mild cognitive impairment. Recently, we and other groups have found evidence of functional alterations in these memory networks even among cognitively intact older individuals with occult amyloid pathology, detected by PET amyloid imaging. Taken together, these findings suggest that the pathophysiological process of AD exerts specific deleterious effects on these distributed memory circuits, even prior to clinical manifestations of significant memory impairment. Interestingly, some of the functional alterations seen in prodromal AD subjects have taken the form of increases in activity relative to baseline, rather than a loss of activity. It remains unclear whether these increases in fMRI activity may be compensatory to maintain memory performance in the setting of early AD pathology or instead, represent evidence of excitotoxicity and impending neuronal failure. Recent studies have also revealed disruption of the intrinsic connectivity of these networks observable even during the resting state in early AD and asymptomatic individuals with high amyloid burden. Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD. C1 [Sperling, Reisa A.; Pihlajamaki, Maija; Vannini, Patrizia; LaViolette, Peter S.; Vitolo, Ottavio V.; Rentz, Dorene M.; Selkoe, Dennis J.; Johnson, Keith A.] Brigham & Womens Hosp, Ctr Alzheimers Res & Treatment, Dept Neurol, Boston, MA 02115 USA. [Sperling, Reisa A.; Dickerson, Bradford C.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Hedden, Trey; Becker, J. Alex; Johnson, Keith A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sperling, Reisa A.; Dickerson, Bradford C.; Vannini, Patrizia; LaViolette, Peter S.; Hedden, Trey] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Sperling, Reisa A.; Dickerson, Bradford C.; Pihlajamaki, Maija; Vannini, Patrizia; Vitolo, Ottavio V.; Rentz, Dorene M.; Selkoe, Dennis J.; Johnson, Keith A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Sperling, RA (reprint author), Brigham & Womens Hosp, Ctr Alzheimers Res & Treatment, Dept Neurol, 221 Longwood Ave, Boston, MA 02115 USA. EM reisa@rics.bwh.harvard.edu OI Kennedy, Kristen/0000-0001-5373-9026 FU National Institute on Aging [P01 AG036694, R01 AG-027435, P50 AG005134]; Alzheimer's Association; Anonymous Medical Foundation FX This work was supported by the National Institute on Aging P01 AG036694; R01 AG-027435; P50 AG005134, the Alzheimer's Association, and an Anonymous Medical Foundation. NR 191 TC 231 Z9 234 U1 6 U2 62 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD MAR PY 2010 VL 12 IS 1 SI SI BP 27 EP 43 DI 10.1007/s12017-009-8109-7 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 572IB UT WOS:000275821100003 PM 20069392 ER PT J AU Tseng, B AF Tseng, Brian TI Best practice in Duchenne muscular dystrophy SO NEUROMUSCULAR DISORDERS LA English DT Letter C1 Massachusetts Gen Hosp, Pediat Neuromuscular Clin, Boston, MA 02114 USA. RP Tseng, B (reprint author), Massachusetts Gen Hosp, Pediat Neuromuscular Clin, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD MAR PY 2010 VL 20 IS 3 BP 217 EP 217 DI 10.1016/j.nmd.2010.02.008 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 584NK UT WOS:000276759100016 PM 20206523 ER PT J AU Zheng, Y Moussally, J Cash, SS Karnam, HB Cole, AJ AF Zheng, Yi Moussally, Jon Cash, Sydney S. Karnam, Havisha B. Cole, Andrew J. TI Intravenous levetiracetam in the rat pilocarpine-induced status epilepticus model: Behavioral, physiological and histological studies SO NEUROPHARMACOLOGY LA English DT Article DE Parenteral; Treatment; Seizure; Chemoconvulsant; Neuronal Injury ID ANTIEPILEPTIC DRUG LEVETIRACETAM; SPONTANEOUS RECURRENT SEIZURES; TEMPORAL-LOBE EPILEPSY; UCB L059; MITOCHONDRIAL DYSFUNCTION; ANTICONVULSANT DRUG; PROFILE; BRAIN; MICE; EPIDEMIOLOGY AB Purpose: Status epilepticus is a neurological emergency associated with neuronal injury, lasting behavioral disturbance, and a high rate of mortality. Intravenous levetiracetam (LEV), an anti-epileptic drug approved to treat partial seizures, has recently been introduced. We sought to determine the effect of LEV administered intravenously in a chemoconvulsant model of status epilepticus. Methods: We examined the effect of intravenous LEV in the rat lithium-pilocarpine model of status epilepticus. Ten or 30 min after the onset of behavioral status epilepticus, animals were treated with LEV (200-1200 mg/kg i.v.) administered in a single bolus. Behavioral responses were recorded. Selected animals had continuous EEG recording before, during and after the administration of LEV. Some animals were sacrificed 24 h after the experiment and processed for histochemical assessment of neuronal injury. Results: When administered 30 min after the onset of behavioral epileptic seizures, transient attenuation of ictal behavior was observed in animals treated with 800 mg/kg or more of LEV. The duration of behavioral attenuation increased sharply as the dose rose to 1000 mg/kg or higher, from a mean of 4-23.6 min. When administered 10 min after seizure onset, 400 mg/kg of LEV resulted in transient ictal behavioral attenuation, and higher doses caused relatively longer periods of attenuation. Pretreatment with LEV prior to pilocarpine also delayed the onset of seizures. EEG recordings, however, showed no significant attenuation of ictal discharge. By contrast, TUNEL staining demonstrated less neuronal injury in hippocampii and other limbic structures in animals that responded behaviorally to LEV. Conclusions: Intravenous administration of LEV in a chemoconvulsant model of status epilepticus results in attenuation of behavioral manifestations of seizure discharge and in reduction of neuronal injury but does not significantly alter ictal discharge recorded by EEG. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Cole, Andrew J.] Massachusetts Gen Hosp, Epilepsy Serv, WACC L 739, Epilepsy Res Lab, Boston, MA 02114 USA. [Zheng, Yi; Moussally, Jon; Cash, Sydney S.; Karnam, Havisha B.; Cole, Andrew J.] Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. [Moussally, Jon] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Moussally, Jon] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Cole, AJ (reprint author), Massachusetts Gen Hosp, Epilepsy Serv, WACC L 739, Epilepsy Res Lab, Fruit St, Boston, MA 02114 USA. EM cole.andrew@mgh.harvard.edu FU UCB Pharma; American Epilepsy FX This study was supported by an investigator initiated grant from UCB Pharma. Dr. Zheng received support from the American Epilepsy NR 38 TC 15 Z9 15 U1 0 U2 1 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 MAR-APR PY 2010 VL 58 IS 4-5 BP 793 EP 798 DI 10.1016/j.neuropharm.2009.12.007 PG 6 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 568TA UT WOS:000275544500013 PM 20026136 ER PT J AU Leritz, EC Salat, DH Milberg, WP Williams, VJ Chapman, CE Grande, LJ Rudolph, JL Schnyer, DM Barber, CE Lipsitz, LA McGlinchey, RE AF Leritz, Elizabeth C. Salat, David H. Milberg, William P. Williams, Victoria J. Chapman, Caroline E. Grande, Laura J. Rudolph, James L. Schnyer, David M. Barber, Colleen E. Lipsitz, Lewis A. McGlinchey, Regina E. TI Variation in Blood Pressure Is Associated With White Matter Microstructure but Not Cognition in African Americans SO NEUROPSYCHOLOGY LA English DT Article DE cerebrovascular risk; blood pressure; diffusion tensor imaging; cognition ID DIFFUSION-TENSOR; RISK-FACTORS; CORPUS-CALLOSUM; BRAIN ATROPHY; OLDER-ADULTS; HYPERTENSION; MRI; HYPERINTENSITIES; LESIONS; AGE AB Although hypertension is a major risk factor for cerebrovascular disease (CVD) and is highly prevalent in African Americans, little is known about how blood pressure (BP) affects brain-behavior relationships in this population. In predominantly Caucasian populations, high BP is associated with alterations in frontal-subcortical white matter and in executive functioning aspects of cognition. We investigated associations among BP, brain structure, and neuropsychological functioning in 52 middle-older-age African Americans without diagnosed history of CVD. All participants underwent diffusion tensor imaging for examination of white matter integrity, indexed by fractional anisotropy (FA). Three regions of interest were derived in the,Interior (genu) and posterior (splenium) corpus callosum and across the whole brain. A brief neuropsychological battery was administered from which composite scores of executive function and memory were derived. Blood pressure was characterized by mean arterial blood pressure (MABP). When controlling for age, higher MABP was associated with lower FA in the genu, and there was a trend for this same relationship with regard to whole-brain FA. When the sample was broken into groups on the basis of treatment for BP regulation (medicated vs. nonmedicated), MABP was related to genu and whole-brain FA only in the nonmedicated group. Neither MABP nor FA was significantly related to either neuropsychological composite score regardless of medication use. These data provide important evidence that variation in BP may contribute to significant alterations in specific neural regions of white matter in nonmedicated individuals without symptoms of overt CVD. C1 [Leritz, Elizabeth C.; Milberg, William P.; Williams, Victoria J.; Chapman, Caroline E.; Grande, Laura J.; Rudolph, James L.; Barber, Colleen E.; McGlinchey, Regina E.] VA Boston Healthcare Syst, Educ & Clin Ctr, Boston, MA USA. [Leritz, Elizabeth C.; Williams, Victoria J.; Rudolph, James L.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Milberg, William P.; Lipsitz, Lewis A.; McGlinchey, Regina E.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Schnyer, David M.] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. [Lipsitz, Lewis A.] Beth Israel Deaconess Med Ctr, Gerontol Div, Hebrew Senior Life Inst Aging Res, Boston, MA USA. RP Leritz, EC (reprint author), 150 S Huntington Ave,GRECC 182 JP, Boston, MA 02130 USA. EM bleritz@nmr.mgh.harvard.edu RI McGlinchey, Regina/R-1971-2016; OI Schnyer, David/0000-0002-7472-2853 FU NIA NIH HHS [R03 AG029861, K01 AG024898, K01AG24898, P01AG004390, P60 AG008812, P60AG08812, R03 AG029861-02]; NINDS NIH HHS [F32 NS051942, F32NS051942, K23 NS062148, K23 NS062148-01, K23NS062148]; NINR NIH HHS [R01 NR010827, R01NR010827] NR 65 TC 22 Z9 22 U1 1 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD MAR PY 2010 VL 24 IS 2 BP 199 EP 208 DI 10.1037/a0018108 PG 10 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 567XV UT WOS:000275483100008 PM 20230114 ER PT J AU Kilgore, M Miller, CA Fass, DM Hennig, KM Haggarty, SJ Sweatt, JD Rumbaugh, G AF Kilgore, Mark Miller, Courtney A. Fass, Daniel M. Hennig, Krista M. Haggarty, Stephen J. Sweatt, J. David Rumbaugh, Gavin TI Inhibitors of Class 1 Histone Deacetylases Reverse Contextual Memory Deficits in a Mouse Model of Alzheimer's Disease SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Alzheimer's disease; cognition; drug discovery; epigenetics; histone deacetylase inhibitor; fear memory ID LONG-TERM; SYNAPTIC PLASTICITY; CATALYTIC-ACTIVITY; COGNITIVE DEFICIT; FEAR MEMORY; IN-VIVO; ACETYLATION; GENES; THERAPY; CBP AB Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by cognitive impairments that progress to dementia and death. The earliest symptoms of AD present as a relatively pure deficit in memory retrieval. Therefore, drug treatments that intervene in the early stages of AD by rescuing memory deficits could be promising therapies to slow, or even reverse progression of the disease. In this study, we tested the potential of systemic histone deacetylase inhibitor (HDACi) treatment to rescue cognitive deficits in a mouse model of AD. APPswe/PS1dE9 mice showed pronounced contextual memory impairments beginning at 6 months of age. Chronic HDACi injections (2-3 weeks) did not alter contextual memory formation in normal mice, but had profound effects in transgenic animals. Injections of sodium valproate, sodium butyrate, or vorinostat (suberoylanilide hydroxamic acid; Zolinzas (R)) completely restored contextual memory in these mutant mice. Further behavioral testing of the HDACi-treated transgenic mice showed that the newly consolidated memories were stably maintained over a 2-week period. Measurement of the HDAC isoform selectivity profile of sodium valproate, sodium butyrate, and vorinostat revealed the common inhibition of class 1 HDACs (HDAC1, 2, 3, 8) with little effect on the class IIa HDAC family members (HDAC4, 5, 7, 9) and inhibition of HDAC6 only by vorinostat. These preclinical results indicate that targeted inhibition of class I HDAC isoforms is a promising avenue for treating the cognitive deficits associated with early stage AD. Neuropsychopharmacology (2010) 35, 870-880; doi:10.1038/npp.2009.197; published online 9 December 2009 C1 [Kilgore, Mark; Miller, Courtney A.; Sweatt, J. David; Rumbaugh, Gavin] Univ Alabama, Evelyn F McKnight Brain Inst, Dept Neurobiol, Sch Med, Birmingham, AL 35294 USA. [Fass, Daniel M.; Hennig, Krista M.; Haggarty, Stephen J.] Harvard Univ, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02138 USA. [Fass, Daniel M.; Hennig, Krista M.; Haggarty, Stephen J.] MIT, Cambridge, MA 02139 USA. [Fass, Daniel M.; Hennig, Krista M.; Haggarty, Stephen J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. RP Rumbaugh, G (reprint author), Univ Alabama, Evelyn F McKnight Brain Inst, Dept Neurobiol, Sch Med, 972 Shelby Bldg,1825 Univ Blvd, Birmingham, AL 35294 USA. EM grumbaugh@nrc.uab.edu RI Miller, Courtney/E-8651-2010; OI Miller, Courtney/0000-0001-8628-4902; Sweatt, J. David/0000-0003-3567-485X; Haggarty, Stephen J./0000-0002-7872-168X FU NIMH; NINDS; American Health Assistance Foundation; Rotary CWSS International; Philip Morris External Research Program; Evelyn F McKnight Brain Research Foundation; Stanley Medical Research Institute; NARSAD FX We thank Felecia Hester and Ivonne Rivera for technical assistance. The original breeding pairs of the APP/PS1 mouse line were generously provided by Dr Ling Li. This work was supported by the NIMH, NINDS, American Health Assistance Foundation, The Rotary CWSS International, Philip Morris External Research Program, and the Evelyn F McKnight Brain Research Foundation. SJH, DMF, and KMH were supported by the Stanley Medical Research Institute and NARSAD. Dr Ralph Mazitschek generously provided MAZ1600 and MAZ1675 HDAC substrates. We also thank Erik Roberson and others at the UAB Alzheimer's Disease Research Center (ADRC) for critical evaluation of this paper. NR 47 TC 277 Z9 294 U1 8 U2 72 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2010 VL 35 IS 4 BP 870 EP 880 DI 10.1038/npp.2009.197 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 554HA UT WOS:000274424900004 PM 20010553 ER PT J AU de Gelder, B Van den Stock, J Meeren, HKM Sinke, CBA Kret, ME Tamietto, M AF de Gelder, Beatrice Van den Stock, Jan Meeren, Hanneke K. M. Sinke, Charlotte B. A. Kret, Mariska E. Tamietto, Marco TI Standing up for the body. Recent progress in uncovering the networks involved in the perception of bodies and bodily expressions SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Body; Face; Emotion; Action; Facial expressions; Bodily expressions ID HUMAN EXTRASTRIATE CORTEX; NON-CONSCIOUS RECOGNITION; INFERIOR TEMPORAL CORTEX; HUMAN OCCIPITAL CORTEX; EVENT-RELATED FMRI; FACE PERCEPTION; DEVELOPMENTAL PROSOPAGNOSIA; FACIAL EXPRESSIONS; EMOTIONAL FACES; FUNCTIONAL MRI AB Recent studies of monkeys and humans have identified several brain regions that respond to bodies. Researchers have so far mainly addressed the same questions about bodies and bodily expressions that are already familiar from three decades of face and facial expression studies. Our present goal is to review behavioral, electrophysiological and neurofunctional studies on whole body and bodily expression perception against the background of what is known about face perception. We review all currently available evidence in more detail than done so far, but we also argue for a more theoretically motivated comparison of faces and bodies that reflects some broader concerns than only modularity or category specificity of faces or bodies. (C) 2009 Elsevier Ltd. All rights reserved. C1 [de Gelder, Beatrice; Van den Stock, Jan; Meeren, Hanneke K. M.; Sinke, Charlotte B. A.; Kret, Mariska E.; Tamietto, Marco] Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. [de Gelder, Beatrice] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Van den Stock, Jan] Katholieke Univ Leuven, Dept Neurosci, B-3000 Louvain, Belgium. [Sinke, Charlotte B. A.] Maastricht Univ, Dept Cognit Neurosci, NL-6200 MD Maastricht, Netherlands. RP de Gelder, B (reprint author), Tilburg Univ, Cognit & Affect Neurosci Lab, POB 90153, NL-5000 LE Tilburg, Netherlands. EM b.degelder@uvt.nl RI Kret, Mariska/B-4798-2010; Van den Stock, Jan/F-1906-2014; OI Van den Stock, Jan/0000-0001-5756-3195; Tamietto, Marco/0000-0002-8815-8499 FU Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) [400.04081, 451-05-014, 451-07-032]; Human Frontiers of Science Program [RGP54/2004]; European Commission [FP6-NEST-043403] FX Preparation of this manuscript was partly supported by the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO, 400.04081, 451-05-014 and 451-07-032), Human Frontiers of Science Program RGP54/2004 and European Commission (COBOL FP6-NEST-043403) grants. We are grateful to two anonymous reviewers for comments and suggestions. NR 107 TC 101 Z9 101 U1 2 U2 27 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD MAR PY 2010 VL 34 IS 4 BP 513 EP 527 DI 10.1016/j.neubiorev.2009.10.008 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 569JY UT WOS:000275593600003 PM 19857515 ER PT J AU Curry, WT Carter, BS Barker, FG AF Curry, William T., Jr. Carter, Bob S. Barker, Fred G., II TI Racial, Ethnic, and Socioeconomic Disparities in Patient Outcomes After Craniotomy for Tumor in Adult Patients in the United States, 1988-2004 SO NEUROSURGERY LA English DT Article DE Brain; Craniotomy; Health care; Meningioma; Neoplasm; Vestibular schwannoma ID QUALITY CARDIAC-SURGEONS; ACUTE MYOCARDIAL-INFARCTION; ACADEMIC REFERRAL CENTERS; HEALTH-INSURANCE PROGRAM; IN-HOSPITAL MORTALITY; BYPASS GRAFT-SURGERY; PROVIDER CASELOAD; CAROTID-ENDARTERECTOMY; SURGICAL-TREATMENT; BRAIN-TUMORS AB OBJECTIVE: Racial disparities in American health care outcomes are well documented. We investigated racial disparities in hospital mortality and adverse discharge disposition after brain tumor craniotomies performed in the United States from 1988 to 2004. We explored potential explanations for the disparities. METHODS: The data source was the Nationwide Inpatient Sample. We used multivariate ordinal logistic regression corrected for clustering by hospital and adjusted for age, sex, primary payer for care, income in postal code of residence, geographic region, admission type and source, medical comorbidity, treatment year, hospital case volume, and disease-specific factors. Random-effects pooling was also used. RESULTS: A total of 99 665 craniotomies were studied. Hospital mortality and adverse discharge disposition (any discharge other than directly home) were more likely in black patients than others for all tumor types. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for blacks were: hospital craniotomy mortality (OR, 1.64; 95% CI, 1.32-2.03; P < .001), and adverse discharge disposition (OR, 1.43; 95% CI, 1.31-1.56; P < .001). Medicaid patients had higher mortality, while private-pay patients had lower mortality. Hospital annual case volume was lower for black and Hispanic patients and for those with Medicaid as the primary payer in pooled analyses, whereas patients with private insurance received care at higher-volume hospitals. Black patients generally presented with higher disease severity, including more emergency or urgent admissions (OR, 1.71; 95% CI, 1.54-1.89; P < .001); more hemiparesis and hemiplegia for primary tumors, meningiomas, and metastases (P < .04 for all); and more hydrocephalus for acoustic neuromas (P = .1). CONCLUSION: Black patients died more often or had an adverse discharge disposition after tumor craniotomies in the United States in the period studied (1988-2004). Blacks had more severe disease at presentation and were treated at lower-volume hospitals for surgery. Other socially defined patient groups also showed disparities in access and outcomes of care. C1 [Barker, Fred G., II] Massachusetts Gen Hosp, Pappas Ctr Neurooncol, Neurosurg Serv, Boston, MA 02114 USA. [Curry, William T., Jr.; Barker, Fred G., II] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Carter, Bob S.] Univ Calif San Diego, Div Neurosurg, San Diego, CA 92103 USA. RP Barker, FG (reprint author), Massachusetts Gen Hosp, Pappas Ctr Neurooncol, Neurosurg Serv, Yawkey 9E,Fruit St, Boston, MA 02114 USA. EM barker@helix.mgh.harvard.edu NR 89 TC 49 Z9 49 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 MAR PY 2010 VL 66 IS 3 BP 427 EP 437 DI 10.1227/01.NEU.0000365265.10141.8E PG 11 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 559BW UT WOS:000274795800001 PM 20124933 ER PT J AU Radwin, LE Cabral, HJ Chen, L Jennings, BM AF Radwin, Laurel E. Cabral, Howard J. Chen, Leslie Jennings, Bonnie Mowinski TI A Protocol for Capturing Daily Variability in Nursing Care SO NURSING ECONOMICS LA English DT Article ID HEALTH-SERVICES RESEARCH; PATIENT OUTCOMES; QUALITY; EXPERIENCE; HOSPITALS; MORTALITY; IMPACT; MODEL; INTERVENTIONS; ENVIRONMENT AB To meet current and future patient safety and quality requirements, traditional analyses based on data aggregated to the hospital or unit level over months or years may need to change. Nine customized databases were developed, five with patient data (e.g., age, illness severity, perceptions of nursing care quality, desired health outcomes) and four with nurse data (e.g., education, experience). These were merged to create a Patient-Nurse database. Nurse managers, clinicians, and researchers could use the protocol to conduct a more robust analysis of the relationships between nursing system characteristics and patient care processes and outcomes. The protocol described here could be used by nurse managers, clinicians, and researchers to better understand temporal phenomena and patient level data. Through information derived from applying this protocol, staffing decisions can be made to assure the right mix of nurses is available, not just the right number. C1 [Radwin, Laurel E.] Massachusetts Gen Hosp, Inst Patient Care, Boston, MA 02114 USA. [Cabral, Howard J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Chen, Leslie] Takeda Oncol Co, Millennium, Osaka, Japan. [Jennings, Bonnie Mowinski] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Jennings, Bonnie Mowinski] Univ Washington, Seattle, WA 98195 USA. RP Radwin, LE (reprint author), Massachusetts Gen Hosp, Inst Patient Care, Boston, MA 02114 USA. FU AHRQ HHS [HS K08 11625] NR 50 TC 3 Z9 3 U1 1 U2 3 PU JANNETTI PUBLICATIONS, INC PI PITMAN PA EAST HOLLY AVENUE, BOX 56, PITMAN, NJ 08071-0056 USA SN 0746-1739 J9 NURS ECON JI Nurs. Econ. PD MAR-APR PY 2010 VL 28 IS 2 BP 95 EP 105 PG 11 WC Nursing SC Nursing GA 584RY UT WOS:000276771500004 PM 20446380 ER PT J AU Asch, DA Nicholson, S Srinivas, S Herrin, J Epstein, AJ AF Asch, David A. Nicholson, Sean Srinivas, Sindhu Herrin, Jeph Epstein, Andrew J. TI Evaluating Obstetrical Residency Programs Using Patient Outcomes EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. Univ Penn, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. Cornell Univ, Ithaca, NY USA. Yale Univ, New Haven, CT USA. RP Asch, DA (reprint author), Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD MAR PY 2010 VL 65 IS 3 BP 152 EP 153 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 575UQ UT WOS:000276095000005 ER PT J AU Rodriguez, MI Jensen, JT Darney, PD Little, SE Caughey, AB AF Rodriguez, Maria Isabel Jensen, Jeffrey T. Darney, Philip D. Little, Sarah E. Caughey, Aaron B. TI The Financial Effects of Expanding Postpartum Contraception for New Immigrants SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID FAMILY-PLANNING-SERVICES; UNINTENDED PREGNANCY; EMERGENCY MEDICAID; COST; CARE; CALIFORNIA; PROGRAM; SAVINGS AB OBJECTIVE: To estimate the costs of expanding Emergency Medicaid coverage to include postpartum contraception. METHODS: A decision-analytic model was developed using three perspectives: the hospital, state Medicaid programs, and society. Our primary outcome was future reproductive health care costs due to pregnancy in the next 5 years. A Markov structure was use to analyze the probability of pregnancy over a 5-year time period. Model inputs were retrieved from the existing literature and local hospital and Medicaid data related to reimbursements. One-way and multiway sensitivity analyses were conducted. A Monte Carlo simulation was performed to incorporate uncertainty from all of the model inputs simultaneously. RESULTS: Over a 5-year period, provision of contraception would save society $17,792 per woman in future pregnancy costs and incur a loss of $367 for hospitals. In states in which 49% of immigrants remain in the area for 5 years, such a program would save state Medicaid $108 per woman. CONCLUSION: Under federal regulations, new immigrants are restricted to acute, hospital-based care only. Failure to provide the option of contraception postpartum results in increased costs for society and states with long-term immigrants. (Obstet Gynecol 2010;115:552-8) C1 Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Clin & Policy Perinatal Res, San Francisco, CA USA. Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Sci, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Rodriguez, MI (reprint author), San Francisco Gen Hosp, 1001 Potrero Ave,6D15, San Francisco, CA 94110 USA. EM rodriguezmi@obgyn.ucsf.edu OI Jensen, Jeffrey/0000-0002-4733-1224 FU Robert Wood Johnson Foundation [RWJF-61535] FX Funded by an anonymous donor. Dr. Caughey is supported in part by a grant under the Robert Wood Johnson Foundation Physician Faculty Scholars Program (RWJF-61535). NR 26 TC 7 Z9 7 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 MAR PY 2010 VL 115 IS 3 BP 552 EP 558 DI 10.1097/AOG.0b013e3181d06f96 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 563LA UT WOS:000275132300011 PM 20177286 ER PT J AU Richter, HE Burgio, KL Brubaker, L Nygaard, IE Ye, W Weidner, A Bradley, CS Handa, VL Borello-France, D Goode, PS Zyczynski, H Lukacz, ES Schaffer, J Barber, M Meikle, S Spino, C AF Richter, Holly E. Burgio, Kathryn L. Brubaker, Linda Nygaard, Ingrid E. Ye, Wen Weidner, Alison Bradley, Catherine S. Handa, Victoria L. Borello-France, Diane Goode, Patricia S. Zyczynski, Halina Lukacz, Emily S. Schaffer, Joseph Barber, Matthew Meikle, Susan Spino, Cathie CA Pelvic Floor Disorders Network TI Continence Pessary Compared With Behavioral Therapy or Combined Therapy for Stress Incontinence A Randomized Controlled Trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the International-Continence-Society CY SEP 29-OCT 03, 2009 CL San Francisco, CA SP Int Continence Soc ID URINARY-INCONTINENCE; ELECTRICAL-STIMULATION; MUSCLE EXERCISE; WOMEN; MANAGEMENT; VALIDATION AB OBJECTIVE: To compare the effectiveness of a continence pessary to evidence-based behavioral therapy for stress incontinence and to assess whether combined pessary and behavioral therapy is superior to single-modality therapy. METHODS: This was a multisite, randomized clinical trial (Ambulatory Treatments for Leakage Associated with Stress Incontinence [ATLAS]) that randomly assigned 446 women with stress incontinence to pessary, behavioral therapy, or combined treatment. Primary outcome measures, at 3 months, were Patient Global Impression of Improvement and the stress incontinence subscale of the Pelvic Floor Distress Inventory. A priori, to be considered clinically superior, combination therapy had to be better than both single-modality therapies. Outcome measures were repeated at 6 and 12 months. Primary analyses used an intention-to-treat approach. RESULTS: At 3 months, scores from 40% of the pessary group and 49% of the behavioral group were "much better" or "very much better" on the Patient Global Impression of Improvement (P=.10). Compared with the pessary group, more women in the behavioral group reported having no bothersome incontinence symptoms (49% compared with 33%, P=.006) and treatment satisfaction (75% compared with 63%, P=.02). Combination therapy was significantly better than pessary as shown on the Patient Global Impression of Improvement (53%, P=.02) and Pelvic Floor Distress Inventory (44%, P=.05) but not better than behavioral therapy; it was therefore not superior to single-modality therapy. Group differences were not sustained to 12 months on any measure, and patient satisfaction remained above 50% for all treatment groups. CONCLUSION: Behavioral therapy resulted in greater patient satisfaction and fewer bothersome incontinence symptoms than pessary at 3 months, but differences did not persist to 12 months. Combination therapy was not superior to single-modality therapy. C1 [Richter, Holly E.] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35233 USA. Birmingham VA Med Ctr, Birmingham, AL USA. Loyola Univ, Maywood, IL 60153 USA. Univ Utah, Salt Lake City, UT USA. Univ Michigan, Ann Arbor, MI 48109 USA. Duke Univ, Durham, NC USA. Univ Iowa, Iowa City, IA USA. Johns Hopkins Sch Med, Baltimore, MD USA. Duquesne Univ, Pittsburgh, PA 15219 USA. Magee Womens Hosp, Pittsburgh, PA USA. Univ Calif San Diego, San Diego, CA 92103 USA. Univ Texas SW, Dallas, TX USA. Cleveland Clin, Cleveland, OH 44106 USA. NIH, Bethesda, MD 20892 USA. RP Richter, HE (reprint author), Univ Alabama, Dept Obstet & Gynecol, 618 20th St,NHB 219, Birmingham, AL 35233 USA. EM hrichter@uabmc.edu FU NCATS NIH HHS [UL1 TR000005]; NICHD NIH HHS [U10 HD41261, U01 HD041249, U01 HD041249-09, U10 HD 41250, U10 HD041248, U10 HD041250, U10 HD041261, U10 HD041263, U10 HD041267, U10 HD041268, U10 HD054136, U10 HD054214, U10 HD054215, U10 HD054241, U10 HD41248, U10 HD41249, U10 HD41263, U10 HD41267, U10 HD41268, U10 HD54136, U10 HD54214, U10 HD54215, U10 HD54241, UG1 HD054214] NR 23 TC 40 Z9 42 U1 0 U2 4 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 MAR PY 2010 VL 115 IS 3 BP 609 EP 617 DI 10.1097/AOG.0b013e3181d055d4 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 563LA UT WOS:000275132300019 PM 20177294 ER PT J AU Richardson, PG Laubach, J Mitsiades, C Schlossman, RL Doss, D Colson, K Mckenney, ML Noonan, K Warren, DL Ghobrial, IM Munshi, NC Anderson, K AF Richardson, Paul G. Laubach, Jacob Mitsiades, Constantine Schlossman, Robert L. Doss, Deborah Colson, Kathleen Mckenney, Mary L. Noonan, Kimberly Warren, Diane L. Ghobrial, Irene M. Munshi, Nikhil C. Anderson, Kenneth TI Tailoring Treatment for Multiple Myeloma Patients With Relapsed and Refractory Disease SO ONCOLOGY-NEW YORK LA English DT Article ID LENALIDOMIDE PLUS DEXAMETHASONE; EXPANDED ACCESS PROGRAM; PROTEASOME INHIBITOR; RENAL-FAILURE; APEX TRIAL; PHASE-III; IN-VIVO; BORTEZOMIB; SAFETY; EFFICACY AB Responses to treatment of relapsed and refractory multiple myeloma are characteristically short, and median survival is as brief as 6 months. Although prognostic factors in the context of relapsed and refractory disease require further characterization, high-risk patients include those with certain cytogenetic abnormalities, high beta 2-microglobulin, and low serum albumin. The development of novel therapies targeting disease biology and tumor microenvironment has significantly improved the outlook for patients with relapsed and refractory disease, with bortezomib (Velcade), a first-in-class proteasome inhibitor, and the immunomodulatory agents thalidomide (Thalomid) and lenalidomide (Revlimid) constituting "backbone" agents in this setting. More recent approaches for treating relapsed and refractory myeloma that are recommended by the National Comprehensive Cancer Network include single-agent bortezomib, single-agent lenalidomide, bortezomib/dexamethasone, bortezomib plus pegylated liposomal doxorubicin, lenalidomide/dexamethasone, and lenalidomide/bortezomib/dexamethasone. Individualized treatment of progressive myeloma should take into account the time to progression and/or the type of prior therapy. Additional clinical challenges discussed in this article are renal dysfunction, extramedullary disease, and advanced bone disease. Finally, participation in clinical trials is especially encouraged in this patient population. C1 [Richardson, Paul G.; Laubach, Jacob; Schlossman, Robert L.; Ghobrial, Irene M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Richardson, Paul G.; Munshi, Nikhil C.; Anderson, Kenneth] Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma, Boston, MA 02115 USA. RP Richardson, PG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,Dana 1B02, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu FU Millennium Pharmaceuticals, Inc. FX Supported by an educational grant from Millennium Pharmaceuticals, Inc. NR 60 TC 11 Z9 11 U1 0 U2 0 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 MAR PY 2010 VL 24 IS 3 SU 2 BP 22 EP 29 PG 8 WC Oncology SC Oncology GA 800PG UT WOS:000293374800004 PM 20518367 ER PT J AU Nallasamy, N Mehta, M Salas, AH Fay, A AF Nallasamy, Nambi Mehta, Manisha Salas, Adriana Hernandez Fay, Aaron TI Statistics for Oculoplastic Surgeons SO OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Editorial Material ID ORBITAL FRACTURES; ORBITOPATHY; EXPERIENCE C1 [Mehta, Manisha; Salas, Adriana Hernandez; Fay, Aaron] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Nallasamy, Nambi] Harvard Mit Div Hlth Sci & Technol, Boston, MA USA. [Mehta, Manisha] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Fay, A (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM aaron_fay@meei.harvard.edu NR 21 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0740-9303 J9 OPHTHAL PLAST RECONS JI Ophthalmic Plast. Reconstr. Surg. PD MAR-APR PY 2010 VL 26 IS 2 BP 71 EP 75 DI 10.1097/IOP.0b013e3181b8e3d4 PG 5 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 576FI UT WOS:000276129300001 PM 20305501 ER PT J AU Kacmaz, RO Kempen, JH Newcomb, C Daniel, E Gangaputra, S Nussenblatt, RB Rosenbaum, JT Suhler, EB Thorne, JE Jabs, DA Levy-Clarke, GA Foster, CS AF Kacmaz, R. Oktay Kempen, John H. Newcomb, Craig Daniel, Ebenezer Gangaputra, Sapna Nussenblatt, Robert B. Rosenbaum, James T. Suhler, Eric B. Thorne, Jennifer E. Jabs, Douglas A. Levy-Clarke, Grace A. Foster, C. Stephen TI Cyclosporine for Ocular Inflammatory Diseases SO OPHTHALMOLOGY LA English DT Article ID LOW-DOSE CYCLOSPORINE; TERM-FOLLOW-UP; BIRDSHOT RETINOCHOROIDOPATHY; IMMUNOMODULATORY THERAPY; ENDOGENOUS UVEITIS; BEHCETS-SYNDROME; MASKED TRIAL; CYCLOPHOSPHAMIDE; CHOROIDITIS; ARTHRITIS AB Purpose: To evaluate the clinical outcomes of cyclosporine treatment for noninfectious ocular inflammation. Design: Retrospective cohort study. Participants: A total of 373 patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to use cyclosporine as a single noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007 inclusive. Methods: Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage of cyclosporine and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers. Main Outcome Measures: Control of inflammation, sustained control after reducing corticosteroid dosages, and discontinuation of therapy because of toxicity. Results: Of the 373 patients (681 eyes) initiating cyclosporine monotherapy, 33.4% by 6 months and 51.9% by 1 year gained sustained, complete control of inflammation over at least 2 visits spanning at least 28 days. Approximately 25% more improved to a level of slight inflammatory activity by each of these time points. Corticosteroid-sparing success (completely controlled inflammation for at least 28 days with prednisone <= 10 mg/day) was achieved by 22.1% by 6 months and 36.1% within 1 year. Toxicity led to discontinuation of therapy within 1 year by 10.7% of the population. Patients aged more than 55 years were more than 3-fold more likely to discontinue therapy because of toxicity than patients aged 18 to 39 years. Doses of 151 to 250 mg/day tended to be more successful than lower doses and were not associated with a higher discontinuation for toxicity rate; higher doses did not seem to offer a therapeutic advantage. Conclusions: Cyclosporine, with corticosteroid therapy as indicated, was modestly effective for controlling ocular inflammation. Our data support a preference for cyclosporine adult dosing between 151 and 250 mg/day. Although cyclosporine was tolerated by the majority of patients, toxicity was more frequent with increasing age; alternative agents may be preferred for patients aged more than 55 years. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2010; 117: 576-584 (C) 2010 by the American Academy of Ophthalmology. C1 [Kacmaz, R. Oktay; Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Kacmaz, R. Oktay; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Kempen, John H.; Newcomb, Craig] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Ctr Prevent Ophthalmol & Biostat, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Daniel, Ebenezer; Gangaputra, Sapna; Thorne, Jennifer E.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gangaputra, Sapna] Univ Wisconsin, Dept Ophthalmol, Fundus Photog Reading Ctr, Madison, WI USA. [Nussenblatt, Robert B.; Levy-Clarke, Grace A.] NEI, Immunol Lab, Bethesda, MD USA. [Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Internal Med, Dept Ophthalmol, Portland, OR USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Internal Med, Div Rheumatol, Portland, OR USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Kempen, JH (reprint author), Univ Penn, Ctr Prevent Ophthalmol & Biostat, Dept Ophthalmol, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Daniel, Ebenezer/0000-0002-2027-2316 FU National Eye Institute [EY014943]; Research to Prevent Blindness; Paul and Evanina Mackall Foundation; RPB James S. Adams Special Scholar Award; National Eye Institute; Department of Veterans' Affairs FX Supported primarily by National Eye Institute Grant EY014943 (Dr. Kempen). Additional support was provided by Research to Prevent Blindness and the Paul and Evanina Mackall Foundation. Dr. Kempen is an RPB James S. Adams Special Scholar Award recipient. Drs. Jabs and Rosenbaum are Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr. Thorne is an RPB Harrington Special Scholar Award recipient. Dr. Levy-Clarke was previously supported by and Dr. Nussenblatt continues to be supported by intramural funds of the National Eye Institute. Dr. Suhler was supported in part by the Department of Veterans' Affairs. NR 41 TC 80 Z9 82 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2010 VL 117 IS 3 BP 576 EP 584 DI 10.1016/j.ophtha.2009.08.010 PG 9 WC Ophthalmology SC Ophthalmology GA 563BQ UT WOS:000275101000025 PM 20031223 ER PT J AU Lin, HW Vakharia, KT Benjamin, PK Leonard, DS AF Lin, Harrison W. Vakharia, Kalpesh T. Benjamin, Patrice K. Leonard, David S. TI A convenient, practical adapter for bronchotracheoscopy through a tracheostomy tube in a ventilator-dependent patient SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article ID FIBEROPTIC BRONCHOSCOPY; MECHANICAL VENTILATION; LUNG MODEL C1 [Lin, Harrison W.; Vakharia, Kalpesh T.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Lin, Harrison W.; Vakharia, Kalpesh T.; Leonard, David S.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Leonard, David S.] Childrens Hosp, Dept Otolaryngol & Commun Enhancement, Boston, MA 02115 USA. [Benjamin, Patrice K.] Childrens Hosp, Div Crit Care Med, Boston, MA 02115 USA. RP Lin, HW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. EM harrison_lin@meei.harvard.edu FU Royal College of Surgeons Ireland; Ethicon Foundation FX David S. Leonard, supported by grants from the Royal College of Surgeons Ireland and the Ethicon Foundation. NR 5 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD MAR PY 2010 VL 142 IS 3 BP 446 EP 448 DI 10.1016/j.otohns.2009.10.028 PG 3 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 582DA UT WOS:000276574600029 PM 20172398 ER PT J AU Ter-Minassian, M Wang, ZX Asomaning, K Wu, M Liu, CY Paulus, J Liu, G Bradbury, P Su, L Frauenhoffer, C Hooshmand, SM Silver, J De Vivo, I Lin, XH Christiani, DC Kulke, MH AF Ter-Minassian, Monica Wang, Zhaoxi Asomaning, Kofi Wu, Michael Liu, Chen-Yu Paulus, Jessica Liu, Geoffrey Bradbury, Penny Su, Li Frauenhoffer, Christine Hooshmand, Susanne M. Silver, Jamie De Vivo, Immaculata Lin, Xihong Christiani, David C. Kulke, Matthew H. TI A Large-scale SNP Evaluation Reveals an Association of a TSC2 SNP with Sporadic Neuroendocrine Tumor Risk SO PANCREAS LA English DT Meeting Abstract C1 [Ter-Minassian, Monica; Wang, Zhaoxi; Asomaning, Kofi; Wu, Michael; Liu, Chen-Yu; Paulus, Jessica; Liu, Geoffrey; Bradbury, Penny; Su, Li; Frauenhoffer, Christine; Hooshmand, Susanne M.; Silver, Jamie; De Vivo, Immaculata; Lin, Xihong; Christiani, David C.; Kulke, Matthew H.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth,Dana Farber Canc Inst, EOME Program,Dept Biostat,Dept Med Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2010 VL 39 IS 2 BP 281 EP 281 DI 10.1097/01.mpa.0000363948.22305.96 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 561WE UT WOS:000275010000072 ER PT J AU Yao, JC Lombard-Bohas, C Baudin, E Kvols, LK Rougier, P Ruszniewski, P Hoosen, S Peter, JS Haas, T Lebwohl, D Van Cutsem, E Kulke, M Hobday, TJ O'Dorisio, TM Shah, MH Cadiot, G Luppi, G Posey, JA Wiedenmann, B AF Yao, James C. Lombard-Bohas, Catherine Baudin, Eric Kvols, Larry K. Rougier, Philippe Ruszniewski, Philippe Hoosen, Sakina Peter, Jessica St. Haas, Tomas Lebwohl, David Van Cutsem, Eric Kulke, Matthew Hobday, Timothy J. O'Dorisio, Thomas M. Shah, Manisha H. Cadiot, Guillaume Luppi, Gabriele Posey, James A. Wiedenmann, Bertram CA RADIANT-1 Study Grp TI Daily Oral Everolimus Activity in Patients with Metastatic Pancreatic Neuroendocrine Tumors after Failure of Cytotoxic Chemotherapy: A Phase II Trial SO PANCREAS LA English DT Meeting Abstract C1 [Yao, James C.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lombard-Bohas, Catherine] Hosp Civils Lyon, Lyon, France. [Baudin, Eric] Inst Gustave Roussy, Villejuif, France. [Kvols, Larry K.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Rougier, Philippe] Hop Ambroise Pare, Boulogne, Billancourt, France. [Ruszniewski, Philippe] Hop Beaujon, Clichy, France. [Hoosen, Sakina; Peter, Jessica St.; Lebwohl, David] Novartis Oncol, Florham Pk, NJ USA. [Haas, Tomas] Novartis Pharma AG, Basel, Switzerland. [Van Cutsem, Eric] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Kulke, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. [Hobday, Timothy J.] Mayo Clin, Rochester, MN USA. [O'Dorisio, Thomas M.] Univ Iowa, Iowa City, IA USA. [Shah, Manisha H.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Cadiot, Guillaume] Hop Robert Debre, Reims, France. [Luppi, Gabriele] Univ Modena, Azienda Osped, I-41100 Modena, Italy. [Posey, James A.] Univ Alabama, Birmingham, AL USA. [Wiedenmann, Bertram] Univ Berlin, Charite, Campus Virchow Klinikum, Berlin, Germany. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD MAR PY 2010 VL 39 IS 2 BP 282 EP 282 DI 10.1097/01.mpa.0000363952.52799.a1 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 561WE UT WOS:000275010000076 ER PT J AU Mullins, RJ Clark, S Camargo, CA AF Mullins, Raymond J. Clark, Sunday Camargo, Carlos A., Jr. TI Regional variation in infant hypoallergenic formula prescriptions in Australia SO PEDIATRIC ALLERGY AND IMMUNOLOGY LA English DT Article DE epidemiology; vitamin D; food allergy; latitude; longitude; infant formula ID VITAMIN-D INSUFFICIENCY; FOOD ALLERGY; D DEFICIENCY; ULTRAVIOLET-RADIATION; INFECTIOUS-DISEASES; MULTIPLE-SCLEROSIS; SOUTHERN TASMANIA; CHILDHOOD ASTHMA; INNATE IMMUNITY; UNITED-STATES AB There is little information on the regional distribution of food allergy in Australia. We examined the influence of latitude (a marker of sunlight/vitamin D status) on food allergy, as measured by 2007 infant hypoallergenic formula (IHF) prescription rates in children ages 0-2 yrs. Data were compiled from the 52 statistical divisions in mainland Australia plus the island of Tasmania (n = 53 observations). Data from the Australian Department of Health and Aging and the Australian Bureau of Statistics were analysed by statistical division. There was significant regional variability in hypoallergenic formula prescription rates (per 100,000 population/yr), with the highest rates in southern Australia (14,406) and the lowest in the north (721), compared with a national average of 4099. Geographical factors (decreasing latitude and increasing longitude) were associated with a higher rate of IHF prescriptions, such that rates were higher in southern vs. northern regions, and in eastern compared with western regions. Controlling for longitude, physician density and markers of socioeconomic status, southern latitudes were associated with higher hypoallergenic formulae prescription rates [beta, -147.98; 95% confidence interval (CI) = -281.83 to -14.14; p = 0.03]. Controlling for latitude, physician density and markers of socioeconomic status, eastern longitudes were also associated with higher hypoallergenic formulae prescription rates (beta, 89.69; 95% CI = 2.90-176.49; p = 0.04). Among young children, hypoallergenic formula prescription rates are more common in the southern and eastern regions of Australia. These data provide support for a possible role of sun exposure/vitamin D status (amongst other potential factors) in the pathogenesis of food allergy. C1 [Mullins, Raymond J.] John James Med Ctr, Deakin, ACT 2600, Australia. [Mullins, Raymond J.] Australian Natl Univ, Sch Med, Canberra, ACT, Australia. [Mullins, Raymond J.] Univ Canberra, Fac Hlth, Canberra, ACT 2601, Australia. [Clark, Sunday] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Dept Med, Boston, MA USA. RP Mullins, RJ (reprint author), John James Med Ctr, Suite 1,175 Strickland Crescent, Deakin, ACT 2600, Australia. EM rmullins@allergycapital.com.au RI Osborne, Nicholas/N-4915-2015; OI Osborne, Nicholas/0000-0002-6700-2284; Mullins, Raymond/0000-0002-0267-1591 NR 56 TC 25 Z9 25 U1 0 U2 10 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0905-6157 J9 PEDIAT ALLERG IMM-UK JI Pediatr. Allergy Immunol. PD MAR PY 2010 VL 21 IS 2 BP E413 EP E420 DI 10.1111/j.1399-3038.2009.00962.x PN 2 PG 8 WC Allergy; Immunology; Pediatrics SC Allergy; Immunology; Pediatrics GA 703QX UT WOS:000285997200008 PM 19943914 ER PT J AU Isong, IA Zuckerman, KE Rao, SR Kuhlthau, KA Winickoff, JP Perrin, JM AF Isong, Inyang A. Zuckerman, Katharine E. Rao, Sowmya R. Kuhlthau, Karen A. Winickoff, Jonathan P. Perrin, James M. TI Association Between Parents' and Children's Use of Oral Health Services SO PEDIATRICS LA English DT Article DE children; parents; oral health services; dental use; NHIS ID DENTAL-CARE; INSURANCE-COVERAGE; DISPARITIES; PATTERNS; VISITS AB OBJECTIVE: Several parental factors influence children's use of oral health services. Some localized studies have shown that children's dental use patterns correlate positively with those of their parents. The objective of this study was to investigate associations between parents' and children's oral health-seeking behaviors among a representative sample of US children. METHODS: We used the 2007 National Health Interview Survey to analyze a sample of children aged 2 to 17 years, matched with 1 parent. Using logistic regression, we examined associations between parents' and children's use of dental services and deferred dental care because of cost. RESULTS: The sample included 6107 child-parent pairs. Overall, 77% of children and 64% of parents had a dental visit in the previous 12 months. Adjusting for sociodemographic and use variables, children were more likely to have a dental visit when their parents also had a dental visit (adjusted odds ratio: 3.36 [95% confidence interval: 2.71-4.18]), compared with children of parents who did not have a dental visit. In addition, compared with children of parents who did not defer seeking dental care, children of parents who deferred their dental care because of cost were more likely to have care deferred because of cost as well (adjusted odds ratio: 12.47 [95% confidence interval: 9.09-17.11]). CONCLUSIONS: Parental oral health-seeking behaviors for themselves may have an important effect on oral health-seeking behaviors on behalf of their children, regardless of the child's insurance status. Comprehensive strategies to eliminate barriers that target parents and not just children may help to address children's underuse of oral health services. Pediatrics 2010;125:502-508 C1 [Isong, Inyang A.; Zuckerman, Katharine E.; Kuhlthau, Karen A.; Winickoff, Jonathan P.; Perrin, James M.] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, Harvard Pediat Hlth Serv Res Program, Boston, MA 02114 USA. [Rao, Sowmya R.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Isong, IA (reprint author), Massachusetts Gen Hosp Children, Ctr Child & Adolescent Hlth Policy, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM iisong@partners.org FU Health Resources and Services Administration [T32 HP10018]; Department of Health and Human Services FX Dr Isong's work is supported by a National Research Service Award (T32 HP10018) from the Health Resources and Services Administration, Department of Health and Human Services. We thank Cecilia Vieira and Dr Kenneth Soyemi for support and contributions to the study design and analyses. NR 31 TC 15 Z9 15 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAR PY 2010 VL 125 IS 3 BP 502 EP 508 DI 10.1542/peds.2009-1417 PG 7 WC Pediatrics SC Pediatrics GA 573WJ UT WOS:000275945700013 PM 20123775 ER PT J AU Winickoff, JP Healey, EA Regan, S Park, ER Cole, C Friebely, J Rigotti, NA AF Winickoff, Jonathan P. Healey, Erica A. Regan, Susan Park, Elyse R. Cole, Clare Friebely, Joan Rigotti, Nancy A. TI Using the Postpartum Hospital Stay to Address Mothers' and Fathers' Smoking: The NEWS Study SO PEDIATRICS LA English DT Article DE smoking; tobacco; pediatrics; postpartum; parent; smoking cessation; tobacco control; quitline; telephone counseling ID CESSATION INTERVENTIONS; UNITED-STATES; SMOKERS; PREGNANCY; TRENDS; WOMEN; RISK; OPPORTUNITY; NICOTINE; BEHAVIOR AB OBJECTIVE: The objective of this study was to test the feasibility and acceptability of introducing an intervention to address mothers' and fathers' smoking during the postpartum hospitalization. METHODS: During a 14-month period (February 2005 to April 2006), we assessed the smoking status of both parents of all newborns who were delivered at a hospital child birth center. Parents who were current smokers (1 cigarette, even a puff, in past 30 days) or recent quitters (smoked since 1 month before conception) were eligible for the study. Parents were assigned to intervention or usual care control condition on the basis of day of study enrollment. Smoking outcomes were assessed at 3 months by telephone survey and cotinine confirmation; quitline use was assessed at 3 months by using quitline database. RESULTS: A total of 101 (64%) of 159 eligible parents enrolled in the study (n = 53 control subject, n = 48 intervention), including 72 (71%) current smokers and 29 (29%) recent quitters. All parents in the intervention group received the in-hospital counseling session, 94% had a fax sent to a provider, and 36 (75%) accepted quitline enrollment. In an intention-to-treat analysis that included both current smokers and recent quitters, self-reported 7-day abstinence decreased from 31% to 25% among intervention parents versus 38% to 23% among control subjects (effect size 9.4%; nonsignificant). Among current smokers at baseline who were reached at follow-up (n = 36), self-reported 24-hour quit attempts were higher in the intervention group versus control group (64% vs 18%; P = .005), whereas the cotinine-confirmed 7-day abstinence rates at follow-up were 9% in the intervention group and 3% in the control group (nonsignificant). CONCLUSIONS: Enrolling mothers and fathers into tobacco treatment services during the immediate postpartum hospital stay is feasible and seems to stimulate quit attempts. The birth of an infant presents a teachable moment to reach both parents and to provide cessation assistance. Pediatrics 2010;125:518-525 C1 [Winickoff, Jonathan P.; Healey, Erica A.; Friebely, Joan] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. [Winickoff, Jonathan P.; Healey, Erica A.; Regan, Susan; Park, Elyse R.; Friebely, Joan; Rigotti, Nancy A.] Massachusetts Gen Hosp, Div Gen Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Cole, Clare] Massachusetts Gen Hosp, Obstetr Nursing Dept, Boston, MA 02114 USA. [Winickoff, Jonathan P.; Regan, Susan; Park, Elyse R.; Friebely, Joan; Rigotti, Nancy A.] Harvard Univ, Sch Med, Boston, MA USA. RP Winickoff, JP (reprint author), Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Policy, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM jwinickoff@partners.org FU Robert Wood Johnson Foundation [RWJF 051803]; Flight Attendant Medical Research Institute [FAMRI 024032, K24 HL0440]; NCI [K07 CA100213 A 01]; American Academy of Pediatrics Julius B. Richmond Center of Excellence FX Dr Winickoff was supported primarily by a grant from the Robert Wood Johnson Foundation (RWJF 051803). Additional effort support for Dr Winickoff was provided by the Flight Attendant Medical Research Institute (FAMRI 024032) and NCI (K07 CA100213 A 01) and the American Academy of Pediatrics Julius B. Richmond Center of Excellence also supported by FAMRI. Dr Rigotti was supported by K24 HL0440. NR 36 TC 35 Z9 35 U1 0 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAR PY 2010 VL 125 IS 3 BP 518 EP 525 DI 10.1542/peds.2009-0356 PG 8 WC Pediatrics SC Pediatrics GA 573WJ UT WOS:000275945700015 PM 20123776 ER PT J AU Johnson, ES Weinstein, JR Thorp, ML Platt, RW Petrik, AF Yang, XH Anderson, S Smith, DH AF Johnson, Eric S. Weinstein, Jessica R. Thorp, Micah L. Platt, Robert W. Petrik, Amanda F. Yang, Xiuhai Anderson, Sharon Smith, David H. TI Predicting the risk of hyperkalemia in patients with chronic kidney disease starting lisinopril SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE hyperkalemia; chronic kidney disease; ACE-inhibitors; risk score; cohort study; adverse effects ID CONVERTING ENZYME-INHIBITORS; RENIN-ANGIOTENSIN SYSTEM; PROGNOSTIC RESEARCH; THERAPY; MODEL; GUIDELINES AB Purpose Angiotensin-converting enzyme (ACE) inhibitors are recommended for patients with chronic kidney disease (CKD) because they slow disease progression. But physicians' concerns about the risk of hyperkalemia (elevated serum potassium level), a potentially fatal adverse effect, may limit optimal management with ACE-inhibitors. We synthesized known predictors of hyperkalemia into a prognostic risk score to predict the risk of hyperkalemia. Methods We assembled a retrospective cohort of adult patients with possible CKD (at least one estimated glomerular filtration rate (eGFR) value less than 60 ml/min/1.73 m(2)) who started an ACE-inhibitor (i.e., incident users) between 1998 and 2006 at a health maintenance organization. We followed patients for hyperkalemia: (1) potassium value >5.5 mmol/L; or (2) diagnosis code for hyperkalemia. Cox regression synthesized a priori predictors recorded in the electronic medical record into a risk score. Results We followed 5171 patients and 145 experienced hyperkalemia, a 90-day risk of 2.8%. Predictors included: age, eGFR, diabetes, heart failure, potassium supplements, potassium-sparing diuretics, and a high dose for the ACE-inhibitor (lisinopril). The risk score separated high-risk patients (top quintile, observed risk of 6.9%) from low-risk patients (bottom quintile, observed risk of 0.7%). Predicted and observed risks agreed within 1% for each quintile. The risk increased gradually in relation to declining eGFR with no apparent threshold for contraindicating ACE-inhibitors. Conclusions The risk score separated high-risk patients (who may need more intensive laboratory monitoring) from low-risk patients. The risk score should be validated in other populations before it is ready for use in clinical practice. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Johnson, Eric S.; Petrik, Amanda F.; Yang, Xiuhai; Smith, David H.] Kaiser Permanente NW, Ctr Hlth Res, Portland, OR 97227 USA. [Weinstein, Jessica R.; Anderson, Sharon] Oregon Hlth & Sci Univ, Dept Med, Div Nephrol & Hypertens, Portland, OR 97201 USA. [Thorp, Micah L.] Kaiser Permanente NW, Dept Nephrol, Portland, OR 97227 USA. [Platt, Robert W.] McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ, Canada. [Anderson, Sharon] Portland VA Med Ctr, Portland, OR USA. RP Johnson, ES (reprint author), Kaiser Permanente NW, Ctr Hlth Res, 3800 N Interstate Ave, Portland, OR 97227 USA. EM Eric.S.Johnson@kpchr.org RI Platt, Robert/G-5847-2012; OI Platt, Robert/0000-0002-5981-8443 FU Oregon Clinical and Translational Research Institute (OCTRI) [UL1 RR024140]; National Center for Research Resources (NCRR); National Institutes of Health (NIH) FX This study and manuscript were sponsored by the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NI,H), and NIH Roadmap for Medical Research. NR 21 TC 16 Z9 16 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD MAR PY 2010 VL 19 IS 3 BP 266 EP 272 DI 10.1002/pds.1923 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 570QT UT WOS:000275693700007 PM 20112435 ER PT J AU Girardi, P Serafini, G Pompili, M Innamorati, M Tatarelli, R Baldessarini, RJ AF Girardi, P. Serafini, G. Pompili, M. Innamorati, M. Tatarelli, R. Baldessarini, R. J. TI Prospective, Open Study of Long-Acting Injected Risperidone versus Oral Antipsychotics in 88 Chronically Psychotic Patients SO PHARMACOPSYCHIATRY LA English DT Article ID STABLE PATIENTS; SCHIZOAFFECTIVE DISORDER; OPEN-LABEL; FLUPHENAZINE DECANOATE; COMPARATIVE EFFICACY; RESOURCE UTILIZATION; CLINICAL-PRACTICE; SCHIZOPHRENIA; SAFETY; DRUGS AB Introduction: A long-acting, injected, carbohydrate-microsphere preparation of risperidone (RLAI; Risperdal Consta (R)) is reported to be safe and effective in chronic psychotic illnesses but, as its long-term and comparative efficacy remain unclear, this study compared clinical status during oral antipsychotic treatment versus conversion to RLAI. Methods: Psychotic patients (n = 88; initial BPRS = 93 +/- 5) were treated for 6 months with clinically chosen oral medication and then converted to biweekly RLAI for the first 6 months (6-6 months matched mirror comparison) and then for another 18 months. Clinical status in the two treatment periods and in the 18 months of follow-up was compared with measures including BPRS improvement (primary outcome), CGI variants and SF-36 ratings. Results: RLAI (at a mean dose of 47 mg/2 weeks at six and up to 23.1 +/- 3.3 months) was associated with major improvements in all outcome measures (p < 0.001). Initial BPRS scores fell by an average of 50% within six months; hospitalizations declined from 19.8% to 0%, and rates of adverse events were reduced by 2.5- to 7.4-fold. Such benefits were sustained during 18 months of follow-up with RLAI-treatment. Conclusions: The findings are limited by the lack of a parallel control treatment, such as with oral risperidone or another antipsychotic, lack of blinded assessments, and a moderate number of subjects. Nevertheless, the findings add to indications that RLAI can be an effective and well-tolerated treatment-option for chronically psychotic patients. C1 [Girardi, P.; Serafini, G.; Pompili, M.; Tatarelli, R.] Univ Roma La Sapienza, Dept Psychiat, St Andrea Hosp, Rome, Italy. [Pompili, M.; Baldessarini, R. J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, McLean Div, Boston, MA USA. [Innamorati, M.] Univ Europea Roma, Dept Psychol, Rome, Italy. RP Serafini, G (reprint author), Univ Rome, Dept Psychiat, St Andrea Hosp, 1037 Via Grottarossa, I-00189 Rome, Italy. EM gianluca.serafini@uniroma1.it RI Innamorati, Marco/H-8877-2013; OI Innamorati, Marco/0000-0003-1389-2290; Tatarelli, Roberto/0000-0003-4396-2632; Pompili, Maurizio/0000-0003-1886-4977 FU Bruce J. Anderson Foundation; McLean Private Donors Psychopharmacology Research Fund FX Support by a grant from the Bruce J. Anderson Foundation and the McLean Private Donors Psychopharmacology Research Fund (RJB) is gratefully acknowledged. NR 66 TC 8 Z9 8 U1 0 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0176-3679 J9 PHARMACOPSYCHIATRY JI Pharmacopsychiatry PD MAR PY 2010 VL 43 IS 2 BP 66 EP 72 DI 10.1055/s-0029-1239541 PG 7 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 570LW UT WOS:000275680800005 PM 20099224 ER PT J AU Liu, TJ Jackevicius, CA AF Liu, Tina J. Jackevicius, Cynthia A. TI Drug Interaction Between Clopidogrel and Proton Pump Inhibitors SO PHARMACOTHERAPY LA English DT Review DE proton pump inhibitor; PPI; omeprazole; clopidogrel; drug-drug interaction; thienopyridine ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PERCUTANEOUS CORONARY INTERVENTION; PEPTIC-ULCER DISEASE; EXPERT CONSENSUS DOCUMENT; ANTIPLATELET THERAPY; ELDERLY PERSONS; CARDIOVASCULAR EVENTS; PLATELET INHIBITION; CIGARETTE-SMOKING; CONTROLLED TRIAL AB Proton pump inhibitors (PPIs) have been recommended for reducing the risk of gastrointestinal bleeding associated with dual antiplatelet therapy (aspirin plus clopidogrel) However, Studies have found decreased efficacy of clopidogrel when concurrently administered with a PPI To determine the mechanism of and evidence for the potential interaction between clopidogrel and PPIs, along with the clinical implications of this drug Interaction, we reviewed recently published reports of trials that examined the interaction A MEDLINE database search (1966-September 2009) for English-language reports of clinical trials in human Subjects was performed, Supplemented by a manual search of reference lists Four trials that examined surrogate Outcomes and eight trials that examined clinical Outcomes were included in this review. Two surrogate outcome studies showed that PPIs negatively affected clopidogrel response and increased platelet aggregation, whereas the other two did not filed a significant difference between groups receiving PPIs and not receiving PPIs Three of four published clinical outcomes Studies and three of four unpublished clinical outcomes Studies available as abstracts found a significant association between PPI use and rates of acute myocardial Infarction, rehospitalization, death, or Stroke. Most of the currently available data, primarily from Observational Studies, show that some PPIs may decrease clopidogrel's antiplatelet effectiveness, with increased cardiac adverse outcomes wheel clopidogrel is combined with PPIs. Although current data do not show causation of adverse outcomes with PPI use because the available data are conflicting, this topic is still controversial Careful risk-benefit assessment IS required before prescribing PPIs for individual patients taking dual antiplatelet therapy. More evidence from randomized controlled trials is needed to clarify this drug interaction dilemma. C1 [Liu, Tina J.; Jackevicius, Cynthia A.] Western Univ Hlth Sci, Coll Pharm, Dept Pharm Practice, Pomona, CA 91766 USA. [Liu, Tina J.; Jackevicius, Cynthia A.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pharm, Los Angeles, CA USA. [Jackevicius, Cynthia A.] Univ Toronto, Toronto Gen Hosp, Dept Pharm,Dept Hlth Policy Management & Evaluat, Univ Hlth Network,Fac Med, Toronto, ON M5G 1L7, Canada. [Jackevicius, Cynthia A.] Inst Clin Evaluat Sci, Toronto, ON, Canada. RP Liu, TJ (reprint author), Western Univ Hlth Sci, Coll Pharm, Dept Pharm Practice, 309 E 2nd St, Pomona, CA 91766 USA. NR 64 TC 12 Z9 12 U1 0 U2 4 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 MAR PY 2010 VL 30 IS 3 BP 275 EP 289 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 566FT UT WOS:000275356200008 PM 20180611 ER PT J AU La Fountaine, MF Wecht, JM Spungen, AM Bauman, WA AF La Fountaine, M. F. Wecht, J. M. Spungen, A. M. Bauman, W. A. TI Intra-inter visit reproducibility of short-term linear and nonlinear measurement of heart rate variability in tetraplegia and neurologically intact controls SO PHYSIOLOGICAL MEASUREMENT LA English DT Article DE tetraplegia; heart rate variability; entropy; reproducibility; reliability; short-term recordings ID SPINAL-CORD-INJURY; CARDIOVASCULAR CONTROL; ATRIAL-FIBRILLATION; SPECTRAL-ANALYSIS; RELIABILITY; COMPLEXITY; DYNAMICS; AGE; RECORDINGS; STANDARDS AB Heart rate variability (HRV) from the frequency domain and three calculations of entropy (En), approximate (ApEn), sample (SampEn) and Lempel-Ziv (LZEn), were assessed for intra- and inter-visit reproducibility from short-term recordings in persons with tetraplegia and neurologically intact controls. The intraclass correlation coefficient (ICC) was calculated for multiple comparisons to determine the reproducibility in both groups during a 4h visit and across three visits. By ICC in both groups, ApEn, SampEn and LZEn possessed excellent intra- (>= 0.87) and inter-visit reproducibility (>= 0.90). In contrast, frequency domain measures were collectively less concise. In general on intra- and inter-visit comparisons for both groups, high frequency (HF) measures were more reliable than low frequency (LF). In control subjects relative to other units of expression, normalized units (nu) of LF had the best intra- visit reliability across all comparisons. This was not the case on inter-visit comparisons where absolute (>= 0.74) and natural log (ln) (>= 0.66) representations of LF were more reliable. In the group with tetraplegia, LFln was the most reliable for comparisons up to or including 180 min (>= 0.60) and two visits (>= 0.63). Thus, calculations of En and HF HRV appear to be more reliable than LF HRV and less confounded by small sample sizes. C1 [La Fountaine, M. F.; Wecht, J. M.; Spungen, A. M.; Bauman, W. A.] James J Peters VA Med Ctr, Ctr Excellence Med Consequences SCI, Bronx, NY USA. [Spungen, A. M.; Bauman, W. A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Wecht, J. M.; Spungen, A. M.; Bauman, W. A.] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. RP La Fountaine, MF (reprint author), James J Peters VA Med Ctr, Ctr Excellence Med Consequences SCI, Bronx, NY USA. EM michael.lafountaine@va.gov FU Veteran Affairs Rehabilitation Research and Development Service [B4162C, B3600R]; James J Peters VA Medical Center FX This research was supported by the Veteran Affairs Rehabilitation Research and Development Service (#B4162C, #B3600R), and the James J Peters VA Medical Center. The authors would like to extend their gratitude to Dr Joseph P Weir of Des Moines University, Osteopathic Medical Center, for his statistical assistance and programming prowess which contributed significantly to the development of this paper. NR 39 TC 7 Z9 7 U1 0 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0967-3334 J9 PHYSIOL MEAS JI Physiol. Meas. PD MAR PY 2010 VL 31 IS 3 BP 363 EP 374 DI 10.1088/0967-3334/31/3/006 PG 12 WC Biophysics; Engineering, Biomedical; Physiology SC Biophysics; Engineering; Physiology GA 559SQ UT WOS:000274848400006 PM 20130343 ER PT J AU Millet, YA Danna, CH Clay, NK Songnuan, W Simon, MD Werck-Reichhart, D Ausubel, FM AF Millet, Yves A. Danna, Cristian H. Clay, Nicole K. Songnuan, Wisuwat Simon, Matthew D. Werck-Reichhart, Daniele Ausubel, Frederick M. TI Innate Immune Responses Activated in Arabidopsis Roots by Microbe-Associated Molecular Patterns SO PLANT CELL LA English DT Article ID SYSTEMIC ACQUIRED-RESISTANCE; PSEUDOMONAS-SYRINGAE; SALICYLIC-ACID; PHYTOTOXIN CORONATINE; NONHOST RESISTANCE; METHYL JASMONATE; PLANT DEFENSE; ALTERNARIA-BRASSICICOLA; PHYTOALEXIN CAMALEXIN; RHIZOSPHERE BACTERIA AB Despite the fact that roots are the organs most subject to microbial interactions, very little is known about the response of roots to microbe-associated molecular patterns (MAMPs). By monitoring transcriptional activation of beta-glucuronidase reporters and MAMP-elicited callose deposition, we show that three MAMPs, the flagellar peptide Flg22, peptidoglycan, and chitin, trigger a strong tissue-specific response in Arabidopsis thaliana roots, either at the elongation zone for Flg22 and peptidoglycan or in the mature parts of the roots for chitin. Ethylene signaling, the 4-methoxy-indole-3-ylmethylglucosinolate biosynthetic pathway, and the PEN2 myrosinase, but not salicylic acid or jasmonic acid signaling, play major roles in this MAMP response. We also show that Flg22 induces the cytochrome P450 CYP71A12-dependent exudation of the phytoalexin camalexin by Arabidopsis roots. The phytotoxin coronatine, an Ile-jasmonic acid mimic produced by Pseudomonas syringae pathovars, suppresses MAMP-activated responses in the roots. This suppression requires the E3 ubiquitin ligase COI1 as well as the transcription factor JIN1/MYC2 but does not rely on salicylic acid-jasmonic acid antagonism. These experiments demonstrate the presence of highly orchestrated and tissue-specific MAMP responses in roots and potential pathogen-encoded mechanisms to block these MAMP-elicited signaling pathways. C1 [Millet, Yves A.; Danna, Cristian H.; Clay, Nicole K.; Songnuan, Wisuwat; Simon, Matthew D.; Ausubel, Frederick M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Millet, Yves A.; Danna, Cristian H.; Clay, Nicole K.; Songnuan, Wisuwat; Simon, Matthew D.; Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Millet, Yves A.; Werck-Reichhart, Daniele] CNRS, Inst Plant Mol Biol, Unite Propre Rech 2357, Strasbourg, France. [Songnuan, Wisuwat] Mahidol Univ, Dept Plant Sci, Bangkok 10400, Thailand. RP Ausubel, FM (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. EM ausubel@molbio.mgh.harvard.edu FU National Science Foundation [MCB-0519898]; National Institutes of Health [GM048707]; Helen Hay Whitney Foundation FX This research was funded by National Science Foundation Grant MCB-0519898 and National Institutes of Health Grant GM048707. M. D. S. is supported by a Helen Hay Whitney Foundation fellowship. We thank Carol Bender for providing the COR-deficient mutants of Pst DC3000, Alan Collmer and Brian Kvitko for the nonpolar hrc mutant of Pst DC3000 CUCPB5112, Corne Pieterse for the P. fluorescens strain WCS417r, Yuki Ichinose for the PEN3pro: GUS line, and Jeffrey Dangl, Jane Glazebrook, John Celenza, and Naoto Shibuya for fls2, cyp71A12, cyp79B2 cyp79B3, and cerk1-2 mutants, respectively. NR 98 TC 180 Z9 186 U1 8 U2 81 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 1040-4651 J9 PLANT CELL JI Plant Cell PD MAR PY 2010 VL 22 IS 3 BP 973 EP 990 DI 10.1105/tpc.109.069658 PG 18 WC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology SC Biochemistry & Molecular Biology; Plant Sciences; Cell Biology GA 587IJ UT WOS:000276983900032 PM 20348432 ER PT J AU Cho, YH Sheen, J Yoo, SD AF Cho, Young-Hee Sheen, Jen Yoo, Sang-Dong TI Low Glucose Uncouples Hexokinase1-Dependent Sugar Signaling from Stress and Defense Hormone Abscisic Acid and C2H4 Responses in Arabidopsis SO PLANT PHYSIOLOGY LA English DT Article ID ENCODES; PLANTS C1 [Cho, Young-Hee; Yoo, Sang-Dong] Sungkyunkwan Univ, Dept Biol Sci, Suwon 440746, Gyeong Gi, South Korea. [Cho, Young-Hee; Sheen, Jen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol,Dept Genet, Boston, MA 02114 USA. RP Yoo, SD (reprint author), Sungkyunkwan Univ, Dept Biol Sci, Suwon 440746, Gyeong Gi, South Korea. EM sangdong@skku.edu FU National Science Foundation [IOB-0217191, DBI-0077692]; National Institutes of Health [R01 GM060493]; SungKyunKwan University promotion program; SungKyunKwan University [2009-0444-000]; National Research Foundation [2009-0068627, 2009-0075514] FX This work was supported by the National Science Foundation (grant nos. IOB-0217191 and DBI-0077692 to J. S.), the National Institutes of Health (grant no. R01 GM060493 to J. S.), the SungKyunKwan University promotion program (to Y.-H. C.), SungKyunKwan University (grant no. 2009-0444-000 to S.-D. Y.), and National Research Foundation (grant nos. 2009-0068627 and 2009-0075514 to S.-D. Y.). NR 16 TC 30 Z9 30 U1 1 U2 12 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 0032-0889 J9 PLANT PHYSIOL JI Plant Physiol. PD MAR PY 2010 VL 152 IS 3 BP 1180 EP 1182 DI 10.1104/pp.109.148957 PG 3 WC Plant Sciences SC Plant Sciences GA 578XG UT WOS:000276329500006 PM 20034964 ER PT J AU Marusyk, A Porter, CC Zaberezhnyy, V DeGregori, J AF Marusyk, Andriy Porter, Christopher C. Zaberezhnyy, Vadym DeGregori, James TI Irradiation Selects for p53-Deficient Hematopoietic Progenitors SO PLOS BIOLOGY LA English DT Article ID P53 TUMOR-SUPPRESSOR; WILD-TYPE P53; IN-VIVO; INDUCED TUMORIGENESIS; IONIZING-RADIATION; INDUCED APOPTOSIS; MICE DEFICIENT; DNA-DAMAGE; HUMAN SKIN; MUTATIONS AB Identification and characterization of mutations that drive cancer evolution constitute a major focus of cancer research. Consequently, dominant paradigms attribute the tumorigenic effects of carcinogens in general and ionizing radiation in particular to their direct mutagenic action on genetic loci encoding oncogenes and tumor suppressor genes. However, the effects of irradiation are not limited to genetic loci that encode oncogenes and tumor suppressors, as irradiation induces a multitude of other changes both in the cells and their microenvironment which could potentially affect the selective effects of some oncogenic mutations. P53 is a key tumor suppressor, the loss of which can provide resistance to multiple genotoxic stimuli, including irradiation. Given that p53 null animals develop T-cell lymphomas with high penetrance and that irradiation dramatically accelerates lymphoma development in p53 heterozygous mice, we hypothesized that increased selection for p53-deficient cells contributes to the causal link between irradiation and induction of lymphoid malignancies. We sought to determine whether ionizing irradiation selects for p53-deficient hematopoietic progenitors in vivo using mouse models. We found that p53 disruption does not provide a clear selective advantage within an unstressed hematopoietic system or in previously irradiated BM allowed to recover from irradiation. In contrast, upon irradiation p53 disruption confers a dramatic selective advantage, leading to long-term expansion of p53-deficient clones and to increased lymphoma development. Selection for cells with disrupted p53 appears to be attributable to several factors: protection from acute irradiation-induced ablation of progenitor cells, prevention of irradiation-induced loss of clonogenic capacity for stem and progenitor cells, improved long-term maintenance of progenitor cell fitness, and the disabling/elimination of competing p53 wild-type progenitors. These studies indicate that the carcinogenic effect of ionizing irradiation can in part be explained by increased selection for cells with p53 disruption, which protects progenitor cells both from immediate elimination and from long-term reductions in fitness following irradiation. C1 [Marusyk, Andriy; Porter, Christopher C.; Zaberezhnyy, Vadym; DeGregori, James] Univ Colorado, Denver Sch Med, Dept Biochem & Mol Genet, Aurora, CO USA. [Marusyk, Andriy; DeGregori, James] Univ Colorado, Denver Sch Med, Program Mol Biol, Aurora, CO USA. [Porter, Christopher C.; DeGregori, James] Univ Colorado, Denver Sch Med, Dept Pediat, Aurora, CO USA. [DeGregori, James] Univ Colorado, Denver Sch Med, Integrated Dept Immunol, Aurora, CO USA. RP Marusyk, A (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM james.degregori@ucdenver.edu OI Porter, Christopher C/0000-0001-8774-0180 FU National Institutes of Health (NIH) [RO1 CA109657, K12 CA086913, 2 P30 CA 46934] FX Funding: JD and CCP are supported by the National Institutes of Health (NIH)(RO1 CA109657 and K12 CA086913, respectively). The Cancer Center Flow Cytometry Core is supported by NIH grant 2 P30 CA 46934. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 65 Z9 67 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD MAR PY 2010 VL 8 IS 3 AR e1000324 DI 10.1371/journal.pbio.1000324 PG 17 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 602GB UT WOS:000278125400004 PM 20208998 ER PT J AU Chiang, CWK Gajdos, ZKZ Korn, JM Kuruvilla, FG Butler, JL Hackett, R Guiducci, C Nguyen, TT Wilks, R Forrester, T Haiman, CA Henderson, KD Le Marchand, L Henderson, BE Palmert, MR McKenzie, CA Lyon, HN Cooper, RS Zhu, XF Hirschhorn, JN AF Chiang, Charleston W. K. Gajdos, Zofia K. Z. Korn, Joshua M. Kuruvilla, Finny G. Butler, Johannah L. Hackett, Rachel Guiducci, Candace Nguyen, Thutrang T. Wilks, Rainford Forrester, Terrence Haiman, Christopher A. Henderson, Katherine D. Le Marchand, Loic Henderson, Brian E. Palmert, Mark R. McKenzie, Colin A. Lyon, Helen N. Cooper, Richard S. Zhu, Xiaofeng Hirschhorn, Joel N. TI Rapid Assessment of Genetic Ancestry in Populations of Unknown Origin by Genome-Wide Genotyping of Pooled Samples SO PLOS GENETICS LA English DT Article ID NUCLEOTIDE-POLYMORPHISM ASSOCIATION; DNA POOLS; STRATIFICATION; IDENTIFICATION; MICROARRAYS; AMERICANS; VARIANTS; DISEASE; ARRAYS; SNPS AB As we move forward from the current generation of genome-wide association (GWA) studies, additional cohorts of different ancestries will be studied to increase power, fine map association signals, and generalize association results to additional populations. Knowledge of genetic ancestry as well as population substructure will become increasingly important for GWA studies in populations of unknown ancestry. Here we propose genotyping pooled DNA samples using genome-wide SNP arrays as a viable option to efficiently and inexpensively estimate admixture proportion and identify ancestry informative markers (AIMs) in populations of unknown origin. We constructed DNA pools from African American, Native Hawaiian, Latina, and Jamaican samples and genotyped them using the Affymetrix 6.0 array. Aided by individual genotype data from the African American cohort, we established quality control filters to remove poorly performing SNPs and estimated allele frequencies for the remaining SNPs in each panel. We then applied a regression-based method to estimate the proportion of admixture in each cohort using the allele frequencies estimated from pooling and populations from the International HapMap Consortium as reference panels, and identified AIMs unique to each population. In this study, we demonstrated that genotyping pooled DNA samples yields estimates of admixture proportion that are both consistent with our knowledge of population history and similar to those obtained by genotyping known AIMs. Furthermore, through validation by individual genotyping, we demonstrated that pooling is quite effective for identifying SNPs with large allele frequency differences (i.e., AIMs) and that these AIMs are able to differentiate two closely related populations ( HapMap JPT and CHB). C1 [Chiang, Charleston W. K.; Gajdos, Zofia K. Z.; Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Chiang, Charleston W. K.; Gajdos, Zofia K. Z.; Korn, Joshua M.; Kuruvilla, Finny G.; Hackett, Rachel; Guiducci, Candace; Lyon, Helen N.; Hirschhorn, Joel N.] Harvard & Massachusetts Inst Technol, Program Med & Populat Genet, Broad Inst, Cambridge, MA USA. [Chiang, Charleston W. K.; Gajdos, Zofia K. Z.; Butler, Johannah L.; Nguyen, Thutrang T.; Lyon, Helen N.; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Chiang, Charleston W. K.; Gajdos, Zofia K. Z.; Butler, Johannah L.; Nguyen, Thutrang T.; Lyon, Helen N.; Hirschhorn, Joel N.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Chiang, Charleston W. K.; Gajdos, Zofia K. Z.; Butler, Johannah L.; Nguyen, Thutrang T.; Lyon, Helen N.; Hirschhorn, Joel N.] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Korn, Joshua M.; Kuruvilla, Finny G.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Korn, Joshua M.; Kuruvilla, Finny G.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Wilks, Rainford] Univ W Indies, Epidemiol Res Unit, Res Inst Trop Med, Kingston 7, Jamaica. [Forrester, Terrence; McKenzie, Colin A.] Univ W Indies, Trop Metab Res Unit, Res Inst Trop Med, Kingston 7, Jamaica. [Haiman, Christopher A.; Henderson, Brian E.] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [Henderson, Katherine D.] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA 91010 USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr Hawaii, Program Epidemiol, Honolulu, HI 96813 USA. [Palmert, Mark R.] Hosp Sick Children, Div Endocrinol, Toronto, ON M5G 1X8, Canada. [Palmert, Mark R.] Univ Toronto, Dept Pediat, Toronto, ON, Canada. [Cooper, Richard S.] Loyola Univ Chicago, Dept Prevent Med & Epidemiol, Stritch Sch Med, Maywood, IL USA. [Zhu, Xiaofeng] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. RP Chiang, CWK (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM joelh@broadinstitute.org OI Chiang, Charleston/0000-0002-0668-7865 FU NSF; National Institutes of Health [R01DK075787, R37HL45508, R01HL53353, R01HL074166, R01HD048960] FX This work was supported by a graduate research fellowship from NSF to CWKC and grants from National Institutes of Health to JNH (R01DK075787), to RSC (R37HL45508 and R01HL53353), to XZ (R01HL074166), and to MRP (R01HD048960). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 13 Z9 13 U1 0 U2 4 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 MAR PY 2010 VL 6 IS 3 AR e1000866 DI 10.1371/journal.pgen.1000866 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 578RE UT WOS:000276311400020 PM 20221249 ER PT J AU Penrose, K de Castro, MC Werema, J Ryan, ET AF Penrose, Katherine de Castro, Marcia Caldas Werema, Japhet Ryan, Edward T. TI Informal Urban Settlements and Cholera Risk in Dar es Salaam, Tanzania SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID HEALTH; INDIA; URBANIZATION; ENVIRONMENT; CHALLENGES; OUTBREAK; DIARRHEA; KOLKATA; WEALTH; IMPACT AB Background: As a result of poor economic opportunities and an increasing shortage of affordable housing, much of the spatial growth in many of the world's fastest-growing cities is a result of the expansion of informal settlements where residents live without security of tenure and with limited access to basic infrastructure. Although inadequate water and sanitation facilities, crowding and other poor living conditions can have a significant impact on the spread of infectious diseases, analyses relating these diseases to ongoing global urbanization, especially at the neighborhood and household level in informal settlements, have been infrequent. To begin to address this deficiency, we analyzed urban environmental data and the burden of cholera in Dar es Salaam, Tanzania. Methodology/Principal Findings: Cholera incidence was examined in relation to the percentage of a ward's residents who were informal, the percentage of a ward's informal residents without an improved water source, the percentage of a ward's informal residents without improved sanitation, distance to the nearest cholera treatment facility, population density, median asset index score in informal areas, and presence or absence of major roads. We found that cholera incidence was most closely associated with informal housing, population density, and the income level of informal residents. Using data available in this study, our model would suggest nearly a one percent increase in cholera incidence for every percentage point increase in informal residents, approximately a two percent increase in cholera incidence for every increase in population density of 1000 people per km 2 in Dar es Salaam in 2006, and close to a fifty percent decrease in cholera incidence in wards where informal residents had minimally improved income levels, as measured by ownership of a radio or CD player on average, in comparison to wards where informal residents did not own any items about which they were asked. In this study, the range of access to improved sanitation and improved water sources was quite narrow at the ward level, limiting our ability to discern relationships between these variables and cholera incidence. Analysis at the individual household level for these variables would be of interest. Conclusions/Significance: Our results suggest that ongoing global urbanization coupled with urban poverty will be associated with increased risks for certain infectious diseases, such as cholera, underscoring the need for improved infrastructure and planning as the world's urban population continues to expand. C1 [Penrose, Katherine; de Castro, Marcia Caldas] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Werema, Japhet] Minist Lands & Human Settlements Dev, Dar Es Salaam, Tanzania. [Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Ryan, Edward T.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Ryan, Edward T.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Penrose, K (reprint author), Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, 665 Huntington Ave, Boston, MA 02115 USA. EM kpenrose@post.harvard.edu FU Michael von Clemm Traveling Fellowship Fund; Department of Global Health and Population at the Harvard School of Public Health; National Institutes of Health, including the National Institute of Allergy and Infectious Diseases [AI077883, AI058935] FX This work was supported in part by the Michael von Clemm Traveling Fellowship Fund, the Department of Global Health and Population at the Harvard School of Public Health, and grants from the National Institutes of Health, including the National Institute of Allergy and Infectious Diseases AI077883 and AI058935. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 18 Z9 20 U1 0 U2 13 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 MAR PY 2010 VL 4 IS 3 AR e631 DI 10.1371/journal.pntd.0000631 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 578RG UT WOS:000276312200017 PM 20300569 ER PT J AU Hur, C Hayeck, TJ Yeh, JM Richards, EB Spechler, SJ Gazelle, GS Kong, CY AF Hur, Chin Hayeck, Tristan J. Yeh, Jennifer M. Richards, Ethan B. Spechler, Stuart J. Gazelle, G. Scott Kong, Chung Yin TI Development, Calibration, and Validation of a US White Male Population-Based Simulation Model of Esophageal Adenocarcinoma SO PLOS ONE LA English DT Article ID GASTROESOPHAGEAL-REFLUX DISEASE; BARRETTS-ESOPHAGUS; GASTRIC CARDIA; CLINICAL SPECTRUM; UNITED-STATES; CANCER-RISK; PREVALENCE; SYMPTOMS; SURVEILLANCE; TRENDS AB Background: The incidence of esophageal adenocarcinoma (EAC) has risen rapidly in the U. S. and western world. The aim of the study was to begin the investigation of this rapid rise by developing, calibrating, and validating a mathematical disease simulation model of EAC using available epidemiologic data. Methods: The model represents the natural history of EAC, including the essential biologic health states from normal mucosa to detected cancer. Progression rates between health states were estimated via calibration, which identified distinct parameter sets producing model outputs that fit epidemiologic data; specifically, the prevalence of pre-cancerous lesions and EAC cancer incidence from the published literature and Surveillance, Epidemiology, and End Results (SEER) data. As an illustrative example of a clinical and policy application, the calibrated and validated model retrospectively analyzed the potential benefit of an aspirin chemoprevention program. Results: Model outcomes approximated calibration targets; results of the model's fit and validation are presented. Approximately 7,000 cases of EAC could have been prevented over a 30-year period if all white males started aspirin chemoprevention at age 40 in 1965. Conclusions: The model serves as the foundation for future analyses to determine a cost-effective screening and management strategy to prevent EAC morbidity and mortality. C1 [Hur, Chin; Hayeck, Tristan J.; Gazelle, G. Scott; Kong, Chung Yin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Hur, Chin; Hayeck, Tristan J.; Richards, Ethan B.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Hur, Chin; Gazelle, G. Scott; Kong, Chung Yin] Harvard Univ, Sch Med, Boston, MA USA. [Yeh, Jennifer M.; Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Spechler, Stuart J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Hur, C (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. EM chur@mgh-ita.org OI Hur, Chin/0000-0002-2819-7576 FU NIH/NCI [CA107060, CA133141] FX Grant support: NIH/NCI Grant CA107060 (C. H.) and NIH/NCI Grant CA133141 (C. Y. K.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 7 Z9 7 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 1 PY 2010 VL 5 IS 3 AR e9483 DI 10.1371/journal.pone.0009483 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 561RT UT WOS:000274997100022 PM 20208996 ER PT J AU Hazan, R He, JX Xiao, GP Dekimpe, V Apidianakis, Y Lesic, B Astrakas, C Deziel, E Lepine, F Rahme, LG AF Hazan, Ronen He, Jianxin Xiao, Gaoping Dekimpe, Valerie Apidianakis, Yiorgos Lesic, Biliana Astrakas, Christos Deziel, Eric Lepine, Francois Rahme, Laurence G. TI Homeostatic Interplay between Bacterial Cell-Cell Signaling and Iron in Virulence SO PLOS PATHOGENS LA English DT Article ID PSEUDOMONAS QUINOLONE SIGNAL; QUORUM-SENSING SYSTEMS; CYSTIC-FIBROSIS PATIENTS; AERUGINOSA PAO1; GENE-REGULATION; DROSOPHILA-MELANOGASTER; TRANSCRIPTOME ANALYSIS; HOMOSERINE LACTONES; EXPRESSION ANALYSIS; REGULATORY PROTEIN AB Pathogenic bacteria use interconnected multi-layered regulatory networks, such as quorum sensing (QS) networks to sense and respond to environmental cues and external and internal bacterial cell signals, and thereby adapt to and exploit target hosts. Despite the many advances that have been made in understanding QS regulation, little is known regarding how these inputs are integrated and processed in the context of multi-layered QS regulatory networks. Here we report the examination of the Pseudomonas aeruginosa QS 4-hydroxy-2-alkylquinolines (HAQs) MvfR regulatory network and determination of its interaction with the QS acyl-homoserine-lactone (AHL) RhlR network. The aim of this work was to elucidate paradigmatically the complex relationships between multi-layered regulatory QS circuitries, their signaling molecules, and the environmental cues to which they respond. Our findings revealed positive and negative homeostatic regulatory loops that fine-tune the MvfR regulon via a multi-layered dependent homeostatic regulation of the cell-cell signaling molecules PQS and HHQ, and interplay between these molecules and iron. We discovered that the MvfR regulon component PqsE is a key mediator in orchestrating this homeostatic regulation, and in establishing a connection to the QS rhlR system in cooperation with RhlR. Our results show that P. aeruginosa modulates the intensity of its virulence response, at least in part, through this multi-layered interplay. Our findings underscore the importance of the homeostatic interplay that balances competition within and between QS systems via cell-cell signaling molecules and environmental cues in the control of virulence gene expression. Elucidation of the fine-tuning of this complex relationship offers novel insights into the regulation of these systems and may inform strategies designed to limit infections caused by P. aeruginosa and related human pathogens. C1 [Hazan, Ronen; He, Jianxin; Xiao, Gaoping; Apidianakis, Yiorgos; Lesic, Biliana; Astrakas, Christos; Rahme, Laurence G.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Hazan, Ronen; He, Jianxin; Xiao, Gaoping; Apidianakis, Yiorgos; Lesic, Biliana; Astrakas, Christos; Rahme, Laurence G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hazan, Ronen; He, Jianxin; Xiao, Gaoping; Apidianakis, Yiorgos; Lesic, Biliana; Astrakas, Christos; Rahme, Laurence G.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Dekimpe, Valerie; Deziel, Eric; Lepine, Francois] INRS Inst Armand Frappier, Laval, PQ, Canada. RP Hazan, R (reprint author), Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. EM rahme@molbio.mgh.harvard.edu RI Deziel, Eric/A-7678-2008; OI Deziel, Eric/0000-0002-4609-0115; Apidianakis, Yiorgos/0000-0002-7465-3560 FU Claflin Distinguished Scholar Award; National Institute of Health [AI063433]; Shriners Hospitals [8494]; Shriners Research grants [8770, 8850] FX This work was supported by The Claflin Distinguished Scholar Award, Shriners Research grants #8770 and #8850 and National Institute of Health grant AI063433 to LGR. RH was supported by a Shriners Hospitals Research Fellowship (#8494). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 39 Z9 41 U1 2 U2 16 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 MAR PY 2010 VL 6 IS 3 AR e1000810 DI 10.1371/journal.ppat.1000810 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 596XY UT WOS:000277720400020 PM 20300606 ER PT J AU Mochon, AB Ye, J Kayala, MA Wingard, JR Clancy, CJ Nguyen, MH Felgner, P Baldi, P Liu, HP AF Mochon, A. Brian Ye, Jin Kayala, Matthew A. Wingard, John R. Clancy, Cornelius J. Nguyen, M. Hong Felgner, Philip Baldi, Pierre Liu, Haoping TI Serological Profiling of a Candida albicans Protein Microarray Reveals Permanent Host-Pathogen Interplay and Stage-Specific Responses during Candidemia SO PLOS PATHOGENS LA English DT Article ID GENE-EXPRESSION; TRANSCRIPTIONAL RESPONSE; INVASIVE CANDIDIASIS; SYSTEMIC CANDIDIASIS; SACCHAROMYCES-CEREVISIAE; NORMALIZATION METHODS; ANTIBODY-RESPONSES; OXIDATIVE STRESS; DRUG-RESISTANCE; IMMUNE-RESPONSE AB Candida albicans in the immunocompetent host is a benign member of the human microbiota. Though, when host physiology is disrupted, this commensal-host interaction can degenerate and lead to an opportunistic infection. Relatively little is known regarding the dynamics of C. albicans colonization and pathogenesis. We developed a C. albicans cell surface protein microarray to profile the immunoglobulin G response during commensal colonization and candidemia. The antibody response from the sera of patients with candidemia and our negative control groups indicate that the immunocompetent host exists in permanent host-pathogen interplay with commensal C. albicans. This report also identifies cell surface antigens that are specific to different phases (i.e. acute, early and mid convalescence) of candidemia. We identified a set of thirteen cell surface antigens capable of distinguishing acute candidemia from healthy individuals and uninfected hospital patients with commensal colonization. Interestingly, a large proportion of these cell surface antigens are involved in either oxidative stress or drug resistance. In addition, we identified 33 antigenic proteins that are enriched in convalescent sera of the candidemia patients. Intriguingly, we found within this subset an increase in antigens associated with heme-associated iron acquisition. These findings have important implications for the mechanisms of C. albicans colonization as well as the development of systemic infection. C1 [Mochon, A. Brian; Ye, Jin; Baldi, Pierre; Liu, Haoping] Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92717 USA. [Kayala, Matthew A.; Baldi, Pierre] Univ Calif Irvine, Inst Genom & Bioinformat, Irvine, CA 92717 USA. [Wingard, John R.] Univ Florida, Coll Med, Dept Med, Gainesville, FL USA. [Clancy, Cornelius J.; Nguyen, M. Hong] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Kayala, Matthew A.; Baldi, Pierre] Univ Calif Irvine, Dept Comp Sci, Irvine, CA 92717 USA. [Felgner, Philip] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. [Felgner, Philip] Univ Calif Irvine, Pacific SW Ctr Res Emerging Infect, Irvine, CA 92717 USA. RP Mochon, AB (reprint author), Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92717 USA. EM h4liu@uci.edu FU National Institute of Allergy and Infectious Diseases [P01AI061537]; National Institute of General Medical Sciences [R01GM/AI55155] FX National Institute of Allergy and Infectious Diseases (P01AI061537) and National Institute of General Medical Sciences (R01GM/AI55155). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 45 Z9 64 U1 0 U2 3 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 MAR PY 2010 VL 6 IS 3 AR e1000827 DI 10.1371/journal.ppat.1000827 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 596XY UT WOS:000277720400035 PM 20361054 ER PT J AU Basile, JN Bloch, MJ AF Basile, Jan N. Bloch, Michael J. TI Identifying and Managing Factors That Interfere with or Worsen Blood Pressure Control SO POSTGRADUATE MEDICINE LA English DT Article DE blood pressure; hypertension; cardiovascular disease ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; AMERICAN-HEART-ASSOCIATION; OXIDE DONATOR NAPROXCINOD; RESISTANT HYPERTENSION; SCIENTIFIC STATEMENT; CYCLOOXYGENASE-2 INHIBITORS; TREATING OSTEOARTHRITIS; ANTIDEPRESSANT DRUGS; CLINICAL-PRACTICE; OLDER PATIENTS AB Hypertension is a major risk factor for ischemic heart disease, stroke, and heart failure. Even moderate blood pressure ( BP) elevation can have a significant impact on outcomes. Maintaining BP within recommended levels significantly reduces the risk of cardiovascular morbidity and mortality. Yet, more than one-third of people receiving treatment for hypertension in the United States have uncontrolled BP. When faced with a patient whose BP is no longer controlled, clinicians need to develop a differential diagnosis of potential contributing factors. These factors may include BP measurement issues, poor adherence to antihypertensive medications, therapeutic inertia on the part of clinicians, lifestyle changes, secondary causes of hypertension, or ingestion of substances that interfere with BP control. Patients who demonstrate a deterioration in BP control should be questioned about adherence, recent changes to diet and lifestyle, signs and symptoms of secondary causes of hypertension, and use of any concomitant medications or other substances that may be known to increase BP or interfere with antihypertensive therapy. Common substances that can interfere with BP control include nonsteroidal anti-inflammatory drugs ( NSAIDs), oral contraceptives, glucocorticoids, antidepressants, decongestants, alcohol, or other stimulants like cocaine and methamphetamines. Because of the high prevalence of both osteoarthritis and hypertension among elderly people, NSAIDs are a common potential factor in this age group. In the face of worsening BP control, clinicians must actively investigate potential contributing factors and appropriately increase or adjust antihypertensive therapy. C1 [Basile, Jan N.] Med Univ S Carolina, Div Gen Internal Med Geriatr, Charleston, SC 29414 USA. [Basile, Jan N.] Ralph H Johnson VA Med Ctr, Charleston, SC 29414 USA. [Bloch, Michael J.] Univ Nevada, Sch Med, Reno, NV 89557 USA. [Bloch, Michael J.] Univ Nevada, St Marys Risk Reduct Ctr, Reno, NV 89557 USA. RP Basile, JN (reprint author), Med Univ S Carolina, Div Gen Internal Med Geriatr, Charleston, SC 29414 USA. EM basilejn@musc.edu FU NicOx FX Editorial support was provided by Catherine Rees on behalf of the Lippincott CME Institute, through an educational grant provided by NicOx. NR 80 TC 3 Z9 3 U1 1 U2 4 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 MAR PY 2010 VL 122 IS 2 BP 35 EP 48 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 642VK UT WOS:000281248900004 PM 20203454 ER PT J AU Somarouthu, B Abbara, S Kalva, SP AF Somarouthu, Bhanusupriya Abbara, Suhny Kalva, Sanjeeva P. TI Diagnosing Deep Vein Thrombosis SO POSTGRADUATE MEDICINE LA English DT Article DE venous thromboembolism; deep venous thrombosis; pulmonary embolism; Wells clinical score; D-dimer test; duplex ultrasound ID CT PULMONARY ANGIOGRAPHY; VENOUS THROMBOSIS; D-DIMER; VENOGRAPHY; THROMBOEMBOLISM; METAANALYSIS; RISK AB In this article, we discuss the approach for diagnosing deep vein thrombosis (DVT) in different patient populations. Clinical features and probability assessment guide further diagnostic tests. D-dimer testing is used as screening test; however, duplex ultrasound remains the primary confirmatory test. Computed tomography and magnetic resonance imaging are used only in select patient populations, such as when ultrasound results are equivocal, in patients suspected of central venous DVT, or as a part of combined protocol for diagnosis of pulmonary embolism. Contrast phlebography and plethysmography do not have much of a role during routine diagnosis of DVT. C1 [Somarouthu, Bhanusupriya; Abbara, Suhny; Kalva, Sanjeeva P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiovasc Imaging & Intervent,Dept Radiol, Boston, MA 02114 USA. RP Somarouthu, B (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiovasc Imaging & Intervent,Dept Radiol, GRB 297,55 Fruit St, Boston, MA 02114 USA. EM bsomarouthu@partners.org NR 23 TC 4 Z9 10 U1 1 U2 3 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 MAR PY 2010 VL 122 IS 2 BP 66 EP 73 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 642VK UT WOS:000281248900007 PM 20203457 ER PT J AU Nurmikko, AV Donoghue, JP Hochberg, LR Patterson, WR Song, YK Bull, CW Borton, DA Laiwalla, F Park, S Ming, Y Aceros, J AF Nurmikko, Arto V. Donoghue, John P. Hochberg, Leigh R. Patterson, William R. Song, Yoon-Kyu Bull, Christopher W. Borton, David A. Laiwalla, Farah Park, Sunmee Ming, Yin Aceros, Juan TI Listening to Brain Microcircuits for Interfacing With External World-Progress in Wireless Implantable Microelectronic Neuroengineering Devices SO PROCEEDINGS OF THE IEEE LA English DT Article DE Biomedical devices; brain science; neural engineering; neural signal recording ID NEURAL RECORDING-SYSTEM; CORTICAL-NEURONS; MOTOR CORTEX; PRIMATES; TETRAPLEGIA; TELEMETRY; COMPUTER; ARRAYS; ENSEMBLES; VELOCITY AB Acquiring neural signals at high spatial and temporal resolution directly from brain microcircuits and decoding their activity to interpret commands and/or prior planning activity, such as motion of an arm or a leg, is a prime goal of modern neurotechnology. Its practical aims include assistive devices for subjects whose normal neural information pathways are not functioning due to physical damage or disease. On the fundamental side, researchers are striving to decipher the code of multiple neural microcircuits which collectively make up nature's amazing computing machine, the brain. By implanting biocompatible neural sensor probes directly into the brain, in the form of microelectrode arrays, it is now possible to extract information from interacting populations of neural cells with spatial and temporal resolution at the single cell level. With parallel advances in application of statistical and mathematical techniques tools for deciphering the neural code, extracted populations or correlated neurons, significant understanding has been achieved of those brain commands that control, e.g., the motion of an arm in a primate (monkey or a human subject). These developments are accelerating the work on neural prosthetics where brain derived signals may be employed to bypass, e.g., an injured spinal cord. One key element in achieving the goals for practical and versatile neural prostheses is the development of fully implantable wireless microelectronic "brain-interfaces" within the body, a point of special emphasis of this paper. C1 [Nurmikko, Arto V.] Brown Univ, Dept Phys, Div Engn, Providence, RI 02912 USA. [Nurmikko, Arto V.; Donoghue, John P.; Hochberg, Leigh R.] Brown Univ, Brown Inst Brain Sci, Providence, RI 02912 USA. [Donoghue, John P.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Hochberg, Leigh R.] Vet Hlth Adm, Dept Vet Affairs, Rehabil Res & Dev Serv, Ctr Restorat & Regenerat Med, Providence, RI 02908 USA. [Hochberg, Leigh R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Massachusetts Gen Hosp,Dept Neurol, Boston, MA 02114 USA. [Hochberg, Leigh R.] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Boston, MA 02114 USA. [Song, Yoon-Kyu] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Seoul 151742, South Korea. RP Nurmikko, AV (reprint author), Brown Univ, Dept Phys, Div Engn, Providence, RI 02912 USA. EM Arto_Nurmikko@brown.edu; John_Donoghue@brown.edu; Leigh_Hochberg@brown.edu; William_Patterson_III@Brown.EDU; songyk@snu.ac.kr; Christopher_Bull@brown.edu; David_Borton@brown.edu; Farah_Laiwalla@brown.edu; Sunmee_Park@brown.edu; Yin_Ming@brown.edu; Juan_Aceros@brown.edu FU National Institute of Health (NIBIB and NCMRR/NICHD) [1R01EB007401-01]; Office of Naval Research [N0014-06-0185]; National Science Foundation [0937848] FX This research was supported by the National Institute of Health (NIBIB and NCMRR/NICHD) under Bioengineering Research Partnership Program (1R01EB007401-01), the Office of Naval Research under Neuroengineering Program (N0014-06-0185), and the National Science Foundation under the EFRI Program (#0937848). NR 60 TC 58 Z9 59 U1 2 U2 20 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9219 J9 P IEEE JI Proc. IEEE PD MAR PY 2010 VL 98 IS 3 BP 375 EP 388 DI 10.1109/JPROC.2009.2038949 PG 14 WC Engineering, Electrical & Electronic SC Engineering GA 565MR UT WOS:000275298100003 PM 21654935 ER PT J AU Qian, DZ Rademacher, BLS Pittsenbarger, J Huang, CY Myrthue, A Higano, CS Garzotto, M Nelson, PS Beer, TM AF Qian, David Z. Rademacher, Brooks L. S. Pittsenbarger, Janet Huang, Chung-Ying Myrthue, Anne Higano, Celestia S. Garzotto, Mark Nelson, Peter S. Beer, Tomasz M. TI CCL2 Is Induced by Chemotherapy and Protects Prostate Cancer Cells From Docetaxel-Induced Cytotoxicity SO PROSTATE LA English DT Article DE prostate cancer; chemotherapy resistance; CCL2; inflammation ID N-TERMINAL KINASE; IN-VIVO; KAPPA-B; NEOADJUVANT DOCETAXEL; IMPORTANT MEDIATOR; GROWTH; ANGIOGENESIS; ACTIVATION; APOPTOSIS; PATHWAYS AB BACKGROUND. Metastatic prostate cancer is either inherently resistant to chemotherapy or rapidly acquires this phenotype after chemotherapy exposure. In this study, we identified a docetaxel-induced resistance mechanism centered on CCL2. METHODS. We compared the gene expression profiles in individual human prostate cancer specimens before and after exposure to chemotherapy collected from previously untreated patients who participated in a clinical trial of preoperative chemotherapy. Subsequently, we used the gain- and loss-of-function approach in vitro to identify a potential mechanism underlying chemotherapy resistance. RESULTS. Among the molecular signatures associated with treatment, several genes that regulate the inflammatory response and chemokine activity were upregulated including a significant increase in transcripts encoding the CC chemokine CCL2. Docetaxel increased CCL2 expression in prostate cancer cell lines in vitro. CCL2-specific siRNA inhibited LNCaP and LAPC4 cell proliferation and enhanced the growth inhibitory effect of low-dose docetaxel. In contrast, overexpression of CCL2 or recombinant CCL2 protein stimulated prostate cancer cell proliferation and rescued cells from docetaxel-induced cytotoxicity. This protective effect of CCL2 was associated with activation of the ERK/MAP kinase and PI3K/AKT, inhibition of docetaxel-induced Bcl2 phosphorylation at serine 70, phosphorylation of Bad, and activation of caspase-3. The addition of a PI3K/AKT inhibitor Ly294002 reversed the CCL2 protection and was additive to docetaxel-induced toxicity. CONCLUSION. These results support a mechanism of chemotherapy resistance mediated by cellular stress responses involving the induction of CCL2 expression and suggest that inhibiting CCL2 activity could enhance therapeutic responses to taxane-based therapy. Prostate 70: 433442, 2010. (C) 2009 Wiley-Liss, Inc. C1 [Beer, Tomasz M.] Oregon Hlth & Sci Univ, Dept Med, Div Hematol & Med Oncol, Portland, OR 97239 USA. [Huang, Chung-Ying; Nelson, Peter S.] Fred Hutchinson Canc Res Ctr, Div Human Biol & Clin Res, Seattle, WA 98104 USA. [Higano, Celestia S.; Nelson, Peter S.] Univ Washington, Div Med Oncol, Seattle, WA 98195 USA. [Garzotto, Mark] Oregon Hlth & Sci Univ, Div Urol, Portland VA Med Ctr, Portland, OR 97239 USA. RP Beer, TM (reprint author), Oregon Hlth & Sci Univ, Dept Med, Div Hematol & Med Oncol, 3303 SW Bond,CH14R, Portland, OR 97239 USA. EM beert@ohsu.edu FU Aventis Pharmaceuticals [16080]; OSI, Inc. [031.G0008]; NIH [3M01RR00334-33S2, 1 R01 CA119125-01, U54CA126540]; PNW Prostate SPORE [CA97186] FX Grant sponsor: Aventis Pharmaceuticals; Grant number: 16080; Grant sponsor: OSI, Inc.; Grant number: 031.G0008; Grant sponsor: NIH; Grant numbers: 3M01RR00334-33S2, 1 R01 CA119125-01, U54CA126540; Grant sponsor: PNW Prostate SPORE; Grant number: CA97186. NR 40 TC 36 Z9 41 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAR 1 PY 2010 VL 70 IS 4 BP 433 EP 442 DI 10.1002/pros.21077 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 566OS UT WOS:000275382600009 PM 19866475 ER PT J AU Saylor, PJ Smith, MR AF Saylor, P. J. Smith, M. R. TI Bone health and prostate cancer SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Review DE bone metastases; osteoclast; bisphosphonate; zoledronic acid; skeletal-related events; denosumab ID ANDROGEN-DEPRIVATION THERAPY; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; ORAL SODIUM CLODRONATE; ZOLEDRONIC ACID; FRACTURE RISK; DOUBLE-BLIND; MULTIPLE-MYELOMA; MINERAL DENSITY; BREAST-CANCER AB Bone metastases are a substantial burden to men with advanced prostate cancer as they often cause pain and can cause fractures and spinal cord compression. Osteoblasts and osteoclasts are both pathologically activated in the setting of prostate cancer bone metastases. As osteoclast activation is associated with disease progression, skeletal complications and death, osteoclast-targeted therapies are a rational approach to disease management. Zoledronic acid is standard of care for castrationresistant prostate cancer with bone metastases as it reduces the risk for skeletal-related events. Additional trials are needed to better define the ideal dose, frequency and duration of zoledronic acid therapy. No bisphosphonate has yet been shown to prevent bone metastases or to benefit men with androgen-sensitive disease. Denosumab is an experimental osteoclast-targeted monoclonal antibody against receptor activator of nuclear factor-jB ligand. Two ongoing phase III trials are expected to define its efficacy in preventing bone metastases and disease-related skeletal events in men with prostate cancer. Androgen-deprivation therapy (ADT) for prostate cancer is associated with osteoporosis and fragility fractures. Several bisphosphonates have been shown to improve bone mineral density in men receiving ADT. Two recent phase III trials have shown that denosumab and toremifene reduce the incidence of fragility fractures in these men. The World Health Organization has developed a fracture risk assessment model (FRAX) for the general population to guide the selection of patients who may benefit from pharmacotherapy. In the absence of a prostate cancer-specific algorithm, we advocate the use of FRAX for men receiving ADT. Prostate Cancer and Prostatic Diseases (2010) 13, 20-27; doi:10.1038/pcan.2009.50; published online 10 November 2009 C1 [Saylor, P. J.; Smith, M. R.] Massachusetts Gen Hosp, Ctr Canc, Dept Oncol, Boston, MA 02114 USA. RP Saylor, PJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Oncol, 55 Fruit St,Lawrence House,POB-2, Boston, MA 02114 USA. EM psaylor@partners.org FU NCI NIH HHS [K24 CA121990, K24 CA121990-03] NR 74 TC 26 Z9 28 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD MAR PY 2010 VL 13 IS 1 BP 20 EP 27 DI 10.1038/pcan.2009.50 PG 8 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 553WM UT WOS:000274397500004 PM 19901958 ER PT J AU Papakostas, TD Pieretti-Vanmarcke, R Nicolaou, F Thanos, A Trichonas, G Koufomichali, X Anago, K Donahoe, PK Teixeira, J MacLaughlin, DT Vavvas, D AF Papakostas, Thanos D. Pieretti-Vanmarcke, Rafael Nicolaou, Fotini Thanos, Aristomenis Trichonas, George Koufomichali, Xanthi Anago, Kosisochukwu Donahoe, Patricia K. Teixeira, Jose MacLaughlin, David T. Vavvas, Demetrios TI Development of an efficiently cleaved, bioactive, highly pure FLAG-tagged recombinant human Mullerian Inhibiting Substance SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE Mullerian Inhibiting Substance (MIS); Purification; FLAG tag; Bioactivity ID II RECEPTOR; IN-VIVO; DUCT REGRESSION; EXPRESSION; HORMONE; GROWTH; CANCER; CELLS; IMMUNOASSAY; FAMILY AB Mullerian Inhibiting Substance (MIS), a member of the TGF-beta family, causes regression of the Mullerian duct in male embryos, after binding to Mullerian Inhibiting Substance Receptor II (MISRII). it has also been extensively demonstrated that it can inhibit proliferation of various cancer cell lines such as ovarian, prostate, and breast cancer in vitro and in vivo. Hence, the availability of a recombinant, epitope tagged, bioactive MIS is important for the selection of patients for treatment and for probing novel molecular targets for MIS in various tissues. To this end, we have expressed a recombinant, internally FLAG-tagged form of hMIS with the tag (DYKDDDDK) immediately after the cleavage site (427-428) of MIS at the C-terminus with a modified dibasic cleavage motif sequence. We show that this construct results in a highly pure, endogenously processed (cleaved) FLAG MIS, that causes complete regression of the Mullerian Duct in an organ culture assay. In addition, purified FLAG MIS was able to bind and affinity purify both transfected and endogenous MIS type II receptor. The availability of this fully functional, epitope tagged form of MIS should facilitate scale-up for preclinical and clinical use and should also be used for the study of MIS binding proteins and for tracking in pharmacokinetic studies. (C) 2009 Elsevier Inc. All rights reserved. C1 [Papakostas, Thanos D.; Thanos, Aristomenis; Trichonas, George; Koufomichali, Xanthi; Vavvas, Demetrios] Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm,Angiogenesis Lab, Boston, MA 02115 USA. [Pieretti-Vanmarcke, Rafael; Nicolaou, Fotini; Anago, Kosisochukwu; Donahoe, Patricia K.; MacLaughlin, David T.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp,Pediat Surg Res Labs, Boston, MA 02115 USA. [Teixeira, Jose] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Dept Obstet & Gynecol, Boston, MA USA. RP Vavvas, D (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Massachusetts Eye & Ear Infirm,Angiogenesis Lab, 325 Cambridge St, Boston, MA 02115 USA. EM maclaugh@helix.mgh.harvard.edu; demetrios_vavvas@meei.harvard.edu OI Teixeira, Jose/0000-0002-6438-5064; Vavvas, Demetrios/0000-0002-8622-6478 FU Bacardi Fund; Research To Prevent Blindness Foundation; Lions Eye Research Fund; Nikolaos D. Pateras Foundation; Alexandros S. Onassis Foundation; NIH [CA17393] FX Bacardi Fund (TDP and DV), Research To Prevent Blindness Foundation (TDP, DV), Lions Eye Research Fund (DV), Nikolaos D. Pateras Foundation (TOP), Alexandros S. Onassis Foundation (DV) and NIH CA17393 (PKD). NR 30 TC 4 Z9 4 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 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAR PY 2010 VL 70 IS 1 BP 32 EP 38 DI 10.1016/j.pep.2009.09.004 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 557OS UT WOS:000274679500005 PM 19755162 ER PT J AU Faraone, SV Mick, E AF Faraone, Stephen V. Mick, Eric TI Molecular Genetics of Attention Deficit Hyperactivity Disorder SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Attention deficit/hyperactivity disorder; ADHD; Genetics ID DOPAMINE TRANSPORTER GENE; FAMILY-BASED ASSOCIATION; BETA-HYDROXYLASE GENE; ALPHA-2A ADRENERGIC-RECEPTOR; GENOME-WIDE ASSOCIATION; MONOAMINE-OXIDASE-A; HAN CHINESE SUBJECTS; ACETYLCHOLINE-RECEPTOR-ALPHA-4 SUBUNIT GENE; SEASONAL AFFECTIVE-DISORDER; RISK COMMUNITY SAMPLE AB Although twin studies demonstrate that ADHD is a highly heritable condition, molecular genetic studies suggest that the genetic architecture of ADHD is complex. The handful of genome-wide linkage and association scans that have been conducted thus far show divergent findings and are, therefore, not conclusive. Similarly, many of the candidate genes reviewed here (ie, DBH, MAOA, SLC6A2, TPH-2, SLC6A4, CHRNA4, GRIN2A) are theoretically compelling from neurobiological systems perspective but available data are sparse and inconsistent. However, candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder, with meta-analyses supportive of a role of the genes coding for DRD4, DRD5, SLC6A3, SNAP-25, and HTR1B in the etiology of ADHD. C1 [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. [Mick, Eric] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Mick, Eric] Harvard Univ, Sch Med, 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 OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [R13 MH059126, R01 MH066877, R01 MH066877-08, R13 MH059126-11] NR 166 TC 163 Z9 173 U1 9 U2 72 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 MAR PY 2010 VL 33 IS 1 BP 159 EP + DI 10.1016/j.psc.2009.12.004 PG 23 WC Psychiatry SC Psychiatry GA 601KQ UT WOS:000278058400011 PM 20159345 ER PT J AU Schwartz, S Hoyte, J James, T Conoscenti, L Johnson, R Liebschutz, J AF Schwartz, Sonia Hoyte, Joel James, Thea Conoscenti, Lauren Johnson, Renee Liebschutz, Jane TI Challenges to Engaging Black Male Victims of Community Violence in Healthcare Research: Lessons Learned From Two Studies SO PSYCHOLOGICAL TRAUMA-THEORY RESEARCH PRACTICE AND POLICY LA English DT Article DE African American; qualitative research; community violence; research participation ID POSTTRAUMATIC-STRESS; RACIAL-DIFFERENCES; AFRICAN-AMERICANS; CULTURAL MISTRUST; MEDICAL-RESEARCH; INJURED YOUTH; PARTICIPATION; WILLINGNESS; EMERGENCY; ATTITUDES AB A dearth of literature exists on barriers to conducting research with Black male victims of community violence, despite the need for evidence-based postinjury interventions. This study used qualitative data from a cross-sectional interview study (n = 16) and a pilot intervention study (n = 11) conducted in Boston, MA to identify challenges and facilitators to conducting research with Black male victims of community violence, particularly with regard to recruitment and maintenance of a study sample. Qualitative methods, including Grounded Theory and ethnography, were used to analyze the data. Challenges included a fear of police involvement, an impression of "snitching" when disclosing personal information, mistrust of research motives, suspicion of the informed consent process, the emotional impact of the trauma itself, and logistical issues. Facilitators to research included monetary incentives and motivation to help oneself and others. Participant recommendations on recruitment methods relating to approach and timing are provided. Findings from this study may assist in the planning of research studies for Black male victims of community violence. C1 [Schwartz, Sonia; Liebschutz, Jane] Boston Med Ctr, Gen Internal Med Sect, Clin Addict Res & Educ Unit, Boston, MA 02118 USA. [Schwartz, Sonia] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Hoyte, Joel] Tufts Univ, Dept Community Hlth, Medford, MA 02155 USA. [James, Thea] Boston Med Ctr, Dept Emergency Med, Boston, MA 02118 USA. [Conoscenti, Lauren] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Schwartz, Sonia; Liebschutz, Jane] Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02118 USA. RP Liebschutz, J (reprint author), Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, 801 Massachusetts Ave,2nd Floor, Boston, MA 02118 USA. EM jane.liebschutz@bmc.org FU NIDA NIH HHS [K23 DA016665, K23 DA016665-01A1] NR 32 TC 5 Z9 5 U1 3 U2 9 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1942-9681 J9 PSYCHOL TRAUMA-US JI Psychol. Trauma PD MAR PY 2010 VL 2 IS 1 BP 54 EP 62 DI 10.1037/a0019020 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 741AJ UT WOS:000288835200008 PM 20526412 ER PT J AU Hinton, DE Hofmann, SG Orr, SP Pitman, RK Pollack, MH Pole, N AF Hinton, Devon E. Hofmann, Stefan G. Orr, Scott P. Pitman, Roger K. Pollack, Mark H. Pole, Nnamdi TI A Psychobiocultural Model of Orthostatic Panic Among Cambodian Refugees: Flashbacks, Catastrophic Cognitions, and Reduced Orthostatic Blood-Pressure Response SO PSYCHOLOGICAL TRAUMA-THEORY RESEARCH PRACTICE AND POLICY LA English DT Article DE orthostatic hypotension; panic disorder; PTSD; blood pressure; Cambodian refugees ID POSTTRAUMATIC-STRESS-DISORDER; ANXIETY SENSITIVITY; ATTACKS; PTSD; PSYCHOPHYSIOLOGY; CHALLENGE; SEVERITY AB This paper investigates cognitive and physiological precursors of orthostatic panic (OP), that is, panic upon standing, which is a key complaint among traumatized Cambodian refugees. Prior research links OP to hypotension (lower blood pressure) and catastrophic cognitions. A clinical sample of 102 Cambodian refugees were assessed for posttraumatic stress disorder (PTSD), recent OP attacks, and anticipatory anxiety before engaging in an orthostatic challenge (OC) task during which they were monitored for blood pressure. After the task, they were assessed for OC-induced culture-related catastrophic cognitions, flashbacks, and panic attacks. We found that participants with recent OP (n = 60) had more PTSD, greater anticipatory anxiety before the OC, a larger drop in systolic blood pressure during the OC, more OC-induced catastrophic cognitions and flashbacks, and more severe OC-induced panic attack symptoms. Regression models showed that the severity of OC-induced panic symptoms was predicted by the magnitude of SBP drop and mediated by more severe catastrophic cognitions and flashbacks. Implications of the findings for cross-cultural psychopathology research and the treatment of both panic and PTSD in Cambodian refugees are discussed. C1 [Hinton, Devon E.] Arbour Counseling Serv, SE Asian Clin, Lowell, MA 01852 USA. [Hinton, Devon E.; Orr, Scott P.; Pitman, Roger K.; Pollack, Mark H.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Hofmann, Stefan G.] Boston Univ, Boston, MA 02215 USA. [Pole, Nnamdi] Smith Coll, Dept Psychol, Northampton, MA 01063 USA. RP Hinton, DE (reprint author), Arbour Counseling Serv, SE Asian Clin, 10 Bridge St,Simpson Block, Lowell, MA 01852 USA. EM devon_hinton@hms.harvard.edu RI Hofmann, Stefan/B-8769-2014 OI Hofmann, Stefan/0000-0002-3548-9681 NR 39 TC 9 Z9 9 U1 0 U2 10 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 1942-9681 J9 PSYCHOL TRAUMA-US JI Psychol. Trauma PD MAR PY 2010 VL 2 IS 1 BP 63 EP 70 DI 10.1037/a0018978 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 741AJ UT WOS:000288835200009 ER PT J AU Tobias, MC O'Neill, J Hudkins, M Bartzokis, G Dean, AC London, ED AF Tobias, Marc C. O'Neill, Joseph Hudkins, Matthew Bartzokis, George Dean, Andrew C. London, Edythe D. TI White-matter abnormalities in brain during early abstinence from methamphetamine abuse SO PSYCHOPHARMACOLOGY LA English DT Article DE Diffusion tensor imaging (DTI); Methamphetamine; Frontal white matter; Corpus callosum; Perforant path; Psychiatric symptoms ID MAGNETIC-RESONANCE SPECTROSCOPY; DIFFUSION TENSOR MRI; PSYCHIATRIC-SYMPTOMS; STRUCTURAL ABNORMALITIES; ALZHEIMERS-DISEASE; CORPUS-CALLOSUM; USERS; MYELINATION; INVENTORY; ADDICTION AB Previous studies revealed microstructural abnormalities in prefrontal white matter and corpus callosum of long-term abstinent chronic methamphetamine abusers. In view of the importance of the early abstinence period in treatment retention, we compared 23 methamphetamine-dependent subjects abstinent from methamphetamine for 7-13 days with 18 healthy comparison subjects. As certain metabolic changes in the brain first manifest after early abstinence from methamphetamine, it is also possible that microstructural white-matter abnormalities are not yet present during early abstinence. Using diffusion tensor imaging at 1.5 T, fractional anisotropy (FA) was measured in prefrontal white matter at four inferior-superior levels parallel to the anterior commissure-posterior commissure (AC-PC) plane. We also sampled FA in the corpus callosum at the midline and at eight bilateral, fiber-tract sites in other regions implicated in effects of methamphetamine. The methamphetamine group exhibited lower FA in right prefrontal white matter above the AC-PC plane (11.9% lower; p = 0.007), in midline genu corpus callosum (3.9%; p = 0.019), in left and right midcaudal superior corona radiata (11.0% in both hemispheres, p's = 0.020 and 0.016, respectively), and in right perforant fibers (7.3%; p = 0.025). FA in left midcaudal superior corona radiata was correlated with depressive and generalized psychiatric symptoms within the methamphetamine group. The findings support the idea that methamphetamine abuse produces microstructural abnormalities in white matter underlying and interconnecting prefrontal cortices and hippocampal formation. These effects are already present during the first weeks of abstinence from methamphetamine and are linked to psychiatric symptoms assessed during this period. C1 [Tobias, Marc C.; O'Neill, Joseph; Hudkins, Matthew; Bartzokis, George; Dean, Andrew C.; London, Edythe D.] Univ Calif Los Angeles, Semel Inst Neurosci & Biobehav Studies, Los Angeles, CA 90024 USA. [O'Neill, Joseph] Univ Calif Los Angeles, Semel Inst Neurosci, Div Child & Adolescent Psychiat, Los Angeles, CA 90024 USA. [Bartzokis, George; London, Edythe D.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. [London, Edythe D.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90024 USA. [Bartzokis, George] Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. RP O'Neill, J (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci, Div Child & Adolescent Psychiat, 760 Westwood Plaza 58-227A, Los Angeles, CA 90024 USA. EM joneill@mednet.ucla.edu RI Bartzokis, George/K-2409-2013 FU National Institute on Drug Abuse [P20DA022539, R01DA020726, R03DA20512, R21DA023192]; National Center for Research Resources [MOIRR00865]; Katherine K. and Thomas P. Pike Chair; Marjorie Green Family Trust (EDL) FX This work was supported by grants from the National Institute on Drug Abuse (P20DA022539, R01DA020726, R03DA20512, and R21DA023192; EDL and JON) and by the National Center for Research Resources grant MOIRR00865 (UCLA General Clinical Research Center). Additional funding was provided by endowments from the Katherine K. and Thomas P. Pike Chair in Addiction Studies and the Marjorie Green Family Trust (EDL). NR 67 TC 34 Z9 40 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2010 VL 209 IS 1 BP 13 EP 24 DI 10.1007/s00213-009-1761-7 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 553YZ UT WOS:000274404000002 PM 20101394 ER PT J AU Farabaugh, A Locascio, JJ Yap, L Growdon, J Fava, M Crawford, C Matthews, J McCutchen, J Buchin, J Pava, J Alpert, JE AF Farabaugh, Amy Locascio, Joseph J. Yap, Liang Growdon, John Fava, Maurizio Crawford, Christine Matthews, John McCutchen, Jesse Buchin, Jacqueline Pava, Joel Alpert, Jonathan E. TI Cognitive-Behavioral Therapy for Patients With Parkinson's Disease and Comorbid Major Depressive Disorder SO PSYCHOSOMATICS LA English DT Article ID CONTROLLED-TRIAL; PREVALENCE; RECOVERY; RELAPSE AB Background: Depression has been recognized as a common feature of Parkinson's disease (PD), and is the most prevalent psychiatric disorder in PD patients. Objective: The authors sought to determine whether cognitive-behavioral therapy (CBT) is effective in the treatment of depression within the context of PD (dPD). Method: The authors enrolled 8 depressed PD patients into an open treatment study of 12 weeks of individual CBT treatment. Results: There was a significant linear decrease in mean Hamilton Rating Scale for Depression (17-item) scores over Weeks 0 to 12, and 57% of patients (4/7) met criteria for remission at endpoint. Conclusion: This uncontrolled study suggests that CBT may be effective in treating dPD and may be an alternative or adjunct to pharmacological treatment. (Psychosomatics 2010; 51:124-129) C1 [Farabaugh, Amy] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Farabaugh, A (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 15 Parkman St,Wac 812, Boston, MA 02114 USA. EM afarabaugh@partners.org OI Alpert, Jonathan/0000-0002-4332-908X NR 38 TC 24 Z9 25 U1 9 U2 15 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 MAR-APR PY 2010 VL 51 IS 2 BP 124 EP 129 PG 6 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 573FZ UT WOS:000275895200005 PM 20332287 ER PT J AU Peteet, JR Maytal, G Rokni, H AF Peteet, John R. Maytal, Guy Rokni, Haleh TI Unimaginable Loss: Contingent Suicidal Ideation in Family Members of Oncology Patients SO PSYCHOSOMATICS LA English DT Article AB Background: Family members of patients with cancer may reveal to the medical team that they are considering suicide after their loved one dies. No literature is available indicating how to assess risk and to intervene with these individuals. Objective: The authors describe various alerting signs and seek to improve awareness and approaches to suicide prevention. Method: The authors present five cases of potential contingent suicide. Results: Family members struggling with anticipatory grief challenge the clinical team at several points of decision-making. Conclusion: Close coordination among members of the patient's treatment team and psychiatric consultants is crucial for helping vulnerable family members move safely into adequately supported bereavement. (Psychosomatics 2010; 51:166-170) C1 [Peteet, John R.; Maytal, Guy; Rokni, Haleh] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. RP Peteet, JR (reprint author), Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, 44 Binney St, Boston, MA 02115 USA. EM jpeteet@partners.org NR 6 TC 1 Z9 1 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 MAR-APR PY 2010 VL 51 IS 2 BP 166 EP 170 PG 5 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 573FZ UT WOS:000275895200010 PM 20332292 ER PT J AU Okechukwu, CA Krieger, N Chen, J Sorensen, G Li, Y Barbeau, EM AF Okechukwu, Cassandra A. Krieger, Nancy Chen, Jarvis Sorensen, Glorian Li, Yi Barbeau, Elizabeth M. TI The Association of Workplace Hazards and Smoking in a US Multiethnic Working-Class Population SO PUBLIC HEALTH REPORTS LA English DT Article ID RACIAL-DISCRIMINATION; CIGARETTE-SMOKING; SEXUAL-HARASSMENT; SOCIAL HAZARDS; UNITED-STATES; SELF-REPORT; HEALTH; RISK; CONSEQUENCES; PREVALENCE AB Objective. We investigated the extent to which smoking status was associated with exposure to occupational (e.g., dust, chemicals, noise, and ergonomic strain) and social (e.g., abuse, sexual harassment, and racial discrimination) workplace hazards in a sample of U.S. multiethnic working-class adults. Methods. United for Health is a cross-sectional study designed to investigate the combined burden of occupational and social workplace hazards in relation to race/ethnicity, gender, and wage and to evaluate related health effects in a working-class population. Using validated measures, we collected data from 1,282 multiethnic working-class participants using audio computer-assisted interviews. We used multiple imputation methods to impute data for those missing data. Crude and adjusted logistic odds ratios (ORs) were modeled to estimate ORs and 95% confidence intervals (CIs). Results. The prevalence of smoking was highest among non-Hispanic white workers (38.3%) and lowest for foreign-born workers (13.1%). We found an association between racial discrimination and smoking (OR=1.12, 95% Cl 1.01, 1.25). The relationship between smoking and sexual harassment, although not significant, was different for black women compared with men (OR=1.79, 95% Cl 0.99, 3.22). We did not find any associations by workplace abuse or by any of the occupational hazards. Conclusion. These results indicate that racial discrimination might be related to smoking in working-class populations and should be considered in tobacco-control efforts that target this high-risk population. C1 [Okechukwu, Cassandra A.] Univ Calif San Francisco & Berkeley, Robert Wood Johnson Hlth & Soc Scholars Program, Berkeley, CA 94709 USA. [Krieger, Nancy; Chen, Jarvis; Sorensen, Glorian; Li, Yi] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Barbeau, Elizabeth M.] Hlth Dialog Inc, Boston, MA USA. [Sorensen, Glorian; Li, Yi] Ctr Community Based Res, Dana Farber Canc Inst, Boston, MA USA. RP Okechukwu, CA (reprint author), Univ Calif San Francisco & Berkeley, Robert Wood Johnson Hlth & Soc Scholars Program, 3333 Calif St,Ste 465, Berkeley, CA 94709 USA. EM cassandrao@post.harvard.edu FU National Institute of Occupational Safety and Health [R01 OH07366-01]; Centers for Disease Control and Prevention/Association of Schools of Public Health Prevention Research Center FX The United for Health study was funded by grant #R01 OH07366-01 from the National Institute of Occupational Safety and Health to Elizabeth Barbeau. Cassandra Okechukwu was supported by the Centers for Disease Control and Prevention/Association of Schools of Public Health Prevention Research Center Fellowship. NR 53 TC 10 Z9 10 U1 1 U2 2 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 MAR-APR PY 2010 VL 125 IS 2 BP 225 EP 233 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 556OG UT WOS:000274599900010 PM 20297749 ER PT J AU Held, KD Kochevar, IE AF Held, Kathryn D. Kochevar, Irene E. TI Betsy Middleton Sutherland (1943-2009) IN MEMORIAM SO RADIATION RESEARCH LA English DT Biographical-Item C1 [Held, Kathryn D.; Kochevar, Irene E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Held, KD (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 3 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD MAR PY 2010 VL 173 IS 3 BP 401 EP 402 DI 10.1667/RR2082.1 PG 2 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 570OQ UT WOS:000275688000017 ER PT J AU Singh, AK Nachiappan, AC Verma, HA Uppot, RN Blake, MA Saini, S Boland, GW AF Singh, Ajay K. Nachiappan, Arun C. Verma, Hetal A. Uppot, Raul N. Blake, Michael A. Saini, Sanjay Boland, Giles W. TI Postoperative Imaging in Liver Transplantation: What Radiologists Should Know SO RADIOGRAPHICS LA English DT Article ID HEPATIC-ARTERY STENOSIS; VASCULAR COMPLICATIONS; BILIARY COMPLICATIONS; HEPATOBILIARY SCINTIGRAPHY; BILE LEAK; DIAGNOSIS; EXPERIENCE; THROMBOSIS; CT; CHOLANGIOGRAPHY AB Liver transplantation is now frequently used in the treatment of end-stage liver disease. Therefore, it is important that radiologists be aware of common anastomotic techniques and expected postoperative imaging findings. Imaging is most useful in evaluating for posttransplantation complications, which are broadly classified into vascular, biliary, and other complications. Hepatic artery thrombosis is the most significant complication and is often associated with graft failure. Radiologists have multiple modalities at their disposal for optimal evaluation. Doppler ultrasonography (US) is the preliminary imaging modality for gross evaluation of the liver parenchyma, biliary tree, and vasculature for abnormalities. When US findings are indeterminate or there is persistent clinical suspicion for an abnormality, computed tomography (CT) is often performed. The major indications for CT are detection of bile leak, hemorrhage, and abscess, but CT is also useful in the assessment of the vasculature. T-tube cholangiography and magnetic resonance cholangio-pancreatography are the best noninvasive imaging tools for evaluating for biliary stricture. Some investigators would argue that endoscopic retrograde cholangiopancreatography (ERCP) is a better diagnostic imaging modality; however, ERCP is invasive. Hepatobiliary scintigraphy is optimal for the evaluation of biliary leakage. Early detection of posttransplantation complications will help lower morbidity rates and will likely allow graft salvage in selected cases. (C)RSNA, 2010.radiographics.rsna.org C1 [Singh, Ajay K.; Nachiappan, Arun C.; Uppot, Raul N.; Blake, Michael A.; Saini, Sanjay; Boland, Giles W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Verma, Hetal A.] Univ Massachusetts, Mem Med Ctr, Dept Radiol, Worcester, MA 01605 USA. RP Singh, AK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 175 Cambridge St,2nd Floor, Boston, MA 02114 USA. EM mghpartners@yahoo.com FU Mersucy Systems FX S. S. received a research grant from Mersucy Systems, G. W. is a principal with RCG HealthCare Consulting; all other authors have no financial relationships to disclose. NR 37 TC 35 Z9 38 U1 0 U2 0 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 MAR PY 2010 VL 30 IS 2 BP 339 EP 351 DI 10.1148/rg.302095124 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 569SV UT WOS:000275622400005 PM 20228321 ER PT J AU Chung, JH Ghoshhajra, BB Rojas, CA Dave, BR Abbara, S AF Chung, Jonathan H. Ghoshhajra, Brian B. Rojas, Carlos A. Dave, Bhavika R. Abbara, Suhny TI CT Angiography of the Thoracic Aorta SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Thoracic aortic aneurysm; Aortic dissection; Aortic transection; Intramural hematoma; Aortic coarctation; CT angiography; MDCT ID COMPUTED-TOMOGRAPHY; NATURAL-HISTORY; ASCENDING AORTA; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; INTERNATIONAL REGISTRY; INTRAMURAL HEMORRHAGE; BALLOON ANGIOPLASTY; IMAGING FEATURES; DISSECTION IRAD; HELICAL CT AB Patients with thoracic aortic diseases may be completely asymptomatic (as in thoracic aortic aneurysms) or present acutely with severe chest pain (as in acute aortic dissections). Thoracic aortic disease is often occult until a life-threatening complication occurs or the disease is discovered incidentally on imaging. Multidetector-row computed tomography (MDCT) can be used to diagnose various acute and chronic abnormalities of the aorta, including aortic aneurysms, aortic dissection, intramural hematoma, penetrating atherosclerotic ulcer, traumatic aortic transection, and congenital malformations. This article reviews the MDCT appearance of various thoracic aortic diseases. C1 [Abbara, Suhny] Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Chung, Jonathan H.; Ghoshhajra, Brian B.; Rojas, Carlos A.; Dave, Bhavika R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Abbara, S (reprint author), Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,GRB 290, Boston, MA 02114 USA. EM sabbara@partners.org RI Ghoshhajra, Brian/J-2114-2016 OI Ghoshhajra, Brian/0000-0002-3865-3432 NR 86 TC 11 Z9 13 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 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD MAR PY 2010 VL 48 IS 2 BP 249 EP + DI 10.1016/j.rcl.2010.02.001 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 625AY UT WOS:000279865000004 PM 20609873 ER PT J AU Almandoz, JED Romero, JM Pomerantz, SR Lev, MH AF Almandoz, Josser E. Delgado Romero, Javier M. Pomerantz, Stuart R. Lev, Michael H. TI Computed Tomography Angiography of the Carotid and Cerebral Circulation SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE CT angiography; Neuroradiology; Multidetector row CT; Acute stroke ID DIGITAL-SUBTRACTION-ANGIOGRAPHY; ROW CT ANGIOGRAPHY; PRIMARY INTRACEREBRAL HEMORRHAGE; ANEURYSMAL SUBARACHNOID HEMORRHAGE; CONTRAST-INDUCED NEPHROPATHY; ACUTE STROKE PATIENTS; RUPTURED INTRACRANIAL ANEURYSMS; LUMINAL DIAMETER MEASUREMENTS; INITIAL CLINICAL-EXPERIENCE; PREDICTS HEMATOMA EXPANSION AB As a result of the development of multidetector row computed tomography (CT) technology, multidetector CT angiography is rapidly becoming the preferred examination for the initial evaluation of an increasing number of clinical neurovascular applications such as carotid artery steno-occlusive disease, acute ischemic and hemorrhagic stroke, subarachnoid hemorrhage, and cerebral vasospasm. This article reviews the most recent literature on these topics, provides the reader with useful clinical tips for performing and interpreting these increasingly complex diagnostic examinations, presents illustrative cases, and looks at future developments in this vibrant area of neuroradiology research. C1 [Almandoz, Josser E. Delgado] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, Div Neuroradiol, St Louis, MO 63110 USA. [Almandoz, Josser E. Delgado; Romero, Javier M.; Pomerantz, Stuart R.; Lev, Michael H.] Harvard Univ, Div Neuroradiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Almandoz, JED (reprint author), Washington Univ, Sch Med, Mallinckrodt Inst Radiol, Div Neuroradiol, Campus Box 8131,510 S Kingshighway Blvd, St Louis, MO 63110 USA. EM delgadoj@mir.wustl.edu NR 114 TC 13 Z9 14 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 MAR PY 2010 VL 48 IS 2 BP 265 EP + DI 10.1016/j.rcl.2010.02.007 PG 19 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 625AY UT WOS:000279865000005 ER PT J AU Perez-Johnston, R Lenhart, DK Sahani, DV AF Perez-Johnston, Rocio Lenhart, Dipti K. Sahani, Dushyant V. TI CT Angiography of the Hepatic and Pancreatic Circulation SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Multidetector computed tomography angiography; Hepatic imaging; Pancreatic imaging ID PORTAL-VEIN THROMBOSIS; BUDD-CHIARI-SYNDROME; ROW HELICAL CT; MULTIDETECTOR COMPUTED-TOMOGRAPHY; SPLANCHNIC ARTERY ANEURYSMS; HEPATOCELLULAR-CARCINOMA; CONTRAST ENHANCEMENT; PERFUSION DISORDERS; DYSPLASTIC NODULES; NONCIRRHOTIC LIVER AB Multidetector computed tomography angiography (MDCTA) is an established, non-invasive, and effective imaging method to evaluate the liver and the pancreas primarily for neoplasm staging and presurgical planning. However, its role has also extended into a variety of other clinical indications. Technological advances in MDCT scanners and post processing now offer new opportunities with CTA, but the challenges of protocol optimization should be confronted appropriately to meet the new expectations. In this review, we focus on the technical details with MDCTA protocols for liver and pancreas and briefly discuss the common pathologic conditions where CTA is now considered integral to patient management. C1 [Perez-Johnston, Rocio; Lenhart, Dipti K.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Imaging, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Imaging, 270 White,55 Fruit St, Boston, MA 02114 USA. EM dsahani@partners.org NR 55 TC 7 Z9 7 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 0033-8389 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD MAR PY 2010 VL 48 IS 2 BP 311 EP + DI 10.1016/j.rcl.2010.02.021 PG 21 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 625AY UT WOS:000279865000007 PM 20609876 ER PT J AU Lee, JM McMahon, PM Kong, CY Kopans, DB Ryan, PD Ozanne, EM Halpern, EF Gazelle, GS AF Lee, Janie M. McMahon, Pamela M. Kong, Chung Y. Kopans, Daniel B. Ryan, Paula D. Ozanne, Elissa M. Halpern, Elkan F. Gazelle, G. Scott TI Cost-effectiveness of Breast MR Imaging and Screen-Film Mammography for Screening BRCA1 Gene Mutation Carriers SO RADIOLOGY LA English DT Article ID HIGH FAMILIAL RISK; OVARIAN-CANCER; DECISION-ANALYSIS; WOMEN; SURVEILLANCE; PREDISPOSITION; ULTRASOUND; OOPHORECTOMY; GUIDELINES; CARCINOMA AB Purpose: To evaluate the clinical effectiveness and cost- effectiveness of screening strategies in which MR imaging and screen-film mammography were used, alone and in combination, in women with BRCA1 mutations. Materials and Methods: Because this study did not involve primary data collection from individual patients, institutional review board approval was not needed. By using a simulation model, we compared three annual screening strategies for a cohort of 25-year-old BRCA1 mutation carriers, as follows: (a) screen-film mammography, (b) MR imaging, and (c) combined MR imaging and screen-film mammography (combined screening). The model was used to estimate quality-adjusted life-years (QALYs) and lifetime costs. Incremental cost-effectiveness ratios were calculated. Input parameters were obtained from the medical literature, existing databases, and calibration. Costs (2007 U.S. dollars) and quality-of-life adjustments were derived from Medicare reimbursement rates and the medical literature. Sensitivity analysis was performed to evaluate the effect of uncertainty in parameter estimates on model results. Results: In the base-case analysis, annual combined screening was most effective (44.62 QALYs), and had the highest cost ($110973), followed by annual MR imaging alone (44.50 QALYs, $108641), and annual mammography alone (44.46 QALYs, $100336). Adding annual MR imaging to annual mammographic screening cost $69125 for each additional QALY gained. Sensitivity analysis indicated that, when the screening MR imaging cost increased to $960 (base case, $577), or breast cancer risk by age 70 years decreased below 58% (base case, 65%), or the sensitivity of combined screening decreased below 76% (base case, 94%), the cost of adding MR imaging to mammography exceeded $100000 per QALY. Conclusion: Annual combined screening provides the greatest life expectancy and is likely cost-effective when the value placed on gaining an additional QALY is in the range of $50000-$100000. (C) RSNA, 2010 C1 [Lee, Janie M.; McMahon, Pamela M.; Kong, Chung Y.; Kopans, Daniel B.; Ozanne, Elissa M.; Halpern, Elkan F.; Gazelle, G. Scott] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lee, Janie M.; McMahon, Pamela M.; Kong, Chung Y.; Ozanne, Elissa M.; Halpern, Elkan F.; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Ryan, Paula D.] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. [Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM jlee45@partners.org FU National Cancer Institute [K07CA128816]; Breast Cancer Surveillance Consortium [U01CA63740, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040] FX This research was supported by the National Cancer Institute (grant K07CA128816) and the Breast Cancer Surveillance Consortium (grants U01CA63740, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040).; Authors stated no financial relationship to disclose. NR 44 TC 31 Z9 31 U1 0 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 MAR PY 2010 VL 254 IS 3 BP 793 EP 800 DI 10.1148/radiol.09091086 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 559CA UT WOS:000274796200020 PM 20177093 ER PT J AU Nishino, M Patrick, JL Connors, JM AF Nishino, Mizuki Patrick, James L. Connors, Jean M. TI Case 155: Lane-Hamilton Syndrome SO RADIOLOGY LA English DT Editorial Material ID IDIOPATHIC PULMONARY HEMOSIDEROSIS; CELIAC-DISEASE; HEMORRHAGE C1 [Nishino, Mizuki; Patrick, James L.] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Connors, Jean M.] Brigham & Womens Hosp, Dana Farber Canc Inst, Div Hematol, Boston, MA 02115 USA. RP Nishino, M (reprint author), Dana Farber Canc Inst, Dept Radiol, 44 Binney St,DL 101, Boston, MA 02115 USA. EM Mizuki_Nishino@dfci.harvard.edu NR 11 TC 3 Z9 3 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 MAR PY 2010 VL 254 IS 3 BP 985 EP 988 DI 10.1148/radiol.09082062 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 559CA UT WOS:000274796200043 PM 20177110 ER PT J AU Abujudeh, H Kaewlai, R AF Abujudeh, Hani Kaewlai, Rathachai TI E-Mail Alert System Enables Communication of Important but Nonurgent Radiologic Findings Response SO RADIOLOGY LA English DT Letter C1 [Abujudeh, Hani; Kaewlai, Rathachai] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Abujudeh, H (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,FND 213D, Boston, MA 02114 USA. EM habujudeh@partners.org NR 3 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 MAR PY 2010 VL 254 IS 3 BP 991 EP 992 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 559CA UT WOS:000274796200048 ER PT J AU Pastor-Soler, NM Fisher, JS Sharpe, R Hill, E Van Hoek, A Brown, D Breton, S AF Pastor-Soler, Nuria M. Fisher, Jane S. Sharpe, Richard Hill, Eric Van Hoek, Alfred Brown, Dennis Breton, Sylvie TI Aquaporin 9 expression in the developing rat epididymis is modulated by steroid hormones SO REPRODUCTION LA English DT Article ID MALE REPRODUCTIVE-SYSTEM; NEONATAL ESTROGEN EXPOSURE; EFFERENT DUCTS; POSTNATAL-DEVELOPMENT; CAUDA-EPIDIDYMIDIS; WATER CHANNEL; VAS-DEFERENS; FLUID REABSORPTION; EPITHELIAL-CELLS; INITIAL SEGMENT AB Fluid and solute transport across the epithelium of the male excurrent duct is important for sperm maturation and storage. Aquaporin 9 (AQP9), which allows permeation of water and neutral solutes, is abundant throughout the male reproductive tract, where it is expressed at the apical membrane of rat epididymal principal cells as early as at I week of age. We evaluated the effect of neonatal exposure to: 1) a GNRH antagonist (GNRHa); 2) diethylstilbestrol (DES); 3) ethinyl estradiol (EE); 4) DES plus testosterone (DES + TE); and 5) the anti-androgen flutamide on AQP9 expression in the epididymis of peripubertal rats. Control groups received the vehicle alone. In 25-day-old rats, quantification of the mean pixel intensity of immunofluorescence-stained sections showed a significant decrease in AQP9 staining in the apical membrane of epididymal principal cells after treatments with GNRHa, DES, or flutamide, compared to controls. These results were confirmed by western blotting. While EE induced a marked decrease in AQP9 levels by western blotting, the decrease in AQP9-associated fluorescence was not significant compared to controls. DES + TE-treated rats showed levels of AQP9 protein similar to controls, indicating maintenance of AQP9 expression by testosterone treatment in the presence of DES. Our data show that expression of AQP9 in the developing rat epididymis is downregulated by neonatal DES, GNRHa, EE, and flutamide, and that the effects mediated by estrogens can be prevented by testosterone administration. Reproduction (2010) 139 613-621 C1 [Pastor-Soler, Nuria M.; Hill, Eric; Van Hoek, Alfred; Brown, Dennis; Breton, Sylvie] Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. [Pastor-Soler, Nuria M.; Hill, Eric; Van Hoek, Alfred; Brown, Dennis; Breton, Sylvie] Massachusetts Gen Hosp, Ctr Syst Biol, Div Nephrol, Boston, MA 02114 USA. [Pastor-Soler, Nuria M.; Van Hoek, Alfred; Brown, Dennis; Breton, Sylvie] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Fisher, Jane S.; Sharpe, Richard] Ctr Reprod Biol, Queens Med Res Inst, MRC, Human Reprod Sci Unit, Edinburgh EH16 4TJ, Midlothian, Scotland. RP Breton, S (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, 185 Cambridge St,Suite CPZN 8-204, Boston, MA 02114 USA. EM breton.sylvie@mgh.harvard.edu RI Sharpe, Richard/D-2725-2013 OI Sharpe, Richard/0000-0003-1686-8085 FU NIH [HD45821, DK38452]; NIH NRSA [HD08684]; European Union [QLK4-1999-01422] FX This work was supported by NIH grants HD45821 (S Breton), DK38452 (D Brown and S Breton). N M Pastor-Soler was supported by an NIH NRSA award HD08684. J S Fisher was supported by contract QLK4-1999-01422 from the European Union. NR 55 TC 21 Z9 21 U1 0 U2 1 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1470-1626 J9 REPRODUCTION JI Reproduction PD MAR PY 2010 VL 139 IS 3 BP 613 EP 621 DI 10.1530/REP-09-0284 PG 9 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 563PH UT WOS:000275144500013 PM 19948840 ER PT J AU Wang, N Guo, LK Rueda, BR Tilly, JL AF Wang, Ning Guo, Lankai Rueda, Bo R. Tilly, Jonathan L. TI Stabilization of TAp63 by CABLES1 Mediates Radiotherapy-Induced Oocyte Death SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Wang, Ning; Guo, Lankai; Rueda, Bo R.; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Vincent Ctr Reprod Biol,Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 4 BP 67A EP 68A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600006 ER PT J AU Doyle, JO Guo, LK Tilly, JL Rueda, BR Lee, HJ AF Doyle, Joseph O. Guo, Lankai Tilly, Jonanthan L. Rueda, Bo R. Lee, Ho-Joon TI Germ Cell Expansion in Cables1-Null Male Mice. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Doyle, Joseph O.; Guo, Lankai; Tilly, Jonanthan L.; Rueda, Bo R.; Lee, Ho-Joon] Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 276 BP 142A EP 143A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600275 ER PT J AU Janakiraman, V Kaimal, A Ecker, J AF Janakiraman, Vanitha Kaimal, Anjali Ecker, Jeffrey TI Are Induced and Spontaneous Labor Different in the Second Stage? SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Janakiraman, Vanitha; Kaimal, Anjali; Ecker, Jeffrey] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 457 BP 195A EP 195A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600456 ER PT J AU Powe, CE Thadhani, R Tjoa, ML Khankin, E Ye, J Ecker, J Schneyer, A Karumanchi, SA AF Powe, Camille E. Thadhani, Ravi Tjoa, May Lee Khankin, Eliyahu Ye, Jun Ecker, Jeffrey Schneyer, Alan Karumanchi, S. Ananth TI First Trimester FSTL3 Levels in Pregnancies Complicated by Subsequent Gestational Diabetes Mellitus SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Powe, Camille E.; Thadhani, Ravi; Ye, Jun; Ecker, Jeffrey] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Tjoa, May Lee; Khankin, Eliyahu; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA USA. [Tjoa, May Lee; Khankin, Eliyahu; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Boston, MA USA. Univ Massachusetts, Pioneer Life Sci Inst, Amhearst, MA USA. [Schneyer, Alan; Karumanchi, S. Ananth] Howard Hughes Med Inst, Chevy Chase, MD USA. [Powe, Camille E.; Thadhani, Ravi; Ecker, Jeffrey; Karumanchi, S. Ananth] Harvard Univ, Sch Med, Boston, MA USA. RI Khankin, Eli/M-7648-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 476 BP 201A EP 201A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558600475 ER PT J AU Janakiraman, V Wylie, BJ AF Janakiraman, Vanitha Wylie, Blair J. TI Sheehan's Syndrome during Pregnancy: A Case Report and Review of the Literature. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Janakiraman, Vanitha; Wylie, Blair J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 849 BP 309A EP 310A PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601323 ER PT J AU Woods, DC White, YAR Wood, AW Tilly, JL AF Woods, Dori C. White, Yvonne A. R. Wood, Antony W. Tilly, Jonathan L. TI Isolation of VASA-Positive Cells Using Immunomagnetic Cell Sorting. SO REPRODUCTIVE SCIENCES LA English DT Meeting Abstract CT 57th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 24-27, 2010 CL Orlando, FL SP Soc Gynecol Investigat C1 [Woods, Dori C.; White, Yvonne A. R.; Wood, Antony W.; Tilly, Jonathan L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Ctr Reprod Biol,Vincent OB GYN Serv, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD MAR PY 2010 VL 17 IS 3 SU S MA 949 BP 338A EP 338A PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 568XE UT WOS:000275558601422 ER PT J AU Mauri, T Berra, L Kumwilaisak, K Pivi, S Ufberg, JW Kueppers, F Pesenti, A Bigatello, LM AF Mauri, Tommaso Berra, Lorenzo Kumwilaisak, Kanya Pivi, Silvia Ufberg, Jacob W. Kueppers, Friedrich Pesenti, Antonio Bigatello, Luca M. TI Lateral-Horizontal Patient Position and Horizontal Orientation of the Endotracheal Tube to Prevent Aspiration in Adult Surgical Intensive Care Unit Patients: A Feasibility Study SO RESPIRATORY CARE LA English DT Article DE lateral-horizontal position; pepsin; prevention; aspiration of gastric contents; ventilator-associated pneumonia ID VENTILATOR-ASSOCIATED PNEUMONIA; GASTRIC CONTENTS; PULMONARY ASPIRATION; SEMIRECUMBENT POSITION; TRACHEAL INTUBATION; RANDOMIZED-TRIAL; PRONE-POSITION; BODY POSITION; PEPSIN; COLONIZATION AB BACKGROUND: Recent data suggest that during mechanical ventilation the lateral-horizontal patient position (in which the endotracheal tube is horizontal) decreases the risk of ventilator-associated pneumonia, compared to the recommended semi-recumbent position (in which the endotracheal tube slopes downward into the trachea). We tested the feasibility of the lateral-horizontal patient position, measured the incidence of aspiration of gastric contents, and watched for any adverse effects related to the lateral-horizontal position. METHODS: Ten adult intensive care unit patients were ventilated for 64 hours in the standard semi-recumbent position, and ten for 12 24 hours in the lateral-horizontal position. Tracheal secretions were collected every 8 hours and every 4 hours, respectively, and tested for pepsin, which is a marker of gastric contents. We also recorded clinical, physiologic, and outcome variables. RESULTS: The patients remained stable during ventilation in the lateral-horizontal position, and no adverse events occurred. Pepsin was detected in the trachea of 7 semi-recumbent patients and in five of the lateral-horizontal patients (P = .32). The number of ventilator-free days was 8 days (range 0-21 days) in the semi-recumbent patients, versus 24 days (range 12-25 days) in the lateral-horizontal patients (P = .04). CONCLUSIONS: Implementing the lateral-horizontal position for 12-24 hours in adult intubated intensive care unit patients is feasible, and our patients had no adverse events. The incidence of aspiration of gastric contents in the lateral-horizontal position seems to be similar to that in the semi-recumbent position. C1 [Bigatello, Luca M.] Harvard Univ, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Mauri, Tommaso; Pesenti, Antonio] Univ Milano Bicocca, Dept Perioperat Med & Intens Care, San Gerardo Hosp, Monza, Italy. [Kumwilaisak, Kanya] Chulalongkorn Univ, Dept Anesthesia, Bangkok, Thailand. [Pivi, Silvia] St Orsola Marcello Malpighi Hosp, Dept Anesthesia, Bologna, Italy. [Ufberg, Jacob W.; Kueppers, Friedrich] Temple Univ, Dept Med, Sch Med, Philadelphia, PA 19122 USA. RP Bigatello, LM (reprint author), Harvard Univ, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM lbigatello@partners.org RI Pesenti, Antonio/H-7483-2012 NR 31 TC 28 Z9 31 U1 0 U2 0 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 J9 RESP CARE JI Respir. Care PD MAR PY 2010 VL 55 IS 3 BP 294 EP 302 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 576VL UT WOS:000276177600003 PM 20196878 ER PT J AU Shiotani, A Haruma, K Nishi, R Fujita, M Kamada, T Honda, K Kusunoki, H Hata, J Graham, DY AF Shiotani, Akiko Haruma, Ken Nishi, Ryuji Fujita, Minoru Kamada, Tomoari Honda, Keisuke Kusunoki, Hiroaki Hata, Jiro Graham, David Y. TI Randomized, double-blind, pilot study of geranylgeranylacetone versus placebo in patients taking low-dose enteric-coated aspirin. Low-dose aspirin-induced small bowel damage SO SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; GASTRIC-MUCOSAL CELLS; VIDEO CAPSULE ENDOSCOPY; INTESTINAL PERMEABILITY; EXPERIMENTAL PATHOLOGY; FIBROSING COLONOPATHY; HEALTHY-SUBJECTS; PLUS OMEPRAZOLE; INJURY; INFLAMMATION AB Objective. Low-dose enteric-coated aspirin is increasingly being used for prevention of cardiovascular disease. The aim of this study was to evaluate whether geranylgeranylacetone (GGA) could prevent aspirin-induced small bowel injury. Material and methods. This was a prospective, randomized, double-blind, pilot study of GGA versus placebo in subjects taking low-dose enteric-coated aspirin. Young healthy volunteers were enrolled and each received 100 mg of enteric-coated aspirin per day plus either GGA (150 mg/day) or matching placebo for 7 days. Video capsule endoscopy of the small bowel and the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire were performed before and after the administration of aspirin. Results. Twenty volunteers were evaluated. There was no significant difference in the number of lesions in any category between those receiving or not receiving GGA. Large erosions or ulcers were observed in 12 (60%; 95% confidence interval 36%- 80%) aspirin users. Mucosal breaks were most frequently found in the latter half of the proximal small bowel. Conclusions. Short-term administration of low-dose enteric-coated aspirin was associated with visible small bowel damage in the majority of users. We could not prove that aspirin-induced small bowel mucosal injury was prevented by GGA. C1 [Shiotani, Akiko; Haruma, Ken; Nishi, Ryuji; Fujita, Minoru; Kamada, Tomoari] Kawasaki Med Univ, Dept Internal Med, Okayama, Japan. [Honda, Keisuke; Kusunoki, Hiroaki] Kawasaki Med Univ, Dept Comprehens Med, Okayama, Japan. [Hata, Jiro] Kawasaki Med Univ, Dept Clin Pathol & Lab Med, Okayama, Japan. [Graham, David Y.] VA Med Ctr, Dept Med, Houston, TX USA. [Graham, David Y.] Baylor Coll Med, Houston, TX 77030 USA. RP Shiotani, A (reprint author), 577 Matsushima, Kurashiki, Okayama 7010192, Japan. EM shiotani@med.kawasaki-m.ac.jp NR 36 TC 42 Z9 42 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA KARL JOHANS GATE 5, NO-0154 OSLO, NORWAY SN 0036-5521 J9 SCAND J GASTROENTERO JI Scand. J. Gastroenterol. PD MAR PY 2010 VL 45 IS 3 BP 292 EP 298 DI 10.3109/00365520903453182 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 559VR UT WOS:000274856600005 PM 19968611 ER PT J AU Kim, MA Tura, E Potkin, SG Fallon, JH Manoach, DS Calhoun, VD Turner, JA AF Kim, Miyoung A. Tura, Emanuela Potkin, Steven G. Fallon, James H. Manoach, Dara S. Calhoun, Vince D. Turner, Jessica A. CA FBIRN TI Working memory circuitry in schizophrenia shows widespread cortical inefficiency and compensation SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Working memory; Functional magnetic resonance imaging; Partial least squares; Multivariate analysis; Neurocircuitry ID DORSOLATERAL PREFRONTAL CORTEX; MATTER VOLUME ABNORMALITIES; PARTIAL LEAST-SQUARES; EVENT-RELATED FMRI; DYSFUNCTION; PERFORMANCE; ACTIVATION; RETRIEVAL; TASK; MRI AB Background: Working memory studies in schizophrenia (SZ), using functional magnetic resonance imaging (fMRI) and univariate analyses, have led to observations of hypo- or hyperactivation of discrete Cortical regions and subsequent interpretations (e.g. neural inefficiencies). We employed a data-driven, multivariate analysis to identify the patterns of brain-behavior relationships in SZ during working memory. Methods: fMRI scans were collected from 13 SZ and 18 healthy control (HC) participants performing a modified Sternberg item recognition paradigm with three memory loads. We applied partial least squares analysis (PLS) to assess brain activation during the task both alone and with behavioral measures (accuracy and response time, RT) as covariates. Results: While the HC primary pattern was not affected by increasing load demands, SZ participants showed an exaggerated change in the Blood Oxygenation Level Dependent (BOLD) signal from the low to moderate memory load conditions and subsequent decrease in the greatest memory load, in frontal, motor, parietal and subcortical areas. With behavioral covariates, the separate groups identified distinct brain-behavior relationships and circuits. Increased activation of the middle temporal gyrus was associated with greater accuracy and faster RT only in SZ. Conclusions: The inverted U-shaped curves in the SZ BOLD signal in the same areas that show flat activation in the HC data indicate widespread neural inefficiency in working memory in SZ. While both groups performed the task with similar levels of accuracy, participants with schizophrenia show a compensatory network of different sub-regions of the prefrontal Cortex, parietal lobule. and the temporal gyri in this working memory task. (C) 2009 Elsevier B.V. All rights reserved. C1 [Kim, Miyoung A.; Potkin, Steven G.; Fallon, James H.; Turner, Jessica A.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92617 USA. [Tura, Emanuela] Univ British Columbia, Fac Med, Vancouver, BC V6T 1Z3, Canada. [Manoach, Dara S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Manoach, Dara S.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Calhoun, Vince D.] Mind Res Network, Albuquerque, NM 87131 USA. [Calhoun, Vince D.] Univ New Mexico, Dept ECE, Albuquerque, NM 87131 USA. RP Turner, JA (reprint author), 5251 Calif Ave,Suite 240, Irvine, CA 92617 USA. EM jessica.turner@uci.edu RI Potkin, Steven/A-2021-2013; Calhoun, Vince/H-7146-2013; Turner, Jessica/H-7282-2015; OI Calhoun, Vince/0000-0001-9058-0747; Turner, Jessica/0000-0003-0076-8434; Potkin, Steven/0000-0003-1028-1013 FU Functional Imaging Biomedical Informatics Research Network (FBIRN) [U24 RR021392]; National Center for Research Resources; National Institutes of Health FX Support for this research was provided in part by the Functional Imaging Biomedical Informatics Research Network (FBIRN) (U24 RR021392), National Center for Research Resources, and the National Institutes of Health. The members of the FBIRN project all deserve acknowledgement for their significant efforts,but unfortunately, they are too numerous to mention. Please visit http://www.fbim.org for more information regarding key personnel. Parts of these analyses were presented at the Annual Meeting of the Society for Neuroscience in 2007. NR 47 TC 31 Z9 32 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 MAR PY 2010 VL 117 IS 1 BP 42 EP 51 DI 10.1016/j.schres.2009.12.014 PG 10 WC Psychiatry SC Psychiatry GA 569FO UT WOS:000275582200005 PM 20096539 ER PT J AU Williams, ME AF Williams, Mark E. TI Improving Outcomes for Diabetic Patients on Dialysis-An Introduction SO SEMINARS IN DIALYSIS LA English DT Article C1 [Williams, Mark E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Med, Boston, MA 02115 USA. [Williams, Mark E.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Williams, ME (reprint author), 1 Joslin Pl, Boston, MA 02215 USA. EM mark.williams@joslin.harvard.edu NR 1 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 0894-0959 J9 SEMIN DIALYSIS JI Semin. Dial. PD MAR-APR PY 2010 VL 23 IS 2 BP 127 EP 128 DI 10.1111/j.1525-139X.2010.00715.x PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 583FH UT WOS:000276658300001 PM 20525105 ER PT J AU Williams, ME AF Williams, Mark E. TI Diabetic CKD/ESRD 2010: A Progress Report? SO SEMINARS IN DIALYSIS LA English DT Article ID STAGE RENAL-DISEASE; UNITED-STATES; NEPHROPATHY; PREVALENCE; LOSARTAN; PROJECTIONS; POPULATION; SURVIVAL; DIALYSIS; THERAPY AB Both in the United States and many regions of the world, chronic kidney disease and end-stage renal disease (ESRD) in patients with diabetes mellitus have reached epidemic proportions in recent years. The large prevalent diabetic ESRD population in the US involves remarkable risk in African Americans and an increasing population of elderly diabetic patients, including many octogenarians. In the US and globally, over 90% of diabetic ESRD patients have type 2 diabetes. The multinational epidemic of diabetic ESRD has been linked to increases in the prevalence of diabetes in many populations, related to obesity, ageing, and physical inactivity. It is anticipated that the worldwide prevalence of diabetes over the next 20 years will reach a level twice that of the year 2000. The excessive morbidity and mortality of the diabetic ESRD population are well documented. However, the growth in incidence and prevalence rates for diabetic ESRD has remained somewhat stable in the US in recent years, and new data suggest that the incidence of ESRD expressed per diabetic population may finally be declining, suggesting that proven therapies are making "progress on progression.". C1 [Williams, Mark E.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Med, Boston, MA 02115 USA. [Williams, Mark E.] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Williams, ME (reprint author), 1 Joslin Pl, Boston, MA 02215 USA. EM mark.williams@joslin.harvard.edu NR 29 TC 29 Z9 30 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-0959 EI 1525-139X J9 SEMIN DIALYSIS JI Semin. Dial. PD MAR-APR PY 2010 VL 23 IS 2 BP 129 EP 133 DI 10.1111/j.1525-139X.2009.00698.x PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 583FH UT WOS:000276658300002 PM 20210917 ER PT J AU Mahnensmith, RL Zorzanello, M Hsu, YH Williams, ME AF Mahnensmith, Rex L. Zorzanello, Mary Hsu, Yueh-Han Williams, Mark E. TI A Quality Improvement Model for Optimizing Care of the Diabetic End-Stage Renal Disease Patient SO SEMINARS IN DIALYSIS LA English DT Article ID BLOOD-GLUCOSE CONTROL; GLYCEMIC CONTROL; HEMODIALYSIS-PATIENTS; DIALYSIS UNIT; COMPLICATIONS; SURVIVAL AB Persons with diabetes mellitus whose kidney disease progresses to end-stage requiring dialysis have poorer outcomes compared to nondiabetic patients who commence maintenance dialysis. In the diabetic patient without renal failure, sustained strict glycemic, lipid, and blood pressure (BP) control can retard or thwart diabetic complications such as retinopathy, neuropathy, coronary disease, and peripheral vascular disease. Achieving these outcomes requires multidisciplinary collaborative care. Best care of the diabetic person requires a dedicated clinician who knows the patient well, who closely follows the course of clinical problems, who provides frequent assessments and interventions, and who also directs care to other agencies, clinics, and specialized clinicians who provide expert focused evaluations and interventions aimed at specific clinical concerns. Diabetic patients who reach end-stage renal disease (ESRD) have even greater clinical need of a dedicated principal care clinician than the diabetic patient who has minimal or moderate kidney disease. The diabetic patient with ESRD exhibits greater fluctuations in glucose and BP due to dialysis-related diet patterns and fluid balances and has more active cardiovascular problems due to the combined influences of calcium, phosphorus, and lipid imbalances. These problems warrant exceptional care that includes frequent surveillance and monitoring with timely interventions if patient outcomes are to be improved. We present here a quality improvement model for optimizing care of the diabetic dialysis patient that relies on a dedicated practitioner who can evaluate and intervene on the multiple variables within and beyond the dialysis clinic that impact the patient's health. We present three detailed clinical care pathways that the dedicated clinician can follow. We believe that patient outcomes can be improved with this approach that provides customized problem-focused care, collaborates with the dialysis-provider team, and extends and directs diabetic self-care, home-care, and specialized clinical care in the challenging areas of cardiac and peripheral vascular disease, glycemic control, lipid control, infection prevention, and BP management. C1 [Mahnensmith, Rex L.; Zorzanello, Mary] Yale Univ, Nephrol Sect, Dept Internal Med, Sch Med, New Haven, CT 06520 USA. [Hsu, Yueh-Han] Chia Yi Christian Hosp, Nephrol Sect, Dept Internal Med, Chiayi, Taiwan. [Williams, Mark E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Med, Sch Med, Boston, MA 02215 USA. [Williams, Mark E.] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Mahnensmith, RL (reprint author), Yale Univ, Nephrol Sect, Dept Internal Med, Sch Med, POB 208029, New Haven, CT 06520 USA. EM rex.mahnensmith@yale.edu NR 18 TC 6 Z9 6 U1 0 U2 1 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 MAR-APR PY 2010 VL 23 IS 2 BP 206 EP 213 DI 10.1111/j.1525-139X.2010.00717.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 583FH UT WOS:000276658300013 PM 20525109 ER PT J AU Zhang, ZL Rosenbaum, J Zhong, WW Lim, C Hinrichs, D AF Zhang, Zili Rosenbaum, James T. Zhong, Wenwei Lim, Carmen Hinrichs, David J. TI Costimulation of Th17 cells: adding fuel or putting out the fire in the inflamed gut? SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE CD4+T cells; Costimulatory molecules; Crohn's disease; Inflammatory bowel disease; Th17 cells; Ulcerative colitis ID INFLAMMATORY-BOWEL-DISEASE; CD4(+) T-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ACTIVE CROHNS-DISEASE; NF-KAPPA-B; HUMAN COLONIC MYOFIBROBLASTS; GENOME-WIDE ASSOCIATION; HEPATITIS-A VIRUS; ULCERATIVE-COLITIS; RHEUMATOID-ARTHRITIS AB Inflammatory bowel disease, typified by Crohn's disease and ulcerative colitis, is a common disorder characterized by recurrent and serious inflammation of the gastrointestinal tract. It is well documented that T cells play a pivotal role in the development of inflammatory bowel disease. Th17 cells are a unique T cell subpopulation implicated in inflammatory bowel disease and many other autoimmune/inflammatory diseases. However, the regulatory mechanism of Th17 activation and proliferation has not been defined completely. Recent studies have shown that the ligation of several costimulatory receptor-ligand pairs contributes to the activation, differentiation, and proliferation of T lymphocytes including the Th17 subset. In this review, we will discuss the emerging evidence on the role of Th17 cells in inflammatory bowel disease pathogenesis as well as the effect of costimulatory molecules on Th17 development and consider if the need for such costimulation of T lymphocytes provides a target for the development of novel therapeutic strategy. C1 [Zhang, Zili; Zhong, Wenwei] Oregon Hlth & Sci Univ, Dept Pediat, CDRC, Portland, OR 97239 USA. [Rosenbaum, James T.; Lim, Carmen] Oregon Hlth & Sci Univ, Dept Internal Med, Portland, OR 97239 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97239 USA. [Hinrichs, David J.] Portland VA Med Ctr, Portland, OR 97239 USA. RP Zhang, ZL (reprint author), Oregon Hlth & Sci Univ, Dept Pediat, CDRC, 707 Gaines St, Portland, OR 97239 USA. EM zhangzi@ohsu.edu FU National Institutes of Health [HD033703-10, EY016788, EY013093, EY006484]; Digestive Health and Nutrition Foundation/CCFA Young Investigator Award; Research to Prevent Blindness; Stan and Madelle Rosenfeld Family Trust; Kuzell Family Arthritis Research Foundation FX We thank Judie McDonald for help in preparing the manuscript. This study was supported by National Institutes of Health Grants HD033703-10 (ZZ), EY016788 (ZZ), EY013093 (JTR), and EY006484 (JTR) as well as Child Digestive Health and Nutrition Foundation/CCFA Young Investigator Award (ZZ). JTR is a scholar supported by Research to Prevent Blindness. Funds from the Stan and Madelle Rosenfeld Family Trust and the Kuzell Family Arthritis Research Foundation also contributed to this work. NR 167 TC 4 Z9 4 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1863-2297 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD MAR PY 2010 VL 32 IS 1 BP 55 EP 70 DI 10.1007/s00281-009-0190-3 PG 16 WC Immunology; Pathology SC Immunology; Pathology GA 567RR UT WOS:000275464800006 PM 20119686 ER PT J AU Pezzolesi, MG Skupien, J Mychaleckyj, JC Warram, JH Krolewski, AS AF Pezzolesi, Marcus G. Skupien, Jan Mychaleckyj, Josyf C. Warram, James H. Krolewski, Andrzej S. TI Insights to the Genetics of Diabetic Nephropathy Through a Genome-Wide Association Study of the GoKinD Collection SO SEMINARS IN NEPHROLOGY LA English DT Review DE Genome-wide association; diabetic nephropathy; type 1 diabetes; imputation ID STAGE RENAL-DISEASE; AFRICAN-AMERICANS; KIDNEY-DISEASE; INTERSTITIAL FIBROSIS; SUSCEPTIBILITY GENES; CHROMOSOME 3Q; TGF-BETA; SCAN; POLYMORPHISM; POPULATION AB The Genetics of Kidneys in Diabetes (Go KinD) study was initiated to facilitate research aimed at identifying genes involved in diabetic nephropathy (DN) in type 1 diabetes. In this review, we present an overview of this study and the various reports that have used its collection. At the forefront of these efforts is the recent genome-wide association scan implemented on the Go KinD collection. We highlight the results from our analysis of these data and describe compelling evidence from animal models that further support the potential role of associated loci in the susceptibility of DN. To enhance our analysis of genetic associations in GoKinD, using genome-wide imputation, we expanded our analysis of this collection to include genotype data from more than 2.4 million common single nucleotide polymorphisms. We illustrate the added utility of this enhanced dataset through the comprehensive fine-mapping of candidate genomic regions previously linked with DN and the targeted investigation of genes involved in candidate pathways implicated in its pathogenesis. Collectively, genome-wide association and genome-wide imputation data from the GoKinD collection will serve as a springboard for future investigations into the genetic basis of DN in type 1 diabetes. Semin Nephrol 30:126-140 (C) 2010 Elsevier Inc. All rights reserved. C1 [Pezzolesi, Marcus G.; Skupien, Jan; Krolewski, Andrzej S.] Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, Boston, MA 02215 USA. [Pezzolesi, Marcus G.; Skupien, Jan; Warram, James H.; Krolewski, Andrzej S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Mychaleckyj, Josyf C.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. RP Krolewski, AS (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, Rm 368,1 Joslin Pl, Boston, MA 02215 USA. EM Andrzej.Krolewski@joslin.harvard.edu FU National Institutes of Health [DK77532, T32 DK007260-31]; Juvenile Diabetes Research Foundation [3-2009-397]; Centers for Disease Control (CDC) [PL 105-33, 106-554, 107-360] FX Supported in part by National Institutes of Health grants DK77532 (ASK.) and T32 DK007260-31 (M.G.P.), and Juvenile Diabetes Research Foundation grant 3-2009-397 (J.S.).; Funding support for the GAIN Search for Susceptibility Genes for Diabetic Nephropathy in Type 1 Diabetes (GoKinD study participants) study was provided by the Juvenile Diabetes Research Foundation (JDRF), and the Centers for Disease Control (CDC) (PL 105-33, 106-554, and 107-360 administered by the National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK) and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The dataset used for the analyses described in this manuscript were obtained from the database of Genotype and Phenotype (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000018.vl.p1. We thank Dr. Nancy J. Cox and her colleagues for resolving the differential bias in genotype calls in the initial release of these data. NR 43 TC 13 Z9 14 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 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD MAR PY 2010 VL 30 IS 2 BP 126 EP 140 DI 10.1016/j.semnephrol.2010.01.004 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA 582CY UT WOS:000276574400004 PM 20347642 ER PT J AU Hough, S AF Hough, Sigmund TI From the Editor 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 MAR PY 2010 VL 28 IS 1 BP 1 EP 1 DI 10.1007/s11195-010-9153-9 PG 1 WC Rehabilitation SC Rehabilitation GA 554XI UT WOS:000274469100001 ER PT J AU Bailar-Heath, M Hough, S AF Bailar-Heath, MaryBeth Hough, Sigmund TI pleasureABLE: Sexual device manual for persons with disabilities SO SEXUALITY AND DISABILITY LA English DT Book Review C1 [Bailar-Heath, MaryBeth] VA Boston Healthcare Syst, Psychol Serv 116B, Boston, MA 02130 USA. [Hough, Sigmund] VA Boston Healthcare Syst, Spinal Cord Injury Serv SCI 128, W Roxbury, MA 02132 USA. RP Bailar-Heath, M (reprint author), VA Boston Healthcare Syst, Psychol Serv 116B, 150 S Huntington Ave, Boston, MA 02130 USA. EM MaryBeth.Bailar-Heath@va.gov; Sigmund_Hough@hms.harvard.edu NR 1 TC 2 Z9 2 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 MAR PY 2010 VL 28 IS 1 BP 61 EP 62 DI 10.1007/s11195-009-9142-z PG 2 WC Rehabilitation SC Rehabilitation GA 554XI UT WOS:000274469100007 ER PT J AU Insalaco, B AF Insalaco, Brie A. TI Enabling Romance: A Guide to Love, Sex, and Relationships for People with Disabilities SO SEXUALITY AND DISABILITY LA English DT Book Review C1 [Insalaco, Brie A.] VA Boston Healthcare Syst, Psychol Serv, W Roxbury, MA 02132 USA. [Insalaco, Brie A.] VA Boston Healthcare Syst, Spinal Cord Injury Serv SCI 128, W Roxbury, MA 02132 USA. RP Insalaco, B (reprint author), VA Boston Healthcare Syst, Psychol Serv, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM brie.insalaco@va.gov NR 3 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0146-1044 J9 SEX DISABIL JI Sex. Disabil. PD MAR PY 2010 VL 28 IS 1 BP 63 EP 64 DI 10.1007/s11195-009-9141-0 PG 2 WC Rehabilitation SC Rehabilitation GA 554XI UT WOS:000274469100008 ER PT J AU Santry, HP Alam, HB AF Santry, Heena P. Alam, Hasan B. TI FLUID RESUSCITATION: PAST, PRESENT, AND THE FUTURE SO SHOCK LA English DT Review DE Resuscitation; hemorrhage; crystalloid; colloid; hypertonic fluid; hyperoncotic fluid; blood substitute; artificial oxygen carriers; cellular injury; inflammation; immunomodulation; review ID HYPERTONIC SALINE-DEXTRAN; SEVERE HEMORRHAGIC-SHOCK; LACTATED RINGERS SOLUTION; BOVINE POLYMERIZED HEMOGLOBIN; I TRAUMA CENTER; ABDOMINAL COMPARTMENT SYNDROME; MASSIVE TRANSFUSION PROTOCOL; ACUTE RESPIRATORY-DISTRESS; ACTIVATED PROTEIN-KINASE; USA MULTICENTER TRIAL AB Hemorrhage remains a major cause of preventable death following both civilian and military trauma. The goals of resuscitation in the face of hemorrhagic shock are restoring end-organ perfusion and maintaining tissue oxygenation while attempting definitive control of bleeding. However, if not performed properly, resuscitation can actually exacerbate cellular injury caused by hemorrhagic shock, and the type of fluid used for resuscitation plays an important role in this injury pattern. This article reviews the historical development and scientific underpinnings of modern resuscitation techniques. We summarized data from a number of studies to illustrate the differential effects of commonly used resuscitation fluids, including isotonic crystalloids, natural and artificial colloids, hypertonic and hyperoncotic solutions, and artificial oxygen carriers, on cellular injury and how these relate to clinical practice. The data reveal that a uniformly safe, effective, and practical resuscitation fluid when blood products are unavailable and direct hemorrhage control is delayed has been elusive. Yet, it is logical to prevent this cellular injury through wiser resuscitation strategies than attempting immunomodulation after the damage has already occurred. Thus, we describe how some novel resuscitation strategies aimed at preventing or ameliorating cellular injury may become clinically available in the future. C1 [Santry, Heena P.; Alam, Hasan B.] Harvard Univ, Div Trauma Emergency Surg & Surg Crit Care, Massachusetts Gen Hosp, Dept Surg,Med Sch, Boston, MA 02114 USA. RP Alam, HB (reprint author), Harvard Univ, Div Trauma Emergency Surg & Surg Crit Care, Massachusetts Gen Hosp, Dept Surg,Med Sch, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM hbalam@partners.org FU ONR; US Army MRMC; Defense Advanced Research Projects Agency; NIH FX Dr Alam thanks the ONR, US Army MRMC, Defense Advanced Research Projects Agency, and NIH for research support. NR 170 TC 120 Z9 138 U1 2 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD MAR PY 2010 VL 33 IS 3 BP 229 EP 241 DI 10.1097/SHK.0b013e3181c30f0c PG 13 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 564FE UT WOS:000275197900002 PM 20160609 ER PT J AU Vallabhaneni, R Kaczorowski, DJ Yaakovian, MD Rao, J Zuckerbraun, BS AF Vallabhaneni, Raghuveer Kaczorowski, David J. Yaakovian, Michael D. Rao, Jayashree Zuckerbraun, Brian S. TI HEME OXYGENASE 1 PROTECTS AGAINST HEPATIC HYPOXIA AND INJURY FROM HEMORRHAGE VIA REGULATION OF CELLULAR RESPIRATION SO SHOCK LA English DT Article DE Heme oxygenase; carbon monoxide; hemorrhage; hypoxia; hepatocytes; liver; respiration ID CARBON-MONOXIDE; NITRIC-OXIDE; RAT-LIVER; EXPRESSION PATTERN; GENE-TRANSFER; SHOCK; ACTIVATION; STRESS; RESUSCITATION; INHIBITION AB Heme oxygenase 1 (HO-1) is an important regulator of the cellular response to stress and inflammation. These investigations test the hypothesis that HO-1 overexpression protects against hemorrhage-induced hypoxia by regulating cellular respiration and oxygen availability. Male C57BL/6 mice or primary mouse hepatocytes were treated with adenoviral gene transfer of HO-1 (AdHO-1) or beta-galactosidase (AdLacZ). Mice were subjected to hemorrhagic shock and resuscitation or cannulation without hemorrhage. AdHO-1 prevented hemorrhagic shock/resuscitation-induced liver injury. In addition, AdHO-1 prevented hemorrhage-induced liver hypoxia and depletion of adenosine triphosphate. In vitro, HO-1 overexpression resulted in decreased cellular respiration under hypoxic conditions as determined by oxygen consumption and cytochrome c oxidase activity. This resulted in increased intracellular oxygen levels in the setting of low oxygen tensions. In conclusion, HO-1 overexpression protects the liver against hemorrhage-induced injury. This may be secondary to the ability of HO-1 to protect against bioenergetic failure via regulation of cellular respiration. C1 [Vallabhaneni, Raghuveer; Kaczorowski, David J.; Yaakovian, Michael D.; Rao, Jayashree; Zuckerbraun, Brian S.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. [Zuckerbraun, Brian S.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Zuckerbraun, BS (reprint author), NW653 MUH,3459 5th Ave, Pittsburgh, PA 15213 USA. EM zuckerbraunbs@upmc.edu NR 40 TC 19 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD MAR PY 2010 VL 33 IS 3 BP 274 EP 281 DI 10.1097/SHK.0b013e3181b0f566 PG 8 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 564FE UT WOS:000275197900009 PM 19536046 ER PT J AU Holzel, BK Carmody, J Evans, KC Hoge, EA Dusek, JA Morgan, L Pitman, RK Lazar, SW AF Hoelzel, Britta K. Carmody, James Evans, Karleyton C. Hoge, Elizabeth A. Dusek, Jeffery A. Morgan, Lucas Pitman, Roger K. Lazar, Sara W. TI Stress reduction correlates with structural changes in the amygdala SO SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE LA English DT Article DE stress; amygdala; gray matter; MRI; mindfulness ID SMALLER HIPPOCAMPAL VOLUME; RECURRENT MAJOR DEPRESSION; MEDIAL PREFRONTAL CORTEX; VOXEL-BASED MORPHOMETRY; CEREBRAL-BLOOD-FLOW; EMOTIONAL STIMULI; BIPOLAR DISORDER; PANIC DISORDER; MATTER VOLUME; GRAY-MATTER AB Stress has significant adverse effects on health and is a risk factor for many illnesses. Neurobiological studies have implicated the amygdala as a brain structure crucial in stress responses. Whereas hyperactive amygdala function is often observed during stress conditions, cross-sectional reports of differences in gray matter structure have been less consistent. We conducted a longitudinal MRI study to investigate the relationship between changes in perceived stress with changes in amygdala gray matter density following a stress-reduction intervention. Stressed but otherwise healthy individuals (N = 26) participated in an 8-week mindfulness-based stress reduction intervention. Perceived stress was rated on the perceived stress scale (PSS) and anatomical MR images were acquired pre- and post-intervention. PSS change was used as the predictive regressor for changes in gray matter density within the bilateral amygdalae. Following the intervention, participants reported significantly reduced perceived stress. Reductions in perceived stress correlated positively with decreases in right basolateral amygdala gray matter density. Whereas prior studies found gray matter modifications resulting from acquisition of abstract information, motor and language skills, this study demonstrates that neuroplastic changes are associated with improvements in a psychological state variable. C1 [Hoelzel, Britta K.; Evans, Karleyton C.; Morgan, Lucas; Pitman, Roger K.; Lazar, Sara W.] Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Hoelzel, Britta K.] Univ Giessen, Bender Inst Neuroimaging, D-35394 Giessen, Germany. [Carmody, James] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Dusek, Jeffery A.] Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Boston, MA 02114 USA. [Dusek, Jeffery A.] Abbott NW Hosp, Penny George Inst Hlth & Healing, Minneapolis, MN 55407 USA. RP Holzel, BK (reprint author), Massachusetts Gen Hosp, 149 13th St, Charlestown, MA 02129 USA. EM britta@nmr.mgh.harvard.edu RI Hoge, Elizabeth/H-5879-2012; Lazar, Sara/G-3809-2012 OI Hoge, Elizabeth/0000-0002-5513-2292; Lazar, Sara/0000-0003-1126-8363 FU National Institutes of Health-NCCAM [R21-AT003425-01A2]; British Broadcasting Company (BBC); Marie Curie International Outgoing Fellowship; National Institutes of Health funding [K01AT00694] FX This research was funded by the National Institutes of Health-NCCAM (R21-AT003425-01A2) and the British Broadcasting Company (BBC). B.K.H. is supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme. S.W.L. was supported by National Institutes of Health funding K01AT00694. The funders had no role in study design, data collection and analysis, decision to publisher preparation of the manuscript. We thank C. Legro and the Center for Mindfulness for conducting the MBSR intervention, J. Bates, L. Shin and C. Linnman for critical reading of the manuscript; and S. Yerramsetti, N. Olendzki, C. Congleton, D. McCaffrey and A. McCallister for technical support. NR 79 TC 129 Z9 135 U1 3 U2 67 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1749-5016 J9 SOC COGN AFFECT NEUR JI Soc. Cogn. Affect. Neurosci. PD MAR PY 2010 VL 5 IS 1 BP 11 EP 17 DI 10.1093/scan/nsp034 PG 7 WC Neurosciences; Psychology; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 631AT UT WOS:000280319500002 PM 19776221 ER PT J AU Kayser, K Feldman, BN Borstelmann, NA Daniels, AA AF Kayser, Karen Feldman, Barry N. Borstelmann, Nancy A. Daniels, Ann A. TI Effects of a Randomized Couple-based Intervention on Quality of Life of Breast Cancer Patients and Their Partners SO SOCIAL WORK RESEARCH LA English DT Article DE breast cancer; couples; psychosocial intervention; quality of life ID EARLY-STAGE BREAST; GROUP PSYCHOSOCIAL SUPPORT; PSYCHOLOGICAL DISTRESS; POSTTRAUMATIC GROWTH; WOMEN; ADJUSTMENT; SURVIVORS; HUSBANDS; MASTECTOMY; EXPERIENCE AB The purpose of this study was to determine the effectiveness of a couple-based intervention on the quality of life (QOL) of early-stage breast cancer patients and their partners. A randomized controlled design was used to assign couples to either the hospital standard social work services (SSWS) or a couple-based intervention, the Partners in Coping Program (PICP). QOL was measured at three times during the first year after the diagnosis. A series of analyses of covariance revealed that QOL of patients and partners in the PICP arm improved at time 2 and time 3 and was consistently higher than the QOL of couples in the SSWS arm, controlling for QOL at time 1. However, differences between the two arms on QOL were not statistically significant. Patients in the PICP who were in relationships of shorter lengths and were receiving chemotherapy made the greatest gains in their QOL, suggesting that these types of patients would benefit more from a couple-based approach to their illness. On the basis of the findings, the authors suggest future directions for intervention research and for social work practitioners who are looking for efficient and effective ways to deliver psychosocial services to cancer patients. C1 [Kayser, Karen] Boston Coll, Grad Sch Social Work, Chestnut Hill, MA 02467 USA. [Feldman, Barry N.] Univ Massachusetts, Med Ctr, Psychiat Serv Publ Safety, Worcester, MA USA. [Borstelmann, Nancy A.] Dana Farber Canc Inst, Patient & Family Support Serv, Boston, MA 02115 USA. Massachusetts Gen Hosp Social Serv, Boston, MA USA. RP Kayser, K (reprint author), Boston Coll, Grad Sch Social Work, 140 Commonwealth Ave, Chestnut Hill, MA 02467 USA. EM kayserk@bc.edu NR 51 TC 19 Z9 19 U1 1 U2 14 PU NATL ASSOC SOCIAL WORKERS PI WASHINGTON PA 750 FIRST ST, NE, STE 700, WASHINGTON, DC 20002-4241 USA SN 1070-5309 J9 SOC WORK RES JI Soc. Work Res. PD MAR PY 2010 VL 34 IS 1 BP 20 EP 32 PG 13 WC Social Work SC Social Work GA 804YE UT WOS:000293690600003 ER PT J AU Frisbie, JH AF Frisbie, J. H. TI Response to the letter to the editor by J Silver 'Re: Case report: a fatal metastasis of Klebsiella pneumonia of the lungs' SO SPINAL CORD LA English DT Letter C1 VA Boston Healthcare Syst, Res Serv, W Roxbury, MA USA. RP Frisbie, JH (reprint author), VA Boston Healthcare Syst, Res Serv, W Roxbury, MA USA. EM jfrisbie@comcast.net NR 6 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2010 VL 48 IS 3 BP 270 EP 270 DI 10.1038/sc.2010.8 PG 1 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 564DZ UT WOS:000275194800016 PM 20142833 ER PT J AU Ballen, K AF Ballen, Karen TI Challenges in Umbilical Cord Blood Stem Cell Banking for Stem Cell Reviews and Reports SO STEM CELL REVIEWS AND REPORTS LA English DT Article DE Cord blood; Transplantation; Banking ID HEMATOPOIETIC STEM; UNRELATED DONORS; BONE-MARROW; MYOCARDIAL-INFARCTION; ACUTE-LEUKEMIA; HEMATOLOGIC MALIGNANCIES; PEDIATRIC-PATIENTS; PERIPHERAL-BLOOD; PLACENTAL BLOOD; T-CELLS AB Twenty years has passed since the first report of a successful cord blood transplant was reported in 1989 in a child with Fanconi's anemia. During these 20 years, the cord blood field has had dramatic growth, with over 400,000 cord blood units donated and stored worldwide for unrelated use. Approximately, 14,000 unrelated cord blood transplants have been performed to date for patients with hematologic malignancies and bone marrow disorders, and who do not have matched family or unrelated donors. In contrast, about 900,000 cord blood units have been stored privately for personal use, with about 100 autologous transplants performed. Twenty years ago, due to the low cell dose, cord blood transplants were only performed in children. Today, with the use of better banking techniques, reduced intensity transplants, and double cord blood transplantation, the majority of cord blood transplants are being performed in adults. In this chapter, we review the scientific basis for cord blood transplantation, and outcome data in both pediatric and adult transplantation. We will then focus on the recent concerns regarding private and public cord blood banking. Finally, we discuss the future of cord blood transplantation, and the exciting work beginning outside of oncology. C1 Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02214 USA. RP Ballen, K (reprint author), Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Zero Emerson,Suite 118, Boston, MA 02214 USA. EM kballen@partners.org NR 59 TC 21 Z9 24 U1 0 U2 7 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1550-8943 J9 STEM CELL REV REP JI Stem Cell Rev. Rep. PD MAR PY 2010 VL 6 IS 1 BP 8 EP 14 DI 10.1007/s12015-009-9105-x PG 7 WC Cell & Tissue Engineering; Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 574HT UT WOS:000275980700002 PM 19997789 ER PT J AU Jimenez-Conde, J Biffi, A Rahman, R Kanakis, A Butler, C Sonni, S Massasa, E Cloonan, L Gilson, A Capozzo, K Cortellini, L Ois, A Cuadrado-Godia, E Rodriguez-Campello, A Furie, KL Roquer, J Rosand, J Rost, NS AF Jimenez-Conde, Jordi Biffi, Alessandro Rahman, Rosanna Kanakis, Allison Butler, Christi Sonni, Shruti Massasa, Efi Cloonan, Lisa Gilson, Aaron Capozzo, Karen Cortellini, Lynelle Ois, Angel Cuadrado-Godia, Elisa Rodriguez-Campello, Ana Furie, Karen L. Roquer, Jaume Rosand, Jonathan Rost, Natalia S. TI Hyperlipidemia and Reduced White Matter Hyperintensity Volume in Patients With Ischemic Stroke SO STROKE LA English DT Article DE white matter disease; leukoaraiosis; hyperlipidemia; risk factors ID INTRACEREBRAL HEMORRHAGE; RISK-FACTOR; NORTHERN MANHATTAN; ROTTERDAM-SCAN; CHOLESTEROL; LESIONS; LEUKOARAIOSIS; DISEASE; SEVERITY; PROFILE AB Background and Purpose-White matter hyperintensity (WMH), or leukoaraiosis, is a radiologic finding generally assumed to reflect diseased small cerebral vasculature. WMH has significant functional impact through its relation to cognitive decline and risk of ischemic and hemorrhagic stroke. Accumulating evidence suggests that some manifestations of small-vessel disease such as intracerebral hemorrhage are associated with low levels of cholesterol. We sought to determine the relation between hyperlipidemia and WMH severity in patients with acute ischemic stroke (AIS). Methods-We analyzed 2 independent, hospital-based AIS cohorts. Demographic and clinical data were collected prospectively. WMH was measured using semiautomated volumetric image analysis and a semiquantitative visual grading scale. Univariate and multivariable regression analyses were used to assess the relation between WMH severity and study variables. Results-A total of 631 and 504 subjects in the first and second cohorts, respectively, were included. In univariate analyses, advancing age and hypertension were associated with severity of WMH (P < 0.001) in both cohorts. In the multivariable analysis, after controlling for age, sex, and significant risk factors in the univariate and age-adjusted analyses, patients with a history of hyperlipidemia had less severe WMH in both cohorts (P < 0.01). Conclusions-Results from 2 independent cohorts demonstrate that AIS patients with a history of hyperlipidemia have less severe WMH at the time of stroke. These data support the hypothesis that hyperlipidemia may play a relatively protective role in cerebral small-vessel disease. (Stroke. 2010;41:37-442.) C1 [Jimenez-Conde, Jordi; Biffi, Alessandro; Rahman, Rosanna; Kanakis, Allison; Butler, Christi; Sonni, Shruti; Massasa, Efi; Cloonan, Lisa; Gilson, Aaron; Capozzo, Karen; Cortellini, Lynelle; Furie, Karen L.; Rosand, Jonathan; Rost, Natalia S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Jimenez-Conde, Jordi; Biffi, Alessandro; Rahman, Rosanna; Kanakis, Allison; Butler, Christi; Sonni, Shruti; Massasa, Efi; Cloonan, Lisa; Gilson, Aaron; Capozzo, Karen; Cortellini, Lynelle; Furie, Karen L.; Rosand, Jonathan; Rost, Natalia S.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. MIT, Program Med & Populat Genet, Broad Inst, Boston, MA USA. [Jimenez-Conde, Jordi; Biffi, Alessandro; Rahman, Rosanna; Cloonan, Lisa; Rosand, Jonathan; Rost, Natalia S.] Harvard Univ, Boston, MA 02115 USA. [Jimenez-Conde, Jordi; Ois, Angel; Cuadrado-Godia, Elisa; Rodriguez-Campello, Ana; Roquer, Jaume] Univ Autonoma Barcelona, Neurovasc Res Unit, Dept Neurol, E-08193 Barcelona, Spain. [Jimenez-Conde, Jordi; Cuadrado-Godia, Elisa; Roquer, Jaume] Univ Autonoma Barcelona, Program Inflammat & Cardiovasc Disorders, Inst Municipal Invest Med, Hosp del Mar,Dept Med, E-08193 Barcelona, Spain. RP Rost, NS (reprint author), Massachusetts Gen Hosp, Dept Neurol, 175 Cambridge St,Ste 300, Boston, MA 02114 USA. EM nrost@partners.org RI Roquer, Jaume/D-9483-2011; JIMENEZ-CONDE, JORDI/C-1941-2012 FU Bugher Foundation-American Stroke Association; National Institute of Neurological Disorders and Stroke [5P50NS051343, R01 NS04217]; National Institutes of Health/National Institute of Neurological Disorders and Stroke [K23NS42720]; Deane Institute for Integrative Study of Atrial Fibrillation and Stroke; Ministerio de Sanidad y Consumo de EspaPa; Instituto de Salud Carlos III [PI051737, CM06100067, RD06/0009] FX This study was funded in part by the Bugher Foundation-American Stroke Association, National Institute of Neurological Disorders and Stroke (5P50NS051343, R01 NS04217), National Institutes of Health/National Institute of Neurological Disorders and Stroke grant K23NS42720, the Deane Institute for Integrative Study of Atrial Fibrillation and Stroke, and the Ministerio de Sanidad y Consumo de EspaPa, Instituto de Salud Carlos III with the following grants: "Registro BASICMAR" Funding for Research in Health (PI051737), Contract for Research Training for Professionals with Specialty (CM06100067), and Grant from Spanish Research Networks "Red HERACLES" (RD06/0009). NR 39 TC 31 Z9 34 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2010 VL 41 IS 3 BP 437 EP 442 DI 10.1161/STROKEAHA.109.563502 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 559DA UT WOS:000274799600005 PM 20133919 ER PT J AU Canfield, KM Smyth, E Batki, SL AF Canfield, Kelly M. Smyth, Emily Batki, Steven L. TI Methadone Maintenance Patients' Knowledge, Attitudes, Beliefs, and Experiences Concerning Treatment for Hepatitis C Virus Infection SO SUBSTANCE USE & MISUSE LA English DT Article DE hepatitis C; treatment; knowledge; attitudes; beliefs; experiences; methadone; opioid; substance use; psychiatry ID INJECTION-DRUG USERS; FOLLOW-UP; RISK REDUCTION; UNITED-STATES; US CITIES; HIV; PREVALENCE; THERAPY; SEROCONVERSION; EPIDEMIOLOGY AB Hepatitis C virus (HCV) knowledge, attitudes, beliefs, and experiences (KABE) of 64 HCV antibody positive methadone maintenance treatment (MMT) patients were assessed in conjunction with acceptability of an on-site semi-structured HCV education session, HCV RNA diagnostic testing, HCV treatment motivational assessment, and initiation of HCV treatment. The KABE interviews were conducted in 2006 and 2007 in an urban New York State MMT clinic in affiliation with a NIDA-funded HCV research project. The majority had basic knowledge of HCV disease, but poor understanding of HCV testing and treatment. While the majority of participants expressed fear of HCV treatment side effects, 88% accepted HCV RNA testing and 78% expressed willingness to start HCV treatment with the majority of chronically infected choosing to start HCV treatment medications. Study limitations and implications are discussed. C1 [Canfield, Kelly M.] SUNY Upstate Med Univ, Addict Psychiat Res Program, Dept Psychiat, Syracuse, NY 13210 USA. [Batki, Steven L.] Univ Calif San Francisco, Dept Psychiat, Sch Med, San Francisco, CA 94143 USA. [Batki, Steven L.] San Francisco VA Med Ctr, Addict Psychiat Res Program, San Francisco, CA USA. RP Canfield, KM (reprint author), SUNY Upstate Med Univ, Addict Psychiat Res Program, Dept Psychiat, 450 E Adams St, Syracuse, NY 13210 USA. EM canfielk@upstate.edu FU National Institutes of Health (NIH)/National Institute on Drug Abuse (NIDA) [RO1 DA 016764] FX This work was supported by National Institutes of Health (NIH)/National Institute on Drug Abuse (NIDA) grant RO1 DA 016764. NIDA had no further role in study design; in the collection, analysis, and interpretation of the data; in the writing of this report; and in the decision to submit the paper for publication. NR 59 TC 8 Z9 8 U1 0 U2 7 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1082-6084 J9 SUBST USE MISUSE JI Subst. Use Misuse PD MAR PY 2010 VL 45 IS 4 BP 496 EP 514 DI 10.3109/10826080903452538 PG 19 WC Substance Abuse; Psychiatry; Psychology SC Substance Abuse; Psychiatry; Psychology GA 560DJ UT WOS:000274881900003 PM 20141461 ER PT J AU Derevianko, AY Schwaitzberg, SD Tsuda, S Barrios, L Brooks, DC Callery, MP Fobert, D Irias, N Rattner, DW Jones, DB AF Derevianko, Alexandre Y. Schwaitzberg, Steven D. Tsuda, Shawn Barrios, Limaris Brooks, David C. Callery, Mark P. Fobert, David Irias, Noel Rattner, David W. Jones, Daniel B. TI Malpractice carrier underwrites Fundamentals of Laparoscopic Surgery training and testing: a benchmark for patient safety SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article DE Abdominal; Clinical papers, trials, research; Education; Quality control; Surgical; Training, courses ID CRISIS RESOURCE-MANAGEMENT; OPERATING-ROOM; SURGICAL RESIDENTS; SKILL ACQUISITION; TECHNICAL SKILL; PREDICTS RATE; SIMULATOR; PROFICIENCY; PERFORMANCE; EDUCATION AB Fundamentals of Laparoscopic Surgery (FLS) is a validated program developed by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) to educate and assess competency in minimally invasive surgery (MIS). This study reports the first malpractice carrier-sponsored FLS course for surgeons in practice underwritten by the Controlled Risk Insurance Company of Harvard's Risk Management Foundation (CRICO/RMF). The study investigated the participating surgeons' pattern of MIS skills acquisition, subjective laparoscopic comfort level, operative activity, and perception of the FLS role in surgical education, credentialing, and patient safety. A 1-day postgraduate continuous medical education (CME) course consisted of didactic presentations of the leading MIS faculty, proctored FLS hands-on training, psychomotor testing, and cognitive computer-based examination. Voluntary anonymous pre- and postcourse surveys were distributed to the participants at registration and at completion of both the didactic teaching and the skills modules of the program. The course was attended by 37 practicing surgeons in the Harvard system, and 86% of the survey forms were returned. The major driving forces for attending the course were directive from the chief/chairman (50%), improvement in MIS didactic knowledge (56%), and the belief that FLS would become a standard such as advanced trauma life support (ATLS), advanced cardiac life support (ACLS), or the like (53%). Surgeons reported that the FLS exam content was appropriate (Likert 4.41 +/- A 0.91) and that mastery of the course material would improve safety (Likert 4.13 +/- A 0.79) and technical knowledge of MIS (Likert 4.03 +/- A 1.00). This unique cooperative effort between a liability carrier, a professional surgical society, and proactive surgeons should be considered a model for advancing competency and patient safety. The survey results indicate a positive view of FLS in surgical training, safety, and MIS education. C1 [Derevianko, Alexandre Y.; Callery, Mark P.; Fobert, David; Irias, Noel; Jones, Daniel B.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Sect Minimally Invas Surg, Boston, MA 02215 USA. [Schwaitzberg, Steven D.; Barrios, Limaris] Cambridge Hlth Alliance, Cambridge, MA USA. [Tsuda, Shawn] Univ Nevada, Sch Med, Las Vegas, NV USA. [Brooks, David C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Rattner, David W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Jones, DB (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Sect Minimally Invas Surg, 330 Brookline Ave, Boston, MA 02215 USA. EM aderevia@bidmc.harvard.edu; djones1@bidmc.harvard.edu NR 48 TC 23 Z9 23 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 J9 SURG ENDOSC JI Surg. Endosc. PD MAR PY 2010 VL 24 IS 3 BP 616 EP 623 DI 10.1007/s00464-009-0617-x PG 8 WC Surgery SC Surgery GA 554WV UT WOS:000274467500020 PM 19688400 ER PT J AU Li, Y Huang, XF Deng, C Meyer, B Wu, AM Yu, YH Ying, WH Yang, GY Yenari, MA Wang, Q AF Li, Yun Huang, Xu-Feng Deng, Chao Meyer, Barbara Wu, Aimin Yu, Yinghua Ying, Weihai Yang, Guo-Yuan Yenari, Midori A. Wang, Qing TI Alterations in 5-HT(2A) Receptor Binding in Various Brain Regions Among 6-Hydroxydopamine-Induced Parkinsonian Rats SO SYNAPSE LA English DT Article DE Parkinson's disease; serotonin; 5-HT(2A) receptors; tyrosine hydroxylase; striatum; downregulation ID IN-VIVO MICRODIALYSIS; DOPAMINE RELEASE; SEROTONIN RECEPTORS; PREFRONTAL CORTEX; ANIMAL-MODEL; DISEASE; MECHANISMS; BEHAVIORS; TRANSDUCTION; HALOPERIDOL AB The serotonergic system has close interactions with the dopaminergic system and is strongly implicated in the pathophysiological mechanisms and therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate regional changes in 5-hydroxytryptamine (5-HT) 2A receptors in the rat brain 3 weeks after unilateral medial forebrain bundle lesion by 6-hydroxydopamine (6-OHDA). 5-HT 2A receptor distributions and alterations in the postmortem rat brain were detected by [(3)H]ketanserin-binding autoradiography. In the 6-OHDA-induced Parkinson's rat model, nigrostriatal dopaminergic neuron loss significantly mediated the decreased [(3)H]ketanserin binding, predominantly in the agranular insular cortex (17.3%, P = 0.03), cingulate cortex (18.2%, P < 0.001), prefrontal cortex (8%, P = 0.043), primary somatosensory cortex (17.7%, P = 0.002), and caudate putamen (14.5%, P = 0.02) compared to controls while a profound reduction of tyrosine hydroxylase (TH) immunostaining in the striatum was also observed. Alterations in [(3)H]ketanserin binding in the examined brain areas may represent the specific regions that mediate cognitive dysfunctions via the serotonin system. The downregulation of 5-HT(2A) receptor binding in this study also provides indirect evidence for plasticity in the serotonergic system in the rat brains. This study contributes to a better understanding of the critical roles of 5-HT(2A) receptors in treating neurodegenerative disorders and implicates 5-HT(2A) receptors as a novel therapeutic target in the treatment of PD. Synapse 64:224-230, 2010. (C)2009 Wiley-Liss, Inc. C1 [Wang, Qing] Sun Yat Sen Univ, Affiliated Hosp 3, Dept Neurol, Guangzhou 510630, Guangdong, Peoples R China. [Li, Yun; Huang, Xu-Feng; Deng, Chao; Meyer, Barbara; Yu, Yinghua; Wang, Qing] Univ Wollongong, Sch Hlth Sci, Ctr Translat Neurosci, Wollongong, NSW 2522, Australia. [Li, Yun] Cent S Univ, Xiangya Hosp 2, Dept Ophthalmol & Visual Sci, Changsha, Hunan, Peoples R China. [Li, Yun] Hunan Engn Ctr Combinatorial Biosynth & Nat Prod, Changsha, Hunan, Peoples R China. [Ying, Weihai; Yang, Guo-Yuan] Shanghai Jiao Tong Univ, Med X Res Inst, Shanghai 200032, Peoples R China. [Yenari, Midori A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. [Yenari, Midori A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Wang, Q (reprint author), Sun Yat Sen Univ, Affiliated Hosp 3, Dept Neurol, 600 Tianhe Rd, Guangzhou 510630, Guangdong, Peoples R China. EM denniswq@yahoo.com RI Huang, Xu-Feng/D-6053-2013; Huang, Xu-Feng/H-7408-2015; Deng, Chao/F-4417-2016; OI Huang, Xu-Feng/0000-0002-5895-2253; Deng, Chao/0000-0003-1147-5741; Yu, Yinghua/0000-0003-2508-7512 FU Sun Yat-Sen University [A77]; FRC; University of Wollongong 2007/2008 Australia; Australia National Health Medical Research Council [514640] FX Third Affiliated Hospital of Sun Yat-Sen University; Contract grant number: A77; FRC small grant, University of Wollongong 2007/2008 Australia; Australia National Health Medical Research Council; Contract grant number: 514640. NR 33 TC 24 Z9 24 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD MAR PY 2010 VL 64 IS 3 BP 224 EP 230 DI 10.1002/syn.20722 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 544RU UT WOS:000273677600006 PM 19862688 ER PT J AU Toschi, L Cappuzzo, F AF Toschi, Luca Cappuzzo, Federico TI Impact of biomarkers on non-small cell lung cancer treatment SO TARGETED ONCOLOGY LA English DT Review DE NSCLC; Chemotherapy; ERCC1; EGFR; Tyrosine kinase inhibitors ID GROWTH-FACTOR-RECEPTOR; MESSENGER-RNA EXPRESSION; PHASE-III TRIAL; GENE COPY NUMBER; CISPLATIN PLUS GEMCITABINE; EQUILIBRATIVE NUCLEOSIDE TRANSPORTER-1; PLATINUM-BASED CHEMOTHERAPY; PREVIOUSLY TREATED PATIENTS; BETA-TUBULIN EXPRESSION; SINGLE-AGENT GEFITINIB AB Chemotherapy represents the mainstay of non-small cell lung cancer (NSCLC) treatment, but response is usually observed in only one out of three patients. Massive efforts have been carried out to identify biomarkers that might help clinicians to choose appropriate drugs, by identifying potentially sensitive subjects and spare toxicities in patients who are unlikely to benefit from treatment. Low excision repair cross-complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) levels have been associated with increased sensitivity to cisplatin and gemcitabine, respectively, while reduced class III beta-tubulin expression has been associated with taxane activity. Initial prospective studies showed the feasibility of a customized approach based on biomarker assessment, and phase III trials will hopefully provide further validation of this approach. The impact of biomarkers for patient selection has now been well established for tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), with EGFR mutations emerging as the most reliable predictor for improved outcome. Relevant clinical issues are represented by the identification of patients who can be reasonably excluded from treatment and by the development of therapeutic approaches able to overcome acquired resistance to anti-EGFR strategies. C1 [Cappuzzo, Federico] IRCCS, Ist Clin Humanitas, I-20089 Rozzano, Italy. [Toschi, Luca] Dana Farber Canc Inst, Boston, MA 02215 USA. RP Cappuzzo, F (reprint author), IRCCS, Ist Clin Humanitas, Via Manzoni 56, I-20089 Rozzano, Italy. EM luca_toschi@dfci.harvard.edu; federico.cappuzzo@humanitas.it RI Mendez, Pedro /J-8955-2016; OI Mendez, Pedro /0000-0001-6713-7907; Cappuzzo, Federico/0000-0002-6295-6767 NR 138 TC 13 Z9 14 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1776-2596 J9 TARGET ONCOL JI Target. Oncol. PD MAR PY 2010 VL 5 IS 1 BP 5 EP 17 DI 10.1007/s11523-010-0132-y PG 13 WC Oncology SC Oncology GA 609EA UT WOS:000278636700003 PM 20443070 ER PT J AU Davies, PL Spiller, OB Beeton, ML Maxwell, NC Remold-O'Donnell, E Kotecha, S AF Davies, Philip L. Spiller, O. Brad Beeton, Michael L. Maxwell, Nicola C. Remold-O'Donnell, Eileen Kotecha, Sailesh TI Relationship of proteinases and proteinase inhibitors with microbial presence in chronic lung disease of prematurity SO THORAX LA English DT Article ID RESPIRATORY-DISTRESS-SYNDROME; POLYMERASE-CHAIN-REACTION; BRONCHOPULMONARY DYSPLASIA; NEUTROPHIL ELASTASE; BRONCHOALVEOLAR LAVAGE; PRETERM INFANTS; INFLAMMATION; FLUID; MATRIX-METALLOPROTEINASE-9; IMBALANCE AB Background A proteolytic imbalance has been implicated in the development of "classical" chronic lung disease of prematurity (CLD). However, in "new" CLD this pattern has changed. This study examines the longitudinal relationship between neutrophil proteinases and their inhibitors in ventilated preterm infants and their relationship to microbial colonisation. Methods Serial bronchoalveolar lavage fluid was obtained from ventilated newborn preterm infants. Neutrophil elastase (NE) activity, cell counts, metalloproteinase (MMP)-9, MMP-9/TIMP-1 complex, SerpinB1 concentration and percentage of SerpinB1 and alpha(1)-antitrypsin (AAT) in complex with elastase were measured. The presence of microbial genes was examined using PCR for 16S rRNA genes. Results Statistically more infants who developed CLD had NE activity in at least one sample (10/20) compared with infants with resolved respiratory distress syndrome (RDS) (2/17). However, NE activity was present in a minority of samples, occurring as episodic peaks. Peak levels of MMP-9, MMP-9/TIMP-1 complex, percentage of AAT and SerpinB1 in complex and cell counts were all statistically greater in infants developing CLD than in infants with resolved RDS. Peak values frequently occurred as episodic spikes and strong temporal relationships were noted between all markers. The peak values for all variables were significantly correlated to each other. The presence of bacterial 16S rRNA genes was asso Conclusion NE activity and MMP-9 appear to be important in the development of "new" CLD with both proteinase and inhibitor concentrations increasing episodically, possibly in response to postnatal infection. C1 [Davies, Philip L.; Spiller, O. Brad; Beeton, Michael L.; Maxwell, Nicola C.; Kotecha, Sailesh] Cardiff Univ, Dept Child Hlth, Sch Med, Cardiff CF14 4XN, S Glam, Wales. [Remold-O'Donnell, Eileen] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Remold-O'Donnell, Eileen] Harvard Univ, Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA. [Remold-O'Donnell, Eileen] Harvard Univ, Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA. RP Spiller, OB (reprint author), Cardiff Univ, Dept Child Hlth, Sch Med, 5th Floor,Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM SpillerB@cardiff.ac.uk FU Arriva Pharmaceuticals Inc; NIH [HL066548]; Wellcome Trust FX Arriva Pharmaceuticals Inc, 1010 Atlantic Avenue, Alameda, CA 94501, USA. Other funders: NIH (HL066548) to ERO and Wellcome Trust. NR 35 TC 22 Z9 26 U1 1 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD MAR PY 2010 VL 65 IS 3 BP 246 EP 251 DI 10.1136/thx.2009.116061 PG 6 WC Respiratory System SC Respiratory System GA 576PV UT WOS:000276158700014 PM 20335295 ER PT J AU Hershman, JM Liwanpo, L AF Hershman, Jerome M. Liwanpo, Llanyee TI How Does Sunitinib Cause Hypothyroidism? SO THYROID LA English DT Editorial Material ID RENAL-CELL CARCINOMA; THYROTOXICOSIS; THYROIDITIS; CANCER C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Vet Adm Greater Los Angeles Healthcare Syst, Dept Med, Endocrinol & Diabet Div, Los Angeles, CA USA. RP Hershman, JM (reprint author), VA Med Ctr W Los Angeles, Endocrinol 111D,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jhershmn@ucla.edu NR 16 TC 10 Z9 10 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD MAR PY 2010 VL 20 IS 3 BP 243 EP 244 DI 10.1089/thy.2010.1620 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 562IX UT WOS:000275044600002 PM 20187779 ER PT J AU Vanderburg, CR Davis, DA Diamond, RE Kao, PF Delalle, I AF Vanderburg, Charles R. Davis, David A. Diamond, Rachel E. Kao, Patricia F. Delalle, Ivana TI Capzb2 PROTEIN EXPRESSION IN THE BRAINS OF PATIENTS DIAGNOSED WITH ALZHEIMER'S DISEASE AND HUNTINGTON'S DISEASE SO TRANSLATIONAL NEUROSCIENCE LA English DT Article DE Actin capping protein; Alzheimer's; Huntington's AB The silencing of actin capping protein beta 2, Capzb2, by RNAi in developing cultured neurons results in short, dystrophic neurites reminiscent of cytoskeletal changes seen in diverse neurodegenerative diseases, including Alzheimer's disease (AD) and Huntington's disease (HD). Actin and tubulin are two major cytoskeletal proteins indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that Capzb2 binds tubulin and, in the presence of microtubule- associated protein tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons results in short neurites with abnormal growth cones. Decreased neurite length is found in both AD and HD. In the first step towards uncovering the possible role of Capzb2 in these diseases, we studied Capzb2 protein expression in the postmortem brains of AD and HD patients. To determine whether disease-specific changes in Capzb2 protein accompany the progression of neurodegeneration, we performed Western Blot analysis of prefrontal cortices (PFC) and hippocampi (HPC) in AD patients and of PFC and heads of caudate nuclei (HCN) in HD patients. Our results show disease- and area-specific dynamics in the levels of Capzb2 protein expression in the progressive stages of AD and HD. C1 [Vanderburg, Charles R.; Diamond, Rachel E.] Massachusetts Gen Hosp, Adv Tissue Res Ctr, Harvard NeuroDiscovery Ctr, Charlestown, MA 02129 USA. [Davis, David A.; Kao, Patricia F.; Delalle, Ivana] Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA 02118 USA. RP Vanderburg, CR (reprint author), Massachusetts Gen Hosp, Adv Tissue Res Ctr, Harvard NeuroDiscovery Ctr, Bldg 114,16th St, Charlestown, MA 02129 USA. EM idelalle@bu.edu FU PHS [T32 AG00015-21] FX We thank Karlotta Fitch of MADRC for procurement of selected tissue samples and Dr. Zhigang Xie for helpful discussions. David Davis and Patricia Kao were supported by PHS grant T32 AG00015-21. NR 19 TC 0 Z9 0 U1 0 U2 1 PU VERSITA PI WARSAW PA SOLIPSKA 14A-1, 02-482 WARSAW, POLAND SN 2081-3856 J9 TRANSL NEUROSCI JI Transl. Neurosci. PD MAR PY 2010 VL 1 IS 1 BP 55 EP 58 DI 10.2478/v10134-010-0008-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA V20PX UT WOS:000208153000010 ER PT J AU Jin, G Sun, PZ Singhal, AB Ayata, C Lo, EH AF Jin, Guang Sun, Phillip Zhe Singhal, Aneesh B. Ayata, Cenk Lo, Eng H. TI First-Order Mathematical Modeling of Brain Swelling in Focal Cerebral Ischemia SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Neuroprotection; Edema; Infarction AB Edema is an important part of the pathophysiology of stroke. However, it remains unclear how brain swelling may influence the progression and measurement of infarction after cerebral ischemia. Initial studies in a mouse model of transient middle cerebral artery occlusion demonstrated that infarction grew from 24 to 72 h after stroke onset. Comparison of 24-h versus 72-h brains suggested that tissue swelling developed in both infarcted and non-infarcted ipsilateral regions. Volumes of infarction differed, depending on the method of calculation: direct, indirect, or normalized. A simple first-order model was constructed dividing total brain into three subsets, comprising normal contralateral tissue, non-infarcted ipsilateral tissue, and infarcted ipsilateral tissue. Each subset was then defined as a ratio of original volumes plus additional swollen volumes. By changing the relative portion of swelling assigned to infarct versus non-infarct, our model demonstrated that direct, indirect, and normalized calculations led to different thresholds for matching absolute infarct volumes. In this proof-of-principle study, we described a mathematical model to simulate the distribution of brain swelling and infarct development over time. Our findings suggest that accurate quantitation of infarct volumes depends on relative distributions of edema that may occur in both infarcted as well as non-infarcted brain. C1 [Jin, Guang; Sun, Phillip Zhe; Singhal, Aneesh B.; Ayata, Cenk; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02129 USA. [Jin, Guang; Sun, Phillip Zhe; Singhal, Aneesh B.; Ayata, Cenk; Lo, Eng H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02129 USA. RP Lo, EH (reprint author), MGH E 149-2401, Boston, MA 02129 USA. EM Lo@helix.mgh.harvard.edu FU NIH; AHA FX This study is supported in part by grants from the NIH and the AHA. NR 18 TC 5 Z9 5 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 EI 1868-601X J9 TRANSL STROKE RES JI Transl. Stroke Res. PD MAR PY 2010 VL 1 IS 1 BP 65 EP 70 DI 10.1007/s12975-009-0009-5 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA V23EP UT WOS:000208326400010 PM 24323451 ER PT J AU Johnson, EE Ricketts, TA AF Johnson, Earl E. Ricketts, Todd A. TI Dispensing Rates of Four Common Hearing Aid Product Features: Associations With Variations in Practice Among Audiologists SO TRENDS IN AMPLIFICATION LA English DT Article DE hearing aid; product features; dispensing rates; variability; audiologists AB The purpose of the study was to develop and examine a list of potential variables that may account for variability in the dispensing rates of four common hearing aid features. A total of 29 potential variables were identified and placed into the following categories: (1) characteristics of the audiologist, (2) characteristics of the hearing aids dispensed by the audiologist, (3) characteristics of the audiologist's patient population, and (4) evidence-based practice grades of recommendation for each feature. The potentially associative variables then were examined using regression analyses from the responses of 257 audiologists to a dispensing practice survey. There was a direct relation between price and level of hearing aid technology with the frequency of dispensing product features. There was also a direct relation between the belief by the audiologist that a feature might benefit patients and the frequency of dispensing that feature. In general, the results suggested that personal differences among audiologists and the hearing aids audiologists choose to dispense are related more strongly to dispensing rates of product features than to differences in characteristics of the patient population served by audiologists. An additional finding indicated that evidence-based practice recommendations were inversely related to dispensing rates of product features. This finding, however, may not be the result of dispensing trends as much as hearing aid manufacturing trends. C1 [Johnson, Earl E.] US Dept Vet Affairs, Mountain Home, TN 37684 USA. [Johnson, Earl E.] E Tennessee State Univ, Johnson City, TN 37614 USA. [Ricketts, Todd A.] Vanderbilt Univ, Bill Wilkerson Ctr, Nashville, TN USA. RP Johnson, EE (reprint author), US Dept Vet Affairs, Mountain Home, TN 37684 USA. EM earl.johnson@va.gov FU Dan Maddox Hearing Aid Research Laboratory at Vanderbilt University; Mountain Home; TN VAMC Auditory; Vestibular Research Enhancement Award Program; U.S. Department of Veterans Affairs Rehabilitation Research and Development Office FX The authors disclosed receipt of the following financial support for the research and/or authorship of this article:; Dan Maddox Hearing Aid Research Laboratory at Vanderbilt University.; Mountain Home, TN VAMC Auditory and Vestibular Research Enhancement Award Program (sponsored by the U.S. Department of Veterans Affairs Rehabilitation Research and Development Office). NR 90 TC 1 Z9 1 U1 1 U2 5 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 MAR PY 2010 VL 14 IS 1 BP 12 EP 45 DI 10.1177/1084713810362988 PG 34 GA V25ZP UT WOS:000208516200002 PM 20457726 ER PT J AU Anderson, RM Weindruch, R AF Anderson, Rozalyn M. Weindruch, Richard TI Metabolic reprogramming, caloric restriction and aging SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID ACTIVATED PROTEIN-KINASE; LIFE-SPAN EXTENSION; MITOCHONDRIAL OXYGEN-CONSUMPTION; SKELETAL-MUSCLE CELLS; GENE-EXPRESSION; DIETARY RESTRICTION; ADIPOSE-TISSUE; POSTTRANSLATIONAL MODIFICATIONS; ENERGY-EXPENDITURE; MAMMALIAN TARGET AB Caloric restriction (CR) without malnutrition slows the aging process and extends lifespan in diverse species by unknown mechanisms. The inverse linear relationship between calorie intake and lifespan suggests that regulators of energy metabolism are important in the actions of CR. Studies in several species reveal tissue-specific changes in energy metabolism with CR and suggest that metabolic reprogramming plays a critical role in its mechanism of aging retardation. We herein describe common signatures of CR and suggest how they can slow aging. We discuss recent advances in understanding the function of key metabolic regulators that probably coordinate the response to altered nutrient availability with CR and how the pathways they regulate can retard the aging process. C1 [Anderson, Rozalyn M.; Weindruch, Richard] Univ Wisconsin, Geriatr Res Educ & Clin Ctr, William S Middleton Mem Vet Hosp, Madison, WI 53705 USA. [Anderson, Rozalyn M.; Weindruch, Richard] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Anderson, Rozalyn M.; Weindruch, Richard] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI 53706 USA. RP Anderson, RM (reprint author), Univ Wisconsin, Geriatr Res Educ & Clin Ctr, William S Middleton Mem Vet Hosp, Madison, WI 53705 USA. EM rmanderson5@wisc.edu FU National Institutes of Health/ National Institute on Aging (NIH/NIA) [AG11915]; NIH/National Cancer Institute (NIH/NCI) [CA103697]; NIH/National Center for Research Resources/Clinical and Translational Science Awards (NIH/NCRR/CTSA) [UL1RR025011] FX This work was supported by grants from National Institutes of Health/ National Institute on Aging (NIH/NIA) (AG11915), NIH/National Cancer Institute (NIH/NCI) (CA103697) and NIH/National Center for Research Resources/Clinical and Translational Science Awards (NIH/NCRR/CTSA) (UL1RR025011). We thank Mike Polewski and Josef Clarke for critical reading of the manuscript. NR 71 TC 102 Z9 105 U1 4 U2 23 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD MAR PY 2010 VL 21 IS 3 BP 134 EP 141 DI 10.1016/j.tem.2009.11.005 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 576HW UT WOS:000276136100002 PM 20004110 ER PT J AU Liu, YY Brent, GA AF Liu, Yan-Yun Brent, Gregory A. TI Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID CHOLESTEROL 7-ALPHA-HYDROXYLASE GENE; CARBOXYLASE-ALPHA TRANSCRIPTION; THYROTROPIN-RELEASING-HORMONE; NONALCOHOLIC FATTY LIVER; ELEMENT-BINDING PROTEIN; RETINOID-X-RECEPTOR; PEROXISOME-PROLIFERATOR; RESPONSE ELEMENT; DENSITY-LIPOPROTEIN; PPAR-ALPHA AB Thyroid hormone influences diverse metabolic pathways important in lipid and glucose metabolism, lipolysis and regulation of body weight. Recently, it has been recognized that thyroid hormone receptor interacts with transcription factors that predominantly respond to nutrient signals including the peroxisome proliferator-activated receptors, liver X receptor and others. Crosstalk between thyroid hormone signaling and these nutrient responsive factors occurs through a variety of mechanisms: competition for retinoid X receptor heterodimer partners, DNA binding sites and transcriptional cofactors. This review focuses on the mechanisms of interaction of thyroid hormone signaling with other metabolic pathways and the importance of understanding these interactions to develop therapeutic agents for treatment of metabolic disorders, such as dyslipidemias, obesity and diabetes. C1 [Brent, Gregory A.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Angeles Healthcare Syst, Mol Endocrinol Lab,Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Angeles Healthcare Syst, Mol Endocrinol Lab,Dept Physiol, Los Angeles, CA 90073 USA. RP Brent, GA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Angeles Healthcare Syst, Mol Endocrinol Lab,Dept Med, Los Angeles, CA 90073 USA. EM gbrent@ucla.edu FU National Institutes of Health [RO1 DK67233] FX Supported by National Institutes of Health grant RO1 DK67233 to G.B. NR 73 TC 52 Z9 57 U1 1 U2 12 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD MAR PY 2010 VL 21 IS 3 BP 166 EP 173 DI 10.1016/j.tem.2009.11.004 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 576HW UT WOS:000276136100006 PM 20015660 ER PT J AU Chin, KR Lonner, JH Jupiter, BS Jupiter, JB AF Chin, K. R. Lonner, J. H. Jupiter, B. S. Jupiter, J. B. TI The surgeon as a hand patient. The clinical and psychological impact of hand and wrist fractures SO UNFALLCHIRURG LA German DT Article DE Surgeons; Hand injuries; Psychological; Motivated ID INJURIES; PHYSICIAN; STUDENTS AB To gain insight into the management of patients with hand and wrist injuries, a series of clinical and psychological analyses was performed on 9 surgeons, each of whom underwent operative fixation of a hand or wrist fracture. The results of these analyses suggest that the functional outcome after hand surgery was affected by the surgeons' personality, motivation, and ability to accept and adapt to the injury, the nature of the injury, and the importance of the hand to the surgeons' careers. Surgeons are highly motivated and compulsive individuals who consider their career involvement a major source of identity and self-worth. Most returned to their operative duties ahead of the schedule set by their hand surgeons (average, 25 days after surgery), regarded their injuries as a positive challenge, and changed their lifestyles after injury to protect their hands. C1 [Jupiter, J. B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hand Surg Serv,Dept Orthopaed Surg, Boston, MA 02114 USA. RP Jupiter, JB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hand Surg Serv,Dept Orthopaed Surg, WACC 527, Boston, MA 02114 USA. NR 17 TC 1 Z9 1 U1 2 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0177-5537 J9 UNFALLCHIRURG JI Unfallchirurg PD MAR PY 2010 VL 113 IS 3 BP 175 EP 179 DI 10.1007/s00113-010-1760-5 PG 5 WC Emergency Medicine; Surgery SC Emergency Medicine; Surgery GA 567CS UT WOS:000275420500002 PM 20217302 ER PT J AU Oh, WK Landrum, MB Lamont, EB McNeil, BJ Keating, NL AF Oh, William K. Landrum, Mary Beth Lamont, Elizabeth B. McNeil, Barbara J. Keating, Nancy L. TI Does Oral Antiandrogen Use Before Leuteinizing Hormone-releasing Hormone Therapy in Patients With Metastatic Prostate Cancer Prevent Clinical Consequences of a Testosterone Flare? SO UROLOGY LA English DT Article ID DISEASE FLARE; COMORBIDITY INDEX; CARCINOMA; ANALOG; FLUTAMIDE; AGONIST; RISK AB OBJECTIVES To investigate whether oral antiandrogen therapy before initiation of leuteinizing hormone-releasing hormone (LHRH) agonists was associated with fewer clinical flares. LHRH agonists are associated with initial testosterone rises that may cause clinical disease flares in men with metastatic prostate cancer. METHODS We identified newly diagnosed metastatic prostate cancer patients treated in Veterans Affairs Hospitals from 2001-2004 with LHRH agonists with or without prior antiandrogen therapy. We assessed spinal cord compression, radiation therapy, fractures, bladder outlet obstruction, and narcotic prescriptions for pain within 30 days of starting LHRH therapy. RESULTS Of 1566 metastatic prostate cancer patients treated with LHRH agonists, 1245 (79.5%) patients received oral antiandrogens before initiating LHRH agonist treatment. Hispanic men, married patients, and those without prior cancer were treated less often with oral antiandrogens (all P <= .05). Complication rates did not differ by receipt of oral antiandrogens (all P >= .17). Spinal cord compression and pathologic fractures were extremely rare whether antiandrogens were used or not. In adjusted analysis, there was no decrease in odds of any event for treatment with an antiandrogen within 6 days (OR, 1.04, 95% CI, 0.78-1.40) or >= 7 days (OR, 0.95, 95% CI, 0.72-1.25) before LHRH agonist treatment. CONCLUSIONS Antiandrogen therapy before LHRH agonists in metastatic prostate cancer was not associated with differences in fractures, spinal cord compression, bladder outlet obstruction, or narcotic prescriptions. Rates of spinal cord compression or fracture were < 1% in the first 30 days after beginning LHRH agonist therapy regardless of antiandrogen use. UROLOGY 75: 642-647, 2010. (C) 2010 Elsevier Inc. C1 [Oh, William K.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Adult Oncol, Boston, MA 02114 USA. Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. RP Oh, WK (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Dana 1230,44 Binney St, Boston, MA 02115 USA. EM william_oh@dfci.harvard.edu RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 19 TC 11 Z9 11 U1 0 U2 3 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 MAR PY 2010 VL 75 IS 3 BP 642 EP 647 DI 10.1016/j.urology.2009.08.008 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 572GB UT WOS:000275814500047 PM 19962733 ER PT J AU Geisler, BP AF Geisler, Benjamin P. TI Health State Survey-Derived Utilities in Cost-Utility Analysis-A Call to Action SO VALUE IN HEALTH LA English DT Editorial Material C1 [Geisler, Benjamin P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA USA. [Geisler, Benjamin P.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Oncol, Boston, MA USA. [Geisler, Benjamin P.] UMIT, Dept Publ Hlth Med Decis Making & Hlth Technol As, Hall In Tirol, Austria. RP Geisler, BP (reprint author), Massachusetts Gen Hosp, Beth Israel Deaconess Med Ctr, 38 Calvin St, Somerville, MA 02143 USA. EM ben.geisler@gmail.com RI Geisler, Benjamin/A-9244-2010 OI Geisler, Benjamin/0000-0003-1704-6067 NR 1 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 1098-3015 J9 VALUE HEALTH JI Value Health PD MAR-APR PY 2010 VL 13 IS 2 BP 159 EP 159 DI 10.1111/j.1524-4733.2009.00665.x PG 1 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 557KP UT WOS:000274668300001 PM 19912598 ER PT J AU Rollins, SM Schuch, R AF Rollins, Sean M. Schuch, Raymond TI Crowd control Bacillus anthracis and quorum sensing SO VIRULENCE LA English DT Editorial Material ID VIBRIO-CHOLERAE; BACTERIA; SPORULATION; COMMUNICATION C1 [Schuch, Raymond] Rockefeller Univ, Dept Bacterial Pathogenesis & Immunol, New York, NY 10021 USA. [Rollins, Sean M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. [Rollins, Sean M.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Rollins, Sean M.] Massachusetts Coll Pharm & Hlth Sci, Boston, MA USA. RP Schuch, R (reprint author), Rockefeller Univ, Dept Bacterial Pathogenesis & Immunol, 1230 York Ave, New York, NY 10021 USA. EM schuchr@rockefeller.edu OI Rollins, Sean/0000-0002-3724-1989 NR 20 TC 2 Z9 3 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD MAR-APR PY 2010 VL 1 IS 2 BP 57 EP 59 DI 10.4161/viru.1.2.11051 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 788TU UT WOS:000292468100001 PM 21178417 ER PT J AU Williams-Roberts, H Chang, YC Losina, E Freedberg, KA Walensky, RP AF Williams-Roberts, Hazel Chang, Yuchiao Losina, Elena Freedberg, Kenneth A. Walensky, Rochelle P. TI Frequent HIV testing among participants of a routine HIV testing program SO VIRULENCE LA English DT Article DE HIV/AIDS; frequent HIV testing; routine testing; Orasure; Massachusetts ID RISK BEHAVIORS; CARE SETTINGS; SAN-FRANCISCO; MEN; PREDICTORS; PREVENTION; PHYSICIANS; MAGNITUDE; HIV/AIDS; TESTERS AB Massachusetts developed a routine HIV testing program in four sites from January-September 2002. Of the 2,502 patients tested, 453 (18.1%) reported >= 2 HIV tests within the prior three years. In multivariate analyses, frequent HIV testing was associated with younger age (18-30 years, OR = 1.42), a history of injection drug use (OR = 6.35), and men who had sex with men (OR = 3.49). Participants who reported multiple sexual partners (OR = 2.17) and high risk sexual behavior (OR = 2.02) were significantly more likely to have had a prior HIV test. Patients whose HIV risk was unknown had the highest association with frequent testing (OR = 13.18). Because characteristics of frequent HIV testers may inform behavioral interventions, there is a need to understand the motivation for repeatedly accessing HIV testing services. C1 [Chang, Yuchiao; Losina, Elena; Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Chang, Yuchiao; Losina, Elena; Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Chang, Yuchiao; Losina, Elena; Freedberg, Kenneth A.; Walensky, Rochelle P.] Harvard Univ, Ctr AIDS Res CFAR, Boston, MA 02115 USA. [Losina, Elena; Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Losina, Elena; Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Walensky, RP (reprint author), Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. EM rwalensky@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU Massachusetts Department of Public Health, AIDS Bureau, National Institute of Mental Health [R01 MH073445, R01 MH65869]; National Institute of Allergy and Infectious Diseases [K24 AI062476]; Harvard University Center for AIDS Research [P30 AI060354] FX This work was supported by Massachusetts Department of Public Health, AIDS Bureau, National Institute of Mental Health (R01 MH073445, R01 MH65869), and National Institute of Allergy and Infectious Diseases (K24 AI062476) and the Harvard University Center for AIDS Research (P30 AI060354). The authors would like to thank Bethany L. Morris for her technical assistance. NR 30 TC 6 Z9 6 U1 1 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2150-5594 J9 VIRULENCE JI Virulence PD MAR-APR PY 2010 VL 1 IS 2 BP 68 EP 71 DI 10.4161/viru.1.2.10570 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 788TU UT WOS:000292468100004 PM 21178419 ER PT J AU Lewis, MS Gallun, FJ Gordon, J Lilly, DJ Crandell, C AF Lewis, M. Samantha Gallun, Frederick J. Gordon, Jane Lilly, David J. Crandell, Carl TI A Pilot Investigation Regarding Speech-Recognition Performance in Noise for Adults with Hearing Loss in the FM plus HA Listening Condition SO VOLTA REVIEW LA English DT Article ID MULTIPLE-SCLEROSIS; INTELLIGIBILITY; MICROPHONE; RECEPTION; SYSTEMS; AMPLIFICATION; PERCEPTION; AIDS AB While the concurrent use of the hearing aid (HA) microphone with frequency modulation (FM) technology can decrease speech-recognition performance, the FM+HA condition is still an important setting for users of both HA and FM technology. The primary goal of this investigation was to evaluate the effect of attenuating HA gain in the FM+HA listening condition on the signal-to-noise ratio for 50% sentence recognition in two situations: (1) when speech was presented to the FM transmitter microphone and (2) when speech was presented to the HA microphone. A second goal was to determine whether measures based on the Articulation Index (AI) could be used to predict speech-recognition performance. The best speech-recognition performance for the first situation occurred when the HA gain was attenuated by 20 decibels (dB), while the best performance for the second situation occurred when there was 0 dB of attenuation. The AI measures were directly related to speech-recognition performance. C1 [Lewis, M. Samantha; Gallun, Frederick J.; Gordon, Jane; Lilly, David J.] Portland VA Med Ctr, NCRAR, Portland, OR USA. [Lewis, M. Samantha; Gallun, Frederick J.] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97201 USA. [Lilly, David J.] Univ Iowa, Dept Speech Pathol & Audiol, Iowa City, IA 52242 USA. [Crandell, Carl] Univ Florida, Dept Commun Sci & Disorders, Gainesville, FL USA. RP Lewis, MS (reprint author), Portland VA Med Ctr, NCRAR, Portland, OR USA. RI Gallun, Frederick/G-3792-2012 OI Gallun, Frederick/0000-0002-4145-2199 NR 45 TC 1 Z9 1 U1 1 U2 1 PU ALEXANDER GRAHAM BELL ASSOC FOR THE DEAF PI WASHINGTON PA 3417 VOLTA PLACE NW, WASHINGTON, DC 20007 USA SN 0042-8639 J9 VOLTA REV JI Volta Rev. PD SPR PY 2010 VL 110 IS 1 BP 31 EP 54 PG 24 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 589FJ UT WOS:000277131900003 ER PT J AU Muljo, SA Kanellopoulou, C Aravind, L AF Muljo, S. A. Kanellopoulou, C. Aravind, L. TI MicroRNA targeting in mammalian genomes: genes and mechanisms SO WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE LA English DT Review ID ALGA CHLAMYDOMONAS-REINHARDTII; PIWI-INTERACTING RNAS; C-ELEGANS; CAENORHABDITIS-ELEGANS; MESSENGER-RNA; TRANSCRIPTION FACTORS; REGULATORY RNA; POSTTRANSCRIPTIONAL REGULATION; TETRAHYMENA-THERMOPHILA; CELL DIFFERENTIATION AB We briefly review the history of microRNA (miRNA) research and some of the lessons learnt. To provide some insights as to how and why miRNAs came into existence, we consider the evolution of the RNA interference machinery, miRNA genes, and their targets. We highlight the importance of systems biology approaches to integrate miRNAs as an essential subnetwork for modulating gene expression programs. Building accurate computational models that can simulate highly complex cell-specific gene expression patterns in mammals will lead to a better understanding of miRNAs and their targets in physiological and pathological situations. The impact of miRNAs on medicine, either as potential disease predisposing factors, biomarkers, or therapeutics, is highly anticipated and has started to reveal itself. (C) 2010 John Wiley & Sons, Inc. WIREs Syst Biol Med 2010 2 148-161 C1 [Muljo, S. A.] NIAID, Integrat Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Kanellopoulou, C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Muljo, SA (reprint author), NIAID, Integrat Immunobiol Unit, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM muljos@niaid.nih.gov RI Muljo, Stefan/F-5671-2015 OI Muljo, Stefan/0000-0003-1013-446X FU US NIH; NIAID; NCBI, NLM FX We thank anonymous reviewers for their helpful suggestions and apologize in advance that we could not cite all the relevant papers. S.A.M. and L.A. are supported by the Intramural Research Program of the US NIH, NIAID and NCBI, NLM respectively. C.K. is a Claudia Adams Barr Fellow in David Livingston's laboratory (DFCI). NR 119 TC 15 Z9 15 U1 1 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1939-5094 J9 WIRES SYST BIOL MED JI Wiley Interdiscip. Rev.-Syst. Biol PD MAR-APR PY 2010 VL 2 IS 2 BP 148 EP 161 DI 10.1002/wsbm.53 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 674CQ UT WOS:000283711700004 PM 20836019 ER PT J AU Papakostas, GI Charles, D Fava, M AF Papakostas, George I. Charles, Dana Fava, Maurizio TI Are typical starting doses of the selective serotonin reuptake inhibitors sub-optimal? A meta-analysis of randomized, double-blind, placebo-controlled, dose-finding studies in major depressive disorder SO WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY LA English DT Article DE SSRI; dose; depression; efficacy; tolerability ID ALTERNATIVE PSYCHOMETRIC APPROACH; FLUOXETINE THERAPY; PATTERN-ANALYSIS; CLINICAL-TRIALS; ESCITALOPRAM; CITALOPRAM; OUTPATIENTS; SERTRALINE; MODERATE; SCALE AB The purpose of this meta-analysis is to examine the relationship between selective serotonin reuptake inhibitor (SSRI) starting dose and treatment outcome in major depressive disorder (MDD). Medline/Pubmed, EMBASE, the Cochrane database, as well as a number of online clinical trial registries were searched for double-blind, placebo-controlled, fixed-dose trials comparing different starting doses of SSRIs for MDD. Data from nine trials (n=2340) were combined using a random-effects model. Patients randomized to receive the usual starting dose (10 mg escitalopram; 20 mg fluoxetine, paroxetine, citalopram; 50 mg sertraline and fluvoxamine) were less likely to respond than patients who received higher starting doses (RR=0.9; P=0.04; response rate 50.8 vs. 54.8%). The rate of discontinuation due to adverse events was lower among the usual starting dose group (9.8%) compared to the higher starting dose group (16.5%). Initiating treatment with SSRIs at doses higher than those typically used in clinical trials/settings is associated with higher response rates but also higher rates of discontinuation due to intolerance. Developing treatment strategies allowing clinicians to deliver higher initial SSRI doses while enhancing the tolerability of treatment may represent an alternative approach to improving the efficacy of treatment of MDD. C1 [Papakostas, George I.] Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program,Sch Med, Boston, MA 02114 USA. RP Papakostas, GI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Depress Clin & Res Program,Sch Med, 50 Staniford St Suite 401, Boston, MA 02114 USA. EM gpapakostas@partners.org RI Papakostas, George/I-6905-2013 OI Papakostas, George/0000-0002-2465-5103 FU NIMH [K23 MH069629]; Bristol-Myers Squibb Company; PAMLAB LLC; Pfizer Inc.; Abbott Laboratories; Alkermes; Aspect Medical Systems; Astra-Zeneca; Cephalon; Eli Lilly Company; Forest Pharmaceuticals Inc.; GlaxoSmithkline; J & J Pharmaceuticals; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Novartis; Organon Inc.; PamLab, LLC; Pharmavite; Roche; Sanofi/Synthelabo; Solvay Pharmaceuticals, Inc.; Wyeth-Ayerst Laboratories FX This work was supported by NIMH grant K23 MH069629 (awarded to GIP).; George Papakostas has served as a consultant for the Aphios Corporation, Bristol-Myers Squibb Company, GlaxoSmithKline, Evotec Ltd, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, PAMLAB LLC, Pfizer Inc., and Wyeth Inc., has received honoraria from Evotec Ltd, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, PAMLAB LLC, Pfizer Inc, and Titan Pharmaceuticals, and has received research support from Bristol-Myers Squibb Company, PAMLAB LLC, and Pfizer Inc. Dana Charles has no conflicts of interest. Maurizio Fava has received research support from Abbott Laboratories, Alkermes, Aspect Medical Systems, Astra-Zeneca, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, J & J Pharmaceuticals, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis, Organon Inc., PamLab, LLC, Pfizer Inc, Pharmavite, Roche, Sanofi/Synthelabo, Solvay Pharmaceuticals, Inc., Wyeth-Ayerst Laboratories; has served as an advisor/consultant for Aspect Medical Systems, Astra-Zeneca, Bayer AG, Biovail Pharmaceuticals, Inc., BrainCells, Inc. Bristol-Myers Squibb Company, Cephalon, Compellis, Cypress Pharmaceuticals, Dov Pharmaceuticals, Eli Lilly & Company, EPIX Pharmaceuticals, Fabre-Kramer Pharmaceuticals, Inc., Forest Pharmaceuticals Inc., GlaxoSmithkline, Grunenthal GmBH, Janssen Pharmaceutica, Jazz Pharmaceuticals, J & J Pharmaceuticals, Knoll Pharmaceutical Company, Lundbeck, MedAvante, Inc., Neuronetics, Novartis, Nutrition 21, Organon Inc., PamLab, LLC, Pfizer Inc, PharmaStar, Pharmavite, Roche, Sanofi/Synthelabo, Sepracor, Solvay Pharmaceuticals, Inc., Somaxon, Somerset Pharmaceuticals, Wyeth-Ayerst Laboratories; has served as a speaker for Astra-Zeneca, Boehringer-Ingelheim, Bristol-Myers Squibb Company, Cephalon, Eli Lilly & Company, Forest Pharmaceuticals Inc., GlaxoSmithkline, Novartis, Organon Inc., Pfizer Inc, PharmaStar, Wyeth-Ayerst Laboratories; and has equity holdings in Compellis, MedAvante. NR 32 TC 19 Z9 19 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1562-2975 J9 WORLD J BIOL PSYCHIA JI World J. Biol. Psychiatry PD MAR PY 2010 VL 11 IS 2 BP 300 EP 307 DI 10.3109/15622970701432528 PN 2 PG 8 WC Psychiatry SC Psychiatry GA 679EH UT WOS:000284143000017 PM 20218793 ER PT J AU Weiner, J Yamada, K Ishikawa, Y Moran, S Etter, J Shimizu, A Smith, RN Sachs, DH AF Weiner, Joshua Yamada, Kazuhiko Ishikawa, Yoshinori Moran, Shannon Etter, Justin Shimizu, Akira Smith, Rex Neal Sachs, David H. TI Prolonged survival of GalT-KO swine skin on baboons SO XENOTRANSPLANTATION LA English DT Article DE allografts; galT-KO; skin; xenografts; xenotransplantation ID WHITE-GRAFT REACTION; RED DUROC PIG; MINIATURE SWINE; ANIMAL-MODEL; WOUND EXCISION; TRANSPLANTATION; EXPRESSION; REJECTION; CELLS; SIMILARITIES AB Background: Allogeneic skin is currently the best alternative to autologous skin as a temporary treatment for severe burns, but it has several drawbacks. As a potential alternative, we have evaluated GalT-KO swine skin, which lacks expression of the Gal epitope, to investigate the effect of eliminating this epitope on survival of pig-to-baboon skin grafts. Methods: Two adult baboons that had fully recovered from previous T cell depletion received simultaneous skin grafts from: (i) GalT-KO swine, (ii) Gal-positive swine, (iii) a third-party baboon, and (iv) self (control skin). Recipients were treated with cyclosporin for 12 days and the survival, gross appearance, and histology of the grafts were compared. Results: In both baboons, the GalT-KO skin survived longer than either the Gal-positive swine skin or the allogeneic skin. Early rejection of the Gal-positive skin appeared to be mediated by cytotoxic preformed anti-Gal IgM antibodies, while the rejection of GalT-KO skin appeared to result from cellular mechanisms. Conclusions: GalT-KO skin may have potential clinical benefits as an alternative to allogeneic skin as a temporary treatment for severe skin injuries. C1 [Weiner, Joshua; Yamada, Kazuhiko; Ishikawa, Yoshinori; Moran, Shannon; Etter, Justin; Shimizu, Akira; Smith, Rex Neal; Sachs, David H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02115 USA. RP Sachs, DH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Bldg 149-9019,13th St, Boston, MA 02115 USA. EM David.Sachs@tbrc.mgh.harvard.edu FU Department of Defense [DR080729]; NIH/NIAID [5P01AI45897-09] FX This work was supported in part by grants from the Department of Defense (Grant Number: DR080729) and the NIH/NIAID (Grant Number: 5P01AI45897-09). NR 26 TC 8 Z9 9 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD MAR-APR PY 2010 VL 17 IS 2 BP 147 EP 152 DI 10.1111/j.1399-3089.2010.00576.x PG 6 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 583GG UT WOS:000276661000025 PM 20522247 ER PT J AU Wang, YT Wang, H Wang, SM Fu, YW Yang, YG AF Wang, Yuantao Wang, Hui Wang, Shumei Fu, Yaowen Yang, Yong-Guang TI Survival and function of CD47-deficient thymic grafts in mice SO XENOTRANSPLANTATION LA English DT Article DE CD47; macrophage; thymus; xenotransplantation ID DENDRITIC CELL; CD47; TOLERANCE; TRANSPLANTATION; MACROPHAGES; REJECTION; BARRIER AB Background: We have previously shown that the interspecies incompatibility of CD47 plays an important role in triggering rejection of xenogeneic hematopoietic cells by macrophages. However, it remains unknown whether CD47 incompatibility also contributes to the rejection of non-hematopoietic xenografts. Aims: Here, we investigated the role of CD47 in preventing macrophage-mediated rejection of thymic epithelial cells in a mouse model of thymic transplantation across the CD47 barrier. Methods: Wild-type (WT) and CD47 KO mice were thymectomized and treated with T cell-depleting mAbs, and implanted with fetal thymus from syngeneic WT or CD47 KO donors. Results: Transplantation of CD47 KO mouse thymus led to T cell recovery in thymectomized, T cell-depleted WT mice. Similar to the control WT mouse thymic grafts, CD47 KO mouse thymic grafts showed a normal distribution of thymocyte subsets, and almost all of the thymocytes were recipient origin. Furthermore, histological analysis confirmed long-term survival of CD47 KO mouse thymic epithelial cells in WT mouse recipients. Conclusions: These results demonstrate that, unlike hematopoietic cells, CD47 KO mouse thymus can survive and function in WT mice. Furthermore, our data implicate that the role of CD47 in xenograft rejection may differ for different types of xenografts, and that CD47 incompatibility is unlikely to impede thymic xenotransplantation, a potential approach to inducing xenotolerance, by triggering macrophage-mediated rejection. C1 [Wang, Hui] Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Sch Med,MGH E, Boston, MA 02129 USA. [Wang, Yuantao; Fu, Yaowen] Jilin Univ, Hosp 1, Changchun 130023, Jilin, Peoples R China. RP Wang, H (reprint author), Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Sch Med,MGH E, Bldg 149-5102,13th St, Boston, MA 02129 USA. EM hui.wang@tbrc.mgh.harvard.edu; fuyaowen@medmail.com.cn FU NIH [R01 AI064569, P01 AI 045897]; AHA/NCRP [0930361N]; NSFC [30872308]; China Scholarship Council [CSC300001]; First Hospital of Jilin University; Jilin Provincial Science & Technology Department [20070729-16, 200705136] FX The authors thank Drs Kaz Yamada and Hannes Kalscheuer for critical review of this manuscript and Mr Orlando Moreno for outstanding animal husbandry. This work was supported by grants from NIH (R01 AI064569 and P01 AI 045897), AHA/NCRP Scientist Development Grant (#0930361N) and NSFC (30872308). Y.W. is partially supported by an award from China Scholarship Council (CSC300001) and grants from The First Hospital of Jilin University and Jilin Provincial Science & Technology Department (20070729-16 and 200705136). NR 14 TC 7 Z9 7 U1 2 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD MAR-APR PY 2010 VL 17 IS 2 BP 160 EP 165 DI 10.1111/j.1399-3089.2010.00578.x PG 6 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 583GG UT WOS:000276661000027 PM 20522249 ER PT J AU Paik, EJ de Jong, JLO Pugach, E Opara, P Zon, LI AF Paik, Elizabeth J. de Jong, Jill L. O. Pugach, Emily Opara, Praise Zon, Leonard I. TI A Chemical Genetic Screen in Zebrafish for Pathways Interacting with cdx4 in Primitive Hematopoiesis SO ZEBRAFISH LA English DT Article ID EXPRESSION; EMBRYOS; PSORIASIS; HINDBRAIN; DEHYDROGENASE; PROGENITORS; SUPPRESSION; INHIBITORS; MUTATION; DISEASES AB cdx4, a caudal-related homeodomain-containing transcription factor, functions as a regulator of hox genes, thereby playing a critical role in anterior-posterior (A-P) patterning during embryogenesis. In zebrafish, homozygous deletion of the cdx4 gene results in a mutant phenotype known as kugelig, with aberrant A-P patterning and severe anemia characterized by decreased gata1 expression in the posterior lateral mesoderm. To identify pathways that interact with cdx4 during primitive hematopoiesis, we conducted a chemical genetic screen in the cdx4 mutant background for compounds that increase gata1 expression in cdx4 mutants. Among 2640 compounds that were tested, we discovered two compounds that rescued gata1 expression in the cdx4-mutant embryos. The strongest rescue was observed with bergapten, a psoralen compound found in bergamont oil. Another member of the psoralen family, 8-methoxypsoralen, was also found to rescue gata1 expression in cdx4-mutant embryos. The psoralen compounds also disrupted normal A-P patterning of embryos. These compounds modify the cdx4-mutant phenotype and will help elucidate signaling pathways that act downstream or parallel to the cdx4-hox pathway. C1 [Zon, Leonard I.] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Zon, LI (reprint author), Childrens Hosp, Stem Cell Program, 300 Longwood Ave,Karp 7, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu FU NIH [5K08DK074595, 2R01HL048801-15A2]; Howard Hughes Medical Institute FX The authors thank the ICCB at Harvard Medical School for providing the chemical libraries used in the screen. The authors also thank R. White for insightful suggestions, and other members of the Zon Laboratory for helpful discussions. This work was supported by grants from the NIH (5K08DK074595 to J.L.O.d.; 2R01HL048801-15A2 to L.I.Z.) and the Howard Hughes Medical Institute (to L.I.Z.). NR 36 TC 18 Z9 18 U1 1 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-8547 J9 ZEBRAFISH JI Zebrafish PD MAR PY 2010 VL 7 IS 1 SI SI BP 61 EP 68 DI 10.1089/zeb.2009.0643 PG 8 WC Developmental Biology; Zoology SC Developmental Biology; Zoology GA 587XM UT WOS:000277029700008 PM 20415644 ER PT J AU Wang, Z Inslicht, SS Metzler, TJ Henn-Haase, C McCaslin, SE Tong, HQ Neylan, TC Marmar, CR AF Wang, Zhen Inslicht, Sabra S. Metzler, Thomas J. Henn-Haase, Clare McCaslin, Shannon E. Tong, Huiqi Neylan, Thomas C. Marmar, Charles R. TI A prospective study of predictors of depression symptoms in police SO PSYCHIATRY RESEARCH LA English DT Article DE Depression; Childhood trauma; Self-worth; Work stress ID CHILDHOOD SEXUAL-ABUSE; POSTTRAUMATIC-STRESS; MAJOR DEPRESSION; WORK STRESS; SELF-ESTEEM; TRAUMA; VULNERABILITY; DISORDER; OFFICERS; RISK AB Police work is one of the most stressful occupations. Previous research has indicated that work stress and trauma exposure may place individuals at heightened risk for the development of depression symptomatology. This prospective longitudinal study was designed to examine predictors of depression symptoms in police service. Participants comprised 119 healthy police recruits from an ongoing prospective study. They completed baseline measures of depression symptoms, childhood trauma exposure, neuroticism, and self-worth during academy training. Follow-up measures of depression symptoms, PTSD symptoms, critical incident exposure, negative life events, and routine work environment stress were assessed after 12 months of police service. Hierarchical linear regression analysis was conducted to examine predictors of current levels of depression symptoms, controlling for baseline depression symptoms and current PTSD symptoms. Greater childhood trauma exposure, lower self-worth during training, and greater perceived work stress in the first year of police service predicted greater depression symptoms at 12 months. Depression symptoms at 1 year of police service were partly independent from PTSD symptoms at 12 months. Greater childhood trauma exposure and lower self-worth during training may be important variables to screen as risk factors for duty-related depression. Strategies to reduce routine work environment stress have the potential to decrease duty-related depression in law enforcement. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Wang, Zhen] Shanghai Jiao Tong Univ, Shanghai Mental Hlth Ctr, Shanghai 200030, Peoples R China. [Wang, Zhen; Inslicht, Sabra S.; Metzler, Thomas J.; Henn-Haase, Clare; McCaslin, Shannon E.; Tong, Huiqi; Neylan, Thomas C.; Marmar, Charles R.] San Francisco VA Med Ctr, San Francisco, CA USA. [Wang, Zhen; Inslicht, Sabra S.; Metzler, Thomas J.; Henn-Haase, Clare; McCaslin, Shannon E.; Neylan, Thomas C.; Marmar, Charles R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Wang, Z (reprint author), Vet Adm Med Ctr, PTSD Res Program, 4150 Clement St 116P, San Francisco, CA 94121 USA. EM wangzhen@smhc.org.cn FU National Institute of Mental Health [R01-MH056350-06] FX This research was supported by National Institute of Mental Health grant (R01-MH056350-06) to Dr. Marmar. We thank the police cadets who volunteered their time to participate in this research. NR 42 TC 32 Z9 35 U1 7 U2 27 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 FEB 28 PY 2010 VL 175 IS 3 BP 211 EP 216 DI 10.1016/j.psychres.2008.11.010 PG 6 WC Psychiatry SC Psychiatry GA 560BY UT WOS:000274878000005 PM 20044144 ER PT J AU Cannon, CP AF Cannon, Christopher P. TI Balancing the benefits of statins versus a new risk-diabetes SO LANCET LA English DT Editorial Material ID 14 RANDOMIZED-TRIALS; LOWERING TREATMENT; METAANALYSIS; CHOLESTEROL; PREVENTION; EFFICACY; GUIDELINES; MELLITUS; DISEASE; SAFETY C1 [Cannon, Christopher P.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Cannon, Christopher P.] Harvard Univ, Sch Med, Boston, MA USA. [Cannon, Christopher P.] TIMI Study Off, Boston, MA 02115 USA. RP Cannon, CP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM cpcannon@partners.org NR 11 TC 14 Z9 16 U1 0 U2 2 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 FEB 27 PY 2010 VL 375 IS 9716 BP 700 EP 701 DI 10.1016/S0140-6736(10)60234-6 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 564JW UT WOS:000275211200005 PM 20167360 ER PT J AU Durst, R Goldstein, K Horowitz, Y Baggish, A Gare, M Hasin, Y Lotan, C Horowitz, M AF Durst, Ronen Goldstein, Kobi Horowitz, Yuval Baggish, Aaron Gare, Meir Hasin, Yonathan Lotan, Chaim Horowitz, Michal TI Hypothyroid dependent myocardial angiotensin receptor trafficking is involved in improved cardiac performance after heat acclimation SO LIFE SCIENCES LA English DT Article DE Myocardial heat acclimation; RAS; Angiotensin II receptors; Elthroxine; Cardiac mechanical performance ID THYROID-HORMONE; EXPERIMENTAL HYPERTHYROIDISM; RENIN; SYSTEM; RATS; PROTECTION; STRESS; HYPERTROPHY; MECHANISMS; EXPRESSION AB Aims: The renin-angiotensin system (RAS) plays a key role in heat acclimation, a process which induces adaptive changes in cardiac function. These changes are mediated in part by reduced thyroid hormone activity and improve myocardial function during and following exposure to various (non-heat) stresses such as ischemia. The aim of this study was to examine the role of RAS in the development of the heat acclimated protected heart. Main methods: Three treatment groups were used: (1) C, controls; (2) AC, heat acclimated rats (1 mo 34 degrees C,); and (3) HAEL, heat acclimated euthyroid rats treated with 3 ng/ml of eltroxine. A Langendorff perfusion apparatus was used to measure hemodynamic parameters at baseline and following administration of angiotensin-II, losartan and PD123319 in isolated hearts. Protein and mRNA levels of angiotensin receptors were measured. Key findings: Both C and HAEL animals showed increased contractility and a drop in coronary flow during angiotensin II exposure whereas AC animals did not have an inotropic response or vasoconstriction. Significantly different patterns of AT1 and AT2 receptor densities (a 50% reduction and a 30% increase in outer cell membrane AT1 and AT2 receptors respectively) were observed in AC animals compared to the other two groups. AT receptor mRNA levels were similar in all treatment groups. Significance: The attenuated response of heat acclimated hearts to angiotensin is mediated by reduced thyroxine levels and is associated with a shift in AT1 receptors from the outer to the inner membrane. This shift appears to be caused by modified posttranslational trafficking of AT receptors. (C) 2010 Elsevier Inc. All rights reserved. C1 [Durst, Ronen; Baggish, Aaron] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Durst, Ronen; Lotan, Chaim] Hadassah Hebrew Univ, Med Ctr, Div Cardiol, Jerusalem, Israel. [Goldstein, Kobi; Horowitz, Yuval; Gare, Meir; Horowitz, Michal] Hebrew Univ Jerusalem, Fac Med Dent, Environm Physiol Lab, Jerusalem, Israel. [Goldstein, Kobi; Horowitz, Yuval; Gare, Meir; Horowitz, Michal] Hebrew Univ Jerusalem, Dept Physiol, Jerusalem, Israel. [Hasin, Yonathan] Baruch Padeh Med Ctr, Cardiovasc Inst, Lower Galilee, Israel. RP Durst, R (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. EM rdurst@partners.org FU Berman Foundation FX This work was supported by a grant provided to Dr. Durst and Dr. Horowitz by the Berman Foundation.; This study was part of Mr. Kobi Goldstein's master's thesis and Dr. Yuval Horowitz's doctoral thesis. NR 21 TC 3 Z9 3 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD FEB 27 PY 2010 VL 86 IS 9-10 BP 331 EP 336 DI 10.1016/j.lfs.2010.01.002 PG 6 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 560NR UT WOS:000274909900006 PM 20093128 ER PT J AU Ishikawa, Y Hirakata, A Griesemer, AD Etter, J Moran, S Weiner, J Shimizu, A Yamada, K AF Ishikawa, Yoshinori Hirakata, Atsushi Griesemer, Adam D. Etter, Justin Moran, Shannon Weiner, Joshua Shimizu, Akira Yamada, Kazuhiko TI Tolerance and Long-Lasting Peripheral Chimerism After Allogeneic Intestinal Transplantation in MGH Miniature Swine SO TRANSPLANTATION LA English DT Article DE Intestinal transplantation; Tolerance; MHC; Miniature swine ID VERSUS-HOST-DISEASE; MAJOR HISTOCOMPATIBILITY COMPLEX; SMALL-BOWEL TRANSPLANTATION; MISMATCHED RENAL-ALLOGRAFTS; BONE-MARROW TRANSPLANTATION; REGULATORY T-CELLS; CLASS-I; COMPOSITE THYMOKIDNEYS; THYMIC TRANSPLANTATION; PARENTERAL-NUTRITION AB Background and Objective. Clinical intestinal transplantation (Int-Tx) is limited by high rates of rejection, infection, and graft versus host disease. To improve clinical outcomes and eliminate the comorbidities associated with chronic immunosuppression, the induction of donor-specific tolerance to intestinal grafts is desirable, especially in the pediatric population. This study determined the ability of intestinal grafts to facilitate tolerance induction in major histocompatibility complex (MHC)-inbred miniature swine. Methods. Seven MGH-miniature swine received heterotopic intestinal grafts, two across MHC-matched, minor-antigen disparities, three across a class I MHC disparity with 12 days of cyclosporine A, and two across a class I MHC disparity without an immunosuppressant. Chimerism was assessed by FACS analysis and immunohistochemistry. Cell-mediated lympholysis assays were used to assess antidonor responses. Results. Two animals receiving intestinal grafts without an immunosuppressant developed antidonor IgG in 14 days and rejected these completely. All other grafts were accepted with 12 days of cyclosporine A across both MHC-matched and MHC class I barriers. Cell-mediated lympholysis assays showed donor-specific unresponsiveness by day 30 across MHC class I barriers. Greater than 15% peripheral donor cell chimerism persisted for more than 60 days after MHC-matched Int-Tx. Although less than 1.5% peripheral donor cell chimerism was seen during the maintenance period after class I-mismatched Int-Tx, 5% to 10% myeloid chimerism was found in the peripheral blood 14 to 90 clays after Int-Tx. FACS analysis demonstrated that 1% to 2% of lymphocytes in the graft mesenteric lymph nodes were CD4(+)/CD25(high+)/Foxp3(+) cells. Conclusion. To our knowledge, this is the first demonstration of tolerance induction and persistence of chimerism in a large animal intestinal transplant model. C1 [Yamada, Kazuhiko] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Transplantat Biol Res Ctr, Organ Transplantat Tolerance & Xenotransplantat L, Boston, MA 02129 USA. RP Yamada, K (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Transplantat Biol Res Ctr, Organ Transplantat Tolerance & Xenotransplantat L, MGH E,13th St,CNY-149 9019, Boston, MA 02129 USA. EM kaz.yamada@tbrc.nigh.harvard.edu NR 43 TC 4 Z9 5 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD FEB 27 PY 2010 VL 89 IS 4 BP 417 EP 426 DI 10.1097/TP.0b013e3181ca8848 PG 10 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 559WJ UT WOS:000274858700008 PM 20177343 ER PT J AU Govern, CC Chakraborty, AK AF Govern, Christopher C. Chakraborty, Arup K. TI For T Cell Receptors, Some Breakups Might Not Last Forever SO IMMUNITY LA English DT Editorial Material ID ACTIVATION; TCR; AFFINITIES; KINETICS; LIGANDS; BINDING; CD8 C1 [Govern, Christopher C.; Chakraborty, Arup K.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Chakraborty, Arup K.] MIT & Harvard, Ragon Inst, Massachusetts Gen Hosp, Boston, MA 02129 USA. RP Chakraborty, AK (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM arupc@mit.edu NR 9 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB 26 PY 2010 VL 32 IS 2 BP 141 EP 142 DI 10.1016/j.immuni.2010.02.005 PG 2 WC Immunology SC Immunology GA 566BX UT WOS:000275346000001 PM 20189475 ER PT J AU Haining, WN Wherry, EJ AF Haining, W. Nicholas Wherry, E. John TI Integrating Genomic Signatures for Immunologic Discovery SO IMMUNITY LA English DT Article ID GENE-EXPRESSION PROFILES; T-CELL DIFFERENTIATION; YELLOW-FEVER VACCINE; SET ENRICHMENT ANALYSIS; CHRONIC VIRAL-INFECTION; MEMORY DIFFERENTIATION; STEM-CELLS; B-CELLS; EFFECTOR; RESPONSES AB Understanding heterogeneity in adaptive immune responses is essential to dissect pathways of memory B and T cell differentiation and to define correlates of protective immunity. Traditionally, immunologists have deconvoluted this heterogeneity with flow cytometry-with combinations of markers to define signatures that represent specific lineages, differentiation states, and functions. Genome-scale technologies have become widely available and provide the ability to define expression signatures-sets of genes-that represent discrete biological properties of cell populations. Because genomic signatures can serve as surrogates of a phenotype, function, or cell state, they can integrate phenotypic information between experiments, cell types, and species. Here, we discuss how integration of well-defined expression signatures across experimental conditions together with functional analysis of their component genes could provide new opportunities to dissect the complexity of the adaptive immune response and map the immune response to vaccines and pathogens. C1 [Haining, W. Nicholas] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Wherry, E. John] Wistar Inst Anat & Biol, Program Immunol, Philadelphia, PA 19104 USA. RP Haining, WN (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM nicholas_haining@dfci.harvard.edu; jwherry@wistar.org FU NIH [AI082630, AI071309, HHSN266200500030C]; Dana Foundation FX W.N.H. and E.J.W. are supported by grants from the NIH (AI082630 to both W.N.H. and E.J.W.; AI071309 and HHSN266200500030C to E.J.W.) and from the Dana Foundation. NR 82 TC 42 Z9 43 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 FEB 26 PY 2010 VL 32 IS 2 BP 152 EP 161 DI 10.1016/j.immuni.2010.02.001 PG 10 WC Immunology SC Immunology GA 566BX UT WOS:000275346000006 PM 20189480 ER PT J AU Butler, PL Mallampalli, RK AF Butler, Phillip L. Mallampalli, Rama K. TI Cross-talk between Remodeling and de Novo Pathways Maintains Phospholipid Balance through Ubiquitination SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CTP-PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE; CHOLINE-PHOSPHATE CYTIDYLYLTRANSFERASE; PLATELET-ACTIVATING-FACTOR; ADULT-RAT LUNG; PHOSPHATIDYLCHOLINE BIOSYNTHESIS; II CELLS; LYSOPHOSPHATIDYLCHOLINE ACYLTRANSFERASE; ACYL-COA; CHOLINEPHOSPHATE CYTIDYLYLTRANSFERASE; MOLECULAR DETERMINANTS AB Phosphatidylcholine (PtdCho), the major phospholipid of animal membranes, is generated by its remodeling and de novo synthesis. Overexpression of the remodeling enzyme, LPCAT1 (acyl-CoA: lysophosphatidylcholine acyltransferase) in epithelia decreased de novo PtdCho synthesis without significantly altering cellular PtdCho mass. Overexpression of LPCAT1 increased degradation of CPT1 (cholinephosphotransferase), a resident Golgi enzyme that catalyzes the terminal step for de novo PtdCho synthesis. CPT1 degradation involved its multiubiquitination and processing via the lysosomal pathway. CPT1 mutants harboring arginine substitutions at multiple carboxyl-terminal lysines exhibited proteolytic resistance to effects of LPCAT1 overexpression in cells and restored de novo PtdCho synthesis. Thus, cross-talk between phospholipid remodeling and de novo pathways involves ubiquitin-lysosomal processing of a key molecular target that mechanistically provides homeostatic control of cellular PtdCho content. C1 Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Biochem, Iowa City, IA 52242 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Internal Med, Pittsburgh, PA 15213 USA. RP Mallampalli, RK (reprint author), UPMC Montefiore, NW628,3459 5th Ave, Pittsburgh, PA 15213 USA. EM mallampallirk@upmc.edu FU National Institutes of Health R01 [HL097376, HL096376, HL098174, HL081784, HL068135]; Department of Veterans Affairs FX This work was supported, in whole or in part, by National Institutes of Health R01 Grants HL097376, HL096376, HL098174, HL081784, and HL068135 (to R. K. M.). This work was also supported by a Merit Review Award from the Department of Veterans Affairs. NR 55 TC 24 Z9 24 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 26 PY 2010 VL 285 IS 9 BP 6246 EP 6258 DI 10.1074/jbc.M109.017350 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 566JW UT WOS:000275367500029 PM 20018880 ER PT J AU Latif, R Michalek, K Morshed, SA Davies, TF AF Latif, Rauf Michalek, Krzysztof Morshed, Syed Ahmed Davies, Terry F. TI A Tyrosine Residue on the TSH Receptor Stabilizes Multimer Formation SO PLOS ONE LA English DT Article ID HUMAN THYROTROPIN RECEPTOR; PROTEIN-COUPLED RECEPTORS; NEGATIVE COOPERATIVITY; STIMULATING-HORMONE; LIPID RAFTS; OLIGOMERIZATION; COMPLEX; ECTODOMAIN; AUTOANTIBODIES; DIMERIZATION AB Background: The thyrotropin stimulating hormone receptor (TSHR) is a G protein coupled receptor (GPCR) with a large ectodomain. The ligand, TSH, acting via this receptor regulates thyroid growth and thyroid hormone production and secretion. The TSH receptor (TSHR) undergoes complex post -translational modifications including intramolecular cleavage and receptor multimerization. Since monomeric and multimeric receptors coexist in cells, understanding the functional role of just the TSHR multimers is difficult. Therefore, to help understand the physiological significance of receptor multimerization, it will be necessary to abrogate multimer formation, which requires identifying the ectodomain and endodomain interaction sites on the TSHR. Here, we have examined the contribution of the ectodomain to constitutive multimerization of the TSHR and determined the possible residue(s) that may be involved in this interaction. Methodology/Principal Findings: We studied ectodomain multimer formation by expressing the extracellular domain of the TSHR linked to a glycophosphotidyl (GPI) anchor in both stable and transient expression systems. Using co-immunoprecipitation and FRET of tagged receptors, we established that the TSH receptor ectodomain was capable of multimerization even when totally devoid of the transmembrane domain. Further, we studied the effect of two residues that likely made critical contact points in this interaction. We showed that a conserved tyrosine residue (Y116) on the convex surface of the LRR3 was a critical residue in ectodomain multimer formation since mutation of this residue to serine totally abrogated ectodomain multimers. This abrogation was not seen with the mutation of cysteine 176 on the inner side of the LRR5, demonstrating that inter-receptor disulfide bonding was not involved in ectodomain multimer formation. Additionally, the Y116 mutation in the intact wild type receptor enhanced receptor degradation. Conclusions/Significance: These data establish the TSH receptor ectodomain as one site of multimerization, independent of the transmembrane region, and that this interaction was primarily via a conserved tyrosine residue in LRR3. C1 [Latif, Rauf; Michalek, Krzysztof; Morshed, Syed Ahmed; Davies, Terry F.] Mt Sinai Sch Med, James J Peters VA Med Ctr, Thyroid Res Unit, New York, NY 10029 USA. [Michalek, Krzysztof] Karol Marcinkowski Univ Med Sci, Dept Endocrinol Metab & Internal Dis, Poznan, Poland. RP Latif, R (reprint author), Mt Sinai Sch Med, James J Peters VA Med Ctr, Thyroid Res Unit, New York, NY 10029 USA. EM rauf.latif@mssm.edu FU National Institutes of Health (NIH) [DK069713, DK052464]; VA Merit Award program; David Owen Segal Endowment FX National Institutes of Health (NIH) grants DK069713, DK052464, the VA Merit Award program (TFD) and the David Owen Segal Endowment (to KM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 43 TC 10 Z9 10 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 26 PY 2010 VL 5 IS 2 AR e9449 DI 10.1371/journal.pone.0009449 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 561RS UT WOS:000274997000015 PM 20195479 ER PT J AU Park, EJ Peixoto, A Imai, Y Goodarzi, A Cheng, GY Carman, CV von Andrian, UH Shimaoka, M AF Park, Eun Jeong Peixoto, Antonio Imai, Yoichi Goodarzi, Ahmad Cheng, Guiying Carman, Christopher V. von Andrian, Ulrich H. Shimaoka, Motomu TI Distinct roles for LFA-1 affinity regulation during T-cell adhesion, diapedesis, and interstitial migration in lymph nodes SO BLOOD LA English DT Article ID ANTIGEN (LFA)-1-DEFICIENT MICE; INTEGRIN LFA-1; I-DOMAIN; BLOOD-VESSELS; CRYSTAL-STRUCTURE; DENDRITIC CELLS; A-DOMAIN; ARREST; LIGAND; ENDOTHELIUM AB During the course of homing to lymph nodes (LNs), T cells undergo a multistep adhesion cascade that culminates in a lymphocyte function-associated antigen 1 (LFA-1)-dependent firm adhesion to the luminal surface of high endothelial venules (HEVs). The importance of LFA-1 affinity regulation in supporting T-cell arrest on HEVs has been well established, however, its importance in the postadhesion phase, which involves intraluminal crawling and diapedesis to the extravascular space, remains elusive. Here we have shown that LFA-1 affinity needs to be appropriately regulated to support these essential steps in the homing cascade. Genetically engineered T cells that were unable to properly down-regulate LFA-1 affinity underwent enhanced, chemokine-independent arrest in HEVs but showed perturbed intravascular crawling to transmigration sites and compromised diapedesis across HEVs. By contrast, the extravascular migration of T cells was insensitive to the affinity-enhancing LFA-1 mutation. These results highlight the requirement for balanced LFA-1 affinity regulation in intravascular and transvascular, but not extravascular, T-cell migration in LNs. (Blood. 2010;115:1572-1581) C1 [Park, Eun Jeong; Peixoto, Antonio; Imai, Yoichi; Goodarzi, Ahmad; Cheng, Guiying; von Andrian, Ulrich H.; Shimaoka, Motomu] Immune Dis Inst, Boston, MA USA. [Park, Eun Jeong; Peixoto, Antonio; Imai, Yoichi; Goodarzi, Ahmad; Cheng, Guiying; von Andrian, Ulrich H.; Shimaoka, Motomu] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA USA. [Park, Eun Jeong; Imai, Yoichi; Shimaoka, Motomu] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Peixoto, Antonio; Goodarzi, Ahmad; Cheng, Guiying; von Andrian, Ulrich H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Carman, Christopher V.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Carman, Christopher V.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP von Andrian, UH (reprint author), 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM uva@hms.harvard.edu; shimaoka@idi.harvard.edu RI von Andrian, Ulrich/A-5775-2008; Carman, Christopher/L-8108-2016 OI Carman, Christopher/0000-0001-7358-2548 FU Arthritis Foundation (C.V.C.); National Institutes of Health grants [AI061663, HL56949, AR42689, AI069259, AI072252, AI078897, AI063421, HL048675]; GlaxoSmithKline-Immune Disease Institute alliance fellowship FX We gratefully acknowledge Jianghai Zhu and Can Xie for modeling; Timothy A. Springer for his valuable advice; Mario R. Capecchi for the self-excision cassette used in pACN-TV vector; Klaus Rajewsky for Bruce-4 embryonic stem cells; and Myriam Wlodarczyk for helpful discussions. We thank Mary Mohrin, Ronnie Yoo, Whitney Silkworth, Yoshiteru Sasaki, Thomas Schurpf, and Harry Leung for technical assistance.; This work was supported by grants from the Arthritis Foundation (C.V.C.) and the National Institutes of Health grants AI061663, HL56949, AR42689, AI069259, AI072252, and AI078897 (U.H.v.A.), AI063421, and HL048675 (M.S.). E.J.P. is partly supported by the GlaxoSmithKline-Immune Disease Institute alliance fellowship. NR 49 TC 42 Z9 42 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 25 PY 2010 VL 115 IS 8 BP 1572 EP 1581 DI 10.1182/blood-2009-08-237917 PG 10 WC Hematology SC Hematology GA 561KB UT WOS:000274974200016 PM 20023213 ER PT J AU Thiery, J Keefe, D Saffarian, S Martinvalet, D Walch, M Boucrot, E Kirchhausen, T Lieberman, J AF Thiery, Jerome Keefe, Dennis Saffarian, Saviz Martinvalet, Denis Walch, Michael Boucrot, Emmanuel Kirchhausen, Tomas Lieberman, Judy TI Perforin activates clathrin- and dynamin-dependent endocytosis, which is required for plasma membrane repair and delivery of granzyme B for granzyme-mediated apoptosis SO BLOOD LA English DT Article ID TARGET-CELLS; COATED PITS; CA2+ INFLUX; DEATH; CYTOTOXICITY; RECEPTORS; DEPLETION; GRANULES; LYSOSOMES; PATHWAYS AB Cytotoxic T lymphocytes and natural killer cells destroy target cells via the polarized exocytosis of lytic effector proteins, perforin and granzymes, into the immunologic synapse. How these molecules enter target cells is not fully understood. It is debated whether granzymes enter via perforin pores formed at the plasma membrane or whether perforin and granzymes are first endocytosed and granzymes are then released from endosomes into the cytoplasm. We previously showed that perforin disruption of the plasma membrane induces a transient Ca(2+) flux into the target cell that triggers a wounded membrane repair response in which lysosomes and endosomes donate their membranes to reseal the damaged membrane. Here we show that perforin activates clathrin- and dynamin-dependent endocytosis, which removes perforin and granzymes from the plasma membrane to early endosomes, preserving outer brane integrity. Inhibiting clathrin- or dynamin-dependent endocytosis death by perforin and granzyme B apoptosis to necrosis. Thus by endocytosis to preserve membrane integrity, perforin facilitates granzyme and avoids the proinflammatory necrotic death of a membrane-damaged (Blood. 2010;115:1582-1593) C1 [Lieberman, Judy] Harvard Univ, Immune Dis Inst, Sch Med, Boston, MA 02115 USA. [Thiery, Jerome; Keefe, Dennis; Saffarian, Saviz; Martinvalet, Denis; Walch, Michael; Boucrot, Emmanuel; Kirchhausen, Tomas; Lieberman, Judy] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Thiery, Jerome; Keefe, Dennis; Martinvalet, Denis; Walch, Michael; Lieberman, Judy] Harvard Univ, Dept Pediat, Sch Med, Boston, MA 02115 USA. [Saffarian, Saviz; Boucrot, Emmanuel; Kirchhausen, Tomas] Harvard Univ, Dept Cell Biol, Sch Med, Boston, MA 02115 USA. RP Lieberman, J (reprint author), Harvard Univ, Immune Dis Inst, Sch Med, Warren Alpert Bldg,Rm 255,200 Longwood Ave, Boston, MA 02115 USA. EM lieberman@idi.harvard.edu RI Lieberman, Judy/A-2717-2015 FU National Institutes of Health [AI063430]; Swiss National Science Foundation (M.W.); Human Frontier Science Program Organization (E.B.) FX We thank Eric Marino for assistance with microscopy and Sonia Sharma for experimental assistance.; This work was supported by National Institutes of Health grant AI063430 (J.L.) and fellowships from the Swiss National Science Foundation (M.W.) and the Human Frontier Science Program Organization (E.B.). NR 45 TC 50 Z9 51 U1 0 U2 4 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 FEB 25 PY 2010 VL 115 IS 8 BP 1582 EP 1593 DI 10.1182/blood-2009-10-246116 PG 12 WC Hematology SC Hematology GA 561KB UT WOS:000274974200017 PM 20038786 ER PT J AU Pitman, MB Lewandrowski, K Shen, J Sahani, D Brugge, W Fernandez-del Castillo, C AF Pitman, Martha Bishop Lewandrowski, Kent Shen, Jian Sahani, Dushyant Brugge, William Fernandez-del Castillo, Carlos TI Pancreatic Cysts Preoperative Diagnosis and Clinical Management SO CANCER CYTOPATHOLOGY LA English DT Review DE pancreas; endoscopic ultrasound; fine-needle aspiration biopsy; endoscopic ultrasound fine-needle aspiration; intraductal papillary mucinous neoplasm; mucinous cyst; pancreatic cysts; cyst fluid analysis; carcinoembryonic antigen; molecular analysis; KRAS ID FINE-NEEDLE-ASPIRATION; PAPILLARY MUCINOUS NEOPLASMS; K-RAS MUTATIONS; ENDOSCOPIC ULTRASOUND; FLUID ANALYSIS; SEROUS-CYSTADENOMA; CYTOLOGIC FEATURES; MOLECULAR ANALYSIS; LESS-THAN-OR-EQUAL-TO-3 CM; SEQUENTIAL ACCUMULATION AB Preoperative diagnosis of pancreatic cysts benefits from integrating the clinical, radiological, and cytological features. As patient management algorithms evolve to increasingly nonsurgical options, accuracy in distinguishing mucinous from nonmucinous and benign from malignant mucinous cysts is important. This review focuses on pseudocysts, serous cystadenomas, intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Patients with pseudocysts almost always present with pancreatitis and are usually medically managed. Radiological studies reveal a unilocular cyst mostly in the pancreatic tail. Cyst fluid is thin, with high amylase but low carcinoembryonic antigen (CEA) levels. DNA mutations are absent. Serous cystadenomas are benign and do not require resection. Patients are usually asymptomatic and have microcystic or macrocystic masses anywhere in the pancreas. Cytology is frequently nondiagnostic. CEA and amylase levels are low. DNA analysis may reveal loss of heterozygosity (LOH) at 3p if associated with Von Hippel-Lindau disease. Neoplastic mucinous cysts are highly variable in their presentation. Most are resected. Mucinous cystic neoplasms typically arise in the body or tail of the pancreas of middle-aged women and demonstrate a septated cyst without dilatation of the main pancreatic duct. Branch duct IPMNs are more common in the pancreatic head of elderly men. Main duct dilatation correlates with main duct or combined type IPMN. Both types of mucinous cysts produce variable amounts of mucin. Cytologically nonmalignant but atypical epithelial cells, even when scant, are an indication of a high risk for malignancy. High CEA level supports a mucinous cyst, as do KRAS mutation and good quality DNA levels. KRAS mutation and multiple LOH support malignancy. Cancer (Cancer Cytopathol) 2010;118:1-13. (C) 2009 American Cancer Society. C1 [Pitman, Martha Bishop; Lewandrowski, Kent; Shen, Jian] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sahani, Dushyant] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Brugge, William] Massachusetts Gen Hosp, Div Gastroenterol, Dept Med, Boston, MA 02114 USA. [Fernandez-del Castillo, Carlos] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Pitman, MB (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM mpitman@partners.org NR 90 TC 67 Z9 67 U1 0 U2 5 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 FEB 25 PY 2010 VL 118 IS 1 BP 1 EP 13 DI 10.1002/cncy.20059 PG 13 WC Oncology; Pathology SC Oncology; Pathology GA 561QA UT WOS:000274992000001 PM 20043327 ER PT J AU Andrews-Hanna, JR Reidler, JS Sepulcre, J Poulin, R Buckner, RL AF Andrews-Hanna, Jessica R. Reidler, Jay S. Sepulcre, Jorge Poulin, Renee Buckner, Randy L. TI Functional-Anatomic Fractionation of the Brain's Default Network SO NEURON LA English DT Article ID STIMULUS-INDEPENDENT THOUGHT; MONKEY RETROSPLENIAL CORTEX; CONSCIOUS RESTING STATE; SOCIAL COGNITION; MACAQUE MONKEY; EPISODIC MEMORY; PARAHIPPOCAMPAL CORTICES; ALZHEIMERS-DISEASE; CINGULATE CORTEX; WANDERING MINDS AB One of the most consistent observations in human functional imaging is that a network of brain regions referred to as the "default network" increases its activity during passive states. Here we explored the anatomy and function of the default network across three studies to resolve divergent hypotheses about its contributions to spontaneous cognition and active forms of decision making. Analysis of intrinsic activity revealed the network comprises multiple, dissociated components. A midline core (posterior cingulate and anterior medial prefrontal cortex) is active when people make self-relevant, affective decisions. In contrast, a medial temporal lobe subsystem becomes engaged when decisions involve constructing a mental scene based on memory. During certain experimentally directed and spontaneous acts of future-oriented thought, these dissociated components are simultaneously engaged, presumably to facilitate construction of mental models of personally significant events. C1 [Andrews-Hanna, Jessica R.; Reidler, Jay S.; Sepulcre, Jorge; Poulin, Renee; Buckner, Randy L.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Andrews-Hanna, Jessica R.; Sepulcre, Jorge; Buckner, Randy L.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Buckner, Randy L.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Buckner, Randy L.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Sepulcre, Jorge; Buckner, Randy L.] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Andrews-Hanna, Jessica R.; Reidler, Jay S.; Sepulcre, Jorge; Poulin, Renee; Buckner, Randy L.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. RP Andrews-Hanna, JR (reprint author), Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA. OI Reidler, Jay/0000-0002-9615-5351 FU Howard Hughes Medical Institute; NIA NIH HHS [AG-021910, R01 AG021910, R01 AG021910-05, R01 AG034556, R01 AG034556-01, R01 AG034556-02, R01 AG034556-03] NR 76 TC 704 Z9 721 U1 15 U2 97 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 25 PY 2010 VL 65 IS 4 BP 550 EP 562 DI 10.1016/j.neuron.2010.02.005 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 566HD UT WOS:000275359800013 PM 20188659 ER PT J AU Flynn, TR Hunter, GJ Johnson, MM AF Flynn, Thomas R. Hunter, George J. Johnson, Matthew M. TI A Man with a Lesion on the Tongue Syphilis of the oral cavity SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DISORDERS; CANCER C1 [Flynn, Thomas R.] Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Cambridge, MA 02138 USA. [Hunter, George J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Johnson, Matthew M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Flynn, Thomas R.] Harvard Univ, Sch Med, Dept Oral & Maxillofacial Surg, Cambridge, MA 02138 USA. [Hunter, George J.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Johnson, Matthew M.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Flynn, TR (reprint author), Harvard Univ, Sch Dent Med, Dept Oral & Maxillofacial Surg, Cambridge, MA 02138 USA. NR 19 TC 5 Z9 5 U1 1 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 25 PY 2010 VL 362 IS 8 BP 740 EP 748 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 559SA UT WOS:000274845600014 PM 20181976 ER PT J AU Levanon, K Ng, V Piao, HY Zhang, Y Chang, MC Roh, MH Kindelberger, DW Hirsch, MS Crum, CP Marto, JA Drapkin, R AF Levanon, K. Ng, V. Piao, H. Y. Zhang, Yi Chang, M. C. Roh, M. H. Kindelberger, D. W. Hirsch, M. S. Crum, C. P. Marto, J. A. Drapkin, R. TI Primary ex vivo cultures of human fallopian tube epithelium as a model for serous ovarian carcinogenesis SO ONCOGENE LA English DT Article DE ovarian cancer; fallopian tube; primary cell culture; cancer biomarkers; DNA damage and repair ID CELL-CYCLE; IN-VITRO; CANCER; DIFFERENTIATION; CARCINOMA; HE-4; PATHOGENESIS; RECEPTOR; OVIDUCT; MARKERS AB Recent studies suggest that some serous ovarian carcinomas (SOCs) arise from the fallopian tube (FT) epithelium rather than the ovarian surface epithelium. This hypothesis places emphasis on the FT secretory epithelial cell as a cell-of-origin. Herein, we report the development of a novel ex vivo primary human FT epithelium culture system that faithfully recapitulates the in vivo epithelium, as shown by morphological, ultrastructural and immunophenotypic analyses. Mass spectrometry-based proteomics reveal that these cultures secrete proteins previously identified as biomarkers for ovarian cancer. We also use this culture system to study the response of the FT epithelium to genotoxic stress and find that the secretory cells exhibit a distinct response to DNA damage when compared with neighboring ciliated cells. The secretory cells show a limited ability to resolve the damage over time, potentially leaving them more susceptible to accumulation of additional mutagenic injury. This divergent response is confirmed with in situ studies using tissue samples, further supporting the use of this ex vivo culture system to investigate FT epithelial pathobiology. We anticipate that this novel culture system will facilitate the study of SOC pathogenesis, and propose that similar culture systems could be developed for other organ site-specific epithelia. Oncogene (2010) 29, 1103-1113; doi: 10.1038/onc.2009.402; published online 23 November 2009 C1 [Levanon, K.; Ng, V.; Piao, H. Y.; Drapkin, R.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Zhang, Yi; Marto, J. A.] Dana Farber Canc Inst, Dept Canc Biol, Ctr Prote, Boston, MA 02115 USA. [Chang, M. C.; Roh, M. H.; Kindelberger, D. W.; Hirsch, M. S.; Crum, C. P.; Drapkin, R.] Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, Boston, MA 02115 USA. RP Drapkin, R (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Ctr Mol Oncol Pathol, JF215D,44 Binney St, Boston, MA 02115 USA. EM ronny_drapkin@dfci.harvard.edu RI Drapkin, Ronny/E-9944-2016; Chang, Martin/J-2329-2016 OI Drapkin, Ronny/0000-0002-6912-6977; FU National Cancer Institute [P50 CA105009, K08 CA108748, R21 CA124688]; Ovarian Cancer Research Fund; Phi Beta Psi Sorority Charitable Trust; Fannie E. Ripple Foundation; Robert and Deborah First Fund; Randi and Joel Cutler Ovarian Cancer Research Fund; Columbia Hospital for Women Research Foundation; Marsha Rivkin Foundation Scientific Scholar Award; AACR-George and Patricia Sehl Fellowship; American Physicians Fellowship; Emmanuel G Rosenblatt Foundation FX We thank Phil Karp, Thomas Moninger and Drs Paola Vermeer and Joseph Zabner (University of Iowa) for their enthusiastic support and assistance in establishing the FT ex vivo culture system, Drs Steve Cannistra, Glenn Dranoff and David Livingston for thoughtful suggestions and comments on the paper and Drs Tom Benjamin and Dawei Li for the Sall2 antibody. Special thanks goes to the faculty, technicians, residents and fellows of the division of Women's and Perinatal Pathology in the Department of Pathology at the Brigham and Women's Hospital, Boston, MA, for the allocation of tissues. This work was supported by the National Cancer Institute [P50 CA105009, K08 CA108748 and R21 CA124688], Ovarian Cancer Research Fund (Individual Investigator Award and Program Project Development Award), Phi Beta Psi Sorority Charitable Trust, Fannie E. Ripple Foundation, Robert and Deborah First Fund, Randi and Joel Cutler Ovarian Cancer Research Fund, the Columbia Hospital for Women Research Foundation, Marsha Rivkin Foundation Scientific Scholar Award, AACR-George and Patricia Sehl Fellowship for Cancer Genetics Research and the American Physicians Fellowship for Medicine in Israel-Claire and Emmanuel G Rosenblatt Foundation Grant. NR 39 TC 104 Z9 113 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 25 PY 2010 VL 29 IS 8 BP 1103 EP 1113 DI 10.1038/onc.2009.402 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 560ON UT WOS:000274912100002 PM 19935705 ER PT J AU Rodriguez-Garcia, M Climent, N Oliva, H Casanova, V Franco, R Leon, A Gatell, JM Garcia, F Gallart, T AF Rodriguez-Garcia, Marta Climent, Nuria Oliva, Harold Casanova, Victor Franco, Rafael Leon, Agathe Gatell, Jose M. Garcia, Felipe Gallart, Teresa TI Increased alpha-Defensins 1-3 Production by Dendritic Cells in HIV-Infected Individuals Is Associated with Slower Disease Progression SO PLOS ONE LA English DT Article ID COPY NUMBER VARIATION; ANTIRETROVIRAL THERAPY; BETA-DEFENSIN; ANTIMICROBIAL DEFENSINS; UNINFECTED INDIVIDUALS; ANTIGEN PRESENTATION; INNATE IMMUNITY; PLASMA-LEVELS; HOST-DEFENSE; T-CELLS AB Background: Defensins are natural endogenous antimicrobial peptides with potent anti-HIV activity and immunomodulatory effects. We recently demonstrated that immature dendritic cells (DC) produce alpha-defensins1-3 and that alpha-defensins1- 3 modulate DC generation and maturation. Since DC-HIV interaction plays a critical role during the first steps of HIV infection, we investigated the possible impact of alpha-defensins1-3 production by DC on disease progression. Methodology/Principal Findings: Monocyte-derived DC (MDDC) were analyzed comparatively in healthy controls (HC) and HIV-infected patients, including untreated "elite'' and "viremic'' controllers, untreated viremic non-controllers and antiretroviral-treated patients. We found that production of alpha-defensins1-3 was significantly increased in MDDC from HIV-infected patients versus HC, and this increase was mainly due to that observed in controllers, while in non-controllers the increase was not statistically significant (controllers vs. HC, p<0.005; controllers vs. non-controllers p<0.05). Secreted alpha-defensins1-3 by immature MDDC positively correlated with CD4 T cell counts in controllers, but not in non-controllers. Moreover, independently of their clinical classification, HIV-infected patients with higher alpha-defensins1-3 secretion by immature MDDC showed slower disease progression, measured as no decrease in the number of CD4+ T-cells below 350 cell/mm(3), lower increase of plasma viral load and no initiation of treatment over time. Plasma alpha-defensins1-3 levels lacked any relationship with immunologic and virologic parameters. Conclusions/Significance: High production of alpha-defensins1-3 by immature DCs appears as a host protective factor against progression of HIV-1infection, suggesting potential diagnostic, therapeutic and preventive implications. This protective effect may arise from the activity of alpha-defensins1-3 to damage the virions prior and/or after their internalization by immature DC, and hence favoring a more efficient viral processing and presentation to HIV-specific CD4+ T cells, without or with a minor rate of transmission of infectious HIV-1 virions. C1 [Rodriguez-Garcia, Marta; Climent, Nuria; Oliva, Harold; Gallart, Teresa] Hosp Clin Barcelona, Serv Immunol, Barcelona, Spain. [Rodriguez-Garcia, Marta; Climent, Nuria; Oliva, Harold; Leon, Agathe; Gatell, Jose M.; Garcia, Felipe; Gallart, Teresa] IDIBAPS, AIDS Res Grp, Barcelona, Spain. [Rodriguez-Garcia, Marta; Climent, Nuria; Oliva, Harold; Leon, Agathe; Gatell, Jose M.; Garcia, Felipe; Gallart, Teresa] Catalonian Ctr HIV Vaccines HIVACAT, Barcelona, Spain. [Casanova, Victor; Franco, Rafael] Univ Barcelona, Sch Med, Hosp Clin Barcelona, Barcelona, Spain. [Casanova, Victor; Franco, Rafael] Dept Biochem & Mol Biol, Barcelona, Spain. [Franco, Rafael] Univ Barcelona, Fac Biol, Barcelona, Spain. [Franco, Rafael] Univ Navarra, Ctr Invest Med Aplicada, E-31080 Pamplona, Spain. [Leon, Agathe; Gatell, Jose M.; Garcia, Felipe] Hosp Clin Barcelona, Infect Dis & AIDS Unit, Barcelona, Spain. RP Rodriguez-Garcia, M (reprint author), Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02114 USA. EM TGALLART@clinic.ub.es RI Franco, Rafael/C-3694-2015; Garcia, Felipe/F-4242-2014 OI Franco, Rafael/0000-0003-2549-4919; Garcia, Felipe/0000-0001-7658-5832 FU Spanish Ministry of Health [FIS2003-1200, FIS2006-1259]; Spanish Ministry of Education and Science [SAF2005-05566, FIPSE36536-2005]; Foundation for the Investigation and Prevention of AIDS in Spain; Ministry of Health [ISCIII-RETIC RD06/006]; "Prof. Maximo Soriano Foundation''; [FIPSE36750] FX This study was mainly supported by Research Grants FIS2003-1200 and FIS2006-1259 (T. G.) from the Spanish Ministry of Health. Additional support was also received from the research grants SAF2005-05566 (J.M.G.) from the Spanish Ministry of Education and Science, FIPSE36536-2005 (T. G.), the Foundation for the Investigation and Prevention of AIDS in Spain, ISCIII-RETIC RD06/006 from the Spanish Cooperative Network of AIDS Research Groups from the Ministry of Health (J.M.G., F. G., T. G.), and FIPSE36750 (R. F.). "Prof. Maximo Soriano Foundation'' contributed in the financial support of the PhD studies of H. A. This Foundation honors the memory of Maximo Soriano, a full Professor of Medicine of the Faculty of Medicine of the University of Barcelona. It is totally academic and aimed to promote biomedical and clinical research in the field of infectious diseases. M. R-G. is the recipient of a research award "Emili Letang'' (Hospital Clinic, Barcelona). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 32 Z9 33 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 25 PY 2010 VL 5 IS 2 AR e9436 DI 10.1371/journal.pone.0009436 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 560SY UT WOS:000274924300021 PM 20195543 ER PT J AU DiPaola, RS Chen, H Stein, M Vaughn, D Patrick-Miller, L Carducci, M Roth, B White, E Wilding, G AF DiPaola, Robert S. Chen, Yu-Hui Stein, Mark Vaughn, David Patrick-Miller, Linda Carducci, Michael Roth, Bruce White, Eileen Wilding, George TI A randomized phase II trial of mitoxantrone, estramustine and vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in patients with metastatic castrate-resistant prostate cancer: ECOG 3899 SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID ADVANCED MALIGNANCIES; 13-CIS-RETINOIC ACID; EXPRESSION; COMBINATION; APOPTOSIS; DOCETAXEL; ALPHA; CELLS AB Background: To test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and vinorelbine (MEV) will have clinical activity in men with metastatic castrate-resistant prostate cancer (CRPC). Methods: 70 patients were treated with either MEV (Arm A) in a 3-week cycle or CRA/IFN/TAX with an 8-week cycle (Arm B). Patients were assessed for response, toxicity, quality of life (QOL), and the effect of treatment on Bcl2 levels in peripheral blood mononuclear cells (PBMC). Results: The PSA response rates were 50% and 23%, measurable disease response rates (CR+PR) 14% and 15%, and median overall survival 19.4 months and 13.9 months on Arm A and Arm B respectively. Transient grade 4 neutropenia occurred in 18 and 2 patients, and grade 3 to 4 thrombosis in 7 patients and 1 patient in Arm A and Arm B respectively. Patients on Arm B reported a clinically significant decline in QOL between baseline and week 9/10 (.71 s.d.), and a significantly lower level of QOL than Arm A (p = 0.01). As hypothesized, Bcl-2 levels decreased with CRA/IFN therapy only in Arm B (p = 0.03). Conclusions: Treatment with MEV was well tolerated and demonstrated clinical activity in patients with CRPC. Given the adverse effect of CRA/IFN/TAX on QOL, the study of other novel agents that target Bcl-2 family proteins is warranted. The feasibility of measuring Bcl-2 protein in a cooperative group setting is hypothesis generating and supports further study as a marker for Bcl-2 targeted therapy. C1 [DiPaola, Robert S.; Stein, Mark; Patrick-Miller, Linda] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, Canc Inst New Jersey, New Brunswick, NJ 08903 USA. [Chen, Yu-Hui] Harvard, Dana Farber Canc Ctr, Dept Biostat, Boston, MA USA. [Vaughn, David] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Carducci, Michael] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Roth, Bruce] Vanderbilt Univ, Dept Med, Nashville, TN USA. [White, Eileen] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08855 USA. [Wilding, George] Univ Wisconsin, Dept Med, Madison, WI USA. RP DiPaola, RS (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, Canc Inst New Jersey, New Brunswick, NJ 08903 USA. EM dipaolrs@umdnj.edu FU NCI NIH HHS [U24 CA114737, U10 CA066636, U10 CA023318] NR 17 TC 9 Z9 9 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 24 PY 2010 VL 8 AR 20 DI 10.1186/1479-5876-8-20 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 567MV UT WOS:000275451900001 PM 20178647 ER PT J AU Fonarow, GC Reeves, MJ Zhao, X Olson, DM Smith, EE Saver, JL Schwamm, LH AF Fonarow, Gregg C. Reeves, Mathew J. Zhao, Xin Olson, DaiWai M. Smith, Eric E. Saver, Jeffrey L. Schwamm, Lee H. CA Get Guidelines-Stroke Steering Com TI Age-Related Differences in Characteristics, Performance Measures, Treatment Trends, and Outcomes in Patients With Ischemic Stroke SO CIRCULATION LA English DT Article DE aging; mortality; outcome assessment; registries; stroke ID TISSUE-PLASMINOGEN ACTIVATOR; QUALITY-OF-CARE; CASE-FATALITY; SHORT-TERM; MORTALITY; OLDER; ATTACK; DETERMINANTS; GUIDELINES AB Background-Prior studies have suggested lower use of guideline-recommended therapy and worse poststroke outcomes in older patients. We sought to examine age-related differences in characteristics, performance measures, temporal trends, and early clinical outcomes for acute ischemic stroke in a large contemporary cohort. Methods and Results-The relationships between age and clinical characteristics, performance measures, and in-hospital outcomes were analyzed in 502 036 ischemic stroke admissions from 1256 hospitals in the Get With the Guidelines-Stroke program from 2003 to 2009. Data were analyzed by age groups (<50, 50 to 59, 60 to 69, 70 to 79, 80 to 89, and >= 90 years) and with age as a continuous variable. Seven predefined performance measures and 2 summary measures were analyzed. Mean age of ischemic stroke patients was 71.0+/-14.6 years; 52.5% were women. Older patients were more likely to have a history of atrial fibrillation or hypertension and less likely to be black, Hispanic, or current/recent smokers. Although modest age-related differences in each individual performance measure were identified, there were substantial temporal improvements in performance measures from 2003 to 2009 in each age group, and many age-related treatment gaps were narrowed or eliminated over time. Older patients were less likely to be discharged home (adjusted odds ratio, 0.69; 95% confidence interval, 0.68 to 0.69) and more likely to die in hospital (adjusted odds ratio, 1.27; 95% confidence interval, 1.25 to 1.29) for each 10-year age increase. Conclusions-Older patients with ischemic stroke differ in clinical characteristics and experience higher in-hospital mortality than younger patients. Performance measure-based treatment rates improved substantially over time for ischemic stroke patients in all age groups, resulting in smaller age-related treatment gaps. (Circulation. 2010; 121:879-891.) C1 [Fonarow, Gregg C.] Univ Calif Los Angeles, Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Div Cardiol,CHS, Los Angeles, CA 90095 USA. [Saver, Jeffrey L.] Univ Calif Los Angeles, Div Neurol, Los Angeles, CA 90095 USA. [Reeves, Mathew J.] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Zhao, Xin; Olson, DaiWai M.] Duke Clin Res Ctr, Durham, NC USA. [Smith, Eric E.] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada. [Schwamm, Lee H.] Massachusetts Gen Hosp, Div Neurol, Boston, MA 02114 USA. RP Fonarow, GC (reprint author), Univ Calif Los Angeles, Med Ctr, Ahmanson UCLA Cardiomyopathy Ctr, Div Cardiol,CHS, 10833 LeConte Ave,Room 47-123, Los Angeles, CA 90095 USA. EM gfonarow@mednet.ucla.edu RI Smith, Eric/C-5443-2012 OI Schwamm, Lee/0000-0003-0592-9145; Saver, Jeffrey/0000-0001-9141-2251; Smith, Eric/0000-0003-3956-1668 FU American Heart Association/American Stroke Association; Pfizer Inc (New York, NY); Merck-Schering Plough (North Wales, Pa); NIH; BMS/Sanofi; Ferrer; Boehringer Ingelheim FX GWTG is funded by the American Heart Association/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), which did not participate in the design, analysis, manuscript preparation, or approval of this manuscript.; Dr Fonarow has received research support from the NIH and received honoraria from and served as a consultant or on the advisory board for Pfizer, Merck/Schering Plough, and BMS/Sanofi. Drs Fonarow and Saver are employed by UCLA, which holds a patent on retriever devices for stroke. Dr Fonarow has served as chair of the American Heart Association GWTG Steering Committee. Dr Reeves has served as a consultant to or on the advisory board for the Michigan Stroke Registry. Dr Saver was an unpaid investigator in a trial by Boehringer Ingelheim and received devices from Concentric Medical for use in a NIH trial. Dr Saver has received honoraria from Ferrer and Boehringer Ingelheim; served as a consultant to or on the advisory board for CoAxia, Talecris, Concentric Medical, and Cygnis; and is a member of an American Heart Association GWTG Science Subcommittee. The other authors report no conflicts. NR 24 TC 71 Z9 72 U1 1 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 FEB 23 PY 2010 VL 121 IS 7 BP 879 EP 891 DI 10.1161/CIRCULATIONAHA.109.892497 PG 13 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 559CI UT WOS:000274797500008 PM 20142445 ER PT J AU Hughes, RAC Gorson, KC Cros, D Griffin, J Pollard, J Vallat, JM Maurer, SL Riester, K Davar, G Dawson, K Sandrock, A AF Hughes, R. A. C. Gorson, K. C. Cros, D. Griffin, J. Pollard, J. Vallat, J. -M. Maurer, S. L. Riester, K. Davar, G. Dawson, K. Sandrock, A. CA Avonex CIDP Study Grp TI Intramuscular interferon beta-1a in chronic inflammatory demyelinating polyradiculoneuropathy SO NEUROLOGY LA English DT Article ID RELAPSING MULTIPLE-SCLEROSIS; RANDOMIZED CONTROLLED-TRIAL; PLASMA-EXCHANGE; DOUBLE-BLIND; POLYNEUROPATHY AB Objective: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shares immunologic features with multiple sclerosis (MS). Because IM interferon beta-1a (IM IFN beta-1a) is an effective and safe treatment for MS, we conducted a dose-ranging efficacy study of IFN beta-1a in patients with CIDP. Methods: Adults with IV immunoglobulin (IVIg)-dependent CIDP (n = 67) were enrolled in this 32-week double-blind trial and randomized to IM IFN beta-1a. Patients received 30 mu g once weekly plus placebo (n = 12), IM IFN beta-1a 60 mu g once weekly plus placebo (n = 11), IM IFN beta-1a 30 mu g twice weekly (n = 11), IM IFN beta-1a 60 mu g twice weekly (n = 11), or placebo twice weekly (n = 22). Participants were maintained on IVIg through week 16, when IVIg was discontinued. Patients who worsened were restarted on IVIg. The primary outcome was total IVIg dose (g/kg) administered from week 16 to 32. Results: There was no difference in total IVIg dose administered after week 16 for patients treated with IFN beta-1a (1.20 g/kg) compared with placebo (1.34 g/kg; p = 0.75). However, exploratory analyses suggested IFN beta-1a significantly reduced total dose of IVIg compared with placebo for participants who required either high-dose IVIg (>0.95 g/kg per month) or had greater weakness at baseline (Medical Research Council sum score <51). Adverse events included flu-like symptoms, headache, and fatigue in the IFN beta-1a groups. Conclusions: Interferon beta-1a (IFN beta-1a) therapy did not provide significant benefit over IV immunoglobulin (IVIg) therapy alone for patients with chronic inflammatory demyelinating polyradiculoneuropathy. However, IFN beta-1a might be beneficial for patients with more severe disability or those needing high doses of IVIg. Level of evidence: This study was designed to provide Class I evidence for the safety and efficacy of IM IFN beta-1a in the treatment of CIDP but has been subsequently classified as Class II due to a >20% patient dropout rate. Thus, this randomized, controlled clinical trial provides Class II evidence of no effect on primary and secondary endpoints of 4 dosage regimens of IM IFN beta-1a added to IVIg in persons with CIDP. Neurology(R) 2010; 74: 651-657 C1 [Gorson, K. C.] Tufts Univ, Dept Neurol, St Elizabeths Med Ctr, Sch Med, Boston, MA 02135 USA. [Hughes, R. A. C.] Kings Coll London, London WC2R 2LS, England. [Cros, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Griffin, J.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Pollard, J.] Univ Sydney, Sydney, NSW 2006, Australia. [Vallat, J. -M.] Serv & Lab Neurol, Limoges, France. [Maurer, S. L.] Sci Connex, Newtown, PA USA. [Riester, K.; Davar, G.; Dawson, K.; Sandrock, A.] Biogen Idec Inc, Cambridge, MA USA. RP Gorson, KC (reprint author), Tufts Univ, Dept Neurol, St Elizabeths Med Ctr, Sch Med, 736 Cambridge St, Boston, MA 02135 USA. EM Kenneth.gorson.md@caritaschristi.org FU Talecris Biotherapeutics; Biogen Idec; Baxter International Inc.; Alexion Pharmaceuticals, Inc.; NIH/NINDS [5R01NS41269]; Adelson Program in Neurological Repair and Regeneration; National Multiple Sclerosis Society; Nancy Davis Foundation; Robert Packard Center for ALS Research at Johns Hopkins; Bayer Schering Pharma; French Minister of Health FX Dr. Hughes serves on scientific advisory boards for Talecris Biotherapeutics, Alexion Pharmaceuticals, Inc., Baxter International Inc., Genzyme Corporation, LFB, Octapharma, and Biogen Idec; has received funding for travel from Talecris Biotherapeutics; serves as Coordinating Editor of the Cochrane Database of Systematic Reviews; and has received consultancy fees and research support to his department from Biogen Idec. Dr. Gorson has received research support from Baxter International Inc. and Alexion Pharmaceuticals, Inc. Dr. Cros has received honoraria from Biogen Idec; receives royalties for publication of Peripheral Neuropathy (Lippincott Williams & Wilkins, 2001); and has served as a consultant for FoldRx Pharmaceuticals. Dr. Griffin serves on a scientific advisory board for Biogen Idec; serves as Editor-in-Chief of Nature Reviews in Neurology; receives royalties from the publication of Kelley's Textbook of Internal Medicine, 4th ed. (Lippincott Williams & Wilkins, 2001), Current Therapy in Neurological Disorders, 7th ed. (Elsevier B. V., 2006), and Myelin Biology & Disorders, 2 Volume Set (Academic Press, 2004); serves as a consultant for Alnylam Pharmaceuticals and Johnson & Johnson; and receives research support from the NIH/NINDS (5R01NS41269 [PI]), the Adelson Program in Neurological Repair and Regeneration, the National Multiple Sclerosis Society, the Nancy Davis Foundation, and the Robert Packard Center for ALS Research at Johns Hopkins. Dr. Pollard serves on a scientific advisory board for Biogen Idec; has received funding for travel and honoraria from Bayer Schering Pharma; serves on the editorial boards of Clinical Neuroscience and the Journal of the Neurological Sciences; and has received research support to his department from Biogen Idec. Dr. Vallat receives research support from the French Minister of Health. Dr. Maurer is an employee of Scientific Connexions, whose work on this manuscript was supported by Biogen Idec. K. Riester is a full-time employee of (company statistician) and holds equity interest in Biogen Idec. Dr. Davar is a full-time employee of and holds equity interest in Biogen Idec. Dr. Dawson is a full-time employee of and holds equity interest in Biogen Idec. Dr. Sandrock is a full-time employee of (Senior VP, Neurology R&D) and holds equity interest in Biogen Idec. NR 26 TC 52 Z9 53 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 23 PY 2010 VL 74 IS 8 BP 651 EP 657 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 559CE UT WOS:000274796900007 PM 20177118 ER PT J AU Tsigkou, O Pomerantseva, I Spencer, JA Redondo, PA Hart, AR O'Doherty, E Lin, YF Friedrich, CC Daheron, L Lin, CP Sundback, CA Vacanti, JP Neville, C AF Tsigkou, Olga Pomerantseva, Irina Spencer, Joel A. Redondo, Patricia A. Hart, Alison R. O'Doherty, Elisabeth Lin, Yunfeng Friedrich, Claudia C. Daheron, Laurence Lin, Charles P. Sundback, Cathryn A. Vacanti, Joseph P. Neville, Craig TI Engineered vascularized bone grafts SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE endothelial cell; mesenchymal stem cell; pericyte; vasculogenesis ID ENDOTHELIAL PROGENITOR CELLS; FIBROBLAST GROWTH-FACTOR; MESENCHYMAL STEM-CELLS; ANGIOGENESIS IN-VITRO; EXTRACELLULAR-MATRIX; COLLAGEN MATRICES; BLOOD-VESSELS; CORD BLOOD; TISSUE; DIFFERENTIATION AB Clinical protocols utilize bone marrow to seed synthetic and decellularized allogeneic bone grafts for enhancement of scaffold remodeling and fusion. Marrow-derived cytokines induce host neovascularization at the graft surface, but hypoxic conditions cause cell death at the core. Addition of cellular components that generate an extensive primitive plexus-like vascular network that would perfuse the entire scaffold upon anastomosis could potentially yield significantly higher-quality grafts. We used a mouse model to develop a two-stage protocol for generating vascularized bone grafts using mesenchymal stem cells (hMSCs) from human bone marrow and umbilical cord-derived endothelial cells. The endothelial cells formed tube-like structures and subsequently networks throughout the bone scaffold 4-7 days after implantation. hMSCs were essential for stable vasculature both in vitro and in vivo; however, contrary to expectations, vasculature derived from hMSCs briefly cultured in medium designed to maintain a proliferative, nondifferentiated state was more extensive and stable than that with hMSCs with a TGF-beta-induced smooth muscle cell phenotype. Anastomosis occurred by day 11, with most hMSCs associating closely with the network. Although initially immature and highly permeable, at 4 weeks the network was mature. Initiation of scaffold mineralization had also occurred by this period. Some human-derived vessels were still present at 5 months, but the majority of the graft vasculature had been functionally remodeled with host cells. In conclusion, clinically relevant progenitor sources for pericytes and endothelial cells can serve to generate highly functional microvascular networks for tissue engineered bone grafts. C1 [Tsigkou, Olga; Pomerantseva, Irina; Redondo, Patricia A.; Hart, Alison R.; O'Doherty, Elisabeth; Lin, Yunfeng; Friedrich, Claudia C.; Daheron, Laurence; Sundback, Cathryn A.; Vacanti, Joseph P.; Neville, Craig] Harvard Univ, Sch Med, Ctr Regenerat Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tsigkou, Olga; Pomerantseva, Irina; Redondo, Patricia A.; Hart, Alison R.; O'Doherty, Elisabeth; Friedrich, Claudia C.; Sundback, Cathryn A.; Vacanti, Joseph P.; Neville, Craig] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Spencer, Joel A.; Lin, Charles P.] Harvard Univ, Sch Med, Adv Microscopy Program, Massachusetts Gen Hosp,Ctr Syst Biol, Boston, MA 02114 USA. [Spencer, Joel A.; Lin, Charles P.] Harvard Univ, Sch Med, Wellman Ctr Photomed, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Spencer, Joel A.] Tufts Univ, Ctr Sci & Technol, Dept Biomed Engn, Medford, MA 02155 USA. RP Neville, C (reprint author), Harvard Univ, Sch Med, Ctr Regenerat Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM neville@helix.mgh.harvard.edu RI Spencer, Joel/A-4590-2013; Lin, Yunfeng/M-5438-2013; Lin, Yunfeng/H-3393-2011; OI Lin, Yunfeng/0000-0003-1224-6561; Lin, Yunfeng/0000-0003-1224-6561; Tsigkou, Olga/0000-0002-5250-8610 FU Stanley H. Durwood Foundation; Harvard Stem Cell Institute; Massachusetts General Hospital FX We thank Katelyn McGovern (Massachusetts General Hospital) for assistance with analyzing confocal images and Dr. Patrick Au (Massachusetts General Hospital) for assistance with preparing the engineered blood vessel model. This work was sponsored by a grant from the Stanley H. Durwood Foundation and the Harvard Stem Cell Institute. Imaging studies were supported by the Massachusetts General Hospital Advanced Microscopy Program start-up fund. NR 38 TC 88 Z9 98 U1 1 U2 32 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 FEB 23 PY 2010 VL 107 IS 8 BP 3311 EP 3316 DI 10.1073/pnas.0905445107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900009 PM 20133604 ER PT J AU Hattori, H Subramanian, KK Sakai, J Jia, YH Li, YT Porter, TF Loison, F Sarraj, B Kasorn, A Jo, H Blanchard, C Zirkle, D McDonald, D Pai, SY Serhan, CN Luo, HR AF Hattori, Hidenori Subramanian, Kulandayan K. Sakai, Jiro Jia, Yonghui Li, Yitang Porter, Timothy F. Loison, Fabien Sarraj, Bara Kasorn, Anongnard Jo, Hakryul Blanchard, Catlyn Zirkle, Dorothy McDonald, Douglas Pai, Sung-Yun Serhan, Charles N. Luo, Hongbo R. TI Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chronic granulomatous disease; innate immunity; NADPH oxidase ID CHRONIC GRANULOMATOUS-DISEASE; TUMOR-SUPPRESSOR PTEN; NADPH OXIDASE; ACTIN POLYMERIZATION; HYDROGEN-PEROXIDE; INHIBITION; PATHWAYS; PI(3,4,5)P-3; INFLAMMATION; GRADIENTS AB Neutrophil chemotaxis plays an essential role in innate immunity, but the underlying cellular mechanism is still not fully characterized. Here, using a small-molecule functional screening, we identified NADPH oxidase-dependent reactive oxygen species as key regulators of neutrophil chemotactic migration. Neutrophils with pharmacologically inhibited oxidase, or isolated from chronic granulomatous disease (CGD) patients and mice, formed more frequent multiple pseudopodia and lost their directionality as they migrated up a chemoattractant concentration gradient. Knocking down NADPH oxidase in differentiated neutrophil-like HL60 cells also led to defective chemotaxis. Consistent with the in vitro results, adoptively transferred CGD murine neutrophils showed impaired in vivo recruitment to sites of inflammation. Together, these results present a physiological role for reactive oxygen species in regulating neutrophil functions and shed light on the pathogenesis of CGD. C1 [Hattori, Hidenori; Subramanian, Kulandayan K.; Sakai, Jiro; Jia, Yonghui; Li, Yitang; Loison, Fabien; Sarraj, Bara; Kasorn, Anongnard; Jo, Hakryul; Blanchard, Catlyn; Zirkle, Dorothy; Luo, Hongbo R.] Harvard Univ, Sch Med, Dept Pathol, Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Hattori, Hidenori; Subramanian, Kulandayan K.; Sakai, Jiro; Jia, Yonghui; Li, Yitang; Loison, Fabien; Sarraj, Bara; Kasorn, Anongnard; Jo, Hakryul; Blanchard, Catlyn; Zirkle, Dorothy; Luo, Hongbo R.] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Porter, Timothy F.; Serhan, Charles N.] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Ctr Expt Therapeut & Reperfus Injury, Boston, MA 02115 USA. [McDonald, Douglas] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [McDonald, Douglas] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Pai, Sung-Yun] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Pai, Sung-Yun] Childrens Hosp, Combined Dept Pediat Hematol Oncol, Boston, MA 02115 USA. RP Luo, HR (reprint author), Harvard Univ, Sch Med, Dept Pathol, Dana Farber Harvard Canc Ctr, 44 Binney St, Boston, MA 02115 USA. EM hongbo.luo@childrens.harvard.edu RI Loison, Fabien/G-3385-2014 OI Sakai, Jiro/0000-0002-2526-2766; Loison, Fabien/0000-0002-6678-1730 FU National Institutes of Health (NIH) [HL066987, HL085100, AI076471, HL092020, GM076084]; American Cancer Society FX The authors thank Leslie Silberstein, John Manis, Li Cai, and Narayanaswamy Ramesh for helpful discussions; and Dan Stevens from Hirata Corp for assistance with the EZ-TAXIScan device. B.S. was supported by National Institutes of Health (NIH) training Grant HL066987. H. L. was supported by NIH Grants HL085100, AI076471, HL092020, and GM076084, and a Research Scholar Grant from the American Cancer Society. NR 27 TC 66 Z9 67 U1 2 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 23 PY 2010 VL 107 IS 8 BP 3546 EP 3551 DI 10.1073/pnas.0914351107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900050 PM 20142487 ER PT J AU Tomassy, GS De Leonibusa, E Jabaudon, D Lodato, S Alfano, C Mele, A Macklis, JD Studer, M AF Tomassy, Giulio Srubek De Leonibusa, Elvira Jabaudon, Denis Lodato, Simona Alfano, Christian Mele, Andrea Macklis, Jeffrey D. Studer, Michele TI Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE arealization; subcerebral projection neurons; neocortex development; corticofugal neurons; nuclear receptor; behavior ID DEVELOPING CEREBRAL-CORTEX; SUBCORTICAL PROJECTION NEURONS; MAMMALIAN CORTEX; PYRAMIDAL TRACT; FATE; IMPAIRMENTS; ACQUISITION; PERFORMANCE; GENERATION; NEOCORTEX/ AB Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUPTFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise. C1 [Jabaudon, Denis; Macklis, Jeffrey D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg,Ctr Nervous Syst Repair, Boston, MA 02114 USA. [Tomassy, Giulio Srubek; De Leonibusa, Elvira; Lodato, Simona; Alfano, Christian; Studer, Michele] Telethon Inst Genet & Med, Dev Disorders Program, I-80131 Naples, Italy. [De Leonibusa, Elvira; Mele, Andrea] Univ Rome, Psychobiol Lab, Dept Genet & Mol Biol, I-00185 Rome, Italy. [Jabaudon, Denis; Macklis, Jeffrey D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Ctr Nervous Syst Repair, Boston, MA 02114 USA. [Jabaudon, Denis; Macklis, Jeffrey D.] Harvard Univ, Sch Med, Program Neurosci, Massachusetts Gen Hosp,Nayef Al Rodhan Labs, Boston, MA 02114 USA. [Jabaudon, Denis; Macklis, Jeffrey D.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Boston, MA 02114 USA. [Jabaudon, Denis; Macklis, Jeffrey D.] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02114 USA. [Jabaudon, Denis] Univ Geneva, Dept Basic Neurosci, Geneva, Switzerland. [Jabaudon, Denis] Univ Geneva, Neurol Clin, Geneva, Switzerland. [Studer, Michele] Univ Nice Sophia Antipolis, Lab Genet Dev Normal & Pathol, F-06108 Nice, France. [Studer, Michele] INSERM, U636, F-06108 Nice, France. RP Macklis, JD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurosurg,Ctr Nervous Syst Repair, Boston, MA 02114 USA. EM jeffrey_macklis@hms.harvard.edu; michele.studer@unice.fr RI Mele, Andrea/E-7741-2015; Lodato, Simona/A-3525-2017; OI Lodato, Simona/0000-0001-6498-2590; Jabaudon, Denis/0000-0003-2438-4769 FU Italian Telethon Foundation; European Community [LSHM-CT-2004-005139]; U. S. National Institutes of Health [NS45523, NS49553]; Harvard Stem Cell Institute; Spastic Paraplegia Foundation; Massachusetts Spinal Cord Injury research program; Travis Roy Foundation; Central Nervous System Research; Emily and Robert Pearlstein Fund for Nervous System Repair; Swiss National Science Foundation; Novartis Foundation FX We thank J. Sanes for the gift of the Thy1-STOP-YFP mice (to J. D. M.); R. Hevner for the TBR1 antibody; C. Minieri, A. De Maio, F. Russo, T. Yamamoto, and E. Sievert for technical assistance; G. Andolfi for genotyping; and M. Giordano for animal husbandry. This work was supported by the Italian Telethon Foundation, the European Community FP6 program under Grant LSHM-CT-2004-005139, and by the "Compagnia San Paolo," Program of Neuroscience (to M. S.), and partially supported by grants from the U. S. National Institutes of Health (NS45523 and NS49553), the Harvard Stem Cell Institute, the Spastic Paraplegia Foundation, the Massachusetts Spinal Cord Injury research program, the Travis Roy Foundation, the Jane and Lee Seidman Fund for Central Nervous System Research, and the Emily and Robert Pearlstein Fund for Nervous System Repair (to J. D. M.). D. J. was partially supported by the Swiss National Science Foundation and the Novartis Foundation. NR 34 TC 50 Z9 53 U1 2 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 FEB 23 PY 2010 VL 107 IS 8 BP 3576 EP 3581 DI 10.1073/pnas.0911792107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900055 PM 20133588 ER PT J AU Wolfer, A Wittner, BS Irimia, D Flavin, RJ Lupien, M Gunawardane, RN Meyer, CA Lightcap, ES Tamayo, P Mesirov, JP Liu, XS Shioda, T Toner, M Loda, M Brown, M Brugge, JS Ramaswamy, S AF Wolfer, Anita Wittner, Ben S. Irimia, Daniel Flavin, Richard J. Lupien, Mathieu Gunawardane, Ruwanthi N. Meyer, Clifford A. Lightcap, Eric S. Tamayo, Pablo Mesirov, Jill P. Liu, X. Shirley Shioda, Toshi Toner, Mehmet Loda, Massimo Brown, Myles Brugge, Joan S. Ramaswamy, Sridhar TI MYC regulation of a "poor-prognosis" metastatic cancer cell state SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE breast cancer; biomarkers; invasion and migration; transcriptional profiling ID BREAST-CANCER; C-MYC; MAMMARY TUMORIGENESIS; IN-SITU; GENE; SIGNATURE; ESTROGEN; PROGRESSION; MECHANISMS; MICROARRAY AB Gene expression signatures are used in the clinic as prognostic tools to determine the risk of individual patients with localized breast tumors developing distant metastasis. We lack a clear understanding, however, of whether these correlative biomarkers link to a common biological network that regulates metastasis. We find that the c-MYC oncoprotein coordinately regulates the expression of 13 different "poor-outcome" cancer signatures. In addition, functional inactivation of MYC in human breast cancer cells specifically inhibits distant metastasis in vivo and invasive behavior in vitro of these cells. These results suggest that MYC oncogene activity (as marked by "poor-prognosis" signature expression) may be necessary for the translocation of poor-outcome human breast tumors to distant sites. C1 [Wolfer, Anita; Wittner, Ben S.; Irimia, Daniel; Flavin, Richard J.; Lupien, Mathieu; Gunawardane, Ruwanthi N.; Shioda, Toshi; Toner, Mehmet; Loda, Massimo; Brown, Myles; Brugge, Joan S.; Ramaswamy, Sridhar] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Wolfer, Anita; Wittner, Ben S.; Shioda, Toshi] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Irimia, Daniel; Toner, Mehmet] Massachusetts Gen Hosp E, Ctr Engn Med, Charlestown, MA 02129 USA. [Irimia, Daniel; Toner, Mehmet] Shriners Hosp Children, Boston, MA 02114 USA. [Flavin, Richard J.; Loda, Massimo] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Lupien, Mathieu; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Meyer, Clifford A.; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Lightcap, Eric S.] Millennium Pharmaceut Inc, Cambridge, MA 02139 USA. [Tamayo, Pablo; Mesirov, Jill P.; Loda, Massimo; Brugge, Joan S.; Ramaswamy, Sridhar] Broad Inst, Cambridge, MA 02142 USA. [Ramaswamy, Sridhar] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Brugge, JS (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM joan_brugge@hms.harvard.edu; sridhar@mgh.harvard.edu OI Brown, Myles/0000-0002-8213-1658; Irimia, Daniel/0000-0001-7347-2082 FU National Cancer Institute [K08 CA100339, P50 CA89393]; Richard & Susan Smith Family Foundation; Howard Hughes Medical Institute; Sidney Kimmel Foundation; Breast Cancer Research Foundation; Susan G. Komen Foundation [FAS0703860, KG0905151]; U.S. Department of Defense [DAMD17-03-1-0408]; Swiss National Science Foundation; Emma Muschamp Foundation FX We thank Daniel Haber, Nick Dyson, and Nabeel Bardeesy for discussions and advice and Kat Coser, Ipsita Dey-Guha, Giuseppe Fedele, and Giorgia Zadra for technical assistance. This work was supported by the National Cancer Institute (Grants K08 CA100339 and P50 CA89393, to S. R.), the Richard & Susan Smith Family Foundation (a New Investigator Award to S. R.), the Howard Hughes Medical Institute (Physician-Scientist Early Career Award to S. R.), the Sidney Kimmel Foundation (Translational Science Award to S. R.), the Breast Cancer Research Foundation (J. S. B.), the Susan G. Komen Foundation (Grants FAS0703860 and KG0905151, to T. S.), U.S. Department of Defense (Award DAMD17-03-1-0408, to R. N. G.), the Swiss National Science Foundation (A. W.), and the Emma Muschamp Foundation (A. W.). NR 43 TC 74 Z9 76 U1 1 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 FEB 23 PY 2010 VL 107 IS 8 BP 3698 EP 3703 DI 10.1073/pnas.0914203107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KN UT WOS:000275130900076 PM 20133671 ER PT J AU Cobb, JP AF Cobb, J. Perren TI Engineering Health in the Intensive Care Unit SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID MANAGEMENT; SERVICES; STATES C1 [Cobb, J. Perren] Massachusetts Gen Hosp, Crit Care Ctr, Boston, MA 02114 USA. [Cobb, J. Perren] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Cobb, JP (reprint author), Massachusetts Gen Hosp, Crit Care Ctr, Gray 444S,55 Fruit St, Boston, MA 02114 USA. EM jpcobb@partners.org NR 7 TC 2 Z9 2 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 22 PY 2010 VL 170 IS 4 BP 319 EP 320 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 559BE UT WOS:000274793900002 PM 20177033 ER PT J AU Oberaigner, W Buchberger, W Frede, T Knapp, R Marth, C Siebert, U AF Oberaigner, Willi Buchberger, Wolfgang Frede, Thomas Knapp, Rudolf Marth, Christian Siebert, Uwe TI Breast cancer incidence and mortality in Tyrol/Austria after fifteen years of opportunistic mammography screening SO BMC PUBLIC HEALTH LA English DT Article ID TEMPORAL VARIATION; COHORT MODELS; AGE PERIOD; PROGRAM; RATES; FINLAND; BENEFITS; AUSTRIA; SWEDEN; WOMEN AB Background: The aim of this study was to analyse breast cancer incidence and mortality in Tyrol from 1970 to 2006, namely after performing more than a decade of opportunistic mammography screening and just before piloting an organised screening programme. Our investigation was conducted on a population level. Methods: To study time trends in breast cancer incidence and mortality, we applied the age-period-cohort model by Poisson regression to the official mortality data covering more than three decades from 1970 to 2006 and to the incidence data ranging from 1988 to 2006. In addition, for incidence data we analysed data on breast cancer staging and compared these with EU guidelines. Results: For the analysis of time trend in breast cancer mortality in age groups 40-79, an age-period-cohort model fits well and shows for years 2002-2006 a statistically significant reduction of 26% (95% CI 13%-36%) in breast cancer mortality as compared to 1992-1996. We see only slight non-significant increases in breast cancer incidence. For the past five years, incidence data show a 10% proportion of in situ cases, and of 50% for cases in stages II+. Conclusions: The opportunistic breast cancer screening programme in Tyrol has only in part exploited the mortality reduction known for organised screening programmes. There seems to be potential for further improvement, and we recommend that an organised screening programme and a detailed screening database be introduced to collect all information needed to analyse the quality indicators suggested by the EU guidelines. C1 [Oberaigner, Willi] Tyrolean State Hosp Ltd, Dept Clin Epidemiol, Canc Registry Tyrol, Innsbruck, Austria. [Oberaigner, Willi; Buchberger, Wolfgang; Siebert, Uwe] UMIT Univ Hlth Sci Med Informat & Technol, Dept Publ Hlth Informat Syst & Hlth Technol Asses, Inst Publ Hlth Med Decis Making & Hlth Technol As, Hall In Tirol, Austria. [Oberaigner, Willi; Siebert, Uwe] Innsbruck Med Univ, Oncotyrol Ctr Personalized Canc Med, Innsbruck, Austria. [Buchberger, Wolfgang] Univ Innsbruck Hosp, A-6020 Innsbruck, Austria. [Frede, Thomas] Innsbruck Med Univ, Dept Radiol, Innsbruck, Austria. [Knapp, Rudolf] Kufstein Cty Hosp, Dept Radiol, Kufstein, Austria. [Marth, Christian] Innsbruck Med Univ, Dept Obstet & Gynecol, Innsbruck, Austria. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Program Hlth Decis Sci, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02115 USA. RP Oberaigner, W (reprint author), Tyrolean State Hosp Ltd, Dept Clin Epidemiol, Canc Registry Tyrol, Innsbruck, Austria. EM willi.oberaigner@iet.at FU ONCOTYROL Center for Personal Cancer Medicine; Federal Ministry for Transport Innovation and Technology (BMVIT); Federal Ministry of Economics and Labour (BMWA); Tyrolean Future Foundation (TZS); Styrian Business Promotion Agency (SFG); UMIT-University for Health Sciences, Medical Informatics and Technology; Innsbruck Medical University; Tyrolean Health Insurance Fund; Tyrolean Health Company FX This work was supported by the ONCOTYROL Center for Personal Cancer Medicine. ONCOTYROL is a COMET Center funded by the Federal Ministry for Transport Innovation and Technology (BMVIT) and the Federal Ministry of Economics and Labour (BMWA), the Tyrolean Future Foundation (TZS) and the Land of Styria represented by the Styrian Business Promotion Agency (SFG) [and supported by UMIT-University for Health Sciences, Medical Informatics and Technology, Innsbruck Medical University, Tyrolean Health Insurance Fund and the Tyrolean Health Company. NR 41 TC 8 Z9 8 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD FEB 20 PY 2010 VL 10 AR 86 DI 10.1186/1471-2458-10-86 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 573DF UT WOS:000275887900001 PM 20170536 ER PT J AU Khambata-Ford, S Harbison, CT Hart, LL Awad, M Xu, LA Horak, CE Dakhil, S Hermann, RC Lynch, TJ Weber, MR AF Khambata-Ford, Shirin Harbison, Christopher T. Hart, Lowell L. Awad, Melissa Xu, Li-An Horak, Christine E. Dakhil, Shaker Hermann, Robert C. Lynch, Thomas J. Weber, Martin R. TI Analysis of Potential Predictive Markers of Cetuximab Benefit in BMS099, a Phase III Study of Cetuximab and First-Line Taxane/Carboplatin in Advanced Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GROWTH-FACTOR-RECEPTOR; METASTATIC COLORECTAL-CANCER; GENE COPY NUMBER; K-RAS MUTATIONS; KRAS MUTATIONS; BRONCHIOLOALVEOLAR-CARCINOMA; PLUS CETUXIMAB; EGFR MUTATIONS; ONCOLOGY-GROUP; GEFITINIB AB Purpose The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is efficacious in multiple tumor types. Patient selection with markers predictive of benefit may enhance its therapeutic index. This retrospective, correlative analysis of the phase III trial BMS099 of cetuximab in advanced non-small-cell lung cancer (NSCLC) was conducted to identify molecular markers for the selection of patients most likely to benefit from cetuximab. Methods In BMS099, 676 chemotherapy-nave patients with stage IIIB (pleural effusion) or stage IV NSCLC of any histology or EGFR expression status were randomly assigned to taxane/carboplatin (T/C) with or without cetuximab. Biomarkers analyzed included K-Ras and EGFR mutations by direct sequencing, EGFR protein expression by immunohistochemistry (IHC), and EGFR gene copy number by fluorescent in situ hybridization (FISH). Relationships between biomarker status and progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) were assessed by log-rank tests per treatment arm for treatment-specific effects and across the total evaluable population. Results Tumor samples were available from 225 randomly assigned patients. K-Ras mutations were found in 17% of evaluable patients (35 of 202 patients), EGFR mutations were found in 10% (17 of 166 patients), EGFR positivity by IHC was found in 89% (131 of 148 patients), and FISH positivity was found in 52% (54 of 104 patients). No significant associations were found between biomarker status and PFS, OS, and ORR in the treatment-specific analyses. Conclusion In contrast with colorectal cancer, and within the limitations of the data set, efficacy parameters did not appear to correlate with K-Ras mutation status or with any of the EGFR-related biomarkers evaluated. Additional exploratory analyses are essential to identify predictive markers and to optimize patient selection for cetuximab therapy in NSCLC. C1 [Khambata-Ford, Shirin] Bristol Myers Squibb Co, Princeton, NJ 08543 USA. Florida Canc Specialists, Ft Myers, FL USA. Canc Ctr Kansas, Wichita, KS USA. NW Georgia Oncol Ctr, Marietta, GA USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Bristol Myers Squibb Co, Wallingford, CT 06492 USA. RP Khambata-Ford, S (reprint author), Bristol Myers Squibb Co, 311 Pennington Rocky Hill Rd,3B-2-06, Princeton, NJ 08543 USA. EM shirin.ford@bms.com FU Bristol-Myers Squibb FX Supported by Bristol-Myers Squibb. NR 49 TC 163 Z9 167 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2010 VL 28 IS 6 BP 918 EP 927 DI 10.1200/JCO.2009.25.2890 PG 10 WC Oncology SC Oncology GA 557EU UT WOS:000274653200006 PM 20100958 ER PT J AU Dahlberg, SE Sandler, AB Brahmer, JR Schiller, JH Johnson, DH AF Dahlberg, Suzanne E. Sandler, Alan B. Brahmer, Julie R. Schiller, Joan H. Johnson, David H. TI Clinical Course of Advanced Non-Small-Cell Lung Cancer Patients Experiencing Hypertension During Treatment With Bevacizumab in Combination With Carboplatin and Paclitaxel on ECOG 4599 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol ID ENDOTHELIAL GROWTH-FACTOR; METASTATIC COLORECTAL-CANCER; PLUS BEVACIZUMAB; BREAST-CANCER; SURVIVAL; ANGIOGENESIS; FLUOROURACIL; LEUCOVORIN; TRIALS; GEMCITABINE AB Purpose Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) with demonstrated efficacy in combination with carboplatin and paclitaxel (PCB) for the treatment of advanced non-small-cell lung cancer (NSCLC). Administration of bevacizumab is postulated to decrease nitric oxide synthesis and lead to hypertension, which may be a physiological sign that the VEGF pathway is more actively being blocked and could result in improved outcomes. Patients and Methods Eastern Cooperative Oncology Group (ECOG) 4599 randomly assigned patients with nonsquamous NSCLC to carboplatin and paclitaxel (PC) versus PCB. Hypertensive patients were compared with nonhypertensive patients with respect to overall survival (OS) and progression-free survival (PFS) using blood pressure data and adverse event data separately. High blood pressure (HBP) by the end of cycle 1 was defined as blood pressure > 150/100 at any previous time or at least a 20-mmHg increase in diastolic blood pressure from baseline. Results In a multivariable Cox model adjusting for HBP as a time-varying covariate, comparing those on PCB with HBP with those on PC gave an OS hazard ratio (HR) of 0.60 (95% CI, 0.43 to 0.81; P = .001); comparing those on PCB without HBP with those on PC alone, the OS HR was 0.86 (95% CI, 0.74 to 1.00; P = .05). Comparing the PCB HBP group with PC gave an adjusted PFS HR of 0.54 (95% CI, 0.41 to 0.73; P < .0001) and comparing those on PCB without HBP to those on PC, the HR was 0.72 (95% CI, 0.62 to 0.84; P < .0001). The 6-month cumulative incidence of hypertension was 6.2% (95% CI, 3.9% to 8.6%). Conclusion Data from ECOG 4599 suggest that onset of HBP during treatment with PCB may be associated with improved outcomes, and additional studies of the downstream effects of VEGF suppression and hypertension are needed. C1 [Dahlberg, Suzanne E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Dahlberg, SE (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, CLSB 11007,44 Binney St, Boston, MA 02115 USA. EM dahlberg@jimmy.harvard.edu FU NCI NIH HHS [CA23318, U10 CA023318] NR 36 TC 124 Z9 132 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2010 VL 28 IS 6 BP 949 EP 954 DI 10.1200/JCO.2009.25.4482 PG 6 WC Oncology SC Oncology GA 557EU UT WOS:000274653200010 PM 20085937 ER PT J AU Courtney, KD Corcoran, RB Engelman, JA AF Courtney, Kevin D. Corcoran, Ryan B. Engelman, Jeffrey A. TI The PI3K Pathway As Drug Target in Human Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID PHOSPHATIDYLINOSITOL KINASE-ACTIVITY; PLECKSTRIN HOMOLOGY DOMAIN; RECEPTOR TYROSINE KINASES; MAMMARY EPITHELIAL-CELLS; PHOSPHOINOSITIDE 3-KINASE; BREAST-CANCER; PROSTATE-CANCER; PROTEIN-KINASE; TUMOR-CELLS; PIK3CA GENE AB The phosphatidylinositol 3-kinase (PI3K) signaling axis impacts on cancer cell growth, survival, motility, and metabolism. This pathway is activated by several different mechanisms in cancers, including somatic mutation and amplification of genes encoding key components. In addition, PI3K signaling may serve integral functions for noncancerous cells in the tumor microenvironment. Consequently, therapeutics targeting the PI3K pathway are being developed at a rapid pace, and preclinical and early clinical studies are beginning to suggest specific strategies to effectively use them. However, the central role of PI3K signaling in a large array of diverse biologic processes raises concerns about its use in therapeutics and increases the need to develop sophisticated strategies for its use. In this review, we will discuss how PI3K signaling affects the growth and survival of tumor cells. From this vantage, we will consider how inhibitors of the PI3K signaling cascade, either alone or in combination with other therapeutics, can most effectively be used for the treatment of cancer. J Clin Oncol 28: 1075-1083. (C) 2010 by American Society of Clinical Oncology C1 [Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Ctr Canc, Boston, MA 02215 USA. RP Engelman, JA (reprint author), Massachusetts Gen Hosp, Ctr Canc, 149 13th St, Charlestown, MA 02129 USA. EM jengelman@partners.org RI lv, xiaoqing/A-2591-2012 FU American Society of Clinical Oncology; Genentech Dana-Farber/Harvard Cancer Center (DF/HCC) Kidney Cancer Career Development Award; National Institutes of Health [CA120060, R01CA140594, R01CA137008]; National Cancer Institute Lung Special Program of Research Excellence (SPORE) [P50CA090578]; DF/HCC Gastrointestinal Cancer SPORE [P50 CA127003]; Ellison Foundation Scholar award; American Association for Cancer Research FX Supported by an American Society of Clinical Oncology Young Investigator Award and a Genentech Dana-Farber/Harvard Cancer Center (DF/HCC) Kidney Cancer Career Development Award (K. D. C.), by National Institutes of Health K08 Grants No. CA120060, No. R01CA140594, and No. R01CA137008, by National Cancer Institute Lung Special Program of Research Excellence (SPORE) Grant No. P50CA090578, DF/HCC Gastrointestinal Cancer SPORE Grant No. P50 CA127003, the Ellison Foundation Scholar award (J. A. E.), and the American Association for Cancer Research Stand Up To Cancer program. NR 108 TC 580 Z9 604 U1 7 U2 74 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 FEB 20 PY 2010 VL 28 IS 6 BP 1075 EP 1083 DI 10.1200/JCO.2009.25.3641 PG 9 WC Oncology SC Oncology GA 557EU UT WOS:000274653200028 PM 20085938 ER PT J AU Gerstner, ER Frosch, MP Batchelor, TT AF Gerstner, Elizabeth R. Frosch, Matthew P. Batchelor, Tracy T. TI Diffusion Magnetic Resonance Imaging Detects Pathologically Confirmed, Nonenhancing Tumor Progression in a Patient With Recurrent Glioblastoma Receiving Bevacizumab SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROLONGS SURVIVAL; KINASE INHIBITOR; GLIOMA; ANTIBODY; GROWTH; EDEMA C1 [Gerstner, Elizabeth R.] Massachusetts Gen Hosp, Ctr Canc, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Dept Pathol, Boston, MA USA. Massachusetts Gen Hosp, Ctr Canc, Div Neurooncol, Boston, MA USA. Massachusetts Gen Hosp, Ctr Canc, Div Hematol & Oncol, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. RP Gerstner, ER (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Neurol, Boston, MA 02114 USA. NR 11 TC 50 Z9 50 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 FEB 20 PY 2010 VL 28 IS 6 BP E91 EP E93 DI 10.1200/JCO.2009.25.0233 PG 3 WC Oncology SC Oncology GA 557EU UT WOS:000274653200029 PM 19933906 ER PT J AU Viswanathan, SR Daley, GQ AF Viswanathan, Srinivas R. Daley, George Q. TI Lin28: A MicroRNA Regulator with a Macro Role SO CELL LA English DT Article ID EMBRYONIC STEM-CELLS; SELF-RENEWAL; POSTTRANSCRIPTIONAL REGULATION; CAENORHABDITIS-ELEGANS; CANCER-CELLS; EXPRESSION; RNA; LIN-28; PROMOTES; TRANSFORMATION C1 [Viswanathan, Srinivas R.; Daley, George Q.] Childrens Hosp, Stem Cell Transplantat Program, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Viswanathan, Srinivas R.; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Viswanathan, Srinivas R.; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Childrens Hosp, Stem Cell Transplantat Program, Div Pediat Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu NR 41 TC 211 Z9 223 U1 1 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 19 PY 2010 VL 140 IS 4 BP 445 EP 449 DI 10.1016/j.cell.2010.02.007 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 557KQ UT WOS:000274668400005 PM 20178735 ER PT J AU Song, CM Qu, ZH Blumm, N Barabasi, AL AF Song, Chaoming Qu, Zehui Blumm, Nicholas Barabasi, Albert-Laszlo TI Limits of Predictability in Human Mobility SO SCIENCE LA English DT Article ID DYNAMICS; NETWORKS; PATTERNS AB A range of applications, from predicting the spread of human and electronic viruses to city planning and resource management in mobile communications, depend on our ability to foresee the whereabouts and mobility of individuals, raising a fundamental question: To what degree is human behavior predictable? Here we explore the limits of predictability in human dynamics by studying the mobility patterns of anonymized mobile phone users. By measuring the entropy of each individual's trajectory, we find a 93% potential predictability in user mobility across the whole user base. Despite the significant differences in the travel patterns, we find a remarkable lack of variability in predictability, which is largely independent of the distance users cover on a regular basis. C1 [Song, Chaoming; Qu, Zehui; Blumm, Nicholas; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Dept Phys, Boston, MA 02115 USA. [Song, Chaoming; Qu, Zehui; Blumm, Nicholas; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Dept Biol, Boston, MA 02115 USA. [Song, Chaoming; Qu, Zehui; Blumm, Nicholas; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Dept Comp Sci, Boston, MA 02115 USA. [Song, Chaoming; Qu, Zehui; Blumm, Nicholas; Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Song, Chaoming; Qu, Zehui; Blumm, Nicholas; Barabasi, Albert-Laszlo] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Qu, Zehui] Univ Elect Sci & Technol China, Sch Engn & Comp Sci, Chengdu 610054, Peoples R China. RP Barabasi, AL (reprint author), Northeastern Univ, Ctr Complex Network Res, Dept Phys, Boston, MA 02115 USA. EM alb@neu.edu FU James S. McDonnell Foundation; NSF [DMR-0426737, IIS-0513650]; Defense Threat Reduction Agency [HDTRA1-08-1-0027]; U.S. Army Research Laboratory [W911NF-09-2-0053]; China Scholarship Council FX We thank M. Gonzales, P. Wang, J. Bagrow, and J. A. Aslam for discussions and comments on the manuscript. This work was supported by the James S. McDonnell Foundation 21st Century Initiative in Studying Complex Systems, NSF within the Information Technology Research (DMR-0426737) and IIS-0513650 programs, the Defense Threat Reduction Agency award HDTRA1-08-1-0027, and the Network Science Collaborative Technology Alliance sponsored by the U.S. Army Research Laboratory under agreement number W911NF-09-2-0053. Z.Q. was supported by a fellowship from the China Scholarship Council. NR 26 TC 726 Z9 779 U1 28 U2 210 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 FEB 19 PY 2010 VL 327 IS 5968 BP 1018 EP 1021 DI 10.1126/science.1177170 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556XE UT WOS:000274625800046 PM 20167789 ER PT J AU Silverman, LB Supko, JG Stevenson, KE Woodward, C Vrooman, LM Neuberg, DS Asselin, BL Athale, UH Clavell, L Cole, PD Kelly, KM Laverdiere, C Michon, B Schorin, M Schwartz, CL O'Brien, JE Cohen, HJ Sallan, SE AF Silverman, Lewis B. Supko, Jeffrey G. Stevenson, Kristen E. Woodward, Christina Vrooman, Lynda M. Neuberg, Donna S. Asselin, Barbara L. Athale, Uma H. Clavell, Luis Cole, Peter D. Kelly, Kara M. Laverdiere, Caroline Michon, Bruno Schorin, Marshall Schwartz, Cindy L. O'Brien, Jane E. Cohen, Harvey J. Sallan, Stephen E. TI Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia SO BLOOD LA English DT Article ID COLI ASPARAGINASE; PROTOCOLS AB Over the past several decades, L-asparaginase, an important component of therapy for acute lymphoblastic leukemia (ALL), has typically been administered intramuscularly rather than intravenously in North America because of concerns regarding anaphylaxis. We evaluated the feasibility of giving polyethylene glycosylated (PEG) asparaginase, the polyethylene glycol conjugate of Escherichia coli L-asparaginase, by intravenous infusion in children with ALL. Between 2005 and 2007, 197 patients (age, 1-17 years) were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-01 and received a single dose of intravenous PEG-asparaginase (2500 IU/m(2)) over 1 hour during remission induction. Serum asparaginase activity more than 0.1 IU/mL was detected in 95%, 88%, and 7% of patients at 11, 18, and 25 days after dosing, respectively. Toxicities included allergy (1.5%), venous thrombosis (2%), and pancreatitis (4.6%). We conclude that intravenous administration of PEG-asparaginase is tolerable in children with ALL, and potentially therapeutic enzyme activity is maintained for at least 2 weeks after a single dose in most patients. This trial was registered at www.clinicaltrials.gov as #NCT00400946. (Blood. 2010; 115: 1351-1353) C1 [Silverman, Lewis B.; Stevenson, Kristen E.; Vrooman, Lynda M.; Neuberg, Donna S.; O'Brien, Jane E.; Sallan, Stephen E.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Silverman, Lewis B.; Stevenson, Kristen E.; Vrooman, Lynda M.; Neuberg, Donna S.; O'Brien, Jane E.; Sallan, Stephen E.] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Silverman, Lewis B.; Stevenson, Kristen E.; Vrooman, Lynda M.; Neuberg, Donna S.; O'Brien, Jane E.; Sallan, Stephen E.] Dana Farber Canc Inst, Dept Computat Biol, Boston, MA 02115 USA. [Silverman, Lewis B.; Vrooman, Lynda M.; Sallan, Stephen E.] Childrens Hosp Boston, Div Hematol Oncol, Boston, MA USA. [Supko, Jeffrey G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Woodward, Christina] Boston Univ, Sch Med, Boston, MA 02215 USA. [Asselin, Barbara L.] Univ Rochester, Med Ctr, Div Pediat Oncol, Rochester, NY 14627 USA. [Athale, Uma H.] McMaster Univ, Div Pediat Hematol Oncol, Hamilton, ON, Canada. [Clavell, Luis] San Jorge Childrens Hosp, Div Pediat Oncol, San Juan, PR USA. [Cole, Peter D.] Childrens Hosp Montefiore, Albert Einstein Coll Med, Div Pediat Hematol Oncol, Bronx, NY USA. [Kelly, Kara M.] Columbia Univ, Morgan Stanley Childrens Hosp New York Presbyteri, Div Pediat Oncol, Med Ctr, New York, NY 10027 USA. [Laverdiere, Caroline] Univ Montreal, Div Hematol & Oncol, Hosp St Justine, Montreal, PQ, Canada. [Michon, Bruno] Ctr Hosp Univ Quebec, Div Hematol Oncol, Quebec City, PQ, Canada. [Schorin, Marshall] Inova Fairfax Hosp Children, Falls Church, VA USA. [Schwartz, Cindy L.] Brown Univ, Div Pediat Hematol Oncol, Hasbro Childrens Hosp, Warren Alpert Med Sch, Providence, RI 02912 USA. [Cohen, Harvey J.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. RP Silverman, LB (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM Lewis_Silverman@dfci.harvard.edu FU National Cancer Institute [5 P01CA068484]; Enzon Pharmaceuticals FX This study was supported by the National Cancer Institute (grant 5 P01CA068484) and in part by Enzon Pharmaceuticals (research funding). NR 12 TC 37 Z9 51 U1 0 U2 4 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 FEB 18 PY 2010 VL 115 IS 7 BP 1351 EP 1353 DI 10.1182/blood-2009-09-245951 PG 3 WC Hematology SC Hematology GA 557KY UT WOS:000274669200007 PM 20007809 ER PT J AU Kharas, MG Okabe, R Ganis, JJ Gozo, M Khandan, T Paktinat, M Gilliland, DG Gritsman, K AF Kharas, Michael G. Okabe, Rachel Ganis, Jared J. Gozo, Maricel Khandan, Tulasi Paktinat, Mahnaz Gilliland, D. Gary Gritsman, Kira TI Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; PLECKSTRIN HOMOLOGY DOMAIN; ACUTE MYELOGENOUS LEUKEMIA; ANTILEUKEMIC ACTIVITY; SIGNALING PATHWAY; LINEAGE CHOICE; HIGH-FREQUENCY; ACTIVATION; MUTATIONS; KINASE AB Human cancers, including acute myeloid leukemia (AML), commonly display constitutive phosphoinositide 3-kinase (PI3K) AKT signaling. However, the exact role of AKT activation in leukemia and its effects on hematopoietic stem cells (HSCs) are poorly understood. Several members of the PI3K pathway, phosphatase and tensin homolog (Pten), the forkhead box, subgroup O (FOXO) transcription factors, and TSC1, have demonstrated functions in normal and leukemic stem cells but are rarely mutated in leukemia. We developed an activated allele of AKT1 that models increased signaling in normal and leukemic stem cells. In our murine bone marrow transplantation model using a myristoylated AKT1 (myr-AKT), recipients develop myeloproliferative disease, T-cell lymphoma, or AML. Analysis of the HSCs in myr-AKT mice reveals transient expansion and increased cycling, associated with impaired engraftment. myr-AKT-expressing bone marrow cells are unable to form cobblestones in long-term cocultures. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) rescues cobblestone formation in myr-AKT expressing bone marrow cells and increases the survival of myr-AKT mice. This study demonstrates that enhanced AKT activation is an important mechanism of transformation in AML and that HSCs are highly sensitive to excess AKT/mTOR signaling. (Blood. 2010; 115: 1406-1415) C1 [Kharas, Michael G.; Okabe, Rachel; Ganis, Jared J.; Gozo, Maricel; Khandan, Tulasi; Paktinat, Mahnaz; Gilliland, D. Gary; Gritsman, Kira] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA. [Ganis, Jared J.; Gilliland, D. Gary; Gritsman, Kira] Harvard Univ, Sch Med, Boston, MA USA. [Gilliland, D. Gary; Gritsman, Kira] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Gilliland, D. Gary] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Gritsman, K (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St,Smith 970C, Boston, MA 02115 USA. EM kgritsman@partners.org FU American Society of Hematology Fellow Scholar Award; Ruth L. Kirschtein NRSA Award; Howard Hughes Medical Institute FX This work was supported in part by the American Society of Hematology Fellow Scholar Award (K. G.), the Ruth L. Kirschtein NRSA Award (K. G.), and the Howard Hughes Medical Institute (D. G. G.). NR 32 TC 125 Z9 132 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 FEB 18 PY 2010 VL 115 IS 7 BP 1406 EP 1415 DI 10.1182/blood-2009-06-229443 PG 10 WC Hematology SC Hematology GA 557KY UT WOS:000274669200013 PM 20008787 ER PT J AU Beroukhim, R Mermel, CH Porter, D Wei, G Raychaudhuri, S Donovan, J Barretina, J Boehm, JS Dobson, J Urashima, M Mc Henry, KT Pinchback, RM Ligon, AH Cho, YJ Haery, L Greulich, H Reich, M Winckler, W Lawrence, MS Weir, BA Tanaka, KE Chiang, DY Bass, AJ Loo, A Hoffman, C Prensner, J Liefeld, T Gao, Q Yecies, D Signoretti, S Maher, E Kaye, FJ Sasaki, H Tepper, JE Fletcher, JA Tabernero, J Baselga, J Tsao, MS Demichelis, F Rubin, MA Janne, PA Daly, MJ Nucera, C Levine, RL Ebert, BL Gabriel, S Rustgi, AK Antonescu, CR Ladanyi, M Letai, A Garraway, LA Loda, M Beer, DG True, LD Okamoto, A Pomeroy, SL Singer, S Golub, TR Lander, ES Getz, G Sellers, WR Meyerson, M AF Beroukhim, Rameen Mermel, Craig H. Porter, Dale Wei, Guo Raychaudhuri, Soumya Donovan, Jerry Barretina, Jordi Boehm, Jesse S. Dobson, Jennifer Urashima, Mitsuyoshi Mc Henry, Kevin T. Pinchback, Reid M. Ligon, Azra H. Cho, Yoon-Jae Haery, Leila Greulich, Heidi Reich, Michael Winckler, Wendy Lawrence, Michael S. Weir, Barbara A. Tanaka, Kumiko E. Chiang, Derek Y. Bass, Adam J. Loo, Alice Hoffman, Carter Prensner, John Liefeld, Ted Gao, Qing Yecies, Derek Signoretti, Sabina Maher, Elizabeth Kaye, Frederic J. Sasaki, Hidefumi Tepper, Joel E. Fletcher, Jonathan A. Tabernero, Josep Baselga, Jose Tsao, Ming-Sound Demichelis, Francesca Rubin, Mark A. Janne, Pasi A. Daly, Mark J. Nucera, Carmelo Levine, Ross L. Ebert, Benjamin L. Gabriel, Stacey Rustgi, Anil K. Antonescu, Cristina R. Ladanyi, Marc Letai, Anthony Garraway, Levi A. Loda, Massimo Beer, David G. True, Lawrence D. Okamoto, Aikou Pomeroy, Scott L. Singer, Samuel Golub, Todd R. Lander, Eric S. Getz, Gad Sellers, William R. Meyerson, Matthew TI The landscape of somatic copy-number alteration across human cancers SO NATURE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; EMBRYONIC STEM-CELLS; LUNG-CANCER; CHROMOSOMAL BREAKPOINT; MALIGNANT-MELANOMA; ADAPTER PROTEINS; ARRAY CGH; GENES; GENOME; AMPLIFICATION AB A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappa B pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types. C1 [Beroukhim, Rameen; Mermel, Craig H.; Wei, Guo; Raychaudhuri, Soumya; Barretina, Jordi; Boehm, Jesse S.; Dobson, Jennifer; Pinchback, Reid M.; Haery, Leila; Greulich, Heidi; Reich, Michael; Winckler, Wendy; Lawrence, Michael S.; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Liefeld, Ted; Gao, Qing; Daly, Mark J.; Ebert, Benjamin L.; Gabriel, Stacey; Garraway, Levi A.; Golub, Todd R.; Lander, Eric S.; Getz, Gad; Meyerson, Matthew] Broad Inst MIT & Harvard, Canc Program, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Beroukhim, Rameen; Mermel, Craig H.; Wei, Guo; Raychaudhuri, Soumya; Barretina, Jordi; Boehm, Jesse S.; Dobson, Jennifer; Pinchback, Reid M.; Haery, Leila; Greulich, Heidi; Reich, Michael; Winckler, Wendy; Lawrence, Michael S.; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Liefeld, Ted; Gao, Qing; Daly, Mark J.; Ebert, Benjamin L.; Gabriel, Stacey; Garraway, Levi A.; Golub, Todd R.; Lander, Eric S.; Getz, Gad; Meyerson, Matthew] Broad Inst MIT & Harvard, Med & Populat Genet Grp, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Lander, Eric S.] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA. [Beroukhim, Rameen; Mermel, Craig H.; Barretina, Jordi; Dobson, Jennifer; Haery, Leila; Greulich, Heidi; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Yecies, Derek; Signoretti, Sabina; Janne, Pasi A.; Letai, Anthony; Garraway, Levi A.; Loda, Massimo; Golub, Todd R.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Beroukhim, Rameen; Mermel, Craig H.; Barretina, Jordi; Dobson, Jennifer; Haery, Leila; Greulich, Heidi; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Yecies, Derek; Signoretti, Sabina; Janne, Pasi A.; Letai, Anthony; Garraway, Levi A.; Loda, Massimo; Golub, Todd R.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Beroukhim, Rameen; Mermel, Craig H.; Barretina, Jordi; Dobson, Jennifer; Haery, Leila; Greulich, Heidi; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Yecies, Derek; Signoretti, Sabina; Janne, Pasi A.; Letai, Anthony; Garraway, Levi A.; Loda, Massimo; Golub, Todd R.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Beroukhim, Rameen; Mermel, Craig H.; Barretina, Jordi; Dobson, Jennifer; Haery, Leila; Greulich, Heidi; Weir, Barbara A.; Tanaka, Kumiko E.; Chiang, Derek Y.; Bass, Adam J.; Hoffman, Carter; Prensner, John; Yecies, Derek; Signoretti, Sabina; Janne, Pasi A.; Letai, Anthony; Garraway, Levi A.; Loda, Massimo; Golub, Todd R.; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Beroukhim, Rameen; Raychaudhuri, Soumya; Ligon, Azra H.; Greulich, Heidi; Bass, Adam J.; Signoretti, Sabina; Fletcher, Jonathan A.; Janne, Pasi A.; Ebert, Benjamin L.; Loda, Massimo] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen; Raychaudhuri, Soumya; Ligon, Azra H.; Greulich, Heidi; Bass, Adam J.; Signoretti, Sabina; Fletcher, Jonathan A.; Janne, Pasi A.; Ebert, Benjamin L.; Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Beroukhim, Rameen; Greulich, Heidi; Ebert, Benjamin L.; Lander, Eric S.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Beroukhim, Rameen; Greulich, Heidi; Ebert, Benjamin L.; Lander, Eric S.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Beroukhim, Rameen; Greulich, Heidi; Ebert, Benjamin L.; Lander, Eric S.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Beroukhim, Rameen; Greulich, Heidi; Ebert, Benjamin L.; Lander, Eric S.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Cho, Yoon-Jae; Pomeroy, Scott L.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Nucera, Carmelo] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. [Porter, Dale; Donovan, Jerry; Mc Henry, Kevin T.; Loo, Alice; Sellers, William R.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. [Urashima, Mitsuyoshi] Jikei Univ, Sch Med, Div Mol Epidemiol, Minato Ku, Tokyo 1058461, Japan. [Maher, Elizabeth] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Kaye, Frederic J.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20889 USA. [Kaye, Frederic J.] Natl Naval Med Ctr, Bethesda, MD 20889 USA. [Sasaki, Hidefumi] Nagoya City Univ, Sch Med, Dept Surg 2, Nagoya, Aichi 4678601, Japan. [Chiang, Derek Y.; Tepper, Joel E.] Univ N Carolina, Sch Med, Lineberger Comprehens Canc Ctr, Dept Genet & Radiat Oncol, Chapel Hill, NC 27599 USA. [Tabernero, Josep; Baselga, Jose] Vall Hebron Univ Hosp, Res Inst, Vall Hebron Inst Oncol, Med Oncol Program, Barcelona 08035, Spain. [Tabernero, Josep; Baselga, Jose] Autonomous Univ Barcelona, E-08035 Barcelona, Spain. [Tsao, Ming-Sound] Princess Margaret Hosp, Univ Hlth Network, Dept Pathol, Toronto, ON M5G 2M9, Canada. [Tsao, Ming-Sound] Princess Margaret Hosp, Univ Hlth Network, Div Appl Mol Oncol, Toronto, ON M5G 2M9, Canada. [Tsao, Ming-Sound] Ontario Canc Inst, Toronto, ON M5G 2M9, Canada. [Demichelis, Francesca; Rubin, Mark A.] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA. [Daly, Mark J.] Massachusetts Gen Hosp, Richard B Simches Res Ctr, Ctr Human Genet Res, Boston, MA 02114 USA. [Levine, Ross L.; Antonescu, Cristina R.; Ladanyi, Marc; Singer, Samuel] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Levine, Ross L.; Antonescu, Cristina R.; Ladanyi, Marc; Singer, Samuel] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Rustgi, Anil K.] Univ Penn, Dept Med, GI Div, Philadelphia, PA 19104 USA. [Rustgi, Anil K.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Rustgi, Anil K.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Beer, David G.] Univ Michigan, Dept Surg, Thorac Surg Sect, Ann Arbor, MI 48109 USA. [True, Lawrence D.] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. [Okamoto, Aikou] Jikei Univ, Sch Med, Dept Obstet & Gynecol, Minato Ku, Tokyo 1058461, Japan. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Lander, ES (reprint author), Broad Inst MIT & Harvard, Canc Program, Cambridge Ctr 7, Cambridge, MA 02142 USA. EM lander@broadinstitute.org; gadgetz@broadinstitute.org; william.sellers@novartis.com; matthew_meyerson@dfci.harvard.edu RI kaye, frederic/E-2437-2011; Meyerson, Matthew/E-7123-2012; Chiang, Daisy/C-9481-2011; Levine, Rodney/D-9885-2011; OI Chiang, Daisy/0000-0002-8205-4285; Chiang, Derek/0000-0002-1131-6065; Boehm, Jesse/0000-0002-6795-6336; Yecies, Derek/0000-0001-8534-4651; Rubin, Mark/0000-0002-8321-9950; Demichelis, Francesca/0000-0002-8266-8631 FU National Institutes of Health (NIH) [P50CA90578, R01CA109038, R01CA109467, P01CA085859, P01CA 098101, K08CA122833]; Doris Duke Charitable Foundation; Sarah Thomas Monopoli Lung Cancer Research Fund; Seaman Corporation Fund for Lung Cancer Research; Lucas Foundation FX This work was supported by grants from the National Institutes of Health (NIH) (Dana-Farber/Harvard Cancer Center and Pacific Northwest Prostate Cancer SPOREs, P50CA90578, R01CA109038, R01CA109467, P01CA085859, P01CA 098101 and K08CA122833), the Doris Duke Charitable Foundation, the Sarah Thomas Monopoli Lung Cancer Research Fund, the Seaman Corporation Fund for Lung Cancer Research, and the Lucas Foundation. Medulloblastoma samples were obtained in collaboration with the Children's Oncology Group. N. Vena provided technical assistance with FISH, and I. Mellinghoff, P. S. Mischel, L. Liau and T. F. Cloughesy provided DNA samples. We thank T. Ried, R. Weinberg and B. Vogelstein for critical review of the manuscript and for comments about its context in the field of cancer genetics. NR 49 TC 1241 Z9 1256 U1 12 U2 152 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 18 PY 2010 VL 463 IS 7283 BP 899 EP 905 DI 10.1038/nature08822 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556HZ UT WOS:000274582700036 PM 20164920 ER PT J AU Gill, IS Aron, M Gervais, DA Jewett, MAS AF Gill, Inderbir S. Aron, Monish Gervais, Debra A. Jewett, Michael A. S. TI Small Renal Mass SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LAPAROSCOPIC PARTIAL NEPHRECTOMY; NEPHRON-SPARING SURGERY; CELL CARCINOMA; RADIOFREQUENCY ABLATION; RADICAL NEPHRECTOMY; TUMOR SIZE; PATHOLOGICAL FEATURES; COMPUTED-TOMOGRAPHY; ACTIVE SURVEILLANCE; NATURAL-HISTORY AB A 65-year-old man with a history of well-controlled hypertension presents for a follow-up visit after an incidental finding of a small mass in the right kidney on an abdominal computed tomographic (CT) scan. (The scan had been ordered to evaluate pain in the lower quadrant, which resolved.) The mass is 3.2 cm in its largest dimension, anterior, heterogeneous, and solid, and it is in the right renal hilum near the main renal artery, vein, and ureter; the left kidney appears normal. The patient feels well, and his physical examination is unremarkable. His serum creatinine level is 1.2 mg per deciliter (106 mu mol per liter). How should this patient be further evaluated and treated? C1 [Gill, Inderbir S.; Aron, Monish] Univ So Calif, Keck Sch Med, Inst Urol, Ctr Robot Surg & Adv Laparoscopy, Los Angeles, CA 90089 USA. [Gervais, Debra A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Jewett, Michael A. S.] Univ Toronto, Princess Margaret Hosp, Dept Surg Oncol, Div Urol, Toronto, ON, Canada. RP Gill, IS (reprint author), Univ So Calif, Keck Sch Med, Inst Urol, Ctr Robot Surg & Adv Laparoscopy, 1441 Eastlake Ave,Suite 7416, Los Angeles, CA 90089 USA. EM gillindy@gmail.com FU Covidien; Pfizer; Novartis; Glaxo-Smith-Kline; Viventia Biotech; Wyeth FX Dr. Gill reports having equity options in Hansen Medical; Dr. Gervais, receiving grant support from Covidien; and Dr. Jewett, receiving consulting fees from Pfizer, Novartis, Glaxo-Smith-Kline, and Viventia Biotech and grant support from Wyeth. No other potential conflict of interest relevant to this article was reported. NR 49 TC 138 Z9 149 U1 1 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 18 PY 2010 VL 362 IS 7 BP 624 EP 634 DI 10.1056/NEJMcp0910041 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 556ED UT WOS:000274571200010 PM 20164486 ER PT J AU Radhakrishnan, J Uppot, RN Colvin, RB AF Radhakrishnan, Jai Uppot, Raul N. Colvin, Robert B. TI A Man with HIV Infection, Proteinuria, and Edema Fibrillary glomerulonephritis associated with hepatitis C virus infection. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ESSENTIAL MIXED CRYOGLOBULINEMIA; VIRAL-INFECTION; IMMUNOTACTOID GLOMERULONEPHRITIS; PATHOLOGICAL FEATURES; GLOMERULOPATHY; COINFECTION C1 [Radhakrishnan, Jai] Columbia Univ, Dept Med, Div Nephrol, Med Ctr, New York, NY 10027 USA. [Uppot, Raul N.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Colvin, Robert B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Uppot, Raul N.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Colvin, Robert B.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Radhakrishnan, J (reprint author), Columbia Univ, Dept Med, Div Nephrol, Med Ctr, New York, NY 10027 USA. NR 35 TC 4 Z9 4 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 18 PY 2010 VL 362 IS 7 BP 636 EP 646 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 556ED UT WOS:000274571200013 PM 20164488 ER PT J AU Saha, S Coffman, DD Smits, AK AF Saha, Somnath Coffman, Darren D. Smits, Ariel K. TI Giving Teeth to Comparative-Effectiveness Research - The Oregon Experience SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Saha, Somnath] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Gen Internal Med Sect, Portland, OR 97201 USA. [Saha, Somnath] Oregon Hlth & Sci Univ, Div Gen Internal Med & Geriatr, Portland, OR 97201 USA. [Smits, Ariel K.] Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97201 USA. [Saha, Somnath; Coffman, Darren D.; Smits, Ariel K.] Oregon Hlth Serv Commiss, Salem, OR USA. RP Saha, S (reprint author), Oregon Hlth & Sci Univ, Portland VA Med Ctr, Gen Internal Med Sect, Portland, OR 97201 USA. NR 5 TC 12 Z9 12 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 FEB 18 PY 2010 VL 362 IS 7 DI 10.1056/NEJMp0912938 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 556ED UT WOS:000274571200004 PM 20130249 ER PT J AU Wang, YX Radfar, S Liu, SH Riker, AI Khong, HT AF Wang, Yixiang Radfar, Soroosh Liu, Suhu Riker, Adam I. Khong, Hung T. TI Mitf-Mdel, a novel melanocyte/melanoma-specific isoform of microphthalmia-associated transcription factor-M, as a candidate biomarker for melanoma SO BMC MEDICINE LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; METASTATIC MELANOMA; MALIGNANT-MELANOMA; TIETZ-SYNDROME; GENE; CELLS; MUTATIONS; MARKER; LINEAGE; IDENTIFICATION AB Background: Melanoma incidence is on the rise and advanced melanoma carries an extremely poor prognosis. Treatment options, including chemotherapy and immunotherapy, are limited and offer low response rates and transient efficacy. Thus, identification of new melanocyte/melanoma antigens that serve as potential novel candidate biomarkers in melanoma is an important area for investigation. Methods: Full length MITF-M and its splice variant cDNA were cloned from human melanoma cell line 624 mel by reverse transcription polymerase chain reaction (RT-PCR). Expression was investigated using regular and quantitative RT-PCR in three normal melanocytes (NHEM), 31 melanoma cell lines, 21 frozen melanoma tissue samples, 18 blood samples (pheripheral blood mononuclear cell; PBMC) from healthy donors and 12 non-melanoma cancer cell lines, including three breast, five glioma, one sarcoma, two kidney and one ovarian cancer cell lines. Results: A novel splice variant of MITF-M, which we named MITF-Mdel, was identified. The predicted MITF-Mdel protein contains two in frame deletions, 56- and 6-amino acid deletions in exon 2 (from V32 to E87) and exon 6 (from A187 to T192), respectively. MITF-Mdel was widely expressed in melanocytes, melanoma cell lines and tissues, but almost undetectable in non-melanoma cell lines or PBMC from healthy donors. Both isoforms were expressed significantly higher in melanoma tissues than in cell lines. Two of 31 melanoma cell lines expressed only one isoform or the other. Conclusion: MITF-Mdel, a novel melanocyte/melanoma-specific isoform of MITF-M, may serve as a potential candidate biomarker for diagnostic and follow-up purposes in melanoma. C1 [Khong, Hung T.] Univ S Alabama, Mitchell Canc Inst, Mobile, AL 36604 USA. [Wang, Yixiang] Peking Univ, Res Lab Oral & Maxillofacial Surg, Sch Stomatol, Beijing 100871, Peoples R China. [Radfar, Soroosh] Yale Univ, Sch Med, Dept Internal Med, Hematol Sect, New Haven, CT 06510 USA. [Liu, Suhu] Dana Farber Canc Inst, Boston, MA 02115 USA. [Riker, Adam I.] Ochsner Canc Inst, Dept Surg, New Orleans, LA 70121 USA. RP Khong, HT (reprint author), Univ S Alabama, Mitchell Canc Inst, 1660 Springhill Ave, Mobile, AL 36604 USA. EM hkhong@usouthal.edu OI Wang, Yixiang/0000-0001-5291-9826 NR 29 TC 6 Z9 8 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD FEB 17 PY 2010 VL 8 AR 14 DI 10.1186/1741-7015-8-14 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 569ZG UT WOS:000275640800001 PM 20163701 ER PT J AU Van Cleave, J Gortmaker, SL Perrin, JM AF Van Cleave, Jeanne Gortmaker, Steven L. Perrin, James M. TI Dynamics of Obesity and Chronic Health Conditions Among Children and Youth SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; SCHOOL-AGE-CHILDREN; BODY-MASS INDEX; EARLY-CHILDHOOD; PROSPECTIVE COHORT; CONDUCT DISORDER; MATERNAL OBESITY; CEREBRAL-PALSY; UNITED-STATES; US CHILDREN AB Context Rates of obesity and other childhood chronic conditions have increased over recent decades. Patterns of how conditions change over time have not been widely examined. Objective To evaluate change in prevalence of obesity and other chronic conditions in US children, including incidence, remission, and prevalence. Design, Setting, and Participants Prospective study using the National Longitudinal Survey of Youth-Child Cohort (1988-2006) of 3 nationally representative cohorts of children. Children were aged 2 through 8 years at the beginning of each study period, and cohorts were followed up for 6 years, from 1988 to 1994 ( cohort 1, n=2337), 1994 to 2000 ( cohort 2, n=1759), and 2000 to 2006 (n=905). Main Outcome Measures Parent report of a child having a health condition that limited activities or schooling or required medicine, special equipment, or specialized health services and that lasted at least 12 months. Obesity was defined as a body mass index at or above the 95th percentile for age. Chronic conditions were grouped into 4 categories: obesity, asthma, other physical conditions, and behavior/learning problems. Results The end-study prevalence of any chronic health condition was 12.8% (95% confidence interval [CI], 11.2%-14.5%) for cohort 1 in 1994, 25.1% ( 95% CI, 22.7%-27.6%) for cohort 2 in 2000, and 26.6% ( 95% CI, 23.5%-29.9%) for cohort 3 in 2006. There was substantial turnover in chronic conditions: 7.4% ( 95% CI, 6.5%-8.3%) of participants in all cohorts had a chronic condition at the beginning of the study that persisted to the end, 9.3% ( 95% CI, 8.3%-10.3%) reported conditions at the beginning that resolved within 6 years, and 13.4% ( 95% CI, 12.3%-14.6%) had new conditions that arose during the 6-year study period. The prevalence of having a chronic condition during any part of the 6-year study period was highest for cohort 3 (51.5%; 95% CI, 47.3%-55.0%), and there were higher rates among male ( adjusted odds ratio [AOR], 1.24; 95% CI, 1.07-1.42), Hispanic ( AOR, 1.36; 95% CI, 1.11-1.67), and black ( AOR, 1.60; 95% CI, 1.35-1.90) youth. Conclusions Prevalence of chronic conditions among children and youth increased from 1988 to 2006. However, presence of these conditions was dynamic over each 6-year cohort. JAMA. 2010; 303(7):623-630 www.jama.com C1 [Van Cleave, Jeanne; Perrin, James M.] MassGen Hosp Children, Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. [Van Cleave, Jeanne; Perrin, James M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Gortmaker, Steven L.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. RP Van Cleave, J (reprint author), MassGen Hosp Children, Ctr Child & Adolescent Hlth Policy, 50 Staniford St 901, Boston, MA 02114 USA. EM jvancleave@partners.org FU Robert Wood Johnson Foundation [033659]; Centers for Disease Control and Prevention [U48DP00064]; Maternal and Child Health Bureau [U53MC04773] FX Preparation of this work was supported by a Robert Wood Johnson Foundation Investigator Award in Health Policy Research (grant 033659), the Centers for Disease Control and Prevention (Prevention Research Centers grant U48DP00064), and a cooperative agreement with the Maternal and Child Health Bureau (U53MC04773). Role of the Sponsor: The funding agencies had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript. NR 50 TC 169 Z9 169 U1 3 U2 24 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 FEB 17 PY 2010 VL 303 IS 7 BP 623 EP 630 DI 10.1001/jama.2010.104 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 555NK UT WOS:000274518600020 PM 20159870 ER PT J AU Wu, HY Hudry, E Hashimoto, T Kuchibhotla, K Rozkalne, A Fan, ZY Spires-Jones, T Xie, H Arbel-Ornath, M Grosskreutz, CL Bacskai, BJ Hyman, BT AF Wu, Hai-Yan Hudry, Eloise Hashimoto, Tadafumi Kuchibhotla, Kishore Rozkalne, Anete Fan, Zhanyun Spires-Jones, Tara Xie, Hong Arbel-Ornath, Michal Grosskreutz, Cynthia L. Bacskai, Brian J. Hyman, Bradley T. TI Amyloid beta Induces the Morphological Neurodegenerative Triad of Spine Loss, Dendritic Simplification, and Neuritic Dystrophies through Calcineurin Activation SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HIPPOCAMPAL SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; TRANSGENIC MICE; MOUSE MODEL; IN-VIVO; MULTIPHOTON MICROSCOPY; COGNITIVE DECLINE; MEMORY DEFICITS; PROTEIN-KINASE; CONGO RED AB Amyloid beta (A beta)-containing plaques are surrounded by dystrophic neurites in the Alzheimer's disease (AD) brain, but whether and how plaques induce these neuritic abnormalities remain unknown. We tested the hypothesis that soluble oligomeric assemblies of A beta, which surround plaques, induce calcium-mediated secondary cascades that lead to dystrophic changes in local neurites. We show that soluble A beta oligomers lead to activation of the calcium-dependent phosphatase calcineurin (CaN) (PP2B), which in turn activates the transcriptional factor nuclear factor of activated T cells (NFAT). Activation of these signaling pathways, even in the absence of A beta, is sufficient to produce a virtual phenocopy of A beta-induced dystrophic neurites, dendritic simplification, and dendritic spine loss in both neurons in culture and in the adult mouse brain. Importantly, the morphological deficits in the vicinity of A beta deposits in a mouse model of AD are ameliorated by CaN inhibition, supporting the hypothesis that CaN-NFAT are aberrantly activated by A beta and that CaN-NFAT activation is responsible for disruption of neuronal structure near plaques. In accord with this, we also detect increased levels of an active form of CaN and NFATc4 in the nuclear fraction from the cortex of patients with AD. Thus, A beta appears to mediate the neurodegeneration of AD, at least in part, by activation of CaN and subsequent NFAT-mediated downstream cascades. C1 [Wu, Hai-Yan; Hudry, Eloise; Hashimoto, Tadafumi; Kuchibhotla, Kishore; Rozkalne, Anete; Fan, Zhanyun; Spires-Jones, Tara; Xie, Hong; Arbel-Ornath, Michal; Bacskai, Brian J.; Hyman, Bradley T.] Massachusetts Gen Hosp, Alzheimers Dis Res Lab, Dept Neurol, Charlestown, MA 02129 USA. [Kuchibhotla, Kishore] Harvard Univ, Program Biophys, Cambridge, MA 02138 USA. [Grosskreutz, Cynthia L.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. RP Hyman, BT (reprint author), Massachusetts Gen Inst Neurodegenerat Dis, 114 16th St, Charlestown, MA 02129 USA. EM bhyman@partners.org RI Hashimoto, Tadafumi/A-7723-2013 FU National Institutes of Health [AG08487, EB000768, EY13399]; French Foundation FX This work was supported by National Institutes of Health Grants AG08487, EB000768, and EY13399 and a French Foundation award. We thank Dr. Jeffery D. Molkentin (Cincinnati Children's Hospital) for providing the following constructs: CaN, CaN inhibitory peptide (hAKAP79), and NFAT luciferase reporter. We thank Daniel Joyner for primary neuron preparation, and Meihua Deng, Kelly Han, and Luxiang Cao for technical assistance. NR 63 TC 169 Z9 172 U1 2 U2 18 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 17 PY 2010 VL 30 IS 7 BP 2636 EP 2649 DI 10.1523/JNEUROSCI.4456-09.2010 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 556OD UT WOS:000274599600026 PM 20164348 ER PT J AU Choi, JK Dedeoglu, A Jenkins, BG AF Choi, Ji-Kyung Dedeoglu, Alpaslan Jenkins, Bruce G. TI Longitudinal monitoring of motor neuron circuitry in FALS rats using in-vivo phMRI SO NEUROREPORT LA English DT Article DE amphetamine; amyotrophic lateral sclerosis; hSOD1 G93A; motor circuitry; pharmacologic MRI; transgenic rat ID AMYOTROPHIC-LATERAL-SCLEROSIS; SENSORIMOTOR CORTEX; RECEPTOR-BINDING; SPORADIC ALS; DOPAMINE; GLUTAMATE; AMPHETAMINE; MODELS; PLASTICITY; STROKE AB Amyotrophic lateral sclerosis (ALS) presents challenges for diagnosis and objective monitoring of disease progression. We show, using pharmacologic MRI, that alterations in motor circuitry can be characterized using a passive stimulus in a rat model of familial ALS as a function of symptom progression. Presymptomatic familial ALS rats had a pattern of activation to amphetamine that was statistically indistinguishable from the wild-type controls. In contrast, symptomatic rats showed significantly decreased response in sensorimotor cortex and increased response in M2 motor cortex, caudate/putamen, and thalamus. These results are similar to findings in humans of altered response to motor tasks in ALS. It may be plausible to use a passive amphetamine challenge as a biomarker to assess progression of the disease and efficacy of potential treatments. NeuroReport 21:157-162 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Choi, Ji-Kyung; Jenkins, Bruce G.] Massachusetts Gen Hosp, Dept Radiol, Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Choi, Ji-Kyung; Jenkins, Bruce G.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Dedeoglu, Alpaslan] VA Med Ctr, Dept Vet Affairs, Boston, MA USA. [Dedeoglu, Alpaslan] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. [Dedeoglu, Alpaslan] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Jenkins, BG (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula Martinos Ctr Biomed Imaging, 149-2301 13th St, Charlestown, MA 02129 USA. EM bgj@nmr.mgh.harvard.edu OI Dedeoglu, Alpaslan/0000-0003-1156-0874 FU NIH/NIDA [5R01DA016187]; Amyotrophic Lateral Sclerosis Association (ALSA) FX NIH/NIDA 5R01DA016187; Amyotrophic Lateral Sclerosis Association (ALSA). NR 26 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD FEB 17 PY 2010 VL 21 IS 3 BP 157 EP 162 DI 10.1097/WNR.0b013e328330eb9e PG 6 WC Neurosciences SC Neurosciences & Neurology GA 554UK UT WOS:000274460500001 PM 20118741 ER PT J AU Chen, L McKenna, JT Leonard, MZ Yanagawa, Y McCarley, RW Brown, RE AF Chen, Lichao McKenna, James T. Leonard, Michael Z. Yanagawa, Yuchio McCarley, Robert W. Brown, Ritchie E. TI GAD67-GFP knock-in mice have normal sleep-wake patterns and sleep homeostasis SO NEUROREPORT LA English DT Article DE electroencephalogram; electromyogram; glutamate decarboxylase 67; green fluorescent protein; nonrapid eye movement sleep; rapid eye movement sleep; sleep deprivation ID GLUTAMIC-ACID DECARBOXYLASE; GREEN FLUORESCENT PROTEIN; EYE-MOVEMENT SLEEP; GAMMA-AMINOBUTYRIC-ACID; TRANSGENIC MICE; GABAERGIC NEURONS; SEX-DIFFERENCES; 2 FORMS; MOUSE; GENES AB Gamma-aminobutyric acid (GABA) ergic neurons are important for controlling sleep and wakefulness but are difficult to identify, limiting their study. Knock-in mice with GABAergic neurons labeled by expression of green fluorescent protein (GFP) under control of the glutamate decarboxylase 67 (GAD67) promoter are now extensively used in neuroscience. However, it is unknown whether these mice have a normal sleep phenotype. Compared with wild-type control mice, GAD67-GFP knock-in mice had the same amount of non-rapid eye movement (NREM) sleep and rapid-eye movement (REM) sleep, a similar diurnal distribution of sleep, no NREM or REM sleep differences in electroencephalogram power, and normal sleep rebound following 6-h sleep deprivation. Our results suggest GAD67-GFP knock-in mice are an excellent tool for study of GABAergic neurons involved in sleep-wake regulation. NeuroReport 21:216-220 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Chen, Lichao; McKenna, James T.; Leonard, Michael Z.; McCarley, Robert W.; Brown, Ritchie E.] VA Boston Healthcare Syst, Neurosci Lab, Brockton, MA 02301 USA. [Chen, Lichao; McKenna, James T.; Leonard, Michael Z.; McCarley, Robert W.; Brown, Ritchie E.] Harvard Univ, Sch Med, Dept Psychiat, Brockton, MA 02301 USA. [Yanagawa, Yuchio] Gunma Univ, Dept Genet & Behav Neurosci, Grad Sch Med, Maebashi, Gumma 371, Japan. [Yanagawa, Yuchio] Japan Sci & Technol Agcy, CREST, Chiyoda Ku, Tokyo, Japan. RP Brown, RE (reprint author), VA Boston Healthcare Syst, Neurosci Lab, Res 151C,940 Belmont St, Brockton, MA 02301 USA. EM Ritchie_Brown@hms.harvard.edu RI McCarley, Robert/N-5562-2014; OI McCarley, Robert/0000-0001-5705-7495; Brown, Ritchie/0000-0002-7164-4132 FU VA Merit Award; NIMH [R01 MH039683]; MEXT, Japan; Takeda Science Foundation FX The authors would like to thank Yunren Bolortuya, Youngsoo Kim, and Ana N. Ticlea for assistance with the sleep deprivation procedure. This study was supported by VA Merit Award and NIMH grant R01 MH039683 (to R.WM.) and Grants-in-Aids for Scientific Research from MEXT, Japan and Takeda Science Foundation (to Y.Y.). NR 25 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD FEB 17 PY 2010 VL 21 IS 3 BP 216 EP 220 DI 10.1097/WNR.0b013e32833655c4 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 554UK UT WOS:000274460500012 PM 20051926 ER PT J AU Rato, S Maia, S Brito, PM Resende, L Pereira, CF Moita, C Freitas, RP Moniz-Pereira, J Hacohen, N Moita, LF Goncalves, J AF Rato, Sylvie Maia, Sara Brito, Paula M. Resende, Leonor Pereira, Carina F. Moita, Catarina Freitas, Rui P. Moniz-Pereira, Jose Hacohen, Nir Moita, Luis Ferreira Goncalves, Joao TI Novel HIV-1 Knockdown Targets Identified by an Enriched Kinases/Phosphatases shRNA Library Using a Long-Term Iterative Screen in Jurkat T-Cells SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; LENTIVIRAL VECTORS; DRUGGABLE GENOME; HUMAN HOMOLOG; TAT PROTEIN; EED; REPLICATION; KINASES; DRUG; VPR AB HIV-1 is a complex retrovirus that uses host machinery to promote its replication. Understanding cellular proteins involved in the multistep process of HIV-1 infection may result in the discovery of more adapted and effective therapeutic targets. Kinases and phosphatases are a druggable class of proteins critically involved in regulation of signal pathways of eukaryotic cells. Here, we focused on the discovery of kinases and phosphatases that are essential for HIV-1 replication but dispensable for cell viability. We performed an iterative screen in Jurkat T-cells with a short-hairpin-RNA (shRNA) library highly enriched for human kinases and phosphatases. We identified 14 new proteins essential for HIV-1 replication that do not affect cell viability. These proteins are described to be involved in MAPK, JNK and ERK pathways, vesicular traffic and DNA repair. Moreover, we show that the proteins under study are important in an early step of HIV-1 infection before viral integration, whereas some of them affect viral transcription/translation. This study brings new insights for the complex interplay of HIV1/host cell and opens new possibilities for antiviral strategies. C1 [Rato, Sylvie; Maia, Sara; Brito, Paula M.; Resende, Leonor; Pereira, Carina F.; Moniz-Pereira, Jose; Goncalves, Joao] Univ Lisbon, Fac Farm, URIA Ctr Patogenese Mol, P-1699 Lisbon, Portugal. [Rato, Sylvie; Maia, Sara; Brito, Paula M.; Resende, Leonor; Pereira, Carina F.; Moita, Catarina; Freitas, Rui P.; Moita, Luis Ferreira; Goncalves, Joao] Univ Lisbon, Fac Med, Inst Mol Med, P-1699 Lisbon, Portugal. [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Charlestown, MA USA. [Hacohen, Nir] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Hacohen, Nir] MIT, Cambridge, MA 02139 USA. RP Rato, S (reprint author), Univ Lisbon, Fac Farm, URIA Ctr Patogenese Mol, P-1699 Lisbon, Portugal. EM joao.goncalves@ff.ul.pt RI Maia, Sara/B-2513-2013; Brito, Paula/H-3693-2013; Moita, Luis/L-1296-2013; iMed.ULisboa, iMed.ULisboa/C-6292-2014; Goncalves, Joao/B-2013-2008; iMed.ULisboa, M2B /B-5277-2014; OI Maia, Sara/0000-0001-8638-0566; Brito, Paula/0000-0002-0105-6968; Moita, Luis/0000-0003-0707-315X; Ferreira Moita, Catarina/0000-0002-9910-2343; Rato, Sylvie/0000-0002-0204-0335; Goncalves, Joao/0000-0002-1245-3715; Moniz-Pereira, Jose/0000-0002-8779-2017 FU Fundacao para Ciencia e Tecnologia [PTDC/SAU-MII/65346/2006, PTDC/SAU-MII/69280/2006, PTDC/SAU-MII/78333/2006] FX This work was supported by Fundacao para Ciencia e Tecnologia (PTDC/SAU-MII/65346/2006, PTDC/SAU-MII/69280/2006 and PTDC/SAU-MII/78333/2006)(www.fct.mctes.pt). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 24 Z9 24 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 17 PY 2010 VL 5 IS 2 AR e9276 DI 10.1371/journal.pone.0009276 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556KU UT WOS:000274590600029 PM 20174665 ER PT J AU Bluestone, JA Krensky, AM Turka, LA Rotrosen, D Matthews, JB AF Bluestone, Jeffrey A. Krensky, Alan M. Turka, Laurence A. Rotrosen, Daniel Matthews, Jeffrey B. TI Ten Years of the Immune Tolerance Network: An Integrated Clinical Research Organization SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article AB The U. S. National Institutes of Health Roadmap and the U. S. Food and Drug Administration's Critical Path Initiative have endorsed the establishment of large academic clinical research networks as part of the solution to the growing divide between increased R&D spending and the lagging number of new drugs making it to market. Clearly, the role of these networks as translational science incubators that complement industry-sponsored programs is laudable and much-needed. However, the path to success for such organizations is less clear. Here, drawing on the experiences of the Immune Tolerance Network, a multidisciplinary clinical research network founded in 1999, we discuss some of the barriers inherent in developing such consortia and off er firsthand insight into the planning, resources, and organizational infrastructure required for a successful research program. C1 [Bluestone, Jeffrey A.; Krensky, Alan M.; Turka, Laurence A.; Matthews, Jeffrey B.] Univ Calif San Francisco, Immune Tolerance Network, San Francisco, CA 94107 USA. [Bluestone, Jeffrey A.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Bluestone, Jeffrey A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Krensky, Alan M.] NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Turka, Laurence A.] Harvard Univ, Beth Israel Deaconess Med Ctr Boston, Sch Med, Transplant Inst, Boston, MA 02115 USA. [Rotrosen, Daniel] NIAID, Div Allergy & Transplantat, Bethesda, MD 20817 USA. RP Bluestone, JA (reprint author), Univ Calif San Francisco, Immune Tolerance Network, San Francisco, CA 94107 USA. EM jbluest@diabetes.ucsf.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD FEB 17 PY 2010 VL 2 IS 19 AR 19cm7 DI 10.1126/scitranslmed.3000672 PG 4 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 591MA UT WOS:000277303600002 PM 20371484 ER PT J AU Chapko, MK Yee, HS Monto, A Dominitz, JA AF Chapko, Michael K. Yee, Helen S. Monto, Alexander Dominitz, Jason A. TI Cost-effectiveness of hepatitis A vaccination for individuals with chronic hepatitis C SO VACCINE LA English DT Article DE Hepatitis A; Vaccine; Cost-effectiveness ID CHRONIC LIVER-DISEASE; UNITED-STATES; VIRUS-INFECTION; 2 STRATEGIES; US VETERANS; PREVALENCE; PREVENTION; IMMUNITY; ADULTS AB The incidence of hepatitis A infection in the United States has decreased dramatically in recent years because of childhood immunization programs. A decision analysis of the cost-effectiveness of hepatitis A vaccination for adults with hepatitis C was conducted. No vaccination strategy is cost-effective for adults with hepatitis C using the recent lower anticipated hepatitis A incidence, private sector costs, and a cost-effectiveness criterion of $100,000/QALY. Vaccination is cost-effective only for individuals who have cleared the hepatitis C virus when Department of Veterans Affairs costs are used. The recommendation to vaccinate adults with hepatitis C against hepatitis A should be reconsidered. Published by Elsevier Ltd. C1 [Chapko, Michael K.; Dominitz, Jason A.] VA Puget Sound Hlth Care Syst, Hepatitis C Resource Ctr, Seattle, WA 98101 USA. [Chapko, Michael K.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Yee, Helen S.; Monto, Alexander] San Francisco VA, Hepatitis C Resource Ctr, San Francisco, CA USA. [Yee, Helen S.] Univ Calif San Francisco, Dept Clin Pharmacy, San Francisco, CA 94143 USA. [Monto, Alexander] Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. [Dominitz, Jason A.] Univ Washington, Dept Med, Div Gastroenterol, Seattle, WA USA. RP Chapko, MK (reprint author), VA Puget Sound Hlth Care Syst, Hepatitis C Resource Ctr, Metropolitan Pk W,Suite 1400,1100 Olive Way, Seattle, WA 98101 USA. EM chapko@u.washington.edu OI Dominitz, Jason/0000-0002-8070-7086 NR 35 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 17 PY 2010 VL 28 IS 7 BP 1726 EP 1731 DI 10.1016/j.vaccine.2009.12.019 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 563TX UT WOS:000275158500010 PM 20044051 ER PT J AU Abdel-Motal, UM Wang, SX Awad, A Lu, S Wigglesworth, K Galili, U AF Abdel-Motal, Ussama M. Wang, Shixia Awad, Amany Lu, Shan Wigglesworth, Kim Galili, Uri TI Increased immunogenicity of HIV-1 p24 and gp120 following immunization with gp120/p24 fusion protein vaccine expressing alpha-gal epitopes SO VACCINE LA English DT Article DE HIV; Vaccine; Immunogenicity; Alpha-gal epitopes ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANTI-GAL; PRESENTING CELLS; IMMUNE-COMPLEXES; GALACTOSYL IGG; FC-RECEPTORS; TUMOR-CELLS; ALPHA-1,3GALACTOSYLTRANSFERASE; RESPONSES; MACAQUES AB Developing an effective HIV-1 vaccine will require strategies to enhance antigen presentation to the immune system. In a previous study we demonstrated a marked increase in immunogenicity of the highly glycosylated HIV-1 gp120 protein following enzymatic addition of alpha-gal epitopes to the carbohydrate chains. In the present study we determined whether gp120(alpha gal) can also serve as an effective platform for targeting other HIV-1 proteins to APC and thus increase immunogenicity of both proteins. For this purpose we produced a recombinant fusion protein between gp120 and the HIV-1 Matrix p24 protein (gp120/p24). Multiple alpha-gal epitopes were synthesized enzymatically on the gp120 portion of the fusion protein to generate a gp120(alpha gal)/p24 vaccine. Immune responses to gp120(alpha gal)/p24 compared to gp120/p24 vaccine lacking alpha-gal epitopes were evaluated in alpha 1,3galactosyltransferase knockout (KO) mice. These mice lack alpha-gal epitopes and, therefore, are capable of producing the anti-Gal antibody. T cell responses to p24, as assessed by ELISPOT and by CD8+ T cells intracellular staining assays for IFN gamma, was on average 12- and 10-fold higher, respectively, in gp120 alpha(gal)/p24 immunized mice than in mice immunized with gp120/p24. In addition, cellular and humoral immune responses against gp120 were higher by 10-30-fold in mice immunized with gp120(alpha gal)/p24 than in gp120/p24 immunized mice. Our data suggest that the alpha-gal epitopes on the gp120 portion of the fusion protein can significantly augment the immunogenicity of gp120, as well as that of the fused viral protein which lacks alpha-gal epitopes. This strategy of anti-Gal mediated targeting to APC may be used for production of effective HIV-1 vaccines comprised of various viral proteins fused to gp120. Published by Elsevier Ltd. C1 [Abdel-Motal, Ussama M.; Wigglesworth, Kim; Galili, Uri] Univ Massachusetts, Dept Surg, Sch Med, Worcester, MA 01655 USA. [Wang, Shixia; Lu, Shan] Univ Massachusetts, Dept Med, Sch Med, Worcester, MA 01655 USA. [Awad, Amany] Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA. RP Abdel-Motal, UM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. EM Ussama_abdel-motal@dfci.harvard.edu OI Lu, Shan/0000-0002-8417-7588 FU University of Massachusetts Center for AIDS Research (CFAR) [P30 A1042845]; NIH [R01 A165250] FX This work was supported by the University of Massachusetts Center for AIDS Research (CFAR) (P30 A1042845) and NIH grant R01 A165250. NR 40 TC 8 Z9 8 U1 2 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 17 PY 2010 VL 28 IS 7 BP 1758 EP 1765 DI 10.1016/j.vaccine.2009.12.015 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 563TX UT WOS:000275158500014 PM 20034607 ER PT J AU Foy, R Hempel, S Rubenstein, L Suttorp, M Seelig, M Shanman, R Shekelle, PG AF Foy, Robbie Hempel, Susanne Rubenstein, Lisa Suttorp, Marika Seelig, Michelle Shanman, Roberta Shekelle, Paul G. TI Meta-analysis: Effect of Interactive Communication Between Collaborating Primary Care Physicians and Specialists SO ANNALS OF INTERNAL MEDICINE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; DISEASE MANAGEMENT PROGRAM; MENTAL-HEALTH-SERVICES; GENERAL-PRACTICE; UNITED-STATES; DIABETES CARE; PSYCHIATRIC-CONSULTATION; QUALITY IMPROVEMENT; LIAISON PSYCHIATRY; CLINICAL-TRIALS AB Background: Whether collaborative care models that enable interactive communication (timely, 2-way exchange of pertinent clinical information directly between primary care and specialist physicians) improve patient outcomes is uncertain. Purpose: To assess the effects of interactive communication between collaborating primary care physicians and key specialists on outcomes for patients receiving ambulatory care. Data Sources: PubMed, PsycInfo, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and Web of Science through June 2008 and secondary references, with no language restriction. Study Selection: Studies that evaluated the effects of interactive communication between collaborating primary care physicians and specialists on outcomes for patients with diabetes, psychiatric conditions, or cancer. Data Extraction: Contextual, intervention, and outcome data from 23 studies were extracted by one reviewer and checked by another. Study quality was assessed with a 13-item checklist. Disagreement was resolved by consensus. Main outcomes for analysis were selected by reviewers who were blinded to study results. Data Synthesis: Meta-analysis indicated consistent effects across 11 randomized mental health studies (pooled effect size, -0.41 [95% CI, -0.73 to -0.10]), 7 nonrandomized mental health studies (pooled effect size, -0.47 [CI, -0.84 to -0.09]), and 5 nonrandomized diabetes studies (pooled effect size, -0.64 [CI, -0.93 to -0.34]). These findings remained robust to sensitivity analyses. Meta-regression indicated studies that included interventions to enhance the quality of information exchange had larger effects on patient outcomes than those that did not (-0.84 vs. -0.27; P = 0.002). Limitations: Because collaborative interventions were inherently multifaceted, the efficacy of interactive communication by itself cannot be established. Inclusion of study designs with lower internal validity increased risk for bias. No studies involved oncologists. Conclusion: Consistent and clinically important effects suggest a potential role of interactive communication for improving the effectiveness of primary care-specialist collaboration. C1 [Foy, Robbie] Univ Leeds, Leeds Inst Hlth Sci, Leeds LS2 9LJ, W Yorkshire, England. RAND Hlth Div, So Calif Evidence Based Practice Ctr, Santa Monica, CA USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Grp Hlth Cooperat Puget Sound, Seattle, WA USA. RP Foy, R (reprint author), Univ Leeds, Leeds Inst Hlth Sci, Charles Thackrah Bldg,101 Clarendon Rd, Leeds LS2 9LJ, W Yorkshire, England. EM r.foy@leeds.ac.uk FU RAND Health's Comprehensive Assessment of Reform Options Initiative; Veterans Affairs Center for the Study of Provider Behavior; Commonwealth Fund; Health Foundation FX RAND Health's Comprehensive Assessment of Reform Options Initiative, the Veterans Affairs Center for the Study of Provider Behavior, The Commonwealth Fund, and the Health Foundation. NR 99 TC 51 Z9 51 U1 4 U2 15 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 16 PY 2010 VL 152 IS 4 BP 247 EP U95 DI 10.7326/0003-4819-152-4-201002160-00010 PG 20 WC Medicine, General & Internal SC General & Internal Medicine GA 560AF UT WOS:000274873300007 PM 20157139 ER PT J AU Singer, DE Chang, YC Go, AS AF Singer, Daniel E. Chang, Yuchiao Go, Alan S. TI The Net Clinical Benefit of Warfarin Anticoagulation in Atrial Fibrillation IN RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Singer, Daniel E.; Chang, Yuchiao] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Go, Alan S.] Kaiser Permanente No Calif, Oakland, CA 94612 USA. RP Singer, DE (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 4 TC 0 Z9 0 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 FEB 16 PY 2010 VL 152 IS 4 BP 265 EP 265 DI 10.7326/0003-4819-152-4-201002160-00018 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 560AF UT WOS:000274873300013 ER PT J AU Swanlund, JM Kregel, KC Oberley, TD AF Swanlund, Jamie M. Kregel, Kevin C. Oberley, Terry D. TI Investigating autophagy Quantitative morphometric analysis using electron microscopy SO AUTOPHAGY LA English DT Editorial Material DE autophagy; electron microscopy; immunogold; morphometry; ultrastructure ID MONITORING AUTOPHAGY; LOCALIZATION; MITOCHONDRIA; HEPATOCYTES; DEGRADATION; MEMBRANES; PROTEINS; TISSUES; PATHWAY; DISEASE AB Autophagy is a compensatory pathway involving isolation and subsequent degradation of cytosolic material and organelles in eukaryotic cells.(1) The autophagic process can provide a "house-keeping" function by removing damaged proteins and organelles in a selective or nonselective fashion in order to exert a protective effect following stress.(2) Remarkably, after being discovered to be much more of a targeted process than a random one, the role of autophagy became implicated in many normal cellular and disease processes.(3) Several methodologies are routinely employed to monitor the entire autophagic process.(4) Microtubule-associated protein light chain 3, a mammalian homolog of yeast Atg8, has been widely used as a specific marker to monitor autophagy in numerous cell types.(5) While monitoring autophagic flux is extremely important, it is also beneficial to perform a detailed analysis by electron microscopy (EM) to evaluate changes in various autophagic structures, quantify the areas involved, and determine if any particular organelle(s) or area of the cell cytoplasm is being targeted for degradation.(6) The following article describes methods to localize and quantify subcellular areas of autophagy using transmission EM. Also discussed are methods for subcellular localization of specific proteins by employing immunogold EM; this method becomes particularly useful in detecting early changes in cellular homeostasis that may occur before later signs of cellular insult can be observed morphologically. C1 [Swanlund, Jamie M.; Oberley, Terry D.] William S Middleton Mem Vet Adm Med Ctr, Dept Pathol & Lab Med, Madison, WI USA. [Kregel, Kevin C.] Univ Iowa, Dept Radiat Oncol, Free Radical & Radiat Biol Program, Iowa City, IA USA. [Kregel, Kevin C.] Univ Iowa, Dept Integrat Physiol, Iowa City, IA USA. [Oberley, Terry D.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol & Lab Med, Madison, WI USA. RP Oberley, TD (reprint author), William S Middleton Mem Vet Adm Med Ctr, Dept Pathol & Lab Med, Madison, WI USA. EM toberley@wisc.edu FU NIA NIH HHS [R01 AG012350-08] NR 30 TC 31 Z9 37 U1 0 U2 15 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD FEB 16 PY 2010 VL 6 IS 2 BP 270 EP 277 PG 8 WC Cell Biology SC Cell Biology GA 577CI UT WOS:000276198100008 PM 19923921 ER PT J AU You, Z Cao, XH Taylor, AB Hart, PJ Levine, RL AF You, Zheng Cao, Xiaohang Taylor, Alexander B. Hart, P. John Levine, Rodney L. TI Characterization of a Covalent Polysulfane Bridge in Copper-Zinc Superoxide Dismutase SO BIOCHEMISTRY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; CU,ZN-SUPEROXIDE DISMUTASE; DISULFIDE REDUCTION; HYDROGEN-PEROXIDE; WILD-TYPE; BIOPHYSICAL PROPERTIES; DIMER STABILITY; LABILE SULFUR; DNA CLEAVAGE; FAMILIAL ALS AB In the course of studies on human copper-zinc Superoxide dismutase (SOD1), We observed a modified form of the protein whose mass wits increased by 158 mass units. The covalent modification Was characterized, and we established that it is a novel heptasulfane bridge connecting the two Cys111 residues in the SOD1 homodimer. The heptasulfane bridge was visualized directly in the crystal structure of it recombinant human mutant SODI, H46R/H48Q, produced in yeast. The modification is reversible, with the bridge being cleaved by thiols, by cyanide, and by unfolding of the protein to expose the polysulfane. The polysulfane bridge can be introduced in vitro by incubation of purified SOD1 with elemental sulfur, even under anaerobic conditions and in the presence of a metal chelator. Because polysulfanes and polysulfides can catalyze the generation of reactive oxygen and sulfur species, the modification may endow SOD1 with a toxic gain of function. C1 [You, Zheng; Levine, Rodney L.] NHLBI, Biochem Lab, Bethesda, MD 20892 USA. [Cao, Xiaohang; Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Cao, Xiaohang; Taylor, Alexander B.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Hart, P. John] S Texas Vet Hlth Care Syst, Dept Vet Affairs, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, Bldg 3, Bethesda, MD 20892 USA. EM rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural NIH HHS [ZIA HL000225-32]; NINDS NIH HHS [NS39112, R01 NS039112, R01 NS039112-08] NR 67 TC 21 Z9 21 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 16 PY 2010 VL 49 IS 6 BP 1191 EP 1198 DI 10.1021/bi901844d PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 553CI UT WOS:000274342000016 PM 20052996 ER PT J AU Cella, D Michaelson, MD Bushmakin, AG Cappelleri, JC Charbonneau, C Kim, ST Li, JZ Motzer, RJ AF Cella, D. Michaelson, M. D. Bushmakin, A. G. Cappelleri, J. C. Charbonneau, C. Kim, S. T. Li, J. Z. Motzer, R. J. TI Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-alpha in a phase III trial: final results and geographical analysis SO BRITISH JOURNAL OF CANCER LA English DT Article DE health-related quality of life; metastatic renal cell carcinoma; patient-reported outcomes; receptor tyrosine kinase inhibitor; sunitinib ID TYROSINE KINASE INHIBITOR; PATTERN-MIXTURE MODELS; REPORTED OUTCOMES; CANCER-PATIENTS; BREAST-CANCER; IN-VIVO; SU11248; THERAPY; SINGLE; SCALE AB BACKGROUND: In a randomised phase III trial, sunitinib significantly improved efficacy over interferon-alpha (IFN-alpha) as first-line therapy for metastatic renal cell carcinoma (mRCC). We report the final health-related quality of life (HRQoL) results. METHODS: Patients (n = 750) received oral sunitinib 50 mg per day in 6-week cycles (4 weeks on, 2 weeks off treatment) or subcutaneous IFN-alpha 9 million units three times weekly. Health-related quality of life was assessed with nine end points: the Functional Assessment of Cancer Therapy-General and its four subscales, FACT-Kidney Symptom Index (FKSI-15) and its Disease-Related Symptoms subscale (FKSI-DRS), and EQ-5D questionnaire's EQ-5D Index and visual analogue scale. Data were analysed using mixed-effects model (MM), supplemented with pattern-mixture models (PMM), for the total sample and the US and European Union (EU) subgroups. RESULTS: Patients receiving sunitinib reported better scores in the primary end point, FKSI-DRS, across all patient populations (P < 0.05), and in nine, five, and six end points in the total sample, in the US and EU groups respectively (P < 0.05). There were no significant differences between the US and EU groups for all end points with the exception of the FKSI item 'I am bothered by side effects of treatment' (P = 0.02). In general, MM and PMM results were similar. CONCLUSION: Patients treated with sunitinib in this study had improved HRQoL, compared with patients treated with IFN-a. Treatment differences within the US cohort did not differ from those within the EU cohort. British Journal of Cancer (2010) 102, 658-664. doi:10.1038/sj.bjc.6605552 www.bjcancer.com Published online 26 January 2010 (C) 2010 Cancer Research UK C1 [Cella, D.] Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Michaelson, M. D.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Bushmakin, A. G.; Cappelleri, J. C.] Pfizer Global Res & Dev, New London, CT 06320 USA. [Charbonneau, C.] Pfizer Global Res & Dev, New York, NY 10017 USA. [Kim, S. T.; Li, J. Z.] Pfizer Oncol, San Diego, CA 92121 USA. [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Cella, D (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med Social Sci, Robert H Lurie Comprehens Canc Ctr, Rubloff Bldg 9th Floor,750 N Lake Shore Dr, Chicago, IL 60611 USA. EM d-cella@northwestern.edu OI Michaelson, Dror/0000-0001-9249-6338 FU Pfizer Inc. FX Editorial assistance was provided by ACUMED (Tytherington, UK) and the study was funded by Pfizer Inc. using data derived from a clinical trial sponsored by Pfizer Inc. (ClinicalTrials.gov identifier: NCT00083889). We thank Xin Huang (Pfizer Inc., La Jolla, CA, USA) for providing additional statistical analyses. MDM and RJM are principal study investigators. NR 30 TC 29 Z9 31 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 16 PY 2010 VL 102 IS 4 BP 658 EP 664 DI 10.1038/sj.bjc.6605552 PG 7 WC Oncology SC Oncology GA 556PZ UT WOS:000274604900005 PM 20104222 ER PT J AU Mathew, M Tay, E Cusi, K AF Mathew, Manoj Tay, Eric Cusi, Kenneth TI Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects SO CARDIOVASCULAR DIABETOLOGY LA English DT Article ID CORONARY-ARTERY-DISEASE; HUMAN ATHEROSCLEROTIC LESIONS; CELLULAR ADHESION MOLECULES; INSULIN-RESISTANCE SYNDROME; TYPE-2 DIABETES-MELLITUS; SKELETAL-MUSCLE CELLS; E-SELECTIN; METABOLIC SYNDROME; MYOCARDIAL-INFARCTION; INFLAMMATORY MARKERS AB Background: CVD in obesity and T2DM are associated with endothelial activation, elevated plasma vascular inflammation markers and a prothrombotic state. We examined the contribution of FFA to these abnormalities following a 48-hour physiological increase in plasma FFA to levels of obesity and diabetes in a group of healthy subjects. Methods: 40 non-diabetic subjects (age = 38 +/- 3 yr, BMI = 28 +/- 1 kg/m(2), FPG = 95 +/- 1 mg/dl, HbA(1c) = 5.3 +/- 0.1%) were admitted twice and received a 48-hour infusion of normal saline or low-dose lipid. Plasma was drawn for intracellular (ICAM-1) and vascular (VCAM-1) adhesion molecules-1, E-selectin (sE-S), myeloperoxidase (MPO) and total plasminogen inhibitor-1 (tPAI-1). Insulin sensitivity was measured by a hyperglycemic clamp (M/I). Results: Lipid infusion increased plasma FFA to levels observed in obesity and T2DM and reduced insulin sensitivity by 27% (p = 0.01). Elevated plasma FFA increased plasma markers of endothelial activation ICAM-1 (138 +/- 10 vs. 186 +/- 25 ng/ml), VCAM-1 (1066 +/- 67 vs. 1204 +/- 65 ng/ml) and sE-S (20 +/- 1 vs. 24 +/- 1 ng/ml) between 13-35% and by >= 2-fold plasma levels of myeloperoxidase (7.5 +/- 0.9 to 15 +/- 25 ng/ml), an inflammatory marker of future CVD, and tPAI-1 (9.7 +/- 0.6 to 22.5 +/- 1.5 ng/ml), an indicator of a prothrombotic state (all p = 0.01). The FFA-induced increase was independent from the degree of adiposity, being of similar magnitude in lean, overweight and obese subjects. Conclusions: An increase in plasma FFA within the physiological range observed in obesity and T2DM induces markers of endothelial activation, vascular inflammation and thrombosis in healthy subjects. This suggests that even transient (48-hour) and modest increases in plasma FFA may initiate early vascular abnormalities that promote atherosclerosis and CVD. C1 [Mathew, Manoj; Tay, Eric; Cusi, Kenneth] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Diabet Div, San Antonio, TX 78229 USA. [Cusi, Kenneth] Audie L Murphy Mem Vet Adm Med Ctr, San Antonio, TX 78229 USA. RP Cusi, K (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Diabet Div, San Antonio, TX 78229 USA. EM cusi@uthscsa.edu FU VA Merit Award; Veterans Affairs Medical Research Fund; National Center for Research Resources [UL 1RR025767] FX The project described was supported by a VA Merit Award, the Veterans Affairs Medical Research Fund and by Award Number UL 1RR025767 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources of the National Institutes of Health. NR 66 TC 56 Z9 59 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2840 J9 CARDIOVASC DIABETOL JI Cardiovasc. Diabetol. PD FEB 16 PY 2010 VL 9 AR 9 DI 10.1186/1475-2840-9-9 PG 9 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism SC Cardiovascular System & Cardiology; Endocrinology & Metabolism GA 570NJ UT WOS:000275684700001 PM 20158910 ER PT J AU Ahmed, MI Gladden, JD Litovsky, SH Lloyd, SG Gupta, H Inusah, S Denney, T Powell, P McGiffin, DC Dell'Italia, LJ AF Ahmed, Mustafa I. Gladden, James D. Litovsky, Silvio H. Lloyd, Steven G. Gupta, Himanshu Inusah, Seidu Denney, Thomas, Jr. Powell, Pamela McGiffin, David C. Dell'Italia, Louis J. TI Increased Oxidative Stress and Cardiomyocyte Myofibrillar Degeneration in Patients With Chronic Isolated Mitral Regurgitation and Ejection Fraction > 60% SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE mitral regurgitation; oxidative stress; magnetic resonance imaging; tissue tagging ID LEFT-VENTRICULAR FUNCTION; VALVE REPAIR; XANTHINE OXIDOREDUCTASE; HUMAN FIBROBLASTS; WALL STRESS; EXERCISE; RECONSTRUCTION; REPLACEMENT; DYSFUNCTION; INHIBITION AB Objectives This study assessed myocardial damage in patients with chronic isolated mitral regurgitation (MR) and left ventricular ejection fraction (LVEF) > 60%. Background Typically, MR patients have decreased LVEF after mitral valve (MV) repair despite normal pre-operative LVEF. Methods Twenty-seven patients with isolated MR had left ventricular (LV) biopsies taken at time of MV repair. Magnetic resonance imaging with tissue tagging was performed in 40 normal subjects and in MR patients before and 6 months after MV repair. Results LVEF (66 +/- 5% to 54 +/- 9%, p < 0.0001) and LV end-diastolic volume index (108 +/- 28 ml/m(2) to 78 +/- 24 ml/m(2), p < 0.0001) decreased, whereas left ventricular end-systolic (LVES) volume index was 60% above normal pre- and post-MV repair (p < 0.05). The LV circumferential and longitudinal strain rates decreased below normal following MV repair (6.38 +/- 1.38 vs. 5.11 +/- 1.28, p = 0.0009, and 7.51 +/- 2.58 vs. 5.31 +/- 1.61, percentage of R to R interval, p < 0.0001), as LVES stress/LVES volume index ratio was depressed at baseline and following MV repair versus normal subjects (0.25 +/- 0.10 and 0.28 +/- 0.05 vs. 0.33 +/- 0.12, p < 0.01). LV biopsies demonstrated cardiomyocyte myofibrillar degeneration versus normal subjects (p = 0.035). Immunostaining and immunoblotting demonstrated increased xanthine oxidase in MR versus normal subjects (p < 0.05). Lipofuscin deposition was increased in cardiomyocytes of MR versus normal subjects (0.62 +/- 0.20 vs. 0.33 +/- 0.11, percentage of area: p < 0.01). Conclusions Decreased LV strain rates and LVES wall stress/LVES volume index following MV repair indicate contractile dysfunction, despite pre-surgical LVEF > 60%. Increased oxidative stress could cause myofibrillar degeneration and lipofuscin accumulation resulting in LV contractile dysfunction in MR. (J Am Coll Cardiol 2010;55:671-9) (C) 2010 by the American College of Cardiology Foundation C1 [Dell'Italia, Louis J.] UAB, Ctr Heart Failure Res, Div Cardiol, Dept Med, Birmingham, AL 35294 USA. [Ahmed, Mustafa I.; Gladden, James D.; Litovsky, Silvio H.; Lloyd, Steven G.; Gupta, Himanshu; Inusah, Seidu; Powell, Pamela; McGiffin, David C.; Dell'Italia, Louis J.] UAB, Ctr Heart Failure Res, Dept Cardiovasc Surg, Birmingham, AL 35294 USA. [Ahmed, Mustafa I.; Gladden, James D.; Litovsky, Silvio H.; Lloyd, Steven G.; Gupta, Himanshu; Inusah, Seidu; Powell, Pamela; McGiffin, David C.; Dell'Italia, Louis J.] UAB, Ctr Heart Failure Res, Dept Pathol, Birmingham, AL 35294 USA. [Ahmed, Mustafa I.; Gladden, James D.; Litovsky, Silvio H.; Lloyd, Steven G.; Gupta, Himanshu; Inusah, Seidu; Powell, Pamela; McGiffin, David C.; Dell'Italia, Louis J.] UAB, Ctr Heart Failure Res, Dept Biostat, Birmingham, AL 35294 USA. [Dell'Italia, Louis J.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Denney, Thomas, Jr.] Auburn Univ, Samuel Ginn Coll Engn, Auburn, AL 36849 USA. RP Dell'Italia, LJ (reprint author), UAB, Ctr Heart Failure Res, Div Cardiol, Dept Med, 434 BMR2,901 19th St S, Birmingham, AL 35294 USA. EM loudell@uab.edu FU NHLBI NIH HHS [P50 HL077100-05, P50 HL077100] NR 32 TC 46 Z9 47 U1 0 U2 2 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 FEB 16 PY 2010 VL 55 IS 7 BP 671 EP 679 DI 10.1016/j.jacc.2009.08.074 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 556JT UT WOS:000274587600011 PM 20170794 ER PT J AU Xin, W Mullen, TE Kiely, R Min, J Feng, X Cao, Y O'Malley, L Shen, Y Chu-Shore, C Mole, SE Goebel, HH Sims, K AF Xin, W. Mullen, T. E. Kiely, R. Min, J. Feng, X. Cao, Y. O'Malley, L. Shen, Y. Chu-Shore, C. Mole, S. E. Goebel, H. H. Sims, K. TI CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL SO NEUROLOGY LA English DT Article ID NEURONAL CEROID-LIPOFUSCINOSIS; TRANSMEMBRANE PROTEIN; MUTANT MICE; DISEASES; ENCODES AB Objectives: To explore a potential expansion of the phenotypic and genotypic characteristics of Finnish variant late-infantile neuronal ceroid lipofuscinosis (NCL), we screened a collection of 47 patients with clinically diagnosed NCL in whom no molecular diagnosis had been made. Methods: We used PCR amplification of genomic DNA, followed by fluorescent-labeled dideoxynucleotide chain termination sequencing and multiplex ligation-dependent probe amplification, to screen our cohort of patients for mutations in CLN5. We collected ethnic background, clinical, and pathologic information, as available, to clarify the breadth of CLN5 disease expression and to explore possible genotype-phenotype correlations. Results: We identified 10 patients with pathogenic CLN5 mutations, including 11 mutations not previously described: 4 missense, 5 out-of-frame insertion/deletion mutations, and 2 large intragenic deletions. We also documented 3 previously reported CLN5 mutations. The age at disease onset in this cohort is predominantly juvenile rather than late infantile. Importantly, we have identified 2 adult-onset patients who share a common pathogenic allele. The majority of patients presented with motor and visual impairments and not seizures. In those patients with available longitudinal data, most had progressed to global neurodevelopmental and visual failure with seizures within 1 to 4 years. Conclusions: Our study suggests that CLN5 mutations 1) are more common in patients with neuronal ceroid lipofuscinosis (NCL) than previously reported, 2) are found in non-Finnish NCL patients of broad ethnic diversity, and 3) can be identified in NCL patients with disease onset in adult and juvenile epochs. CLN5 genetic testing is warranted in a wider population with clinical and pathologic features suggestive of an NCL disorder. Neurology (R) 2010; 74: 565-571 C1 [Xin, W.; Chu-Shore, C.; Sims, K.] Massachusetts Gen Hosp, Neurogenet DNA Diagnost Lab, Dept Neurol, Boston, MA 02114 USA. [Xin, W.; Mullen, T. E.; Kiely, R.; Min, J.; Feng, X.; Cao, Y.; O'Malley, L.; Shen, Y.; Sims, K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Mole, S. E.] UCL, MRC Lab Mol Cell Biol, London WC1E 6BT, England. [Goebel, H. H.] Johannes Gutenberg Univ Mainz, Dept Neuropathol, Med Ctr, Mainz, Germany. RP Sims, K (reprint author), Neurogenet Massachusetts Gen Hosp, Simches Res Bldg,5-238,185 Cambridge St, Boston, MA 02114 USA. EM ksims@partners.org OI Mole, Sara/0000-0003-4385-4957 FU Batten Disease Support and Research Association FX Study funding: Supported by the Batten Disease Support and Research Association. NR 26 TC 22 Z9 22 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 16 PY 2010 VL 74 IS 7 BP 565 EP 571 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 555MX UT WOS:000274517100008 PM 20157158 ER PT J AU Ben-Zvi, I Aranow, C Mackay, M Stanevsky, A Kamen, DL Marinescu, LM Collins, CE Gilkeson, GS Diamond, B Hardin, JA AF Ben-Zvi, Ilan Aranow, Cynthia Mackay, Meggan Stanevsky, Anfisa Kamen, Diane L. Marinescu, L. Manuela Collins, Christopher E. Gilkeson, Gary S. Diamond, Betty Hardin, John A. TI The Impact of Vitamin D on Dendritic Cell Function in Patients with Systemic Lupus Erythematosus SO PLOS ONE LA English DT Article ID INDUCIBLE GENE-EXPRESSION; INTERFERON-ALPHA ACTIVITY; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; 1,25-DIHYDROXYVITAMIN D-3; MULTIPLE-SCLEROSIS; AUTOIMMUNE-DISEASE; D DEFICIENCY; IFN-ALPHA; RHEUMATOID-ARTHRITIS; MICROARRAY ANALYSIS AB Background: Excessive activity of dendritic cells (DCs) is postulated as a central disease mechanism in Systemic Lupus Erythematosus (SLE). Vitamin D is known to reduce responsiveness of healthy donor DCs to the stimulatory effects of Type I IFN. As vitamin D deficiency is reportedly common in SLE, we hypothesized that vitamin D might play a regulatory role in the IFN alpha amplification loop in SLE. Our goals were to investigate the relationship between vitamin D levels and disease activity in SLE patients and to investigate the effects of vitamin D on DC activation and expression of IFN alpha-regulated genes in vitro. Methodology/Principal Findings: In this study, 25-OH vitamin D (25-D) levels were measured in 198 consecutively recruited SLE patients. Respectively, 29.3% and 11.8% of African American and Hispanic SLE patient had 25-D levels <10 ng/ml. The degree of vitamin D deficiency correlated inversely with disease activity; R = -.234, p = .002. In 19 SLE patients stratified by 25-D levels, there were no differences between circulating DC number and phenotype. Monocyte-derived DCs (MDDCs) of SLE patients were normally responsive to the regulatory effects of vitamin D in vitro as evidenced by decreased activation in response to LPS stimulation in the presence of 1,25-D. Additionally, vitamin D conditioning reduced expression of IFN alpha-regulated genes by healthy donor and SLE MDDCs in response to factors in activating SLE plasma. Conclusions/Significance: We report on severe 25-D deficiency in a substantial percentage of SLE patients tested and demonstrate an inverse correlation with disease activity. Our results suggest that vitamin D supplementation will contribute to restoring immune homeostasis in SLE patients through its inhibitory effects on DC maturation and activation. We are encouraged to support the importance of adequate vitamin D supplementation and the need for a clinical trial to assess whether vitamin D supplementation affects IFN alpha activity in vivo and, most importantly, improves clinical outcome. C1 [Ben-Zvi, Ilan; Aranow, Cynthia; Mackay, Meggan; Stanevsky, Anfisa; Diamond, Betty] Feinstein Inst Med Res, Div Autoimmune & Musculoskeletal Dis, Manhasset, NY 11030 USA. [Marinescu, L. Manuela; Hardin, John A.] Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA. [Kamen, Diane L.; Gilkeson, Gary S.] Med Univ S Carolina, Div Rheumatol, Charleston, SC 29425 USA. [Collins, Christopher E.; Gilkeson, Gary S.] Ralph H Johnson Vet Adm Med Ctr, Dept Med, Charleston, SC USA. [Hardin, John A.] NIAID, NIH, Washington, DC USA. RP Ben-Zvi, I (reprint author), Feinstein Inst Med Res, Div Autoimmune & Musculoskeletal Dis, Manhasset, NY 11030 USA. EM johnhardin@arthritis.org OI Ben-Zvi, Ilan/0000-0002-9160-3098 FU National Institutes of Health [P60 AR049459, RR01070, AR052364]; National Institutes of Health (National Institute of Allergy and Infectious Disease) and the Autoimmunity Centers of Excellence; Autoimmunity Centers of Excellence; American College of Rheumatology Research and Education Foundation; Alliance for Lupus Research; NIAMS FX This work is supported by grants from the National Institutes of Health to GSG (P60 AR049459) and DLK (General Clinical Research Center grant #RR01070); by grants from the National Institutes of Health (National Institute of Allergy and Infectious Disease) and the Autoimmunity Centers of Excellence to BD, MM, CA, and JAH; by an American College of Rheumatology Research and Education Foundation award to DLK; and by a grant from the Alliance for Lupus Research to JAH. Additional support for DLK: K23 Award from NIAMS: NIH K23 AR052364. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 66 Z9 73 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 FEB 16 PY 2010 VL 5 IS 2 AR e9193 DI 10.1371/journal.pone.0009193 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556KT UT WOS:000274590500003 PM 20169063 ER PT J AU Khankin, EV Mutter, WP Tamez, H Yuan, HT Karumanchi, SA Thadhani, R AF Khankin, Eliyahu V. Mutter, Walter P. Tamez, Hector Yuan, Hai-Tao Karumanchi, S. Ananth Thadhani, Ravi TI Soluble Erythropoietin Receptor Contributes to Erythropoietin Resistance in End-Stage Renal Disease SO PLOS ONE LA English DT Article ID CHRONIC KIDNEY-DISEASE; INCIDENT HEMODIALYSIS-PATIENTS; TRANSFERRIN RECEPTOR; INDUCED DIFFERENTIATION; STIMULATING AGENTS; ANEMIA MANAGEMENT; ENDOTHELIAL-CELLS; DIALYSIS PATIENTS; EPOETIN-ALPHA; VITAMIN-D AB Background: Erythropoietin is a growth factor commonly used to manage anemia in patients with chronic kidney disease. A significant clinical challenge is relative resistance to erythropoietin, which leads to use of successively higher erythropoietin doses, failure to achieve target hemoglobin levels, and increased risk of adverse outcomes. Erythropoietin acts through the erythropoietin receptor (EpoR) present in erythroblasts. Alternative mRNA splicing produces a soluble form of EpoR (sEpoR) found in human blood, however its role in anemia is not known. Methods and Findings: Using archived serum samples obtained from subjects with end stage kidney disease we show that sEpoR is detectable as a 27kDa protein in the serum of dialysis patients, and that higher serum sEpoR levels correlate with increased erythropoietin requirements. Soluble EpoR inhibits erythropoietin mediated signal transducer and activator of transcription 5 (Stat5) phosphorylation in cell lines expressing EpoR. Importantly, we demonstrate that serum from patients with elevated sEpoR levels blocks this phosphorylation in ex vivo studies. Finally, we show that sEpoR is increased in the supernatant of a human erythroleukaemia cell line when stimulated by inflammatory mediators such as interleukin-6 and tumor necrosis factor alpha implying a link between inflammation and erythropoietin resistance. Conclusions: These observations suggest that sEpoR levels may contribute to erythropoietin resistance in end stage renal disease, and that sEpoR production may be mediated by pro-inflammatory cytokines. C1 [Khankin, Eliyahu V.; Mutter, Walter P.; Tamez, Hector; Yuan, Hai-Tao; Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Khankin, Eliyahu V.; Mutter, Walter P.; Tamez, Hector; Yuan, Hai-Tao; Karumanchi, S. Ananth; Thadhani, Ravi] Harvard Univ, Sch Med, Boston, MA USA. [Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Karumanchi, S. Ananth] Beth Israel Deaconess Med Ctr, Howard Hughes Med Inst, Boston, MA 02215 USA. RP Khankin, EV (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. EM sananth@bidmc.harvard.edu RI Khankin, Eli/M-7648-2013 FU Beth Israel Deaconess Medical Center; Massachusetts General Hospital; Satellite Research; Normon S. Coplon Grant FX This work was supported by Department of Medicine seed funds from the Beth Israel Deaconess Medical Center and the Massachusetts General Hospital. S. A. K. is an investigator of the Howard Hughes Medical Institute. Work was also funded by Satellite Research, Normon S. Coplon Grant to W. P. M. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 19 Z9 20 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 16 PY 2010 VL 5 IS 2 AR e9246 DI 10.1371/journal.pone.0009246 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556KT UT WOS:000274590500024 PM 20169072 ER PT J AU Rucci, F Notarangelo, LD Fazeli, A Patrizi, L Hickernell, T Paganini, T Coakley, KM Detre, C Keszei, M Walter, JE Feldman, L Cheng, HL Poliani, PL Wang, JH Balter, BB Recher, M Andersson, EM Zha, S Giliani, S Terhorst, C Alt, FW Yan, CT AF Rucci, Francesca Notarangelo, Luigi D. Fazeli, Alex Patrizi, Laura Hickernell, Thomas Paganini, Tiziana Coakley, Kristen M. Detre, Cynthia Keszei, Marton Walter, Jolan E. Feldman, Lauren Cheng, Hwei-Ling Poliani, Pietro Luigi Wang, Jing H. Balter, Barbara B. Recher, Mike Andersson, Emma-Maria Zha, Shan Giliani, Silvia Terhorst, Cox Alt, Frederick W. Yan, Catherine T. TI Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genomic instability; immunodeficiency; lymphocytes; nonhomologous end joining; immune dysregulation ID SEVERE COMBINED IMMUNODEFICIENCY; DEPENDENT PROTEIN-KINASE; CLASS SWITCH RECOMBINATION; V(D)J RECOMBINATION; OMENN-SYNDROME; B-CELLS; LYMPHOCYTE DEVELOPMENT; EMBRYONIC LETHALITY; MURINE MODEL; ARTEMIS AB DNA ligase IV (LIG4) is an essential component of the nonhomologous end-joining (NHEJ) repair pathway and plays a key role in V(D)J recombination. Hypomorphic LIG4 mutations in humans are associated with increased cellular radiosensitivity, microcephaly, facial dysmorphisms, growth retardation, developmental delay, and a variable degree of immunodeficiency. We have generated a knock-in mouse model with a homozygous Lig4 R278H mutation that corresponds to the first LIG4 mutation reported in humans. The phenotype of homozygous mutant mice Lig4(R278H/R278H) (Lig4(R/R)) includes growth retardation, a decreased life span, a severe cellular sensitivity to ionizing radiation, and a very severe, but incomplete block in T and B cell development. Peripheral T lymphocytes show an activated and anergic phenotype, reduced viability, and a restricted repertoire, reminiscent of human leaky SCID. Genomic instability is associated with a high rate of thymic tumor development. Finally, Lig4(R/R) mice spontaneously produce low-affinity antibodies that include autoreactive specificities, but are unable to mount high-affinity antibody responses. These findings highlight the importance of LIG4 in lymphocyte development and function, and in genomic stability maintenance, and provide a model for the complex phenotype of LIG4 syndrome in humans. C1 [Rucci, Francesca; Notarangelo, Luigi D.; Patrizi, Laura; Walter, Jolan E.; Recher, Mike; Andersson, Emma-Maria] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Rucci, Francesca; Notarangelo, Luigi D.; Patrizi, Laura; Walter, Jolan E.; Recher, Mike; Andersson, Emma-Maria] Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. [Fazeli, Alex; Hickernell, Thomas; Coakley, Kristen M.; Cheng, Hwei-Ling; Wang, Jing H.; Zha, Shan; Alt, Frederick W.; Yan, Catherine T.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Paganini, Tiziana; Giliani, Silvia] Univ Brescia, Dept Pediat, Angelo Nocivelli Inst Mol Med, I-25123 Brescia, Italy. [Detre, Cynthia; Keszei, Marton; Balter, Barbara B.; Terhorst, Cox] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Immunol, Boston, MA 02115 USA. [Feldman, Lauren] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol,Div Expt Pathol, Boston, MA 02215 USA. [Poliani, Pietro Luigi] Univ Brescia, Dept Pathol, I-25123 Brescia, Italy. RP Notarangelo, LD (reprint author), Childrens Hosp, Div Immunol, 300 Longwood Ave, Boston, MA 02115 USA. EM luigi.notarangelo@childrens.harvard.edu; alt@enders.tch.harvard.edu RI Poliani, Pietro Luigi/E-8145-2010; Keszei, Marton/F-3295-2014; Wang, Jing/M-7813-2015; Notarangelo, Luigi/F-9718-2016 OI Poliani, Pietro Luigi/0000-0002-5662-8978; Keszei, Marton/0000-0002-1158-2179; Wang, Jing/0000-0003-4343-2527; Notarangelo, Luigi/0000-0002-8335-0262 FU National Institutes of Health [P01 AI076210-01A1, CA 09382-26]; Manton Foundation FX We thank Drs. Michel Nussenzweig, Harvey Cantor, and Jianzhu Chen for critical reading of the manuscript. This work was partially supported by the National Institutes of Health Grant P01 AI076210-01A1 ( to L. D.N. and F. W. A.) and by the Manton Foundation ( L. D.N.). F. W. A. is a Howard Hughes Investigator. C.T.Y. is a recipient of a V Foundation Scholar Award and a grant from the Emerald Foundation. J.H.W. and S.Z. are recipients of a special fellowship from the Leukemia & Lymphoma Society of America. J.H.W. is also the recipient of National Institutes of Health Training Grant CA 09382-26. NR 48 TC 22 Z9 22 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 FEB 16 PY 2010 VL 107 IS 7 BP 3024 EP 3029 DI 10.1073/pnas.0914865107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556OC UT WOS:000274599500058 PM 20133615 ER PT J AU Boboila, C Jankovic, M Yan, CT Wang, JH Wesemann, DR Zhang, TT Fazeli, A Feldman, L Nussenzweig, A Nussenzweig, M Alt, FW AF Boboila, Cristian Jankovic, Mila Yan, Catherine T. Wang, Jing H. Wesemann, Duane R. Zhang, Tingting Fazeli, Alex Feldman, Lauren Nussenzweig, Andre Nussenzweig, Michel Alt, Frederick W. TI Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE class switch recombination; DNA double-strand repair; nonhomologous end-joining; switch region internal deletions ID CLASS-SWITCH RECOMBINATION; STRAND BREAK REPAIR; REGION RECOMBINATION; DNA-REPAIR; B-CELLS; SOMATIC HYPERMUTATION; V(D)J RECOMBINATION; MAMMALIAN-CELLS; ERROR-PRONE; MU REGION AB Class switch recombination (CSR) in B lymphocytes is initiated by introduction of multiple DNA double-strand breaks (DSBs) into switch (S) regions that flank immunoglobulin heavy chain (IgH) constant region exons. CSR is completed by joining a DSB in the donor S mu to a DSB in a downstream acceptor S region (e. g., S gamma 1) by end-joining. In normal cells, many CSR junctions are mediated by classical nonhomologous end-joining (C-NHEJ), which employs the Ku70/80 complex for DSB recognition and XRCC4/DNA ligase 4 for ligation. Alternative end-joining (A-EJ) mediates CSR, at reduced levels, in the absence of C-NHEJ, even in combined absence of Ku70 and ligase 4, demonstrating an A-EJ pathway totally distinct from C-NHEJ. Multiple DSBs are introduced into S mu during CSR, with some being rejoined or joined to each other to generate internal switch deletions (ISDs). In addition, S-region DSBs can be joined to other chromosomes to generate translocations, the level of which is increased by absence of a single C-NHEJ component (e. g., XRCC4). We asked whether ISD and S-region translocations occur in the complete absence of C-NHEJ (e. g., in Ku70/ligase 4 double-deficient B cells). We found, unexpectedly, that B-cell activation for CSR generates substantial ISD in both S mu and S gamma 1 and that ISD in both is greatly increased by the absence of C-NHEJ. IgH chromosomal translocations to the c-myc oncogene also are augmented in the combined absence of Ku70 and ligase 4. We discuss the implications of these findings for A-EJ in normal and abnormal DSB repair. C1 [Boboila, Cristian; Wang, Jing H.; Wesemann, Duane R.; Zhang, Tingting; Fazeli, Alex; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Boboila, Cristian; Wang, Jing H.; Wesemann, Duane R.; Zhang, Tingting; Fazeli, Alex; Alt, Frederick W.] Childrens Hosp, Boston, MA 02115 USA. [Boboila, Cristian; Wang, Jing H.; Wesemann, Duane R.; Zhang, Tingting; Fazeli, Alex; Alt, Frederick W.] Immune Dis Inst, Boston, MA 02115 USA. [Boboila, Cristian; Wang, Jing H.; Wesemann, Duane R.; Zhang, Tingting; Fazeli, Alex; Nussenzweig, Michel; Alt, Frederick W.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Jankovic, Mila; Nussenzweig, Michel] Rockefeller Univ, Lab Mol Immunol, New York, NY USA. [Yan, Catherine T.; Feldman, Lauren] Beth Israel Deaconess Med Ctr, Dept Pathol, Div Expt Pathol, Boston, MA 02215 USA. [Wesemann, Duane R.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Nussenzweig, Andre] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Nussenzweig, Andre] NIH, Bethesda, MD 20892 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu RI Wang, Jing/M-7813-2015 OI Wang, Jing/0000-0003-4343-2527 FU National Institutes of Health (NIH) [AI031541, CA092625, AI037526, T32CA09382-26]; Leukemia and Lymphoma Society of America; Cancer Research Institute FX We thank Klaus Rajewsky, Bjoern Schwer, Monica Gostissa, and Maria-Vivienne Boboila for stimulating discussions, and we thank Michael Lieber, Wesley Dunnick, and Kefei Yu for critical review of the manuscript. This work was supported by National Institutes of Health (NIH) Grants AI031541 and CA092625 ( F. W. A.) and AI037526 (M.N.). J.H.W. was supported by a Leukemia and Lymphoma Society of America Special Fellowship and by NIH Training Grant T32CA09382-26. C. B. is supported by a Cancer Research Institute training grant NR 47 TC 94 Z9 96 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 FEB 16 PY 2010 VL 107 IS 7 BP 3034 EP 3039 DI 10.1073/pnas.0915067107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556OC UT WOS:000274599500060 PM 20133803 ER PT J AU Zhang, TT Franklin, A Boboila, C McQuay, A Gallagher, MP Manis, JP Khamlichi, AA Alt, FW AF Zhang, Tingting Franklin, Andrew Boboila, Cristian McQuay, Amy Gallagher, Michael P. Manis, John P. Khamlichi, Ahmed Amine Alt, Frederick W. TI Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM switch regions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYTIDINE DEAMINASE AID; S-GAMMA REGIONS; SOMATIC HYPERMUTATION; R-LOOPS; IMMUNOGLOBULIN GENES; DNA DEAMINATION; CELL LINE; RECOMBINATION; TRANSCRIPTION; EXPRESSION AB Ig heavy chain (IgH) class-switch recombination(CSR) replaces the IgH C mu constant region exons with one of several sets of downstream IgH constant region exons (e. g., C gamma, C epsilon, or C alpha), which affects switching from IgM to another IgH class (e.g., IgG, IgE, or IgA). Activation-induced cytidine deaminase (AID) initiates CSR by promoting DNA double-strand breaks (DSBs) within switch (S) regions flanking the donor C mu (S mu) and a downstream acceptor CH (e.g., S gamma, S epsilon, S alpha) that are then joined to complete CSR. DSBs generated in S mu frequently are joined within S mu to form internal switch region deletions (ISD). AID-induced ISD and mutations have been considered rare in downstream S regions, suggesting that AID targeting to these S regions requires its prior recruitment to S mu. We have now assayed for CSR and ISD in B cells lacking S mu (S mu(-/-) B cells). In S mu(-/-) B cells activated for CSR to IgG1 and IgE, CSR to IgG1 was greatly reduced; but, surprisingly, CSR to IgE occurred at nearly normal levels. Moreover, normal B cells had substantial S gamma 1 ISD and increased mutations in and near S gamma 1, and levels of both were greatly increased in S mu(-/-) B cells. Finally, S mu(-/-) B cells underwent downstream CSR between S gamma 1 and S epsilon on alleles that lacked S mu CSR to these sequences. Our findings show that AID targets downstream S regions independently of CSR with S mu and implicate an alternative pathway for IgE class switching that involves generation and joining of DSBs within two different downstream S regions before S mu joining. C1 [Zhang, Tingting; Franklin, Andrew; Boboila, Cristian; McQuay, Amy; Gallagher, Michael P.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Zhang, Tingting; Franklin, Andrew; Boboila, Cristian; McQuay, Amy; Gallagher, Michael P.; Manis, John P.; Alt, Frederick W.] Childrens Hosp, Boston, MA 02115 USA. [Zhang, Tingting; Franklin, Andrew; Boboila, Cristian; McQuay, Amy; Gallagher, Michael P.; Alt, Frederick W.] Immune Dis Inst, Boston, MA 02115 USA. [Zhang, Tingting; Franklin, Andrew; Boboila, Cristian; McQuay, Amy; Gallagher, Michael P.; Alt, Frederick W.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Manis, John P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Khamlichi, Ahmed Amine] Univ Toulouse, CNRS, UMR 5089, IPBS, F-31077 Toulouse, France. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu FU National Institutes of Health [AI031541, CA092625]; Cancer Research Institute; Howard Hughes Medical Institute FX We thank Jing H. Wang, Duane Wesemann, Yu Nee Lee, Feilong Meng, and Michael G. Kharas for stimulating discussions and Michael Lieber and Barry Sleckman for critical review of the manuscript. This work was supported by National Institutes of Health Grants AI031541 and CA092625 ( to F. W. A.). C. B. is supported by a Cancer Research Institute training grant. F. W. A. is an investigator of the Howard Hughes Medical Institute. NR 42 TC 21 Z9 22 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 FEB 16 PY 2010 VL 107 IS 7 BP 3040 EP 3045 DI 10.1073/pnas.0915072107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556OC UT WOS:000274599500061 PM 20133637 ER PT J AU Ferris, AL Wu, XL Hughes, CM Stewart, C Smith, SJ Milne, TA Wang, GG Shun, MC Allis, CD Engelman, A Hughes, SH AF Ferris, Andrea L. Wu, Xiaolin Hughes, Christina M. Stewart, Claudia Smith, Steven J. Milne, Thomas A. Wang, Gang G. Shun, Ming-Chieh Allis, C. David Engelman, Alan Hughes, Stephen H. TI Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromatin; histone marks; lentiviral vectors ID HUMAN-IMMUNODEFICIENCY-VIRUS; AVIAN-SARCOMA VIRUS; HUMAN GENOME; CHROMATIN-BINDING; TARGET SITES; HISTONE H3; LEDGF/P75; REPLICATION; IDENTIFICATION; RETROTRANSPOSON AB Lens epithelium-derived growth factor (LEDGF) fusion proteins can direct HIV-1 DNA integration to novel sites in the host genome. The C terminus of LEDGF contains an integrase binding domain (IBD), and the N terminus binds chromatin. LEDGF normally directs integrations to the bodies of expressed genes. Replacing the N terminus of LEDGF with chromatin binding domains (CBDs) from other proteins changes the specificity of HIV-1 DNA integration. We chose two well-characterized CBDs: the plant homeodomain (PHD) finger from ING2 and the chromodomain from heterochromatin binding protein 1 alpha (HP1 alpha). The ING2 PHD finger binds H3K4me3, a histone mark that is associated with the transcriptional start sites of expressed genes. The HP1 alpha chromodomain binds H3K9me2,3, histone marks that are widely distributed throughout the genome. A fusion protein in which the ING2 PHD finger was linked to the LEDGF IBD directed integrations near the start sites of expressed genes. A similar fusion protein in which the HP1 alpha chromodomain was linked to the LEDGF IBD directed integrations to sites that differed from both the PHD finger fusion-directed and LEDGF-directed integration sites. The ability to redirect HIV-1 DNA integration may help solve the problems associated with the activation of oncogenes when retroviruses are used in gene therapy. C1 [Ferris, Andrea L.; Smith, Steven J.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Wu, Xiaolin; Stewart, Claudia] SAIC Frederick Inc, Lab Mol Technol, Frederick, MD 21702 USA. [Hughes, Christina M.; Milne, Thomas A.; Wang, Gang G.; Allis, C. David] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA. [Shun, Ming-Chieh; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov RI Wang, G Greg/L-6666-2014; Milne, Tom/E-1872-2016 OI Wang, G Greg/0000-0002-7210-9940; Milne, Tom/0000-0002-0413-4271 FU National Institutes of Health (NIH) (National Cancer Institute) [AI039394, T32 AI007386, GM53122]; Rockefeller University; Emerald Foundation; [HHSN261200800001E] FX We thank John Coffin and Alex Ruthenburg for helpful discussions; Kathleen Noer and Roberta Matthai of the Center for Cancer Research-Frederick Flow Cytometry Core for cell sorting; Alan Kane and Jiro Wada for helpwith thefigures; and Jeff Skaar and Teresa Burdette for help with themanuscript. This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH) (National Cancer Institute). A portion of this funding was under Contract no. HHSN261200800001E. Research in the laboratory of A. E. was supported by NIH Grant AI039394, and M.-C. S. was supported in part by NIH Training Grant T32 AI007386. Research in the laboratory of C. D. A. was supported by NIH Method to Extend Research in Time Award GM53122 and The Rockefeller University. C. M. H. was supported by the Emerald Foundation. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 34 TC 77 Z9 77 U1 0 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 FEB 16 PY 2010 VL 107 IS 7 BP 3135 EP 3140 DI 10.1073/pnas.0914142107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556OC UT WOS:000274599500077 PM 20133638 ER PT J AU Cannon, CP Rhee, KE Califf, RM Boden, WE Hirsch, AT Alberts, MJ Cable, G Shao, MY Ohman, EM Steg, PG Eagle, KA Bhatt, DL AF Cannon, Christopher P. Rhee, Karen E. Califf, Robert M. Boden, William E. Hirsch, Alan T. Alberts, Mark J. Cable, Greg Shao, Mingyuan Ohman, E. Magnus Steg, P. Gabriel Eagle, Kim A. Bhatt, Deepak L. CA REACH Registry Investigators TI Current Use of Aspirin and Antithrombotic Agents in the United States Among Outpatients With Atherothrombotic Disease (from the REduction of Atherothrombosis for Continued Health [REACH] Registry) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; SECONDARY PREVENTION; RANDOMIZED-TRIALS; COLLABORATIVE METAANALYSIS; BLEEDING COMPLICATIONS; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; ANTIPLATELET THERAPY; VASCULAR-DISEASE; CORONARY AB Despite its proven efficacy, low cost, and wide availability, aspirin remains underused. We examined current aspirin use and determined factors that influence its use among outpatients in the United States (US). The REduction of Atherothrombosis for Continued Health (REACH) Registry is an international, prospective, longitudinal study of >68,000 outpatients with established atherothrombosis or >= 3 atherothrombotic risk factors. The rates of aspirin use were compared in various patient subgroups. Multivariate logistic regression models were constructed to determine the factors influencing the baseline use of aspirin and other antithrombotic agents in the US population. Approximately 70% of 25,686 US outpatients were treated with aspirin, with greater use in the Midwest and among men, whites, and those aged <65 years. Among aspirin users, 18% took other antiplatelet agents and 6% took oral anticoagulants. Low-dose aspirin (<= 100 mg/day) was used in approximately 2/3 of aspirin users. Of patients not taking aspirin, 1/2 were receiving oral anticoagulants or other antiplatelet agents. However, 15% of patients used no antithrombotic agent at all. Female gender, current smoking, or having diabetes mellitus were predictors of a lack of antithrombotic use; white race, atrial fibrillation or vascular disease, the use of other risk-reducing medications, or treatment by a cardiologist were associated with a greater likelihood of receiving antithrombotic therapy. In conclusion, approximately 1/4 of US patients with vascular disease are not treated with aspirin for secondary prevention, and 15% are not treated with any antithrombotic agent. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:445-452) C1 [Cannon, Christopher P.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Cannon, Christopher P.] Harvard Univ, Sch Med, Boston, MA USA. [Rhee, Karen E.] Miriam Hosp, Providence, RI 02906 USA. [Califf, Robert M.] Duke Clin Res Inst, Durham, NC USA. [Boden, William E.] Buffalo Gen Hosp, Buffalo, NY 14203 USA. [Boden, William E.] SUNY Buffalo, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. [Hirsch, Alan T.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Hirsch, Alan T.] Minneapolis Heart Inst Fdn, Minneapolis, MN USA. [Alberts, Mark J.] Northwestern Univ, Sch Med, Chicago, IL USA. [Cable, Greg] Sanofi Aventis, Dept Biostat, Bridgewater, MA USA. [Shao, Mingyuan] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Ohman, E. Magnus] Duke Univ, Med Ctr, Durham, NC USA. [Steg, P. Gabriel] Univ Paris 07, AP HP, INSERM, U698, Paris, France. [Eagle, Kim A.] Univ Michigan, Ctr Cardiovasc, Ann Arbor, MI 48109 USA. [Bhatt, Deepak L.] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Cannon, CP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM cpcannon@partners.org FU Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership, New York, New York FX The REduction of Atherothrombosis for Continued Health (REACH) Registry, statistical support, and editorial assistance were supported by the Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership, New York, New York. The REACH Registry has been endorsed by the World Heart Federation, Geneva, Switzerland. NR 18 TC 33 Z9 34 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2010 VL 105 IS 4 BP 445 EP 452 DI 10.1016/j.amjcard.2009.10.014 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 602JZ UT WOS:000278136700004 PM 20152237 ER PT J AU Ahmadi, N Tsimikas, S Hajsadeghi, F Saeed, A Nabavi, V Bevinal, MA Kadakia, J Flores, F Ebrahimi, R Budoff, MJ AF Ahmadi, Naser Tsimikas, Sotirios Hajsadeghi, Fereshteh Saeed, Anila Nabavi, Vahid Bevinal, Manzoor A. Kadakia, Jigar Flores, Ferdinand Ebrahimi, Ramin Budoff, Matthew J. TI Relation of Oxidative Biomarkers, Vascular Dysfunction, and Progression of Coronary Artery Calcium SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; OXIDIZED PHOSPHOLIPIDS; RISK-FACTORS; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR EVENTS; PROGNOSTIC VALUE; STATIN THERAPY; CLINICAL-TRIAL; ATHEROSCLEROSIS; DISEASE AB The relation between oxidative stress and coronary artery calcium (CAC) progression is currently not well described. The present study evaluated the relation among the biomarkers of oxidative stress, vascular dysfunction, and CAC. Sixty asymptomatic subjects participated in a randomized trial evaluating the effect of aged garlic extract plus supplement versus placebo and underwent measurement of CAC. The postcuff deflation temperature-rebound index of vascular function was assessed using a reactive hyperemia procedure. The content of oxidized phospholipids (OxPL) on apolipoprotein B-100 (apoB) particles detected by antibody E06 (OxPL/apoB), lipoprotein(a), IgG and IgM autoantibodies to malondialdehyde low-density lipoprotein and apoB-immune complexes were measured at baseline and after 12 months of treatment. CAC progression was defined as an annual increase in CAC >15%. Vascular dysfunction was defined according to the tertiles of temperature-rebound at 1 year of follow-up. From baseline to 12 months, a strong inverse correlation was noted between an increase in CAC scores and increases in temperature-rebound (r(2) = -0.90), OxPL/apoB (r(2) = -0.85), and lipoprotein(a) (r(2) = -0.81) levels (p <0.0001 for all). The improvement in temperature-rebound correlated positively with the increases in OxPL/apoB (r(2) = 0.81, p = 0.0008) and lipoprotein(a) (r(2) = 0.79, p = 0.0001) but inversely with autoantibodies to malondialdehyde low-density lipoprotein and apoB-immune complexes. The greatest CAC progression was noted with the lowest tertiles of increases in temperature-rebound, OxPL/apoB and lipoprotein(a) and the highest tertiles of increases in IgG and IgM malondialdehyde low-density lipoprotein. In conclusion, the present results have documented a strong relation among markers of oxidative stress, vascular dysfunction, and progression of coronary atherosclerosis. Increases in OxPL/apoB and lipoprotein(a) correlated strongly with increases in vascular function and predicted a lack of progression of CAC. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:459-466) C1 [Ahmadi, Naser; Hajsadeghi, Fereshteh; Saeed, Anila; Nabavi, Vahid; Bevinal, Manzoor A.; Kadakia, Jigar; Flores, Ferdinand; Budoff, Matthew J.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Tsimikas, Sotirios] Univ Calif San Diego, Vasc Med Program, San Diego, CA 92103 USA. [Ebrahimi, Ramin] Univ Calif Los Angeles, Vet Affairs Greater Los Angeles Hlth Care Syst, Los Angeles, CA USA. RP Budoff, MJ (reprint author), Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. EM mbudoff@labiomed.org NR 30 TC 30 Z9 30 U1 2 U2 4 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 FEB 15 PY 2010 VL 105 IS 4 BP 459 EP 466 DI 10.1016/j.amjcard.2009.09.052 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 602JZ UT WOS:000278136700006 PM 20152239 ER PT J AU LaMarr, B Valdez, C Driscoll, K Ryan, M AF LaMarr, Brandon Valdez, Connie Driscoll, Katie Ryan, Mary TI Influence of pharmacist intervention on prescribing of angiotensin-converting-enzyme inhibitors, angiotensin II-receptor blockers, and aspirin for diabetic patients SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE American Diabetes Association; Angiotensin antagonists; Angiotensin-converting-enzyme inhibitors; Aspirin; Diabetes mellitus; Education; Interventions; Pharmaceutical services; Pharmacists; Physicians; Platelet aggregation inhibitors; Prescribing; Protocols; Rational therapy ID MICROVASCULAR COMPLICATIONS; BLOOD-PRESSURE; MANAGEMENT AB Purpose. The influence of pharmacist intervention on the prescribing of angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II-receptor blockers (ARBs), and aspirin for patients with diabetes was evaluated. Methods. A retrospective chart review was performed for diabetic patients seen in a family medicine clinic. Patients were included in the analyses if they were 18-88 years old, had a diagnosis of type 1 or type 2 diabetes, had been seen in the family medicine clinic between July 2006 and October 2008, and had received a consultation by pharmacy services. All selected charts were reviewed to assess appropriate use of ACE inhibitor, ARB, and aspirin therapy, as recommended by American Diabetes Association (ADA) guidelines, before and after pharmacist intervention. Typical pharmacist interventions consisted of direct consultation with the prescriber and therapeutic education sessions conducted by pharmacy personnel. All patients were seen and evaluated by pharmacy personnel before meeting with the prescriber. Results. Before pharmacist intervention, 41 (59%) of 70 patients were receiving appropriate ACE inhibitor or ARB therapy and 24 (34%) of 71 patients were receiving appropriate aspirin therapy as recommended by ADA. After pharmacist intervention, 63 (90%) of 70 patients were receiving appropriate ACE inhibitor or ARB therapy and 48 (68%) of 71 patients were receiving appropriate aspirin therapy as recommended by ADA (p < 0.0001 for both differences). Conclusion. A pharmacy intervention program in a primary care setting was associated with a significant increase in prescriber adherence to ADA guidelines for ACE inhibitor or ARB therapy and for aspirin therapy in diabetic patients. C1 [LaMarr, Brandon] So Arizona Vet Affairs Healthcare Syst, Tucson, AZ 85723 USA. [Valdez, Connie] Univ Colorado Denver, Sch Pharm, Dept Clin Pharm, Aurora, CO USA. [Driscoll, Katie] Denver Vet Affairs Med Ctr, Denver, CO USA. [Driscoll, Katie] Eastern Colorado Vet Affairs Hlth Care Syst, Serv Pharm, Denver, CO USA. [Ryan, Mary] Childrens Hosp, Aurora, CO USA. RP LaMarr, B (reprint author), So Arizona Vet Affairs Healthcare Syst, 3601 S 6th Ave 13-119, Tucson, AZ 85723 USA. EM brandon.lamarr2@va.gov NR 17 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD FEB 15 PY 2010 VL 67 IS 4 BP 290 EP 294 DI 10.2146/ajhp090009 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 556DV UT WOS:000274569900009 PM 20133534 ER PT J AU Bajpayee, A Edd, JF Chang, A Toner, M AF Bajpayee, Anurag Edd, Jon F. Chang, Anthony Toner, Mehmet TI Concentration of Glycerol in Aqueous Microdroplets by Selective Removal of Water SO ANALYTICAL CHEMISTRY LA English DT Article ID VITRIFICATION; OOCYTES; DROPLET; EMBRYOS; CELLS AB A major roadblock to the vitrification of cells is the requirement of high concentrations of cryoprotectant (CPA) chemicals and the damage caused by prolonged exposure of cells to these high concentrations above the glass transition temperature. These effects are minimized with controlled CPA loading. Certain organic oils, such as soybean oil, are made of triacylglycerols and are capable of dissolving small amounts of water, a property which is enhanced significantly as temperature is increased. This phenomenon was exploited here to accomplish temperature-controlled concentration of glycerol in single water droplets dispersed in the organic phase. Emulsions of aqueous solutions of glycerol in soybean oil were made and subjected to a temperature increase of 10 degrees C from room temperature. Upon increasing temperature, water dissolved into the oil, rendering the 15-20 mu m droplets concentrated an average of 3.6 times and 2.6 times for 1 and 2 M starting concentrations, respectively, with the oil-insoluble glycerol in 90-110 s. This phenomenon could be used to dynamically concentrate CPAs within cell-containing droplets which may then be vitrified before being exposed to high temperatures for fatally long times. C1 [Bajpayee, Anurag; Edd, Jon F.; Chang, Anthony; Toner, Mehmet] Harvard Univ, Massachusetts Gen Hosp, Sch Med, BioMicroElectroMech Syst Resource Ctr, Boston, MA 02129 USA. [Bajpayee, Anurag; Edd, Jon F.; Chang, Anthony; Toner, Mehmet] Shriners Hosp Children, Boston, MA 02129 USA. [Bajpayee, Anurag] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Toner, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, BioMicroElectroMech Syst Resource Ctr, Boston, MA 02129 USA. EM mtoner@hms.harvard.edu FU National Institutes of Health [DK046270, P41 EB002503] FX The authors thank Daniel T. Chiu for helpful discussions (with M.T.) and for critical reading of the manuscript. This study was partially funded by the National Institutes of Health Grants DK046270 and P41 EB002503. NR 19 TC 10 Z9 10 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD FEB 15 PY 2010 VL 82 IS 4 BP 1288 EP 1291 DI 10.1021/ac9022742 PG 4 WC Chemistry, Analytical SC Chemistry GA 554WK UT WOS:000274466100019 PM 20102162 ER PT J AU Dewal, N Freedman, ML LaFramboise, T Pe'er, I AF Dewal, Ninad Freedman, Matthew L. LaFramboise, Thomas Pe'er, Itsik TI Power to detect selective allelic amplification in genome-wide scans of tumor data SO BIOINFORMATICS LA English DT Article ID OVARIAN-CANCER SUSCEPTIBILITY; RECEPTOR GENE-MUTATIONS; CELL LUNG-CANCER; BREAST-CANCER; PROSTATE-CANCER; MYELOPROLIFERATIVE NEOPLASMS; COLORECTAL-CANCER; ASSOCIATION SCAN; JAK2 HAPLOTYPE; HYBRIDIZATION AB Motivation: Somatic amplification of particular genomic regions and selection of cellular lineages with such amplifications drives tumor development. However, pinpointing genes under such selection has been difficult due to the large span of these regions. Our recently-developed method, the amplification distortion test (ADT), identifies specific nucleotide alleles and haplotypes that confer better survival for tumor cells when somatically amplified. In this work, we focus on evaluating ADT's power to detect such causal variants across a variety of tumor dataset scenarios. Results: Towards this end, we generated multiple parameter-based, synthetic datasets-derived from real data-that contain somatic copy number aberrations (CNAs) of various lengths and frequencies over germline single nucleotide polymorphisms (SNPs) genome-wide. Gold-standard causal sub-regions were assigned within these CNAs, followed by an assessment of ADT's ability to detect these sub-regions. Results indicate that ADT possesses high sensitivity and specificity in large sample sizes across most parameter cases, including those that more closely reflect existing SNP and CNA cancer data. C1 [Dewal, Ninad] Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA. [Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Freedman, Matthew L.] Broad Inst Harvard & MIT, Med & Populat Genet Program, Cambridge, MA 02142 USA. [LaFramboise, Thomas] Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. [Pe'er, Itsik] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA. RP Dewal, N (reprint author), Columbia Univ, Dept Biomed Informat, New York, NY 10032 USA. EM ninad.dewal@dbmi.columbia.edu FU National Institutes of Health and National Library of Medicine [5T15 LM007079-14]; Department of Biomedical Informatics, Columbia University; National Institutes of Health [1 R01 CA131341-01A1] FX National Institutes of Health and National Library of Medicine [5T15 LM007079-14 to the Medical Informatics Research Training Program, Department of Biomedical Informatics, Columbia University]; and the National Institutes of Health [1 R01 CA131341-01A1]. NR 49 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2010 VL 26 IS 4 BP 518 EP 528 DI 10.1093/bioinformatics/btp694 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 555CI UT WOS:000274484300010 PM 20031965 ER PT J AU Otto, MW Tolin, DF Simon, NM Pearlson, GD Basden, S Meunier, SA Hofmann, SG Eisenmenger, K Krystal, JH Pollack, MH AF Otto, Michael W. Tolin, David F. Simon, Naomi M. Pearlson, Godfrey D. Basden, Shawnee Meunier, Suzanne A. Hofmann, Stefan G. Eisenmenger, Katherine Krystal, John H. Pollack, Mark H. TI Efficacy of D-Cycloserine for Enhancing Response to Cognitive-Behavior Therapy for Panic Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Cognitive-behavior therapy; d-cycloserine; panic disorder ID OBSESSIVE-COMPULSIVE DISORDER; RANDOMIZED CONTROLLED-TRIAL; SOCIAL ANXIETY DISORDER; EXPOSURE THERAPY; FEAR EXTINCTION; CONDITIONED FEAR; SEVERITY SCALE; PSYCHOTHERAPY; FACILITATION; PHARMACOTHERAPY AB Background: Traditional combination strategies of cognitive-behavior therapy plus pharmacotherapy have met with disappointing results for anxiety disorders. Enhancement of cognitive-behavior therapy with d-cycloserine (DCS) pharmacotherapy represents a novel strategy for improving therapeutic learning from cognitive-behavior therapy that remains untested in panic disorder. Method: This is a randomized, double-blind, placebo-controlled augmentation trial examining the addition of isolated doses of 50 mg cl-cycloserine or pill placebo to brief exposure-based cognitive-behavior therapy. Randomized participants were 31 outpatients meeting DSM-IV criteria for panic disorder with or without agoraphobia, who were offered five sessions of manualized cognitive-behavior therapy emphasizing exposure to feared internal sensations (interoceptive exposure) but also including informational, cognitive, and situational exposure interventions. Doses of study drug were administered 1 hour before cognitive-behavior therapy sessions 3 to 5. The primary outcome measures were the Panic Disorder Severity Scale (PDSS) and Clinicians' Global Impressions of Severity. Results: Results indicated large effect sizes for the additive benefit of cl-cycloserine augmentation of cognitive-behavior therapy for panic disorder. At posttreatment and 1 month follow-up, participants who received cl-cycloserine versus placebo had better outcomes on the PDSS and global severity of disorder and were significantly more likely to have achieved clinically significant change status (77% vs. 33%). There were no significant adverse effects associated with DCS administration. Conclusions: This pilot study extends support for the role of cl-cycloserine in enhancing therapeutic learning from exposure-based cognitive-behavior therapy and is the first to do so in a protocol emphasizing exposure to feared internal sensations of anxiety in panic disorder. C1 [Otto, Michael W.; Basden, Shawnee; Hofmann, Stefan G.; Eisenmenger, Katherine] Boston Univ, Ctr Anxiety & Related Disorders, Boston, MA 02215 USA. [Tolin, David F.; Pearlson, Godfrey D.; Meunier, Suzanne A.] Hartford Hosp, Inst Living, Hartford, CT 06115 USA. [Tolin, David F.; Pearlson, Godfrey D.; Krystal, John H.] Yale Univ, Sch Med, New Haven, CT USA. [Simon, Naomi M.; Pollack, Mark H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Simon, Naomi M.; Pollack, Mark H.] Harvard Univ, Sch Med, Boston, MA USA. RP Otto, MW (reprint author), Boston Univ, Ctr Anxiety & Related Disorders, 648 Beacon St,Floor 6, Boston, MA 02215 USA. EM mwotto@bu.edu RI Hofmann, Stefan/B-8769-2014 OI Hofmann, Stefan/0000-0002-3548-9681 NR 38 TC 123 Z9 124 U1 6 U2 22 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 FEB 15 PY 2010 VL 67 IS 4 BP 365 EP 370 DI 10.1016/j.biopsych.2009.07.036 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 554RC UT WOS:000274451100011 PM 19811776 ER PT J AU Abusief, ME Missmer, SA Ginsburg, ES Weeks, JC Partridge, AH AF Abusief, Mary E. Missmer, Stacey A. Ginsburg, Elizabeth S. Weeks, Jane C. Partridge, Ann H. TI The Effects of Paclitaxel, Dose Density, and Trastuzumab on Treatment-Related Amenorrhea in Premenopausal Women With Breast Cancer SO CANCER LA English DT Article DE cyclophosphamide; dose-dense regimens; doxorubicin; menopausal status; tamoxifen; trastuzumab; amenorrhea; paclitaxel ID ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIAL; OVARIAN-FUNCTION; YOUNG-WOMEN; IMPACT; DOCETAXEL; THERAPY; RISK AB BACKGROUND: Little information is available regarding the effects of new adjuvant treatment regimens on menstrual functioning in premenopausal women with early breast cancer. METHODS: The authors conducted a retrospective review of data from premenopausal women who received treatment for early breast cancer to evaluate the rates of amenorrhea in follow-up. The women who were included received treatment with either doxorubicin and cyclophosphamide (AC) or combined AC and paclitaxel (T) (AC-T) given either every 3 weeks, or as a dose-dense (DD) regimen, or as AC followed by weekly T with trastuzumab or followed by trastuzumab (AC-T+trastuzumab). A multivariate logistic regression analysis was conducted to evaluate amenorrhea during follow-up. RESULTS: Of 431 patients who were eligible for analysis, the average age at diagnosis was 13 years (range, 25-55 years), 61% of women received AC only, and 39% received AC-T. Of the 39% who received AC-T, 49% of women received DID therapy, 14% received AC-T + trastuzumab, and 71% of all patients received tamoxifen (TAM). The median follow-up was 33 months (range, 6-114 months). After adjusting for age, weight, gravidity, parity, age at menarche, smoking, alcohol use, TAM use, type and regimen of chemotherapy, and use of trastuzumab, the likelihood of remaining amenorrheic was not statistically different in patients who received AC-T versus AC (odds ratio [OR], 1.59; 95% confidence interval [0], 0.8-3.2), DD treatment versus treatment every 3 weeks (OR, 0.56; 95% CI, 0.25-1.3), or AC-T + trastuzumab (OR, 0.6; 95% CI, 0.22-1.61). Amenorrhea was associated significantly with TAM use and age at diagnosis. CONCLUSIONS: Recent advances in the adjuvant treatment of early breast cancer do not appear to have increased the risk of amenorrhea in premenopausal women. Cancer 2010;116:791-8. (C) 2010 American Cancer Society. C1 [Abusief, Mary E.; Missmer, Stacey A.; Ginsburg, Elizabeth S.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Abusief, Mary E.; Missmer, Stacey A.; Ginsburg, Elizabeth S.; Weeks, Jane C.; Partridge, Ann H.] Harvard Univ, Sch Med, Boston, MA USA. [Missmer, Stacey A.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Missmer, Stacey A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Weeks, Jane C.; Partridge, Ann H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Partridge, AH (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM ahpartridge@partners.org NR 37 TC 48 Z9 49 U1 1 U2 4 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 FEB 15 PY 2010 VL 116 IS 4 BP 791 EP 798 DI 10.1002/cncr.24835 PG 8 WC Oncology SC Oncology GA 552TF UT WOS:000274315800005 PM 20052714 ER PT J AU Dosoretz, AM Chen, MH Salenius, SA Ross, RH Dosoretz, DE Katin, MJ Mantz, C Nakfoor, BM D'Amico, AV AF Dosoretz, Amy M. Chen, Ming-Hui Salenius, Sharon A. Ross, Rudolf H. Dosoretz, Daniel E. Katin, Michael J. Mantz, Constantine Nakfoor, Bruce M. D'Amico, Anthony V. TI Mortality in Men With Localized Prostate Cancer Treated With Brachytherapy With or Without Neoadjuvant Hormone Therapy SO CANCER LA English DT Article; Proceedings Paper CT 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and Oncology CY SEP 21-25, 2008 CL Boston, MA SP Amer Soc Therapeut Radiol & Oncol DE prostate cancer; mortality; brachytherapy; androgen deprivation; neoadjuvant hormone therapy; radiation therapy ID ANDROGEN DEPRIVATION THERAPY; RANDOMIZED-TRIAL; EXTERNAL-BEAM; RADIATION-THERAPY; SUPPRESSION; RADIOTHERAPY; SURVIVAL; IMPACT; RISK AB BACKGROUND: Discrepancies exist regarding the impact of neoadjuvant hormone therapy (NHT) on the risk of all-cause mortality (ACM) in men who receive brachytherapy for localized prostate cancer. Therefore, the objective of the current study was to examine the effect of NHT on the risk of ACM in men with prostate cancer who receive with brachytherapy. METHODS: The study cohort included 2474 men with localized prostate cancer who either received NHT (N = 1083) or did not receive NHT (N = 1391) and brachytherapy without supplemental external beam radiation between 1991 and 2005 at centers within the 21st Century Oncology Consortium. All men had at least 2 years of follow-up. Low-risk, intermediate-risk, and high-risk disease was present in 65%, 23%, and 12% of men, respectively. A Cox regression multivariate analysis was used to evaluate the risk of ACM in men who received NHT compared with all others adjusting for age, prostate-specific antigen level, Gleason score, and tumor classification. RESULTS: After a median follow-up of 4.8 years (interquartile range, 3.3-7.5 years) and adjusting for known prostate cancer prognostic factors and age, treatment with NHT was associated significantly with an increased risk of ACM (adjusted hazard ratio, 1.24; 95% confidence interval, 1.01-1.53; P = .04) in men aged >= 73 years. In men who were younger than the median age of 73 years, hormone therapy use was not significant (P = .34). CONCLUSIONS: Compared with men who were younger than the median age of 73 years, men aged >= 73 years with localized prostate cancer who received brachytherapy and NHT had an increased risk of ACM compared with men who did not receive NHT. Cancer 2010;116:837-42. (C) 2010 American Cancer Society. C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Dosoretz, Amy M.] Harvard Radiat Oncol Program, Dept Radiat Oncol, Boston, MA USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Salenius, Sharon A.; Ross, Rudolf H.; Dosoretz, Daniel E.; Katin, Michael J.; Mantz, Constantine; Nakfoor, Bruce M.] 21st Century Oncol Inc, Dept Radiat Oncol, Ft Myers, FL USA. [D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM adamico@lroc.harvard.edu NR 18 TC 12 Z9 13 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 FEB 15 PY 2010 VL 116 IS 4 BP 837 EP 842 DI 10.1002/cncr.24750 PG 6 WC Oncology SC Oncology GA 552TF UT WOS:000274315800011 PM 20052734 ER PT J AU McCleary, NJ Niedzwiecki, D Hollis, D Saltz, LB Schaefer, P Whittom, R Hantel, A Benson, A Goldberg, R Meyerhardt, JA AF McCleary, Nadine Jackson Niedzwiecki, Donna Hollis, Donna Saltz, Leonard B. Schaefer, Paul Whittom, Renaud Hantel, Alexander Benson, Al Goldberg, Richard Meyerhardt, Jeffrey A. TI Impact of Smoking on Patients With Stage III Colon Cancer Results From Cancer and Leukemia Group B 89803 SO CANCER LA English DT Article DE colorectal cancer; smoking; cancer recurrence; cancer survival; adjuvant chemotherapy ID ADVANCED COLORECTAL ADENOMA; CIGARETTE-SMOKING; FOLLOW-UP; EPIDEMIOLOGIC EVIDENCE; RISK; WOMEN; POLYMORPHISMS; COMPLETENESS; MORTALITY; SMOKERS AB BACKGROUND: Cigarette smoking has been shown to increase the risk of developing colorectal cancer, particularly smoking early in life. Little is known about the impact of tobacco use on colon cancer recurrence among colon cancer survivors. METHODS: The authors prospectively collected lifetime smoking history from stage III colon cancer patients enrolled in a phase 3 trial via self-report questionnaires during and 6 months after completion of adjuvant chemotherapy. Smoking status was defined as never, current, or past. Lifetime pack-years were defined as number of lifetime packs of cigarettes. Patients were followed for recurrence or death. RESULTS: Data on smoking history were captured on 1045 patients with stage III colon cancer receiving adjuvant therapy (46% never smokers; 44% past; 10% current). The adjusted hazard ratio (HR) for disease-free survival (DFS) was 0.99 (95% confidence interval [CI], 0.701,41), 1.17 (95% CI 0.89-1.55), and 1.22 (95% CI 0.92-1.61) for lifetime pack-years 0-10, 10-20, and 20+, respectively, compared with never smoking (P = .16). In a preplanned exploratory analysis of smoking intensity early in life, the adjusted HR for 12+ pack-years before age 30 years for DFS was 1.37 (95% CI, 1.02-1.84) compared with never smoking (P = .04). The adjusted HR for DFS was 1.18 (95% CI, 0.92-1.50) for past smokers and 1.10 (95% CI, 0.73-1.64) for current smokers, compared with never smokers. CONCLUSIONS: Total tobacco usage early in life may be an important, independent prognostic factor of cancer recurrences and mortality in patients with stage III colon cancer. Cancer 2010;116:957-66. (C) 2010 American Cancer Society. C1 [McCleary, Nadine Jackson; Meyerhardt, Jeffrey A.] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02113 USA. [Niedzwiecki, Donna; Hollis, Donna] Duke Univ, Ctr Stat, Canc & Leukemia Grp B, Durham, NC USA. [Saltz, Leonard B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Schaefer, Paul] Toledo Community Hosp, Oncol Program, Toledo, OH USA. [Whittom, Renaud] Sacred Heart Hosp Montreal, Montreal, PQ, Canada. [Hantel, Alexander] Loyola Univ, Dept Med, Maywood, IL 60153 USA. [Benson, Al] NW Med Ctr, Div Hematol Oncol, Chicago, IL USA. [Goldberg, Richard] Univ Chicago, Hematol Oncol Sect, Chicago, IL 60637 USA. RP McCleary, NJ (reprint author), Dana Farber Canc Inst, Div Med Oncol, 44 Binney St, Boston, MA 02113 USA. EM njackson2@partners.org OI Saltz, Leonard/0000-0001-8353-4670 FU NCI NIH HHS [R01 CA118553-03, CA17145, CA31946, CA32101, CA32291, CA33601, CA35415, CA38926, CA46282, CA47559, CA77651, P50 CA127003, P50 CA127003-01, R01 CA118553, U10 CA031946, U10 CA033601]; NCRR NIH HHS [UL1 RR025741] NR 27 TC 25 Z9 25 U1 0 U2 2 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 FEB 15 PY 2010 VL 116 IS 4 BP 957 EP 966 DI 10.1002/cncr.24866 PG 10 WC Oncology SC Oncology GA 552TF UT WOS:000274315800025 PM 20052723 ER PT J AU Marina, O Hainz, U Biernacki, MA Zhang, WD Cai, A Duke-Cohan, JS Liu, FL Brusic, V Neuberg, D Kutok, JL Alyea, EP Canning, CM Soiffer, RJ Ritz, J Wu, CJ AF Marina, Ovidiu Hainz, Ursula Biernacki, Melinda A. Zhang, Wandi Cai, Ann Duke-Cohan, Jonathan S. Liu, Fenglong Brusic, Vladimir Neuberg, Donna Kutok, Jeffery L. Alyea, Edwin P. Canning, Christine M. Soiffer, Robert J. Ritz, Jerome Wu, Catherine J. TI Serologic Markers of Effective Tumor Immunity against Chronic Lymphocytic Leukemia Include Nonmutated B-Cell Antigens SO CANCER RESEARCH LA English DT Article; Proceedings Paper CT 49th Annual Meeting of the American-Society-of-Hematology CY DEC 08-11, 2007 CL Atlanta, GA SP Amer Soc Hematol ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; REACTIVE T-CELLS; ALLOGENEIC TRANSPLANTATION; PROTEIN; EXPRESSION; CANCER; MALIGNANCIES; PROGRESSION; REMISSION AB Patients with chronic lymphocytic leukemia (CLL) who relapse after allogeneic transplant may achieve durable remission following donor lymphocyte infusion (DLI), showing the potency of donor-derived immunity in eradicating tumors. We sought to elucidate the antigenic basis of the effective graft-versus-leukemia (GvL) responses associated with DLI for the treatment of CLL by analyzing the specificity of plasma antibody responses developing in two DLI-treated patients who achieved long-term remission without graft-versus-host disease. By probing high-density protein microarrays with patient plasma, we discovered 35 predominantly intracellular antigens that elicited high-titer antibody reactivity greater in post-DLI than in pre-DLI plasma. Three antigens-C6orf130, MDS032, and ZFYVE19-were identified by both patients. Along with additional candidate antigens DAPK3, SERBP1, and OGFOD1, these proteins showed higher transcript and protein expression in B cells and CLL cells compared with normal peripheral blood mononuclear cells. DAPK3 and the shared antigens do not represent minor histocompatibility antigens, as their sequences are identical in both donor and tumor. Although ZFYVE19, DAPK3, and OGFOD1 elicited minimal antibody reactivity in 12 normal subjects and 12 chemotherapy-treated CLL patients, 5 of 12 CLL patients with clinical GvL responses were serologically reactive to these antigens. Moreover, antibody reactivity against these antigens was temporally correlated with clinical disease regression. These B-cell antigens represent promising biomarkers of effective anti-CLL immunity. Cancer Res; 70(4); 1344-55. (C) 2010 AACR. C1 [Wu, Catherine J.] Harvard Inst Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Hainz, Ursula; Biernacki, Melinda A.; Duke-Cohan, Jonathan S.; Alyea, Edwin P.; Canning, Christine M.; Soiffer, Robert J.; Ritz, Jerome; Wu, Catherine J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Liu, Fenglong; Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Cai, Ann; Duke-Cohan, Jonathan S.; Kutok, Jeffery L.; Alyea, Edwin P.; Soiffer, Robert J.; Ritz, Jerome; Wu, Catherine J.] Harvard Univ, Sch Med, Boston, MA USA. [Kutok, Jeffery L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Alyea, Edwin P.; Soiffer, Robert J.; Ritz, Jerome; Wu, Catherine J.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Marina, Ovidiu] William Beaumont Hosp, Transit Year Program, Royal Oak, MI 48072 USA. [Biernacki, Melinda A.] Univ Connecticut, Sch Med, Farmington, CT USA. RP Wu, CJ (reprint author), Harvard Inst Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Room 416,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM cwu@partners.org OI Duke-Cohan, Jonathan/0000-0002-9478-9609; Ritz, Jerome/0000-0001-5526-4669 FU Howard Hughes Medical Institute; NCI NIH HHS [P01 CA155258, 5R21CA115043-2, P01 CA078378, P50 CA100707, R21 CA115043, R21 CA132232, R21 CA132232-02] NR 48 TC 19 Z9 19 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2010 VL 70 IS 4 BP 1344 EP 1355 DI 10.1158/0008-5472.CAN-09-3143 PG 12 WC Oncology SC Oncology GA 607FY UT WOS:000278485700009 PM 20124481 ER PT J AU Terada, N Shimizu, Y Kamba, T Inoue, T Maeno, A Kobayashi, T Nakamura, E Kamoto, T Kanaji, T Maruyama, T Mikami, Y Toda, Y Matsuoka, T Okuno, Y Tsujimoto, G Narumiya, S Ogawa, O AF Terada, Naoki Shimizu, Yosuke Kamba, Tomomi Inoue, Takahiro Maeno, Atsushi Kobayashi, Takashi Nakamura, Eijiro Kamoto, Toshiyuki Kanaji, Toshiya Maruyama, Takayuki Mikami, Yoshiki Toda, Yoshinobu Matsuoka, Toshiyuki Okuno, Yasushi Tsujimoto, Gozoh Narumiya, Shuh Ogawa, Osamu TI Identification of EP4 as a Potential Target for the Treatment of Castration-Resistant Prostate Cancer Using a Novel Xenograft Model SO CANCER RESEARCH LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ANDROGEN RECEPTOR; COLORECTAL-CANCER; PROSTAGLANDIN E-2; INTESTINAL POLYPOSIS; ANTIGEN LEVELS; KNOCKOUT MICE; CELL-LINE; EXPRESSION; PROGRESSION AB More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type androgen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues confirmed that EP4 expression was higher in CRPC compared with hormone-naive prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the absence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC. Cancer Res; 70(4); 1606-15. (C) 2010 AACR. C1 [Ogawa, Osamu] Kyoto Univ, Grad Sch Med, Dept Urol, Sakyo Ku, Kyoto 6068507, Japan. [Mikami, Yoshiki] Kyoto Univ Hosp, Dept Diagnost Pathol, Kyoto 606, Japan. [Toda, Yoshinobu] Kyoto Univ, Grad Sch Med, Anat Ctr, Kyoto 6068507, Japan. [Matsuoka, Toshiyuki; Narumiya, Shuh] Kyoto Univ, Fac Med, Dept Pharmacol, Kyoto 6068507, Japan. [Okuno, Yasushi; Tsujimoto, Gozoh] Kyoto Univ, Grad Sch Pharmaceut Sci, Dept Genom Drug Discovery Sci, Kyoto 6068507, Japan. [Nakamura, Eijiro] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kamoto, Toshiyuki] Miyazaki Univ, Dept Urol, Miyazaki, Japan. [Kanaji, Toshiya; Maruyama, Takayuki] Ono Pharmaceut Co Ltd, Res Headquarters, Dev Res Labs, Osaka, Japan. RP Ogawa, O (reprint author), Kyoto Univ, Grad Sch Med, Dept Urol, Sakyo Ku, 54 Shogoinkawahara Cho, Kyoto 6068507, Japan. EM ogawao@kuhp.kyoto-u.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan FX Grant Support; Grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 48 TC 42 Z9 42 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2010 VL 70 IS 4 BP 1606 EP 1615 DI 10.1158/0008-5472.CAN-09-2984 PG 10 WC Oncology SC Oncology GA 607FY UT WOS:000278485700035 PM 20145136 ER PT J AU McDermott, U Pusapati, RV Christensen, JG Gray, NS Settleman, J AF McDermott, Ultan Pusapati, Raju V. Christensen, James G. Gray, Nathanael S. Settleman, Jeff TI Acquired Resistance of Non-Small Cell Lung Cancer Cells to MET Kinase Inhibition Is Mediated by a Switch to Epidermal Growth Factor Receptor Dependency SO CANCER RESEARCH LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; GASTROINTESTINAL STROMAL TUMORS; GEFITINIB RESISTANCE; IMATINIB RESISTANCE; DOMAIN MUTATIONS; AMPLIFICATION; SENSITIVITY; CARCINOMAS; THERAPY; PHASE AB Cancer cells harboring MET amplification display striking sensitivity to selective small molecule inhibitors of MET kinase, prompting their clinical evaluation. Similar to the experience with traditional therapeutics, most patients responding to treatment with such molecular targeted therapeutics ultimately relapse with drug-resistant disease. In this study we modeled acquired resistance to experimental MET kinase inhibitor PF2341066 in MET-amplified non-small cell lung carcinoma (NSCLC) cell lines to identify drug resistance mechanisms that may arise in clinic. We found that activation of the epidermal growth factor receptor (EGFR) pathway emerges as a resistance mechanism in MET-amplified cells after prolonged exposure to PF2341066. Whereas combined inhibition of MET and EGFR kinases in MET-dependent NSCLC cells did not enhance their initial sensitivity to PF2341066, this combination dramatically suppressed the eventual emergence of drug-resistant clones after prolonged drug exposure. Conversely, activation of the EGFR pathway increased the yield of PF2341066-resistant clones, confirming the significance of this pathway in conferring resistance. Our findings support an intimate relationship between the EGFR and MET signaling pathways in NSCLC, and they suggest that combination treatment with MET and EGFR kinase inhibitors may be beneficial in MET-amplified NSCLC by reducing selection for drug resistant clones. Cancer Res; 70(4); 1625-34. (C) 2010 AACR. C1 [Settleman, Jeff] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Therapeut,Canc Ctr, Charlestown, MA 02129 USA. [Christensen, James G.] Pfizer Global Res & Dev, La Jolla Labs, Oncol Res Unit, San Diego, CA USA. [Gray, Nathanael S.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Settleman, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Therapeut,Canc Ctr, 149 13th St, Charlestown, MA 02129 USA. EM Settleman@helix.mgh.harvard.edu OI McDermott, Ultan/0000-0001-9032-4700 FU NCI [P20 CA090578]; NIH [RO1 CA115830] FX NCI Specialized Programs of Research Excellence in Lung Cancer award P20 CA090578 and NIH RO1 CA115830 (J. Settleman). NR 26 TC 74 Z9 75 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2010 VL 70 IS 4 BP 1625 EP 1634 DI 10.1158/0008-5472.CAN-09-3620 PG 10 WC Oncology SC Oncology GA 607FY UT WOS:000278485700037 PM 20124471 ER PT J AU Witzke, C Don, CW Cubeddu, RJ Herrero-Garibi, J Pomerantsev, E Caldera, A McCarty, D Inglessis, I Palacios, IF AF Witzke, Christian Don, Creighton W. Cubeddu, Roberto J. Herrero-Garibi, Jesus Pomerantsev, Eugene Caldera, Angel McCarty, David Inglessis, Ignacio Palacios, Igor F. TI Impact of Rapid Ventricular Pacing During Percutaneous Balloon Aortic Valvuloplasty in Patients with Critical Aortic Stenosis: Should we be using it? SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE aortic valvuloplasty; rapid ventricular pacing, aortic stenosis, vascular complications ID EUROSCORE MULTINATIONAL DATABASE; EUROPEAN CARDIAC-SURGERY; CARDIOGENIC-SHOCK; ELDERLY PATIENTS; HEART-DISEASE; RISK-FACTORS; VALVES AB Background: Rapid ventricular pacing (RP) during percutaneous balloon aortic valvuloplasty (BAV) facilitates balloon positioning by preventing the "watermelon seeding" effect during balloon inflation. The clinical consequences of RP BAV have never been compared with standard BAV in which rapid pacing in not used. We evaluated the immediate results and in-hospital adverse events of patients with severe aortic stenosis (AS) undergoing BAV with and without RP. Methods: This is a retrospective study of patients with severe AS undergoing retrograde BAV. Patients who underwent BAV with RP were compared to those who did not receive RP during BAV. Procedural outcomes, complications, and in-hospital adverse events were compared between both groups. Stratified analyses were performed to evaluate RP in pre-specified subsets for confounding and effect modification. Results: Between January 2005 and December 2008, 111 consecutive patients underwent retrograde BAV at Massachusetts General Hospital. Sixty-seven patients underwent BAV with RP. Nearly 90% of patients were NYHA class III or IV and the mean AVA was 0.64 cm(2). Baseline characteristics and balloon sizes were similar in the two groups. The average post-BAV AVA was smaller in the RP group compared to the no-RP group (0.87 v. 1.02 cm(2), p = 0.02). Pre and post-cardiac output, in-hospital mortality, myocardial infarction, stroke, frequency of cardiopulmonary arrest, vasopressor use, and major complications were similar in the two groups. Conclusions: 1) RP allows precise balloon placement during BAV. 2) RP BAV is associated with lower post-BAV AVA. 3) RP BAV may be safely performed in patients with high-risk cardiac features. (C) 2009 Wiley-Liss, Inc. C1 [Witzke, Christian; Don, Creighton W.; Cubeddu, Roberto J.; Herrero-Garibi, Jesus; Pomerantsev, Eugene; Caldera, Angel; McCarty, David; Inglessis, Ignacio; Palacios, Igor F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Boston, MA USA. RP Witzke, C (reprint author), Fruit Strett, Boston, MA 02114 USA. EM cwitzke@partners.org NR 25 TC 27 Z9 29 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD FEB 15 PY 2010 VL 75 IS 3 BP 444 EP 452 DI 10.1002/ccd.22289 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 564QG UT WOS:000275230200029 PM 19937778 ER PT J AU Camidge, DR Herbst, RS Gordon, MS Eckhardt, SG Kurzrock, R Durbin, B Ing, J Tohnya, TM Sager, J Ashkenazi, A Bray, G Mendelson, D AF Camidge, D. Ross Herbst, Roy S. Gordon, Michael S. Eckhardt, S. Gail Kurzrock, Razelle Durbin, Blythe Ing, Josephine Tohnya, Tanyifor M. Sager, Jason Ashkenazi, Avi Bray, Gordon Mendelson, David TI A Phase I Safety and Pharmacokinetic Study of the Death Receptor 5 Agonistic Antibody PRO95780 in Patients with Advanced Malignancies SO CLINICAL CANCER RESEARCH LA English DT Article ID APOPTOSIS-INDUCING LIGAND; LUNG-TUMOR GROWTH; MONOCLONAL-ANTIBODY; IMPROVE SURVIVAL; SOLID TUMORS; CELL-LINES; CANCER; APOMAB; CHEMOTHERAPY; RESISTANCE AB Purpose: PRO95780 is a fully human IgG1 monoclonal antibody that triggers the extrinsic apoptosis pathway through death receptor 5. This first-in-human study assessed the safety, tolerability, pharmacokinetics, and any early evidence of efficacy of PRO95780 in patients with advanced malignancies. Experimental Design: Target concentrations were predicted to occur at 10 mg/kg. Patients received up to eight cycles of PRO95780 i.v. using a 3+3 dose escalation design at 1 to 20 mg/kg every 14 days (every 28 days in cycle 1; stage 1), with cohort expansion at either the maximum tolerated dose or 10 mg/kg, whichever was lower (stage 2). Patients were evaluated for response every other cycle. Results: The maximum tolerated dose was not reached within this study. Four (8%) of 50 patients reported adverse events of greater than grade 2 at least possibly related to PRO95780, including 2 patients with reversible grade 3 transaminase elevation. The mean terminal half-life was 8.8 to 19.3 days, with dose-dependent increases in exposure (peak plasma concentration and area under the concentration) across 1 to 15 mg/kg. Most patients treated with 10 mg/kg or above achieved trough concentration above the target efficacious concentration at day 15 with moderate accumulation after multiple doses. No objective responses occurred, although three minor responses were observed in patients with colorectal and granulosa cell ovarian cancers (each treated with 4 mg/kg) and chondrosarcoma (10 mg/kg). Conclusions: PRO95780 is safe and well tolerated at doses up to 20 mg/kg. Evidence of activity was noted in several different tumor types at 4 and 10 mg/kg. Pharmacokinetic analysis supports a dosing regimen of 10 to 15 mg/kg every 2 to 3 weeks. Clin Cancer Res; 16(4); 1256-63. (C) 2010 AACR. C1 [Camidge, D. Ross] Univ Colorado Denver, Dept Med Oncol, Aurora, CO 80045 USA. [Herbst, Roy S.; Kurzrock, Razelle] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Gordon, Michael S.; Mendelson, David] Premiere Oncol Arizona, Scottsdale, AZ USA. [Durbin, Blythe; Ing, Josephine; Tohnya, Tanyifor M.; Ashkenazi, Avi; Bray, Gordon] Genentech Inc, San Francisco, CA 94080 USA. [Sager, Jason] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Camidge, DR (reprint author), Univ Colorado Denver, Dept Med Oncol, 1665 N Ursula St,Room 2256,POB 6510,Mail Stop F-7, Aurora, CO 80045 USA. EM ross.camidge@uchsc.edu NR 29 TC 91 Z9 92 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2010 VL 16 IS 4 BP 1256 EP 1263 DI 10.1158/1078-0432.CCR-09-1267 PG 8 WC Oncology SC Oncology GA 607ZG UT WOS:000278545200019 PM 20145186 ER PT J AU Skylar, A Hong, FX Chory, J Weigel, D Wu, XL AF Skylar, Anna Hong, Fangxin Chory, Joanne Weigel, Detlef Wu, Xuelin TI STIMPY mediates cytokinin signaling during shoot meristem establishment in Arabidopsis seedlings SO DEVELOPMENT LA English DT Article DE Arabidopsis; STIMPY; Cytokinin signaling; Meristem ID GENE-EXPRESSION SYSTEM; B RESPONSE REGULATORS; APICAL-BASAL AXIS; ROOT-MERISTEM; TRANSCRIPTION FACTORS; CELL-DIFFERENTIATION; HOBBIT GENE; PLANTS; MAINTENANCE; THALIANA AB The establishment of the primary meristems through proliferation after germination is essential for plant post-embryonic development. Cytokinins have long been considered a key regulator of plant cell division. Here we show that cytokinins are essential for early seedling development of Arabidopsis. Loss of cytokinin perception leads to a complete failure of meristem establishment and growth arrest after germination. We also present evidence that cytokinin signaling is involved in activation of the homeobox gene STIMPY (STIP or WOX9) expression in meristematic tissues, which is essential for maintaining the meristematic fate. Cytokinin-independent STIP expression is able to partially compensate for the shoot apical meristem growth defects in mutants that cannot sense cytokinin. These findings identify a new branch of the cytokinin signaling network, linking cytokinin to the process of meristem and seedling establishment. C1 [Skylar, Anna; Wu, Xuelin] Univ So Calif, Los Angeles, CA 90089 USA. [Hong, Fangxin] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Chory, Joanne; Weigel, Detlef] Salk Inst Biol Studies, Plant Biol Lab, La Jolla, CA 92037 USA. [Chory, Joanne] Salk Inst Biol Studies, Howard Hughes Med Inst, La Jolla, CA 92037 USA. [Weigel, Detlef] Max Planck Inst Dev Biol, Dept Mol Biol, D-72076 Tubingen, Germany. RP Wu, XL (reprint author), Univ So Calif, Los Angeles, CA 90089 USA. EM xuelinwu@usc.edu RI Weigel, Detlef/C-1418-2008 OI Weigel, Detlef/0000-0002-2114-7963 FU NIH [GM62932] FX We thank Eric Schaller for comments and suggestions; Liang Chen for her help in statistical analysis; the Arabidopsis stock center for providing the ARR5::GUS reporter line; Tatsuo Kakimoto for the ahk2-2 ahk3-3/+cre1-12 seeds; Takafumi Yamashino for the arr1-3 arr10-5 arr12-1 seeds; Wolfram Brenner and Thomas Schmulling for the CEL files of the BA treatments; Jihoon Ahn for the pJHAG transformation vector; Norm Arnheim and the Arnheim lab for their help in qPCR; and Steve Ruzin and Denise Schichnes at the UC Berkeley CNR Biological Imaging Facility for their help in microwave processing. Work at the Salk Institute was supported by NIH grant GM62932. J. C. is an investigator of the Howard Hughes Medical Institute and D. W. is a Director of the MaxPlanck Institute. Deposited in PMC for release after 6 months. NR 50 TC 33 Z9 38 U1 1 U2 14 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 FEB 15 PY 2010 VL 137 IS 4 BP 541 EP 549 DI 10.1242/dev.041426 PG 9 WC Developmental Biology SC Developmental Biology GA 549BR UT WOS:000274016900002 PM 20110319 ER PT J AU Meeker, JD Calafat, AM Hauser, R AF Meeker, John D. Calafat, Antonia M. Hauser, Russ TI Urinary Bisphenol A Concentrations in Relation to Serum Thyroid and Reproductive Hormone Levels in Men from an Infertility Clinic SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID IN-VITRO; INHIBIN-B; MICROARRAY ANALYSIS; HUMAN EXPOSURE; SERTOLI-CELLS; MICE; RATS; SPERMATOGENESIS; ANDROGEN; SPERM AB Human exposure to bisphenol A (BPA) is widespread. Animal studies have demonstrated that BPA can alter endocrine function, but human studies are limited. For the present study, we measured urinary BPA concentrations and serum thyroid and reproductive hormone levels in 167 men recruited through an infertility clinic. BPA was detected in 89% of urine samples with a median (range) of 1.3 (<0.4 - 36.4) ng/mL. In multivariable regression models adjusted for potential confounders, BPA concentrations in urine collected on the same day as a blood sample were inversely associated with serum levels of inhibin B and estradiol-testosterone ratio (E-2:T) and positively associated with follicle-stimulating hormone (FSH) and FSH:inhibin B ratio. Because BPA is metabolized quickly and multiple urine measures may better reflect exposure than a single measure, we also considered among a subset of the men the BPA concentrations in repeated urine samples collected weeks or months following serum sample collection. In these analyses, the effect estimates remained consistent for FSH and E-2:T but were somewhat weakened for inhibin B. In addition,we observed inverse relationships between urinary BPA concentrations and free androgen index (ratio of testosterone to sex hormone binding globulin), estradiol, and thyroid stimulating hormone. Our results suggest that urinary BPA concentrations may be associated with altered hormone levels in men, but these findings need to be substantiated through further research. C1 [Meeker, John D.] Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Calafat, Antonia M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Hauser, Russ] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, Androl Lab, Boston, MA 02114 USA. [Hauser, Russ] Massachusetts Gen Hosp, Vitro Fertilizat Unit, Boston, MA 02114 USA. RP Meeker, JD (reprint author), Univ Michigan, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. EM meekerj@umich.edu OI zaraat, javad/0000-0001-5341-7481; Meeker, John/0000-0001-8357-5085 FU National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) [ES009718, ES00002] FX Work supported by grants ES009718 and ES00002 from the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). We gratefully acknowledge Xiaoyun Ye, Amber Bishop, Tao Jia, and Jack Reidy (CDC, Atlanta, GA) for measuring the urinary concentrations of BPA. We thank the study research nurses, Jennifer Ford and Myra Keller, and are especially appreciative of the willingness of study subjects to participate. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. NR 45 TC 96 Z9 101 U1 4 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X EI 1520-5851 J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD FEB 15 PY 2010 VL 44 IS 4 BP 1458 EP 1463 DI 10.1021/es9028292 PG 6 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA 553EC UT WOS:000274347800048 PM 20030380 ER PT J AU Li, G Margueron, R Ku, MC Chambon, P Bernstein, BE Reinberg, D AF Li, Gang Margueron, Raphael Ku, Manching Chambon, Pierre Bernstein, Bradley E. Reinberg, Danny TI Jarid2 and PRC2, partners in regulating gene expression SO GENES & DEVELOPMENT LA English DT Article DE Polycomb; chromatin; Histone methylation; Jarid2 ID EMBRYONIC STEM-CELLS; HISTONE METHYLTRANSFERASE ACTIVITY; POLYCOMB-REPRESSIVE COMPLEX-2; TARGET GENES; DEVELOPMENTAL REGULATORS; CARDIAC DEVELOPMENT; CHROMATIN-STRUCTURE; NUCLEAR-PROTEIN; JUMONJI GENE; IN-VIVO AB The Polycomb group proteins foster gene repression profiles required for proper development and unimpaired adulthood, and comprise the components of the Polycomb-Repressive Complex 2 (PRC2) including the histone H3 Lys 27 (H3K27) methyltransferase Ezh2. How mammalian PRC2 accesses chromatin is unclear. We found that Jarid2 associates with PRC2 and stimulates its enzymatic activity in vitro. Jarid2 contains a Jumonji C domain, but is devoid of detectable histone demethylase activity. Instead, its artificial recruitment to a promoter in vivo resulted in corecruitment of PRC2 with resultant increased levels of di- and trimethylation of H3K27 (H3K27me2/3). Jarid2 colocalizes with Ezh2 and MTF2, a homolog of Drosophila Pcl, at endogenous genes in embryonic stem (ES) cells. Jarid2 can bind DNA and its recruitment in ES cells is interdependent with that of PRC2, as Jarid2 knockdown reduced PRC2 at its target promoters, and ES cells devoid of the PRC2 component EED are deficient in Jarid2 promoter access. In addition to the well-documented defects in embryonic viability upon down-regulation of Jarid2, ES cell differentiation is impaired, as is Oct4 silencing. C1 [Li, Gang; Ku, Manching; Bernstein, Bradley E.; Reinberg, Danny] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. [Li, Gang; Margueron, Raphael; Reinberg, Danny] NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. [Ku, Manching; Bernstein, Bradley E.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Ku, Manching; Bernstein, Bradley E.] Harvard Univ, Cambridge, MA 02142 USA. [Ku, Manching; Bernstein, Bradley E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Chambon, Pierre] Univ Strasbourg, INSERM, CNRS, ICS,IGBMC,Dept Funct Genom, F-67404 Illkirch Graffenstaden, France. RP Reinberg, D (reprint author), NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. EM reinbd01@nyumc.org RI Margueron, Raphael/B-9996-2015; LI, GANG/O-1409-2016 OI Margueron, Raphael/0000-0002-9093-7977; LI, GANG/0000-0003-3203-8567 FU NIH [GM64844, R37GM37120]; HHMI FX We are grateful to Dr. L. Vales for comments on the manuscript and active discussions. This work was supported by grants from the NIH (GM64844 and R37GM37120 to D. R.) and by HHMI (to B. B. and D. R.). NR 50 TC 238 Z9 240 U1 2 U2 24 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 15 PY 2010 VL 24 IS 4 BP 368 EP 380 DI 10.1101/gad.1886410 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 556GD UT WOS:000274577100006 PM 20123894 ER PT J AU Seong, IS Woda, JM Song, JJ Lloret, A Abeyrathne, PD Woo, CJ Gregory, G Lee, JM Wheeler, VC Walz, T Kingston, RE Gusella, JF Conlon, RA MacDonald, ME AF Seong, Ihn Sik Woda, Juliana M. Song, Ji-Joon Lloret, Alejandro Abeyrathne, Priyanka D. Woo, Caroline J. Gregory, Gillian Lee, Jong-Min Wheeler, Vanessa C. Walz, Thomas Kingston, Robert E. Gusella, James F. Conlon, Ronald A. MacDonald, Marcy E. TI Huntingtin facilitates polycomb repressive complex 2 SO HUMAN MOLECULAR GENETICS LA English DT Article ID HISTONE METHYLTRANSFERASE ACTIVITY; DISEASE GENE HOMOLOG; SECONDARY STRUCTURE; IN-VIVO; EMBRYONIC LETHALITY; MOUSE DEVELOPMENT; PROTEIN-SEQUENCE; IMPORTIN-BETA; REPEAT; POLYGLUTAMINE AB Huntington's disease (HD) is caused by expansion of the polymorphic polyglutamine segment in the huntingtin protein. Full-length huntingtin is thought to be a predominant HEAT repeat alpha-solenoid, implying a role as a facilitator of macromolecular complexes. Here we have investigated huntingtin's domain structure and potential intersection with epigenetic silencer polycomb repressive complex 2 (PRC2), suggested by shared embryonic deficiency phenotypes. Analysis of a set of full-length recombinant huntingtins, with different polyglutamine regions, demonstrated dramatic conformational flexibility, with an accessible hinge separating two large alpha-helical domains. Moreover, embryos lacking huntingtin exhibited impaired PRC2 regulation of Hox gene expression, trophoblast giant cell differentiation, paternal X chromosome inactivation and histone H3K27 tri-methylation, while full-length endogenous nuclear huntingtin in wild-type embryoid bodies (EBs) was associated with PRC2 subunits and was detected with trimethylated histone H3K27 at Hoxb9. Supporting a direct stimulatory role, full-length recombinant huntingtin significantly increased the histone H3K27 tri-methylase activity of reconstituted PRC2 in vitro, and structure-function analysis demonstrated that the polyglutamine region augmented full-length huntingtin PRC2 stimulation, both in Hdh(Q111) EBs and in vitro, with reconstituted PRC2. Knowledge of full-length huntingtin's alpha-helical organization and role as a facilitator of the multi-subunit PRC2 complex provides a novel starting point for studying PRC2 regulation, implicates this chromatin repressive complex in a neurodegenerative disorder and sets the stage for further study of huntingtin's molecular function and the impact of its modulatory polyglutamine region. C1 [Seong, Ihn Sik; Woda, Juliana M.; Lloret, Alejandro; Gregory, Gillian; Lee, Jong-Min; Wheeler, Vanessa C.; Gusella, James F.; MacDonald, Marcy E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Song, Ji-Joon; Woo, Caroline J.; Kingston, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Dept Mol Biol, Dept Genet,Med Sch, Boston, MA 02114 USA. [Walz, Thomas] Harvard Univ, Sch Med, Dept Cell Biol, Howard Hughes Med Inst, Boston, MA 02115 USA. [Conlon, Ronald A.] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. RP MacDonald, ME (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Simches Res Bldg,Room 5414,185 Cambridge St, Boston, MA 02421 USA. EM macdonam@helix.mgh.harvard.edu RI Song, Ji-Joon/C-1721-2011 FU National Institutes of Health NINDS [NS32765, NS16367, NS49206]; Huntington's Disease Society of America Coalition for the Cure; Hereditary Disease Foundation FX This work was supported by the National Institutes of Health NINDS grants NS32765, NS16367, NS49206; the Huntington's Disease Society of America Coalition for the Cure; and an anonymous donor. T. W. is an investigator of the Howard Hughes Medical Institute. J. M. W. received the Milton Wexler Postdoctoral Fellowship from the Hereditary Disease Foundation. J.- J. S. was a recipient of the Jane Coffin Childs Memorial Fund for Medical Research. NR 59 TC 53 Z9 54 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 15 PY 2010 VL 19 IS 4 BP 573 EP 583 DI 10.1093/hmg/ddp524 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 545AA UT WOS:000273702200002 PM 19933700 ER PT J AU Karp, DR Marthandan, N Marsh, SGE Ahn, C Arnett, FC DeLuca, DS Diehl, AD Dunivin, R Eilbeck, K Feolo, M Guidry, PA Helmberg, W Lewis, S Mayes, MD Mungall, C Natale, DA Peters, B Petersdorf, E Reveille, JD Smith, B Thomson, G Waller, MJ Scheuermann, RH AF Karp, David R. Marthandan, Nishanth Marsh, Steven G. E. Ahn, Chul Arnett, Frank C. DeLuca, David S. Diehl, Alexander D. Dunivin, Raymond Eilbeck, Karen Feolo, Michael Guidry, Paula A. Helmberg, Wolfgang Lewis, Suzanna Mayes, Maureen D. Mungall, Chris Natale, Darren A. Peters, Bjoern Petersdorf, Effie Reveille, John D. Smith, Barry Thomson, Glenys Waller, Matthew J. Scheuermann, Richard H. TI Novel sequence feature variant type analysis of the HLA genetic association in systemic sclerosis SO HUMAN MOLECULAR GENETICS LA English DT Article ID HLA-DQB1 1ST DOMAIN; DNA TOPOISOMERASE-I; T-CELL-RECEPTOR; AUTOANTIBODY RESPONSE; RHEUMATOID-ARTHRITIS; HAPLOTYPE METHOD; AMINO-ACIDS; SCLERODERMA; ANTIBODIES; PEPTIDE AB We describe a novel approach to genetic association analyses with proteins sub-divided into biologically relevant smaller sequence features (SFs), and their variant types (VTs). SFVT analyses are particularly informative for study of highly polymorphic proteins such as the human leukocyte antigen (HLA), given the nature of its genetic variation: the high level of polymorphism, the pattern of amino acid variability, and that most HLA variation occurs at functionally important sites, as well as its known role in organ transplant rejection, autoimmune disease development and response to infection. Further, combinations of variable amino acid sites shared by several HLA alleles (shared epitopes) are most likely better descriptors of the actual causative genetic variants. In a cohort of systemic sclerosis patients/controls, SFVT analysis shows that a combination of SFs implicating specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk. C1 [Karp, David R.] UT SW Med Ctr, Div Rheumat Dis, Dept Internal Med, Dallas, TX 75390 USA. [Marthandan, Nishanth; Guidry, Paula A.; Scheuermann, Richard H.] UT SW Med Ctr, Dept Pathol, Dallas, TX 75390 USA. [Marsh, Steven G. E.; Waller, Matthew J.] Royal Free Hosp, Anthony Nolan Res Inst, London NW3 2QG, England. [Ahn, Chul; Scheuermann, Richard H.] UT SW Med Ctr, Dept Clin Sci, Dallas, TX 75390 USA. [Arnett, Frank C.; Mayes, Maureen D.; Reveille, John D.] UT Houston, Dept Internal Med, Houston, TX 77030 USA. [DeLuca, David S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Diehl, Alexander D.] Jackson Lab, Bar Harbor, ME 04609 USA. [Dunivin, Raymond; Feolo, Michael] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Eilbeck, Karen] Univ Utah, Dept Human Genet, Salt Lake City, UT 84122 USA. [Helmberg, Wolfgang] Med Univ Graz, Dept Blood Grp Serol & Transfus Med, A-8036 Graz, Austria. [Lewis, Suzanna; Mungall, Chris] Univ Calif Berkeley, Lawrence Berkeley Lab, Berkeley, CA 94720 USA. [Natale, Darren A.] Georgetown Univ, Med Ctr, Washington, DC 20057 USA. [Peters, Bjoern] La Jolla Inst Allergy & Immunol, Ctr Infect Dis, La Jolla, CA 92109 USA. [Petersdorf, Effie] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. [Smith, Barry] SUNY Buffalo, Dept Philosophy, Buffalo, NY 14203 USA. [Smith, Barry] SUNY Buffalo, New York State Ctr Excellence Bioinformat & Life, Buffalo, NY 14203 USA. [Thomson, Glenys] Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. RP Karp, DR (reprint author), UT SW Med Ctr, Div Rheumat Dis, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM david.karp@utsouthwestern.edu RI Diehl, Alexander/G-9883-2016; Smith, Barry/A-9525-2011; OI Diehl, Alexander/0000-0001-9990-8331; Smith, Barry/0000-0003-1384-116X; Lewis, Suzanna/0000-0002-8343-612X; Scheuermann, Richard/0000-0003-1355-892X FU National Institutes of Health [N01-AI40076, N01-AR02251, P50-AR054144, UL1-RR024148, UL1-RR024982] FX This work was supported by the National Institutes of Health [contracts N01-AI40076 and N01-AR02251; grants P50-AR054144, UL1-RR024148 and UL1-RR024982]. NR 39 TC 19 Z9 19 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 15 PY 2010 VL 19 IS 4 BP 707 EP 719 DI 10.1093/hmg/ddp521 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 545AA UT WOS:000273702200013 PM 19933168 ER PT J AU Boboila, C Yan, C Wesemann, DR Jankovic, M Wang, JH Manis, J Nussenzweig, A Nussenzweig, M Alt, FW AF Boboila, Cristian Yan, Catherine Wesemann, Duane R. Jankovic, Mila Wang, Jing H. Manis, John Nussenzweig, Andre Nussenzweig, Michel Alt, Frederick W. TI Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID STRAND BREAK REPAIR; DEPENDENT PROTEIN-KINASE; B-CELL DEVELOPMENT; V(D)J RECOMBINATION; SOMATIC HYPERMUTATION; DEFICIENT LYMPHOCYTES; EMBRYONIC LETHALITY; MAMMALIAN-CELLS; IV; KU80 AB The classical nonhomologous end-joining (C-NHEJ) DNA double-strand break (DSB) repair pathway employs the Ku70/80 complex (Ku) for DSB recognition and the XRCC4/DNA ligase 4 (Lig4) complex for ligation. During IgH class switch recombination (CSR) in B lymphocytes, switch (S) region DSBs are joined by C-NHEJ to form junctions either with short microhomologies (MHs; "MH-mediated" joins) or no homologies ("direct" joins). In the absence of XRCC4 or Lig4, substantial CSR occurs via "alternative" end-joining (A-EJ) that generates largely MH-mediated joins. Because upstream C-NHEJ components remain in XRCC4- or Lig4-deficient B cells, residual CSR might be catalyzed by C-NHEJ using a different ligase. To address this, we have assayed for CSR in B cells deficient for Ku70, Ku80, or both Ku70 and Lig4. Ku70- or Ku80-deficient B cells have reduced, but still substantial, CSR. Strikingly, B cells deficient for both Ku plus Lig4 undergo CSR similarly to Ku-deficient B cells, firmly demonstrating that an A-EJ pathway distinct from C-NHEJ can catalyze CSR end-joining. Ku-deficient or Ku-plus Lig4-deficient B cells are also biased toward MH-mediated CSR joins; but, in contrast to XRCC4- or Lig4-deficient B cells, generate substantial numbers of direct CSR joins. Our findings suggest that more than one form of A-EJ can function in CSR. C1 [Boboila, Cristian; Wesemann, Duane R.; Wang, Jing H.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Manis, John] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Boboila, Cristian; Wesemann, Duane R.; Wang, Jing H.; Manis, John; Alt, Frederick W.] Childrens Hosp, Boston, MA 02115 USA. [Boboila, Cristian; Wesemann, Duane R.; Wang, Jing H.; Alt, Frederick W.] Beth Israel Deaconess Med Ctr, Immune Dis Inst, Boston, MA 02115 USA. [Boboila, Cristian; Wesemann, Duane R.; Wang, Jing H.; Nussenzweig, Michel; Alt, Frederick W.] Beth Israel Deaconess Med Ctr, Howard Hughes Med Inst, Boston, MA 02115 USA. [Yan, Catherine] Beth Israel Deaconess Med Ctr, Div Expt Pathol, Dept Pathol, Boston, MA 02115 USA. [Wesemann, Duane R.] Brigham & Womens Hosp, Dept Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Nussenzweig, Andre] NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. [Nussenzweig, Andre] NIH, Bethesda, MD 20892 USA. [Jankovic, Mila; Nussenzweig, Michel] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu RI Wang, Jing/M-7813-2015 OI Wang, Jing/0000-0003-4343-2527 FU National Institutes of Health [AI031541, CA092625, AI037526, T32CA09382-26]; Cancer Research Institute FX This work was supported by National Institutes of Health grants AI031541 and CA092625 to FWA, NIH grant AI037526 to MN and T32CA09382-26 to JHW. CB is supported by a Cancer Research Institute training grant. FWA and MN are investigators of the Howard Hughes Medical Institute. NR 50 TC 77 Z9 78 U1 1 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 15 PY 2010 VL 207 IS 2 BP 417 EP 427 DI 10.1084/jem.20092449 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 555FO UT WOS:000274493900017 PM 20142431 ER PT J AU Riol-Blanco, L Lazarevic, V Awasthi, A Mitsdoerffer, M Wilson, BS Croxford, A Waisman, A Kuchroo, VK Glimcher, LH Oukka, M AF Riol-Blanco, Lorena Lazarevic, Vanja Awasthi, Amit Mitsdoerffer, Meike Wilson, Brian S. Croxford, Andy Waisman, Ari Kuchroo, Vijay K. Glimcher, Laurie H. Oukka, Mohamed TI IL-23 Receptor Regulates Unconventional IL-17-Producing T Cells That Control Bacterial Infections SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LISTERIA-MONOCYTOGENES INFECTION; COLONY-STIMULATING FACTOR; INTERFERON-GAMMA; IL-17 PRODUCTION; HOST-DEFENSE; IN-VIVO; IMMUNE-RESPONSE; INNATE IMMUNITY; CUTTING EDGE; REQUIREMENT AB IL-23 plays an important role in autoimmune tissue inflammation and induces the generation of not fully characterized effector cells that mediate protection against pathogens. In this paper, we established the essential role of IL-23R in the host response against intracellular pathogens. IL-23 was critical for the expansion or maintenance of gamma delta and double negative (DN) alpha beta T cells. These cells were rapidly recruited to the site of infection and produced large amounts of IL-17, IFN-gamma, and TNF-alpha. Notably, DN T cells transferred into L monocytogenes-infected RAG2(-/-) mice prevented bacterial growth, confirming their protective role against intracellular pathogens. Our results show that IL-23 regulates the function of IL-17-producing gamma delta and DN T cells, two essential components of the early protective immune response directed against intracellular pathogens. The Journal of Immunology, 2010, 184: 1710-1720. C1 [Oukka, Mohamed] Seattle Childrens Res Inst, Seattle, WA 98105 USA. [Riol-Blanco, Lorena; Awasthi, Amit; Mitsdoerffer, Meike; Kuchroo, Vijay K.] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Glimcher, Laurie H.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Lazarevic, Vanja; Glimcher, Laurie H.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Wilson, Brian S.] Massachusetts Gen Hosp, Diabet Res Labs, Cambridge, MA 02139 USA. [Croxford, Andy; Waisman, Ari] Johannes Gutenberg Univ Mainz, Dept Med 1, D-6500 Mainz, Germany. [Oukka, Mohamed] Univ Washington, Sch Med, Dept Immunol, Seattle, WA 98101 USA. RP Oukka, M (reprint author), Seattle Childrens Res Inst, 1900 9th Ave, Seattle, WA 98105 USA. EM moukka@u.washington.edu RI Waisman, Ari/C-7383-2015 OI Waisman, Ari/0000-0003-4304-8234 FU National Institutes of Health [R01AI073542-01, 1R01NS045937-01, 2R01NS35685-06, 2R37NS30843-11, 1R01A144880-03, 2P01A139671-07, 1P01NS38037-04, 1R01NS046414, AI32412, P01 AI56296]; National Multiple Sclerosis Society [RG-2571-D-9, RG-3882-A-1]; Juvenile Diabetes Research Foundation Center for Immunological Tolerance at Harvard Medical School the National Institutes of Health; Ellison Medical Foundation; Human Frontiers Science Program; Irvington Institute; National Multiple Sclerosis Society; Deutsche Forschungsgemeinschaft FX This work was supported by National Institutes of Health Grants R01AI073542-01 (to M.O.), 1R01NS045937-01, 2R01NS35685-06, 2R37NS30843-11, 1R01A144880-03, 2P01A139671-07, 1P01NS38037-04, and 1R01NS046414 (to V.K.K.), AI32412 and P01 AI56296 (to L.H.G.); National Multiple Sclerosis Society Grants RG-2571-D-9 (to V.K.K.) and RG-3882-A-1 (to M.O.); the Juvenile Diabetes Research Foundation Center for Immunological Tolerance at Harvard Medical School the National Institutes of Health Javits Neuroscience Investigator Award (to V.K.K.): the Ellison Medical Foundation (to L.H.G); a postdoctoral fellowship from the Human Frontiers Science Program (to L. R.-B.); a fellowship from the Irvington Institute (to V.L.); a postdoctoral fellowship from the National Multiple Sclerosis Society (to A.A.) and the Deutsche Forschungsgemeinschaft (to M.M.). NR 45 TC 64 Z9 64 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 FEB 15 PY 2010 VL 184 IS 4 BP 1710 EP 1720 DI 10.4049/jimmunol.0902796 PG 11 WC Immunology SC Immunology GA 556IU UT WOS:000274585100006 PM 20083652 ER PT J AU DeKruyff, RH Bu, X Ballesteros, A Santiago, C Chim, YLE Lee, HH Karisola, P Pichavant, M Kaplan, GG Umetsu, DT Freeman, GJ Casasnovas, JM AF DeKruyff, Rosemarie H. Bu, Xia Ballesteros, Angela Santiago, Cesar Chim, Yee-Ling E. Lee, Hyun-Hee Karisola, Piia Pichavant, Muriel Kaplan, Gerardo G. Umetsu, Dale T. Freeman, Gordon J. Casasnovas, Jose M. TI T Cell/Transmembrane, Ig, and Mucin-3 Allelic Variants Differentially Recognize Phosphatidylserine and Mediate Phagocytosis of Apoptotic Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TIM GENE FAMILY; IMMUNE-RESPONSES; IN-VIVO; PERIPHERAL TOLERANCE; AIRWAY INFLAMMATION; AUTOIMMUNE-DISEASE; ACTIVATION; RECEPTOR; MECHANISMS; EXPOSURE AB T cell/transmembrane, Ig, and mucin (TIM) proteins, identified using a congenic mouse model of asthma, critically regulate innate and adaptive immunity. TIM-1 and TIM-4 are receptors for phosphatidylserine (PtdSer), exposed on the surfaces of apoptotic cells. Herein, we show with structural and biological studies that TIM-3 is also a receptor for PtdSer that binds in a pocket on the N-terminal IgV domain in coordination with a calcium ion. The TIM-3/PtdSer structure is similar to that of TIM-4/PtdSer, reflecting a conserved PtdSer binding mode by TIM family members. Fibroblastic cells expressing mouse or human TIM-3 bound and phagocytosed apoptotic cells, with the BALB/c allelic variant of mouse TIM-3 showing a higher capacity than the congenic C.D2 Es-Hba-allelic variant. These functional differences were due to structural differences in the BC loop of the IgV domain of the TIM-3 polymorphic variants. In contrast to fibroblastic cells, T or B cells expressing TIM-3 formed conjugates with but failed to engulf apoptotic cells. Together these findings indicate that TIM-3-expressing cells can respond to apoptotic cells, but the consequence of TIM-3 engagement of PtdSer depends on the polymorphic variants of and type of cell expressing TIM-3. These findings establish a new paradigm for TIM proteins as PtdSer receptors and unify the function of the TIM gene family, which has been associated with asthma and autoimmunity and shown to modulate peripheral tolerance. The Journal of Immunology, 2010,184: 1918-1930. C1 [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [DeKruyff, Rosemarie H.; Chim, Yee-Ling E.; Lee, Hyun-Hee; Karisola, Piia; Pichavant, Muriel; Umetsu, Dale T.] Harvard Univ, Sch Med, Div Immunol, Childrens Hosp Boston, Cambridge, MA 02138 USA. [DeKruyff, Rosemarie H.; Chim, Yee-Ling E.; Lee, Hyun-Hee; Karisola, Piia; Pichavant, Muriel; Umetsu, Dale T.] Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA. [Bu, Xia; Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Ballesteros, Angela; Santiago, Cesar; Casasnovas, Jose M.] Consejo Super Invest Cient, Ctr Nacl Biotecnol, Madrid, Spain. [Kaplan, Gerardo G.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Freeman, GJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM gordon_freeman@dfci.harvard.edu 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 [P01 AI054456, HL069507]; Ministerio de Ciencia e Innovacion [BFU2005-05972, BFU2008-00971] FX This work was supported by National Institutes of Health Grants P01 AI054456 (to D.T.U., G.J.F., R.H.D., and G.G.K.) and HL069507 (to R.H.D.) and Ministerio de Ciencia e Innovacion Grants BFU2005-05972 and BFU2008-00971 (to J.M.C.). NR 46 TC 79 Z9 85 U1 0 U2 11 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2010 VL 184 IS 4 BP 1918 EP 1930 DI 10.4049/jimmunol.0903059 PG 13 WC Immunology SC Immunology GA 556IU UT WOS:000274585100028 PM 20083673 ER PT J AU Lombardi, V Stock, P Singh, AK Kerzerho, J Yang, W Sullivan, BA Li, XM Shiratsuchi, T Hnatiuk, NE Howell, AR Yu, KOA Porcelli, SA Tsuji, M Kronenberg, M Wilson, SB Akbari, O AF Lombardi, Vincent Stock, Philippe Singh, Abinav K. Kerzerho, Jerome Yang, Wen Sullivan, Barbara A. Li, Xiangming Shiratsuchi, Takayuki Hnatiuk, Nathan E. Howell, Amy R. Yu, Karl O. A. Porcelli, Steven A. Tsuji, Moriya Kronenberg, Mitchell Wilson, S. Brian Akbari, Omid TI A CD1d-Dependent Antagonist Inhibits the Activation of Invariant NKT Cells and Prevents Development of Allergen-Induced Airway Hyperreactivity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID KILLER T-CELLS; ANTIGEN PRESENTATION; EXPERIMENTAL ASTHMA; MOUSE MODEL; RECOGNITION; LIGAND; EXPOSURE; CD1D; HYPERRESPONSIVENESS; INFLAMMATION AB The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyperreactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidyl-ethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of alpha-galactosylceramide (alpha-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to alpha-GalCer and competes with alpha-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the alpha-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma. The Journal of Immunology, 2010,184: 2107-2115. C1 [Akbari, Omid] Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Div Mol Microbiol & Immunol, Los Angeles, CA 90033 USA. [Stock, Philippe] Univ Hosp Charite, Dept Pediat Pneumol & Immunol, Berlin, Germany. [Yang, Wen; Wilson, S. Brian] Harvard Univ, Sch Med, Diabet Res Labs, Massachusetts Gen Hosp, Cambridge, MA 02139 USA. [Sullivan, Barbara A.; Kronenberg, Mitchell] La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. [Li, Xiangming; Shiratsuchi, Takayuki; Tsuji, Moriya] Rockefeller Univ, HIV & Malaria Vaccine Program, Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. [Hnatiuk, Nathan E.; Howell, Amy R.] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA. [Yu, Karl O. A.; Porcelli, Steven A.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. RP Akbari, O (reprint author), Univ So Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Div Mol Microbiol & Immunol, NRT 5505,1450 Biggy St, Los Angeles, CA 90033 USA. EM bwilson@rics.bwh.harvard.edu; akbari@usc.edu OI Tsuji, Moriya/0000-0001-8587-277X FU National Institutes of Health Public Health Service [R01 AI066020, R37 AI71922, RO1 AI45889]; German Research Foundation [STO 467/4-2] FX This work was supported by the National Institutes of Health Public Health Service Grant R01 AI066020 (to O.A.), R37 AI71922 (to M.K.), and RO1 AI45889 (to S.A.P.) and by the German Research Foundation STO 467/4-2 (to P.S.). NR 55 TC 24 Z9 26 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2010 VL 184 IS 4 BP 2107 EP 2115 DI 10.4049/jimmunol.0901208 PG 9 WC Immunology SC Immunology GA 556IU UT WOS:000274585100045 PM 20083656 ER PT J AU Attardi, BJ Page, ST Hild, SA Coss, CC Matsumoto, AM AF Attardi, Barbara J. Page, Stephanie T. Hild, Sheri A. Coss, Christopher C. Matsumoto, Alvin M. TI Mechanism of action of bolandiol (19-nortestosterone-3 beta, 17 beta-diol), a unique anabolic steroid with androgenic, estrogenic, and progestational activities SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Androgens; Transactivation; Aromatization; 5 alpha-Reductase; Ventral prostate; Seminal vesicles; Levator ani; Androgen receptors; Progestin receptors; Estrogen receptors ID RESISTANCE-TRAINED MEN; BONE-MINERAL DENSITY; SELECTIVE MODULATION; RECEPTOR MODULATORS; BODY-COMPOSITION; MUSCLE MASS; HUMAN URINE; PROSTATE; TRANSCRIPTION; CELLS AB Bolandiol is a synthetic anabolic steroid that increases lean body mass and bone mineral density without significant stimulation of sex accessory glands in castrate adult male rats. Since bolandiol suppresses gonadotropins and endogenous testosterone (T) production, we investigated its mechanism of action. We compared the potency of bolandiol in vitro and in vivo with T, 5 alpha-dihydrotestosterone (DHT), 19-nortestosterome (19-NT) and estradiol (E(2)). Bolandiol bound with lower affinity to the recombinant rat androgen receptor (AR) than the other androgens and had low, but measurable, affinity for recombinant human progestin receptors (PR-A, PR-B), and estrogen receptors (ER alpha and beta-1). Functional agonist activity was assessed in transcription assays mediated by AR. PR, or ER. Bolandiol was stimulatory in all these assays, but only 4-9% as potent as T, DHT, and 19-NT via AR, 1% as potent as progesterone via PR, and 3% and 1% as potent as E(2) acting through ER alpha or ER beta, respectively. In immature castrate rats, bolandiol was equipotent to T in stimulating growth of the levator ani muscle but less potent than T in stimulating growth of the sex accessory glands. Bolandiol also stimulated uterine weight increases in immature female rats, which were partly blocked by ICI 182,780, but it was not aromatized in vitro by recombinant human aromatase. In contrast to T, stimulation of sex accessory gland weights by bolandiol was not inhibited by concomitant treatment with the dual 5 alpha-reductase inhibitor dutastericle. As bolandiol exhibits tissue selectivity in vivo, it may act via AR, PR, and/or ER, utilize alternative signaling pathway(s) or transcriptional coregulators, and/or be metabolized to a more potent selective steroid. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Attardi, Barbara J.] BIOQUAL Inc, Mol Endocrinol Lab, Rockville, MD 20850 USA. [Page, Stephanie T.; Matsumoto, Alvin M.] Univ Washington, Sch Med, Seattle, WA USA. [Coss, Christopher C.] GTx Inc, Memphis, TN 38163 USA. [Matsumoto, Alvin M.] VA Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA USA. RP Attardi, BJ (reprint author), BIOQUAL Inc, Mol Endocrinol Lab, 9600 Med Ctr Dr, Rockville, MD 20850 USA. EM bjattardi@verizon.net FU NIH [NO1-HD-2-3338]; BIOQUAL, Inc.; NIA [K23 AG027238-01] FX This work was supported by contract NIH NO1-HD-2-3338 awarded to BIOQUAL, Inc. and NIA Grant K23 AG027238-01 A1 awarded to STP. We would like to thank Dr. June Lee of the Contraception and Reproductive Health Branch of NICHD, Project Officer on the contract and Dr. Richard Blye, former Project Officer, for their support, and Trung Pham, Laurent Pessaint, Jessica Pray, jean Engbring, Bruce Till, David Gropp and Anne Semon for technical help. NR 37 TC 6 Z9 6 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD FEB 15 PY 2010 VL 118 IS 3 BP 151 EP 161 DI 10.1016/j.jsbmb.2009.11.008 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 559ZT UT WOS:000274872100003 PM 19941958 ER PT J AU Duda, JE AF Duda, John E. TI Olfactory system pathology as a model of Lewy neurodegenerative disease SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT 9th International Congress on Mental Dysfunction and Other Non-Motor Features in Parkinsons Disease and Related Disorderes CY OCT 16-19, 2008 CL Dresden, GERMANY DE Olfaction; Parkinson's disease; Lewy bodies; Neurodegeneration; Pathophysiology ID IDIOPATHIC PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; ESSENTIAL TREMOR; BRAIN PATHOLOGY; BODY PATHOLOGY; BULB; DYSFUNCTION; BODIES; TAU; DEMENTIA AB Olfactory dysfunction has gained recognition as an early and nearly universal feature of Lewy body Parkinson's disease (PD) Recently. research efforts have focused on the use of early non-motor symptoms of PD as early biomarkers and have Suggested that investigating neurodegeneration in the aspects of the nervous system subserving these symptoms may offer important insights into the pathophysiology of Lewy body PD Therefore, there has been interest in characterizing the pathology observed in the olfactory bulb and system of patients with PD, dementia with Lewy bodies and perhaps more importantly, in subjects with incidental Lewy pathology, defined as people with Lewy pathology without evidence of Parkinsonism or dementia during life. The olfactory bulb may be ideally suited to investigations into the pathophysiology of the Lewy body disorders as it is one of the few areas of the brain wherein the entirety of neurons susceptible to Lewy neurodegeneration. including the dendritic arborization, cell soma, axon and synaptic terminals, can be examined in the same preparation Interestingly, there is a lack of Lewy neurodegeneration in the dopaminergic neurons of the olfactory bulb and paradoxically, an apparent increase in dopaminergic neurons in some PD patients compared to controls In this report, the known neuropathology of the olfactory system in PD will be reviewed and the advantages of investigating degeneration of the olfactory bulb as a model of Lewy neurodegeneration will be discussed Published by Elsevier B V C1 [Duda, John E.] Philadelphia VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr MS 127, Philadelphia, PA 19104 USA. [Duda, John E.] Univ Penn, Dept Neurol, Sch Med, Philadelphia, PA 19104 USA. RP Duda, JE (reprint author), Philadelphia VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr MS 127, 3900 Woodland Ave, Philadelphia, PA 19104 USA. NR 41 TC 27 Z9 28 U1 0 U2 1 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 FEB 15 PY 2010 VL 289 IS 1-2 SI SI BP 49 EP 54 DI 10.1016/j.jns.2009.08.042 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 560TL UT WOS:000274925700012 PM 19783257 ER PT J AU Blackburn, SD Crawford, A Shin, H Polley, A Freeman, GJ Wherry, EJ AF Blackburn, Shawn D. Crawford, Alison Shin, Haina Polley, Antonio Freeman, Gordon J. Wherry, E. John TI Tissue-Specific Differences in PD-1 and PD-L1 Expression during Chronic Viral Infection: Implications for CD8 T-Cell Exhaustion SO JOURNAL OF VIROLOGY LA English DT Article ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; REVERSIBLE IMMUNE DYSFUNCTION; UP-REGULATION; THERAPEUTIC VACCINATION; DISEASE PROGRESSION; PROGRAMMED DEATH-1; HIV-INFECTION; PERSISTENCE; LIGANDS; MICE AB The PD-1/PD-L pathway plays a major role in regulating T-cell exhaustion during chronic viral infections in animal models, as well as in humans, and blockade of this pathway can revive exhausted CD8+ T cells. We examined the expression of PD-1 and its ligands, PD-L1 and PD-L2, in multiple tissues during the course of chronic viral infection and determined how the amount of PD-1 expressed, as well as the anatomical location, influenced the function of exhausted CD8 T cells. The amount of PD-1 on exhausted CD8 T cells from different anatomical locations did not always correlate with infectious virus but did reflect viral antigen in some tissues. Moreover, lower expression of PD-L1 in some locations, such as the bone marrow, favored the survival of PD-1(Hi) exhausted CD8 T cells, suggesting that some anatomical sites might provide a survival niche for subpopulations of exhausted CD8 T cells. Tissue-specific differences in the function of exhausted CD8 T cells were also observed. However, while cytokine production did not strictly correlate with the amount of PD-1 expressed by exhausted CD8 T cells from different tissues, the ability to degranulate and kill were tightly linked to PD-1 expression regardless of the anatomical location. These observations have implications for human chronic infections and for therapeutic interventions based on blockade of the PD-1 pathway. C1 [Blackburn, Shawn D.; Crawford, Alison; Shin, Haina; Polley, Antonio; Wherry, E. John] Wistar Inst Anat & Biol, Program Immunol, Philadelphia, PA 19104 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med, Dept Med Oncol,Dana Farber Canc Ctr, Boston, MA 02115 USA. RP Wherry, EJ (reprint author), Wistar Inst Anat & Biol, Program Immunol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM jwherry@wistar.org FU National Institutes of Health [AI071309, AI56299, HHSN26620050030C]; Grand Challenges in Global Health Initiative; Dana Foundation; Ellison Medical Foundation FX This study was supported by the National Institutes of Health (NIH; AI071309, AI56299, and HHSN26620050030C), the Foundation for the NIH through the Grand Challenges in Global Health Initiative, The Dana Foundation, and The Ellison Medical Foundation. NR 43 TC 52 Z9 53 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB 15 PY 2010 VL 84 IS 4 BP 2078 EP 2089 DI 10.1128/JVI.01579-09 PG 12 WC Virology SC Virology GA 546ZB UT WOS:000273853200040 PM 19955307 ER PT J AU Moldovan, GL Madhavan, MV Mirchandani, KD McCaffrey, RM Vinciguerra, P D'Andrea, AD AF Moldovan, George-Lucian Madhavan, Mahesh V. Mirchandani, Kanchan D. McCaffrey, Ryan M. Vinciguerra, Patrizia D'Andrea, Alan D. TI DNA Polymerase POLN Participates in Cross-Link Repair and Homologous Recombination SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ANEMIA CORE COMPLEX; SENSITIVITY PROTEIN MUS308; FANCONI-ANEMIA; PATHWAY; GENE; IDENTIFICATION; BREAKS; FANCD2; ROLES; PCNA AB All cells rely on DNA polymerases to duplicate their genetic material and to repair or bypass DNA lesions. In humans, 16 polymerases have been identified, and each bears specific functions in genome maintenance. We identified here the recently discovered polymerase POLN to be involved in repair of DNA cross-links. Such DNA lesions are highly toxic and are believed to be repaired by the sequential activity of nucleotide excision repair, translesion synthesis, and homologous recombination mechanisms. By functionally assaying its role in these processes, we unraveled an unexpected involvement of POLN in homologous recombination. Moreover, we obtained evidence for physical and functional interaction of POLN with factors belonging to the Fanconi anemia pathway, a master regulator of cross-link repair. Finally, we show that POLN interacts and cooperates in DNA repair with the helicase HEL308, which shares a common origin with POLN in the Drosophila mus308 gene. Our data indicate that this novel polymerase-helicase complex participates in homologous recombination repair and is essential for cellular protection against DNA cross-links. C1 [Moldovan, George-Lucian; Madhavan, Mahesh V.; Mirchandani, Kanchan D.; McCaffrey, Ryan M.; Vinciguerra, Patrizia; D'Andrea, Alan D.] Harvard Univ, Dept Radiat Oncol, Dana Farber Canc Inst, Sch Med, Boston, MA 02215 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Dept Radiat Oncol, Dana Farber Canc Inst, Sch Med, 44 Binney St, Boston, MA 02215 USA. EM alan_dandrea@dfci.harvard.edu OI George-Lucian, Moldovan/0000-0003-3825-149X FU Human Frontiers Science Program Organization; Swiss Foundation for Grants in Medicine and Biology; NIH [RO1DK43889, RO1HL52725, PO1DK50654, U19A1067751] FX G.-L. M. is supported by a Human Frontiers Science Program Organization postdoctoral fellowship. P. V. is recipient of a postdoctoral fellowship from the Swiss Foundation for Grants in Medicine and Biology. This study was supported by NIH grants RO1DK43889, RO1HL52725, PO1DK50654, and U19A1067751 to A. D. D. NR 40 TC 53 Z9 53 U1 2 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 FEB 15 PY 2010 VL 30 IS 4 BP 1088 EP 1096 DI 10.1128/MCB.01124-09 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 548RI UT WOS:000273983500019 PM 19995904 ER PT J AU Rosas, HD Lee, SY Bender, AC Zaleta, AK Vangel, M Yu, P Fischl, B Pappu, V Onorato, C Cha, JH Salat, DH Hersch, SM AF Rosas, H. Diana Lee, Stephanie Y. Bender, Alexander C. Zaleta, Alexandra K. Vangel, Mark Yu, Peng Fischl, Bruce Pappu, Vasanth Onorato, Christina Cha, Jang-Ho Salat, David H. Hersch, Steven M. TI Altered white matter microstructure in the corpus callosum in Huntington's disease: Implications for cortical "disconnection" SO NEUROIMAGE LA English DT Article ID DIFFUSION-TENSOR MRI; WALLERIAN DEGENERATION; MULTIPLE-SCLEROSIS; RETINAL ISCHEMIA; CEREBRAL-CORTEX; WATER; BRAIN; HETEROGENEITY; MITOCHONDRIA; CONNECTIONS AB The corpus callosum (CC) is the major conduit for information transfer between the cerebral hemispheres and plays an integral role in relaying sensory, motor and cognitive information between homologous cortical regions. The majority of fibers that make up the CC arise from large pyramidal neurons in layers III and V, which project contra-laterally. These neurons degenerate in Huntington's disease (HD) in a topographically and temporally selective way. Since any focus of cortical degeneration could be expected to secondarily deafferent homologous regions of cortex, we hypothesized that regionally selective cortical degeneration would be reflected in regionally selective degeneration of the CC. We used conventional T1-weighted, diffusion tensor imaging (DTI), and a modified corpus callosum segmentation scheme to examine the CC in healthy controls, huntingtin gene-carriers and symptomatic HID subjects. We measured mid-sagittal callosal cross-sectional thickness and several DTI parameters, including fractional anisotropy (FA), which reflects the degree of white matter organization, radial diffusivity, a suggested index of myelin integrity, and axial diffusivity, a suggested index of axonal damage of the CC. We found a topologically selective pattern of alterations in these measures in pre-manifest subjects that were more extensive in early symptomatic HD subjects and that correlated with performance on distinct cognitive measures, suggesting an important role for disrupted inter-hemispheric transfer in the clinical symptoms of HID. Our findings provide evidence for early degeneration of commissural pyramidal neurons in the neocortex, loss of cortico-cortical connectivity, and functional compromise of associative cortical processing. (C) 2009 Elsevier Inc. All rights reserved. C1 [Rosas, H. Diana; Lee, Stephanie Y.; Bender, Alexander C.; Zaleta, Alexandra K.; Pappu, Vasanth; Salat, David H.] Massachusetts Gen Hosp, Ctr Neuroimaging Aging & Neurodegenerat Dis, Charlestown, MA 02129 USA. [Rosas, H. Diana; Lee, Stephanie Y.; Bender, Alexander C.; Zaleta, Alexandra K.; Vangel, Mark; Yu, Peng; Fischl, Bruce; Pappu, Vasanth; Salat, David H.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Rosas, H. Diana; Lee, Stephanie Y.; Bender, Alexander C.; Zaleta, Alexandra K.; Pappu, Vasanth; Onorato, Christina; Cha, Jang-Ho; Hersch, Steven M.] Harvard Univ, Sch Med, Boston, MA USA. [Rosas, H. Diana; Lee, Stephanie Y.; Bender, Alexander C.; Zaleta, Alexandra K.; Pappu, Vasanth; Onorato, Christina; Cha, Jang-Ho; Hersch, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Rosas, H. Diana; Lee, Stephanie Y.; Bender, Alexander C.; Zaleta, Alexandra K.; Vangel, Mark; Yu, Peng; Fischl, Bruce; Pappu, Vasanth; Salat, David H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Yu, Peng; Fischl, Bruce] MIT, Harvard MIT Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Rosas, HD (reprint author), Massachusetts Gen Hosp, Ctr Neuroimaging Aging & Neurodegenerat Dis, 149 13th St,Room 2275, Charlestown, MA 02129 USA. EM rosas@helix.mgh.harvard.edu RI Yu, Peng/A-2877-2010 FU NIH [NS042861, NS058792, K01AG024898, NR010827]; Athinoula A. Martinos Foundation; High Q Foundation; National Center for Research Resources [P41-RR14075, R01 RR16594-01A1]; NCRR BIRN [BIRN002, U24 RR021382]; National Institute for Biomedical Imaging and Bioengineering [R01 EB001550]; National Institute for Neurological Disorders and Stroke [R01 NS052585]; National Institute on Aging [AG02238]; Mental Illness and Neuroscience Discovery (MIND) Institute; National Institutes of Health FX Supported for this research was provided by in part by NIH NS042861, NS058792, NIH K01AG024898, NR010827, the Athinoula A. Martinos Foundation, the High Q Foundation, the National Center for Research Resources (P41-RR14075, R01 RR16594-01A1 and the NCRR BIRN Morphometric Project BIRN002, U24 RR021382), the National Institute for Biomedical Imaging and Bioengineering (R01 EB001550), the National Institute for Neurological Disorders and Stroke (R01 NS052585), the National Institute on Aging (AG02238) as well as the Mental Illness and Neuroscience Discovery (MIND) Institute, and is part of the National Alliance for Medical Image Computing (NAMIC), funded by the National Institutes of Health through the NIH Roadmap. We are especially grateful to the New England HDSA Center of Excellence and its patients, who so generously contributed to this work. NR 51 TC 106 Z9 108 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 FEB 15 PY 2010 VL 49 IS 4 BP 2995 EP 3004 DI 10.1016/j.neuroimage.2009.10.015 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 549OW UT WOS:000274064500012 PM 19850138 ER PT J AU Savadjiev, P Kindlmann, GL Bouix, S Shenton, ME Westin, CF AF Savadjiev, Peter Kindlmann, Gordon L. Bouix, Sylvain Shenton, Martha E. Westin, Carl-Fredrik TI Local white matter geometry from diffusion tensor gradients SO NEUROIMAGE LA English DT Article DE Diffusion tensor imaging; Magnetic resonance imaging; Fiber geometry; Rotation tangents; Fiber dispersion; Fiber curving; Schizophrenia ID DT-MRI DATA; FIBER TRACTOGRAPHY; SEGMENTATION; QUANTIFICATION; APPROXIMATION; SCHIZOPHRENIA; FRAMEWORK; CALCULUS; TRACTS; BRAIN AB We introduce a mathematical framework for computing geometrical properties of white matter fibers directly from diffusion tensor fields. The key idea is to isolate the portion of the gradient of the tensor field corresponding to local variation in tensor orientation, and to project it onto a coordinate frame of tensor eigenvectors. The resulting eigenframe-centered representation then makes it possible to define scalar indices (or measures) that describe the local white matter geometry directly from the diffusion tensor field and its gradient, without requiring prior tractography. We derive new scalar indices of (1) fiber dispersion and (2) fiber curving, and we demonstrate them on synthetic and in vivo data. Finally, we illustrate their applicability to a group study on schizophrenia. (C) 2009 Elsevier Inc. All rights reserved. C1 [Savadjiev, Peter; Bouix, Sylvain; Shenton, Martha E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Psychiat Neuroimaging Lab,Dept Psychiat, Boston, MA 02115 USA. [Savadjiev, Peter; Shenton, Martha E.; Westin, Carl-Fredrik] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Kindlmann, Gordon L.] Univ Chicago, Dept Comp Sci, Chicago, IL 60637 USA. [Kindlmann, Gordon L.] Univ Chicago, Computat Inst, Chicago, IL 60637 USA. [Shenton, Martha E.] Harvard Univ, Sch Med, Neurosci Lab, Dept Psychiat,VA Boston Healthcare Syst, Brockton, MA 02401 USA. RP Savadjiev, P (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Psychiat Neuroimaging Lab,Dept Psychiat, Boston, MA 02115 USA. EM petersv@bwh.harvard.edu OI Bouix, Sylvain/0000-0003-1326-6054 FU NIH [R01MH074794, P41RR013218, U41RR019703, U54EB005149, R01MH50740, K05MH070047, P50MH080272, R01MH082918, R03TW008134]; Department of Veteran Affairs Merit Awards; VA Schizophrenia Center; Center for Integration of Medicine and Innovative Technology Soldier in Medicine Award FX The authors are grateful to Thomas J. Whitford for helpful discussions and comments. This work was supported by NIH grants R01MH074794 (C.F.W., P.S.), P41RR013218 (C.F.W.), U41RR019703 (C.F.W.), U54EB005149 (M.E.S.), R01MH50740 (M.E.S., P.S., S.B.), K05MH070047 (M.E.S.), P50MH080272 (M.E.S., P.S., S.B.), R01MH082918 (S.B.), R03TW008134 (M.E.S., S.B.), Department of Veteran Affairs Merit Awards (M.E.S., S.B.), VA Schizophrenia Center grant (M.E.S., S.B.), and Center for Integration of Medicine and Innovative Technology Soldier in Medicine Award (S.B.). NR 36 TC 11 Z9 11 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2010 VL 49 IS 4 BP 3175 EP 3186 DI 10.1016/j.neuroimage.2009.10.073 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 549OW UT WOS:000274064500028 PM 19896542 ER PT J AU Kremen, WS Prom-Wormley, E Panizzon, MS Eyler, LT Fischl, B Neale, MC Franz, CE Lyons, MJ Pacheco, J Perry, ME Stevens, A Schmitt, JE Grant, MD Seidman, LJ Thermenos, HW Tsuang, MT Eisen, SA Dale, AM Fennema-Notestine, C AF Kremen, William S. Prom-Wormley, Elizabeth Panizzon, Matthew S. Eyler, Lisa T. Fischl, Bruce Neale, Michael C. Franz, Carol E. Lyons, Michael J. Pacheco, Jennifer Perry, Michele E. Stevens, Allison Schmitt, J. Eric Grant, Michael D. Seidman, Larry J. Thermenos, Heidi W. Tsuang, Ming T. Eisen, Seth A. Dale, Anders M. Fennema-Notestine, Christine TI Genetic and environmental influences on the size of specific brain regions in midlife: The VETSA MRI study (vol 49, pg 1213, 2010) SO NEUROIMAGE LA English DT Correction C1 [Kremen, William S.; Panizzon, Matthew S.; Eyler, Lisa T.; Franz, Carol E.; Perry, Michele E.; Tsuang, Ming T.; Fennema-Notestine, Christine] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Kremen, William S.; Tsuang, Ming T.] Univ Calif San Diego, Ctr Behav Genom, La Jolla, CA 92093 USA. [Kremen, William S.; Eyler, Lisa T.; Tsuang, Ming T.] VA San Diego Healthcare Syst, La Jolla, CA USA. [Prom-Wormley, Elizabeth; Neale, Michael C.; Schmitt, J. Eric] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. [Prom-Wormley, Elizabeth; Neale, Michael C.; Schmitt, J. Eric] Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. [Fischl, Bruce; Pacheco, Jennifer; Stevens, Allison] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Fischl, Bruce; Pacheco, Jennifer; Stevens, Allison] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lyons, Michael J.; Grant, Michael D.] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Perry, Michele E.] Univ Calif San Diego, Dept Cognit Neurosci, La Jolla, CA 92093 USA. [Seidman, Larry J.; Thermenos, Heidi W.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Eisen, Seth A.] Washington Univ, Dept Med, St Louis, MO USA. [Eisen, Seth A.] Washington Univ, Dept Psychiat, St Louis, MO USA. [Eisen, Seth A.] Dept Vet Affairs, Washington, DC USA. [Dale, Anders M.; Fennema-Notestine, Christine] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. RP Kremen, WS (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr MC 0738, La Jolla, CA 92093 USA. EM wkremen@ucsd.edu RI Lyons, Michael/B-6119-2011 NR 1 TC 2 Z9 2 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2010 VL 49 IS 4 BP 3499 EP 3502 DI 10.1016/j.neuroimage.2009.12.015 PG 4 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 549OW UT WOS:000274064500062 ER PT J AU Tang, WT Chung, E Kim, YH So, PTC Sheppard, CJR AF Tang, Wai Teng Chung, Euiheon Kim, Yang-Hyo So, Peter T. C. Sheppard, Colin J. R. TI Surface-plasmon-coupled emission microscopy with a spiral phase plate SO OPTICS LETTERS LA English DT Article ID RESONANCE AB The surface plasmon-coupled emission microscope provides high sensitivity for surface imaging. However, it suffers from a distorted donut-shape point-spread function (PSF). Here we report an effective yet simple method to correct for the distortion by introducing a spiral phase plate. This modification converts the donut PSF into one that is single lobed, which is preferable for imaging. The optical performance of the system is characterized and compared with previous publications. This technique provides more than twofold lateral resolution enhancement. (C) 2010 Optical Society of America C1 [Tang, Wai Teng; Sheppard, Colin J. R.] Natl Univ Singapore, Div Bioengn, Singapore 117576, Singapore. [Tang, Wai Teng] Natl Univ Singapore, Singapore MIT Alliance, Singapore 117576, Singapore. [Chung, Euiheon] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab, Boston, MA 02114 USA. [Kim, Yang-Hyo; So, Peter T. C.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [So, Peter T. C.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Sheppard, Colin J. R.] Natl Univ Singapore, Dept Biol Sci, Singapore 117576, Singapore. RP Sheppard, CJR (reprint author), Natl Univ Singapore, Div Bioengn, 9 Engn Dr 1, Singapore 117576, Singapore. EM colin@nus.edu.sg RI Sheppard, Colin/B-9593-2008; OI Chung, Euiheon/0000-0002-3326-6927 FU Singapore-MIT Alliance (SMA) FX This research was funded by the Singapore-MIT Alliance (SMA). NR 13 TC 14 Z9 14 U1 0 U2 5 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 FEB 15 PY 2010 VL 35 IS 4 BP 517 EP 519 PG 3 WC Optics SC Optics GA 562LO UT WOS:000275052300024 PM 20160803 ER PT J AU Jakkula, E Leppa, V Sulonen, AM Varilo, T Kallio, S Kemppinen, A Purcell, S Koivisto, K Tienari, P Sumelahti, ML Elovaara, I Pirttila, T Reunanen, M Aromaa, A Oturai, AB Sondergaard, HB Harbo, HF Mero, IL Gabriel, SB Mirel, DB Hauser, SL Kappos, L Polman, C De Jager, PL Hafler, DA Daly, MJ Palotie, A Saarela, J Peltonen, L AF Jakkula, Eveliina Leppa, Virpi Sulonen, Anna-Maija Varilo, Teppo Kallio, Suvi Kemppinen, Anu Purcell, Shaun Koivisto, Keijo Tienari, Pentti Sumelahti, Maria-Liisa Elovaara, Irina Pirttila, Tuula Reunanen, Mauri Aromaa, Arpo Oturai, Annette Bang Sondergaard, Helle Bach Harbo, Hanne F. Mero, Inger-Lise Gabriel, Stacey B. Mirel, Daniel B. Hauser, Stephen L. Kappos, Ludwig Polman, Chris De Jager, Philip L. Hafler, David A. Daly, Mark J. Palotie, Aarno Saarela, Janna Peltonen, Leena TI Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID HYPER-IGE SYNDROME; SUSCEPTIBILITY LOCI; FINLAND; REPLICATION; MUTATIONS; RECEPTOR; FAMILIES; DISEASE; CD58; DYSTROGLYCAN AB Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with 1) < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT-3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits. C1 [Jakkula, Eveliina; Leppa, Virpi; Sulonen, Anna-Maija; Varilo, Teppo; Kallio, Suvi; Kemppinen, Anu; Palotie, Aarno; Saarela, Janna; Peltonen, Leena] Univ Helsinki, Inst Mol Med Finland, FIN-00290 Helsinki, Finland. [Leppa, Virpi] Univ Helsinki, Helsinki Biomed Grad Sch, FIN-00290 Helsinki, Finland. [Varilo, Teppo; Peltonen, Leena] Univ Helsinki, Dept Med Genet, FIN-00290 Helsinki, Finland. [Tienari, Pentti] Univ Helsinki, Biomedicum Helsinki, Dept Neurol, Neurosci Programme, FIN-00290 Helsinki, Finland. [Jakkula, Eveliina; Leppa, Virpi; Sulonen, Anna-Maija; Varilo, Teppo; Kallio, Suvi; Kemppinen, Anu; Saarela, Janna; Peltonen, Leena] Natl Inst Hlth & Welf, Unit Publ Hlth Genom, Helsinki 00271, Finland. [Aromaa, Arpo] Natl Inst Hlth & Welf, Unit Living Condit Hlth & Wellbeing, Helsinki 00271, Finland. [Jakkula, Eveliina; Purcell, Shaun; Gabriel, Stacey B.; Mirel, Daniel B.; De Jager, Philip L.; Daly, Mark J.; Palotie, Aarno; Peltonen, Leena] MIT & Harvard, Broad Inst, Program Med & Populat Genet & Genet Anal Platform, Cambridge, MA 02142 USA. [Purcell, Shaun; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Koivisto, Keijo] Cent Hosp Seinajoki, Seinajoki 60220, Finland. [Sumelahti, Maria-Liisa] Tampere Univ, Sch Publ Hlth, Tampere 33014, Finland. [Elovaara, Irina] Tampere Univ Hosp, Dept Neurol, Tampere 33521, Finland. [Pirttila, Tuula] Kuopio Univ Hosp, Dept Neurol & Neurosci, Kuopio 70211, Finland. [Reunanen, Mauri] Oulu Univ Hosp, Dept Neurol, Oulu 90014, Finland. [Oturai, Annette Bang; Sondergaard, Helle Bach] Univ Copenhagen Hosp, Rigshosp, Danish Multiple Sclerosis Res Ctr, DK-2100 Copenhagen, Denmark. [Harbo, Hanne F.; Mero, Inger-Lise] Oslo Univ Hosp, Dept Neurol, Ulleval, Norway. [Harbo, Hanne F.; Mero, Inger-Lise] Univ Oslo, N-0407 Oslo, Norway. [Mero, Inger-Lise] Oslo Univ Hosp, Rikshosp, Inst Immunol, N-0027 Oslo, Norway. [Hauser, Stephen L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Kappos, Ludwig] Univ Basel, Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. [Kappos, Ludwig] Univ Basel, Univ Basel Hosp, Dept Neuroradiol & Biomed, CH-4031 Basel, Switzerland. [Polman, Chris] Vrije Univ Amsterdam, Med Ctr, Dept Neurol, NL-1085 Amsterdam, Netherlands. [De Jager, Philip L.] Brigham & Womens Hosp, Program Translat NeuroPsychiat Genorn, Boston, MA 02035 USA. [Hafler, David A.] Brigham & Womens Hosp, Dept Neurol, Div Mol Immunol, Boston, MA 02035 USA. [Hafler, David A.] Harvard Univ, Sch Med, Boston, MA 02035 USA. [Hafler, David A.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA. [Palotie, Aarno; Peltonen, Leena] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. RP Peltonen, L (reprint author), Univ Helsinki, Inst Mol Med Finland, FIN-00290 Helsinki, Finland. EM leena@sanger.ac.uk RI Hauser, Stephen/J-2978-2016; Tienari, Pentti/A-4893-2012; Saarela, Janna/E-5369-2014 OI Saarela, Janna/0000-0002-0853-6219; Varilo, Teppo/0000-0002-5839-8854; FU NCRR NIH HHS [U54 RR020278]; NIMH NIH HHS [R01 MH071425]; NINDS NIH HHS [R01 NS043559, R01 NS 43559]; Wellcome Trust [089061/Z/09/Z] NR 54 TC 105 Z9 110 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB 12 PY 2010 VL 86 IS 2 BP 285 EP 291 DI 10.1016/j.ajhg.2010.01.017 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 556ZS UT WOS:000274637200020 PM 20159113 ER PT J AU Goldman, JA Garlick, JD Kingston, RE AF Goldman, Joseph A. Garlick, Joseph D. Kingston, Robert E. TI Chromatin Remodeling by Imitation Switch (ISWI) Class ATP-dependent Remodelers Is Stimulated by Histone Variant H2A.Z SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOSOME SURFACE; PROMOTERS; COMPLEXES; TRANSCRIPTION; SWI/SNF; GENES; RECEPTOR; REGIONS; GENOME; ALTERS AB ATP-dependent chromatin remodeling complexes rearrange nucleosomes by altering the position of DNA around the histone octamer. Although chromatin remodelers and the histone variant H2A.Z colocalize on transcriptional control regions, whether H2A.Z directly affects remodeler association or activity is unclear. We determined the relative association of remodelers with H2A.Z chromatin and tested whether replacement of H2A.Z in a nucleosome altered the activity of remodeling enzymes. Many families of remodelers showed increased association with H2A.Z chromatin, but only the ISWI family of chromatin remodelers showed stimulated activity in vitro. An acidic patch on the nucleosome surface, extended by inclusion of H2A.Z in nucleosomes and essential for viability, is required for ISWI stimulation. We conclude that H2A.Z incorporation increases nucleosome remodeling activity of the largest class of mammalian remodelers (ISWI) and that it correlates with increased association of other remodelers to chromatin. This reveals two possible modes for regulation of a remodeler by a histone variant. C1 [Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02215 USA. RP Kingston, RE (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM Kingston@molbio.mgh.harvard.edu NR 39 TC 26 Z9 28 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 12 PY 2010 VL 285 IS 7 BP 4645 EP 4651 DI 10.1074/jbc.M109.072348 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 565FN UT WOS:000275274800043 PM 19940112 ER PT J AU Korsgren, C Peters, LL Lux, SE AF Korsgren, Catherine Peters, Luanne L. Lux, Samuel E. TI Protein 4.2 Binds to the Carboxyl-terminal EF-hands of Erythroid alpha-Spectrin in a Calcium- and Calmodulin-dependent Manner SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RED-BLOOD-CELLS; MEMBRANE SKELETON; HEREDITARY SPHEROCYTOSIS; CYTOPLASMIC DOMAIN; ANION TRANSPORT; BETA-SPECTRIN; ACTIN-BINDING; BAND-3; ANKYRIN; COMPLEX AB Spectrin and protein 4.1 cross-link F-actin protofilaments into a network called the membrane skeleton. Actin and 4.1 bind to one end of beta-spectrin. The adjacent end of alpha-spectrin, called the EF-domain, is calmodulin-like, with calcium-dependent and calcium-independent EF-hands. It has no known function. However, the sph(1J)/sph(1J) mouse has very fragile red cells and lacks the last 13 amino acids in the EF-domain, suggesting the domain is critical for skeletal integrity. Using pulldown binding assays, we find the alpha-spectrin EF-domain either alone or incorporated into a mini-spectrin binds native and recombinant protein 4.2 at a previously identified region of 4.2 (G(3) peptide). Native 4.2 binds with an affinity comparable with other membrane skeletal interactions (K(d) = 0.30 mu M). EF-domains bearing the sph(1J) mutation are inactive. Binding of protein 4.2 to band 3 (K(d) = 0.45 mu M) does not interfere with the spectrin-4.2 interaction. Spectrin-4.2 binding is amplified by micromolar concentrations of Ca(2+) (but not Mg(2+)) by three to five times. Calmodulin also binds to the EF-domain (K(d) = 17 mu M), and Ca(2+)-calmodulin blocks Ca(2+)-dependent binding of protein 4.2 but not Ca(2+)-independent binding. The data suggest that protein 4.2 is located near protein 4.1 at the spectrin-actin junctions. Because proteins 4.1 and 4.2 also bind to band 3, the erythrocyte anion channel, we suggest that one or both of these proteins cause a portion of band 3 to localize near the spectrin-actin junctions and provide another point of attachment between the membrane skeleton and the lipid bilayer. C1 [Lux, Samuel E.] Harvard Univ, Dept Med, Childrens Hosp, Div Hematol Oncol,Sch Med, Boston, MA 02115 USA. [Korsgren, Catherine; Lux, Samuel E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Peters, Luanne L.; Lux, Samuel E.] Jackson Lab, Bar Harbor, ME 04609 USA. RP Lux, SE (reprint author), Harvard Univ, Dept Med, Childrens Hosp, Div Hematol Oncol,Sch Med, HU260-1,300 Longwood Ave, Boston, MA 02115 USA. EM lux@enders.tch.harvard.edu FU National Institutes of Health [RO1 HL081608, RO1 HL088468] FX This work was supported, in whole or in part, by National Institutes of Health Grants RO1 HL081608 (to S. E. L.) and RO1 HL088468 (to L. L. P.). NR 83 TC 14 Z9 14 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 12 PY 2010 VL 285 IS 7 BP 4757 EP 4770 DI 10.1074/jbc.M109.056200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 565FN UT WOS:000275274800054 PM 20007969 ER PT J AU Kaufmann, BB Hung, DT AF Kaufmann, Benjamin B. Hung, Deborah T. TI The Fast Track to Multidrug Resistance SO MOLECULAR CELL LA English DT Editorial Material ID MUTATION-RATES; BACTERIA AB In this issue of Molecular Cell, Kohanski et al. (2010) demonstrate that even subinhibitory concentrations of bactericidal antibiotics result in the generation of reactive oxygen species, leading to an increase in mutation rate and the emergence of multidrug-resistant bacterial strains. C1 [Kaufmann, Benjamin B.; Hung, Deborah T.] Broad Inst, Infect Dis Initiat, Cambridge, MA 02141 USA. [Kaufmann, Benjamin B.; Hung, Deborah T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hung, DT (reprint author), Broad Inst, Infect Dis Initiat, Cambridge, MA 02141 USA. EM hung@molbio.mgh.harvard.edu NR 9 TC 17 Z9 20 U1 2 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 12 PY 2010 VL 37 IS 3 BP 297 EP 298 DI 10.1016/j.molcel.2010.01.027 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 558UY UT WOS:000274774600002 PM 20159549 ER PT J AU Saran, N Lyszkiewicz, M Pommerencke, J Witzlau, K Vakilzadeh, R Ballmaier, M von Boehmer, H Krueger, A AF Saran, Namita Lyszkiewicz, Marcin Pommerencke, Jens Witzlau, Katrin Vakilzadeh, Ramin Ballmaier, Matthias von Boehmer, Harald Krueger, Andreas TI Multiple extrathymic precursors contribute to T-cell development with different kinetics SO BLOOD LA English DT Article ID COMMON LYMPHOID PROGENITORS; MOUSE BONE-MARROW; THYMIC PROGENITORS; BLOOD; IDENTIFICATION; HETEROGENEITY; THYMOPOIESIS; EXPRESSION; LINEAGES; SELECTIN AB T-cell development in the thymus depends on continuous supply of T-cell progenitors from bone marrow (BM). Several extrathymic candidate progenitors have been described that range from multipotent cells to lymphoid cell committed progenitors and even largely T-lineage committed precursors. However, the nature of precursors seeding the thymus under physiologic conditions has remained largely elusive and it is not known whether there is only one physiologic T-cell precursor population or many. Here, we used a competitive in vivo assay based on depletion rather than enrichment of classes of BM-derived precursor populations, thereby only minimally altering physiologic precursor ratios to assess the contribution of various extrathymic precursors to T-lineage differentiation. We found that under these conditions multiple precursors, belonging to both multipotent progenitor (MPP) and common lymphoid progenitor (CLP) subsets have robust T-lineage potential. However, differentiation kinetics of different precursors varied considerably, which might ensure continuous thymic output despite gated importation of extrathymic precursors. In conclusion, our data suggest that the thymus functions to impose T-cell fate on any precursor capable of filling the limited number of progenitor niches. (Blood. 2010;115:1137-1144) C1 [Saran, Namita; Lyszkiewicz, Marcin; Pommerencke, Jens; Witzlau, Katrin; Vakilzadeh, Ramin; Krueger, Andreas] Hannover Med Sch, Inst Immunol, D-30625 Hannover, Germany. [Ballmaier, Matthias] Hannover Med Sch, Dept Pediat Hematol & Oncol, D-30625 Hannover, Germany. [von Boehmer, Harald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Krueger, A (reprint author), Hannover Med Sch, Inst Immunol, OE5240,Carl Neuberg Str 1, D-30625 Hannover, Germany. EM krueger.andreas@mh-hannover.de RI Krueger, Andreas/B-9427-2009 OI Krueger, Andreas/0000-0001-7873-7334 FU German Research Foundation [KR2320/2-1, EXC62]; National Institutes of Health [5R01 AI051378] FX We are grateful to Jasmin Bolter, Stefanie Willenzon, and Mathias Herberg for technical assistance and animal care, and to Christina Reimer and Mathias Rhein for help with cell sorting. We thank Juan Carlos Zuniga-Pflucker for providing OP9-DL1 cells and Immo Prinz and Reinhold Forster for helpful discussions and critical reading of the paper.; This work was supported by grants from the German Research Foundation (DFG, Emmy-Noether Program, KR2320/2-1 and EXC62, "Rebirth"; A.K.) and the National Institutes of Health (5R01 AI051378; H.v.B.). NR 31 TC 28 Z9 28 U1 0 U2 0 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 FEB 11 PY 2010 VL 115 IS 6 BP 1137 EP 1144 DI 10.1182/blood-2009-07-230821 PG 8 WC Hematology SC Hematology GA 554JN UT WOS:000274431400008 PM 20009033 ER PT J AU Fehr, T Lucas, CL Kurtz, J Onoe, T Zhao, GZ Hogan, T Vallot, C Rao, A Sykes, M AF Fehr, Thomas Lucas, Carrie L. Kurtz, Josef Onoe, Takashi Zhao, Guiling Hogan, Timothy Vallot, Casey Rao, Anjana Sykes, Megan TI A CD8 T cell-intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo SO BLOOD LA English DT Article ID MARROW-TRANSPLANTATION; TRANSCRIPTION FACTOR; PD-1 EXPRESSION; CYCLOSPORINE-A; LYMPHOCYTES; ANTI-CD40L; ACTIVATION; RECIPIENTS; BLOCKADE; ANTIBODY AB Previous studies have indicated that blockade of signaling through the T-cell receptor (TCR)/calcineurin/nuclear factor of activated T cells ( NFAT) pathway impairs transplantation tolerance induced with anti-CD154 antibody. By using an allogeneic bone marrow transplantation model, we examined the role of the TCR/calcineurin/NFAT pathway for tolerance induction with anti-CD154. Calcineurin blockade by cyclosporine A led to a failure of CD8 but not CD4 tolerance, and experiments in NFAT1(-/-) mice replicated this effect. Studies in thymectomized mice demonstrated that blockade of the calcineurin/NFAT pathway after bone marrow transplantation led to a failure of peripheral CD8 tolerance. Moreover, CD8 adoptive transfer studies demonstrated that NFAT1 is cell-intrinsically required for peripheral CD8 tolerance. NFAT1 deficiency did not impair CD8 T-cell upregulation of PD1, which is required for CD8 tolerance in this model. NFAT1 has previously been shown to have a role in CD4 cells for anergy induction and for programming CD4 cells to become regulatory cells. By generating mice lacking NFAT1 in CD4 but not CD8 cells, we demonstrate that NFAT1 is neither required for CD4 tolerance induction nor for their regulatory function on CD8 T cells. Thus, our study reveals a CD8 T cell intrinsic NFAT1 requirement for CD8 tolerance in vivo. (Blood. 2010;115:1280-1287) C1 [Fehr, Thomas; Lucas, Carrie L.; Kurtz, Josef; Onoe, Takashi; Zhao, Guiling; Hogan, Timothy; Vallot, Casey; Sykes, Megan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. [Fehr, Thomas] Univ Zurich Hosp, Div Nephrol, CH-8091 Zurich, Switzerland. [Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA. [Rao, Anjana] Immune Dis Inst, Boston, MA USA. RP Sykes, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH E Bldg 149-5102,13th St, Boston, MA 02129 USA. EM megan.sykes@tbrc.mgh.harvard.edu FU National Institutes of Health [RO1HL49915]; Swiss Foundation; Walter and Gertrud Siegenthaler Foundation (Medical Faculty, University of Zurich, Switzerland); National Defense Science and Engineering Graduate Fellowship FX We thank Annette Oxenius and Ronjon Chakraverty for their critical review of the manuscript, Orlando Moreno for outstanding animal husbandry and technical assistance, and Gena Coleman for expert assistance with the manuscript.; This work was supported by National Institutes of Health grant RO1HL49915. T.F. was supported by a research fellowship of the Swiss Foundation for Medical and Biological Grants (with support of Novartis Switzerland) and a research fellowship of the Walter and Gertrud Siegenthaler Foundation (Medical Faculty, University of Zurich, Switzerland). C.L. was supported by the National Defense Science and Engineering Graduate Fellowship. NR 26 TC 17 Z9 17 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 FEB 11 PY 2010 VL 115 IS 6 BP 1280 EP 1287 DI 10.1182/blood-2009-07-230680 PG 8 WC Hematology SC Hematology GA 554JN UT WOS:000274431400024 PM 20007805 ER PT J AU Boxer, MB Jiang, JK Vander Heiden, MG Shen, M Skoumbourdis, AP Southall, N Veith, H Leister, W Austin, CP Park, HW Inglese, J Cantley, LC Auld, DS Thomas, CJ AF Boxer, Matthew B. Jiang, Jian-kang Vander Heiden, Matthew G. Shen, Min Skoumbourdis, Amanda P. Southall, Noel Veith, Henrike Leister, William Austin, Christopher P. Park, Hee Won Inglese, James Cantley, Lewis C. Auld, Douglas S. Thomas, Craig J. TI Evaluation of Substituted N,N '-Diarylsulfonamides as Activators of the Tumor Cell Specific M2 Isoform of Pyruvate Kinase SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CANCER CELLS; M-GENE; GROWTH; RAT; IDENTIFICATION; METABOLISM; LIBRARIES; ISOZYMES; ASSAYS AB The metabolism of cancer cells is altered to support rapid proliferation. Pharmacological activators of a tumor cell specific pyruvate kinase isozyme (PKM2) may be an approach for altering the classic Warburg effect characteristic of aberrant metabolism in cancer cells yielding a novel anti proliferation strategy. In this manuscript, we detail the discovery of a series of Substituted N,N'-diarylsulfonamides as activators of PKM2. The synthesis of numerous analogues and the evaluation of structure-activity relationships are presented as well as assessments of mechanism and selectivity. Several agents are found that have good potencies and appropriate solubility for use as chemical probes of PKM2 including 55 (AC(50) = 43 nM, maximum response = 84%; solubility = 7.3 mu g/mL), 56 (AC(50) = 99 nM, maximum response 84%; solubility = 5.7 mu g/mL), and 58 (AC(50) = 38 nM, maximum response = 82%; solubility 51.2 mu g/mL). The small molecules described here represent first-in-class activators of PKM2 C1 [Boxer, Matthew B.; Jiang, Jian-kang; Shen, Min; Skoumbourdis, Amanda P.; Southall, Noel; Veith, Henrike; Leister, William; Austin, Christopher P.; Inglese, James; Auld, Douglas S.; Thomas, Craig J.] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20850 USA. [Vander Heiden, Matthew G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Vander Heiden, Matthew G.; Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Park, Hee Won] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L5, Canada. [Park, Hee Won] Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada. [Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02115 USA. RP Thomas, CJ (reprint author), NHGRI, NIH, Chem Genom Ctr, 9800 Med Ctr Dr,Bldg B,Room 3005 MSC 3370, Bethesda, MD 20892 USA. EM craigt@nhgri.nih.gov RI Southall, Noel/H-8991-2012; Cantley, Lewis/D-1800-2014 OI Southall, Noel/0000-0003-4500-880X; Cantley, Lewis/0000-0002-1298-7653 FU National Institutes of Health; National Human Genome Research Institute National Institutes of Health; Canadian Institutes for Health Research [1097737]; Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmith Kline, Karolinska Institutet; Knut and Alice Wallenberg Foundation; Ontario Innovation Trust; Ontario Ministry for Research and Innovation, Merck Co., Inc.; Novartis Research Foundation; Swedish Agency for Innovation Systems; Swedish Foundation for Strategic Research; Wellcome Trust; [R03 (1R03MH085679-01)] FX We thank Jeremy Smith, Paul Shinn, and Danielle van Leer for assistance with compound management. We thank Allison Mandich for critical reading of this manuscript. This research was supported by the Molecular Libraries Program of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute National Institutes of Health, and R03 (1R03MH085679-01). The Structural Genomics Consortium is it registered charity (no. 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmith Kline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research, and the Wellcome Trust. NR 27 TC 57 Z9 58 U1 1 U2 17 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 FEB 11 PY 2010 VL 53 IS 3 BP 1048 EP 1055 DI 10.1021/jm901577g PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 552EN UT WOS:000274270900012 PM 20017496 ER PT J AU Stone, JH Papaliodis, GN Dunbar, MR Stone, JR AF Stone, John H. Papaliodis, George N. Dunbar, Mark R. Stone, James R. TI A Man with Arthralgias, Oral Ulcers, Vision Loss, and Vocal-Cord Paralysis Temporal-artery findings consistent with mild involvement by active giant-cell arteritis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID WEGENERS-GRANULOMATOSIS; POLYMYALGIA-RHEUMATICA; BEHCETS-SYNDROME; DISEASE; MANIFESTATIONS; MANAGEMENT; BIOPSY; COMPLICATIONS; DIAGNOSIS; THERAPY C1 [Stone, John H.] Massachusetts Gen Hosp, Dept Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Stone, James R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Papaliodis, George N.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Stone, John H.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Papaliodis, George N.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Stone, James R.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Dunbar, Mark R.] N Fulton Eye Ctr, Roswell, GA USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Dept Rheumatol Allergy & Immunol, Boston, MA 02114 USA. FU Genentech FX Dr. J.H. Stone reports receiving grant support from Genentech and consulting fees from Merck and Stryker; and Dr. J.R. Stone, consulting fees from Taser International, Proteon Therapeutics, GlaxoSmithKline, and Merck. No other potential conflict of interest relevant to this article was reported. Financial and other disclosures provided by the authors are available with the full text of this article at NEJM.org. NR 45 TC 6 Z9 6 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 11 PY 2010 VL 362 IS 6 BP 537 EP 546 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 553WJ UT WOS:000274397200014 PM 20147720 ER PT J AU Khodarev, N Ahmad, R Rajabi, H Pitroda, S Kufe, T McClary, C Joshi, MD MacDermed, D Weichselbaum, R Kufe, D AF Khodarev, N. Ahmad, R. Rajabi, H. Pitroda, S. Kufe, T. McClary, C. Joshi, M. D. MacDermed, D. Weichselbaum, R. Kufe, D. TI Cooperativity of the MUC1 oncoprotein and STAT1 pathway in poor prognosis human breast cancer SO ONCOGENE LA English DT Article DE MUC1; STAT1; breast cancer; IFN gamma; auto-inductive loop; inflammation ID CARCINOMA-ASSOCIATED ANTIGEN; BETA-CATENIN; TRANSCRIPTION FACTOR; C-SRC; APOPTOTIC RESPONSE; GENE-TRANSCRIPTION; DNA-DAMAGE; CELLS; ACTIVATION; EXPRESSION AB Signal transducer and activator of transcription 1 (STAT1) is activated in the inflammatory response to interferons. The MUC1 oncoprotein is overexpressed in human breast cancers. Analysis of genes differentially expressed in MUC1-transformed cells has identified a network linking MUC1 and STAT1 that is associated with cellular growth and inflammation. The results further show that the MUC1-C subunit associates with STAT1 in cells and the MUC1-C cytoplasmic domain binds directly to the STAT1 DNA-binding domain. The interaction between MUC1-C and STAT1 is inducible by IFN gamma in non-malignant epithelial cells and constitutive in breast cancer cells. Moreover, the MUC1-STAT1 interaction contributes to the activation of STAT1 target genes, including MUC1 itself. Analysis of two independent databases showed that MUC1 and STAT1 are coexpressed in about 15% of primary human breast tumors. Coexpression of MUC1 and the STAT1 pathway was found to be significantly associated with decreased recurrence-free and overall survival. These findings indicate that (i) MUC1 and STAT1 function in an auto-inductive loop, and (ii) activation of both MUC1 and the STAT1 pathway in breast tumors confers a poor prognosis for patients. Oncogene (2010) 29, 920 -929; doi:10.1038/onc.2009.391; published online 16 November 2009 C1 [Ahmad, R.; Rajabi, H.; Kufe, T.; McClary, C.; Joshi, M. D.; Kufe, D.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Khodarev, N.; Pitroda, S.; MacDermed, D.; Weichselbaum, R.] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute [CA97098, CA111423] FX This work was supported by Grants CA97098 and CA111423 awarded by the National Cancer Institute. NR 46 TC 36 Z9 41 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 11 PY 2010 VL 29 IS 6 BP 920 EP 929 DI 10.1038/onc.2009.391 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 553WP UT WOS:000274397800014 PM 19915608 ER PT J AU Hurwitz, MD AF Hurwitz, Mark D. TI Today's Thermal Therapy: Not Your Father's Hyperthermia Challenges and Opportunities in Application of Hyperthermia for the 21st Century Cancer Patient SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Review DE hyperthermia; thermal therapy; review ID HEAT-SHOCK; RADIATION-THERAPY; RANDOMIZED-TRIAL; PLUS HYPERTHERMIA; PROSTATE-CANCER; ONCOLOGY GROUP; PHASE-III; IN-VITRO; TUMORS; PROTEIN AB The realization that hyperthermia was an ideal complementary treatment to radiation and certain chemotherapeutic agents front a biologic perspective led to great enthusiasm for this modality over a quarter of a Century ago. Unfortunately, this well-deserved enthusiasm quickly become tempered because Of the inability to effectively, beat tumors, particularly deep-seated ones with Cumbersome first generation technology Coupled with still-emerging understandings of thermal biology. Today as before, both challenges and opportunities remain in the application of hyperthermia for cancer patients. The lessons learned from the introduction of hyperthermia. a generation ago, are providing focus for application of this still-promising modality in today's clinic. These areas of challenge and opportunity include: thermal biology treatment planning, delivery, and monitoring, successful high-quality clinical trials; and integration of thermal therapy with emerging technologies and therapeutic strategies both established and evolving. The progress made in understanding of thermal biology, physics, and bioengineering, Coupled with advances in complementary clinical treatment modalities have all contributed to the next generation of clinical thermal therapy. C1 [Hurwitz, Mark D.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. RP Hurwitz, MD (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,ASB1 L2, Boston, MA 02115 USA. EM mhurwitz@lroc.harvard.edu NR 43 TC 20 Z9 20 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD FEB 10 PY 2010 VL 33 IS 1 BP 96 EP 100 DI 10.1097/COC.0b013e3181817a75 PG 5 WC Oncology SC Oncology GA 554CQ UT WOS:000274413500020 PM 19636240 ER PT J AU Gonzalez, RG Hakimelahi, R Schaefer, PW Roccatagliata, L Sorensen, AG Singhal, AB AF Gonzalez, R. Gilberto Hakimelahi, Reza Schaefer, Pamela W. Roccatagliata, Luca Sorensen, A. Gregory Singhal, Aneesh B. TI Stability of large diffusion/perfusion mismatch in anterior circulation strokes for 4 or more hours SO BMC NEUROLOGY LA English DT Article ID ACUTE ISCHEMIC-STROKE; CEREBRAL-BLOOD-FLOW; DIFFUSION; MRI; THROMBOLYSIS; EVOLUTION; OCCLUSION; TISSUE; VOLUME; BRAIN AB Background: The stability of hypoperfused brain tissue in stroke patients with major artery occlusions is unknown. The purpose of this study was to determine the persistence of a diffusion/perfusion mismatch in patients with ICA or proximal MCA occlusions. Methods: Fourteen patients with ICA and/or proximal MCA occlusion and a diffusion/perfusion mismatch at presentation were studied. All were enrolled in a pilot randomized study of normobaric oxygen therapy. None received thrombolytic therapy; 8 received normobaric oxygen and 6 room air. Diffusion/perfusion MRI was performed at baseline, 4 hours, 24 hours, and 1 week. Abnormal DWI, ADC, and MTT volumes were determined using standard image analysis methods. Results: The mean time from symptom onset to baseline MRI was 7.5 +/- 1 hours. Across all 4 time points there was a significant difference in DWI lesion (ANOVA, P < 0.0001) and abnormal MTT volumes (ANOVA, P < 0.01) with the 24 hour and 1 week abnormal volumes different from the earlier studies. However, comparing baseline and 4 hour scans, there was no significant interval change in the mean abnormal DWI volume (29.4 +/- 8.2 ml vs. 28.1 +/- 7.4 ml) or abnormal MTT volumes (137 +/- 17.7 ml vs. 130.9 +/- 13.8). By 24 hours, only 2 patients did not maintain a mismatch of 20% or greater. Conclusions: Patients who present outside the time window for thrombolytic therapy, and who have a large diffusion/perfusion mismatch on MRI may have a stable mismatch for 4 or more hours. C1 [Gonzalez, R. Gilberto; Hakimelahi, Reza; Schaefer, Pamela W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroradiol Div,Dept Radiol, Boston, MA 02114 USA. [Roccatagliata, Luca] Univ Genoa, Dept Neurosci, I-16132 Genoa, Italy. [Sorensen, A. Gregory] Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Radiol, Boston, MA 02114 USA. [Singhal, Aneesh B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Gonzalez, RG (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroradiol Div,Dept Radiol, Boston, MA 02114 USA. EM rggonzalez@partners.org FU Lawrence Award, Hinduja Foundation, NY; [R01-NS051412]; [P50-NS051343]; [R01-NS38477] FX Supported in part by R01-NS051412, P50-NS051343, R01-NS38477, and the Lawrence Award, Hinduja Foundation, NY NR 19 TC 16 Z9 16 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD FEB 10 PY 2010 VL 10 AR 13 DI 10.1186/1471-2377-10-13 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 566LW UT WOS:000275373100001 PM 20146800 ER PT J AU Blumenthal, K Volpp, KG AF Blumenthal, Karen Volpp, Kevin G. TI Enhancing the Effectiveness of Food Labeling in Restaurants SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CONSUMER VIEWS; CHOICES; INFORMATION C1 [Blumenthal, Karen; Volpp, Kevin G.] Univ Penn, Ctr Hlth Incent, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Univ Penn, Dept Hlth Care Management, Wharton Sch, Philadelphia, PA 19104 USA. [Blumenthal, Karen; Volpp, Kevin G.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. RP Volpp, KG (reprint author), Univ Penn, Ctr Hlth Incent, Leonard Davis Inst Hlth Econ, 1232 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM volpp70@wharton.upenn.edu NR 10 TC 21 Z9 21 U1 0 U2 10 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 FEB 10 PY 2010 VL 303 IS 6 BP 553 EP 554 DI 10.1001/jama.2010.85 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 553PG UT WOS:000274378700028 PM 20145233 ER PT J AU Mroz, EA Rocco, JW AF Mroz, Edmund A. Rocco, James W. TI Functional p53 Status As a Biomarker for Chemotherapy Response in Oral-Cavity Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID SQUAMOUS-CELL CARCINOMA; NECK-CANCER; P73-DEPENDENT APOPTOSIS; TUMOR RESPONSE; HEAD; SURVIVAL; POLYMORPHISM; CISPLATIN; MUTATIONS; IMPACT C1 [Mroz, Edmund A.; Rocco, James W.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Mroz, Edmund A.; Rocco, James W.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Rocco, James W.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. RP Mroz, EA (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 20 TC 5 Z9 6 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 FEB 10 PY 2010 VL 28 IS 5 BP 715 EP 717 DI 10.1200/JCO.2009.26.3475 PG 4 WC Oncology SC Oncology GA 553LN UT WOS:000274368300004 PM 20048171 ER PT J AU Sanghani, M Truong, PT Raad, RA Niemierko, A Lesperance, M Olivotto, IA Wazer, DE Taghian, AG AF Sanghani, Mona Truong, Pauline T. Raad, Rita Abi Niemierko, Andrzej Lesperance, Mary Olivotto, Ivo A. Wazer, David E. Taghian, Alphonse G. TI Validation of a Web-Based Predictive Nomogram for Ipsilateral Breast Tumor Recurrence After Breast Conserving Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED CLINICAL-TRIAL; SURGICAL ADJUVANT BREAST; LOCAL RECURRENCE; LOCOREGIONAL FAILURE; CANCER; RADIOTHERAPY; IRRADIATION; MASTECTOMY; SURGERY; LUMPECTOMY AB Purpose IBTR! version 1.0 is a web-based tool that uses literature-derived relative risk ratios for seven clinicopathologic variables to predict ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT). Preliminary testing demonstrated over-estimation in high-risk subgroups. This study uses two independent population-based datasets to create and validate a modified nomogram, IBTR! version 2.0. Methods Cox regression modeling was performed on 7,811 patients treated with BCT at the British Columbia Cancer Agency (median follow-up, 9.4 years). Population-based hazard ratios were generated for the seven variables in the original nomogram. A modified nomogram was then tested against 664 patients from Massachusetts General Hospital (median follow-up, 9.3 years). The mean predicted and observed 10-year estimates were compared for the entire cohort and for four groups predefined by nomogram-predicted risks: group 1: less than 3%; group 2: 3% to 5%; group 3: 5% to 10%; and group 4: more than 10%. Results IBTR! version 2.0 predicted an overall 10-year IBTR estimate of 4.0% (95% CI, 3.8 to 4.2), while the observed estimate was 2.8% (95% CI, 1.6 to 4.7; P = .10). The predicted and observed IBTR estimates were: group 1 (n = 283): 2.2% versus 1.3%, P = .40; group 2 (n = 237): 3.8% versus 3.5%, P = .80; group 3 (n = 111): 6.7% versus 3.2%, P = .05; and group 4 (n = 33): 12.5% versus 8.7%, P = .50. Conclusion IBTR! version 2.0 is accurate in the majority of patients with a low to moderate risk of in-breast recurrence. The nomogram still overestimates risk in a minority of patients with higher risk features. Validation in a larger prospective data set is warranted. C1 [Taghian, Alphonse G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Tufts Med Ctr, Dept Radiat Oncol, Boston, MA USA. Brown Univ, Rhode Isl Hosp, Dept Radiat Oncol, Providence, RI 02903 USA. British Columbia Canc Agcy, Div Radiat Oncol, Vancouver Isl Ctr, Vancouver, BC, Canada. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Univ Victoria, Dept Math & Stat, Victoria, BC V8W 2Y2, Canada. RP Taghian, AG (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02114 USA. EM ataghian@partners.org FU Jane Mailloux Research Fund; Blanche Montesi Fund; Tim Levy Fund; National Institutes of Health (NIH) [CA21239, CA50628]; Canadian Breast Cancer Foundation, British Columbia FX Supported in part by the Jane Mailloux Research Fund, Blanche Montesi Fund, Tim Levy Fund for breast cancer research, Grants No. NIH CA21239 and CA50628 from the National Institutes of Health, and the Canadian Breast Cancer Foundation, British Columbia/Yukon Chapter. NR 25 TC 30 Z9 31 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 FEB 10 PY 2010 VL 28 IS 5 BP 718 EP 722 DI 10.1200/JCO.2009.22.6662 PG 5 WC Oncology SC Oncology GA 553LN UT WOS:000274368300005 PM 20048188 ER PT J AU Schiller, GJ O'Brien, SM Pigneux, A DeAngelo, DJ Vey, N Kell, J Solomon, S Stuart, RK Karsten, V Cahill, AL Albitar, MX Giles, FJ AF Schiller, Gary J. O'Brien, Susan M. Pigneux, Arnaud DeAngelo, Daniel J. Vey, Norbert Kell, Jonathan Solomon, Scott Stuart, Robert K. Karsten, Verena Cahill, Ann L. Albitar, Maher X. Giles, Francis J. TI Single-Agent Laromustine, A Novel Alkylating Agent, Has Significant Activity in Older Patients With Previously Untreated Poor-Risk Acute Myeloid Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HEMATOPOIETIC-CELL TRANSPLANTATION; LOW-DOSE CYTARABINE; MYELODYSPLASTIC SYNDROME; CLORETAZINE VNP40101M; COMORBIDITY INDEX; PHASE-I; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; ANTINEOPLASTIC ACTIVITY; REFRACTORY LEUKEMIA; PRODRUG CLORETAZINE AB Purpose An international phase II study of laromustine (VNP40101M), a sulfonylhydrazine alkylating agent, was conducted in patients age 60 years or older with previously untreated poor-risk acute myeloid leukemia (AML). Patients and Methods Laromustine 600 mg/m(2) was administered as a single 60-minute intravenous infusion. Patients were age 70 years or older or 60 years or older with at least one additional risk factor-unfavorable AML karyotype, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2, and/or cardiac, pulmonary, or hepatic comorbidities. Results Eighty-five patients (median age, 72 years; range, 60 to 87 years) were treated. Poor-risk features included age 70 years or older, 78%; adverse karyotype, 47%; PS of 2, 41%; pulmonary disease, 77%; cardiac disease, 73%; and hepatic disease, 3%. Ninety-six percent of patients had at least two risk factors, and 39% had at least four risk factors. The overall response rate (ORR) was 32%, with 20 patients (23%) achieving complete response (CR) and seven (8%) achieving CR with incomplete platelet recovery (CRp). ORR was 20% in patients with adverse cytogenetics; 32% in those age 70 years or older; 32% in those with PS of 2; 32% in patients with baseline pulmonary dysfunction; 34% in patients with baseline cardiac dysfunction; and 27% in 33 patients with at least four risk factors. Twelve (14%) patients died within 30 days of receiving laromustine therapy. Median overall survival was 3.2 months, with a 1-year survival of 21%; the median duration of survival for those who achieved CR/CRp was 12.4 months, with a 1-year survival of 52%. Conclusion Laromustine has significant single-agent activity in elderly patients with poor-risk AML. Adverse events are predominantly myelosuppressive or respiratory. Response rates are consistent across a spectrum of poor-risk features. C1 [Giles, Francis J.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Quest Diagnost Nichols Inst, San Juan Capistrano, CA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Inst J Paoli I Calmettes, F-13009 Marseille, France. Hop Haut Leveque, Bordeaux, France. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Wales Hosp, Cardiff CF4 4XW, S Glam, Wales. Northside Hosp, Blood & Marrow Transplant Grp, Atlanta, GA USA. Med Univ S Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA. Vion Pharmaceut, New Haven, CT USA. RP Giles, FJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, 7979 Wurzbach Rd,Mail Code 8026,Urschel Tower,Sui, San Antonio, TX 78229 USA. EM frankgiles@aol.com OI Stuart, Robert/0000-0001-7549-8008 FU Vion Pharmaceuticals, New Haven, CT FX Supported by Vion Pharmaceuticals, New Haven, CT. NR 52 TC 28 Z9 29 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2010 VL 28 IS 5 BP 815 EP 821 DI 10.1200/JCO.2009.24.2008 PG 7 WC Oncology SC Oncology GA 553LN UT WOS:000274368300019 PM 20026800 ER PT J AU Wagner, AJ Malinowska-Kolodziej, I Morgan, JA Qin, W Fletcher, CDM Vena, N Ligon, AH Antonescu, CR Ramaiya, NH Demetri, GD Kwiatkowski, DJ Maki, RG AF Wagner, Andrew J. Malinowska-Kolodziej, Izabela Morgan, Jeffrey A. Qin, Wei Fletcher, Christopher D. M. Vena, Natalie Ligon, Azra H. Antonescu, Cristina R. Ramaiya, Nikhil H. Demetri, George D. Kwiatkowski, David J. Maki, Robert G. TI Clinical Activity of mTOR Inhibition With Sirolimus in Malignant Perivascular Epithelioid Cell Tumors: Targeting the Pathogenic Activation of mTORC1 in Tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; ADVANCED SOFT-TISSUE; ANGIOMYOLIPOMA; LYMPHANGIOLEIOMYOMATOSIS; RAPAMYCIN; NEOPLASMS; SARCOMAS; PATIENT; PECOMA; GENE AB Purpose Perivascular epithelioid cell tumors (PEComas) represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. There is no known effective therapy for PEComa, and the molecular pathophysiology of aberrant mTOR signaling provided us with a scientific rationale to target this pathway therapeutically. On this mechanistic basis, we treated three consecutive patients with metastatic PEComa with an oral mTOR inhibitor, sirolimus. Patients and Methods Patients with advanced PEComa were treated with sirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined by computed tomography scans obtained at the clinical discretion of the treating physicians. Tumors were assessed for immunohistochemical evidence of mTORC1 activation and genetic evidence of alterations in TSC1 and TSC2. Results Radiographic responses to sirolimus were observed in all patients. PEComas demonstrated loss of TSC2 protein expression and evidence of baseline mTORC1 activation. Homozygous loss of TSC1 was identified in one PEComa. Conclusion Inhibition of mTORC1, pathologically activated by loss of the TSC1/TSC2 tumor suppressor complex, is a rational mechanistic target for therapy in PEComas. The clinical activity of sirolimus in PEComa additionally strengthens the pathobiologic similarities linking PEComas to other neoplasms related to the tuberous sclerosis complex. C1 [Wagner, Andrew J.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Brigham & Womens Hosp, Div Translat Med, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Canc Ctr, Ctr Mol Oncol Pathol, Dana Farber Canc Inst, Boston, MA USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Med, Melanoma & Sarcoma Serv, New York, NY 10021 USA. RP Wagner, AJ (reprint author), Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 44 Binney St, Boston, MA 02115 USA. EM Andrew_Wagner@dfci.harvard.edu RI Malinowska, Izabela/A-4816-2013 FU sPECial Fund for PEComa Research; D.K. Ludwig Fund for Cancer Research FX Supported in part by the sPECial Fund for PEComa Research and by the Virginia and D.K. Ludwig Fund for Cancer Research (to the Dana-Farber/Harvard Ludwig Center). NR 17 TC 114 Z9 127 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2010 VL 28 IS 5 BP 835 EP 840 DI 10.1200/JCO.2009.25.2981 PG 6 WC Oncology SC Oncology GA 553LN UT WOS:000274368300022 PM 20048174 ER PT J AU Henderson, TO Hlubocky, FJ Wroblewski, KE Diller, L Daugherty, CK AF Henderson, Tara O. Hlubocky, Fay J. Wroblewski, Kristen E. Diller, Lisa Daugherty, Christopher K. TI Physician Preferences and Knowledge Gaps Regarding the Care of Childhood Cancer Survivors: A Mailed Survey of Pediatric Oncologists SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID 2ND MALIGNANT NEOPLASMS; YOUNG-ADULT SURVIVORS; LONG-TERM SURVIVORS; FOLLOW-UP CARE; HEALTH-CARE; 5-YEAR SURVIVORS; ADOLESCENT CANCER; LATE MORTALITY; DELPHI PANEL; TRANSITION AB Purpose Little is known about physicians' attitudes and knowledge regarding the health care needs of childhood cancer survivors (CCS). We sought to obtain pediatric cancer physicians' self-reported attitudes and knowledge regarding this population. Methods A mailed survey was sent to 1,159 pediatric oncologists in the United States. Results A total of 655 surveys were returned (ie, 57% response rate). Median age of respondents was 47 years (range, 31 to 82 years); 57% were men. Respondents practiced for a median 14 years (range, 1 to 50 years) and reported seeing a median of 21 patients per week (range, 0 to 250 patients per week). When comfort levels in caring for CCS were described (ie, 1 = very uncomfortable; 7 = very comfortable), respondents were most comfortable with survivors <= 21 years (mean +/- standard deviation, 6.2 +/- 1.3 level), were less comfortable (5.0 +/- 1.5 level) with those older than 21 years but less than 30 years old, and were uncomfortable with CCS >= 30 years (2.9 +/- 1.7 level). In response to a clinical vignette of a 29-year-old woman treated with mantle radiation for Hodgkin's lymphoma at 16 years of age, and on the basis of available guidelines, 34% of respondents did not appropriately recommend yearly breast cancer surveillance; 43% of respondents did not appropriately recommend cardiac surveillance; and 24% of respondents did not appropriately recommend yearly thyroid surveillance. Those with greater self-reported familiarity with available long-term follow-up (LTFU) guidelines (odds ratio [OR], 1.33; 95% CI, 1.15 to 1.54) and with receipt of training in the care of CCS (OR, 1.73; 95% CI, 1.18 to 2.52) were more likely to have answered all three questions correctly. Conclusion Pediatric oncologists express a range of preferences with regard to LTFU of CCS. Many appear unfamiliar with LTFU surveillance guidelines. J Clin Oncol 28: 878-883. (C) 2009 by American Society of Clinical Oncology C1 [Henderson, Tara O.] Univ Chicago, Sect Pediat Hematol Oncol & Stem Cell Transplanta, Chicago, IL 60637 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. RP Henderson, TO (reprint author), Univ Chicago, Sect Pediat Hematol Oncol & Stem Cell Transplanta, 5841 S Maryland Ave,MC 4060, Chicago, IL 60637 USA. EM thenderson@uchicago.edu FU National Institutes of Health [K07CA134935-02] FX Supported in part by National Institutes of Health Grant No. K07CA134935-02 (T.O.H.). NR 39 TC 39 Z9 39 U1 1 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 FEB 10 PY 2010 VL 28 IS 5 BP 878 EP 883 DI 10.1200/JCO.2009.25.6107 PG 6 WC Oncology SC Oncology GA 553LN UT WOS:000274368300029 PM 20038717 ER PT J AU Pozdnyakova, O Spieler, PJ Abraham, J Freedman, AS Kutok, JL AF Pozdnyakova, Olga Spieler, Paul J. Abraham, John Freedman, Arnold S. Kutok, Jeffery L. TI Epstein-Barr Virus-Associated Diffuse Large B-Cell Lymphoma in an Immunocompetent Woman SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LYMPHOPROLIFERATIVE DISORDERS; DISEASE C1 [Pozdnyakova, Olga; Kutok, Jeffery L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Spieler, Paul J.] Anna Jacques Hosp, Dept Hematol Oncol, Newburyport, MA USA. [Abraham, John] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Freedman, Arnold S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Pozdnyakova, O (reprint author), Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. FU NCI NIH HHS [P01 CA092625] NR 6 TC 2 Z9 2 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 FEB 10 PY 2010 VL 28 IS 5 BP E75 EP E78 DI 10.1200/JCO.2009.23.1423 PG 4 WC Oncology SC Oncology GA 553LN UT WOS:000274368300035 PM 19917837 ER PT J AU Sohani, AR Ferry, JA Chang, PS Abramson, JS AF Sohani, Aliyah R. Ferry, Judith A. Chang, Priscilla S. Abramson, Jeremy S. TI Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma During Therapy With Alemtuzumab for T-Cell Prolymphocytic Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; LYMPHOPROLIFERATIVE DISORDERS; CHEMOTHERAPY; FLUDARABINE; CAMPATH-1H; DISEASE C1 [Sohani, Aliyah R.; Ferry, Judith A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sohani, Aliyah R.; Ferry, Judith A.; Chang, Priscilla S.; Abramson, Jeremy S.] Harvard Univ, Sch Med, Boston, MA USA. [Chang, Priscilla S.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Abramson, Jeremy S.] Massachusetts Gen Hosp, Ctr Canc, Ctr Lymphoma, Boston, MA 02114 USA. RP Sohani, AR (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 12 TC 8 Z9 8 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 FEB 10 PY 2010 VL 28 IS 5 BP E69 EP E72 DI 10.1200/JCO.2009.24.4194 PG 4 WC Oncology SC Oncology GA 553LN UT WOS:000274368300033 PM 19917859 ER PT J AU Bennett, GG Herring, SJ Puleo, E Stein, EK Emmons, KM Gillman, MW AF Bennett, Gary G. Herring, Sharon J. Puleo, Elaine Stein, Evelyn K. Emmons, Karen M. Gillman, Matthew W. TI Web-based Weight Loss in Primary Care: A Randomized Controlled Trial SO OBESITY LA English DT Article ID OBESITY MANAGEMENT; LOSS PROGRAM; INTERVENTIONS; TECHNOLOGY; PHYSICIANS; ADULTS; RISK; MAIL AB Evidence is lacking regarding effective and sustainable weight loss approaches for use in the primary care setting. We conducted a 12-week randomized controlled trial to evaluate the short-term efficacy of a web-based weight loss intervention among 101 primary care patients with obesity and hypertension. Patients had access to a comprehensive website that used a moderate-intensity weight loss approach designed specifically for web-based implementation. Patients also participated in four (two in-person and two telephonic) counseling sessions with a health coach. Intent-to-treat analysis showed greater weight loss at 3 months (-2.56 kg; 95% CI -3.60, -1.53) among intervention participants (-2.28 +/- 3.21 kg), relative to usual care (0.28 +/- 1.87 kg). Similar findings were observed among intervention completers (-3.05 kg; 95% CI -4.24, -1.85). High rates of participant retention (84%) and website utilization were observed, with the greatest weight loss found among those with a high frequency of website logins (quartile 4 vs. 1: -4.16 kg; 95% CI -1.47, -6.84). The intervention's approach promoted moderate weight loss at 12 weeks, though greater weight loss was observed among those with higher levels of website utilization. Efficacious web-based weight loss interventions can be successfully offered in the primary care setting. C1 [Bennett, Gary G.; Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Bennett, Gary G.; Stein, Evelyn K.; Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Herring, Sharon J.; Gillman, Matthew W.] Harvard Pilgrim Hlth Care, Dept Ambulatory Care & Prevent, Boston, MA USA. [Puleo, Elaine] Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. RP Bennett, GG (reprint author), Duke Univ, BennettLab, Durham, NC 27710 USA. EM gary.bennett@duke.edu RI Kattelmann, Kendra/E-8225-2013 FU Sanofi aventis; National Cancer Institute [1K22Ca126992-01, 1K05Ca124415-01a1]; Health Resources and Services administration and the Department [5 T32 HP11001-19] FX We gratefully acknowledge the efforts of Carol Shlossman. This study was supported by an unrestricted grant from Sanofi aventis. G. G. B. is also supported by grant 1K22Ca126992- 01 from the National Cancer Institute. S. J. H. was supported by an institutional Ruth L. Kirschstein National Research Service award (5 T32 HP11001-19) from the Health Resources and Services administration and the Department of ambulatory Care and Prevention at Harvard Medical School and Harvard Pilgrim Health Care in Boston, Massachusetts. K. M. E. is supported by grant 1K05Ca124415-01a1 from the National Cancer Institute. G. G. B. is now at Duke University (http://bennettlab.org). None of the funding sources had any involvement with the design and conduct of the study; collection, management, analysis, and interpretation of the data or preparation, review, or approval of the manuscript. The corresponding author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This manuscript represents valid work that has not been published elsewhere nor is it being considered for publication elsewhere. all authors take responsibility for the integrity of this manuscript and have made substantial contributions toward conception, design, acquisition of data, analysis and interpretation of data as well as the writing of the manuscript and final approval of the submitted work. NR 32 TC 76 Z9 76 U1 4 U2 20 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 FEB 10 PY 2010 VL 18 IS 2 BP 308 EP 313 DI 10.1038/oby.2009.242 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 551KX UT WOS:000274208600015 PM 19696764 ER PT J AU Hovik, H Chen, T AF Hovik, Hedda Chen, Tsute TI Dynamic probe selection for studying microbial transcriptome with high-density genomic tiling microarrays SO BMC BIOINFORMATICS LA English DT Article ID OLIGONUCLEOTIDE MICROARRAYS; SECONDARY STRUCTURE; GENE-EXPRESSION; DESIGN CRITERIA; NONCODING RNAS; DNA; ARRAYS; HYBRIDIZATION; IDENTIFICATION; OPTIMIZATION AB Background: Current commercial high-density oligonucleotide microarrays can hold millions of probe spots on a single microscopic glass slide and are ideal for studying the transcriptome of microbial genomes using a tiling probe design. This paper describes a comprehensive computational pipeline implemented specifically for designing tiling probe sets to study microbial transcriptome profiles. Results: The pipeline identifies every possible probe sequence from both forward and reverse-complement strands of all DNA sequences in the target genome including circular or linear chromosomes and plasmids. Final probe sequence lengths are adjusted based on the maximal oligonucleotide synthesis cycles and best isothermality allowed. Optimal probes are then selected in two stages - sequential and gap-filling. In the sequential stage, probes are selected from sequence windows tiled alongside the genome. In the gap-filling stage, additional probes are selected from the largest gaps between adjacent probes that have already been selected, until a predefined number of probes is reached. Selection of the highest quality probe within each window and gap is based on five criteria: sequence uniqueness, probe self-annealing, melting temperature, oligonucleotide length, and probe position. Conclusions: The probe selection pipeline evaluates global and local probe sequence properties and selects a set of probes dynamically and evenly distributed along the target genome. Unique to other similar methods, an exact number of non-redundant probes can be designed to utilize all the available probe spots on any chosen microarray platform. The pipeline can be applied to microbial genomes when designing high-density tiling arrays for comparative genomics, ChIP chip, gene expression and comprehensive transcriptome studies. sdss C1 [Chen, Tsute] Forsyth Inst, Dept Mol Genet, Boston, MA USA. [Hovik, Hedda] Univ Oslo, Dept Oral Biol, Fac Dent, Oslo, Norway. RP Chen, T (reprint author), Forsyth Inst, Dept Mol Genet, Boston, MA USA. EM tchen@forsyth.org FU National Institute for Dental and Craniofacial Research [R21 DE018803-01A1] FX HH was supported by a PhD stipend and mobility grant from the Faculty of Dentistry, University of Oslo, Oslo, Norway. This project was funded by a grant from National Institute for Dental and Craniofacial Research (grant No. R21 DE018803-01A1). We gratefully acknowledge Wen-Han Yu and Khoi Nguyen for the design and implementation of the project web site. We also thank Dr. Ingar Olsen for valuable comments on the manuscript. NR 52 TC 7 Z9 8 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 FEB 9 PY 2010 VL 11 AR 82 DI 10.1186/1471-2105-11-82 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 568UV UT WOS:000275549800001 PM 20144223 ER PT J AU Antonov, J Popovici, V Delorenzi, M Wirapati, P Baltzer, A Oberli, A Thurlimann, B Giobbie-Hurder, A Viale, G Altermatt, HJ Aebi, S Jaggi, R AF Antonov, Janine Popovici, Vlad Delorenzi, Mauro Wirapati, Pratyaksha Baltzer, Anna Oberli, Andrea Thuerlimann, Beat Giobbie-Hurder, Anita Viale, Giuseppe Altermatt, Hans Joerg Aebi, Stefan Jaggi, Rolf TI Molecular risk assessment of BIG 1-98 participants by expression profiling using RNA from archival tissue SO BMC CANCER LA English DT Article ID EARLY BREAST-CANCER; KI-67 LABELING INDEX; GENE-EXPRESSION; POSTMENOPAUSAL WOMEN; PREDICTIVE-VALUE; GRADE INDEX; PROGNOSTIC SIGNATURE; CLINICAL-APPLICATION; ENDOCRINE THERAPY; RANDOMIZED-TRIAL AB Background: The purpose of the work reported here is to test reliable molecular profiles using routinely processed formalin-fixed paraffin-embedded (FFPE) tissues from participants of the clinical trial BIG 1-98 with a median follow-up of 60 months. Methods: RNA from fresh frozen (FF) and FFPE tumor samples of 82 patients were used for quality control, and independent FFPE tissues of 342 postmenopausal participants of BIG 1-98 with ER-positive cancer were analyzed by measuring prospectively selected genes and computing scores representing the functions of the estrogen receptor (eight genes, ER_8), the progesterone receptor (five genes, PGR_5), Her2 (two genes, HER2_2), and proliferation (ten genes, PRO_10) by quantitative reverse transcription PCR (qRT-PCR) on TaqMan Low Density Arrays. Molecular scores were computed for each category and ER_8, PGR_5, HER2_2, and PRO_10 scores were combined into a RISK_25 score. Results: Pearson correlation coefficients between FF- and FFPE-derived scores were at least 0.94 and high concordance was observed between molecular scores and immunohistochemical data. The HER2_2, PGR_ 5, PRO_10 and RISK_25 scores were significant predictors of disease free-survival (DFS) in univariate Cox proportional hazard regression. PRO_10 and RISK_25 scores predicted DFS in patients with histological grade II breast cancer and in lymph node positive disease. The PRO_10 and PGR_ 5 scores were independent predictors of DFS in multivariate Cox regression models incorporating clinical risk indicators; PRO_10 outperformed Ki-67 labeling index in multivariate Cox proportional hazard analyses. Conclusions: Scores representing the endocrine responsiveness and proliferation status of breast cancers were developed from gene expression analyses based on RNA derived from FFPE tissues. The validation of the molecular scores with tumor samples of participants of the BIG 1-98 trial demonstrates that such scores can serve as independent prognostic factors to estimate disease free survival (DFS) in postmenopausal patients with estrogen receptor positive breast cancer. Trial Registration: Current Controlled Trials: NCT00004205 C1 [Antonov, Janine; Baltzer, Anna; Oberli, Andrea; Aebi, Stefan; Jaggi, Rolf] Univ Bern, Dept Clin Res, Bern, Switzerland. [Popovici, Vlad; Delorenzi, Mauro; Wirapati, Pratyaksha] SIB, Natl Ctr Competence Res Mol Oncol, Lausanne, Switzerland. [Thuerlimann, Beat] Kantonsspital, Senol Ctr Eastern Switzerland, St Gallen, Switzerland. [Giobbie-Hurder, Anita] Dana Farber Canc Inst, Ctr Stat, Int Breast Canc Study Grp, Boston, MA 02115 USA. [Viale, Giuseppe] Univ Milan, European Inst Oncol, Div Pathol & Lab Med, Milan, Italy. [Altermatt, Hans Joerg] Pathol Langgasse, Bern, Switzerland. [Aebi, Stefan] Univ Hosp Bern, CH-3010 Bern, Switzerland. [Thuerlimann, Beat; Aebi, Stefan] Swiss Grp Clin Canc Res SAKK, Bern, Switzerland. RP Jaggi, R (reprint author), Univ Bern, Dept Clin Res, Bern, Switzerland. EM rolf.jaggi@dkf.unibe.ch RI Popovici, Vlad/C-2039-2008; Aebi, Stefan/F-2004-2010 OI Popovici, Vlad/0000-0002-1311-9188; Aebi, Stefan/0000-0002-3383-9449 FU Cancer Research Switzerland/Oncosuisse; NCCR "Molecular Oncology"; Bernese Cancer League; US NCI [CA-75362]; Novartis [BIG 1-98]; Swedish Cancer Society; The Cancer Council Australia; Australian New Zealand Breast Cancer Trials Group; Frontier Science and Technology Research Foundation; Swiss Group for Clinical Cancer Research (SAKK); Foundation for Clinical Cancer Research of Eastern Switzerland FX We thank all patients, physicians and pathologists who participated in the BIG 1-98 trial. We thank the IBCSG for providing material and corresponding clinicopathological data. We thank Dr. M. Schobesberger and K. Price for helpful discussions and critical reading of the manuscript and R. Kammler for preparing FFPE material. This work was supported by Cancer Research Switzerland/Oncosuisse, the NCCR "Molecular Oncology" and the Bernese Cancer League. The IBCSG Statistical Center receives funding from the US NCI (CA-75362). The BIG 1-98 trial was financed by Novartis and coordinated by the International Breast Cancer Study Group (funded by the Swedish Cancer Society, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research (SAKK), Cancer Research Switzerland/Oncosuisse and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK). NR 55 TC 6 Z9 6 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD FEB 9 PY 2010 VL 10 AR 37 DI 10.1186/1471-2407-10-37 PG 13 WC Oncology SC Oncology GA 564JD UT WOS:000275208200003 PM 20144231 ER PT J AU Farwell, WR Taylor, EN AF Farwell, Wildon R. Taylor, Eric N. TI Serum anion gap, bicarbonate and biomarkers of inflammation in healthy individuals in a national survey SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Article ID NUTRITION EXAMINATION SURVEY; BLOOD-CELL COUNT; CEREBROVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; LEUKOCYTE COUNT; US ADULTS; MORTALITY; RISK; CANCER; ACIDIFICATION AB Background: In vitro data suggest that lower extracellular pH activates the immune system. We conducted a population-based study of the relation between serum acid-base status and inflammation. Methods: We examined the serum anion gap and serum levels of bicarbonate and inflammatory biomarkers in nolo healthy adults who participated in the National Health and Nutrition Examination Survey during 1999-2006. We excluded participants who had chronic disease, recent infection and an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m(2). Results: The mean values of serum anion gap, bicarbonate level, leukocyte count and C-reactive protein level were all within normal limits. After adjustment for age, sex, ethnic background, body mass index, serum albumin level and other factors, we found that a higher anion gap and lower bicarbonate level were associated with a higher leukocyte count and higher C-reactive protein level. Compared with participants in the lowest quartile of anion gap, those in the highest quartile had a leukocyte count that was 1.0 x 10(9)/L higher and a C-reactive protein level that was 10.9 nmol/L higher (p < 0.01). Compared with participants in the highest quartile of bicarbonate level, those in the lowest quartile had a leukocyte count that was 0.7 x 10(9)/L higher and a C-reactive protein level that was 4.0 nmol/L higher (p <= 0.02). A higher anion gap and lower bicarbonate level were also associated with a higher platelet count, a larger mean platelet volume and a higher ferritin level. Interpretation: A higher serum anion gap and lower bicarbonate level were associated with higher levels of inflammatory biomarkers in a healthy sample of the general population. Further studies are needed to elucidate the relation between acid-base status and inflammation. C1 [Farwell, Wildon R.] VA Boston Healthcare Syst, MAVERIC, Boston, MA 02130 USA. [Farwell, Wildon R.] Harvard Univ, Brigham & Womens Hosp, Div Aging, Dept Med,Med Sch, Boston, MA 02115 USA. [Taylor, Eric N.] Harvard Univ, Brigham & Womens Hosp, Dept Med, Div Renal,Med Sch, Boston, MA 02115 USA. [Taylor, Eric N.] Harvard Univ, Brigham & Womens Hosp, Dept Med, Channing Lab,Med Sch, Boston, MA 02115 USA. RP Farwell, WR (reprint author), VA Boston Healthcare Syst, MAVERIC, 150 S Huntington Ave, Boston, MA 02130 USA. EM wildon.farwell@va.gov FU US National Institutes of Health [DK73381] FX The study was supported by the US National Institutes of Health (grant no. DK73381). The study sponsor was not involved in the design or conduct of the study, the collection, management, analysis or interpretation of the data, or the preparation, review or approval of the manuscript. NR 22 TC 1 Z9 1 U1 0 U2 1 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD FEB 9 PY 2010 VL 182 IS 2 BP 134 EP 141 DI 10.1503/cmaj.090329 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 549OA UT WOS:000274060900004 ER PT J AU Choi, AI Li, YM Deeks, SG Grunfeld, C Volberding, PA Shlipak, MG AF Choi, Andy I. Li, Yongmei Deeks, Steven G. Grunfeld, Carl Volberding, Paul A. Shlipak, Michael G. TI Association Between Kidney Function and Albuminuria With Cardiovascular Events in HIV-Infected Persons SO CIRCULATION LA English DT Article DE cardiovascular diseases; glomerular filtration rate; heart failure; HIV; proteinuria ID OF-VETERANS-AFFAIRS; IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; INTIMA-MEDIA THICKNESS; MYOCARDIAL-INFARCTION; DISEASE; DEATH; MORTALITY; RISK; ASCERTAINMENT AB Background-Cardiovascular disease (CVD) is now a leading cause of death in HIV-infected persons; however, risk markers for CVD are ill defined in this population. We examined the association between longitudinal measures of kidney function and albuminuria with risk of atherosclerotic CVD and heart failure in a contemporary cohort of HIV-infected individuals. Methods and Results-We followed a national sample of 17 264 HIV-infected persons receiving care in the Veterans Health Administration for (1) incident CVD, defined as coronary, cerebrovascular, or peripheral arterial disease, and (2) incident heart failure. Rates of CVD and heart failure were at least 6-fold greater in the highest-risk patients with an estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m(2) and albuminuria >300 mg/dL versus those with no evidence of kidney disease (eGFR >= 60 mL/min per 1.73 m2 and no albuminuria). After multivariable adjustment, eGFR levels 45 to 59, 30 to 44, and <30 mL/min per 1.73 m2 were associated with hazard ratios for incident CVD of 1.46 (95% confidence interval, 1.15 to 1.86), 2.03 (1.47 to 2.82), and 1.99 (1.46 to 2.70) compared with eGFR >= 60 mL/min per 1.73 m2. Similarly, albuminuria levels 30, 100, and >= 300 mg/dL had hazard ratios for CVD of 1.28 (1.09 to 1.51), 1.48 (1.15 to 1.90), and 1.71 (1.30 to 2.27) compared with absent albuminuria. The associations between eGFR and albuminuria with heart failure were larger in magnitude and followed the same trends. Conclusions-In this national sample of HIV-infected persons, eGFR and albuminuria levels were strongly associated with risk of CVD and heart failure. Kidney function and albuminuria provide complementary prognostic information that may aid CVD risk stratification in HIV-infected persons. (Circulation. 2010; 121: 651-658.) C1 [Choi, Andy I.; Li, Yongmei; Grunfeld, Carl; 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. [Deeks, Steven G.] San Francisco Gen Hosp, Posit Hlth Program, San Francisco, CA 94110 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 RI Max, Mad/E-5238-2010 OI Max, Mad/0000-0001-6966-6829 FU NCRR NIH HHS [KL2 RR024130, KL2RR024130]; NIA NIH HHS [R03 AG034871, 1R03AG034871-01, R03 AG034871-01]; NIAID NIH HHS [K24 AI069994, K24AI069994]; NIDDK NIH HHS [K23 DK080645, K23 DK080645-02, K23DK080645-01A1, R01 DK066488, R01DK066488-01] NR 44 TC 88 Z9 93 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 FEB 9 PY 2010 VL 121 IS 5 BP 651 EP 658 DI 10.1161/CIRCULATIONAHA.109.898585 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 553JO UT WOS:000274362800007 PM 20100969 ER PT J AU Singh, JP Abraham, WT AF Singh, Jagmeet P. Abraham, William T. TI Enhancing the Response to Cardiac Resynchronization Therapy Is It Time to Individualize the Left Ventricular Pacing Site? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE biventricular pacing; cardiac resynchronization therapy; heart failure ID ACUTE HEMODYNAMIC-RESPONSE; CORONARY VENOUS ANATOMY; CHRONIC HEART-FAILURE; BUNDLE-BRANCH BLOCK; PREDICTS; ACTIVATION; INSIGHTS C1 [Abraham, William T.] Ohio State Univ, Med Ctr, Div Cardiovasc Med, Columbus, OH 43210 USA. [Singh, Jagmeet P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Heart, Boston, MA USA. RP Abraham, WT (reprint author), Ohio State Univ, Med Ctr, Div Cardiovasc Med, 473 W 12th Ave,Room 110P DHLRI, Columbus, OH 43210 USA. EM william.abraham@osumc.edu NR 15 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 FEB 9 PY 2010 VL 55 IS 6 BP 576 EP 578 DI 10.1016/j.jacc.2009.10.017 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 551TB UT WOS:000274232000008 PM 19931363 ER PT J AU Arias, DAA McCarty, N Lua, L Maldonado, RA Shinohara, ML Cantor, H AF Arias, Diana A. Alvarez McCarty, Nami Lua, Linrong Maldonado, Roberto A. Shinohara, Mari L. Cantor, Harvey TI Unexpected role of clathrin adaptor AP-1 in MHC-dependent positive selection of T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adaptor protein; immunologic synapse; T cell development; T cell receptor ID IMMUNOLOGICAL SYNAPSE; NEGATIVE SELECTION; ANTIGEN RECEPTORS; GENE-EXPRESSION; DOWN-REGULATION; BINDING-SITE; THYMOCYTES; COMPLEX; DISTINCT; ACTIVATION AB Trafficking of transmembrane receptors to a specific intracellular compartment is conducted by adaptor molecules that bind to target motifs within the cytoplasmic domains of cargo proteins. We generated mice containing a lymphoid-specific deficiency of AP-1 using RNAi knockdown technology. Inhibition of AP-1 expression in thymocytes blocks progression from double-positive immature thymocytes, resulting in complete absence of CD4(+) single-positive thymocytes and severe reduction of CD3(+)CD8(+) single-positive thymocytes. Analysis of the contribution of AP-1 deficiency on the interaction between mature CD4(+) T cells and antigen-presenting cells revealed that AP-1 is essential to efficient immune synapse formation and associated T cell activation, suggesting a possible mechanism of AP-1 function in thymocyte development. C1 [McCarty, Nami; Lua, Linrong; Shinohara, Mari L.; Cantor, Harvey] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Arias, Diana A. Alvarez; McCarty, Nami; Lua, Linrong; Maldonado, Roberto A.; Shinohara, Mari L.; Cantor, Harvey] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cantor, H (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM harvey_cantor@dfci.harvard.edu OI Lu, Linrong/0000-0002-0171-4115 FU National Institutes of Health Research [AI 37562, 48125]; DFCI/NIH [T32 AI007386, T32 CA070083] FX We thank the Dana-Farber Cancer Institute (DFCI) Flow Cytometry Facility, the NeuroDiscovery Imaging Center at Harvard University, and Alison Angel and Dr. Hye-Jung Kim for help with manuscript preparation. This work was supported in part by National Institutes of Health Research Grants AI 37562 and 48125 and The Claudia Adams Barr Program (DFCI) (to H. C.); T32 AI007386 (to N.M. and L. L.); and T32 CA070083 (to M. L. S.) from DFCI/NIH. NR 43 TC 1 Z9 1 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 9 PY 2010 VL 107 IS 6 BP 2556 EP 2561 DI 10.1073/pnas.0913671107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554AO UT WOS:000274408100037 ER PT J AU Leavenworth, JW Schellack, C Kim, HJ Lu, L Spee, P Cantor, H AF Leavenworth, Jianmei W. Schellack, Carola Kim, Hye-Jung Lu, Linrong Spee, Pieter Cantor, Harvey TI Analysis of the cellular mechanism underlying inhibition of EAE after treatment with anti-NKG2A F(ab ')(2) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE natural killer; CD94; Qa-1b; multiple sclerosis ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; NATURAL-KILLER-CELLS; REGULATORY T-CELLS; MULTIPLE-SCLEROSIS; CUTTING EDGE; ACTIVATION; RECEPTOR; FAMILY; SAP; CYTOTOXICITY AB Autoimmune encephalomyelitis may be ameliorated experimentally by enhancing NK cell-mediated elimination of activated auto-reactive T cells through a mutation that interrupts the interaction between Qa-1(b) and CD94/NKG2A. Here we evaluate the ability of an anti-NKG2A F(ab')(2) Ab to enhance elimination of autoreactive T cells and reduce experimental autoimmune encephalomyelitis (EAE). Anti-NKG2A F(ab')(2) treatment diminishes progression of both myelin oligodendrocyte glycoprotein (MOG)-induced EAE in intact C57BL/6 mice and after adoptive transfer of disease-causing T cells. Analyses of the underlying mechanism revealed that administration of anti-NKG2A F(ab')(2) Ab reduces CD4(+) T recall responses to MOG and skews the proportion of IL-17- and IFN gamma-producing CD4(+) T cells toward the protective IL-4- and IL-10-secreting CD4(+) T cell subpopulations. CD94/NKG2A-dependent inhibition of inflammatory damage to spinal cord is associated with decreased infiltration of T cells and reduced microglia activation in the central nervous system. Because anti-NKG2A F(ab')(2) treatment had no detectable effect on the numbers or activity of T and B lymphocytes and NK cells in peripheral lymphoid tissues, this anti-NKG2A-based approach may represent a safe and effective therapy for this CNS disorder. C1 [Leavenworth, Jianmei W.; Kim, Hye-Jung; Cantor, Harvey] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Leavenworth, Jianmei W.; Kim, Hye-Jung; Cantor, Harvey] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Schellack, Carola] Novo Nordisk AS, Dept Immunopharmacol, DK-2760 Malov, Denmark. [Lu, Linrong] Zhejiang Univ, Sch Med, Inst Immunol, Hangzhou 310058, Zhejiang, Peoples R China. [Spee, Pieter] Novo Nordisk AS, Dept NK Cell Biol, DK-2760 Malov, Denmark. RP Cantor, H (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM harvey_cantor@dfci.harvard.edu RI Lu, Linrong/A-1429-2013; OI Lu, Linrong/0000-0002-0171-4115 FU NIH [AI 037562]; Novo Nordisk [T32 CA070083] FX This work was supported in part by NIH Research Grant AI 037562 and a gift from The Leroy and Shoshana Schecter Research Foundation to H. C., and a Collaborative Sponsored Research Agreement with Novo Nordisk and T32 CA070083 to J.W.L. NR 34 TC 28 Z9 29 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 9 PY 2010 VL 107 IS 6 BP 2562 EP 2567 DI 10.1073/pnas.0914732107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554AO UT WOS:000274408100038 PM 20133787 ER PT J AU Mukasa, A Wykosky, J Ligon, KL Chin, L Cavenee, WK Furnari, F AF Mukasa, Akitake Wykosky, Jill Ligon, Keith L. Chin, Lynda Cavenee, Webster K. Furnari, Frank TI Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tumorigenicity; gliomblastoma; epidermal growth factor receptor ID CONFERS ENHANCED TUMORIGENICITY; HUMAN GLIOBLASTOMA CELLS; GENE-EXPRESSION; MALIGNANT GLIOMAS; KINASE INHIBITORS; MULTIFORME; AMPLIFICATION; RESISTANCE; BRAIN; OVEREXPRESSION AB Epidermal growth factor receptor (EGFR) gene amplification is the most common genetic alteration in high-grade glioma, and approximate to 50% of EGFR-amplified tumors also harbor a constitutively active mutant form of the receptor, Delta EGFR. Although Delta EGFR greatly enhances tumor growth and is thus an attractive target for anti-glioma therapies, recent clinical experiences with EGFR kinase inhibitors have been disappointing, because resistance is common and tumors eventually recur. Interestingly, it has not been established whether Delta EGFR is required for maintenance of glioma growth in vivo, and, by extension, if it truly represents a rational therapeutic target. Here, we demonstrate that in vivo silencing of regulatable Delta EGFR with doxycycline attenuates glioma growth and, therefore, that it is crucial for maintenance of enhanced tumorigenicity. Similar to the clinical experience, tumors eventually regained aggressive growth after a period of stasis, but interestingly, without re-expression of Delta EGFR. To determine how tumors acquired this ability, we found that a unique gene, KLHDC8, herein referred to as S Delta E (Substitute for Delta EGFR Expression)-1, is highly expressed in these tumors, which have escaped dependence on Delta EGFR. S Delta E-1 is also expressed in human gliomas and knockdown of its expression in Delta EGFR-independent "escaper" tumors suppressed tumor growth. Taken together, we conclude that Delta EGFR is required for both glioma establishment and maintenance, and that gliomas undergo selective pressure in vivo to employ alternative compensatory pathways to maintain aggressiveness in the event of EGFR silencing. Such alternative pathways function as substitutes for Delta EGFR signaling and should therefore be considered as potential targets for additional therapy. C1 [Mukasa, Akitake; Wykosky, Jill; Cavenee, Webster K.; Furnari, Frank] Univ Calif San Diego, Ludwig Inst Canc Res, San Diego, CA 92039 USA. [Cavenee, Webster K.; Furnari, Frank] Univ Calif San Diego, Ctr Canc, San Diego, CA 92039 USA. [Ligon, Keith L.; Chin, Lynda] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ligon, Keith L.; Chin, Lynda] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Ligon, Keith L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ligon, Keith L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Cavenee, WK (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, San Diego, CA 92039 USA. EM wcavenee@ucsd.edu; ffurnari@ucsd.edu FU SUMITOMO Life Social Welfare Services Foundation; Paul Taylor/American Brain Tumor Association; National Institutes of Health [P01 CAO95616]; Goldhirsh Foundation FX GBM clinical samples were kindly provided by Dr. Ryo Nishikawa, Department of Neuro-Oncology, Saitama Medical University, Saitama, Japan. A. M. was supported in part by a fellowship from the SUMITOMO Life Social Welfare Services Foundation and the Paul Taylor/American Brain Tumor Association Fellowship. These studies were supported in part by National Institutes of Health Grant P01 CAO95616 (to W. K. C., F. F., K. L., and L. C.) and the Goldhirsh Foundation (F. F.). W. K. C. is a fellow of the National Foundation for Cancer Research. NR 36 TC 37 Z9 40 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 9 PY 2010 VL 107 IS 6 BP 2616 EP 2621 DI 10.1073/pnas.0914356107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554AO UT WOS:000274408100047 PM 20133782 ER PT J AU Carreras, I Yuruker, S Aytan, N Hossain, L Choi, JK Jenkins, BG Kowall, NW Dedeoglu, A AF Carreras, Isabel Yuruker, Sinan Aytan, Nurgul Hossain, Lokman Choi, Ji-Kyung Jenkins, Bruce G. Kowall, Neil W. Dedeoglu, Alpaslan TI Moderate exercise delays the motor performance decline in a transgenic model of ALS SO BRAIN RESEARCH LA English DT Article DE Stereological method; Motor neuron; Amyotrophic lateral sclerosis; Exercise ID AMYOTROPHIC-LATERAL-SCLEROSIS; GROWTH-FACTOR-I; SUPEROXIDE-DISMUTASE GENE; ADULT DENTATE GYRUS; MOUSE MODEL; PHYSICAL-ACTIVITY; SPINAL-CORD; PROLONGS SURVIVAL; SYNAPTIC PLASTICITY; NEURON DEGENERATION AB The relationship between exercise and amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by motor neuron loss, rapidly progressive weakness and early death has been controversial. We studied the effect of a high (HEX and moderate-level exercise (MEX) on body weight, motor performance and motor neuron counts in the ventral horn of spinal cords in a transgenic mouse model of ALS (G93A-SOD1) that overexpresses a mutated form of the human SOD1 gene that is a cause of familial ALS. These transgenic mice show several similarities to the human disease, including rapid progressive motor weakness from 100 days of age and premature death at around 135 days of age. Mice were exposed to high or mid-level exercise of left sedentary (SED). At 70, 95 and 120 days of age, spinal cords were processed following euthanasia. Motor neurons larger than 15 mu m in diameter were counted with a design-based stereological protocol using an optical fractionator probe in the ventral horn of different regions of the cord and compared to wild-type littermates. Moderate exercise delayed the onset of motor deficit by over a week. High exercise slightly but significantly hastened the onset of motor performance deficits. Motor neuron density in the lumbar cord was significantly higher in MEX group compared to SED at 95 days of age. These results show the beneficial effects of moderate exercise on the preservation of motor performance that correlates with higher motor neuron density in the ventral horn of the lumbar spinal cord in G93A mice. Published by Elsevier B.V. C1 [Dedeoglu, Alpaslan] VA Boston Healthcare Syst, Res & Dev Serv, Res GRECC, Boston, MA 02130 USA. [Carreras, Isabel] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. [Yuruker, Sinan] Hacettepe Univ, Sch Med, Dept Histol & Embryol, Ankara, Turkey. [Yuruker, Sinan; Aytan, Nurgul; Kowall, Neil W.; Dedeoglu, Alpaslan] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Choi, Ji-Kyung; Jenkins, Bruce G.; Dedeoglu, Alpaslan] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Choi, Ji-Kyung; Jenkins, Bruce G.; Dedeoglu, Alpaslan] Harvard Univ, Sch Med, Boston, MA USA. RP Dedeoglu, A (reprint author), VA Boston Healthcare Syst, Res & Dev Serv, Res GRECC, Bldg 1A-151,150 S Huntington Ave, Boston, MA 02130 USA. EM dedeoglu@bu.edu RI Kowall, Neil/G-6364-2012; Yuruker, Sinan/O-7364-2016; OI Kowall, Neil/0000-0002-6624-0213; Dedeoglu, Alpaslan/0000-0003-1156-0874 FU Department of Veteran Affairs; NIH [P30 AG13846] FX This research is supported by grants from the Department of Veteran Affairs (Merit Award) to AD, NIH (ADCC grant P30 AG13846) to NWK and AD. There is no conflict of interest. The authors thank Sukru N. Kaymakcalan, Brendon Kapinos and Kerry Cormier for their technical help in establishing the exercise protocol and spinal cord processing. NR 70 TC 30 Z9 31 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 8 PY 2010 VL 1313 BP 192 EP 201 DI 10.1016/j.brainres.2009.11.051 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 559YQ UT WOS:000274869100019 PM 19968977 ER PT J AU Aste-Amezaga, M Zhang, NY Lineberger, JE Arnold, BA Toner, TJ Gu, MC Huang, LY Vitelli, S Vo, KT Haytko, P Zhao, JZ Baleydier, F L'Heureux, S Wang, HF Gordon, WR Thoryk, E Andrawes, MB Tiyanont, K Stegmaier, K Roti, G Ross, KN Franlin, LL Wang, H Wang, FB Chastain, M Bett, AJ Audoly, LP Aster, JC Blacklow, SC Huber, HE AF Aste-Amezaga, Miguel Zhang, Ningyan Lineberger, Janet E. Arnold, Beth A. Toner, Timothy J. Gu, Mingcheng Huang, Lingyi Vitelli, Salvatore Vo, Kim T. Haytko, Peter Zhao, Jing Zhang Baleydier, Frederic L'Heureux, Sarah Wang, Hongfang Gordon, Wendy R. Thoryk, Elizabeth Andrawes, Marie Blanke Tiyanont, Kittichoat Stegmaier, Kimberly Roti, Giovanni Ross, Kenneth N. Franlin, Laura L. Wang, Hui Wang, Fubao Chastain, Michael Bett, Andrew J. Audoly, Laurent P. Aster, Jon C. Blacklow, Stephen C. Huber, Hans E. TI Characterization of Notch1 Antibodies That Inhibit Signaling of Both Normal and Mutated Notch1 Receptors SO PLOS ONE LA English DT Article ID GAMMA-SECRETASE INHIBITOR; ACUTE LYMPHOBLASTIC-LEUKEMIA; BREAST-CANCER; PROTEOLYTIC ACTIVATION; THERAPEUTIC TARGET; PANCREATIC-CANCER; REGULATORY REGION; STRUCTURAL BASIS; MAMMALIAN NOTCH; MODIFIES NOTCH AB Background: Notch receptors normally play a key role in guiding a variety of cell fate decisions during development and differentiation of metazoan organisms. On the other hand, dysregulation of Notch1 signaling is associated with many different types of cancer as well as tumor angiogenesis, making Notch1 a potential therapeutic target. Principal Findings: Here we report the in vitro activities of inhibitory Notch1 monoclonal antibodies derived from cell-based and solid-phase screening of a phage display library. Two classes of antibodies were found, one directed against the EGF-repeat region that encompasses the ligand-binding domain (LBD), and the second directed against the activation switch of the receptor, the Notch negative regulatory region (NRR). The antibodies are selective for Notch1, inhibiting Jag2-dependent signaling by Notch1 but not by Notch 2 and 3 in reporter gene assays, with EC(50) values as low as 5 +/- 3 nM and 0.13 +/- 0.09 nM for the LBD and NRR antibodies, respectively, and fail to recognize Notch4. While more potent, NRR antibodies are incomplete antagonists of Notch1 signaling. The antagonistic activity of LBD, but not NRR, antibodies is strongly dependent on the activating ligand. Both LBD and NRR antibodies bind to Notch1 on human tumor cell lines and inhibit the expression of sentinel Notch target genes, including HES1, HES5, and DTX1. NRR antibodies also strongly inhibit ligand-independent signaling in heterologous cells transiently expressing Notch1 receptors with diverse NRR "class I" point mutations, the most common type of mutation found in human T-cell acute lymphoblastic leukemia (T-ALL). In contrast, NRR antibodies failed to antagonize Notch1 receptors bearing rare "class II" or "class III" mutations, in which amino acid insertions generate a duplicated or constitutively sensitive metalloprotease cleavage site. Signaling in T-ALL cell lines bearing class I mutations is partially refractory to inhibitory antibodies as compared to cell-penetrating gamma-secretase inhibitors. Conclusions/Significance: Antibodies that compete with Notch1 ligand binding or that bind to the negative regulatory region can act as potent inhibitors of Notch1 signaling. These antibodies may have clinical utility for conditions in which inhibition of signaling by wild-type Notch1 is desired, but are likely to be of limited value for treatment of T-ALLs associated with aberrant Notch1 activation. C1 [Aste-Amezaga, Miguel; Zhang, Ningyan; Lineberger, Janet E.; Arnold, Beth A.; Toner, Timothy J.; Gu, Mingcheng; Huang, Lingyi; Vitelli, Salvatore; Vo, Kim T.; Haytko, Peter; Zhao, Jing Zhang; Franlin, Laura L.; Wang, Hui; Wang, Fubao; Audoly, Laurent P.; Huber, Hans E.] Merck Res Labs, Dept Biol Res, West Point, PA 19486 USA. [Thoryk, Elizabeth; Bett, Andrew J.] Merck Res Labs, Dept Vaccines, West Point, PA USA. [Chastain, Michael] Merck Res Labs, Dept Mol Profiling & Pharmacol, West Point, PA USA. [Baleydier, Frederic; L'Heureux, Sarah; Wang, Hongfang; Gordon, Wendy R.; Andrawes, Marie Blanke; Tiyanont, Kittichoat; Aster, Jon C.; Blacklow, Stephen C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Stegmaier, Kimberly; Roti, Giovanni] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Stegmaier, Kimberly; Ross, Kenneth N.] Broad Inst, Canc Program, Cambridge, MA USA. RP Aste-Amezaga, M (reprint author), Merck Res Labs, Dept Biol Res, West Point, PA 19486 USA. EM jose_asteamezaga@merck.com FU NIH (National Institutes of Health) [P01 119070, R01 CA092433]; Leukemia and Lymphoma Society; William Lawrence and Blanche Hughes Foundation FX Funding: This work was supported in part by NIH (National Institutes of Health) grants P01 119070 and R01 CA092433 (JCA, SCB), a SCOR (Specialized Center of Research) award from the Leukemia and Lymphoma Society (JCA, SCB, KS), and the William Lawrence and Blanche Hughes Foundation (JCA, SCB, KS). WRG is a Leukemia and Lymphoma Society special fellow. The funding organizations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 74 Z9 75 U1 2 U2 12 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 FEB 8 PY 2010 VL 5 IS 2 AR e9094 DI 10.1371/journal.pone.0009094 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554NU UT WOS:000274442500006 PM 20161710 ER PT J AU Shea, KL Xiang, WY LaPorta, VS Licht, JD Keller, C Basson, MA Brack, AS AF Shea, Kelly L. Xiang, Wanyi LaPorta, Vincent S. Licht, Jonathan D. Keller, Charles Basson, M. Albert Brack, Andrew S. TI Sprouty1 Regulates Reversible Quiescence of a Self-Renewing Adult Muscle Stem Cell Pool during Regeneration SO CELL STEM CELL LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; MYOGENIC SATELLITE CELLS; SKELETAL-MUSCLE; PROGENITOR CELLS; GENE-EXPRESSION; PAX7; PROLIFERATION; DISTINCT; FGF; DIFFERENTIATION AB Satellite cells are skeletal muscle stem cells capable of self-renewal and differentiation after transplantation, but whether they contribute to endogenous muscle fiber repair has been unclear. The transcription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool. By using a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cell cycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while others contribute to muscle fiber formation. We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinase signaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated in proliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence. We show that Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair. Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair. C1 [Shea, Kelly L.; Xiang, Wanyi; LaPorta, Vincent S.; Brack, Andrew S.] Harvard Univ, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Xiang, Wanyi] Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02114 USA. [Licht, Jonathan D.] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Div Hematol Oncol, Chicago, IL 60611 USA. [Keller, Charles] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Basson, M. Albert] Kings Coll London, Dept Craniofacial Dev, London SE1 9RT, England. RP Brack, AS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM brack.andrew@mgh.harvard.edu RI Basson, M. Albert/C-5565-2009; OI Keller, Charles/0000-0003-2505-7487; Basson, M. Albert/0000-0001-9834-7528 FU MGH; Orthopedic Department (NIGH); Wellcome Trust [WT080470]; Medical Research Council [G0601104]; NIH [R01 CA059998]; NIH/NCI [1K08CA90438] FX The authors would like to thank Brad Olwin (University of Colorado), Prajakta Ghatpande, Gail Martin (USCF), and Thomas Rando (Stanford University) for the generous provision of reagents. Supported by MGH start-up funds to A.S.B., Orthopedic Department (NIGH) to W.X., Wellcome Trust (WT080470) and Medical Research Council (G0601104) to M.A.B., NIH (R01 CA059998) to J.D.L., and NIH/NCI (1K08CA90438) to C.K. NR 50 TC 100 Z9 102 U1 5 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD FEB 5 PY 2010 VL 6 IS 2 BP 117 EP 129 DI 10.1016/j.stem.2009.12.015 PG 13 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 555OC UT WOS:000274520800007 PM 20144785 ER PT J AU Nishimura, EK Suzuki, M Igras, V Du, JY Lonning, S Miyachi, Y Roes, J Beermann, F Fisher, DE AF Nishimura, Emi K. Suzuki, Misa Igras, Vivien Du, Jinyan Lonning, Scott Miyachi, Yoshiki Roes, Juergen Beermann, Friedrich Fisher, David E. TI Key Roles for Transforming Growth Factor beta in Melanocyte Stem Cell Maintenance SO CELL STEM CELL LA English DT Article ID TGF-BETA; IN-VIVO; DOPACHROME TAUTOMERASE; MASTER REGULATOR; SELF-RENEWAL; HAIR CYCLE; NICHE; SKIN; DIFFERENTIATION; ACTIVATION AB Melanocyte stem cells in the bulge area of hair follicles are responsible for hair pigmentation, and defects in them cause hair graying. Here we describe the process of melanocyte stem cell entry into the quiescent state and show that niche-derived transforming growth factor beta (TGF-beta) signaling plays important roles in this process. In vitro, TGF-beta not only induces reversible cell cycle arrest, but also promotes melanocyte immaturity by clownregulating MITF, the master transcriptional regulator of melanocyte differentiation, and its downstream melanogenic genes. In vivo, TGF-beta signaling is activated in melanocyte stem cells when they reenter the quiescent noncycling state during the hair cycle and this process requires Bcl2 for cell survival. Furthermore, targeted TGF-beta type II receptor (TGFbRII) deficiency in the melanocyte lineage causes incomplete maintenance of melanocyte stem cell immaturity and results in mild hair graying. These data demonstrate that the TGF-beta signaling pathway is one of the key niche factors that regulate melanocyte stem cell immaturity and quiescence. C1 [Nishimura, Emi K.] Tokyo Med & Dent Univ, Med Res Inst, Dept Stem Cell Biol, Chiyoda Ku, Tokyo 1010062, Japan. [Nishimura, Emi K.; Suzuki, Misa] Kanazawa Univ, Div Stem Cell Med, Canc Res Inst, Kanazawa, Ishikawa 9200934, Japan. [Igras, Vivien; Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02114 USA. [Igras, Vivien; Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Melanoma Program Med Oncol, Boston, MA 02114 USA. [Du, Jinyan] Broad Inst Biomed Res, Boston, MA 02115 USA. [Du, Jinyan] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lonning, Scott] Genzyme Corp, Cambridge, MA 01701 USA. [Miyachi, Yoshiki] Kyoto Univ, Grad Sch Med, Dept Dermatol, Sakyo Ku, Kyoto 6068507, Japan. [Roes, Juergen] UCL, Windeyer Inst Med Sci, Dept Med, London W1P 6DB, England. [Beermann, Friedrich] Ecole Polytech Fed Lausanne, Sch Life Sci, Swiss Inst Expt Canc Res ISREC, CH-1015 Lausanne, Switzerland. RP Nishimura, EK (reprint author), Tokyo Med & Dent Univ, Med Res Inst, Dept Stem Cell Biol, Chiyoda Ku, 2-3-10 Kandasurugadai, Tokyo 1010062, Japan. EM nishscm@tmd.ac.jp FU Uehara Memorial Foundation; Kato Memorial Bioscience Foundation; NIH; Melanoma Research Alliance FX We thank Dr. Tetsuo Watabe, Dr. Kohei Miyazono, Dr. Elaine Fuchs, Dr. Vincent Hearing, and Dr. Elizabeth Hearing for antibodies, Dr. Ian Jackson for the Dct-LacZ transgenic mice, and Dr. Hans Widlund for discussion. The research was funded by grants from the Uehara Memorial Foundation, the Kato Memorial Bioscience Foundation (to E.K.N.), and grants from the NIH and the Melanoma Research Alliance (to D.E.F., who is also a Distinguished Clinical Scholar of the Doris Duke Medical Foundation). NR 53 TC 85 Z9 91 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD FEB 5 PY 2010 VL 6 IS 2 BP 130 EP 140 DI 10.1016/j.stem.2009.12.010 PG 11 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 555OC UT WOS:000274520800008 PM 20144786 ER PT J AU Peterfy, M Harris, TE Fujita, N Reue, K AF Peterfy, Miklos Harris, Thurl E. Fujita, Naoya Reue, Karen TI Insulin-stimulated Interaction with 14-3-3 Promotes Cytoplasmic Localization of Lipin-1 in Adipocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MG2+-DEPENDENT PHOSPHATIDATE PHOSPHATASE; SUBCELLULAR-LOCALIZATION; RAT HEPATOCYTES; DEPENDENT ACTIVATION; MAMMALIAN TARGET; KINASE-ACTIVITY; RAF-1 KINASE; FATTY-ACIDS; PHOSPHORYLATION; PROTEINS AB Lipin-1 is a bifunctional protein involved in lipid metabolism and adipogenesis. Lipin-1 plays a role in the biosynthesis of triacylglycerol through its phosphatidate phosphatase activity and also acts as a transcriptional co-activator of genes involved in oxidative metabolism. Lipin-1 resides in the cytoplasm and translocates to the endoplasmic reticulum membrane to catalyze the phosphatidate phosphatase reaction. It also possesses a nuclear localization signal, which is required for its translocation to the nucleus and may therefore be important for lipin-1 co- activator function. Thus, subcellular localization may be an important factor in the regulation of this protein. Here, we show that the nuclear localization signal alone is not sufficient for lipin-1 nuclear localization, and identify lipin-1 interaction with 14-3-3 as a determinant of its subcellular localization. We demonstrate that lipin-1 interacts with 14-3-3 proteins and that overexpression of 14-3-3 promotes the cytoplasmic localization of lipin-1 in 3T3-L1 adipocytes. The effect of 14-3-3 is mediated through a serine-rich domain in lipin-1. Functional mapping of the 14-3-3-interacting region within the serine-rich domain indicates redundancy and cooperativity among several sites, including five phosphorylated serine and threonine residues. Insulin stimulation of 3T3-L1 adipocytes results in increased lipin-1 phosphorylation, enhanced interaction with 14-3-3, and predominantly cytoplasmic localization. In summary, our studies suggest that insulin may modulate the cellular function of lipin-1 by regulating its subcellular localization through interactions with 14-3-3 proteins. C1 [Reue, Karen] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Peterfy, Miklos] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Peterfy, Miklos] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Harris, Thurl E.] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA. [Fujita, Naoya] Japanese Fdn Canc Res, Ctr Canc Chemotherapy, Tokyo 1358550, Japan. RP Reue, K (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Gonda 6506A,695 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM reuek@ucla.edu FU National Institutes of Health [HL28481, DK28312]; American Diabetes Association [23018]; Cedars-Sinai Medical Center FX This work was supported, in whole or in part, by National Institutes of Health Grants HL28481 (to M. P. and K. R.) and DK28312 (to T. E. H.). This work was also supported by American Diabetes Association Grant 23018 (to M. P.) and the Cedars-Sinai Medical Center (to M. P.). NR 47 TC 39 Z9 40 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 5 PY 2010 VL 285 IS 6 BP 3857 EP 3864 DI 10.1074/jbc.M109.072488 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564YF UT WOS:000275254000039 PM 19955570 ER PT J AU Samuvel, DJ Sundararaj, KP Li, YC Lopes-Virella, MF Huang, Y AF Samuvel, Devadoss J. Sundararaj, Kamala P. Li, Yanchun Lopes-Virella, Maria F. Huang, Yan TI Adipocyte-Mononuclear Cell Interaction, Toll-like Receptor 4 Activation, and High Glucose Synergistically Up-regulate Osteopontin Expression via an Interleukin 6-mediated Mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LOW-GRADE INFLAMMATION; DIET-INDUCED OBESITY; ADIPOSE-TISSUE; INSULIN-RESISTANCE; MACROPHAGE INFILTRATION; HUMAN MONOCYTES; DISEASE; FIBROBLASTS; CYTOKINE; ADHESION AB Although it has been reported that osteopontin, a matrix glycoprotein and proinflammatory cytokine, mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance, it remains unclear how osteopontin is up-regulated in adipose tissue in obese humans and animals. In this study, we incubated U937 mononuclear cells with adipocytes in a transwell system and studied how cell interaction regulated osteopontin expression. Results showed that coculture of U937 cells with adipocytes led to a marked increase in osteopontin production when compared with that released by independent cultures of U937 cells. Moreover, lipopolysaccharide or palmitic acid-induced TLR4 activation and high glucose further augmented the coculture-stimulated osteopontin secretion. Similar observations were made in the coculture of human primary monocytes and adipocytes. Real time PCR studies showed that coculture of U937 cells and adipocytes increased osteopontin mRNA in U937 cells, but not adipocytes, suggesting that adipocyte-derived soluble factor may stimulate osteopontin expression by U937 cells. In our studies to explore the underlying mechanism, we found that the neutralizing antibodies against interleukin (IL)-6 or IL-6 small interfering RNA transfection in adipocytes effectively inhibited coculture-stimulated osteopontin expression, suggesting that IL-6 released by adipocytes plays an essential role in the coculture-stimulated osteopontin expression by U937 cells. In conclusion, this study has demonstrated that cell interaction, TLR4 activation, and high glucose up-regulate osteopontin expression, and adipocyte-derived IL-6 played a major role in the up-regulation. C1 [Lopes-Virella, Maria F.; Huang, Yan] Med Univ S Carolina, Dept Med, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. [Samuvel, Devadoss J.; Sundararaj, Kamala P.; Li, Yanchun; Lopes-Virella, Maria F.; Huang, Yan] Med Univ S Carolina, Dept Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. RP Huang, Y (reprint author), 114 Doughty St, Charleston, SC 29403 USA. EM huangyan@musc.edu FU National Institutes of Health [DE16353]; Department of Veterans Affairs FX This work was supported by National Institutes of Health Grant DE16353 (to Y.H.). This work was also supported by a Merit Review grant from the Department of Veterans Affairs (to Y.H.). NR 33 TC 20 Z9 20 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 5 PY 2010 VL 285 IS 6 BP 3916 EP 3927 DI 10.1074/jbc.M109.033951 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564YF UT WOS:000275254000045 PM 20007708 ER PT J AU Saxena, G Chen, JQ Shalev, A AF Saxena, Geetu Chen, Junqin Shalev, Anath TI Intracellular Shuttling and Mitochondrial Function of Thioredoxin-interacting Protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNAL-REGULATING KINASE-1; BETA-CELL APOPTOSIS; OXIDATIVE STRESS; GENE-EXPRESSION; MAMMALIAN THIOREDOXIN; CARDIAC-HYPERTROPHY; GLUCOSE TOXICITY; BINDING-PROTEINS; REDOX REGULATION; IMPORTIN-ALPHA AB The thioredoxin-interacting protein TXNIP is a ubiquitously expressed redox protein that promotes apoptosis. Recently, we found that TXNIP deficiency protects against type 1 and 2 diabetes by inhibiting beta cell apoptosis and maintaining pancreatic beta cell mass, indicating that TXNIP plays a key role in beta cell biology. However, very little is known about the intracellular localization and function of TXNIP, and although TXNIP has been thought to be a cytoplasmic protein, our immunohistochemistry studies in beta cells surprisingly revealed a nuclear TXNIP localization, suggesting that TXNIP may shuttle within the cell. Using immunohistochemistry/confocal imaging and cell fractionation/co-immunoprecipitation, we found that, under physiological conditions, TXNIP is localized primarily in the nucleus of pancreatic beta cells, whereas oxidative stress leads to TXNIP shuttling into the mitochondria. In mitochondria, TXNIP binds to and oxidizes Trx2, thereby reducing Trx2 binding to ASK1 and allowing for ASK1 phosphorylation/activation, resulting in induction of the mitochondrial pathway of apoptosis with cytochrome c release and caspase-3 cleavage. TXNIP overexpression and Trx2 (but not cytosolic Trx1) silencing mimic these effects. Thus, we discovered that TXNIP shuttles between subcellular compartments in response to oxidative stress and identified a novel redox-sensitive mitochondrial TXNIP-Trx2-ASK1 signaling cascade. C1 [Shalev, Anath] Univ Wisconsin, Dept Med, Clin Sci Ctr H4 526, Madison, WI 53792 USA. William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53792 USA. RP Shalev, A (reprint author), Univ Wisconsin, Dept Med, Clin Sci Ctr H4 526, 600 Highland Ave, Madison, WI 53792 USA. EM as7@medicine.wisc.edu FU National Institutes of Health [R01DK-078752]; NIDDK [R21HL-089205]; NHLBI; American Diabetes Association [7-07-CD-22]; Juvenile Diabetes Research Foundation [1-2007-790]; William S. Middleton Memorial Veterans Hospital FX This work was supported, in whole or in part, by National Institutes of Health Grants R01DK-078752 from NIDDK and R21HL-089205 from NHLBI (to A. S.). This work was also supported by American Diabetes Association Grant 7-07-CD-22 and Juvenile Diabetes Research Foundation Grant 1-2007-790) (to A. S.) and is the result of work supported by resources and use of facilities at the William S. Middleton Memorial Veterans Hospital (Madison, WI). NR 43 TC 84 Z9 86 U1 6 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 FEB 5 PY 2010 VL 285 IS 6 BP 3997 EP 4005 DI 10.1074/jbc.M109.034421 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564YF UT WOS:000275254000053 PM 19959470 ER PT J AU Juranic, N Atanasova, E Filoteo, AG Macura, S Prendergast, FG Penniston, JT Strehler, EE AF Juranic, Nenad Atanasova, Elena Filoteo, Adelaida G. Macura, Slobodan Prendergast, Franklyn G. Penniston, John T. Strehler, Emanuel E. TI Calmodulin Wraps around Its Binding Domain in the Plasma Membrane Ca2+ Pump Anchored by a Novel 18-1 Motif SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; TARGET RECOGNITION; PEPTIDE COMPLEX; MULTIDIMENSIONAL NMR; CRYSTAL-STRUCTURE; CALCIUM-BINDING; ISOFORM 4B; KINASE; ACTIVATION; PROTEINS AB Using solution NMR spectroscopy, we obtained the structure of Ca2+-calmodulin (holoCaM) in complex with peptide C28 from the binding domain of the plasma membrane Ca2+-ATPase (PMCA) pump isoform 4b. This provides the first atomic resolution insight into the binding mode of holoCaM to the full-length binding domain of PMCA. Structural comparison of the previously determined holoCaM.C20 complex with this holoCaM.C28 complex supports the idea that the initial binding step is represented by (holoCaM.C20) and the final bound complex by (holoCaM.C28). This affirms the existing multi-step kinetic model of PMCA4b activation by CaM. The complex exhibits a new binding motif in which holoCaM is wrapped around helical C28 peptide using two anchoring residues from the peptide at relative positions 18 and 1. The anchors correspond to Phe-1110 and Trp-1093, respectively, in full-length PMCA4b, and the peptide and CaM are oriented in an anti-parallel manner. This is a greater sequence distance between anchors than in any of the known holoCaM complexes with a helical peptide. Analysis of the geometry of holoCaM-peptide binding for the cases where the target peptide adopts an alpha(D)-helix with its anchors buried in the main hydrophobic pockets of the two CaM lobes establishes that only relative sequential positions of 10, 14, 17, and 18 are allowed for the second anchor. C1 [Juranic, Nenad; Strehler, Emanuel E.] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Prendergast, Franklyn G.] Mayo Clin, Coll Med, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. [Penniston, John T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Juranic, N (reprint author), Mayo Clin, Coll Med, Dept Biochem & Mol Biol, 200 1st St SW, Rochester, MN 55905 USA. EM juranic.nenad@mayo.edu FU National Institutes of Health [NS51769] FX This work was supported, in whole or in part, by National Institutes of Health Grant NS51769. Portions of this work have been presented in abstract form at the Keystone Conference on Frontiers of NMR in Biology, February 15-20, 2009 in Santa Fe, NM. NR 45 TC 23 Z9 23 U1 1 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 FEB 5 PY 2010 VL 285 IS 6 BP 4015 EP 4024 DI 10.1074/jbc.M109.060491 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564YF UT WOS:000275254000055 PM 19996092 ER PT J AU Zhang, YY Dong, YL Wu, X Lu, Y Xu, ZP Knapp, A Yue, Y Xu, TJ Xie, ZC AF Zhang, Yiying Dong, Yuanlin Wu, Xu Lu, Yan Xu, Zhipeng Knapp, Andrew Yue, Yun Xu, Tiejun Xie, Zhongcong TI The Mitochondrial Pathway of Anesthetic Isoflurane-induced Apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMYLOID PROTEIN-LEVELS; ALZHEIMERS-DISEASE; CASPASE-3 ACTIVATION; CALCIUM HOMEOSTASIS; CELL-DEATH; SEVOFLURANE; DEMENTIA; EXPOSURE; LINK; BAX AB The common inhalation anesthetic isoflurane has been shown to induce apoptosis, which then leads to accumulation of beta-amyloid protein, the hallmark feature of Alzheimer disease neuropathogenesis. The underlying molecular mechanism of the isoflurane-induced apoptosisis largely unknown. We, therefore, set out to assess whether isoflurane can induce apoptosis by regulating Bcl-2 family proteins, enhancing reactive oxygen species (ROS) accumulation, and activating the mitochondrial pathway of apoptosis. We performed these studies in cultured cells, primary neurons, and mice. Here we show for the first time that treatment with 2% isoflurane for 6 h can increase pro-apoptotic factor Bax levels, decrease antiapoptotic factor Bcl-2 levels, increase ROS accumulation, facilitate cytochrome c release from the mitochondria to the cytosol, induce activation of caspase-9 and caspase-3, and finally cause apoptosis as compared with the control condition. We have further found that isoflurane can increase the mRNA levels of Bax and reduce the mRNA levels of Bcl-2. The isoflurane-induced ROS accumulation can be attenuated by the intracellular calcium chelator BAPTA. Finally, the anesthetic desflurane does not induce activation of mitochondrial pathway of apoptosis. These results suggest that isoflurane may induce apoptosis through Bcl-2 family proteins- and ROS-associated mitochondrial pathway of apoptosis. These findings, which have identified at least partially the molecular mechanism by which isoflurane induces apoptosis, will promote more studies aimed at studying the potential neurotoxic effects of anesthetics. C1 [Xie, Zhongcong] Harvard Univ, Massachusetts Gen Hosp,MassGen Inst Neurodegenera, Dept Anesthesia Crit Care & Pain Med,Sch Med,Dept, Geriatr Anesthesia Res Unit,Genet & Aging Res Uni, Charlestown, MA 02129 USA. [Wu, Xu] China Med Univ, Fac Forens Med, Dept Forens Pathol, Shenyang 110001, Peoples R China. [Lu, Yan] China Med Univ, Affiliated Shengjing Hosp, Hlth Minist Congenital Malformat, Key Lab, Shenyang 110004, Liaoning, Peoples R China. Capital Med Univ, Beijing Chaoyang Hosp, Dept Anesthesia, Beijing 100020, Peoples R China. [Zhang, Yiying; Xu, Tiejun] Xuzhou Med Coll, Dept Anat & Neurobiol, Xuzhou 221002, Peoples R China. RP Xie, ZC (reprint author), Harvard Univ, Massachusetts Gen Hosp,MassGen Inst Neurodegenera, Dept Anesthesia Crit Care & Pain Med,Sch Med,Dept, Geriatr Anesthesia Res Unit,Genet & Aging Res Uni, 114 16th St 3750, Charlestown, MA 02129 USA. EM zxie@partners.org FU National Institutes of Health [K08 NS048140, R21 AG029856, R01 GM088801]; Alzheimer Association FX This work was supported, in whole or in part, by National Institutes of Health Grants K08 NS048140, R21 AG029856, and R01 GM088801. This work was also supported by an American Geriatrics Society Jahnigen Award and an Investigator- initiated Research Grant from the Alzheimer Association (to Z. X.). NR 31 TC 82 Z9 91 U1 1 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 5 PY 2010 VL 285 IS 6 BP 4025 EP 4037 DI 10.1074/jbc.M109.065664 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564YF UT WOS:000275254000056 PM 20007710 ER PT J AU Hertzberg, L Vendramini, E Ganmore, I Cazzaniga, G Schmitz, M Chalker, J Shiloh, R Iacobucci, I Shochat, C Zeligson, S Cario, G Stanulla, M Strehl, S Russell, LJ Harrison, CJ Bornhauser, B Yoda, A Rechavi, G Bercovich, D Borkhardt, A Kempski, H Kronnie, GT Bourquin, JP Domany, E Izraeli, S AF Hertzberg, Libi Vendramini, Elena Ganmore, Ithamar Cazzaniga, Gianni Schmitz, Maike Chalker, Jane Shiloh, Ruth Iacobucci, Ilaria Shochat, Chen Zeligson, Sharon Cario, Gunnar Stanulla, Martin Strehl, Sabine Russell, Lisa J. Harrison, Christine J. Bornhauser, Beat Yoda, Akinori Rechavi, Gideon Bercovich, Dani Borkhardt, Arndt Kempski, Helena Kronnie, Geertruy Te Bourquin, Jean-Pierre Domany, Eytan Izraeli, Shai TI Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group SO BLOOD LA English DT Article ID THYMIC STROMAL LYMPHOPOIETIN; ACUTE MEGAKARYOBLASTIC LEUKEMIA; CELL-SURFACE EXPRESSION; ERYTHROPOIETIN RECEPTOR; GENE; MUTATIONS; LYMPHOMA; CHILDHOOD; CYTOKINE; DIFFERENTIATION AB We report gene expression and other analyses to elucidate the molecular characteristics of acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS). We find that by gene expression DS-ALL is a highly heterogeneous disease not definable as a unique entity. Nevertheless, 62% (33/53) of the DS-ALL samples analyzed were characterized by high expression of the type I cytokine receptor CRLF2 caused by either immunoglobulin heavy locus (IgH@) translocations or by interstitial deletions creating chimeric transcripts P2RY8-CRLF2. In 3 of these 33 patients, a novel activating somatic mutation, F232C in CRLF2, was identified. Consistent with our previous research, mutations in R683 of JAK2 were identified in 10 specimens (19% of the patients) and, interestingly, all 10 had high CRLF2 expression. Cytokine receptor-like factor 2 (CRLF2) and mutated Janus kinase 2 (Jak2) cooperated in conferring cytokine-independent growth to BaF3 pro-B cells. Intriguingly, the gene expression signature of DS-ALL is enriched with DNA damage and BCL6 responsive genes, suggesting the possibility of B-cell lymphocytic genomic instability. Thus, DS confers increased risk for genetically highly diverse ALLs with frequent overexpression of CRLF2, associated with activating mutations in the receptor itself or in JAK2. Our data also suggest that the majority of DS children with ALL may benefit from therapy blocking the CRLF2/JAK2 pathways. (Blood. 2010;115:1006-1017) C1 [Izraeli, Shai] Chaim Sheba Med Ctr, Pediat Hematol Oncol Dept, Pediat Hematooncol & Canc Res Ctr, IL-52621 Tel Hashomer, Ramat Gan, Israel. [Hertzberg, Libi; Ganmore, Ithamar; Shochat, Chen; Rechavi, Gideon; Izraeli, Shai] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Hertzberg, Libi; Domany, Eytan] Weizmann Inst Sci, Dept Phys Complex Syst, IL-76100 Rehovot, Israel. [Vendramini, Elena; Kronnie, Geertruy Te] Univ Padua, Dept Pediat, Hematooncol Lab, Padua, Italy. [Cazzaniga, Gianni] Univ Milano Bicocca, Clin Paediat, Ctr Ric Tettamanti, Osped San Gerardo, Monza, Italy. [Schmitz, Maike; Bornhauser, Beat; Bourquin, Jean-Pierre] Univ Zurich, Univ Childrens Hosp, Dept Pediat Oncol, Zurich, Switzerland. [Chalker, Jane; Kempski, Helena] Great Ormond St Hosp Sick Children, Camelia Botnar Labs, Paediat Malignancy Cytogenet Unit, London, England. [Chalker, Jane; Kempski, Helena] Inst Child Hlth, London, England. [Iacobucci, Ilaria] Univ Bologna, Dept Hematol Oncol L&A Seragnoli, Bologna, Italy. [Shochat, Chen; Bercovich, Dani] Migal Galilee Biotechnol Ctr, Human Mol Genet & Pharmacogenet Lab, Kiryat Shmona, Israel. [Shochat, Chen; Bercovich, Dani] Tel Hai Acad Coll, Tel Hai, Israel. [Cario, Gunnar; Stanulla, Martin] Univ Hosp Schleswig Holstein, Dept Pediat, Kiel, Germany. [Strehl, Sabine] St Anna Childrens Hosp, Childrens Canc Res Inst, A-1090 Vienna, Austria. [Russell, Lisa J.; Harrison, Christine J.] Univ Newcastle, No Inst Canc Res, Leukaemia Res Cytogenet Grp, Newcastle Upon Tyne, Tyne & Wear, England. [Yoda, Akinori] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Borkhardt, Arndt] Univ Dusseldorf, Clin Pediat Oncol Hematol & Clin Immunol, Childrens Univ Hosp, Dusseldorf, Germany. RP Izraeli, S (reprint author), Chaim Sheba Med Ctr, Pediat Hematol Oncol Dept, Pediat Hematooncol & Canc Res Ctr, IL-52621 Tel Hashomer, Ramat Gan, Israel. EM sizraeli@sheba.health.gov.il RI Stanulla, Martin/D-2528-2010; Cario, Gunnar/D-2535-2010; Russell, Lisa/F-5309-2012; DOMANY, EYTAN/K-1560-2012; Bornhauser, Beat/M-4437-2014; OI Strehl, Sabine/0000-0002-0179-0628 FU Israel Ministry of Science; Israeli Ministry of trade; Israeli Ministry of Health; German Israeli Foundation; Israeli Science Foundation and Morasha program; US Israel Binational Science Foundation; Children with Leukemia UK; Curtis Katz; Wolfson Foundation; Foulkes Foundation; Ridgefield Foundation; Converging Technologies Program; Constantiner Institute for Molecular Genetics; Hans Altschuler-Stiftung; Swiss National Science Foundation; Leukemia Research Fund, UK; PRIN/Programmi di ricerca di Relevante Interesse Nazionale, Rome; European LeukemiaNet; AIRC; AIL; Fondazione Del Monte di Bologna e Ravenna FX We thank Dr T. Enver for supplying the pHRSINCSGW lentivirus plasmid and Dr Kitamura for providing the CRLF2 expression construct. We thank N. Amariglio, G. Basso, V. Binder, A. Biondi, S. Bresolin, O. Haas, J. Harbott, M. Grazia, G. Martinelli, M. Schrappe, S. Orkin, D. Weinstock, A. Yitzhaky, Y. Shinar, A. Ovadia, and the members of E. Domany's and S. Izraeli's groups, in particular Y. Birger and E. Ben-Meir, for their important contributions to the study.; Funding for this study was provided by the Israel Ministry of Science (E. D. and S. I.), Israeli Ministry of trade (D. B. and S. I.), Israeli Ministry of Health (S. I.), German Israeli Foundation (S. I. and A. B.), Israeli Science Foundation and Morasha program (S. I.), US Israel Binational Science Foundation (S. I.), Children with Leukemia UK (S. I.), Curtis Katz (S. I.), Wolfson Foundation (E. D. and S. I.), Foulkes Foundation (L. H. and I. G.), The Ridgefield Foundation (E. D.), Converging Technologies Program (L. H.), Constantiner Institute for Molecular Genetics (I. G.), Hans Altschuler-Stiftung (S. I. and J. P. B.), Swiss National Science Foundation (J. P. B.), Leukemia Research Fund, UK (C. H. and L. J. R.), PRIN/Programmi di ricerca di Relevante Interesse Nazionale, Rome (GteK), European LeukemiaNet, AIRC, AIL, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006 (II). Reagents for the AIEOP GEP study were supplied by Roche Molecular Diagnostics in the framework of the MILE study. 49; This study has been performed as partial fulfillment of the requirement for a PhD degree from the TelAviv University Faculty of Medicine to L. H., I. G., and C. S. NR 47 TC 149 Z9 153 U1 0 U2 9 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 FEB 4 PY 2010 VL 115 IS 5 BP 1006 EP 1017 DI 10.1182/blood-2009-08-235408 PG 12 WC Hematology SC Hematology GA 552KA UT WOS:000274287500014 PM 19965641 ER PT J AU Stam, RW Den Boer, ML Schneider, P de Boer, J Hagelstein, J Valsecchi, MG de Lorenzo, P Sallan, SE Brady, HJM Armstrong, SA Pieters, R AF Stam, Ronald W. Den Boer, Monique L. Schneider, Pauline de Boer, Jasper Hagelstein, Jill Valsecchi, Maria G. de Lorenzo, Paola Sallan, Stephen E. Brady, Hugh J. M. Armstrong, Scott A. Pieters, Rob TI Association of high-level MCL-1 expression with in vitro and in vivo prednisone resistance in MLL-rearranged infant acute lymphoblastic leukemia SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MULTIPLE-MYELOMA; DRUG-RESISTANCE; CYTOCHROME-C; CELLS; APOPTOSIS; CHILDREN; IDENTIFICATION; SENSITIVITY; THERAPY AB MLL-rearranged acute lymphoblastic leukemia (ALL) represents an unfavorable type of leukemia that often is highly resistant to glucocorticoids such as prednisone and dexamethasone. Because response to prednisone largely determines clinical outcome of pediatric patients with ALL, overcoming resistance to this drug may be an important step toward improving prognosis. Here, we show how gene expression profiling identifies high-level MCL-1 expression to be associated with prednisolone resistance in MLL-rearranged infant ALL, as well as in more favorable types of childhood ALL. To validate this observation, we determined MCL-1 expression with quantitative reverse transcription-polymerase chain reaction in a cohort of MLL-rearranged infant ALL and pediatric noninfant ALL samples and confirmed that high-level MCL-1 expression is associated with prednisolone resistance in vitro. In addition, MCL-1 expression appeared to be significantly higher in MLL-rearranged infant patients who showed a poor response to prednisone in vivo compared with prednisone good responders. Finally, down-regulation of MCL-1 in prednisolone- resistant MLL-rearranged leukemia cells by RNA interference, to some extent, led to prednisolone sensitization. Collectively, our findings suggest a potential role for MCL-1 in glucocorticoid resistance in MLL-rearranged infant ALL, but at the same time strongly imply that high-level MCL-1 expression is not the sole mechanism providing resistance to these drugs. (Blood. 2010;115:1018-1025) C1 [Stam, Ronald W.; Den Boer, Monique L.; Schneider, Pauline; Hagelstein, Jill; Pieters, Rob] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat Oncol Hematol, NL-3000 CB Rotterdam, Netherlands. [de Boer, Jasper; Brady, Hugh J. M.] UCL, Inst Child Hlth, Mol Haematol & Canc Biol Unit, London, England. [de Boer, Jasper; Brady, Hugh J. M.] UCL, Great Ormond St Hosp Children, London, England. [Valsecchi, Maria G.; de Lorenzo, Paola] Univ Milano Bicocca, Dept Clin Med Prevent & Biotechnol, Sect Med Stat, Monza, Italy. [Sallan, Stephen E.; Armstrong, Scott A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sallan, Stephen E.; Armstrong, Scott A.] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. RP Stam, RW (reprint author), Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Pediat Oncol Hematol, Rm Sp 2456,Dr Molewaterpl 60,POB 2060, NL-3000 CB Rotterdam, Netherlands. EM r.stam@erasmusmc.nl RI de Boer, Jasper/B-5067-2013; OI de Boer, Jasper/0000-0002-3220-8776; Brady, Hugh/0000-0002-3152-067X FU Sophia Foundation for Medical Research (SSWO) [455]; Leukemia Research Fund; Dutch Cancer Society [EMCR 2005-2662] FX We thank the members and participating hospitals of INTERFANT-99 for supporting this study by providing leukemic samples. Members of INTERFANT-99 are M. Campbell (Programa Infantil Nacional de Drogas Atineoplasicas), M. Felice (Argentina), A. Ferster (Children's Leukemia Group), I. Hann and A. Vora (UK Children's Cancer Study Group), L. Hovi (Nordic Society of Paediatric Haematology and Oncology), G. Janka-Schaub (Cooperative Study Group for Treatment of ALL), C. K. Li (Hong Kong), G. Mann (Berlin- Frankfurt- Munster Group- Austria), F. Mechinaud (French ALL Group), R. Pieters (Dutch Childhood Oncology Group), G. de Rossi and A. Biondi (Associazione Italiana Ematologia Oncologia Pediatrica), J. Rubnitz (St Jude Children's Research Hospital), M. Schrappe (Berlin- Frankfurt- Munster GroupGermany), L. Silverman (Dana- Farber Cancer Institute), J. Stary (Czech Paediatric Haematology), R. Suppiah (Australian and New Zealand Children's Haematology/ Oncology Group), T. Szczepanski (Polish Paediatric Leukemia and Lymphoma Study Group), and M. Valscecchi and P. de Lorzenzo (Trial Operating Center).; This work was supported by the Sophia Foundation for Medical Research (SSWO grant 455), the Leukemia Research Fund (J. d. B.), and the Dutch Cancer Society (grant EMCR 2005-2662, R. W. S.). NR 33 TC 41 Z9 44 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 4 PY 2010 VL 115 IS 5 BP 1018 EP 1025 DI 10.1182/blood-2009-02-205963 PG 8 WC Hematology SC Hematology GA 552KA UT WOS:000274287500015 PM 19965632 ER PT J AU Walters, RG Jacquemont, S Valsesia, A de Smith, AJ Martinet, D Andersson, J Falchi, M Chen, F Andrieux, J Lobbens, S Delobel, B Stutzmann, F Moustafa, JSES Chevre, JC Lecoeur, C Vatin, V Bouquillon, S Buxton, JL Boute, O Holder-Espinasse, M Cuisset, JM Lemaitre, MP Ambresin, AE Brioschi, A Gaillard, M Giusti, V Fellmann, F Ferrarini, A Hadjikhani, N Campion, D Guilmatre, A Goldenberg, A Calmels, N Mandel, JL Le Caignec, C David, A Isidor, B Cordier, MP Dupuis-Girod, S Labalme, A Sanlaville, D Beri-Dexheimer, M Jonveaux, P Leheup, B Ounap, K Bochukova, EG Henning, E Keogh, J Ellis, RJ MacDermot, KD van Haelst, MM Vincent-Delorme, C Plessis, G Touraine, R Philippe, A Malan, V Mathieu-Dramard, M Chiesa, J Blaumeiser, B Kooy, RF Caiazzo, R Pigeyre, M Balkau, B Sladek, R Bergmann, S Mooser, V Waterworth, D Reymond, A Vollenweider, P Waeber, G Kurg, A Palta, P Esko, T Metspalu, A Nelis, M Elliott, P Hartikainen, AL McCarthy, MI Peltonen, L Carlsson, L Jacobson, P Sjostrom, L Huang, N Hurles, ME O'Rahilly, S Farooqi, IS Mannik, K Jarvelin, MR Pattou, F Meyre, D Walley, AJ Coin, LJM Blakemore, AIF Froguel, P Beckmann, JS AF Walters, R. G. Jacquemont, S. Valsesia, A. de Smith, A. J. Martinet, D. Andersson, J. Falchi, M. Chen, F. Andrieux, J. Lobbens, S. Delobel, B. Stutzmann, F. Moustafa, J. S. El-Sayed Chevre, J. -C. Lecoeur, C. Vatin, V. Bouquillon, S. Buxton, J. L. Boute, O. Holder-Espinasse, M. Cuisset, J. -M. Lemaitre, M. -P. Ambresin, A. -E. Brioschi, A. Gaillard, M. Giusti, V. Fellmann, F. Ferrarini, A. Hadjikhani, N. Campion, D. Guilmatre, A. Goldenberg, A. Calmels, N. Mandel, J. -L. Le Caignec, C. David, A. Isidor, B. Cordier, M. -P. Dupuis-Girod, S. Labalme, A. Sanlaville, D. Beri-Dexheimer, M. Jonveaux, P. Leheup, B. Ounap, K. Bochukova, E. G. Henning, E. Keogh, J. Ellis, R. J. MacDermot, K. D. van Haelst, M. M. Vincent-Delorme, C. Plessis, G. Touraine, R. Philippe, A. Malan, V. Mathieu-Dramard, M. Chiesa, J. Blaumeiser, B. Kooy, R. F. Caiazzo, R. Pigeyre, M. Balkau, B. Sladek, R. Bergmann, S. Mooser, V. Waterworth, D. Reymond, A. Vollenweider, P. Waeber, G. Kurg, A. Palta, P. Esko, T. Metspalu, A. Nelis, M. Elliott, P. Hartikainen, A. -L. McCarthy, M. I. Peltonen, L. Carlsson, L. Jacobson, P. Sjostrom, L. Huang, N. Hurles, M. E. O'Rahilly, S. Farooqi, I. S. Maennik, K. Jarvelin, M. -R. Pattou, F. Meyre, D. Walley, A. J. Coin, L. J. M. Blakemore, A. I. F. Froguel, P. Beckmann, J. S. TI A new highly penetrant form of obesity due to deletions on chromosome 16p11.2 SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; CIRCULAR BINARY SEGMENTATION; COPY NUMBER VARIATION; FRAMESHIFT MUTATION; MENTAL-RETARDATION; CHILDHOOD OBESITY; RISK LOCI; AUTISM; MICRODELETION; INDIVIDUALS AB Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution(1). Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component(1). Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge(2). Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >= 40 kg m(-2) or BMI standard deviation score >= 4; P = 6.43 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme'(4) in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts. C1 [Walters, R. G.; de Smith, A. J.; Andersson, J.; Falchi, M.; Moustafa, J. S. El-Sayed; Buxton, J. L.; Walley, A. J.; Blakemore, A. I. F.; Froguel, P.] Univ London Imperial Coll Sci Technol & Med, Sect Genom Med, London W12 0NN, England. [Walters, R. G.; Elliott, P.; Jarvelin, M. -R.; Coin, L. J. M.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England. [Jacquemont, S.; Martinet, D.; Gaillard, M.; Fellmann, F.; Ferrarini, A.; Beckmann, J. S.] CHU Vaudois, Serv Genet Med, CH-1011 Lausanne, Switzerland. [Valsesia, A.; Bergmann, S.; Beckmann, J. S.] Univ Lausanne, Dept Med Genet, CH-1015 Lausanne, Switzerland. [Valsesia, A.] Univ Lausanne, Ludwig Inst Canc Res, CH-1015 Lausanne, Switzerland. [Valsesia, A.; Bergmann, S.] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland. [Chen, F.; Hadjikhani, N.] Ecole Polytech Fed Lausanne, Brain Mind Inst, CH-1015 Lausanne, Switzerland. [Andrieux, J.; Bouquillon, S.] Ctr Hosp Reg Univ, Med Genet Lab, F-59000 Lille, France. [Lobbens, S.; Stutzmann, F.; Chevre, J. -C.; Lecoeur, C.; Vatin, V.; Meyre, D.; Froguel, P.] Inst Pasteur, Inst Biol 8090, CNRS, F-59800 Lille, France. [Delobel, B.] Hop St Vincent de Paul, Ctr Genet Chromosom, GHICL, F-59020 Lille, France. [Boute, O.; Holder-Espinasse, M.] CHU Lille, Serv Genet Clin, Hop Jeanne Flandre, F-59000 Lille, France. [Cuisset, J. -M.; Lemaitre, M. -P.] Ctr Hosp Reg Univ, Serv Neuropediat, F-59000 Lille, France. [Ambresin, A. -E.] CHU Vaudois, Unite Multidisciplinaire Sante Adolescents, CH-1011 Lausanne, Switzerland. [Brioschi, A.] CHU Vaudois, Serv Neuropsychol & Neurorehabil, CH-1011 Lausanne, Switzerland. [Giusti, V.] CHU Vaudois, Serv Endocrinol, CH-1011 Lausanne, Switzerland. [Hadjikhani, N.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Campion, D.; Guilmatre, A.] Fac Med, INSERM, U614, F-76183 Rouen, France. [Goldenberg, A.] CHU Rouen, Serv Genet, F-76031 Rouen, France. [Calmels, N.; Mandel, J. -L.] Nouvel Hop Civil, Lab Diagnost Genet, F-67091 Strasbourg, France. [Le Caignec, C.; David, A.; Isidor, B.] CHU Nantes, Serv Genet Med, F-44093 Nantes, France. [Le Caignec, C.] Inst Thorax, UMR915, INSERM, F-44007 Nantes, France. [Cordier, M. -P.; Dupuis-Girod, S.; Labalme, A.; Sanlaville, D.] Hop Hotel Dieu, Hosp Civils Lyon, Serv Genet, F-69288 Lyon, France. [Sanlaville, D.] Univ Lyon 1, EA 4171, F-69622 Villeurbanne, France. [Beri-Dexheimer, M.; Jonveaux, P.; Leheup, B.] Nancy Univ, Ctr Hosp Univ, Genet Lab, F-54511 Vandoeuvre Les Nancy, France. [Leheup, B.] Univ Henri Poincare, Med Sch Nancy EA4368, F-54003 Nancy, France. [Ounap, K.] Univ Tartu, Childrens Hosp, United Labs, Dept Genet, EE-50406 Tartu, Estonia. [Bochukova, E. G.; Henning, E.; Keogh, J.; O'Rahilly, S.; Farooqi, I. S.] Univ Cambridge, Metab Res Labs, Inst Metab Sci, Addenbrookes Hosp, Cambridge CB2 0QQ, England. [Ellis, R. J.; MacDermot, K. D.; van Haelst, M. M.] Northwick Pk & St Marks Hosp, NW Thames Reg Genet Serv, Harrow HA1 3UJ, Middx, England. [Vincent-Delorme, C.] Ctr Hosp Arras, F-62000 Arras, France. [Plessis, G.] Ctr Hosp Univ Clemenceau, Serv Genet Med, F-14033 Caen, France. [Touraine, R.] Ctr Hosp Univ Hop Nord, Serv Genet, F-42055 St Etienne, France. [Philippe, A.; Malan, V.] Univ Paris 05, Hop Necker Enfants Malad, Dept Genet, F-75015 Paris, France. [Philippe, A.; Malan, V.] Univ Paris 05, Hop Necker Enfants Malad, INSERM, U781, F-75015 Paris, France. [Mathieu-Dramard, M.] Ctr Hosp Univ, Serv Genet Clin, F-80054 Amiens, France. [Chiesa, J.] Ctr Hosp Univ Caremeau, Lab Cytogenet, F-30029 Nimes, France. [Blaumeiser, B.; Kooy, R. F.] Univ Hosp & Univ Antwerp, Dept Med Genet, B-2650 Edegem, Belgium. [Caiazzo, R.; Pattou, F.] INSERM, U859, F-59045 Lille, France. [Caiazzo, R.; Pigeyre, M.; Pattou, F.] Univ Lille Nord France, CHU Lille, F-59037 Lille, France. [Balkau, B.] INSERM, U780, IFR69, F-94807 Villejuif, France. [Sladek, R.] McGill Univ, Montreal, PQ H3A 1A4, Canada. [Sladek, R.] Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A4, Canada. [Sladek, R.] McGill Univ, Dept Med & Human Genet, Montreal, PQ H3A 1B1, Canada. [Mooser, V.; Waterworth, D.] GlaxoSmithKline Inc, Div Genet, Philadelphia, PA 19101 USA. [Reymond, A.] Univ Lausanne, Ctr Integrat Genom, CH-1015 Lausanne, Switzerland. [Vollenweider, P.; Waeber, G.] CHU Vaudois, Dept Med, CH-1011 Lausanne, Switzerland. [Kurg, A.; Palta, P.; Maennik, K.] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia. [Esko, T.; Metspalu, A.; Nelis, M.] Univ Tartu, Estonian Genome Project, EE-50410 Tartu, Estonia. [Esko, T.; Metspalu, A.; Nelis, M.] Estonian Bioctr, EE-51010 Tartu, Estonia. [Hartikainen, A. -L.] Univ Oulu, Dept Obstet & Gynaecol, SF-90220 Oulu, Finland. [McCarthy, M. I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [McCarthy, M. I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Peltonen, L.; Huang, N.; Hurles, M. E.] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England. [Peltonen, L.] Biomedicum, Inst Mol Med, Helsinki 00290, Finland. [Peltonen, L.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Carlsson, L.; Jacobson, P.; Sjostrom, L.] Sahlgrens Acad, Dept Mol & Clin Med, S-41345 Gothenburg, Sweden. [Carlsson, L.; Jacobson, P.; Sjostrom, L.] Sahlgrens Acad, Ctr Cardiovasc & Metab Res, S-41345 Gothenburg, Sweden. [Jarvelin, M. -R.] Natl Publ Hlth Inst, Dept Child & Adolescent Hlth, Oulu 90101, Finland. [Jarvelin, M. -R.] Univ Oulu, Inst Hlth Sci, SF-90220 Oulu, Finland. [Jarvelin, M. -R.] Univ Oulu, Bioctr Oulu, SF-90220 Oulu, Finland. RP Froguel, P (reprint author), Univ London Imperial Coll Sci Technol & Med, Sect Genom Med, London W12 0NN, England. EM p.froguel@imperial.ac.uk; jacques.beckmann@chuv.ch RI Kurg, Ants/J-2616-2015; Le Caignec, Cedric/K-8467-2015; Isidor, Bertrand/L-2435-2015; Kooy, Frank/F-5276-2014; Ounap, Katrin/Q-1103-2016; Philippe, Anne/E-5587-2017; Walley, Andrew/D-2573-2009; Valsesia, Armand/F-1724-2010; Walters, Robin/E-6069-2010; Hadjikhani, Nouchine/C-2018-2008; Meyre, David/D-7315-2011; Beckmann, Jacques S /A-9772-2008; Caiazzo, Robert/D-1958-2013; Falchi, Mario/F-5956-2013; Colaus, PsyColaus/K-6607-2013; Dupuis-Girod, Sophie/D-6268-2014; sanlaville, damien/M-4716-2014; Coin, Lachlan/A-9001-2014; Chevre, Jean-Claude/C-3943-2015; Buxton, Jessica/I-4033-2014 OI Le Caignec, Cedric/0000-0002-0598-653X; Isidor, Bertrand/0000-0001-6480-126X; Kooy, Frank/0000-0003-2024-0485; CHEN, Fei/0000-0003-2077-3812; El-Sayed Moustafa, Julia Sarah/0000-0001-6963-6654; Walley, Andrew/0000-0001-7707-7549; Carlsson Ekander, Lena/0000-0003-4145-6242; caiazzo, robert/0000-0001-5383-0540; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Farooqi, Sadaf/0000-0001-7609-3504; Sladek, Robert/0000-0002-2730-1204; Palta, Priit/0000-0001-9320-7008; Bochukova, Elena/0000-0003-0275-1548; Bergmann, Sven/0000-0002-6785-9034; Walters, Robin/0000-0002-9179-0321; Hadjikhani, Nouchine/0000-0003-4075-3106; Beckmann, Jacques S /0000-0002-9741-1900; sanlaville, damien/0000-0001-9939-2849; Coin, Lachlan/0000-0002-4300-455X; Chevre, Jean-Claude/0000-0002-5329-5231; Buxton, Jessica/0000-0002-0918-9335 FU Wellcome Trust; Medical Research Council (MRC) [G0500539]; Swiss National Foundation [310000-112552, 33CSCO-122661]; RCUK; Swiss National Fund [320030_122674]; Synapsis Foundation; University of Lausanne; Ludwig Institute for Cancer Research; Swiss Institute of Bioinformatics; le Conseil Regional Nord Pas de Calais/FEDER; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne; Estonian Government [SF0180142s08]; EU; FP7 [201413 ENGAGE, 212111 BBMRI]; ECOGENE [205419]; Genome Canada; Genome Quebec; Swedish Research Council [K2008-65X-20753-01-4, K2007-55X-11285-13, 529-2002-6671]; Swedish Foundation for Strategic Research; Swedish Diabetes Foundation; Ake Wiberg Foundation; Foundations of the National Board of Health and Welfare; Jeansson Foundations; Magn Bergvall Foundation; Tore Nilson Foundation; Royal Physiographic Society; INNOVA-VINNMER; Swedish federal government; INSERM; CNAMTS; Lilly; Novartis Pharma; Sanofi-Aventis; Association Diabete Risque Vasculaire; Federation Francaise de Cardiologie; La Fondation de France; ALFEDIAM; ONIVINS; Ardix Medical, Bayer Diagnostics; Becton Dickinson; Cardionics; Merck Sante; Novo Nordisk; Pierre Fabre; Roche and Topcon; Academy of Finland [104781, 120315]; University Hospital Oulu; Biocenter, University of Oulu, Finland; European Commission [QLG1-CT-2000-01643]; NHLBI [5R01HL087679-02, 1RL1MH083268-01]; NIH/NIMH [5R01MH63706: 02]; ENGAGE [HEALTH-F4-2007-201413]; [SF0180026s09] FX A.J.W., A. I. F. B. and P. F. are supported by grants from the Wellcome Trust and the Medical Research Council (MRC). J.S.B. is supported by a grant from the Swiss National Foundation (310000-112552). L.J.M.C. is supported by an RCUK Fellowship. S.J. is funded by Swiss National Fund 320030_122674 and the Synapsis Foundation, University of Lausanne. A. V. is funded by the Ludwig Institute for Cancer Research. S. B. is supported by the Swiss Institute of Bioinformatics. I. S. F. and M. E. H. are funded by the Wellcome Trust and the MRC. We thank the DHOS (Direction de l'Hospitalisation et de l'Organisation des Soins) from the French Ministry of Health for their support in the development of several array CGH platforms in France. We thank le Conseil Regional Nord Pas de Calais/FEDER' for their financial support. Part of the CoLaus computation was performed at the Vital-IT center for high-performance computing of the Swiss Institute of Bioinformatics. The CoLaus authors thank Y. Barreau, M. Firmann, V. Mayor, A.-L. Bastian, B. Ramic, M. Moranville, M. Baumer, M. Sagette, J. Ecoffey and S. Mermoud for data collection. The CoLaus study was supported by grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne and by the Swiss National Foundation (33CSCO-122661). K. M., A. K., T. E., M.N. and A. M. received support from targeted financing from Estonian Government SF0180142s08, and P. P. from SF0180026s09; and from the EU through the European Regional Development Fund. T. E., M.N. and A. M. received support from FP7 grants (201413 ENGAGE, 212111 BBMRI, ECOGENE (no. 205419, EBC)). The genotyping of the Estonian Genome Project samples were performed in the Estonian Biocentre Genotyping Core Facility. The EGPUT authors thank V. Soo for technical help in genotyping. The Northwick Park authors acknowledge support from the NIHR Biomedical Research Centre Scheme and the Hammersmith Hospital Charity Trustees. Genome Canada and Genome Quebec funded the genotyping of DESIR subjects. Work on the SOS sib pair cohort was supported by grants from the Swedish Research Council (K2008-65X-20753-01-4, K2007-55X-11285-13, 529-2002-6671), the Swedish Foundation for Strategic Research to Sahlgrenska Center for Cardiovascular and Metabolic Research, the Swedish Diabetes Foundation, the Ake Wiberg Foundation, Foundations of the National Board of Health and Welfare, the Jeansson Foundations, the Magn Bergvall Foundation, the Tore Nilson Foundation, the Royal Physiographic Society (Nilsson-Ehle Foundation), VINNOVA-VINNMER, and the Swedish federal government under the LUA/ALF agreement. The DESIR study has been supported by INSERM, CNAMTS, Lilly, Novartis Pharma and Sanofi-Aventis, by INSERM (Reseaux en Sante Publique, Interactions entre les determinants de la sante), by the Association Diabete Risque Vasculaire, the Federation Francaise de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Sante, Novo Nordisk, Pierre Fabre, Roche and Topcon. Northern Finland Birth Cohort 1966 (NFBC1966) was supported by the Academy of Finland (project grants 104781, 120315 and Center of Excellence in Complex Disease Genetics), University Hospital Oulu, Biocenter, University of Oulu, Finland, the European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/NIMH (5R01MH63706: 02), the ENGAGE project and grant agreement HEALTH-F4-2007-201413, and the MRC (studentship grant G0500539).; The NFBC authors than P. Rantakallio for the launch of NFBC1966 and initial data collection, S. Vaara for data collection, T. Ylitalo for administration, M. Koiranen for data management, and O. Tornwall and M. Jussila for DNA biobanking. NR 41 TC 234 Z9 243 U1 4 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 4 PY 2010 VL 463 IS 7281 BP 671 EP U104 DI 10.1038/nature08727 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 551GB UT WOS:000274193900038 PM 20130649 ER PT J AU Swensen, SJ Meyer, GS Nelson, EC Hunt, GC Pryor, DB Weissberg, JI Kaplan, GS Daley, J Yates, GR Chassin, MR James, BC Berwick, DM AF Swensen, Stephen J. Meyer, Gregg S. Nelson, Eugene C. Hunt, Gordon C., Jr. Pryor, David B. Weissberg, Jed I. Kaplan, Gary S. Daley, Jennifer Yates, Gary R. Chassin, Mark R. James, Brent C. Berwick, Donald M. TI Cottage Industry to Postindustrial Care - The Revolution in Health Care Delivery SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Swensen, Stephen J.] Mayo Clin, Rochester, MN 55905 USA. [Meyer, Gregg S.] Massachusetts Gen Hosp, Ctr Qual & Safety, Boston, MA 02114 USA. [Meyer, Gregg S.] Massachusetts Gen Phys Org, Boston, MA USA. [Nelson, Eugene C.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Hunt, Gordon C., Jr.] Sutter Hlth, Sacramento, CA USA. [Pryor, David B.] Ascens Hlth, St Louis, MO USA. [Weissberg, Jed I.] Kaiser Permanente, Oakland, CA USA. [Kaplan, Gary S.] Virginia Mason Hlth Syst, Seattle, WA USA. [Daley, Jennifer] Partners Community Healthcare, Boston, MA USA. [Yates, Gary R.] Sentara Healthcare, Norfolk, VA USA. [Chassin, Mark R.] Joint Commiss, Oak Brook Terrace, IL USA. [James, Brent C.] Intermt Healthcare, Salt Lake City, UT USA. [Berwick, Donald M.] Inst Healthcare Improvement, Cambridge, MA USA. RP Swensen, SJ (reprint author), Mayo Clin, Rochester, MN 55905 USA. NR 5 TC 50 Z9 53 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 4 PY 2010 VL 362 IS 5 DI 10.1056/NEJMp0911199 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 551FV UT WOS:000274193300004 PM 20089956 ER PT J AU Ambrogini, E Almeida, M Martin-Milian, M Paik, JH DePinho, RA Han, L Goellner, J Weinstein, RS Jilka, RL O'Brien, CA Manolagas, SC AF Ambrogini, Elena Almeida, Maria Martin-Milian, Marta Paik, Ji-Hye DePinho, Ronald A. Han, Li Goellner, Joseph Weinstein, Robert S. Jilka, Robert L. O'Brien, Charles A. Manolagas, Stavros C. TI FoxO-Mediated Defense against Oxidative Stress in Osteloblasts, Is Indispensable for Skeletal Homeostasis in Mice SO CELL METABOLISM LA English DT Article ID FORKHEAD TRANSCRIPTION FACTOR; DEFICIENCY BONE LOSS; PROTEIN-KINASE B; T-CELL-FACTOR; BETA-CATENIN; KAPPA-B; LIFE-SPAN; OSTEOCLAST DIFFERENTIATION; SEX STEROIDS; CRUCIAL ROLE AB Aging increases oxidative stress and osteoblast apoptosis and decreases bone mass, whereas forkhead box O (FoxO) transcription factors defend against oxidative stress by activating genes involved in free radical scavenging and apoptosis. Conditional deletion of FoxO1, FoxO3, and FoxO4 in 3-month-old mice resulted in an increase in oxidative stress in bone and osteoblast apoptosis and a decrease in the number of osteoblasts, the rate of bone formation, and bone mass at cancellous and cortical sites. The effect of the deletion on osteoblast apoptosis was cell autonomous and resulted from oxidative stress. Conversely, overexpression of a FoxO3 transgene in mature osteoblasts decreased oxidative stress and osteoblast apoptosis and increased osteoblast number, bone formation rate, and vertebral bone mass. We conclude that FoxO-dependent oxidative defense provides a mechanism to handle the oxygen free radicals constantly generated by the aerobic metabolism of osteoblasts and is thereby indispensable for bone mass homeostasis. C1 [Ambrogini, Elena; Almeida, Maria; Martin-Milian, Marta; Han, Li; Goellner, Joseph; Weinstein, Robert S.; Jilka, Robert L.; O'Brien, Charles A.; Manolagas, Stavros C.] Univ Arkansas Med Sci, Ctr Osteoporosis & Metab Bone Dis, Div Endocrinol & Metab, Little Rock, AR 72205 USA. [Ambrogini, Elena; Almeida, Maria; Martin-Milian, Marta; Han, Li; Goellner, Joseph; Weinstein, Robert S.; Jilka, Robert L.; O'Brien, Charles A.; Manolagas, Stavros C.] Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Genet, Boston, MA 02115 USA. RP Manolagas, SC (reprint author), Univ Arkansas Med Sci, Ctr Osteoporosis & Metab Bone Dis, Div Endocrinol & Metab, Little Rock, AR 72205 USA. EM manolagasstavros@uams.edu FU National Institutes of Health [P01 AG13918, R01 AR49794]; Department of Veterans Affairs; University of Arkansas for Medical Sciences; University of Pisa, Italy; Marques de Valdecilla Foundation, Santander, Spain; Robert A. and Renee E. Beffer Foundation Institute for Innovative Cancer Science; [DRG 190006] FX This work was supported by the National Institutes of Health (P01 AG13918, R01 AR49794), the Department of Veterans Affairs (Merit Review grants to S.C.M., R.S.W., and R.L.J. and a VA Research Enhancement Award Program), and Tobacco Settlement funds provided by the University of Arkansas for Medical Sciences. E.A. is supported by a PhD fellowship from the University of Pisa, Italy. M.M.-M. is the recipient of an award from Marques de Valdecilla Foundation, Santander, Spain. J.-H.P. is Damon Runyon Fellow (DRG 190006). R.A.D, is an American Cancer Society Research Professor and supported by the Robert A. and Renee E. Beffer Foundation Institute for Innovative Cancer Science. We thank A. Warren, K. Vyas, A. DeLoose, X. Diu, W. Webb, C. Wicker III, S. Berryhill, R. Shelton, and T. Chambers for technical assistance. NR 66 TC 115 Z9 120 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD FEB 3 PY 2010 VL 11 IS 2 BP 136 EP 146 DI 10.1016/j.cmet.2009.12.009 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 555ON UT WOS:000274521900006 PM 20142101 ER EF