FN Thomson Reuters Web of Science™ VR 1.0 PT B AU Kraut, JA Nagami, GT AF Kraut, Jeffrey A. Nagami, Glenn T. BE Singh, AK Williams, GH TI Metabolic Acidosis of Chronic Kidney Disease SO TEXTBOOK OF NEPHRO-ENDOCRINOLOGY LA English DT Article; Book Chapter ID CHRONIC-RENAL-FAILURE; NA+-H+ EXCHANGE; SODIUM-BICARBONATE TREATMENT; NUTRITION EXAMINATION SURVEY; SERUM ELECTROLYTE PATTERNS; PROXIMAL TUBULE SEGMENTS; 3RD NATIONAL-HEALTH; HEMODIALYSIS-PATIENTS; ANGIOTENSIN-II; GROWTH-HORMONE C1 [Kraut, Jeffrey A.; Nagami, Glenn T.] VA Greater Los Angeles Hlth Care Syst, UCLA Membrane Biol Lab, Div Nephrol Med & Res Serv, Los Angeles, CA 90073 USA. [Kraut, Jeffrey A.; Nagami, Glenn T.] UCLA David Geffen Sch Med, Los Angeles, CA 90073 USA. RP Kraut, JA (reprint author), VA Greater Los Angeles Hlth Care Syst, UCLA Membrane Biol Lab, Div Nephrol Med & Res Serv, Los Angeles, CA 90073 USA. NR 210 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-08-092046-7; 978-0-12-373870-7 PY 2009 BP 457 EP 481 DI 10.1016/B978-0-12-373870-7.00029-6 PG 25 WC Endocrinology & Metabolism; Gastroenterology & Hepatology SC Endocrinology & Metabolism; Gastroenterology & Hepatology GA BA4PI UT WOS:000336096500030 ER PT S AU Medarova, Z Kumar, M Ng, SW Moore, A AF Medarova, Zdravka Kumar, Mohanraja Ng, Shu-wing Moore, Anna BE ReidhaarOlson, JF Rondinone, CM TI Development and Application of a Dual-Purpose Nanoparticle Platform for Delivery and Imaging of siRNA in Tumors SO THERAPEUTIC APPLICATIONS OF RNAI: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE RNA interference; magnetic resonance imaging; near-infrared optical imaging; magnetic nanoparticles; myristoylated polyarginine ID GENE; RNA; BIODISTRIBUTION; CELLS AB The vision Of Using a single therapeutic agent with sufficient generality to allow application to a wide variety of diseases yet Specific enough to permit intervention at single molecular stages of the pathology, is rapidly becoming a reality through the emergence: of RNA interference. RNA interference can be Used to inhibit the expression of virtually any gene and, at the same time, has single-nucleotide specificity. Major challenges in applying RNA interference in vivo are adequate deliver, of the siRNA molecule to the tissue of interest and methods of monitoring this delivery in a noninvasive manner. With this in mind, we have developed all approach not only to deliver siRNA to tumors, but also to track the Success of the deliver), by noninvasive imaging. To accomplish this, we designed a dual-function probe, MN-NIRF-siRNA, which consists of magnetic nanoparticles (MN) for magnetic resonance imaging (MRI), labeled with Cy5.5 dye for near-infrared in vivo optical imaging (NIRF), conjugated to myristoylated polyarginine peptides (MPAPs) for translocation of the complex into the cytosol, and carrying siRNA targeting tumor-specific genes. Administration of MN-NIRF-siRNA to tumor-bearing mice allowed LIS to monitor the delivery of the agent to tumors by MRI and NIRF imaging and resulted in efficient silencing of the target genes. This approach can significantly advance the therapeutic potential of RNA interference by providing a way not only to effectively shuttle siRNA to target sites but also to noninvasively assess the bioavailability of the siRNA molecule. C1 [Medarova, Zdravka; Kumar, Mohanraja; Moore, Anna] Harvard Univ, Massachusetts Gen Hosp, Mol Imaging Program,Dept Radiol,Sch Med, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Boston, MA 02115 USA. [Ng, Shu-wing] Harvard Univ, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Div Gynecol Oncol,Med Sch, Boston, MA 02115 USA. RP Medarova, Z (reprint author), Harvard Univ, Massachusetts Gen Hosp, Mol Imaging Program,Dept Radiol,Sch Med, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Boston, MA 02115 USA. FU NCI NIH HHS [K99 CA129070] NR 18 TC 13 Z9 14 U1 0 U2 4 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-60327-294-0 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2009 VL 555 BP 1 EP 13 DI 10.1007/978-1-60327-295-7_1 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA BKX23 UT WOS:000269519800001 PM 19495684 ER PT S AU Kim, DH Rossi, JJ AF Kim, Daniel H. Rossi, John J. BE ReidhaarOlson, JF Rondinone, CM TI Transcriptional Gene Silencing Using Small RNAs SO THERAPEUTIC APPLICATIONS OF RNAI: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE RNAi; siRNA; microRNA; TGS; chromatin; epigenetic; methylation; transcription ID HUMAN-CELLS; METHYLATION; DNA AB RNA interference is a potent gene silencing pathway initiated by short molecules of double-stranded RNA. Small interfering RNAs (siRNAs) with full sequence complementarity to mRNAs induce cleavage of their target transcripts in the cytoplasm. Recent evidence has shown, however, that siRNAs call also function ill the nucleus of mammalian cells to affect changes in chromatin structure. When targeted to promoter regions, siRNAs load into the effector protein Argonaute-1 (AGO1) and direct the formation of silent chromatin domains. This mechanism is known as transcriptional gene silencing (TGs), and the development of TGS as a novel therapeutic modality would be applicable to chronic diseases where long-term, heritable silencing of target genes is warranted. Here we discuss how small RNAs call be used to direct TGs in mammalian cells. C1 [Kim, Daniel H.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Massachusetts Gen Hosp,Dept Mol Biol, Boston, MA 02115 USA. [Kim, Daniel H.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Rossi, John J.] Beckman Res Inst City Hope, Grad Sch Biol Sci, Duarte, CA USA. [Rossi, John J.] Beckman Res Inst City Hope, Div Mol Biol, Duarte, CA USA. RP Kim, DH (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Massachusetts Gen Hosp,Dept Mol Biol, Boston, MA 02115 USA. FU Howard Hughes Medical Institute; NIAID NIH HHS [R01-AI42552, R37-AI29329] NR 8 TC 8 Z9 8 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-60327-294-0 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2009 VL 555 BP 119 EP 125 DI 10.1007/978-1-60327-295-7_9 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA BKX23 UT WOS:000269519800009 PM 19495692 ER PT B AU Drappatz, J Norden, AD Wen, PY AF Drappatz, Jan Norden, Andrew D. Wen, Patrick Y. BE Erdmann, VA Reifenberger, G Barciszewski, J TI Treatment of High-Grade Gliomas in Adults SO THERAPEUTIC RIBONUCLEIC ACIDS IN BRAIN TUMORS LA English DT Article; Book Chapter ID PHASE-II TRIAL; RECURRENT MALIGNANT GLIOMA; MONOCLONAL-ANTIBODY 81C6; BRAIN-TUMOR CONSORTIUM; THERAPY-ONCOLOGY-GROUP; DIAGNOSED ANAPLASTIC OLIGODENDROGLIOMAS; RECURSIVE PARTITIONING ANALYSIS; BEVACIZUMAB PLUS IRINOTECAN; PROMOTER METHYLATION STATUS; ENDOTHELIAL GROWTH-FACTOR AB Surgery, radiation therapy, and chemotherapy with temozolomide are the mainstays of treatment for patients with high-grade gliomas. The addition of temozolomide leads to a significant improvement in 2-year survival compared to radiation alone, although 2-year survival remains less than 30%. Responsiveness to temozolomide depends on the activity of O6-methylguanine-DNA methyltransferase in tumor cells. Increasing evidence suggests that certain molecular pathways are selectively upregulated in tumor cells. Some of these pathways have been shown to be instrumental in proliferation, migration, invasion, angiogenesis, and survival in preclinical models and therefore represent attractive therapeutic targets. This chapter will summarize the current standard of care of the different treatment modalities and some of the novel therapies undergoing evaluation. C1 [Drappatz, Jan; Norden, Andrew D.; Wen, Patrick Y.] Brigham & Womens Hosp, Dept Neurol, Div Neurooncol, Boston, MA 02115 USA. [Drappatz, Jan; Norden, Andrew D.; Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. [Norden, Andrew D.; Wen, Patrick Y.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Drappatz, J (reprint author), Brigham & Womens Hosp, Dept Neurol, Div Neurooncol, 44 Binney St, Boston, MA 02115 USA. EM Jan_Drappatz@dfci.harvard.edu NR 179 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY BN 978-3-642-00474-2 PY 2009 BP 355 EP 382 DI 10.1007/978-3-642-00475-9_16 D2 10.1007/978-3-642-00475-9 PG 28 WC Biochemistry & Molecular Biology; Oncology; Medicine, Research & Experimental; Clinical Neurology SC Biochemistry & Molecular Biology; Oncology; Research & Experimental Medicine; Neurosciences & Neurology GA BLY74 UT WOS:000271459000016 ER PT J AU Raffetto, JD AF Raffetto, Joseph D. TI Dermal pathology, cellular biology, and inflammation in chronic venous disease SO THROMBOSIS RESEARCH LA English DT Article DE Venous ulcer; Lipodermatosclerosis; Chronic venous disease; Fibrosis; Inflammation; Leukocyte; Fibroblasts; Growth factors; Matrix metalloproteinase (MMP); Mitogen activated protein kinase (MAPK) ID ACTIVATED PROTEIN-KINASE; WOUND FLUID; ULCER FIBROBLASTS; GROWTH-FACTORS; LEG ULCERS; INSUFFICIENCY; MATRIX; SENESCENCE; EXPRESSION; SKIN AB The pathophysiology of venous dermal pathology in chronic venous disease (CVD) is reflective of a complex interplay that involves sustained venous hypertension, inflammation, cytokine and matrix metalloproteinase (MMP) activation, and altered cellular function. Endothelial expression of specific adhesion molecules recruits (leukocytes, and diapedesis of these cells into the dermal microvasculature promotes an inflammatory response with activation of cytokines and proteinases. Altered cell function enhances a state of vulnerability in the surrounding tissues initiating specific changes associated with venous disease. Ultimately, the persistent inflammatory-proteinase activity leads to advanced chronic venous insufficiency (CVI) and ulcer formation. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Raffetto, Joseph D.] VA Boston HCS, Div Vasc Surg, W Roxbury, MA 02132 USA. [Raffetto, Joseph D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Raffetto, JD (reprint author), VA Boston HCS, Div Vasc Surg, 1400 VFW Pkwy,Surg 112, W Roxbury, MA 02132 USA. EM joseph.raffetto@med.va.gov NR 28 TC 32 Z9 34 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0049-3848 J9 THROMB RES JI Thromb. Res. PY 2009 VL 123 BP S66 EP S71 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 437BZ UT WOS:000265462200014 PM 19303508 ER PT B AU Krieger, N Emmons, KM Williams, D AF Krieger, Nancy Emmons, Karen M. Williams, David BE Koh, HK TI Defining, Investigating, and Addressing Cancer Inequities: Critical Issues SO TOWARD THE ELIMINATION OF CANCER DISPARITIES: CLINICAL AND PUBLIC HEALTH PERSPECTIVES LA English DT Article; Book Chapter ID DISPARITIES GEOCODING PROJECT; AFRICAN-AMERICAN WOMEN; RACIAL RESIDENTIAL SEGREGATION; POPULATION-BASED ANALYSIS; HEALTH IMPACT ASSESSMENT; PUBLIC-HEALTH; BREAST-CANCER; SOCIAL DISPARITIES; SOCIOECONOMIC-STATUS; PROSTATE-CANCER AB Research and action to address social disparities in cancer require clarity about what constitutes and causes these persistent and onerous inequities in health. Currently, both scientific literature and government documents exhibit important disagreements, confused terminology, and considerable, if not deliberate, vagueness about the meaning of the phrase "cancer disparities." To help clarify what is meant by social disparities in cancer and what this means for efforts to investigate their causes and act to rectify them, this chapter offers a definition of cancer inequities that is premised on the causal contention that health inequities, by definition, arise from social inequity and considers its implications for developing a multidisciplinary research agenda for 'Investigating and addressing social inequalities in cancer. Tackling this issue will require rigorous and critical frameworks, questions, and methods derived from multiple disciplines and will necessarily involve epidemiologic, clinical, and intervention research, both quantitative and qualitative. At issue is making conscious research choices about which types of disparities we study, in relation to which aspect of cancer, so as to improve the likelihood our research will help inform a society-wide discourse about the extent of, origins of, and remedies for social injustices in cancer, thereby aiding efforts to eliminate health inequities. C1 [Krieger, Nancy; Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Krieger, N (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Dana Farber Canc Inst, Kresge 717,677 Huntington Ave, Boston, MA 02115 USA. EM nkrieger@hsph.harvard.edu NR 120 TC 2 Z9 2 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-89442-3 PY 2009 BP 3 EP 28 DI 10.1007/978-0-387-89443-0_1 D2 10.1007/978-0-387-89443-0 PG 26 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA BKN85 UT WOS:000268727300001 ER PT B AU Shields, AE Fullerton, SM Olden, K AF Shields, Alexandra E. Fullerton, Stephanie M. Olden, Kenneth BE Koh, HK TI Genes, Environment, and Cancer Disparities SO TOWARD THE ELIMINATION OF CANCER DISPARITIES: CLINICAL AND PUBLIC HEALTH PERSPECTIVES LA English DT Article; Book Chapter ID MICROSOMAL EPOXIDE HYDROLASE; NONPOLYPOSIS COLORECTAL-CANCER; CUMULATIVE CIGARETTE-SMOKING; GENOME-WIDE ASSOCIATION; DNA-REPAIR GENES; S-TRANSFERASE M1; BREAST-CANCER; LUNG-CANCER; HEALTH DISPARITIES; PROSTATE-CANCER C1 [Shields, Alexandra E.] Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Boston, MA 02115 USA. [Fullerton, Stephanie M.] Univ Washington, Dept Med Hist & Eth, Seattle, WA 98195 USA. [Fullerton, Stephanie M.] Univ Washington, Ctr Genom & Healthcare Equal, Seattle, WA 98195 USA. [Olden, Kenneth] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Shields, Alexandra E.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Shields, Alexandra E.] Massachusetts Gen Hosp Partners HealthCare, Inst Hlth Policy, Boston, MA USA. RP Shields, AE (reprint author), Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Boston, MA 02115 USA. OI Fullerton, Stephanie/0000-0002-0938-6048 NR 116 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-89442-3 PY 2009 BP 49 EP 82 DI 10.1007/978-0-387-89443-0_3 D2 10.1007/978-0-387-89443-0 PG 34 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA BKN85 UT WOS:000268727300003 ER PT B AU Sorensen, G Sembajwe, G Harley, A Quintiliani, L AF Sorensen, Glorian Sembajwe, Grace Harley, Amy Quintiliani, Lisa BE Koh, HK TI Work and Occupation: Important Indicators of Socioeconomic Position and Life Experiences Influencing Cancer Disparities SO TOWARD THE ELIMINATION OF CANCER DISPARITIES: CLINICAL AND PUBLIC HEALTH PERSPECTIVES LA English DT Article; Book Chapter ID COMPREHENSIVE HEALTH-PROMOTION; EFFORT-REWARD IMBALANCE; TIME PHYSICAL-ACTIVITY; DISEASE MANAGEMENT PROGRAMS; CORONARY-HEART-DISEASE; WHITE-COLLAR WORKERS; MIDDLE-AGED MEN; UNITED-STATES; CIGARETTE-SMOKING; COLON-CANCER C1 [Sorensen, Glorian; Sembajwe, Grace; Harley, Amy; Quintiliani, Lisa] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Sorensen, Glorian; Sembajwe, Grace; Harley, Amy; Quintiliani, Lisa] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Sorensen, G (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. NR 179 TC 2 Z9 2 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-89442-3 PY 2009 BP 83 EP 105 DI 10.1007/978-0-387-89443-0_4 D2 10.1007/978-0-387-89443-0 PG 23 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA BKN85 UT WOS:000268727300004 ER PT B AU Wallington, SF Brawley, OW Holmes, MD AF Wallington, Sherrie Flynt Brawley, Otis W. Holmes, Michelle D. BE Koh, HK TI Socioeconomic Status and Breast Cancer Disparities SO TOWARD THE ELIMINATION OF CANCER DISPARITIES: CLINICAL AND PUBLIC HEALTH PERSPECTIVES LA English DT Article; Book Chapter ID BLACK-AND-WHITE; HEALTH-INSURANCE COVERAGE; AGE-RELATED DISPARITIES; AFRICAN-AMERICAN WOMEN; UNITED-STATES; ADJUVANT CHEMOTHERAPY; RACIAL-DISCRIMINATION; CARCINOMA TREATMENT; SCREENING PRACTICES; TREATMENT PATTERNS C1 [Wallington, Sherrie Flynt] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Wallington, Sherrie Flynt] Dana Farber Canc Inst, Boston, MA 02115 USA. [Holmes, Michelle D.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Brawley, Otis W.] Amer Canc Soc, Atlanta, GA 30329 USA. [Brawley, Otis W.] Emory Univ, Atlanta, GA 30322 USA. RP Wallington, SF (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM sherrie_wallington@dfci.harvard.edu NR 128 TC 0 Z9 0 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-89442-3 PY 2009 BP 137 EP 160 DI 10.1007/978-0-387-89443-0_6 D2 10.1007/978-0-387-89443-0 PG 24 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA BKN85 UT WOS:000268727300006 ER PT B AU del Carmen, M Diaz-Montez, T AF del Carmen, Marcela Diaz-Montez, Teresa BE Koh, HK TI Disparities and Cervical Cancer SO TOWARD THE ELIMINATION OF CANCER DISPARITIES: CLINICAL AND PUBLIC HEALTH PERSPECTIVES LA English DT Article; Book Chapter ID HUMAN-PAPILLOMAVIRUS INFECTION; LOW-INCOME WOMEN; SPECIAL POPULATIONS NETWORKS; AFRICAN-AMERICAN WOMEN; UNITED-STATES; PRIMARY-CARE; ETHNIC DISPARITIES; HEALTH DISPARITIES; SCREENING-PROGRAM; UTERINE CERVIX C1 [del Carmen, Marcela] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol, Boston, MA 02115 USA. [Diaz-Montez, Teresa] Johns Hopkins Med Inst, Div Gynecol Oncol, Baltimore, MD 21205 USA. RP del Carmen, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gynecol Oncol, Boston, MA 02115 USA. EM mdelcarmen@partners.org NR 81 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-89442-3 PY 2009 BP 203 EP 225 DI 10.1007/978-0-387-89443-0_9 D2 10.1007/978-0-387-89443-0 PG 23 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA BKN85 UT WOS:000268727300009 ER PT B AU Viswanath, K Emmons, KM AF Viswanath, K. Emmons, Karen M. BE Koh, HK TI Health Communication and Communication Inequalities in Addressing Cancer Disparities SO TOWARD THE ELIMINATION OF CANCER DISPARITIES: CLINICAL AND PUBLIC HEALTH PERSPECTIVES LA English DT Article; Book Chapter ID DISEASE MANAGEMENT CALLS; OF-THE-LITERATURE; WORLD-WIDE-WEB; INFORMATION-SEEKING; DECISION-MAKING; UNITED-STATES; BREAST-CANCER; FOLLOW-UP; SOCIAL EPIDEMIOLOGY; SMOKING PREVALENCE C1 [Viswanath, K.; Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. RP Viswanath, K (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. EM Vish_viswanath@dfci.harvard.edu NR 132 TC 3 Z9 3 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-89442-3 PY 2009 BP 277 EP 298 DI 10.1007/978-0-387-89443-0_12 D2 10.1007/978-0-387-89443-0 PG 22 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA BKN85 UT WOS:000268727300012 ER PT B AU Donelan, K AF Donelan, Karen BE Koh, HK TI Overcoming Barriers to Cancer Care: Patient and Public Perspectives SO TOWARD THE ELIMINATION OF CANCER DISPARITIES: CLINICAL AND PUBLIC HEALTH PERSPECTIVES LA English DT Article; Book Chapter ID RANDOMIZED CONTROLLED-TRIAL; HEALTH-CARE; RACIAL DISPARITIES; INSURANCE STATUS; AMBULATORY-CARE; FOLLOW-UP; RACE; NAVIGATION; ACCESS; BREAST C1 Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. RP Donelan, K (reprint author), Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. EM kdonelan@partners.org NR 67 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES BN 978-0-387-89442-3 PY 2009 BP 299 EP 315 DI 10.1007/978-0-387-89443-0_13 D2 10.1007/978-0-387-89443-0 PG 17 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA BKN85 UT WOS:000268727300013 ER PT J AU Luther, E Mahoney, J Chu, G Protopropov, A Holden, E AF Luther, Ed Mahoney, John Chu, Gerry Protopropov, Alexei Holden, Elena TI Multiparameter Automated Analysis of Chromatically Stained Tissue Sections by Laser-Scanning Cytometry SO TOXICOLOGIC PATHOLOGY LA English DT Meeting Abstract C1 [Luther, Ed; Mahoney, John; Chu, Gerry; Protopropov, Alexei; Holden, Elena] CompuCyte Corp, Cambridge, MA USA. [Mahoney, John; Chu, Gerry; Protopropov, Alexei] Dana Farber Canc Inst, Boston, MA 02115 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 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JAN PY 2009 VL 37 IS 1 MA P81 BP 148 EP 148 PG 1 WC Pathology; Toxicology SC Pathology; Toxicology GA 463XE UT WOS:000267466500094 ER PT J AU Stowell, CP Trieu, MQ Chuang, H Katz, N Quarrington, C AF Stowell, Christopher P. Trieu, My-Quyen Chuang, Han Katz, Nathaniel Quarrington, Carole TI Ultrasound-enabled topical anesthesia for pain reduction of phlebotomy for whole blood donation SO TRANSFUSION LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; LOW-FREQUENCY SONOPHORESIS; LIDOCAINE IONTOPHORESIS; CLINICAL-TRIAL; INTRAVENOUS INSERTION; LIPOSOMAL LIDOCAINE; EUTECTIC MIXTURE; LOCAL-ANESTHESIA; RETURN RATES; DOUBLE-BLIND AB BACKGROUND: Ultrasound-facilitated delivery of topical anesthetics has been used to achieve effective anesthesia within 5 minutes for venipuncture and the insertion of intravenous access devices, but has never been studied for blood donation. STUDY DESIGN AND METHODS: This study was a single-center, prospective, randomized, sham treatment-controlled, single-blinded clinical evaluation. Repeat donors were randomly assigned to undergo treatment with ultrasound and topical anesthetic or sham ultrasound and placebo anesthetic before phlebotomy for whole blood donation. The primary outcome measures were pain assessments using the Verbal Categorical Scale (VCS) and the Visual Analogue Scale and the assessment of skin irritation at the target site. RESULTS: One-hundred subjects were enrolled and all completed the study. Compared to the sham/placebo control group, donors receiving ultrasound/anesthetic had lower pain scores on the VCS (1.81 +/- 0.67 vs. 2.17 +/- 0.68; p = 0.01) and Visual Analog Scale (17.2 +/- 15.5 vs. 27.6 +/- 19.5; p = 0.006). The proportion of subjects in the treatment group who experienced skin irritation (8%) was similar to that in the control group (2%; p = 0.20). CONCLUSION: Ultrasound-enhanced delivery of topical anesthetic was demonstrated to be a safe means of quickly achieving clinically meaningful reduction in the pain of phlebotomy for whole blood donation compared to sham/placebo treatment. C1 [Stowell, Christopher P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Blood Transfus Serv,Dept Pathol, Boston, MA 02114 USA. Echo Therapeut Inc, Franklin, MA USA. Analges Res, Needham, MA USA. Massachusetts Gen Hosp, Clin Res Program, Boston, MA 02114 USA. RP Stowell, CP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Blood Transfus Serv,Dept Pathol, GRJ 148,55 Fruit St, Boston, MA 02114 USA. EM cstowell@partners.org FU Echo Therapeutics, Inc. FX Supported by Echo Therapeutics, Inc. NR 35 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JAN PY 2009 VL 49 IS 1 BP 146 EP 153 DI 10.1111/j.1537-2995.2008.01939.x PG 8 WC Hematology SC Hematology GA 387XA UT WOS:000261983700020 PM 18954400 ER PT J AU Pan, Y Sawalha, AH AF Pan, Yujun Sawalha, Amr H. TI Epigenetic regulation and the pathogenesis of systemic lupus erythematosus SO TRANSLATIONAL RESEARCH LA English DT Article ID DRUG-INDUCED LUPUS; CD4(+) T-CELLS; DNA METHYLATION INHIBITORS; MRL-LPR/LPR MOUSE; GENE-EXPRESSION; IN-VITRO; HISTONE MODIFICATIONS; AUTOIMMUNE-DISEASE; SYNGENEIC MICE; RENAL-DISEASE AB The pathogenesis of systemic lupus erythematosus (SLE) is incompletely understood. Studies in both lupus animal models and human disease indicate a clear role for epigenetic defects, particularly DNA methylation, in the pathogenesis of lupus. T-cell DNA from active lupus patients is hypomethylated, which results in overexpression of methylation-regulated genes, T-cell autoreactivity, and autoimmunity in vivo. Inducing an extracellular signal-regulated kinase (ERK) signaling defect in T cells using a transgenic mouse model resulted in reduced DNA methyltransferase 1 (DNMT1) expression, overexpression of methylation-sensitive genes, and anti-double-stranded DNA (anti-dsDNA) antibody production. ERK signaling is known to be defective in lupus T cells, and this defect is now explained by impaired T-cell protein kinase C (PKC) delta activation. Herein, we discuss how defective epigenetic regulation is involved in the pathogenesis of lupus, which includes both DNA methylation and histone modification changes. (Translational Research 2009;153:4-10) C1 Univ Oklahoma, Hlth Sci Ctr, Oklahoma Med Res Fdn, Arthrit & Immunol Program,Dept Med, Oklahoma City, OK USA. US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. RP Sawalha, AH (reprint author), 825 NE 13th St,MS 24, Oklahoma City, OK 73104 USA. EM amr-sawalha@omrf.ouhsc.edu FU National Center for Research Resources [P20-RR015577]; National Institute of Allergy and Infectious Diseases [R03AI076729]; Arthritis National Research Foundation; University of Oklahoma College of Medicine FX Supported by NIH Grant P20-RR015577 from the National Center for Research Resources and NIH Grant R03AI076729 from the National Institute of Allergy and Infectious Diseases, as well as by funding from the Arthritis National Research Foundation and the University of Oklahoma College of Medicine. NR 56 TC 58 Z9 64 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-5244 J9 TRANSL RES JI Transl. Res. PD JAN PY 2009 VL 153 IS 1 BP 4 EP 10 DI 10.1016/j.trsl.2008.10.007 PG 7 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 392TU UT WOS:000262325900002 PM 19100952 ER PT J AU Aoyama, A Ng, CY Millington, TM Boskovic, S Murakami, T Wain, JC Houser, SL Madsen, JC Kawai, T Allan, JS AF Aoyama, A. Ng, C. Y. Millington, T. M. Boskovic, S. Murakami, T. Wain, J. C. Houser, S. L. Madsen, J. C. Kawai, T. Allan, J. S. TI Comparison of Lung and Kidney Allografts in Induction of Tolerance by a Mixed-Chimerism Approach in Cynomolgus Monkeys SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 22nd International Congress of the Transplantation-Society CY AUG 10-14, 2008 CL Local Org Comm, Sydney, AUSTRALIA SP Transplantat Soc, Transplantat Soc Australia & New Zealand HO Local Org Comm ID TRANSPLANTATION; REGIMEN AB Background, We have previously reported the successful induction of renal allograft tolerance in non-human primates using a nonmyeloablative conditioning regimen to produce it mixed-chimeric state in the recipient. In the present study, we applied this same technique to lung allotransplantation in cynomolgus monkeys. Methods. Nine pairs of fully major histocompatibility complex (MHC)-mismatched cynomolgus monkeys were used. The conditioning regimen consisted of total body irradiation, thymic irradiation, and antithymocyte globulin. The recipients underwent lung and bone marrow transplantation, followed by anti-CD154 monoclonal antibody (mAb), and it 1-month course of cyclosporine. The regimen included anti-CD8 mAb in the last 5 recipients and alpha 1-antitripsin in the last 3 recipients. The results were compared with 8 recipients that received kidney allografts using the same regimen. Results. Transient chimerism developed in all lung recipients, as was previously seen in the kidney recipients. Nonetheless, the lung recipients rejected their allografts significant earlier than the kidney recipients (P <.01.). Conclusions. Despite the successful induction of mixed chimerism in recipients of fully MHC-mismatched lung allografts, we have not observed long-term graft survival, as has been seen in an analogous kidney model. Strategies to overcome this problem include organ-specific modifications of the transplant regimen. C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Transplant Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Allan, JS (reprint author), 55 Fruit St,Blake 1570, Boston, MA 02114 USA. EM jallan@partners.org FU NHLBI NIH HHS [P01 HL018646]; NIAID NIH HHS [NIH U19 AI066705, U19 AI066705, U19 AI066705-010003, U19 AI066705-020003, U19 AI066705-030003, U19 AI066705-040003] NR 6 TC 15 Z9 16 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0041-1345 J9 TRANSPL P JI Transplant. Proc. PD JAN-FEB PY 2009 VL 41 IS 1 BP 429 EP 430 DI 10.1016/j.transproceed.2008.08.147 PG 2 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 412UG UT WOS:000263749100112 PM 19249572 ER PT J AU Cowart, LA AF Cowart, L. Ashley TI Sphingolipids: players in the pathology of metabolic disease SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID INDUCED INSULIN-RESISTANCE; CYTOSOLIC PHOSPHOLIPASE A(2); TANDEM MASS-SPECTROMETRY; SATURATED FATTY-ACIDS; HUMAN SKELETAL-MUSCLE; PROTEIN-KINASE-C; CERAMIDE SYNTHESIS; SPHINGOSINE 1-PHOSPHATE; TNF-ALPHA; SERINE PALMITOYLTRANSFERASE AB The contribution of aberrant production of bioactive lipids to pathophysiological changes associated with obesity has risen to the forefront of lipid research. Increased diacylglycerol has been appreciated as a cause of insulin resistance, but emerging data support a role for sphingolipids in other metabolic diseases including obesity, diabetes, atherosclerosis and metabolic syndrome. Recent data demonstrate that elevation of plasma free fatty acids promotes aberrant sphingolipid production and composition in various tissues including skeletal muscle, pancreas and adipocytes. Moreover, rectifying these aberrant sphingolipid profiles often attenuates pathologies associated with their production. Although data thus far generate more questions than they answer, they indicate a major contribution of sphingolipids to pathologies associated with obesity. This review summarizes recent work in these areas. C1 [Cowart, L. Ashley] Med Univ S Carolina, Charleston, SC 29401 USA. [Cowart, L. Ashley] Ralph H Johnson VA Med Ctr, Charleston, SC 29401 USA. RP Cowart, LA (reprint author), Med Univ S Carolina, 114 Doughty St Rm 423, Charleston, SC 29401 USA. EM cowartl@musc.edu NR 89 TC 51 Z9 52 U1 1 U2 7 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 JAN PY 2009 VL 20 IS 1 BP 34 EP 42 DI 10.1016/j.tem.2008.09.004 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 400VX UT WOS:000262898600005 PM 19008117 ER PT J AU Polyak, K Haviv, I Campbell, IG AF Polyak, Kornelia Haviv, Izhak Campbell, Ian G. TI Co-evolution of tumor cells and their microenvironment SO TRENDS IN GENETICS LA English DT Review ID STROMAL-EPITHELIAL INTERACTIONS; CANCER-ASSOCIATED FIBROBLASTS; HUMAN BREAST TISSUES; GENETIC ALTERATIONS; HUMAN COLON; MICRODISSECTED STROMA; TP53 MUTATIONS; MAMMARY-GLAND; IN-SITU; PROGRESSION AB Increasing evidence indicates that tumor-stromal cell interactions have a crucial role in tumor initiation and progression. These interactions modify cellular compartments, leading to the co-evolution of tumor cells and their microenvironment. Although the importance of microenvironmental alterations in tumor development is recognized, the molecular mechanisms underlying these changes are only now beginning to be understood. Epigenetic and gene expression changes have consistently been reported in cancer-associated stromal cells and the influence of the host genotype on tumorigenesis is also well documented. However, the presence of clonally selected somatic genetic alterations within the tumor microenvironment has been controversial. A thorough understanding of the co-evolution of these two cellular compartments will require carefully executed molecular studies combined with mathematical modeling. C1 [Polyak, Kornelia] Dana Farber Canc Inst, Boston, MA 02115 USA. [Polyak, Kornelia] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Haviv, Izhak] Baker IDI Inst, Blood & DNA Profiling Facil, Melbourne, Vic 3000, Australia. [Haviv, Izhak] Univ Melbourne, Sch Med, Dept Biochem, Melbourne, Vic 3010, Australia. [Campbell, Ian G.] Peter MacCallum Canc Ctr, VBCRC Canc Genet Lab, Melbourne, Vic 3002, Australia. [Campbell, Ian G.] Univ Melbourne, Sch Med, Dept Pathol, Melbourne, Vic 3010, Australia. RP Polyak, K (reprint author), Dana Farber Canc Inst, 44 Binney St,D740C, Boston, MA 02115 USA. EM kornelia_polyak@dfci.harvard.edu RI Peng, Chunwei/F-6788-2010; campbell, Ian/F-6006-2011 FU NCI NIH HHS [CA116235, CA89393] NR 75 TC 253 Z9 260 U1 9 U2 64 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD JAN PY 2009 VL 25 IS 1 BP 30 EP 38 DI 10.1016/j.tig.2008.10.012 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 405JB UT WOS:000263218000009 PM 19054589 ER PT S AU Marselli, L Sgroi, DC Bonner-Weir, S Weir, GC AF Marselli, Lorella Sgroi, Dennis C. Bonner-Weir, Susan Weir, Gordon C. BE Stocker, C TI Laser Capture Microdissection of Human Pancreatic beta-Cells and RNA Preparation for Gene Expression Profiling SO TYPE 2 DIABETES: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Human beta-cell; Laser capture microdissection; RNA extraction; RNA integrity; Type 2 diabetes ID ISLETS; HYPERGLYCEMIA; ANTIOXIDANT; PATHWAYS; STRESS; TISSUE AB Human beta-cell gene profiling is a powerful tool for understanding beta-cell biology in normal and pathological conditions. The assessment is complicated when isolated islets arc studied because of contamination by non-beta-cells and the exposure to the trauma of isolation that causes changes in gene expression. These limitations can be overcome by dissecting the beta-cells from the pancreatic tissue directly Using the laser capture microdissection (LCM) technique. LCM allows the sampling of specific cell types from tissue sections. The technique requires morphological criteria or specific stains for targeted cells, and the protocols must preserve the condition of the sought-after macromolecules. We have developed a protocol of rapid tissue dehydration followed by identification of human beta-cells by their intrinsic autofluorescence, which allows laser microdissection for gene-profiling studies. C1 [Marselli, Lorella; Bonner-Weir, Susan; Weir, Gordon C.] Joslin Diabet Ctr, Div Res, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. [Marselli, Lorella; Bonner-Weir, Susan; Weir, Gordon C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Sgroi, Dennis C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Pathol Unit, Boston, MA USA. RP Marselli, L (reprint author), Joslin Diabet Ctr, Div Res, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. NR 10 TC 16 Z9 16 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-934115-15-2 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2009 VL 560 BP 87 EP 98 DI 10.1007/978-1-59745-448-3_8 D2 10.1007/978-1-59745-448-3 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA BKY53 UT WOS:000269616400008 PM 19504246 ER PT S AU Li, WC AF Li, Wan-Chun BE Stocker, C TI In Vitro Transdifferentiation of Human Hepatoma Cells into Pancreatic-Like Cells SO TYPE 2 DIABETES: METHODS AND PROTOCOLS SE Methods in Molecular Biology LA English DT Article; Book Chapter DE Liver; Transdifferentiation; HepG2; Pdx1 ID BETA-CELLS; LIVER; INSULIN; DIFFERENTIATION; EXPRESSION; METAPLASIA; ENDOCRINE; PHENOTYPE; ENDODERM; PDX-1 AB Transdifferentiation is defined as an irreversible switch in postnatal life of one differentiated cell to another. Transdifferentiation from different Cellular origins into pancreatic-like P-cells is of clinical significance since this approach may offer a potential cure for diabetes. In order to achieve this goal, the liver is considered as a suitable candidate due to its close developmental relationship to the pancreas, its large size and a well-documented regenerative capacity that could provide enough original tissues to initiate the transdifferentiation procedure. In this chapter, we describe a protocol to overexpress Pdx1, a master regulator essential for pancreas development in the Cultured human liver cell line, HepG2. C1 Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. RP Li, WC (reprint author), Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. NR 26 TC 0 Z9 0 U1 1 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA SN 1064-3745 BN 978-1-934115-15-2 J9 METHODS MOL BIOL JI Methods Mol. Biol. PY 2009 VL 560 BP 99 EP 110 DI 10.1007/978-1-59745-448-3_9 D2 10.1007/978-1-59745-448-3 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA BKY53 UT WOS:000269616400009 PM 19504247 ER PT B AU Muratoglu, OK AF Muratoglu, Orhun K. BE Kurtz, SM TI Highly Crosslinked and Melted UHMWPE SO UHMWPE BIOMATERIALS HANDBOOK: ULTRA-HIGH MOLECULAR WEIGHT POLYETHYLENE IN TOTAL JOINT REPLACEMENT AND MEDICAL DEVICES, 2ND EDITION LA English DT Article; Book Chapter ID MOLECULAR-WEIGHT POLYETHYLENE; TOTAL KNEE ARTHROPLASTY; TOTAL HIP-ARTHROPLASTY; MECHANICAL-PROPERTIES; PROSTHETIC APPLICATIONS; PROPAGATION RESISTANCE; CLINICAL-PERFORMANCE; GAMMA-STERILIZATION; ACETABULAR LINERS; TIBIAL INSERTS C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Muratoglu, OK (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 38 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-08-088444-8; 978-0-12-374721-1 PY 2009 BP 197 EP 204 DI 10.1016/B978-0-12-374721-1.00013-4 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials; Polymer Science SC Engineering; Materials Science; Polymer Science GA BHF66 UT WOS:000325264300014 ER PT B AU Oral, E Muratoglu, OK AF Oral, Ebru Muratoglu, Orhun K. BE Kurtz, SM TI Highly Crosslinked UHMWPE Doped with Vitamin E SO UHMWPE BIOMATERIALS HANDBOOK: ULTRA-HIGH MOLECULAR WEIGHT POLYETHYLENE IN TOTAL JOINT REPLACEMENT AND MEDICAL DEVICES, 2ND EDITION LA English DT Article; Book Chapter ID MOLECULAR-WEIGHT POLYETHYLENE; ELECTRON-SPIN-RESONANCE; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; TOTAL HIP-ARTHROPLASTY; AGE-RELATED CATARACT; ALPHA-TOCOPHEROL; CARDIOVASCULAR-DISEASE; MECHANICAL-PROPERTIES; CLINICAL-TRIAL C1 [Oral, Ebru; Muratoglu, Orhun K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Oral, E (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 100 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-08-088444-8; 978-0-12-374721-1 PY 2009 BP 221 EP 236 DI 10.1016/B978-0-12-374721-1.00015-8 PG 16 WC Engineering, Biomedical; Materials Science, Biomaterials; Polymer Science SC Engineering; Materials Science; Polymer Science GA BHF66 UT WOS:000325264300016 ER PT B AU Bragdon, CR AF Bragdon, Charles R. BE Kurtz, SM TI Clinical Surveillance of UHMWPE Using Radiographic Methods SO UHMWPE BIOMATERIALS HANDBOOK: ULTRA-HIGH MOLECULAR WEIGHT POLYETHYLENE IN TOTAL JOINT REPLACEMENT AND MEDICAL DEVICES, 2ND EDITION LA English DT Article; Book Chapter ID TOTAL-HIP-ARTHROPLASTY; CROSS-LINKED POLYETHYLENE; LOW-FRICTION ARTHROPLASTY; MOLECULAR-WEIGHT POLYETHYLENE; RADIO STEREOMETRIC ANALYSIS; FEMORAL-HEAD PENETRATION; BACKED ACETABULAR CUPS; SYNOVIAL-LIKE MEMBRANE; BONE-CEMENT INTERFACE; WEAR DEBRIS C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bragdon, CR (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 97 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-08-088444-8; 978-0-12-374721-1 PY 2009 BP 423 EP 432 DI 10.1016/B978-0-12-374721-1.00028-6 PG 10 WC Engineering, Biomedical; Materials Science, Biomaterials; Polymer Science SC Engineering; Materials Science; Polymer Science GA BHF66 UT WOS:000325264300029 ER PT J AU Lee, SWH Liong, ML Yuen, KH Leong, WS Khan, N Cheah, PY Krieger, JN AF Lee, Shaun Wen Huey Liong, Men Long Yuen, Kah Hay Leong, Wing Seng Khan, Nurzalina Cheah, Phaik Yeong Krieger, John N. TI Prostatitis-Like Symptoms: Diagnosis and Management in a Malaysian Primary Care Population SO UROLOGIA INTERNATIONALIS LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-Infection-and-Inflammation CY MAY, 2005 CL San Antonio, TX SP Soc Infect Inflammat DE Chronic pelvic pain; Prostatitis syndromes; Primary care management ID PELVIC PAIN SYNDROME; QUESTIONNAIRE SURVEY; UROLOGISTS; MEN; TRIAL AB Background: Little is known about how primary care physicians (PCPs) in Asia diagnose and manage prostatitis-like symptoms. This study investigated the clinical diagnosis of and care provided for prostatitis-like symptoms by PCPs in a Malaysian population, and compared these findings to reports from other areas. Methods: All members of the Penang Private Medical Practitioners' Society were asked to complete a self-administered survey. Nonresponders were contacted after 3 weeks and received a telephone request after 6 weeks. Results: Of the 786 practitioners contacted, 669 considered themselves to be PCPs, including 279 (42%) who responded to the survey. Adult males with prostatitis-like symptoms typically constitute <1% of the patients seen by PCPs. Most PCPs (72%) believe that prostatitis-like symptoms are caused by bacterial infection. 61% of PCPs base their diagnosis of prostatitis-like symptoms on clinical history, a physical examination and dipstick urinalysis. Standard management was to prescribe 1 or 2 courses of antimicrobials. Conclusions: Despite the 8.7% prevalence found in a previous survey in this population, prostatitis remains underdiagnosed in Malaysia. In contrast to many other clinical settings, urologists in Malaysia see a large proportion of newly diagnosed and treatment-naive prostatitis patients, providing an opportunity for clinical diagnostic and treatment studies. Copyright (C) 2009 S. Karger AG, Basel C1 [Liong, Men Long; Leong, Wing Seng] Lam Wah Ee Hosp, Dept Urol, George Town, Malaysia. [Lee, Shaun Wen Huey; Yuen, Kah Hay; Khan, Nurzalina; Cheah, Phaik Yeong] Univ Sci Malaysia, Sch Pharmaceut Sci, George Town, Malaysia. [Krieger, John N.] Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, Dept Urol Surg,Dept Urol, Seattle, WA 98108 USA. RP Krieger, JN (reprint author), Univ Washington, Sch Med, VA Puget Sound Hlth Care Syst, Dept Urol Surg,Dept Urol, 1660 S Columbian Way, Seattle, WA 98108 USA. EM jkrieger@u.washington.edu RI Yuen, Kah Hay /F-9059-2010; Khan, Nurzalina/E-3875-2012; OI Lee, Shaun/0000-0001-7361-6576 NR 19 TC 1 Z9 1 U1 0 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0042-1138 J9 UROL INT JI Urol.Int. PY 2009 VL 82 IS 1 BP 32 EP 37 DI 10.1159/000176022 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 395UR UT WOS:000262549500008 PM 19172094 ER PT J AU Eisner, BH Dretler, SP AF Eisner, Brian H. Dretler, Stephen P. TI Use of the Stone Cone for Prevention of Calculus Retropulsion during Holmium:YAG Laser Lithotripsy: Case Series and Review of the Literature SO UROLOGIA INTERNATIONALIS LA English DT Article DE Retropulsion; Ureteroscopy; Lithotripsy ID SHOCK-WAVE LITHOTRIPSY; DISTAL URETERAL STONES; YAG LASER; PERCUTANEOUS NEPHROLITHOTOMY; PNEUMATIC LITHOTRIPSY; IN-VITRO; MIGRATION; URETEROSCOPY; LITHOCLAST; EXPERIENCE AB Background: Stone retropulsion during ureteroscopic lithotripsy leads to additional procedures for residual calculi. The Stone Cone (Boston Scientific, Natick, Mass., USA) is a device designed to prevent stone migration. Objective: To determine the incidence of calculus retropulsion and additional procedures after ureteroscopy with intracorporeal lithotripsy while using the Stone Cone. Materials and Methods: A retrospective review of patients with obstructing ureteral calculi who underwent ureteroscopy and holmium:YAG laser lithotripsy using the Stone Cone as a backstop over a 3-year period at an academic medical center was performed. 133 patients underwent ureteroscopy with holmium: YAG laser lithotripsy using the Stone Cone to prevent calculus retroplusion. Success was defined as no residual fragments 1 2 mm in size, no changes from semirigid to flexible ureteroscope, and no additional procedures. Post-operative imaging was abdominal plain radiography or computed tomography. A MEDLINE search was performed to indentify all English clinical studies of the Stone Cone. Results: Of the 133 uses of the Stone Cone, there were 2 (1.5%) residual retropulsed fragments >2 mm which required an additional procedure. There were no changes to flexible ureteroscope secondary to stone retropulsion in 105 cases of semirigid ureteroscopy. There was no instance of ureteral obstruction from residual 2-mm fragments. There were no ureteral strictures or hydronephrosis among 91 patients with long-term follow-up imaging. A review of the literature was performed which yielded 4 clinical publications and 90 reported cases using the Stone Cone with 100% success. Two of these studies showed statistically significant improvement when compared with control patients. Conclusions: The Stone Cone minimized stone retropulsion during ureteroscopic laser lithotripsy. The Stone Cone offers the urologist greater certainty during ureteroscopy and may decrease the number of clinically significant residual calculi. Copyright (C) 2009 S. Karger AG, Basel C1 [Eisner, Brian H.; Dretler, Stephen P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol,Kidney Stone Ctr, Boston, MA 02114 USA. RP Eisner, BH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol,Kidney Stone Ctr, 55 Fruit St, Boston, MA 02114 USA. EM beisner@partners.org NR 23 TC 19 Z9 25 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0042-1138 J9 UROL INT JI Urol.Int. PY 2009 VL 82 IS 3 BP 356 EP 360 DI 10.1159/000209372 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 447VI UT WOS:000266219700021 PM 19440028 ER PT B AU Goodman, A Goff, B AF Goodman, Annekathryn Goff, Barbara BE Muggia, F Oliva, E TI Endometrial Cancer: Screening, Diagnosis, and Surgical Staging SO UTERINE CANCER: SCREENING, DIAGNOSIS, AND TREATMENT SE Current Clinical Oncology Series LA English DT Article; Book Chapter DE Endometrial cancer; Heredity; Screening; Endometrial biopsy; Surgical staging ID CERVICAL CYTOLOGY; TAMOXIFEN; WOMEN; CARCINOMA; RISK; ADENOCARCINOMA; CELLS; OVARY; BREAST AB Through case studies, the authors point out environmental and hereditary factors that contribute to increased risk of developing endometrial cancer and how to apply screening modalities in pre- and postmenopausal women. Attention is drawn to certain anatomic abnormalities that prevent vaginal bleeding - the most common symptom related to cancer. Diagnostic tests that are available to pursue various aspects of the diagnosis in a sequential fashion are described, culminating in the endometrial biopsy. Recommendations for screening and diagnosis in the asymptomatic as well as the symptomatic patients are summarized. Surgical staging represents the final event in the diagnostic workup. Instances when Such staging can be modified to deal with various comorbidities are delineated. C1 [Goodman, Annekathryn] Massachusetts Gen Hosp, Gillette Ctr Womens Canc, Div Gynecol Oncol, Boston, MA 02114 USA. [Goff, Barbara] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. RP Goodman, A (reprint author), Massachusetts Gen Hosp, Gillette Ctr Womens Canc, Div Gynecol Oncol, Boston, MA 02114 USA. EM agoodman@partners.org NR 40 TC 1 Z9 1 U1 1 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-58829-736-5 J9 CURR CLIN ONCOL PY 2009 BP 13 EP 24 DI 10.1007/978-1-60327-044-1_2 D2 10.1007/978-1-60327-044-1 PG 12 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA BKO02 UT WOS:000268740900002 ER PT B AU Saksena, MA Lee, SI AF Saksena, Mansi A. Lee, Susanna I. BE Muggia, F Oliva, E TI Imaging in the Diagnosis and Treatment of Endomet(r)ial Cancer SO UTERINE CANCER: SCREENING, DIAGNOSIS, AND TREATMENT SE Current Clinical Oncology Series LA English DT Article; Book Chapter DE Endometrial imaging; Ultrasound; MRI; Sonohysterography; CT/PET ID TRANS-ABDOMINAL SONOGRAPHY; DEEP MYOMETRIAL INVASION; ENDOMETRIAL CANCER; TRANSVAGINAL SONOGRAPHY; PREOPERATIVE ASSESSMENT; POSTMENOPAUSAL WOMEN; COMPUTED-TOMOGRAPHY; PATHOLOGICAL CORRELATION; F-18-FDG PET; FDG-PET AB Ultrasound, sonohysterography (SHG) magnetic resonance imaging, computed tomography (CT), and positron emission tomography (PET) are tools available for diagnosis and for post-treatment surveillance. The transvaginal ultrasound has. a well-defined role in women presenting with postmenopausal bleeding. Magnetic resonance imaging (MRI) provides the most accurate modality for preoperative staging in patients with early disease; CT and PET are helpful in the detection of distant metastases. sonohysterography is a less-invasive alternative to hysteroscopy. C1 [Saksena, Mansi A.; Lee, Susanna I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Lee, SI (reprint author), Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. EM slee0@partners.org NR 59 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-58829-736-5 J9 CURR CLIN ONCOL PY 2009 BP 25 EP 50 DI 10.1007/978-1-60327-044-1_3 D2 10.1007/978-1-60327-044-1 PG 26 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA BKO02 UT WOS:000268740900003 ER PT B AU Soslow, RA Oliva, E AF Soslow, Robert A. Oliva, Esther BE Muggia, F Oliva, E TI Uterine Cancer: Pathology SO UTERINE CANCER: SCREENING, DIAGNOSIS, AND TREATMENT SE Current Clinical Oncology Series LA English DT Article; Book Chapter DE endometrioid; serous; clear cell; mixed carcinomas; leiomyosarcoma; endometrial stromal sarcoma; carcinosarcoma; low-grade mullerian adenosarcoma; PEComa; intravenous leiomyomatosis ID SMOOTH-MUSCLE TUMORS; ENDOMETRIAL STROMAL SARCOMAS; PERIVASCULAR EPITHELIOID CELL; PAPILLARY SEROUS CARCINOMA; MIXED MULLERIAN TUMORS; SEX-CORD TUMORS; MITOTICALLY ACTIVE LEIOMYOMAS; UNUSUAL MORPHOLOGIC FEATURES; UNUSUAL HISTOLOGIC FEATURES; FEMALE GENITAL-TRACT AB Endometrioid adenocarcinoma is the most common type of endometrial carcinoma (approximately 85%). By definition, it should resemble, at least focally, proliferative-type endometrium with tubular glands lined by mitotically active columnar cells. Common problems in diagnosis involve its distinction from complex atypical hyperplasia, endocervical adenocarcinoma, serous carcinoma, clear cell carcinoma, and carcinosarcoma. Pure serous carcinomas comprise about 10% of endometrial cancers. The term "serous" refers to shared characteristics with cells lining the fallopian tube, particularly the tumor cells' columnar shape, eosinophilic cytoplasm and tendency to form papillae. However, some serous carcinomas are not papillary but glandular. Importantly, all serous carcinomas exhibit marked nuclear pleomorphism and most demonstrate discrepancies between architectural differentiation and cytologic features. Clear cell carcinoma is the third most common endometrial carcinoma subtype, even though it represents < 5% of cases. Epidemiologic features of patients with clear cell carcinoma are obscure because of this tumor's rarity, difficulties in diagnostic reproducibility and accumulating evidence that there are perhaps several subtypes of clear cell carcinoma. Most clear cell carcinomas are composed of cells with clear cytoplasm, but this feature is not restricted to clear cell carcinoma and some clear cell carcinomas may contain cells with eosinophilic cytoplasm. Other subtypes of endometrial carcinoma are rare and include squamous, transitional, small cell, and mixed cell types. Among pure mesenchymal tumors of the uterus, leiomyosarcoma is the most common. Microscopic criteria to establish the diagnosis of leiomyosarcoma include the combination of two of the following: cytologic atypia, mitotic activity and tumor cell necrosis. The threshold for mitotic activity varies for spindled, epithelioid and myxoid subtypes. A variety of uterine tumors enter in the differential diagnosis, including several variants of leiomyoma (mitotically active, apoplectic, with bizarre nuclei, highly cellular, and hydropic). Low-grade endometrial stromal sarcomas are composed of a homogenous Population of small cells with scant cytoplasm resembling proliferative-type endometrial stroma. They show a diffuse growth and infiltrate the uterine wall in a permeative (not destructive) fashion and may have prominent intravascular growth. Carcinosarcomas (malignant mixed mullerian tumors) are biphasic tumors typically composed of highly malignant epithelial and stromal/mesenchymal elements. The histogenesis of these tumors has evolved in recent years and it is now accepted that they either arise from a common pluripotential cell with divergent differentiation or that the sarcomatous component develops from the carcinomatous component by a metaplastic process or dedifferentiation. Other less common mixed or mesenchymal tumors include 1) low-grade mullerian adenosarcoma (composed of benign-appearing glands and malignant stroma); 2) PEComa, which is composed of epithelioid cells that are typically positive for HMB-45 and may be associated with tuberous sclerosis; and 3) intravenous leiomyomatosis which shows a proliferation of smooth muscle cells within vascular spaces. Even though the smooth muscle proliferation is benign it can behave aggressively from the clinical point of view. C1 [Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Soslow, Robert A.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM eoliva@partners.org NR 152 TC 3 Z9 3 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-58829-736-5 J9 CURR CLIN ONCOL PY 2009 BP 51 EP 86 DI 10.1007/978-1-60327-044-1_4 D2 10.1007/978-1-60327-044-1 PG 36 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA BKO02 UT WOS:000268740900004 ER PT B AU Baker, PM Oliva, E AF Baker, Patricia M. Oliva, Esther BE Muggia, F Oliva, E TI Prognostic Factors in Uterine Cancer SO UTERINE CANCER: SCREENING, DIAGNOSIS, AND TREATMENT SE Current Clinical Oncology Series LA English DT Article; Book Chapter DE Stage; Myometrial invasion; Differentiation; Histologic subtype; Lymphovascular invasion ID MIXED MULLERIAN TUMORS; ENDOMETRIAL STROMAL SARCOMA; PAPILLARY SEROUS CARCINOMA; GYNECOLOGIC-ONCOLOGY-GROUP; POSITIVE PERITONEAL CYTOLOGY; CLEAR-CELL-CARCINOMA; PROGESTERONE-RECEPTOR EXPRESSION; LYMPHVASCULAR SPACE INVOLVEMENT; FLOW-CYTOMETRIC ANALYSIS; SMOOTH-MUSCLE TUMORS AB Pathologic staging determines the management of patients with endometrial adenocarcinoma and uterine sarcomas following the initial surgery and it is an essential component of the initial assessment. FIGO stage, tumor subtype, grade of differentiation, myometrial invasion, lymphovascular invasion, and other factors that guide the treatment decisions covered in the subsequent chapters are extensively discussed. C1 [Oliva, Esther] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Baker, Patricia M.] Univ Manitoba, Dept Pathol, Hlth Sci Ctr, Winnipeg, MB R3T 2N2, Canada. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. EM eoliva@partners.org; eoliva@partners.org NR 264 TC 1 Z9 1 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-58829-736-5 J9 CURR CLIN ONCOL PY 2009 BP 105 EP 141 DI 10.1007/978-1-60327-044-1_6 D2 10.1007/978-1-60327-044-1 PG 37 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA BKO02 UT WOS:000268740900006 ER PT B AU del Carmen, MG Horowitz, NS AF del Carmen, Marcela G. Horowitz, Neil S. BE Muggia, F Oliva, E TI Treatment for Advanced and Recurrent Carcinoma: Combined Modalities SO UTERINE CANCER: SCREENING, DIAGNOSIS, AND TREATMENT SE Current Clinical Oncology Series LA English DT Article; Book Chapter DE Endometrial cancer; Radiation; Surgery in stage IV and recurrences; Chemotherapy; Hormones ID GYNECOLOGIC-ONCOLOGY-GROUP; RISK ENDOMETRIAL CANCER; MALIGNANT PERITONEAL CYTOLOGY; ISOLATED VAGINAL RECURRENCES; MEDROXYPROGESTERONE ACETATE; RADIATION-THERAPY; STAGE-IV; INTERSTITIAL BRACHYTHERAPY; POSTOPERATIVE RADIOTHERAPY; CYTOREDUCTIVE SURGERY AB The contribution of chemotherapy has provided new opportunities for exploring the combination of local and systemic modalities in both early and advanced stages of endometrial carcinoma. The following circumstances are discussed: (1) radiation therapy for locally recurrent endometrial cancer; (2) surgery for stage IV and recurrent endometrial cancer; and (3) advanced stage endometrial cancer consolidating with postoperative and post-chemotherapy radiation therapy. Integration of hormones is also discussed. C1 [del Carmen, Marcela G.; Horowitz, Neil S.] Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Div Gynecol Oncol, Boston, MA 02114 USA. RP del Carmen, MG (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Div Gynecol Oncol, Boston, MA 02114 USA. EM mdelcarmen@partners.org NR 63 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-58829-736-5 J9 CURR CLIN ONCOL PY 2009 BP 237 EP 249 DI 10.1007/978-1-60327-044-1_13 D2 10.1007/978-1-60327-044-1 PG 13 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA BKO02 UT WOS:000268740900013 ER PT B AU Krasner, C Hensley, ML AF Krasner, Carolyn Hensley, Martee L. BE Muggia, F Oliva, E TI Management of Uterine Sarcomas SO UTERINE CANCER: SCREENING, DIAGNOSIS, AND TREATMENT SE Current Clinical Oncology Series LA English DT Article; Book Chapter DE Uterine sarcomas; Carcinosarcoma; Leiomyosarcoma; Endometrial stromal sarcoma; Gemcitabine Docetaxel; Hormones ID GYNECOLOGIC-ONCOLOGY-GROUP; ENDOMETRIAL STROMAL SARCOMA; PHASE-II TRIAL; MIXED MULLERIAN TUMORS; ADJUVANT RADIATION-THERAPY; MESODERMAL TUMORS; STAGE-I; COMBINATION CHEMOTHERAPY; TREATMENT FAILURES; PROGNOSTIC-FACTORS AB Leiomyosarcomas, endometrial stromal sarcomas, and carcinosarcomas differ widely in tumor biology and their treatment is being addressed in separate trials. Unfortunately, therapeutic progress is slow because of the relatively rarity of these tumors. Recent trials using well defined patient Populations are helping to define the effect hormonal and chemotherapeutic strategies. C1 [Krasner, Carolyn] Massachusetts Gen Hosp, Dept Med Oncol, Gillette Ctr Womens Canc, Boston, MA 02114 USA. [Hensley, Martee L.] Mem Sloan Kettering Canc Ctr, Dept Med, Gynecol Med Oncol Serv, New York, NY 10021 USA. RP Krasner, C (reprint author), Massachusetts Gen Hosp, Dept Med Oncol, Gillette Ctr Womens Canc, Boston, MA 02114 USA. EM ckrasner@partners.org NR 80 TC 0 Z9 0 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DR, STE 208, TOTOWA, NJ 07512-1165 USA BN 978-1-58829-736-5 J9 CURR CLIN ONCOL PY 2009 BP 251 EP 265 DI 10.1007/978-1-60327-044-1_14 D2 10.1007/978-1-60327-044-1 PG 15 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA BKO02 UT WOS:000268740900014 ER PT S AU Matthews, AGW Oettinger, MA AF Matthews, Adam G. W. Oettinger, Marjorie A. BE Ferrier, P TI Regulation of RAG Transposition SO V(D)J RECOMBINATION SE Advances in Experimental Medicine and Biology LA English DT Article ID DNA-LIGASE IV; STRAND BREAK REPAIR; SEVERE COMBINED IMMUNODEFICIENCY; IMPAIRED V(D)J RECOMBINATION; LEAKY SCID PHENOTYPE; END-JOINING FACTOR; IN-VIVO; SACCHAROMYCES-CEREVISIAE; MEDIATED TRANSPOSITION; GENOMIC INSTABILITY AB V(D)J recombination is initiated by the lymphoid specific proteins RAG I and RAG2, which together constitute the V(D)J recombinase. However, the RAG1/2 complex can also act as a transposase, inserting the broken DNA molecules generated during V(D)J recombination into an unrelated piece of DNA. This process, termed RAG transposition, can potentially cause insertional mutagenesis, chromosomal translocations and genomic instability. This review focuses on the mechanism and regulation of RAG transposition. We first provide a brief overview of the biochemistry of V(D)J recombination. We then discuss the discovery of RAG transposition and present an overview of the RAG transposition pathway. Using this pathway as a framework, we discuss the factors and forces that regulate RAG transposition. C1 [Matthews, Adam G. W.; Oettinger, Marjorie A.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Matthews, Adam G. W.; Oettinger, Marjorie A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Matthews, AGW (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM agwmatthews@gmail.com FU NIGMS NIH HHS [R01 GM048026] NR 98 TC 5 Z9 5 U1 0 U2 3 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0065-2598 BN 978-1-4419-0295-5 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 2009 VL 650 BP 16 EP 31 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA BKB51 UT WOS:000267690600002 PM 19731798 ER PT J AU Ghose, C Calderwood, SB Ryan, ET AF Ghose, Chandrabali Calderwood, Stephen B. Ryan, Edward T. BE Barrett, ADT Stanberry, LR TI Cholera SO VACCINES FOR BIODEFENSE AND EMERGING AND NEGLECTED DISEASES LA English DT Article; Book Chapter ID RURAL EAST-PAKISTAN; VACCINE CVD 103-HGR; CONTROLLED FIELD TRIAL; RECOMBINANT-B-SUBUNIT; LIVE ORAL VACCINE; MANNOSE-SENSITIVE HEMAGGLUTININ; INTESTINAL ANTIBODY-RESPONSES; TOXIN-COREGULATED PILI; WHOLE-CELL VACCINE; VIBRIO-CHOLERAE AB Cholera is a life-threatening diarrheal disease with epidemic potential caused by the Gram negative bacterium Vibrio cholerae, serogroups O1 and O139. Since most cases of cholera are either not detected or not reported, the global burden of cholera is not known with certainty; however, cholera causes significant morbidity and mortality worldwide, with an estimated 5-7 million cases occurring each year, resulting in greater than 100,000 deaths per year. At present, the world is experiencing its seventh recorded pandemic, and cholera is endemic in many countries in Asia, Africa, and Latin America. Large outbreaks, especially among impoverished or displaced persons, occur on a regular basis, and cholera may spread through travel or migration of infected individuals, including even short-term travelers or visitors. Natural infection with V. cholerae O1 or O139 induces long-lasting protective immunity against subsequent disease. Protection against cholera correlates best with the vibriocidal antibodies thought to be largely directed against V. cholerae lipopolysaccharide (LPS), although anti-LPS serum IgG levels have not been shown to correlate with protection against cholera. It is hypothesized that the vibriocidal response may be a surrogate marker for as yet poorly understood mucosal immune responses, since it is unclear why a serum complement-binding-based assay would predict protection against a noninvasive intestinal pathogen such as V. cholerae. In an effort to ameliorate the morbidity and mortality associated with cholera, several parenteral and oral cholera vaccines have been developed since the 1880s. Commercial production of the killed parenteral vaccine most widely available in the 20th century was recently discontinued. Currently, an oral killed cholera vaccine (rBS-WC) is the only international commercially available cholera vaccine, and is only available in some countries. No cholera vaccine is currently commercially available in the United States. Following repetitive administration in large field trials, rBS-WC induces approximately 85% protective immunity for at least 6 months, although protection wans over the subsequent 2-3 years following vaccination. An oral killed whole vaccine that targets both V. cholerae O1 and O139 is also available and used programmatically in Vietnam. A number of live attenuated cholera vaccines have also been developed, including classical O1 derivative CVD 103-HgR, and El Tor O1 derivative Peru-15. These live attenuated vaccines have been shown to be safe and immunogenic in volunteers, although their protective efficacy has not yet been demonstrated in large randomized field trials. Subunit vaccines and additional anti-O139 cholera vaccines are presently in earlier stages of development. To better understand immunity protective against cholera, high throughput genomic, proteomic, and immunomic technologies are being applied to V. cholerae C1 [Ghose, Chandrabali; Calderwood, Stephen B.; Ryan, Edward T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Ghose, Chandrabali] Aaron Diamond AIDS Res Ctr, New York, NY USA. [Ryan, Edward T.] Massachusetts Gen Hosp, Trop & Geog Med Ctr, Boston, MA 02114 USA. [Calderwood, Stephen B.; Ryan, Edward T.] Harvard Univ, Sch Med, Boston, MA USA. [Ryan, Edward T.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Ghose, C (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. NR 131 TC 0 Z9 0 U1 0 U2 7 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA BN 978-0-08-091902-7 PY 2009 BP 869 EP 889 DI 10.1016/B978-0-12-369408-9.00045-7 PG 21 WC Public, Environmental & Occupational Health; Immunology; Infectious Diseases SC Public, Environmental & Occupational Health; Immunology; Infectious Diseases GA BCR60 UT WOS:000311106000047 ER PT J AU Geisler, BP Siebert, U Gazelle, GS Cohen, DJ Gohler, A AF Geisler, Benjamin P. Siebert, Uwe Gazelle, G. Scott Cohen, David J. Goehler, Alexander TI Deterministic Sensitivity Analysis for First-Order Monte Carlo Simulations: A Technical Note SO VALUE IN HEALTH LA English DT Article DE decision analysis model; Markov model; methods; microsimulation; modeling AB Monte Carlo microsimulations have gained increasing popularity in decision-analytic modeling because they can incorporate discrete events. Although deterministic sensitivity analyses are essential for interpretation of results, it remains difficult to combine these alongside Monte Carlo simulations in standard modeling packages without enormous time investment. Our purpose was to facilitate one-way deterministic sensitivity analysis of TreeAge Markov state-transition models requiring first-order Monte Carlo simulations. Using TreeAge Pro Suite 2007 and Microsoft Visual Basic for EXCEL, we constructed a generic script that enables one to perform automated deterministic one-way sensitivity analyses in EXCEL employing microsimulation models. In addition, we constructed a generic EXCEL-worksheet that allows for use of the script with little programming knowledge. Linking TreeAge Pro Suite 2007 and Visual Basic enables the performance of deterministic sensitivity analyses of first-order Monte Carlo simulations. There are other potentially interesting applications for automated analysis. C1 [Geisler, Benjamin P.; Siebert, Uwe; Gazelle, G. Scott; Goehler, Alexander] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Geisler, Benjamin P.; Siebert, Uwe; Gazelle, G. Scott; Goehler, Alexander] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA 02114 USA. [Geisler, Benjamin P.; Siebert, Uwe; Goehler, Alexander] UMIT Univ Hlth Sci Med Informat & Technol, Dept Publ Hlth Med Decis Making & Hlth Technol As, Hall in Tyrol, Austria. [Geisler, Benjamin P.] Charite Univ Med Berlin, Inst Social Med Epidemiol & Hlth Econ, D-13353 Berlin, Germany. [Geisler, Benjamin P.; Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Boston, MA 02114 USA. [Cohen, David J.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. RP Geisler, BP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, 101 Merrimac St,Floor 10, Boston, MA 02114 USA. EM ben@mgh-ita.org RI Geisler, Benjamin/A-9244-2010 OI Geisler, Benjamin/0000-0003-1704-6067 NR 3 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 1098-3015 J9 VALUE HEALTH JI Value Health PD JAN-FEB PY 2009 VL 12 IS 1 BP 96 EP 97 DI 10.1111/j.1524-4733.2008.00411.x PG 2 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 397XX UT WOS:000262696800014 PM 18647259 ER PT J AU Gohler, A Geisler, BP Manne, JM Kosiborod, M Zhang, ZF Weintraub, WS Spertus, JA Gazelle, GS Siebert, U Cohen, DJ AF Goehler, Alexander Geisler, Benjamin P. Manne, Jennifer M. Kosiborod, Mikhail Zhang, Zefeng Weintraub, William S. Spertus, John A. Gazelle, G. Scott Siebert, Uwe Cohen, David J. TI Utility Estimates for Decision-Analytic Modeling in Chronic Heart Failure-Health States Based on New York Heart Association Classes and Number of Rehospitalizations SO VALUE IN HEALTH LA English DT Article DE EQ-5D; heart failure; quality of life; quality-adjusted life-years; utilities ID EUROQOL AB For economic evaluations of chronic heart failure (CHF) management strategies, utilities are not currently available for disease proxies commonly used in Markov models. Our objective was to estimate utilities for New York Heart Association (NYHA) classification and number of cardiovascular rehospitalizations. EuroQol 5D data from the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study trial were used to estimate utilities as a function of NYHA classification and number of cardiovascular rehospitalizations. In multivariate regression analyses adjusted for age (60 years), female sex and absence of further comorbidities, utilities for NYHA classes I-IV were 0.90, 0.83, 0.74, and 0.60 (P-value < 0.001 for trend). For cardiovascular rehospitalizations 0, 1, 2 and >= 3, the associated utilities were 0.88, 0.85, 0.84, and 0.82 (P-value < 0.001 for trend). NYHA class and number of cardiovascular rehospitalizations are established proxies for CHF progression and can be linked to utilities when used as health states in a Markov model. NYHA class should be used when feasible. C1 [Goehler, Alexander; Geisler, Benjamin P.; Gazelle, G. Scott; Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA 02114 USA. [Goehler, Alexander; Geisler, Benjamin P.; Siebert, Uwe] Univ Hlth Sci Med Informat & Technol, UMIT, Dept Publ Hlth Med Decis Making & Hlth Technol As, Innsbruck, Austria. [Manne, Jennifer M.; Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Kosiborod, Mikhail; Spertus, John A.; Cohen, David J.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Kosiborod, Mikhail; Spertus, John A.; Cohen, David J.] Univ Missouri, Kansas City, MO 64110 USA. [Zhang, Zefeng; Weintraub, William S.] Christiana Care Hlth Syst, Newark, DE USA. RP Gohler, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM alex@mgh-ita.org RI Geisler, Benjamin/A-9244-2010 OI Geisler, Benjamin/0000-0003-1704-6067 NR 11 TC 31 Z9 31 U1 0 U2 6 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 JAN-FEB PY 2009 VL 12 IS 1 BP 185 EP 187 DI 10.1111/j.1524-4733.2008.00425.x PG 3 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 397XX UT WOS:000262696800028 PM 18647251 ER PT J AU Buhlmann, U Wilhelm, S Glaesmer, H Brahler, E Rief, W AF Buhlmann, Ulrike Wilhelm, Sabine Glaesmer, Heide Braehler, Elmar Rief, Winfried TI Body Dysmorphic Symptoms Inventory: A Screening Instrument SO VERHALTENSTHERAPIE LA German DT Article DE Body dysmorphic disorder; Self-rating inventory; General population; Body image ID DISORDER; PREVALENCE AB Body Dysmorphic Symptoms Inventory: A Screening Instrument Background: Body dysmorphic disorder (BDD) is characterised by an excessive preoccupation with an imagined or slight imperfection in appearance. So far there are only few German-language instruments for the assessment of BDD. Thus, the goal of the current study was to develop a BDD questionnaire and to test its psychometric characteristics in the general population. Methods: 45 individuals with BDD (who met DSM-IV criteria, based on self-descriptions) and 45 control subjects participated in this study. Results: The FKS showed good internal consistency as well as discriminant validity. Conclusion: Our results suggest that the FKS is a reliable and valid self-report instrument. Future studies should evaluate the FKS in clinical samples. C1 [Buhlmann, Ulrike] Humboldt Univ, AG Klin Psychol, D-12489 Berlin, Germany. [Wilhelm, Sabine] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wilhelm, Sabine] Harvard Univ, Sch Med, Boston, MA USA. [Glaesmer, Heide; Braehler, Elmar] Univ Leipzig, Leipzig, Germany. [Rief, Winfried] Univ Marburg, D-35032 Marburg, Germany. RP Buhlmann, U (reprint author), Humboldt Univ, AG Klin Psychol, Rudower Chaussee 18, D-12489 Berlin, Germany. EM ulrike.buhlmann@hu-berlin.de NR 11 TC 10 Z9 10 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1016-6262 J9 VERHALTENSTHERAPIE JI Verhaltenstherapie PY 2009 VL 19 IS 4 BP 237 EP 242 DI 10.1159/000246278 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 534KB UT WOS:000272893900004 ER PT J AU Taft, CT Monson, CM Hebenstreit, CL King, DW King, LA AF Taft, Casey T. Monson, Candice M. Hebenstreit, Claire L. King, Daniel W. King, Lynda A. TI Examining the Correlates of Aggression Among Male and Female Vietnam Veterans SO VIOLENCE AND VICTIMS LA English DT Article DE aggression; veterans; war zone; trauma; posttraumatic stress disorder AB This study examined the correlates of general aggression among a nationally representative sample of male and female Vietnam veterans (N = 1,632). Findings indicated that the rates of aggression for men and women were 41% and 32%, respectively, and men appeared to perpetrate relatively more acts of severe aggression. Correlates of aggression for men included lower socioeconomic status and age, minority status, unemployment, degree of exposure to the malevolent war-zone environment and perceived threat in the war zone, posttraumatic stress disorder, antisocial personality disorder, major depressive episode, alcohol abuse/dependence, and drug abuse/dependence. For women, only lower age and unemployment were associated with aggression. Findings highlight the importance of developing models for aggression among those experiencing military deployments. C1 [Taft, Casey T.; Monson, Candice M.; Hebenstreit, Claire L.; King, Daniel W.; King, Lynda A.] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Taft, Casey T.; Monson, Candice M.; King, Daniel W.; King, Lynda A.] Boston Univ, Sch Med, Boston, MA 02215 USA. RP Taft, CT (reprint author), VA Boston Healthcare Syst, 116B-2,150 S Huntington Ave, Boston, MA 02130 USA. EM casey.taft@va.gov NR 34 TC 14 Z9 14 U1 1 U2 2 PU SPRINGER PUBLISHING CO PI NEW YORK PA 11 WEST 42ND STREET, NEW YORK, NY 10036 USA SN 0886-6708 J9 VIOLENCE VICTIMS JI Violence Vict. PY 2009 VL 24 IS 5 BP 639 EP 652 DI 10.1891/0886-6708.24.5.639 PG 14 WC Criminology & Penology SC Criminology & Penology GA V18EW UT WOS:000207989100006 PM 19852404 ER PT J AU Robinson, CM Shariati, F Zaitshik, J Gillaspy, AF Dyer, DW Chodosh, J AF Robinson, Christopher M. Shariati, Fatemeh Zaitshik, Jeremy Gillaspy, Allison F. Dyer, David W. Chodosh, James TI Human adenovirus type 19: Genomic and bioinformatics analysis of a keratoconjunctivitis isolate SO VIRUS RESEARCH LA English DT Article DE Human adenovirus type 19; Epidemic keratoconjunctivitis; Genome ID EPIDEMIC KERATOCONJUNCTIVITIS; SAUDI-ARABIA; SIALIC-ACID; PROTEINS; GASTROENTERITIS; TROPISM; VECTOR; EYE AB Human adenovirus type 19 (HAdV-19) is a major etiologic agent of epidemic keratoconjunctivitis (EKC), a common and severe eye infection associated with long-term visual morbidity due to persistent corneal inflammation. Ironically, while the prototype strain of HAdV-19 does not cause eye infections, other isolates of the serotype have caused major outbreaks of EKC. Here we have sequenced a clinical isolate of HAdV-19 (HAdV-19 strain C) from a human patient with EKC. Global pairwise alignment of HAdV-19C to other HAdV species D serotypes identified areas of sequence divergence in the penton base (host cell internalization signal), hexon (principal viral capsid structural protein), E3 (site of immunomodulatory genes), and fiber (host cell-binding ligand) regions. Comparison of HAdV-19 strain C to the recently sequenced HAdV-37, another EKC causing serotype, identified sequence diversity in the penton base and hexon, but sequence conservation in the E3 and fiber regions. Elucidation of the HAdV-19C genome will facilitate future studies into the pathogenesis of EKC, and may shed light on the genetic determinants of corneal tropism. (C) 2008 Elsevier B.V. All rights reserved. C1 [Robinson, Christopher M.; Shariati, Fatemeh; Chodosh, James] Univ Oklahoma, Hlth Sci Ctr, Dean A McGee Eye Inst, Mol Pathogenesis Eye Infect Res Ctr, Oklahoma City, OK USA. [Shariati, Fatemeh; Chodosh, James] Univ Oklahoma, Hlth Sci Ctr, Dept Ophthalmol, Oklahoma City, OK USA. [Robinson, Christopher M.; Gillaspy, Allison F.; Dyer, David W.; Chodosh, James] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. [Chodosh, James] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK 73190 USA. [Zaitshik, Jeremy; Gillaspy, Allison F.; Dyer, David W.] Univ Oklahoma, Hlth Sci Ctr, Lab Genom & Bioinformat, Oklahoma City, OK 73190 USA. RP Chodosh, J (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Howe Lab,Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM james.chodosh@meei.harvard.edu FU NIH [EY013124, EY015222, EY012190, P20 RR017703, P20 RR015564, T32 A1007633]; Research to Prevent Blindness Physician-Scientist Merit Award FX We thank Nicole Benton for her technical assistance in sequencing. Research support was provided through NIH grants EY013124, EY015222, EY012190, P20 RR017703, P20 RR015564, T32 A1007633 and a Research to Prevent Blindness Physician-Scientist Merit Award (to J.C.). NR 32 TC 21 Z9 23 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD JAN PY 2009 VL 139 IS 1 BP 122 EP 126 DI 10.1016/j.virusres.2008.10.001 PG 5 WC Virology SC Virology GA 396QR UT WOS:000262606700017 PM 19000724 ER PT S AU El-Shewy, HM Luttrell, LM AF El-Shewy, Hesham M. Luttrell, Louis M. BE Litwack, G TI INSULIN-LIKE GROWTH FACTOR-2/MANNOSE-6 PHOSPHATE RECEPTORS SO VITAMINS AND HORMONES INSULIN AND IGFS SE Vitamins and Hormones LA English DT Review; Book Chapter ID FACTOR-II RECEPTOR; MANNOSE 6-PHOSPHATE RECEPTOR; TUMOR-SUPPRESSOR GENE; GRANULE-MEDIATED APOPTOSIS; AMINO-ACID-SEQUENCE; TYPE-2 IGF RECEPTOR; CASEIN KINASE-II; G-PROTEIN; GRANZYME-B; HUMAN-SERUM AB The insulin-like growth factor type 2/mannose-6-phosphate (IGF-2/M6P) receptor is a multifunctional single transmembrane glycoprotein that is known to regulate diverse biological functions. It is composed of a large extracytoplasmic domain, a single transmembrane region and a short cytoplasmic tail that lacks intrinsic catalytic activity. The receptor cycles continuously between intracellular compartments and the plasma membrane, and at steady state is predominantly localized in the trans-Golgi network and endosomal compartments, and to a lesser extent on the cell surface. The receptor binds IGF-2 with higher affinity than IGF-1 and does not bind insulin. It interacts, via distinct sites, with lysosomal enzymes and a variety of other M6P-containing ligands. IGF-2/M6P receptors perform diverse cellular functions related to lysosome biogenesis and the regulation of growth and development. It regulates extracellular IGF-2 concentrations, modulating signaling through the growth-stimulatory IGF-1 receptor pathway. It appears to mediate the uptake and processing of M6P-containing cytokines and peptide hormones, such as transforming growth factor-beta, leukemia inhibitory factor, and proliferin. Some data suggest that the IGF-2/M6P receptor also functions in signal transduction by transactivating G protein-coupled sphingosine 1-phosphate receptors. Genetic evidence clearly supports a role for IGF-2/M6P receptors in organ development and growth, and recent data indicate that it may play an important role in tumor progression. (C) 2009 Elsevier Inc. C1 [El-Shewy, Hesham M.; Luttrell, Louis M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Luttrell, Louis M.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29401 USA. [Luttrell, Louis M.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. RP El-Shewy, HM (reprint author), Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. NR 199 TC 39 Z9 40 U1 1 U2 9 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0083-6729 BN 978-0-12-374408-1 J9 VITAM HORM JI Vitam. Horm. PY 2009 VL 80 BP 667 EP 697 DI 10.1016/S0083-6729(08)00624-9 PG 31 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA BJB99 UT WOS:000264638200024 PM 19251055 ER PT J AU Staropoli, JF Stowell, CP Tuncer, HH Marques, MB AF Staropoli, J. F. Stowell, C. P. Tuncer, H. H. Marques, M. B. TI An inquiry into the relationship between ABO blood group and thrombotic thrombocytopenic purpura SO VOX SANGUINIS LA English DT Article DE ABO blood group; ADAMTS13; therapeutic plasma exchange; TTP; von Willebrand factor ID VON-WILLEBRAND-FACTOR; HEMOLYTIC-UREMIC SYNDROME; FACTOR-CLEAVING PROTEASE; ADAMTS13; VWF; PROTEOLYSIS; MUTATIONS; DIAGNOSIS; ASSAY; TTP AB ABO blood group accounts for up to 40% of the variability in plasma von Willebrand factor (VWF) levels, which vary in the rank order AB > B > A > O > Bombay. This may be due in part to the influence of ABO-associated oligosaccharides on the proteolysis of VWF by the metalloprotease ADAMTS13, which is markedly deficient in thrombotic thrombocytopenic purpura (TTP). Using ABO blood group as a surrogate for baseline VWF levels as well as susceptibility to proteolysis by ADAMST13, we set out to determine whether ABO blood group influences the clinical course of TTP. We conducted a retrospective analysis of the clinical course of 76 patients with primary, sporadic TTP treated at two institutions over the past 10 years. We found no significant differences between group O and non-O patients with respect to presenting platelet count and lactate dehydrogenase concentration, maximum serum creatinine concentration, and total number of therapeutic plasma exchanges per episode. Substrate-related contributors to the highly variable phenotype and clinical course of TTP warrant further investigation. C1 [Staropoli, J. F.; Stowell, C. P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Tuncer, H. H.] Rush Univ, Med Ctr, Sect Hematol & Stem Cell Transplantat, Chicago, IL 60612 USA. [Marques, M. B.] Univ Alabama, Dept Pathol, Birmingham, AL 35249 USA. RP Marques, MB (reprint author), Univ Alabama, Birmingham Hosp, Dept Pathol, WP P230,619 19th St S, Birmingham, AL 35249 USA. EM mmarques@uab.edu OI Marques, Marisa/0000-0002-6689-7856 NR 21 TC 7 Z9 7 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0042-9007 J9 VOX SANG JI Vox Sang. PY 2009 VL 96 IS 4 BP 344 EP 348 DI 10.1111/j.1423-0410.2009.01164.x PG 5 WC Hematology SC Hematology GA 433FP UT WOS:000265190000011 PM 20701734 ER PT J AU Harley, AE Odoms-Young, A Beard, B Katz, ML Heaney, CA AF Harley, Amy E. Odoms-Young, Angela Beard, Binta Katz, Mira L. Heaney, Catherine A. TI African American Social and Cultural Contexts and Physical Activity: Strategies for Navigating Challenges to Participation SO WOMEN & HEALTH LA English DT Article DE physical activity; African Americans; women; qualitative research ID WOMEN; DISEASE; OVERWEIGHT; INACTIVITY; EXERCISE; BELIEFS; HEALTH; POLICY; LIVES AB We examined the influence of social and cultural contexts on participation in recommended levels of physical activity (PA) among African American women using a grounded theory approach. Data were collected through in-depth interviews and focus groups with 15 physically active African American women. Participants described social and cultural factors that served as challenges for participation in PA. Of particular importance, participants discussed their strategies for overcoming these challenges to initiate and maintain an active lifestyle. Strategies emerged to address three main areas: lack of PA exposure, PA norms and beliefs, and hair maintenance. Understanding contextually appropriate strategies to assist African American women in long-term PA maintenance will help inform effective health promotion efforts to reduce the burden of sedentary lifestyle and chronic disease in this community of women. C1 [Harley, Amy E.; Beard, Binta] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Harley, Amy E.; Beard, Binta] Dana Farber Canc Inst, Boston, MA 02115 USA. [Odoms-Young, Angela] Univ Illinois, Coll Appl Hlth Sci, Chicago, IL USA. [Katz, Mira L.] Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. [Heaney, Catherine A.] Stanford Prevent Res Ctr, Stanford, CA USA. RP Harley, AE (reprint author), 1020 N 12th St,Suite 4180, Milwaukee, WI 53233 USA. EM harley@uwm.edu NR 38 TC 18 Z9 18 U1 2 U2 13 PU HAWORTH PRESS INC PI BINGHAMTON PA 10 ALICE ST, BINGHAMTON, NY 13904-1580 USA SN 0363-0242 J9 WOMEN HEALTH JI Women Health PY 2009 VL 49 IS 1 BP 84 EP 100 AR PII 909229936 DI 10.1080/03630240802690861 PG 17 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 428BS UT WOS:000264823600006 PM 19485236 ER PT J AU Ketchen, B Armistead, L Cook, S AF Ketchen, Bethany Armistead, Lisa Cook, Sarah TI HIV Infection, Stressful Life Events, and Intimate Relationship Power: The Moderating Role of Community Resources for Black South African Women SO WOMEN & HEALTH LA English DT Article DE South African women; HIV; relationship power; community-based resources ID GENDER-BASED VIOLENCE; RISK-FACTORS; SEXUAL RISK; EMPOWERMENT; HIV/AIDS; PREDICTORS; EDUCATION; PARTNERS; HEALTH AB Background: Black women in South Africa are vulnerable with limited power in intimate relationships. This study explored whether stressful life events and/or HIV infection were associated with relationship power and whether the impact was moderated by community resources. Method: One hundred four women living with HIV and 152 women not living with HIV participated in individual interviews. Results: Undesirable life changes were negatively associated with relationship control. HIV infection and women's knowledge of community resources were associated with mutual decision-making, while frequency of family use of community resources was negatively related to female dominated decisions. Women living with HIV perceived their male partners as less dominant when they perceived their community resources to be more helpful. Conclusions: Power in intimate relationships may enhance the quality and length of life for black South African women living with HIV. Knowledge of and perceived helpfulness of community resources are avenues for promoting relationship power. C1 [Armistead, Lisa; Cook, Sarah] Georgia State Univ, Dept Psychol, Atlanta, GA 30303 USA. [Ketchen, Bethany] San Francisco VA Med Ctr, San Francisco, CA USA. RP Armistead, L (reprint author), Georgia State Univ, Dept Psychol, POB 5010, Atlanta, GA 30303 USA. EM lparmistead@gsu.edu FU NICHD NIH HHS [R03 HD046371, R03 HD046371-01A1, R03HD046371] NR 45 TC 13 Z9 13 U1 2 U2 6 PU HAWORTH PRESS INC PI BINGHAMTON PA 10 ALICE ST, BINGHAMTON, NY 13904-1580 USA SN 0363-0242 J9 WOMEN HEALTH JI Women Health PY 2009 VL 49 IS 2-3 BP 197 EP 214 AR PII 912434829 DI 10.1080/03630240902963648 PG 18 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 459KN UT WOS:000267101100006 PM 19533510 ER PT S AU Krishnan, SM Vanicatte, M Lee, I Goldman, JM AF Krishnan, S. M. Vanicatte, M. Lee, I. Goldman, J. M. BE Dossel, O Schlegel, WC TI Incorporating interoperability Functionality for Increasing Patient Safety with PCA-Included Multiple Infusion Therapy SO WORLD CONGRESS ON MEDICAL PHYSICS AND BIOMEDICAL ENGINEERING, VOL 25, PT 12 SE IFMBE Proceedings LA English DT Proceedings Paper CT 11th International Congress of the IUPESM/World Congress on Medical Physics and Biomedical Engineering CY SEP 07-12, 2009 CL Munich, GERMANY SP IUPESM, Int Org Med Phys (IOMP) DE Interoperability; Multiple delivery systems; Safety improvement; Intercommunication AB Implementation of interoperability in an infusion therapy system intends to enhance safety, by allowing intercommunication among medical devices connected to a patient. Some postoperative specific cases entail the patient with multiple drug delivery devices. As adverse drug events (ADEs) can occur with the use of infusion pumps, the multiplication of those devices at the patient's bedside establishes the need of multi-modalities safety feature. The designed system propose to integrate an interoperability feature in a multiple drug delivery modules infusion therapy, including a PCA treatment, creating pertinent interactions allowing the system to respond promptly to medication errors alerts, by suspending one or more drug deliveries thanks to standby orders. An Intelligent Interoperability Manager (IIM) is linked to a group of infusion devices, a patient monitoring device, and to a hospital information system (HIS), accessible anytime for treatment information consultation. If the situation is considered to be critical, the IIM sends proper alert signals. Diverse critical situations are simulated, in a conventional multi-infusions therapy system, and in interoperability implemented system. In the first case, the time between alarm event and clinician intervention presents a significant delay, potentially leading to deterioration of patient condition. In the second case, abnormal values are detected and the system's decision-making unit reacts according to the situation. Thus, the proposed design emphasizes that interoperability functionality can enhance both safety and treatment management in the delicate system of multiple modules infusion therapy. C1 [Krishnan, S. M.] Wentworth Inst Technol, Biomed Engn Program, Boston, MA USA. [Vanicatte, M.; Lee, I.] Univ Penn, Dept Comp & Informat Sci, Philadelphia, PA USA. [Goldman, J. M.] Massachusetts Gen Hosp, Dept Anesthesia, CIMIT, Boston, MA USA. RP Krishnan, SM (reprint author), Wentworth Inst Technol, Biomed Engn Program, Boston, MA USA. EM krishnans@wit.edu FU NSF [CNS-0509327, CNS-0834524]; WIT FX This research was supported in part by NSF CNS-0509327 and NSF CNS-0834524 and in part by WIT Fund. NR 16 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013, UNITED STATES SN 1680-0737 BN 978-3-642-03892-1 J9 IFMBE PROC PY 2009 VL 25 IS 12 BP 415 EP + PG 2 WC Engineering, Biomedical SC Engineering GA BQW97 UT WOS:000282043300120 ER PT B AU Weinberg, B Khanicheh, A Sivak, M Unluhisarcikli, O Morel, G Shannon, J Kelliher, J Sabadosa, M Bonmassar, G Patritti, B Bonato, P Mavroidis, C AF Weinberg, B. Khanicheh, A. Sivak, M. Unluhisarcikli, O. Morel, G. Shannon, J. Kelliher, J. Sabadosa, M. Bonmassar, G. Patritti, B. Bonato, P. Mavroidis, C. GP IEEE TI Variable Resistance Hand Device Using an Electro-Rheological Fluid Damper SO WORLD HAPTICS 2009: THIRD JOINT EUROHAPTICS CONFERENCE AND SYMPOSIUM ON HAPTIC INTERFACES FOR VIRTUAL ENVIRONMENT AND TELEOPERATOR SYSTEMS, PROCEEDINGS LA English DT Proceedings Paper CT 3rd Joint EuroHaptics Conference Symposium on Haptic Interfaces for Virtual Environment and Teleoperator Systems CY MAR 18-20, 2009 CL Salt Lake City, UT SP IEEE Robot & Automat Soc, IEEE Tech Comm Hapt ID FUNCTIONAL MRI; MOTOR FUNCTION; FMRI; REHABILITATION; STIMULATOR; MOTION; STROKE; SYSTEM AB This paper presents the design, fabrication, control and testing of the third generation prototype of a novel, one degree of freedom (DOF) Variable Resistance Hand Device (VRHD) that was designed for isotonic, isokinetic, and variable resistance grasp and release exercises. Its principle functionality is derived from an electro-rheological fluid based controllable damper that allows continuously variable modulation of dynamic resistance throughout its stroke. The VRHD system consists of the patient actuated device, the control electronics and software, the practitioner graphical interface and the patient's virtual reality game software. VRHD was designed and experimentally shown to be fully Magnetic Resonance Imaging (MRI) compatible so that it can be used in brain MR imaging during handgrip rehabilitation. C1 [Weinberg, B.; Khanicheh, A.; Sivak, M.; Unluhisarcikli, O.; Mavroidis, C.] Northeastern Univ, Dept Mech & Ind Engn, Boston, MA 02115 USA. [Morel, G.] Univ Paris 06, Inst Syst Intelligent & Robot, F-75005 Paris, France. [Shannon, J.; Kelliher, J.; Sabadosa, M.] WGI Inc, Southwick, MA USA. [Bonmassar, G.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Patritti, B.; Bonato, P.] Spaulding Rehabil Hosp, Boston, MA USA. RP Mavroidis, C (reprint author), Northeastern Univ, Dept Mech & Ind Engn, Boston, MA 02115 USA. EM mavro@coe.neu.edu FU WGI Inc., Southwick, MA, USA FX This work was supported by WGI Inc., Southwick, MA, USA. The help provided by Marlena Pelliccio, Fernanda Romaguera, and Chiara Mancinelli in the physical therapy evaluations is acknowledged and appreciated. NR 16 TC 2 Z9 2 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-3858-7 PY 2009 BP 529 EP + DI 10.1109/WHC.2009.4810899 PG 2 WC Computer Science, Artificial Intelligence; Computer Science, Cybernetics; Computer Science, Hardware & Architecture SC Computer Science GA BJK69 UT WOS:000266714300087 ER PT S AU Giampietro, PF Dunwoodie, SL Kusumi, K Pourquie, O Tassy, O Offiah, AC Cornier, AS Alman, BA Blank, RD Raggio, CL Glurich, I Turnpenny, PD AF Giampietro, Philip F. Dunwoodie, Sally L. Kusumi, Kenro Pourquie, Olivier Tassy, Olivier Offiah, Amaka C. Cornier, Alberto S. Alman, Benjamin A. Blank, Robert D. Raggio, Cathleen L. Glurich, Ingrid Turnpenny, Peter D. BE Smith, M TI Progress in the Understanding of the Genetic Etiology of Vertebral Segmentation Disorders in Humans SO YEAR IN HUMAN AND MEDICAL GENETICS 2009 SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article DE congenital vertebral malformation; spondylothoracic dysostosis; Agagille syndrome; congenital scoliosis; Klippel-Feil syndrome; VACTERL; CHARGE syndrome; teratogens; Jarcho-Levin syndrome; ICVAS; array-based CGH; DLL3; Wnt3A; T(Brachyury); Tbx6; SLC35A3; MESP2 LFNG; PAX1 JAG1; NOTCH2; CHD7 ID JARCHO-LEVIN-SYNDROME; KLIPPEL-FEIL-SYNDROME; NOTCH SIGNALING PATHWAY; RECESSIVE SPONDYLOCOSTAL DYSOSTOSIS; NEURAL-TUBE DEFECTS; LUNATIC-FRINGE GENE; CONGENITAL SCOLIOSIS; HUMAN T; IDIOPATHIC SCOLIOSIS; ALAGILLE-SYNDROME AB Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement, and functional distress. This review explores (1) recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes; (2) outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformation; and (3) complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and non-syndromic congenital vertebral malformation. Discussion includes exploration of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation, and translational value of research efforts to clinical management and genetic counseling of affected individuals and their families. C1 [Giampietro, Philip F.] Marshfield Clin Fdn Med Res & Educ, Dept Med Genet Serv, Marshfield, WI 54449 USA. [Dunwoodie, Sally L.] Univ New S Wales, Victor Chang Cardiac Res Inst, Darlinghurst, NSW, Australia. [Kusumi, Kenro] Arizona State Univ, Sch Life Sci, Tempe, AZ USA. [Pourquie, Olivier] Howard Hughes Med Inst, Kansas City, MO USA. [Pourquie, Olivier; Tassy, Olivier] Stowers Inst Med Res, Kansas City, MO USA. [Offiah, Amaka C.] Great Ormond St Hosp Sick Children, Dept Radiol, London WC1N 3JH, England. [Cornier, Alberto S.] Ponce Sch Med, Dept Biochem, Div Genet, Ponce, PR USA. [Cornier, Alberto S.] La Concepcion Hosp, Dept Mol Med, San German, PR USA. [Alman, Benjamin A.] Univ Toronto, Hosp Sick Children, Div Orthopaed Surg, Toronto, ON M5G 1X8, Canada. [Alman, Benjamin A.] Univ Toronto, Hosp Sick Children, Program Dev & Stem Cell Biol, Toronto, ON M5G 1X8, Canada. [Blank, Robert D.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI USA. [Blank, Robert D.] William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI 53705 USA. [Raggio, Cathleen L.] Hosp Special Surg, Dept Pediat Orthoped, New York, NY 10021 USA. [Glurich, Ingrid] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. [Turnpenny, Peter D.] Royal Devon & Exeter Hosp, Exeter EX2 5DW, Devon, England. [Turnpenny, Peter D.] Peninsula Med Sch, Exeter, Devon, England. RP Giampietro, PF (reprint author), Marshfield Clin Fdn Med Res & Educ, Dept Med Genet Serv, 1000 N Oak Ave, Marshfield, WI 54449 USA. EM giampietro.philip@marshfieldclinic.org RI Kusumi, Kenro/J-2626-2012; Offiah, Amaka/G-2911-2010; OI Kusumi, Kenro/0000-0002-1458-4540; Offiah, Amaka/0000-0001-8991-5036; Pourquie, Olivier/0000-0001-5189-1227; Dunwoodie, Sally/0000-0002-2069-7349; Blank, Robert Daniel/0000-0003-2950-1944 FU Marshfield Clinic Research Foundation FX The authors thank Marshfield Clinic Research Foundation for its support through the assistance of Marie Flelsner and Alice Stargardt. NR 149 TC 16 Z9 16 U1 2 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXEN, ENGLAND SN 0077-8923 BN 978-1-57331-731-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2009 VL 1151 BP 38 EP 67 DI 10.1111/j.1749-6632.2008.03452.x PG 30 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA BIW37 UT WOS:000263365700004 PM 19154516 ER PT J AU Smith, JL Williams, JW Owen, RR Rubenstein, LV Chaney, E AF Smith, Jeffrey L. Williams, John W., Jr. Owen, Richard R. Rubenstein, Lisa V. Chaney, Edmund TI Developing a national dissemination plan for collaborative care for depression: QUERI Series SO IMPLEMENTATION SCIENCE LA English DT Article ID IMPLEMENTATION RESEARCH; QUALITY; STRATEGIES; MANAGEMENT; PHARMACOTHERAPY; INTERVENTIONS; OUTCOMES; IMPROVE; SYSTEM AB Background: Little is known about effective strategies for disseminating and implementing complex clinical innovations across large healthcare systems. This paper describes processes undertaken and tools developed by the U. S. Department of Veterans Affairs (VA) Mental Health Quality Enhancement Research Initiative (MH-QUERI) to guide its efforts to partner with clinical leaders to prepare for national dissemination and implementation of collaborative care for depression. Methods: An evidence-based quality improvement (EBQI) process was used to develop an initial set of goals to prepare the VA for national dissemination and implementation of collaborative care. The resulting product of the EBQI process is referred to herein as a "National Dissemination Plan" (NDP). EBQI participants included: a) researchers with expertise on the collaborative care model for depression, clinical quality improvement, and implementation science, and b) VA clinical and administrative leaders with experience and expertise on how to adapt research evidence to organizational needs, resources and capacity. Based on EBQI participant feedback, drafts of the NDP were revised and refined over multiple iterations before a final version was approved by MH-QUERI leadership. 'Action Teams' were created to address each goal. A formative evaluation framework and related tools were developed to document processes, monitor progress, and identify and act upon barriers and facilitators in addressing NDP goals. Results: The National Dissemination Plan suggests that effectively disseminating collaborative care for depression in the VA will likely require attention to: Guidelines and Quality Indicators (4 goals), Training in Clinical Processes and Evidence-based Quality Improvement (6 goals), Marketing (7 goals), and Informatics Support (1 goal). Action Teams are using the NDP as a blueprint for developing infrastructure to support system-wide adoption and sustained implementation of collaborative care for depression. To date, accomplishments include but are not limited to: conduct of a systematic review of the literature to update VA depression treatment guidelines to include the latest evidence on collaborative care for depression; training for clinical staff on TIDES (Translating Initiatives for Depression into Effective Solutions project) care; spread of TIDES care to new VA facilities; and integration of TIDES depression assessment tools into a planned update of software used in delivery of VA mental health services. Thus far, common barriers encountered by Action Teams in addressing NDP goals include: a) limited time to address goals due to competing tasks/priorities, b) frequent turnover of key organizational leaders/stakeholders, c) limited skills and training among team members for addressing NDP goals, and d) difficulty coordinating activities across Action Teams on related goals. Conclusion: MH-QUERI has partnered with VA organizational leaders to develop a focused yet flexible plan to address key factors to prepare for national dissemination and implementation of collaborative care for depression. Early indications suggest that the plan is laying an important foundation that will enhance the likelihood of successful implementation and spread across the VA healthcare system. C1 [Smith, Jeffrey L.; Owen, Richard R.] Cent Arkansas Vet Healthcare Syst, VA Mental Hlth Qual Enhancement Res Initiat, N Little Rock, AR 72114 USA. [Williams, John W., Jr.] Durham VA Med Ctr HSR&D, Durham, NC 27705 USA. [Rubenstein, Lisa V.] VA Greater Los Angeles Healthcare Syst, VA HSR&D Ctr Study Healthcare Provider Behav, Sepulveda, CA 91343 USA. [Chaney, Edmund] VA Puget Sound Healthcare Syst, VA HSR&D Ctr Excellence, Seattle, WA 98101 USA. RP Smith, JL (reprint author), Cent Arkansas Vet Healthcare Syst, VA Mental Hlth Qual Enhancement Res Initiat, 2200 Ft Roots Dr,Bldg 58 152 NLR, N Little Rock, AR 72114 USA. EM Jeffrey.Smith6@va.gov; willi007@mc.duke.edu; Richard.Owen2@va.gov; lisar@rand.org; chaney@u.washington.edu FU VA HSRD Service [MNH 98-001, MNT 03-215] FX The study was funded by VA HSR&D Service, MNH 98-001, MNT 03-215. NR 51 TC 29 Z9 30 U1 1 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD DEC 31 PY 2008 VL 3 AR 59 DI 10.1186/1748-5908-3-59 PG 12 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 432TI UT WOS:000265156700003 PM 19117524 ER PT J AU Meier, A Fisher, A Sidhu, HK Chang, JJ Wen, TF Streeck, H Alter, G Silvestri, G Altfeld, M AF Meier, Angela Fisher, Amelia Sidhu, Harlyn K. Chang, Judy J. Wen, Tom F. Streeck, Hendrick Alter, Galit Silvestri, Guido Altfeld, Marcus TI Rapid loss of dendritic cell and monocyte responses to TLR ligands following venipuncture SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Innate immunity; Antigen presenting cells; Dendritic cells; Monocytes; Toll like receptors; Vaccine trials ID NONHUMAN-PRIMATES; EXPRESSION; MAGNITUDE; SHIPMENT; IMMUNITY; QUALITY; MEMORY AB Blood samples from multiple sites are collected in multicenter trials, and frequently shipped to centralized laboratories for processing and comparable experimental evaluation. It is therefore of crucial interest to assess the preservation of immune cell functions after overnight shipment of whole blood. Here we evaluated the ability of pDCs, mDCs and monocytes to respond to TLR ligands at multiple timepoints following venipuncture as compared to immediate processing. Our results demonstrate a profound impairment of APC function, in particular of IFN-alpha production of pDCs, if whole blood was processed later than 6 h after venipuncture. Overnight shipment or extended rest of whole blood before processing therefore severely compromises the ability of APCs to respond to TLR ligands, and this has to be taken into consideration when designing multicenter trials. (C) 2008 Elsevier B.V. All rights reserved. C1 [Meier, Angela; Sidhu, Harlyn K.; Chang, Judy J.; Wen, Tom F.; Streeck, Hendrick; Alter, Galit; Altfeld, Marcus] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners AIDS Res Ctr, Boston, MA 02115 USA. [Fisher, Amelia; Silvestri, Guido] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Silvestri, Guido] Yerkes Natl Primate Res Ctr, Atlanta, GA USA. RP Altfeld, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners AIDS Res Ctr, Boston, MA 02115 USA. EM maltfeld@partners.org FU National Institutes of Health [1R24AI071806-OlA2] FX This study was supported by the National Institutes of Health (1R24AI071806-OlA2). NR 17 TC 6 Z9 6 U1 3 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD DEC 31 PY 2008 VL 339 IS 2 BP 132 EP 140 DI 10.1016/j.jim.2008.09.007 PG 9 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 384NJ UT WOS:000261751200003 PM 18848564 ER PT J AU Devor, A Hillman, EMC Tian, PF Waeber, C Teng, IC Ruvinskaya, L Shalinsky, MH Zhu, HH Haslinger, RH Narayanan, SN Ulbert, I Dunn, AK Lo, EH Rosen, BR Dale, AM Kleinfeld, D Boas, DA AF Devor, Anna Hillman, Elizabeth M. C. Tian, Peifang Waeber, Christian Teng, Ivan C. Ruvinskaya, Lana Shalinsky, Mark H. Zhu, Haihao Haslinger, Robert H. Narayanan, Suresh N. Ulbert, Istvan Dunn, Andrew K. Lo, Eng H. Rosen, Bruce R. Dale, Anders M. Kleinfeld, David Boas, David A. TI Stimulus-Induced Changes in Blood Flow and 2-Deoxyglucose Uptake Dissociate in Ipsilateral Somatosensory Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE blood flow; cerebral cortex; corpus callosum; glucose consumption; inhibition; metabolism ID INTRINSIC OPTICAL SIGNALS; RESONANCE-IMAGING SIGNAL; FUNCTIONAL ACTIVATION; NEURONAL-ACTIVITY; VISUAL-CORTEX; HEMOGLOBIN CONCENTRATION; SPECTROSCOPIC ANALYSIS; SURROUND INHIBITION; ELECTRICAL-ACTIVITY; HEMODYNAMIC-CHANGES AB The present study addresses the relationship between blood flow and glucose consumption in rat primary somatosensory cortex ( SI) in vivo. We examined bilateral neuronal and hemodynamic changes and 2-deoxyglucose (2DG) uptake, as measured by autoradiography, in response to unilateral forepaw stimulation. In contrast to the contralateral forepaw area, where neuronal activity, blood oxygenation/flow and 2DG uptake increased in unison, we observed, in the ipsilateral SI, a blood oxygenation/flow decrease and arteriolar vasoconstriction in the presence of increased 2DG uptake. Laminar electrophysiological recordings revealed an increase in ipsilateral spiking consistent with the observed increase in 2DG uptake. The vasoconstriction and the decrease in blood flow in the presence of an increase in 2DG uptake in the ipsilateral SI contradict the prominent metabolic hypothesis regarding the regulation of cerebral blood flow, which postulates that the state of neuroglial energy consumption determines the regional blood flow through the production of vasoactive metabolites. We propose that other factors, such as neuronal (and glial) release of messenger molecules, might play a dominant role in the regulation of blood flow in vivo in response to a physiological stimulus. C1 [Devor, Anna; Hillman, Elizabeth M. C.; Ruvinskaya, Lana; Shalinsky, Mark H.; Haslinger, Robert H.; Narayanan, Suresh N.; Ulbert, Istvan; Rosen, Bruce R.; Boas, David A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Waeber, Christian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke & Neurovasc Regulat Lab, Boston, MA 02129 USA. [Zhu, Haihao; Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02129 USA. [Devor, Anna; Tian, Peifang; Teng, Ivan C.; Dale, Anders M.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Devor, Anna; Dale, Anders M.] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA. [Kleinfeld, David] Univ Calif San Diego, Dept Phys, La Jolla, CA 92093 USA. [Ulbert, Istvan] Hungarian Acad Sci, Inst Psychol, H-1068 Budapest, Hungary. [Ulbert, Istvan] Peter Pazmany Catholic Univ, Dept Informat Technol, H-1083 Budapest, Hungary. [Dunn, Andrew K.] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. RP Devor, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Bldg 149,13th St,Mailcode 149-2301, Boston, MA 02129 USA. EM adevor@nmr.mgh.harvard.edu RI Waeber, Christian/A-8333-2009; Hillman, Elizabeth/B-9854-2009; Ulbert, Istvan/F-2213-2010; Dale, Anders/A-5180-2010; Dunn, Andrew/I-9527-2014; OI Waeber, Christian/0000-0001-6078-0027; Hillman, Elizabeth M. C./0000-0001-5511-1451 FU National Institute of Neurological Disorders and Stroke [NS-051188, NS-057476, P01NS-055104, NS-48422, NS-053684, NS-059832]; National Institute of Biomedical Imaging and BioEngineering [EB00790, EB003832, EB2066]; National Center for Research Resources [RR021907] FX This work was supported by National Institute of Neurological Disorders and Stroke ( Grants NS-051188 to A. D., NS-057476 to D. A. B., P01NS-055104 and NS-48422 to E. H. L., NS-053684 to E. M. C. H., and NS-059832 to D. K.), National Institute of Biomedical Imaging and BioEngineering ( Grants EB00790 to A. M. D., EB003832 to D. K., and EB2066 to B. R. R.), and National Center for Research Resources ( Grant RR021907 to D. K.). We thank Rick Buxton for critical reading of this manuscript. NR 77 TC 91 Z9 93 U1 0 U2 7 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 31 PY 2008 VL 28 IS 53 BP 14347 EP 14357 DI 10.1523/JNEUROSCI.4307-08.2008 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 390AX UT WOS:000262137800003 PM 19118167 ER PT J AU Kline, AE Hoffman, AN Cheng, JP Zafonte, RD Massucci, JL AF Kline, Anthony E. Hoffman, Ann N. Cheng, Jeffrey P. Zafonte, Ross D. Massucci, Jaime L. TI Chronic administration of antipsychotics impede behavioral recovery after experimental traumatic brain injury SO NEUROSCIENCE LETTERS LA English DT Article DE Antipsychotics; Beam-walk; Controlled cortical impact; Functional recovery; Haloperidol; Learning and memory; Morris water maze; Neurobehavior; Risperidone; Traumatic brain injury ID 5-HT1A RECEPTOR AGONIST; CONTROLLED CORTICAL IMPACT; WATER MAZE PERFORMANCE; ATYPICAL ANTIPSYCHOTICS; CORTEX INJURY; RATS; HALOPERIDOL; SENSORIMOTOR; HYPOTHERMIA; EXPERIENCE AB Antipsychotics are often administered to traumatic brain injured (TBI) patients as a means of controlling agitation, albeit the rehabilitative consequences of this intervention are not well known. Hence. the goal of this study was to evaluate the effects of risperidone (RISP) and haloperidol (HAL) on behavioral outcome after experimental TBI. Anesthetized rats received either a cortical impact or sham injury and then were randomly assigned to five TBI (RISP 0.045 mg/kg, RISP 0.45 mg/kg, RISP 4.5 mg/kg, HAL 0.5 mg/kg and VEHicle 1 ml/kg) and three Sham (RISP 4.5 mg/kg, HAL 0.5 mg/kg and VEH 1 mL/kg) groups. Treatments began 24 h after surgery and were provided once daily for 19 days. Behavior was assessed with established motor (beam-balance/walk) and cognitive (spatial learning/memory in a water maze) tasks on post-operative days 1-5 and 14-19, respectively. RISP and HAL delayed motor recovery, impaired the acquisition of spatial learning, and slowed swim speed relative to VEH in both TBI and sham groups. These data indicate that chronic administration of RISP and HAL impede behavioral recovery after TBI and impair performance in uninjured controls. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Kline, Anthony E.] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA 15213 USA. [Massucci, Jaime L.] Christiana Care Hlth Syst, Emergency Med, Newark, DE 19718 USA. [Kline, Anthony E.; Hoffman, Ann N.; Cheng, Jeffrey P.] Univ Pittsburgh, Safar Ctr Resuscitat Res, Pittsburgh, PA 15213 USA. [Kline, Anthony E.] Univ Pittsburgh, Ctr Neurosci, Pittsburgh, PA 15213 USA. [Kline, Anthony E.] Univ Pittsburgh, Ctr Neural Basic Cognit, Pittsburgh, PA 15213 USA. [Zafonte, Ross D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Zafonte, Ross D.] Spaulding Rehabil Hosp, Boston, MA 02114 USA. [Zafonte, Ross D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kline, AE (reprint author), Univ Pittsburgh, Dept Phys Med & Rehabil, 3471 5th Ave,Suite 201, Pittsburgh, PA 15213 USA. EM klineae@upmc.edu OI Cheng, Jeffrey/0000-0001-8285-3207 FU NIH [HD043851, HD046700] FX This work was supported by NIH grants HD043851 and HD046700 (AEK). NR 25 TC 36 Z9 36 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 31 PY 2008 VL 448 IS 3 BP 263 EP 267 DI 10.1016/j.neulet.2008.10.076 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 385CM UT WOS:000261790700008 PM 18983891 ER PT J AU Laouar, A Manocha, M Haridas, V Manjunath, N AF Laouar, Amale Manocha, Monika Haridas, Viraga Manjunath, N. TI Concurrent Generation of Effector and Central Memory CD8 T Cells during Vaccinia Virus Infection SO PLOS ONE LA English DT Article AB It is generally thought that during the contraction phase of an acute anti-viral T cell reponse, the effector T cells that escape activation-induced cell death eventually differentiate into central memory T cells over the next several weeks. Here we report that antigen-specific CD8T cells with the phenotype and function of central memory cells develop concomitantly with effector T cells during vaccinia virus (vv) infection. As soon as 5 days after an intraperitoneal infection with vv, we could identify a subset of CD44(hi) and CD62L(+) vv-specific CD8 T cells in the peritoneal exudate lymphocytes. This population constituted approximately 10% of all antigen-specific T cells and like central memory T cells, they also expressed high levels of CCR7 and IL-7R but expressed little granzyme B. Importantly, upon adoptive transfer into naive congenic hosts, CD62L(+), but not CD62L(-) CD8 T cells were able to expand and mediate a rapid recall response to a new vv challenge initiated 6 weeks after transfer, confirming that the CD62L(+) vv-specific CD8 T cells are bonafide memory cells. Our results are thus consistent with the branched differentiation model, where effector and memory cells develop simultaneously. These results are likely to have implications in the context of vaccine design, particularly those based on vaccinia virus recombinants. C1 [Laouar, Amale; Manocha, Monika; Haridas, Viraga; Manjunath, N.] Harvard Univ, Sch Med, Immune Dis Inst Inc, Boston, MA 02115 USA. [Laouar, Amale; Manocha, Monika; Haridas, Viraga; Manjunath, N.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Laouar, A (reprint author), Harvard Univ, Sch Med, Immune Dis Inst Inc, Boston, MA 02115 USA. EM laouar@cbr.med.harvard.edu; manjunath.swamy@ttuhsc.edu FU NIH/NIAID FX NIH/NIAID. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 19 Z9 20 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 31 PY 2008 VL 3 IS 12 AR e4089 DI 10.1371/journal.pone.0004089 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437DO UT WOS:000265466600010 PM 19116651 ER PT J AU Lage, K Hansen, NT Karlberg, EO Eklund, AC Roque, FS Donahoe, PK Szallasi, Z Jensen, TS Brunak, S AF Lage, Kasper Hansen, Niclas Tue Karlberg, E. Olof Eklund, Aron C. Roque, Francisco S. Donahoe, Patricia K. Szallasi, Zoltan Jensen, Thomas Skot Brunak, Soren TI A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE proteomics; systems biology; computational biology ID PROTEIN INTERACTION NETWORK; SEX-DETERMINATION; SACCHAROMYCES-CEREVISIAE; STEROIDOGENIC FACTOR-1; MASS-SPECTROMETRY; HUMAN PHENOME; MOUSE; DIFFERENTIATION; SOX9; DAX1 AB Heritable diseases are caused by germ-line mutations that, despite tissuewide presence, often lead to tissue-specific pathology. Here, we make a systematic analysis of the link between tissue-specific gene expression and pathological manifestations in many human diseases and cancers. Diseases were systematically mapped to tissues they affect from disease-relevant literature in PubMed to create a disease-tissue covariation matrix of high-confidence associations of > 1,000 diseases to 73 tissues. By retrieving > 2,000 known disease genes, and generating 1,500 disease-associated protein complexes, we analyzed the differential expression of a gene or complex involved in a particular disease in the tissues affected by the disease, compared with nonaffected tissues. When this analysis is scaled to all diseases in our dataset, there is a significant tendency for disease genes and complexes to be overexpressed in the normal tissues where defects cause pathology. In contrast, cancer genes and complexes were not overexpressed in the tissues from which the tumors emanate. We specifically identified a complex involved in XY sex reversal that is testis-specific and down-regulated in ovaries. We also identified complexes in Parkinson disease, cardiomyopathies, and muscular dystrophy syndromes that are similarly tissue specific. Our method represents a conceptual scaffold for organism-spanning analyses and reveals an extensive list of tissue-specific draft molecular pathways, both known and unexpected, that might be disrupted in disease. C1 [Lage, Kasper; Donahoe, Patricia K.] Massachusetts Gen Hosp, MassGen Hosp Children, Pediat Surg Res Labs, Boston, MA 02114 USA. [Lage, Kasper; Hansen, Niclas Tue; Karlberg, E. Olof; Eklund, Aron C.; Roque, Francisco S.; Szallasi, Zoltan; Jensen, Thomas Skot; Brunak, Soren] Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Lage, Kasper; Donahoe, Patricia K.; Szallasi, Zoltan] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Karlberg, E. Olof] Stockholm Univ, Stockholm Bioinformat Ctr, SE-11421 Stockholm, Sweden. [Szallasi, Zoltan] Harvard Mit Div Hlth Sci & Technol, Childrens Hosp Informat Program, Boston, MA 02115 USA. [Brunak, Soren] Univ Copenhagen, Novo Nordisk Fdn, Ctr Prot Res, DK-2200 Copenhagen N, Denmark. RP Donahoe, PK (reprint author), Massachusetts Gen Hosp, MassGen Hosp Children, Pediat Surg Res Labs, 55 Fruit St, Boston, MA 02114 USA. EM pdonahoe@partners.org; brunak@cbs.dtu.dk OI Szallasi, Zoltan/0000-0001-5395-7509; Eklund, Aron Charles/0000-0003-0861-1001 FU Villum Kann Rasmussen Foundation; Simon Spies Foundation; National Institute of Child Health and Development [CD RO1 HD0551-50]; National Institutes of Health FX We thank Matthias Mann, Jiri Bartek, Gert- Jan B. van Ommen, Barbara Pober, and Jonathan Rosand for valuable input on the manuscript and project, Anders Lendager and Lene Hep from MAPT for help with the figures, Zenia Marian Storling for assistance wtih the initial analyses, Kasper Fugger and Christopher Workman for helpful discussions, and Olga Rigina for curating the PPI databases. This work was supported by Villum Kann Rasmussen Foundation, the Simon Spies Foundation, National Institute of Child Health and Development Grant CD RO1 HD0551-50, and the National Institutes of Health NR 47 TC 130 Z9 130 U1 2 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 30 PY 2008 VL 105 IS 52 BP 20870 EP 20875 DI 10.1073/pnas.0810772105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 389LB UT WOS:000262092800055 PM 19104045 ER PT J AU Brockman, MA Knipe, DM AF Brockman, Mark A. Knipe, David M. TI Herpes simplex virus as a tool to define the role of complement in the immune response to peripheral infection SO VACCINE LA English DT Review DE Innate immunity; Immune evasion; Antigen presentation ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIBODY-MEDIATED PROTECTION; FOLLICULAR DENDRITIC CELLS; NATURAL IMMUNOGLOBULIN-M; TYPE-1 GLYCOPROTEIN GC; NECROSIS-FACTOR-ALPHA; ADAPTIVE IMMUNITY; VIRAL-INFECTION; MONOCLONAL-ANTIBODY; LATENT INFECTION AB A complex network of interactions exist between the innate and adaptive immune pathways, which act together to elicit a broad and durable host response following pathogen infection. The importance of the complement system in the host's defense against viruses has become increasingly clear as a result of detailed studies using transgenic mouse models that disrupt specific components of this host immune mechanism. We have utilized herpes simplex virus and replication-defective mutant strains to examine the impact of the complement system on development and maintenance of humoral immune responses. Here we review work from our group and others that highlights the central role that complement proteins C3 and C4 and complement receptors Cr1/Cr2 play during viral infection. We discuss the implications of these results in the context of pathogen infection and Current vaccine strategies. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Knipe, David M.] Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. [Brockman, Mark A.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. RP Knipe, DM (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. EM david_knipe@hms.harvard.edu OI Brockman, Mark/0000-0001-6432-1426 FU NIH HIVRAD [AI46006]; NIH [AI57552] FX Research in DMK's laboratory on HSV vaccines and vaccine vectors is Supported by NIH HIVRAD grant AI46006 and NIH grant AI57552. We thank Michael Carroll and Admar Verschoor for their collaboration in the Studies of HSV and complement. NR 104 TC 3 Z9 3 U1 0 U2 5 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 DEC 30 PY 2008 VL 26 BP I94 EP I99 DI 10.1016/j.vaccine.2008.11.062 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 402HT UT WOS:000263005500017 PM 19388172 ER PT J AU Carroll, MC AF Carroll, Michael C. TI Complement and humoral immunity SO VACCINE LA English DT Review DE Humoral immunity; Innate immunity; Complement receptors ID ZONE B-CELLS; HERPES-SIMPLEX-VIRUS; LYMPH-NODE; ANTIBODY-RESPONSES; SUBCAPSULAR SINUS; DENDRITIC CELLS; LYMPHOCYTES-B; RECEPTOR; ANTIGEN; MICE AB The complement system was discovered almost a century ago as an important effector in antibody-dependent killing of microorganisms. Since this early period much was learned about the biochemistry and structure of complement proteins and their function in mediating inflammation. More recently, a prominent role for complement was identified in linkage of innate and adaptive immunity. In this review, I will discuss our current understanding of the importance of complement in enhancing the humoral immune response to both model antigens and pathogens. As discussed below, it is evident that the complement system participates in marking of "foreign" pathogens and "presenting" them to B cells in a manner that enhances both antibody production and long-term memory. In this special issue of Vaccine, we see examples of how complement is critical in the immune response to bacterial and vital pathogens. Moreover, the finding that most organisms have co-evolved proteins to evade complement detection underscores its importance in host protection. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Carroll, Michael C.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Carroll, Michael C.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Carroll, MC (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, 800 Huntington Ave, Boston, MA 02115 USA. EM carroll@idi.harvard.edu FU NIH FX I thank both current and former member of the laboratory that contributed to many of the ideas and concepts discussed in this review. The work is supported by grants from NIH. NR 51 TC 21 Z9 21 U1 3 U2 15 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 DEC 30 PY 2008 VL 26 BP I28 EP I33 DI 10.1016/j.vaccine.2008.11.022 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 402HT UT WOS:000263005500006 PM 19388161 ER PT J AU Gonzalez, SF Jayasekera, JP Carroll, MC AF Gonzalez, Santiago Fernandez Jayasekera, Jerome Priyantha Carroll, Michael C. TI Complement and natural antibody are required in the long-term memory response to influenza virus SO VACCINE LA English DT Article DE Complement; Natural antibody IgM; Memory response; Influenza virus ID B-CELL RESPONSE; FOLLICULAR DENDRITIC CELLS; HUMORAL IMMUNE-RESPONSE; ACQUIRED-IMMUNITY; MICE DEFICIENT; VIRAL-INFECTION; COMPONENT C3; RECEPTORS 1; IGG; LYMPHOCYTES AB Complement, complement receptors and natural antibody (IgM) are important factors in the immune response against pathogens. Previous studies have indicated a role for C3, the complement receptors CD35/CD21 (CR1/CR2), and IgM in the immune response to influenza virus. Nevertheless, their contribution to the long-term memory response to this pathogen remains unknown. To elucidate this role, we characterized the secondary response on mice deficient of CR1/CR2 (Cr2-/-), C3 (C3-/-), secreted IgM (mu s-/-) and the double knockout C3-/-mu s-/-. Overall, our results suggest that C3, IgM and CR1/CR2 play crucial roles in the maintenance of long-term memory to influenza virus, possibly through the development of memory B cells and long-term antibody secretion. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Carroll, Michael C.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat & Pathol, Boston, MA 02115 USA. RP Carroll, MC (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, 800 Huntington Ave, Boston, MA 02115 USA. EM carroll@idi.harvard.edu NR 43 TC 4 Z9 4 U1 0 U2 4 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 DEC 30 PY 2008 VL 26 BP I86 EP I93 DI 10.1016/j.vaccine.2008.11.057 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 402HT UT WOS:000263005500016 ER PT J AU Delmonico, FL McBride, MA AF Delmonico, Francis L. McBride, Maureen A. TI Analysis of the Wait List and Deaths Among Candidates Waiting for a Kidney Transplant SO TRANSPLANTATION LA English DT Article DE Kidney; Wait; List ID ORGAN DONATION; SYSTEM AB Background. The status (active vs. inactive) and the characteristics of patients waiting for a kidney transplant and those dying on the kidney waiting list were analyzed to make a current assessment of the kidney waitlist. Candidates designated as inactive on the kidney waiting list were examined to determine total length of time with inactive status and total time on the list. Methods. The number and proportion of kidney waitlist candidates with inactive status at any point in time on the waiting list has increased substantially over the last several years. At the end of 2007, 24,624 candidates on the kidney waiting list (32.8%) were categorized as inactive compared with 9186 (16.1%) at the end of 2003. Results. The percentage of patients who died categorized as inactive on the kidney waiting list has also increased markedly from 31% (n = 1197) in 2003 to 52% (2431) in 2007. Among the 2431 candidates, who died with inactive status while waiting for a kidney during 2007, 1281 (53%) were inactive for longer than I year over the entire course of their time on the waiting list, and 1132 (47%) were not listed as active status consecutively for more than I year before their death. Conclusion. "Inactive" patients are not eligible to receive all offer for a deceased donor kidney, even though they are on the list. Patients who died inactive and never received an offer for a kidney during the period of listing are not served well by extended periods of inactivity. C1 [Delmonico, Francis L.] Massachusetts Gen Hosp, Dept Surg, Transplantat Ctr, Boston, MA 02114 USA. [McBride, Maureen A.] United Network Organ Sharing, Richmond, VA USA. RP Delmonico, FL (reprint author), Massachusetts Gen Hosp, Dept Surg, Transplantat Ctr, 55 Fruit Street,White Bldg 505, Boston, MA 02114 USA. EM francis_delmonico@neob.org FU Health Resources and Services Administration [234-2005-370011C] FX This work was supported by Health Resources and Services Administration contract 234-2005-370011C. NR 4 TC 23 Z9 24 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD DEC 27 PY 2008 VL 86 IS 12 BP 1678 EP 1683 DI 10.1097/TP.0b013e31818fe694 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 388XL UT WOS:000262053500010 PM 19104404 ER PT J AU Meltzer, AJ Weiss, MJ Veillette, GR Sahara, H Ng, CY Cochrane, ME Houser, SL Sachs, DH Rosengard, BR Madsen, JC Wain, JC Allan, JS AF Meltzer, Andrew J. Weiss, Matthew J. Veillette, Gregory R. Sahara, Hisashi Ng, Choo Y. Cochrane, Meghan E. Houser, Stuart L. Sachs, David H. Rosengard, Bruce R. Madsen, Joren C. Wain, John C. Allan, James S. TI Repetitive Gastric Aspiration Leads to Augmented Indirect Allorecognition After Lung Transplantation in Miniature Swine SO TRANSPLANTATION LA English DT Article DE Lung transplantation; Gastroesophageal reflux disease; Tolerance ID GASTROESOPHAGEAL-REFLUX DISEASE; INDIRECT RECOGNITION; ALLOGRAFT DYSFUNCTION; FUNDOPLICATION; HISTOCOMPATIBILITY; PREVALENCE; RECIPIENTS; REJECTION; FIBROSIS AB Introduction. Lung transplant recipients with documented gastroesophageal reflux disease (GERD) are at increased risk for graft dysfunction. Here, we present the first large-animal model of gastric aspiration after allogeneic lung transplantation and some preliminary data demonstrating the effect of chronic aspiration on the direct and indirect pathways of allorecognition. Methods. Left orthotopic lung transplants (n=3) were performed in miniature swine across a major histocompatibility complex class I disparity, followed by 12 days of high-dose cyclosporine A. At the time of transplantation, a transtracheal catheter was placed at the carina, above the bronchial anastomosis. A gastrostomy tube was placed for daily aspiration of gastric contents. Subsequently, graft lungs were instilled with gastric aspirate daily (3 mL/hr X 8 hr/day) for 50 days. Recipients were followed up with daily complete blood count, scheduled chest radiographs, and biopsies. In vitro studies, including cell-mediated lympholysis, mixed lymphocyte reactions, and peptide proliferation assays, were performed. Results from these three recipients were compared with those of historical controls (n=6) who were treated identically, except for the tracheal cannulation and simulated gastric aspiration. Results. Two of the experimental animals were euthanized with nonviable lungs soon after the postoperative day 50 biopsy. In both cases the native lung was normal. The third animal survived over 180 days without the evidence of chronic rejection. After immunosuppressive treatment, all animals demonstrated donor-specific hyporesponsiveness by assays of direct alloresponse (cell-mediated lympholysis, mixed lymphocyte reaction). A significant response to synthetic donor-derived class I peptide, however, was seen in all animals. A more pronounced and diffuse response was seen in the animals rejecting their grafts. The historical controls showed medium-term graft survival with evidence of chronic rejection in the majority of animals, as previously reported. Conclusion. In a model of GERD after lung transplantation, a spectrum of clinical outcomes was observed. The in vitro data suggest that acid reflux enhances the indirect alloresponse to processed donor class I antigen, giving mechanistic insight into the manner in which GERD may be deleterious to the transplanted lung. C1 [Wain, John C.; Allan, James S.] Massachusetts Gen Hosp, Dept Surg, Div Thorac Dis, Massachusetts Gen Hosp Transplant Ctr, Boston, MA 02114 USA. [Meltzer, Andrew J.; Weiss, Matthew J.; Veillette, Gregory R.; Sahara, Hisashi; Ng, Choo Y.; Cochrane, Meghan E.; Houser, Stuart L.; Sachs, David H.; Rosengard, Bruce R.; Madsen, Joren C.; Allan, James S.] Massachusetts Gen Hosp, Massachusetts Gen Hosp Transplant Ctr, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Meltzer, Andrew J.; Weiss, Matthew J.; Veillette, Gregory R.; Sahara, Hisashi; Ng, Choo Y.; Cochrane, Meghan E.; Houser, Stuart L.; Sachs, David H.; Rosengard, Bruce R.; Madsen, Joren C.; Wain, John C.; Allan, James S.] Harvard Univ, Sch Med, Boston, MA USA. [Houser, Stuart L.] Massachusetts Gen Hosp, Massachusetts Gen Hosp Transplant Ctr, Dept Pathol, Boston, MA 02114 USA. [Rosengard, Bruce R.; Madsen, Joren C.] Massachusetts Gen Hosp, Massachusetts Gen Hosp Transplant Ctr, Dept Surg, Div Cardiac Surg, Boston, MA 02114 USA. RP Allan, JS (reprint author), Massachusetts Gen Hosp, Dept Surg, Div Thorac Dis, Massachusetts Gen Hosp Transplant Ctr, 55 Fruit St, Boston, MA 02114 USA. EM jallan@partners.org FU NIH [R01 HL67110]; The International Society for Heart and Lung Transplantation; The Thoracic Surgery Foundation for Research and Education FX This work was Supported by NIH (R01 HL67110), The International Society for Heart and Lung Transplantation (M.J.W.), and The Thoracic Surgery Foundation for Research and Education (H.S.). NR 20 TC 11 Z9 11 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 DEC 27 PY 2008 VL 86 IS 12 BP 1824 EP 1829 DI 10.1097/TP.0b013e318190afe6 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 388XL UT WOS:000262053500035 PM 19104429 ER PT J AU Scrima, A Konickova, R Czyzewski, BK Kawasaki, Y Jeffrey, PD Groisman, R Nakatani, Y Iwai, S Pavletich, NP Thoma, NH AF Scrima, Andrea Konickova, Renata Czyzewski, Bryan K. Kawasaki, Yusuke Jeffrey, Philip D. Groisman, Regina Nakatani, Yoshihiro Iwai, Shigenori Pavletich, Nikola P. Thomae, Nicolas H. TI Structural Basis of UV DNA-Damage Recognition by the DDB1-DDB2 Complex SO CELL LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; PIGMENTOSUM GROUP-E; GROUP-E CELLS; XERODERMA-PIGMENTOSUM; BINDING-PROTEIN; UBIQUITIN LIGASE; PYRIMIDINE DIMERS; DIFFRACTION DATA; XPC COMPLEX; DDB2 AB Ultraviolet (UV) light-induced pyrimidine photodimers are repaired by the nucleotide excision repair pathway. Photolesions have biophysical parameters closely resembling undamaged DNA, impeding discovery through damage surveillance proteins. The DDB1-DDB2 complex serves in the initial detection of UV lesions in vivo. Here we present the structures of the DDB1-DDB2 complex alone and bound to DNA containing either a 6-4 pyrimidine-pyrimidone photodimer (6-4PP) lesion or an abasic site. The structure shows that the lesion is held exclusively by the WD40 domain of DDB2. A DDB2 hairpin inserts into the minor groove, extrudes the photodimer into a binding pocket, and kinks the duplex by similar to 40 degrees. The tightly localized probing of the photolesions, combined with proofreading in the photodimer pocket, enables DDB2 to detect lesions refractory to detection by other damage surveillance proteins. The structure provides insights into damage recognition in chromatin and suggests a mechanism by which the DDB1-associated CUL4 ubiquitin ligase targets proteins surrounding the site of damage. C1 [Czyzewski, Bryan K.; Jeffrey, Philip D.; Pavletich, Nikola P.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10021 USA. [Scrima, Andrea; Konickova, Renata; Thomae, Nicolas H.] Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland. [Kawasaki, Yusuke; Iwai, Shigenori] Osaka Univ, Grad Sch Engn Sci, Osaka 5608531, Japan. [Groisman, Regina] Univ Paris Sud, Inst Andre Lwoff, CNRS, FRE 2944, F-94801 Villejuif, France. [Nakatani, Yoshihiro] Dana Farber Canc Inst, Boston, MA 02115 USA. [Nakatani, Yoshihiro] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Pavletich, NP (reprint author), Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10021 USA. EM pavletin@mskcc.org; nicolas.thoma@fmi.ch FU Swiss Light Source at the Paul Scherrer Institute, Villigen, Switzerland; Human Frontier Science Program (HFSP); Swiss National Fond [31-120205]; Novartis Research Foundation; European Molecular Biology Organization (EMBO) FX We thank Norman Kairies for crystallographic support. We would like to thank Fritz Thoma, Hanspeter Naegeli, and Susan Gasser for discussions relating to DNA repair in the context of chromatin. We thank Hans Widmer for help and support. Part of this work was performed at the Swiss Light Source at the Paul Scherrer Institute, Villigen, Switzerland. Y.N. and S.I. acknowledge funding from the Human Frontier Science Program (HFSP). Funding in the laboratory of N.H.T. is provided by the Swiss National Fond (SNF;#31-120205) and the Novartis Research Foundation. A. S. gratefully acknowledges funding from the European Molecular Biology Organization (EMBO). NR 59 TC 179 Z9 186 U1 3 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD DEC 26 PY 2008 VL 135 IS 7 BP 1213 EP 1223 DI 10.1016/j.cell.2008.10.045 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 387ZJ UT WOS:000261989800013 PM 19109893 ER PT J AU Hitomi, JI Christofferson, DE Ng, A Yao, JH Degterev, A Xavier, RJ Yuan, JY AF Hitomi, Junichi Christofferson, Dana E. Ng, Aylwin Yao, Jianhua Degterev, Alexei Xavier, Ramnik J. Yuan, Junying TI Identification of a Molecular Signaling Network that Regulates a Cellular Necrotic Cell Death Pathway SO CELL LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; NEGATIVE REGULATOR; L929 CELLS; APOPTOSIS; PROTEIN; DATABASE; DOMAIN; RIP1; CYLD AB Stimulation of death receptors by agonists such as FasL and TNF alpha activates apoptotic cell death in apoptotic-competent conditions or a type of necrotic cell death dependent on RIP1 kinase, termed necroptosis, in apoptotic-deficient conditions. In a genomewide siRNA screen for regulators of necroptosis, we identify a set of 432 genes that regulate necroptosis, a subset of 32 genes that act downstream and/or as regulators of RIP1 kinase, 32 genes required for death-receptor-mediated apoptosis, and 7 genes involved in both necroptosis and apoptosis. We show that the expression of subsets of the 432 genes is enriched in the immune and nervous systems, and cellular sensitivity to necroptosis is regulated by an extensive signaling network mediating innate immunity. Interestingly, Bmf, a BH3-only Bcl-2 family member, is required for death-receptor-induced necroptosis. Our study defines a cellular signaling network that regulates necroptosis and the molecular bifurcation that controls apoptosis and necroptosis. C1 [Hitomi, Junichi; Christofferson, Dana E.; Yao, Jianhua; Degterev, Alexei; Yuan, Junying] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Yuan, JY (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, 240 Longwood Ave, Boston, MA 02115 USA. EM jyuan@hms.harvard.edu FU National Institute of Health [DP1OD000580]; National Institute on Aging [R37 AG012859-14]; National Institute on Neurological Disorders and Stroke [U01NS050560]; NIH Director's Pioneer Award; National Institute of Allergy and Infectious Diseases [AI062773, DK43351]; Mochida Memorial Foundation for Medical and Pharmaceutical Research; Uehara Memorial Foundation; Japan Society for Promotion of Science; Crohn's and Colitis Foundation of America FX We thank Dodzie Sogah, Marta Lipinski, and Caroline Yi for helpful comments on this manuscript. We are grateful for the support of Caroline Shamu, Stewart Rudnicki, Sean Johnston, and David Wrobel at the ICCB Longwood Facility during screening. We thank S. C. Sun (University of Texas, M. D. Anderson Cancer Center) and J. Blenis (Harvard Medical School) for CYLD antibody and FADD def Jurkat cells, respectively. This work was supported in part by grants from the National Institute of Health (DP1OD000580), the National Institute on Aging (R37 AG012859-14), the National Institute on Neurological Disorders and Stroke (U01NS050560), NIH Director's Pioneer Award (to J.Y.), and the National Institute of Allergy and Infectious Diseases (AI062773) and DK43351 (to R. J. X.). J. H. was supported in part by fellowships from the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Uehara Memorial Foundation, and the Japan Society for Promotion of Science. A.N. is a recipient of a Fellowship Award from the Crohn's and Colitis Foundation of America. NR 49 TC 467 Z9 495 U1 8 U2 67 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 26 PY 2008 VL 135 IS 7 BP 1311 EP 1323 DI 10.1016/j.cell.2008.10.044 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 387ZJ UT WOS:000261989800021 PM 19109899 ER PT J AU Shi, LH Ko, S Kim, S Echchgadda, I Oh, TS Song, CS Chatterjee, B AF Shi, Liheng Ko, Soyoung Kim, Soyoung Echchgadda, Ibtissam Oh, Tae-Sung Song, Chung S. Chatterjee, Bandana TI Loss of Androgen Receptor in Aging and Oxidative Stress through Myb Protooncoprotein-regulated Reciprocal Chromatin Dynamics of p53 and Poly(ADP-ribose) Polymerase PARP-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FACTOR-KAPPA-B; TRANSCRIPTIONAL REPRESSION; HEPATOCELLULAR-CARCINOMA; CALORIE RESTRICTION; PROSTATE-CANCER; RAT-LIVER; GENE; COREPRESSOR; EXPRESSION; ALPHA AB Poly(ADP-ribosyl)ation of transcription factors and coregulators, mediated by the poly(ADP-ribose) polymerase PARP-1, has been emerging as an important epigenetic mechanism that controls transcriptional dynamics in response to diverse intra- and extracellular signals. PARP-1 activity is also implicated in the regulation of mammalian lifespan. Herein we show that transcriptional down-regulation of androgen receptor (AR) in the aging rat liver and in oxidatively stressed hepatoma cells involves exchange of a PARP-1-associated, p/CAF-containing coactivator assembly for a p53-interacting, Groucho/TLE1-, and mSin3A-induded corepressor complex at an age- and oxidant-responsive DNA element (age- dependent factor (ADF) element) in the AR promoter. The coregulator switch is mediated by B-Myb and c-Myb, which bind to the ADF element and physically associate with PARP-1 and the tumor suppressor p53. Heterogeneous nuclear ribonucleoprotein K, residing at the ADF element in association with PARP-1, may serve a platform role in stabilizing the activating complex. PARP-1 coactivated B-Myb- and c-Myb-mediated transactivation of the AR promoter, and p53 antagonized the B-Myb/c-Myb-induced AR promoter activation. PARP-1, heterogeneous nuclear ribonucleoprotein K, B-Myb, and c-Myb each serves as a positive regulator of cellular AR content, whereas p53 negatively regulates AR expression. Our results identify a shared, PARP-1-regulated sensing mechanism that coordinates transcriptional repression of AR during aging and in response to oxidative stress. This study may provide insights as to how advancing age and intracellular redox balance might influence androgen-regulated physiology. C1 [Shi, Liheng; Ko, Soyoung; Kim, Soyoung; Echchgadda, Ibtissam; Oh, Tae-Sung; Song, Chung S.; Chatterjee, Bandana] Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, Dept Mol Med, San Antonio, TX 78245 USA. [Chatterjee, Bandana] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Chatterjee, B (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Inst Biotechnol, Dept Mol Med, 15355 Lambda Dr, San Antonio, TX 78245 USA. EM chatterjee@uthscsa.edu FU National Institutes of Health [AG-10486, AG-19660] FX This work was supported, in whole or in part, by National Institutes of Health Grants AG-10486 and AG-19660. This work was also supported by a merit review grant from Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 53 TC 17 Z9 18 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 26 PY 2008 VL 283 IS 52 BP 36474 EP 36485 DI 10.1074/jbc.M805980200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 385VA UT WOS:000261840500045 PM 18945670 ER PT J AU Zuo, Y Zhuang, DZ Han, R Isaac, G Tobin, JJ Mckee, M Welti, R Brissette, JL Fitzgerald, ML Freeman, MW AF Zuo, Ying Zhuang, Debbie Z. Han, Rong Isaac, Giorgis Tobin, Jennifer J. Mckee, Mary Welti, Ruth Brissette, Janice L. Fitzgerald, Michael L. Freeman, Mason W. TI ABCA12 Maintains the Epidermal Lipid Permeability Barrier by Facilitating Formation of Ceramide Linoleic Esters SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CASSETTE TRANSPORTER 1; HARLEQUIN ICHTHYOSIS; TANGIER-DISEASE; PULMONARY SURFACTANT; LAMELLAR GRANULES; RESPIRATORY-FAILURE; GAUCHER-DISEASE; GENE ABCR; MUTATIONS; MICE AB Harlequin ichthyosis is a congenital scaling syndrome of the skin in which affected infants have epidermal hyperkeratosis and a defective permeability barrier. Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis, but the molecular function of the protein is unknown. To investigate the activity of ABCA12, we generated Abca12 null mice and analyzed the impact on skin function and lipid content. Abca12(-/-) mice are born with a thickened epidermis and die shortly after birth, as water rapidly evaporates from their skin. In vivo skin proliferation measurements suggest a lack of desquamation of the skin cells, rather than enhanced proliferation of basal layer keratinocytes, accounts for the 5-fold thickening of the Abca12(-/-) stratum corneum. Electron microscopy revealed a loss of the lamellar permeability barrier in Abca12(-/-) skin. This was associated with a profound reduction in skin linoleic esters of long-chain omega-hydroxyceramides and a corresponding increase in their glucosyl ceramide precursors. Because omega-hydroxyceramides are required for the barrier function of the skin, these results establish that ABCA12 activity is required for the generation of long-chain ceramide esters that are essential for the development of normal skin structure and function. C1 [Zuo, Ying; Zhuang, Debbie Z.; Tobin, Jennifer J.; Fitzgerald, Michael L.; Freeman, Mason W.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Zuo, Ying; Zhuang, Debbie Z.; Tobin, Jennifer J.; Fitzgerald, Michael L.; Freeman, Mason W.] Massachusetts Gen Hosp, Lipid Metab Unit, Boston, MA 02114 USA. [Zuo, Ying; Zhuang, Debbie Z.; Tobin, Jennifer J.; Fitzgerald, Michael L.; Freeman, Mason W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Han, Rong; Brissette, Janice L.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02114 USA. [Mckee, Mary] Massachusetts Gen Hosp, Ctr Membrane Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Isaac, Giorgis; Welti, Ruth] Kansas State Univ, Div Biol, Manhattan, KS 66506 USA. RP Freeman, MW (reprint author), Massachusetts Gen Hosp, Dept Med, Simches 7214,185 Cambridge St, Boston, MA 02114 USA. EM freeman@molbio.mgh.harvard.edu OI Han, Rong/0000-0002-5766-8277 FU National Institutes of Health [RR020345, HL074136]; Inflammatory Bowel Disease [DK43351]; Boston Area Diabetes and Endocrinology Research Center Award [DK57521]; National Science Foundation (NSF) [MCB0455318, 0521587]; NSF EPSCoR [EPS-0236913]; State of Kansas through Kansas Technology Enterprise Corporation; Kansas State University; NIH [P20 RR16475]; National Center for Research Resources FX This work was supported, in whole or in part, by National Institutes of Health Grants RR020345 (to M.W.F.) and HL074136 (to M.L.F.). The electron microscopy core is supported by an Inflammatory Bowel Disease Grant (DK43351) and a Boston Area Diabetes and Endocrinology Research Center Award (DK57521). The Kansas Lipidomics Research Center (KLRC) was supported by National Science Foundation (NSF) Grants MCB0455318 and DBI 0521587, and NSF EPSCoR Grant EPS-0236913, with matching support from the State of Kansas through Kansas Technology Enterprise Corporation and Kansas State University. The KLRC was also supported by Kansas Idea Network of Biomedical Research Excellence from NIH Grant P20 RR16475, from the Idea Network of Biomedical Research Excellence program of the National Center for Research Resources. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 42 TC 55 Z9 57 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 26 PY 2008 VL 283 IS 52 BP 36624 EP 36635 DI 10.1074/jbc.M807377200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 385VA UT WOS:000261840500061 PM 18957418 ER PT J AU Zimmer, M Ebert, BL Neil, C Brenner, K Papaioannou, L Melas, A Tolliday, N Lamb, J Pantopoulos, K Golub, T Iliopoulos, O AF Zimmer, Michael Ebert, Benjamin L. Neil, Christopher Brenner, Keith Papaioannou, Loannis Melas, Antonia Tolliday, Nicola Lamb, Justin Pantopoulos, Kostas Golub, Todd Iliopoulos, Othon TI Small-Molecule Inhibitors of HIF-2a Translation Link Its 5 ' UTR Iron-Responsive Element to Oxygen Sensing SO MOLECULAR CELL LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR; MESSENGER-RNA TRANSLATION; REGULATORY PROTEIN-1; TRANSCRIPTIONAL ACTIVITY; DEPENDENT DEGRADATION; MAMMALIAN TARGET; BINDING; EXPRESSION; VHL; HYDROXYLATION AB Cells transiently adapt to hypoxia by globally decreasing protein translation. However, specific proteins needed to respond to hypoxia evade this translational repression. The mechanisms of this phenomenon remain unclear. We screened for and identified small molecules that selectively decrease HIF-2a translation in an mTOR-independent manner, by enhancing the binding of Iron-Regulatory Protein 1 (IRP1) to a recently reported iron-responsive element (IRE) within the 5'-untranslated region (UTR) of the HIF-2a message. Knocking down the expression of IRP1 by shRNA abolished the effect of the compounds. Hypoxia derepresses HIF-2a. translation by disrupting the IRP1-HIF-2a IRE interaction. Thus, this chemical genetic analysis describes a molecular mechanism by which translation of the HIF-2a message is maintained during conditions of cellular hypoxia through inhibition of IRP-1-dependent repression. It also provides the chemical tools for studying this phenomenon. C1 [Zimmer, Michael; Neil, Christopher; Brenner, Keith; Papaioannou, Loannis; Melas, Antonia; Iliopoulos, Othon] Massachusetts Gen Hosp, Dept Med, Hematol Oncol Unit, Boston, MA 02114 USA. [Zimmer, Michael; Neil, Christopher; Brenner, Keith; Papaioannou, Loannis; Melas, Antonia; Iliopoulos, Othon] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Ebert, Benjamin L.; Lamb, Justin; Golub, Todd] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA. [Tolliday, Nicola] Harvard Univ, Sch Med, ICCB, Boston, MA 02115 USA. [Pantopoulos, Kostas] McGill Univ, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada. [Pantopoulos, Kostas] McGill Univ, Dept Med, Montreal, PQ H3T 1E2, Canada. RP Iliopoulos, O (reprint author), Massachusetts Gen Hosp, Dept Med, Hematol Oncol Unit, Boston, MA 02114 USA. EM oiliopoulos@partners.org RI Pantopoulos, Kostas/A-9668-2008 FU NIH [5R01CA104574]; National Cancer Institute's Initiative for Chemical Genetics [N01-CO-12400] FX We thank Drs. Matthias Hentze and Betty Leibold for invaluable advice and reagents. We acknowledge the significant contributions of Tim Mitchison and Carolyn Shamu of the Harvard Institute of Chemistry and Cell Biology through continuous discussion of data, of Drs. Nick Dyson and Jeff Settleman for critically reading the manuscript, and of Billy Andriopoulos for technical advice. We also thank Michele Pagano for the pCMV and pCMV-SL constructs: Betty Liebold for the Ferritin-L probe and IRP2 antibody; and Jim Rocco for the pLentiLox3.7 puromycin, hygromycin, and blasticidin vectors. This work has been supported by the NIH 5R01CA104574 (to 0.1.), the VHL Family Alliance Award, the Dana- Farber/Harvard Cancer Center Kidney Cancer Program Developmental Award (to M.Z.), and the National Cancer Institute's Initiative for Chemical Genetics (contract no. N01-CO-12400). NR 47 TC 91 Z9 92 U1 2 U2 6 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 DEC 26 PY 2008 VL 32 IS 6 BP 838 EP 848 DI 10.1016/j.molcel.2008.12.004 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 390SO UT WOS:000262184200013 PM 19111663 ER PT J AU Zhu, JH Luo, BH Xiao, T Zhang, CZ Nishida, N Springer, TA AF Zhu, Jianghai Luo, Bing-Hao Xiao, Tsan Zhang, Chengzhong Nishida, Noritaka Springer, Timothy A. TI Structure of a Complete Integrin Ectodomain in a Physiologic Resting State and Activation and Deactivation by Applied Forces SO MOLECULAR CELL LA English DT Article ID CRYSTAL-STRUCTURE; EXTENDED CONFORMATIONS; EXTRACELLULAR SEGMENT; CYTOPLASMIC DOMAINS; ELECTRON-MICROSCOPY; ALPHA-SUBUNIT; OUTSIDE-IN; ADHESION; LIGAND; TRANSMEMBRANE AB The complete ectodomain of integrin alpha(IIb)beta(3) reveals a bent, closed, low-affinity conformation, the beta knee, and a mechanism for linking cytoskeleton attachment to high affinity for ligand. Ca and Mg ions in the recognition site, including the synergistic metal ion binding site (SyMBS), are loaded prior to ligand binding. Electrophilicity of the ligand-binding Mg ion is increased in the open conformation. The beta(3) knee passes between the beta(3)-PSI and alpha(IIb)beta(3)knob to bury the lower beta leg in a cleft, from which it is released for extension. Different integrin molecules in crystals and EM reveal breathing that appears on pathway to extension. Tensile force applied to the extended ligand-receptor complex stabilizes the closed, low-affinity conformation. By contrast, an additional lateral force applied to the beta subunit to mimic attachment to moving actin filaments stabilizes the open, high-affinity conformation. This mechanism propagates allostery over long distances and couples cytoskeleton attachment of integrins to their high-affinity state. C1 [Zhu, Jianghai; Luo, Bing-Hao; Xiao, Tsan; Zhang, Chengzhong; Nishida, Noritaka; Springer, Timothy A.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Zhu, Jianghai; Luo, Bing-Hao; Xiao, Tsan; Zhang, Chengzhong; Nishida, Noritaka; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, 200 Longwood Ave, Boston, MA 02115 USA. EM springer@idi.harvard.edu RI Xiao, Tsan/A-8590-2010; Nishida, Noritaka/E-7087-2010; Xiao, Tsan/I-7616-2013; Zhu, Jianghai/B-7339-2014 OI Xiao, Tsan/0000-0001-9688-475X; FU NIH [HL-48675]; NSF Teragrid [TG-MCB080088T] FX Supported by NIH grant HL-48675 and NSF Teragrid allocation TG-MCB080088T. We thank Junichi Takagi for a critical review of the manuscript. NR 47 TC 233 Z9 237 U1 1 U2 19 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 DEC 26 PY 2008 VL 32 IS 6 BP 849 EP 861 DI 10.1016/j.molcel.2008.11.018 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 390SO UT WOS:000262184200014 PM 19111664 ER PT J AU Fan, BJ Chen, T Grosskreutz, C Pasquale, L Rhee, D DelBono, E Haines, JL Wiggs, JL AF Fan, Bao Jian Chen, Teresa Grosskreutz, Cynthia Pasquale, Louis Rhee, Douglas DelBono, Elizabeth Haines, Jonathan L. Wiggs, Janey L. TI Lack of association of polymorphisms in homocysteine metabolism genes with pseudoexfoliation syndrome and glaucoma SO MOLECULAR VISION LA English DT Article ID OPEN-ANGLE GLAUCOMA; METHYLENETETRAHYDROFOLATE REDUCTASE GENE; COMMON SEQUENCE VARIANTS; LOXL1 GENE; EXFOLIATION GLAUCOMA; JAPANESE POPULATION; C677T VARIANT; UNITED-STATES; MUTATIONS; LINKAGE AB Purpose: To evaluate genes involved in homocysteine metabolism as secondary risk factors for pseudoexfoliation syndrome (PXFS) and the associated glaucoma (PXFG). Methods: One hundred eighty-six unrelated patients with PXFS, including 140 patients with PXFG and 127 unrelated control subjects were recruited from the Massachusetts Eye and Ear Infirmary. All the patients and controls were Caucasian of European ancestry. Seventeen tag SNPs from 5 genes (methylenetetrahydrofolate reductase [MTHFR], methionine synthase [MTR], methionine synthase reductase [MTRR], methylenetetrahydrofolate dehydrogenase [MTHFD1], and cystathionine beta-synthase [CBS]) were genotyped. Single-SNP association was analyzed using Fisher's exact test (unconditional) or logistic regression after conditioning on the effects of age and three LOXL1 SNPs (rs1048661, rs3825942, and rs2165241). Interaction analysis was performed between the homocysteine and LOXL1 SNPs using logistic regression. Haplotype analysis and the set-based test were used to test for association of individual genes. Multiple comparisons were corrected using the Bonferroni method. Results: One SNP (rs8006686) in MTHFD1 showed a nominally significant association with PXFG (p=0.015, OR=2.23). None of the seventeen SNPs tested were significantly associated with PXFS or PXFG after correcting for multiple comparisons (Bonferroni corrected p>0.25). After controlling for the effects of age and three associated LOXL1 SNPs, none of the seventeen tested SNPs were associated with PXFS (p>0.12). No significant interaction effects on PXFS were identified between the homocysteine and LOXL1 SNPs (p>0.06). Haplotype analysis and the set-based test did not find significant association of individual genes with PXFS (p>0.23 and 0.20, respectively). Conclusions: Five genes that are critical components of the homocysteine metabolism pathway were evaluated as secondary factors for PXFS and PXFG. Our results suggest that these genes are not significant risk factors for the development of these conditions. C1 [Fan, Bao Jian; Chen, Teresa; Grosskreutz, Cynthia; Pasquale, Louis; Rhee, Douglas; DelBono, Elizabeth; Wiggs, Janey L.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Haines, Jonathan L.] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. RP Wiggs, JL (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM janey_wiggs@meei.harvard.edu RI Haines, Jonathan/C-3374-2012; OI Fan, Baojian/0000-0002-6851-2737 FU NIH [EY015882, P30EY014104] FX This work was supported in part by NIH Grants EY015882 and P30EY014104. NR 44 TC 11 Z9 12 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD DEC 26 PY 2008 VL 14 IS 283-88 BP 2484 EP 2491 PG 8 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 414IS UT WOS:000263857700004 PM 19112534 ER PT J AU Cestari, DM Metson, RB Cunnane, ME Faquin, WC Savar, A Murali, MR AF Cestari, Dean M. Metson, Ralph B. Cunnane, Mary E. Faquin, William C. Savar, Aaron Murali, Mandakolathur R. TI Case 40-2008: A 26-Year-Old Man with Blurred Vision SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ALLERGIC FUNGAL SINUSITIS; CHRONIC RHINOSINUSITIS C1 [Cestari, Dean M.] Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Metson, Ralph B.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Cunnane, Mary E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Faquin, William C.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cestari, Dean M.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Metson, Ralph B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Cunnane, Mary E.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Faquin, William C.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cestari, DM (reprint author), Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. NR 13 TC 4 Z9 4 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 25 PY 2008 VL 359 IS 26 BP 2825 EP 2833 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 387KJ UT WOS:000261950800012 PM 19109578 ER PT J AU Spandidos, A Wang, XW Wang, HJ Dragnev, S Thurber, T Seed, B AF Spandidos, Athanasia Wang, Xiaowei Wang, Huajun Dragnev, Stefan Thurber, Tara Seed, Brian TI A comprehensive collection of experimentally validated primers for Polymerase Chain Reaction quantitation of murine transcript abundance SO BMC GENOMICS LA English DT Article ID REAL-TIME PCR; SYBR-GREEN-I; COPY-NUMBER VARIANTS; RT-PCR; ENZYMATIC AMPLIFICATION; OLIGONUCLEOTIDE PROBES; DNA AMPLIFICATION; HUMAN GENOME; BETA-GLOBIN; FLUORESCENCE AB Background: Quantitative polymerase chain reaction (QPCR) is a widely applied analytical method for the accurate determination of transcript abundance. Primers for QPCR have been designed on a genomic scale but non-specific amplification of non-target genes has frequently been a problem. Although several online databases have been created for the storage and retrieval of experimentally validated primers, only a few thousand primer pairs are currently present in existing databases and the primers are not designed for use under a common PCR thermal profile. Results: We previously reported the implementation of an algorithm to predict PCR primers for most known human and mouse genes. We now report the use of that resource to identify 17483 pairs of primers that have been experimentally verified to amplify unique sequences corresponding to distinct murine transcripts. The primer pairs have been validated by gel electrophoresis, DNA sequence analysis and thermal denaturation profile. In addition to the validation studies, we have determined the uniformity of amplification using the primers and the technical reproducibility of the QPCR reaction using the popular and inexpensive SYBR Green I detection method. Conclusion: We have identified an experimentally validated collection of murine primer pairs for PCR and QPCR which can be used under a common PCR thermal profile, allowing the evaluation of transcript abundance of a large number of genes in parallel. This feature is increasingly attractive for confirming and/or making more precise data trends observed from experiments performed with DNA microarrays. C1 [Spandidos, Athanasia; Wang, Xiaowei; Wang, Huajun; Dragnev, Stefan; Thurber, Tara; Seed, Brian] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Spandidos, Athanasia; Wang, Xiaowei; Wang, Huajun; Dragnev, Stefan; Thurber, Tara; Seed, Brian] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. [Wang, Xiaowei] Washington Univ, Sch Med, Dept Radiat Oncol, Div Bioinformat & Outcomes Res, St Louis, MO 63110 USA. [Dragnev, Stefan] Idearc Media Corp, Waltham, MA 02451 USA. RP Seed, B (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. EM aspandidos@ccib.mgh.harvard.edu; xwang@radonc.wustl.edu; hwang@ccib.mgh.harvard.edu; dragnev@molbio.mgh.harvard.edu; tthurber@ccib.mgh.harvard.edu; bseed@ccib.mgh.harvard.edu FU National Institutes of Health [U01 HL66678] FX We thank our colleagues Chen Liu and Don Dwoske for their technical help, the Automation, Synthesis and Sequencing Core labs of Center for Computational and Integrative Biology at Massachusetts General Hospital for their contributions and Naifang Lu for the 129 ES cell mouse genomic DNA. This work was supported by the National Institutes of Health Program for Genomic Applications, grant U01 HL66678. NR 59 TC 82 Z9 82 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 24 PY 2008 VL 9 AR 633 DI 10.1186/1471-2164-9-633 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 403VP UT WOS:000263110400001 PM 19108745 ER PT J AU Binshtok, AM Wang, H Zimmermann, K Amaya, F Vardeh, D Shi, L Brenner, GJ Ji, RR Bean, BP Woolf, CJ Samad, TA AF Binshtok, Alexander M. Wang, Haibin Zimmermann, Katharina Amaya, Fumimasa Vardeh, Daniel Shi, Lin Brenner, Gary J. Ji, Ru-Rong Bean, Bruce P. Woolf, Clifford J. Samad, Tarek A. TI Nociceptors Are Interleukin-1 beta Sensors SO JOURNAL OF NEUROSCIENCE LA English DT Article DE nociception; inflammation; interleukin; excitability; sodium channel; dorsal root ganglion ID DORSAL-ROOT GANGLION; RESISTANT NA+ CURRENT; SODIUM-CHANNEL NA(V)1.8; NECROSIS-FACTOR-ALPHA; PROTEIN-KINASE-C; TETRODOTOXIN-RESISTANT; SLOW INACTIVATION; DRG NEURONS; PROINFLAMMATORY CYTOKINES; INFLAMMATORY PAIN AB A cardinal feature of inflammation is heightened pain sensitivity at the site of the inflamed tissue. This results from the local release by immune and injured cells of nociceptor sensitizers, including prostaglandin E(2), bradykinin, and nerve growth factor, that reduce the threshold and increase the excitability of the peripheral terminals of nociceptors so that they now respond to innocuous stimuli: the phenomenon of peripheral sensitization. We show here that the proinflammatory cytokine interleukin-1 beta (IL-1 beta), in addition to producing inflammation and inducing synthesis of several nociceptor sensitizers, also rapidly and directly activates nociceptors to generate action potentials and induce pain hypersensitivity. IL-1 beta acts in a p38 mitogen-activated protein kinase ( p38 MAP kinase)-dependent manner, to increase the excitability of nociceptors by relieving resting slow inactivation of tetrodotoxin-resistant voltage-gated sodium channels and also enhances persistent TTX-resistant current near threshold. By acting as an IL-1 beta sensor, nociceptors can directly signal the presence of ongoing tissue inflammation. C1 [Samad, Tarek A.] Wyeth Res, Neurosci Discovery, Pain Mol Neurobiol Grp, Princeton, NJ 08852 USA. [Binshtok, Alexander M.; Wang, Haibin; Amaya, Fumimasa; Vardeh, Daniel; Shi, Lin; Brenner, Gary J.; Woolf, Clifford J.; Samad, Tarek A.] Massachusetts Gen Hosp, Neural Plast Res Grp, Charlestown, MA 02129 USA. [Binshtok, Alexander M.; Wang, Haibin; Amaya, Fumimasa; Vardeh, Daniel; Shi, Lin; Brenner, Gary J.; Woolf, Clifford J.; Samad, Tarek A.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Zimmermann, Katharina] Harvard Univ, Sch Med, Childrens Hosp, Dept Cardiol,Howard Hughes Med Inst, Boston, MA 02115 USA. [Zimmermann, Katharina] Harvard Univ, Sch Med, Childrens Hosp, Dept Neurobiol, Boston, MA 02115 USA. [Ji, Ru-Rong] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Pain Res Ctr, Boston, MA 02115 USA. RP Samad, TA (reprint author), Wyeth Res, Neurosci Discovery, Pain Mol Neurobiol Grp, 865 Ridge Rd, Princeton, NJ 08852 USA. EM samadt@wyeth.com OI Zimmermann, Katharina/0000-0003-2529-0692 FU National Institutes of Health FX This work was supported by the National Institutes of Health (C.J.W.). We thank Dr. Huijuan Hu for helpful discussion. NR 52 TC 198 Z9 205 U1 0 U2 15 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 DEC 24 PY 2008 VL 28 IS 52 BP 14062 EP 14073 DI 10.1523/JNEUROSCI.3795-08.2008 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 387XW UT WOS:000261985900006 PM 19109489 ER PT J AU Koenigsknecht-Talboo, J Meyer-Luehmann, M Parsadanian, M Garcia-Alloza, M Finn, MB Hyman, BT Bacskai, BJ Holtzman, DM AF Koenigsknecht-Talboo, Jessica Meyer-Luehmann, Melanie Parsadanian, Maia Garcia-Alloza, Monica Finn, Mary Beth Hyman, Bradley T. Bacskai, Brian J. Holtzman, David M. TI Rapid Microglial Response Around Amyloid Pathology after Systemic Anti-A beta Antibody Administration in PDAPP Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE microglia; beta-amyloid; passive immunization; Alzheimer's disease; neuritic plaques; cerebral amyloid angiopathy ID PROTEIN TRANSGENIC MICE; ALZHEIMERS-DISEASE; IN-VIVO; MOUSE MODEL; PRECURSOR PROTEIN; MEDIATED CLEARANCE; PLAQUE-FORMATION; IMMUNOTHERAPY; ANGIOPATHY; MECHANISMS AB Aggregation of amyloid-beta (A beta) peptide in the brain in the form of neuritic plaques and cerebral amyloid angiopathy (CAA) is a key feature of Alzheimer's disease (AD). Microglial cells surround aggregated A beta and are believed to play a role in AD pathogenesis. A therapy for AD that has entered clinical trials is the administration of anti-A beta antibodies. One mechanism by which certain anti-A beta antibodies have been proposed to exert their effects is via antibody-mediated microglial activation. Whether, when, or to what extent microglial activation occurs after systemic administration of anti-A beta antibodies has not been fully assessed. We administered an anti-A beta antibody (m3D6) that binds aggregated A beta to PDAPP mice, an AD mouse model that was bred to contain fluorescent microglia. Three days after systemic administration of m3D6, there was a marked increase in both the number of microglial cells and processes per cell visualized in vivo by multiphoton microscopy. These changes required the Fc domain of m3D6 and were not observed with an antibody specific to soluble A beta. These findings demonstrate that some effects of antibodies that recognize aggregated A beta are rapid, involve microglia, and provide insight into the mechanism of action of a specific passive immunotherapy for AD. C1 [Koenigsknecht-Talboo, Jessica; Parsadanian, Maia; Finn, Mary Beth; Holtzman, David M.] Washington Univ, Dept Neurol, Sch Med, St Louis, MO 63110 USA. [Koenigsknecht-Talboo, Jessica; Parsadanian, Maia; Finn, Mary Beth; Holtzman, David M.] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA. [Meyer-Luehmann, Melanie; Garcia-Alloza, Monica; Hyman, Bradley T.; Bacskai, Brian J.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. RP Holtzman, DM (reprint author), Washington Univ, Dept Neurol, Sch Med, 660 S Euclid Ave,Campus Box 8111, St Louis, MO 63110 USA. EM holtzman@neuro.wustl.edu OI Meyer-Luehmann, Melanie/0000-0003-3661-2220 FU National Institutes of Health [F32 AG029044, NS32636]; Washington University [P30 NS057105]; Eli Lilly and Co. FX This work was supported by National Institutes of Health Grants F32 AG029044 and NS32636, a Neuroscience Blueprint Center Core Grant P30 NS057105 to Washington University, and Eli Lilly and Co. We thank E. Nolley and K. Hyrc for technical assistance. NR 42 TC 82 Z9 83 U1 0 U2 3 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 DEC 24 PY 2008 VL 28 IS 52 BP 14156 EP 14164 DI 10.1523/JNEUROSCI.4147-08.2008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 387XW UT WOS:000261985900015 PM 19109498 ER PT J AU Volpp, KG Loewenstein, G Troxel, AB Doshi, J Price, M Laskin, M Kimmel, SE AF Volpp, Kevin G. Loewenstein, George Troxel, Andrea B. Doshi, Jalpa Price, Maureen Laskin, Mitchell Kimmel, Stephen E. TI A test of financial incentives to improve warfarin adherence SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID ACUTE ISCHEMIC-STROKE; ATRIAL-FIBRILLATION; BLEEDING COMPLICATIONS; ANTITHROMBOTIC THERAPY; RANDOMIZED-TRIAL; RISK-FACTORS; ANTICOAGULATION; PREVENTION; BEHAVIOR; ASPIRIN AB Background: Sub-optimal adherence to warfarin places millions of patients at risk for stroke and bleeding complications each year. Novel methods are needed to improve adherence for warfarin. We conducted two pilot studies to determine whether a lottery-based daily financial incentive is feasible and improves warfarin adherence and anticoagulation control. Methods: Volunteers from the University of Pennsylvania Anticoagulation Management Center who had taken warfarin for at least 3 months participated in either a pilot study with a lottery with a daily expected value of $5 (N = 10) or a daily expected value of $3 (N = 10). All subjects received use of an Informedix Med-eMonitor (TM) System with a daily reminder feature. If subjects opened up their pill compartments appropriately, they were entered into a daily lottery with a 1 in 5 chance of winning $10 and a 1 in 100 chance of winning $100 (pilot 1) or a 1 in 10 chance of winning $10 and a 1 in 100 chance of winning $100 (pilot 2). The primary study outcome was proportion of incorrect warfarin doses. The secondary outcome was proportion of INR measurements not within therapeutic range. Within-subject pre-post comparisons were done of INR measurements with comparisons with either historic means or within-subject comparisons of incorrect warfarin doses. Results: In the first pilot, the percent of out-of-range INRs decreased from 35.0% to 12.2% during the intervention, before increasing to 42% post-intervention. The mean proportion of incorrect pills taken during the intervention was 2.3% incorrect pills, compared with a historic mean of 22% incorrect pill taking in this clinic population. Among the five subjects who also had MEMS cap adherence data from warfarin use in our prior study, mean incorrect pill taking decreased from 26% pre-pilot to 2.8% in the pilot. In the second pilot, the time out of INR range decreased from 65.0% to 40.4%, with the proportion of mean incorrect pill taking dropping to 1.6%. Conclusion: A daily lottery-based financial incentive demonstrated the potential for significant improvements in missed doses of warfarin and time out of INR range. Further testing should be done of this approach to determine its effectiveness and potential application to both warfarin and other chronic medications. C1 [Volpp, Kevin G.; Doshi, Jalpa] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Volpp, Kevin G.; Loewenstein, George; Troxel, Andrea B.; Doshi, Jalpa; Kimmel, Stephen E.] Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Doshi, Jalpa; Kimmel, Stephen E.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Doshi, Jalpa] Univ Penn, Wharton Sch, Dept Hlth Care Management, Philadelphia, PA 19104 USA. [Loewenstein, George] Carnegie Mellon Univ, Dept Social & Decis Sci, Pittsburgh, PA 15213 USA. [Troxel, Andrea B.; Price, Maureen; Kimmel, Stephen E.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Troxel, Andrea B.; Price, Maureen; Kimmel, Stephen E.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Laskin, Mitchell] Univ Penn, Hosp Univ Penn, Dept Pharm Serv, Philadelphia, PA 19104 USA. RP Volpp, KG (reprint author), Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. EM volpp70@mail.med.upenn.edu; gl20@andrew.cmu.edu; atroxel@mail.med.upenn.edu; jdoshi@mail.med.upenn.edu; maureenpprice@hotmail.com; mitchell.laskin@uphs.upenn.edu; stevek@mail.med.upenn.edu OI Troxel, Andrea/0000-0002-1393-3075 FU NHLBI [R01HL066176]; AHRQ [P01-HS11530]; VA HSRD; [P20RR020741] FX This work was supported by NHLBI R01HL066176 and AHRQ P01-HS11530. Dr. Kimmel is also supported by P20RR020741. Dr. Volpp was also supported by a Research Career Transition Award from VA HSR&D. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Dr. Kimmel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 36 TC 91 Z9 92 U1 4 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD DEC 23 PY 2008 VL 8 AR 272 DI 10.1186/1472-6963-8-272 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 404WT UT WOS:000263184400001 PM 19102784 ER PT J AU Atkins, BD Yoshida, S Pellman, D AF Atkins, Benjamin D. Yoshida, Satoshi Pellman, David TI Symmetry Breaking: Scaffold Plays Matchmaker for Polarity Signaling Proteins SO CURRENT BIOLOGY LA English DT Editorial Material ID CELL POLARITY; BUDDING-YEAST; CDC42P; PHOSPHORYLATION; LOCALIZATION; POLARIZATION; MECHANISM; PATHWAY; GTPASES; GROWTH C1 [Atkins, Benjamin D.; Yoshida, Satoshi; Pellman, David] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Pellman, David] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Atkins, BD (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM David_Pellman@dfci.harvard.edu RI Yoshida, Satoshi/C-5016-2011 NR 20 TC 2 Z9 2 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD DEC 23 PY 2008 VL 18 IS 24 BP R1130 EP R1132 DI 10.1016/j.cub.2008.11.005 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 389JW UT WOS:000262089700014 PM 19108767 ER PT J AU Zhou, DW Medoff, BD Chen, LF Li, LQ Zhang, XF Praskova, M Liu, M Landry, A Blumberg, RS Boussiotis, VA Xavier, R Avruch, J AF Zhou, Dawang Medoff, Benjamin D. Chen, Lanfen Li, Lequn Zhang, Xian-feng Praskova, Maria Liu, Matthew Landry, Aimee Blumberg, Richard S. Boussiotis, Vassiliki A. Xavier, Ramnik Avruch, Joseph TI The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naive T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Mob1; Mst1 knockout; RAPL; hippo; Stk4 ID TUMOR-SUPPRESSOR; HIPPO PATHWAY; PROMOTES APOPTOSIS; DENDRITIC CELL; PROTEIN-KINASE; SIZE-CONTROL; ACTIVATION; DROSOPHILA; GROWTH; MST1 AB The Mst1 and Mst2 protein kinases are the mammalian homologs of hippo, a major inhibitor of cell proliferation in Drosophila. Mst1 is most abundant in lymphoid tissues. Mice lacking Mst1 exhibit markedly reduced levels of the Mst1 regulatory protein Nore1B/RAPL in lymphoid cells, whereas Mst2 abundance is unaltered. Mst1-null mice exhibit normal T cell development but low numbers of mature naive T cells with relatively normal numbers of effector/memory T cells. In vitro, the Mst1-deficient naive T cells exhibit markedly greater proliferation in response to stimulation of the T cell receptor whereas the proliferative responses of the Mst1-null effector/memory T cell cohort is similar to wild type. Thus, elimination of Mst1 removes a barrier to the activation and proliferative response of naive T cells. The levels of Mst1 and Nore1B/RAPL in wild-type effector/memory T cells are approximately 10% those seen in wild-type naive T cells, which may contribute to the enhanced proliferative responses of the former. Freshly isolated Mst1-null T cells exhibit high rates of ongoing apoptosis, a likely basis for their low numbers in vivo; they also exhibit defective clustering of LFA-1, as previously observed for Nore1B/RAPL-deficient T cells. Among known Mst1 substrates, only the phosphorylation of the cell cycle inhibitory proteins MOBKL1A/B is lost entirely in TCR-stimulated, Mst1-deficient T cells. Mst1/2-catalyzed MOBKL1A/B phosphorylation slows proliferation and is therefore a likely contributor to the anti-proliferative action of Mst1 in naive T cells. The Nore1B/RAPL-Mst1 complex is a negative regulator of naive T cell proliferation. C1 [Zhou, Dawang; Zhang, Xian-feng; Praskova, Maria; Liu, Matthew; Avruch, Joseph] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Chen, Lanfen; Blumberg, Richard S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Gastroenterol Hepatol & Endoscopy,Dept Med, Boston, MA 02114 USA. [Li, Lequn; Boussiotis, Vassiliki A.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Serv, Boston, MA 02114 USA. [Landry, Aimee; Xavier, Ramnik] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Medoff, Benjamin D.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Boussiotis, Vassiliki A.] Massachusetts Gen Hosp, Units Med Serv, Boston, MA 02114 USA. RP Avruch, J (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, 185 Cambridge St, Boston, MA 02114 USA. EM avruch@molbio.mgh.harvard.edu RI Chen, Lanfen/B-7975-2016; OI Chen, Lanfen/0000-0002-9413-1284; Zhou, Dawang/0000-0002-9053-5249 FU National Institutes of Health FX We thank R. Gerzsten and S. Pillai for discussion and advice and H. Lu, E. Mizoguchi, Y. Yin, R. Tyszkowski, and S. Sinha for technical support. J.A. is grateful to Brian Seed for important suggestions. Support from the National Institutes of Health (to R. S. B., V. B., and J. A.) is acknowledged. NR 41 TC 63 Z9 64 U1 2 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 23 PY 2008 VL 105 IS 51 BP 20321 EP 20326 DI 10.1073/pnas.0810773105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 388BP UT WOS:000261995600056 PM 19073936 ER PT J AU Luo, B Cheung, HW Subramanian, A Sharifnia, T Okamoto, M Yang, XP Hinkle, G Boehm, JS Beroukhim, R Weir, BA Mermel, C Barbie, DA Awad, T Zhou, XC Nguyen, TY Piqani, B Li, C Golub, TR Meyerson, M Hacohen, N Hahn, WC Lander, ES Sabatini, DM Root, DE AF Luo, Biao Cheung, Hiu Wing Subramanian, Aravind Sharifnia, Tanaz Okamoto, Michael Yang, Xiaoping Hinkle, Greg Boehm, Jesse S. Beroukhim, Rameen Weir, Barbara A. Mermel, Craig Barbie, David A. Awad, Tarif Zhou, Xiaochuan Nguyen, Tuyen Piqani, Bruno Li, Cheng Golub, Todd R. Meyerson, Matthew Hacohen, Nir Hahn, William C. Lander, Eric S. Sabatini, David M. Root, David E. TI Highly parallel identification of essential genes in cancer cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE oncogene; pooled library; RNAi; screen; shRNA ID MAMMALIAN SWI/SNF COMPLEXES; LENTIVIRAL RNAI LIBRARY; LUNG-CANCER; TOPOISOMERASE-II; EGFR MUTATIONS; BREAST-CANCER; PROTEIN; SCREEN; RESISTANCE; ETOPOSIDE AB More complete knowledge of the molecular mechanisms underlying cancer will improve prevention, diagnosis and treatment. Efforts such as The Cancer Genome Atlas are systematically characterizing the structural basis of cancer, by identifying the genomic mutations associated with each cancer type. A powerful complementary approach is to systematically characterize the functional basis of cancer, by identifying the genes essential for growth and related phenotypes in different cancer cells. Such information would be particularly valuable for identifying potential drug targets. Here, we report the development of an efficient, robust approach to perform genome-scale pooled shRNA screens for both positive and negative selection and its application to systematically identify cell essential genes in 12 cancer cell lines. By integrating these functional data with comprehensive genetic analyses of primary human tumors, we identified known and putative oncogenes such as EGFR, KRAS, MYC, BCR-ABL, MYB, CRKL, and CDK4 that are essential for cancer cell proliferation and also altered in human cancers. We further used this approach to identify genes involved in the response of cancer cells to tumoricidal agents and found 4 genes required for the response of CML cells to imatinib treatment: PTPN1, NF1, SMARCB1, and SMARCE1, and 5 regulators of the response to FAS activation, FAS, FADD, CASP8, ARID1A and CBX1. Broad application of this highly parallel genetic screening strategy will not only facilitate the rapid identification of genes that drive the malignant state and its response to therapeutics but will also enable the discovery of genes that participate in any biological process. C1 [Luo, Biao; Cheung, Hiu Wing; Subramanian, Aravind; Sharifnia, Tanaz; Okamoto, Michael; Yang, Xiaoping; Hinkle, Greg; Boehm, Jesse S.; Beroukhim, Rameen; Weir, Barbara A.; Mermel, Craig; Barbie, David A.; Nguyen, Tuyen; Piqani, Bruno; Golub, Todd R.; Meyerson, Matthew; Hacohen, Nir; Hahn, William C.; Lander, Eric S.; Sabatini, David M.; Root, David E.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Zhou, Xiaochuan] Atact Technol Inc, Houston, TX 77054 USA. [Awad, Tarif] Affymetrix Inc, Santa Clara, CA 95051 USA. [Cheung, Hiu Wing; Beroukhim, Rameen; Weir, Barbara A.; Mermel, Craig; Barbie, David A.; Meyerson, Matthew; Hahn, William C.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Cheung, Hiu Wing; Beroukhim, Rameen; Weir, Barbara A.; Mermel, Craig; Barbie, David A.; Golub, Todd R.; Meyerson, Matthew; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Cheung, Hiu Wing; Beroukhim, Rameen; Weir, Barbara A.; Mermel, Craig; Barbie, David A.; Golub, Todd R.; Meyerson, Matthew; Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Golub, Todd R.; Sabatini, David M.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Lander, Eric S.; Sabatini, David M.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Lander, Eric S.; Sabatini, David M.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Li, Cheng] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Lander, ES (reprint author), Broad Inst MIT & Harvard, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM lander@broad.mit.edu; droot@broad.mit.edu RI Meyerson, Matthew/E-7123-2012; OI Boehm, Jesse/0000-0002-6795-6336 FU RNAi Consortium (TRC); Academia Sinica; Bristol-Myers Squibb; Ontario Institute for Cancer Research; Sigma-Aldrich; Croucher Foundation FX We thank Preeti Gupta and Mike Mittman for assistance with Affymetrix microarray design; Jinyan Du, Casey Gates, Leigh Brody, Nathan Berkowitz, Neelum Khattak, Daniel Lam, Brian Wong, Jordi Barretina, and Cindy Nguyen for technical assistance and materials; and Pablo Tamayo, Preeti Gupta, Mike Mittman, Serena Silver, Jennifer Grenier, and Glenn Cowley for helpful discussions. This work is a project of The RNAi Consortium (TRC), financially supported by past and present consortium members: Academia Sinica, Bristol-Myers Squibb, Broad Institute, Eli Lilly, Novartis, Ontario Institute for Cancer Research, and Sigma-Aldrich. H. W. C. was supported by the Croucher Foundation. NR 41 TC 244 Z9 251 U1 4 U2 22 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 DEC 23 PY 2008 VL 105 IS 51 BP 20380 EP 20385 DI 10.1073/pnas.0810485105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 388BP UT WOS:000261995600066 PM 19091943 ER PT J AU Brooks, DG Ha, SJ Elsaesser, H Sharpe, AH Freeman, GJ Oldstone, MBA AF Brooks, David G. Ha, Sang-Jun Elsaesser, Heidi Sharpe, Arlene H. Freeman, Gordon J. Oldstone, Michael B. A. TI IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE T-cell exhaustion; virus persistence; functional restoration; immune regulation; immunosuppression ID HEPATITIS-C-VIRUS; INTERLEUKIN-10 RECEPTOR; DEFICIENT MICE; CLEARANCE; RESPONSES; EXHAUSTION; EXPRESSION; BLOCKING; REPLICATION; LYMPHOCYTES AB Suppression of T-cell responses by host-derived regulatory factors is a key event leading to viral persistence. Antibody blockade of either IL-10 or programmed death-ligand 1 (PD-L1) during viral persistence enhances T-cell function and reduces viral titers. Because blockade of these immunoregulatory networks represents a powerful approach to establish immune control during persistent infection, it is important to determine whether these immunoinhibitory factors act independently or jointly and if combined blockade of these factors further enhances T-cell immunity and viral clearance. Herein, we demonstrate that the IL-10 and PD-L1 immunosuppressive pathways are mechanistically distinct. As a result, simultaneous blockade of IL-10 and PD-L1 was significantly more effective in restoring antiviral T-cell responses than blockade of either alone, and led to substantially enhanced control of an established persistent viral infection. Thus, combinatorial blockade of multiple immune-regulatory molecules may ultimately restore the T-cell responses required to tip the balance from viral persistence to immune-mediated control or elimination of persistent infection. C1 [Brooks, David G.] Univ Calif Los Angeles, David Geffen Sch Med, UCLA AIDS Inst, Los Angeles, CA 90095 USA. [Brooks, David G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA 90095 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Dept Med, Boston, MA 02115 USA. [Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Sharpe, Arlene H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ha, Sang-Jun] Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Ha, Sang-Jun] Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Elsaesser, Heidi; Oldstone, Michael B. A.] Scripps Res Inst, Dept Infectol, La Jolla, CA 92037 USA. [Elsaesser, Heidi; Oldstone, Michael B. A.] Scripps Res Inst, Dept Immunol & Microbial Sci, Viral Immunobiol Lab, La Jolla, CA 92037 USA. RP Brooks, DG (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA 90095 USA. EM dbrooks@em.ucla.edu; mbaobo@scripps.edu OI Ha, Sang-Jun/0000-0002-1192-6031 FU National Institutes of Health [AI077012, AI009484, AI045927, P01 AI056299, R37 AI038310]; Korean Engineering and Science Foundation FX This is publication number 19361 from the Viral Immunobiology Laboratory, Department of Immunology and Microbial Sciences at The Scripps Research Institute. This work was supported by National Institutes of Health Grants AI077012 (to D. G. B.), AI009484, AI045927 (to M.B.A.O.), P01 AI056299 (to A. H. S. and G.J.F.), R37 AI038310 (to A.H.S.), and a postdoctoral fellowship from the Korean Engineering and Science Foundation (to S-J.H.). NR 36 TC 94 Z9 97 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 23 PY 2008 VL 105 IS 51 BP 20428 EP 20433 DI 10.1073/pnas.0811139106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 388BP UT WOS:000261995600074 PM 19075244 ER PT J AU Mandal, AK Jones, PB Bair, AM Christmas, P Miller, D Yamin, TTD Wisniewski, D Menke, J Evans, JF Hyman, BT Bacskai, B Chen, M Lee, DM Nikolic, B Soberman, RJ AF Mandal, Asim K. Jones, Phillip B. Bair, Angela M. Christmas, Peter Miller, Douglas Yamin, Ting-ting D. Wisniewski, Douglas Menke, John Evans, Jilly F. Hyman, Bradley T. Bacskai, Brian Chen, Mei Lee, David M. Nikolic, Boris Soberman, Roy J. TI The nuclear membrane organization of leukotriene synthesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE inflammation; multiprotein complex; 5-lipoxygenase; 5-lipoxygenase-activating protein ID 5-LIPOXYGENASE-ACTIVATING PROTEIN; POLYMORPHONUCLEAR LEUKOCYTES; SIGNALING COMPLEXES; HUMAN-NEUTROPHILS; CRYSTAL-STRUCTURE; C-4 SYNTHASE; B-4; IDENTIFICATION; BIOSYNTHESIS; LOCALIZATION AB Leukotrienes (LTs) are signaling molecules derived from arachidonic acid that initiate and amplify innate and adaptive immunity. In turn, how their synthesis is organized on the nuclear envelope of myeloid cells in response to extracellular signals is not understood. We define the supramolecular architecture of LT synthesis by identifying the activation-dependent assembly of novel multiprotein complexes on the outer and inner nuclear membranes of mast cells. These complexes are centered on the integral membrane protein 5-Lipoxygenase-Activating Protein, which we identify as a scaffold protein for 5-Lipoxygenase, the initial enzyme of LT synthesis. We also identify these complexes in mouse neutrophils isolated from inflamed joints. Our studies reveal the macromolecular organization of LT synthesis. C1 [Mandal, Asim K.; Bair, Angela M.; Christmas, Peter; Nikolic, Boris; Soberman, Roy J.] Massachusetts Gen Hosp, Renal Unit, Charlestown, MA 02129 USA. [Jones, Phillip B.; Hyman, Bradley T.; Bacskai, Brian] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Jones, Phillip B.; Hyman, Bradley T.; Bacskai, Brian] Massachusetts Gen Hosp, Alzheimers Dis Res Lab, Charlestown, MA 02129 USA. [Chen, Mei; Lee, David M.] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA. [Miller, Douglas; Yamin, Ting-ting D.; Wisniewski, Douglas; Menke, John; Evans, Jilly F.] Merck Res Labs, Rahway, NJ 07065 USA. RP Soberman, RJ (reprint author), Massachusetts Gen Hosp, Renal Unit, Bldg 149 Navy Yard,13th St, Charlestown, MA 02129 USA. EM Soberman@helix.mgh.harvard.edu OI Jones, Phillip/0000-0003-0525-6323 FU National Institutes of Health [R56 AI068771, R01 AI068771, 5R01 GM61823, 5P50 NS010828, 5R01 AG08487, 5R01 EB000768, R01 AI 059746, P01 AI065858, T32 DK001540]; Merck Research Labs, Rahway NJ; Merck and Merck Frosst; Fidelity Foundation; Arthritis Foundation Fellowship FX The authors would like to thank Drs. Marty Springer (Merck Research Labs) and Bob Young, Merck Frosst, Canada, for their support. The work was supported by R56 AI068771 and R01 AI068771, 5R01 GM61823 (AM, AMB, BN, PC, and RJS); 5P50 NS010828 (PJ); 5R01 AG08487 (BH); 5R01 EB000768 (BB); and R01 AI 059746 and P01 AI065858 (DML and MC) T32 DK001540 (A. M. B.) from the National Institutes of Health. Grants from Merck Research Labs, Rahway NJ (PC) and a charitable gift from Merck and Merck Frosst (RJS); and a grant form the Fidelity Foundation (BH), and an Arthritis Foundation Fellowship (MC). NR 32 TC 43 Z9 45 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 23 PY 2008 VL 105 IS 51 BP 20434 EP 20439 DI 10.1073/pnas.0808211106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 388BP UT WOS:000261995600075 PM 19075240 ER PT J AU Parkkonen, L Andersson, J Hamalainen, M Hari, R AF Parkkonen, Lauri Andersson, Jesper Hamalainen, Matti Hari, Riitta TI Early visual brain areas reflect the percept of an ambiguous scene SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bistable perception; frequency tagging; human; magnetoencephalography; visual system ID BINOCULAR-RIVALRY; CONSCIOUS PERCEPTION; COORDINATE SYSTEM; CORTICAL SURFACE; NEURAL ACTIVITY; CORTEX; ORGANIZATION; INFERENCE; FIGURES; VISION AB When a visual scene allows multiple interpretations, the percepts may spontaneously alternate despite the stable retinal image and the invariant sensory input transmitted to the brain. To study the brain basis of such multi-stable percepts, we superimposed rapidly changing dynamic noise as regional tags to the Rubin vase-face figure and followed the corresponding tag-related cortical signals with magnetoencephalography. The activity already in the earliest visual cortical areas, the primary visual cortex included, varied with the perceptual states reported by the observers. These percept-related modulations most likely reflect top-down influences that accentuate the neural representation of the perceived object in the early visual cortex and maintain the segregation of objects from the background. C1 [Parkkonen, Lauri; Andersson, Jesper; Hari, Riitta] Aalto Univ, Brain Res Unit, Low Temp Lab, FIN-02015 Helsinki, Finland. [Andersson, Jesper] Univ Oxford, John Radcliffe Hosp, Oxford Ctr Funct Magnet Resonance Imaging Brain, Oxford OX3 9DU, England. [Hamalainen, Matti] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hamalainen, Matti] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Hari, Riitta] Univ Helsinki, Cent Hosp, Dept Clin Neurophysiol, FIN-00290 Helsinki, Finland. RP Parkkonen, L (reprint author), Aalto Univ, Brain Res Unit, Low Temp Lab, FIN-02015 Helsinki, Finland. EM lauri@neuro.hut.fi; hari@neuro.hut.fi RI Parkkonen, Lauri/G-6755-2012; Hamalainen, Matti/C-8507-2013; Hari, Riitta/J-1880-2012 OI Parkkonen, Lauri/0000-0002-0130-0801; Hari, Riitta/0000-0002-3142-2703 FU Academy of Finland (National Centers of Excellence Program 2006-2011); Finnish Cultural Foundation; Sigrid Juselius Foundation; The Center for Functional Neuroimaging Technologies National Institutes of Health [P41 RR14075] FX We thank Simo Vanni, Topi Tanskanen, and Catherine Nangini for discussions and comments on the manuscript; Gregory Appelbaum for discussions; and Jari Kainulainen and Veli-Matti Saarinen for help in the measurements. This work was supported by the Academy of Finland (National Centers of Excellence Program 2006-2011), the Finnish Cultural Foundation, and the Sigrid Juselius Foundation, and The Center for Functional Neuroimaging Technologies National Institutes of Health Grant P41 RR14075. NR 32 TC 27 Z9 28 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 23 PY 2008 VL 105 IS 51 BP 20500 EP 20504 DI 10.1073/pnas.0810966105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 388BP UT WOS:000261995600086 PM 19074267 ER PT J AU Cannon, CP AF Cannon, Christopher P. TI Mixed Dyslipidemia, Metabolic Syndrome, Diabetes Mellitus, and Cardiovascular Disease: Clinical Implications SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; DENSITY-LIPOPROTEIN SIZE; PRIOR MYOCARDIAL-INFARCTION; NONFASTING TRIGLYCERIDES; INSULIN-RESISTANCE; OLDER-ADULTS; RISK; MORTALITY; PREVALENCE; MEN AB Metabolic syndrome and type 2 diabetes mellitus are individually associated with increased cardiovascular risk; furthermore, the combination of metabolic syndrome with diabetes accentuates this risk. An atherogenic dyslipidemia characterized by elevated triglycerides, low high-density lipoprotein cholesterol, or both conditions is a key modifiable risk factor associated with both conditions. As the development of this atherogenic mixed dyslipidemia precedes the onset of overt glycemia and the clinical diagnosis of diabetes, early effective intervention is recommended to reduce the risk of premature cardiovascular disease morbidity and mortality. (c) 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102[suppl]:5L-9L) 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. RP Cannon, CP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM cpcannnon@partners.org FU Accumetrics; Astra Zeneca; Bristol-Myers Squibb; GlaxoSmithKline; Merck; sanofi-aventis; Schering Plough FX Christopher P. Cannon, MD, has received research grants from Accumetrics, Astra Zeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, sanofi-aventis and Schering Plough; before 2007, he received speaker honoraria froth Accumetrics, AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer Inc., sanofi-aventis and Schering Plough; was a consultant or advisory board member for Astra Zeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Pfizer Inc., sanofi-aventis and Schering Plough; has stock ownership and is a clinical advisor to Automedics Medical Systems. NR 36 TC 39 Z9 42 U1 0 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 DEC 22 PY 2008 VL 102 IS 12A BP 5L EP 9L DI 10.1016/j.amjcard.2008.09.067 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 391OG UT WOS:000262242000002 PM 19084083 ER PT J AU Wang, JH Alt, FW Gostissa, M Datta, A Murphy, M Alimzhanov, MB Coakley, KM Rajewsky, K Manis, JP Yan, CT AF Wang, Jing H. Alt, Frederick W. Gostissa, Monica Datta, Abhishek Murphy, Michael Alimzhanov, Marat B. Coakley, Kristen M. Rajewsky, Klaus Manis, John P. Yan, Catherine T. TI Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID DNA-LIGASE IV; END-JOINING PATHWAY; STRAND BREAK REPAIR; V(D)J RECOMBINATION; CHROMOSOMAL TRANSLOCATIONS; LYMPHOCYTE DEVELOPMENT; SOMATIC HYPERMUTATION; GENOMIC INSTABILITY; EMBRYONIC LETHALITY; ANTIBODY-RESPONSES AB Nonhomologous end-joining (NHEJ) repairs DNA double-strand breaks (DSBs) during V(D)J recombination in developing lymphocytes and during immunoglobulin (Ig) heavy chain (IgH) class switch recombination (CSR) in peripheral B lymphocytes. We now show that CD21-cre-mediated deletion of the Xrcc4 NHEJ gene in p53-deficient peripheral B cells leads to recurrent surface Ig-negative B lymphomas ("CXP lymphomas"). Remarkably, CXP lymphomas arise from peripheral B cells that had attempted both receptor editing (secondary V[D]J recombination of Ig kappa and Ig lambda light chain genes) and IgH CSR subsequent to Xrcc4 deletion. Correspondingly, CXP tumors frequently harbored a CSR-based reciprocal chromosomal translocation that fused IgH to c-myc, as well as large chromosomal deletions or translocations involving Ig kappa or Ig lambda, with the latter fusing Ig lambda to oncogenes or to IgH. Our findings reveal peripheral B cells that have undergone both editing and CSR and show them to be common progenitors of CXP tumors. Our studies also reveal developmental stage-specific mechanisms of c-myc activation via IgH locus translocations. Thus, Xrcc4/p53-deficient pro-B lymphomas routinely activate c-myc by gene amplification, whereas Xrcc4/p53-deficient peripheral B cell lymphomas routinely ectopically activate a single c-myc copy. C1 [Wang, Jing H.; Alt, Frederick W.; Gostissa, Monica; Datta, Abhishek; Murphy, Michael; Coakley, Kristen M.; Yan, Catherine T.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Wang, Jing H.; Alt, Frederick W.; Gostissa, Monica; Datta, Abhishek; Murphy, Michael; Coakley, Kristen M.; Manis, John P.; Yan, Catherine T.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. [Wang, Jing H.; Alt, Frederick W.; Gostissa, Monica; Datta, Abhishek; Murphy, Michael; Alimzhanov, Marat B.; Coakley, Kristen M.; Rajewsky, Klaus; Yan, Catherine T.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Wang, Jing H.; Alt, Frederick W.; Gostissa, Monica; Datta, Abhishek; Murphy, Michael; Coakley, Kristen M.; Yan, Catherine T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Rajewsky, Klaus; Manis, John P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, 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) [5P01 CA92625]; NRSA [T32 CA7008]; Leukemia and Lymphoma Society (LLS); Howard Hughes Medical Institute FX This work was supported by National Institutes of Health (NIH) grants 5P01 CA92625 ( to F. W. Alt and K. Rajewsky), an NIH postdoctoral training grant NRSA T32 CA7008 ( to C. T. Yan), Leukemia and Lymphoma Society (LLS) senior fellowships ( to J.H. Wang and M. Gostissa), a LLS fellowship ( to A. Datta). F. W. Alt is an investigator for the Howard Hughes Medical Institute. NR 62 TC 52 Z9 59 U1 0 U2 2 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 DEC 22 PY 2008 VL 205 IS 13 BP 3079 EP 3090 DI 10.1084/jem.20082271 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 450VH UT WOS:000266428700014 PM 19064702 ER PT J AU Salthouse, C Hildebrand, S Weissleder, R Mahmood, U AF Salthouse, Christopher Hildebrand, Scott Weissleder, Ralph Mahmood, Umar TI Design and demonstration of a small-animal up-conversion imager SO OPTICS EXPRESS LA English DT Article ID IN-VIVO; UPCONVERTING NANOPHOSPHORS AB This first small-animal up-conversion imager (SAUCI) was developed and used for in-vivo imaging of up-converting nanoparticles (UCNs.) Unlike traditional fluorophores, UCNs absorb multiple lower-energy photons and emit a single higher-energy photon. This unique physical process makes it possible to image deeper into tissue with lower background signals. In vivo imaging of particle accumulation in the liver was demonstrated following intravenous injection of particles. (C) 2008 Optical Society of America C1 [Salthouse, Christopher; Hildebrand, Scott; Weissleder, Ralph; Mahmood, Umar] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. RP Mahmood, U (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, 149 13th St, Charlestown, MA 02129 USA. EM mahmood@helix.mgh.harvard.edu FU NIH [R01EB001872, U01-HL080731, T32EB002102] FX The authors would like to thank Fangwei Shao for her assistance in this work. This research was supported by NIH grants R01EB001872 "In vivo Multichannel Fluorescence Imaging", U01-HL080731 "Translational Program of Excellence in Nanotechnology", and T32EB002102 training grant "Postgraduate Program in Radiological Sciences." NR 11 TC 28 Z9 30 U1 0 U2 7 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD DEC 22 PY 2008 VL 16 IS 26 BP 21731 EP 21737 DI 10.1364/OE.16.021731 PG 7 WC Optics SC Optics GA 390YX UT WOS:000262200700061 PM 19104605 ER PT J AU Wu, HM Zhao, QY Berbeco, RI Nishioka, S Shirato, H Jiang, SB AF Wu, Huanmei Zhao, Qingya Berbeco, Ross I. Nishioka, Seiko Shirato, Hiroki Jiang, Steve B. TI Gating based on internal/external signals with dynamic correlation updates SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID EXTERNAL RESPIRATORY SURROGATES; GATED RADIOTHERAPY; LUNG-TUMORS; ORGAN MOTION; REAL-TIME; SIMULATION; DELIVERY; MARKERS AB Precise localization of mobile tumor positions in real time is critical to the success of gated radiotherapy. Tumor positions are usually derived from either internal or external surrogates. Fluoroscopic gating based on internal surrogates, such as implanted fiducial markers, is accurate however requiring a large amount of imaging dose. Gating based on external surrogates, such as patient abdominal surface motion, is non-invasive however less accurate due to the uncertainty in the correlation between tumor location and external surrogates. To address these complications, we propose to investigate an approach based on hybrid gating with dynamic internal/external correlation updates. In this approach, the external signal is acquired at high frequency (such as 30 Hz) while the internal signal is sparsely acquired (such as 0.5 Hz or less). The internal signal is used to validate and update the internal/external correlation during treatment. Tumor positions are derived from the external signal based on the newly updated correlation. Two dynamic correlation updating algorithms are introduced. One is based on the motion amplitude and the other is based on the motion phase. Nine patients with synchronized internal/external motion signals are simulated retrospectively to evaluate the effectiveness of hybrid gating. The influences of different clinical conditions on hybrid gating, such as the size of gating windows, the optimal timing for internal signal acquisition and the acquisition frequency are investigated. The results demonstrate that dynamically updating the internal/external correlation in or around the gating window will reduce false positive with relatively diminished treatment efficiency. This improvement will benefit patients with mobile tumors, especially greater for early stage lung cancers, for which the tumors are less attached or freely floating in the lung. C1 [Wu, Huanmei] Indiana Univ, IUPUI, Sch Informat, Purdue Sch Engn & Technol, Indianapolis, IN 46204 USA. [Zhao, Qingya] Purdue Univ, Sch Hlth Sci, W Lafayette, IN 47907 USA. [Berbeco, Ross I.] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Berbeco, Ross I.] Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Nishioka, Seiko] NTT East Japan Sapporo Hosp, Sapporo, Hokkaido, Japan. [Shirato, Hiroki] Hokkaido Univ, Grad Sch Med, Sapporo, Hokkaido, Japan. [Jiang, Steve B.] Univ Calif San Diego, Sch Med, Dept Radiat Oncol, San Diego, CA 92103 USA. RP Wu, HM (reprint author), Indiana Univ, IUPUI, Sch Informat, Purdue Sch Engn & Technol, Indianapolis, IN 46204 USA. EM hw9@iupui.edu; sbjiang@ucsd.edu RI Shirato, Hiroki/A-7068-2010 NR 21 TC 33 Z9 33 U1 0 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD DEC 21 PY 2008 VL 53 IS 24 BP 7137 EP 7150 DI 10.1088/0031-9155/53/24/009 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 378GW UT WOS:000261310200009 PM 19033643 ER PT J AU Lannen, PK Wolfe, J Prigerson, HG Onelov, E Kreicbergs, UC AF Lannen, Patrizia K. Wolfe, Joanne Prigerson, Holly G. Onelov, Erik Kreicbergs, Ulrika C. TI Unresolved Grief in a National Sample of Bereaved Parents: Impaired Mental and Physical Health 4 to 9 Years Later SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COMPLICATED GRIEF; TRAUMATIC GRIEF; DIAGNOSTIC-CRITERIA; GENDER-DIFFERENCES; DEPRESSION; CANCER; CHILD; RISK; MORTALITY; SYMPTOMS AB Purpose To assess unresolved parental grief, the associated long-term impact on mental and physical health, and health service use. Patients and Methods This anonymous, mail-in questionnaire study was performed as a population-based investigation in Sweden between August 2001 and October 2001. Four hundred forty-nine parents who lost a child as a result of cancer 4 to 9 years earlier completed the survey ( response rate, 80%). One hundred ninety-one ( 43%) of the bereaved parents were fathers, and 251 ( 56%) were mothers. Bereaved parents were asked whether or not, and to what extent, they had worked through their grief. They were also asked about their physical and psychological well-being. For outcomes of interest, we report relative risk ( RR) with 95% CIs as well as unadjusted odds ratios and adjusted odds ratios. Results Parents with unresolved grief reported significantly worsening psychological health ( fathers: RR, 3.6; 95% CI, 2.0 to 6.4; mothers: RR, 2.9; 95% CI, 1.9 to 4.4) and physical health ( fathers: RR, 2.8; 95% CI, 1.8 to 4.4; mothers: RR, 2.3; 95% CI, 1.6 to 3.3) compared with those who had worked through their grief. Fathers with unresolved grief also displayed a significantly higher risk of sleep difficulties ( RR, 6.7; 95% CI, 2.5 to 17.8). Mothers, however, reported increased visits with physicians during the previous 5 years ( RR, 1.7; 95% CI, 1.1 to 2.6) as well as a greater likelihood of taking sick leave when they had not worked through their grief ( RR, 2.1; 95% CI, 1.2 to 3.5). Conclusion Parents who have not worked through their grief are at increased risk of long-term mental and physical morbidity, increased health service use, and increased sick leave. C1 [Lannen, Patrizia K.] Univ Bern, Inst Social & Prevent Med, Dept Psychol, CH-3012 Bern, Switzerland. Childrens Hosp, Phyllis F Cantor Ctr, Dept Psychooncol & Palliat Care Res, Boston, MA 02115 USA. Childrens Hosp, Dept Pediat Oncol, Boston, MA 02115 USA. Childrens Hosp, Ctr Outcomes & Policy Res, Dana Farber Canc Inst, Boston, MA 02115 USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Karolinska Inst, Div Clin Canc Epidemiol, Stockholm, Sweden. Karolinska Inst, Dept Women & Childs Hlth, Stockholm, Sweden. RP Lannen, PK (reprint author), Univ Bern, Inst Social & Prevent Med, Dept Psychol, CH-3012 Bern, Switzerland. EM plannen@ispm.unibe.ch FU Swedish Children's Cancer Foundation; Swedish Society for Medical Research; Swiss Cancer League [KLS-01645-02-2005]; National Cancer Institute [CA096746]; Charles H. Hood Foundation [NCI 5 K07 CA096746] FX Supported by grants from the Swedish Children's Cancer Foundation, grants from the Swedish Society for Medical Research, Grant No. KLS-01645-02-2005 from the Swiss Cancer League, Grant No. CA096746 from the National Cancer Institute, and a Child Health Research Grant No. NCI 5 K07 CA096746 from the Charles H. Hood Foundation. NR 37 TC 50 Z9 50 U1 4 U2 16 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 DEC 20 PY 2008 VL 26 IS 36 BP 5870 EP 5876 DI 10.1200/JCO.2007.14.6738 PG 7 WC Oncology SC Oncology GA 385WF UT WOS:000261843600008 PM 19029425 ER PT J AU Peppercorn, J Burstein, H Miller, FG Winer, E Joffe, S AF Peppercorn, Jeffrey Burstein, Harold Miller, Franklin G. Winer, Eric Joffe, Steve TI Self-Reported Practices and Attitudes of US Oncologists Regarding Off-Protocol Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HIGH-DOSE CHEMOTHERAPY; BREAST-CANCER; CLINICAL-TRIALS; AMERICAN ONCOLOGISTS; PARTICIPATION; INTERFERON; DECISION; SOCIETY; DRUGS; VIEWS AB Purpose Investigational cancer therapies being tested in clinical trials may be available outside of trials, or off-protocol (OPRx). We evaluated the practices and attitudes among US oncologists with regard to this controversial practice. Methods We mailed an anonymous survey to a random sample of US medical oncologists evaluating frequency and prevalence of OPRx and evaluated the correlation between demographic factors, attitudes, and practice. Results One hundred forty-six (31%) of 471 oncologists responded. Ninety-three percent reported ever discussing and 81% ever prescribing OPRx. Academic oncologists were more likely than community oncologists to have ever provided OPRx (89% v 75%; P = .06), to discuss OPRx at least once/month (41% v 19%; P = .0004), and to deny requests for OPRx at least once/month (16% v 2%; P = .004). While 61% of oncologists believed that patients should be discouraged from OPRx, only 31% felt it should not be available. With regard to trial recruitment, 53% felt that informed consent requires discussion of OPRx, 34% disagree, and 26% feel that patients should be provided OPRx on request, while 56% disagree. There was lack of consensus on access to OPRx in scenarios based on open trials at the time of the survey, such as adjuvant trastuzumab, which 41% would provide, 59% would not. Conclusion US oncologists report common discussion and use of OPRx, but attitudes and practices may vary substantially. There is need for greater debate regarding OPRx in oncology, further definition of the ethical and clinical issues at stake, and development of guidelines in this area. C1 [Peppercorn, Jeffrey] Duke Univ, Med Ctr, Div Med Oncol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Durham, NC 27710 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NIH, Bethesda, MD 20892 USA. RP Peppercorn, J (reprint author), Duke Univ, Med Ctr, Div Med Oncol, Box 3446, Durham, NC 27710 USA. EM jeffrey.peppercorn@duke.edu OI Joffe, Steven/0000-0002-0667-7384 FU American Society of Clinical Oncology Foundation; Breast Cancer Research Foundation; Greenwall Foundation FX Supported by the American Society of Clinical Oncology Foundation (J.P.), Breast Cancer Research Foundation (J.P.), and by the Greenwall Foundation Faculty Scholars Program in Bioethics (J.P.) NR 24 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 20 PY 2008 VL 26 IS 36 BP 5994 EP 6000 DI 10.1200/JCO.2008.18.1420 PG 7 WC Oncology SC Oncology GA 385WF UT WOS:000261843600026 PM 19029413 ER PT J AU McMillan, P Korvatska, E Poorkaj, P Evstafjeva, Z Robinson, L Greenup, L Leverenz, J Schellenberg, GD D'Souza, I AF McMillan, Pamela Korvatska, Elena Poorkaj, Parvoneh Evstafjeva, Zana Robinson, Linda Greenup, Lynne Leverenz, James Schellenberg, Gerard D. D'Souza, Ian TI Tau Isoform Regulation Is Region- and Cell-Specific in Mouse Brain SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE splicing; phosphorylation; Alzheimer's disease; frontotemporal dementia; 3-repeat and 4-repeat tau; tauopathy ID PROGRESSIVE SUPRANUCLEAR PALSY; PAIRED HELICAL FILAMENTS; PARKINSONISM-DEMENTIA COMPLEX; ALZHEIMERS-DISEASE; MICROTUBULE-BINDING; PROTEIN-TAU; NEURODEGENERATIVE DISORDERS; CORTICOBASAL DEGENERATION; NEUROFIBRILLARY TANGLES; WHITE-MATTER AB Tau is a microtubule-associated protein implicated in neurodegenerative tauopathies. Alternative splicing of the tau gene (MAPT) generates six tau isoforms, distinguishable by the exclusion or inclusion of a repeat region of exon 10, which are referred to as 3-repeat (311) and 4-repeat (4R) tau, respectively. We developed transgenic mouse models that express the entire human MAPT gene in the presence and absence of the mouse Mapt gene and compared the expression and regulation of mouse and human tau isoforms during development and in the young adult. We found differences between mouse and human tau in the regulation of exon 10 inclusion. Despite these differences, the isoform splicing pattern seen in normal human brain is replicated in our mouse models. In addition, we found that all tau, both in the neonate and young adult, is phosphorylated. We also examined the normal anatomic distribution of mouse and human tau isoforms in mouse brain. We observed developmental and species-specific variations in the expression of 3R- and 4R-tau within the frontal cortex and hippocampus. In addition, there were differences in the cellular distribution of the isoforms. Mice transgenic for the human MAPT gene exhibited higher levels of neuronal cell body expression of tau compared to wildtype mice. This neuronal cell body expression of tau was limited to the 3R isoform, whereas expression of 4R-tau was more "synaptic like," with granular staining of neuropil rather than in neuronal cell bodies. These developmental and species-specific differences in the regulation and distribution of tau isoforms may be important to the understanding of normal and pathologic tau isoform expression. J. Comp. Neurol. 511:788-803, 2008. (C) 2008 Wiley-Liss, Inc. C1 [McMillan, Pamela; Korvatska, Elena; Evstafjeva, Zana; Robinson, Linda; Schellenberg, Gerard D.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Geriatr Ctr, Seattle, WA 98108 USA. [McMillan, Pamela; Poorkaj, Parvoneh; Greenup, Lynne; Leverenz, James] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [McMillan, Pamela; Greenup, Lynne; Leverenz, James] Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Leverenz, James; Schellenberg, Gerard D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Schellenberg, Gerard D.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Schellenberg, Gerard D.] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [D'Souza, Ian] Forest Res Inst, Seattle, WA 98103 USA. RP Schellenberg, GD (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Geriatr Ctr, 1660 S Columbian Ave, Seattle, WA 98108 USA. EM zachdad@u.washington.edu FU National Institute on Aging (NIA) [POI AG17586, R37 AG 11762-10]; American Health Assistance Foundatiom; Department of Veteran's Affairs FX Grant sponsor: National Institute on Aging (NIA); Grant numbers: POI AG17586 and R37 AG 11762-10; Grant sponsor: American Health Assistance Foundatiom Grant sponsor: Department of Veteran's Affairs. NR 86 TC 53 Z9 53 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD DEC 20 PY 2008 VL 511 IS 6 BP 788 EP 803 DI 10.1002/cne.21867 PG 16 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 371PB UT WOS:000260842300006 PM 18925637 ER PT J AU Mempel, TR Marangoni, F AF Mempel, Thorsten R. Marangoni, Francesco TI CD44 Keeps Tumor Killers Polarized SO IMMUNITY LA English DT Editorial Material ID T-CELL EXTRAVASATION AB In this issue of Immunity, Mrass et al. (2008) report that CD44 critically contributes to the stabilization of polarity in migrating cytotoxic T lymphocytes by anchoring cytoskeletal proteins to the cell membrane at their uropods. C1 [Mempel, Thorsten R.; Marangoni, Francesco] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Charlestown, MA 02129 USA. RP Mempel, TR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Charlestown, MA 02129 USA. EM tmempel@mgh.harvard.edu RI Marangoni, Francesco/I-9087-2012 OI Marangoni, Francesco/0000-0002-2490-849X NR 10 TC 1 Z9 2 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 DEC 19 PY 2008 VL 29 IS 6 BP 843 EP 845 DI 10.1016/j.immuni.2008.12.004 PG 3 WC Immunology SC Immunology GA 388IB UT WOS:000262012400004 PM 19100697 ER PT J AU Choi, YI Duke-Cohan, JS Ahmed, WB Handley, MA Mann, F Epstein, JA Clayton, LK Reinherz, EL AF Choi, Young I. Duke-Cohan, Jonathan S. Ahmed, Wesam B. Handley, Maris A. Mann, Fanny Epstein, Jonathan A. Clayton, Linda K. Reinherz, Ellis L. TI PlexinD1 Glycoprotein Controls Migration of Positively Selected Thymocytes into the Medulla SO IMMUNITY LA English DT Article ID T-CELL DIFFERENTIATION; LYMPHOID ORGAN DEVELOPMENT; EPITHELIAL-CELLS; PROGENITOR LOCALIZATION; THYMIC MEDULLA; CROSS-LINKING; SEMAPHORIN 3E; CHEMOKINE; RECEPTOR; EXPRESSION AB Precise intrathymic cell migration is important for thymocyte maturation and organ architecture. The orchestration of thymocyte trafficking, however, is not well understood at a molecular level. Here, we described highly regulated plexinD1 expression on CD4(+)CD8(+) double positive (DP) thymocytes. PlexinD1 expression was further affected by the engagement of T cell receptor complex. Activation of plexinD1 via the ligand, semaphorin 3E, repressed CCL25 chemokine signaling via its receptor CCR9 in CD69(+) thymocytes. In the absence of plexinD1, CD69(+) thymocytes remained in the cortex, maturing to form ectopic single positive (SP) thymocyte clusters in Plxnd1-deficient fetal liver cell-transplanted mice. As a consequence, the boundary between DID and SP thymocytes; at corticomedullary junctions was disrupted and medullary structures formed under the thymic capsule. These results demonstrate the importance of plexinD1 in directing migration of maturing thymocytes via modulation of biological responses to chemokine gradients. C1 [Choi, Young I.; Duke-Cohan, Jonathan S.; Ahmed, Wesam B.; Handley, Maris A.; Clayton, Linda K.; Reinherz, Ellis L.] Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA. [Choi, Young I.; Duke-Cohan, Jonathan S.; Clayton, Linda K.; Reinherz, Ellis L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Mann, Fanny] Univ Aix Marseille 2, CNRS, UMR 6216, Inst Marseille Luminy, F-13288 Marseille, France. [Epstein, Jonathan A.] Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. [Clayton, Linda K.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Immunobiol Lab, Boston, MA 02115 USA. EM ellis_reinherz@dfci.harvard.edu RI Mann, Fanny/G-2786-2016; OI Duke-Cohan, Jonathan/0000-0002-9478-9609; Mann, Fanny/0000-0003-4839-4347 FU National Institutes of Health [AI19807, AI078340] FX We acknowledge the excellent pathology expertise of S. Signoretti and technical assistance of E. Witten. This work was supported, in part, by National Institutes of Health Grant AI19807 to E.L.R. and AI078340 to L.K.C. NR 39 TC 58 Z9 60 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD DEC 19 PY 2008 VL 29 IS 6 BP 888 EP 898 DI 10.1016/j.immuni.2008.10.008 PG 11 WC Immunology SC Immunology GA 388IB UT WOS:000262012400009 PM 19027330 ER PT J AU Byakika-Tusiime, J Chinn, LW Oyugi, JH Obua, C Bangsberg, DR Kroetz, DL AF Byakika-Tusiime, Jayne Chinn, Leslie W. Oyugi, Jessica H. Obua, Celestino Bangsberg, David R. Kroetz, Deanna L. TI Steady State Bioequivalence of Generic and Innovator Formulations of Stavudine, Lamivudine, and Nevirapine in HIV-Infected Ugandan Adults SO PLOS ONE LA English DT Article AB Background: Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune (R)) or the corresponding brand formulations (Epivir (R), Zerit (R), and Viramune (R)). Methodology/Principal Findings: An open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received lamivudine (150 mg), stavudine (40 mg), and nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC(0-12h) and C(max). Bioequivalence was defined as a geometric mean ratio between the generic and brand name within the 90% confidence interval of 0.8-1.25. The geometric mean ratios and the 90% confidence intervals were: stavudine C(max), 1.3 (0.99-1.71) and AUC(0-12h), 1.1 (0.87-1.38); lamivudine C(max), 0.8 (0.63-0.98) and AUC(0-12h), 0.8 (0.65-0.99); and nevirapine C(max), 1.1 (0.95-1.23) and AUC(0-12h), 1.1 (0.95-1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters. Conclusions/Significant Findings: These findings provide support for the use of Triomune in resource-limited settings, identification of the sources of intersubject variability in these populations is critical. C1 Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Berkeley, CA 94720 USA. [Chinn, Leslie W.; Kroetz, Deanna L.] Univ Calif San Francisco, Dept Biopharm Sci, San Francisco, CA 94143 USA. [Oyugi, Jessica H.] Makerere Univ, Fac Med, Infect Dis Inst, Kampala, Uganda. [Obua, Celestino] Makerere Univ, Dept Pharmacol & Therapeut, Kampala, Uganda. [Bangsberg, David R.] Harvard Univ, Sch Med, Mass Gen Hosp, Harvard Initiative Glob Hlth, Boston, MA USA. RP Byakika-Tusiime, J (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Berkeley, CA 94720 USA. EM deanna.kroetz@ucsf.edu FU AIDS Care and Research in Africa (ACRiA); Doris Duke Charitable Foundation; NIH [GM61390, AA014784, MH54907, AA015287]; Amgen [Fellowship] FX This research was funded by the AIDS Care and Research in Africa (ACRiA) grant, supported by the Doris Duke Charitable Foundation (JB-T) and by NIH grants GM61390 (DLK), AA014784 (DRB), MH54907 (DRB)and AA015287 (DRB). LWC was funded by an Amgen Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 15 TC 7 Z9 7 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 19 PY 2008 VL 3 IS 12 AR e3981 DI 10.1371/journal.pone.0003981 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437AV UT WOS:000265458800004 PM 19096711 ER PT J AU Sankaran, VG Menne, TF Xu, J Akie, TE Lettre, G Van Handel, B Mikkola, HKA Hirschhorn, JN Cantor, AB Orkin, SH AF Sankaran, Vijay G. Menne, Tobias F. Xu, Jian Akie, Thomas E. Lettre, Guillaume Van Handel, Ben Mikkola, Hanna K. A. Hirschhorn, Joel N. Cantor, Alan B. Orkin, Stuart H. TI Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A SO SCIENCE LA English DT Article ID GENOME-WIDE ASSOCIATION; LOCUS-CONTROL REGION; ZINC-FINGER PROTEIN; BETA-THALASSEMIA; COMPLEX; DIFFERENTIATION; VARIANTS; RECRUITS; DISEASE; LINEAGE AB Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here, we examine BCL11A as a potential regulator of HbF expression. The high- HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full- length forms of BCL11A is developmentally restricted to adult erythroid cells. Down- regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta- globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta- hemoglobin disorders. C1 [Sankaran, Vijay G.; Menne, Tobias F.; Xu, Jian; Akie, Thomas E.; Cantor, Alan B.; Orkin, Stuart H.] Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston,Harvard Stem Cell Inst, Boston, MA 02115 USA. [Sankaran, Vijay G.; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Lettre, Guillaume; Hirschhorn, Joel N.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Lettre, Guillaume; Hirschhorn, Joel N.] Childrens Hosp, Div Genet Endocrinol, Boston, MA 02115 USA. [Lettre, Guillaume; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Van Handel, Ben; Mikkola, Hanna K. A.] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Harvard Univ, Sch Med, Div Hematol Oncol, Childrens Hosp Boston,Harvard Stem Cell Inst, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu FU National Heart, Lung, and Blood Institute; NIH [HL32262-26, HL32259-27]; Center of Excellence in Molecular Hematology Award from the National Institute of Digestive and Kidney Diseases; Howard Hughes Medical Institute; Leukaemia Research and Kay Kendall Leukaemia Funds; Medical Scientist Training Program FX We thank J. Snow, P. Tucker, G. Ippolito, B. Lee, M. Leid, T. Nakamura, D. Altshuler, E. Choy, and S. Bonakdar for providing reagents and suggestions. We are grateful to D. Nathan and A. Michelson for critical comments; D. Shao, N. Yudanin, and A. Soriano for experimental assistance; and C. Chen and V. Sankaran for assistance with data analysis. This work was supported by grants from the National Heart, Lung, and Blood Institute, NIH (HL32262-26 and HL32259-27), a Center of Excellence in Molecular Hematology Award from the National Institute of Digestive and Kidney Diseases, NIH, and the Howard Hughes Medical Institute. T. F. M. was supported by the Leukaemia Research and Kay Kendall Leukaemia Funds. V. G. S. was supported by a Medical Scientist Training Program grant from the NIH. Array datasets are deposited at Gene Expression Omnibus (accession no. GSE 13285). A patent application related to this work was filed, and V.G.S. and S.H.O. are inventors on this patent. NR 26 TC 324 Z9 329 U1 6 U2 29 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 DEC 19 PY 2008 VL 322 IS 5909 BP 1839 EP 1842 DI 10.1126/science.1165409 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385FF UT WOS:000261799400053 PM 19056937 ER PT J AU Freudiger, CW Min, W Saar, BG Lu, S Holtom, GR He, CW Tsai, JC Kang, JX Xie, XS AF Freudiger, Christian W. Min, Wei Saar, Brian G. Lu, Sijia Holtom, Gary R. He, Chengwei Tsai, Jason C. Kang, Jing X. Xie, X. Sunney TI Label-Free Biomedical Imaging with High Sensitivity by Stimulated Raman Scattering Microscopy SO SCIENCE LA English DT Article ID IN-VIVO; CARS-MICROSCOPY; SPECTROSCOPY AB Label- free chemical contrast is highly desirable in biomedical imaging. Spontaneous Raman microscopy provides specific vibrational signatures of chemical bonds, but is often hindered by low sensitivity. Here we report a three- dimensional multiphoton vibrational imaging technique based on stimulated Raman scattering ( SRS). The sensitivity of SRS imaging is significantly greater than that of spontaneous Raman microscopy, which is achieved by implementing high- frequency ( megahertz) phase- sensitive detection. SRS microscopy has a major advantage over previous coherent Raman techniques in that it offers background- free and readily interpretable chemical contrast. We show a variety of biomedical applications, such as differentiating distributions of omega- 3 fatty acids and saturated lipids in living cells, imaging of brain and skin tissues based on intrinsic lipid contrast, and monitoring drug delivery through the epidermis. C1 [Freudiger, Christian W.; Min, Wei; Saar, Brian G.; Lu, Sijia; Holtom, Gary R.; Xie, X. Sunney] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Freudiger, Christian W.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [He, Chengwei; Kang, Jing X.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [He, Chengwei; Kang, Jing X.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Tsai, Jason C.] Pfizer Global Med, New York, NY 10017 USA. RP Xie, XS (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. EM xie@chemistry.harvard.edu FU Boehringer Ingelheim Fonds for a Ph.D. Fellowship; Army Research Office for a National Defense Science and Engineering Graduate Fellowship; NIH [CA113605]; U. S. Department of Energy's Basic Energy Sciences [DE-FG02-07ER15875]; NSF [DBI-0649892]; NIH Director's Pioneer Award; Melinda Gates Foundation Gates Foundation; Pfizer Global Medical FX We thank C. Ackermann and S. Zhang for advice on skin imaging; S. Kesari, X. Xu and the MCB Harvard Mouse Facilities for providing mouse tissue; J. Grice and M. Roberts for the loan of a sonicator; and G. Young, X. Xu, M. Ruckel, and P. Sims for helpful discussions. C.W.F. and B.G.S. thank Boehringer Ingelheim Fonds for a Ph.D. Fellowship and the Army Research Office for a National Defense Science and Engineering Graduate Fellowship, respectively. J.X.K. acknowledges support from the NIH (grant CA113605). The Xie Group is grateful to the U. S. Department of Energy's Basic Energy Sciences program (DE-FG02-07ER15875) for supporting high-sensitivity Raman detection. The instrumentation development was supported by NSF (grant DBI-0649892), NIH Director's Pioneer Award (to X.S.X.), the Bill & Melinda Gates Foundation Gates Foundation, and Pfizer Global Medical. Harvard University has filed a patent application based on this work. NR 27 TC 773 Z9 782 U1 35 U2 407 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 DEC 19 PY 2008 VL 322 IS 5909 BP 1857 EP 1861 DI 10.1126/science.1165758 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385FF UT WOS:000261799400059 PM 19095943 ER PT J AU Sarin, H Kanevsky, AS Wu, HT Brimacombe, KR Fung, SH Sousa, AA Auh, S Wilson, CM Sharma, K Aronova, MA Leapman, RD Griffiths, GL Hall, MD AF Sarin, Hemant Kanevsky, Ariel S. Wu, Haitao Brimacombe, Kyle R. Fung, Steve H. Sousa, Alioscka A. Auh, Sungyoung Wilson, Colin M. Sharma, Kamal Aronova, Maria A. Leapman, Richard D. Griffiths, Gary L. Hall, Matthew D. TI Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID IRON-OXIDE NANOPARTICLES; IMAGING CONTRAST AGENTS; DRUG-DELIVERY; CHEMICAL-PROPERTIES; RECURRENT GLIOMAS; MOLECULAR-SIZE; CHEMOTHERAPY; MODEL; PERMEABILITY; DENDRIMERS AB Background: Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells. Methods: Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured in vivo with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed ex vivo with fluorescence imaging. Results: We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells. Conclusion: The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives. C1 [Sarin, Hemant; Sousa, Alioscka A.; Aronova, Maria A.; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth, Bethesda, MD 20892 USA. [Sarin, Hemant; Kanevsky, Ariel S.] Natl Inst Hlth, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Wu, Haitao; Wilson, Colin M.; Griffiths, Gary L.] NHLBI, Imaging Probe Dev Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [Brimacombe, Kyle R.; Hall, Matthew D.] NCI, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Fung, Steve H.] Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. [Auh, Sungyoung] Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Bethesda, MD 20892 USA. [Sharma, Kamal] Natl Canc Inst, Metab Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Sharma, Kamal] US FDA, Div Biol Drug Prod, Off Oncol Prod, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Sarin, H (reprint author), Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth, Bethesda, MD 20892 USA. EM sarinh@mail.nih.gov; kanevskya@mail.nih.gov; wuh3@mail.nih.gov; brimacombek@mail.nih.gov; sfung@partners.org; sousaali@mail.nih.gov; auhs@mail.nih.gov; wilsoncm@mail.nih.gov; kamal.sharma@fda.hhs.gov; aronovaa@mail.nih.gov; leapmanr@mail.nih.gov; griffithsgl@mail.nih.gov; hallma@mail.nih.gov RI Hall, Matthew/B-2132-2010; OI Fung, Steve/0000-0002-1177-682X FU National Institute of Biomedical Imaging Bioengineering (NIBIB); National Cancer Institute (NCI); Radiology and Imaging Sciences Program (CC) FX This study was funded by the National Institute of Biomedical Imaging Bioengineering (NIBIB), National Cancer Institute (NCI), and the Radiology and Imaging Sciences Program (CC). We thank Guofeng Zhang of the Laboratory of Bioengineering and Physical Science (NIBIB) and Yide Mi of the Radiology and Imaging Sciences Program (CC) for technical assistance. We thank Daniel Glen and Rick Reynolds of the Scientific and Statistical Computing Core (National Institute of Mental Health [ NIMH]) for their assistance during our use of the Analysis of Functional NeuroImages (AFNI) software suite for data analyses. NR 71 TC 116 Z9 118 U1 2 U2 38 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD DEC 18 PY 2008 VL 6 AR 80 DI 10.1186/1479-5876-6-80 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 409WS UT WOS:000263537100001 PM 19094226 ER PT J AU Nickel, JC Krieger, JN McNaughton-Collins, M Anderson, RU Pontari, M Shoskes, DA Litwin, MS Alexander, RB White, PC Berger, R Nadler, R O'Leary, M Liong, ML Zeitlin, S Chuai, S Landis, JR Kusek, JW Nyberg, LM Schaeffer, AJ AF Nickel, J. Curtis Krieger, John N. McNaughton-Collins, Mary Anderson, Rodney U. Pontari, Michel Shoskes, Daniel A. Litwin, Mark S. Alexander, Richard B. White, Paige C. Berger, Richard Nadler, Robert O'Leary, Michael Liong, Men Long Zeitlin, Scott Chuai, Shannon Landis, J. Richard Kusek, John W. Nyberg, Leroy M. Schaeffer, Anthony J. CA Chronic Prostatitis Collaborative TI Alfuzosin and Symptoms of Chronic Prostatitis-Chronic Pelvic Pain Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CHRONIC NONBACTERIAL PROSTATITIS; DOUBLE-BLIND TRIAL; QUALITY-OF-LIFE; ALPHA-BLOCKERS; MEN; MULTICENTER; THERAPY; SCALE; INDEX; QUESTIONNAIRE AB Background: In men with chronic prostatitis-chronic pelvic pain syndrome, treatment with alpha-adrenergic receptor blockers early in the course of the disorder has been reported to be effective in some, but not all, relatively small randomized trials. Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of alfuzosin, an alpha-adrenergic receptor blocker, in reducing symptoms in men with chronic prostatitis-chronic pelvic pain syndrome. Participation in the study required diagnosis of the condition within the preceding 2 years and no previous treatment with an alpha-adrenergic receptor blocker. Men were randomly assigned to treatment for 12 weeks with either 10 mg of alfuzosin per day or placebo. The primary outcome was a reduction of at least 4 points (from baseline to 12 weeks) in the score on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (range, 0 to 43; higher scores indicate more severe symptoms). A 4-point decrease is the minimal clinically significant difference in the score. Results: A total of 272 eligible participants underwent randomization, and in both study groups, 49.3% of participants had a decrease of at least 4 points in their total NIH-CPSI score (rate difference associated with alfuzosin, 0.1%; 95% confidence interval, -11.2 to 11.0; P=0.99). In addition, a global response assessment showed similar response rates at 12 weeks: 33.6% in the placebo group and 34.8% in the alfuzosin group (P=0.90). The rates of adverse events in the two groups were also similar. Conclusions: Our findings do not support the use of alfuzosin to reduce the symptoms of chronic prostatitis-chronic pelvic pain syndrome in men who have not received prior treatment with an alpha-blocker. (ClinicalTrials.gov number, NCT00103402.). C1 [Nickel, J. Curtis] Queens Univ, Kingston Gen Hosp, Dept Urol, Kingston, ON K7L 2V7, Canada. [Nickel, J. Curtis] Queens Univ, Dept Urol, Kingston, ON, Canada. [Krieger, John N.; Berger, Richard] Univ Washington, Dept Urol, Seattle, WA USA. [McNaughton-Collins, Mary] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Anderson, Rodney U.] Stanford Univ, Med Ctr, Dept Urol, Stanford, CA 94305 USA. [Pontari, Michel] Temple Univ, Dept Urol, Philadelphia, PA 19122 USA. [Shoskes, Daniel A.] Cleveland Clin, Glickman Urol Inst, Cleveland, OH 44106 USA. [Litwin, Mark S.; Chuai, Shannon] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Litwin, Mark S.; Chuai, Shannon] Univ Calif Los Angeles, David Geffen Sch Med, Dept Hlth Serv, Los Angeles, CA 90095 USA. [Litwin, Mark S.; Chuai, Shannon] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. [Alexander, Richard B.] Univ Maryland, Dept Urol, Baltimore, MD 21201 USA. [White, Paige C.] Univ Mississippi, Dept Surg, Jackson, MS 39216 USA. [Nadler, Robert; Schaeffer, Anthony J.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [O'Leary, Michael] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Liong, Men Long] Univ Sci Malaysia, George Town, Malaysia. [Zeitlin, Scott; Landis, J. Richard] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kusek, John W.; Nyberg, Leroy M.] NIDDKD, Bethesda, MD 20892 USA. RP Nickel, JC (reprint author), Queens Univ, Kingston Gen Hosp, Dept Urol, Kingston, ON K7L 2V7, Canada. EM jcn@queensu.ca RI Landis, J. Richard/A-9330-2010 FU NIDDK NIH HHS [U01 DK065209-04S1, U01 DK065174, U01 DK065174-05, U01 DK065186, U01 DK065186-05, U01 DK065187, U01 DK065187-05, U01 DK065189, U01 DK065189-06, U01 DK065209, U01 DK065209-01, U01 DK065209-02, U01 DK065209-02S1, U01 DK065209-03, U01 DK065209-03S1, U01 DK065209-03S2, U01 DK065209-04, U01 DK065209-04S2, U01 DK065209-05, U01 DK065209-05S1, U01 DK065209-06, U01 DK065257, U01 DK065257-05, U01 DK065266, U01 DK065266-05, U01 DK065268, U01 DK065268-05, U01 DK065277, U01 DK065277-05, U01 DK065287, U01 DK065287-03, U01 DK065297, U01 DK065297-05, U01 DK65174, U01 DK65186, U01 DK65187, U01 DK65189, U01 DK65209, U01 DK65257, U01 DK65266, U01 DK65268, U01 DK65277, U01 DK65287, U01 DK65297] NR 36 TC 67 Z9 76 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 18 PY 2008 VL 359 IS 25 BP 2663 EP 2673 DI 10.1056/NEJMoa0803240 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 384PS UT WOS:000261757300006 PM 19092152 ER PT J AU Scrivani, SJ Keith, DA Kaban, LB AF Scrivani, Steven J. Keith, David A. Kaban, Leonard B. TI Medical Progress: Temporomandibular Disorders SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID PAROXETINE-INDUCED BRUXISM; JOINT DISORDERS; OROFACIAL PAIN; SKELETAL SCINTIGRAPHY; DIABETIC-NEUROPATHY; OCCLUSAL VARIABLES; PHYSICAL-THERAPY; CONTROLLED-TRIAL; MYOFASCIAL PAIN; DOUBLE-BLIND C1 [Keith, David A.; Kaban, Leonard B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Keith, David A.] Harvard Vanguard Med Assoc, Boston, MA USA. [Scrivani, Steven J.] Tufts Univ, Sch Dent Med, Craniofacial Pain & Headache Ctr, Boston, MA 02111 USA. RP Kaban, LB (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, 55 Fruit St,Warren Bldg,Suite 1201, Boston, MA 02114 USA. EM lkaban@partners.org FU GlaxoSmithKline and Endo Pharmaceuticals; AO-Sythes Massachusetts General Hospital Pediatric Oral and Maxillofacial Surgery Fellowship FX Dr. Scrivani reports receiving grant support from GlaxoSmithKline and Endo Pharmaceuticals. Dr. Kaban reports receiving grant support for fellows in his unit who hold AO-Sythes Massachusetts General Hospital Pediatric Oral and Maxillofacial Surgery Fellowship Grants. No other potential conflict of interest relevant to this article was reported. NR 102 TC 116 Z9 133 U1 2 U2 10 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 18 PY 2008 VL 359 IS 25 BP 2693 EP 2705 DI 10.1056/NEJMra0802472 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 384PS UT WOS:000261757300009 PM 19092154 ER PT J AU Abramson, JS Chatterji, M Rahemtullah, A Barnes, JA AF Abramson, Jeremy S. Chatterji, Manjil Rahemtullah, Aliyah Barnes, Jeffrey A. TI A Woman with Splenomegaly and Anemia Splenic marginal-zone lymphoma, with an IgM paraprotein, antiphospholipid antibodies (lupus anticoagulant and IgM anticardiolipin antibody), and autoimmune hemolytic anemia. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID T-CELL LYMPHOMA; VILLOUS LYMPHOCYTES; WALDENSTROMS MACROGLOBULINEMIA; B-CELL; CLINICOPATHOLOGICAL ENTITY; RITUXIMAB MONOTHERAPY; CLINICAL PRESENTATION; PROGNOSTIC-FACTORS; FACTOR-VIII; DISEASE C1 [Abramson, Jeremy S.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Chatterji, Manjil] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Rahemtullah, Aliyah] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Abramson, Jeremy S.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Chatterji, Manjil] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Rahemtullah, Aliyah] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Abramson, JS (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 41 TC 5 Z9 6 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 18 PY 2008 VL 359 IS 25 BP 2707 EP 2718 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 384PS UT WOS:000261757300012 PM 19092156 ER PT J AU Ahmed, S Cannon, CP Giugliano, RP Murphy, SA Morrow, DA Antman, EM Braunwald, E Gibson, CM AF Ahmed, Shaheeda Cannon, Christopher P. Giugliano, Robert P. Murphy, Sabina A. Morrow, David A. Antman, Elliott M. Braunwald, Eugene Gibson, C. Michael TI The independent and combined risk of diabetes and non-endstage renal impairment in non-ST-segment elevation acute coronary syndromes SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Diabetes mellitus; Renal disease; Glomerular filtration rate; Non-ST-segment elevation acute coronary syndrome; Outcomes ID ACUTE MYOCARDIAL-INFARCTION; CONTRAST-INDUCED NEPHROPATHY; BLOOD-PRESSURE RESEARCH; CHRONIC KIDNEY-DISEASE; HEART-FAILURE; CARDIOVASCULAR-DISEASE; SUBSEQUENT MORTALITY; PRIMARY ANGIOPLASTY; RANDOMIZED-TRIAL; N-ACETYLCYSTEINE AB Objectives: To assess the effect of renal impairment (RI) and diabetes (DM) on outcomes in non-ST-segment elevation acute coronary syndromes (NSTE-ACS). Methods: Data were pooled from 13,126 patients in five NSTE-ACS TIMI trials (TIMI 11A and B, TIMI 12, OPUS-TIMI 16, and TACTICS-TIMI 18). Patients were divided based on DM status and RI (none, mild, or moderate if the glomerular filtration rate (GFR, ml/min/ 1.73 m(2)) was >= 90, 60-89 and 30-59 respectively). Results: Patients with DM and moderate RI (n=609) were older and had more prior MI (p<0.01 for all) than other subgroups. Compared with no RI/DM (n=3,832), the 12-month adjusted risks of death, MI, and death/MI increased with advancing RI and were highest with DM and moderate RI (H.R. 1.7, (1.2-2.4), p=0.002; H.R. 2.0 (1.5-2.6), p<0.001; and H.R. 1.7 (1.3-2.2), p<0.001 respectively). These events were also increased with DM and mild RI (H.R. 1.4, (1.0-1.9), p=0.06, H.R. 1.4 (1.1-1.8), p=0.006 and H.R. 1.3 (1.1-1.7), p=0.007 respectively) but not with 1) mild or moderate RI without DM or 2) DM without RI. The interaction terms for RI and DM in their association with MI and death/MI were significant. Conclusions: In the absence of DM, RI and in the absence of RI, DM did not increase the risk of MI or death/MI. However, the combination of RI and DM was associated with a particularly high risk of MI and death/MI suggesting that attention to preserving renal function may be of particular benefit for reducing cardiovascular risk in diabetic patients. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. RP Gibson, CM (reprint author), TIMI Data Coordinating Ctr, 350 Longwood Ave,1st Floor, Boston, MA 02215 USA. EM mgibson@perfuse.org NR 41 TC 4 Z9 4 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD DEC 17 PY 2008 VL 131 IS 1 BP 105 EP 112 DI 10.1016/j.ijcard.2007.09.006 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 377KX UT WOS:000261251200015 PM 18187215 ER PT J AU Jneid, H Fonarow, GC Cannon, CP Hernandez, AF Palacios, IF Maree, AO Wells, Q Bozkurt, B LaBresh, KA Liang, L Hong, YL Newby, LK Fletcher, G Peterson, E Wexler, L AF Jneid, Hani Fonarow, Gregg C. Cannon, Christopher P. Hernandez, Adrian F. Palacios, Igor F. Maree, Andrew O. Wells, Quinn Bozkurt, Biykem LaBresh, Kenneth A. Liang, Li Hong, Yuling Newby, L. Kristin Fletcher, Gerald Peterson, Eric Wexler, Laura CA Get Guidelines Steering Comm Inves TI Sex Differences in Medical Care and Early Death After Acute Myocardial Infarction SO CIRCULATION LA English DT Article DE myocardial infarction; percutaneous coronary intervention; reperfusion; revascularization; sex ID THROMBOLYTIC THERAPY; GENDER-DIFFERENCES; HEART-DISEASE; WOMEN; MORTALITY; MEN; ASSOCIATION; RISK; COMMITTEE; OUTCOMES AB Background-Women receive less evidence-based medical care than men and have higher rates of death after acute myocardial infarction (AMI). It is unclear whether efforts undertaken to improve AMI care have mitigated these sex disparities in the current era. Methods and Results-Using the Get With the Guidelines-Coronary Artery Disease database, we examined sex differences in care processes and in-hospital death among 78 254 patients with AMI in 420 US hospitals from 2001 to 2006. Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had higher unadjusted in-hospital death (8.2% versus 5.7%; P<0.0001) than men. After multivariable adjustment, sex differences in in-hospital mortality rates were no longer observed in the overall AMI cohort (adjusted odds ratio [OR]=1.04; 95% CI, 0.99 to 1.10) but persisted among STEMI patients (10.2% versus 5.5%; P<0.0001; adjusted OR=1.12; 95% CI, 1.02 to 1.23). Compared with men, women were less likely to receive early aspirin treatment (adjusted OR=0.86; 95% CI, 0.81 to 0.90), early beta-blocker treatment (adjusted OR=0.90; 95% CI, 0.86 to 0.93), reperfusion therapy (adjusted OR=0.75; 95% CI, 0.70 to 0.80), or timely reperfusion (door-to-needle time <= 30 minutes: adjusted OR=0.78; 95% CI, 0.65 to 0.92; door-to-balloon time <= 90 minutes: adjusted OR=0.87; 95% CI, 0.79 to 0.95). Women also experienced lower use of cardiac catheterization and revascularization procedures after AMI. Conclusions-Overall, no sex differences in in-hospital mortality rates after AMI were observed after multivariable adjustment. However, women with STEMI had higher adjusted mortality rates than men. The underuse of evidence-based treatments and delayed reperfusion among women represent potential opportunities for reducing sex disparities in care and outcome after AMI. (Circulation. 2008;118:2803-2810.) C1 [Jneid, Hani] Michael E DeBakey VA Med Ctr, Div Cardiol, Houston, TX 77030 USA. [Jneid, Hani; Bozkurt, Biykem] Baylor Coll Med, Houston, TX 77030 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Cannon, Christopher P.] Thrombolysis Myocardial Infarct Grp, Boston, MA USA. [Cannon, Christopher P.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Hernandez, Adrian F.; Liang, Li; Newby, L. Kristin; Peterson, Eric] Duke Clin Res Inst, Durham, NC USA. [Hernandez, Adrian F.; Liang, Li; Newby, L. Kristin; Peterson, Eric] Duke Univ, Med Ctr, Durham, NC USA. [Jneid, Hani; Palacios, Igor F.; Maree, Andrew O.; Wells, Quinn] Massachusetts Gen Hosp, Boston, MA 02114 USA. [LaBresh, Kenneth A.] MassPro Inc, Waltham, MA USA. [Hong, Yuling] Amer Heart Assoc, Natl Ctr, Dallas, TX USA. [Fletcher, Gerald] Mayo Clin, Jacksonville, FL 32224 USA. [Wexler, Laura] Univ Cincinnati, Coll Med, Cincinnati, OH USA. RP Jneid, H (reprint author), Michael E DeBakey VA Med Ctr, Div Cardiol, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM jneid@bcm.tmc.edu RI Wells, Quinn/D-2686-2014; LaBresh, Kenneth/A-6995-2017; Hernandez, Adrian F./A-7818-2016 OI Wells, Quinn/0000-0003-3899-0313; LaBresh, Kenneth/0000-0001-9040-1956; Hernandez, Adrian F./0000-0003-3387-9616 NR 25 TC 204 Z9 221 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 16 PY 2008 VL 118 IS 25 BP 2803 EP 2810 DI 10.1161/CIRCULATIONAHA.108.789800 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 387JO UT WOS:000261948700019 PM 19064680 ER PT J AU Huang, HC Koria, P Parker, SM Selby, L Megeed, Z Rege, K AF Huang, Huang-Chiao Koria, Piyush Parker, Sarah M. Selby, Luke Megeed, Zaki Rege, Kaushal TI Optically Responsive Gold Nanorod-Polypeptide Assemblies SO LANGMUIR LA English DT Article ID ELASTIN-LIKE POLYPEPTIDE; SURFACE-PLASMON RESONANCE; PROTEIN-BASED POLYMERS; SILVER NANOPARTICLES; PATHOGENIC BACTERIA; CONTROLLED-RELEASE; GENE DELIVERY; IN-VITRO; CANCER; SYSTEM AB Environmentally responsive nanoassemblies based on polypeptides and nanoparticles can have a number of promising biological/biomedical applications. We report the generation of gold nanorod (GNR)-elastin-like polypeptide (ELP) nanoassemblies whose optical response can be manipulated based on exposure to near-infrared (NIR) light. Cysteine-containing ELPs were self-assembled on GNRs mediated by gold-thiol bonds, leading to the generation of GNR-ELP nanoassemblies. Exposure of GNR-ELP assemblies to NIR light resulted in the heating of GNRs due to surface plasmon resonance. Heat transfer from the GNRs resulted in an increase in temperature of the self-assembled ELP above its transition temperature (T(t)), which led to a phase transition and aggregation of the GNR-ELP assemblies. This phase transition was detected using an optical readout (increase in optical density); no change in optical behavior was observed in the case of either ELP alone or GNR alone. The optical response was reproducibele and reversible across a number of cycles following exposure to or removal of the laser excitation. Our results indicate that polypeptides may be interfaced with GNRs resulting in optically responsive nanoasssemblies for sensing and drug delivery applications. C1 [Huang, Huang-Chiao; Parker, Sarah M.; Rege, Kaushal] Arizona State Univ, Dept Chem Engn, Tempe, AZ 85287 USA. [Koria, Piyush; Selby, Luke; Megeed, Zaki] Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Koria, Piyush; Selby, Luke; Megeed, Zaki] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Rege, K (reprint author), Arizona State Univ, Dept Chem Engn, ECG 202, Tempe, AZ 85287 USA. EM Kaushal.Rege@asu.edu OI Selby, Luke/0000-0002-0202-9646 FU National Institutes of Health [IR21CA 133618-01]; National Science Foundation [CBET0829128]; state of Arizona; Department of Defense [OC060266] FX The authors thank Dr. Su Lin, Dr. Laimonas Kelbauskas, and Professor Neal Woodbury, Director, Center for Bio-Optical Nanotechnology at The Biodesign Institute, Arizona State University (ASU), for access to the laserfacility. The authors also thank Fred Pend at ASU for invaluable technical assistance. This work was supported by National Institutes of Health Grant IR21CA 133618-01, National Science Foundation Grant CBET0829128, and start-up funds from the state of Arizona to K.R. and a Department of Defense Grant OC060266 to Z.M. NR 51 TC 35 Z9 35 U1 4 U2 48 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD DEC 16 PY 2008 VL 24 IS 24 BP 14139 EP 14144 DI 10.1021/la802842k PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 382UU UT WOS:000261631700046 PM 19360961 ER PT J AU Jeong, JH Wang, ZX Guimaraes, AS Ouyang, X Figueiredo, JL Ding, ZH Jiang, S Guney, I Kang, GH Shin, E Hahn, WC Loda, MF Abate-Shen, C Weissleder, R Chin, L AF Jeong, Joseph H. Wang, Zhenxiong Guimaraes, Alexander S. Ouyang, Xuesong Figueiredo, Jose L. Ding, Zhihu Jiang, Shan Guney, Isil Kang, Gyeong Hoon Shin, Eyoung Hahn, William C. Loda, Massimo F. Abate-Shen, Cory Weissleder, Ralph Chin, Lynda TI BRAF Activation Initiates but Does Not Maintain Invasive Prostate Adenocarcinoma SO PLOS ONE LA English DT Article AB Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAF(V600E)-a mutation found in similar to 10% of human prostate tumors-was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAF(V600E) in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAF(V600E) is not required for its maintenance. C1 [Jeong, Joseph H.; Wang, Zhenxiong; Ding, Zhihu; Jiang, Shan; Guney, Isil; Hahn, William C.; Loda, Massimo F.; Chin, Lynda] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Guimaraes, Alexander S.; Figueiredo, Jose L.; Weissleder, Ralph] Harvard Univ, Sch Med, Mass Gen Hosp, Ctr Syst Biol, Boston, MA 02115 USA. [Ouyang, Xuesong; Abate-Shen, Cory] Columbia Univ, Coll Physicians & Surgeons, Herbert Irving Comprehensive Canc Ctr, Dept Urol & Pathol, New York, NY 10027 USA. [Kang, Gyeong Hoon] Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 151, South Korea. [Shin, Eyoung; Loda, Massimo F.] Harvard Univ, Sch Med, Brigham and Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Hahn, William C.] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA USA. [Chin, Lynda] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Guney, Isil; Hahn, William C.; Loda, Massimo F.] MIT, Broad Inst Harvard, Cambridge, MA USA. [Guimaraes, Alexander S.; Figueiredo, Jose L.; Weissleder, Ralph] Harvard Univ, Sch Med, Mass Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Jeong, JH (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM lynda_chin@dfci.harvard.edu RI Kang, Gyeong Hoon/F-1051-2010; Seoul National University, Pathology/B-6702-2012; Abate-Shen, Cory/O-2520-2014 OI Kang, Gyeong Hoon/0000-0003-2380-6675; Abate-Shen, Cory/0000-0002-5021-0570 FU Department of Defense (DOD) [Prostate Cancer Training Awards]; NIH [PO1 CA089021, RO1 CA109038, RO1 CA076501, UO1 CA084294, R24 CA92782, P50 CA86355, U54 CA119349, UO1 CA84313, RO1 CA93947]; Prostate Cancer Foundation (PCF) Award; DFCI-Novartis Investigator award FX J.H. Jeong and I. Guney are supported by Department of Defense (DOD) Prostate Cancer Training Awards. M.F. Loda is supported by NIH PO1 CA089021, Prostate Cancer Foundation (PCF) Award and DFCI-Novartis Investigator award. W.C. Hahn is supported by NIH RO1 CA109038 and the Prostate Cancer Foundation (PCF) Award. C. Abate-Shen is supported by NIH RO1 CA076501 and UO1 CA084294. R. Weissleder and all imaging studies are supported by NIH R24 CA92782, P50 CA86355, and U54 CA119349. This work is supported by grants from the NIH (UO1 CA84313; RO1 CA93947) to L. Chin. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 28 Z9 29 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 DEC 16 PY 2008 VL 3 IS 12 AR e3949 DI 10.1371/journal.pone.0003949 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437AR UT WOS:000265458400008 PM 19079609 ER PT J AU Falvo, JV Lin, CH Tsytsykova, AV Hwang, PK Thanos, D Goldfeld, AE Maniatis, T AF Falvo, James V. Lin, Charles H. Tsytsykova, Alla V. Hwang, Peter K. Thanos, Dimitris Goldfeld, Anne E. Maniatis, Tom TI A dimer-specific function of the transcription factor NFATp SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE activation domain; CREB-binding protein; dimerization; protein-DNA interactions; TNF ID FACTOR-ALPHA GENE; ACTIVATED T-CELLS; NF-KAPPA-B; CREB-BINDING-PROTEIN; NUCLEAR FACTOR; CRYSTAL-STRUCTURE; DNA; EXPRESSION; PROMOTER; ENHANCER AB The transcription factor NFATp integrates multiple signal transduction pathways through coordinate binding with basic-region leucine zipper (bZIP) proteins and other transcription factors. The NFATp monomer, even in the absence of its activation domains, recruits bZIP proteins to canonical NFAT-bZIP composite DNA elements. By contrast, the NFATp dimer and its bZIP partner bind noncooperatively to the NFAT-bZIP element of the tumor necrosis factor (TNF) gene promoter. This observation raises the possibility that the function of the activation domains of NFATp is dimer-specific. Here, we determine the consensus DNA binding site of the NFATp dimer, describe monomer- and dimer-specific NFATp-DNA contact patterns, and demonstrate that NFATp dimerization and dimer-specific activation subdomains are required for transcriptional activation from the TNF NFAT-bZIP element. We also show that these NFATp subdomains interact with the coactivator CBP (CREB-binding protein), which is required for NFATp-dependent TNF gene transcription. Thus, the context-specific function of the activation domains of NFAT can be potentiated by DNA-directed dimerization. C1 [Falvo, James V.; Tsytsykova, Alla V.; Goldfeld, Anne E.] Immune Dis Inst, Boston, MA 02115 USA. [Falvo, James V.; Tsytsykova, Alla V.; Goldfeld, Anne E.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Lin, Charles H.; Maniatis, Tom] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Lin, Charles H.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Hwang, Peter K.] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA. [Thanos, Dimitris] Acad Athens, Biomed Res Fdn, Inst Mol Biol Genet & Biotechnol, Athens 11527, Greece. [Thanos, Dimitris] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. RP Goldfeld, AE (reprint author), Immune Dis Inst, 800 Huntington Ave, Boston, MA 02115 USA. EM goldfeld@cbrinstitute.org; maniatis@mcb.harvard.edu FU National Institutes of Health Grants [AI-20642, GM-56492, GM-54605]; American Heart Association; March of Dimes, Pew Scholars Program in the Biomedical Sciences; Irma T. Hirschl Trust; Arthritis National Research Foundation; National Cancer Institute/National Institutes of Health [P50 CA89520]; Department of Defense National Defense Science and Engineering FX We thank Junming Yie (Amgen, Inc., Thousand Oaks, CA) and Lin Chen (University of Colorado, Boulder, CO) for providing recombinant NFATp RHR and RHR-N, respectively. We thank Aseem Ansari and Lin Chen for valuable discussions, Robert Fletterick and Christopher Waddling for the use of Insight II, Adele Uglialoro for technical assistance, and Renate Hellmiss-Peralta for graphic artwork. This work was supported by National Institutes of Health Grants AI-20642 ( to T. M.), GM-56492 (to A. E. G.), and GM-54605 (to D. T.); by the American Heart Association (A. E. G.), the March of Dimes, Pew Scholars Program in the Biomedical Sciences, the Irma T. Hirschl Trust (D. T.), the Arthritis National Research Foundation (A. V. T.); by National Cancer Institute/National Institutes of Health Grant P50 CA89520 (to P. K. H.); and by a Department of Defense National Defense Science and Engineering Graduate Fellowship (J. V. F.). NR 56 TC 12 Z9 12 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 DEC 16 PY 2008 VL 105 IS 50 BP 19637 EP 19642 DI 10.1073/pnas.0810648105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385GI UT WOS:000261802300015 PM 19060202 ER PT J AU Chen, HB Xu, CF Ma, JH Eliseenkova, AV Li, WQ Pollock, PM Pitteloud, N Miller, WT Neubert, TA Mohammadi, M AF Chen, Huaibin Xu, Chong-Feng Ma, Jinghong Eliseenkova, Anna V. Li, Wanqing Pollock, Pamela M. Pitteloud, Nelly Miller, W. Todd Neubert, Thomas A. Mohammadi, Moosa TI A crystallographic snapshot of tyrosine trans-phosphorylation in action SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE crystal structure; FGF receptor; RTKs ID GROWTH-FACTOR RECEPTOR; KINASE DOMAIN; STRUCTURAL BASIS; KALLMANN-SYNDROME; CRYSTAL-STRUCTURE; INHIBITION; ACTIVATION; COMPLEX; AUTOPHOSPHORYLATION; AUTOINHIBITION AB Tyrosine trans-phosphorylation is a key event in receptor tyrosine kinase signaling, yet, the structural basis for this process has eluded definition. Here, we present the crystal structure of the FGF receptor 2 kinases caught in the act of trans-phosphorylation of Y769, the major C-terminal phosphorylation site. The structure reveals that enzyme- and substrate-acting kinases engage each other through elaborate and specific interactions not only in the immediate vicinity of Y769 and the enzyme active site, but also in regions that are as much of 18 angstrom away from D626, the catalytic base in the enzyme active site. These interactions lead to an unprecedented level of specificity and precision during the trans-phosphorylation on Y769. Time-resolved mass spectrometry analysis supports the observed mechanism of trans-phosphorylation. Our data provide a molecular framework for understanding the mechanism of action of Kallmann syndrome mutations and the order of trans-phosphorylation reactions in FGFRs. We propose that the salient mechanistic features of Y769 transphosphorylation are applicable to trans-phosphorylation of the equivalent major phosphorylation sites in many other RTKs. C1 [Chen, Huaibin; Xu, Chong-Feng; Ma, Jinghong; Eliseenkova, Anna V.; Neubert, Thomas A.; Mohammadi, Moosa] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA. [Xu, Chong-Feng; Neubert, Thomas A.] NYU, Sch Med, Skirball Inst, Kimmel Ctr Biol & Med, New York, NY 10016 USA. [Li, Wanqing; Miller, W. Todd] SUNY Stony Brook, Sch Med, Dept Physiol & Biophys, Stony Brook, NY 11794 USA. [Pollock, Pamela M.] Translat Genom Res Inst, Canc & Cell Biol Div, Phoenix, AZ 85004 USA. [Pitteloud, Nelly] Massachusetts Gen Hosp, Harvard Ctr Reprod Endocrine Sci, Boston, MA 02114 USA. [Pitteloud, Nelly] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Boston, MA 02114 USA. RP Mohammadi, M (reprint author), NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA. EM moosa.mohammadi@nyumc.org RI PITTELOUD, Nelly/K-2709-2014; OI Mohammadi, Moosa/0000-0003-2434-9437 FU National Institutes of Health [DE13686, CA122091]; National Institutes of Health Shared Instrumentation [S10 RR14662, S10 RR017990]; National Institute of Neurological Disorders and Stroke [P30 NS050276]; National Cancer Institute Core [P30 CA016087] FX We thank Drs. R. Abramowitz and J. Schwanof for synchrotron beamline assistance and Dr. X-P. Kong for comments on the manuscript. Beamlines X-4A and X-4C at the National Synchrotron Light Source, Brookhaven National Laboratory, a DOE facility, are supported by New York Structural Biology Consortium. This work was supported by National Institutes of Health Grants DE13686 (to M. M.) and CA122091 (to W. T. M.). The New York University Protein Analysis Facility is supported by National Institutes of Health Shared Instrumentation Grants S10 RR14662 and S10 RR017990, National Institute of Neurological Disorders and Stroke Grant P30 NS050276, and National Cancer Institute Core Grant P30 CA016087 (to T. A. N.). NR 36 TC 37 Z9 39 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 16 PY 2008 VL 105 IS 50 BP 19660 EP 19665 DI 10.1073/pnas.0807752105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385GI UT WOS:000261802300019 PM 19060208 ER PT J AU Olahova, M Taylor, SR Khazaipoul, S Wang, JL Morgan, BA Matsumoto, K Blackwell, TK Veal, EA AF Olahova, Monika Taylor, Sarah R. Khazaipoul, Siavash Wang, Jinling Morgan, Brian A. Matsumoto, Kunihiro Blackwell, T. Keith Veal, Elizabeth A. TI A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aging; Caenorhabditis elegans; oxidative stress; signaling; chaperone ID HEAT-SHOCK FACTOR; CAENORHABDITIS-ELEGANS; LIFE-SPAN; OXIDATIVE STRESS; C. ELEGANS; FACTOR SKN-1; ANTIOXIDANT; MUTANTS; PROTEIN; MECHANISM AB Oxidative damage caused by reactive oxygen species (ROS) is implicated in many diseases and in aging. Removal of ROS by antioxidant enzymes plays an important part in limiting this damage. For instance, peroxiredoxins (Prx) are conserved, abundant, thioredoxin peroxidase enzymes that function as tumor suppressors. In addition to detoxifying peroxides, studies in single-cell systems have revealed that Prx act as chaperones and redox sensors. However, it is unknown in what manner the different activities of Prx influence stress resistance or longevity in the context of whole animals. Here, we reveal three distinct roles for the 2-Cys Prx, PRDX-2, in the stress resistance of the nematode worm Caenorhabditis elegans. (i) The thioredoxin peroxidase activity of PRDX-2 protects against hydrogen peroxide. (ii) Consistent with a chaperone activity for hyperoxidized PRDX-2, peroxide-induced oxidation of PRDX-2 increases resistance to heat stress. (iii) Unexpectedly, loss of PRDX-2 increases the resistance of C. elegans to some oxidative stress-causing agents, such as arsenite, apparently through a signaling mechanism that increases the levels of other antioxidants and phase II detoxification enzymes. Despite their increased resistance to some forms of oxidative stress, prdx-2 mutants are short-lived. Moreover, intestinal expression of PRDX-2 accounts for its role in detoxification of exogenous peroxide, but not its influence on either arsenite resistance or longevity, suggesting that PRDX-2 may promote longevity and protect against environmental stress through different mechanisms. Together the data reveal that in metazoans Prx act through multiple biochemical activities, and have tissue-specific functions in stress resistance and longevity. C1 [Wang, Jinling; Blackwell, T. Keith] Joslin Diabet Ctr, Boston, MA 02215 USA. [Olahova, Monika; Taylor, Sarah R.; Khazaipoul, Siavash; Morgan, Brian A.; Veal, Elizabeth A.] Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Matsumoto, Kunihiro] Nagoya Univ, Chikusa Ku, Nagoya, Aichi 4648602, Japan. RP Blackwell, TK (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM keith.blackwell@joslin.harvard.edu; e.a.veal@ncl.ac.uk FU National Institutes of Health National Center for Research Resources; Medical Research Council Career Development Award; Medical Research Council studentship; Research Councils UK Academic Fellowship; National Institutes of Health [GM62891] FX We thank Jennifer Tullet, Nigel Robinson, Simon Whitehall, Janet Quinn, and Veal laboratory members for discussions and comments on the manuscript; Ian Hope (University of Leeds, Leeds, United Kingdom) and members of the Blackwell and Matsumoto laboratories for advice and reagents; Yuji Kohara (National Institute of Genetics, Mishima, Japan) for providing prdx-2 cDNA; and Amanda Greenall and Fiona Young for technical assistance. Some nematodestrainsusedin this work were provided by the Caenorhabditis Genetics Center (University of Minnesota, Minneapolis, MN), which is funded by the National Institutes of Health National Center for Research Resources. This work was funded by a Medical Research Council Career Development Award (E.V.), Medical Research Council studentship (S.T.), Research Councils UK Academic Fellowship (E.V.), and National Institutes of Health Grant GM62891 (T.K.B). NR 36 TC 68 Z9 79 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 16 PY 2008 VL 105 IS 50 BP 19839 EP 19844 DI 10.1073/pnas.0805507105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385GI UT WOS:000261802300049 PM 19064914 ER PT J AU D'Alise, AM Auyeung, V Feuerer, M Nishio, J Fontenot, J Benoist, C Mathis, D AF D'Alise, Anna Morena Auyeung, Vincent Feuerer, Markus Nishio, Junko Fontenot, Jason Benoist, Christophe Mathis, Diane TI The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE conventional T cells; regulatory T cells; type 1 diabetes ID TRANSCRIPTION FACTOR FOXP3; NONOBESE DIABETIC MICE; INTERLEUKIN-2 PRODUCTION; MEDIATED SUPPRESSION; CENTRAL TOLERANCE; CLONAL DELETION; AUTOIMMUNITY; ONSET; SELECTION; LINEAGE AB FoxP3(+) regulatory T cells (Tregs) protect against autoimmunity, type 1 diabetes (T1D) in particular, prompting the hypothesis that a deficiency in Tregs is a critical determinant of diabetes susceptibility in NOD mice. However, tests of this hypothesis have yielded contradictory results. We confirmed that NOD mice, compared with reference strains, do not have a primary deficit in Treg numbers in the lymphoid organs, whether in prediabetic mice of any age or in animals with recent-onset diabetes. NOD Tregs did show a defect in standard in vitro T cell suppression assays, particularly at low suppressor/effector ratios. Gene expression profiling revealed the vast majority of transcripts constituting the "Treg signature'' to be normally distributed in NOD Tregs versus CD4(+) T conventional (Tconv) cells, although there were a few differences affecting one or the other population. According to results from criss-cross experiments, the functional inefficacy was not rooted in NOD Tregs, which suppressed as well as their C57BL/6 (B6) counterparts, but rather in NOD Tconv, which were less prone to suppression than were B6 Tconv cells. They also responded more effectively to anti-CD3/28 monoclonal antibody (mAb) stimulation in vitro or to a natural pancreatic antigen in vivo. This difference was independent of autoimmune inflammation, did not map to the idd3 region, and was not due to the overproduction of interleukin-21 in NOD mice. That the immune dysregulation in this T1D model is rooted in the ability of effector T cells to be regulated, rather than in Tregs themselves, has implications for proposed therapeutic interventions. C1 [D'Alise, Anna Morena; Auyeung, Vincent; Feuerer, Markus; Nishio, Junko; Benoist, Christophe; Mathis, Diane] Joslin Diabet Ctr, Immunol Sect, Boston, MA 02215 USA. [D'Alise, Anna Morena; Auyeung, Vincent; Feuerer, Markus; Nishio, Junko; Benoist, Christophe; Mathis, Diane] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. [D'Alise, Anna Morena; Auyeung, Vincent; Feuerer, Markus; Nishio, Junko; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Fontenot, Jason] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. RP Benoist, C (reprint author), Joslin Diabet Ctr, Immunol Sect, Boston, MA 02215 USA. EM cbdm@joslin.harvard.edu FU Juvenile Diabetes Research Foundation [4-2007-1057]; Young Chair funds; Joslin's Diabetes and Endocrinology Research Center cores [P30 DK36836]; University of Perugia; German Research Foundation Emmy-Noether Fellowship [FE 801/1-1]; Charles King Fund; Iacocca Foundation Postdoctoral Fellowship; Harvard Medical School FX We thank S. Vitolo and K. Hattori for assistance with mice, J. LaVecchio and G. Buruzula for help with cytometry, and J.A. Hill for helpful discussions. This work was supported by Juvenile Diabetes Research Foundation Grant 4-2007-1057 and Young Chair funds (to D.M. and C.B.); and Joslin's Diabetes and Endocrinology Research Center cores Grant P30 DK36836; a PhD Fellowship from the University of Perugia (to A.M.D.); German Research Foundation Emmy-Noether Fellowship FE 801/1-1 and the Charles King Fund (to M.F.); an Iacocca Foundation Postdoctoral Fellowship to J.N.; and the Louis W. Gilbert fellowship from Harvard Medical School to (V.A.). NR 47 TC 111 Z9 113 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 DEC 16 PY 2008 VL 105 IS 50 BP 19857 EP 19862 DI 10.1073/pnas.0810713105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385GI UT WOS:000261802300052 PM 19073938 ER PT J AU Shao, HF Burrage, LC Sinasac, DS Hill, AE Ernest, SR O'Brien, W Courtland, HW Jepsen, KJ Kirby, A Kulbokas, EJ Daly, MJ Broman, KW Lander, ES Nadeau, JH AF Shao, Haifeng Burrage, Lindsay C. Sinasac, David S. Hill, Annie E. Ernest, Sheila R. O'Brien, William Courtland, Hayden-William Jepsen, Karl J. Kirby, Andrew Kulbokas, E. J. Daly, Mark J. Broman, Karl W. Lander, Eric S. Nadeau, Joseph H. TI Genetic architecture of complex traits: Large phenotypic effects and pervasive epistasis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromosome substitution; genetic variation; quantitative trait loci ID CHROMOSOME SUBSTITUTION STRAINS; GENOME-WIDE ASSOCIATION; QUANTITATIVE TRAITS; MICE; HEIGHT; YEAST; DISSECTION; CROSSES; HUMANS; LOCI AB The genetic architecture of complex traits underlying physiology and disease in most organisms remains elusive. We still know little about the number of genes that underlie these traits, the magnitude of their effects, or the extent to which they interact. Chromosome substitution strains (CSSs) enable statistically powerful studies based on testing engineered inbred strains that have single, unique, and nonoverlapping genetic differences, thereby providing measures of phenotypic effects that are attributable to individual chromosomes. Here, we report a study of phenotypic effects and gene interactions for 90 blood, bone, and metabolic traits in a mouse CSS panel and 54 traits in a rat CSS panel. Two key observations emerge about the genetic architecture of these traits. First, the traits tend to be highly polygenic: across the genome, many individual chromosome substitutions each had significant phenotypic effects and, within each of the chromosomes studied, multiple distinct loci were found. Second, strong epistasis was found among the individual chromosomes. Specifically, individual chromosome substitutions often conferred surprisingly large effects ( often a substantial fraction of the entire phenotypic difference between the parental strains), with the result that the sum of these individual effects often dramatically exceeded the difference between the parental strains. We suggest that strong, pervasive epistasis may reflect the presence of several phenotypically-buffered physiological states. These results have implications for identification of complex trait genes, developmental and physiological studies of phenotypic variation, and opportunities to engineer phenotypic outcomes in complex biological systems. C1 [Daly, Mark J.; Lander, Eric S.] Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA 02142 USA. [Shao, Haifeng; Burrage, Lindsay C.; Sinasac, David S.; Hill, Annie E.; Ernest, Sheila R.; Nadeau, Joseph H.] Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. [Nadeau, Joseph H.] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Shao, Haifeng; Burrage, Lindsay C.; Nadeau, Joseph H.] Case Western Reserve Univ, Ctr Prote & Bioinformat, Cleveland, OH 44106 USA. [Nadeau, Joseph H.] Case Western Reserve Univ, Dept Elect Engn & Comp Sci, Cleveland, OH 44106 USA. [O'Brien, William] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Courtland, Hayden-William; Jepsen, Karl J.] Mt Sinai Sch Med, Leni & Peter W May Dept Orthopaed, New York, NY 10029 USA. [Kirby, Andrew; Kulbokas, E. J.; Daly, Mark J.] Massachusetts Gen Hosp, Simches Res Ctr, Ctr Human Genet Res, Boston, MA 02114 USA. [Broman, Karl W.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53706 USA. [Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Nadeau, JH (reprint author), Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA 02142 USA. EM lander@broad.mit.edu; jhn4@case.edu OI Broman, Karl/0000-0002-4914-6671 FU National Institutes of Health [T32 GM07250, RR12305]; Canadian Diabetes Association fellowship; National Institutes of Health Training [GM08613]; Charles B. Wang Foundation FX We thank Dr. Joel Hirschhorn for sharing his unpublished SNP scoring method and Dr. James Crow for many thoughtful comments and suggestions. L. C. B. was supported in part by National Institutes of Health Grant T32 GM07250 to the Case Western Reserve University Medical Scientist Training Program. This work was supported by National Institutes of Health Grants RR12305 (to J.H.N.) and AR44927 (to K.J.J.), a Canadian Diabetes Association fellowship (D.S.S.), National Institutes of Health Training Grant GM08613 (to L.C.B.), and a gift from the Charles B. Wang Foundation. NR 33 TC 142 Z9 144 U1 0 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 16 PY 2008 VL 105 IS 50 BP 19910 EP 19914 DI 10.1073/pnas.0810388105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385GI UT WOS:000261802300061 PM 19066216 ER PT J AU Inada, A Nienaber, C Katsuta, H Fujitani, Y Levine, J Morita, R Sharma, A Bonner-Weir, S AF Inada, Akari Nienaber, Cameron Katsuta, Hitoshi Fujitani, Yoshio Levine, Jared Morita, Rina Sharma, Arun Bonner-Weir, Susan TI Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diabetes; islets of Langerhans; lineage tracing ID TYPE-2 DIABETES-MELLITUS; BETA-CELLS; EMBRYONIC-DEVELOPMENT; EPITHELIAL-CELLS; TRANSGENIC MICE; MOUSE PANCREAS; DIFFERENTIATION; ISLETS; GROWTH; REGENERATION AB The regenerative process in the pancreas is of particular interest because diabetes results from an inadequate number of insulin-producing beta cells and pancreatic cancer may arise from the uncontrolled growth of progenitor/stem cells. Continued and substantial growth of islet tissue occurs after birth in rodents and humans, with additional compensatory growth in response to increased demand. In rodents there is clear evidence of pancreatic regeneration after some types of injury, with proliferation of preexisting differentiated cell types accounting for some replacement. Additionally, neogenesis or the budding of new islet cells from pancreatic ducts has been reported, but the existence and identity of a progenitor cell have been debated. We hypothesized that the progenitor cells are duct epithelial cells that after replication undergo a regression to a less differentiated state and then can form new endocrine and exocrine pancreas. To directly test whether ductal cells serve as pancreatic progenitors after birth and give rise to new islets, we generated transgenic mice expressing human carbonic anhydrase II (CAII) promoter: Cre recombinase (Cre) or inducible CreER (TM) to cross with ROSA26 loxP-Stop-loxP LacZ reporter mice. We show that CAII-expressing cells within the pancreas act as progenitors that give rise to both new islets and acini normally after birth and after injury (ductal ligation). This identification of a differentiated pancreatic cell type as an in vivo progenitor of all differentiated pancreatic cell types has implications for a potential expandable source for new islets for replenishment therapy for diabetes. C1 [Inada, Akari; Nienaber, Cameron; Katsuta, Hitoshi; Levine, Jared; Morita, Rina; Sharma, Arun; Bonner-Weir, Susan] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. [Fujitani, Yoshio] Vanderbilt Univ, Dept Cell & Dev Biol, Nashville, TN 37232 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 FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases; Joslin Diabetes Center (Diabetes and Endocrinology Research Center Advanced Microscopy and Flow Cytometry Cores); Juvenile Diabetes Research Foundation; Diabetes and Wellness Foundation; Mary Iaccoca Visiting Scientist Fellowship FX We thank Dr. Tatsuo Takeya (Nara, Japan) for providing the human CAII promoter plasmid; Dr. Philippe Soriano (Fred Hutchinson Cancer Research Center, Seattle, WA) for the R26R reporter mice; Dr. Jun-ichi Miyazaki (Osaka, Japan) for the LoxP flanked-reporter plasmid; Dr. Tomoyuki Akashi for help with implantation of tamoxifen pellets; Jennifer Lock, Chris Cahill, Alevtina Pinkhasov, and Maria Petruzzelli for technical assistance; and Drs. Gordon Weir (Joslin Diabetes Center, Boston, MA), and Chris Wright (Vanderbilt University, Nashville, TN) for many helpful discussions. This study was supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grants to S.B.-W. and to the Joslin Diabetes Center (Diabetes and Endocrinology Research Center Advanced Microscopy and Flow Cytometry Cores), a Juvenile Diabetes Research Foundation grant (S.B.-W.), the Diabetes and Wellness Foundation, and generous private donors. A.I. was a recipient of a Mary Iaccoca Visiting Scientist Fellowship. NR 37 TC 239 Z9 244 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 DEC 16 PY 2008 VL 105 IS 50 BP 19915 EP 19919 DI 10.1073/pnas.0805803105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385GI UT WOS:000261802300062 PM 19052237 ER PT J AU Choi, CS Befroy, DE Codella, R Kim, S Reznick, RM Hwang, YJ Liu, ZX Lee, HY Distefano, A Samuel, VT Zhang, DY Cline, GW Handschin, C Lin, JD Petersen, KF Spiegelman, BM Shulman, GI AF Choi, Cheol Soo Befroy, Douglas E. Codella, Roberto Kim, Sheene Reznick, Richard M. Hwang, Yu-Jin Liu, Zhen-Xiang Lee, Hui-Young Distefano, Alberto Samuel, Varman T. Zhang, Dongyan Cline, Gary W. Handschin, Christoph Lin, Jiandie Petersen, Kitt F. Spiegelman, Bruce M. Shulman, Gerald I. TI Paradoxical effects of increased expression of PGC-1 alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diacylglycerol; fatty acid oxidation; insulin resistance; magnetic resonance spectroscopy; mitochondria ID RECEPTOR-GAMMA COACTIVATOR-1-ALPHA; FATTY-ACID OXIDATION; SKELETAL-MUSCLE; KNOCKOUT MICE; IN-VIVO; UNCOUPLING PROTEIN-3; SUBSTRATE OXIDATION; HEPATIC STEATOSIS; TRIBBLES HOMOLOG; RESISTANCE AB Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1 alpha has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1 alpha in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1 alpha expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy balance, and liver and muscle insulin sensitivity by hyperinsulinemic-euglycemic clamp studies and muscle energetics by using (31)P magnetic resonance spectroscopy in transgenic mice. Increased expression of PGC-1 alpha in muscle resulted in a 2.4-fold increase in mitochondrial density, which was associated with an approximate to 60% increase in the unidirectional rate of ATP synthesis. Surprisingly, there was no effect of increased muscle PGC-1 alpha expression on whole-body energy expenditure, and PGC-1 alpha transgenic mice were more prone to fat-induced insulin resistance because of decreased insulin-stimulated muscle glucose uptake. The reduced insulin-stimulated muscle glucose uptake could most likely be attributed to a relative increase in fatty acid delivery/triglyceride reesterfication, as reflected by increased expression of CD36, acyl-CoA:diacylglycerol acyltransferase 1, and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase, that may have exceeded mitochondrial fatty acid oxidation, resulting in increased intracellular lipid accumulation and an increase in the membrane to cytosol diacylglycerol content. This, in turn, caused activation of PKC theta, decreased insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and skeletal muscle insulin resistance. C1 [Choi, Cheol Soo; Befroy, Douglas E.; Codella, Roberto; Kim, Sheene; Reznick, Richard M.; Hwang, Yu-Jin; Liu, Zhen-Xiang; Lee, Hui-Young; Distefano, Alberto; Samuel, Varman T.; Zhang, Dongyan; Cline, Gary W.; Petersen, Kitt F.; Shulman, Gerald I.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA. [Shulman, Gerald I.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Handschin, Christoph; Lin, Jiandie; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Cell Biol, Boston, MA 02115 USA. [Choi, Cheol Soo] Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Inchon 406840, South Korea. RP Shulman, GI (reprint author), Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. EM gerald.shulman@yale.edu RI Handschin, Christoph/E-6886-2015; Codella, Roberto/L-4460-2016 OI Handschin, Christoph/0000-0003-0603-1097; Codella, Roberto/0000-0003-1608-1899 FU U.S. Public Health Services [R01 DK-40936, U24DK-76169, P30DK-45735]; The Howard Hughes Medical Institute; American Diabetes Association FX We thank Mario Kahn and Xiaoxian Ma for expert technical assistance. This work was supported by U.S. Public Health Services Grants R01 DK-40936, U24DK-76169, and P30DK-45735 (to G.I.S.). G.I.S. is an Investigator of The Howard Hughes Medical Institute and the recipient of a Distinguished Clinical Investigator Award from the American Diabetes Association. NR 43 TC 152 Z9 157 U1 2 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 16 PY 2008 VL 105 IS 50 BP 19926 EP 19931 DI 10.1073/pnas.0810339105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385GI UT WOS:000261802300064 PM 19066218 ER PT J AU Chen, SZ Charness, ME AF Chen, Suzhen Charness, Michael E. TI Ethanol inhibits neuronal differentiation by disrupting activity-dependent neuroprotective protein signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cerebellum; Crk-associated substrate; fetal alcohol spectrum disorders; Fyn kinase ID FETAL ALCOHOL SYNDROME; NEURITE OUTGROWTH; NERVOUS-SYSTEM; PRION PROTEIN; MECHANISMS; PREVENTION; ADHESION; PEPTIDE; GROWTH; DEATH AB The mechanisms by which ethanol damages the developing and adult central nervous system (CNS) remain unclear. Activity-dependent neuroprotective protein (ADNP) is a glial protein that protects the CNS against a wide array of insults and is critical for CNS development. NAPVSIPQ (NAP), a potent active fragment of ADNP, potentiated axon outgrowth in cerebellar granule neurons by activating the sequential tyrosine phosphorylation of Fyn kinase and the scaffold protein Crk-associated substrate (Cas). Pharmacological inhibition of Fyn kinase or expression of a Fyn kinase siRNA abolished NAP-mediated axon outgrowth. Concentrations of ethanol attained after social drinking blocked NAP-mediated axon outgrowth (IC(50) = 17 mM) by inhibiting NAP activation of Fyn kinase and Cas. These findings identify a mechanism for ADNP regulation of glial-neuronal interactions in developing cerebellum and a pathogenesis of ethanol neurotoxicity. C1 [Charness, Michael E.] VA Boston Healthcare Syst, W Roxbury, MA 02132 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Charness, ME (reprint author), VA Boston Healthcare Syst, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM mcharness@hms.harvard.edu OI Charness, Michael/0000-0002-3301-8966 FU National Institute on Alcohol Abuse and Alcoholism [R37AA12974]; Medical Research Service; Department of Veterans Affairs; William Randolph Hearst Fund FX We thank D. Arambula and C. Menkari for excellent technical assistance, Dr. M. Wilkemeyer for helpful discussions during the initial period of this study, and Dr. H. Colognato (State University of New York, Stony Brook, NY) for pSUPER/YFP/FYN siRNA and pSUPER/YFP plasmids. This study was supported in part by National Institute on Alcohol Abuse and Alcoholism Grant R37AA12974 (to M.E.C.), the Medical Research Service, Department of Veterans Affairs (M.E.C), and the William Randolph Hearst Fund (S.C). NR 37 TC 30 Z9 31 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 DEC 16 PY 2008 VL 105 IS 50 BP 19962 EP 19967 DI 10.1073/pnas.0807758105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 385GI UT WOS:000261802300070 PM 19047645 ER PT J AU Birnbaum, J Chai, TC Ali, TZ Polydefkis, M Stone, JH AF Birnbaum, Julius Chai, Toby C. Ali, Tehmina Z. Polydefkis, Michael Stone, John H. TI A 73-Year-Old Woman With Chronic Pelvic Pain, Burning Toes, and an Eighty-Pound Weight Loss SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID SMALL-FIBER NEUROPATHY; INTERSTITIAL CYSTITIS; PERIPHERAL NEUROPATHY; MICROSCOPIC POLYANGIITIS; VASCULITIC NEUROPATHY; PULMONARY-FIBROSIS; WHIPPLES DISEASE; CONTROLLED-TRIAL; BACILLUS; TOOL C1 [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Birnbaum, Julius; Polydefkis, Michael] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Chai, Toby C.; Ali, Tehmina Z.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, 55 Fruit St,Yawkey 2, Boston, MA 02114 USA. EM jhstone@partners.org NR 30 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD DEC 15 PY 2008 VL 59 IS 12 BP 1825 EP 1831 DI 10.1002/art.24051 PG 7 WC Rheumatology SC Rheumatology GA 382DW UT WOS:000261586300020 PM 19035432 ER PT J AU Angers, M Uldry, M Kong, D Gimble, JM Jetten, AM AF Angers, Martin Uldry, Marc Kong, Dong Gimble, Jeffrey M. Jetten, Anton M. TI Mfsd2a encodes a novel major facilitator superfamily domain-containing protein highly induced in brown adipose tissue during fasting and adaptive thermogenesis SO BIOCHEMICAL JOURNAL LA English DT Article DE beta-adrenergic receptor (beta AR); brown adipose tissue (BAT); permease; symporter; thermogenesis ID DIET-INDUCED THERMOGENESIS; BETA-ADRENERGIC-RECEPTORS; ESCHERICHIA-COLI; MELIBIOSE PERMEASE; ENERGY-EXPENDITURE; MEMBRANE TOPOLOGY; TRANSPORTERS; FAMILY; ALPHA; COACTIVATORS AB This study describes the identification of Mfsd2a (major facilitator superfamily domain-containing protein 2a), a novel mammalian major facilitator superfamily domain-containing protein, and ail additional closely related protein, Mfsd2b. Most intron/exon junctions are conserved between the two genes, suggesting that they are derived from a common ancestor. Mfsd2a and Mfsd2b share a 12 transmembrane alpha-helical domain structure that bears greatest similarity to that of the bacterial Na(+)/melibiose symporters. Confocal microscopy demonstrated that Mfsd2a localizes to the endoplasmic reticulum. Mfsd2a is expressed in many tissues and is highly induced in liver and BAT (brown adipose tissue) during fasting. Mfsd2a displays an oscillatory expression profile in BAT and liver, consistent with a circadian rhythm. Although the basal level of Mfsd2a expression is relatively low in mouse BAT, it is greatly induced during cold-induced thermogenesis and after treatment with beta AR (beta-adrenergic receptor) agonists. This induction is totally abolished in beta-less (beta AR-deficient) mice. These findings indicate that Mfsd2a is greatly up-regulated in BAT during thermogenesis and that its induction is controlled by the beta AR signalling pathway. The observed induction of Mfsd2a expression in cultured BAT cells by dibutyryl-cAMP is in agreement with this conclusion. The present study suggests that Mfsd2a plays a role in adaptive thermogenesis. C1 [Angers, Martin; Jetten, Anton M.] NIEHS, Cell Biol Sect, LRB, Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. [Uldry, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kong, Dong] Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol, Boston, MA 02115 USA. [Gimble, Jeffrey M.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Stem Cell Lab, Baton Rouge, LA 70808 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, LRB, Div Intramural Res,NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU NIEHS (National Institute of Environmental Health Sciences); NIH (National Institutes of Health) [Z01-ES-101586]; CNRU (Clinical Nutrition Research Unit) Center [1P30 DK072476]; NIDDK (National Institute of Diabetes and Digestive and Kidney Disease) FX We thank Or John Pritchard and Or Jennifer Perry for their valuable comments on the manuscript, Laura Miller for her assistance with the mice and Or Xiying Wu for his assistance with the circadian rhythm analysis. This research was supported by the Intramural Research Program of the NIEHS (National Institute of Environmental Health Sciences), NIH (National Institutes of Health) (Z01-ES-101586 awarded to A. M.J.) and by a CNRU (Clinical Nutrition Research Unit) Center Grant 1P30 DK072476 entitled 'Nutritional Programming: Environmental and Molecular Interactions' sponsored by the NIDDK (National Institute of Diabetes and Digestive and Kidney Disease) (awarded to J.M.G.). NR 34 TC 21 Z9 25 U1 0 U2 5 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 15 PY 2008 VL 416 BP 347 EP 355 DI 10.1042/BJ20080165 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 384ZA UT WOS:000261781500004 PM 18694395 ER PT J AU Johnson, AD Handsaker, RE Pulit, SL Nizzari, MM O'Donnell, CJ de Bakker, PIW AF Johnson, Andrew D. Handsaker, Robert E. Pulit, Sara L. Nizzari, Marcia M. O'Donnell, Christopher J. de Bakker, Paul I. W. TI SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap SO BIOINFORMATICS LA English DT Article ID GENOME-WIDE ASSOCIATION; LOCI AB The interpretation of genome-wide association results is confounded by linkage disequilibrium between nearby alleles. We have developed a flexible bioinformatics query tool for single-nucleotide polymorphisms (SNPs) to identify and to annotate nearby SNPs in linkage disequilibrium (proxies) based on HapMap. By offering functionality to generate graphical plots for these data, the SNAP server will facilitate interpretation and comparison of genome-wide association study results, and the design of fine-mapping experiments (by delineating genomic regions harboring associated variants and their proxies). C1 [Handsaker, Robert E.; Nizzari, Marcia M.; de Bakker, Paul I. W.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Handsaker, Robert E.; Nizzari, Marcia M.; de Bakker, Paul I. W.] Harvard Univ, Cambridge, MA 02142 USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, NIH, Framingham, MA 01702 USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] Boston Univ, Sch Med, Framingham, MA 01702 USA. [Pulit, Sara L.; de Bakker, Paul I. W.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02215 USA. [Pulit, Sara L.; de Bakker, Paul I. W.] Harvard Univ, Sch Med, Partners HealthCare Ctr Genet & Genom, Boston, MA 02215 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP de Bakker, PIW (reprint author), MIT, Broad Inst, Cambridge, MA 02142 USA. EM debakker@broad.mit.edu RI Johnson, Andrew/G-6520-2013; de Bakker, Paul/B-8730-2009 OI de Bakker, Paul/0000-0001-7735-7858 FU NHLBI's Framingham Heart Study [N01-HC-25195]; NHLBI CARe (Candidate Gene Association Resource) [N01-HC-65226]; Intramural training program of the NHLBI FX Funding: NHLBI's Framingham Heart Study (N01-HC-25195 to A. D. J.); Intramural training program of the NHLBI (to A. D. J.); NHLBI CARe (Candidate Gene Association Resource) grant (N01-HC-65226 to R. E. H.). NR 9 TC 677 Z9 683 U1 1 U2 16 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD DEC 15 PY 2008 VL 24 IS 24 BP 2938 EP 2939 DI 10.1093/bioinformatics/btn564 PG 2 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 380HL UT WOS:000261456700026 PM 18974171 ER PT J AU Camchong, J Dyckman, KA Austin, BP Clementz, BA McDowell, JE AF Camchong, Jazmin Dyckman, Kara A. Austin, Benjamin P. Clementz, Brett A. McDowell, Jennifer E. TI Common Neural Circuitry Supporting Volitional Saccades and Its Disruption in Schizophrenia Patients and Relatives SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Antisaccades; delayed response tasks; inhibition; saccades; schizophrenia; working memory ID DELAYED-RESPONSE TASK; SPATIAL WORKING-MEMORY; DORSOLATERAL PREFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; EYE-MOVEMENT CONTROL; EVENT-RELATED FMRI; VISUALLY GUIDED SACCADES; ANTISACCADE PERFORMANCE; SMOOTH-PURSUIT; BIOLOGICAL RELATIVES AB Background: People with schizophrenia and their biological relatives have deficits in executive control processes such as inhibition and working memory as evidenced by performance abnormalities on antisaccade (AS) and ocular motor delayed response (ODR) tasks. Methods: The present functional magnetic resonance imaging (fMRI) study was conducted to investigate brain activity associated with these putative indices of schizophrenia risk by: 1) directly comparing neural functioning in 15 schizophrenia patients, 13 of their first-degree biological relatives (primarily siblings), and 14 healthy participants; and 2) assessing executive function associated with volitional saccades by using a combination of AS and ODR tasks. Results: Behavioral data showed that patients and relatives both made more volitional saccade errors. Imaging data demonstrated that within the context of preserved activity in some neural regions in patients and relatives, there were two distinct patterns of disruptions in other regions. First, there were deficits observed only in the schizophrenia group (decreased activity in lateral frontal eye field and supplementary eye field), suggesting a change associated with disease manifestation. Second, there were deficits observed in both patients and relatives (decreased activity in middle occipital gyrus, insula, cuneus, anterior cingulate, and Brodmann area 10 in prefrontal cortex), indicating a potential association with disease risk. Conclusions: Results indicate that decreased brain activation in regions involved in managing and evaluating early sensory and attention processing might be associated with poor volitional saccade control and risk for developing schizophrenia. C1 [Camchong, Jazmin] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Camchong, Jazmin] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Dyckman, Kara A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Austin, Benjamin P.; Clementz, Brett A.; McDowell, Jennifer E.] Univ Georgia, BioImaging Res Ctr, Dept Psychol, Athens, GA 30602 USA. [Clementz, Brett A.; McDowell, Jennifer E.] Univ Georgia, BioImaging Res Ctr, Dept Neurosci, Athens, GA 30602 USA. RP McDowell, JE (reprint author), Univ Georgia, BioImaging Res Ctr, Dept Psychol & Neurosci, UGA Psychol Bldg, Athens, GA 30602 USA. EM jemcd@uga.edu FU National Institute of Mental Health [MH001852, MH57886] FX This research was supported in part by grants from the National Institute of Mental Health (MH001852, MH57886). We would like to thank the subjects who participated in this study, Ms. Caroline Chapman for her assistance with recruitment and data collection, and Mr. Gary Washington for technical ass istance. NR 99 TC 34 Z9 35 U1 1 U2 6 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 DEC 15 PY 2008 VL 64 IS 12 BP 1042 EP 1050 DI 10.1016/j.biopsych.2008.06.015 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 382HA UT WOS:000261595400006 PM 18692173 ER PT J AU Turetsky, BI Greenwood, TA Olincy, A Radant, AD Braff, DL Cadenhead, KS Dobie, DJ Freedman, R Green, MF Gur, RE Gur, RC Light, GA Mintz, J Nuechterlein, KH Schork, NJ Seidman, LJ Siever, LJ Silverman, JM Stone, WS Swerdlow, NR Tsuang, DW Tsuang, MT Calkins, ME AF Turetsky, Bruce I. Greenwood, Tiffany A. Olincy, Ann Radant, Allen D. Braff, David L. Cadenhead, Kristin S. Dobie, Dorcas J. Freedman, Robert Green, Michael F. Gur, Raquel E. Gur, Ruben C. Light, Gregory A. Mintz, James Nuechterlein, Keith H. Schork, Nicholas J. Seidman, Larry J. Siever, Larry J. Silverman, Jeremy M. Stone, William S. Swerdlow, Neal R. Tsuang, Debby W. Tsuang, Ming T. Calkins, Monica E. TI Abnormal Auditory N100 Amplitude: A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Endophenotype; evoked potential; gating; heritability; N100; schizophrenia ID EVENT-RELATED POTENTIALS; EVOKED RESPONSE SUPPRESSION; TRAIT LINKAGE ANALYSIS; CORTICAL DYSFUNCTION; GENETICS; RISK; RELIABILITY; DISCORDANT; DISORDERS; INTERVIEW AB Background: N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multisite National Institute of Mental Health (NIMH) initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes. Methods: Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected first-degree relatives, and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click 2/click 1 ratio were dependent variables. Heritability was estimated based on kinships using Solar v.2.1.2. Group differences were examined after subjects were categorized as either "broad" or "narrow," based on the presence (broad) or absence (narrow) of nonpsychotic psychiatric comorbidity. Results: Heritability estimates were.40 and.29 for click1 and click2 amplitudes and.22 for the ratio. Broad and narrow patients both had impaired click 1 amplitudes. Broad relatives, but not narrow relatives, exhibited similar impairments. There were no group differences for either click 2 amplitude or the gating ratio. Conclusions: N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric comorbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype. C1 [Turetsky, Bruce I.; Gur, Raquel E.; Gur, Ruben C.; Calkins, Monica E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Greenwood, Tiffany A.; Braff, David L.; Cadenhead, Kristin S.; Light, Gregory A.; Swerdlow, Neal R.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Olincy, Ann; Freedman, Robert] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. [Radant, Allen D.; Dobie, Dorcas J.; Tsuang, Debby W.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Radant, Allen D.; Dobie, Dorcas J.; Tsuang, Debby W.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Green, Michael F.; Mintz, James; Nuechterlein, Keith H.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Schork, Nicholas J.] Scripps Genom Med, La Jolla, CA USA. [Schork, Nicholas J.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Seidman, Larry J.; Stone, William S.; Tsuang, Ming T.] Harvard Univ, Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr, Sch Med,Publ Psychiat Div, Boston, MA 02215 USA. Harvard Inst Psychiat Epidemiol & Genet, Boston, MA USA. [Siever, Larry J.; Silverman, Jeremy M.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Siever, Larry J.] James J Peters VA Med Ctr, Bronx, NY USA. [Siever, Larry J.] Mental Illness Res Educ & Clin Ctr, Vet Integrated Serv Network 3, Bronx, NY USA. RP Turetsky, BI (reprint author), Univ Penn, Dept Psychiat, 10th Floor Gates Bldg,3400 Spruce St, Philadelphia, PA 19104 USA. EM turetsky@upenn.edu RI Greenwood, Tiffany/F-6356-2012; Tsuang, Debby/L-7234-2016 OI Greenwood, Tiffany/0000-0002-6080-6503; Tsuang, Debby/0000-0002-4716-1894 FU National Institute of Mental Health; Harvard University [RO1-MH06556]; Mount Sinai School of Medicine [RO1-MH065554]; University of California Los Angeles [RO1-MH65707]; University of California San Diego [R01-MH065571]; University of Colorado [RO1-MH65588]; University of Pennsylvania [RO1-MH65578]; University of Washington [RO1-MH65558]; [MH064045]; [MH43292]; [MH79777] FX This research conducted by the Consortium on the Genetics of Schizophrenia (COGS) and supported by collaborative RO1 Grants from the National Institute of Mental Health to the following institutions: Harvard University RO1-MH06556; Mount Sinai School of Medicine RO1-MH065554; University of California Los Angeles RO1-MH65707; University of California San Diego R01-MH065571; University of Colorado RO1-MH65588; University of Pennsylvania RO1-MH65578; and University of Washington RO1-MH65558. Additional grant support for this study was provided by MH064045 (BIT), MH43292 (MFG), and MH79777 (GAL). NR 53 TC 63 Z9 64 U1 1 U2 3 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 DEC 15 PY 2008 VL 64 IS 12 BP 1051 EP 1059 DI 10.1016/j.biopsych.2008.06.018 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 382HA UT WOS:000261595400007 PM 18701089 ER PT J AU Blauvelt, ML Khalili, M Jaung, W Paulsen, J Anderson, AC Wilson, SB Howell, AR AF Blauvelt, Marisa L. Khalili, Maryam Jaung, Weonjoo Paulsen, Janet Anderson, Amy C. Wilson, S. Brian Howell, Amy R. TI alpha-S-GalCer: Synthesis and evaluation for iNKT cell stimulation SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE CD1d; iNKT cells; alpha-S-GalCer; KRN7000 ID NONOBESE DIABETIC MICE; C-GLYCOSIDE ANALOG; NKT CELLS; T-CELLS; THIOGLYCOSIDE ANALOG; GALACTOSYLCERAMIDE; ACTIVATION; PREVENTS; RECEPTOR; KRN7000 AB The synthesis and evaluation for iNKT stimulation of alpha-S-galactosylceramide is reported. Prepared by alkylation of a galactosylthiol, this analog of the potent immunostimulatory agent, KRN7000, did not stimulate iNKT cells either in vitro or in vivo. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Blauvelt, Marisa L.; Khalili, Maryam; Howell, Amy R.] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA. [Paulsen, Janet; Anderson, Amy C.] Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USA. [Jaung, Weonjoo; Wilson, S. Brian] Massachusetts Gen Hosp, Diabet Res Labs, Cambridge, MA 02139 USA. [Jaung, Weonjoo; Wilson, S. Brian] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. RP Howell, AR (reprint author), Univ Connecticut, Dept Chem, 55 N Eagleville Rd, Storrs, CT 06269 USA. EM amy.howell@uconn.edu FU NIH NIAID [AI057519, 2RO1 AI 45051, U19 AI046130]; JDRF [1-2004-771] FX The authors are grateful for financial support provided by NIH NIAID (AI057519: A. R. H.; 2RO1 AI 45051 and U19 AI046130: S. B. W.) and JDRF 1-2004-771 to S. B. W. NR 36 TC 2 Z9 2 U1 2 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD DEC 15 PY 2008 VL 18 IS 24 BP 6968 EP 6970 DI 10.1016/j.bmcl.2008.10.086 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 375VE UT WOS:000261141100015 PM 18993065 ER PT J AU Moore, RN Dasgupta, A Rajaei, N Yarmush, ML Toner, M Larue, L Moghe, PV AF Moore, Rebecca N. Dasgupta, Anouska Rajaei, Nayyereh Yarmush, Martin L. Toner, Mehmet Larue, Lionel Moghe, Prabhas V. TI Enhanced Differentiation of Embryonic Stem Cells Using Co-Cultivation With Hepatocytes SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE embryonic stem cell; liver; E-cadherin; co-culture; hepatocyte; differentiation ID MARROW STROMAL CELLS; IN-VITRO; ONCOSTATIN-M; E-CADHERIN; HEPATIC DIFFERENTIATION; SANDWICH CONFIGURATION; NONPARENCHYMAL CELLS; LIVER DEVELOPMENT; GROWTH-FACTOR; MATURATION AB We examined the effects of co-cultivated hepatocytes on the hepatospecific differentiation of murine embryonic stem (ES) cells. Utilizing an established mouse ES cell line expressing high or low levels of E-cadherin, that we have previously shown to be responsive to hepatotrophic growth factor stimulation (Dasgupta et al., 2005. Biotechnol Bioeng 92(3):257-266), we compared co-cultures of cadherin-expressing ES (CE-ES) cells with cultured rat hepatocytes, allowing for either paracrine interactions (indirect co-cultures) or both juxtacrine and paracrine interactions (direct co-cultures, random and patterned). Hepatospecific differentiation of ES cells was evaluated in terms of hepatic-like cuboidal morphology, heightened gene expression of late maturation marker, glucose-6-phosphatase in relation to early marker, alpha-fetoprotein (AFP), and the intracellular localization of albumin. Hepatocytes co-cultured with growth factor primed CE-ES cells markedly enhanced ES cell differentiation toward the hepatic lineage, an effect that was reversed through E-cadherin blockage and inhibited in control ES cells with reduced cadherin expression. Comparison of single ES cell cultures versus co-cultures show that direct contact co-cultures of hepatocytes and CE-ES cells maximally promoted ES cell commitment towards hepatodifferentiation, suggesting cooperative effects of cadherin-based juxtacrine and paracrine interactions. In contrast, E-cadherin deficient mouse ES (CD-ES) cells co-cultured with hepatocytes failed to show increased G6P expression, confirming the role of E-cadherin expression. To establish whether albumin expression in CE-ES cells was spatially regulated by co-cultured hepatocytes, we co-cultivated CE-ES cells around micropatterned, pre-differentiated rat hepatocytes. Albumin localization was enhanced "globally" within CE-ES cell colonies and was inhibited through E-cadherin antibody blockage in all but an interfacial band of ES cells. Thus, stem cell based cadherin presentation may be an effective tool to induce hepatotrophic differentiation by leveraging both distal/paracrine and contact/juxtacrine interactions with primary cells of the liver. C1 [Moore, Rebecca N.; Rajaei, Nayyereh; Yarmush, Martin L.; Moghe, Prabhas V.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. [Dasgupta, Anouska; Moghe, Prabhas V.] Rutgers State Univ, Dept Chem & Biochem Engn, Piscataway, NJ USA. [Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA USA. [Toner, Mehmet; Larue, Lionel] Inst Curie, CNRS, UMR Dev Genet Melanocytes 146, F-91405 Orsay, France. RP Moghe, PV (reprint author), Rutgers State Univ, Dept Biomed Engn, 599 Taylor Rd, Piscataway, NJ 08854 USA. EM moghe@rci.rutgers.edu RI Larue, Lionel/F-7355-2013; Larue, Lionel/I-6532-2016 FU New Jersey Commission on Science and Technology [NIH EB001046]; NSF CAREER Award [NSF DGE 03333196 C]; Ligue Nationale contre le Cancer (Equipe labellisee) FX Contract grant sponsor: New Jersey Commission on Science and Technology; Contract grant number: NIH EB001046; Contract grant sponsor: NSF CAREER Award; Contract grant number: NSF DGE 03333196 C; ontract grant sponsor: Rutgers University Academic Excellence Fund; Contract grant sponsor: Ligue Nationale contre le Cancer (Equipe labellisee) NR 56 TC 20 Z9 23 U1 0 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD DEC 15 PY 2008 VL 101 IS 6 BP 1332 EP 1343 DI 10.1002/bit.21987 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 373DC UT WOS:000260950200022 PM 18571804 ER PT J AU Rodrigues, NP Boyd, AS Fugazza, C May, GE Guo, YP Tipping, AJ Scadden, DT Vyas, P Enver, T AF Rodrigues, Neil P. Boyd, Ashleigh S. Fugazza, Cristina May, Gillian E. Guo, YanPing Tipping, Alex J. Scadden, David T. Vyas, Paresh Enver, Tariq TI GATA-2 regulates granulocyte-macrophage progenitor cell function SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; TRANSCRIPTION FACTOR GATA-2; BONE-MARROW; LINEAGE COMMITMENT; IN-VIVO; LYMPHOID PROGENITORS; MYELOID PROGENITOR; EXPRESSION; DIFFERENTIATION; IDENTIFICATION AB The zinc finger transcription factor GATA-2 has been implicated in the regulation of hematopoietic stem cells. Herein, we explored the role of GATA-2 as a candidate regulator of the hematopoietic progenitor cell compartment. We showed that bone marrow from GATA-2 heterozygote (GATA-2(+/-)) mice displayed attenuated granulocyte-macrophage progenitor function in colony-forming cell (CFC) and serial replating CFC assays. This defect was mapped to the Lin(-)CD117(+)Sca-1(-)CD34(+)CD16/32(high) granulocyte-macrophage progenitor (GMP) compartment of GATA-2(+/-) marrow, which was reduced in size and functionally impaired in CFC assays and competitive transplantation. Similar functional impairments were obtained using a RNA interference approach to stably knockdown GATA-2 in wild-type GMP. Although apoptosis and cell-cycle distribution remained unperturbed in GATA-2(+/-) GMP, quiescent cells from GATA-2(+/-) GMP exhibited altered functionality. Gene expression analysis showed attenuated expression of HES-1 mRNA in GATA-2-deficient GMP. Binding of GATA-2 to the HES-1 locus was detected in the myeloid progenitor cell line 32Dcl3, and enforced expression of HES-1 expression in GATA-2(+/-) GMP rectified the functional defect, suggesting that GATA-2 regulates myeloid progenitor function through HES-1. These data collectively point to GATA-2 as a novel, pivotal determinant of GMP cell fate. (Blood. 2008;112:4862-4873) C1 [Rodrigues, Neil P.; Boyd, Ashleigh S.; Fugazza, Cristina; May, Gillian E.; Guo, YanPing; Vyas, Paresh; Enver, Tariq] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC,Hematol Unit, Oxford OX3 9DS, England. [Scadden, David T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA USA. [Scadden, David T.] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Enver, T (reprint author), Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC,Hematol Unit, Oxford OX3 9DS, England. EM tenver@gwmail.jr2.ox.ac.uk OI Vyas, Paresh/0000-0003-3931-0914; Fugazza, Cristina/0000-0003-4242-0540 FU Medical Research Council [, MC_U137973817] NR 46 TC 34 Z9 36 U1 3 U2 11 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 DEC 15 PY 2008 VL 112 IS 13 BP 4862 EP 4873 DI 10.1182/blood-2008-01-136564 PG 12 WC Hematology SC Hematology GA 381CR UT WOS:000261513400017 PM 18840712 ER PT J AU Imai, Y Park, EJ Peer, D Peixoto, A Cheng, GY von Andrian, UH Carman, CV Shimaoka, M AF Imai, Yoichi Park, Eun Jeong Peer, Dan Peixoto, Antonio Cheng, Guiying von Andrian, Ulrich H. Carman, Christopher V. Shimaoka, Motomu TI Genetic perturbation of the putative cytoplasmic membrane-proximal salt bridge aberrantly activates alpha(4) integrins SO BLOOD LA English DT Article ID FUNCTION-ASSOCIATED ANTIGEN-1; UNFOLDED PROTEIN RESPONSE; LYMPHOCYTE MIGRATION; T-CELLS; MICE; ADHESIVENESS; CHEMOKINES; ADHESION; DIFFERENTIATION; TRAFFICKING AB alpha(4) integrins play a pivotal role in leukocyte migration and tissue-specific homing. The ability of integrins to bind ligand is dynamically regulated by activation-dependent conformational changes triggered in the cytoplasmic domain. An NMR solution structure defined a putative membrane-proximal salt bridge between the alpha(parallel to b)beta(3) integrin cytoplasmic tails, which restrains integrins in their low-affinity state. However, the physiological importance of this salt bridge in alpha(4) integrin regulation remains to be elucidated. To address this question, we disrupted the salt bridge in murine germ line by mutating the conserved cytoplasmic arginine R(GFFKR) in alpha(4) integrins. In lymphocytes from knock-in mice (alpha(4)-R/A(GFFKR)), alpha 4 beta 1 and alpha 4 beta 7 integrins exhibited constitutively up-regulated ligand binding. However, transmigration of these cells across VCAM-1 and MAdCAM-1 substrates, or across endothelial monolayers, was reduced. Perturbed detachment of the tail appeared to cause the reduced cell migration of alpha 4-R/A(GFFKR) lymphocytes. In vivo, alpha 4-R/A(GFFKR) cells exhibited increased firm adhesion to Peyer patch venules but reduced homing to the gut. Our results demonstrate that the membrane-proximal salt bridge plays a critical role in supporting proper alpha(4) integrin adhesive dynamics. Loss of this interaction destabilizes the nonadhesive conformation, and thereby perturbs the properly balanced cycles of adhesion and deadhesion required for efficient cell migration.(Blood. 2008; 112: 5007-5015) C1 [Imai, Yoichi; Park, Eun Jeong; Peer, Dan; Shimaoka, Motomu] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Imai, Yoichi; Park, Eun Jeong; Peer, Dan; Peixoto, Antonio; Cheng, Guiying; von Andrian, Ulrich H.; Shimaoka, Motomu] Immune Dis Inst, Boston, MA USA. [Peixoto, Antonio; Cheng, Guiying; von Andrian, Ulrich H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Carman, Christopher V.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Carman, Christopher V.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Shimaoka, M (reprint author), 200 Longwood Ave, Boston, MA 02115 USA. EM shimaoka@idi.harvard.edu RI Peer, Dan/A-1785-2011; von Andrian, Ulrich/A-5775-2008; Carman, Christopher/L-8108-2016 OI Peer, Dan/0000-0001-8238-0673; Carman, Christopher/0000-0001-7358-2548 FU Arthritis Foundation (Atlanta); National Institutes of Health (Bethesda, MD) [AI063421, HL048675]; Nakajima Foundation (Tokyo, Japan); Japan Intractable Diseases Research Foundation (Tokyo, Japan); Yamada Science Foundation (Osaka, Japan); Uehara Memorial Foundation (Tokyo, Japan) FX This work was supported by grants from the Arthritis Foundation (Atlanta, GA; C. V. C.) and the National Institutes of Health (Bethesda, MD), AI063421 and HL048675 (M. S.). Y. I. was partially supported by fellowships from the Nakajima Foundation (Tokyo, Japan), the Japan Intractable Diseases Research Foundation (Tokyo, Japan), the Yamada Science Foundation (Osaka, Japan), and the Uehara Memorial Foundation (Tokyo, Japan). NR 38 TC 21 Z9 22 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 15 PY 2008 VL 112 IS 13 BP 5007 EP 5015 DI 10.1182/blood-2008-03-144543 PG 9 WC Hematology SC Hematology GA 381CR UT WOS:000261513400033 PM 18809756 ER PT J AU Nelson, EA Walker, SR Kepich, A Gashin, LB Hideshima, T Ikeda, H Chauhan, D Anderson, KC Frank, DA AF Nelson, Erik A. Walker, Sarah R. Kepich, Alicia Gashin, Laurie B. Hideshima, Teru Ikeda, Hiroshi Chauhan, Dharminder Anderson, Kenneth C. Frank, David A. TI Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3 SO BLOOD LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; MARROW STROMAL CELLS; SIGNAL TRANSDUCER; CANCER-TREATMENT; GROWTH; ACTIVATION; APOPTOSIS; IDENTIFICATION; TRANSCRIPTION; DEPSIPEPTIDE AB Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival. (Blood. 2008; 112: 5095-5102) C1 [Nelson, Erik A.; Walker, Sarah R.; Kepich, Alicia; Gashin, Laurie B.; Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Anderson, Kenneth C.; Frank, David A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Anderson, Kenneth C.; Frank, David A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Anderson, Kenneth C.; Frank, David A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Frank, DA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Mayer 522B,44 Binney St, Boston, MA 02115 USA. EM david_frank@dfci.harvard.edu OI Grossberg, Laurie/0000-0003-3676-868X FU Multiple Myeloma Research Foundation (Norwalk, CT); Brent Leahey Fund (DanaFarber Cancer Institute) FX This work was supported by the Multiple Myeloma Research Foundation (Norwalk, CT) and the Brent Leahey Fund (DanaFarber Cancer Institute). NR 32 TC 53 Z9 54 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 15 PY 2008 VL 112 IS 13 BP 5095 EP 5102 DI 10.1182/blood-2007-12-129718 PG 8 WC Hematology SC Hematology GA 381CR UT WOS:000261513400042 PM 18824601 ER PT J AU Adamia, S Reichert, AA Kuppusamy, H Kriangkum, J Ghosh, A Hodges, JJ Pilarski, PM Treon, SP Mant, MJ Reiman, T Belch, AR Pilarski, LM AF Adamia, Sophia Reichert, Amanda A. Kuppusamy, Hemalatha Kriangkum, Jitra Ghosh, Anirban Hodges, Jennifer J. Pilarski, Patrick M. Treon, Steven P. Mant, Michael J. Reiman, Tony Belch, Andrew R. Pilarski, Linda M. TI Inherited and acquired variations in the hyaluronan synthase 1 (HAS1) gene may contribute to disease progression in multiple myeloma and Waldenstrom macroglobulinemia SO BLOOD 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 CHRONIC LYMPHOCYTIC-LEUKEMIA; LARGE B-CELL; ABERRANT SOMATIC HYPERMUTATION; MARROW PLASMA-CELLS; POINT MUTATIONS; BLADDER-CANCER; BREAST-CANCER; CYCLIN D1; ATM GENE; EXPRESSION AB To characterize genetic contributions toward aberrant splicing of the hyaluronan synthase 1 (HAS1) gene in multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM), we sequenced 3616 bp in HAS1 exons and introns involved in aberrant splicing, from 17 patients. We identified a total of 197 HAS1 genetic variations (GVs), a range of 3 to 24 GVs/patient, including 87 somatic GVs acquired in splicing regions of HAS1. Nearly all newly identified inherited and somatic GVs in MM and/or WM were absent from B chronic lymphocytic leukemia, nonmalignant disease, and healthy donors. Somatic HAS1 GVs recurred in all hematopoietic cells tested, including normal CD34(+) hematopoietic progenitor cells and T cells, or as tumor-specific GVs restricted to malignant B and plasma cells. An in vitro splicing assay confirmed that HAS1 GVs direct aberrant HAS1 intronic splicing. Recurrent somatic GVs may be enriched by strong mutational selection leading to MM and/or WM. (Blood. 2008; 112: 5111-5121) C1 [Adamia, Sophia; Reichert, Amanda A.; Kuppusamy, Hemalatha; Kriangkum, Jitra; Ghosh, Anirban; Hodges, Jennifer J.; Reiman, Tony; Belch, Andrew R.; Pilarski, Linda M.] Univ Alberta, Cross Canc Inst, Dept Oncol, Edmonton, AB T6G 1Z2, Canada. [Pilarski, Patrick M.] Univ Alberta, Cross Canc Inst, Dept Elect & Comp Engn, Edmonton, AB T6G 1Z2, Canada. [Treon, Steven P.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Mant, Michael J.] Univ Alberta, Cross Canc Inst, Dept Med, Edmonton, AB T6G 1Z2, Canada. RP Pilarski, LM (reprint author), Univ Alberta, Cross Canc Inst, Dept Oncol, 11560 Univ Ave, Edmonton, AB T6G 1Z2, Canada. EM lpilarsk@ualberta.ca RI Pilarski, Patrick/C-3485-2008 OI Pilarski, Patrick/0000-0003-1686-2978 NR 63 TC 13 Z9 13 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 DEC 15 PY 2008 VL 112 IS 13 BP 5111 EP 5121 DI 10.1182/blood-2008-02-141770 PG 11 WC Hematology SC Hematology GA 381CR UT WOS:000261513400044 PM 18815290 ER PT J AU Weisberg, E Roesel, J Bold, G Furet, P Jiang, J Cools, J Wright, RD Nelson, E Barrett, R Ray, A Moreno, D Hall-Meyers, E Stone, R Galinsky, I Fox, E Gilliland, G Daley, JF Lazo-Kallanian, S Kung, AL Griffin, JD AF Weisberg, Ellen Roesel, Johannes Bold, Guido Furet, Pascal Jiang, Jingrui Cools, Jan Wright, Renee D. Nelson, Erik Barrett, Rosemary Ray, Arghya Moreno, Daisy Hall-Meyers, Elizabeth Stone, Richard Galinsky, Ilene Fox, Edward Gilliland, Gary Daley, John F. Lazo-Kallanian, Suzan Kung, Andrew L. Griffin, James D. TI Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; TYROSINE KINASE INHIBITOR; ACUTE MYELOGENOUS LEUKEMIA; ACTIVATING MUTATION; QUANTITATIVE-ANALYSIS; RECEPTOR INHIBITOR; GENE-EXPRESSION; IN-VITRO; AML AB An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML. (Blood. 2008; 112: 5161-5170) C1 [Weisberg, Ellen; Jiang, Jingrui; Nelson, Erik; Barrett, Rosemary; Ray, Arghya; Stone, Richard; Galinsky, Ilene; Daley, John F.; Lazo-Kallanian, Suzan; Griffin, James D.] Dana Farber Canc Inst, Dept Med Oncol Hematol Neoplasia, Boston, MA 02115 USA. [Roesel, Johannes; Bold, Guido; Furet, Pascal] Novartis Pharma AG, Basel, Switzerland. [Cools, Jan] Katholieke Univ Leuven VIB, Dep Mol & Dev Genet, Louvain, Belgium. [Wright, Renee D.; Kung, Andrew L.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Wright, Renee D.; Kung, Andrew L.] Childrens Hosp, Boston, MA 02115 USA. [Moreno, Daisy; Hall-Meyers, Elizabeth] Dana Farber Canc Inst, Anim Resources Facil, Boston, MA 02115 USA. [Stone, Richard] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Stone, Richard; Gilliland, Gary] Brigham & Womens Hosp, Boston, MA 02115 USA. [Fox, Edward] Dana Farber Canc Inst, Mol Diagnost Lab, Boston, MA 02115 USA. RP Griffin, JD (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. EM james_griffin@dfci.harvard.edu OI Cools, Jan/0000-0001-6626-5843; Kung, Andrew/0000-0002-9091-488X FU National Institutes of Health (NIH) [CA66996, CA36167, DK50654]; Center of Research Award from the Leukemia & Lymphoma Society FX J. D. G is supported by National Institutes of Health (NIH) grant CA66996 and a Specialized Center of Research Award from the Leukemia & Lymphoma Society. J. D. G. is also supported by NIH grants CA36167 and DK50654. NR 38 TC 18 Z9 18 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 DEC 15 PY 2008 VL 112 IS 13 BP 5161 EP 5170 DI 10.1182/blood-2008-02-138065 PG 10 WC Hematology SC Hematology GA 381CR UT WOS:000261513400049 PM 18820131 ER PT J AU DAmico, AV Chen, MH Renshaw, AA Loffredo, M Kantoff, PW AF DAmico, Anthony V. Chen, Ming-Hui Renshaw, Andrew A. Loffredo, Marian Kantoff, Philip W. TI Causes of Death in Men Undergoing Androgen Suppression Therapy for Newly Diagnosed Localized or Recurrent Prostate Cancer SO CANCER LA English DT Article DE prostate cancer; androgen suppression therapy; survival; comorbidity ID DEPRIVATION THERAPY; RADIATION-THERAPY; RADICAL PROSTATECTOMY; HORMONAL-THERAPY; RADIOTHERAPY; BRACHYTHERAPY; MORTALITY; CARCINOMA; ADJUVANT; SURVIVAL AB BACKGROUND. The authors estimated and characterized mortality after androgen Suppression therapy (AST) use in men with newly diagnosed localized and recurrent prostate cancer. METHODS. The study cohorts comprised 102 men who were randomized to radiation therapy (RT) and AST and 46 men who underwent salvage AST for recurrence from a randomized trial that compared external beam RT and 6 months of AST to RT. Cox regression multivariable analyses were performed to estimate the mortality hazard ratio (HR) in men with moderate to severe as compared with no or minimal comorbidity, adjusting for age and known prostate cancer prognostic factors. RESULTS. After it median follow-up of 8.4 years (interquartile range: 7.2-9.6 years), prostate cancer-specific mortality (PCSM) comprised 13% and 75% of all mortality in men with newly diagnosed localized and recurrent prostate cancer, respectively There was an increased risk of death in men with moderate to severe as compared with no or minimal comorbidity (adjusted HR [AHR], 11.5; 95% confidence interval [CI], 5.2-25.6; P < .001) in men with newly diagnosed localized prostate cancer hot not in men with recurrent prostate cancer (AHR, 2.5; 95% CI, 0.2-37.8; P = .51). CONCLUSIONS. The ability to measure an increase in the risk of death in men with moderate to severe as compared with no or minimal comorbidity undergoing AST decreases as the risk of PCSM increases, which may explain the discordance in the literature regarding the risk of cardiovascular death and AST use. Cancer 2008; 113:3290-7. (C) 2008 American Cancer Society. C1 [DAmico, Anthony V.; Loffredo, Marian] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02215 USA. [DAmico, Anthony V.; Renshaw, Andrew A.; Loffredo, Marian; Kantoff, Philip W.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Renshaw, Andrew A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. RP DAmico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,L-2 Level, Boston, MA 02215 USA. EM adamico@partners.org NR 22 TC 27 Z9 27 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 15 PY 2008 VL 113 IS 12 BP 3290 EP 3297 DI 10.1002/cncr.23970 PG 8 WC Oncology SC Oncology GA 383HQ UT WOS:000261665100003 PM 18980297 ER PT J AU McMahon, PM Kong, CY Weinstein, MC Tramontano, AC Cipriano, LE Johnson, BE Weeks, JC Gazelle, GS AF McMahon, Pamela M. Kong, Chung Yin Weinstein, Milton C. Tramontano, Angela C. Cipriano, Lauren E. Johnson, Bruce E. Weeks, Jane C. Gazelle, G. Scott TI Adopting Helical CT Screening for Lung Cancer Potential Health Consequences During a 15-Year Period SO CANCER LA English DT Article DE lung cancer; mass screening; computer simulation; computed tomography ID COST-EFFECTIVENESS ANALYSIS; COMPUTED-TOMOGRAPHY; SMOKING-CESSATION; SPIRAL CT; RANDOMIZED FEASIBILITY; LIFE EXPECTANCY; BREAST-CANCER; SMOKERS; MORTALITY; DECISION AB BACKGROUND. Simulation modeling call synthesize data from single-arm studies of lung cancer screening and tumor registries to investigate computed tomography (CT) screening. This study estimated changes in lung cancer outcomes through 2005, had chest CT screening been introduced in 1990. METHODS. Hypothetical individuals with smoking histories representative of 6 US cohorts (white males and females aged 50, 60, and 70 years in 1990) were simulated in the Lung Cancer Policy Model, a comprehensive patient-level simulation model Of lung cancer development, screening, and treatment. A no screening scenario corresponded to observed outcomes. We simulated 3 screening scenarios ill current or former smokers with >= 20 pack-years as follows: 1-time screen in 1990; and annual, and twice-annually screenings beginning in 1990 and ending in 2005. Main outcomes were days of life between 1990 and 2005 and life expectancy in 1990 (estimated by simulating life histories past 2005). RESULTS. All screening scenarios yielded reductions (compared with no screening) in long cancer-specific mortality by 2005, with larger reductions predicted for more frequent screening. Compared with no screening, annual screening of ever-smokers with at least 20 pack-years of cigarette exposure provided ever-smokers with an additional 11 to 33 days of life by 2005, or all additional 3-10 weeks of (undiscounted) life expectancy. In sensitivity analyses, the largest effects on gains from annual screening were due to reductions ill screening adherence and increased smoking cessation. CONCLUSIONS. The adoption of CT screening, had it been available in 1990, might have resulted in a modest gain in life expectancy. Cancer 2008;113:3440-9. (C) 2008 American Cancer Society. C1 [McMahon, Pamela M.; Kong, Chung Yin; Tramontano, Angela C.; Cipriano, Lauren E.; Gazelle, G. Scott] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [McMahon, Pamela M.; Kong, Chung Yin; Weinstein, Milton C.; Gazelle, G. Scott] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [McMahon, Pamela M.; Kong, Chung Yin; Weinstein, Milton C.; Gazelle, G. Scott] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Johnson, Bruce E.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Weinstein, Milton C.; Weeks, Jane C.] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Gazelle, G. Scott] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP McMahon, PM (reprint author), Inst Technol Assessment, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM pamela@mgh-ita.org RI Cipriano, Lauren/C-3521-2017 OI Cipriano, Lauren/0000-0001-5568-4516 FU NCI NIH HHS [K99 CA126147, K99 CA126147-02, R00 CA126147, R01 CA097337, R01 CA097337-03S1, R01 CA97337] NR 51 TC 20 Z9 21 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 15 PY 2008 VL 113 IS 12 BP 3440 EP 3449 DI 10.1002/cncr.23962 PG 10 WC Oncology SC Oncology GA 383HQ UT WOS:000261665100020 PM 18988293 ER PT J AU Miller, SM Bowen, DJ Lyle, J Clark, M Mohr, D Wardle, J Ceballos, R Emmons, K Gritz, E Marlow, L AF Miller, Suzanne M. Bowen, Deborah J. Lyle, Jennifer Clark, Melissa Mohr, David Wardle, Jane Ceballos, Rachel Emmons, Karen Gritz, Ellen Marlow, Laura TI Primary Prevention, Aging, and Cancer: Overview and Future Perspectives SO CANCER LA English DT Article; Proceedings Paper CT Society-of-Behavioral-Medicine Preconference on Cancer and Aging - Challenges and Opportunities across the Cancer Control Continuum CY MAR 21, 2007 CL Washington, DC SP Soc Behav Med DE primary prevention; cancer; behavioral research; aging adults; comorbidity ID PHYSICAL-ACTIVITY; SMOKING-CESSATION; OLDER-ADULTS; RISK; HEALTH; INTERVENTION; EXERCISE; MORTALITY; PROGRAM; OBESITY AB Cancer-specific primary prevention efforts for the geriatric population are not understood well and currently are underused despite the rapidly growing elderly population. It has been established that lifestyle changes, such as smoking cessation, dietary changes, and increasing physical activity, decrease the incidence of cancer in younger Populations. However, a Multitude of conceptual, methodological, and dissemination challenges arise when the objective is to apply primary prevention of cancer to the elderly. For this article, the state of the science was reviewed to reveal barriers in the uptake of cancer-specific primary prevention practices, including the lack of data for the applicability of clinical research findings to older populations. Under-representation of older adults in behavioral trials and research programs is hindering progress in understanding the physical health and lifestyle choices of older individuals. Efforts directed toward prevention in terms of promoting health behaviors may be not only clinically advantageous but also cost-effective. In addition, models for translating research findings on primary prevention from younger individuals to the elderly Population needs to be addressed. Practitioners need to gain a better understanding of the opportunities for cancer-specific primary prevention, because such an understanding could enhance the management of chronic disease. Cancer 2008; 113(12 suppl): 3484-92. (C) 2008 American Cancer Society. C1 [Miller, Suzanne M.; Lyle, Jennifer] Fox Chase Canc Ctr, Psychosocial & Behav Med Program, Philadelphia, PA 19111 USA. [Bowen, Deborah J.] Boston Univ, Dept Social & Behav Sci, Boston, MA 02215 USA. [Clark, Melissa] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Mohr, David] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Wardle, Jane; Marlow, Laura] UCL, Dept Epidemiol & Publ Hlth, London, England. [Ceballos, Rachel] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Emmons, Karen] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Gritz, Ellen] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. RP Miller, SM (reprint author), Fox Chase Canc Ctr, Div Populat Sci Psychosocial & Behav Med, 333 Cottman Ave, Philadelphia, PA 19111 USA. EM suzanne.miller@fccc.edu OI Marlow, Laura/0000-0003-1709-2397 FU CCR NIH HHS [RC1 CA145063-01]; NCI NIH HHS [P30 CA06927, R01 CA104979-01A1, RC1 CA145063-01, P30 CA006927-439046, RC1 CA145063, P30 CA006927, R01 CA104979]; NCRR NIH HHS [UL1 RR025741] NR 57 TC 4 Z9 4 U1 3 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 15 PY 2008 VL 113 IS 12 BP 3484 EP 3492 DI 10.1002/cncr.23945 PG 9 WC Oncology SC Oncology GA 384KQ UT WOS:000261744100002 PM 19058141 ER PT J AU Cooper, ML Adami, HO Gronberg, H Wiklund, F Green, FR Rayman, MP AF Cooper, Matthew L. Adami, Hans-Olov Gronberg, Henrik Wiklund, Fredrik Green, Fiona R. Rayman, Margaret P. TI Interaction between Single Nucleotide Polymorphisms in Selenoprotein P and Mitochondrial Superoxide Dismutase Determines Prostate Cancer Risk SO CANCER RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; SELENIUM SUPPLEMENTATION; NUTRITIONAL PREVENTION; HYDROGEN-PEROXIDE; ALPHA-TOCOPHEROL; SUBSEQUENT RISK; SERUM SELENIUM; HUMAN TUMORS; GENE; EXPRESSION AB Selenium may affect prostate cancer risk via its plasma carrier selenoprotein P which shows dramatically reduced expression in prostate cancer tumors and cell lines. The selenoprotein P (SEPP1) Ala234 single nucleotide polymorphism (SNP) allele is associated with lower plasma selenoprotein P in men, reducing the concentration/activity of other antioxidant selenoproteins. Selenium status also modifies the effect of the mitochondrial superoxide dismutase (SOD2) SNP Ala16Val on prostate cancer risk. We investigated the relationship of these SNPs with prostate cancer risk. DNA from 2,975 cases and 1,896 age-matched controls from the population-based Prostate Cancer in Sweden study were genotyped using TaqMan assays. Cases were designated aggressive or nonaggressive prostate cancers at diagnosis by clinical criteria. Association with prostate cancer was investigated by logistic regression; gene-gene interaction using a general linear model. The mean plasma selenium concentration measured in 169 controls was relatively low (76.0 +/- 17.2 mu g/L). SNP genotype distributions were in Hardy-Weinberg equilibrium. SOD2-Ala16+ men were at a greater risk of prostate cancer [odds ratios (OR), 1.19; 95% confidence intervals (CI), 1.03-1.37] compared with SOD2-Va16 homozygotes. Men homozygous for SEPP1-Ala234 who were also SOD2-Ala16+ had a higher risk of prostate cancer (OR, 1.43; 95% CI, 1.17-1.76) and aggressive prostate cancer (OR, 1.60; 95% CI, 1.22-2.09) than those who were SOD2-Val16 homozygotes (interaction, prostate cancer P = 0.05; aggressive prostate cancer P = 0.01). This interaction was stronger in ever-smokers: SOD2-Ala16+ men homozygous for SEPP1-Ala234 had an almost doubled risk of prostate cancer (OR, 1.97; 95% CI, 1.33-2.91; interaction P = 0.001). In a low-selenium population, SOD2-Ala16+ men homozygous for SEPP1-Ala234 are at an increased risk of prostate cancer/aggressive prostate cancer especially if ever-smokers, because they are likely to produce more mitochondrial H(2)O(2) that they cannot remove, thereby promoting prostate tumor cell proliferation and migration. (Cancer Res 2008;68(24):10171-7] C1 [Rayman, Margaret P.] Univ Surrey, Div Nutr Sci, Fac Med & Hlth Sci, Guildford GU2 7XH, Surrey, England. [Adami, Hans-Olov; Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Adami, Hans-Olov] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Adami, Hans-Olov] Dana Farber Harvard Canc Ctr, Boston, MA USA. RP Rayman, MP (reprint author), Univ Surrey, Div Nutr Sci, Fac Med & Hlth Sci, Guildford GU2 7XH, Surrey, England. EM m.rayman@surrey.ac.uk FU Swedish Cancer Society; Swedish Academy of Sciences; NIH [R03CA110893-2]; U.K. Prostate Cancer Charitable Trust; Lalleniand Animal Nutrition, Blagnac, France FX For the CAPS study, Swedish Cancer Society (Cancerfonden) and Swedish Academy of Sciences; for the current investigation, NIH (R03CA110893-2); the U.K. Prostate Cancer Charitable Trust; and Lalleniand Animal Nutrition, Blagnac, France (postgraduate studentship, M.L. Cooper). NR 42 TC 60 Z9 66 U1 2 U2 13 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 DEC 15 PY 2008 VL 68 IS 24 BP 10171 EP 10177 DI 10.1158/0008-5472.CAN-08-1827 PG 7 WC Oncology SC Oncology GA 386FD UT WOS:000261866800022 PM 19074884 ER PT J AU Shi, YJ Frost, PJ Hoang, BQ Benavides, A Sharma, S Gera, JF Lichtenstein, AK AF Shi, Yijiang Frost, Patrick J. Hoang, Bao Q. Benavides, Angelica Sharma, Sanjai Gera, Joseph F. Lichtenstein, Alan K. TI IL-6-Induced Stimulation of c-Myc Translation in Multiple Myeloma Cells Is Mediated by Myc Internal Ribosome Entry Site Function and the RNA-Binding Protein, hnRNP A1 SO CANCER RESEARCH LA English DT Article ID TRANS-ACTING FACTOR; MESSENGER-RNA; AKT ACTIVITY; CYCLIN D1; MTOR INHIBITORS; EXPRESSION; RAPAMYCIN; ONCOGENE; PATHWAY; GROWTH AB Prior work indicates that c-myc translation is up-regulated in multiple myeloma cells. To test a role for interleukin (IL)-6 in myc translation, we studied the IL-6-responsive ANBL-6 and IL-6-autocrine U266 cell lines as well as primary patient samples. IL-6 increased c-myc translation, which was resistant to rapamycin, indicating a mechanism independent of mammalian target of rapamycin (mTOR) and cap-dependent translation. In contrast, the cytokine enhanced cap-independent translation via a stimulatory effect on the myc internal ribosome entry site (IRES). As known IRES-trans-activating factors (ITAF) were unaffected by IL-6, we used a yeast-three-hybrid screen to identify novel ITAFs and identified hnRNP A1 (A1) as a mediator of the IL-6 effect. At specifically interacted with the myc IRES in filter binding assays as well as EMSAs. Treatment of myeloma cells with IL-6 induced serine phosphorylation of A1 and increased its binding to the myc IRES in vivo in myeloma cells. Primary patient samples also showed binding between A1 and the IRES. RNA interference to knock down hnRNP A1 prevented an IL-6 increase in myc protein expression, myc IRES activity, and cell growth. These data point to hnRNP A1 as a critical regulator of c-myc translation and a potential therapeutic target in multiple myeloma. [Cancer Res 2008;68(24):10215-22] C1 [Shi, Yijiang; Frost, Patrick J.; Hoang, Bao Q.; Benavides, Angelica; Sharma, Sanjai; Gera, Joseph F.; Lichtenstein, Alan K.] Greater Los Angeles VA Healthcare Syst, Dept Med, Los Angeles, CA USA. [Shi, Yijiang; Frost, Patrick J.; Hoang, Bao Q.; Benavides, Angelica; Sharma, Sanjai; Gera, Joseph F.; Lichtenstein, Alan K.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. RP Lichtenstein, AK (reprint author), VA W LA Hosp, W111H,Bldg 500,Room 4237,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM alan.lichtenstein@med.va.gov OI Frost, Patrick/0000-0003-3348-5983 FU Veteran's Administration; Multiple Myeloma Research Foundation; NIH [RO1CA111448, RO1CA109312] FX Veteran's Administration, the Multiple Myeloma Research Foundation, and NIH grants RO1CA111448 (A.K. Lichtenstein) and RO1CA109312 (J. Gera). NR 37 TC 34 Z9 34 U1 0 U2 0 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 DEC 15 PY 2008 VL 68 IS 24 BP 10215 EP 10222 DI 10.1158/0008-5472.CAN-08-1066 PG 8 WC Oncology SC Oncology GA 386FD UT WOS:000261866800027 PM 19074889 ER PT J AU Schneider, BP Winer, EP Foulkes, WD Garber, J Perou, CM Richardson, A Sledge, GW Carey, LA AF Schneider, Bryan P. Winer, Eric P. Foulkes, William D. Garber, Judy Perou, Charles M. Richardson, Andrea Sledge, George W. Carey, Lisa A. TI Triple-Negative Breast Cancer: Risk Factors to Potential Targets SO CLINICAL CANCER RESEARCH LA English DT Article ID BASAL EPITHELIAL PHENOTYPE; GENE-EXPRESSION PROFILES; GERMLINE BRCA1 MUTATIONS; ALPHA-B-CRYSTALLIN; SPORADIC BREAST; MOLECULAR SUBTYPES; PHASE-II; TUMORS; CARCINOMAS; PATTERNS AB Triple-negative breast cancer has recently been recognized as an important subgroup of breast cancer with a distinct outcome and therapeutic approach when compared with other subgroups of breast cancer. Triple-negative breast cancer comprises primarily, but not exclusively, a molecularly distinct subtype of breast cancer, the basal-like subtype. We do not yet have an assay to identify basal-like breast cancer in clinical samples, so triple-negative breast cancer has become a commonly used proxy for this subtype. The molecular biology and pathophysiology of triple-negative breast cancer are not completely understood, but understanding is improving rapidly with the advent of sophisticated molecular biology platforms. Moreover, the established risk factors of breast cancer as a whole may not apply to this unique subgroup of patients. Finally, because triple-negative breast cancer is defined by the absence of a target, there are currently limitations to using a tailored therapeutic approach, leaving conventional cytotoxic therapies as the mainstay. Active preclinical and clinical research programs focus on defining the clinical behavior, delineating the risk factors, and more completely understanding the molecular biology of triple-negative breast cancer to improve prevention, optimize conventional agents, and unveil novel therapeutic targets. This CCR focus article will review the current state of the art on triple-negative breast cancer. C1 [Winer, Eric P.; Garber, Judy; Richardson, Andrea] Dana Farber Canc Inst, Boston, MA 02115 USA. [Foulkes, William D.] McGill Univ, Program Canc Genet, Montreal, PQ, Canada. [Perou, Charles M.; Carey, Lisa A.] Univ N Carolina, Chapel Hill, NC USA. RP Schneider, BP (reprint author), Indiana Canc Pavil,Room 473,535 Barnhill Dr, Indianapolis, IN 46202 USA. EM bpschnei@iupui.edu OI foulkes, william/0000-0001-7427-4651; Perou, Charles/0000-0001-9827-2247 NR 65 TC 207 Z9 216 U1 2 U2 20 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 DEC 15 PY 2008 VL 14 IS 24 BP 8010 EP 8018 DI 10.1158/1078-0432.CCR-08-1208 PG 9 WC Oncology SC Oncology GA 384ZL UT WOS:000261782600007 PM 19088017 ER PT J AU Ogino, S Kirkner, GJ Nosho, K Irahara, N Kure, S Shima, K Hazra, A Chan, AT Dehari, R Giovannucci, EL Fuchs, CS AF Ogino, Shuji Kirkner, Gregory J. Nosho, Katsuhiko Irahara, Natsumi Kure, Shoko Shima, Kaori Hazra, Aditi Chan, Andrew T. Dehari, Reiko Giovannucci, Edward L. Fuchs, Charles S. TI Cyclooxygenase-2 Expression Is an Independent Predictor of Poor Prognosis in Colon Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; TUMOR-INFILTRATING LYMPHOCYTES; ADVANCED COLORECTAL-CANCER; CPG ISLAND; MICROSATELLITE INSTABILITY; PATIENT SURVIVAL; GENE-EXPRESSION; DNA METHYLATION; MISMATCH REPAIR; P53 AB Purpose: Cyclooxygenase-2 (COX-2; PTGS2) is considered to play an important role in colorectal carcinogenesis and is often up-regulated in colon cancers. However, previous data on the influence of COX-2 expression on patient outcome have been conflicting. Experimental Design: Using 662 colon cancers (stage I-IV) in two independent prospective cohorts (the Nurses' Health Study and the Health Professionals Follow-up Study), we detected COX-2 overexpression in 548 (83%) tumors by immunohistochemistry. Cox proportional hazards models were used to compute hazard ratios (HR) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and related molecular events, including the CpG island methylation phenotype, microsatellite instability, and p53, CIMP KRAS, and BRAF mutations. Results: During follow-up of the 662 cases, there were 283 deaths, including 163 colon cancer-specific deaths. Patients with COX-2-positive tumors showed a trend towards an inferior colon cancer-specific mortality [HR, 1.37; 95% confidence interval (95% CI), 0.87-2.14], which became significant after adjusting for tumor stage and other predictors of clinical outcome (multivariate HR, 1.70; 95% CI, 1.06-2.74; P = 0.029). Notably, the prognostic effect of COX-2 expression might differ according to p53 status (P(interaction) = 0.04). Compared with tumors with both COX-2 and p53 negative, COX-2-positive tumors were significantly associated with an increased cancer-specific mortality (multivariate HR, 2.12; 95% CI, 1.23-3.65) regardless of p53 status. A similar trend was observed when overall mortality was used as an outcome. Conclusion: COX-2 overexpression is associated with worse survival among colon cancer patients. The effect of COX-2 on clinical outcome may be modified by p53 status. C1 [Ogino, Shuji] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med,Ctr Mol Oncol Pathol,Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Nosho, Katsuhiko; Irahara, Natsumi; Kure, Shoko; Shima, Kaori; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Ogino, Shuji; Hazra, Aditi; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kirkner, Gregory J.; Hazra, Aditi; Chan, Andrew T.; Giovannucci, Edward L.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Dehari, Reiko] Kanagawa Canc Ctr, Dept Pathol, Yokohama, Kanagawa 2410815, Japan. RP Ogino, S (reprint author), Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med,Ctr Mol Oncol Pathol,Dept Pathol, 44 Binney St,Room JF-215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU NIH [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826]; Bennett Family Fund for Targeted Therapies Research; Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance; Japanese Society for Promotion of Science FX NIH grants P01 CA87969, P01 CA55075, P50 CA127003, and K07 CA122826 (S. Ogino); Bennett Family Fund for Targeted Therapies Research; Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance; and Japanese Society for Promotion of Science fellowship (K. Nosho). NR 50 TC 81 Z9 84 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2008 VL 14 IS 24 BP 8221 EP 8227 DI 10.1158/1078-0432.CCR-08-1841 PG 7 WC Oncology SC Oncology GA 384ZL UT WOS:000261782600031 PM 19088039 ER PT J AU Fuchs, CS Goldberg, RM Sargent, DJ Meyerhardt, JA Wolpin, BM Green, EM Pitot, HC Pollak, M AF Fuchs, Charles S. Goldberg, Richard M. Sargent, Daniel J. Meyerhardt, Jeffrey A. Wolpin, Brian M. Green, Erin M. Pitot, Henry C. Pollak, Michael TI Plasma Insulin-like Growth Factors, Insulin-like Binding Protein-3, and Outcome in Metastatic Colorectal Cancer: Results from Intergroup Trial N9741 SO CLINICAL CANCER RESEARCH LA English DT Article ID PLACEBO-CONTROLLED TRIAL; SERUM C-PEPTIDE; FACTOR-I; FACTOR BINDING-PROTEIN-3; IGF-I; DEFICIENT ADULTS; FACTOR (IGF)-I; RISK; MEN; HORMONE AB Purpose: Insulin-like growth factor (IGF)-I and IGF-II stimulate neoplastic cell growth and inhibit apoptosis, whereas IGF-binding protein-3 (IGFBP-3) inhibits the bioavailability of IGF-I and has independent proapoptotic activity. We examined the influence of baseline plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide on outcome among patients receiving first-line chemotherapy for metastatic colorectal cancer. Experimental Design: The plasma levels of IGF-I, IGF-II, IGFBP-3, and C-peptide as well as data on prognostic factors and body size were measured at baseline among 527 patients participating in a randomized trial of first-line chemotherapy for metastatic colorectal cancer. Results: Higher baseline plasma IGFBP-3 levels were associated with a significantly greater chemotherapy response rate (P = 0.03) after adjusting for other prognostic factors, whereas neither IGF-I nor IGF-II levels significantly predicted tumor response. Higher levels of IGF-I, IGF-II, and IGFBP-3 were all univariately associated with improved overall survival (P = 0.0001 for all). In a model that mutually adjusted for IGF-I and IGFBP-3, as well as other prognostic factors, increasing baseline-circulating IGFBP-3 was associated with a significantly longer time to tumor progression (P = 0.03), whereas circulating IGF-I was not associated with disease progression (P = 0.95). Levels of C-peptide were not associated with any measure of patient outcome. Conclusion: Among colorectal cancer patients receiving first-line chemotherapy, increasing levels of IGFBP-3, an endogenous antagonist to IGF-I, are associated with an improved objective treatment response and a prolonged time to cancer progression. The IGF pathway may represent an important target for future treatment strategies. C1 [Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Wolpin, Brian M.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Wolpin, Brian M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Goldberg, Richard M.] Univ N Carolina, Div Hematol Oncol, Chapel Hill, NC USA. [Sargent, Daniel J.; Green, Erin M.] Mayo Clin, Dept Hlth Sci Res, N Cent Canc Treatment Grp, Rochester, MN USA. [Pitot, Henry C.] Mayo Clin, Div Med Oncol, Rochester, MN USA. [Pollak, Michael] Res Inst Jewish Gen Hosp, Montreal, PQ, Canada. [Pollak, Michael] McGill Univ, Montreal, PQ, Canada. RP Fuchs, CS (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, 75 Francis St, Boston, MA 02115 USA. EM cfuchs@partners.org RI Pollak, Michael/G-9094-2011; Goldberg , Richard/M-1311-2013; OI Pollak, Michael/0000-0003-3047-0604; Sargent, Daniel/0000-0002-2684-4741 FU USPHS [CA-118553,, CA-25224, CA-32102, CA-38926, CA-21115, CA-37404, CA-35195, CA-35101, P50 CA127003] FX USPHS grants CA-118553, CA-25224, CA-32102, CA-38926, CA-21115, CA-37404, CA-35195, CA-35101, and P50 CA127003. NR 47 TC 41 Z9 43 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2008 VL 14 IS 24 BP 8263 EP 8269 DI 10.1158/1078-0432.CCR-08-0480 PG 7 WC Oncology SC Oncology GA 384ZL UT WOS:000261782600036 PM 19073970 ER PT J AU Lipsky, BA Holroyd, KJ Zasloff, M AF Lipsky, Benjamin A. Holroyd, Kenneth J. Zasloff, Michael TI Topical versus Systemic Antimicrobial Therapy for Treating Mildly Infected Diabetic Foot Ulcers: A Randomized, Controlled, Double-Blinded, Multicenter Trial of Pexiganan Cream SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID SAMPLE-SIZE REQUIREMENTS; PEPTIDES; SKIN; CLASSIFICATION; CLAVULANATE; DISEASE AB Background. Topical antimicrobial therapy of infected diabetic foot ulcers can focus on the wound and avoid the adverse effects of systemic anti-infective agents. We compared the efficacy of outpatient treatment using an investigational topical antimicrobial peptide, pexiganan acetate cream, with the efficacy of systemic therapy using an oral fluoroquinolone antibiotic, ofloxacin, for mildly infected diabetic foot ulcers. Methods. In 2 consecutive, double-blind, controlled trials (study 303 and study 304), we randomized diabetic patients with a mildly infected diabetic foot ulcer to receive the active topical agent or active oral antibiotic, plus a respective inactive placebo. The primary outcome of interest was clinical cure or improvement of the infection. Secondary outcomes included eradication of wound pathogens and wound healing, which was documented by a semiquantitative scoring system. Results. Overall, 835 patients were randomized; those in each treatment arm were similar with regard to demographic and clinical characteristics. Although study 303 failed to demonstrate equivalence, study 304 and the combined data for the 2 trials demonstrated equivalent results (within the 95% confidence interval) for topical pexiganan and oral ofloxacin in clinical improvement rates (85%-90%), overall microbiological eradication rates (42%-47%), and wound healing rates. The incidence of worsening cellulitis (2%-4%) and amputation (2%-3%) did not differ significantly between treatment arms. Bacterial resistance to ofloxacin emerged in some patients who received ofloxacin, but no significant resistance to pexiganan emerged among patients who received pexiganan. Conclusions. Topical pexiganan might be an effective alternative to oral antibiotic therapy in treating diabetic patients with a mildly infected foot ulcer, and might reduce the risk of selecting antimicrobial-resistant bacteria. Clinical trials registration. NCT00563394 and NCT00563433. C1 [Lipsky, Benjamin A.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98116 USA. [Lipsky, Benjamin A.] Univ Washington, Sch Med, Seattle, WA USA. [Holroyd, Kenneth J.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Zasloff, Michael] Georgetown Univ, Sch Med, Washington, DC USA. RP Lipsky, BA (reprint author), Vet Affairs Puget Sound Hlth Care Syst, S-111-PCC,1660 S Columbian Way, Seattle, WA 98116 USA. EM Benjamin.Lipsky@med.va.gov RI Lipsky, Benjamin/B-4645-2013; OI Lipsky, Benjamin A./0000-0001-9886-5114 FU MacroChem FX At the time these studies were conducted, K.J.H. and M. Z. were employees of, and B. A. L. was a consultant to, Magainin Pharmaceuticals. B. A. L., K. J. H., and M. Z. have served as consultants to MacroChem. B. A. L. has received research grants from and been a consultant and speaker for Ortho McNeil. NR 30 TC 113 Z9 118 U1 1 U2 24 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2008 VL 47 IS 12 BP 1537 EP 1545 DI 10.1086/593185 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 376DO UT WOS:000261163600011 PM 18990064 ER PT J AU Carino, C Olawaiye, AB Cherfils, S Serikawa, T Lynch, MP Rueda, BR Gonzalez, RR AF Carino, Cecilia Olawaiye, Alexander B. Cherfils, Salandre Serikawa, Takehiro Lynch, Maureen P. Rueda, Bo R. Gonzalez, Ruben R. TI Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE leptin; proangiogenesis molecules; endometrial epithelial cells; endometrial cancer; leptin signaling pathways; VEGF; VEGFR2; LIF; LIFR; IL1; IL-1R ID LEUKEMIA INHIBITORY FACTOR; ENDOTHELIAL GROWTH-FACTOR; ACTIVATED PROTEIN-KINASE; IN-VIVO; SIGNAL-TRANSDUCTION; PROMOTES ANGIOGENESIS; RECEPTOR EXPRESSION; MAMMALIAN TARGET; MENSTRUAL-CYCLE; DISTINCT ROLES AB Several proangiogenic/proinflammatory factors involved in endometrial cancer are regulated by leptin, but the signaling mechanisms responsible for these leptin-induced actions are largely unknown. Here, we report that in benign (primary and HES) and cancerous-endometrial epithelial cells (EEC) (An3Ca, SK-UT2 and Ishikawa), leptin in a dose-dependent manner regulates vascular endothelial growth factor, (VEGF); interleukin-1 beta, (IL-1 beta); leukemia inhibitory factor, (LIF) and their respective receptors, VEGFR2, IL-1R tI and LIFR. Remarkably, leptin induces a greater increase in VEGF/VEGFR2 and LIF levels in cancer than in benign cells. However, IL-1 beta was only increased by leptin in benign primary-EEC. Cancer-EEC expressed higher levels of leptin receptor (full-length OB-Rb and short isoforms) in contrast to benign primary-EEC. Leptin-mediated activation of JAK2 (janus kinase 2) was upstream to the activation of PI-3K (phosphatidylinositol-3 kinase) and/or MAPK (mitogen-activated protein kinase) signaling pathways. Leptin induction of cytokines/receptors generally involved JAK2 and MAPK activation, but PI-3K phosphorylation was required for leptin increase of LIF, IL-1/IL-1R tI. Leptin-mediated activation of mTOR (mammalian target of Rapamycin), mainly linked to MAPK, played a central role in leptin regulation of all cytokines and receptors. These results suggest that leptin's effects are cell-specific and could confer a proliferative or cell survival advantage or possibly promote endometrial thickness. Leptin's effects on proangiogenic molecules were more evident in malignant versus benign cells and may imply that there is an underlying shift in leptin-induced cell signaling pathways in endometrial cancer cells. (C) 2008 Wiley-Liss, Inc. C1 [Cherfils, Salandre; Gonzalez, Ruben R.] Morehouse Sch Med, Dept Microbiol Biochem & Immunol, Atlanta, GA 30310 USA. [Carino, Cecilia; Gonzalez, Ruben R.] Boston Biomed Res Inst, Watertown, MA USA. [Olawaiye, Alexander B.; Serikawa, Takehiro; Lynch, Maureen P.; Rueda, Bo R.; Gonzalez, Ruben R.] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Olawaiye, Alexander B.; Serikawa, Takehiro; Lynch, Maureen P.; Rueda, Bo R.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Gonzalez, RR (reprint author), Morehouse Sch Med, Dept Microbiol Biochem & Immunol, 720 Westview Dr, Atlanta, GA 30310 USA. EM rgonzalez@msm.edu FU NIH [RO1 098333]; Susan G. Komen Foundation for the Cure [BC 504370]; Contraceptive Research and Development Program (CONRAD), Eastern Virginia Medical School [CIG-02-87, CIG-06-113, CIG-07-114]; Boston Biomedical Research Institute (Post doctoral Program); Advanced Medical Research Foundation; Cancer Research and Prevention Foundation FX Grain sponsor: NIH: Grant number: RO1 098333: Grant sponsor: Susan G. Komen Foundation for the Cure: Grant number BC 504370: Grant sponsor: Contraceptive Research and Development Program (CONRAD), Eastern Virginia Medical School: Grant numbers: CIG-02-87, CIG-06-113. CIG-07-114: Grant sponsors: Boston Biomedical Research Institute (Post doctoral Program), Advanced Medical Research Foundation, Cancer Research and Prevention Foundation. NR 70 TC 40 Z9 40 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 15 PY 2008 VL 123 IS 12 BP 2782 EP 2790 DI 10.1002/ijc.23887 PG 9 WC Oncology SC Oncology GA 375KO UT WOS:000261112900008 PM 18798554 ER PT J AU Taylor, TN Dolezal, C Tross, S Holmes, WC AF Taylor, Tonya N. Dolezal, Curtis Tross, Susan Holmes, William C. TI Comparison of HIV/AIDS-Specific Quality of Life Change in Zimbabwean Patients at Western Medicine Versus Traditional African Medicine Care Sites SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE AIDS; health care delivery; HIV; sub-Saharan Africa; quality of life; Zimbabwe ID CLINICAL CASE-DEFINITION; HAT-QOL INSTRUMENT; HIV; UGANDA; HEALERS; QUESTIONNAIRE; RELIABILITY; VALIDITY; OUTCOMES; AIDS AB Context: The rollout of antiretroviral treatment (ART) for the 25 million sub-Saharan Africans living with HIV/AIDS has been hampered by the lack of a western medical infrastructure. Given limited infrastructure, many Africans seek and receive HIV care from traditional African healers. This reality calls for culturally sensitive approaches to ART rollout that make use of local alternative health care providers, and an assessment of the potential quality of life (QOL) benefits of traditional African care (TAC) is imperative. Objective: To examine changes in self-reported health status resulting from TAC and western medical care (WC). Design, Setting, and Patients: QOL in 254 consecutively sampled Zimbabwean patients seeking care at TAC and WC sites was assessed over I month. Main Outcome Measures: Shona translations of the HIV/AID-Stargeted QOL instrument and Medical Outcomes Study HIV Health Survey. Results: After adjustment for baseline QOL scores and variables that differed across care sites, all dimensions of both instruments revealed QOL improvements only in the 155 (61%) patients from TAC sites when compared with the 99 (39%) patients from WC sites. These improvements were significant (P <= 0.01) for the HIV/AIDS-targeted QOL instrument dimensions of overall function, health worries, illness mastery; medication worries, and provider trust, and for the Medical Outcomes Study HIV Health Survey dimensions of general health perceptions, physical function, role function, pain, health distress, and energy/fatigue (range of regression coefficients, 10.0-18.3). Conclusions: Patients from TAC versus WC sites demonstrated significantly greater health status improvement across the majority of QOL dimensions assessed over I month. Though these data are from I rural Community and capture only I month of disease progression, they strongly suggest that the potential benefit of integrating TAC sites in ART rollout programs-particularly in resource-poor settings-may go well beyond cultural sensitivity to impact on health itself and the likely related issues of ART adherence. C1 [Taylor, Tonya N.; Dolezal, Curtis; Tross, Susan] New York State Psychiat Inst & Hosp, HIV Ctr Clin & Behav Studies, Dept Psychiat, New York, NY 10032 USA. [Tross, Susan] Columbia Univ, Dept Psychiat, New York, NY USA. [Tross, Susan] Columbia Univ, Dept Pediat, New York, NY 10027 USA. [Holmes, William C.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Holmes, William C.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Taylor, TN (reprint author), New York State Psychiat Inst & Hosp, HIV Ctr Clin & Behav Studies, Dept Psychiat, 1051 Riverside Drive,Unit 15, New York, NY 10032 USA. EM tnt2109@columbia.edu FU National Institute of Mental Health [1-R03-MH62250-01, T32 MH19139]; Social Science Research Council; The University of Pennsylvania; Zimbabwe National Traditional Healers Association; Zimbabwean Medical Research Council; HIV Center for Clinical and Behavioral Studies [P30-MH43520]; Veterans Affairs Health Services Research; Development Research Career Development Award [RCD 03-029] FX Dr. T.N.T and research were supported by funding from the National Institute of Mental Health (1-R03-MH62250-01) and the Social Science Research Council. The University of Pennsylvania, the Zimbabwe National Traditional Healers Association, and the Zimbabwean Medical Research Council provided institutional support for this research. Dr. T.N.T. is currently supported by a training grant from the National Institute of Mental Health (T32 MH19139) at the HIV Center for Clinical and Behavioral Studies (P30-MH43520; Principal Investigator Anke A. Ehrhardt, PhD.). Dr. WC.H.s involvement was supported by a Veterans Affairs Health Services Research and Development Research Career Development Award (grant no. RCD 03-029). NR 29 TC 10 Z9 10 U1 1 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 DEC 15 PY 2008 VL 49 IS 5 BP 552 EP 556 DI 10.1097/QAI.0b013e31818d5be0 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 376YN UT WOS:000261219000014 PM 18989225 ER PT J AU Schelonka, RL Zemlin, M Kobayashi, R Ippolito, GC Zhuang, YX Gartland, GL Szalai, A Fujihashi, K Rajewsky, K Schroeder, HW AF Schelonka, Robert L. Zemlin, Michael Kobayashi, Ryoki Ippolito, Gregory C. Zhuang, Yingxin Gartland, G. Larry Szalai, Alex Fujihashi, Kohtaro Rajewsky, Klaus Schroeder, Harry W., Jr. TI Preferential Use of D(H) Reading Frame 2 Alters B Cell Development and Antigen-Specific Antibody Production SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CDR-H3 REPERTOIRE; GENE; SELECTION; DIVERSITY; RESPONSES; SEGMENT; GP41; NEUTRALIZATION; SUFFICIENT; MATURATION AB All jawed vertebrates limit use of D(H) reading frames (RFs) that are enriched for hydrophobic amino acids. In BALB/c mice, DFL16.1 RF2 encodes valine and isoleucine. To test whether increased use of RF2 affects B cell function, we examined B cell development and Ab production in mice with an IgH allele (Delta D-D mu FS) limited to use of a single, frameshifted DFL61.1 gene segment. We compared the results of these studies to wild-type mice, as well as those previously obtained in mice limited to use of either a single normal D(H) or a single inverted D(H) that forces use of arginine in CDR-H3. All three of the mouse strains limited to a single D(H) produced fewer immature B cells than wild type. However, whereas mice limited to a single normal D(H) achieved normal B cell numbers in the periphery, mice forced to preferentially use RF2 had reduced numbers of mature B cells in the spleen and bone marrow, mirroring the pattern previously observed in mice enriched for charged CDR-H3s. There were two exceptions. B cells in the mice using RF2 normally populated the marginal zone and peritoneal cavity, whereas mice using inverted RF1 had increased numbers of marginal zone B cells and decreased numbers of B1a cells. When challenged with several T-dependent or T-independent Ags, Ag-specific Ab titers in the mice forced to use RF2 were altered. These findings indicate that B cell development and Ag-specific Ab production can be heavily influenced by the global amino acid content of the CDR-H3 repertoire. The Journal of Immunology, 2008, 181: 8409-8415. C1 [Schelonka, Robert L.; Zemlin, Michael; Kobayashi, Ryoki; Ippolito, Gregory C.; Zhuang, Yingxin; Gartland, G. Larry; Szalai, Alex; Fujihashi, Kohtaro; Schroeder, Harry W., Jr.] Univ Alabama, Dept Med, Dept Microbiol, Dept Genet,Dept Pediat Dent, Birmingham, AL 35294 USA. [Zemlin, Michael] Univ Marburg, Dept Pediat, Marburg, Germany. [Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Schelonka, Robert L.; Zemlin, Michael; Kobayashi, Ryoki; Ippolito, Gregory C.; Zhuang, Yingxin; Gartland, G. Larry; Szalai, Alex; Fujihashi, Kohtaro; Schroeder, Harry W., Jr.] Univ Alabama, Dept Pediat, Birmingham, AL 35294 USA. RP Schroeder, HW (reprint author), Univ Alabama, Dept Med, Dept Microbiol, Dept Genet,Dept Pediat Dent, Shelby Bldg 176,3rd Ave S, Birmingham, AL 35294 USA. EM hwsj@uab.edu FU National Institutes of Health [AI07051, AI42732, AI48115, HD043327, TW02130]; Deutsche Forschungsgemeinschaft [SFB/TR22-TPA17]; Alexander von Humholdi-Stiftung [FLF1071957] FX This work was supported in part by National Institutes of Health Grants AI07051, AI42732, AI48115, HD043327, and TW02130; by Deutsche Forschungsgemeinschaft Grant SFB/TR22-TPA17; and by Alexander von Humholdi-Stiftung FLF1071957. NR 40 TC 16 Z9 16 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2008 VL 181 IS 12 BP 8409 EP 8415 PG 7 WC Immunology SC Immunology GA 382CQ UT WOS:000261583000028 PM 19050258 ER PT J AU Zemlin, M Schelonka, RL Ippolito, GC Zemlin, C Zhuang, Y Gartland, GL Nitschke, L Pelkonen, J Rajewsky, K Schroeder, HW AF Zemlin, Michael Schelonka, Robert L. Ippolito, Gregory C. Zemlin, Cosima Zhuang, Yingxin Gartland, G. Larry Nitschke, Lars Pelkonen, Jukka Rajewsky, Klaus Schroeder, Harry W., Jr. TI Regulation of Repertoire Development through Genetic Control of D(H) Reading Frame Preference SO JOURNAL OF IMMUNOLOGY LA English DT Article ID B-CELL DEVELOPMENT; CODING-END SEQUENCE; V(D)J RECOMBINATION; JUNCTIONAL DIVERSITY; ANTIBODY REPERTOIRE; CDR-H3 REPERTOIRE; SUFFICIENT; GENERATION; SELECTION; MEMBRANE AB In jawed vertebrates most expressed Ig H chains use only one of six possible D, reading frames. Reading frame (RF)1, the preferred reading frame, tends to encode tyrosine and glycine, whereas the other five RFs tend to be enriched for either hydrophobic or charged amino acids. Mechanisms proposed to favor use of RF1 include a preference for deletion over inversion that discourages use of inverted RF1, RF2, and RF3; sequence homology between the 5' terminus of the J(H) and the 3' terminus of the D(H) that promotes rearrangement into RF1; an ATG start site upstream of RF2 that permits production of a truncated D mu protein; stop codons in RF3; and, following surface expression of IgM, somatic, presumably Ag receptor-based selection favoring B cells expressing Igs with tyrosine- and glycine-enriched CDR-H3s. By creating an IgH allele limited to the use of a single, frameshifted DFL16.1 D(H) gene segment, we tested the relative contribution of these mechanisms in determining reading frame preference. D mu-mediated suppression via an allelic exclusion-like mechanism dominated over somatic selection in determining the composition of the CDR-H3 repertoire. Evidence of somatic selection for RF1-encoded tyrosine in CDR-H3 was observed, but only among the minority of recirculating, mature B cells that use D(H) in RF1. These observations underscore the extent to which the sequence of the D(H) acts to delimit the diversity of the Ab repertoire. The Journal of Immunology, 2008, 181: 8416-8424. C1 [Zemlin, Michael; Schelonka, Robert L.; Ippolito, Gregory C.; Zhuang, Yingxin; Gartland, G. Larry; Schroeder, Harry W., Jr.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Zemlin, Michael; Schelonka, Robert L.; Ippolito, Gregory C.; Zhuang, Yingxin; Gartland, G. Larry; Schroeder, Harry W., Jr.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Zemlin, Michael; Schelonka, Robert L.; Ippolito, Gregory C.; Zhuang, Yingxin; Gartland, G. Larry; Schroeder, Harry W., Jr.] Univ Alabama, Dept Genet, Birmingham, AL 35294 USA. [Zemlin, Michael; Schelonka, Robert L.; Ippolito, Gregory C.; Zhuang, Yingxin; Gartland, G. Larry; Schroeder, Harry W., Jr.] Univ Alabama, Dept Pediat Dent, Birmingham, AL 35294 USA. [Zemlin, Michael; Schelonka, Robert L.; Ippolito, Gregory C.; Zhuang, Yingxin; Gartland, G. Larry; Schroeder, Harry W., Jr.] Univ Alabama, Dept Pediat, Birmingham, AL 35294 USA. [Zemlin, Michael; Zemlin, Cosima] Univ Marburg, Dept Pediat, Marburg, Germany. [Nitschke, Lars] Univ Erlangen Nurnberg, Dept Genet, Erlangen, Germany. [Pelkonen, Jukka] Univ Kuopio, Dept Clin Microbiol, FIN-70211 Kuopio, Finland. [Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. RP Schroeder, HW (reprint author), Univ Alabama, Dept Med, Shelby Bldg 176,1530 3rd Ave S, Birmingham, AL 35294 USA. EM hwsj@uab.edu FU National Institutes of Health [AI07051, AI42732, AI48115, HD043327, TW02130]; Deutsche Forschungsgemeinschaft [SFB/TR22-TPA17]; Alexander von Humboldt-Stiftung [FLF1071857] FX This work was supported in part by National Institutes of Health Grants AI07051, AI42732, AI48115, HD043327, and TW02130; by Deutsche Forschungsgemeinschaft SFB/TR22-TPA17; and by Alexander von Humboldt-Stiftung FLF1071857. NR 34 TC 21 Z9 21 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2008 VL 181 IS 12 BP 8416 EP 8424 PG 9 WC Immunology SC Immunology GA 382CQ UT WOS:000261583000029 PM 19050259 ER PT J AU Kasuga, K Yang, R Porter, TF Agrawal, N Petasis, NA Irimia, D Toner, M Serhan, CN AF Kasuga, Kie Yang, Rong Porter, Timothy F. Agrawal, Nitin Petasis, Nicos A. Irimia, Daniel Toner, Mehmet Serhan, Charles N. TI Rapid Appearance of Resolvin Precursors in Inflammatory Exudates: Novel Mechanisms in Resolution SO JOURNAL OF IMMUNOLOGY LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; ALPHA-LINOLENIC ACID; DOCOSAHEXAENOIC ACID; ANTIINFLAMMATORY PROPERTIES; MYOCARDIAL-INFARCTION; RHEUMATOID-ARTHRITIS; LIPID MEDIATORS; SUDDEN-DEATH; HUMAN BLOOD; HUMANS AB Resolution of inflammation is essential. Although supplementation of omega-3 fatty acids is widely used, their availability at sites of inflammation is not known. To this end, a multidisciplinary approach was taken to determine the relationship of circulating omega-3 to inflammatory exudates and the generation of resolution signals. In this study, we monitored resolvin precursors in evolving exudates, which initially paralleled increases in edema and infiltrating neutrophils. We also prepared novel microfluidic chambers to capture neutrophills from a drop of blood within minutes that permitted single-cell monitoring. In these, docosahexaenoic acid-derived resolvin D1 rapidly stopped neutrophil migration, whereas precursor docosahexaenoic acid did not. In second organ injury via ischemia-reperfusion, resolvin metabolically stable analogues were potent organ protectors reducing neutrophils. Together, these results indicate that circulating omega-3 fatty acids rapidly appear in inflammatory sites that require conversion to resolvins that control excessive neutrophil infiltration, protect organs, and foster resolution. The Journal of Immunology, 2008, 181: 8677-8687. C1 [Kasuga, Kie; Yang, Rong; Porter, Timothy F.; Serhan, Charles N.] Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Petasis, Nicos A.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. [Agrawal, Nitin; Irimia, Daniel; Toner, Mehmet] Massachusetts Gen Hosp, BioMEMS Resource Ctr, Charlestown, MA 02129 USA. [Agrawal, Nitin; Irimia, Daniel; Toner, Mehmet] Shriners Hosp Children, Boston, MA 02114 USA. [Agrawal, Nitin; Irimia, Daniel; Toner, Mehmet] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Serhan, CN (reprint author), Brigham & Womens Hosp, Ctr Expt Therapeut & Reperfus Injury, Dept Anesthesiol Perioperat & Pain Med, 75 Francis St, Boston, MA 02115 USA. OI Petasis, Nicos/0000-0002-8864-4446; Irimia, Daniel/0000-0001-7347-2082 FU National Institutes of Health [R37-GM38765]; Specialized Center for Oral Inflammation and Resolution [P50-DE016191]; BioMEMS Resource Center [P41-EB002503]; Arthritis Foundation FX This work was supported in part by National Institutes of Health Grant R37-GM38765 (to C.N.S.): the Specialized Center for Oral Inflammation and Resolution, P50-DE016191 (to C,N.S. and N.A.P.) and the BioMEMS Resource Center, P41-EB002503(to M.T. and D.I.). K.K. is the recipient of a postdoctoral fellowship award from the Arthritis Foundation. NR 62 TC 113 Z9 117 U1 0 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2008 VL 181 IS 12 BP 8677 EP 8687 PG 11 WC Immunology SC Immunology GA 382CQ UT WOS:000261583000058 PM 19050288 ER PT J AU Kee, HL Bhaumik, J Diers, JR Mroz, P Hamblin, MR Bocian, DF Lindsey, JS Holten, D AF Kee, Hooi Ling Bhaumik, Jayeeta Diers, James R. Mroz, Pawel Hamblin, Michael R. Bocian, David F. Lindsey, Jonathan S. Holten, Dewey TI Photophysical characterization of imidazolium-substituted Pd(II), In(III), and Zn(II) porphyrins as photosensitizers for photodynamic therapy SO JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY A-CHEMISTRY LA English DT Article DE Photodynamic therapy; Porphyrin; Photosensitizer; Imidazolium; Photophysics ID EXCITED SINGLET-STATE; FLASH-PHOTOLYSIS; CELLULAR UPTAKE; QUANTUM YIELDS; OXYGEN; COMPLEXES; LUMINESCENCE; FLUORESCENCE; MOLECULES; PHARMACOKINETICS AB The photophysical properties of four imidazolium-substituted metalloporphyrins have been assessed to gain insights into the relative efficacy of the compounds for photodynamic therapy (PDT). A set of zinc(II), palladium(II), and chloro-indium(III) porphyrins all bear a net positive charge owing to the diethylimidazolium unit; one zinc chelate bears a negative charge owing to a bis(sulfobutyl)imidazolium unit. The photophysical properties of the cationic and anionic zinc porphyrins are very similar to one another in organic solvents, phosphate-buffered saline, and in the presence of bovine serum albumin. The properties of the zinc and palladium porphyrins bearing charged peripheral groups are generally similar to those of neutral analogs in organic solvents. The palladium porphyrin shows an essentially quantitative yield (>0.99) of the triplet excited state compared to the zinc porphyrins (similar to 0.9), and all are quantitatively quenched (at the diffusion limit) by molecular oxygen in air-saturated fluid solution. If the rate constant and yield of quenching of the triplet excited state by energy or electron transfer to molecular oxygen is the same in the cellular environment as in solution, then these processes combined with the triplet yield contribute only a factor of 1.3 to the higher PDT activity of analogous palladium versus zinc porphyrins, which is much smaller than what is observed. Therefore, other factors such as transient reduction of the excited porphyrin or delivery to the target site must predominantly underlie the difference in PDT efficacy of these sensitizers. (C) 2008 Elsevier B.V. All rights reserved. C1 [Kee, Hooi Ling; Holten, Dewey] Washington Univ, Dept Chem, St Louis, MO 63130 USA. [Bhaumik, Jayeeta; Lindsey, Jonathan S.] N Carolina State Univ, Dept Chem, Raleigh, NC 27695 USA. [Diers, James R.; Bocian, David F.] Univ Calif Riverside, Dept Chem, Riverside, CA 92521 USA. [Mroz, Pawel; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Mroz, Pawel; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Holten, D (reprint author), Washington Univ, Dept Chem, St Louis, MO 63130 USA. EM holten@wustl.edu RI Lindsey, Jonathan/J-7761-2012; OI Hamblin, Michael/0000-0001-6431-4605 FU National Institutes of Health [GM36238, A1050875]; NIH [5T90 DA022871] FX This work was supported by grants from the National Institutes of Health (GM36238 to J.S.L. and A1050875 to M.R.H.). H.L.K. was supported by the Imaging Sciences Pathway training grant from the NIH (5T90 DA022871) at Washington University. NR 52 TC 48 Z9 49 U1 6 U2 21 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1010-6030 J9 J PHOTOCH PHOTOBIO A JI J. Photochem. Photobiol. A-Chem. PD DEC 15 PY 2008 VL 200 IS 2-3 BP 346 EP 355 DI 10.1016/j.jphotochem.2008.08.006 PG 10 WC Chemistry, Physical SC Chemistry GA 385UR UT WOS:000261839600032 PM 20016663 ER PT J AU Issa, NC Wilkinson, RA Griesemer, A Cooper, DKC Yamada, K Sachs, DH Fishman, JA AF Issa, Nicolas C. Wilkinson, Robert A. Griesemer, Adam Cooper, David K. C. Yamada, Kazuhiko Sachs, David H. Fishman, Jay A. TI Absence of Replication of Porcine Endogenous Retrovirus and Porcine Lymphotropic Herpesvirus Type 1 with Prolonged Pig Cell Microchimerism after Pig-to-Baboon Xenotransplantation SO JOURNAL OF VIROLOGY LA English DT Article ID POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE; CROSS-SPECIES TRANSMISSION; BLOOD MONONUCLEAR-CELLS; MINIATURE SWINE; IN-VIVO; NO EVIDENCE; ENDOTHELIAL-CELLS; NONHUMAN-PRIMATES; PRODUCTIVE INFECTION; PERV INFECTION AB Porcine endogenous retrovirus (PERV), porcine cytomegalovirus (PCMV), and porcine lymphotropic herpesvirus (PLHV) are common porcine viruses that may be activated with immunosuppression for xenotransplantation. Studies of viral replication or transmission are possible due to prolonged survival of xenografts in baboon recipients from human decay-accelerating factor transgenic or alpha-1,3-galactosyltransferase gene knockout miniature swine. Ten baboons underwent xenotransplantation with transgenic pig organs. Graft survival was 32 to 179 days. Recipient serial samples of peripheral blood mononuclear cells (PBMC) and plasma were analyzed for PCMV, PERV, and PLHV-1 nucleic acids and viral replication using quantitative PCR assays. The PBMC contained PERV proviral DNA in 10 animals, PLHV-1 DNA in 6, and PCMV in 2. PERV RNA was not detected in any PBMC or serum samples. Plasma PLHV-1 DNA was detected in one animal. Pig cell microchimerism (pig major histocompatibility complex class I and pig mitochondrial cytochrome c oxidase subunit II sequences) was present in all recipients with detectable PERV or PLHV-1 (85.5%). Productive infection of PERV or PLHV-1 could not be demonstrated. The PLHV-1 viral load did not increase in serum over time, despite prolonged graft survival and pig cell microchimerism. There was no association of viral loads with the nature of exogenous immune suppression. In conclusion, PERV provirus and PLHV-1 DNA were detected in baboons following porcine xenotransplantation. Viral detection appeared to be due to persistent pig cell microchimerism. There was no evidence of productive infection in recipient baboons for up to 6 months of xenograft function. C1 [Issa, Nicolas C.; Wilkinson, Robert A.; Fishman, Jay A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Cooper, David K. C.] Univ Pittsburgh, Med Ctr, Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA. [Griesemer, Adam; Yamada, Kazuhiko; Sachs, David H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02114 USA. RP Fishman, JA (reprint author), Transplant Infect Dis & Compromised Host Program, 55 Fruit St,GRJ 504, Boston, MA 02114 USA. EM jfishman@partners.org FU Public Health Services; NIH-NIAID [PO1-AI45897] FX This study was supported by Public Health Services grant NIH-NIAID PO1-AI45897. NR 53 TC 21 Z9 22 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC 15 PY 2008 VL 82 IS 24 BP 12441 EP 12448 DI 10.1128/JVI.01278-08 PG 8 WC Virology SC Virology GA 376DS UT WOS:000261164000044 PM 18829759 ER PT J AU Bhat-Nakshatri, P Wang, GH Appaiah, H Luktuke, N Carroll, JS Geistlinger, TR Brown, M Badve, S Liu, YL Nakshatri, H AF Bhat-Nakshatri, Poornima Wang, Guohua Appaiah, Hitesh Luktuke, Nikhil Carroll, Jason S. Geistlinger, Tim R. Brown, Myles Badve, Sunil Liu, Yunlong Nakshatri, Harikrishna TI AKT Alters Genome-Wide Estrogen Receptor alpha Binding and Impacts Estrogen Signaling in Breast Cancer SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR; GENE-EXPRESSION; GROWTH-FACTOR; NUCLEAR EXPORT; PROTEIN-KINASE; TGF-BETA; CELLS; ACTIVATION; PHOSPHORYLATION; RESISTANCE AB Estrogen regulates several biological processes through estrogen receptor alpha (ER alpha) and ER beta. ER beta-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ER alpha binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ER alpha binding sites, respectively, with similar to 60% overlap. In both cell types, similar to 40% of estrogen-regulated genes associate with ER alpha binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor beta (TGF-beta), NF-kappa B, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-beta treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ER alpha DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ER alpha binding and estrogen- regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ER alpha-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ER alpha-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome. C1 [Bhat-Nakshatri, Poornima; Appaiah, Hitesh; Luktuke, Nikhil; Nakshatri, Harikrishna] Indiana Univ, Sch Med, Dept Surg, Indianapolis, IN 46202 USA. [Wang, Guohua; Liu, Yunlong] Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Carroll, Jason S.; Geistlinger, Tim R.; Brown, Myles] Dana Farber Canc Inst, Dept Med Oncol, Div Mol & Cellular Oncol, Boston, MA 02115 USA. [Carroll, Jason S.; Geistlinger, Tim R.; Brown, Myles] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Carroll, Jason S.; Geistlinger, Tim R.; Brown, Myles] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Badve, Sunil] Indiana Univ, Sch Med, Dept Pathol, Indianapolis, IN 46202 USA. [Badve, Sunil] Indiana Univ, Sch Med, Dept Internal Med, Indianapolis, IN 46202 USA. [Nakshatri, Harikrishna] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Nakshatri, Harikrishna] Indiana Univ, Sch Med, Walther Oncol Ctr, Indianapolis, IN 46202 USA. RP Nakshatri, H (reprint author), Indiana Univ, Sch Med, Dept Surg, R4-202,1044 W Walnut St, Indianapolis, IN 46202 USA. EM hnakshat@iupui.edu RI Nidumanda, HITESH/B-5744-2015; OI Brown, Myles/0000-0002-8213-1658 FU National Institutes of Health [CA89153]; IU Simon Cancer Center Pilot Project; Breast Cancer Research FX This study was supported by a grant from the National Institutes of Health (CA89153) and IU Simon Cancer Center Pilot Project to H.N. H.N. is Marian J. Morrison Professor of Breast Cancer Research. NR 58 TC 47 Z9 47 U1 0 U2 1 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 DEC 15 PY 2008 VL 28 IS 24 BP 7487 EP 7503 DI 10.1128/MCB.00799-08 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 376EO UT WOS:000261166900020 PM 18838536 ER PT J AU Scarcelli, G Kim, P Yun, SH AF Scarcelli, Giuliano Kim, Pilhan Yun, Seok Hyun TI Cross-axis cascading of spectral dispersion SO OPTICS LETTERS LA English DT Article AB We demonstrate a method of cascading multiple diffractive elements for improving the purity of spectral dispersion, The cross-axis cascade was implemented in a two-stage grating spectrograph, resulting in a hundredfold reduction of stray light and a high dynamic range up to -75 dB. The technique can be used for parallel spectral measurements and processing. (C) 2008 Optical Society of America C1 [Yun, Seok Hyun] Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Yun, SH (reprint author), Harvard Univ, Sch Med, 50 Blossom St, Boston, MA 02114 USA. EM syun@hms.harvard.edu RI Kim, Pilhan/C-1836-2011; OI Kim, Pilhan/0000-0001-8388-1840; scarcelli, giuliano/0000-0002-1736-077X FU United States Department of Defense [FA9550-04-1-0079]; Tosteson Postdoctoral Fellowship; Human Frontier Science Program FX This work was funded in part by the United States Department of Defense (FA9550-04-1-0079), Tosteson Postdoctoral Fellowship (G. Scarcelli), and Cross Disciplinary Fellowship from the Human Frontier Science Program (P. Kim). NR 11 TC 9 Z9 9 U1 1 U2 1 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 DEC 15 PY 2008 VL 33 IS 24 BP 2979 EP 2981 DI 10.1364/OL.33.002979 PG 3 WC Optics SC Optics GA 396RO UT WOS:000262609000033 PM 19079512 ER PT J AU Humbert, M Rasmussen, RA Ong, H Kaiser, FMP Hu, SL Ruprecht, RM AF Humbert, Michael Rasmussen, Robert A. Ong, Helena Kaiser, Fabian M. P. Hu, Shiu-Lok Ruprecht, Ruth M. TI Inducing Cross-Clade Neutralizing Antibodies against HIV-1 by Immunofocusing SO PLOS ONE LA English DT Article AB Background: Although vaccines are important in preventing viral infections by inducing neutralizing antibodies (nAbs), HIV-1 has proven to be a difficult target and escapes humoral immunity through various mechanisms. We sought to test whether HIV-1 Env mimics may serve as immunogens. Methodology/Principal Findings: Using random peptide phage display libraries, we identified the epitopes recognized by polyclonal antibodies of a rhesus monkey that had developed high-titer, broadly reactive nAbs after infection with a simian-human immunodeficiency virus (SHIV) encoding env of a recently transmitted HIV-1 clade C (HIV-C). Phage peptide inserts were analyzed for conformational and linear homology using computational analysis; some peptides mimicked various domains of the original HIV-C Env, such as conformational V3 loop epitopes and the conserved linear region of the gp120 C-terminus. Next, we devised a novel prime/boost strategy to test the immunogenicity of such phage-displayed peptides and primed mice only once with HIV-C gp160 DNA followed by boosting with mixtures of recombinant phages. Conclusions/Significance: This strategy, which was designed to focus the immune system on a few Env epitopes (immunofocusing), not only induced HIV-C gp160 binding antibodies andcross-clade nAbs, but also linked a conserved HIV Env region for the first time to the induction of nAbs: the C-terminus of gp120. The identification of conserved antigen mimics may lead to novel immunogens capable of inducing broadly reactive nAbs. C1 [Rasmussen, Robert A.; Ong, Helena; Kaiser, Fabian M. P.; Ruprecht, Ruth M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Humbert, Michael; Rasmussen, Robert A.; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA USA. [Hu, Shiu-Lok] Univ Washington, Natl Primate Res Ctr, Seattle, WA 98195 USA. RP Humbert, M (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM ruth_ruprecht@dfci.harvard.edu FU NIH [PO1 AI048240, R37 AI034266] FX NIH Grant PO1 AI048240 to RMR, RAR, and SLH and R37 AI034266 to RMR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 22 Z9 22 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 DEC 15 PY 2008 VL 3 IS 12 AR e3937 DI 10.1371/journal.pone.0003937 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437AP UT WOS:000265458200004 PM 19081789 ER PT J AU Pedrelli, P Feldman, GC Vorono, S Fava, M Petersen, T AF Pedrelli, Paola Feldman, Greg C. Vorono, Sienna Fava, Maurizio Petersen, Timothy TI Dysfunctional attitudes and perceived stress predict depressive symptoms severity following antidepressant treatment in patients with chronic depression SO PSYCHIATRY RESEARCH LA English DT Article DE Cognitive-diatheses stress model; Antidepressant treatment; Predictors of treatment response ID COGNITIVE THERAPY; PRIMARY-CARE; SELF-ESTEEM; UNIPOLAR DEPRESSION; MAJOR DEPRESSION; MOOD-STATE; PHARMACOTHERAPY; VULNERABILITY; PSYCHOTHERAPY; REACTIVITY AB Many patients continue to experience depressive symptoms after optimal pharmacological treatment. The aim of this study was to investigate whether Beck's cognitive diathesis stress model of depression would help predict the degree of improvement in the depressive symptoms of patients with chronic depression receiving antidepressant treatment. The study investigated the dysfunctional attitudes, perceived stress, and depressive symptoms of 117 patients with chronic depression before and after they were treated with an 8-week Course of fluoxetine. A hierarchical multiple regression analysis showed a significant effect for the interaction between dysfunctional attitudes and perceived stress explaining severity of depressive symptom following antidepressant treatment. Patients with both high perceived stress and high dysfunctional attitudes prior to treatment reported more depressive symptoms at the end of treatment than patients with high perceived stress and lower dysfunctional attitudes. Surprisingly, in the presence of low perceived stress, patients with higher dysfunctional attitudes experienced less depressive symptoms at the end of treatment than patients with lower dysfunctional attitudes. Results suggest the value of taking into consideration both patients' perceived stress and dysfunctional attitudes when assessing treatment for depressive symptoms. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 [Pedrelli, Paola; Feldman, Greg C.; Vorono, Sienna; Fava, Maurizio; Petersen, Timothy] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Feldman, Greg C.] Simmons Coll, Dept Psychol, Boston, MA 02115 USA. RP Pedrelli, P (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, 50 Staniford,Suite 401, Boston, MA 02114 USA. EM PPedrelli@partners.org NR 44 TC 13 Z9 13 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD DEC 15 PY 2008 VL 161 IS 3 BP 302 EP 308 DI 10.1016/j.psychres.2007.08.004 PG 7 WC Psychiatry SC Psychiatry GA 384BN UT WOS:000261718700005 PM 18976817 ER PT J AU Simeon, D Yehuda, R Knutelska, M Schmeidler, J AF Simeon, Daphne Yehuda, Rachel Knutelska, Margaret Schmeidler, James TI Dissociation versus posttraumatic stress: Cortisol and physiological correlates in adults highly exposed to the World Trade Center attack on 9/11 SO PSYCHIATRY RESEARCH LA English DT Article DE Disaster; Cortisol; Heart rate; Dissociation; Posttraumatic stress; Trier Social Stress Test ID PERITRAUMATIC DISSOCIATION; DEPERSONALIZATION DISORDER; CENTER DISASTER; NOREPINEPHRINE; EARTHQUAKE; SURVIVORS; SEVERITY AB Nine months on average after the World Trade Center (WTC) attack, 21 highly exposed adults and 10 healthy controls without major exposure did not differ in cortisol and physiologic measures. Dissociation and posttraumatic stress symptoms were quantified in the exposed group. Dissociation was associated with greater peritraumatic dissociation and, marginally, childhood trauma, lower plasma cortisol levels at 08.00h, and blunted heart rate reactivity to psychosocial stress. Posttraumatic stress was associated with exposure, peritraumatic distress, and early posttraumatic stress, and marginally associated with peritraumatic dissociation; it was not associated with cortisol or physiologic measures. Urinary cortisol differed significantly in its relationship to dissociation versus posttraumatic stress. This small study emphasizes the importance of dissecting the neurobiology of posttraumatic stress versus dissociative traumatic responses. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Simeon, Daphne; Yehuda, Rachel; Knutelska, Margaret; Schmeidler, James] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Yehuda, Rachel] Bronx Vet Affairs Med Ctr, Dept Psychiat, Bronx, NY USA. RP Simeon, D (reprint author), Mt Sinai Sch Med, Dept Psychiat, Psychiat Box 1230,1 Gustave L Levy Pl, New York, NY 10029 USA. EM daphne.simeon@mssm.edu FU [NIH RO1 MH62414]; [NIH MO1 RR0071] FX The research reported was supported in part by NIH RO1 MH62414 supplement to Dr. Simeon and NIH MO1 RR0071 to the Mount Sinai General Clinical Research Center. NR 26 TC 14 Z9 16 U1 2 U2 10 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 DEC 15 PY 2008 VL 161 IS 3 BP 325 EP 329 DI 10.1016/j.psychres.2008.04.021 PG 5 WC Psychiatry SC Psychiatry GA 384BN UT WOS:000261718700008 PM 18930323 ER PT J AU Metzger, LJ Carson, MA Lasko, NB Paulus, LA Orr, SP Pitman, RK Yehuda, R AF Metzger, Linda J. Carson, Margaret A. Lasko, Natasha B. Paulus, Lynn A. Orr, Scott P. Pitman, Roger K. Yehuda, Rachel TI Basal and suppressed salivary cortisol in female Vietnam nurse veterans with and without PTSD SO PSYCHIATRY RESEARCH LA English DT Article DE Stress disorders; Post-traumatic; Dexamethasone; Comorbidity; Depressive disorder ID POSTTRAUMATIC-STRESS-DISORDER; MAJOR DEPRESSIVE DISORDER; PITUITARY-ADRENAL AXIS; CHILD MALTREATMENT; HPA AXIS; DEXAMETHASONE; ABUSE; COMMUNITY; RESPONSES; SURVIVORS AB It has been suggested that discrepant findings regarding low basal cortisol levels and enhanced suppression of cortisol in response to dexamethasone (DEX) administration in post-traumatic stress disorder (PTSD) may reflect individual differences in gender, trauma type, stage of development at trauma occurrence (e.g., childhood vs. adulthood), early pre-traumatic risk factors, or other individual differences. This study examined salivary cortisol levels at 08.00h and 16.00h as well as cortisol response to 0.50 mg DEX in 40 female Vietnam nurse veterans who had current, chronic PTSD (Current) vs. 43 who never had PTSD (Never). Repeated measures analyses of covariance did not reveal significant group differences in cortisol levels or cortisol suppression. Given that nurses who served in Vietnam had similar exposures, ages at exposure, and duration since exposure to previously studied male Vietnam combat veterans, the present lack of evidence for low cortisol and cortisol hyper-suppression in nurses with PTSD Suggests that previous findings of low cortisol and cortisol hyper-suppression in male Vietnam veterans, females sexually abused as children, and other Populations may reflect risk factors beyond simply having PTSD. Published by Elsevier Ireland Ltd. C1 [Yehuda, Rachel] James J Peters VA Med Ctr, PTSD Program, Bronx, NY USA. [Yehuda, Rachel] Mt Sinai Sch Med, Div Traumat Stress Studies, New York, NY 10029 USA. [Metzger, Linda J.; Lasko, Natasha B.; Paulus, Lynn A.; Orr, Scott P.] VA Med Ctr, Res Serv, Manchester, NH 03104 USA. [Metzger, Linda J.; Lasko, Natasha B.; Orr, Scott P.; Pitman, Roger K.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Metzger, Linda J.; Lasko, Natasha B.; Orr, Scott P.; Pitman, Roger K.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Carson, Margaret A.] St Anselm Coll, Dept Nursing, Manchester, NH 03102 USA. RP Yehuda, R (reprint author), James J Peters VA Med Ctr, PTSD Program, Bronx, NY USA. EM Rachel.yehuda@va.gov FU NIMH NIH HHS [R03 MH057386, R03 MH057386-01, #RO3MH57386] NR 25 TC 12 Z9 13 U1 4 U2 10 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 DEC 15 PY 2008 VL 161 IS 3 BP 330 EP 335 DI 10.1016/j.psychres.2008.04.020 PG 6 WC Psychiatry SC Psychiatry GA 384BN UT WOS:000261718700009 PM 18951637 ER PT J AU Swan, EEL Mescher, MJ Sewell, WF Tao, SL Borenstein, JI AF Swan, Erin E. Leary Mescher, Mark J. Sewell, William F. Tao, Sarah L. Borenstein, Jeffrey I. TI Inner ear drug delivery for auditory applications SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Cochlea; Intracochlear; Intratympanic; Hearing; Local drug delivery; Device; Passive; Active; Pharmacokinetics ID SENSORINEURAL HEARING-LOSS; GUINEA-PIG COCHLEA; ROUND WINDOW MEMBRANE; EMBRYONIC STEM-CELLS; SPIRAL GANGLION NEURONS; CISPLATIN-INDUCED OTOTOXICITY; FIBROBLAST-GROWTH-FACTOR; NEUROTROPHIC FACTOR; GENE-THERAPY; IN-VIVO AB Many inner ear disorders cannot be adequately treated by systemic drug delivery. A blood-cochlear barrier exists, similar physiologically to the blood-brain barrier, which limits the concentration and size of molecules able to leave the circulation and gain access to the cells of the inner ear. However, research in novel therapeutics and delivery systems has led to significant progress in the development of local methods of drug delivery to the inner ear. Intratympanic approaches, which deliver therapeutics to the middle ear, rely on permeation through tissue for access to the structures of the inner ear, whereas intracochlear methods are able to directly insert drugs into the inner ear. Innovative drug delivery systems to treat various inner ear ailments such as ototoxicity, sudden sensorineural hearing loss, autoimmune inner ear disease, and for preserving neurons and regenerating sensory cells are being explored. (c) 2008 Elsevier B.V. All rights reserved. C1 [Swan, Erin E. Leary] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Swan, Erin E. Leary; Mescher, Mark J.; Tao, Sarah L.; Borenstein, Jeffrey I.] Charles Stark Draper Lab Inc, Cambridge, MA 02139 USA. [Sewell, William F.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Sewell, William F.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Sewell, William F.] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Swan, EEL (reprint author), MIT, Dept Mech Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM eswan@draper.com FU NIH [5 R01 DC 006848-02]; U.S. government; Charles Stark Draper Laboratory FX This publication was made possible by Grant Number 5 R01 DC 006848-02 from NIH and Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the U.S. government. The authors are grateful to Charles Stark Draper Laboratory for financial support. NR 207 TC 80 Z9 83 U1 0 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X EI 1872-8294 J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD DEC 14 PY 2008 VL 60 IS 15 BP 1583 EP 1599 DI 10.1016/j.addr.2008.08.001 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 383BT UT WOS:000261649800003 PM 18848590 ER PT J AU Jakkula, E Rehnstrom, K Varilo, T Pietilainen, OPH Paunio, T Pedersen, NL Defaire, U Jarvelin, MR Saharinen, J Freimer, N Ripatti, S Purcell, S Collins, A Daly, MJ Palotie, A Peltonen, L AF Jakkula, Eveliina Rehnstroem, Karola Varilo, Teppo Pietilaeinen, Olli P. H. Paunio, Tiina Pedersen, Nancy L. deFaire, Ulf Jaervelin, Marjo-Riitta Saharinen, Juha Freimer, Nelson Ripatti, Samuli Purcell, Shaun Collins, Andrew Daly, Mark J. Palotie, Aarno Peltonen, Leena TI The Genome-wide Patterns of Variation Expose Significant Substructure in a Founder Population SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID FINNISH-DISEASE HERITAGE; LINKAGE DISEQUILIBRIUM; ASSOCIATION; HOMOZYGOSITY; FINLAND; SCHIZOPHRENIA; INDIVIDUALS; HAPLOTYPE; REVEAL; LOCI AB Although high-density SNP genotyping platforms generate a momentum for detailed genome-wide association (GWA) studies, an offshoot is a new insight into population genetics. Here, we present an example in one of the best-known founder populations by scrutinizing ten distinct Finnish early- and late-settlement subpopulations. By determining genetic distances, homozygosity, and patterns of linkage disequilibrium, we demonstrate that population substructure, and even individual ancestry, is detectable at a very high resolution and Supports the concept of multiple historical bottlenecks resulting from consecutive founder effects. Given that genetic studies are currently aiming at identifying smaller and smaller genetic effects, recognizing and controlling for population substructure even at this fine level becomes imperative to avoid confounding and spurious associations. This study provides an example of the power of GWA data sets to demonstrate stratification caused by population history even within a seemingly homogeneous population, like the Finns. Further, the results provide interesting lessons concerning the impact of population history on the genome landscape of humans, as well as approaches to identify rare variants enriched in these subpopulations. C1 [Jakkula, Eveliina; Rehnstroem, Karola; Varilo, Teppo; Pietilaeinen, Olli P. H.; Paunio, Tiina; Saharinen, Juha; Ripatti, Samuli; Peltonen, Leena] Natl Publ Hlth Inst, Dept Mol Med, Helsinki 00290, Finland. [Jakkula, Eveliina; Purcell, Shaun; Daly, Mark J.; Palotie, Aarno; Peltonen, Leena] Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Jakkula, Eveliina; Purcell, Shaun; Daly, Mark J.; Palotie, Aarno; Peltonen, Leena] MIT, Cambridge, MA 02142 USA. [Rehnstroem, Karola; Varilo, Teppo; Peltonen, Leena] Univ Helsinki, Dept Med Genet, FIN-00290 Helsinki, Finland. [Paunio, Tiina] Univ Helsinki, Cent Hosp, Dept Psychiat, FIN-00290 Helsinki, Finland. [Pedersen, Nancy L.; Ripatti, Samuli] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [deFaire, Ulf] Karolinska Inst, Inst Environm Med, SE-17177 Stockholm, Sweden. [Jaervelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London SW7 2AZ, England. [Jaervelin, Marjo-Riitta] Univ Oulu, Dept Publ Hlth Sci & Gen Practice, SF-90220 Oulu, Finland. [Freimer, Nelson] Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA. [Saharinen, Juha] Biomedicum, Genome Informat Unit, Helsinki 00290, Finland. [Freimer, Nelson] Univ Calif Los Angeles, Jane & Terry Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Freimer, Nelson] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90095 USA. [Purcell, Shaun; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Collins, Andrew] Univ Southampton, Human Genet Res Div, Southampton SO16 6YD, Hants, England. [Palotie, Aarno; Peltonen, Leena] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Jakkula, Eveliina; Palotie, Aarno] Univ Helsinki, Finnish Genome Ctr, Inst Mol Med Finland FIMM, FIN-00290 Helsinki, Finland. [Palotie, Aarno] Univ Helsinki, Dept Clin Chem, FIN-00290 Helsinki, Finland. RP Peltonen, L (reprint author), Natl Publ Hlth Inst, Dept Mol Med, Helsinki 00290, Finland. EM leena.peltonen@ktl.fi RI Collins, Andrew/A-6595-2010; Ripatti, Samuli/H-9446-2014; OI Collins, Andrew/0000-0001-7108-0771; Ripatti, Samuli/0000-0002-0504-1202; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Varilo, Teppo/0000-0002-5839-8854 FU National Institutes of Health [1R01HL087679-01]; STAMPEED, GenomEUtwin [QLG2-CT-2002-01254]; EU [LSHM-CT-2006-03 7761]; Nordic Centre of Excellence in Disease Genetics (NCoEDG); Center of Excellence in Complex Disease Genetics of the Academy of Finland; Helsinki University Finnish Genome Center; National Center for Research Resources [U54 RR020278] FX We thank Murat Gunel and Richard Lifton for provision of control Helsinki genotypes prior to publication, and Arpo, Aromaa for access to the Health2000 samples. Jun Z. Li is gratefully acknowledged for providing tools for Fst analysis. The genotyping for this study has been financially supported by National Institutes of Health grant 1R01HL087679-01, STAMPEED, GenomEUtwin (QLG2-CT-2002-01254), EU grant LSHM-CT-2006-03 7761 (Project SGENE), the Nordic Centre of Excellence in Disease Genetics (NCoEDG), the Center of Excellence in Complex Disease Genetics of the Academy of Finland, and the Helsinki University Finnish Genome Center. The Swedish samples were collected with support from the Swedish Foundation for Strategic Research and the Swedish Research Council (M-2005-1112). The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources. NR 34 TC 81 Z9 81 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC 12 PY 2008 VL 83 IS 6 BP 787 EP 794 DI 10.1016/j.ajhg.2008.11.005 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 385NY UT WOS:000261822100014 PM 19061986 ER PT J AU Emanuelli, B Macotela, Y Boucher, J Kahn, CR AF Emanuelli, Brice Macotela, Yazmin Boucher, Jeremie Kahn, C. Ronald TI SOCS-1 deficiency does not prevent diet-induced insulin resistance SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Insulin resistance; Diabetes; Obesity; Cytokines; SOCS; Inflammation; High fat diet ID INDUCED OBESITY; ADIPOSE-TISSUE; LEPTIN SENSITIVITY; PROTEINS; MICE; SUPPRESSORS; RECEPTOR; PHOSPHORYLATION; INFLAMMATION; BETA AB Obesity is associated with inflammation and increased expression of suppressor of cytokine signaling (SOCS) proteins, which inhibit cytokine and insulin signaling. Thus, reducing SOCS expression could prevent the development of obesity-induced insulin resistance. Using SOCS-1 knockout mice, we investigated the contribution of SOCS-1 in the development of insulin resistance induced by a high-fat diet (HFD). SOCS-1 knockout mice on HFD gained 70% more weight, displayed a 2.3-fold increase in epididymal fat pads mass and increased hepatic lipid content. This was accompanied by increased mRNA expression of leptin and the macrophage marker CD68 in white adipose tissue and of SREBP1c and FAS in liver. HFD also induced hyperglycemia in SOCS-1 deficient mice with impairment of glucose and insulin tolerance tests. Thus, despite the role of SOCS proteins in obesity-related insulin resistance, SOCS-1 deficiency alone is not able to prevent insulin resistance induced by a diet rich in fat. (C) 2008 Elsevier Inc. All rights reserved. C1 [Emanuelli, Brice; Macotela, Yazmin; Boucher, Jeremie; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu RI Emanuelli, Brice/M-2097-2016; OI Emanuelli, Brice/0000-0001-5795-5666 FU National Institutes of Health [DK33201]; American Diabetes Association award; Pew Latin American Fellows Program FX This work was supported by National Institutes of Health Grant DK33201. BE acknowledges support from the mentor-based American Diabetes Association award. Y.M. was supported by the Pew Latin American Fellows Program in the Biomedical Sciences and by the minority mentor-based American Diabetes Association award. NR 21 TC 10 Z9 11 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 12 PY 2008 VL 377 IS 2 BP 447 EP 452 DI 10.1016/j.bbrc.2008.09.158 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 378DO UT WOS:000261301600023 PM 18929539 ER PT J AU Raaijmakers, MHGP Scadden, DT AF Raaijmakers, Marc H. G. P. Scadden, David T. TI Divided within: Heterogeneity within Adult stem Cell Pools SO CELL LA English DT Editorial Material ID IN-VIVO AB In this issue, Wilson et al. (2008) demonstrate that there are two functional subsets of hematopoietic stem cells that have distinctive kinetics of cell cycling. They present evidence that cells may transition between the two kinetic states, establishing one subpopulation that is ready to proliferate and another that is a deeply quiescent reserve. C1 [Raaijmakers, Marc H. G. P.; Scadden, David T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. [Raaijmakers, Marc H. G. P.; Scadden, David T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Raaijmakers, Marc H. G. P.; Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Raaijmakers, Marc H. G. P.; Scadden, David T.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Scadden, DT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. EM dscadden@mgh.harvard.edu NR 9 TC 17 Z9 17 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD DEC 12 PY 2008 VL 135 IS 6 BP 1006 EP + DI 10.1016/j.cell.2008.11.034 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 382ZB UT WOS:000261642800015 PM 19070570 ER PT J AU Shum, WWC Da Silva, N Mckee, M Smith, PJS Brown, D Breton, S AF Shum, Winnie Wai Chi Da Silva, Nicolas McKee, Mary Smith, Peter J. S. Brown, Dennis Breton, Sylvie TI Transepithelial Projections from Basal Cells Are Luminal Sensors in Pseudostratified Epithelia SO CELL LA English DT Article ID ANGIOTENSIN-CONVERTING ENZYME; MALE REPRODUCTIVE-TRACT; ENDOTHELIAL NITRIC-OXIDE; EPIDIDYMAL CLEAR CELLS; RAT EPIDIDYMIS; INTERCALATED CELLS; TIGHT JUNCTIONS; MALE-FERTILITY; STEM-CELLS; H+-ATPASE AB Basal cells are by definition located on the basolateral side of several epithelia, and they have never been observed reaching the lumen. Using high-resolution 3D confocal imaging, we report that basal cells extend long and slender cytoplasmic projections that not only reach toward the lumen but can cross the tight junction barrier in some epithelia of the male reproductive and respiratory tracts. In this way, the basal cell plasma membrane is exposed to the luminal environment. In the epididymis, in which luminal acidification is crucial for sperm maturation and storage, these projections contain the angiotensin II type 2 receptor (AGTR2). Activation of AGTR2 by luminal angiotensin II, increases proton secretion by adjacent clear cells, which are devoid of AGTR2. We propose a paradigm in which basal cells scan and sense the luminal environment of pseudostratified epithelia and modulate epithelial function by a mechanism involving crosstalk with other epithelial cells. C1 [Shum, Winnie Wai Chi; Da Silva, Nicolas; McKee, Mary; Brown, Dennis; Breton, Sylvie] Massachusetts Gen Hosp, Div Nephrol, Program Membrane Biol, Ctr Syst Biol, Boston, MA 02114 USA. [Shum, Winnie Wai Chi; Da Silva, Nicolas; Brown, Dennis; Breton, Sylvie] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Smith, Peter J. S.] Marine Biol Lab, Mol Physiol Program, BioCurrents Res Ctr, Woods Hole, MA 02543 USA. RP Breton, S (reprint author), Massachusetts Gen Hosp, Div Nephrol, Program Membrane Biol, Ctr Syst Biol, Boston, MA 02114 USA. EM sbreton@partners.org FU National Institute of Health [HD40793, DK38452, DK42956]; NCRR [P41 RR001395]; Boston Area Diabetes and Endocrinology Research Center [DK57521]; Center for the Study of Inflammatory Bowel Disease [DK43341] FX This work was supported by National Institute of Health grants HD40793 (S. B.), DK38452 (S. B. and D. B.), DK42956 (D. B.), and NCRR P41 RR001395 grant (P.J.S. Smith). The Microscopy Core facility of the MGH Program in Membrane Biology receives support from the Boston Area Diabetes and Endocrinology Research Center (DK57521) and the Center for the Study of Inflammatory Bowel Disease (DK43341). NR 57 TC 64 Z9 70 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 12 PY 2008 VL 135 IS 6 BP 1108 EP 1117 DI 10.1016/j.cell.2008.10.020 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 382ZB UT WOS:000261642800026 PM 19070580 ER PT J AU Song, JJ Kingston, RE AF Song, Ji-Joon Kingston, Robert E. TI WDR5 Interacts with Mixed Lineage Leukemia (MLL) Protein via the Histone H3-binding Pocket SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STRUCTURAL BASIS; MOLECULAR RECOGNITION; H3; COMPLEX AB WDR5 is a component of the mixed lineage leukemia (MLL) complex, which methylates lysine 4 of histone H3, and was identified as a methylated Lys-4 histone H3-binding protein. Here, we present a crystal structure of WDR5 bound to an MLL peptide. Surprisingly, we find that WDR5 utilizes the same pocket shown to bind histone H3 for this MLL interaction. Furthermore, the WDR5-MLL interaction is disrupted preferentially by mono- and di-methylated Lys-4 histone H3 over unmodified and tri-methylated Lys-4 histone H3. These data implicate a delicate interplay between the effector, WDR5, the catalytic subunit, MLL, and the substrate, histone H3, of the MLL complex. We suggest that the activity of the MLL complex might be regulated through this interplay. C1 [Kingston, Robert E.] Harvard Univ, Sch Med, Dept Mol Biol, Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kingston, RE (reprint author), Harvard Univ, Sch Med, Dept Mol Biol, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM kingston@molbio.mgh.harvard.edu RI Song, Ji-Joon/C-1721-2011 FU National Institutes of Health FX This work was supported, in whole or in part, by grants from the National Institutes of Health (to R. E. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 10 TC 79 Z9 82 U1 2 U2 10 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 DEC 12 PY 2008 VL 283 IS 50 BP 35258 EP 35264 DI 10.1074/jbc.M806900200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 380MF UT WOS:000261469100081 PM 18840606 ER PT J AU Cecconia, JP Lopes, AC Duran, FLDS Santos, LC Hoexter, MQ Gentil, AF Canteras, MM de Castro, CC Noren, G Greenberg, BD Rauch, SL Busatto, GF Miguel, EC AF Cecconia, Janaina Philippi Lopes, Antonio Carlos Duran, Fabio Luis de Souza Santos, Luciana Cristina Hoexter, Marcelo Queiroz Gentil, Andre Felix Canteras, Miguel Montes de Castro, Claudio Campi Noren, George Greenberg, Benjamin D. Rauch, Scott L. Busatto, Geraldo F. Miguel, Euripedes Constantino TI Gamma ventral capsulotomy for treatment of resistant obsessive-compulsive disorder: A structural MRI pilot prospective study SO NEUROSCIENCE LETTERS LA English DT Article DE Obsessive-compulsive disorder (OCD); Magnetic resonance imaging (MRI); Voxel-based morphometry; Radiosurgery; Neurosurgery ID GLUCOSE METABOLIC-RATE; NEUROSURGICAL TREATMENT; MATTER ABNORMALITIES; VOLUME REDUCTION; BRAIN-REGIONS; PAROXETINE; DECREASE; THERAPY; CORTEX; SCALE AB Objective: The purpose of this study was to investigate regional structural abnormalities in the brains of five patients with refractory obsessive-compulsive disorder (OCD) submitted to gamma ventral capsulotomy. Methods: We acquired morphometric magnetic resonance imaging (MRI) data before and after 1 year of radiosurgery using a 1.5-T MRI scanner. Images were spatially normalized and segmented using optimized voxel-based morphometry (VBM) methods. Voxelwise statistical comparisons between pre- and post-surgery MRI scans were performed using a general linear model. Findings in regions predicted a priori to show volumetric changes (orbitofrontal cortex, anterior cingulate gyrus, basal ganglia and thalamus) were reported as significant if surpassing a statistical threshold of p<0.001 (uncorrected for multiple comparisons). Results: We detected a significant regional postoperative increase in gray matter volume in the right inferior frontal gyri (Brodmann area 47, BA47) when comparing all patients pre and postoperatively. Conclusions: Our results support the current theory of frontal-striatal-thalamic-cortical (FSTC) circuitry involvement in OCD pathogenesis. Gamma ventral capsulotomy is associated with neurobiological changes in the inferior orbitofrontal cortex in refractory OCD patients. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Cecconia, Janaina Philippi] Univ Sao Paulo, Sch Med, Dept Psychiat,FMUSP, Obsess Compuls Spectrum Disorders Program PROTOC, BR-01060970 Sao Paulo, Brazil. [Hoexter, Marcelo Queiroz] Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo, Brazil. [Canteras, Miguel Montes] Hosp Santa Paula, Inst Neurol Radiosurg, Sao Paulo, Brazil. [Noren, George; Greenberg, Benjamin D.] Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Noren, George; Greenberg, Benjamin D.] Brown Univ, Dept Clin Neurosci Neurosurg, Providence, RI 02912 USA. [Rauch, Scott L.] Harvard Univ, Sch Med, Boston, MA USA. [Rauch, Scott L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Cecconia, JP (reprint author), Univ Sao Paulo, Sch Med, Dept Psychiat,FMUSP, Obsess Compuls Spectrum Disorders Program PROTOC, Dr Ovidio Pires Campos 785,3 Andar,Sala 9, BR-01060970 Sao Paulo, Brazil. EM janainaphilippi@gmail.com RI Miguel, Euripedes/B-2871-2008; Castro, Claudio/J-3139-2012; Duran, Fabio/A-9744-2013; Busatto, Geraldo/D-4431-2009; Duran, Fabio/L-1371-2013; Duran, Fabio/I-5704-2012; Lopes, Antonio/A-7844-2010; Hoexter, Marcelo/D-7620-2013 OI Castro, Claudio/0000-0002-3531-4232; Duran, Fabio/0000-0002-7603-6152; Duran, Fabio/0000-0002-7603-6152; Duran, Fabio/0000-0003-2494-7250; Lopes, Antonio/0000-0002-3075-6795; Hoexter, Marcelo/0000-0002-9302-4380 FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [1999/08560-6, 2005/55628-08]; Conselho Nacional de Desenvolvimento Cientifico a Tecnologico [305548/2005-0] FX This study received financial support in the form of grants to Dr. Miguel from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, Foundation for the Support of Research in the State of Sao Paulo; grant #1999/08560-6 and #2005/55628-08), and from the Conselho Nacional de Desenvolvimento Cientifico a Tecnologico (CNPq, National Counsel of Scientific and Technological Development; grant no. 305548/2005-0). NR 38 TC 18 Z9 18 U1 4 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD DEC 12 PY 2008 VL 447 IS 2-3 BP 138 EP 142 DI 10.1016/j.neulet.2008.09.061 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 381PV UT WOS:000261549300009 PM 18835422 ER PT J AU Ullrich, RT Zander, T Neumaier, B Koker, M Shimamura, T Waerzeggers, Y Borgman, CL Tawadros, S Li, HF Sos, ML Backes, H Shapiro, GI Wolf, J Jacobs, AH Thomas, RK Winkeler, A AF Ullrich, Roland T. Zander, Thomas Neumaier, Bernd Koker, Mirjam Shimamura, Takeshi Waerzeggers, Yannic Borgman, Christa L. Tawadros, Samir Li, Hongfeng Sos, Martin L. Backes, Heiko Shapiro, Geoffrey I. Wolf, Juergen Jacobs, Andreas H. Thomas, Roman K. Winkeler, Alexandra TI Early Detection of Erlotinib Treatment Response in NSCLC by 3 '-Deoxy-3 '-[F-18]-Fluoro-L-Thymidine ([F-18]FLT) Positron Emission Tomography (PET) SO PLOS ONE LA English DT Article AB Background: Inhibition of the epidermal growth factor receptor ( EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking. Methodology/Principal Findings: We performed a systematic comparison of 39-Deoxy-39-[18F]-fluoro-L-thymidine ([F-18]FLT) and 2-[F-18]-fluoro-2-deoxy-D-glucose ([F-18]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [F-18]FLT uptake after only two days of treatment, [F-18]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [F-18]FLT PET but not [F-18]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [F-18]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [F-18]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. Conclusions: [F-18]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [F-18]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC. C1 [Neumaier, Bernd; Koker, Mirjam; Waerzeggers, Yannic; Li, Hongfeng; Sos, Martin L.; Backes, Heiko; Jacobs, Andreas H.; Thomas, Roman K.; Winkeler, Alexandra] Univ Cologne, Max Planck Inst Neurol Res, Max Planck Soc, Fac Med,Klaus Joachim Zulch Labs, Cologne, Germany. [Ullrich, Roland T.; Jacobs, Andreas H.; Winkeler, Alexandra] Ctr Mol Med Cologne CMMC, Cologne, Germany. [Jacobs, Andreas H.] Klin Fulda, Fulda, Germany. [Shimamura, Takeshi; Borgman, Christa L.; Shapiro, Geoffrey I.] Harvard Univ, Med Sch, Dana Farber Canc Inst, Brigham & Womens Hosp, Dept Med Oncol, Boston, MA USA. [Shimamura, Takeshi; Borgman, Christa L.; Shapiro, Geoffrey I.] Harvard Univ, Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA USA. [Zander, Thomas; Tawadros, Samir; Wolf, Juergen; Thomas, Roman K.] Univ Cologne, Ctr Integrated Oncol Koln Bonn, Dept Internal Med I, D-5000 Cologne, Germany. [Thomas, Roman K.] Max Planck Soc, Chem Genom Ctr, Dortmund, Germany. RP Ullrich, RT (reprint author), Univ Cologne, Max Planck Inst Neurol Res, Max Planck Soc, Fac Med,Klaus Joachim Zulch Labs, Cologne, Germany. EM nini@nf.mpg.de FU Koeln Fortune Program, University of Cologne; International Association for the Study of Lung Cancer (IASLC) [fellow]; Deutsche Krebshilfe [107954]; German Ministry of Science and Education as part of the German National Genome Research Network (NGFNplus) program; 6th FW EU grant EMIL [LSHC-CT-2004-503569]; EC-FP6-Project DiMI [LSHB-CT-2005-512146]; EC-FP6-Clinigene [LSBH-CT-06-018933] FX RTU is supported by the Koeln Fortune Program, University of Cologne. RTK is a fellow of the International Association for the Study of Lung Cancer (IASLC). This work was supported by the Deutsche Krebshilfe through grant 107954 to RTK and by the German Ministry of Science and Education as part of the German National Genome Research Network (NGFNplus) program. YW, AHJ and AW are supported by the 6th FW EU grant EMIL (LSHC-CT-2004-503569), EC-FP6-Project DiMI (LSHB-CT-2005-512146) and EC-FP6-Clinigene (LSBH-CT-06-018933). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 62 Z9 63 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 DEC 12 PY 2008 VL 3 IS 12 AR e3908 DI 10.1371/journal.pone.0003908 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 436ZW UT WOS:000265456300001 PM 19079597 ER PT J AU Lukacs-Kornek, V Turley, SJ AF Lukacs-Kornek, Veronika Turley, Shannon J. TI IMMUNOLOGY Chaperone Puts the Brakes On SO SCIENCE LA English DT Editorial Material ID ANTIGEN PRESENTATION; DENDRITIC CELLS; TRAFFICKING; MIGRATION C1 [Lukacs-Kornek, Veronika; Turley, Shannon J.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Lukacs-Kornek, V (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM shannon_turley@dfci.harvard.edu NR 11 TC 2 Z9 2 U1 1 U2 1 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 DEC 12 PY 2008 VL 322 IS 5908 BP 1640 EP 1641 DI 10.1126/science.1168103 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 382LU UT WOS:000261608300027 PM 19074333 ER PT J AU Raff, H Sluss, PM AF Raff, Hershel Sluss, Patrick M. TI Pre-analytical issues for testosterone and estradiol assays SO STEROIDS LA English DT Article; Proceedings Paper CT CDC Workshop on Improving Steroid Hormone Measurements in Patient Care and Research Translation CY MAR 17-18, 2008 CL Atlanta, GA SP Ctr Dis Control, Div Lab Sci DE Pre-analytical error; Testosterone; Estrogen; Biological rhythms ID SEX-HORMONE LEVELS; LUTEINIZING-HORMONE; LABORATORY MEDICINE; STEROID-HORMONES; OLDER MEN; BLOOD; STABILITY; TUBES; SAMPLES; PLASMA AB In order to standardize and harmonize testosterone measurement, it is vital to identify and minimize pre-analytical error as well as standardize them when developing reference intervals. These pre-analytic issues can be separated into technical and biological factors. Technical factors to address are the type of sample (serum vs. plasma), the type of collection tube, and the processing, storage, and handling of the samples. Biological issues include addressing the age of the subject, the time of day and month the sample is drawn, and all of the possible interfering drugs the subject may be taking. We recommend that great attention be paid to these pre-analytical issues before the assay methodologies are harmonized. (C) 2008 Elsevier Inc. All rights reserved. C1 [Raff, Hershel] Aurora St Lukes Med Ctr, Endocrine Res Lab, Milwaukee, WI 53215 USA. [Raff, Hershel] Med Coll Wisconsin, Div Endocrinol Metab & Clin Nutr, Milwaukee, WI 53226 USA. [Sluss, Patrick M.] Massachusetts Gen Hosp, Clin Pathol Core Labs, Boston, MA 02114 USA. [Sluss, Patrick M.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Reference Lab, Boston, MA 02114 USA. RP Raff, H (reprint author), Aurora St Lukes Med Ctr, Endocrine Res Lab, 2801 KK River Pky Suite 245, Milwaukee, WI 53215 USA. EM hraff@mcw.edu NR 32 TC 13 Z9 13 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X EI 1878-5867 J9 STEROIDS JI Steroids PD DEC 12 PY 2008 VL 73 IS 13 SI SI BP 1297 EP 1304 DI 10.1016/j.steroids.2008.05.005 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 377JJ UT WOS:000261247200004 PM 18589466 ER PT J AU Firth, PG Zheng, H Windsor, JS Sutherland, AI Imray, CH Moore, GWK Semple, JL Roach, RC Salisbury, RA AF Firth, Paul G. Zheng, Hui Windsor, Jeremy S. Sutherland, Andrew I. Imray, Christopher H. Moore, G. W. K. Semple, John L. Roach, Robert C. Salisbury, Richard A. TI CHRISTMAS 2008: SPORT Mortality on Mount Everest, 1921-2006: descriptive study SO BRITISH MEDICAL JOURNAL LA English DT Article ID ALTITUDE CEREBRAL EDEMA; EXTREME ALTITUDE; OXYGEN; SICKNESS; PRESSURE; DEATH AB Objective To examine patterns of mortality among climbers on Mount Everest over an 86 year period. Design Descriptive study. Setting Climbing expeditions to Mount Everest, 1921-2006. Participants 14 138 mountaineers; 8030 climbers and 6108 sherpas. Main outcome measure Circumstances of deaths. Results The mortality rate among mountaineers above base camp was 1.3%. Deaths could be classified as involving trauma ( objective hazards or falls, n= 113), as non- traumatic ( high altitude illness, hypothermia, or sudden death, n= 52), or as a disappearance ( body never found, n= 27). During the spring climbing seasons from 1982 to 2006, 82.3% of deaths of climbers occurred during an attempt at reaching the summit. The death rate during all descents via standard routes was higher for climbers than for sherpas ( 2.7% ( 43/ 1585) v 0.4% ( 5/ 1231), P< 0.001; all mountaineers 1.9%). Of 94 mountaineers who died after climbing above 8000 m, 53 ( 56%) died during descent from the summit, 16 ( 17%) after turning back, 9 ( 10%) during the ascent, 4 ( 5%) before leaving the final camp, and for 12 ( 13%) the stage of the summit bid was unknown. The median time to reach the summit via standard routes was earlier for survivors than for non- survivors ( 0900- 0959 v 1300- 1359, P< 0.001). Profound fatigue ( n= 34), cognitive changes ( n= 21), and ataxia ( n= 12) were the commonest symptoms reported in non- survivors, whereas respiratory distress ( n= 5), headache ( n= 0), and nausea or vomiting ( n= 3) were rarely described. Conclusions Debilitating symptoms consistent with high altitude cerebral oedema commonly present during descent from the summit of Mount Everest. Profound fatigue and late times in reaching the summit are early features associated with subsequent death. C1 [Firth, Paul G.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Zheng, Hui] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Windsor, Jeremy S.] Heart Hosp, London, England. [Sutherland, Andrew I.] John Radcliffe Hosp, Nuffield Dept Surg, Oxford OX3 9DU, England. [Imray, Christopher H.] Univ Hosp Coventry, Dept Surg, Coventry, W Midlands, England. [Moore, G. W. K.] Univ Toronto, Dept Phys, Toronto, ON, Canada. [Semple, John L.] Univ Toronto, Dept Surg, Toronto, ON, Canada. [Roach, Robert C.] Univ Colorado, Denver Hlth Sci Ctr, Aurora, CO USA. RP Firth, PG (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. EM pfirth@partners.org RI Moore, Kent/D-8518-2011 OI Moore, Kent/0000-0002-3986-5605 NR 32 TC 43 Z9 43 U1 1 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD DEC 11 PY 2008 VL 337 AR a2654 DI 10.1136/bmj.a2654 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 399CB UT WOS:000262776900004 PM 19074222 ER PT J AU Kim, D Frank, CL Dobbin, MM Tsunemoto, RK Tu, W Peng, PL Guan, JS Lee, BH Moy, LY Giusti, P Broodie, N Mazitschek, R Delalle, I Haggarty, SJ Neve, RL Lu, Y Tsai, LH AF Kim, Dohoon Frank, Christopher L. Dobbin, Matthew M. Tsunemoto, Rachel K. Tu, Weihong Peng, Peter L. Guan, Ji-Song Lee, Byung-Hoon Moy, Lily Y. Giusti, Paola Broodie, Nisha Mazitschek, Ralph Delalle, Ivanna Haggarty, Stephen J. Neve, Rachael L. Lu, YouMing Tsai, Li-Huei TI Deregulation of HDAC1 by p25/Cdk5 in Neurotoxicity SO NEURON LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; CYCLIN-DEPENDENT KINASE-5; NEURONAL CELL-DEATH; AMYOTROPHIC-LATERAL-SCLEROSIS; ALZHEIMERS-DISEASE; DNA-DAMAGE; MOUSE MODEL; OXIDATIVE DAMAGE; HUMAN BRAIN; TRANSCRIPTIONAL REPRESSION AB Aberrant cell-cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of histone deacetylase 1 (HDAC1) activity by p25/Cdk5 induces aberrant cell-cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell-cycle activity and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain of function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an in vivo model for ischemia. Our findings outline a pathological signaling pathway illustrating the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and is a potential target for therapeutics against diseases and conditions involving neuronal death. C1 [Kim, Dohoon; Frank, Christopher L.; Dobbin, Matthew M.; Tsunemoto, Rachel K.; Guan, Ji-Song; Lee, Byung-Hoon; Moy, Lily Y.; Giusti, Paola; Broodie, Nisha; Delalle, Ivanna; Tsai, Li-Huei] MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Kim, Dohoon; Frank, Christopher L.] Harvard Univ, Sch Med, Div Mat Sci, Boston, MA 02120 USA. [Tu, Weihong; Peng, Peter L.; Lu, YouMing] Univ Cent Florida, Burnett Coll Biomed Sci, Orlando, FL 32826 USA. [Mazitschek, Ralph; Haggarty, Stephen J.] MIT, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. [Mazitschek, Ralph; Haggarty, Stephen J.] Harvard Univ, Cambridge, MA 02142 USA. [Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neve, Rachael L.] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat, Belmont, MA 02478 USA. RP Tsai, LH (reprint author), MIT, Dept Brain & Cognit Sci, Picower Inst Learning & Memory, Howard Hughes Med Inst, E25-618, Cambridge, MA 02139 USA. EM lhtsai@mit.edu RI Mazitschek, Ralph/E-3741-2013; OI Mazitschek, Ralph/0000-0002-1105-689X; Broodie, Nisha/0000-0001-6911-328X; Guan, Ji-Song /0000-0001-5219-0289; Haggarty, Stephen J./0000-0002-7872-168X FU NIH P01 [AG27916]; NIH/NINDS [R01 NS051383-01]; American Heart Association [05553413] FX We thank Drs. Bruce Yankner, John Whetstine, Sangki Park, Benjamin Samuels, Fei Lan, and Konstantinos Meletis for helpful discussions. L.-H.T. is an investigator of the Howard Hughes Medical Institute. This work was partially supported by NIH P01 grant AG27916 to L.-H.T. and by NIH/NINDS grant R01 NS051383-01 and American Heart Association grant 05553413 to Y.L. NR 68 TC 143 Z9 149 U1 1 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD DEC 11 PY 2008 VL 60 IS 5 BP 803 EP 817 DI 10.1016/j.neuron.2008.10.015 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 384LQ UT WOS:000261746700012 PM 19081376 ER PT J AU Barry, MJ AF Barry, Michael J. TI Screening for Prostate Cancer among Men 75 Years of Age or Older. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID RADICAL PROSTATECTOMY; UNITED-STATES C1 [Barry, Michael J.] Massachusetts Gen Hosp, John D Stoeckle Ctr Primary Care Innovat, Boston, MA 02114 USA. [Barry, Michael J.] Harvard Univ, Sch Med, Boston, MA USA. RP Barry, MJ (reprint author), Massachusetts Gen Hosp, John D Stoeckle Ctr Primary Care Innovat, Boston, MA 02114 USA. NR 6 TC 7 Z9 7 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 11 PY 2008 VL 359 IS 24 BP 2515 EP 2516 DI 10.1056/NEJMp0807209 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 381KG UT WOS:000261534200002 PM 19073973 ER PT J AU Dzik, WH Laposata, M Hertl, M Sandberg, WS Chatterji, M Misdraji, J AF Dzik, Walter H. Laposata, Michael Hertl, Martin Sandberg, Warren S. Chatterji, Manjil Misdraji, Joseph TI A Man with Hemophilia, Hepatocellular Carcinoma, and Intractable Bleeding Factor VIII deficiency with factor VIII inhibitor, hepatitis C with bridging fibrosis, and hepatocellular carcinoma (stage pT1N0MX). SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ORTHOTOPIC LIVER-TRANSPLANTATION; PLASMINOGEN-ACTIVATOR; NATURAL-HISTORY; RITUXIMAB; FIBRINOLYSIS; PATIENT; DISEASE; BIOPSY; VIRUS; DEATH C1 [Dzik, Walter H.] Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA. [Laposata, Michael; Misdraji, Joseph] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hertl, Martin] Massachusetts Gen Hosp, Dept Transplant Surg, Boston, MA 02114 USA. [Sandberg, Warren S.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Chatterji, Manjil] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Dzik, Walter H.; Misdraji, Joseph] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Hertl, Martin] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Sandberg, Warren S.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. [Chatterji, Manjil] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Dzik, WH (reprint author), Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA. FU Instrumentation Laboratory; BD Diagnostics Preanalytical Systems; Cedars-Sinai Medical Center; Trinity Laboratories; Catalyst Oncology; Cubist Pharmaceuticals; Cystic Fibrosis Foundation FX Dr. Laposata reports receiving consulting fees from Instrumentation Laboratory, BD Diagnostics Preanalytical Systems, Cedars-Sinai Medical Center, Trinity Laboratories, Catalyst Oncology, and Cubist Pharmaceuticals; having an equity interest in American Medical Diagnostics, Medpacks, PocketMedicine, and T2 Biosystems; receiving lecture fees from GlaxoSmithKline and G-2 Reports; and receiving grant support from the Cystic Fibrosis Foundation for one-time instrument purchase. No other potential NR 25 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 11 PY 2008 VL 359 IS 24 BP 2587 EP 2597 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 381KG UT WOS:000261534200012 PM 19073979 ER PT J AU Volpp, KG John, LK Troxel, AB Norton, L Fassbender, J Loewenstein, G AF Volpp, Kevin G. John, Leslie K. Troxel, Andrea B. Norton, Laurie Fassbender, Jennifer Loewenstein, George TI Financial Incentive-Based Approaches for Weight Loss A Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LOSS AVERSION; MONETARY CONTRACTS; OBESITY; HEALTH; OVERWEIGHT; CHOICE; RISK; PREVALENCE; REDUCTION; BEHAVIOR AB Context Identifying effective obesity treatment is both a clinical challenge and a public health priority due to the health consequences of obesity. Objective To determine whether common decision errors identified by behavioral economists such as prospect theory, loss aversion, and regret could be used to design an effective weight loss intervention. Design, Setting, and Participants Fifty- seven healthy participants aged 30- 70 years with a body mass index of 30- 40 were randomized to 3 weight loss plans: monthly weigh- ins, a lottery incentive program, or a deposit contract that allowed for participant matching, with a weight loss goal of 1 lb ( 0.45 kg) a week for 16 weeks. Participants were recruited May- August 2007 at the Philadelphia VA Medical Center in Pennsylvania and were followed up through June 2008. Main Outcome Measures Weight loss after 16 weeks. Results The incentive groups lost significantly more weight than the control group ( mean, 3.9 lb). Compared with the control group, the lottery group lost a mean of 13.1 lb ( 95% confidence interval [ CI] of the difference in means, 1.95- 16.40; P=. 02) and the deposit contract group lost a mean of 14.0 lb ( 95% CI of the difference in means, 3.69- 16.43; P =. 006). About half of those in both incentive groups met the 16- lb target weight loss: 47.4% ( 95% CI, 24.5%- 71.1%) in the deposit contract group and 52.6% ( 95% CI, 28.9%- 75.6%) in the lottery group, whereas 10.5% ( 95% CI, 1.3%- 33.1%; P=. 01) in the control group met the 16- lb target. Although the net weight loss between enrollment in the study and at the end of 7 months was larger in the incentive groups ( 9.2 lb; t= 1.21; 95% CI, - 3.20 to 12.66; P=. 23, in the lottery group and 6.2 lb; t= 0.52; 95% CI, - 5.17 to 8.75; P=. 61 in the deposit contract group) than in the control group ( 4.4 lb), these differences were not statistically significant. However, incentive participants weighed significantly less at 7 months than at the study start ( P=. 01 for the lottery group; P=. 03 for the deposit contract group) whereas controls did not. Conclusions The use of economic incentives produced significant weight loss during the 16 weeks of intervention that was not fully sustained. The longer- term use of incentives should be evaluated. Trial Registration clinicaltrials. gov Identifier: NCT00520611. C1 [Volpp, Kevin G.; Troxel, Andrea B.; Norton, Laurie; Loewenstein, George] Univ Penn, Sch Med, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Norton, Laurie] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Wharton Sch, Philadelphia, PA USA. [Volpp, Kevin G.; Norton, Laurie] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Univ Penn, Sch Med, Wharton Sch, Dept Hlth Care Management, Philadelphia, PA 19104 USA. [Troxel, Andrea B.; Fassbender, Jennifer] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Troxel, Andrea B.; Fassbender, Jennifer] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [John, Leslie K.; Loewenstein, George] Carnegie Mellon Univ, Dept Social & Decis Sci, Pittsburgh, PA 15213 USA. RP Volpp, KG (reprint author), Univ Penn, Sch Med, Leonard Davis Inst Hlth Econ, Ctr Hlth Incent, 1232 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM volpp70@wharton.upenn.edu FU National Institute on Aging [P30 AG12836]; Boettner Center for Pensions and Retirement Security at the University of Pennsylvania; National Institute of Child Health and Development Population Research Infrastructure Program [R24 HD-044964]; University of Pennsylvania [58-4000-70058]; S Department of Agriculture; Economic Research Service; Hewlett Foundation FX This work was supported by grant P30 AG12836 from the National Institute on Aging, the Boettner Center for Pensions and Retirement Security at the University of Pennsylvania, grant R24 HD-044964 from National Institute of Child Health and Development Population Research Infrastructure Program, all at the University of Pennsylvania, and grant 58-4000-70058 from the US Department of Agriculture, Economic Research Service, and the Hewlett Foundation. NR 39 TC 270 Z9 271 U1 7 U2 48 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 10 PY 2008 VL 300 IS 22 BP 2631 EP 2637 DI 10.1001/jama.2008.804 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 380YW UT WOS:000261503000022 PM 19066383 ER PT J AU Lorenz, KA AF Lorenz, Karl A. TI Promoting Efficiency and Quality of Care in the Hummer Health Care System SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID MEDICARE C1 [Lorenz, Karl A.] Univ Calif Los Angeles, Vet Adm Greater Angeles Healthcare Syst, Los Angeles, CA 90024 USA. [Lorenz, Karl A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. [Lorenz, Karl A.] RAND Corp, Santa Monica, CA USA. RP Lorenz, KA (reprint author), Univ Calif Los Angeles, Vet Adm Greater Angeles Healthcare Syst, Los Angeles, CA 90024 USA. NR 10 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 DEC 10 PY 2008 VL 26 IS 35 BP 5664 EP 5665 DI 10.1200/JCO.2008.18.2162 PG 2 WC Oncology SC Oncology GA 381IC UT WOS:000261528200002 PM 19001319 ER PT J AU Setoguchi, S Earle, CC Glynn, R Stedman, M Polinski, JM Corcoran, CP Haas, JS AF Setoguchi, Soko Earle, Craig C. Glynn, Robert Stedman, Margaret Polinski, Jennifer M. Corcoran, Colleen P. Haas, Jennifer S. TI Comparison of Prospective and Retrospective Indicators of the Quality of End-of-Life Cancer Care SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CANCER; MEDICARE; PROGNOSES; OUTCOMES; IMPROVE; CLAIMS; PAIN AB Purpose To compare prospectively and retrospectively defined benchmarks for the quality of end-of-life care, including a novel indicator for the use of opiate analgesia. Methods Linked claims and cancer registry data from 1994 to 2003 for New Jersey and Pennsylvania were used to examine prospective and retrospective benchmarks for seniors with breast, colorectal, lung, or prostate cancer who participated in state pharmaceutical benefit programs. Results Use of opiates, particularly long-acting opiates, was low in both the prospective and retrospective cohorts (9.1% and 10.1%, respectively), which supported the underuse of palliative care at the end-of-life. Although hospice was used more commonly in the retrospective versus prospective cohort, admission to hospice within 3 days of death was similar in both cohorts (28.8% v 26.4%), as was the rate of death in an acute care hospital. Retrospective and prospective measures identified similar physician and hospital patterns of end-of-life care. In multivariate models, a visit with an oncologist was positively associated with the use of chemotherapy, opiates, and hospice. Patients who were cared for by oncologists in small group practices were more likely to receive chemotherapy (retrospective only) and less likely to receive hospice (both) than those in large groups. Compared with patients who were cared for in teaching hospitals, those in other hospitals were more likely to receive chemotherapy (both) and to have toxicity (prospective) but were less likely to receive opiates (both) and hospice (retrospective). Conclusion Retrospective and prospective measures, including a new measure of the use of opiate analgesia, identify some similar physician and hospital patterns of end-of-life care. C1 [Haas, Jennifer S.] Brigham & Womens Hosp, Div Gen Med & Primary Care, Dept Med, Boston, MA 02120 USA. Brigham & Womens Hosp, Div Pharmacoepidemiol, Dept Med, Boston, MA 02120 USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Haas, JS (reprint author), Brigham & Womens Hosp, Div Gen Med & Primary Care, Dept Med, 1620 Tremont St, Boston, MA 02120 USA. EM jhaas@partners.org FU Agency for Healthcare Research and Quality [290-20-050016]; National Cancer Institute; US Department of Health and Human Services; Developing Evidence to Inform Decisions About Effectiveness FX Supported by the Agency for Healthcare Research and Quality Contract No. 290-20-050016, with an interagency agreement from the National Cancer Institute, and by the US Department of Health and Human Services as part of the Developing Evidence to Inform Decisions About Effectiveness program. NR 29 TC 40 Z9 40 U1 2 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2008 VL 26 IS 35 BP 5671 EP 5678 DI 10.1200/JCO.2008.16.3956 PG 8 WC Oncology SC Oncology GA 381IC UT WOS:000261528200005 PM 19001333 ER PT J AU Ogino, S Nosho, K Meyerhardt, JA Kirkner, GJ Chan, AT Kawasaki, T Giovannucci, EL Loda, M Fuchs, CS AF Ogino, Shuji Nosho, Katsuhiko Meyerhardt, Jeffrey A. Kirkner, Gregory J. Chan, Andrew T. Kawasaki, Takako Giovannucci, Edward L. Loda, Massimo Fuchs, Charles S. TI Cohort Study of Fatty Acid Synthase Expression and Patient Survival in Colon Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; BODY-MASS INDEX; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; PROSTATE-CANCER; PHYSICAL-ACTIVITY; GENE; INHIBITION; CARCINOMA; MUTATION AB Purpose Energy balance seems to be important in the pathogenesis of colon cancer. Fatty acid synthase (FASN) is physiologically regulated by energy balance and is often upregulated in colorectal cancer. Nonetheless, the influence of FASN expression on patient outcome is uncertain. Patients and Methods Using the database of 647 patients with colon cancer in two independent cohort studies, FASN overexpression was detected in 84 tumors (13%) by immunohistochemistry. Cox proportional hazards models calculated hazard ratios (HRs) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and related tumoral features, including KRAS, BRAF, p53, microsatellite instability and the CpG island methylation phenotype. Results There were 279 deaths, including 160 colon cancer-specific deaths. FASN overexpression was associated with a significant reduction in colon cancer-specific mortality by both univariate and multivariate analyses (adjusted HR, 0.41; 95% CI, 0.19 to 0.89) and an insignificant trend toward improved overall mortality (adjusted HR, 0.75; 95% CI, 0.50 to 1.13). Notably, the effect of FASN expression on mortality might be different according to body mass index (BMI; P(interaction) = .019); the adjusted HR of overall mortality for FASN overexpression was 0.63 (95% CI, 0.39 to 1.02) among patients with BMI less than 27.5 kg/m(2) and 2.91 (95% CI, 1.19 to 7.12) among those with BMI >= 27.5 kg/m(2). Moreover, the adverse effect of moderate overweight/obesity on overall survival was limited to FASN-positive tumors (adjusted HR, 4.10; 95% CI, 1.14 to 14.8; BMI >= 27.5 kg/m(2) v < 27.5 kg/m(2)). Conclusion Among nonobese patients with colon cancer, tumoral FASN overexpression is associated with improved survival, whereas among moderately overweight or obese patients (BMI >= 27.5 kg/m(2)), FASN overexpression may predict a worse outcome. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Pathol, Channing Lab, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Mol Oncol Pathol,Dana Farber Canc Inst, 44 Binney St,Room JF-215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU National Institutes of Health [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826]; Bennett Family Fund for Targeted Therapies Research; Entertainment Industry Foundation (EIF); EIF National Colorectal Cancer Research Alliance; Japanese Society for Promotion of Science FX Supported by National Institutes of Health Grants No. P01 CA87969, P01 CA55075, P50 CA127003, and K07 CA122826 (S. O.), and in part by the Bennett Family Fund for Targeted Therapies Research, and by the Entertainment Industry Foundation (EIF) through the EIF National Colorectal Cancer Research Alliance. K.N. was supported by a fellowship grant from the Japanese Society for Promotion of Science. NR 50 TC 88 Z9 94 U1 1 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 DEC 10 PY 2008 VL 26 IS 35 BP 5713 EP 5720 DI 10.1200/JCO.2008.18.2675 PG 8 WC Oncology SC Oncology GA 381IC UT WOS:000261528200011 PM 18955444 ER PT J AU Sanoff, HK Sargent, DJ Campbell, ME Morton, RF Fuchs, CS Ramanathan, RK Williamson, SK Findlay, BP Pitot, HC Goldberg, RM AF Sanoff, Hanna K. Sargent, Daniel J. Campbell, Megan E. Morton, Roscoe F. Fuchs, Charles S. Ramanathan, Ramesh K. Williamson, Stephen K. Findlay, Brian P. Pitot, Henry C. Goldberg, Richard M. TI Five-Year Data and Prognostic Factor Analysis of Oxaliplatin and Irinotecan Combinations for Advanced Colorectal Cancer: N9741 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ADJUVANT CHEMOTHERAPY; CONTROLLED-TRIAL; POOLED ANALYSIS; COLON-CANCER; BOLUS AB Purpose In this report, we update survival (OS) and time-to-progression (TTP) data for the Intergroup trial N9741 after a median 5 years of follow-up by using risk-stratified and prognostic factor analyses to determine if treatment outcomes differ in specific patient subgroups. Patients and Methods A total of 1,691 patients were randomly assigned to one of seven fluorouracil-, oxaliplatin-, and irinotecan-containing regimens. OS and TTP were calculated by treatment arm and baseline risk group (on the basis of WBC, performance status, number of sites of disease, and alkaline phosphatase). Multivariate prognostic factor analysis was used to assess clinical factors for their relationships to OS, TTP, response, and toxicity by using Cox and logistic regression models. Results The observed 5-year survival with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) of 9.8% was better than with irinotecan plus bolus fluorouracil and leucovorin (IFL; 3.7%; P = .04) or with bolus irinotecan/oxaliplatin (IROX; 5.1%; P = .128). OS and TTP were significantly longer for FOLFOX (20.2 months and 8.9 months, respectively) than for IFL (14.6 months and 6.1 months, respectively; P < .001 for both) or for IROX (17.3 months and 6.7 months, respectively; P < .001 for both). OS differed by risk group: 20.7 months for low risk, 17.4 months for intermediate risk, and 9.4 months for high risk (P < .001). FOLFOX treatment was superior in all risk groups and was the most powerful prognostic factor for OS, TTP, response rate, and toxicity. Conclusion The 9.8% 5-year OS in patients with metastatic colorectal cancer who were treated with first-line FOLFOX sets a new benchmark. Neither baseline risk group nor any prognostic factor examined was predictive of treatment-specific outcome. However, treatment efficacy and patient longevity varied as a function of risk group. C1 [Goldberg, Richard M.] Univ N Carolina, Dept Med, Div Hematol Oncol, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Mayo Clin, Div Biostat, Rochester, MN USA. IA Oncol Res Assoc, Community Clin Oncol Program, Des Moines, IA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Natl Canc Inst, St Catharines, ON, Canada. RP Goldberg, RM (reprint author), Univ N Carolina, Dept Med, Div Hematol Oncol, 3009 Old Clin Bldg,CB 7305, Chapel Hill, NC 27599 USA. EM goldberg@med.unc.edu RI Goldberg , Richard/M-1311-2013; OI Sargent, Daniel/0000-0002-2684-4741 FU National Institutes of Health [CA25224, CA32102, CA38926, CA21115, CA77202] FX Supported by National Institutes of Health Grants No. CA25224, CA32102, CA38926, CA21115, and CA77202; and by Pfizer Oncology and Sanofi-Aventis. NR 15 TC 141 Z9 149 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2008 VL 26 IS 35 BP 5721 EP 5727 DI 10.1200/JCO.2008.17.7147 PG 7 WC Oncology SC Oncology GA 381IC UT WOS:000261528200012 PM 19001325 ER PT J AU Atkins, MB Hsu, J Lee, S Cohen, GI Flaherty, LE Sosman, JA Sondak, VK Kirkwood, JM AF Atkins, Michael B. Hsu, Jessie Lee, Sandra Cohen, Gary I. Flaherty, Lawrence E. Sosman, Jeffrey A. Sondak, Vernon K. Kirkwood, John M. TI Phase III Trial Comparing Concurrent Biochemotherapy With Cisplatin, Vinblastine, Dacarbazine, Interleukin-2, and Interferon Alfa-2b With Cisplatin, Vinblastine, and Dacarbazine Alone in Patients With Metastatic Malignant Melanoma (E3695): A Trial Coordinated by the Eastern Cooperative Oncology Group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED-TRIAL; SUBCUTANEOUS INTERLEUKIN-2; RECOMBINANT INTERLEUKIN-2; MAINTENANCE BIOTHERAPY; EUROPEAN ORGANIZATION; CHEMOTHERAPY; COMBINATION; SURVIVAL; METAANALYSIS; PROGRESSION AB Purpose Phase II trials with biochemotherapy (BCT) have shown encouraging response rates in metastatic melanoma, and meta-analyses and one phase III trial have suggested a survival benefit. In an effort to determine the relative efficacy of BCT compared with chemotherapy alone, a phase III trial was performed within the United States Intergroup. Patients and Methods Patients were randomly assigned to receive cisplatin, vinblastine, and dacarbazine (CVD) either alone or concurrent with interleukin-2 and interferon alfa-2b (BCT). Treatment cycles were repeated at 21-day intervals for a maximum of four cycles. Tumor response was assessed after cycles 2 and 4, then every 3 months. Results Four hundred fifteen patients were enrolled, and 395 patients (CVD, n = 195; BCT, n = 200) were deemed eligible and assessable. The two study arms were well balanced for stratification factors and other prognostic factors. Response rate was 19.5% for BCT and 13.8% for CVD (P = .140). Median progression-free survival was significantly longer for BCT than for CVD (4.8 v 2.9 months; P = .015), although this did not translate into an advantage in either median overall survival (9.0 v 8.7 months) or the percentage of patients alive at 1 year (41% v 36.9%). More patients experienced grade 3 or worse toxic events with BCT than CVD (95% v 73%; P = .001). Conclusion Although BCT produced slightly higher response rates and longer median progression-free survival than CVD alone, this was not associated with either improved overall survival or durable responses. Considering the extra toxicity and complexity, this concurrent BCT regimen cannot be recommended for patients with metastatic melanoma. C1 [Atkins, Michael B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Greater Baltimore Med Ctr, Baltimore, MD USA. Wayne State Univ, Detroit, MI USA. Vanderbilt Univ, Nashville, TN USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Atkins, MB (reprint author), Beth Israel Deaconess Med Ctr, MASCO Rm 412,375 Longwood Ave, Boston, MA 02215 USA. EM matkins@bidmc.harvard.edu FU Public Health Service [CA23318, CA66636, CA21115, CA16116, CA80775, CA39229, CA14028, CA74811, CA32102, CA27057, CA38926]; National Cancer Institute; National Institutes of Health; Department of Health and Human Services FX Supported in part by Public Health Service Grants No. CA23318, CA66636, CA21115, CA16116, CA80775, CA39229, CA14028, CA74811, CA32102, CA27057, and CA38926 and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair). NR 23 TC 152 Z9 155 U1 1 U2 7 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2008 VL 26 IS 35 BP 5748 EP 5754 DI 10.1200/JCO.2008.17.5448 PG 7 WC Oncology SC Oncology GA 381IC UT WOS:000261528200016 PM 19001327 ER PT J AU Matulonis, UA Horowitz, NS Campos, SM Lee, H Lee, J Krasner, CN Berlin, S Roche, MR Duska, LR Pereira, L Kendall, D Penson, RT AF Matulonis, Ursula A. Horowitz, Neil S. Campos, Susana M. Lee, Hang Lee, Julie Krasner, Carolyn N. Berlin, Suzanne Roche, Maria R. Duska, Linda R. Pereira, Lauren Kendall, Deborah Penson, Richard T. TI Phase II Study of Carboplatin and Pemetrexed for the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL LUNG-CANCER; TRIAL; CHEMOTHERAPY; CISPLATIN; ENZYMES AB Purpose More efficacious, less toxic combinations are needed to treat platinum-sensitive recurrent epithelial ovarian cancer (EOC). Pemetrexed is a multitargeted antifolate with manageable toxicity and has been combined with carboplatin to treat other cancers. Patients and Methods This is a phase II study of carboplatin area under the curve 5 with pemetrexed 500 mg/m(2) administered intravenously on day 1 every 21 days for six cycles or for up to eight cycles if clinical benefit occurred. Eligible patients had platinum-sensitive recurrent EOC, peritoneal serous cancer, or fallopian tube cancer. The primary objective was to determine response rate defined by Response Evaluation Criteria in Solid Tumors; other end points included toxicities, progression-free survival (PFS), and overall survival (OS). Results Forty-five patients were accrued; 44 patients received treatment. Overall response rate was 51.1%; there were no complete responses (0%), 23 confirmed partial responses (51.1%), two unconfirmed partial responses (4.4%), 14 patients with stable disease (31.1%), and two patients with progressive disease after two cycles (4.4%). Grade 3 and 4 hematologic toxicities included neutropenia (41%), thrombocytopenia (23%), and anemia (9%); there were no episodes of febrile neutropenia. Grade 3 and 4 nonhematologic toxicities included fatigue (11%), nausea (5%), vomiting (5%), diarrhea (5%), syncope (5%), and pulmonary embolism (5%). Median PFS time was 7.57 months (95% CI, 6.44 to 10.18 months), mean OS time was 20.3 months, and median OS has not yet been reached with a mean follow-up time of 15.3 months. Conclusion Carboplatin/pemetrexed is a well-tolerated regimen with activity in platinum-sensitive recurrent EOC; further testing of this regimen in platinum-sensitive EOC patients is warranted. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Gynecol Oncol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Hematol & Oncol, Boston, MA 02114 USA. RP Matulonis, UA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM Ursula_matulonis@dfci.harvard.edu FU Eli Lilly Co; Indianapolis, IN FX Supported by Eli Lilly & Co, Indianapolis, IN. NR 18 TC 21 Z9 22 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 DEC 10 PY 2008 VL 26 IS 35 BP 5761 EP 5766 DI 10.1200/JCO.2008.17.0282 PG 6 WC Oncology SC Oncology GA 381IC UT WOS:000261528200018 PM 19001330 ER PT J AU Armand, P Gannamaneni, S Kim, HT Cutler, CS Ho, VT Koreth, J Alyea, EP LaCasce, AS Jacobsen, ED Fisher, DC Brown, JR Canellos, GP Freedman, AS Soiffer, RJ Antin, JH AF Armand, Philippe Gannamaneni, Supriya Kim, Haesook T. Cutler, Corey S. Ho, Vincent T. Koreth, John Alyea, Edwin P. LaCasce, Ann S. Jacobsen, Eric D. Fisher, David C. Brown, Jennifer R. Canellos, George P. Freedman, Arnold S. Soiffer, Robert J. Antin, Joseph H. TI Improved Survival in Lymphoma Patients Receiving Sirolimus for Graft-Versus-Host Disease Prophylaxis After Allogeneic Hematopoietic Stem-Cell Transplantation With Reduced-Intensity Conditioning SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HODGKINS-LYMPHOMA; SINGLE-AGENT; IN-VIVO; RAPAMYCIN; TACROLIMUS; METHOTREXATE; BLOOD; DONOR; PROLIFERATION; INHIBITION AB Purpose Inhibitors of the mammalian target of rapamycin (mTOR) kinase have shown clinical activity in several lymphoma subtypes. Sirolimus, an mTOR inhibitor, also has activity in the treatment and prophylaxis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem-cell transplantation (HSCT). We hypothesized that the use of sirolimus for GVHD prophylaxis in patients with lymphoma might lead to improved survival after transplantation through a decreased incidence of disease progression. Patients and Methods We retrospectively analyzed 190 patients who underwent transplantation for lymphoma. We compared the outcomes of patients who received sirolimus for GVHD prophylaxis with those of patients who received transplantation with a combination of a calcineurin inhibitor and methotrexate without sirolimus. Results Overall survival (OS) after transplantation was significantly superior in the sirolimus group, which was confirmed in multivariable analysis. The benefit was restricted to patients undergoing reduced-intensity conditioning (RIC) HSCT (3-year OS, 66% for sirolimus group v 38% for no-sirolimus group; P = .007; hazard ratio [HR] for mortality in multivariable analysis = 0.5, P < .042). Patients who received sirolimus had a similar incidence of nonrelapse mortality but a decreased incidence of disease progression compared with patients who did not receive sirolimus (3-year cumulative incidence of progression, 42% v 74%, respectively; P < .001; HR for progression in multivariable analysis = 0.4, P = .01). The effect of sirolimus persisted after adjusting for the occurrence of GVHD. No such survival advantage was apparent in a similar comparison of patients who underwent transplantation for diseases other than lymphoma. Conclusion This study suggests that sirolimus can independently decrease the risk of lymphoma progression after RIC HSCT, paving the way for prospective clinical trials. C1 [Armand, Philippe] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Cambridge Hosp, Dept Med, Cambridge, MA 02139 USA. RP Armand, P (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM parmand@partners.org FU National Heart, Lung, and Blood Institute [P01 HL070149]; Leukemia and Lymphoma Society FX Supported in part by Grant No. P01 HL070149 from the National Heart, Lung, and Blood Institute. P. A. is a recipient of a career development award from the Leukemia and Lymphoma Society. NR 31 TC 73 Z9 73 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 DEC 10 PY 2008 VL 26 IS 35 BP 5767 EP 5774 DI 10.1200/JCO.2008.17.7279 PG 8 WC Oncology SC Oncology GA 381IC UT WOS:000261528200019 PM 19001324 ER PT J AU Keating, NL Stoeckert, KA Regan, MM DiGianni, L Garber, JE AF Keating, Nancy L. Stoeckert, Kathryn A. Regan, Meredith M. DiGianni, Lisa Garber, Judy E. TI Physicians' Experiences With BRCA1/2 Testing in Community Settings SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BILATERAL PROPHYLACTIC MASTECTOMY; HORMONE REPLACEMENT THERAPY; CONTRALATERAL BREAST-CANCER; PROSE-STUDY-GROUP; MUTATION CARRIERS; RISK-ASSESSMENT; FAMILY-HISTORY; WOMEN; OOPHORECTOMY; TAMOXIFEN AB Purpose We surveyed a national sample of nonacademic physicians who ordered BRCA1/2 testing to understand their implementation of genetic testing and to assess recommendations for surveillance and cancer risk management of women with positive test results. Patients and Methods We surveyed physicians (N = 611 of 1,050; response rate, 58.2%) practicing in nonacademic settings who ordered BRCA1/2 testing during 2004 to 2005. We described physicians' experiences with testing and used multivariable regression models to identify factors associated with more complete counseling and with recommendations for cancer risk management for a BRCA1 mutation carrier. Results Most physicians (68.2%) usually or always discussed six counseling items before testing. In adjusted analyses, physicians who were assisted by genetic counselors, nurse geneticists, or others (v counseling by themselves), those who spent more than 60 minutes in counseling, and medical oncologists (v surgeons or geneticists) were more likely to discuss all six items (all P < .05). A total of 61.4% of physicians would recommend bilateral prophylactic mastectomy to a 38-year-old BRCA1 mutation carrier who had completed childbearing. After adjustment, geneticists and gynecologists were less likely than medical oncologists and surgeons to recommend prophylactic mastectomy (P < .001), as were physicians in the Northeast versus those in other regions of the United States (P < .01). Conclusion Community-based physicians seem to be successfully incorporating BRCA1/2 testing into their practices. Physicians' recommendations for surveillance of mutation carriers are generally consistent with practice guidelines, yet recommendations for preference-based procedures such as prophylactic mastectomy vary by physician characteristics such as specialty and geographic region. The providers whom patients see for testing may contribute to variations in prophylactic treatments. C1 [Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. RP Keating, NL (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM keating@hcp.med.harvard.edu FU National Human Genome Research Institute ELSI [NHGRI R01 HG02318-0] FX Supported by the National Human Genome Research Institute ELSI program (Grant No. NHGRI R01 HG02318-0). NR 38 TC 21 Z9 21 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 DEC 10 PY 2008 VL 26 IS 35 BP 5789 EP 5796 DI 10.1200/JCO.2008.17.8053 PG 8 WC Oncology SC Oncology GA 381IC UT WOS:000261528200022 PM 19001322 ER PT J AU Gopalan, S Ausubel, FM AF Gopalan, Suresh Ausubel, Frederick M. TI A Metasystem of Framework Model Organisms to Study Emergence of New Host-Microbe Adaptations SO PLOS ONE LA English DT Article ID PSEUDOMONAS-AERUGINOSA; CAENORHABDITIS-ELEGANS; VIRULENCE FACTORS; SECRETION SYSTEM; BACTERIAL; ARABIDOPSIS; DEFENSE; PATHOGENICITY; PATHOGENESIS; INFECTION AB An unintended consequence of global industrialization and associated societal rearrangements is new interactions of microbes and potential hosts (especially mammals and plants), providing an opportunity for the rapid emergence of host-microbe adaptation and eventual establishment of new microbe-related diseases. We describe a new model system comprising the model plant Arabidopsis thaliana and several microbes, each representing different modes of interaction, to study such "maladaptations". The model microbes include human and agricultural pathogens and microbes that are commonly considered innocuous. The system has a large knowledge base corresponding to each component organism and is amenable to high-throughput automation assisted perturbation screens for identifying components that modulate host-pathogen interactions. This would aid in the study of emergence and progression of host-microbe maladaptations in a controlled environment. C1 [Ausubel, Frederick M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Gopalan, Suresh; Ausubel, Frederick M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Gopalan, S (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM gopalan@molbio.mgh.harvard.edu FU NIH [R37 GM48707]; NSF [DBI-0114783]; Inflammatory Bowel Disease [DK43351]; Boston Area Diabetes and Endocrinology Research Center Award [DK57521] FX Funded by grants R37 GM48707 from NIH and DBI-0114783 from NSF to F.M.A. The Microscopy core is partially supported by an Inflammatory Bowel Disease Grant DK43351 and a Boston Area Diabetes and Endocrinology Research Center Award DK57521. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 5 Z9 5 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 10 PY 2008 VL 3 IS 12 AR e3891 DI 10.1371/journal.pone.0003891 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 436ZS UT WOS:000265455700005 PM 19066631 ER PT J AU Driver, JA Djousse, L Logroscino, G Gaziano, JM Kurth, T AF Driver, Jane A. Djousse, Luc Logroscino, Giancarlo Gaziano, J. Michael Kurth, Tobias TI Incidence of cardiovascular disease and cancer in advanced age: prospective cohort study SO BRITISH MEDICAL JOURNAL LA English DT Article ID CORONARY-HEART-DISEASE; LIFETIME RISK; PHYSICIANS HEALTH; ALZHEIMERS-DISEASE; BETA-CAROTENE; MORTALITY; BURDEN; STROKE; CHOLESTEROL; POPULATION AB Objective To investigate the influence of increasing age on the incidence and remaining lifetime risk of cardiovascular disease and cancer in a cohort of older men. Design Prospective cohort study. Setting United States. Participants 22 048 male doctors aged 40- 84 who were free of major disease in 1982. Main outcome measures Incidence and remaining lifetime risk of major cardiovascular disease ( myocardial infarction, stroke, and death from cardiovascular disease) and cancer. Results 3252 major cardiovascular events and 5400 incident cancers were confirmed over 23 years of follow-up. The incidence of major cardiovascular disease continued to increase to age 100. Beginning at age 80, however, major cardiovascular disease was more likely to be diagnosed at death. The incidence of cancer peaked in those aged 80- 89 and then declined. Cancers detected by screening accounted for most of the decline, whereas most cancers for which there was no screening continued to increase to age 100. Unadjusted cumulative incidence overestimated the risk of cardiovascular disease by 16% and cancer by 8.5%. The remaining lifetime risk of cancer at age 40 was 45.1% ( 95% confidence interval 43.8% to 46.3%) and at age 90 was 9.6% ( 7.2% to 11.9%). The remaining lifetime risk of major cardiovascular disease at age 40 was 34.8% ( 33.1% to 36.5%) and at age 90 was 16.7% ( 12.9% to 20.6%). Conclusions In this prospective cohort of men, the incidence of new cardiovascular disease continued to increase after age 80 but was most often diagnosed at death. The decrease in incidence of cancer late in life seemed largely due to a decline in cancers usually detected by screening. These findings suggest that people aged 80 and older have a substantial amount of undiagnosed disease. The remaining lifetime risk of both diseases approached a plateau in the 10th decade. This may be due to decreased detection of disease and reporting of symptoms and increased resistance to disease in those who survive to old age. Accurate estimates of disease risk in an aging population require adjustment for competing risks of mortality. C1 [Driver, Jane A.; Djousse, Luc; Gaziano, J. Michael; Kurth, Tobias] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Aging,Dept Med, Boston, MA 02215 USA. [Logroscino, Giancarlo] Univ Bari, Sch Med, Dept Neurol & Psychiat, Bari, Italy. [Gaziano, J. Michael; Kurth, Tobias] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res Informat Ctr, Boston, MA USA. [Kurth, Tobias] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Driver, JA (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Aging,Dept Med, Boston, MA 02215 USA. EM jdriver@partners.org RI Kurth, Tobias/A-9243-2012; LOGROSCINO, GIANCARLO/K-5148-2016; Djousse, Luc/F-5033-2017 OI Kurth, Tobias/0000-0001-7169-2620; LOGROSCINO, GIANCARLO/0000-0003-0423-3242; Djousse, Luc/0000-0002-9902-3047 FU Hartford Foundation's Center of Excellence in Geriatric Medicine at Harvard Medical School; Eleanor and the Miles Shore 50th anniversary fellowship programme; Harvard Medical School; National Cancer Institute [CA-34944, CA-40360, CA-097193]; National Heart, Lung, and Blood Institute, Bethesda, Maryland [HL-26490, HL-34595] FX The authors' work was independent of the funders. JAD received support for this research from the Hartford Foundation's Center of Excellence in Geriatric Medicine at Harvard Medical School and the Eleanor and the Miles Shore 50th anniversary fellowship programme for scholars in medicine at Harvard Medical School. The Physicians' Health Study is supported by grants CA-34944, CA-40360, and CA-097193 from the National Cancer Institute, and grants HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. NR 30 TC 46 Z9 49 U1 1 U2 9 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD DEC 9 PY 2008 VL 337 AR a2467 DI 10.1136/bmj.a2467 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 399BZ UT WOS:000262776700003 PM 19066258 ER PT J AU Kaelin, WG AF Kaelin, William G., Jr. TI Kidney Cancer: Now Available in a New Flavor SO CANCER CELL LA English DT Editorial Material ID HIF; PROTEIN AB The role of the von Hippel-Lindau tumor suppressor protein (pVHL) in kidney cancer has provided a rationale for treating this disease with hypoxia-inducible factor (HIF) antagonists. In this issue, Simon and coworkers show that the molecular signature of VHL(-/-) kidney cancers is profoundly influenced by whether they produce both HIF2 alpha and HIF1 alpha or HIF2 alpha alone. C1 [Kaelin, William G., Jr.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kaelin, William G., Jr.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Kaelin, WG (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, 75 Francis St, Boston, MA 02115 USA. EM william_kaelin@dfci.harvard.edu NR 12 TC 21 Z9 21 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD DEC 9 PY 2008 VL 14 IS 6 BP 423 EP 424 DI 10.1016/j.ccr.2008.11.005 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 383JU UT WOS:000261670700002 PM 19061830 ER PT J AU Frankel, DS Meigs, JB Massaro, JM Wilson, PWF O'Donnell, CJ D'Agostino, RB Tofler, GH AF Frankel, David S. Meigs, James B. Massaro, Joseph M. Wilson, Peter W. F. O'Donnell, Christopher J. D'Agostino, Ralph B. Tofler, Geoffrey H. TI Von Willebrand Factor, Type 2 Diabetes Mellitus, and Risk of Cardiovascular Disease The Framingham Offspring Study SO CIRCULATION LA English DT Article DE von Willebrand factor; diabetes mellitus; insulin resistance; cardiovascular diseases; epidemiology ID CORONARY-HEART-DISEASE; APPARENTLY HEALTHY-MEN; C-REACTIVE PROTEIN; FUTURE MYOCARDIAL-INFARCTION; EDINBURGH ARTERY; ENDOTHELIAL DYSFUNCTION; VONWILLEBRAND-FACTOR; PLASMA-CONCENTRATION; INSULIN-RESISTANCE; HEMOSTATIC MARKERS AB Background-Von Willebrand factor (vWF) is inconsistently associated with cardiovascular disease (CVD). This might be explained by associations of vWF with type 2 diabetes mellitus and insulin resistance. Methods and Results-We tested whether vWF predicted incident CVD in 3799 Framingham Offspring Study participants, and in particular, among those with type 2 diabetes mellitus or insulin resistance. During 11 years of follow-up, 351 participants developed CVD. In proportional hazards models (with adjustment for age, sex, blood pressure, smoking, body mass index, total and high-density lipoprotein cholesterol, and treatment with aspirin, insulin, antihypertensives, and lipid-lowering medications) with the lowest quartile of the vWF distribution as the referent, the hazard ratio (HR) for CVD was 0.94 in the second quartile, 0.98 in the third, and 1.32 in the highest (P = 0.04 for trend). Additional adjustment for type 2 diabetes mellitus or insulin resistance (homeostasis model) partially attenuated the association (multivariable HRs for top quartile 1.28 and 1.21, respectively). We then stratified the models by diabetes status or the homeostasis model of insulin resistance distribution (top quartile versus lower 3 quartiles). vWF was associated with CVD among participants with diabetes mellitus (HR for top quartile relative to bottom 1.47, P = 0.04 for trend) but not among nondiabetic participants (HR 1.15, P = 0.5) and similarly among insulin-resistant (HR 1.50, P = 0.01) but not insulin-sensitive (HR 1.02, P = 0.9) participants. Conclusions-Higher levels of vWF were associated with risk of CVD in people with type 2 diabetes mellitus or insulin resistance, which suggests that vWF may be a risk factor unique to these populations. (Circulation. 2008; 118: 2533-2539.) C1 [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Frankel, David S.] Univ Penn, Dept Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Massaro, Joseph M.; O'Donnell, Christopher J.; D'Agostino, Ralph B.] NHLBI, Framingham, MA USA. [Wilson, Peter W. F.] Emory Univ, Sch Med, Dept Med, Div Cardiol, Atlanta, GA USA. [Massaro, Joseph M.; D'Agostino, Ralph B.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Tofler, Geoffrey H.] Royal N Shore Hosp, Sydney, NSW, Australia. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jmeigs@partners.org OI Massaro, Joseph/0000-0002-2682-4812 FU American Heart Association [92011960]; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195] FX This study was supported by a Grant-in-Aid from the American Heart Association (No. 92011960 to Dr Massaro) and by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract No. N01-HC-25195). NR 49 TC 47 Z9 50 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 9 PY 2008 VL 118 IS 24 BP 2533 EP 2539 DI 10.1161/CIRCULATIONAHA.108.792986 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 381CJ UT WOS:000261512400008 PM 19029465 ER PT J AU Hakeem, A Bhatti, S Dillie, KS Cook, JR Samad, Z Roth-Cline, MD Chang, SM AF Hakeem, Abdul Bhatti, Sabha Dillie, Kathryn Sullivan Cook, Jeffrey R. Samad, Zainab Roth-Cline, Michelle D. Chang, Su Min TI Predictive Value of Myocardial Perfusion Single-Photon Emission Computed Tomography and the Impact of Renal Function on Cardiac Death SO CIRCULATION LA English DT Article DE prognosis; imaging; kidney disease; scintigraphy; mortality ID CHRONIC KIDNEY-DISEASE; CORONARY-ARTERY-DISEASE; GLOMERULAR-FILTRATION-RATE; INCREMENTAL PROGNOSTIC VALUE; RISK STRATIFICATION; CARDIOVASCULAR OUTCOMES; DIAGNOSTIC-ACCURACY; SERUM CREATININE; BYPASS SURGERY; HEART-FAILURE AB Background-Patients with chronic kidney disease CKD) have worse cardiovascular outcomes than those without CKD. The prognostic utility of myocardial perfusion single-photon emission CT MPS) in patients with varying degrees of renal dysfunction and the impact of CKD on cardiac death prediction in patients undergoing MPS have not been investigated. Methods and Results-We followed up 1652 consecutive patients who underwent stress MPS 32% exercise, 95% gated) for cardiac death for a mean of 2.15 +/- 0.8 years. MPS defects were defined with a summed stress score normal summed stress score < 4, abnormal summed stress score >= 4). Ischemia was defined as a summed stress score >= 4 plus a summed difference score >= 2, and scar was defined as a summed difference score < 2 plus a summed stress score >= 4. Renal function was calculated with the Modified Diet in Renal Disease equation. CKD estimated glomerular filtration rate < 60 mL center dot min(-1) center dot 1.73 m(-2)) was present in 36%. Cardiac death increased with worsening levels of perfusion defects across the entire spectrum of renal function. Presence of ischemia was independently predictive of cardiac death, all-cause mortality, and nonfatal myocardial infarction. Patients with normal MPS and CKD had higher unadjusted cardiac death event rates than those with no CKD and normal MPS 2.7% versus 0.8%, P = 0.001). Multivariate Cox proportional hazards models revealed that both perfusion defects hazard ratio 1.90, 95% CI 1.47 to 2.46) and CKD hazard ratio 1.96, 95% CI 1.29 to 2.95) were independent predictors of cardiac death after accounting for risk factors, left ventricular dysfunction, pharmacological stress, and symptom status. Both MPS and CKD had incremental power for cardiac death prediction over baseline risk factors and left ventricular dysfunction global chi(2) 207.5 versus 169.3, P < 0.0001). Conclusions-MPS provides effective risk stratification across the entire spectrum of renal function. Renal dysfunction is also an important independent predictor of cardiac death in patients undergoing MPS. Renal function and MPS have additive value in risk stratisfying patients with suspected coronary artery disease. Patients with CKD appear to have a relatively less benign prognosis than those without CKD, even in the presence of a normal scan. Circulation. 2008; 118: 2540-2549.) C1 [Hakeem, Abdul; Bhatti, Sabha] Univ Cincinnati, Coll Med, Div Cardiovasc Med, Cincinnati, OH USA. [Dillie, Kathryn Sullivan; Cook, Jeffrey R.; Roth-Cline, Michelle D.] Univ Wisconsin Hosp, Dept Internal Med, Madison, WI USA. Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Madison, WI 53792 USA. [Samad, Zainab] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Chang, Su Min] Methodist DeBakey Heart & Vasc Ctr, Houston, TX USA. RP Hakeem, A (reprint author), Univ Cincinnati Hosp, Acad Hlth Ctr, 231 Albert Sabin Way,POB 670542, Cincinnati, OH 45257 USA. EM ahakeem@gmail.com NR 40 TC 58 Z9 58 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 DEC 9 PY 2008 VL 118 IS 24 BP 2540 EP 2549 DI 10.1161/CIRCULATIONAHA.108.788109 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 381CJ UT WOS:000261512400009 PM 19047585 ER PT J AU Niedre, MJ de Kleine, RH Aikawa, E Kirsch, DG Weissleder, R Ntziachristos, V AF Niedre, Mark J. de Kleine, Ruben H. Aikawa, Elena Kirsch, David G. Weissleder, Ralph Ntziachristos, Vasilis TI Early photon tomography allows fluorescence detection of lung carcinomas and disease progression in mice in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; optical; diffuse; molecular; imaging ID DIFFUSE OPTICAL TOMOGRAPHY; EARLY-ARRIVING PHOTONS; TURBID MEDIA; PROTEASE ACTIVITY; CANCER; ACTIVATION; LOOKING; LIGHT AB Imaging of targeted fluorescent probes offers significant advantages for investigating disease and tissue function in animal models in vivo. Conversely, macroscopic tomographic imaging is challenging because of the high scatter of light in biological tissue and the ill-posed nature of the reconstruction mathematics. In this work, we use the earliest-transmitted photons through Lewis Lung Carcinoma bearing mice, thereby dramatically reducing the effect of tissue scattering. By using a fluorescent probe sensitive to cysteine proteases, the method yielded outstanding imaging performance compared with conventional approaches. Accurate visualization of biochemical abnormalities was achieved, not only in the primary tumor, but also in the surrounding tissue related to cancer progression and inflammatory response at the organ level. These findings were confirmed histologically and with ex vivo fluorescence microscopy. The imaging fidelity demonstrated underscores a method that can use a wide range of fluorescent probes to accurately visualize cellular- and molecular-level events in whole animals in vivo. C1 [Niedre, Mark J.; de Kleine, Ruben H.; Aikawa, Elena; Kirsch, David G.; Weissleder, Ralph; Ntziachristos, Vasilis] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. [Niedre, Mark J.] Northeastern Univ, Dept Elect & Comp Engn, Boston, MA 02115 USA. [Kirsch, David G.] Duke Univ, Dept Radiat Oncol, Durham, NC 27710 USA. [Ntziachristos, Vasilis] Tech Univ Munich, Inst Biol & Med Imaging, D-85764 Munich, Germany. [Ntziachristos, Vasilis] Helmholtz Ctr Munich, D-85764 Munich, Germany. RP Ntziachristos, V (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. EM v.ntziachristos@tum.de FU National Institutes of Health [R01 EB 000750]; National Cancer Institute of Canada; Terry Fox Foundation FX The authors thank Gordon Turner for his contribution, Giannis Zacharakis forhelpinhardwaredevelopment, Kelly Kristoff for assistance in cell culture, Vincent Lok for assistance in histological preparation, and Jose Figuiredo for assistance in animal surgery. This work was supported in part by National Institutes of Health Grant R01 EB 000750 and by the National Cancer Institute of Canada through the Terry Fox Foundation (M. N.). NR 29 TC 85 Z9 85 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 DEC 9 PY 2008 VL 105 IS 49 BP 19126 EP 19131 DI 10.1073/pnas.0804798105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 383XB UT WOS:000261706600021 PM 19015534 ER PT J AU Kimmelman, AC Hezel, AF Aguirre, AJ Zheng, HW Paik, JH Ying, HQ Chu, GC Zhang, JX Sahin, E Yeo, GM Ponugoti, A Nabioullin, R Deroo, S Yang, SD Wang, XX McGrath, JP Protopopova, M Ivanova, E Zhang, JH Feng, B Tsao, MS Redston, M Protopopov, A Xiao, YH Futreal, PA Hahn, WC Klimstra, DS Chin, L DePinho, RA AF Kimmelman, Alec C. Hezel, Aram F. Aguirre, Andrew J. Zheng, Hongwu Paik, Ji-Hye Ying, Haoqiang Chu, Gerald C. Zhang, Jean X. Sahin, Ergun Yeo, Giminna Ponugoti, Aditya Nabioullin, Roustem Deroo, Scott Yang, Shenghong Wang, Xiaoxu McGrath, John P. Protopopova, Marina Ivanova, Elena Zhang, Jianhua Feng, Bin Tsao, Ming S. Redston, Mark Protopopov, Alexei Xiao, Yonghong Futreal, P. Andrew Hahn, William C. Klimstra, David S. Chin, Lynda DePinho, Ronald A. TI Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Pak4; pancreatic cancer; Rac; Rio Kinase3 ID NUCLEOTIDE POLYMORPHISM ARRAYS; ANCHORAGE-INDEPENDENT GROWTH; CELL-CYCLE PROGRESSION; PROTEIN-KINASE; HOMOZYGOUS DELETIONS; SACCHAROMYCES-CEREVISIAE; HYBRIDIZATION REVEALS; RIO KINASES; PAK4; ADENOCARCINOMA AB Pancreas ductal adenocarcinoma (PDAC) is a highly lethal cancer that typically presents as advanced, unresectable disease. This invasive tendency, coupled with intrinsic resistance to standard therapies and genome instability, are major contributors to poor long-term survival. The genetic elements governing the invasive propensity of PDAC have not been well elucidated. Here, in the course of validating resident genes in highly recurrent and focal amplifications in PDAC, we have identified Rio Kinase 3 (RIOK3) as an amplified gene that alters cytoskeletal architecture as well as promotes pancreatic ductal cell migration and invasion. We determined that RIOK3 promotes its invasive activities through activation of the small G protein, Rac. This genomic and functional link to Rac signaling prompted a genome wide survey of other components of the Rho family network, revealing p21 Activated Kinase 4 (PAK4) as another amplified gene in PDAC tumors and cell lines. Like RIOK3, PAK4 promotes pancreas ductal cell motility and invasion. Together, the genomic and functional profiles establish the Rho family GTP-binding proteins as integral to the hallmark invasive nature of this lethal disease. C1 [Kimmelman, Alec C.; Hezel, Aram F.; Aguirre, Andrew J.; Zheng, Hongwu; Paik, Ji-Hye; Ying, Haoqiang; Chu, Gerald C.; Zhang, Jean X.; Nabioullin, Roustem; Hahn, William C.; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kimmelman, Alec C.; Yang, Shenghong; Wang, Xiaoxu] Dana Farber Canc Inst, Harvard Radiat Oncol Program, Boston, MA 02115 USA. [Hahn, William C.; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Zhang, Jean X.; Yeo, Giminna; Ponugoti, Aditya; Nabioullin, Roustem; McGrath, John P.; Protopopova, Marina; Ivanova, Elena; Zhang, Jianhua; Feng, Bin; Protopopov, Alexei; Xiao, Yonghong; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Ctr Appl Canc Sci, Belfer Inst Innovat Canc Sci, Boston, MA 02115 USA. [Chin, Lynda] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Hahn, William C.; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Tsao, Ming S.] Ontario Canc Inst, Univ Hlth Network, Toronto, ON M5G 2M9, Canada. [Tsao, Ming S.] Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. [Klimstra, David S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Redston, Mark] Ameripath, Mol Diagnost, Newton, MA 02464 USA. [Futreal, P. Andrew] Wellcome Trust Sanger Inst, Canc Genome Project, Cambridge CB10 1SA, England. [Hahn, William C.] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Hahn, William C.] MIT, Cambridge, MA 02142 USA. [Hezel, Aram F.] Massachusetts Gen Hosp, Ctr Canc, Tucker Gosnell Ctr Gastrointestinal Canc, Boston, MA 02114 USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM ron_depinho@dfci.harvard.edu OI Zheng, Hongwu/0000-0002-5823-4913 FU National Institutes of Health [K08, U01 CA84313, R01CA84628, P01CA117969-01, RO1 CA099041, RO1 CA93947]; ASCO/PanCan young investigator award; Helen Hay Whitney Foundation; Damon Runyon Cancer Research Foundation; American Brain Tumor Association; Wellcome Trust; National Cancer Institute [P50 CA127003-01, R33 CA128625, U54 CA112962] FX A. C. K. is a recipient of the Leonard B. Holman Research Pathway Fellowship. A. F. H. is supported by National Institutes of Health K08 and an ASCO/PanCan young investigator award. H.Z. was supported by the Helen Hay Whitney Foundation. J.-H.P is a Damon Runyon Fellow, supported by the Damon Runyon Cancer Research Foundation. H.Y. is supported by the American Brain Tumor Association. P. A. F. is supported by the Wellcome Trust. Funding was also provided by National Institutes of Health grants U01 CA84313, R01CA84628 and P01CA117969-01 (to R. A. D) and RO1 CA099041 and RO1 CA93947 (to L. C.) and National Cancer Institute Grants P50 CA127003-01 (to R. A. D. and L. C.) and R33 CA128625 and U54 CA112962 (to W. C. H.). The Rac dominant negative plasmid was a gift from Dr. Andrew Chan (Mount Sinai School of Medicine, New York, NY). The PAK4 expression plasmids were a gift from Dr. J. Silvio Gutkind (NIH/NIDCR, Bethesda, MD). NR 42 TC 84 Z9 84 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 DEC 9 PY 2008 VL 105 IS 49 BP 19372 EP 19377 DI 10.1073/pnas.0809966105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 383XB UT WOS:000261706600063 PM 19050074 ER PT J AU Gan, B Sahin, E Jiang, S Sanchez-Aguilera, A Scott, KL Chin, L Williams, DA Kwiatkowski, DJ DePinho, RA AF Gan, Boyi Sahin, Erguen Jiang, Shan Sanchez-Aguilera, Abel Scott, Kenneth L. Chin, Lynda Williams, David A. Kwiatkowski, David J. DePinho, Ronald A. TI mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE FSCN1; hematopoietic stem cell; Tuberous Sclerosis Complex ID TSC1-TSC2 COMPLEX; KINASE-ACTIVITY; TUBERIN; GROWTH; LETHALITY; DISEASE; TARGET; FASCIN; FOXOS AB The Tuberous Sclerosis Complex component, TSC1, functions as a tumor suppressor via its regulation of diverse cellular processes, particularly cell growth. TSC1 exists in a complex with TSC2 and functions primarily as a key negative regulator of mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis, although the TSC1/TSC2 complex also shows mTORC1-independent outputs to other pathways. Here, we explored the role of TSC1 in various aspects of stem cell biology and dissected the extent to which TSC1 functions are executed via mTORC1-dependent versus mTORC1-independent pathways. Using hematopoietic stem cells (HSCs) as a model system, we demonstrate that somatic deletion of TSC1 produces striking stem cell and derivative effector cell phenotypes characterized by increased HSC cell cycling, mobilization, marked progressive depletion, defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. On the mechanistic level, we further establish that TSC1 regulation of HSC quiescence and long-term repopulating potential and hematopoietic lineage development is mediated through mTORC1 signaling. In contrast, TSC1 regulation of HSC mobilization is effected in an mTORC1-independent manner, and gene profiling and functional analyses reveals the actin-bundling protein FSCN1 as a key TSC1/TSC2 target in the regulation of HSC mobilization. Thus, TSC1 is a critical regulator of HSC self-renewal, mobilization, and multilineage development and executes these actions via both mTORC1-dependent and-independent pathways. C1 [Gan, Boyi; Sahin, Erguen; Jiang, Shan; Scott, Kenneth L.; Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chin, Lynda; DePinho, Ronald A.] Dana Farber Canc Inst, Ctr Appl Canc Sci, Belfer Fdn Inst Innovat Canc Sci, Boston, MA 02115 USA. [Gan, Boyi; Sahin, Erguen; Jiang, Shan; Kwiatkowski, David J.; DePinho, Ronald A.] Harvard Univ, Sch Med, Dept Med & Genet, Boston, MA 02115 USA. [Chin, Lynda] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Kwiatkowski, David J.] Brigham & Womens Hosp, Div Translat Med, Boston, MA 02115 USA. [Sanchez-Aguilera, Abel; Williams, David A.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. RP DePinho, RA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM ron_depinho@dfci.harvard.edu FU National Cancer Institute [R21CA135057]; National Institutes of Health [DK62757]; Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science FX We thank Anton Berns (Netherlands Cancer Institute, Amsterdam) for the Rosa26-CreERT2 mouse strain; Shan (Julia) Zhou for assistance in the animal facility; Carol Lim and Stewart Borden Reed for the assistance with genotyping; Suzan Lazo-Kallanian, John Daley, and Peter Schow for assistance with flow cytometry; Liansheng Zheng, Giovanni Tonon, and David J. Hiller for bioinformatics analysis of gene profiling; Gerry Chu for helpful suggestion on histology; the Dana-Farber Cancer Institute-Broad RNAi Consortium for lentiviral shRNA vectors; and Herald von Boehmer and Yaoqi A. Wangfor helpful discussion. This research was supported by National Cancer Institute Grant R21CA135057 (to R. A. D.). B. G. is the Research Fellow of the Leukemia and Lymphoma Society. K. L. S. is the Research Fellow of American Cancer Society (Grant PF-07-039-01-CSM) and National Institutes of Health grant DK62757 (to D. A. W.). R. A. D. is the American Cancer Society Research Professor and an Ellison Medical Foundation Senior Scholar and is supported by the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science. NR 26 TC 121 Z9 127 U1 1 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 DEC 9 PY 2008 VL 105 IS 49 BP 19384 EP 19389 DI 10.1073/pnas.0810584105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 383XB UT WOS:000261706600065 PM 19052232 ER PT J AU Lu, LR Kim, HJ Werneck, MBF Cantor, H AF Lu, Linrong Kim, Hye-Jung Werneck, Miriam B. F. Cantor, Harvey TI Regulation of CD8(+) regulatory T cells: Interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autoimmunity; CD8 Treg; suppression ID MULTIPLE-SCLEROSIS; RECEPTOR; QA-1; IMMUNOREGULATION; LYMPHOCYTES; VACCINATION; RESPONSES; SUBSETS; MICE AB Regulation of autoreactive CD4 T cells is essential to maintain self-tolerance and prevent autoimmune disease. Although CD8 T regulatory (Treg) cells that recognize self-peptides restricted by Qa-1 (HLA-E in humans) inhibit autoreactive CD4 cells and attenuate experimental autoimmune encephalomyelitis (EAE), the mechanism of this interaction is unclear. We generated Qa-1 mutant knock-in mice that impair Qa-1 binding to the T cell receptor (TCR) and CD94/NKG2A receptors. Analysis of these mice showed that TCR-dependent recognition of Qa-1-peptide complexes on target CD4 cells is essential for suppression by CD8 Treg cells. Further analysis revealed that genetic disruption of the Qa-1-CD94/NKG2A interaction unleashes robust CD8 Treg cell activity that completely abolishes development of EAE. C1 [Cantor, Harvey] Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cantor, H (reprint author), Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. EM harvey_cantor@dfci.harvard.edu RI Werneck, Miriam/H-5802-2012; Lu, Linrong/A-1429-2013; OI Lu, Linrong/0000-0002-0171-4115 FU National Institutes of Health [AI 37562]; National Multiple Sclerosis Society; Schecter Family Research Foundation FX This work was supported by grants from the National Institutes of Health (AI 37562) and the National Multiple Sclerosis Society and a gift from the Schecter Family Research Foundation (to H. C.). L. L. is a Claudia Adams Barr Investigator and NRSA Fellow (T32 AI07386). We thank V. K. Kuchroo for providing the 2D2 TCR transgenic mice, D. Laznik and X. Sun for providing technical assistance, and A. Angel for assisting with manuscript and graphics preparation. NR 20 TC 52 Z9 56 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 DEC 9 PY 2008 VL 105 IS 49 BP 19420 EP 19425 DI 10.1073/pnas.0810383105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 383XB UT WOS:000261706600071 PM 19047627 ER PT J AU Fischer, MA Vogeli, C Stedman, M Ferris, T Brookhart, A Weissman, JS AF Fischer, Michael A. Vogeli, Christine Stedman, Margaret Ferris, Timothy Brookhart, Alan Weissman, Joel S. TI Effect of Electronic Prescribing With Formulary Decision Support on Medication Use and Cost SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID GENERIC DRUGS; INFORMATION-TECHNOLOGY; POTENTIAL SAVINGS; HEALTH-CARE; SYSTEMS; BENEFITS; IMPACT; RECORD; TIME AB Background: Electronic prescribing (e-prescribing) with formulary decision support (FDS) prompts prescribers to prescribe lower-cost medications and may help contain health care costs. In April 2004, 2 large Massachusetts insurers began providing an e-prescribing system with FDS to community-based practices. Methods: Using 18 months (October 1, 2003, to March 31, 2005) of administrative data, we conducted a prepost study with concurrent controls. We first compared the change in the proportion of prescriptions for 3 formulary tiers before and after e-prescribing began, then developed multivariate longitudinal models to estimate the specific effect of e-prescribing when controlling for baseline differences between intervention and control prescribers. Potential savings were estimated using average medication costs by formulary tier. Results: More than 1.5 million patients filled 17.4 million prescriptions during the study period. Multivariate models controlling for baseline differences between prescribers and for changes over time estimated that e-prescribing corresponded to a 3.3% increase (95% confidence interval, 2.7%-4.0%) in tier 1 prescribing. The proportion of prescriptions for tiers 2 and 3 (brand-name medications) decreased correspondingly. e-Prescriptions accounted for 20% of filled prescriptions in the intervention group. Based on average costs for private insurers, we estimated that e-prescribing with FDS at this rate could result in savings of $845 000 per 100 000 patients. Higher levels of e-prescribing use would increase these savings. Conclusions: Clinicians using e-prescribing with FDS were significantly more likely to prescribe tier 1 medications, and the potential financial savings were substantial. Widespread use of e-prescribing systems with FDS could result in reduced spending on medications. C1 [Fischer, Michael A.; Stedman, Margaret; Brookhart, Alan] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. [Vogeli, Christine; Ferris, Timothy; Weissman, Joel S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA USA. RP Fischer, MA (reprint author), Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Ste 3030, Boston, MA 02120 USA. EM mfischer@partners.org OI Stedman, Margaret/0000-0001-9271-8332 FU Agency for Healthcare Research and Quality [R01 HS15175]; National Institutes of Health [AG12084] FX Funding/Support: This study was supported by grant R01 HS15175 from the Agency for Healthcare Research and Quality and career development grant AG12084 (Dr Brookhart) from the National Institutes of Health. NR 25 TC 55 Z9 57 U1 1 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 DEC 8 PY 2008 VL 168 IS 22 BP 2433 EP 2439 DI 10.1001/archinte.168.22.2433 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 380SX UT WOS:000261486600009 PM 19064827 ER PT J AU Sakadzic, S Demirbas, U Mempel, TR Moore, A Ruvinskaya, S Boas, DA Sennaroglu, A Kartner, FX Fujimoto, JG AF Sakadzic, Sava Demirbas, Umit Mempel, Thorsten R. Moore, Anna Ruvinskaya, Svetlana Boas, David A. Sennaroglu, Alphan Kartner, Franz X. Fujimoto, James G. TI Multi-photon microscopy with a low-cost and highly efficient Cr:LiCAF laser SO OPTICS EXPRESS LA English DT Article ID 2-PHOTON FLUORESCENCE EXCITATION; FEMTOSECOND CR3+-LICAF LASER; SATURABLE BRAGG REFLECTORS; PUMPED CRLISAF LASER; SOLID-STATE LASERS; CR-LISAF LASERS; IMAGING IN-VIVO; 2ND-HARMONIC GENERATION; SCANNING MICROSCOPY; 3RD-HARMONIC GENERATION AB Multi-photon microscopy (MPM) is a powerful tool for biomedical imaging, enabling molecular contrast and integrated structural and functional imaging on the cellular and subcellular level. However, the cost and complexity of femtosecond laser sources that are required in MPM are significant hurdles to widespread adoption of this important imaging modality. In this work, we describe femtosecond diode pumped Cr:LiCAF laser technology as a low cost alternative to femtosecond Ti:Sapphire lasers for MPM. Using single mode pump diodes which cost only $150 each, a diode pumped Cr:LiCAF laser generates similar to 70-fs duration, 1.8-nJ pulses at similar to 800 nm wavelengths, with a repetition rate of 100 MHz and average output power of 180 mW. Representative examples of MPM imaging in neuroscience, immunology, endocrinology and cancer research using Cr:LiCAF laser technology are presented. These studies demonstrate the potential of this laser source for use in a broad range of MPM applications. (C) 2008 Optical Society of America C1 [Sakadzic, Sava; Moore, Anna; Ruvinskaya, Svetlana; Boas, David A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,MIT Anthinuola A Martinos Ctr Biomed, Charlestown, MA 02129 USA. [Demirbas, Umit; Sennaroglu, Alphan; Kartner, Franz X.; Fujimoto, James G.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Demirbas, Umit; Sennaroglu, Alphan; Kartner, Franz X.; Fujimoto, James G.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Mempel, Thorsten R.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Sennaroglu, Alphan] Koc Univ, Dept Phys, Laser Res Lab, TR-34450 Istanbul, Turkey. RP Boas, DA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,MIT Anthinuola A Martinos Ctr Biomed, Charlestown, MA 02129 USA. EM dboas@nmr.mgh.harvard.edu; jgfuji@mit.edu RI Demirbas, Umit/F-2981-2011; OI Demirbas, Umit/0000-0001-8420-8965 FU National Institutes of Health [R01-EY11289-23, R01-NS057476-02, R01-CA75289-12, R01NS057476- 01A1, P01-NS05S104-01A1, 4-R00-AI073457]; National Science Foundation [BES-0522845]; Air Force Office of Scientific Research [FA9550-07-1-0101]; Medical Free Electron Laser Program [FA9550-07-1-0101] FX We thank Natalie Elpek, Jonathan J. Liu and Chao Zhou for their help during the experiments and Gary Boas for proofreading the manuscript. This research was sponsored in part by the National Institutes of Health R01-EY11289-23, R01-NS057476-02, R01-CA75289-12, R01NS057476- 01A1, P01-NS05S104-01A1, 4-R00-AI073457; National Science Foundation BES-0522845; Air Force Office of Scientific Research FA9550-07-1-0101 and the Medical Free Electron Laser Program contract FA9550-07-1-0101. NR 90 TC 26 Z9 26 U1 0 U2 6 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD DEC 8 PY 2008 VL 16 IS 25 BP 20848 EP 20863 DI 10.1364/OE.16.020848 PG 16 WC Optics SC Optics GA 381VD UT WOS:000261563100070 PM 19065223 ER PT J AU Lu, HM AF Lu, Hsiao-Ming TI A point dose method for in vivo range verification in proton therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID CURRENT MODULATION; RADIOTHERAPY AB Range uncertainty in proton therapy is a recognized concern. For certain treatment sites, less optimal beam directions are used to avoid the potential risk, but also with reduced benefit. In vivo dosimetry, with implanted or intra-cavity dosimeters, has been widely used for treatment verification in photon/electron therapy. The method cannot, however, verify the beam range for proton treatment, unless we deliver the treatment in a different manner. Specifically, we split the spread-out Bragg peaks in a proton field into two separate fields, each delivering a 'sloped' depth-dose distribution, rather than the usual plateau in a typical proton field. The two fields are 'sloped' in opposite directions so that the total depth-dose distribution retains the constant dose plateau covering the target volume. By measuring the doses received from both fields and calculating the ratio, the water-equivalent path length to the location of the implanted dosimeter can be verified, thus limiting range uncertainty to only the remaining part of the beam path. Production of such subfields has been experimented with a passive scattering beam delivery system. Phantom measurements have been performed to illustrate the application for in vivo beam range verification. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,FHBPTC, Boston, MA 02115 USA. RP Lu, HM (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,FHBPTC, 30 Fruit St, Boston, MA 02115 USA. EM hmlu@partners.org NR 16 TC 28 Z9 28 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD DEC 7 PY 2008 VL 53 IS 23 BP N415 EP N422 DI 10.1088/0031-9155/53/23/N01 PG 8 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 371VE UT WOS:000260859000023 PM 18997263 ER PT J AU Neale, BM Faraone, SV AF Neale, Benjamin M. Faraone, Stephen V. TI Perspective on the Genetics of Attention Deficit/Hyperactivity Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; DEFICIT HYPERACTIVITY DISORDER; COMMON VARIANTS; RISK LOCI; SUSCEPTIBILITY; METAANALYSIS; REPLICATION; MULTIPLE; DISEASE; AUTOPHAGY C1 [Neale, Benjamin M.; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci, Syracuse, NY 13210 USA. [Neale, Benjamin M.] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Neale, Benjamin M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin M.] Broad Inst Harvard, Cambridge, MA USA. [Neale, Benjamin M.] MIT, Cambridge, MA 02139 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 Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [R01MH081803, R01MH62873] NR 36 TC 3 Z9 4 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1334 EP 1336 DI 10.1002/ajmg.b.30875 PG 3 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800002 PM 18951432 ER PT J AU Neale, BM Lasky-Su, J Anney, R Franke, B Zhou, KX Maller, JB Vasquez, AA Asherson, P Chen, W Banasehewski, T Buitelaar, J Ebstein, R Gill, M Miranda, A Oades, RD Roeyers, H Rothenberger, A Sergeant, J Steinhausen, HC Sonuga-Barke, EJS Mulas, F Taylor, E Laird, N Lange, C Daly, M Faraone, SV AF Neale, Benjamin M. Lasky-Su, Jessica Anney, Richard Franke, Barbara Zhou, Kaixin Maller, Julian B. Arias Vasquez, Alejandro Asherson, Philip Chen, Wai Banasehewski, Tobias Buitelaar, Jan Ebstein, Richard Gill, Michael Miranda, Ana Oades, Robert D. Roeyers, Herbert Rothenberger, Aribert Sergeant, Joseph Steinhausen, Hans Christoph Sonuga-Barke, Edmund J. S. Mulas, Fernando Taylor, Eric Laird, Nan Lange, Christoph Daly, Mark Faraone, Stephen V. TI Genome-Wide Association Scan of Attention Deficit Hyperactivity Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE ADHD; genome-wide association; SNP chip; genetic association information network ID DEFICIT/HYPERACTIVITY DISORDER; SIB-PAIRS; LINKAGE; GENETICS; LOCI; DISEQUILIBRIUM; NEUROBIOLOGY; METAANALYSIS; REGION; GENES AB Results of behavioral genetic and molecular genetic studies have converged to suggest that genes substantially contribute to the development of attention deficit/hyperactivity disorder (ADHD), a common disorder with an onset in childhood. Yet, despite numerous linkage and candidate gene studies, strongly consistent and replicable association has eluded detection. To search for ADHD susceptibility genes, we genotyped approximately 600,000 SNPs in 958 ADHD affected family trios. After cleaning the data, we analyzed 438,784 SNPs in 2,803 individuals comprising 909 complete trios using ADHD diagnosis as phenotype. We present the initial TDT findings as well as considerations for cleaning family-based TDT data. None of the SNP association tests achieved genome-wide significance, indicating that larger samples may be required to identify risk loci for ADHD. We additionally identify a systemic bias in family-based association, and suggest that variable missing genotype rates may be the source of this bias. (c) 2008 Wiley-Liss, Inc. C1 [Neale, Benjamin M.; Zhou, Kaixin; Asherson, Philip; Chen, Wai; Sonuga-Barke, Edmund J. S.; Taylor, Eric] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London, England. [Neale, Benjamin M.; Lasky-Su, Jessica; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Neale, Benjamin M.; Daly, Mark] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin M.; Daly, Mark] Broad Inst Harvard, Cambridge, MA USA. [Neale, Benjamin M.; Daly, Mark] MIT, Cambridge, MA 02139 USA. [Lasky-Su, Jessica; Lange, Christoph] Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp, Boston, MA 02115 USA. [Anney, Richard; Gill, Michael] St James Hosp, Trinity Ctr Hlth Sci, Dept Psychiat, Dublin 8, Ireland. [Franke, Barbara; Arias Vasquez, Alejandro; Buitelaar, Jan] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Franke, Barbara; Arias Vasquez, Alejandro] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Maller, Julian B.] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Banasehewski, Tobias] Heidelberg Univ, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherpay, D-6800 Mannheim, Germany. [Ebstein, Richard] Geha MHC, Petah Tiqwa, Israel. [Miranda, Ana] Univ Valencia, Dept Dev & Educ Psychol, Valencia, Spain. [Oades, Robert D.] Univ Clin Child & Adolescent Psychiat, Essen, Germany. [Roeyers, Herbert] Univ Ghent, B-9000 Ghent, Belgium. [Rothenberger, Aribert] Univ Gottingen, Gottingen, Germany. [Sergeant, Joseph] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Steinhausen, Hans Christoph] Univ Zurich, Dept Child & Adolescent Psychait, Zurich, Switzerland. [Sonuga-Barke, Edmund J. S.] Univ Southampton, Inst Disorder Impulse & Attent, Sch Psychol, Southampton, Hants, England. [Sonuga-Barke, Edmund J. S.] NYU, Ctr Child Study, New York, NY USA. [Mulas, Fernando] La Fe Univ Hosp, Fac Med, Dept Neuropaediat, Valencia, Spain. [Laird, Nan; Lange, Christoph; Faraone, Stephen V.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci, Syracuse, NY 13210 USA. RP Faraone, SV (reprint author), SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, 750 E Adams St, Syracuse, NY 13210 USA. EM faraones@upstate.edu RI Arias Vasquez, A./L-4175-2015; Franke, Barbara/D-4836-2009; Sonuga-Barke, Edmund/D-9137-2011; Arias Vasquez, Alejandro/E-4762-2012; Buitelaar, Jan/E-4584-2012; Miranda, Ana/G-8619-2015 OI Gill, Michael/0000-0003-0206-5337; Maller, Julian/0000-0002-1565-9559; Anney, Richard/0000-0002-6083-407X; Faraone, Stephen/0000-0002-9217-3982; Franke, Barbara/0000-0003-4375-6572; Arias Vasquez, Alejandro/0000-0002-4786-0169; Buitelaar, Jan/0000-0001-8288-7757; Miranda, Ana/0000-0001-6998-5686 FU NIH [R01MH62873] FX The IMAGE project is a multi-site, international effort supported by NIH grant R01MH62873 to S.V. Faraone. Site Principal Investigators are Philip Asherson, Tobias Banaschewski, Jan Buitelaar, Richard P. Ebstein, Stephen V. Faraone, Michael Gill, Ana Miranda, Fernando Mulas, Robert D. Oades, Herbert Roeyers, Aribert Rothenberger, Joseph Sergeant, Edmund Sonuga-Barke, and Hans-Christoph Steinhausen. Senior coinvestigators are Margaret Thompson, Pak Sham, Peter McGuffin, Robert Plomin, Ian Craig, and Eric Taylor. Chief Investigators at each site are Rafaela Marco, Nanda Rommelse, Wai Chen, Henrik Uebel, Hanna Christiansen, U. Mueller, Cathelijne Buschgens, Barbara Franke, Lamprini Psychogiou. We thank all the families who kindly participated in this research. NR 45 TC 148 Z9 151 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1337 EP 1344 DI 10.1002/ajmg.b.30866 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800003 PM 18980221 ER PT J AU Lasky-Su, J Neale, BM Franke, B Anney, RJL Zhou, KX Maller, JB Vasquez, AA Chen, W Asherson, P Buitelaar, J Banaschewski, T Ebstein, R Gill, M Miranda, A Mulas, F Oades, RD Roeyers, H Rothenberger, A Sergeant, J Sonuga-Barke, EJS Steinhausen, HC Taylor, E Daly, M Laird, N Lange, C Faraone, SV AF Lasky-Su, Jessica Neale, Benjamin M. Franke, Barbara Anney, Richard J. L. Zhou, Kaixin Maller, Julian B. Arias Vasquez, Alejandro Chen, Wai Asherson, Philip Buitelaar, Jan Banaschewski, Tobias Ebstein, Richard Gill, Michael Miranda, Ana Mulas, Fernando Oades, Robert D. Roeyers, Herbert Rothenberger, Aribert Sergeant, Joseph Sonuga-Barke, Edmund J. S. Steinhausen, Hans Christoph Taylor, Eric Daly, Mark Laird, Nan Lange, Christoph Faraone, Stephen V. TI Genome-Wide Association Scan of Quantitative Traits for Attention Deficit Hyperactivity Disorder Identifies Novel Associations and Confirms Candidate Gene Associations SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE ADHD; genome-wilde association; family-based association; candidate gene; CDH13 ID FAMILY-BASED ASSOCIATION; CHILD-BEHAVIOR CHECKLIST; DEFICIT/HYPERACTIVITY DISORDER; SUSCEPTIBILITY LOCI; BIPOLAR-DISORDER; LINKAGE SCAN; STRUCTURED INTERVIEW; CONDUCT DISORDER; SIB PAIRS; SCHIZOPHRENIA AB Attention deficit hyperactivity disorder (ADHD) is a complex condition with environmental and genetic etiologies. Up to this point, research has identified genetic associations with candidate genes from known biological pathways. In order to identify novel ADHD susceptibility genes, 600,000 SNPs were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. We generated six quantitative phenotypes from 18 ADHD symptoms to be used in genome-wide association analyses. With the PBAT screening algorithm, we identified 2 SNPs, rs6565113 and rs552655 that met the criteria for significance within a specified phenotype. These SNPs are located in intronic regions of genes CDH13 and GFOD1, respectively. CDH13 has been implicated previously in substance use disorders. We also evaluated the association of SNPs from a list of 37 ADHD candidate genes that was specified a priori. These findings, along with association P-values with a magnitude less than 10(-5), are discussed in this manuscript. Seventeen of these candidate genes had association P-values lower then 0.01: SLC6A1, SLC9A9, HES1, ADRB2, HTR1E, DDC, ADRA1A, DBH, DRD2, BDNF, TPH2, HTR2A, SLC6A2, PER1, CHRNA4, SNAP25, and COMT. Among the candidate genes, SLC9A9 had the strongest overall associations with 58 association test P-values lower than 0.01 and multiple association P-values at a magnitude of 10-5 in this gene. In sum, these findings identify novel genetic associations at viable ADHD candidate genes and provide confirmatory evidence for associations at previous candidate genes. Replication of these results is necessary in order to confirm the proposed genetic variants for ADHD. (c) 2008 Wiley-Liss, Inc. C1 [Lasky-Su, Jessica; Lange, Christoph] Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp, Boston, MA 02115 USA. [Neale, Benjamin M.; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Neale, Benjamin M.; Zhou, Kaixin; Chen, Wai; Asherson, Philip; Sonuga-Barke, Edmund J. S.; Taylor, Eric] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Neale, Benjamin M.; Daly, Mark] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin M.; Daly, Mark] Broad Inst Harvard, Cambridge, MA USA. [Neale, Benjamin M.; Daly, Mark] MIT, Cambridge, MA 02139 USA. [Franke, Barbara; Arias Vasquez, Alejandro; Buitelaar, Jan] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Franke, Barbara; Arias Vasquez, Alejandro] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Anney, Richard J. L.; Gill, Michael] St James Hosp, Trinity Ctr Hlth Sci, Dept Psychiat, Dublin 8, Ireland. [Maller, Julian B.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Banaschewski, Tobias] Heidelberg Univ, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, D-6800 Mannheim, Germany. [Ebstein, Richard] Geha MHC, Petah Tiqwa, Israel. [Miranda, Ana] Univ Valencia, Dept Dev & Educ Psychol, Valencia, Spain. [Mulas, Fernando; Faraone, Stephen V.] La Fe Univ Hosp, Dept Neuropaediat, Valencia, Spain. [Oades, Robert D.] Univ Clin Child & Adolescent Psychiat, Essen, Germany. [Rothenberger, Aribert] Univ Gottingen, Gottingen, Germany. [Sergeant, Joseph] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Sonuga-Barke, Edmund J. S.] Univ Southampton, Inst Disorder Impulse & Attent, Sch Psychol, Southampton, Hants, England. [Sonuga-Barke, Edmund J. S.] NYU, Ctr Child Study, New York, NY USA. [Sonuga-Barke, Edmund J. S.] Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. [Steinhausen, Hans Christoph] Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. [Laird, Nan; Lange, Christoph] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci, Syracuse, NY 13210 USA. RP Faraone, SV (reprint author), SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, 750 E Adams St, Syracuse, NY 13210 USA. EM faraones@upstate.edu RI Arias Vasquez, Alejandro/E-4762-2012; Buitelaar, Jan/E-4584-2012; Miranda, Ana/G-8619-2015; Arias Vasquez, A./L-4175-2015; Franke, Barbara/D-4836-2009; Sonuga-Barke, Edmund/D-9137-2011; OI Arias Vasquez, Alejandro/0000-0002-4786-0169; Buitelaar, Jan/0000-0001-8288-7757; Miranda, Ana/0000-0001-6998-5686; Maller, Julian/0000-0002-1565-9559; Franke, Barbara/0000-0003-4375-6572; Gill, Michael/0000-0003-0206-5337; Anney, Richard/0000-0002-6083-407X; Faraone, Stephen/0000-0002-9217-3982 FU NIH [R01MH081803, R01MH62873] FX The IMAGE project is a multi-site, international effort supported by NIH grants R01MH081803 and R01MH62873 to S.V. Faraone. Site Principal Investigators are Philip Ash e rson, Tobias Banaschewski. Jan Buitelaar, Richard P. Ebstein, Stephen V. Faraone, Michael Gill, Aria Miranda, Fernando Mulas, Robert D. Ciades, Herbert Roeyers, Aribert Rothenberger, Joseph Sergeant, Edmund Sonuga-Barke, and HansChristoph Steinhausen. Senior coinvestigators are Margaret Thompson, Pak Sham. Peter McGuffin, Robert Plomin, Ian Craig and Eric Taylor. Chief Investigators at each site are Rafaela Marco, Nanda Rommelse, Wai Chen, Henrik Uebel, Hanna Christiansen, Ueli Mueller, Marieke Altink, Barbara Franke, Lamprini Psychogiou. We thank all the families who kindl,,7 participated in this research. NR 55 TC 176 Z9 181 U1 1 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1345 EP 1354 DI 10.1002/ajmg.b.30867 PG 10 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800004 PM 18821565 ER PT J AU Lasky-Su, J Anney, RJL Neale, BM Franke, B Zhou, K Maller, JB Vasquez, AA Chen, W Asherson, P Buitelaar, J Banaschewski, T Ebstein, R Gill, M Miranda, A Mulas, F Oades, RD Roeyers, H Rothenberger, A Sergeant, J Sonuga-Barke, EJS Steinhausen, HC Taylor, E Daly, M Laird, N Lange, C Faraone, SV AF Lasky-Su, Jessica Anney, Richard J. L. Neale, Benjamin M. Franke, Barbara Zhou, Kaixin Maller, Julian B. Arias Vasquez, Alejandro Chen, Wai Asherson, Philip Buitelaar, Jan Banaschewski, Tobias Ebstein, Richard Gill, Michael Miranda, Ana Mulas, Fernando Oades, Robert D. Roeyers, Herbert Rothenberger, Aribert Sergeant, Joseph Sonuga-Barke, Edmund J. S. Steinhausen, Hans Christoph Taylor, Eric Daly, Mark Laird, Nan Lange, Christoph Faraone, Stephen V. TI Genome-Wide Association Scan of the Time to Onset of Attention Deficit Hyperactivity Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE genomewide association; time-to-onset; ADHD; PBAT ID CONDUCT DISORDER; AGE; FAMILY AB A time-to-onset analysis for family-based samples was performed on the genomewide association (GWAS) data for attention deficit hyperactivity disorder (ADHD) to determine if associations exist with the age at onset of ADHD. The initial dataset consisted of 958 parent-offspring trios that were genotyped on the Perlegen 600,000 SNP array. After data cleaning procedures, 429,981 autosomal SNPs and 930 parent-offspring trios were used found suitable for use and a family-based logrank analysis was performed using that age at first ADHD symptoms as the quantitative trait of interest. No SNP achieved genome-wide significance, and the lowest P-values had a magnitude of 10(-7). Several SNPs among a pre-specified list of candidate genes had nominal associations including SLC9A9, DRD1, ADRB2, SLC6A3, NFIL3, ADRB1, SYT1, HTR2A, ARRB2, and CHRNA4. Of these findings SLC9A9 stood out as a promising candidate, with nominally significant SNPs in six distinct regions of the gene. (c) 2008 Wiley-Liss, Inc. C1 [Lasky-Su, Jessica; Zhou, Kaixin; Lange, Christoph] Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp, Boston, MA 02115 USA. [Anney, Richard J. L.; Gill, Michael] St James Hosp, Trinity Ctr Hlth Sci, Dept Psychiat, Dublin 8, Ireland. [Neale, Benjamin M.; Asherson, Philip; Sonuga-Barke, Edmund J. S.] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Neale, Benjamin M.; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Neale, Benjamin M.; Daly, Mark] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin M.; Daly, Mark] Broad Inst Harvard, Cambridge, MA USA. [Neale, Benjamin M.; Daly, Mark] MIT, Cambridge, MA 02139 USA. [Franke, Barbara; Arias Vasquez, Alejandro; Buitelaar, Jan] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Franke, Barbara; Arias Vasquez, Alejandro] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Maller, Julian B.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Banaschewski, Tobias] Heidelberg Univ, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, D-6800 Mannheim, Germany. [Ebstein, Richard] Geha MHC, Petah Tiqwa, Israel. [Miranda, Ana] Univ Valencia, Dept Dev & Educ Psychol, Valencia, Spain. [Mulas, Fernando] La Fe Univ Hosp, Dept Neuropaediat, Valencia, Spain. [Oades, Robert D.] Univ Clin Child & Adolescent Psychiat, Essen, Germany. [Rothenberger, Aribert] Univ Gottingen, Gottingen, Germany. [Sergeant, Joseph] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Sonuga-Barke, Edmund J. S.] Univ Southampton, Sch Psychol, Inst Disorder Impulse & Attent, Southampton SO17 1BJ, Hants, England. [Sonuga-Barke, Edmund J. S.] NYU, Ctr Child Study, New York, NY USA. [Sonuga-Barke, Edmund J. S.] Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. [Steinhausen, Hans Christoph] Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. [Laird, Nan; Lange, Christoph] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci, Syracuse, NY 13210 USA. RP Faraone, SV (reprint author), SUNY Upstate Med Univ, Dept Psychiat & Behav Sci, 750 E Adams St, Syracuse, NY 13210 USA. EM faraones@upstate.edu RI Franke, Barbara/D-4836-2009; Sonuga-Barke, Edmund/D-9137-2011; Arias Vasquez, Alejandro/E-4762-2012; Buitelaar, Jan/E-4584-2012; Miranda, Ana/G-8619-2015; Arias Vasquez, A./L-4175-2015; OI Franke, Barbara/0000-0003-4375-6572; Faraone, Stephen/0000-0002-9217-3982; Arias Vasquez, Alejandro/0000-0002-4786-0169; Buitelaar, Jan/0000-0001-8288-7757; Miranda, Ana/0000-0001-6998-5686; Maller, Julian/0000-0002-1565-9559; Gill, Michael/0000-0003-0206-5337; Anney, Richard/0000-0002-6083-407X FU NIMH NIH HHS [R01 MH062873-05, R01 MH062873, R01 MH081803, R01MH081803, R01MH62873] NR 18 TC 60 Z9 60 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1355 EP 1358 DI 10.1002/ajmg.b.30869 PG 4 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800005 PM 18937294 ER PT J AU Anney, RJL Lasky-Su, J O'Dushlaine, C Kenny, E Neale, BM Mulligan, A Franke, B Zhou, KX Chen, W Christiansen, H Arias-Vasquez, A Banaschewski, T Buitelaar, J Ebstein, R Miranda, A Mulas, F Oades, RD Roeyers, H Rothenberger, A Sergeant, J Sonuga-Barke, EJS Steinhausen, H Asherson, P Faraone, SV Gill, M AF Anney, Richard J. L. Lasky-Su, Jessica O'Dushlaine, Colm Kenny, Elaine Neale, Benjamin M. Mulligan, Aisling Franke, Barbara Zhou, Kaixin Chen, Wai Christiansen, Hanna Arias-Vasquez, Alejandro Banaschewski, Tobias Buitelaar, Jan Ebstein, Richard Miranda, Ana Mulas, Fernando Oades, Robert D. Roeyers, Herbert Rothenberger, Aribert Sergeant, Joseph Sonuga-Barke, Edmund J. S. Steinhausen, Hans Asherson, Philip Faraone, Stephen V. Gill, Michael TI Conduct Disorder and ADHD: Evaluation of Conduct Problems as a Categorical and Quantitative Trait in the International Multicentre ADHD Genetics Study SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE ADHD; conduct disorder; genome-wide association study; genetic association information network ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; CHILD PSYCHIATRIC-PATIENTS; EXTERNALIZING DISORDERS; ANTISOCIAL-BEHAVIOR; FAMILIAL SUBTYPE; LINKAGE ANALYSIS; SUBSTANCE USE; ASSOCIATION; SCHIZOPHRENIA AB Attention-deficit/hyperactivity disorder (ADHD) is typically characterized by inattention, excessive motor activity, impulsivity, and distractibility. Individuals with ADHD have significant impairment in family and peer relations, academic functioning, and show high co-morbidity with a wide range of psychiatric disorders including oppositional defiant disorder (ODD), conduct disorder (CD), anxiety disorder, depression, substance abuse, and pervasive developmental disorder (PDD). Family studies suggest that ADHD + CD represents a specific subtype of the ADRD disorder with familial risk factors only partly overlapping with those of ADHD alone. We performed a hypothesis-free analysis of the GAIN-ADHD sample to identify markers and genes important in the development of conduct problems in a European cohort of individuals with ADHD. Using the Family-Based Association Test (FBAT) package we examined three measures of conduct problems in 1,043,963 antosomal markers. This study is part of a series of exploratory analyses to identify candidate genes that maybe important in ADHD and ADHD-related traits, such as conduct problems. We did not find genome-wide statistical significance (P < 5 x 10(7)) for any of the tested markers and the three conduct problem traits. Fifty-four markers reached strong GWA signals (P < 10(-5)). We discuss these findings in the context of putative candidate genes and the implications of these findings in the understanding of the etiology of ADHD + CD. We aimed to achieve insight into the genetic etiology of a trait using a hypothesis-free study design and were able to identify a number of biologically interesting markers and genes for follow-up studies. (c) 2008 Wiley-Liss, Inc. C1 [Anney, Richard J. L.; O'Dushlaine, Colm; Kenny, Elaine; Gill, Michael] Trinity Coll Dublin, Dept Neuropsychiat Genet, Dublin 8, Ireland. [Lasky-Su, Jessica] Brigham & Womens Hosp, Channing Labs, Boston, MA 02115 USA. [Neale, Benjamin M.; Zhou, Kaixin; Chen, Wai] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Neale, Benjamin M.] Broad Inst Harvard, Cambridge, MA USA. [Neale, Benjamin M.] MIT, Cambridge, MA 02139 USA. [Neale, Benjamin M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Neale, Benjamin M.] Harvard Univ, Sch Med, Boston, MA USA. [Mulligan, Aisling] Univ Coll Dublin, Catherine McAuley Educ & Res Ctr, Dublin 2, Ireland. [Franke, Barbara; Arias-Vasquez, Alejandro; Buitelaar, Jan] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Franke, Barbara; Arias-Vasquez, Alejandro; Buitelaar, Jan] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Christiansen, Hanna; Oades, Robert D.] Univ Duisburg Essen, Univ Clin Child & Adolescent Psychiat, Essen, Germany. [Banaschewski, Tobias] Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, D-6800 Mannheim, Germany. [Ebstein, Richard] Hebrew Univ Jerusalem, Dept Psychol, IL-91905 Jerusalem, Israel. [Miranda, Ana; Mulas, Fernando] Univ Valencia, Dept Dev & Educ Psychol, Valencia, Spain. [Roeyers, Herbert; Sonuga-Barke, Edmund J. S.] Univ Ghent, Dept Expt Clin Hlth Psychol, B-9000 Ghent, Belgium. [Rothenberger, Aribert] Univ Gottingen, Gottingen, Germany. [Sergeant, Joseph] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Sonuga-Barke, Edmund J. S.] Univ Southampton, Sch Psychol, Southampton SO9 5NH, Hants, England. [Steinhausen, Hans] Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. RP Anney, RJL (reprint author), Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland. EM anneyr@tcd.ie RI Franke, Barbara/D-4836-2009; Sonuga-Barke, Edmund/D-9137-2011; Arias Vasquez, Alejandro/E-4762-2012; Price, Katie/H-1931-2012; Buitelaar, Jan/E-4584-2012; Miranda, Ana/G-8619-2015; Arias Vasquez, A./L-4175-2015; OI Franke, Barbara/0000-0003-4375-6572; Arias Vasquez, Alejandro/0000-0002-4786-0169; Buitelaar, Jan/0000-0001-8288-7757; Miranda, Ana/0000-0001-6998-5686; Anney, Richard/0000-0002-6083-407X; Faraone, Stephen/0000-0002-9217-3982; Mulligan, Aisling/0000-0001-7708-1177 FU NIMH NIH HHS [R01 MH062873, R01 MH081803, R01MH081803, R01MH62873] NR 53 TC 62 Z9 63 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1369 EP 1378 DI 10.1002/ajmg.b.30871 PG 10 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800007 PM 18951430 ER PT J AU Anney, RJL Kenny, E O'Dushlaine, CT Lasky-Su, J Franke, B Morris, DW Neale, BM Asherson, P Faraone, SV Gill, M AF Anney, Richard J. L. Kenny, Elaine O'Dushlaine, Colm T. Lasky-Su, Jessica Franke, Barbara Morris, Derek W. Neale, Benjamin M. Asherson, Philip Faraone, Stephen V. Gill, Michael TI Non-Random Error in Genotype Calling Procedures: Implications for Family-Based and Case-Control Genome-Wide Association Studies SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE GAIN; genome wide association study; genotyping bias; cluster plots ID DISEASES AB The considerable data-handling requirements for genome wide association studies (GWAS) prohibit individual calling of genotypes and create a reliance on sophisticated "genotype-calling algorithms." Despite their obvious utility, the current genotyping platforms and calling-algorithms used are not without their limitations. Specifically, some genotypes are not called due to the ambiguity of the data. Any bias in the missing data could create spurious results. Using data from the Genetic Analysis Information Network (GAIN) we observed that missing genotypes are not randomly distributed throughout the homozygous and heterozygous groups. Using simulation, we examined whether the level and type of missingness observed might influence deviation from the null-hypothesis under common case-control and family-based statistical approaches. Under a case-control model, where missingness is present in a case group but not the controls, we observed bias giving rise to genome-wide significant type-I error for missingness as low as 3%. The family-based association simulations show close to nominal type-I error at 4% genotype missingness. These findings have important implications to study design, quality-control procedures and reporting of findings in GWAS. (c) 2008 Wiley-Liss, Inc. C1 [Anney, Richard J. L.; Kenny, Elaine; O'Dushlaine, Colm T.; Morris, Derek W.; Gill, Michael] Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland. [Lasky-Su, Jessica] Brigham & Womens Hosp, Channing Labs, Boston, MA 02115 USA. [Franke, Barbara] Radboud Univ Nijmegen, Ctr Med, Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Franke, Barbara] Radboud Univ Nijmegen, Ctr Med, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Neale, Benjamin M.; Asherson, Philip] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Neale, Benjamin M.] Broad Inst Harvard, Cambridge, MA USA. [Neale, Benjamin M.] MIT, Cambridge, MA 02139 USA. [Neale, Benjamin M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Neale, Benjamin M.] Harvard Univ, Sch Med, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. RP Anney, RJL (reprint author), Trinity Coll Dublin, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 8, Ireland. EM anneyr@tcd.ie RI Franke, Barbara/D-4836-2009; OI Franke, Barbara/0000-0003-4375-6572; Morris, Derek/0000-0002-3413-570X; Gill, Michael/0000-0003-0206-5337; Anney, Richard/0000-0002-6083-407X; Faraone, Stephen/0000-0002-9217-3982 FU NIH [R01MH62873] FX The scatterplots and clatasets used for the analysis described in this manuscript were obtained from the GAIN Database found at http://www.ncbi.nlni.nih.gov/pi-oiects/gap/ through the dbGAP accession number phs000016.vLpl. The IMAGE project is a multi-site, international effort supported by NIH grant R01MH62873 to S.V. Faraone. Site Principal Investigators are Philip Asherson,Tobias Banaschewski, Jan Buitelaar, Richard P. Ehstein, Stephen V. Faraone, Michael Gill, Ana Miranda, Robert D. Oades, Herbert Roeyers, Aribert Rothenberger, Joseph Sergeant, Edmund Sonuga-Barke, and Hans-Christoph Steinhausen; Senior co-investigators are fan Craig, Peter McGuffin, Robert Plomin, Pak Sharn, Eric Taylor, Iris Manor, Jacques Eisenberg and Margaret Thompson. Chief' Investigators are Evi BitsakOU, Marieke Altink, Wai Chen, Hanna Christiansen, Barbara Franke, Rafaela Marco, U Mueller, Fernando MUlas, Lamprini Psychogiou, Nanda Rommelse, Aisling Mulligan and Henrik Uebel. Other investigators are Cathelijne Buschgens, Frits Boer, Alysa Doyle, Ellen Fliers, Alexander Heise and Ruud Minderaa. We thank all the families who kindly participated in this research. NR 10 TC 5 Z9 6 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1379 EP 1386 DI 10.1002/ajmg.b.30836 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800008 PM 18663727 ER PT J AU Faraone, SV Doyle, AE Lasky-Su, J Sklar, PB D'Angelo, E Gonzalez-Heydrich, J Kratochvil, C Mick, E Klein, K Rezac, AJ Biederman, J AF Faraone, Stephen V. Doyle, Alysa E. Lasky-Su, Jessica Sklar, Pamela B. D'Angelo, Eugene Gonzalez-Heydrich, Joseph Kratochvil, Christopher Mick, Eric Klein, Kristy Rezac, Amy J. Biederman, Joseph TI Linkage Analysis of Attention Deficit Hyperactivity Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE ADHD; linkage analysis; SNPs ID DEFICIT/HYPERACTIVITY DISORDER; RECEPTOR GENE; GENOMEWIDE SCAN; SIB-PAIRS; ASSOCIATION; 17P11; DISEQUILIBRIUM; METAANALYSIS; RELIABILITY; INTERVIEW AB Results of behavioral genetic and molecular genetic studies have converged to suggest that both genes contribute to the development of ADHD. Although prior linkage studies have produced intriguing results, their results have been inconsistent, with no clear pattern of results emerging across studies. We genotyped 5,980 SNPs across the genome in 1,187 individuals from families with children diagnosed with ADHD. We then performed two nonparametric linkage analyses on ADHD families: (1) an affected sibling pair linkage analysis on 217 families with 601 siblings diagnosed with ADHD and (2) a variance components linkage analysis using the number of ADHD symptoms as the phenotype on 260 families with 1,100 phenotyped siblings. The affection status linkage analysis had a maximum LOD score of 1.85 on chromosome 8 at 54.2 cM. The maximum LOD score in the variance components linkage analysis was 0.8 on chromosome 8 at 93.4 cM. The absence of regions of significant or suggestive linkage in these data suggest that there are no genes of large effect contributing to the ADHD phenotype. (c) 2007 Wiley-Liss, Inc. C1 [Faraone, Stephen V.; Lasky-Su, Jessica] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.; Lasky-Su, Jessica] SUNY Upstate Med Univ, Genet Res Program, Syracuse, NY 13210 USA. [Doyle, Alysa E.; Sklar, Pamela B.; Mick, Eric; Biederman, Joseph] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [D'Angelo, Eugene; Gonzalez-Heydrich, Joseph] Harvard Univ, Sch Med, Dept Psychiat, Childrens Hosp Boston, Boston, MA 02115 USA. [Doyle, Alysa E.; Mick, Eric; Klein, Kristy; Biederman, Joseph] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. [Kratochvil, Christopher; Rezac, Amy J.] Univ Nebraska Med Ctr, Omaha, NE 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 NHGRI NIH HHS [N01HG65403]; NICHD NIH HHS [R01 HD037694, R01 HD037999, R01HD37694, R01HD37999]; NIMH NIH HHS [R01 MH066877, R01 MH081803, R01MH66877] NR 43 TC 27 Z9 27 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1387 EP 1391 DI 10.1002/ajmg.b.30631 PG 5 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800009 PM 18081027 ER PT J AU Zhou, KX Dempfle, A Arcos-Burgos, M Bakker, SC Banaschewski, T Biederman, J Buitelaar, J Castellanos, FX Doyle, A Ebstein, RP Ekholm, J Forabosco, P Franke, B Freitag, C Friedel, S Gill, M Hebebrand, J Hinney, A Jacob, C Lesch, KP Loo, SK Lopera, F McCracken, JT McGough, JJ Meyer, J Mick, E Miranda, A Muenkel, M Mulas, F Nelson, SF Nguyen, TT Oades, RD Ogdie, MN Palacio, JD Pineda, D Reif, A Renner, TJ Roeyers, H Romanos, M Rothenberger, A Schafer, H Sergeant, J Sinke, RJ Smalley, SL Sonuga-Barke, EJS Steinhausen, HC van der Meulen, E Walitza, S Warnke, A Lewis, CM Faraone, SV Asherson, P AF Zhou, Kaixin Dempfle, Astrid Arcos-Burgos, Mauricio Bakker, Steven C. Banaschewski, Tobias Biederman, Joseph Buitelaar, Jan Castellanos, F. Xavier Doyle, Alysa Ebstein, Richard P. Ekholm, Jenny Forabosco, Paola Franke, Barbara Freitag, Christine Friedel, Susann Gill, Michael Hebebrand, Johannes Hinney, Anke Jacob, Christian Lesch, Klaus Peter Loo, Sandra K. Lopera, Francisco McCracken, James T. McGough, James J. Meyer, Jobst Mick, Eric Miranda, Ana Muenkel, Maximilian Mulas, Fernando Nelson, Stanley F. Nguyen, T. Trang Oades, Robert D. Ogdie, Matthew N. Palacio, Juan David Pineda, David Reif, Andreas Renner, Tobias J. Roeyers, Herbert Romanos, Marcel Rothenberger, Aribert Schaefer, Helmut Sergeant, Joseph Sinke, Richard J. Smalley, Susan L. Sonuga-Barke, Edmund J. S. Steinhausen, Hans-Christoph van der Meulen, Emma Walitza, Susanne Warnke, Andreas Lewis, Cathryn M. Faraone, Stephen V. Asherson, Philip TI Meta-Analysis of Genome-Wide Linkage Scans of Attention Deficit Hyperactivity Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE ADHD; GSMA; linkage ID DEFICIT/HYPERACTIVITY DISORDER; SEARCH METAANALYSIS; SIB-PAIRS; GENETIC-HETEROGENEITY; BIPOLAR DISORDER; ADHD; ASSOCIATION; AUTISM; 17P11; LOCI AB Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome-wide significant linkage (P-SR = 0.00034, P-OR = 0.04) was identified on chromosome 16 between 64 and 83 Nth. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes. (c) 2008 Wiley-Liss, Inc. C1 [Asherson, Philip] Kings Coll London, Inst Psychiat, MRC, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England. [Dempfle, Astrid; Nguyen, T. Trang; Schaefer, Helmut] Univ Marburg, Inst Med Biometry & Epidemiol, Marburg, Germany. [Arcos-Burgos, Mauricio] Univ Miami, Dept Psychiat & Behav Sci, Leonard M Miller Sch Med, Miami, FL USA. [Arcos-Burgos, Mauricio; Muenkel, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Bakker, Steven C.; Sinke, Richard J.] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. [Banaschewski, Tobias] Heidelberg Univ, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, D-6800 Mannheim, Germany. [Biederman, Joseph; Doyle, Alysa; Mick, Eric; Faraone, Stephen V.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Buitelaar, Jan; Franke, Barbara] Radboud Univ Nijmegen, Dept Psychiat, Donders Ctr Neurosci, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Castellanos, F. Xavier; Sonuga-Barke, Edmund J. S.] NYU, Ctr Child Study, New York, NY USA. [Ebstein, Richard P.] Geha MHC, Petah Tiqwa, Israel. [Ekholm, Jenny; Nelson, Stanley F.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. [Forabosco, Paola; Lewis, Cathryn M.] Kings Coll London, Dept Med & Mol Genet, London WC2R 2LS, England. [Forabosco, Paola] CNR, Ist Genet Popolaz, Alghero, Italy. [Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Freitag, Christine] Saarland Univ Hosp, Dept Child & Adolescent Psychiat, Homburg, Germany. [Friedel, Susann; Hebebrand, Johannes; Hinney, Anke] Univ Duisburg Essen, Dept Child & Adolescent Psychiat, Essen, Germany. [Gill, Michael] St James Hosp, Trinity Ctr Hlth Sci, Dept Psychiat, Dublin 8, Ireland. [Jacob, Christian; Lesch, Klaus Peter; Reif, Andreas] Univ Wurzburg, Dept Psychiat & Psychotherapy, ADHD Clin Res Program, Wurzburg, Germany. [Loo, Sandra K.; McCracken, James T.; McGough, James J.; Smalley, Susan L.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Lopera, Francisco; Palacio, Juan David; Pineda, David] Univ Antioquia, Neurosci Grp, Medellin, Colombia. [Meyer, Jobst] Univ Trier, Dept Neurobehav Genet, Trier, Germany. [Miranda, Ana] Univ Valencia, Dept Dev & Educ Psychol, Valencia, Spain. [Mulas, Fernando] La Fe Univ Hosp, Fac Med, Dept Neuropaediat, Valencia, Spain. [Oades, Robert D.] Univ Clin Child & Adolescent Psychiat, Essen, Germany. [Ogdie, Matthew N.] MIT, Broad Inst, Cambridge, MA 02139 USA. [Renner, Tobias J.; Romanos, Marcel; Walitza, Susanne; Warnke, Andreas] Univ Wurzburg, Dept Child & Adolescent Psychiat & Psychotherapy, ADHD Clin Res Program, Wurzburg, Germany. [Roeyers, Herbert] Univ Ghent, B-9000 Ghent, Belgium. [Rothenberger, Aribert] Univ Gottingen, Gottingen, Germany. [Sergeant, Joseph] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Smalley, Susan L.] Univ Calif Los Angeles, Ctr Neurobehav Genet, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. [Sonuga-Barke, Edmund J. S.] Univ Southampton, Sch Psychol, Inst Disorder Impulse & Attent, Southampton, Hants, England. [Steinhausen, Hans-Christoph] Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. [van der Meulen, Emma] Univ Med Ctr Utrecht, Dept Child & Adolescent Psychiat, Utrecht, Netherlands. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. RP Asherson, P (reprint author), Kings Coll London, Inst Psychiat, MRC, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England. EM p.asherson@iop.kcl.ac.uk RI Franke, Barbara/D-4836-2009; Lewis, Cathryn/A-5225-2010; Nelson, Stanley/D-4771-2009; Sonuga-Barke, Edmund/D-9137-2011; Dempfle, Astrid/D-1513-2012; Hinney, Anke/D-6953-2011; Buitelaar, Jan/E-4584-2012; Renner, Tobias/I-2120-2013; Miranda, Ana/G-8619-2015; Romanos, Marcel/D-7695-2017; Lesch, Klaus-Peter/J-4906-2013 OI Walitza, Susanne/0000-0002-8161-8683; Gill, Michael/0000-0003-0206-5337; Mick, Eric/0000-0001-8505-8145; Castellanos, Francisco/0000-0001-9192-9437; Faraone, Stephen/0000-0002-9217-3982; Franke, Barbara/0000-0003-4375-6572; Lewis, Cathryn/0000-0002-8249-8476; Hinney, Anke/0000-0001-5659-0706; Buitelaar, Jan/0000-0001-8288-7757; Miranda, Ana/0000-0001-6998-5686; Lesch, Klaus-Peter/0000-0001-8348-153X FU NIH [R01HD37694, R01MH62873]; NIMH [MH058277, MH071852]; Deutsche Forschungsgemeinschaft [DFG: KFO 125, SFB 581]; Bundesministerium ftir Bildung und Forschung [BMBF: 01GV0605]; MRC [G0400960] FX The Asherson et al. study is supported by NIH (R01HD37694 and R01MH62873 to S.V.F.). The Ogdie et al. study is supported by NIMH (MH058277 to S.L.S. and MH071852 to S.F.N.), and a fellowship from the Academy of Finland (Ekholm), The Bakker et al. study is supported by the Mammalian Genotyping Service of the Marshfield Medical Research Foundation, and by grants from the Makaria Foundation, the UMC Utrecht's Genvlag program, and the Catharijne Foundation, J.M. and C.F. are supported by the Deutsche Forschungsgemeinschaft (DFG ME 1923/5-1, ME 1923/5-3, GRK 1389/1); M.R., C.J., T.T.N., S.W., T.J.R., A.W., H.S., A.R., and K.P.L. are supported by the Deutsche Forschungsgemeinschaft (DFG: KFO 125, SFB 581) and the Bundesministerium ftir Bildung und Forschung (BMBF: 01GV0605), GSMA methodology development is supported by MRC (G0400960 to C.M.L.). NR 28 TC 98 Z9 99 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1392 EP 1398 DI 10.1002/ajmg.b.30878 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800010 PM 18988193 ER PT J AU Doyle, AE Ferreira, MAR Sklar, PB Lasky-Su, J Petty, C Fusillo, SJ Seidman, LJ Wilicutt, EG Smoller, JW Purcell, S Biederman, J Faraone, SV AF Doyle, Alysa E. Ferreira, Manuel A. R. Sklar, Pamela B. Lasky-Su, Jessica Petty, Carter Fusillo, Steven J. Seidman, Larry J. Wilicutt, Erik G. Smoller, Jordan W. Purcell, Shaun Biederman, Joseph Faraone, Stephen V. TI Multivariate Genomewide Linkage Scan of Neurocognitive Traits and ADHD Symptoms: Suggestive Linkage to 3q13 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Review DE ADHD; multivariate linkage; endophenotype; cognition ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; MULTIPLE ASTHMA TRAITS; VERBAL WORKING-MEMORY; PREPULSE INHIBITION; RESPONSE-INHIBITION; EXECUTIVE FUNCTIONS; DELAY AVERSION; SIB-PAIRS; DEVELOPMENTAL DYSLEXIA AB Family and twin studies suggest that a range of neurocognitive traits index the inherited liability to ADHD; however, the utility of such measures as endophenotypes in molecular genetic studies remains largely untested. The current article examined whether the inclusion of neurocognitive measures in a genomewide linkage analysis of ADHD could aid in identifying QTL linked to the behavioral symptoms of the condition. Data were from an affected sibling pair linkage study of DSM-IV ADHD conducted at Massachusetts General Hospital. The sample included 1,212 individuals from 271 families. ADHD symptoms were assessed with the K-SADS-E. The neurocognitive battery included Wechsler Intelligence Scales subtests, the Stroup, the Wisconsin Card Sorting Test (WCST), the Rey-Osterreith Complex Figure, a working memory CPT, the CVLT and WRAT-III subscales. Evidence for linkage was assessed using a simulation-based method that combines information from univariate analyses into the equivalent of a multivariate test. After correction for multiple trait testing, a region on chromosome 3q13 showed suggestive linkage to all neurocognitive traits examined and inattention symptoms of ADHD. The second highest peak occurred on 22q12 but showed linkage to a single subscale of the WCST. In univariate analysis, this region retained criteria for suggestive linkage to this measure after correction for multiple trait testing. Our primary findings raise the possibility that one or more genes on 3q13 influence neurocognitive functions and behavioral symptoms of inattention. Overall, these data support the utility of neurocognitive traits as ADHD endophenotypes, but also highlight their limited genetic overlap with the disorder. (c) 2008 Wiley-Liss, Inc. C1 [Doyle, Alysa E.; Petty, Carter; Fusillo, Steven J.; Seidman, Larry J.; Biederman, Joseph] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. [Doyle, Alysa E.; Ferreira, Manuel A. R.; Sklar, Pamela B.; Smoller, Jordan W.; Purcell, Shaun] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Doyle, Alysa E.; Ferreira, Manuel A. R.; Sklar, Pamela B.; Seidman, Larry J.; Smoller, Jordan W.; Purcell, Shaun; Biederman, Joseph] Harvard Univ, Sch Med, Boston, MA USA. [Ferreira, Manuel A. R.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Lasky-Su, Jessica] Brigham & Womens Hosp, Channing Labs, Boston, MA 02115 USA. [Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr Publ Psychiat, Boston, MA 02215 USA. [Wilicutt, Erik G.] Univ Colorado, Boulder, CO 80309 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Neurosci & Physiol, Syracuse, NY USA. RP Doyle, AE (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. EM aedoyle@partners.org RI Ferreira, Manuel/D-3609-2013; OI Faraone, Stephen/0000-0002-9217-3982 FU NIH [R21MH080730, R01HD37694]; American Academy of Child and Adolescent Psychiatry in Boston; International Society for Psychiatric Genetics in New York FX This work was funded by NIH grants R21MH080730 to Dr. Doyle and R01HD37694 to Dr. Faraone. Portions of these data were presented in October 2007 at the Annual Meetings of the American Academy of Child and Adolescent Psychiatry in Boston and the International Society for Psychiatric Genetics in New York. The authors wish to thank Kimbery Mullen, Hannah-Lise Schofield and Kristy Klein with their help with data collection. NR 135 TC 28 Z9 28 U1 4 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1399 EP 1411 DI 10.1002/ajmg.b.30868 PG 13 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800011 PM 18973233 ER PT J AU Mick, E Neale, B Middleton, FA McGough, JJ Faraone, SV AF Mick, Eric Neale, Benjamin Middleton, Frank A. McGough, James J. Faraone, Stephen V. TI Genome-Wide Association Study of Response to Methylphenidate in 187 Children With Attention-Deficit/Hyperactivity Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE ADHD; methylphenidate; genome-wide association study; pharmacogenomic ID DEFICIT-HYPERACTIVITY DISORDER; DOPAMINE TRANSPORTER GENE; GLUTAMATE-RECEPTOR; DOSE-RESPONSE; ADHD; DAT1; POLYMORPHISM; ALLELE; SAMPLE; VARIANTS AB We conducted a genome-wide association study of symptom response in an open-label study of a methylphenidate transdermal system (MTS). All DNA extraction and genotyping was conducted at SUNY Upstate Medical University using the Affymetrix Genome-Wide Human SNP Array 6.0. All quality control and association analyses were conducted using the software package PLINK. After data cleaning and quality control, there were 187 subjects (72% (N = 135) male) with mean age 9.2 +/- 2.0 years and 319,722 SNPs available for analysis. The most statistically significant association (rs9627183 and rs11134178; P = 3 x 10(-6)) fell short of the threshold for a genome-wide significant association. The most intriguing association among suggestive findings (rs3792452; P = 2.6 x 10(-5)) was with the metabotropic glutamate receptor 7 gene (GRM7) as it is expressed in brain structures also previously associated with ADHD. Among the 102 available SNPs covering previously studied candidate genes, two SNPs within the norepinephrine transporter gene (NET, SLC6A2) were significant at P <= 1 x 10(-2). These results should be considered preliminary until replicated in larger adequately powered, controlled samples but do suggest that noradrenergic and possibly glutaminergic genes may be involved with response to methylphenidate. (c) 2008 Wiley-Liss, Inc. C1 [Mick, Eric] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Mick, Eric] Harvard Univ, Sch Med, Boston, MA USA. [Mick, Eric; Neale, Benjamin] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Neale, Benjamin] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Neale, Benjamin] Broad Inst Harvard, Cambridge, MA USA. [Neale, Benjamin] MIT, Cambridge, MA 02139 USA. [Middleton, Frank A.; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Middleton, Frank A.; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. [McGough, James J.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. RP Mick, E (reprint author), 55 Fruit St,Warren 705, Boston, MA 02114 USA. EM mick@helix.mgh.harvard.edu OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [U01 MH085518] NR 37 TC 56 Z9 56 U1 2 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1412 EP 1418 DI 10.1002/ajmg.b.30865 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800012 PM 18821564 ER PT J AU Polanczyk, G Faraone, SV Bau, CHD Victor, MM Becker, K Pelz, R Buitelaar, JK Franke, B Kooij, S van der Meulen, E Cheon, KA Mick, E Purper-Ouakil, D Gorwood, P Stein, MA Cook, EH Rohde, LA AF Polanczyk, Guilherme Faraone, Stephen V. Bau, Claiton H. D. Victor, Marcelo M. Becker, Katja Pelz, Reta Buitelaar, Jan K. Franke, Barbara Kooij, Sandra van der Meulen, Emma Cheon, Keun-Ah Mick, Eric Purper-Ouakil, Diane Gorwood, Philip Stein, Mark A. Cook, Edwin H., Jr. Rohde, Luis Augusto TI The Impact of Individual and Methodological Factors in the Variability of Response to Methylphenidate in ADHD Pharmacogenetic Studies from Four Different Continents SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE ADHD; pharmacogenetics; methylphenidate; treatment; meta-regression ID ATTENTION-DEFICIT/HYPERACTIVITY-DISORDER; DEFICIT HYPERACTIVITY DISORDER; RECEPTOR GENE; CHILDREN; ASSOCIATION; POLYMORPHISM; METAANALYSIS; ADOLESCENTS; SYMPTOMS; TRIALS AB Several studies have evaluated the association between individual polymorphisms and response to methylphenidate (MPH) in subjects with attention-deficit/hyperactivity disorder (ADHD). There are few replication studies for each polymorphism of interest and results are sometimes inconsistent in this field. Although data collection from multiple international sites would allow large sample sizes, this approach has been criticized for introducing sampling variability due to differences in ethnicity and methodology between studies. To examine these issues, we aggregated nine pharmacogenetic studies from four different continents and conducted a two stage analysis: (a) we evaluated the role of methodological aspects in the variability of ADHD symptom improvement between studies using meta-regression analysis; (b) we assessed the role of individual characteristies of the subjects in the variability of ADHD symptoms improvement using multivariate regression analysis in the same data sets. At the study level, from five evaluated factors, only the design of the study (open studies vs. randomized controlled trials) was significantly associated with heterogeneity of results (P=0.001). At the individual level, age (P < 0.001), comorbid oppositional defiant disorder (P < 0.001), and pre-treatment scores (P < 0.001) were associated with change of ADHD scores with treatment in the final multivariate model. Our results suggest that joint analyses of pharmacogenetic studies are feasible and promising, since fixed variables, such as the site where the study was conducted, were not related to results. Nevertheless, stratified analyses according to the design of the study must be preferentially conducted and the role of individual factors such as demographic data and comorbid profile as confounders should be assessed. (c) 2008 Wiley-Liss, Inc. C1 [Polanczyk, Guilherme; Rohde, Luis Augusto] Univ Fed Rio Grande do Sul, Child & Adolescent Psychiat Div, Hosp Clin Porto Alegre, ADHD Program, Porto Alegre, RS, Brazil. [Polanczyk, Guilherme] Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. [Bau, Claiton H. D.] Univ Fed Rio Grande do Sul, Dept Genet, Porto Alegre, RS, Brazil. [Bau, Claiton H. D.; Victor, Marcelo M.] Univ Fed Rio Grande do Sul, Adult ADHD Outpatient Clin, Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. [Becker, Katja; Pelz, Reta] Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, D-6800 Mannheim, Germany. [Becker, Katja] Univ Marburg, Fac Med, Dept Child & Adolescent Psychiat & Psychotherapy, Marburg, Germany. [Buitelaar, Jan K.; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Kooij, Sandra] Ctr Mental Hlth, Adult ADHD Program PsyQ, The Hague, Netherlands. [van der Meulen, Emma] Acad Ctr Child & Adolescent Psychiat, Amsterdam, Netherlands. [Cheon, Keun-Ah] Kwandong Univ, Coll Med, Myong Ji Hosp, Dept Psychiat,Div Child & Adolescent Psychiat, Koyang City, Kyunggi, South Korea. [Mick, Eric] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Psychopharmacol Unit, Boston, MA USA. [Purper-Ouakil, Diane] Hop Robert Debre, AP HP, Child & Adolescent Psychopathol Unit, F-75019 Paris, France. [Purper-Ouakil, Diane; Gorwood, Philip] Univ Paris 07, INSERM, IFR02, Fac Xavier Bichat,U675, F-75221 Paris 05, France. [Gorwood, Philip] Hop Louis Mourier, AP HP, F-92701 Colombes, France. [Stein, Mark A.; Cook, Edwin H., Jr.] Univ Illinois, Inst Juvenile Res, HALP Clin, Chicago, IL USA. [Stein, Mark A.; Cook, Edwin H., Jr.] Univ Illinois, Inst Juvenile Res, ADHD Res Ctr, Chicago, IL USA. RP Rohde, LA (reprint author), Univ Fed Rio Grande do Sul, Child & Adolescent Psychiat Div, Hosp Clin Porto Alegre, ADHD Program, Rua Ramiro Barcelos 2350, Porto Alegre, RS, Brazil. EM lrohde@terra.com.br RI Rohde, Luis Augusto/A-6426-2008; Franke, Barbara/D-4836-2009; Polanczyk, Guilherme/C-2345-2012; Buitelaar, Jan/E-4584-2012; Bau, Claiton/C-9980-2013; OI Rohde, Luis Augusto/0000-0002-4552-4188; Franke, Barbara/0000-0003-4375-6572; Polanczyk, Guilherme/0000-0003-2311-3289; Buitelaar, Jan/0000-0001-8288-7757; Bau, Claiton/0000-0001-5644-3845; Purper-Ouakil, Diane/0000-0003-0454-1579; Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982; GORWOOD, Philip/0000-0003-1845-3676 FU Conselho Nacional de Desenvolvimento Cientificto e Tecnoloigico (CNPq, Brazil) [MCT/CNPq 02/2006, 478202/2006-7]; Ministry of Education, Brazil; NIMH [R13MH59126] FX This work was partially supported by research grants from Conselho Nacional de Desenvolvimento Cientificto e Tecnoloigico (CNPq, Brazil) (MCT/CNPq 02/2006, Universal, Grant 478202/2006-7), FIPE, Hospital de Clinicas de Porto Alegre. Dr. Polanczyk holds a doctoral fellowship, Coordenao;ao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Ministry of Education, Brazil. Collaboration among site was facilitated by NIMH conference grant R13MH59126 to S.V. Faraone. NR 35 TC 16 Z9 16 U1 3 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1419 EP 1424 DI 10.1002/ajmg.b.30855 PG 6 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800013 PM 18802923 ER PT J AU Monuteaux, MC Seidman, LJ Faraone, SV Makris, N Spencer, T Valera, E Brown, A Bush, G Doyle, AE Hughes, S Helliesen, M Mick, E Biederman, J AF Monuteaux, Michael C. Seidman, Larry J. Faraone, Stephen V. Makris, Nikos Spencer, Thomas Valera, Eve Brown, Ariel Bush, George Doyle, Alysa E. Hughes, Samantha Helliesen, Meghan Mick, Eric Biederman, Joseph TI A Preliminary Study of Dopamine D4 Receptor Genotype and Structural Brain Alterations in Adults With ADHD SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE DRD4; magnetic resonance imaging; genetic polymorphism; bipolar disorder; neuroanatomy ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; BIPOLAR DISORDER; D-4 RECEPTOR; ASSOCIATION; CORTEX; GENE; DRD4; PARCELLATION; METAANALYSIS AB An emerging literature has demonstrated an association between the dopamine D4 receptor (DRD4) gene and volumetric brain abnormalities in children with ADHD. However, these results have not been extended to adults and have not addressed the impact of comorbidity. Our objective was to examine the DRD4 7R gene and volumetric brain abnormalities in adults with ADHD while accounting for comorbidity with bipolar disorder (BPD). Subjects were male and female adult outpatient referrals stratified into two diagnostic groups: 24 with ADHD, 19 with ADHD and BPD, as well as 20 male and female adult community controls without ADHD or BPD. We measured volumes (cm(3)) of a priori selected brain regions (superior frontal, middle frontal, anterior cingulate, and cerebellum cortices) by structural magnetic resonance imaging. Among adults with ADHD, subjects with the 7-repeat allele of the DRD4 gene had a significantly smaller mean volume in the superior frontal cortex and cerebellum cortex compared to subjects without this allele. In contrast, no such effects were detected in the adults with ADHD + BPD or controls. Our findings suggest that volumetric abnormalities in the dorsolateral prefrontal cortex and cerebellum may represent an intermediate neuroanatomical phenotype between DRD4 genotype and the clinical expression of ADHD in adults, but only in ADHD subjects without comorbid BPD. These result support the heterogeneity of ADHD and provides insights as to its underlying pathophysiology. (c) 2008 Wiley-Liss, Inc. C1 [Monuteaux, Michael C.; Spencer, Thomas; Doyle, Alysa E.; Hughes, Samantha; Helliesen, Meghan; Mick, Eric; Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Seidman, Larry J.] Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr, Publ Psychiat Div, Boston, MA 02215 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, SUNY Genet Res Program, Syracuse, NY USA. [Makris, Nikos; Valera, Eve; Brown, Ariel; Bush, George] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging,MIT, Charlestown, MA USA. RP Monuteaux, MC (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Fruit St,Warren 7, Boston, MA 02114 USA. EM mmonuteaux@partners.org OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU Pediatric Psychopharmacology Council Fund FX We thank Lindsay Barker, Jennifer Burbridge, Michael Cirillo, PhD, 1,isa Denny, ME), Jo-Anne Donatelli, PhD, Christine Fetterer, Jean Prazier, MD, Steve Hodge, Kalika Kelkar, Monica Landi, MSW, Nicole Peace, An ne Peters, Scott Rauch, MD, Michael Schiller, John Schlerf, Williarn S. Stone, PhD and Timothy Wilens, MD. We would also like to recogn ize and thank the Pediatric Psychopharmacology Council Fund for its contributions to this work. NR 36 TC 31 Z9 32 U1 3 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1436 EP 1441 DI 10.1002/ajmg.b.30870 PG 6 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800016 PM 18951431 ER PT J AU Zhou, KX Chen, W Buitelaar, J Banaschewski, T Oades, RD Franke, B Sonuga-Barke, EJS Ebstein, R Eisenberg, J Gill, M Manor, I Miranda, A Mulas, F Roeyers, H Rothenberger, A Sergeant, J Steinhausen, HC Lasky-Su, J Taylor, E Brookes, KJ Xu, XH Neale, BM Rijsdijk, F Thompson, M Asherson, P Faraone, SV AF Zhou, Kaixin Chen, Wai Buitelaar, Jan Banaschewski, Tobias Oades, Robert D. Franke, Barbara Sonuga-Barke, Edmund J. S. Ebstein, Richard Eisenberg, Jacques Gill, Michael Manor, Iris Miranda, Ana Mulas, Fernando Roeyers, Herbert Rothenberger, Aribert Sergeant, Joseph Steinhausen, Hans-Christoph Lasky-Su, Jessica Taylor, Eric Brookes, Keeley J. Xu, Xiaohui Neale, Benjamin M. Rijsdijk, Fruhling Thompson, Margaret Asherson, Philip Faraone, Stephen V. TI Genetic Heterogeneity in ADHD: DAT1 Gene Only Affects Probands Without CD SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE comorbidity; stratification; association ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY-DISORDER; DOPAMINE TRANSPORTER GENE; CONDUCT DISORDER; ASSOCIATION; CHILDREN; SUBTYPES; IDENTIFICATION; METAANALYSIS; COMORBIDITY AB Previous studies have found heterogeneous association between DAT1-3'-UTR-VNTR and attention deficit hyperactivity disorder (ADHD). Various proportions of conduct disorder (CD) comorbidity in their ADHD samples may partially explain the observational discrepancies. Evidence for this comes from family and twin studies which found ADHD probands with CD (ADHD + CD) are genetically different from those without CD (ADHD - CD). Genotypes of 20 DAT1 markers were analyzed in 576 trios, consisting of 141 ADHD + CD and 435 ADHD - CD. In addition to the classical TDT test, a specific genetic heterogeneity test was performed to identify variants that have different transmission patterns in the two phenotypic subgroups. After multiple-test correction, rs40184 and rs2652511 were significant in TDT tests. Further heterogeneity test found the two SNPs had a significant transmission pattern difference between ADHD + CD and ADHD - CD children, indicating that DAT1 has a significantly greater genetic influence on ADHD without CD. Although the result needs further replications, it does highlight the importance of selecting genetically homogeneous samples for molecular genetic analyses of ADHD. (c) 2007 Wiley-Liss, Inc. C1 [Lasky-Su, Jessica; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Zhou, Kaixin; Chen, Wai; Taylor, Eric; Brookes, Keeley J.; Xu, Xiaohui; Neale, Benjamin M.; Rijsdijk, Fruhling; Asherson, Philip] Inst Psychiat, MRC, Social Genet Dev & Psychiat Ctr, London, England. [Buitelaar, Jan; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, NL-6525 ED Nijmegen, Netherlands. [Banaschewski, Tobias; Rothenberger, Aribert] Univ Gottingen, D-3400 Gottingen, Germany. [Banaschewski, Tobias] Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, D-6800 Mannheim, Germany. [Oades, Robert D.] Univ Clin Child & Adolescent Psychiat, Essen, Germany. [Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [Sonuga-Barke, Edmund J. S.; Thompson, Margaret] Univ Southampton, Sch Psychol, Southampton, Hants, England. [Ebstein, Richard; Manor, Iris] Geha Mental Hlth Ctr, ADHD Clin, Petah Tiqwa, Israel. [Eisenberg, Jacques] S Herzog Mem Hosp, Jerusalem, Israel. [Gill, Michael] St James Hosp, Trinity Ctr Hlth Sci, Dept Psychiat, Dublin 8, Ireland. [Miranda, Ana; Mulas, Fernando] Univ Valencia, Dept Dev & Educ Psychol, E-46003 Valencia, Spain. [Roeyers, Herbert] Univ Ghent, B-9000 Ghent, Belgium. [Sergeant, Joseph] Vrije Univ Amsterdam, Dept Clin Neuropsychol, Amsterdam, Netherlands. [Steinhausen, Hans-Christoph] Univ Zurich, Dept Child & Adolescent Psychiat, CH-8006 Zurich, Switzerland. [Lasky-Su, Jessica; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci, Syracuse, NY 13210 USA. [Lasky-Su, Jessica; Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Physiol, Syracuse, NY 13210 USA. [Neale, Benjamin M.] Broad Inst Harvard, Cambridge, MA USA. [Neale, Benjamin M.] MIT, Cambridge, MA 02139 USA. [Neale, Benjamin M.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Faraone, SV (reprint author), SUNY Upstate Med Univ, Dept Psychiat, 750 E Adams St, Syracuse, NY 13210 USA. EM faraones@upstate.edu RI Sonuga-Barke, Edmund/D-9137-2011; Buitelaar, Jan/E-4584-2012; Franke, Barbara/D-4836-2009; Rijsdijk, Fruhling/B-4191-2011; Miranda, Ana/G-8619-2015; OI Buitelaar, Jan/0000-0001-8288-7757; Franke, Barbara/0000-0003-4375-6572; Miranda, Ana/0000-0001-6998-5686; Gill, Michael/0000-0003-0206-5337; Faraone, Stephen/0000-0002-9217-3982 FU NIH [R01MH62873] FX The IMAGE project is a multi-site, international effort supported by NIH grant R01MH62873 to S.V. Faraone. We thank all the families who kindly participated in this research. NR 42 TC 25 Z9 25 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 EI 1552-485X J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1481 EP 1487 DI 10.1002/ajmg.b.30644 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800022 PM 18553640 ER PT J AU Biederman, J Kim, JW Doyle, AE Mick, E Fagerness, J Smoller, JW Faraone, SV AF Biederman, Joseph Kim, Jang Woo Doyle, Alysa E. Mick, Eric Fagerness, Jesen Smoller, Jordan W. Faraone, Stephen V. TI Sexually Dimorphic Effects of Four Genes (COMT, SLC6A2, MAOA, SLC6A4) in Genetic Associations of ADHD: A Preliminary Study SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE gender; attention deficit/hyperactivity disorder; neurobiology ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; CATECHOL-O-METHYLTRANSFERASE; FAMILY-BASED ASSOCIATION; SEROTONIN TRANSPORTER; MONOAMINE-OXIDASE; SEX-DIFFERENCES; PREFERENTIAL TRANSMISSION; SUBTHRESHOLD DIAGNOSES; AGGRESSIVE-BEHAVIOR AB A growing body of literature finds gender differences in ADHD. However, little is known about the causes of these differences. One possibility is that ADHD risk genes have sexually dimorphic effects. We have investigated four ADHD candidate genes (COMT, SLC6A2, MAOA, SLC6A4) for which there is evidence of sexually dimorphic effects. Past neurobiological and genetic studies suggest that COMT, and SLC6A4 variants may have a greater influence on males and that SLC6A2, and MAOA variants may have a greater influence on females. Our results indicate that genetic associations are stronger when stratified by sex and in the same direction as the previous neurobiological studies indicate: associations were stronger in males for COMT, SLC6A4 and stronger in females for SLC6A2, MAOA. Moreover, we found a statistically significant gender effect in the case of COMT (P = 0.007) when we pooled our work with a prior study. In conclusion, we have found some evidence suggesting that the genetic association for these genes with ADHD may be influenced by the sex of the affected individual. Although our results are not fully validated yet, they should motivate further investigation of gender effects in ADHD genetic association studies. (C) 2008 Wiley-Liss, Inc. C1 [Kim, Jang Woo; Smoller, Jordan W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Psychiat & Neurodev Genet Unit,Ctr Human Genet Re, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. RP Biederman, J (reprint author), 55 Fruit St,Warren 705, Boston, MA 02114 USA. EM jbiederman@partners.org OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NIH [R01HD37694, R01HD37999, R01MH66877]; NARSAD FX This work was supported by NIH grants R01HD37694, R01HD37999 and R01MH66877 to S. Faraone and NARSAD Young Investigator Award to JWK. JWK is a NARSAD Sidney R. Baer, Jr. Foundation Investigator. The authors thank Dr. Pamela Sklar and her laboratory for completing the genotyping for this project. NR 68 TC 62 Z9 64 U1 2 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2008 VL 147B IS 8 SI SI BP 1511 EP 1518 DI 10.1002/ajmg.b.30874 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 379SF UT WOS:000261415800027 PM 18937309 ER PT J AU Bell, AJ Chauhan, S Woodson, SA Kallenbach, NR AF Bell, Anthony J., Jr. Chauhan, Seema Woodson, Sarah A. Kallenbach, Neville R. TI Interactions of recombinant HMGB proteins with branched RNA substrates SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE High mobility group proteins; Four-way junction DNA; Ribozyme; DNA binding; RNA binding ID GROUP-I INTRON; DNA-BINDING PROTEINS; 4-WAY JUNCTION DNA; CHROMATIN; RIBOZYME; BOXES; INHIBITION; CATALYSIS; HISTONE; DOMAIN AB The high mobility group protein HMGB1 is a highly abundant chromosomal protein known to interact preferentially with DNA that is branched, bent or otherwise structurally altered. Biologically the protein is thought to facilitate promoter attachment by transcription factors. Recently, however, HMGB1 has been shown to have biological roles beyond that of an architectural DNA-binding protein. Here we investigate the binding interactions of recombinant HMGB1 proteins with two branched RNA's E. coli 5S rRNA and the group I intron ribozyme from Azoarcus pre-tRNA(lle). Using competitive electrophoretic mobility and circular dichroism binding assays, we show that HMGB proteins bind both substrates with high affinity. We also report that a recombinant rat HMGB protein, rHMGB1b, inhibits RNA cleavage by the ribozyme. These results raise the possibility that HMGB proteins possess structure dependent RNA binding activity and can modulate RNA processing as well as transcription. (C) 2008 Elsevier Inc. All rights reserved. C1 [Bell, Anthony J., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol,Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Chauhan, Seema] Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. [Woodson, Sarah A.] Johns Hopkins Univ, TC Jenkins Dept Biophys, Baltimore, MD 21218 USA. [Kallenbach, Neville R.] NYU, Dept Chem, New York, NY 10003 USA. RP Bell, AJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol,Ctr Computat & Integrat Biol, Boston, MA 02114 USA. EM tbell@molbio.mgh.harvard.edu RI Chauhan, Seema/E-8229-2011 NR 27 TC 11 Z9 11 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 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 5 PY 2008 VL 377 IS 1 BP 262 EP 267 DI 10.1016/j.bbrc.2008.09.131 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 370BU UT WOS:000260738500051 PM 18845125 ER PT J AU Milan, DJ Kolpa, HJ Burns, CG MacRae, CA AF Milan, David J. Kolpa, Heather J. Burns, C. G. MacRae, Calum A. TI Micro RNA-21 Targeting of Programmed Cell Death 4 is Required for Valve Development SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Milan, David J.; Kolpa, Heather J.; Burns, C. G.; MacRae, Calum A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD DEC 5 PY 2008 VL 103 IS 12 BP 1494 EP 1494 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 379TK UT WOS:000261418900023 ER PT J AU Aikawa, E Aikawa, M Libby, P Figueiredo, JL Rusanescu, G Fukuda, D Kohler, RH Shi, GP Weissleder, R AF Aikawa, Elena Aikawa, Masanori Libby, Peter Figueiredo, Jose-Luiz Rusanescu, Gabriel Fukuda, Daiju Kohler, Rainer H. Shi, Guo-Ping Weissleder, Ralph TI Novel Role of Elastolytic Cathepsin Activity in Accelerated Osteogenesis in Atherosclerosis and Inflamed Aortic Valves Determined by Molecular Imaging SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc C1 [Aikawa, Elena; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. [Aikawa, Masanori; Libby, Peter; Fukuda, Daiju; Shi, Guo-Ping] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD DEC 5 PY 2008 VL 103 IS 12 BP 1499 EP 1499 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 379TK UT WOS:000261418900041 ER PT J AU Geraldes, P Yagi, K Ohshiro, Y He, ZH Maeno, Y Yamamoto-Hiraoka, J Rask-Madsen, C Chung, SW Perrella, MA King, GL AF Geraldes, Pedro Yagi, Kunimasa Ohshiro, Yuzuru He, Zhiheng Maeno, Yasuhiro Yamamoto-Hiraoka, Junko Rask-Madsen, Christian Chung, Su Wol Perrella, Mark A. King, George L. TI Selective Regulation of Heme Oxygenase-1 Expression and Function by Insulin through IRS1/Phosphoinositide 3-Kinase/Akt-2 Pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NRF2 TRANSCRIPTION FACTOR; PROTEIN-KINASE-C; OXIDATIVE STRESS; RETINAL CAPILLARIES; EPITHELIAL-CELLS; SODIUM ARSENITE; GENE-EXPRESSION; DIABETIC-RATS; NITRIC-OXIDE; ANTIOXIDANT AB Heme oxygenase 1 (HO-1) is a representative mediator of antioxidants and cytoprotectants against various stress stimuli including oxidants in vascular cells. Intensive insulin treatment can delay the onset and progression of diabetic retinopathy and other vascularopathies, yet little is known about insulin regulation of anti-apoptotic and antioxidant molecules such as HO-1 in vascular cells. Intravitreous injection or in vitro addition of insulin increased HO-1 protein expression in rat retina and in cultured bovine retinal pericytes, retinal endothelial cells, and retinal pigment epithelial cells. In bovine retinal pericytes, insulin induced mRNA and protein expression of HO-1 in a time- and concentration-dependent manner. Using HO-1 promoter analysis, the luciferase reporter assay showed that induction of HO-1 expression by insulin is mediated by additional response elements in the ho-1 promoter gene, which was not responsive to antioxidants. Insulin-induced HO-1 mRNA expression through activation of PI3-kinase/Akt pathway without affecting ERK and p38 MAPK. Overexpression of an adenoviral vector of native IRS1, IRS2, and Akt dominant negative or small interfering RNA transfection of Akt1 and Akt2 targeted gene demonstrated that insulin regulated HO-1 expression via IRS1 and Akt2 pathway, selectively. Further, insulin treatment prevented H(2)O(2)-induced NF-kappa B and caspase-8 activation and apoptosis via the IRS1/PI3K/Akt2/HO-1 pathway in the pericytes. In conclusion, we suggest that the anti-apoptotic properties of insulin are mediated partly by increasing HO-1 expression at transcriptional level via IRS1/PI3K/Akt2 activation, a potential explanation for how insulin is retarding the progression of microvascular complications induced by diabetes. C1 [Geraldes, Pedro; Yagi, Kunimasa; Ohshiro, Yuzuru; He, Zhiheng; Maeno, Yasuhiro; Yamamoto-Hiraoka, Junko; Rask-Madsen, Christian; King, George L.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Chung, Su Wol] Univ Ulsan, Coll Nat Sci, Sch Biol Sci & Technol, Ulsan 630749, South Korea. [Chung, Su Wol; Perrella, Mark A.] Brigham & Womens Hosp, Div Pulm & Crit Care, Boston, MA 02215 USA. [King, George L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP King, GL (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM George.King@joslin.harvard.edu FU National Institutes of Health [5 R01 DK053105-09A1, NEI 5 R01 EY016150-02, P30 DK36836, R01HL60788]; American Diabetes Association Research [1-08-RA-93] FX This work was supported, in whole or in part, by National Institutes of Health Grants 5 R01 DK053105-09A1 and NEI 5 R01 EY016150-02 (to G. L. K.), Grant P30 DK36836, and Grant R01HL60788 (to M. A. P.). This work was also supported by American Diabetes Association Research Grant 1-08-RA-93. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 54 TC 37 Z9 38 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 DEC 5 PY 2008 VL 283 IS 49 BP 34327 EP 34336 DI 10.1074/jbc.M807036200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 377UY UT WOS:000261277700060 PM 18854316 ER PT J AU Mulligan, P Westbrook, TF Ottinger, M Pavlova, N Chang, B Macia, E Shi, YJ Barretina, J Liu, JS Howley, PM Elledge, SJ Shi, Y AF Mulligan, Peter Westbrook, Thomas F. Ottinger, Matthias Pavlova, Natalya Chang, Bin Macia, Eric Shi, Yu-Jiang Barretina, Jordi Liu, Jinsong Howley, Peter M. Elledge, Stephen J. Shi, Yang TI CDYL Bridges REST and Histone Methyltransferases for Gene Repression and Suppression of Cellular Transformation SO MOLECULAR CELL LA English DT Article ID RESTRICTIVE SILENCER FACTOR; CO-REPRESSOR; TRANSCRIPTIONAL REPRESSION; NEURONAL GENES; CERVICAL-CARCINOMA; EXPRESSION; COMPLEX; DEACETYLASE; PROTEIN; CELLS AB The neuronal gene repressor REST/NRSF recruits corepressors, including CoREST, to modify histones and repress transcription. REST also functions as a tumor suppressor, but the mechanism remains unclear. We identified chromodomain on Y-like (CDYL) as a REST corepressor that physically bridges REST and the histone methylase G9a. to repress transcription. Importantly, RNAi knockdown of REST, CDYL, and G9a, but not CoREST, induced oncogenic transformation of immortalized primary human cells and derepression of the proto-oncogene TrkC. Significantly, transgenic expression of TrkC also induced transformation. This implicates CDYL-G9a, but not CoREST, in REST suppression of transformation, possibly by oncogene repression. CDYL knockdown also augments transformation in a cell culture model of cervical cancer, where loss of heterozygosity of the CDYL locus occurs. These findings demonstrate molecular strategies by which REST carries out distinct biological functions via different corepressors and provide critical insights into the role of histone-modifying complexes in regulating cellular transformation. C1 [Mulligan, Peter; Ottinger, Matthias; Shi, Yu-Jiang; Howley, Peter M.; Shi, Yang] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Westbrook, Thomas F.; Pavlova, Natalya; Elledge, Stephen J.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Harvard Partners Ctr Genet & Genom,Dept Genet, Boston, MA 02115 USA. [Westbrook, Thomas F.; Liu, Jinsong] Baylor Coll Med, Dept Mol & Human Genet, Dept Biochem & Mol Biol, Houston, TX 77030 USA. [Chang, Bin] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Chang, Bin] Shihezi Univ, Sch Med, Dept Pathol & Lab Xinjiang Endem & Ethn Dis, Shihezi 832002, Xinjiang, Peoples R China. [Macia, Eric] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Barretina, Jordi] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Shi, Y (reprint author), Harvard Univ, Sch Med, Dept Pathol, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM yshi@hms.harvard.edu FU NIH [GM071004, PO1 CA050661]; Howard Hughes Medical Institute; Susan G. Komen Breast Cancer Foundation [PDF0403175]; Constellation Pharmaceuticals FX We gratefully acknowledge the assistance of Benedikt Kessler and Eric Spooner of the Harvard Medical School PFPC in completing the mass spectrometric analysis. We thank Gail Mandel for providing REST antibody and reagents, Grace Gill and Jian Ouyang for His-CoREST, Agata Smogorzewska for pMSCV-neo-HPV16-E6/E7, Karl Munger for NOK cells, and Yoshihiro Nakatani and Bijan Sobhian for G9a antibody and expression plasmid. We also thank Grace Gill, Keith Blackwell, Wade Harper, and their laboratories for critical discussion of the project. This work was supported by NIH grants GM071004 (to Y.S.) and PO1 CA050661 (to P.M.H.). S.J.E is an investigator with the Howard Hughes Medical Institute, and T.F.W. is funded by grant PDF0403175 from the Susan G. Komen Breast Cancer Foundation. Y.S. is a cofounder of Constellation Pharmaceuticals and member of its scientific advisory board. NR 37 TC 64 Z9 75 U1 0 U2 6 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 DEC 5 PY 2008 VL 32 IS 5 BP 718 EP 726 DI 10.1016/j.molcel.2008.10.025 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 381MF UT WOS:000261539700013 PM 19061646 ER PT J AU Chien, KR Domian, IJ Parker, KK AF Chien, Kenneth R. Domian, Ibrahim J. Parker, Kevin Kit TI Cardiogenesis and the Complex Biology of Regenerative Cardiovascular Medicine SO SCIENCE LA English DT Review ID BONE-MARROW-CELLS; ACUTE MYOCARDIAL-INFARCTION; HEMATOPOIETIC STEM-CELLS; PROGENITOR CELLS; CARDIAC PROGENITORS; SMOOTH-MUSCLE; MAMMALIAN HEART; ARTERIAL POLE; DIFFERENTIATION; CARDIOMYOCYTE AB The heart is a complex organ system composed of a highly diverse set of muscle and nonmuscle cells. Understanding the pathways that drive the formation, migration, and assembly of these cells into the heart muscle tissue, the pacemaker and conduction system, and the coronary vasculature is a central problem in developmental biology. Efforts to unravel the biological complexity of in vivo cardiogenesis have identified a family of closely related multipotent cardiac progenitor cells. These progenitors must respond to non- cell- autonomous signaling cues to expand, differentiate, and ultimately integrate into the three- dimensional heart structures. Coupling tissue- engineering technologies with patient- specific cardiac progenitor biology holds great promise for the development of human cell models of human disease and may lay the foundation for novel approaches in regenerative cardiovascular medicine. C1 [Chien, Kenneth R.; Domian, Ibrahim J.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Chien, Kenneth R.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Chien, Kenneth R.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Parker, Kevin Kit] Harvard Univ, Sch Engn & Appl Sci, Dis Biophys Grp, Cambridge, MA 02138 USA. RP Chien, KR (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM kchien@partners.org NR 47 TC 148 Z9 155 U1 2 U2 49 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 5 PY 2008 VL 322 IS 5907 BP 1494 EP 1497 DI 10.1126/science.1163267 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 379DU UT WOS:000261377400036 PM 19056974 ER PT J AU Maherali, N Hochedlinger, K AF Maherali, Nimet Hochedlinger, Konrad TI Guidelines and Techniques for the Generation of Induced Pluripotent Stem Cells SO CELL STEM CELL LA English DT Review ID HUMAN SOMATIC-CELLS; SMALL-MOLECULE COMPOUNDS; LENTIVIRAL VECTORS; HUMAN FIBROBLASTS; DEFINED FACTORS; SERUM-FREE; IN-VIVO; MOUSE; EXPRESSION; INDUCTION AB Direct reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) provides an invaluable resource for regenerative medicine, enabling the generation of patient-specific cells of any lineage without the use of embryonic material. A variety of methods exist for iPSC derivation, all reliant upon manipulation of a select group of transcription factors. We compare the currently reported protocols, identify essential steps common to these methods, and suggest minimal criteria for defining fully reprogrammed cells. In addition, specific procedures aimed to optimize reproducible iPSC derivation are presented, with an emphasis on standardization of certain parameters for accurate comparison between independent experiments. C1 [Maherali, Nimet; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Maherali, Nimet; Hochedlinger, Konrad] Harvard Stem Cell Inst, Ctr Canc, Dept Stem Cell & Regenerat Biol, Boston, MA 02114 USA. [Maherali, Nimet] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Hochedlinger, K (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, 185 Cambridge St, Boston, MA 02114 USA. EM khochedlinger@helix.mgh.harvard.edu FU Natural Sciences and Engineering Research Council of Canada; Alberta Scholarship Programs; NIH Director's Innovator Award; Harvard Stem Cell Institute; Kimmel Foundation; V Foundation FX We thank Todd Meyerrose, Jose Polo, Matthias Stadtfeld, and Jochen Utikal for discussion and critical reading of the manuscript, and Tom DeCesare for figure contributions. N.M. is supported by the Natural Sciences and Engineering Research Council of Canada and Alberta Scholarship Programs. K.H. is supported by an NIH Director's Innovator Award, the Harvard Stem Cell Institute, the Kimmel Foundation, and the V Foundation. NR 76 TC 293 Z9 310 U1 16 U2 82 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD DEC 4 PY 2008 VL 3 IS 6 BP 595 EP 605 DI 10.1016/j.stem.2008.11.008 PG 11 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 383JW UT WOS:000261670900008 PM 19041776 ER PT J AU Hurtado, A Holmes, KA Geistlinger, TR Hutcheson, IR Nicholson, RI Brown, M Jiang, J Howat, WJ Ali, S Carroll, JS AF Hurtado, Antoni Holmes, Kelly A. Geistlinger, Timothy R. Hutcheson, Iain R. Nicholson, Robert I. Brown, Myles Jiang, Jie Howat, William J. Ali, Simak Carroll, Jason S. TI Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen SO NATURE LA English DT Article ID BREAST-CANCER CELLS; MCF-7 CELLS; RESISTANCE; COACTIVATOR; EXPRESSION; ACTIVATION; AIB1; TRANSCRIPTION; SURVIVAL; THERAPY AB Crosstalk between the oestrogen receptor (ER) and ERBB2/HER-2 pathways has long been implicated in breast cancer aetiology and drug eresponse(1), yet no direct connection at a transcriptional level has been shown. Here we show that oestrogen-ER and tamoxifen ER complexes directly repress ERBB2 transcription by means of a cis- regulatory element within the ERBB2 gene in human cell lines. We implicate the paired box 2 gene product ( PAX2), in a previously unrecognized role, as a crucial mediator of ER repression of ERBB2 by the anti- cancer drug tamoxifen. Weshow that PAX2 and the ER co-activator AIB-1/SRC-3 compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ER-PAX2 links these two breast cancer subtypes and suggests that aggressive ERBB2- positive tumours can originate from ER- positive luminal tumours by circumventing this repressive mechanism. These data provide mechanistic insight into the molecular basis of endocrine resistance in breast cancer. C1 [Hurtado, Antoni; Holmes, Kelly A.; Howat, William J.; Carroll, Jason S.] Cambridge Res Inst, Canc Res UK, Li Ka Shing Ctr, Cambridge CB2 0RE, England. [Geistlinger, Timothy R.; Brown, Myles] Dana Farber Canc Inst, Boston, MA 02115 USA. [Geistlinger, Timothy R.; Brown, Myles] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hutcheson, Iain R.; Nicholson, Robert I.] Cardiff Univ, Tenovus Ctr Canc Res, Welsh Sch Pharm, Cardiff CF10 3XF, Wales. [Jiang, Jie; Ali, Simak] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London W12 0NN, England. RP Carroll, JS (reprint author), Cambridge Res Inst, Canc Res UK, Li Ka Shing Ctr, Robinson Way, Cambridge CB2 0RE, England. EM jason.carroll@cancer.org.uk OI Brown, Myles/0000-0002-8213-1658 FU National Institute of Diabetes and Digestive and Kidney Disease [R01DK074967]; National Cancer Institute [P01CA8011105]; DF/HCC Breast Cancer SPORE; University of Cambridge; Cancer Research UK; Hutchison Whampoa Limited FX We thank D. Carroll, S.-F. Chin, I. Mills, C. Massie and P. Edwards for discussions; J. Mitchell for histology work; M. Eldridge, S. Vowler and B. Adryan for bioinformatic help; S. Buttiglieri for the p-TARGET-PAX2 construct; J. Eeckhoute for the pcDNA- AIB- 1 construct; and M. Iddawela for the gift of Herceptin. This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Disease (R01DK074967 to M. B.) and the National Cancer Institute (P01CA8011105, and the DF/HCC Breast Cancer SPORE Grant to M. B.). We acknowledge support from the University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. NR 30 TC 171 Z9 176 U1 1 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 4 PY 2008 VL 456 IS 7222 BP 663 EP U93 DI 10.1038/nature07483 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 378QW UT WOS:000261340000046 PM 19005469 ER PT J AU Di Bisceglie, AM Shiffman, ML Everson, GT Lindsay, KL Everhart, JE Wright, EC Lee, WM Lok, AS Bonkovsky, HL Morgan, TR Ghany, MG Morishima, C Snow, KK Dienstag, JL AF Di Bisceglie, Adrian M. Shiffman, Mitchell L. Everson, Gregory T. Lindsay, Karen L. Everhart, James E. Wright, Elizabeth C. Lee, William M. Lok, Anna S. Bonkovsky, Herbert L. Morgan, Timothy R. Ghany, Marc G. Morishima, Chihiro Snow, Kristin K. Dienstag, Jules L. CA HALT-C Trial Investigators TI Prolonged Therapy of Advanced Chronic Hepatitis C with Low-Dose Peginterferon SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HEPATOCELLULAR-CARCINOMA; INTERFERON THERAPY; VIRUS-INFECTION; TRIAL; RIBAVIRIN; NONRESPONDERS; INHIBITOR; CIRRHOSIS; ALPHA-2A; RISK AB Background: In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain. Methods: We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 microg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points. Results: We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81 to 1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07). Conclusions: Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164.). C1 [Di Bisceglie, Adrian M.] St Louis Univ, Sch Med, Div Gastroenterol & Hepatol, Dept Internal Med, St Louis, MO 63110 USA. [Shiffman, Mitchell L.] Virginia Commonwealth Univ, Med Ctr, Richmond, VA USA. [Everson, Gregory T.] Univ Colorado, Sch Med, Denver, CO 80202 USA. [Lindsay, Karen L.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Everhart, James E.; Wright, Elizabeth C.; Ghany, Marc G.] NIDDKD, Bethesda, MD 20892 USA. [Lee, William M.] Univ Texas Dallas, SW Med Ctr, Dallas, TX USA. [Lok, Anna S.] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Farmington, CT USA. [Morgan, Timothy R.] Univ Calif Irvine, Irvine, CA USA. [Morgan, Timothy R.] Vet Affairs Long Beach Healthcare Syst, Long Beach, CA USA. [Morishima, Chihiro] Univ Washington, Seattle, WA 98195 USA. [Snow, Kristin K.] New England Res Inst, Watertown, MA 02172 USA. [Dienstag, Jules L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Dienstag, Jules L.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Di Bisceglie, AM (reprint author), St Louis Univ, Sch Med, Div Gastroenterol & Hepatol, Dept Internal Med, 3635 Vista Ave, St Louis, MO 63110 USA. EM dibiscam@slu.edu RI Lok, Anna /B-8292-2009; OI Yang, Shuman/0000-0002-9638-0890 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; National Cancer Institute,; National Center for Minority Health and Health Disparities; National Center for Research Resources; National Institute on Alcohol Abuse and Alcoholism [K24 AA13736]; Hoffmann-La Roche; Idenix Pharmaceuticals; Novartis; Vertex Pharmaceuticals; Bristol- Myers Squibb; Abbott; Schering-Plough; Anadys; GlobeImmune; Pharmasset; SciClone Pharmaceuticals; Clinical Care Options; Gilead; Geneva Foundation; Hoffmann La Roche; Biolex; Valeant Pharmaceuticals; GlaxoSmithKline; Novartis/Human Genome Sciences; King Pharmaceuticals; Peregrine Pharmaceuticals; Roche Diagnostics; ZymoGenetics; Wyeth Pharmaceuticals; Eli Lilly; FibroGen; AstraZeneca; Siemens; Ovation Pharmaceuticals; Boehringer-Ingelheim; Cardax Pharmaceuticals; Achillion Pharmaceuticals; Avant Immunotherapeutics; CombinatoRx; Cubist Pharmaceuticals; Nucleonics; Oxxon; Metabasis; Amgen; Biogen; EnablEd and Clinical Care Options FX Supported by contracts from the National Institute of Diabetes and Digestive and Kidney Diseases, with additional support from the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, the National Center for Research Resources, and the National Institute on Alcohol Abuse and Alcoholism (K24 AA13736); and by Hoffmann-La Roche through a Cooperative Research and Development Agreement with the National Institutes of Health.; Dr. Di Bisceglie reports receiving consulting fees from Hoffmann-La Roche, Idenix Pharmaceuticals, Novartis, Vertex Pharmaceuticals, Bristol- Myers Squibb, Abbott, Schering-Plough, Anadys, GlobeImmune, Pharmasset, and SciClone Pharmaceuticals; lecture fees from Novartis and Clinical Care Options; and grant support from Hoffmann- La Roche, Idenix Pharmaceuticals, Vertex Pharmaceuticals, Bristol-Myers Squibb, GlobeImmune, Pharmasset, Gilead, Geneva Foundation, and SciClone Pharmaceuticals; Dr. Shiffman, receiving consulting fees from Hoffmann La Roche, Biolex, Valeant Pharmaceuticals, and GlaxoSmithKline; lecture fees from Hoffmann-La Roche; and grant support from Schering-Plough, Valeant Pharmaceuticals, Vertex Pharmaceuticals, and Hoffmann-La Roche; Dr. Everson, receiving consulting fees from Hoffmann-La Roche and Vertex Pharmaceuticals, lecture fees from Hoffmann-La Roche, and grant support from Hoffmann-La Roche, Schering- Plough, Vertex Pharmaceuticals, Pharmasset, and Novartis/Human Genome Sciences; Dr. Lindsay, receiving consulting fees from Hoffmann-La Roche, Bristol-Myers Squibb, Human Genome Sciences, Idenix Pharmaceuticals, King Pharmaceuticals, Peregrine Pharmaceuticals, Roche Diagnostics, Valeant Pharmaceuticals, and ZymoGenetics; grant support from Hoffmann-La Roche, Idenix Pharmaceuticals, Human Genome Sciences, Schering- Plough, Valeant Pharmaceuticals, Vertex Pharmaceuticals, and Wyeth Pharmaceuticals; and lecture fees from Clinical Care Options; Dr. Lee, receiving consulting fees from Eli Lilly, FibroGen, and AstraZeneca and grant support from Hoffmann-La Roche, Schering-Plough, Vertex Pharmaceuticals, GlaxoSmithKline, Siemens, GlobeImmune, and Bristol- Myers Squibb; Dr. Lok, receiving consulting fees and grant support from Hoffmann-La Roche and Schering-Plough; Dr. Bonkovsky, receiving consulting fees from Novartis, Ovation Pharmaceuticals, and Boehringer- Ingelheim; lecture fees from Ovation Pharmaceuticals; and grant support from Novartis, Vertex Pharmaceuticals, and Hoffmann-La Roche; Dr. Morgan, receiving consulting fees from Hoffmann-La Roche, Vertex Pharmaceuticals, Cardax Pharmaceuticals, and Valeant Pharmaceuticals and lecture fees and grant support from Hoffmann-La Roche and Schering- Plough; and Dr. Dienstag, receiving consulting fees from Achillion Pharmaceuticals, Avant Immunotherapeutics, CombinatoRx, Bristol- Myers Squibb, Cubist Pharmaceuticals, Nucleonics, Pharmasset, SciClone Pharmaceuticals, Human Genome Sciences, Oxxon, Metabasis, Schering- Plough, Amgen, AstraZeneca, Biogen, Vertex Pharmaceuticals, Wyeth Pharmaceuticals, and Gilead; receiving lecture fees from EnablEd and Clinical Care Options; receiving grant support from Vertex Pharmaceuticals; and holding stock options in Metabasis, Achillion Pharmaceuticals, and Nucleonics. No other potential conflict of interest relevant to this article was reported. NR 20 TC 277 Z9 281 U1 1 U2 4 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 4 PY 2008 VL 359 IS 23 BP 2429 EP 2441 DI 10.1056/NEJMoa0707615 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 378MT UT WOS:000261325900004 PM 19052125 ER PT J AU Massie, BM Carson, PE McMurray, JJ Komajda, M McKelvie, R Zile, MR Anderson, S Donovan, M Iverson, E Staiger, C Ptaszynska, A AF Massie, Barry M. Carson, Peter E. McMurray, John J. Komajda, Michel McKelvie, Robert Zile, Michael R. Anderson, Susan Donovan, Mark Iverson, Erik Staiger, Christoph Ptaszynska, Agata CA I-PRESERVE Investigators TI Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VENTRICULAR SYSTOLIC FUNCTION; BRAIN NATRIURETIC PEPTIDE; DIASTOLIC DYSFUNCTION; CLINICAL CHARACTERISTICS; CARDIOVASCULAR OUTCOMES; RANDOMIZED TRIAL; MECHANISMS; PROGNOSIS; MORBIDITY; MORTALITY AB Background: Approximately 50% of patients with heart failure have a left ventricular ejection fraction of at least 45%, but no therapies have been shown to improve the outcome of these patients. Therefore, we studied the effects of irbesartan in patients with this syndrome. Methods: We enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II, III, or IV heart failure and an ejection fraction of at least 45% and randomly assigned them to receive 300 mg of irbesartan or placebo per day. The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). Secondary outcomes included death from heart failure or hospitalization for heart failure, death from any cause and from cardiovascular causes, and quality of life. Results: During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes. Conclusions: Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction. (ClinicalTrials.gov number, NCT00095238.). C1 [Massie, Barry M.] Vet Affairs Med Ctr, San Francisco, CA 94121 USA. [Carson, Peter E.] Georgetown Univ, Washington, DC USA. [Carson, Peter E.] Vet Affairs Med Ctr, Washington, DC 20422 USA. [McMurray, John J.] Univ Glasgow, British Heart Fdn Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Komajda, Michel] Univ Paris 06, Paris, France. [Komajda, Michel] Grp Hosp Pitie Salpetriere, F-75634 Paris, France. [McKelvie, Robert] McMaster Univ, Hamilton, ON, Canada. [Zile, Michael R.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Zile, Michael R.] Med Univ S Carolina, Charleston, SC 29425 USA. [Anderson, Susan; Iverson, Erik] Univ Wisconsin, Madison, WI USA. [Donovan, Mark; Ptaszynska, Agata] Bristol Myers Squibb Co, Princeton, NJ USA. [Staiger, Christoph] Sanofi Aventis, Bridgewater, NJ USA. RP Massie, BM (reprint author), Vet Affairs Med Ctr, 111C,4150 Clement St, San Francisco, CA 94121 USA. EM barry.massie@va.gov RI van Veldhuisen, Dirk Jan/E-8967-2014; Casademont, Jordi/A-6828-2010; Colquhoun, David/F-9078-2013; Brito, Dulce/G-9650-2016; Ponikowski, Piotr/O-6454-2015; Hradec, Jaromir/S-2388-2016; OI Casademont, Jordi/0000-0002-8100-1827; Brito, Dulce/0000-0003-1278-1847; Ponikowski, Piotr/0000-0002-3391-7064; Hradec, Jaromir/0000-0001-7597-8239; mcmurray, john/0000-0002-6317-3975 FU Bristol-Myers Squibb; Sanofi-Aventis; Merck; Duke Clinical Research Institute; Momentum Research; Novartis; GlaxoSmithKline; Scios-Johnson Johnson; Corthera; Niles Therapeutics; AstraZeneca; Servier; Pfizer FX Supported by Bristol-Myers Squibb and Sanofi-Aventis.; Dr. Massie reports receiving grant support from Bristol-Myers Squibb, Sanofi-Aventis, and Merck, consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, Merck, Duke Clinical Research Institute, Momentum Research, Novartis, GlaxoSmithKline, Scios-Johnson & Johnson, Corthera, and Niles Therapeutics, and lecture fees from Merck; Dr. Carson, receiving consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, and Merck and lecture fees from AstraZeneca and Novartis; Dr. McMurray, receiving support from Bristol-Myers Squibb (to Glasgow University) for his work on this trial; Dr. Komajda, receiving consulting fees from Bristol-Myers Squibb and Servier and lecture fees from Servier, Sanofi-Aventis, and AstraZeneca; Dr. McKelvie, receiving consulting fees from Bristol-Myers Squibb and Sanofi-Aventis and lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, Pfizer, Merck, and AstraZeneca; Dr. Zile, receiving consulting fees from Bristol-Myers Squibb and Sanofi-Aventis; Ms. Anderson, being employed by the Statistical Data Analysis Center at the University of Wisconsin - Madison, which conducted statistical analysis for this trial, supported by Bristol- Myers Squibb and Sanofi-Aventis; Drs. Donovan and Ptaszynska, being employees of and having an equity interest in Bristol- Myers Squibb; and Dr. Staiger, being an employee of and having an equity interest in Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.; We thank clinical scientists Jean-Michel Bocquet and Magalie Thuault for their care in handling the logistics of the trial. NR 36 TC 639 Z9 672 U1 0 U2 23 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 DEC 4 PY 2008 VL 359 IS 23 BP 2456 EP 2467 DI 10.1056/NEJMoa0805450 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 378MT UT WOS:000261325900006 PM 19001508 ER PT J AU Al-Noori, S Sanders, NM Taborsky, GJ Wilkinson, CW Figlewicz, DP AF Al-Noori, Salwa Sanders, Nicole M. Taborsky, Gerald J. Wilkinson, Charles W. Figlewicz, Dianne P. TI Acute THPVP inactivation decreases the glucagon and sympathoadrenal responses to recurrent hypoglycemia (vol 1194, pg 65, 2008) SO BRAIN RESEARCH LA English DT Correction C1 [Al-Noori, Salwa; Wilkinson, Charles W.; Figlewicz, Dianne P.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Sanders, Nicole M.; Taborsky, Gerald J.; Figlewicz, Dianne P.] Vet Affairs Puget Sound Hlth Care Syst, Div Endocrinol Metab & Geriatr Res, Seattle, WA USA. [Taborsky, Gerald J.; Figlewicz, Dianne P.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Wilkinson, Charles W.] Vet Affairs Puget Sound Hlth Care Syst, Educ & Clin Ctr, Seattle, WA USA. RP Al-Noori, S (reprint author), Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. EM saan@u.washington.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD DEC 3 PY 2008 VL 1243 BP 175 EP 175 DI 10.1016/j.brainres.2008.08.035 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 384YL UT WOS:000261780000021 ER PT J AU Stetler, RA Cao, GD Gao, YQ Zhang, F Wang, SP Weng, ZF Vosler, P Zhang, LL Signore, A Graham, SH Chen, J AF Stetler, R. Anne Cao, Guodong Gao, Yanqin Zhang, Feng Wang, Suping Weng, Zhongfang Vosler, Peter Zhang, Lili Signore, Armando Graham, Steven H. Chen, Jun TI Hsp27 Protects against Ischemic Brain Injury via Attenuation of a Novel Stress-Response Cascade Upstream of Mitochondrial Cell Death Signaling SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cerebral ischemia; neuroprotection; heat shock proteins; apoptosis signaling kinase-1; JNK; mitochondria ID FOCAL CEREBRAL-ISCHEMIA; HEAT-SHOCK-PROTEIN; APOPTOSIS-INDUCING FACTOR; CYTOCHROME-C; REGULATING KINASE-1; GLUCOSE DEPRIVATION; NEURONAL CULTURES; AKT ACTIVATION; UP-REGULATION; MAP KINASE AB Heat shock protein 27 (Hsp27), a recently discovered member of the heat shock protein family, is markedly induced in the brain after cerebral ischemia and other injury states. In non-neuronal systems, Hsp27 has potent cell death-suppressing functions. However, the mechanism of Hsp27-mediated neuroprotection has not yet been elucidated. Using transgenic and viral overexpression of Hsp27, we investigated the molecular mechanism by which Hsp27 exerts its neuroprotective effect. Overexpression of Hsp27 conferred long-lasting tissue preservation and neurobehavioral recovery, as measured by infarct volume, sensorimotor function, and cognitive tasks up to 3 weeks following focal cerebral ischemia. Examination of signaling pathways critical to neuronal death demonstrated that Hsp27 overexpression led to the suppression of the MKK4/JNK kinase cascade. While Hsp27 overexpression did not suppress activation of an upstream regulatory kinase of the MKK/JNK cascade, ASK1, Hsp27 effectively inhibited ASK1 activity via a physical association through its N-terminal domain and the kinase domain of ASK1. The N-terminal region of Hsp27 was required for neuroprotective function against in vitro ischemia. Moreover, knockdown of ASK1 or inhibition of the ASK1/MKK4 cascade effectively inhibited cell death following neuronal ischemia. This underscores the importance of this kinase cascade in the progression of ischemic neuronal death. Inhibition of PI3K had no effect on Hsp27-mediated neuroprotection, suggesting that Hsp27 does not promote cell survival via activation of PI3K/Akt. Based on these findings, we conclude that overexpression of Hsp27 confers long-lasting neuroprotection against ischemic brain injury via a previously unexplored association and inhibition of ASK1 kinase signaling. C1 [Stetler, R. Anne; Cao, Guodong; Zhang, Feng; Wang, Suping; Weng, Zhongfang; Vosler, Peter; Zhang, Lili; Signore, Armando; Graham, Steven H.; Chen, Jun] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. [Stetler, R. Anne; Cao, Guodong; Zhang, Feng; Wang, Suping; Weng, Zhongfang; Vosler, Peter; Zhang, Lili; Signore, Armando; Graham, Steven H.; Chen, Jun] Univ Pittsburgh, Sch Med, Ctr Cerebrovasc Dis Res, Pittsburgh, PA 15213 USA. [Stetler, R. Anne; Cao, Guodong; Gao, Yanqin; Chen, Jun] Fudan Univ, Sch Med, State Key Lab Med Neurobiol, Shanghai 200032, Peoples R China. [Stetler, R. Anne; Cao, Guodong; Zhang, Feng; Wang, Suping; Signore, Armando; Graham, Steven H.; Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst Pittsburgh, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA 15261 USA. RP Chen, J (reprint author), Univ Pittsburgh, Dept Neurol, 507 S Biomed Sci Tower,200 Lothrop St, Pittsburgh, PA 15261 USA. EM chenj2@upmc.edu RI Gao, Yanqin/I-6790-2016 OI Gao, Yanqin/0000-0002-4915-9819 FU National Institutes of Health-National Institute of Neurological Disorders and Stroke [NS43802, NS45048, NS36736, NS 56118]; VA Merit Review; American Heart Association [0725503U, 0715254U]; Chinese Natural Science Foundation [30470592, 30670642] FX This work was supported by National Institutes of Health-National Institute of Neurological Disorders and Stroke Grants NS43802, NS45048, NS36736, and NS 56118 and VA Merit Review Grant ( to J. C.). Additional support was provided by the American Heart Association to R. A. S. (0725503U) and P. V. (0715254U), and by the Chinese Natural Science Foundation ( Grants 30470592 and 30670642 to Y.G.). We thank Drs. Lin Zhang and Jian Yu ( Pittsburgh Cancer Institute) for providing adenovirus vectors expressing Bax and PUMA. We thank Carol Culver for editorial assistance and Pat Strickler for secretarial support. NR 77 TC 72 Z9 76 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 3 PY 2008 VL 28 IS 49 BP 13038 EP 13055 DI 10.1523/JNEUROSCI.4407-08.2008 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 379DZ UT WOS:000261378100003 PM 19052195 ER PT J AU Kong, J Gollub, RL Polich, G Kirsch, I LaViolette, P Vangel, M Rosen, B Kaptchuk, TJ AF Kong, Jian Gollub, Randy L. Polich, Ginger Kirsch, Irving LaViolette, Peter Vangel, Mark Rosen, Bruce Kaptchuk, Ted J. TI A Functional Magnetic Resonance Imaging Study on the Neural Mechanisms of Hyperalgesic Nocebo Effect SO JOURNAL OF NEUROSCIENCE LA English DT Article DE nocebo; nocebo effect; hyperalgesia; hyperalgesic nocebo effect; functional connectivity; spontaneous fMRI; resting state; placebo effect; expectancy; expectancy manipulation; sham acupuncture ID VERBAL PAIN DESCRIPTORS; PLACEBO ANALGESIA; BRAIN ACTIVITY; ANTERIOR CINGULATE; OPIOID ACTIVITY; RATIO SCALES; NETWORK; EXPECTATIONS; ACUPUNCTURE; MODULATION AB Previous studies suggest that nocebo effects, sometimes termed "negative placebo effects," can contribute appreciably to a variety of medical symptoms and adverse events in clinical trials and medical care. In this study, using a within-subject design, we combined functional magnetic resonance imaging (fMRI) and an expectation/conditioning manipulation model to investigate the neural substrates of nocebo hyperalgesia using heat pain on the right forearm. Thirteen subjects completed the study. Results showed that, after administering inert treatment, subjective pain intensity ratings increased significantly more on nocebo regions compared with the control regions in which no expectancy/conditioning manipulation was performed. fMRI analysis of hyperalgesic nocebo responses to identical calibrated noxious stimuli showed signal increases in brain regions including bilateral dorsal anterior cingulate cortex (ACC), insula, superior temporal gyrus; left frontal and parietal operculum, medial frontal gyrus, orbital prefrontal cortex, superior parietal lobule, and hippocampus; right claustrum/putamen, lateral prefrontal gyrus, and middle temporal gyrus. Functional connectivity analysis of spontaneous resting-state fMRI data from the same cohort of subjects showed a correlation between two seed regions (left frontal operculum and hippocampus) and pain network including bilateral insula, operculum, ACC, and left S1/M1. In conclusion, we found evidence that nocebo hyperalgesia may be predominantly produced through an affective-cognitive pain pathway ( medial pain system), and the left hippocampus may play an important role in this process. C1 [Kong, Jian; Gollub, Randy L.; Polich, Ginger; LaViolette, Peter] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Kong, Jian; Gollub, Randy L.; LaViolette, Peter; Vangel, Mark; Rosen, Bruce] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MIT,Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Gollub, Randy L.; Vangel, Mark] Massachusetts Gen Hosp, Clin Res Ctr Biomed Imaging Core, Charlestown, MA 02129 USA. [Kirsch, Irving] Univ Hull, Dept Psychol, Kingston Upon Hull HU6 7RX, N Humberside, England. [Kaptchuk, Ted J.] Harvard Univ, Sch Med, Osher Inst, Boston, MA 02215 USA. RP Kong, J (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Bldg 149,13th St,Suite 2661, Charlestown, MA 02129 USA. EM kongj@nmr.mgh.harvard.edu OI Gollub, Randy L./0000-0002-9434-4044 FU National Institutes of Health-National Center for Complementary and Alternative Medicine [K01-AT003883, P01-AT002048, K24-AT004095, R21-AT00949]; National Center for Research Resources [M01-RR-01066]; Mallinckrodt General Clinical Research Center Biomedical Imaging Core [P41-RR14075]; MIND Research Network (Delaware) [FG03-99ER62764] FX This work was supported by National Institutes of Health-National Center for Complementary and Alternative Medicine Grants K01-AT003883 (J.K.), P01-AT002048 (B.R.), K24-AT004095 (T.J. K.), and R21-AT00949 ( R. L. G.); National Center for Research Resources Grants M01-RR-01066 for Mallinckrodt General Clinical Research Center Biomedical Imaging Core and P41-RR14075 for Center for Functional Neuroimaging Technologies; and MIND Research Network (Delaware) Grant FG03-99ER62764 (B. R.). NR 58 TC 110 Z9 115 U1 4 U2 31 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 DEC 3 PY 2008 VL 28 IS 49 BP 13354 EP 13362 DI 10.1523/JNEUROSCI.2944-08.2008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 379DZ UT WOS:000261378100035 PM 19052227 ER PT J AU Freedman, RA Winer, EP AF Freedman, Rachel A. Winer, Eric P. TI Reducing Disparities in Breast Cancer Care-A Daunting but Essential Responsibility SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID LEUKEMIA GROUP-B; PATIENT NAVIGATION; RACIAL-DIFFERENCES; RANDOMIZED-TRIALS; 15-YEAR SURVIVAL; INSURANCE STATUS; WOMEN; DIAGNOSIS; OPPORTUNITIES; CHEMOTHERAPY C1 [Freedman, Rachel A.; Winer, Eric P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Winer, Eric P.] Susan G Komen Cure, Dallas, TX USA. RP Winer, EP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM ewiner@partners.org NR 32 TC 5 Z9 5 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD DEC 3 PY 2008 VL 100 IS 23 BP 1661 EP 1663 DI 10.1093/jnci/djn412 PG 3 WC Oncology SC Oncology GA 380JQ UT WOS:000261462400003 PM 19033563 ER PT J AU Kerlikowske, K Walker, R Miglioretti, DL Desai, A Ballard-Barbash, R Buist, DSM AF Kerlikowske, Karla Walker, Rod Miglioretti, Diana L. Desai, Arati Ballard-Barbash, Rachel Buist, Diana S. M. TI Obesity, Mammography Use and Accuracy, and Advanced Breast Cancer Risk SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BODY-MASS INDEX; ADULT WEIGHT CHANGE; CARCINOMA IN-SITU; SCREENING MAMMOGRAPHY; UNITED-STATES; POSTMENOPAUSAL WOMEN; COHORT; POPULATION; OVERWEIGHT; GROWTH AB Being overweight or obese is associated with increased breast cancer risk and disease severity among postmenopausal women, but whether extent of mammography use and accuracy modify this association and further contribute to increases in disease severity at diagnosis among overweight and obese women is unclear. We prospectively collected data during 1996-2005 on 287 115 postmenopausal women not using hormone therapy (HT) who underwent 614 562 mammography examinations; 4446 women were diagnosed with breast cancer within 12 months of a mammography examination. We calculated rates per 1000 mammography examinations of large (> 15 mm), advanced-stage (IIb, III, or IV), high-grade (3 or 4), estrogen receptor (ER)-positive and -negative, and screen-detected and non-screen-detected breast cancer across body mass index (BMI, kg/m(2)) groups defined as normal (18.5-24.9), overweight (25.0-29.9), obese class I (30.0-34.9), and obese class II/III (>= 35.0), adjusting for age, race/ethnicity, and mammography registry and use. All statistical tests were two-sided. Adjusted rates per 1000 mammography examinations of overall breast cancer increased across BMI groups (6.6 normal, 7.4 overweight, 7.9 obese I, 8.5 obese II/III; P(trend) < .001), as did rates of advanced disease, including large invasive (2.3 normal, 2.6 overweight, 2.9 obese I, 3.2 obese II/III; P(trend) < .001), advanced-stage (0.8 normal, 0.9 overweight, 1.3 obese I, 1.5 obese II/III; P(trend) < .001), and high nuclear grade (1.5 normal, 1.7 overweight, 1.7 obese I, 1.9 obese II/III; P(trend) = .10) tumors. Rates of ER-positive tumors increased across BMI groups (P(trend) < .001); rates of ER-negative tumors did not. Rates of screen-detected cancers were higher among overweight and obese women than normal and underweight women, but rates of non-screen-detected (false-negative) cancers were similar. Rates of advanced breast cancer increased across BMI groups regardless of extent of mammography use. Patterns of mammography use and mammography accuracy are not the primary reasons for higher rates of advanced breast cancer among overweight and obese postmenopausal women not using HT; thus, biologic differences in breast tumor development and/or progression may be important. C1 [Kerlikowske, Karla] Univ Calif San Francisco, Gen Internal Med Sect, San Francisco Vet Affairs Med Ctr, Dept Vet Affairs, San Francisco, CA 94121 USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94121 USA. [Walker, Rod; Miglioretti, Diana L.; Buist, Diana S. M.] Grp Hlth Ctr Hlth Studies, Seattle, WA USA. [Miglioretti, Diana L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Desai, Arati] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Kerlikowske, K (reprint author), Univ Calif San Francisco, Gen Internal Med Sect, San Francisco Vet Affairs Med Ctr, Dept Vet Affairs, 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM karla.kerlikowske@ucsf.edu FU NCI [U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040] FX NCI-funded Breast Cancer Surveillance Consortium cooperative agreement (U01CA63740, U01CA86076, U01CA86082, U01CA63736, U01CA70013, U01CA69976, U01CA63731, U01CA70040). The collection of cancer incidence data used in this study was supported in part by several state public health departments and cancer registries throughout the United States. For a full description of these sources, please see: http://breastscreening.cancer.gov/work/acknowledgement.html. NR 46 TC 41 Z9 43 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD DEC 3 PY 2008 VL 100 IS 23 BP 1724 EP 1733 DI 10.1093/jnci/djn388 PG 10 WC Oncology SC Oncology GA 380JQ UT WOS:000261462400012 PM 19033562 ER PT J AU Ogino, S Nosho, K Kirkner, GJ Kawasaki, T Chan, AT Schernhammer, ES Giovannucci, EL Fuchs, CS AF Ogino, Shuji Nosho, Katsuhiko Kirkner, Gregory J. Kawasaki, Takako Chan, Andrew T. Schernhammer, Eva S. Giovannucci, Edward L. Fuchs, Charles S. TI A Cohort Study of Tumoral LINE-1 Hypomethylation and Prognosis in Colon Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ISLAND METHYLATOR PHENOTYPE; GLOBAL DNA METHYLATION; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; CHROMOSOMAL INSTABILITY; CIMP-LOW; DEMETHYLATION; EXPRESSION; LEVEL; LIVER AB Genome-wide DNA hypomethylation plays has an important role in genomic instability and colorectal carcinogenesis. However, the relationship between cellular DNA methylation level and patient outcome remains uncertain. Using 643 colon cancers in two independent prospective cohorts, we quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) elements using pyrosequencing, which is a good indicator of global DNA methylation level. We used Cox proportional hazard models to calculate hazard ratios (HRs) of colon cancer-specific and overall mortality, adjusting for patient and tumoral features, including CpG island methylator phenotype (CIMP). Statistical tests were two-sided. LINE-1 hypomethylation was linearly associated with a statistically significant increase in colon cancer-specific mortality (for a 30% decrease in LINE-1 methylation: multivariable HR = 2.37, 95% confidence interval [CI] = 1.42 to 3.94; P(trend) < .001) and overall mortality (multivariable HR = 1.85, 95% CI = 1.25 to 2.75; P(trend) = .002). The association was consistent across the two independent cohorts and strata of clinical and molecular characteristics, including sex, age, tumor location, stage, and CIMP, microsatellite instability, KRAS, BRAF, p53, and chromosomal instability status. In conclusion, tumoral LINE-1 hypomethylation is independently associated with shorter survival among colon cancer patients. C1 [Ogino, Shuji] Harvard Univ, Sch Med, Brigham & Womens Hosp,Ctr Mol Oncol Pathol, Dana Farber Canc Inst,Dept Pathol, Boston, MA 02115 USA. [Kirkner, Gregory J.; Chan, Andrew T.; Schernhammer, Eva S.; Giovannucci, Edward L.; Fuchs, Charles S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Channing Lab,Dept Med, Boston, MA 02115 USA. [Ogino, Shuji; Nosho, Katsuhiko; Kawasaki, Takako; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ogino, Shuji; Schernhammer, Eva S.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Schernhammer, Eva S.] Ludwig Boltzmann Inst Appl Canc Res, Vienna, Austria. RP Ogino, S (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp,Ctr Mol Oncol Pathol, Dana Farber Canc Inst,Dept Pathol, 44 Binney St,Rm JF 215C, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU US National Institute of Health [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826]; Bennett Family Fund; Entertainment Industry Foundation; Japan Society for Promotion of Science FX The US National Institute of Health (P01 CA87969, P01 CA55075, P50 CA127003, and K07 CA122826 to S.O.); the Bennett Family Fund; the Entertainment Industry Foundation. K. Nosho was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of National Cancer Institute or National Institutes of Health. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the manuscript for publication; or the writing of the manuscript. NR 46 TC 187 Z9 190 U1 4 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD DEC 3 PY 2008 VL 100 IS 23 BP 1734 EP 1738 DI 10.1093/jnci/djn359 PG 5 WC Oncology SC Oncology GA 380JQ UT WOS:000261462400013 PM 19033568 ER PT J AU Bryson, CL Au, DH Sun, HL Williams, EC Kivlahan, DR Bradley, KA AF Bryson, Chris L. Au, David H. Sun, Haili Williams, Emily C. Kivlahan, Daniel R. Bradley, Katharine A. TI Alcohol Screening Scores and Medication Nonadherence SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; ANTIRETROVIRAL THERAPY ADHERENCE; TYPE-2 DIABETES-MELLITUS; PRIMARY-CARE PATIENTS; CONSUMPTION QUESTIONS; OBJECTIVE ASSESSMENT; PREVENTIVE-SERVICES; PROBLEM DRINKING; HIV-INFECTION; MENTAL-HEALTH AB Background: Medication nonadherence is common and is associated with adverse outcomes. Alcohol misuse may be a risk factor for nonadherence; however, evidence is limited. Objective: To identify whether alcohol misuse, as identified by a simple screening tool, is associated in a dose-response manner with increased risk for medication nonadherence in veterans attending primary care clinics. Design: Secondary analysis of cohort data collected prospectively from 1997 to 2000 as part of a randomized, controlled trial. Setting: 7 Veterans Affairs primary care clinics. Participants: 5473 patients taking a statin, 3468 patients taking oral hypoglycemic agents, and 13 729 patients taking antihypertensive medications. Measurements: Patients completed the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) questionnaire, a validated 3-question alcohol misuse screening test. Their scores were categorized into nondrinkers; low-level alcohol use; and mild, moderate, and severe alcohol misuse. Medication adherence, defined as having medications available for at least 80% of the observation days, was measured from pharmacy records for either 90 days or 1 year after the alcohol screening date. Logistic regression was used to estimate the predicted proportions of adherent patients in each AUDIT-C group and adjusted for demographic and clinical covariates. Results: The proportion of patients treated for hypertension and hyperlipidemia who were nonadherent increased with higher AUDIT-C scores. For 1-year adherence to statins, the percentage of adherent patients was lower in the 2 highest alcohol misuse groups ( adjusted percentage of adherent patients, 58% [95% CI, 52% to 65%] and 55% [ CI, 47% to 63%]) than in the nondrinker group (66% [ CI, 64% to 68%]). For 1-year adherence to antihypertensive regimens, the percentage of adherent patients was lower in the 3 highest alcohol misuse groups ( adjusted percentage of adherent patients, 61% [ CI, 58% to 64%]; 60% [ CI, 56% to 63%]; and 56% [ CI, 52% to 60%]) than in the nondrinker group ( 64% [ CI, 63% to 65%]). No statistically significant differences were observed for oral hypoglycemics in adjusted analyses. Limitation: This observational study cannot address whether changes in drinking lead to changes in adherence and may not be generalizable to other populations. Conclusion: Alcohol misuse, as measured by a brief screening questionnaire, was associated with increased risk for medication nonadherence. C1 [Bryson, Chris L.] Vet Affairs Puget Sound Healthcare Syst, Hlth Serv Res & Dev Serv, Hlth Serv Res & Dev NW Ctr Excellence, Seattle, WA 98101 USA. Univ Washington, Seattle, WA 98195 USA. RP Bryson, CL (reprint author), Vet Affairs Puget Sound Healthcare Syst, Hlth Serv Res & Dev Serv, Hlth Serv Res & Dev NW Ctr Excellence, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM christopher.bryson@va.gov; haili.sun@va.gov FU Department of Veterans Affairs [SDR 96-002, IIR 99-376]; Veterans Health Administration; Health Services Research & Development Service; AUDIT-C as a Scaled Marker for Health Risks in VA Medical Outpatients [IAC 05-206]; Development Service Career Development Awards [RCD 03-177, RCD 00-018] FX By the Department of Veterans Affairs, Veterans Health Administration, Health Services Research & Development Service (AUDIT-C as a Scaled Marker for Health Risks in VA Medical Outpatients; IAC 05-206). The ACQUIP was funded by Department of Veterans Affairs grants SDR 96-002 and IIR 99-376. Drs. Bryson and Au were supported by Department of Veterans Affairs, Veterans Health Administration, Health Services Research & Development Service Career Development Awards (RCD 03-177 and RCD 00-018). NR 44 TC 60 Z9 61 U1 4 U2 7 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 DEC 2 PY 2008 VL 149 IS 11 BP 795 EP W165 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 383AA UT WOS:000261645300003 PM 19047026 ER PT J AU Furie, KL Kelly, PJ AF Furie, Karen L. Kelly, Peter J. TI Nutritional supplements A new strategy to enhance stroke recovery? SO NEUROLOGY LA English DT Editorial Material C1 [Furie, Karen L.] Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler MGH Stroke Res Ctr, Boston, MA 02114 USA. [Kelly, Peter J.] Univ Coll Dublin, Mater Univ Hosp, Dublin 2, Ireland. RP Furie, KL (reprint author), Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler MGH Stroke Res Ctr, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM kfurie@partners.org NR 7 TC 0 Z9 1 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC 2 PY 2008 VL 71 IS 23 BP 1852 EP 1853 DI 10.1212/01.wnl.0000333246.69699.f0 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 377RJ UT WOS:000261268000004 PM 18945999 ER PT J AU VanHook, AM Lee, SW Ongusaha, PP AF VanHook, Annalisa M. Lee, Sam W. Ongusaha, Pat P. TI Science Signaling Podcast: 02 December 2008 SO SCIENCE SIGNALING LA English DT Editorial Material DE Science Signaling; signal transduction; ultraviolet light; UVB; radiation; DNA damage; apoptosis; JNK; ROCK1; Rho; kinase; JIP-3; MAPK AB This is a conversation with Sam Lee and Pat Ongusaha, authors of a Research Article published in the 25 November issue of Science Signaling. Drs. Lee and Ongusaha discuss the connection between Rho-associated kinase 1 (ROCK1) and Jun N-terminal kinase (JNK) signaling in the apoptotic response to ultraviolet B irradiation. C1 [VanHook, Annalisa M.] Amer Assoc Advancement Sci, Washington, DC 20005 USA. [Lee, Sam W.; Ongusaha, Pat P.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Lee, Sam W.; Ongusaha, Pat P.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP VanHook, AM (reprint author), Amer Assoc Advancement Sci, 1200 New York Ave NW, Washington, DC 20005 USA. NR 1 TC 0 Z9 0 U1 2 U2 2 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD DEC 2 PY 2008 VL 1 IS 48 AR pc13 DI 10.1126/scisignal.148pc13 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA V10XV UT WOS:000207497600001 ER PT J AU Ginde, AA Cagliero, E Nathan, DM Camargo, CA AF Ginde, Adit A. Cagliero, Enrico Nathan, David M. Camargo, Carlos A., Jr. TI Point-of-care Glucose and Hemoglobin A1c in Emergency Department Patients without Known Diabetes: Implications for Opportunistic Screening SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE diabetes; screening; glucose; hemoglobin A1c; emergency medicine; public health ID INCREASED BLOOD-PRESSURE; PLASMA-GLUCOSE; GLYCOSYLATED HEMOGLOBIN; US POPULATION; MELLITUS; COMPLICATIONS; MULTICENTER; DIAGNOSIS; MEDICINE; HBA(1C) AB The objectives were to evaluate the correlation between random glucose and hemoglobin A1c (HbA1c) in emergency department (ED) patients without known diabetes and to determine the ability of diabetes screening in the ED to predict outpatient diabetes. This was a cross-sectional study at an urban academic ED. The authors enrolled consecutive adult patients without known diabetes during eight 24-hour periods. Point-of-care (POC) random capillary glucose and HbA1c levels were tested, as well as laboratory HbA1c in a subset of patients. Participants with HbA1c >= 6.1% were scheduled for oral glucose tolerance test (OGTT). The 265 enrolled patients were 47% female and 80% white, with a median age of 42 years. Median glucose and HbA1c levels were 93 mg/dL (interquartile range [IQR] = 82-108) and 5.8% (IQR = 5.5-6.2), respectively. The correlation between POC and laboratory HbA1c was r = 0.96, with mean difference 0.33% (95% confidence interval [CI] = 0.27% to 0.39%). Glucose threshold >= 120 mg/dL had 89% specificity and 26% sensitivity for predicting the 76 (29%) patients with abnormal HbA1c; >= 140 mg/dL had 98% specificity and 14% sensitivity. The correlation between random glucose and HbA1c was moderate (r = 0.60) and was affected by age, gender, prandial status, corticosteroid use, and current injury. Only 38% of participants with abnormal HbA1c returned for OGTTs; 38% had diabetes, 34% had impaired fasting glucose/impaired glucose tolerance, and 28% had normal glucose tolerance. ED patients have a high prevalence of undiagnosed diabetes. Although screening with POC random glucose and HbA1c is promising, improvement in follow-up with confirmatory testing and initiation of treatment is needed before opportunistic ED screening can be recommended. C1 [Ginde, Adit A.] Univ Colorado, Dept Emergency Med, Denver Sch Med, Aurora, CO USA. [Ginde, Adit A.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Emergency Med, Sch Med, Boston, MA 02215 USA. [Cagliero, Enrico; Nathan, David M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Diabet, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Ginde, AA (reprint author), Univ Colorado, Dept Emergency Med, Denver Sch Med, Aurora, CO USA. EM adit.ginde@ucdenver.edu RI Siry, Bonnie/D-7189-2017 FU Bayer Healthcare Diabetes Care (Tarrytown, NY); Mallinckrodt General Clinical Research Center at Massachusetts General Hospital [M01-RR-01066]; National Institutes of Health; National Center for Research Resources; General Clinical Research Centers Program; Emergency Medicine Foundation Research Fellowship Grant (Dallas, TX); Earle Charlton Fund for Innovative Diabetes Research FX This study was funded by an investigator-initiated grant from Bayer Healthcare Diabetes Care (Tarrytown, NY) and by the Mallinckrodt General Clinical Research Center at Massachusetts General Hospital (Grant M01-RR-01066, National Institutes of Health, National Center for Research Resources, General Clinical Research Centers Program). AAG was supported by the Emergency Medicine Foundation Research Fellowship Grant (Dallas, TX). DMN is supported in part by the Earle Charlton Fund for Innovative Diabetes Research. NR 26 TC 17 Z9 17 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2008 VL 15 IS 12 BP 1241 EP 1247 DI 10.1111/j.1553-2712.2008.00240.x PG 7 WC Emergency Medicine SC Emergency Medicine GA 379KI UT WOS:000261394700003 PM 18785943 ER PT J AU Hwang, U Richardson, L Livote, E Harris, B Spencer, N Morrison, RS AF Hwang, Ula Richardson, Lynne Livote, Elayne Harris, Ben Spencer, Natasha Morrison, R. Sean TI Emergency Department Crowding and Decreased Quality of Pain Care SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE emergency department; quality of care; pain ID MYOCARDIAL-INFARCTION; MEDICINE RESEARCH; CANCER PAIN; REAL-TIME; MANAGEMENT; VALIDATION; ETHNICITY; ANALGESIA; FRACTURE; TRAUMA AB The objective of this study was to evaluate the association of emergency department (ED) crowding factors with the quality of pain care. This was a retrospective observational study of all adult patients (>= 18 years) with conditions warranting pain care seen at an academic, urban, tertiary care ED from July 1 to July 31, 2005, and December 1 to December 31, 2005. Patients were included if they presented with a chief complaint of pain and a final ED diagnosis of a painful condition. Predictor ED crowding variables studied were 1) census, 2) number of admitted patients waiting for inpatient beds (boarders), and 3) number of boarders divided by ED census (boarding burden). The outcomes of interest were process of pain care measures: documentation of clinician pain assessment, medications ordered, and times of activities (e.g., arrival, assessment, ordering of medications). A total of 1,068 patient visits were reviewed. Fewer patients received analgesic medication during periods of high census (> 50th percentile; parameter estimate = -0.47; 95% confidence interval [CI] = -0.80 to -0.07). There was a direct correlation with total ED census and increased time to pain assessment (Spearman r = 0.33, p < 0.0001), time to analgesic medication ordering (r = 0.22, p < 0.0001), and time to analgesic medication administration (r = 0.25, p < 0.0001). There were significant delays (> 1 hour) for pain assessment and the ordering and administration of analgesic medication during periods of high ED census and number of boarders, but not with boarding burden. ED crowding as measured by patient volume negatively impacts patient care. Greater numbers of patients in the ED, whether as total census or number of boarders, were associated with worse pain care. C1 [Hwang, Ula; Richardson, Lynne; Harris, Ben] Mt Sinai Sch Med, Dept Emergency Med, New York, NY 10029 USA. [Hwang, Ula; Morrison, R. Sean] Mt Sinai Sch Med, Brookdale Dept Geriatr & Adult Dev, New York, NY USA. [Morrison, R. Sean] Mt Sinai Sch Med, Lillian & Benjamin Hertzberg Palliat Care Inst, New York, NY USA. [Hwang, Ula; Livote, Elayne; Morrison, R. Sean] James J Peters Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. RP Hwang, U (reprint author), Mt Sinai Sch Med, Dept Emergency Med, New York, NY 10029 USA. EM ula.hwang@mountsinai.org FU Jahnigen Career Development Award; American Geriatrics Society (UH); Mid-Career Investigator Award in Patient-Oriented Research [K24 AG022345]; National Institute on Aging (RSM) FX This study was supported by a Jahnigen Career Development Award administered by the American Geriatrics Society (UH) and a Mid-Career Investigator Award in Patient-Oriented Research (K24 AG022345) from the National Institute on Aging (RSM). NR 43 TC 60 Z9 62 U1 2 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2008 VL 15 IS 12 BP 1248 EP 1255 DI 10.1111/j.1553-2712.2008.00267.x PG 8 WC Emergency Medicine SC Emergency Medicine GA 379KI UT WOS:000261394700004 PM 18945239 ER PT J AU Kansagra, SM Rao, SR Sullivan, AF Gordon, JA Magid, DJ Kaushal, R Camargo, CA Blumenthal, D AF Kansagra, Susan M. Rao, Sowmya R. Sullivan, Ashley F. Gordon, James A. Magid, David J. Kaushal, Rainu Camargo, Carlos A., Jr. Blumenthal, David TI A Survey of Workplace Violence Across 65 US Emergency Departments SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE emergency department; violence; weapons; safety; workplace ID HEALTH-CARE; METAL DETECTORS; URBAN EMERGENCY; TRAUMA VICTIMS; SAFETY; ATTITUDES; AGGRESSION; RESIDENTS; HOSPITALS; PROGRAM AB Workplace violence is a concerning issue. Healthcare workers represent a significant portion of the victims, especially those who work in the emergency department (ED). The objective of this study was to examine ED workplace violence and staff perceptions of physical safety. Data were obtained from the National Emergency Department Safety Study (NEDSS), which surveyed staff across 69 U.S. EDs including physicians, residents, nurses, nurse practitioners, and physician assistants. The authors also conducted surveys of key informants (one from each site) including ED chairs, medical directors, nurse managers, and administrators. The main outcome measures included physical attacks against staff, frequency of guns or knives in the ED, and staff perceptions of physical safety. A total of 5,695 staff surveys were distributed, and 3,518 surveys from 65 sites were included in the final analysis. One-fourth of surveyed ED staff reported feeling safe sometimes, rarely, or never. Key informants at the sampled EDs reported a total of 3,461 physical attacks (median of 11 attacks per ED) over the 5-year period. Key informants at 20% of EDs reported that guns or knives were brought to the ED on a daily or weekly basis. In multivariate analysis, nurses were less likely to feel safe "most of the time" or "always" when compared to other surveyed staff. This study showed that violence and weapons in the ED are common, and nurses were less likely to feel safe than other ED staff. C1 [Kansagra, Susan M.; Blumenthal, David] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Rao, Sowmya R.] Harvard Univ, Sch Med, Ctr Biostat, Massachusetts Gen Hosp, Boston, MA USA. [Sullivan, Ashley F.; Gordon, James A.; Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Dept Emergency Med, Massachusetts Gen Hosp, Boston, MA USA. [Rao, Sowmya R.; Gordon, James A.; Camargo, Carlos A., Jr.; Blumenthal, David] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Magid, David J.] Colorado Permanente Med Grp, Clin Res Unit, Denver, CO USA. [Kaushal, Rainu] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Kaushal, Rainu] New York Presbyterian Hosp, New York, NY USA. RP Kansagra, SM (reprint author), Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM kansagras@gmail.com FU Agency for Healthcare Research and Quality [5 R01 HS013099] FX This project was supported by Grant 5 R01 HS013099 from the Agency for Healthcare Research and Quality. NR 31 TC 39 Z9 41 U1 2 U2 22 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2008 VL 15 IS 12 BP 1268 EP 1274 DI 10.1111/j.1553-2712.2008.00282.x PG 7 WC Emergency Medicine SC Emergency Medicine GA 379KI UT WOS:000261394700007 PM 18976337 ER PT J AU Tsai, CL Sobrino, JA Camargo, CA AF Tsai, Chu-Lin Sobrino, Justin A. Camargo, Carlos A., Jr. TI National Study of Emergency Department Visits for Acute Exacerbation of Chronic Obstructive Pulmonary Disease, 1993-2005 SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE chronic obstructive pulmonary disease; emergency department; epidemiology; exacerbation; quality of care ID CLINICAL-PRACTICE GUIDELINE; QUALITY-OF-CARE; UNITED-STATES; CONTROLLED-TRIAL; ORAL PREDNISONE; LUNG-FUNCTION; MANAGEMENT; COPD; DIAGNOSIS; EPIDEMIOLOGY AB Little is known about recent trends in U.S. emergency department (ED) visits for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) or about ED management of AECOPD. This study aimed to describe the epidemiology of ED visits for AECOPD and to evaluate concordance with guideline-recommended care. Data were obtained from National Hospital Ambulatory Medical Care Survey (NHAMCS). ED visits for AECOPD, during 1993 to 2005, were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Concordance with guideline recommendations was evaluated using process measures. Over the 13-year study period, there was an average annual 0.6 million ED visits for AECOPD, and the visit rates for AECOPD were consistently high (3.2 per 1,000 U.S. population; P(trend) = 0.13). The trends in the use of chest radiograph, pulse oximetry, or bronchodilator remained stable (all P(trend) > 0.5). By contrast, the use of systemic corticosteroids increased from 29% in 1993-1994 to 60% in 2005, antibiotics increased from 14% to 42%, and methylxanthines decreased from 15% to < 1% (all P(trend) < 0.001). Multivariable analysis showed patients in the South (vs. the Northeast) were less likely to receive systemic corticosteroids (odds ratio [OR] = 0.6; 95% confidence interval [CI] = 0.4 to 0.9). The high burden of ED visits for AECOPD persisted. Overall concordance with guideline-recommended care for AECOPD was moderate, and some emergency treatments had improved over time. C1 [Tsai, Chu-Lin; Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Dept Emergency Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Tsai, Chu-Lin; Camargo, Carlos A., Jr.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Sobrino, Justin A.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Tsai, CL (reprint author), Harvard Univ, Sch Med, Dept Emergency Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM ctsai2@partners.org OI TSAI, CHU-LIN/0000-0003-4639-1513 NR 37 TC 12 Z9 14 U1 2 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2008 VL 15 IS 12 BP 1275 EP 1283 DI 10.1111/j.1553-2712.2008.00284.x PG 9 WC Emergency Medicine SC Emergency Medicine GA 379KI UT WOS:000261394700008 PM 18976335 ER PT J AU Catlin, EA Cadge, W Ecklund, EH Gage, EA Zollfrank, RAA AF Catlin, Elizabeth Ann Cadge, Wendy Ecklund, Elaine Howard Gage, Elizabeth A. Zollfrank, Reverend Angelika Annette TI The Spiritual and Religious Identities, Beliefs, and Practices of Academic Pediatricians in the United States SO ACADEMIC MEDICINE LA English DT Article ID INTENSIVE-CARE; PHYSICIANS; LIFE; ATTITUDES; END; DECISIONS; HEALTH AB Purpose Physicians' spiritual and religious identities, beliefs, and practices are beginning to be explored. The objective of this study was to gather descriptive information about personal religion and spirituality from a random sample of academic American pediatricians and to compare this information with similar data from the public. Method In 2005, a Web-based survey of a random sample of 208 pediatrician faculty from 13 academic centers ranked by the US News & World Report as "honor roll" hospitals was conducted. Surveys elicited information about personal beliefs and practices as well as their influence on decisions about patient care and clinical practice. Multiple questions were replicated from the General Social Survey to enable comparisons with the public. Descriptive statistics were generated, and logistic regression analyses were conducted on relevant variables. Results Nearly 88% of respondents were raised in a religious tradition, but just 67.2% claimed current religious identification. More than half (52.6%) reported praying privately; additional spiritual practices reported included relaxation techniques (38.8%), meditation (29.3%), sacred readings (26.7%), and yoga (19%). The majority of academic pediatricians (58.6%) believed that personal spiritual or religious beliefs influenced their interactions with patients/colleagues. These odds increased 5.1-fold when academic pediatricians attended religious services monthly or more (P < .05). Conclusions Compared with the American public, a notably smaller proportion of academic pediatricians reported a personal religious identity. The majority believed spiritual and religious beliefs influenced their practice of pediatrics. Whether secular or faith-based belief systems measurably modify academic pediatric practice is unknown. C1 [Catlin, Elizabeth Ann; Zollfrank, Reverend Angelika Annette] Massachusetts Gen Hosp, Chaplaincy Dept, Boston, MA 02114 USA. [Catlin, Elizabeth Ann] Massachusetts Gen Hosp Children, Neonatol Unit, Serv Pediat, Boston, MA USA. [Catlin, Elizabeth Ann] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Cadge, Wendy] Brandeis Univ, Dept Sociol, Waltham, MA USA. [Ecklund, Elaine Howard] Rice Univ, Dept Sociol, Houston, TX USA. [Gage, Elizabeth A.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. RP Catlin, EA (reprint author), Massachusetts Gen Hosp, Chaplaincy Dept, 175 Cambridge St,Suite 516, Boston, MA 02114 USA. EM ecatlin@partners.org FU Louisville Institute, Louisville, Kentucky; Robert Wood Johnson Foundation; John Templeton Foundation, Elaine Howard Ecklund, PI [11,299] FX Dr. Catlin received grant support from the Louisville Institute, Louisville, Kentucky. Dr. Cadge was supported by the Robert Wood Johnson Foundation Scholars in Health Policy Research Program at Harvard University. This data collection was funded by grant #11,299 from the John Templeton Foundation, Elaine Howard Ecklund, PI. NR 20 TC 13 Z9 13 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD DEC PY 2008 VL 83 IS 12 BP 1146 EP 1152 DI 10.1097/ACM.0b013e31818c64a5 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 466IM UT WOS:000267654800017 PM 19202482 ER PT J AU Caldeiro, RM Malte, CA Calsyn, DA Baer, JS Nichol, P Kivlahan, DR Saxon, AJ AF Caldeiro, Ryan M. Malte, Carol A. Calsyn, Donald A. Baer, John S. Nichol, Paul Kivlahan, Daniel R. Saxon, Andrew J. TI The association of persistent pain with out-patient addiction treatment outcomes and service utilization SO ADDICTION LA English DT Article DE Addiction; co-morbidity; pain; out-patient treatment; outcomes; prospective data; service utilization ID POSTTRAUMATIC-STRESS-DISORDER; HEPATITIS-C; METHADONE-MAINTENANCE; DEPENDENT PATIENTS; SUBSTANCE-ABUSE; PREVALENCE; CHEMOKINES; VETERANS; BARRIERS; COSTS AB To estimate the prevalence of persistent pain among veterans in out-patient addiction treatment and examine associated addiction treatment outcomes and medical and psychiatric service use. Analysis of data from a prospective randomized controlled trial comparing on-site versus referral primary care of veterans with substance dependence (n = 582), excluding opioid dependence who had at least one follow-up interview during the 12-month study period in a Veterans Affairs (VA) out-patient addiction treatment center. Pain status was classified as persistent (pain was rated moderate to very severe at all time-points), low (pain was rated none to mild at all time-points) or intermittent (all others). Main outcome measures were addiction treatment retention, addiction severity index (ASI) alcohol and drug composite scores, VA service utilization and treatment costs. A total of 33.2% of veterans reported persistent pain and 47.3% reported intermittent pain. All groups benefited from addiction treatment, but veterans with persistent pain were in treatment for an estimated 35.1 fewer days [95% confidence interval (CI) = -64.1, -6.1, P = 0.018], less likely to be abstinent from alcohol or drugs at 12 months [odds ratio (OR)(adj) = 0.52; 95% CI = 0.30,0.89; P = 0.018], had worse ASI alcohol composite scores at 12 months (beta(adj) = 0.09; 95% CI = 0.02,0.15; P = 0.007), were more likely to be medically hospitalized (OR(adj) = 2.70; 95% CI = 1.02,7.13; P = 0.046) and had higher total service costs compared to those with low pain ($17 766 versus $13 261, P = 0.012). Persistent pain is common among veterans in out-patient addiction treatment and is associated with poorer rates of abstinence, worse alcohol use severity and greater service utilization and costs than those with low pain. C1 [Caldeiro, Ryan M.; Calsyn, Donald A.; Kivlahan, Daniel R.; Saxon, Andrew J.] Univ Washington, Med Ctr, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Malte, Carol A.; Calsyn, Donald A.; Baer, John S.; Nichol, Paul; Kivlahan, Daniel R.; Saxon, Andrew J.] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Malte, Carol A.; Calsyn, Donald A.; Baer, John S.; Kivlahan, Daniel R.; Saxon, Andrew J.] Univ Washington, Ctr Excellence Substance Abuse Treatment & Educ, Seattle, WA 98195 USA. [Baer, John S.] Univ Washington, Dept Psychol, Seattle, WA 98195 USA. [Nichol, Paul] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Caldeiro, RM (reprint author), Univ Washington, Med Ctr, Dept Psychiat & Behav Sci, 1959 NE Pacific St,Box 356560, Seattle, WA 98195 USA. EM caldeiro@u.washington.edu FU Department of Veterans Affairs; Veterans Health Administration; Health Services Research and Development Service [SUI 99-109-1]; Center of Excellence in Substance Abuse Treatment and Education at VA Puget Sound Health Care System FX The research reported here was supported by Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service, grant no. SUI 99-109-1, and by the Center of Excellence in Substance Abuse Treatment and Education at VA Puget Sound Health Care System. Dr Saxon is currently the Director of Addiction Patient Care Line VA Puget Sound Health Care System. 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. Carol A. Malte had full access to all the data inthe study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 26 TC 33 Z9 33 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD DEC PY 2008 VL 103 IS 12 BP 1996 EP 2005 DI 10.1111/j.1360-0443.2008.02358.x PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 369ZF UT WOS:000260731700021 PM 18855809 ER PT J AU Nadon, NL Strong, R Miller, RA Nelson, J Javors, M Sharp, ZD Peralba, JM Harrison, DE AF Nadon, N. L. Strong, R. Miller, R. A. Nelson, J. Javors, M. Sharp, Z. D. Peralba, J. M. Harrison, D. E. TI Design of aging intervention studies: the NIA interventions testing program SO AGE LA English DT Article DE Anti-aging; Lifespan; Longevity; Mice ID GENETICALLY HETEROGENEOUS MICE; CONVERTING ENZYME-INHIBITORS; TERT-BUTYL NITRONE; QUANTITATIVE TRAIT LOCI; ACID PHENETHYL ESTER; LIFE-SPAN; BODY-WEIGHT; SPIN-TRAP; ANTIOXIDANT PROPERTIES; CALORIC RESTRICTION AB The field of biogerontology has made great strides towards understanding the biological processes underlying aging, and the time is ripe to look towards applying this knowledge to the pursuit of aging interventions. Identification of safe, inexpensive, and non-invasive interventions that slow the aging process and promote healthy aging could have a significant impact on quality of life and health care expenditures for the aged. While there is a plethora of supplements and interventions on the market that purport to slow aging, the evidence to validate such claims is generally lacking. Here we describe the development of an aging interventions testing program funded by the National Institute on Aging (NIA) to test candidate interventions in a model system. The development of this program highlights the challenges of long-term intervention studies and provides approaches to cope with the stringent requirements of a multi-site testing program. C1 [Nadon, N. L.] NIA, Biol Aging Program, Bethesda, MD 20892 USA. [Strong, R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Nelson, J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Strong, R.; Nelson, J.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Aging Inst, San Antonio, TX 78229 USA. [Miller, R. A.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Miller, R. A.] Univ Michigan, Geriatr Ctr, Ann Arbor, MI 48109 USA. [Miller, R. A.] VA Med Ctr, Ann Arbor, MI USA. [Javors, M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Sharp, Z. D.; Peralba, J. M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. [Harrison, D. E.] Jackson Labs, Bar Harbor, ME USA. [Strong, R.] S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Nadon, NL (reprint author), NIA, Biol Aging Program, 7201 Wisconsin Ave GW 2C231, Bethesda, MD 20892 USA. EM nadonn@nia.nih.gov FU National Institutes of Health [U01-AG-022307, U01-AG-022303, U01-AG-022308] FX This work was support by grants from the National Institutes of Health U01-AG-022307 ( R. S.), U01-AG-022303 ( R. A. M.) and U01-AG-022308 ( D. E. H.). NR 82 TC 58 Z9 60 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 J9 AGE JI Age PD DEC PY 2008 VL 30 IS 4 BP 187 EP 199 DI 10.1007/s11357-008-9048-1 PG 13 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 413LJ UT WOS:000263794300001 PM 19424842 ER PT J AU Chen, LJ Na, R Gu, MJ Salmon, AB Liu, YH Liang, HY Qi, WB Van Remmen, H Richardson, A Ran, QT AF Chen, Liuji Na, Ren Gu, Mingjun Salmon, Adam B. Liu, Yuhong Liang, Hanyu Qi, Wenbo Van Remmen, Holly Richardson, Arlan Ran, Qitao TI Reduction of mitochondrial H(2)O(2) by overexpressing peroxiredoxin 3 improves glucose tolerance in mice SO AGING CELL LA English DT Article DE aging; diabetes; mitochondria; oxidative stress; peroxiredoxin 3; reactive oxygen species ID CELLULAR GLUTATHIONE-PEROXIDASE; PROTEIN-TYROSINE PHOSPHATASES; INSULIN-RESISTANCE; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; INCREASED SENSITIVITY; ANTIOXIDANT DEFENSE; MULTIPLE FORMS; ROS PRODUCTION; LIFE-SPAN AB H(2)O(2) is a major reactive oxygen species produced by mitochondria that is implicated to be important in aging and pathogenesis of diseases such as diabetes; however, the cellular and physiological roles of mitochondrial H(2)O(2) remain poorly understood. Peroxiredoxin 3 (Prdx3/Prx3) is a thioredoxin peroxidase localized in mitochondria. To understand the cellular and physiological roles of mitochondrial H(2)O(2) in aging and pathogenesis of age-associated diseases, we generated transgenic mice overexpressing Prdx3 (Tg(PRDX3) mice). Tg(PRDX3) mice overexpress Prdx3 in a broad range of tissues, and the Prdx3 overexpression occurs exclusively in the mitochondria. As a result of increased Prdx3 expression, mitochondria from Tg(PRDX3) mice produce significantly reduced amount of H(2)O(2), and cells from Tg(PRDX3) mice have increased resistance to stress-induced cell death and apoptosis. Interestingly, Tg(PRDX3) mice show improved glucose homeostasis, as evidenced by their reduced levels of blood glucose and increased glucose clearance. Tg(PRDX3) mice are also protected against hyperglycemia and glucose intolerance induced by high-fat diet feeding. Our results further show that the inhibition of GSK3 may play a role in mediating the improved glucose tolerance phenotype in Tg(PRDX3) mice. Thus, our results indicate that reduction of mitochondrial H(2)O(2) by overexpressing Prdx3 improves glucose tolerance. C1 [Chen, Liuji; Gu, Mingjun; Liu, Yuhong; Liang, Hanyu; Qi, Wenbo; Van Remmen, Holly; Richardson, Arlan; Ran, Qitao] Univ Texas Hlth Sci Ctr San Antonio, Dept Cell & Struct Biol, San Antonio, TX 78229 USA. [Chen, Liuji; Na, Ren; Gu, Mingjun; Salmon, Adam B.; Liu, Yuhong; Liang, Hanyu; Qi, Wenbo; Van Remmen, Holly; Richardson, Arlan; Ran, Qitao] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Van Remmen, Holly; Richardson, Arlan; Ran, Qitao] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Ran, QT (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Texas Res Pk Campus,15355 Lambda Dr, San Antonio, TX 78245 USA. EM ran@uthscsa.edu RI Liang, Hanyu/A-1066-2010 FU Department of Veteran Affairs; NIA/NIH FX The study was supported by a Merit Review Award (Q. R.) from the Department of Veteran Affairs and a Nathan Shock Center award (A. R.) from NIA/NIH. NR 62 TC 58 Z9 60 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD DEC PY 2008 VL 7 IS 6 BP 866 EP 878 DI 10.1111/j.1474-9726.2008.00432.x PG 13 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 376LF UT WOS:000261184400009 PM 18778410 ER PT J AU Kao, J Vicuna, R House, JA Rumsfeld, JS Ting, HH Spertus, JA AF Kao, John Vicuna, Ricardo House, John A. Rumsfeld, John S. Ting, Henry H. Spertus, John A. CA Natl Cardiovasc Data CathPCI Regis TI Disparity in drug-eluting stent utilization by insurance type SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; INVASIVE CARDIAC PROCEDURES; COMPLEX CORONARY STENOSES; COLLEGE-OF-CARDIOLOGY; BARE-METAL STENTS; COST-EFFECTIVENESS; HEALTH-CARE; PREMATURE DISCONTINUATION; AMERICAN-COLLEGE; ARTERY LESIONS AB Background Because of the expense of drug-eluting stents (DES) and associated adjuvant therapy, nonclinical, socioeconomic factors may be associated with DES use in clinical practice. Methods Data on 112,588 patients from the National Cardiovascular Data CathPCI Registry (NCDR) between 2004 and 2005 with "on-label" indications for DES were analyzed. Insurance status was categorized as No Insurance, Governmental, and Private Insurance. Hierarchical multivariable logistic regression analyses were used to evaluate the association between insurance status and DES use, after adjusting for patient and procedural characteristics. Results Drug-eluting stent use was >96% during the study period, with utilization significantly associated with insurance status. Compared with patients with Private Insurance, patients with No Insurance (odds ratio 0.44, 95% confidence interval 0.37-0.53) and Government Insurance (odds ratio 0.73, 95% confidence interval 0.67-0.80) were significantly less likely to receive a DES than a bare metal stent. Repeat analysis of patients <65 years of age demonstrated virtually identical results. Conclusions Despite the high penetration of DES, significant associations between insurance status and DES utilization were identified. This indicates that disparities in health care based on socioeconomic factors extend to DES utilization and highlights the need to address such disparities as novel therapies emerge. (Am Heart J 2008; 156:1133-40.) C1 [Kao, John] Univ Illinois, Div Cardiol, Chicago, IL 60612 USA. [House, John A.; Spertus, John A.] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [House, John A.; Spertus, John A.] Univ Missouri, Kansas City, MO 64110 USA. [House, John A.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Rumsfeld, John S.] Univ Colorado, Denver, CO 80202 USA. [Ting, Henry H.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. RP Kao, J (reprint author), Univ Illinois, Div Cardiol, 840 S Wood St,Suite 926,M-C 715, Chicago, IL 60612 USA. EM jokao@uic.edu NR 45 TC 10 Z9 11 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD DEC PY 2008 VL 156 IS 6 BP 1133 EP 1140 DI 10.1016/j.ahj.2008.07.012 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 380SC UT WOS:000261484500017 PM 19033009 ER PT J AU Cooper, LT Hare, JM Tazelaar, HD Edwards, WD Starling, RC Deng, MC Menon, S Mullen, GM Jaski, B Bailey, KR Cunningham, MW Dec, GW AF Cooper, Leslie T., Jr. Hare, Joshua M. Tazelaar, Henry D. Edwards, William D. Starling, Randall C. Deng, Mario C. Menon, Santosh Mullen, G. Martin Jaski, Brian Bailey, Kent R. Cunningham, Madeleine W. Dec, G. William CA Giant Cell Myocarditis Treatment T TI Usefulness of Immunosuppression for Giant Cell Myocarditis SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article AB Giant cell myocarditis (GCM) is a rare and highly lethal disorder. The only multicenter case series with treatment data lacked cardiac function assessments and had a retrospective design. We conducted a prospective, multicenter study of immunosuppression including cyclosporine and steroids for acute, microscopically-confirmed GCM. From June 1999 to June 2005 in a standard protocol, 11 subjects received high dose steroids and cyclosporine, and 9 subjects received muromonab-CD3. In these, 7 of 11 were women, the mean age was 60 +/- 15 years, and the mean time from symptom onset to presentation was 27 +/- 33 days. During 1 year of treatment, I subject died of respiratory complications on day 178, and 2 subjects received heart transplantations on clays 2 and 27, respectively. Serial endomyocardial biopsies revealed that after 4 weeks of treatment the degree of necrosis, cellular inflammation, and giant cells decreased (p = 0.001). One patient who completed the trial subsequently died of a fatal GCM recurrence after withdrawal of immunosuppression. Her case demonstrates for the first time that there is a risk of recurrent, sometimes fatal, GCM after cessation of immunosuppression. In conclusion, this prospective study of immunosuppression for GCM confirms retrospective case reports that such therapy improves long-term Survival. Additionally, withdrawal of immunosuppression can be associated with fatal GCM recurrence. (C) 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102:1535-1539) C1 [Cooper, Leslie T., Jr.] Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Hare, Joshua M.] Univ Miami, Div Cardiol, Miami, FL USA. [Tazelaar, Henry D.] Mayo Clin, Dept Pathol, Scottsdale, AZ USA. [Edwards, William D.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Starling, Randall C.] Cleveland Clin, Med Ctr, Div Cardiol, Cleveland, OH 44106 USA. [Deng, Mario C.] Columbia Univ, Med Ctr, Div Cardiol, New York, NY USA. [Menon, Santosh] Ohio Heart & Vasc Ctr, Cincinnati, OH USA. [Mullen, G. Martin] Cardiovasc Associates, Elk Grove Village, IL USA. [Jaski, Brian] Sharp Mem Hosp & Rehabil Ctr, San Diego, CA USA. [Bailey, Kent R.] Mayo Clin, Dept Biostat, Rochester, MN USA. [Cunningham, Madeleine W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. [Dec, G. William] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Cooper, LT (reprint author), Mayo Clin, Div Cardiovasc Dis, Rochester, MN 55905 USA. EM cooper.leslie@mayo.edu FU FDA HHS [FD-RO-1-001986]; NHLBI NIH HHS [R13 HL074877-01A1] NR 10 TC 75 Z9 77 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 DEC 1 PY 2008 VL 102 IS 11 BP 1535 EP 1539 DI 10.1016/j.amjcard.2008.07.041 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 382DQ UT WOS:000261585700021 PM 19026310 ER PT J AU Raghupathy, A Nienaber, CA Harris, KM Myrmel, T Fattori, R Sechtem, U Oh, J Trimarchi, S Cooper, JV Booher, A Eagle, K Isselbacher, E Bossone, E AF Raghupathy, Arun Nienaber, Christoph A. Harris, Kevin M. Myrmel, Truls Fattori, Rossella Sechtem, Udo Oh, Jae Trimarchi, Santi Cooper, Jeanna V. Booher, Anna Eagle, Kim Isselbacher, Eric Bossone, Eduardo CA Int Registry Acute Aortic Discussi TI Geographic Differences in Clinical Presentation, Treatment, and Outcomes in Type A Acute Aortic Dissection (from the International Registry of Acute Aortic Dissection) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DIAGNOSIS; IRAD; ECHOCARDIOGRAPHY; EXPERIENCE; MANAGEMENT; DISEASE AB Although several studies have provided robust evidence about global differences for several cardiovascular emergencies, such as myocardial infarction and stroke, data were limited for aortic disease. The aim was to explore geographic variation in type A acute aortic dissection (TA-AAD) in a large group of consecutive patients. Patients (n = 615) from the IRAD with TA-AAD were studied with respect to presenting symptoms and signs, diagnosis, management, and outcomes in Europe versus North America. Compared with Europeans, North Americans were more likely to be older and present with atypical features and without many of the classic chest X-ray findings of AAD. In the North American cohort, electrocardiographic findings showed higher rates of nonspecific ST changes and a trend toward ST-elevation or new myocardial infarction (North Americans vs Europeans 7.9% vs 4.4%; p = 0.09). Use of imaging studies to confirm the diagnosis of AAD varied between North American and European centers. North American centers performed an average of 1.6 imaging studies compared with 1.8 in the European group (p = 0.002). Furthermore, they were significantly less likely to use computed tomography and significantly more likely to use transesophageal examination as part of the overall diagnostic algorithm. Compared with Europeans, TA-AAD occurred at smaller aortic diameters and there was a substantial delay to presentation and diagnosis in North Americans. No significant differences for early mortality rates were observed between the 2 groups. In conclusion, geographic differences in presentation and initial management were highlighted, but this did not translate into a difference in early mortality. (c) 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102:1562-1566) C1 [Bossone, Eduardo] CNR, Lecce, Italy. [Raghupathy, Arun; Cooper, Jeanna V.; Booher, Anna; Eagle, Kim] Univ Michigan, Ann Arbor, MI 48109 USA. [Nienaber, Christoph A.] Univ Rostock, Rostock, Germany. [Harris, Kevin M.] Minneapolis Heart Inst, Minneapolis, MN USA. [Myrmel, Truls] Univ Tromso Hosp, N-9012 Tromso, Norway. [Fattori, Rossella] Univ Hosp S Orsola, Bologna, Italy. [Sechtem, Udo] Robert Bosch Krankenhaus, Stuttgart, Germany. [Oh, Jae] Mayo Clin, Rochester, MN USA. [Trimarchi, Santi] Policlin San Donato, IRCCS, Milan, Italy. [Isselbacher, Eric] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Bossone, E (reprint author), CNR, Lecce, Italy. EM ebossone@hotmail.com RI Trimarchi, Santi/J-7361-2016 OI Trimarchi, Santi/0000-0001-5996-3264 FU University of Michigan Faculty Group Practice; Varbedian Fund for Aortic Research, Ann Arbor, Michigan FX This work was supported by grants from the University of Michigan Faculty Group Practice and the Varbedian Fund for Aortic Research, Ann Arbor, Michigan. NR 22 TC 19 Z9 22 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 1 PY 2008 VL 102 IS 11 BP 1562 EP 1566 DI 10.1016/j.amjcard.2008.07.049 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 382DQ UT WOS:000261585700026 PM 19026315 ER PT J AU Misra, M Katzman, DK Cord, J Manning, SJ Mickley, D Herzog, DB Miller, KK Klibanski, A AF Misra, Madhusmita Katzman, Debra K. Cord, Jennalee Manning, Stephanie J. Mickley, Diane Herzog, David B. Miller, Karen K. Klibanski, Anne TI Percentage extremity fat, but not percentage trunk fat, is lower in adolescent boys with anorexia nervosa than in healthy adolescents SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID REGIONAL BODY-COMPOSITION; SECRETORY DYNAMICS; BONE METABOLISM; GROWTH-HORMONE; ACQUIRED HYPOGONADISM; GIRLS; TESTOSTERONE; MEN; MASS; THERAPY AB Background: Anorexia nervosa (AN) is a condition of severe undernutrition associated with altered regional fat distribution in females. Although primarily a disease of females, AN is increasingly being recognized in males and is associated with hypogonadism. Testosterone is a major regulator of body composition in males, and testosterone administration in adults decreases visceral fat. However, the effect of low testosterone and other hormonal alterations on body composition in boys with AN is not known. Objective: We hypothesized that testosterone deficiency in boys with AN is associated with higher trunk fat, as opposed to extremity fat, compared with control subjects. Design: We assessed body composition using dual-energy X-ray absorptiometry and measured fasting testosterone, estradiol, insulin-like growth factor-1, leptin, and active ghrelin concentrations in 15 boys with AN and in 15 control subjects of comparable maturity aged 12-19 y. Results: Fat and lean mass in AN boys was 69% and 86% of that in control subjects. Percentage extremity fat and extremity lean mass were lower in boys with AN (P = 0.003 and 0.0008); however, percentage trunk fat and the trunk to extremity fat ratio were higher after weight was adjusted for (P = 0.005 and 0.003). Testosterone concentrations were lower in boys with AN, and, on regression modeling, positively predicted percentage extremity lean mass and inversely predicted percentage trunk fat and trunk to extremity fat ratio. Other independent predictors of regional body composition were bone age and weight. Conclusions: In adolescent boys with AN, higher percentage trunk fat, higher trunk to extremity fat ratio, lower percentage extremity fat, and lower extremity lean mass (adjusted for weight) are related to the hypogonadal state. Am J Clin Nutr 2008; 88: 1478-84. C1 [Misra, Madhusmita; Cord, Jennalee; Miller, Karen K.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Misra, Madhusmita; Cord, Jennalee; Herzog, David B.; Miller, Karen K.; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA USA. [Misra, Madhusmita] Massachusetts Gen Hosp Children, Pediat Endocrinol Unit, Boston, MA USA. [Katzman, Debra K.; Manning, Stephanie J.] Hosp Sick Kids, Div Adolescent Med, Toronto, ON, Canada. [Mickley, Diane] Wilkins Ctr Eating Disorders, Greenwich, CT USA. [Herzog, David B.] Massachusetts Gen Hosp, Harris Ctr, Boston, MA 02114 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457,55 Fruit St, Boston, MA 02114 USA. EM mmisra@partners.org FU NIH [R01 DK 062249, K23 RR018851, M01-RR-01066] FX Supported by NIH grants R01 DK 062249, K23 RR018851, and M01-RR-01066. NR 33 TC 9 Z9 9 U1 0 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC 1 PY 2008 VL 88 IS 6 BP 1478 EP 1484 DI 10.3945/ajcn.2008.26273 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 380EO UT WOS:000261449200005 PM 19064506 ER PT J AU Hosoya, Y Tay, FR Garcia-Godoy, F Pashley, DH AF Hosoya, Yumiko Tay, Franklin R. Garcia-Godoy, Franklin Pashley, David H. TI Ultrastructural examination of one-step self-etch adhesive bonded primary sound and caries-affected dentin SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID DUAL-CURED COMPOSITES; PRIMARY TOOTH DENTIN; NANOLEAKAGE EXPRESSION; PERMEABLE MEMBRANES; ELASTIC-MODULUS; CARIOUS DENTIN; CANINE DENTIN; SINGLE-BOTTLE; NANO-HARDNESS; IN-VIVO AB Purpose: To examine the ultrastructure and silver nanoleakage of the resin-dentin interfaces in sound and caries-affected primary tooth dentin bonded with a 4-META one-step self-etch adhesive. Methods: Each of five sound and carious primary molars was bonded with Hybrid Bond. Resin-dentin interfaces were observed with TEM micrographs obtained from silver-impregnated, unstained and undemineralized sections of bonded sound and caries-affected primary dentin, and stained and undemineralized sections of bonded sound and caries affected primary dentin without silver impregnation. Results: For sound dentin, silver nanoleakage was observed extensively in the patent dentin tubules, within the dentin beneath the hybrid layer, within the hybrid layer in some specimens, and as water trees that partially protruded into the overlying adhesive layer. The hybrid layer was about 1 mu m thick. Smear plugs in the dentin tubules and smear on the ground dentin protruded in the hybrid layer. Remnants of demineralized smear were observed overlying the adhesive layer. For caries-affected dentin, the hybrid layer was obscure. Dentin tubules were occluded with mineral deposits. There were no water trees or nanoleakage in the adhesive layer or hybrid layer. However, smear remnants were observed in the adhesive layer and large silver deposits were observed in the highly porous underlying caries-affected dentin. (Am J Dent 2008;21:368-372). C1 [Hosoya, Yumiko] Nagasaki Univ, Grad Sch Biomed Sci Med & Dent Sci, Unit Translat Med, Dept Pediat Dent, Nagasaki 8528588, Japan. [Tay, Franklin R.; Pashley, David H.] Med Coll Georgia, Sch Dent, Dept Oral Biol & Maxillofacial Pathol, Augusta, GA 30912 USA. [Garcia-Godoy, Franklin] Nova SE Univ, Ft Lauderdale, FL 33314 USA. [Garcia-Godoy, Franklin] Forsyth Inst, Boston, MA USA. RP Hosoya, Y (reprint author), Nagasaki Univ, Grad Sch Biomed Sci Med & Dent Sci, Unit Translat Med, Dept Pediat Dent, 1-7-1 Sakamoto, Nagasaki 8528588, Japan. EM hosoya@nagasaki-u.ac.jp FU Japanese Society [18592242]; NIDCR [DE 014911, DE 015306] FX This study was supported in part by Central grant sponsor: Japanese Society for the Promotion of Science 18592242 and by grants DE 014911 and DE 015306 from NIDCR. NR 43 TC 3 Z9 4 U1 0 U2 0 PU MOSHER & LINDER, INC PI WESTON PA 318 INDIAN TRACE SUITE 500, WESTON, FL 33326 USA SN 0894-8275 J9 AM J DENT JI Am. J. Dent. PD DEC PY 2008 VL 21 IS 6 BP 368 EP 372 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 385NO UT WOS:000261821100006 PM 19146129 ER PT J AU Porciani, PF Vano, M Radovic, I Goracci, C Grandini, S Garcia-Godoy, F Ferrari, M AF Porciani, Pier F. Vano, Michele Radovic, Ivana Goracci, Cecilia Grandini, Simone Garcia-Godoy, Franklin Ferrari, Marco TI Fracture resistance of fiber posts: Combinations of several small posts vs. standardized single post SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID ENDODONTICALLY TREATED TEETH; SEM EVALUATION; RESTORATIONS; PLACEMENT; THICKNESS; SURVIVAL; CEMENT AB Purpose: To determine the fracture resistance of different sizes of standardized single fiber posts and the combinations of multiple small experimental posts. Methods: Single posts in three different sizes (l, 2 and 3; DT Light Posts, RTD; DT), as control, and seven different combinations of experimental small posts (Abrasive Technology), reproducing the sizes of several endodontic files were cemented in endodontic resin blocks. The combinations of small posts were made combining 2-4 small posts so as to reach the sizes of standardized DT posts. The posts were loaded at an angle of 45 to the long axis of the block using a crosshead speed of 1 mm/minute until specimen failure. Ten posts/combinations were tested. Statistical analysis was performed using one-way ANOVA followed by Tamhane test for the post hoc comparisons (P< 0.05). Results: For the single posts, fracture resistance increased when increasing the diameter of the post. The use of multiple posts resulted in fracture resistances comparable to that of the single post for two of the three diameters studied (DT1 and DT2). For the largest diameter (DT3), the use of multiple posts resulted in lower fracture resistances than did the single post. (Am J Dent 2008;21:373-376). C1 [Porciani, Pier F.; Vano, Michele; Radovic, Ivana; Goracci, Cecilia] Univ Siena, Dept Dent Mat & Restorat Dent, I-53100 Siena, Italy. [Vano, Michele] Univ Pisa, Dept Oral Surg, I-56100 Pisa, Italy. [Radovic, Ivana] Univ Belgrade, Fac Dent, Clin Pediat & Prevent Dent, Belgrade, Serbia. [Grandini, Simone] Univ Siena, Dept Endodont & Restorat Dent, I-53100 Siena, Italy. [Garcia-Godoy, Franklin] Nova SE Univ, Coll Dent Med, Ft Lauderdale, FL 33314 USA. [Garcia-Godoy, Franklin] Forsyth Inst, Boston, MA USA. [Ferrari, Marco] Univ Siena, Sch Dent Med, Dept Prosthodont & Dent Mat & Restorat Dent, I-53100 Siena, Italy. [Ferrari, Marco] Tufts Univ, Sch Dent Med, Boston, MA 02111 USA. RP Porciani, PF (reprint author), Piazza Pietro Leopoldo 8, I-50134 Florence, Italy. EM piercateads1@libero.it NR 22 TC 9 Z9 10 U1 0 U2 0 PU MOSHER & LINDER, INC PI WESTON PA 318 INDIAN TRACE SUITE 500, WESTON, FL 33326 USA SN 0894-8275 J9 AM J DENT JI Am. J. Dent. PD DEC PY 2008 VL 21 IS 6 BP 373 EP 376 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 385NO UT WOS:000261821100007 PM 19146130 ER PT J AU Kramer, N Garcia-Godoy, F Lohbauer, U Schneider, K Assmann, I Frankenberger, R AF Kraemer, Norbert Garcia-Godoy, Franklin Lohbauer, Ulrich Schneider, Katja Assmann, Irene Frankenberger, Roland TI Preparation for invasive pit and fissure sealing: Air-abrasion or bur? SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID ENAMEL PREPARATION; BOND STRENGTH; EFFICIENCY; DENTISTRY; COMPOSITE; SEALANT; CARIES AB Purpose: To evaluate the effect of different air-abrasion devices on substance loss on flattened enamel, preparation extent, and microleakage of invasive pit and fissure sealings. Methods: 150 freshly extracted caries-free human third molars were used. 60 teeth (n=10) were embedded, enamel surfaces were polished to #1200, and six air abrasion devices abraded specimens for 5 seconds. Substance loss was profilometrically recorded as maximum and mean width, and maximum and mean depth. From 90 intact teeth (n=10), fissures were enlarged by air abrasion (Rondoflex 27 mu m/50 mu m, Airsonic Mini Sandblaster, CoJet Prep, PrepStart, Primus CPE), or treated with a diamond bur (De Craene), or using a metal bur (Fissurotomy Micro NTF), or with oscillating diamond tips (SONICSeal). Prepared fissures were etched and rinsed and sealed with a light-curing sealant (Helioseal). After four weeks water storage and subsequent 2,000 thermocycles (5 degrees C/55 degrees C), microleakage was assessed with 5% methylene blue for 3 minutes at 30G on cross cuts at x40 magnification. Furthermore the parameters upper fissure width, prepared and unprepared area, penetration depth of the sealer, and area of voids were recorded. Results: For substance loss on flattened enamel, CoJet Prep and Mini Sandblaster revealed the widest abrasion areas, PrepStart produced the deepest craters (P< 0.05). Regarding preparation characteristics, rotary burs and PrepStart caused significantly less substance loss than the other devices (P< 0.05). Due to the etch&rinse approach, microleakage was generally minimal. Only after air abrasion with Rondoflex (50 mu m) significantly less complete sealings were recorded (P< 0.05). (Am J Dent 2008;21:383-387). C1 [Kraemer, Norbert] Univ Med Ctr Carl Gustav Carus, Dept Pediat Dent, Dresden, Germany. [Garcia-Godoy, Franklin] Nova SE Univ, Coll Dent Med, Ft Lauderdale, FL 33314 USA. [Garcia-Godoy, Franklin] Forsyth Inst, Boston, MA USA. [Lohbauer, Ulrich] Univ Erlangen Nurnberg, Mat Sci Lab, Erlangen, Germany. [Frankenberger, Roland] Univ Erlangen Nurnberg, Dent Clin 1, Erlangen, Germany. RP Frankenberger, R (reprint author), Gluckstr 11, D-91054 Erlangen, Germany. EM frankbg@dent.uni-erlangen.de NR 34 TC 1 Z9 1 U1 0 U2 5 PU MOSHER & LINDER, INC PI WESTON PA 318 INDIAN TRACE SUITE 500, WESTON, FL 33326 USA SN 0894-8275 J9 AM J DENT JI Am. J. Dent. PD DEC PY 2008 VL 21 IS 6 BP 383 EP 387 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 385NO UT WOS:000261821100009 PM 19146132 ER PT J AU Spiegel, BMR Chey, WD Chang, L AF Spiegel, Brennan M. R. Chey, William D. Chang, Lin TI Bacterial Overgrowth and Irritable Bowel Syndrome: Unifying Hypothesis or a Spurious Consequence of Proton Pump Inhibitors? SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Editorial Material ID GASTROESOPHAGEAL-REFLUX DISEASE; COGNITIVE-BEHAVIORAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; DOUBLE-BLIND; PSYCHOLOGICAL TREATMENT; BREATH TESTS; SYMPTOMS; OMEPRAZOLE; PLACEBO; IBS AB Some studies indicate that small intestinal bacterial overgrowth (SIBO), as measured by hydrogen breath tests (HBT), is more prevalent in patients with irritable bowel syndrome (IBS) vs. matched controls without IBS. Although the data are conflicting, this observation has led to the hypothesis that SIBO may be a primary cause of IBS. Yet, it remains unclear whether SIBO is truly fundamental to the pathophysiology of IBS, or is instead a mere epiphenomenon or bystander of something else altogether. We hypothesize that SIBO might be a byproduct of the disproportionate use of proton pump inhibitors (PPIs) in IBS, as follows: (1) IBS patients are more likely than controls to receive PPI therapy; (2) PPI therapy may promote varying forms of SIBO by eliminating gastric acid; and (3) existing studies linking SIBO to IBS have not adjusted for or excluded the use of PPI therapy. When linked together, these premises form the basis for a simple and testable hypothesis: the relationship between SIBO and IBS may be confounded by PPIs. Our article explores these premises, lays out the argument supporting this "PPI hypothesis," discusses potential implications, and outlines next steps to further investigate this possibility. (Am J Gastroenterol 2008;103:2972-2976). C1 [Spiegel, Brennan M. R.] VA Greater Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Spiegel, Brennan M. R.; Chang, Lin] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Chey, William D.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Spiegel, Brennan M. R.; Chang, Lin] Ctr Neurobiol Stress CNS, Los Angeles, CA USA. [Spiegel, Brennan M. R.; Chang, Lin] Univ Calif Los Angeles, VA Ctr Outcomes Res & Educ, Los Angeles, CA USA. RP Spiegel, BMR (reprint author), VA Greater Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 115,Room 215, Los Angeles, CA 90073 USA. FU NCCIH NIH HHS [1 R24 AT002681, R24 AT002681, R24 AT002681-01]; NIAMS NIH HHS [AR46122-01, R01 AR046122, R01 AR046122-01]; NIDDK NIH HHS [2P30DK 041301-17, P30 DK041301, P30 DK041301-17, P50 DK064539, P50 DK064539-019001, P50 DK64539] NR 40 TC 40 Z9 41 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD DEC PY 2008 VL 103 IS 12 BP 2972 EP 2976 DI 10.1111/j.1572-0241.2008.01992.x PG 5 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 378YN UT WOS:000261361200004 PM 19086951 ER PT J AU Thia, KT Sandborn, WJ Lewis, JD Loftus, EV Feagan, BG Steinhart, AH Hanauer, SB Persson, T Sands, BE AF Thia, Kelvin T. Sandborn, William J. Lewis, James D. Loftus, Edward V., Jr. Feagan, Brian G. Steinhart, A. Hillary Hanauer, Stephen B. Persson, Tore Sands, Bruce E. TI Defining the Optimal Response Criteria for the Crohn's Disease Activity Index for Induction Studies in Patients With Mildly to Moderately Active Crohn's Disease SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID CERTOLIZUMAB PEGOL; MAINTENANCE THERAPY; RANDOMIZED-TRIAL; CLINICAL-TRIALS; ORAL BUDESONIDE; NATALIZUMAB; PREDNISOLONE; ADALIMUMAB; INFLIXIMAB; EFFICACY AB OBJECTIVES: The Crohn's Disease Activity Index (CDAI) is used to judge efficacy in clinical trials. We explored the effect of CDAI response definitions for induction on study efficiency. METHODS: We analyzed primary CDAI data from induction studies in patients with mildly to moderately active Crohn's disease, not receiving concomitant aminosalicylates, corticosteroids, or immunomodulator therapy, and without fistulizing or stricturing complications. The 12 definitions of clinical response included: CDAI decrease from baseline by 50, 70, 100, or 150 points; decrease by 25% from baseline and by 70 or 100 points; CDAI < 100 or 150 points; CDAI < 150 points plus decrease by 70 or 100 points; CDAI < 150 points at any time sustained for the duration of the trial; or decrease in the CDAI by 70 points for the last two consecutive visits. Response definitions were ranked according to ability to optimize the effect difference between treatment arms. The effect of time, baseline disease activity (CDAI 200-299 or >= 300 points), and previous surgical resections on response definitions were evaluated and ranked. Multivariate analysis on additional factors of age (< 40 or >= 40 yr), gender and duration of disease (< 2 or >= 2 yr) were performed to determine predictors of response when applied to these CDAI definitions. RESULTS: Treatment effect differences in placebo-controlled studies were maximized by response definitions that incorporated either a decrease CDAI >= 70 points for the last two consecutive visits or decrease in baseline CDAI >= 100 points, and remained optimal when evaluated for the composite effect of time, baseline activity, and prior resections. A decrease in baseline CDAI >= 100 points had some advantages over a decrease CDAI >= 70 points over two visits in terms of study efficiency, as it produced a lower control response rate and was not influenced by any of the baseline factors. CONCLUSION: Clinical trial efficiency for induction studies in patients with mildly to moderately active Crohn's disease can be improved by using either a decrease in CDAI by >= 70 points for the last two consecutive visits or a decrease in baseline CDAI by >= 100 points as the primary end point for the trial. These findings are valid for patients with ileocecal Crohn's disease not refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients who do not have stricturing or penetrating complications. It is unclear if these CDAI response criteria would similarly increase study efficiency in trials that recruited patients with moderately to severely active disease, patients refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients with stricturing or penetrating complications. (Am J Gastroenterol 2008;103:3123-3131). C1 [Sands, Bruce E.] Massachusetts Gen Hosp, MGH Crohns & Colitis Ctr, Boston, MA 02114 USA. [Sands, Bruce E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Thia, Kelvin T.; Sandborn, William J.; Loftus, Edward V., Jr.] Mayo Clin, Miles & Shirley Fiterman Ctr Digest Dis, Rochester, MN USA. [Lewis, James D.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Feagan, Brian G.] Univ Western Ontario, Robarts Res Inst, London, ON, Canada. [Steinhart, A. Hillary] Univ Toronto, Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Hanauer, Stephen B.] Univ Chicago, Chicago, IL 60637 USA. [Persson, Tore] AstraZeneca R& D, Lund, Sweden. RP Sands, BE (reprint author), Massachusetts Gen Hosp, MGH Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. RI Loftus, Edward/E-8304-2011; Feagan, Brian/M-4283-2015 FU AstraZeneca FX Financial support: Statistical analysis was provided by AstraZeneca, otherwise none. NR 28 TC 13 Z9 13 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD DEC PY 2008 VL 103 IS 12 BP 3123 EP 3131 DI 10.1111/j.1572-0241.2008.02176.x PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 378YN UT WOS:000261361200025 PM 18786111 ER PT J AU George, CJ Korc, B Ross, JS AF George, Claudene J. Korc, Beatriz Ross, Joseph S. TI Appropriate Proton Pump Inhibitor Use Among Older Adults: A Retrospective Chart Review SO AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY LA English DT Article DE proton pump inhibitors; polypharmacy; outpatient ID DIFFICILE-ASSOCIATED DISEASE; ACID-SUPPRESSIVE THERAPY; PRIMARY-CARE; HOSPITALIZED-PATIENTS; GENERAL-PRACTICE; RISK; MEDICATION; OVERUSE; DRUGS; QUALITY AB Background: Proton pump inhibitors (PPIs) arc widely used, but not always with a clear indication. Nonindicated use is of particular concern among older adults, who may have multiple comorbidities and take more medications, increasing their risk for adverse drug reactions. Objective: This study examined the appropriateness Of PPI use at an outpatient geriatric practice and the association between particular patient characteristics and appropriate use of these medications. Methods: This was a retrospective chart review of a group of randomly identified community-dwelling adults aged >= 65 years with a current prescription for a PPI (as of August 2006) from a geriatric ambulatory care practice within all urban academic medical center. The main outcome was appropriateness Of PPI use, categorized as indicated, possibly indicated, or not indicated, based on US Food and Drug Administration-approved indications and national gastroenterology guidelines. Results: Out of similar to 2500 patients in the geriatric practice, 702 (similar to 28%) were identified as having a current prescription for a PPI. From these, 110 charts were randomly selected for review, of which 10 were excluded based on predefined criteria. The sample was 79% female and 46% white, with a mean age of 82.8 years (range, 66-99 years). PPI use was indicated in 64% of these patients, possibly indicated in 7%, and not indicated in 29%. Compared with indicated PPI use, nonindicated use was significantly associated with use for <1 year (relative risk = 2.20; 95% CI, 1.00-4.86; P = 0.05). Nonindicated PPI use was not significantly associated with age, female sex, nonwhite race, or PPI initiation in the inpatient setting. Conclusion: Almost 30% of patients receiving a PPI in this academic geriatric practice had no documented indication for PPI use. (Am J Geriatr Pharmacother. 2008;6:249-254) (C) 2008 Excerpta Medica Inc. C1 [George, Claudene J.] Albert Einstein Coll Med, Montefiore Med Ctr, Div Geriatr, Dept Med, Bronx, NY 10467 USA. [Korc, Beatriz; Ross, Joseph S.] Mt Sinai Sch Med, Dept Geriatr & Adult Dev, New York, NY USA. [Ross, Joseph S.] James J Peters Vet Adm Med Ctr, HSR&D Targeted Res Enhancement Program, Bronx, NY USA. [Ross, Joseph S.] James J Peters Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. RP George, CJ (reprint author), Albert Einstein Coll Med, Montefiore Med Ctr, Div Geriatr, Dept Med, 111 E 210th St, Bronx, NY 10467 USA. EM clgeorge@montefiore.org FU Department of Veterans Affairs Health Services Research and Development Service [TRP-02-149]; Hartford Foundation FX This project was not directly supported by any external grants or funds. Dr. Ross is currently supported by Department of Veterans Affairs Health Services Research and Development Service project no. TRP-02-149 and the Hartford Foundation. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. Neither the Department of Veterans Affairs nor the Hartford Foundation had any role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. Dr. Ross was a consultant at the request of plaintiffs in litigation against Merck and Co., Inc., in relation to rofecoxib. NR 25 TC 24 Z9 26 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 1543-5946 J9 AM J GERIATR PHARMAC JI Am. J. Geriatr. Pharmacother. PD DEC PY 2008 VL 6 IS 5 BP 249 EP 254 DI 10.1016/j.amjopharm.2008.12.001 PG 6 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 391FS UT WOS:000262219800003 PM 19161927 ER PT J AU Van Cott, E AF Van Cott, E. TI COLLEGE OF AMERICAN PATHOLOGISTS COAGULATION RESOURCE COMMITTEE: IMPROVING LABORATORY PRACTICES SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Meeting Abstract C1 [Van Cott, E.] Massachusetts Gen Hosp, Coagulat Lab, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2008 VL 83 IS 12 BP 946 EP 946 PG 1 WC Hematology SC Hematology GA 383AI UT WOS:000261646100034 ER PT J AU Resnick, HE Schuur, JD Heineman, J Stone, R Weissman, JS AF Resnick, Helaine E. Schuur, Jeremiah D. Heineman, Janice Stone, Rohyn Weissman, Joel S. TI Advance Directives in Nursing Home Residents Aged >= 65 Years: United States 2004 SO AMERICAN JOURNAL OF HOSPICE & PALLIATIVE MEDICINE LA English DT Article DE advance directives; nursing home; survey; long term care; aging ID SELF-DETERMINATION ACT; LIFE DECISION-MAKING; FACILITIES; DOCUMENTS; ADMISSION AB In 1996, 53% of US nursing home residents had advance directives. This report defines documentation of advance directives in a nationally representative survey of US nursing home residents. aged >= 65 years in 2004, as well as advance directive use in relation to demographic factors and receipt of specialty services including hospice/palliative care. In 2004, advance directives were documented in 69.9% of US nursing home residents aged >= 65 years and in 93.6% of residents receiving hospice/palliative care. Documentation of advance directives increased substantially between 1996 and 2004 and is nearly universal among residents receiving hospice/palliative care services. However in 2004, 3 of every 10 US nursing home residents did not have ducumentation of advance care plans. Continued efforts are needed to promote the importance of advance care planning among US nursing home residents. C1 [Resnick, Helaine E.; Heineman, Janice; Stone, Rohyn] Amer Assoc Homes & Serv Aging, Inst Future Aging Serv, Washington, DC 20008 USA. [Resnick, Helaine E.] Georgetown Univ, Dept Med, Washington, DC USA. [Schuur, Jeremiah D.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. [Schuur, Jeremiah D.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Weissman, Joel S.] Harvard Univ, Sch Publ Hlth, Inst Hlth Policy, Massachusetts Gen Hosp,Dept Hlth Policy & Managem, Boston, MA 02115 USA. [Weissman, Joel S.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Resnick, HE (reprint author), Amer Assoc Homes & Serv Aging, Inst Future Aging Serv, 2519 Connecticut Ave,NW, Washington, DC 20008 USA. EM hresnick@aahsa.org NR 11 TC 20 Z9 20 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1049-9091 J9 AM J HOSP PALLIAT ME JI Am. J. Hosp. Palliat. Med. PD DEC-JAN PY 2008 VL 25 IS 6 BP 476 EP 482 DI 10.1177/1049909108322295 PG 7 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 385JD UT WOS:000261809600009 PM 18843133 ER PT J AU Kaufman, JS AF Kaufman, James S. TI Racial Differences in Erythropoietin Responsiveness SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; INCIDENT HEMODIALYSIS-PATIENTS; HEMATOCRIT VALUES; HEMOGLOBIN LEVELS; EPOETIN-ALPHA; ANEMIA; MORTALITY; LEVEL; RACE C1 Boston Univ, Renal Sect 111 RE, VA Boston Healthcare Syst, Sch Med, Boston, MA 02130 USA. RP Kaufman, JS (reprint author), Boston Univ, Renal Sect 111 RE, VA Boston Healthcare Syst, Sch Med, 150 S Huntington Ave, Boston, MA 02130 USA. EM james.kaufman@va.gov NR 19 TC 3 Z9 3 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 2008 VL 52 IS 6 BP 1035 EP 1038 DI 10.1053/j.ajkd.2008.10.002 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 380UD UT WOS:000261489800002 PM 19026356 ER PT J AU Fried, L Hebah, N Finkelstein, F Piraino, B AF Fried, Linda Hebah, Nasser Finkelstein, Fredric Piraino, Beth TI Association of Kt/V and Creatinine Clearance With Outcomes in Anuric Peritoneal Dialysis Patients SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Peritoneal dialysis; adequacy; mortality; hospitalization ID SURVIVAL; ADEQUACY; MORTALITY; TARGETS; EAPOS AB Background: The 2006 Kidney Disease Outcomes Quality Initiative recommended a minimum total Kt/V of 1.7, eliminated creatinine clearance (Ccr) as a target, and recommended the use of ideal body weight to calculate Kt/V. We assessed these recommendations as predictors of outcomes in anuric peritoneal dialysis patients. Study Design: Retrospective observational study using administrative data. Setting & Participants: 1,432 peritoneal dialysis patients with anuria from January 1, 1994, to January 31, 2005, in a national sample (1,428 with Kt/V, 1,416 with Ccr). Predictors: Kt/V and Ccr at anuria; Kt/V based on actual body weight and ideal body weight. Outcomes & Measurements: Association of dialysis adequacy with mortality and time to first hospitalization after anuria assessed by using accelerated failure time models. Results: 293 anuric patients had Kt/V less than 1.7, 366 had Kt/V of 1.7 to 2.0, and 769 had Kt/V greater than 2.0, using actual body weight for calculation. In unadjusted analyses, Kt/V calculated using actual body weight both less than 1.7 (-41.3%; 95% confidence interval [Cl], -55.5 to -22.6) and 1.7 to 2.0 (-26.1 %; 95% Cl, -42.6 to -4.6) were associated with shorter time to mortality. Kt/V calculated using actual body weight less than 1.7 was associated with shorter time to hospitalization (-38.1 %; 95% Cl, -50.0 to -23.4), but Kt/V calculated using actual body weight of 1.7 to 2.0 was not a significant predictor (-3.3%; 95% Cl, -21.1 to 18.6). After adjustment, Kt/V calculated using actual body weight less than 1.7 remained associated with mortality (-25.3%; 95% Cl, -41.1 to -4.8) and hospitalization (-33.4%; 95% Cl, -47.1 to -16.0). Ccr did not predict mortality. In unadjusted analysis, Ccr was not associated with hospitalization, but after adjustment, Ccr less than 50 L/wk/1.73 m(2) was significantly associated with shorter time to hospitalization (-19.9%; 95% Cl, -35.0 to -1.3). Kt/V using ideal body weight was not a significant predictor in adjusted models. Limitations: This study was nonrandomized, with few malnourished patients. In addition, there is a potential for informative censoring for transfer to hemodialysis therapy before anuria. Conclusions: Kt/V calculated using actual body weight less than 1.7 in anuric peritoneal dialysis patients is associated with increased mortality and hospitalization. Use of ideal body weight to calculate Kt/V weakened the associations with outcomes and therefore cannot be recommended. C1 [Fried, Linda] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA 15240 USA. [Fried, Linda; Piraino, Beth] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Hebah, Nasser] Dialysis Clin Inc, Nashville, TN USA. [Finkelstein, Fredric] Yale Univ, Hosp St Raphael, Renal Res Inst, New Haven, CT USA. RP Fried, L (reprint author), VA Pittsburgh Healthcare Syst, Renal Sect, Univ Dr,Mailstop 111F-U, Pittsburgh, PA 15240 USA. EM linda.fried@va.gov OI Piraino, Beth/0000-0001-5061-0841 NR 25 TC 7 Z9 8 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 2008 VL 52 IS 6 BP 1122 EP 1130 DI 10.1053/j.ajkd.2008.05.013 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 380UD UT WOS:000261489800013 PM 18617306 ER PT J AU Aujesky, D Fine, MJ AF Aujesky, Drahomir Fine, Michael J. TI Community-Acquired Pneumonia: Treatment at Home or in the Hospital? SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID LOW-RISK PATIENTS; GUIDELINES; CARE C1 [Aujesky, Drahomir] Univ Lausanne, Div Gen Internal Med, Lausanne, Switzerland. [Fine, Michael J.] VA Pittsburgh Healthcare Syst, VA Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Fine, Michael J.] Univ Pittsburgh, Dept Med, Div Gen Internal Med, Pittsburgh, PA 15260 USA. RP Aujesky, D (reprint author), CHU Vaudois, Serv Med Interne, BH 10-622, CH-1011 Lausanne, Switzerland. EM drahomir.aujesky@chuv.ch NR 7 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD DEC PY 2008 VL 121 IS 12 BP 1038 EP 1040 DI 10.1016/j.amjmed.2008.08.016 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 387XO UT WOS:000261985100018 PM 19028194 ER PT J AU Limsukon, A Barack, BM Hoo, GWS AF Limsukon, Atikun Barack, Bruce M. Hoo, Guy W. Soo TI Can't Take a Deep Breath SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID DIAPHRAGMATIC-HERNIA C1 [Limsukon, Atikun] Cedars Sinai Med Ctr, Div Pulm & Crit Care Med, Los Angeles, CA 90048 USA. [Limsukon, Atikun; Hoo, Guy W. Soo] W Los Angeles VA Healthcare Ctr, Pulm & Crit Care Sect, Los Angeles, CA USA. [Limsukon, Atikun; Barack, Bruce M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Barack, Bruce M.; Hoo, Guy W. Soo] W Los Angeles VA Healthcare Ctr, Dept Thorac Radiol, Los Angeles, CA USA. RP Limsukon, A (reprint author), 11301 Wilshire Blvd,111Q, Los Angeles, CA 90073 USA. EM atikun.limsukon@cshs.org NR 17 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD DEC PY 2008 VL 121 IS 12 BP 1055 EP 1057 DI 10.1016/j.amjmed.2008.09.004 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 387XO UT WOS:000261985100024 PM 19028200 ER PT J AU Stefancyk, AL AF Stefancyk, Amanda L. TI Nurses Participate in Presenting Patients in Rounds: Part 2 SO AMERICAN JOURNAL OF NURSING LA English DT Article C1 Massachusetts Gen Hosp, Gen Med Unit, Boston, MA 02114 USA. RP Stefancyk, AL (reprint author), Massachusetts Gen Hosp, Gen Med Unit, White 10, Boston, MA 02114 USA. EM astefancyk@Partners.org NR 1 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-936X J9 AM J NURS JI Am. J. Nurs. PD DEC PY 2008 VL 108 IS 12 BP 30 EP 31 PG 2 WC Nursing SC Nursing GA 381MD UT WOS:000261539400016 PM 19033904 ER PT J AU Carr, D Utzschneider, K Tong, J Gaba, K Brunzell, J Easterling, T Kahn, S AF Carr, Darcy Utzschneider, Kristina Tong, Jenny Gaba, Kersten Brunzell, John Easterling, Thomas Kahn, Steven TI WOMEN WITH A HISTORY OF PREECLAMPSIA HAVE AN ATHEROGENIC LIPID PROFILE AND ENDOTHELIAL DYSFUNCTION BUT NO DIFFERENCE IN ADIPOSITY OR INSULIN SENSITIVITY SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 29th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 26-31, 2009 CL San Diego, CA SP Soc Mat Fetal Med C1 [Utzschneider, Kristina; Kahn, Steven] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Tong, Jenny] Univ Cincinnati, Cincinnati, OH 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 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2008 VL 199 IS 6 MA 240 BP S78 EP S78 DI 10.1016/j.ajog.2008.09.268 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 391AV UT WOS:000262205700240 ER PT J AU Kaimal, A Little, S Odibo, A Stamilio, D Caughey, A AF Kaimal, Anjali Little, Sarah Odibo, Anthony Stamilio, David Caughey, Aaron TI INDUCTION OF LABOR AT 39 WEEKS IN NULLIPAROUS WOMEN: IS IT COST-EFFECTIVE? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 29th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 26-31, 2009 CL San Diego, CA SP Soc Mat Fetal Med C1 [Kaimal, Anjali; Caughey, Aaron] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Little, Sarah] Brigham & Womens Massachusetts Gen Hosp, Boston, MA USA. [Odibo, Anthony; Stamilio, David] Washington Univ, St Louis, MO 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 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2008 VL 199 IS 6 MA 203 BP S68 EP S68 DI 10.1016/j.ajog.2008.09.230 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 391AV UT WOS:000262205700203 ER PT J AU Katz, D Ecker, J Leffert, L Pian-Smith, M AF Katz, Daniel Ecker, Jeffrey Leffert, Lisa Pian-Smith, May TI NON-INVASIVE CARDIOVASCULAR PROFILING: DIFFERENCES BETWEEN PATIENTS WITH PREECLAMPSIA AND THOSE WITH GESTATIONAL HYPERTENSION SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 29th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 26-31, 2009 CL San Diego, CA SP Soc Mat Fetal Med C1 [Katz, Daniel; Ecker, Jeffrey; Leffert, Lisa; Pian-Smith, May] Massachusetts Gen Hosp, Boston, MA 02114 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 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2008 VL 199 IS 6 MA 833 BP S235 EP S235 DI 10.1016/j.ajog.2008.09.864 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 391AV UT WOS:000262205700826 ER PT J AU Riley, L Celi, A Onderdonk, A Roberts, D Ellice, L AF Riley, Laura Celi, Ann Onderdonk, Andrew Roberts, Drucilla Ellice, Lieberman TI EPIDURAL-RELATED FEVER: A NON-INFECTIOUS STATE SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 29th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 26-31, 2009 CL San Diego, CA SP Soc Mat Fetal Med C1 [Riley, Laura; Roberts, Drucilla] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Celi, Ann] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ellice, Lieberman] Harvard Univ, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2008 VL 199 IS 6 MA 83 BP S37 EP S37 DI 10.1016/j.ajog.2008.09.109 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 391AV UT WOS:000262205700084 ER PT J AU Steinberg, G Rauh-Hain, JA Ecker, J Lee, C Khankin, EV Cohen, B Rana, S Karumanchi, SA Thadhani, R Lim, KH AF Steinberg, Guy Rauh-Hain, Jose Alejandro Ecker, Jeffrey Lee, Chulmin Khankin, Eliyahu V. Cohen, Bruce Rana, Sarosh Karumanchi, S. Ananth Thadhani, Ravi Lim, Kee-Hak TI SECOND TRIMESTER SERUM SOLUBLE FAS (SFAS) LEVELS ARE LOWER IN SGS PREGNANCIES SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 29th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 26-31, 2009 CL San Diego, CA SP Soc Mat Fetal Med C1 [Steinberg, Guy; Lee, Chulmin; Khankin, Eliyahu V.; Cohen, Bruce; Rana, Sarosh; Karumanchi, S. Ananth; Lim, Kee-Hak] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Rauh-Hain, Jose Alejandro; Ecker, Jeffrey; Thadhani, Ravi] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Khankin, Eli/M-7648-2013 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 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2008 VL 199 IS 6 MA 395 BP S120 EP S120 DI 10.1016/j.ajog.2008.09.424 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 391AV UT WOS:000262205700394 ER PT J AU Wylie, BJ Singh, N Singh, MP Macleod, WB Yeboah-Antwi, K Hamer, DH AF Wylie, B. J. Singh, N. Singh, M. P. Macleod, W. B. Yeboah-Antwi, K. Hamer, D. H. TI IMPACT OF BIOMASS COOK SMOKE EXPOSURE ON BIRTH WEIGHT SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 29th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 26-31, 2009 CL San Diego, CA SP Soc Mat Fetal Med C1 [Wylie, B. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singh, N.; Singh, M. P.] Nat Inst Malaria Res, Jabalpur, India. [Macleod, W. B.; Yeboah-Antwi, K.; Hamer, D. H.] Boston Univ, Ctr Int Hlth & Dev, Boston, MA 02215 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 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2008 VL 199 IS 6 MA 637 BP S183 EP S183 DI 10.1016/j.ajog.2008.09.667 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 391AV UT WOS:000262205700631 ER PT J AU Kempen, JH Gangaputra, S Daniel, E Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Suhler, EB Thorne, JE Foster, CS Jabs, DA Helzlsouer, KJ AF Kempen, John H. Gangaputra, Sapna Daniel, Ebenezer Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Suhler, Eric B. Thorne, Jennifer E. Foster, C. Stephen Jabs, Douglas A. Helzlsouer, Kathy J. TI Long-term Risk of Malignancy Among Patients Treated With Immunosuppressive Agents for Ocular Inflammation: A Critical Assessment of the Evidence SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Editorial Material ID POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER; RENAL-TRANSPLANT RECIPIENTS; NECROSIS-FACTOR ANTAGONISTS; NON-HODGKINS-LYMPHOMA; RHEUMATOID-ARTHRITIS; MYCOPHENOLATE-MOFETIL; SKIN-CANCER; FOLLOW-UP; LIVER-TRANSPLANTATION; ORGAN-TRANSPLANTATION C1 [Kempen, John H.] Univ Penn, Ctr Prevent Ophthalmol & Biostat, Dept Ophthalmol, Scheie Eye Inst,Ocular Inflammat Serv, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Ctr Clin Epidemiol & Biostat, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Gangaputra, Sapna; Daniel, Ebenezer; Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.; Jabs, Douglas A.; Helzlsouer, Kathy J.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD USA. [Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Helzlsouer, Kathy J.] St Johns Mercy Med Ctr, Ctr Prevent & Res, Baltimore, MD USA. RP Kempen, JH (reprint author), Univ Penn, Ctr Prevent Ophthalmol & Biostat, Dept Ophthalmol, Scheie Eye Inst,Ocular Inflammat Serv, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Daniel, Ebenezer/0000-0002-2027-2316 FU NEI NIH HHS [EY014943, R01 EY014943, R01 EY014943-05, R56 EY014943] NR 96 TC 49 Z9 50 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD DEC PY 2008 VL 146 IS 6 BP 802 EP 812 DI 10.1016/j.ajo.2008.04.035 PG 11 WC Ophthalmology SC Ophthalmology GA 378UH UT WOS:000261349200003 PM 18579112 ER PT J AU Kacmaz, RO Kempen, JH Newcomb, C Gangaputra, S Daniel, E Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Suhler, EB Thorne, JE Jabs, DA Foster, CS AF Kacmaz, R. Oktay Kempen, John H. Newcomb, Craig Gangaputra, Sapna Daniel, Ebenezer Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Suhler, Eric B. Thorne, Jennifer E. Jabs, Douglas A. Foster, C. Stephen CA Systemic Immunosuppressive Therapy TI Ocular Inflammation in Behcet Disease: Incidence of Ocular Complications and of Loss of Visual Acuity SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID INFLIXIMAB TREATMENT; PROGNOSTIC-FACTORS; RISK; EPIDEMIOLOGY; INVOLVEMENT; UVEITIS; VISION; TRIAL AB PURPOSE: To estimate the risk of structural ocular complications and loss of visual acuity (VA) in cases of Behcet disease (BD) and to evaluate potential risk and protective factors for these events. 0 DESIGN: Retrospective cohort study. METHODS: A total of 168 consecutive patients with 1313,associated ocular inflammation treated at five academic center ocular inflammation subspecialty practices were included. Clinical data for these patients were ascertained by standardized chart review. Main outcome measures included VA, structural ocular complications of inflammation, and intraocular pressure (lop). RESULTS: Over a median follow-up of 1.05 years, the incidence of specific structural complications and IOP disturbances were common: the incidence rate of any ocular complication was 0.45 per eye-year (EY). Rates of loss of VA to 20/50 or worse and to 20/200 or worse were 0.12 per EY and 0.09 per EY, respectively. Risk factors for loss of VA during follow-up were persistent inflammatory activity, presence of posterior synechiae, presence of hypotony, and presence of elevated IOP. In a time-dependent analysis, current activity of ocular in, flammation was associated with an increased risk of loss of VA to 20/50 or worse (relative risk [RR], 2.45; 95% confidence interval [CI], 1.1 to 5.5; P =.03) and to 20/200 or worse (RR, 2.67; 95% CI, 1.2 to 5.8; P= .01). CONCLUSIONS: Loss of VA and occurrence of ocular complications were common in patients with ocular inflammation associated with BD, even with aggressive therapy. Ongoing inflammation during follow-up, presence or occurrence of posterior synechiae, hypotony, and elevated IOP were associated with an increased risk of loss of VA. (Am J Ophthalmol 2008;146:828-836. (C) 2008 by Elsevier Inc. All rights reserved.) C1 [Kacmaz, R. Oktay; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA 02142 USA. [Kempen, John H.; Newcomb, Craig] Univ Penn, Ocular Inflammat Serv, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Ctr Prevent Ophthalmol & Biostat, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig] Univ Penn, Ctr Clin Epidemiol & Biostat, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Gangaputra, Sapna; Daniel, Ebenezer; Rosenbaum, James T.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Foster, CS (reprint author), Massachusetts Eye Res & Surg Inst, 5 Cambridge Ctr,8th Floor, Cambridge, MA 02142 USA. EM sfoster@mersi.us OI Daniel, Ebenezer/0000-0002-2027-2316 FU NATIONAL EYE INSTITUTE, NATIONAL INSTITUTES of Health, Bethesda, Maryland [EY014943]; Paul and Evanina Mackall Foundation, Philadelphia, Pennsylvania; Research to Prevent Blindness Inc (RPB), New York, New York FX THIS STUDY WAS SUPPORTED PRIMARILY BY GRANT EY014943 FROM THE NATIONAL EYE INSTITUTE, NATIONAL INSTITUTES of Health, Bethesda, Maryland (Dr Kempen). Additional support was provided by the Paul and Evanina Mackall Foundation, Philadelphia, Pennsylvania, and Research to Prevent Blindness Inc (RPB), New York, New York. Dr Kempen is a Research to Prevent Blindness James S. Adams Special Scholar Award recipient. Dr Thorne is a Research to Prevent Blindness Harrington Special Scholar Award recipient. Drs Jabs and Rosenbaum are a Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr Levy-Clarke was previously and Dr Nussenblatt continues to be supported by intramural funds of the National Eye Institute. The authors indicate no financial conflict of interest. Involved in conception and design (R.O.K., J.H.K., C.N., S.G., E.D., G.A.L.-C., R.B.N., J.T.R., E.B.S., J.E.T., D.A.J., C.S.F.); analysis and interpretation (R.O.K., J.H.K., C.W.N.); writing the article (R.O.K., J.H.K.); critical review of the article (R.O.K., J.H.K., C.N., S.G., E.D., G.A.L.-C., R.B.N., J.T.R., E.B.S., J.E.T., D.A.J., C.S.F.); final approval of the article (R.O.K., J.H.K., C.N., S.G., E.D., G.A.L.,C., R.B.N., J.T.R., E.B.S., J.E.T., D.A.J., C.S.F.); data collection (R.O.K., J.H.K., S.G., E.D.); provision of resources (R.O.K., J.H.K., C.N., S.G., E.D., G.A.L.-C., R.B.N., J.T.R., E.B.S., J.E.T., D.A.J., C.S.F.); statistical expertise (J.H.K., C.W.N.); obtaining funding (J.H.K.); literature search (R.O.K., J.H.K.); and administrative, technical, or logistic support (R.O.K., J.H.K., C.N., S.G., E.D., G.A.L.-C., R.B.N., J.T.R., E.B.S., J.E.T., D.A.J., C.S.F.). The SITE Cohort Study was conducted with the approval of the following institutional review boards: University of Pennsylvania Office of Regulatory Affairs (PENN); Johns Hopkins School of Medicine Institutional Review Board no. 3 (Wilmer/JHU); New England Institutional Review Board (MERSI); Massachusetts Eye & Ear Infirmary Institutional Review Board (MEEI); Oregon Health & Sciences University Institutional Review Board (Casey/OHSU); Combined Neurosciences (CNS) Institutional Review Board of the Clinical Center (CC), National Eye Institute. The study was conducted in accordance with the precepts of the Declaration of Helsinki. NR 28 TC 43 Z9 44 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD DEC PY 2008 VL 146 IS 6 BP 828 EP 836 DI 10.1016/j.ajo.2008.06.019 PG 9 WC Ophthalmology SC Ophthalmology GA 378UH UT WOS:000261349200006 PM 18708181 ER PT J AU Suhler, EB Lloyd, MJ Choi, D Rosenbaum, JT Austin, DF AF Suhler, Eric B. Lloyd, Michael J. Choi, Dongseok Rosenbaum, James T. Austin, Donald F. TI Incidence and Prevalence of Uveitis in Veterans Affairs Medical Centers of the Pacific Northwest SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID EPIDEMIOLOGY; BLINDNESS; FINLAND AB PURPOSE: To ascertain the frequency of uveitis in Veterans Affairs (VA) patients in the Pacific Northwest and to compare disease rates with those in previously published epidemiologic studies. DESIGN: Cross-sectional, population based-study. METHODS: The medical records of 152,267 patients seen at six VA Medical Centers in Oregon and Washington during fiscal year 2004 were searched for uveitis-related Internation Classification of Diseases 9th edition codes. Cases were reviewed and classified anatomically, by associated systemic disease, and as incident or prevalent. Only definite cases were used for disease rate calculations. RESULTS: This study found a crude incidence of 25.6 cases/100,000 person-years and a crude prevalence of 69 cases/100,000 persons. The most common anatomic location for uveitis was anterior. Approximately half of cases were idiopathic, with human leukocyte antigen, B27-related diseases being the most common identified cause. There was no statistical evidence of increased or decreased incidence with age, although uveitis seemed to be more prevalent in the younger age groups. CONCLUSIONS: Our data are consistent with those of most published population based studies on the epidemiologic features of uveitis, but we detected significantly lower incidence and prevalence than those reported in a recently published study from Kaiser Permanente. The significance of and possible explanations for the differences between our data and that published by the Kaiser group are discussed. (Am J Ophthalmol 2008;146: 890-896. Published by Elsevier Inc.) C1 [Suhler, Eric B.; Lloyd, Michael J.; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97239 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Choi, Dongseok; Austin, Donald F.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA. RP Suhler, EB (reprint author), Oregon Hlth & Sci Univ, Casey Eye Inst, 3375 SW Terwilliger Blvd, Portland, OR 97239 USA. EM suhlere@ohsu.edu FU RESEARCH TO PREVENT BLINDNESS, NEW YORK, NEW YORK FX THIS STUDY WAS SUPPORTED BY A GRANT FROM RESEARCH TO PREVENT BLINDNESS, NEW YORK, NEW YORK (UNRESTRICTED Grant to the Casey Eye Institute, Senior Scholar Award to Dr Rosenbaum); and the Rosenfeld Family Trust, Portland, Oregon (Dr Rosenbaum). The authors indicate no financial conflict of interest. Involved in design of study (E.B.S., M.J.L., J.T.R., D.F.A.); data analysis and interpretation (E.B.S., M.J.L., D.C., J.T.R., D.F.A.); writing and critical revision of the article (E.B.S., M.J.L., J.T.R., D.F.A.); statistical expertise (E.B.S., D.C., D.F.A.); and preparation, review, and approval of the manuscript (E.B.S., M.J.L., D.C., J.T.R., D.F.A.). This Study was approved by the Institutional Review Boards (IRBs) and Research and Development Committees of the Portland Veterans Affairs Medical Center, the Puget Sound Veterans Affairs Medical Center, and the Veterans Integrated Service Network 20 IRB, which has jurisdiction over research studies performed on patients seen at the White City, Oregon, Roseburg, Oregon, Walla Walla, Washington, and Spokane, Washington, VA facilities. All IRBs waived the requirement for informed consent in this noninterventional chart review Study. NR 17 TC 49 Z9 52 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD DEC PY 2008 VL 146 IS 6 BP 890 EP 896 DI 10.1016/j.ajo.2008.09.014 PG 7 WC Ophthalmology SC Ophthalmology GA 378UH UT WOS:000261349200014 PM 19027424 ER PT J AU Pietramaggiori, G Scherer, SS Cervi, D Klelment, G Orgill, DP AF Pietramaggiori, Giorgio Scherer, Saja S. Cervi, David Klelment, Giannoula Orgill, Dennis P. TI Tumors Stimulate Platelet Delivery of Angiogenic Factors in Vivo An Unexpected Benefit SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ENDOTHELIAL-CELLS; CHRONIC WOUNDS; GROWTH-FACTOR; RICH PLASMA; METASTASIS; CANCER; ENDOSTATIN; EXPRESSION; PROTEINS; RELEASE AB The interaction between platelets and the tumor microenvironment results in the modulation of angiogenesis, although the mechanisms governing this regulation remain unclear. This study explores the differences in the communication between wounded tissues and healthy, tumor-conditioned, and frozen platelets. Platelet-rich plasma obtained from healthy (PRP) or tumor-bearing (TPRP) mice was applied to dorsal, full-thickness wounds on diabetic mice. Wound heating was evaluated using macroscopic criteria and a staging system based on angiogenesis and stromal cell proliferation. Proteomic analysis was used to compare the levels of angiogenic proteins contained in the platelet preparations. TPRP-treated wounds reached 90% wound closure 5.6 to 9.5 days earlier than PRP-treated and nontreated wounds, respectively. TPRP induced a fourfold increase in stromal cell proliferation compared with nontreated. wounds, and a 2.5-fold increase compared with PRP-treated wounds. TPRP induced the highest stimulation of angiogenesis with a fourfold increase compared with nontreated. controls. On day 21, wounds treated with TPRP showed a typical architecture with thick collagen bundles. Although the levels of angiogenesis regulators detected via SELDI-ToF were similar between the PRP and TPRP treatment regimens, the enhanced healing capacity of TPRP suggests improved platelet delivery as indicated by frozen TPRP preparations that had lost most of their pro-angiogenic drive. in conclusion, these results show that intact tumor-conditioned platelets display an improved ability to deliver angiogenesis regulators to wounded tissues. (Am J Pathol 2008,173:1609-1616; DOI: 10.2353/ajpath.2008.080474) C1 [Pietramaggiori, Giorgio; Scherer, Saja S.; Orgill, Dennis P.] Brigham & Womens Hosp, Div Plast Surg, Boston, MA 02115 USA. [Pietramaggiori, Giorgio; Scherer, Saja S.; Orgill, Dennis P.] Harvard Univ, Sch Med, Boston, MA USA. [Cervi, David; Klelment, Giannoula] Harvard Univ, Childrens Hosp, Vasc Biol Program, Dept Surg, Boston, MA 02115 USA. [Pietramaggiori, Giorgio] Univ Geneva, Div Plast Surg, CH-1211 Geneva, Switzerland. [Klelment, Giannoula] Harvard Univ, Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA. RP Orgill, DP (reprint author), Brigham & Womens Hosp, Div Plast Surg, 75 Francis St, Boston, MA 02115 USA. EM dorgill@partners.org OI Orgill, Dennis/0000-0002-8279-7310 NR 26 TC 24 Z9 26 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2008 VL 173 IS 6 BP 1609 EP 1616 DI 10.2353/ajpath.2008.080474 PG 8 WC Pathology SC Pathology GA 377LU UT WOS:000261253500003 PM 18988799 ER PT J AU Nigrovic, PA Gray, DHD Jones, T Hallgren, J Kuo, FC Chaletzky, B Gurish, M Mathis, D Benoist, C Lee, DM AF Nigrovic, Peter A. Gray, Daniel H. D. Jones, Tatiana Hallgren, Jenny Kuo, Frank C. Chaletzky, Blair Gurish, Michael Mathis, Diane Benoist, Christophe Lee, David M. TI Genetic Inversion in Mast Cell-Deficient W(sh) Mice Interrupts Corin and Manifests as Hematopoietic and Cardiac Aberrancy SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID C-KIT EXPRESSION; TYROSINE KINASE; TRICHINELLA-SPIRALIS; NATRIURETIC-PEPTIDE; MEDIATED ARTHRITIS; TRYPTASE MMCP-6; TEC KINASE; TISSUE; LOCUS; MELANOGENESIS AB Mast cells participate in pathophysiological processes that range from antimicrobial defense to anaphylaxis and inflammatory arthritis. Much of the groundwork for the understanding of mast cells was established in mice that lacked mast cells through defects in either stem cell factor or its receptor, Kit. Among available strains, C57BL/6-Kit(W-sh) (W(sh)) mice are experimentally advantageous because of their background strain and fertility. However, the genetic inversion responsible for the W(sh) phenotype remains poorly defined, and its effects beyond the mast cell have been incompletely characterized. We report that W(sh) animals exhibit splenomegaly with expanded myeloid and megakaryocyte populations. Hematopoietic abnormalities extend to the bone marrow and are reflected by neutrophilia and thrombocytosis. in contrast, mast cell-deficient WBB6F1-Kit(W)/Kit(W-v) (W/W(v)) mice display mild neutropenia, but no changes in circulating platelet numbers. To help define the basis for the W(sh) phenotype, a "DNA walking" strategy was used to identify the precise location of the 3' breakpoint, which was found to reside 67.5 kb upstream of Kit. The 5' breakpoint disrupts corin, a cardiac protease responsible for the activation of atrial natriuretic peptide. Consistent with this result, transcription of full-length corin is ablated and W(sh) mice develop symptoms of cardiomegaly. Studies performed using mast cell-deficient strains must consider the capacity of associated abnormalities to either expose or compensate for the missing mast cell lineage. (Am J Pathol 2008, 173:1693-1701; DOI: 10.2353/ajpath.2008.080407) C1 [Nigrovic, Peter A.; Jones, Tatiana; Hallgren, Jenny; Chaletzky, Blair; Gurish, Michael; Mathis, Diane; Benoist, Christophe; Lee, David M.] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Nigrovic, Peter A.] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Gray, Daniel H. D.; Mathis, Diane; Benoist, Christophe] Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02215 USA. [Kuo, Frank C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Lee, DM (reprint author), Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, 1 Jimmy Fund Way,Smith 552B, Boston, MA 02115 USA. EM dlee@rics.bwh.harvard.edu RI Gray, Daniel/A-3293-2013; OI Gray, Daniel/0000-0002-8457-8242; Hallgren Martinsson, Jenny/0000-0002-3685-5364 FU Juvenile Diabetes Research Foundation [P01 AI065858-02]; Australian National Health and Medical Research Council; Cogan Family Foundation; [K08-AR051321]; [R01-AI059745] FX Supported by K08-AR051321 (P.A.N.); Australian National Health and Medical Research Council CJ Martin Overseas Biomedical Fellowship (D.H.D.G); Juvenile Diabetes Research Foundation, P01 AI065858-02, Young Chair funds (D.M.,.C.B.); and R01-AI059745, P01 AI065858-02, and the Cogan Family Foundation (D.M.L.). NR 41 TC 116 Z9 116 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2008 VL 173 IS 6 BP 1693 EP 1701 DI 10.2353/ajpath.2008.080407 PG 9 WC Pathology SC Pathology GA 377LU UT WOS:000261253500011 PM 18988802 ER PT J AU Farassati, F Pan, WH Yamoutpour, F Henke, S Piedra, M Frahm, S Al-Tawil, S Mangrum, WI Parada, LF Rabkin, SD Martuza, RL Kurtz, A AF Farassati, Faris Pan, Weihong Yamoutpour, Farnaz Henke, Susann Piedra, Mark Frahm, Silke Al-Tawil, Said Mangrum, Wells I. Parada, Luis F. Rabkin, Samuel D. Martuza, Robert L. Kurtz, Andreas TI Ras Signaling Influences Permissiveness of Malignant Peripheral Nerve Sheath Tumor Cells to Oncolytic Herpes SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; PROSTATE-CANCER CELLS; HUMAN BREAST-CANCER; SIMPLEX-VIRUS TYPE-1; PHASE-I TRIAL; NEUROFIBROMATOSIS TYPE-1; REOVIRUS ONCOLYSIS; NONHUMAN-PRIMATES; SAFETY EVALUATION; NF1 GENE AB Lack of expression of neurofibromin in neurofibromatosis I and its lethal derivative, malignant peripheral nerve sheath tumors (MPNSTs), is thought to result in the overactivation of the Ras signaling pathway. Our previous studies have shown that cells with overactivation in the Ras pathway are more permissive to infection with herpes simplex virus 1 and its mutant version R3616. in this study, we show that among five different mouse MPNST cell fines, only the ones with elevated levels of Ras signaling are highly permissive to infection with oncolytic herpes G207. Specific inhibitors of the Ras, ERK, and JNK pathways all reduced the synthesis of viral proteins in MPNST cells. The cell lines that contained lower levels of Ras and decreased activation of downstream signaling components underwent an enhancement in apoptosis upon exposure to G207. Additionally, mouse SW10 Schwann cells were able to become infected by parental herpes but were found to be resistant to G207. The immortalization of these cell lines with the expression of SV40 large T antigen increased the levels of Ras activation and permissiveness to oncolytic herpes. A Ras/Raf kinase inhibitor reduced the synthesis of both herpes simplex virus-1 and G207 proteins in SW10 cells. The results of this study, therefore, introduce Ras signaling as a divergent turning point for the response of MPNST cells to an assault by oncolytic herpes. (Am J Pathol 2008, 173:1861-1872; DOI: 10.2353/ajpath.2008.080376) C1 [Farassati, Faris; Pan, Weihong; Yamoutpour, Farnaz; Al-Tawil, Said] Univ Minnesota, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Henke, Susann; Frahm, Silke; Rabkin, Samuel D.; Martuza, Robert L.; Kurtz, Andreas] Massachusetts Gen Hosp, Dept Neurosurg, Mol Neurosurg Lab, Charlestown, MA USA. [Piedra, Mark; Mangrum, Wells I.] Mayo Clin Rochester, Rochester, MN USA. [Parada, Luis F.] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA. RP Farassati, F (reprint author), Univ Kansas, Sch Med, Div Hematol Oncol & Transplantat, Dept Med, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM ffarassati@kumc.edu RI rabkin, samuel/C-2443-2012; Parada, luis/B-9400-2014 OI rabkin, samuel/0000-0003-2344-2795; FU National Institutes of Health [R01-NS032677]; Department of Defense [NF050014] FX Supported by the National Institutes of Health (R01-NS032677 to R.L.M.) and the Department of Defense (NF050014 to F.F.). NR 75 TC 22 Z9 22 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2008 VL 173 IS 6 BP 1861 EP 1872 DI 10.2353/ajpath.2008.080376 PG 12 WC Pathology SC Pathology GA 377LU UT WOS:000261253500026 PM 18988803 ER PT J AU Cooper, RA Tolerico, M Kaminski, BA Spaeth, D Ding, D Cooper, R AF Cooper, Rory A. Tolerico, Michelle Kaminski, Beth Ann Spaeth, Donald Ding, Dan Cooper, Rosemarie TI Quantifying Wheelchair Activity of Children A Pilot Study SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Child; Wheelchairs; Rehabilitation; Activity ID PHYSICAL-ACTIVITY; POWERED MOBILITY; ACTIVITY MONITOR; ENERGY-COST; USERS; MYELOMENINGOCELE; PROPULSION; BEHAVIORS; VALIDITY; STRAIN AB Objective: The purpose of this study was to investigate mobility-related wheelchair activity of children in their community setting. Design: Mobility-related wheelchair activity data from 18 community-dwelling children (9 manual and 9 electric powered) were collected using custom-designed data logging devices. The children were between 8 and 17 yrs of age and independently used a wheelchair as their primary means of mobility. A data logging device was installed on their wheelchair for 7 days. However, because the device was attached and removed at different times of the day, the first and last days of the study period were not analyzed. Therefore, a total of 5 days of data were used to investigate wheelchair activity. Results: Overall, the children who used manual wheelchairs traveled on an average of 1602.31 m/day (SD, 976.78) at a speed of 0.67 m/sec (SID, 0.12), and the children who used electric-powered wheelchairs drove 1752.42 m/day (SD, 835.14) at a speed of 0.75 m/sec (SID, 0.35). It was also calculated that the average daily number of starts/stops per thousand meters the manual and electric-powered wheelchair users completed were 166.77 (SD, 64.32) and 112.53 (SD, 62.27), respectively. A comparison of mobility-related wheelchair activity revealed a significant (P = 0.008) difference in the average daily distance traveled between genders, with the boys traveling further than the girls. Conclusions: The mobility data obtained from the children wheelchair users suggest that one possible factor of variability among wheelchair activity is between genders. The data collected provide us with direction for future research in this area. C1 [Cooper, Rory A.; Tolerico, Michelle; Spaeth, Donald; Ding, Dan; Cooper, Rosemarie] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA 15206 USA. [Cooper, Rory A.; Spaeth, Donald; Cooper, Rosemarie] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Cooper, Rory A.; Tolerico, Michelle] Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Cooper, Rory A.] Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA USA. [Kaminski, Beth Ann] Childrens Inst, Pittsburgh, PA USA. RP Cooper, RA (reprint author), VA Pittsburgh Healthcare Syst, Human Engn Res Labs, 7180 Highland Dr,Bldg 4,2nd Floor E,151R1 H, Pittsburgh, PA 15206 USA. RI Schmoelz, Camilie/D-1707-2012 OI Schmoelz, Camilie/0000-0003-2221-9954 FU U.S. Department of Education; National Institute for Disability and Rehabilitation Research (NIDRR); Rehabilitation Service Administration [H129E990004]; Spinal Cord Injury Model System Center [H133N000019] FX Part of the material presented in this manuscript was published as an abstract in the Proceedings of the 28th Annual RESNA Conference, 2005. The material is based upon work supported by the U.S. Department of Education, National Institute for Disability and Rehabilitation Research (NIDRR), Rehabilitation Service Administration Training Grant (H129E990004) and NIDRR, Spinal Cord Injury Model System Center (H133N000019). NR 20 TC 13 Z9 13 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD DEC PY 2008 VL 87 IS 12 BP 977 EP 983 DI 10.1097/PHM.0b013e31818dfe74 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 376QR UT WOS:000261198600002 PM 19033759 ER PT J AU Dicianno, BE Kurowski, BG Yang, JMJ Chancellor, MB Bejjani, GK Fairman, AD Lewis, N Sotirake, J AF Dicianno, Brad E. Kurowski, Brad G. Yang, Jennifer Marie J. Chancellor, Michael B. Bejjani, Ghassan K. Fairman, Andrea D. Lewis, Nancy Sotirake, Jennifer TI Rehabilitation and Medical Management of the Adult with Spina Bifida SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Review DE Adult; Myelomeningocele; Hydrocephalus; Rehabilitation; Review; Tethered Cord Syndrome; Transitional Care ID TETHERED CORD SYNDROME; QUALITY-OF-LIFE; CLEAN INTERMITTENT CATHETERIZATION; NEUROGENIC BLADDER DYSFUNCTION; ANTEGRADE CONTINENCE ENEMA; EVERYDAY PHYSICAL-ACTIVITY; BEARING UPPER EXTREMITY; DEEP VENOUS THROMBOSIS; BONE-MINERAL DENSITY; LONG-TERM OUTCOMES AB As the life expectancy of individuals with spina bifida increases, a lifelong need for management of many health issues in a rehabilitation setting has emerged in recent years. Physiatrists, in consultation with a variety of adult specialists, are particularly well suited to manage the common musculoskeletal, skin, bowel, bladder, renal, neurological, and other issues that arise in the adult population. This article reviews the last 20 yrs of literature pertinent to the rehabilitative care of this population, summarizes current evidence-based practice, and identifies key areas in which scientific evidence is lacking and future research is needed. C1 [Dicianno, Brad E.; Yang, Jennifer Marie J.] VA Pittsburgh Healthcare Syst, Human Engn Res Labs, Pittsburgh, PA 15206 USA. [Dicianno, Brad E.; Lewis, Nancy; Sotirake, Jennifer] Univ Pittsburgh, Med Ctr, Adult Outpatient Spina Bifida Clin, Pittsburgh, PA USA. [Dicianno, Brad E.; Kurowski, Brad G.; Yang, Jennifer Marie J.; Lewis, Nancy] Univ Pittsburgh, Med Ctr, Dept Phys Med & Rehabil, Pittsburgh, PA USA. [Chancellor, Michael B.] William Beaumont Hosp, Dept Urol, Royal Oak, MI 48072 USA. [Bejjani, Ghassan K.] UPMC Presybterian Shadyside, Dept Neurosurg, Pittsburgh, PA USA. [Fairman, Andrea D.] Spina Bifida Assoc Western PA, Pittsburgh, PA USA. [Dicianno, Brad E.; Fairman, Andrea D.] Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA USA. [Sotirake, Jennifer] UPMC, Dept Nutr, Pittsburgh, PA USA. RP Dicianno, BE (reprint author), VA Pittsburgh Healthcare Syst, Human Engn Res Labs, 7180 Highland Dr,Bldg 4,2nd Floor E,151R1-H, Pittsburgh, PA 15206 USA. OI Dicianno, Brad/0000-0003-0738-0192 NR 360 TC 17 Z9 17 U1 5 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 EI 1537-7385 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD DEC PY 2008 VL 87 IS 12 BP 1026 EP 1050 DI 10.1097/PHM.0b013e31818de070 PG 25 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 376QR UT WOS:000261198600009 PM 18923330 ER PT J AU Nunes, P Hasler, U McKee, M Lu, HAJ Bouley, R Brown, D AF Nunes, Paula Hasler, Udo McKee, Mary Lu, Hua A. J. Bouley, Richard Brown, Dennis TI A fluorimetry-based ssYFP secretion assay to monitor vasopressin-induced exocytosis in LLC-PK1 cells expressing aquaporin-2 SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE recycling; antidiuretic hormone; phosphorylation; epithelial cells; kidney ID RENAL COLLECTING DUCT; GREEN FLUORESCENT PROTEIN; EPITHELIAL-CELLS; PRINCIPAL CELLS; PLASMA-MEMBRANE; WATER CHANNEL; AQP2 PHOSPHORYLATION; LIVING CELLS; CYCLIC-AMP; TRAFFICKING AB Nunes P, Hasler U, McKee M, Lu H, Bouley R, Brown D. A fluorimetry-based ssYFP secretion assay to monitor vasopressin-induced exocytosis in LLC-PK1 cells expressing aquaporin-2. Am J Physiol Cell Physiol 295: C1476-C1487, 2008. First published September 17, 2008; doi:10.1152/ajpcell.00344.2008.-Vasopressin (VP)-induced exocytosis was dissected in native and aquaporin-2 (AQP2)-expressing renal LLC-PK1 cells by a fluorimetric exocytosis assay based on soluble secreted yellow fluorescent protein (ssYFP). YFP was targeted to the secretory pathway by addition of an 18-amino acid signal peptide from hen egg white lysozyme. Immunofluorescence labeling, together with analysis of Alexa 555-dextran internalization, revealed that ssYFP is exclusively located in the secretory pathway. Immunofluorescence and immunogold electron microscopy showed significant colocalization of ssYFP and AQP2. Fluorimetry and Western blot analysis demonstrated similar constitutive ssYFP secretion in native LLC-PK1 and AQP2-expressing cells. In AQP2-expressing cells, a twofold increase in ssYFP secretion was observed within 15 min of VP stimulation. This transient burst of ssYFP secretion was abolished by the PKA inhibitor H-89 and was not observed in native cells. The endocytotic inhibitor methyl-beta-cyclodextrin, which also promotes membrane accumulation of AQP2, had no effect on ssYFP secretion. Although cells expressing phosphorylation-deficient AQP2-S256A showed significantly lower baseline levels of constitutive secretion, VP induced a significant increase in exocytosis. Our data indicate that 1) this assay can monitor exocytosis in cultured epithelial cells, 2) VP has an acute stimulatory effect on ssYFP secretion in AQP2-expressing, but not native, cells, and 3) phosphorylation of AQP2 at S256 may be involved in the regulation of constitutive AQP2 exocytosis and play only a minor role in the VP-induced burst. These results support the idea that, in addition to its role in reducing AQP2 endocytosis, VP increases AQP2 exocytosis. C1 [Nunes, Paula] Massachusetts Gen Hosp, Div Nephrol, Program Membrane Biol, MGH Ctr Syst Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Nunes, P (reprint author), Massachusetts Gen Hosp, Div Nephrol, Program Membrane Biol, MGH Ctr Syst Biol, Simches Res Bldg,185 Cambridge St,CPZN 8150, Boston, MA 02114 USA. EM pnunes@fas.harvard.edu RI Nunes-Hasler, Paula/N-4337-2015 OI Nunes-Hasler, Paula/0000-0002-4598-685X FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK-38452, K08 DK-075940-01]; National Sciences and Engineering Research Council; Swiss FSBMB Fellowship; Massachusetts General Hospital; National Kidney Foundation Young Investigator Award; Boston Area Diabetes and Endocrinology Research Center [DK-57521]; Center for the Study of Inflammatory Bowel Disease [DK-43341] FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant DK-38452. P. Nunes is supported by a doctoral-level postgraduate scholarship from the National Sciences and Engineering Research Council, U. Hasler by a Swiss FSBMB Fellowship, as well as an ECOR Fellowship awarded by Massachusetts General Hospital, R. Bouley by a National Kidney Foundation Young Investigator Award, and H. A. J. Lu by NIDDK Grant K08 DK-075940-01. The microscopy core facility of the Massachusetts General Hospital Program in Membrane Biology receives additional support from the Boston Area Diabetes and Endocrinology Research Center (NIDDK Grant DK-57521) and the Center for the Study of Inflammatory Bowel Disease (NIDDK Grant DK-43341). NR 62 TC 21 Z9 22 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD DEC PY 2008 VL 295 IS 6 BP C1476 EP C1487 DI 10.1152/ajpcell.00344.2008 PG 12 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 401AH UT WOS:000262910000003 PM 18799651 ER PT J AU Yuan, JZ Lugea, A Zheng, L Gukovsky, I Edderkaoui, M Rozengurt, E Pandol, SJ AF Yuan, Jingzhen Lugea, Aurelia Zheng, Ling Gukovsky, Ilya Edderkaoui, Mouad Rozengurt, Enrique Pandol, Stephen J. TI Protein kinase D1 mediates NF-kappa B activation induced by cholecystokinin and cholinergic signaling in pancreatic acinar cells SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE PKC delta; PKC epsilon; pancreatitis; carbachol; cerulein ID COLONIC EPITHELIAL-CELLS; D-DEPENDENT ACTIVATION; C-DELTA; INTERLEUKIN-8 EXPRESSION; LYSOPHOSPHATIDIC ACID; INFLAMMATORY RESPONSE; LOOP PHOSPHORYLATION; CATALYTIC ACTIVATION; TRANSDUCTION PATHWAY; OXIDATIVE STRESS AB The transcription factor NF-kappa B plays a critical role in inflammatory and cell death responses during acute pancreatitis. Previous studies in our laboratory demonstrated that protein kinase C (PKC) isoforms PKC delta and epsilon are key regulators of NF-kappa B activation induced by cholecystokinin-8 (CCK-8), tumor necrosis factor-alpha, and ethanol. However, the downstream participants in regulating NF-kappa B activation in exocrine pancreas remain poorly understood. Here, we demonstrate that protein kinase D1 (PKD1) is a key downstream target of PKC delta and PKC epsilon in pancreatic acinar cells stimulated by two major secretagogues, CCK-8 and the cholinergic agonist carbachol (CCh), and that PKD1 is necessary for NF-kappa B activation induced by CCK-8 and CCh. Both CCK-8 and CCh dose dependently induced a rapid and striking activation of PKD1 in rat pancreatic acinar cells, as measured by in vitro kinase assay and by phosphorylation at PKD1 activation loop (Ser744/748) or autophosphorylation site (Ser916). The phosphorylation and activation of PKD1 correlated with NF-kappa B activity stimulated by CCK-8 or CCh, as measured by NF-kappa B DNA binding. Either inhibition of PKC delta or epsilon by isoform-specific inhibitory peptides, genetic deletion of PKC delta and epsilon in pancreatic acinar cells, or knockdown of PKD1 by using small interfering RNAs in AR42J cells resulted in a marked decrease in PKD1 and NF-kappa B activation stimulated by CCK-8 or CCh. Conversely, overexpression of PKD1 resulted in augmentation of CCK-8 and CCh-stimulated NF-kappa B activation. Finally, the kinetics of PKD1 and NF-kappa B activation during cerulein-induced rat pancreatitis showed that both PKD1 and NF-kappa B activation were early events during acute pancreatitis and that their time courses of response were similar. Our results identify PKD1 as a novel early convergent point for PKC delta and epsilon in the signaling pathways mediating NF-kappa B activation in pancreatitis. C1 [Yuan, Jingzhen] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, W Los Angeles VA Healthcare Ctr, Los Angeles, CA 90073 USA. [Yuan, Jingzhen; Lugea, Aurelia; Gukovsky, Ilya; Pandol, Stephen J.] Univ Calif Los Angeles, USC, Res Ctr Alcohol Liver & Pancreat Dis, Los Angeles, CA 90024 USA. [Yuan, Jingzhen; Lugea, Aurelia; Gukovsky, Ilya; Edderkaoui, Mouad; Rozengurt, Enrique; Pandol, Stephen J.] Univ Calif Los Angeles, CURE Digest Dis Res Ctr, Los Angeles, CA 90024 USA. RP Yuan, JZ (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, W Los Angeles VA Healthcare Ctr, Bldg 258,Rm 340,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jzyuan@ucla.edu FU Department of Veterans Affairs Merit; National Institute on Alcohol Abuse and Alcoholism [P50-A11999]; National Institute of Diabetes and Digestive and Kidney Diseases [DK-55003] FX This study was supported by the Department of Veterans Affairs Merit Grant and National Institute on Alcohol Abuse and Alcoholism Grant P50-A11999 (to USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases). E. Rozengurt is supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-55003. NR 59 TC 24 Z9 25 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD DEC PY 2008 VL 295 IS 6 BP G1190 EP G1201 DI 10.1152/ajpgi.90452.2008 PG 12 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 379GP UT WOS:000261385000006 PM 18845574 ER PT J AU Raher, MJ Thibault, HB Buys, ES Kuruppu, D Shimizu, N Brownell, AL Blake, SL Rieusset, J Kaneki, M Derumeaux, G Picard, MH Bloch, KD Scherrer-Crosbie, M AF Raher, Michael J. Thibault, Helene B. Buys, Emmanuel S. Kuruppu, Darshini Shimizu, Nobuyuki Brownell, Anna-Liisa Blake, Sarah L. Rieusset, Jennifer Kaneki, Masao Derumeaux, Genevieve Picard, Michael H. Bloch, Kenneth D. Scherrer-Crosbie, Marielle TI A short duration of high-fat diet induces insulin resistance and predisposes to adverse left ventricular remodeling after pressure overload SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE heart failure; myocardial perfusion ID SKELETAL-MUSCLE; HEART-FAILURE; ESSENTIAL-HYPERTENSION; CARDIAC-HYPERTROPHY; GLUCOSE-METABOLISM; MICE; DYSFUNCTION; MORTALITY; CARDIOMYOPATHY; DECARBOXYLASE AB A short duration of high-fat diet induces insulin resistance and predisposes to adverse left ventricular remodeling after pressure overload. Am J Physiol Heart Circ Physiol 295: H2495-H2502, 2008. First published October 31, 2008; doi:10.1152/ajpheart.00139.2008.-Insulin resistance is an increasingly prevalent condition in humans that frequently clusters with disorders characterized by left ventricular (LV) pressure overload, such as systemic hypertension. To investigate the impact of insulin resistance on LV remodeling and functional response to pressure overload, C57BL6 male mice were fed a high-fat (HFD) or a standard diet (SD) for 9 days and then underwent transverse aortic constriction (TAC). LV size and function were assessed in SD- and HFD-fed mice using serial echocardiography before and 7, 21, and 28 days after TAC. Serial echocardiography was also performed on nonoperated SD- and HFD-fed mice over a period of 6 wk. LV perfusion was assessed before and 7 and 28 days after TAC. Nine days of HFD induced systemic and myocardial insulin resistance (assessed by myocardial (18)F-fluorodeoxyglucose uptake), and myocardial perfusion response to acetylcholine was impaired. High-fat feeding for 28 days did not change LV size and function in nonbanded mice; however, TAC induced greater hypertrophy, more marked LV systolic and diastolic dysfunction, and decreased survival in HFD-fed compared with SD- fed mice. Compared with SD-fed mice, myocardial perfusion reserve was decreased 7 days after TAC, and capillary density was decreased 28 days after TAC in HFD-fed mice. A short duration of HFD induces insulin resistance in mice. These metabolic changes are accompanied by increased LV remodeling and dysfunction after TAC, highlighting the impact of insulin resistance in the development of pressure-overload-induced heart failure. C1 [Thibault, Helene B.; Picard, Michael H.; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Div Cardiol, Dept Med, Boston, MA 02114 USA. [Raher, Michael J.; Thibault, Helene B.; Buys, Emmanuel S.; Blake, Sarah L.; Bloch, Kenneth D.; Scherrer-Crosbie, Marielle] Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Kuruppu, Darshini; Brownell, Anna-Liisa] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kuruppu, Darshini; Shimizu, Nobuyuki; Brownell, Anna-Liisa; Kaneki, Masao] Harvard Univ, Sch Med, Boston, MA USA. [Shimizu, Nobuyuki; Kaneki, Masao] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Shimizu, Nobuyuki; Kaneki, Masao] Shriners Hosp Children, Boston, MA USA. [Rieusset, Jennifer] Inst Natl Sante & Rech Med, IFR62, U870, Oullins, France. [Derumeaux, Genevieve] Univ Lyon 1, Inst Natl Sante & Rech Med E 0226, F-69365 Lyon, France. 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 OI Picard, Michael/0000-0002-9264-3243 FU Harvard Clinical Nutrition Research Center; Federation Francaise de Cardiologie; National Institutes of Health (NIH) [DK 58127, R01 HL70896]; Shriners Hospitals Philanthropy FX The present study was supported by a grant of the Harvard Clinical Nutrition Research Center (M. Scherrer-Crosbie), a grant of the Federation Francaise de Cardiologie (H. B. Thibault), National Institutes of Health (NIH) Grant DK 58127 (M. Kaneki), Shriners Hospitals Philanthropy (M. Kaneki), and NIH Grant R01 HL70896 (K. D. Bloch). NR 28 TC 35 Z9 35 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2008 VL 295 IS 6 BP H2495 EP H2502 DI 10.1152/ajpheart.00139.2008 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 379MH UT WOS:000261399900033 PM 18978196 ER PT J AU Wang, XW Chai, H Wang, ZH Lin, PH Yao, QZ Chen, CY AF Wang, Xinwen Chai, Hong Wang, Zehao Lin, Peter H. Yao, Qizhi Chen, Changyi TI Serum amyloid A induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE endothelial nitric oxide synthase; reactive oxygen species; antioxidant; mitogen-activated protein kinase; nuclear factor-kappa B ID C-REACTIVE PROTEIN; NITRIC-OXIDE SYNTHASE; NF-KAPPA-B; ACUTE-PHASE; GENE-EXPRESSION; POSTTRANSCRIPTIONAL REGULATION; CARDIOVASCULAR-DISEASE; HUMAN NEUTROPHILS; OXIDATIVE STRESS; HEART-DISEASE AB Wang X, Chai H, Wang Z, Lin PH, Yao Q, Chen C. Serum amyloid A induces endothelial dysfunction in porcine coronary arteries and human coronary artery endothelial cells. Am J Physiol Heart Circ Physiol 295: H2399-H2408, 2008. First published October 17, 2008; doi: 10.1152/ajpheart. 00238.2008.-The objective of this study was to determine the effects and mechanisms of serum amyloid A (SAA) on coronary endothelial function. Porcine coronary arteries and human coronary arterial endothelial cells (HCAECs) were treated with SAA (0, 1, 10, or 25 mu g/ml). Vasomotor reactivity was studied using a myograph tension system. SAA significantly reduced endothelium-dependent vasorelaxation of porcine coronary arteries in response to bradykinin in a concentration-dependent manner. SAA significantly decreased endothelial nitric oxide (NO) synthase (eNOS) mRNA and protein levels as well as NO bioavailability, whereas it increased ROS in both artery rings and HCAECs. In addition, the activities of internal antioxidant enzymes catalase and SOD were decreased in SAA-treated HCAECs. Bio-plex immunoassay analysis showed the activation of JNK, ERK2, and I kappa B-alpha after SAA treatment. Consequently, the antioxidants seleno-L-methionine and Mn(III) tetrakis( 4-benzoic acid) porphyrin and specific inhibitors for JNK and ERK1/2 effectively blocked the SAA-induced eNOS mRNA decrease and SAA-induced decrease in endothelium-dependent vasorelaxation in porcine coronary arteries. Thus, SAA at clinically relevant concentrations causes endothelial dysfunction in both porcine coronary arteries and HCAECs through molecular mechanisms involving eNOS downregulation, oxidative stress, and activation of JNK and ERK1/2 as well as NF-kappa B. These findings suggest that SAA may contribute to the progress of coronary artery disease. C1 [Chen, Changyi] Baylor Coll Med, Michael E DeBakey Dept Surg, Div Vasc Surg & Endovasc Therapy, Houston, TX 77030 USA. Baylor Coll Med, Mol Surgeon Res Ctr, Houston, TX 77030 USA. Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. RP Chen, CY (reprint author), Baylor Coll Med, Michael E DeBakey Dept Surg, Div Vasc Surg & Endovasc Therapy, 1 Baylor Pl,Mail Stop BCM390, Houston, TX 77030 USA. EM jchen@bcm.tmc.edu RI Chai, Hong/H-5438-2011 FU National Institutes of Health Research [HL-076345, DE-15543, AT-003094, EB-002436, HL-083471]; Michael E. DeBakey Department of Surgery; Baylor College of Medicine; Michael E. DeBakey Veterans Affairs Medical Center FX This work was partially supported by National Institutes of Health Research Grants HL-076345 (to P. H. Lin), DE-15543 (to Q. Yao), AT-003094 (to Q. Yao), EB-002436 (to C. Chen), and HL-083471 (to C. Chen) as well as by the Michael E. DeBakey Department of Surgery, Baylor College of Medicine, and Michael E. DeBakey Veterans Affairs Medical Center (Houston, TX). NR 55 TC 28 Z9 31 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2008 VL 295 IS 6 BP H2399 EP H2408 DI 10.1152/ajpheart.00238.2008 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 379MH UT WOS:000261399900023 PM 18931033 ER PT J AU John, J Ramanathan, L Siegel, JM AF John, Joshi Ramanathan, Lalini Siegel, Jerome M. TI Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE rapid eye movement sleep; histamine; microdialysis; biosensor; cortex ID HISTAMINERGIC TUBEROMAMMILLARY NEURONS; IN-VIVO MICRODIALYSIS; CEREBRAL-CORTEX; OREXIN-A; HYPOCRETIN NEURONS; LOCUS-COERULEUS; GABA RELEASE; MOUSE-BRAIN; CELL GROUPS; REM-SLEEP AB John J, Ramanathan L, Siegel JM. Rapid changes in glutamate levels in the posterior hypothalamus across sleep-wake states in freely behaving rats. Am J Physiol Regul Integr Comp Physiol 295: R2041-R2049, 2008. First published September 24, 2008; doi:10.1152/ajpregu.90541.2008. The histamine-containing posterior hypothalamic region (PH-TMN) plays a key role in sleep-wake regulation. We investigated rapid changes in glutamate release in the PH-TMN across the sleep-wake cycle with a glutamate biosensor that allows the measurement of glutamate levels at 1- to 4-s resolution. In the PH-TMN, glutamate levels increased in active waking (AW) and rapid eye movement (REM) sleep compared with quiet waking and nonrapid eye movement (NREM) sleep. There was a rapid (0.6 +/- 1.8 s) and progressive increase in glutamate levels at REM sleep onset. A reduction in glutamate levels consistently preceded the offset of REM sleep by 8 +/- 3 s. Short-duration sleep deprivation resulted in a progressive increase in glutamate levels in the PH-TMN, perifornical-lateral hypothalamus (PF-LH), and cortex. We found that in the PF-LH, glutamate levels took a longer time to return to basal values compared with the time it took for glutamate levels to increase to peak values during AW onset. This is in contrast to other regions we studied in which the return to baseline values after AW was quicker than their rise with waking onset. In summary, we demonstrated an increase in glutamate levels in the PH-TMN with REM/AW onset and a drop in glutamate levels before the offset of REM. High temporal resolution measurement of glutamate levels reveals dynamic changes in release linked to the initiation and termination of REM sleep. C1 Vet Affairs Greater Los Angeles Hlth Care Syst, North Hills, CA USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. RP Siegel, JM (reprint author), Univ Calif Los Angeles, Neurobiol Res 151A3,16111 Plummer St,Sepulveda VA, North Hills, CA 91343 USA. EM JSiegel@UCLA.edu FU Medical Research Services of Department of Veterans Affairs [HL-41370, MH-64109] FX Funding for this study was provided by Grants HL-41370 and MH-64109 and by the Medical Research Services of Department of Veterans Affairs. NR 51 TC 24 Z9 24 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD DEC PY 2008 VL 295 IS 6 BP R2041 EP R2049 DI 10.1152/ajpregu.90541.2008 PG 9 WC Physiology SC Physiology GA 381TV UT WOS:000261559700038 PM 18815208 ER PT J AU Comper, WD Hilliard, LM Nikolic-Paterson, DJ Russo, LM AF Comper, Wayne D. Hilliard, Lucinda M. Nikolic-Paterson, David J. Russo, Leileata M. TI Disease-dependent mechanisms of albuminuria SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Review DE proximal tubular cell; albumin retrieval; albumin degradation ID GLOMERULAR CAPILLARY WALL; STREPTOZOTOCIN-DIABETIC RATS; OPOSSUM KIDNEY-CELLS; SPONTANEOUSLY HYPERTENSIVE-RATS; NEGATIVELY CHARGED FICOLL; PROXIMAL TUBULE CELLS; SIZE-SELECTIVITY; HEPARAN-SULFATE; BASEMENT-MEMBRANE; DEXTRAN SULFATE AB The mechanism of albuminuria is perhaps one of the most complex yet important questions in renal physiology today. Recent studies have directly demonstrated that the normal glomerulus filters substantial amounts of albumin and that charge selectivity plays little or no role in preventing this process. This filtered albumin is then processed by proximal tubular cells by two distinct pathways; dysfunction in either one of these pathways gives rise to discrete forms of albuminuria. Most of the filtered albumin is returned to the peritubular blood supply by a retrieval pathway. Albuminuria in the nephrotic range would arise from retrieval pathway dysfunction. The small quantities of filtered albumin that are not retrieved undergo obligatory lysosomal degradation before urinary excretion as small peptide fragments. This degradation pathway is sensitive to metabolic factors responsible for hypertrophy and fibrosis, particularly molecules such as angiotensin II and transforming growth factor-beta 1, whose production is stimulated by hyperglycemic and hypertensive environments. Dysfunction in this degradation pathway leads to albuminuria below the nephrotic range. These new insights into albumin filtration and processing argue for a reassessment of the role of podocytes and the slit diaphragm as major direct determinants governing albuminuria, provide information on how glomerular morphology and "tubular" albuminuria may be interrelated, and offer a new rationale for drug development. C1 [Comper, Wayne D.; Hilliard, Lucinda M.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia. [Comper, Wayne D.] CVK Res, New York, NY USA. [Nikolic-Paterson, David J.] Monash Med Ctr, Dept Nephrol, Clayton, Vic 3168, Australia. [Nikolic-Paterson, David J.] Monash Univ, Monash Med Ctr, Dept Med, Clayton, Vic, Australia. [Russo, Leileata M.] Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. [Russo, Leileata M.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Russo, Leileata M.] Harvard Univ, Sch Med, Boston, MA USA. RP Comper, WD (reprint author), Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia. EM wcomper@hotmail.com FU CVK Research; Juvenile Diabetes Research Foundation Transition Award FX This work was supported by CVK Research. L. M. Russo is the recipient of a Juvenile Diabetes Research Foundation Transition Award. NR 130 TC 80 Z9 83 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 2008 VL 295 IS 6 BP F1589 EP F1600 DI 10.1152/ajprenal.00142.2008 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 379GQ UT WOS:000261385100001 PM 18579704 ER PT J AU Lee, DBN Jamgotchian, N Allen, SG Abeles, MB Ward, HJ AF Lee, David B. N. Jamgotchian, Nora Allen, Suni G. Abeles, Michael B. Ward, Harry J. TI A lipid-protein hybrid model for tight junction SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Review DE lipid rafts; lipid leaflets; claudins; hemifusion ID TRANSEPITHELIAL ELECTRICAL-RESISTANCE; MEMBRANE MICRODOMAIN LOCALIZATION; CLOSTRIDIUM-DIFFICILE TOXINS; POLYUNSATURATED FATTY-ACIDS; EPITHELIAL BARRIER FUNCTION; CACO-2 CELL MONOLAYERS; ANNEXIN II TETRAMER; CANINE KIDNEY-CELLS; BASIC-AMINO-ACIDS; MDCK-CELLS AB The epithelial tight junction (TJ) was first described ultrastructurally as a fusion of the outer lipid leaflets of the adjoining cell membrane bilayers (hemifusion). The discovery of an increasing number of integral TJ and TJ-associated proteins has eclipsed the original lipid-based model with the wide acceptance of a protein-centric model for the TJ. In this review, we stress the importance of lipids in TJ structure and function. A lipid-protein hybrid model accommodates a large body of information supporting the lipidic characteristics of the TJ, harmonizes with the accumulating evidence supporting the TJ as an assembly of lipid rafts, and focuses on an important, but relatively unexplored, field of lipid-protein interactions in the morphology, physiology, and pathophysiology of the TJ. C1 [Lee, David B. N.; Jamgotchian, Nora; Allen, Suni G.; Abeles, Michael B.] Vet Affairs Greater Los Angeles Healthcare Syst, Vet Integrated Serv Network 22, Nephrol Sect, Los Angeles, CA USA. [Lee, David B. N.; Jamgotchian, Nora; Allen, Suni G.; Abeles, Michael B.] Vet Affairs Greater Los Angeles Healthcare Syst, Vet Integrated Serv Network 22, Epithelial Biol Lab, Los Angeles, CA USA. [Ward, Harry J.] Rancho Los Amigos Med Ctr, Div Nephrol, Los Angeles, CA USA. [Lee, David B. N.; Ward, Harry J.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Lee, DBN (reprint author), Vet Adm Med Ctr, Dept Med 111, 16111 Plummer St, North Hills, CA 91343 USA. EM dbnlee@ucla.edu FU National Institutes of Health [1RO1 DK/HD-51948]; Department of Veterans Affairs Merit Review Board; UCLA Council on Research/Faculty Research Grant Program FX This work was supported in part by National Institutes of Health Grant 1RO1 DK/HD-51948, the Department of Veterans Affairs Merit Review Board, and the UCLA Council on Research/Faculty Research Grant Program (2006-2007). NR 118 TC 12 Z9 13 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 2008 VL 295 IS 6 BP F1601 EP F1612 DI 10.1152/ajprenal.00097.2008 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 379GQ UT WOS:000261385100002 PM 18701633 ER PT J AU Nagami, GT Chang, JA Plato, ME Santamaria, R AF Nagami, Glenn T. Chang, Jenny A. Plato, Megan E. Santamaria, Rafael TI Acid loading in vivo and low pH in culture increase angiotensin receptor expression: enhanced ammoniagenic response to angiotensin II SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE ammoniagenesis; angiotensin type receptor; cell surface; acidosis; colchicine ID PROXIMAL TUBULE SEGMENTS; HUMAN AT(1) RECEPTOR; METABOLIC-ACIDOSIS; N-GLYCOSYLATION; SECRETION; CELLS; RAT; ALDOSTERONE; INHIBITION; MEMBRANES AB The proximal tubule defends the body against acid challenges by enhancing its production and secretion of ammonia. Our previous studies demonstrated an enhanced ammoniagenic response of the proximal tubule to ANG II added to the lumen in vitro after an in vivo acid challenge. The present study examined the effect of NH(4)Cl acid loading in vivo on renal cortical type 1 ANG II (AT(1)) receptor expression, the effect of low pH on AT(1) receptor expression in a proximal tubule cells in culture, and their response to ANG II. A short-term (18 h) NH(4)Cl load in vivo resulted in increased renal cortical AT(1) receptor mRNA expression and increased brush-border membrane AT(1) receptor protein expression levels. Changing the cell culture pH from 7.4 to 7.0 for at least 2 h increased cell surface expression of AT1 receptors and enhanced the stimulatory effect of ANG II on ammonia production rates. This increased ammoniagenic response to ANG II and the early enhancement of cell surface expression induced by exposure of the cultured proximal tubule cells to pH 7.0 were prevented by treatment with colchicine. These results suggest that, after acid challenges, the enhanced ammoniagenic response of the proximal tubule to ANG II is, in part, mediated by increased AT(1) receptor cell surface expression and that the enhancement of receptor expression plays an important role in the early response of the proximal tubule to acid challenges. C1 [Nagami, Glenn T.] VA Greater Los Angeles Healthcare Syst, Nephrol Sect, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Nagami, GT (reprint author), VA Greater Los Angeles Healthcare Syst, Nephrol Sect, Dept Med, Mail Code 111L,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM glenn.nagami@va.gov NR 33 TC 7 Z9 7 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 2008 VL 295 IS 6 BP F1864 EP F1870 DI 10.1152/ajprenal.90410.2008 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 379GQ UT WOS:000261385100029 PM 18945827 ER PT J AU Singh, AK Leeman, J Shankar, S Ferrucci, JT AF Singh, Ajay K. Leeman, Joshua Shankar, Sridhar Ferrucci, Joseph T. TI Core Biopsy with Curved Needle Technique SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE biopsy gun; core biopsy; CT-guided biopsy; curved needle biopsy; fine-needle aspiration ID ASPIRATION BIOPSY; PERCUTANEOUS BIOPSY; MESOTHELIOMA; LESIONS; RISK AB OBJECTIVE. The purpose of this study was to define the technique and study the feasibility of curved needle biopsy performed with a coaxial core biopsy system. CONCLUSION. Curved core needle biopsy is a simple and feasible technique with a high technical success rate even with suboptimal coaxial needle placement. With the technique, different parts of a focal lesion can be biopsied without manipulation of the coaxial needle. This feature may help in avoiding injury to vital structures. C1 [Singh, Ajay K.; Leeman, Joshua; Shankar, Sridhar; Ferrucci, Joseph T.] Univ Massachusetts, Mem Med Ctr, Dept Radiol, Worcester, MA 01605 USA. [Singh, Ajay K.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Singh, AK (reprint author), Univ Massachusetts, Mem Med Ctr, Dept Radiol, Worcester, MA 01605 USA. EM asingh1@partners.org NR 19 TC 7 Z9 8 U1 0 U2 2 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2008 VL 191 IS 6 BP 1745 EP 1750 DI 10.2214/AJR.08.1165 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 374HZ UT WOS:000261035700019 PM 19020246 ER PT J AU Shi, AA Lee, SI AF Shi, Ann A. Lee, Susanna I. TI Algorithmic Workup of Abnormal Vaginal Bleeding with Endovaginal Sonography and Sonohysterography: Self-Assessment Module SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE algorithm; endometrium; premenopause; postmenopause; tamoxifen ID ENDOMETRIAL ABNORMALITIES; BREAST-CANCER; TAMOXIFEN; ULTRASOUND; POLYPS; WOMEN AB The educational objectives for this self-assessment module on endovaginal sonography and sonohysterography are for the participant to exercise, self-assess, and improve his or her understanding of the imaging evaluation of abnormal vaginal bleeding and to gain familiarity with the algorithm for the workup for endometrial disorders. C1 [Shi, Ann A.; Lee, Susanna I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Shi, AA (reprint author), Montefiore Med Ctr, Dept Radiol, 111 E 210th St, Bronx, NY 10467 USA. EM ashi@montefiore.org NR 13 TC 1 Z9 1 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2008 VL 191 IS 6 SU S BP S74 EP S78 DI 10.2214/AJR.07.7114 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 373TJ UT WOS:000260996100005 PM 19018053 ER PT J AU Shi, AA Lee, SI AF Shi, Ann A. Lee, Susanna I. TI Radiological Reasoning: Algorithmic Workup of Abnormal Vaginal Bleeding with Endovaginal Sonography and Sonohysterography SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE algorithm; endometrium; premenopause; postmenopause; tamoxifen ID CANCER RECEIVING TAMOXIFEN; BREAST-CANCER; TRANSVAGINAL ULTRASONOGRAPHY; ENDOMETRIAL ABNORMALITIES; POSTMENOPAUSAL WOMEN; HYSTEROSONOGRAPHY; HYSTEROSCOPY; US; ULTRASOUND; DIAGNOSIS AB The workup of endometrial abnormalities can be a confusing task for radiologists because one must take into account the patient's clinical history, imaging findings, and a wide array of diagnostic options. We present two cases, one of a premenopausal woman presenting with vaginal bleeding and another of a postmenopausal woman taking tamoxifen who has abnormal findings on endovaginal sonography. The evaluations of these patients serve to illustrate the diagnostic algorithm for identification of endometrial pathology. C1 [Shi, Ann A.; Lee, Susanna I.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Shi, AA (reprint author), Montefiore Med Ctr, Dept Radiol, 111 E 210th St, Bronx, NY 10467 USA. EM ashi@montefiore.org NR 28 TC 6 Z9 7 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2008 VL 191 IS 6 SU S BP S68 EP S73 DI 10.2214/AJR.07.7067 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 373TJ UT WOS:000260996100004 PM 19018052 ER PT J AU Reinold, MM Macrina, LC Wilk, KE Dugas, JR Cain, EL Andrews, JR AF Reinold, Michael M. Macrina, Leonard C. Wilk, Kevin E. Dugas, Jeffrey R. Cain, E. Lyle Andrews, James R. TI The Effect of Neuromuscular Electrical Stimulation of the Infraspinatus on Shoulder External Rotation Force Production After Rotator Cuff Repair Surgery SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article DE shoulder; glenohumeral; rehabilitation; exercise; rotator cuff ID ANTERIOR CRUCIATE LIGAMENT; TOTAL KNEE ARTHROPLASTY; QUADRICEPS FEMORIS MUSCLE; REFLEX INHIBITION; JOINT EFFUSION; THIGH MUSCLES; STRENGTH; RECONSTRUCTION; SUBLUXATION; INJURY AB Background: Muscle weakness, particularly of shoulder external rotation, is common after rotator cuff repair surgery. Neuromuscular electrical stimulation has been shown to be an effective adjunct in the enhancement of muscle recruitment. Hypothesis: Shoulder external rotation peak force can be enhanced by neuromuscular electrical stimulation after rotator cuff repair surgery. Study Design: Controlled laboratory study. Methods: Thirty-nine patients (20 men, 19 women) who had undergone rotator cuff repair surgery were tested a mean of 10.5 days after surgery. Testing consisted of placing patients supine with the shoulder in 45 degrees of abduction, neutral rotation, and 15 degrees of horizontal adduction. Neuromuscular electrical stimulation was applied to the infraspinatus muscle belly and inferior to the spine of the scapula. Placement was confirmed by palpating the muscle during a resisted isometric contraction of the external rotators. Patients performed 3 isometric shoulder external rotation contractions with and without neuromuscular electrical stimulation, each with a 5-second hold against a handheld dynamometer. Neuromuscular electrical stimulation was applied at maximal intensity within comfort at 50 pulses per second, symmetrical waveform, and a 1-second ramp time. The 3 trials under each condition were recorded, and an average was taken. The order of testing was randomized for each patient tested. A paired samples t test was used to determine significant differences between conditions (P < .05). Each group was also divided based on age, rotator cuff tear size, number of days postoperative, and neuromuscular electrical stimulation intensity. Analysis of variance models were used to determine the influence of these variables on external rotation force production (P < .05). Results: Peak force production was significantly greater (P < .001) when tested with neuromuscular electrical stimulation (3.75 kg) as opposed to without neuromuscular electrical stimulation (3.08 kg) for all groups tested. There was no significant difference based on the size of the tear, age of the patient, number of days after surgery, or level of neuromuscular electrical stimulation intensity. Conclusion: Peak shoulder external rotation force was significantly increased by 22% when tested with neuromuscular electrical stimulation after rotator cuff repair surgery. Neuromuscular electrical stimulation significantly increased force production regardless of the age of the patient, size of the tear, intensity of the current, or the number of days postoperative. Clinical Relevance: Neuromuscular electrical stimulation may be used concomitantly with exercises to enhance the amount of force production and potentially minimize the inhibition of the rotator cuff after repair surgery. C1 [Reinold, Michael M.] Boston Red Sox Baseball Club, Boston, MA 02215 USA. [Reinold, Michael M.] Massachusetts Gen Hosp, Sports Med Serv, Boston, MA 02114 USA. [Macrina, Leonard C.; Wilk, Kevin E.] Champ Sports Med, Birmingham, AL USA. [Wilk, Kevin E.; Dugas, Jeffrey R.; Cain, E. Lyle; Andrews, James R.] Amer Sports Med Inst, Birmingham, AL USA. [Dugas, Jeffrey R.; Cain, E. Lyle; Andrews, James R.] Andrews Sports Med & Orthopaed Ctr, Birmingham, AL USA. RP Reinold, MM (reprint author), Boston Red Sox Baseball Club, Fenway Pk,4 Yawkey Way, Boston, MA 02215 USA. EM mreinold@redsox.com NR 25 TC 14 Z9 16 U1 1 U2 10 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0363-5465 J9 AM J SPORT MED JI Am. J. Sports Med. PD DEC PY 2008 VL 36 IS 12 BP 2317 EP 2321 DI 10.1177/0363546508322479 PG 5 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 382PZ UT WOS:000261619200005 PM 18757763 ER PT J AU Sepehr, A Mino-Kenudson, M Ogawa, F Brugge, WR Deshpande, V Lauwers, GY AF Sepehr, Alireza Mino-Kenudson, Mari Ogawa, Fumihiro Brugge, William R. Deshpande, Vikram Lauwers, Gregory Y. TI IgG4+ to IgG+ Plasma Cells Ratio of Ampulla Can Help Differentiate Autoimmune Pancreatitis From Other "Mass Forming" Pancreatic Lesions SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article; Proceedings Paper CT 96th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 24-30, 2007 CL San Diego, CA SP US & Canadian Acad Pathol DE autoimmune pancreatitis; major ampulla; endoscopy; IgG4; IgG4/IgG ratio ID LYMPHOPLASMACYTIC SCLEROSING PANCREATITIS; IDIOPATHIC CHRONIC-PANCREATITIS; SERUM IGG4; CLINICOPATHOLOGICAL FEATURES; INFLAMMATORY PSEUDOTUMOR; DISEASE; INFILTRATION; PANCREATICODUODENECTOMY; AUTOANTIBODIES; CHOLANGITIS AB Autoimmune pancreatitis (AIP) shows a unique spectrum of histologic features and commonly presents with an abundant IgG4-positive (IgG4+) plasma cell infiltration. However, differentiating AIP from other mass lesions, particularly pancreatic cancer [invasive ductal carcinoma (IDC)] can be clinically challenging. In this study, we evaluated the validity of IgG4 and IgG immunohistochemistry of ampullary and periampullary tissue for the diagnosis of AIR Our study group consisted of 14 resected AIP cases with appropriate ampullary sections. Superficial ampullary tissue and "shouldering" duodenal mucosa were evaluated for several histologic variables. Immunohistochemistry for IgG4 and IgG was performed. The number of IgG4 and IgG-positive plasma cells was counted and an IgG4+ to IgG+ plasma cells ratio (IgG4/IgG ratio) was evaluated. A control cohort was composed of IDC (n = 30) and chronic pancreatitis (CP) (n = 29). Although an overlap was present between the groups, the overall inflammation and number of plasma cells in and around the ampulla was significantly increased in AIP compared with CP and IDC. Furthermore, although there was some overlap in the crude number of IgG4+ plasma cells of the ampullary and duodenal tissue between AIP, IDC, and CP, an IgG4/IgG ratio, especially of the ampulla, seems diagnostically useful in differentiating AIP from other "mass forming" lesions. When a cut-off of 0.10 was applied, the diagnostic sensitivity and specificity of the ampullary IgG4/IgG ratio was 86% and 95%, respectively. In conclusion, evaluation of ampullary histology and IgG4/IgG ratio might be proven beneficial in discriminating AIP from other mass forming pancreatic lesions. C1 [Sepehr, Alireza; Mino-Kenudson, Mari; Ogawa, Fumihiro; Deshpande, Vikram; Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Gastrointestinal Pathol Serv, Boston, MA 02114 USA. [Brugge, William R.] Massachusetts Gen Hosp, Dept Internal Med, Dept Gastroenterol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Ogawa, Fumihiro] Saitama Med Univ, Dept Pathol, Saitama, Japan. RP Mino-Kenudson, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, Gastrointestinal Pathol Serv, 55 Fruit St, Boston, MA 02114 USA. EM mminokenudson@partners.org NR 37 TC 30 Z9 33 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2008 VL 32 IS 12 BP 1770 EP 1779 DI 10.1097/PAS.0b013e318185490a PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 379TQ UT WOS:000261419500003 PM 18779730 ER PT J AU Harris, EI Lewin, DN Wang, HLL Lauwes, GY Srivastava, A Shyr, Y Shakhtour, B Revetta, F Washington, MK AF Harris, Elizabeth I. Lewin, David N. Wang, Hanlin L. Lauwes, Gregory Y. Srivastava, Amitabh Shyr, Yu Shakhtour, Bashar Revetta, Frank Washington, Mary K. TI Lymphovascular Invasion in Colorectal Cancer An Interobserver Variability Study SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE lymphovascular invasion; colorectal carcinoma; colon cancer; interobserver study; CD31; D2-40 ID LYMPH-NODE METASTASIS; BLOOD-VESSEL INVASION; PROGNOSTIC-FACTORS; VENOUS INVASION; RECTAL-CANCER; CLINICAL-SIGNIFICANCE; HISTOLOGIC FEATURES; ABDOMINOPERINEAL RESECTION; VASCULAR INVASION; NEURAL INVASION AB Background: Lymphovascular invasion (LVI) in colorectal cancer (CRC) is considered a strong stage-independent prognostic factor and influences decisions regarding, adjuvant chemotherapy in patients with stage II tumors. However. the degree of interobserver agreement among pathologists for LVI in CRC is largely unknown. This Study Was Undertaken to examine Such interobserver variability, and we hypothesized that the use of immunohistocheimcal markers for vascular and lymphatic channels Could improve interobserver agreement. Design: Fifty cases of American Joint Committee on Cancer stage 11 moderately differentiated CRC from 1990 to 2005 from the pathology archives were selected, mucinous, medullary, and other recognized special subtypes were excluded. Fifty hematoxylin and eosin (H&E) slides (I from each case) were circulated to 6 gastrointestinal pathologists, who independently assessed small and large vessel invasion. No diagnostic guidelines were given to the participating pathologists, each was instructed to apply the criteria for LVI that lie or she used in daily practice. Immunohistochemistry (IHC) for D2-40 and CD31 was performed oil corresponding paraffin blocks. The IHC slides were randomized, recirculated, and rescored for LVI. Results were analyzed by kappa (K) statistics. which correct for agreement by chance, and for percentage agreement. Results: The average K Values were determined for the H&E slides (large and small vessel), CD31 (small vessel), and D2-40 (small vessel) (Fig. I). Agreement was fair for H&E small vessel invasion [kappa = 0.28, 95% confidence interval (Cl): 0.22-0.34]. The least agreement was seen in interpretation of H&E large vessel invasion (kappa = 0.18; 95%Cl: 0.11-0.26). Agreement was not improved by use Of immunohistochemical Stains: CD31 (large vessel, K = 0.42, 95%Cl: 0.20-0.63. small vessel, kappa = 0.26 95%Cl: 0.10-0.42) and D2-40 (kappa = 0.31 95%Cl: 0.21-0.42). Conclusions: Interobserver variability in diagnosis of LVI was substantial oil H&E slides and did not improve upon use of IHC. Agreement in evaluation of large vessel invasion was only slightly higher than Would be seen by chance alone. This study highlights the need for criteria ill evaluation of LVI, as this assessment may impact patient prognosis and thus change the course of clinical treatment. C1 [Harris, Elizabeth I.] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA. [Shyr, Yu; Shakhtour, Bashar] Vanderbilt Univ, Dept Biostat, Nashville, TN 37232 USA. [Lewin, David N.] MUSC Med Center, Dept Pathol, Charleston, SC USA. [Wang, Hanlin L.] Cedars Sinai Med Ctr, Dept Pathol, Los Angeles, CA 90048 USA. [Lauwes, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Srivastava, Amitabh] Dartmouth Hitchcock Med Ctr, Dept Pathol, Lebanon, NH 03766 USA. RP Harris, EI (reprint author), Vanderbilt Univ, Med Ctr, Dept Pathol, C-3322 Med Ctr N, Nashville, TN 37232 USA. EM Elizabeth.harris@vanderbilt.edu RI Srivastava, Amitabh/A-9386-2009 FU NCI NIH HHS [P50 CA095103-01, P50 CA095103-019001, P50 CA95103, P50 CA095103] NR 33 TC 59 Z9 61 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2008 VL 32 IS 12 BP 1816 EP 1821 DI 10.1097/PAS.0b013e3181816083 PG 6 WC Pathology; Surgery SC Pathology; Surgery GA 379TQ UT WOS:000261419500008 PM 18779725 ER PT J AU Nascimento, AF Raut, CP Fletcher, CDM AF Nascimento, Alessandra F. Raut, Chandrajit P. Fletcher, Christopher D. M. TI Primary Angiosarcoma of the Breast Clinicopathologic Analysis of 49 Cases, Suggesting That Grade is not Prognostic SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article; Proceedings Paper CT 96th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 24-30, 2007 CL San Diego, CA SP US & Canadian Acad Pathol DE breast; soft tissue; angiosarcoma; histologic grade; sarcoma ID SOFT-TISSUE; CARCINOMA; SARCOMA; CANCER; DIFFERENTIATION; HYPERPLASIA; RADIATION; SERIES; TUMOR AB Mammary angiosarcoma is a rare neoplasm, accounting for about 0.05%,, of all primary malignancies of the breast. It is currently believed that histologic grading of mammary angiosarcomas plays an important role in prognostication. Forty-nine cases of primary angiosarcoma of the breast were retrieved from our files. Clinical details and follow-up information were obtained from referring pathologists and clinicians. and by chart review. All statistics were performed using Fisher exact test and only P < 0.05 was considered significant. Recurrence-free survival and overall survival Curves were established using Statistica software version 5.5 (StatSoft Inc). All patients were female with ages ranging from 15 to 74 years (mean 41.5. median 40). Peak incidence was between the ages of 30 and 50 years. All tumors examined were located within breast parenchyma with or without minor cutaneous involvement. The right side was more commonly affected than the left side (66% vs. 29.5%). Tumor was bilateral at presentation in 2 cases (4.5%). Tumor size varied from 0.7 to 25 cm (mean 6.7, median 5). Most patients presented with a palpable, painless mass. Two patients had a history of prior radiation treatment for breast carcinoma. Histologically, primary tumors were graded using Rosen's 3-tier system: 17 tumors (35.4%) as low grade, 17 (35.4%,) as intermediate grade, and 14 (29.2%) as high grade. Forty-six patients were treated surgically.. 11 underwent chemotherapy, and 12 patients received radiotherapy. Follow-up was available in 41 patients (83.7%, median duration 29 mo). Ten patients (24.4%) showed evidence of local recurrence within I I to 60 months (median 36) after diagnosis. Twenty-four patients (58.5%) thus far have developed metastases, which were most commonly to lung, liver, skin, and bone. Time interval between diagnosis and metastasis ranged from 2 to 144 months (median 34). Eighteen patients (44%,) so far have died of disease and I died of presumably disseminated breast carcinoma. Five patients (12.2%) are alive with disease and 15 patients (36.6%) are alive with no evidence of disease. Statistical analysis evaluating correlation between tumor made and size, and rate of local recurrence. metastasis, and death owing to disease showed no significant difference among, tumors of different grades. The median recurrence-free and overall survival rates for the entire cohort were 2.8 and 5.7 years, respectively. In conclusion. mammary angiosarcoma is a rare disease that affects relatively younger patients. This tumor seems to have an overall similar clinical course as other types of angiosarcoma arising in skin or soft tissue, it carries a moderate risk of local recurrence. and a high risk of metastasis and death. In this large series, there is no correlation between histologic grade and patient Outcome, more in line with angiosarcomas at other sites. C1 [Nascimento, Alessandra F.; Fletcher, Christopher D. M.] Brigham & Womens Hosp, Dept Pathol, Ctr Sarcoma & Bone Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Raut, Chandrajit P.] Brigham & Womens Hosp, Dept Surg, Ctr Sarcoma & Bone Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Nascimento, Alessandra F.; Raut, Chandrajit P.; Fletcher, Christopher D. M.] Harvard Univ, Sch Med, Boston, MA USA. RP Fletcher, CDM (reprint author), Brigham & Womens Hosp, Dept Pathol, Ctr Sarcoma & Bone Oncol, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. EM cfletcher@partners.org NR 23 TC 51 Z9 58 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2008 VL 32 IS 12 BP 1896 EP 1904 DI 10.1097/PAS.0b013e318176dbc7 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 379TQ UT WOS:000261419500015 PM 18813119 ER PT J AU Mortensen, EM Restrepo, MI Copeland, LA Pugh, JA Anzueto, A AF Mortensen, Eric M. Restrepo, Marcos I. Copeland, Laurel A. Pugh, Jacqueline A. Anzueto, Antonio TI Association of Hydrophilic Versus Lipophilic Angiotensin-Converting Enzyme Inhibitor Use on Pneumonia-Related Mortality SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE Angiotensin-converting enzyme; Pneumonia; Mortality ID COMMUNITY-ACQUIRED PNEUMONIA; RESPIRATORY-DISTRESS-SYNDROME; CHRONIC HEART-FAILURE; ANTIMICROBIAL THERAPY; RECEPTOR BLOCKERS; RISK; POLYMORPHISM; REDUCTION; STATINS; SYSTEM AB Background: Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors may have beneficial effects for patients with or at risk for pneumonia. However, other studies have not found a survival benefit. Other research suggests that ACE inhibitors that are lipophilic may be superior to hydrophilic ACE inhibitors in terms of tissue penetration and inhibition of ACF. Our aim was to examine the associations of prior outpatient use of lipophilic and hydrophilic ACE inhibitors on mortality for patients hospitalized with community-acquired pneumonia. Methods: A retrospective cohort study of subjects hospitalized with pneumonia at 2 tertiary teaching hospitals. We examined whether the prior outpatient use of hydrophilic or lipophilic ACE inhibitors was associated with 30-day mortality in a logistic regression analysis that adjusted for potential confounders using a propensity score. Results: Data were abstracted on 787 subjects at the 2 hospitals. In our cohort, 240% (n = 186) were on ACE inhibitors at presentation: I I I lipophilic and 74 hydrophilic. Mortality was 9.21% at 30 days. In the multivariable model, lipophilic ACE inhibitor use (odds ratio 0.3, 95% confidence interval 0.1-0.8), but not hydrophilic ACE inhibitor use (0.7, 0.3-1.7), was significantly associated with 30-day mortality. Conclusions: Our study suggests that future research of ACE inhibitors in pneumonia must describe the specific medications received. Confirmatory studies are needed, as well as research to determine the mechanism(s) of this protective effect. C1 [Mortensen, Eric M.; Restrepo, Marcos I.; Copeland, Laurel A.] S Texas Vet Healthcare Syst, VERDICT Res Ctr, San Antonio, TX 78284 USA. [Mortensen, Eric M.; Pugh, Jacqueline A.] Univ Texas Hlth Sci Ctr San Antonio, Div Gen Med, San Antonio, TX 78229 USA. [Restrepo, Marcos I.; Anzueto, Antonio] Univ Texas Hlth Sci Ctr San Antonio, Div Pulm & Crit Care Med, San Antonio, TX 78229 USA. [Copeland, Laurel A.] Univ Texas Hlth Sci Ctr San Antonio, Div Psychiat, San Antonio, TX 78229 USA. RP Mortensen, EM (reprint author), S Texas Vet Healthcare Syst, VERDICT Res Ctr, 7400 Merton Minter Blvd 11C6, San Antonio, TX 78284 USA. EM mortensene@uthscsa.edu RI Restrepo, Marcos/H-4442-2014; OI Pugh, Jacqueline/0000-0003-4933-141X; Mortensen, Eric/0000-0002-3880-5563; Copeland, Laurel/0000-0002-9478-0209 FU Howard Hughes Medical Institute [00378-001] NR 27 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD DEC PY 2008 VL 336 IS 6 BP 462 EP 466 DI 10.1097/MAJ.0b013e31817149ed PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 384VR UT WOS:000261772800003 PM 19092318 ER PT J AU Delmonico, FL Harmon, WE AF Delmonico, Francis L. Harmon, William E. TI Pediatric Kidney Transplantation in the United States: The Current Realities SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material C1 [Delmonico, Francis L.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Harmon, William E.] Childrens Hosp, Dept Nephrol, Boston, MA 02115 USA. RP Delmonico, FL (reprint author), Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM Francis_Delmonico@neob.org NR 1 TC 5 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2008 VL 8 IS 12 BP 2487 EP 2488 DI 10.1111/j.1600-6143.2008.02453.x PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 374OM UT WOS:000261053600005 PM 19032219 ER PT J AU Abecassis, MM Burke, R Cosimi, AB Matas, AJ Merion, RM Millman, D Roberts, JP Klintmalm, GB AF Abecassis, M. M. Burke, R. Cosimi, A. B. Matas, A. J. Merion, R. M. Millman, D. Roberts, J. P. Klintmalm, G. B. CA On behalf Amer Soc Transplant Sur TI Organ transplant programs: Federal agencies have acted to improve oversight, but implementation issues remain SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Medicaid; medicare; regulation ID COST AB The Centers for Medicare and Medicaid Services (CMS) has developed a set of regulations that spell out the Conditions of Participation (CoPs) for provider hospitals that wish to be certified (and thus eligible for reimbursement) by Medicare for transplant services. The American Society of Transplant Surgeons (ASTS) Council has played a major role in providing CMS with advice and guidance in the development and ongoing implementation of these conditions through a process of fruitful dialogue. In this report, we highlight the events that led to the development of the regulations and describe the process to date in implementing the CoPs. We have raised some important questions regarding the effectiveness of the regulations for improving safety, and we have highlighted the cost associated with their implementation. This report has been vetted by and represents the opinions of the Council of the ASTS. C1 [Abecassis, M. M.] Northwestern Univ, Chicago, IL 60611 USA. [Burke, R.; Millman, D.] Powers Pyle Sutter & Verville, Washington, DC USA. [Cosimi, A. B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Matas, A. J.] Univ Minnesota, Minneapolis, MN USA. [Merion, R. M.] Univ Michigan, Ann Arbor, MI 48109 USA. [Roberts, J. P.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Klintmalm, G. B.] Baylor Univ, Dallas, TX USA. RP Abecassis, MM (reprint author), Northwestern Univ, Chicago, IL 60611 USA. EM mabecass@nmh.org RI Abecassis, Michael/F-7977-2011 NR 15 TC 22 Z9 22 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2008 VL 8 IS 12 BP 2496 EP 2502 DI 10.1111/j.1600-6143.2008.02434.x PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 374OM UT WOS:000261053600008 PM 19032221 ER PT J AU Hisashi, Y Yamada, K Kuwaki, K Tseng, YL Dor, FJMF Houser, SL Robson, SC Schuurman, HJ Cooper, DKC Sachs, DH Colvin, RB Shimizu, A AF Hisashi, Y. Yamada, K. Kuwaki, K. Tseng, Y.-L. Dor, F. J. M. F. Houser, S. L. Robson, S. C. Schuurman, H.-J. Cooper, D. K. C. Sachs, D. H. Colvin, R. B. Shimizu, A. TI Rejection of Cardiac Xenografts Transplanted from alpha 1,3-Galactosyltransferase Gene-Knockout (GalT-KO) Pigs to Baboons SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Acute rejection; baboon; cellular rejection; chronic rejection; humoral rejection; xenotransplantation ID HEART-TRANSPLANTATION; THROMBOTIC MICROANGIOPATHY; ALLOGRAFT VASCULOPATHY; TRANSGENIC PIGS; XENOTRANSPLANTATION; ANTIBODIES; DONORS; CELLS; SUPPRESSION; EXPERIENCE AB The use of alpha 1,3-galactosyltransferase gene-knockout (GalT-KO) swine donors in discordant xenotransplantation has extended the survival of cardiac xenografts in baboons following transplantation. Eight baboons received heterotopic cardiac xenografts from GalT-KO swine and were treated with a chronic immunosuppressive regimen. The pathologic features of acute humoral xenograft rejection (AHXR), acute cellular xenograft rejection (ACXR) and chronic rejection were assessed in the grafts. No hyperacute rejection developed and one graft survived up to 6 months after transplantation. However, all GalT-KO heart grafts underwent graft failure with AHXR, ACXR and/or chronic rejection. AHXR was characterized by interstitial hemorrhage and multiple thrombi in vessels of various sizes. ACXR was characterized by TUNEL(+) graft cell injury with the infiltration of T cells (including CD3 and TIA-1(+) cytotoxic T cells), CD4(+) cells, CD8(+) cells, macrophages and a small number of B and NK cells. Chronic xenograft vasculopathy, a manifestation of chronic rejection, was characterized by arterial intimal thickening with TUNEL(+) dead cells, antibody and complement deposition, and/or cytotoxic T-cell infiltration. In conclusion, despite the absence of the Gal epitope, acute and chronic antibody and cell-mediated rejection developed in grafts, maintained by chronic immunosupression, presumably due to de novo responses to non-Gal antigens. C1 [Hisashi, Y.; Yamada, K.; Kuwaki, K.; Tseng, Y.-L.; Dor, F. J. M. F.; Cooper, D. K. C.; Sachs, D. H.; Shimizu, A.] Harvard Univ, Sch Med, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Houser, S. L.; Colvin, R. B.; Shimizu, A.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Robson, S. C.] Harvard Univ, Sch Med, Dept Med, Beth Israel Deaconess Med Ctr,Transplant Ctr, Boston, MA 02115 USA. [Schuurman, H.-J.; Shimizu, A.] Immerge BioTherapeut Inc, Cambridge, MA USA. [Shimizu, A.] Nippon Med Sch, Dept Pathol, Tokyo 113, Japan. RP Shimizu, A (reprint author), Harvard Univ, Sch Med, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM Akira.Shimizu@tbrc.mgh.harvard.edu RI Dor, Frank/E-1032-2013 OI Dor, Frank/0000-0001-7845-3075 FU NIH [1PO1 A145897]; Research Agreement between Immerge BioTherapeutics, Inc.; Massachusetts General Hospital; Ter Meulen Fund from the Royal Netherlands Academy of Arts and Sciences; Prof Michael-van Vloten Fund; Netherland-America Foundation; Japanese Society for the Promotion of Science, [C18591787, C20591900] FX The authors thank Ms. Emma Samelson-Jones for her special support in editing the manuscript. The authors would also like to thank Novartis Pharma AG (Basel, Switzerland) for generously providing anti-CD154 mAb and Immerge BioTherapeutics, Inc. (Cambridge, MA) for the supply of LoCD2b mAb and cobra venom factor. This work was supported in part by NIH Program Project 1PO1 A145897 and by a Sponsored Research Agreement between Immerge BioTherapeutics, Inc. and the Massachusetts General Hospital. F. J. M. F. D. was a recipient of grants from the Ter Meulen Fund from the Royal Netherlands Academy of Arts and Sciences, the Prof Michael-van Vloten Fund and the Netherland-America Foundation. A. S. was a recipient of a grant from the Japanese Society for the Promotion of Science, grant-in-aid for scientific research (C18591787; C20591900). NR 41 TC 50 Z9 56 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD DEC PY 2008 VL 8 IS 12 BP 2516 EP 2526 DI 10.1111/j.1600-6143.2008.02444.x PG 11 WC Surgery; Transplantation SC Surgery; Transplantation GA 374OM UT WOS:000261053600012 PM 19032222 ER PT J AU Croda, J Medeiros, MA Greenwald, R Sun, J Mcbride, A Peacock, SJ Choy, HA Haake, DA Homma, A Reis, MG Esfandiari, J Lyashchenko, KP Ko, AI AF Croda, Julio Medeiros, Marco A. Greenwald, Rena Sun, Jenny Mcbride, Alan Peacock, Sharon J. Choy, Henry A. Haake, David A. Homma, Akira Reis, Mitermayer G. Esfandiari, Javan Lyashchenko, Konstantin P. Ko, Albert I. TI IDENTIFICATION OF IMUNODOMINANT REGIONS OF LEPTOSPIRAL IMMUNOGLOBUILIN-LIKE PROTEINS FOR USE IN THE DIAGNOSIS OF LEPTOSPIROSIS SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY DEC 07-11, 2008 CL New Orleans, LA SP Amer Soc Trop Med & Hyg C1 [Croda, Julio; Mcbride, Alan; Reis, Mitermayer G.; Ko, Albert I.] Brazilian Minist Hlth, Goncalo Moniz Inst, Oswaldo Cruz Fdn, Salvador, BA, Brazil. [Medeiros, Marco A.; Homma, Akira] Brazilian Minist Hlth, Oswaldo Cruz Fdn, Rio De Janeiro, Brazil. [Greenwald, Rena; Sun, Jenny; Esfandiari, Javan; Lyashchenko, Konstantin P.] Chembio Diagnost Syst Inc, Medford, NY USA. [Peacock, Sharon J.] Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand. [Choy, Henry A.; Haake, David A.] Univ Calif Los Angeles, Dept Med, Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90024 USA. [Choy, Henry A.; Haake, David A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. [Ko, Albert I.] Cornell Univ, Weill Med Coll, Div Int Med & Infect Dis, Ithaca, NY USA. RI Ko, Albert/P-2343-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2008 VL 79 IS 6 MA 68 BP 20 EP 21 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 382ZT UT WOS:000261644600069 ER PT J AU Harris, AM Chowdhury, F Begum, YA Faruque, AS Svennerholm, AM Harris, JB Ryan, ET Cravioto, A Calderwood, SB Qadri, F AF Harris, Aaron M. Chowdhury, Fahima Begum, Yasmin Ara Faruque, Abu S. Svennerholm, Ann-Mari Harris, Jason B. Ryan, Edward T. Cravioto, Alejandro Calderwood, Stephen B. Qadri, Firdausi TI SHIFTING PREVALENCE OF MAJOR DIARRHEAL PATHOGENS IN PATIENTS SEEKING HOSPITAL CARE DURING FLOODS IN 1998, 2004, AND 2007 IN DHAKA, BANGLADESH SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY DEC 07-11, 2008 CL New Orleans, LA SP Amer Soc Trop Med & Hyg C1 [Harris, Aaron M.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Chowdhury, Fahima; Begum, Yasmin Ara; Faruque, Abu S.; Cravioto, Alejandro; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Svennerholm, Ann-Mari] Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden. [Harris, Jason B.; Ryan, Edward T.; Calderwood, Stephen B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 6 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2008 VL 79 IS 6 MA 365 BP 107 EP 107 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 382ZT UT WOS:000261644600365 ER PT J AU Charles, RC Harris, JB Lebrun, LM Chase, M Sheikh, A Larocque, RC Krastins, B Saracino, D Rosenberg, I Tarique, A Calderwood, SB Hohmann, E Qadri, F Parker, K Ryan, ET AF Charles, Richelle C. Harris, Jason B. Lebrun, Lauren M. Chase, Michael Sheikh, Alaullah Larocque, Regina C. Krastins, Brian Saracino, David Rosenberg, Ian Tarique, Abdullah Calderwood, Stephen B. Hohmann, Elizabeth Qadri, Fircluasi Parker, Kenneth Ryan, Edward T. TI PROTEOMIC ANALYSIS OF THE PHOP REGULON IN SALMONELLA ENTERICA SEROVARS TYPHI AND TYPHIMURIUM SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY DEC 07-11, 2008 CL New Orleans, LA SP Amer Soc Trop Med & Hyg C1 [Charles, Richelle C.; Harris, Jason B.; Lebrun, Lauren M.; Chase, Michael; Larocque, Regina C.; Calderwood, Stephen B.; Hohmann, Elizabeth; Ryan, Edward T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sheikh, Alaullah; Tarique, Abdullah; Qadri, Fircluasi] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Krastins, Brian; Saracino, David; Rosenberg, Ian; Parker, Kenneth] Harvard Partners Ctr Genet & Genom, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2008 VL 79 IS 6 MA 414 BP 122 EP 123 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 382ZT UT WOS:000261644600414 ER PT J AU Harris, AM Harris, JB Bhuiyan, S Chowdhury, F Khan, AI Faruque, AS LaRocque, RC Ryan, ET Qadri, F Calderwood, SB AF Harris, Aaron M. Harris, Jason B. Bhuiyan, Saruar Chowdhury, Fahima Khan, Ashraful I. Faruque, Abu S. LaRocque, Regina C. Ryan, Edward T. Qadri, Firdausi Calderwood, Stephen B. TI MEMORY B CELL RESPONSES IN PATIENTS WITH DEHYDRATING DIARRHEA CAUSED BY VIBRIO CHOLERAE O1 SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY DEC 07-11, 2008 CL New Orleans, LA SP Amer Soc Trop Med & Hyg C1 [Harris, Aaron M.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Harris, Jason B.; LaRocque, Regina C.; Ryan, Edward T.; Calderwood, Stephen B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bhuiyan, Saruar; Chowdhury, Fahima; Khan, Ashraful I.; Faruque, Abu S.; Qadri, Firdausi] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2008 VL 79 IS 6 MA 415 BP 123 EP 123 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 382ZT UT WOS:000261644600415 ER PT J AU Wylie, BJ Singh, N Hashmi, AH Singh, MP Tuchman, J Sabin, L Yeboah-Antwi, K Hussain, M Banerjee, C Dash, AP Hamer, DH AF Wylie, Blair J. Singh, Neeru Hashmi, Ahmar H. Singh, Mrigendra P. Tuchman, Jordan Sabin, Lora Yeboah-Antwi, Kojo Hussain, Mobassir Banerjee, Camellia Dash, Aditya P. Hamer, Davidson H. TI KNOWLEDGE AND UTILIZATION OF MALARIA PREVENTION STRATEGIES IN PREGNANCY IN TWO STATES OF INDIA SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY DEC 07-11, 2008 CL New Orleans, LA SP Amer Soc Trop Med & Hyg C1 [Wylie, Blair J.] Massachusetts Gen Hosp, Dept Obstet, Boston, MA 02114 USA. [Singh, Neeru; Singh, Mrigendra P.; Hussain, Mobassir] Natl Inst Malaria Res, Field Stn, Jabalpur, India. [Hashmi, Ahmar H.; Tuchman, Jordan; Sabin, Lora; Yeboah-Antwi, Kojo; Banerjee, Camellia; Hamer, Davidson H.] Ctr Int Hlth & Dev, Boston, MA USA. [Dash, Aditya P.] Natl Inst Malaria Res, Delhi, India. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2008 VL 79 IS 6 MA 602 BP 178 EP 178 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 382ZT UT WOS:000261644600601 ER PT J AU Kelly, JX Smilkstein, M Melendez, V Cooper, R Winter, R Hinrichs, D Riscoe, M AF Kelly, Jane X. Smilkstein, Martin Melendez, Victor Cooper, Roland Winter, Rolf Hinrichs, Dave Riscoe, Mike TI OPTIMIZATION OF DUAL-FUNCTION ACRIDONE ANTIMALARIALS: IMPROVED EFFICACY AND SYNERGY WITH PIPERAQUINE SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY DEC 07-11, 2008 CL New Orleans, LA SP Amer Soc Trop Med & Hyg C1 [Kelly, Jane X.; Smilkstein, Martin; Winter, Rolf; Hinrichs, Dave; Riscoe, Mike] Portland VA Med Ctr, Portland, OR USA. [Melendez, Victor] Walter Reed Army Inst Res, Silver Spring, MD USA. [Cooper, Roland] Old Dominion Univ, Norfolk, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2008 VL 79 IS 6 MA 760 BP 224 EP 224 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 382ZT UT WOS:000261644601125 ER PT J AU Hamer, DH Wylie, BJ Singh, MP Yeboah-Antwi, K Tuchman, J Gupta, P Brooks, MI Shukla, MM Sabin, L Dash, AP Singh, N AF Hamer, Davidson H. Wylie, Blair J. Singh, Mrigendra P. Yeboah-Antwi, Kojo Tuchman, Jordan Gupta, Priti Brooks, Mohamad I. Shukla, Man M. Sabin, Lora Dash, Aditya P. Singh, Neeru TI BURDEN OF DISEASE DUE TO MALARIA IN PREGNANCY AMONG WOMEN ATTENDING ANTENATAL CLINICS AND HOSPITALIZED FOR MALARIA IN THE STATE OF JHARKHAND, INDIA SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY DEC 07-11, 2008 CL New Orleans, LA SP Amer Soc Trop Med & Hyg C1 [Dash, Aditya P.] Natl Inst Malaria Res, Delhi, India. [Hamer, Davidson H.; Yeboah-Antwi, Kojo; Tuchman, Jordan; Brooks, Mohamad I.; Sabin, Lora] Ctr Int Hlth & Dev, Boston, MA USA. [Singh, Mrigendra P.; Gupta, Priti; Shukla, Man M.; Singh, Neeru] Natl Inst Malaria Res Field Stn, Jabalpur, Madhya Pradesh, India. [Wylie, Blair J.] Massachusetts Gen Hosp, Dept OB GYN, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2008 VL 79 IS 6 MA 1006 BP 295 EP 295 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 382ZT UT WOS:000261644601370 ER PT J AU Hamer, DH Singh, MP Wylie, BJ Yeboah-Antwi, K Tuchman, J Shukla, MM Brooks, MI Sabin, L Dash, AF Singh, N AF Hamer, Davidson H. Singh, Mrigendra P. Wylie, Blair J. Yeboah-Antwi, Kojo Tuchman, Jordan Shukla, Man M. Brooks, Mohamad I. Sabin, Lora Dash, Aditya F. Singh, Neeru TI BURDEN OF DISEASE DUE TO MALARIA IN PREGNANCY AMONG PREGNANT WOMEN ATTENDING DELIVERY UNITS IN THE STATE OF JHARKHAND, INDIA SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY DEC 07-11, 2008 CL New Orleans, LA SP Amer Soc Trop Med & Hyg C1 [Dash, Aditya F.] Natl Inst Malaria Res, Delhi, India. [Wylie, Blair J.] Massachusetts Gen Hosp, Dept OB GYN, Boston, MA 02114 USA. [Singh, Mrigendra P.; Shukla, Man M.; Singh, Neeru] Natl Inst Malaria Res Field Stn, Jabalpur, Madhya Pradesh, India. [Hamer, Davidson H.; Yeboah-Antwi, Kojo; Tuchman, Jordan; Brooks, Mohamad I.; Sabin, Lora] Ctr Int Hlth & Dev, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2008 VL 79 IS 6 MA 1008 BP 296 EP 296 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 382ZT UT WOS:000261644601372 ER PT J AU Cserti-Gazdewich, CM Mpimbaza, A Dhabangi, A Musoke, C Ssewanyana, I Ddungu, H Barungi-Nabukeera, N Nakiboneka-Ssenabulya, D Dzik, WH AF Cserti-Gazdewich, Christine M. Mpimbaza, Arthur Dhabangi, Aggrey Musoke, Charles Ssewanyana, Isaac Ddungu, Henry Barungi-Nabukeera, Nicolette Nakiboneka-Ssenabulya, Deborah Dzik, Walter H. TI CLINICAL SYNDROMES OF PLASMODIUM FALCIPARUM MALARIA INFECTION IN KAMPALA, UGANDA: INITIAL RESULTS FROM THE CYTOADHERENCE IN PEDIATRIC MALARIA (CPM) CASE-CONTROL STUDY SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene CY DEC 07-11, 2008 CL New Orleans, LA SP Amer Soc Trop Med & Hyg C1 [Cserti-Gazdewich, Christine M.] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada. [Mpimbaza, Arthur] Uganda Malaria Surveillance Project, Kampala, Uganda. [Dhabangi, Aggrey] Makerere Univ, Fac Med, Dept Child Hlth & Dev Ctr, Kampala, Uganda. [Musoke, Charles] Mulago Hosp Acute Care Unit, Kampala, Uganda. [Ssewanyana, Isaac] Joint Clin Res Ctr, CTL Lab, Kampala, Uganda. [Ddungu, Henry] Mulago Hosp, Dept Haematol, Kampala, Uganda. [Barungi-Nabukeera, Nicolette; Nakiboneka-Ssenabulya, Deborah] Makerere Univ, Fac Med, Dept Paediat & Child Hlth, Kampala, Uganda. [Dzik, Walter H.] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 2008 VL 79 IS 6 MA 1189 BP 349 EP 349 PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 382ZT UT WOS:000261644601552 ER PT J AU Velmahos, GC AF Velmahos, George C. TI Comment on Incidental Pulmonary Embolism Identified on Chest CT During Initial Trauma Evaluation SO AMERICAN SURGEON LA English DT Editorial Material ID DEEP VENOUS THROMBOSIS C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. RP Velmahos, GC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM gvelmahos@partners.org NR 6 TC 0 Z9 0 U1 0 U2 0 PU SOUTHEASTERN SURGICAL CONGRESS PI ATLANTA PA 141 WEST WIEUCA RD, STE B100, ATLANTA, GA 30342 USA SN 0003-1348 J9 AM SURGEON JI Am. Surg. PD DEC PY 2008 VL 74 IS 12 BP 1149 EP 1150 PG 2 WC Surgery SC Surgery GA 381HM UT WOS:000261526500003 ER PT J AU Mashour, GA Kheterpal, S Vanaharam, V Shanks, A Wang, LYJ Sandberg, WS Tremper, KK AF Mashour, George A. Kheterpal, Sachin Vanaharam, Vishnu Shanks, Amy Wang, Luke Y. -J Sandberg, Warren S. Tremper, Kevin K. TI The Extended Mallampati Score and a Diagnosis of Diabetes Mellitus Are Predictors of Difficult Laryngoscopy in the Morbidly Obese SO ANESTHESIA AND ANALGESIA LA English DT Article ID TRACHEAL INTUBATION; CLINICAL SIGN AB BACKGROUND: The modified Mallampati (MMP) classification is a standard method of oropharyngeal evaluation for predicting difficult laryngoscopy. Previous studies have demonstrated that the predictive value of the MMP is improved when the patient's craniocervical junction is extended rather than neutral (Extended Mallampati Score, EMS). In the present study, we compared the predictive value of the MMP and EMS in the morbidly obese. METHODS: We performed a prospective study of adult patients with a Body Mass Index (BMI) >= 40 over a 12-mo period comparing the MMP and EMS. The performance-of the MMP, EMS, and other commonly used tests was compared for the ability to predict difficult laryngoscopy, defined as a Cormack-Lehane grade of 3 or 4. Positioning and direct laryngoscopic techniques were not standardized. The incidence of difficult laryngoscopy and difficult intubation was compared in patients with BMI >= or <40. RESULTS: Three-hundred-forty-six patients with a BMI >= 40 were evaluated with both the MMP and EMS and received direct laryngoscopy. On average, craniocervical extension decreased the MMP class (P < 0.0001). Compared to the MMP, the EMS improved specificity and predictive value while maintaining sensitivity. Compared to the MMP and other tests, an EMS class of 3 or 4 and a diagnosis of diabetes mellitus were the only statistically significant predictors of difficult laryngoscopy in the morbidly obese. There was no difference in the incidence of difficult laryngoscopy or intubation in the morbidly obese compared to patients with a BMI <40. CONCLUSIONS: The EMS was superior to the MMP in the prediction of difficult laryngoscopy in the morbidly obese population. A diagnosis of diabetes mellitus also warrants further investigation as a predictor of difficult laryngoscopy in this Population. Finally, this study supports previous findings that morbid obesity is not itself a predictor of difficult laryngoscopy or intubation. C1 [Mashour, George A.; Kheterpal, Sachin; Shanks, Amy; Wang, Luke Y. -J; Tremper, Kevin K.] Univ Michigan, Sch Med, Dept Anesthesiol, Ann Arbor, MI USA. [Vanaharam, Vishnu; Sandberg, Warren S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. RP Mashour, GA (reprint author), 1H247 UH,Box 0048,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM gmashour@umich.edu OI Sandberg, Warren/0000-0002-9246-777X FU Institutional and Departmental Funds FX Supported by Institutional and Departmental Funds. NR 12 TC 29 Z9 31 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 2008 VL 107 IS 6 BP 1919 EP 1923 DI 10.1213/ane.0b013e31818a9946 PG 5 WC Anesthesiology SC Anesthesiology GA 376PZ UT WOS:000261196800026 PM 19020139 ER PT J AU Schmidt, UH Kumwilaisak, K Bittner, E George, E Hess, D AF Schmidt, Ulrich H. Kumwilaisak, Kanya Bittner, Edward George, Edward Hess, Dean TI Effects of Supervision by Attending Anesthesiologists on Complications of Emergency Tracheal Intubation SO ANESTHESIOLOGY LA English DT Article ID RAPID-SEQUENCE INTUBATION; ENDOTRACHEAL INTUBATION; AIRWAY MANAGEMENT; ETOMIDATE AB Background: Emergent intubation is associated with a high complication rate. These intubations are often performed by resident physicians in teaching hospitals. The authors evaluated whether supervision by an anesthesia-trained intensivist decreases complications of emergent intubations. Methods: The authors performed a prospective cohort study in an Academic Tertiary Care Hospital. They enrolled 322 consecutive patients who required emergent intubation between November 1, 2006, and April 15, 2008. Emergency intubations are performed by anesthesia residents during their surgical intensive care unit rotation. An attending anesthesiologist was assigned to supervise these intubations at predetermined periods. A respiratory., therapist assisted with airway management and ventilation. Information related to the intubation, detailing patient demographics, indication for intubation, attending anesthesiologist presence, medications used, and immediate complications, was recorded. Disposition and duration of mechanical ventilation were also recorded. Results: There were no differences in demographics, clinical characteristics, or illness severity among patients intubated with and without attending supervision. Attending physician supervision was associated with a significant decrease in complications (6.1% vs. 21.7%; P = 0.0001). There was no difference in ventilator-free days or 30-day mortality. Conclusion: Supervision by an attending anesthesiologist was associated with a decreased incidence of complications during emergent intubations. C1 [Schmidt, Ulrich H.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Schmidt, UH (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Gray 4,55 Fruit St, Boston, MA 02114 USA. EM uschmidt@partners.org NR 26 TC 65 Z9 66 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD DEC PY 2008 VL 109 IS 6 BP 973 EP 977 DI 10.1097/ALN.0b013e31818ddb90 PG 5 WC Anesthesiology SC Anesthesiology GA 378GR UT WOS:000261309700009 PM 19034093 ER PT J AU Streckenbach, SC AF Streckenbach, Scott C. TI Intraoperative Pacemaker Rate Changes Associated with the Rest Mode SO ANESTHESIOLOGY LA English DT Article ID ACTIVITY VARIANCE; HEART-RATE AB ANESTHESIOLOGISTS frequently are required to provide perioperative management for patients with cardiac rhythm management devices. Here, I describe a case in which despite efforts to ensure that the anesthesia care team Understood the pacemaker and its settings, unanticipated pacing events occurred that created confusion about the status of the pacemaker in a pacemaker-dependent patient. The confusion was created by a relatively new function found in many current Pacemakers, a rest mode. C1 Harvard Univ, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Streckenbach, SC (reprint author), Harvard Univ, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Sch Med, 55 Fruit St, Boston, MA 02114 USA. EM sstreckenbach@partners.org NR 4 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD DEC PY 2008 VL 109 IS 6 BP 1137 EP 1139 DI 10.1097/ALN.0b013e31818db8a6 PG 3 WC Anesthesiology SC Anesthesiology GA 378GR UT WOS:000261309700027 PM 19034111 ER PT J AU Boudreaux, ED Baumann, BM Perry, J Marks, D Francies, S Camargo, CA Ziedonis, D AF Boudreaux, Edwin D. Baumann, Brigitte M. Perry, Jeneva Marks, Donald Francies, Susanna Camargo, Carlos A., Jr. Ziedonis, Douglas TI Emergency Department Initiated Treatments for Tobacco (EDITT): A Pilot Study SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Tobacco; Intervention; Emergency medicine ID BRIEF MOTIVATIONAL INTERVENTION; SMOKING-CESSATION; SMOKERS; PHYSICIANS; ABSTINENCE; SYSTEM; STAGE; CARE AB Emergency departments (EDs) have strong potential to initiate tobacco interventions with economically disadvantaged populations. We piloted three ED-initiated tobacco interventions and derived parameter estimates for future trials. The study enrolled adult patients being treated in an urban ED who were daily smokers. Exclusion criteria included severe illness or pain, isolation (for contagion), altered mental status, an insurmountable language barrier, temporary residence, and lack of telephone access. Subjects in the Bedside + Booster group received motivational counseling by a trained counselor at the bedside, up to three telephone sessions post-visit, and a self-help guide. Subjects in the Faxed Referral group had their personal contact information faxed to the hospital's tobacco dependence clinic, whereupon they received identical treatment as the Bedside + Booster group, but all sessions occurred over the telephone (i.e., no bedside counseling). The Standard Referral group received the self-help guide and a referral to the hospital's tobacco dependence clinic. We used a 2:2:1 randomization schedule to maximize our experience with the motivational interventions. Outcomes were assessed at 1 and 3 months. We enrolled 90 subjects. Of the 36 subjects assigned to the Bedside + Booster condition, 31 (87%) completed bedside counseling and at least one booster session, while 22 (61%) completed the maximum four sessions. Of the 37 subjects assigned to the Faxed Referral group, 28 (76%) completed at least one telephone session, while 19 (51%) completed the maximum four sessions. Quit attempts over the 3 months ranged from 18% (Standard Referral) to 57% (Faxed Referral). Seven-day abstinence was attained by 8% (Bedside + Booster), 14% (Faxed Referral), and 6% (Standard Referral) at 3 months. Motivational cessation counseling can be feasibly initiated during the ED encounter with minimal medical staff involvement. Adequately powered trials are needed to study ED-initiated interventions that include post-visit follow-up. C1 [Boudreaux, Edwin D.; Baumann, Brigitte M.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Camden, NJ 08103 USA. [Boudreaux, Edwin D.; Baumann, Brigitte M.] Cooper Univ Hosp, Dept Emergency Med, Camden, NJ USA. [Boudreaux, Edwin D.] Cooper Univ Hosp, Dept Psychiat, Camden, NJ USA. [Boudreaux, Edwin D.] Cooper Canc Inst, Camden, NJ USA. [Perry, Jeneva; Marks, Donald; Francies, Susanna] LaSalle Univ, Dept Psychol, Philadelphia, PA USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Boston, MA USA. [Ziedonis, Douglas] Univ Massachusetts, Dept Psychiat, Worcester, MA 01605 USA. RP Boudreaux, ED (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Camden, NJ 08103 USA. EM boudreaux-edwin@cooperhealth.edu OI Boudreaux, Edwin/0000-0002-3223-6371 FU NIDA NIH HHS [DA-16698-01, K23 DA016698] NR 33 TC 17 Z9 17 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2008 VL 36 IS 3 BP 314 EP 325 DI 10.1007/s12160-008-9066-3 PG 12 WC Psychology, Multidisciplinary SC Psychology GA 385AU UT WOS:000261786100011 PM 19050988 ER PT J AU Stein, DJ Flessner, CA Franklin, M Keuthen, NJ Lochner, C Woods, DW AF Stein, Dan J. Flessner, Christopher A. Franklin, Martin Keuthen, Nancy J. Lochner, Christine Woods, Douglas W. TI Is Trichotillomania a Stereotypic Movement Disorder? An Analysis of Body-Focused Repetitive Behaviors in People with Hair-Pulling SO ANNALS OF CLINICAL PSYCHIATRY LA English DT Article DE Stereotypic Movement Disorder; Trichotillomania; Body-Focused Repetitive Behaviors; Hair-Pulling; Nail-Biting; Skin-Picking ID OBSESSIVE-COMPULSIVE DISORDER; COLLEGE-STUDENTS; SKIN-PICKING; PREVALENCE; PHENOMENOLOGY; POPULATION; SUBTYPES; HABITS AB Background. Stereotypic; movement disorder (SAID) is characterized by nonfunctional repetitive movements, is typically diagnosed in people with intellectual disability, and by definition excludes people with trichotillomania (TTM). Nevertheless, hair-pulling may be one of a number of body-focused repetitive behaviors (BFRBs) that are seen in the general population. Comorbidity, of symptoms might support the idea that they tire indicative of an underlying stereotypic disorder, and we therefore explored their frequency in people with hair-pulling. Methods. Participants were recruited with the help of the Trichotillomania Learning Center, the largest advocacy group for people with hair-pulling. Participants completed a self-report survey on the Internet, which included questions about tire presence of both hair-pulling and other BFRBs. Measures included the Massachusetts General Hospital Hairpulling Scale (MGH-HS), the Milwaukee Inventory for Subtypes of Trichotillomania-Adult Version (MIST-A), the Depression and Anxiety Stress Scale (DASS), and the Sheehan Disabilty Scale (SDS). Results. The majority of participants with hair-pulling (70%) report the presence of other BFRBs, roost commonly skin-picking and nail-biting. There were particularly strong associations between the total number of BFRBs and increased scores on ratings of focused hair-pulling, depression, anxiety, stress, and functional impairment. Similar results were found in participants who met more rigorous criteria for trichotillomania. Conclusions. This study is limited by its self-report nature, and by the lack of detailed information on the phenomenology of comorbid BFRBs. While further nosological research is needed, the high rates of these behaviors in people with hair-pulling, and their association with increased disability, is consistent with previous clinical observations, and supports the argument that trichotillomania can usefully be conceptualized as a stereotypic disorder. Speculatively, this argument may be especially valid in trichotillomania patients with snore focused hair-pulling symptoms. C1 [Stein, Dan J.] Univ Cape Town, Dept Psychiat, Groote Schuur Hosp, ZA-7925 Cape Town, South Africa. [Flessner, Christopher A.; Woods, Douglas W.] Univ Wisconsin, Milwaukee, WI 53201 USA. [Franklin, Martin] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Keuthen, Nancy J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Lochner, Christine] Univ Stellenbosch, ZA-7600 Stellenbosch, South Africa. RP Stein, DJ (reprint author), Univ Cape Town, Dept Psychiat, Groote Schuur Hosp, S-2 Anzio Rd, ZA-7925 Cape Town, South Africa. EM dan.stein@uct.ac.za RI Citations, TLC SAB/C-4006-2011; Flessner, Christopher/K-1483-2015; Stein, Dan/A-1752-2008 OI Stein, Dan/0000-0001-7218-7810 FU Trichotillomania Learning Center FX This study was funded in part by the Trichotillomania Learning Center. Dr. Stein is supported by the Medical Research Council of South Africa. NR 29 TC 26 Z9 26 U1 1 U2 11 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1040-1237 J9 ANN CLIN PSYCHIATRY JI Ann. Clin. Psychiatry PD DEC PY 2008 VL 20 IS 4 BP 194 EP 198 DI 10.1080/10401230802435625 PG 5 WC Psychiatry SC Psychiatry GA 384EI UT WOS:000261726700002 PM 19034750 ER PT J AU Hazen, EP Reichert, EL Piacentini, JC Miguel, EC Do Rosario, MC Pauls, D Geller, DA AF Hazen, Eric P. Reichert, Elizabeth L. Piacentini, John C. Miguel, Euripedes Constantino Do Rosario, Maria Conceicao Pauls, David Geller, Daniel A. TI Case Series: Sensory Intolerance as a Primary Symptom of Pediatric OCD SO ANNALS OF CLINICAL PSYCHIATRY LA English DT Article DE Obsessive Compulsive Disorder; Sensory Phenomena; Children ID OBSESSIVE-COMPULSIVE DISORDER; TOURETTES DISORDER; REPETITIVE BEHAVIORS; RIGHT EXPERIENCES; ADOLESCENTS; CHILDREN; FEATURES; ONSET AB Introduction. Marked intolerance or intrusive re-experiencing of ordinary sensory stimuli that in turn drive functionally impairing compulsive behaviors are occasionally seen in voting children with OCD. Methods. We describe a number of children with DSM-IV OCD ascertained from of family genetic study of pediatric OCD, whose intolerance: of ordinary sensory stimuli created significant subjective distress and time-consuming ritualistic behavior that was clinically impairing. Results. In each case these sensory symptoms were the primary presenting symptoms and were experienced in the absence of intrusive thoughts, images, or ideas associated with "conventional" OCD symptoms. Conclusions. These symptoms suggest abnormalities in sensory processing and integration in at least a subset of OCD patients. Recognition of these sensory symptoms and sensory-driven behaviors as part of the broad phenotypic Variation in children with OCD could help clinicians more easily identify OCD patients and,facilitate treatment. C1 [Hazen, Eric P.; Reichert, Elizabeth L.; Geller, Daniel A.] Massachusetts Gen Hosp, Dept Psychiat, Clin Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Piacentini, John C.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Miguel, Euripedes Constantino] Univ Sao Paulo, Sch Med, Dept Psychiat, Sao Paulo, Brazil. [Do Rosario, Maria Conceicao] Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo, Brazil. [Pauls, David] Massachusetts Gen Hosp, Dept Psychiat, PNGU, Boston, MA 02114 USA. RP Geller, DA (reprint author), MGH, Pediat OCD Program, YAW 6A,Fruit St, Boston, MA 02114 USA. EM dageller@partern.org RI Miguel, Euripedes/B-2871-2008; Piacentini, John/C-4645-2011; do Rosario, Maria Conceicao/E-5213-2012 OI do Rosario, Maria Conceicao/0000-0002-9687-0072 FU NIMH [K08 MH01481]; Wallace Foundation; Obsessive Compulsive Foundation; Tourette Syndrome Association; McIngvale Family Foundation; NIH; NINDS FX This work has been funded by: NIMH K08 MH01481 and the Wallace Foundation. Dr. Daniel Geller receives/d research support from, is/has been a speaker for, or is/has been on the advisory board for the following Pharmaceutical Companies: Shire, Eli Lilly, Pfizer, Bristol-Myers-Squibb, Novartis, Forest Laboratories, and GlaxoSmithKline. Other Sources of Research Support include Private Foundations: Obsessive Compulsive Foundation, Tourette Syndrome Association, Wallace Foundation, McIngvale Family Foundation and NIH: NIMH, NINDS. NR 27 TC 14 Z9 14 U1 2 U2 8 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1040-1237 J9 ANN CLIN PSYCHIATRY JI Ann. Clin. Psychiatry PD DEC PY 2008 VL 20 IS 4 BP 199 EP 203 DI 10.1080/10401230802437365 PG 5 WC Psychiatry SC Psychiatry GA 384EI UT WOS:000261726700003 PM 19034751 ER PT J AU Howland, RH Wilson, MG Kornstein, SG Clayton, AH Trivedi, MH Wohlreich, MM Fava, M AF Howland, Robert H. Wilson, Michael G. Kornstein, Susan G. Clayton, Anita H. Trivedi, Madhukar H. Wohlreich, Madelaine M. Fava, Maurizio TI Factors Predicting Reduced Antidepressant Response: Experience with the SNRI Duloxetine in Patients with Major Depression SO ANNALS OF CLINICAL PSYCHIATRY LA English DT Article DE Depression; Duloxetine; Predictors; Response; Clinical trial ID STAR-ASTERISK-D; TREATMENT-RESISTANT DEPRESSION; CLINICAL-TRIALS; ATYPICAL DEPRESSION; GENDER-DIFFERENCES; OPEN-LABEL; DISORDER; VENLAFAXINE; OUTPATIENTS; SERTRALINE AB Background: To identify putative demographic and clinical variables that correlate with antidepressant response to the SNRI duloxetine in major depression. Methods: The effect of 130 candidate treatment outcome predictors was examined on 3 dependent treatment outcome measures related to depression: l) depression symptom outcome measured by HAMD-17 total and HAMD-17 percent change from baseline to endpoint, 2) remission (HAMD-17 <= 7 at endpoint) and response (>= 50% reduction in HAMD-17 from baseline to endpoint) rates, and 3) time to response (days to >= 50% reduction in HAMD-17). Results: Eleven variables had an overall predictive index of >= 20% and were associated with poorer treatment outcome: HAMD-17 total, duration of current MDD episode, leaden paralysis, fatigue, HAMA total, HAMA items 2 (aid 8, HAMD-17 anxiety/somatization subscale, anxiety-related comorbid conditions, and VAS overall pain mid pain while awake. Conclusions: Our results highlight the clinical relevance of more severe and/or persistent levels of depression, psychiatric and medical comorbidity, and symptoms characteristic of atypical depression (leaden paralysis and fatigue) and confirm findings from other studies that such patients may respond less well or take longer to respond to pharmacotherapy. Consistent with previous SNRI studies, we found no significant association between age, gender, and race/ethnicity and treatment outcome. C1 [Howland, Robert H.] Univ Pittsburgh, Western Psychiat Inst & Clin, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Wilson, Michael G.] Indiana Univ, Dept Psychiat, Indianapolis, IN 46204 USA. [Kornstein, Susan G.] Virginia Commonwealth Univ, Sch Med, Dept Psychiat, Richmond, VA USA. [Clayton, Anita H.] Univ Virginia Hlth Syst, Ctr Psychiat Clin Res, Charlottesville, VA USA. [Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Depress & Anxiety Disorders Program, Dallas, TX 75390 USA. [Wohlreich, Madelaine M.] Eli Lilly & Co, US Med Div Neurosci, Indianapolis, IN 46285 USA. [Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Howland, RH (reprint author), Univ Pittsburgh, Western Psychiat Inst & Clin, Sch Med, Dept Psychiat, 3811 Ohara St, Pittsburgh, PA 15213 USA. EM HowlandRH@upmc.edu RI Howland, Robert/K-6937-2015 OI Howland, Robert/0000-0002-6533-6010 FU Eli Lilly and Company, Indianapolis. IN, USA; National Institutes of Mental Health; Department of Health and Human Services; Pfizer; BristolMyersSquibb; GlaxoSmithKline; Biovail Laboratories; Novartis Pharmaceuticals FX We also thank the many patients who generously agreed to participate in this clinical trial, and the Clinical Operations staff and statistical analysts of the Duloxetine Antidepressant Team for their excellent implementation of the trial. NR 61 TC 28 Z9 28 U1 1 U2 5 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 1040-1237 J9 ANN CLIN PSYCHIATRY JI Ann. Clin. Psychiatry PD DEC PY 2008 VL 20 IS 4 BP 209 EP 218 DI 10.1080/10401230802437639 PG 10 WC Psychiatry SC Psychiatry GA 384EI UT WOS:000261726700005 PM 19034753 ER PT J AU Pottenger, BC Diercks, DB Bhatt, DL AF Pottenger, Brent C. Diercks, Deborah B. Bhatt, Deepak L. TI Regionalization of Care for ST-Segment Elevation Myocardial Infarction: Is It Too Soon? SO ANNALS OF EMERGENCY MEDICINE LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; GEOGRAPHIC INFORMATION-SYSTEM; EMERGENCY MEDICAL-SERVICES; PRIMARY STROKE CENTERS; UNITED-STATES; 12-LEAD ELECTROCARDIOGRAMS; INTERHOSPITAL TRANSFER; HOSPITAL PERSPECTIVE; THROMBOLYTIC THERAPY; FIBRINOLYTIC THERAPY AB Interest in regionalization of the care of acute ST-segment elevation myocardial infarction (STEMI) has gained momentum recently. Optimal treatment of STEMI involves balancing time to treatment and reperfusion options. Primary percutaneous coronary intervention, when performed in a timely fashion, has been shown to be more effective than fibrinolysis. However, numerous practical barriers prevent many STEMI patients from receiving primary percutaneous coronary intervention. In an effort to increase beneficial primary percutaneous coronary intervention administration to STEMI patients, health care leaders have proposed regionalized STEMI care networks with advanced emergency medical services (EMS) involvement. Constructing regionalized STEMI networks presents a policy challenge because this shift in STEMI care would require changes in current EMS and emergency medicine practices. Therefore, we present various perspectives and issues that decisionmakers and system organizers must address properly before deciding whether to adopt this new model of care. Reorganizing STEMI care in a manner analogous to how trauma and stroke care are currently triaged and treated appeals intuitively; however, given the absence of evidence that STEMI regionalization actually improves patient outcomes and is cost-effective, more research is needed to determine whether STEMI regionalization is an efficient model for providing evidence-based care. The concept of STEMI regionalization represents an effort to inform policy according to evidence-based medicine, but real-world quality, geospatial, financial, cost, business, resource, and practice barriers present obstacles to implementing this concept efficiently and effectively. (Ann Emerg Med. 2008;52:677-685.] C1 [Diercks, Deborah B.] Univ Calif, Dept Emergency Med, Davis Med Ctr, Sacramento, CA 95661 USA. [Pottenger, Brent C.] Univ So Calif, Sch Policy Planning & Dev, Sacramento, CA USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Diercks, DB (reprint author), Univ Calif, Dept Emergency Med, Davis Med Ctr, 2315 Stockton Blvd,PSSB 2100, Sacramento, CA 95661 USA. EM dbdiercks@ucdavis.edu NR 55 TC 13 Z9 16 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD DEC PY 2008 VL 52 IS 6 BP 677 EP 685 DI 10.1016/j.annemergmed.2008.06.004 PG 9 WC Emergency Medicine SC Emergency Medicine GA 381MJ UT WOS:000261540200012 PM 18755524 ER PT J AU Xie, ZC Culley, DJ Dong, YL Zhang, GH Zhang, B Moir, RD Frosch, MP Crosby, G Tanzi, RE AF Xie, Zhongcong Culley, Deborah J. Dong, Yuanlin Zhang, Guohua Zhang, Bin Moir, Robert D. Frosch, Matthew P. Crosby, Gregory Tanzi, Rudolph E. TI The Common Inhalation Anesthetic Isoflurane Induces Caspase Activation and Increases Amyloid beta-Protein Level In Vivo SO ANNALS OF NEUROLOGY LA English DT Article ID MIDDLE CEREBRAL-ARTERY; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; TRANSGENIC MICE; APOPTOSIS; CLEAVAGE; GAMMA; RAT; OLIGOMERIZATION; ACCUMULATION AB objective: An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid (beta-protein (A beta) in cultured cells. However, the in vivo relevance has not been addressed. Methods: We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and A beta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction. \ Results: Here we show or the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BALE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and A beta tip to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the A beta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo. Interpretation: Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane tray promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation. C1 [Xie, Zhongcong; Dong, Yuanlin; Zhang, Guohua; Zhang, Bin; Moir, Robert D.; Tanzi, Rudolph E.] Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Genet & Aging Res Unit, Charlestown, MA 02129 USA. [Xie, Zhongcong; Dong, Yuanlin; Zhang, Guohua; Zhang, Bin; Moir, Robert D.; Frosch, Matthew P.; Tanzi, Rudolph E.] Harvard Univ, Sch Med, Charlestown, MA USA. [Xie, Zhongcong; Dong, Yuanlin; Zhang, Guohua; Zhang, Bin; Tanzi, Rudolph E.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Charlestown, MA 02129 USA. [Culley, Deborah J.; Crosby, Gregory] Brigham & Womens Hosp, Dept Anesthesia, Boston, MA 02115 USA. [Culley, Deborah J.; Crosby, Gregory] Harvard Univ, Sch Med, Boston, MA USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Neurol, Mass Gen Inst Neurodegenerat Dis, Alzheimer Res Unit, Charlestown, MA 02129 USA. RP Xie, ZC (reprint author), Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Genet & Aging Res Unit, 114 16th St,3750, Charlestown, MA 02129 USA. EM zxie@partners.org; gcrosby@zeus.bwh.harvard.edu; tanzi@helix.mgh.harvard.edu FU NIH [K08NINDS048140, R21NIA029856, K08NIGMS077057, R01NIA20253, R37MH 60009]; American Geriatrics Society; Alzheimer's Association; Harvard UniversityDepartment of Anesthesi and Critical Care; Massachusetts General Hospital and Harvard Medical School FX tThis research was supported by the NIH (K08NINDS048140, ZX; R21NIA029856, ZX; K08NIGMS077057, D.J.C.; R01NIA20253, G.C.; R37MH 60009, R.E.T.), Jahnigen Career Development Award from the American Geriatrics Society (Z.X.), Investigator Initiated Research Grant from the Alzheimer's Association (Z.X.), the William Milton Fund of Harvard University (Z.X.), Jahnigen Career Development Award from the American Geriatrics Society (D.J.C.), the Cure Alzheimer's Fund (R.E.T.), and Department of Anesthesi and Critical Care, Massachusetts General Hospital and Harvard Medical School (Y.D., B.Z.). The cost of anesthetic isoflurane was provided by the Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School. NR 35 TC 139 Z9 159 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2008 VL 64 IS 6 BP 618 EP 627 DI 10.1002/ana.21548 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 389RL UT WOS:000262112100005 PM 19006075 ER PT J AU Chou, S Smith, EE Badjatia, N Nogueira, RG Sims, J Ogiluy, CC Rordorf, G Ayata, C Ning, MM Lo, EH Feske, SK AF Chou, Sherry (Hsiang-Yi) Smith, Eric E. Badjatia, Neeraj Nogueira, Raul G. Sims, John, II Ogiluy, Christopher C. Rordorf, Guy Ayata, Cenk Ning, MingMing Lo, Eng H. Feske, Steven K. TI Prophylactic Statin Use and Physiologic Markers of Delayed Cerebral Vasospasm following Aneurysmal Subarachnoid Hemorrhage SO ANNALS OF NEUROLOGY LA English DT Meeting Abstract CT 133rd Annual Meeting of the American-Neurological-Association CY SEP 21-24, 2008 CL Salt Lake City, UT SP Amer Neurol Assoc ID TRIAL C1 [Chou, Sherry (Hsiang-Yi); Feske, Steven K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Cambridge, MA 02138 USA. [Ning, MingMing] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Clin Proteom Res Ctr,Dept Neurol, Cambridge, MA 02138 USA. [Badjatia, Neeraj] Columbia Univ, Coll Phys & Surg, Dept Neurol & Neurosurg, New York, NY 10027 USA. [Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Dept Radiol, Sch Med,Neuroprotect Res Lab, Cambridge, MA 02138 USA. [Ogiluy, Christopher C.] Harvard Univ, Massachusetts Gen Hosp, Dept Neurosurg, Sch Med, Cambridge, MA 02138 USA. [Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Neuroprotect Res Lab, Cambridge, MA 02138 USA. RI Chou, Sherry/G-5779-2015; Smith, Eric/C-5443-2012 OI Smith, Eric/0000-0003-3956-1668 NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2008 VL 64 IS 6 BP S158 EP S159 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 389RL UT WOS:000262112100057 ER PT J AU Kang, PB Kho, AT White, AJ Eisenberg, I North, KN Zatz, M Brown, RH Kunkel, LM AF Kang, P. B. Kho, A. T. White, A. J. Eisenberg, I. North, K. N. Zatz, M. Brown, R. H., Jr. Kunkel, L. M. TI LAMA4 and Laminin-a4 Expression in Dysferlin-Deficient versus Dystrophin-Deficient Human Skeletal Muscle SO ANNALS OF NEUROLOGY LA English DT Meeting Abstract CT 133rd Annual Meeting of the American-Neurological-Association CY SEP 21-24, 2008 CL Salt Lake City, UT SP Amer Neurol Assoc C1 [Kang, P. B.; White, A. J.; Eisenberg, I.; Kunkel, L. M.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Kang, P. B.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Kho, A. T.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [North, K. N.] Childrens Hosp Westmead, Sydney, NSW, Australia. [Zatz, M.] Univ Sao Paulo, Sao Paulo, Brazil. [Brown, R. H., Jr.] Massachusetts Gen Hosp, Day Lab Neuromuscular Res, Boston, MA 02114 USA. [Kunkel, L. M.] Howard Hughes Med Inst, Chevy Chase, MD USA. RI Zatz, Mayana/M-5338-2015 OI Zatz, Mayana/0000-0003-3970-8025 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2008 VL 64 IS 6 BP S148 EP S148 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 389RL UT WOS:000262112100035 ER PT J AU Sims, JR Lee, SW Topalkara, K Qiu, JH Moskowitz, MA AF Sims, John R. Lee, Sae-Won Topalkara, Kamil Qiu, Jianhua Moskowitz, Michael A. TI Sonic Hedgehog Regulates Ischemia/Hypoxia-induced Neural Progenitor Proliferation SO ANNALS OF NEUROLOGY LA English DT Meeting Abstract CT 133rd Annual Meeting of the American-Neurological-Association CY SEP 21-24, 2008 CL Salt Lake City, UT SP Amer Neurol Assoc C1 [Sims, John R.; Lee, Sae-Won; Topalkara, Kamil; Qiu, Jianhua; Moskowitz, Michael A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab,Dept Radiol, Charlestown, MA USA. [Sims, John R.; Lee, Sae-Won; Topalkara, Kamil; Qiu, Jianhua; Moskowitz, Michael A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab,Neurosci Ctr, Charlestown, MA USA. [Sims, John R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab,Dept Neurol, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2008 VL 64 IS 6 BP S154 EP S154 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 389RL UT WOS:000262112100048 ER PT J AU Luthy, SK Ng, AK Silver, B Degnan, KO Fisher, DC Freedman, AS Mauch, PM AF Luthy, S. K. Ng, A. K. Silver, B. Degnan, K. O. Fisher, D. C. Freedman, A. S. Mauch, P. M. TI Response to low-dose involved-field radiotherapy in patients with non-Hodgkin's lymphoma SO ANNALS OF ONCOLOGY LA English DT Article ID FOLLICULAR LYMPHOMA; RADIATION-THERAPY; LOCAL RADIOTHERAPY; STAGE-I AB Background: The purpose of this study was to analyze response to palliative low-dose involved-field radiotherapy (LD-IF-RT) (two 2-Gy fractions), explore factors predicting for response, and determine the time course to subsequent treatment. Patients and methods: Thirty-three patients with advanced or recurrent indolent non-Hodgkin's lymphoma (NHL) received LD-IF-RT to 43 sites. Response was assessed by physical examination and radiographic studies. Median follow-up for individual sites was 14 months. Fisher's exact test was used to evaluate prognostic factors for response and in-field progression. Results: Overall response was 95%. Thirty-six sites (84%) had a complete response (CR), five sites (12%) had a partial response, and two sites (5%) had progressive disease. The CR rate of head and neck sites was significantly higher than that of pelvic and/or inguinofemoral sites (95% versus 64%, P = 0.04). The CR rate was significantly higher for sites <= 40 mm than for sites > 40 mm (90% versus 56%, P = 0.04). Ten sites (23%) had in-field progression diagnosed at a median of 9 months. Sixteen patients (48%) received systemic treatment at a median of 8 months. Fourteen patients (42%) did not require additional treatment. Conclusions: LD-IF-RT for selected NHL subtypes has excellent local CR and in-field control rates and may postpone the need for systemic therapy. C1 [Luthy, S. K.; Ng, A. K.; Silver, B.; Degnan, K. O.; Mauch, P. M.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [Fisher, D. C.; Freedman, A. S.] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Ng, AK (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,L2, Boston, MA 02115 USA. EM ang@lroc.harvard.edu NR 14 TC 17 Z9 17 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD DEC PY 2008 VL 19 IS 12 BP 2043 EP 2047 DI 10.1093/annonc/mdn529 PG 5 WC Oncology SC Oncology GA 376FC UT WOS:000261168500010 PM 18647962 ER PT J AU Martinez-Alvernia, EA Mankarious, LA AF Martinez-Alvernia, Efrain A. Mankarious, Leila A. TI Matrix Metalloproteinases 2 and 9 Are Concentrated in the Luminal Aspect of the Cricoid Cartilage, Diminish With Loss of Perichondrium, and Are Reinstated by Transforming Growth Factor Beta 3 SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE cricoid development; metalloproteinase; subglottic stenosis; transforming growth factor AB Objectives: We determined the location of matrix metalloprotemases (MMP) 2 and 9, and whether the luminal perichondrium or transforming growth factor (TGF) beta 3 influences the presence of MMP-2 and/or -9 within the chondrocytes of the cricoid cartilage. Methods: Subglottises from 15 neonatal mice were divided into group A (N = 5; luminal epithelium intact, grown in basic medium), group B (N = 5; epithelium-free, with sections of luminal perichondrium removed, grown in basic medium), and group C (N = 5; epithelium-free, with sections of luminal perichondrium removed, grown in basic medium with supplemental TGF-beta 3). Immunohistochemical analysis was done to identify MMP-2 and -9 distributions. Results: Group A demonstrated concentrations of MMP-2 and -9 in the luminal perichondrial and adjacent chondrocytes with a gradual decrease in signal intensity toward the outer perichondrium. Group B showed findings similar to those in group A, but in the region of removed perichondrium, the adjacent chondrocytes lost MMP-2 and -9 signal. The group C rings demonstrated reestablishment of MMP-2 and -9 signal in regions of luminal perichondrial loss. Conclusions: Localization of MMP-2 and -9 is predominantly in the luminal perichondrium and gradually decreases toward the outer perichondrium. The luminal perichondrium maintains expression of MMP-2 and -9 within the adjacent chondrocytes. Exogenous TGF-beta 3 reestablishes production of at least MMP-9, and probably MMP-2, in cricoid cartilages missing luminal perichondrium. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Mankarious, LA (reprint author), 243 Charles St, Boston, MA 02114 USA. FU National Institutes of Health [KO8 HL070116] FX Supported by National Institutes of Health grant KO8 HL070116. This study was performed in accordance with the PHS Policy on Humane Care and Use of Laboratory Animals, the NIH Guide for the Care and Use of Laboratory Animals, and the Animal Welfare Act (7 U.S.C. et seq.); the animal use protocol was approved by.the Institutional Animal Care and Use Committee (IACUC) of Massachusetts Eye and Ear Infirmary. NR 6 TC 3 Z9 5 U1 0 U2 1 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD DEC PY 2008 VL 117 IS 12 BP 925 EP 930 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA 386AX UT WOS:000261855800011 PM 19140540 ER PT J AU Schwartzman, A Mascarenhas, WF Taylor, JE AF Schwartzman, Armin Mascarenhas, Walter F. Taylor, Jonathan E. TI INFERENCE FOR EIGENVALUES AND EIGENVECTORS OF GAUSSIAN SYMMETRIC MATRICES SO ANNALS OF STATISTICS LA English DT Article DE Random matrix; maximum likelihood; likelihood ratio test; orthogonally invariant; submanifold; curved exponential family ID LIKELIHOOD RATIO TESTS; DIFFUSION-TENSOR MRI; STATISTICAL-ANALYSIS; EXPONENTIAL FAMILIES; GEOMETRY; REGRESSION AB This article presents maximum likelihood estimators (MLEs) and log-likelihood ratio (LLR) tests for the eigenvalues and eigenvectors of Gaussian random symmetric matrices of arbitrary dimension, where the observations are independent repeated samples from one or two populations. These inference problems are relevant in the analysis of diffusion tensor imaging data and polarized cosmic background radiation data, where the observations are, respectively, 3 x 3 and 2 x 2 symmetric positive definite matrices. The parameter sets involved in the inference problems for eigenvalues and eigenvectors are subsets of Euclidean space that are either affine subspaces, embedded submanifolds that are invariant under orthogonal transformations or polyhedral convex cones. We show that for a class of sets that includes the ones considered in this paper, the MLEs of the mean parameter do not depend on the covariance parameters if and only if the covariance structure is orthogonally invariant. Closed-form expressions for the MLEs and the associated LLRs are derived for this covariance structure. C1 [Schwartzman, Armin] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Schwartzman, Armin] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Mascarenhas, Walter F.] Univ Sao Paulo, Dept Ciencia Comp, Inst Matemat & Estatist, BR-05508090 Sao Paulo, Brazil. [Taylor, Jonathan E.] Stanford Univ, Dept Stat, Stanford, CA 94305 USA. RP Schwartzman, A (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. EM armins@hsph.harvard.edu; walterfm@ime.usp.br; jonathan.taylor@stanford.edu RI Mascarenhas, Walter/B-1538-2013; OI Schwartzman, Armin/0000-0001-5335-1611 FU William R. and Sara Hart Kimball Stanford Graduate Fellowship; Statistical and Applied Mathematical Sciences Institute; CNPq [309470/2006-4]; NSF [DMS-04-0.5970] FX Supported in part by NSF Grant DMS-04-0.5970. NR 34 TC 12 Z9 12 U1 0 U2 2 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 0090-5364 J9 ANN STAT JI Ann. Stat. PD DEC PY 2008 VL 36 IS 6 BP 2886 EP 2919 DI 10.1214/08-AOS628 PG 34 WC Statistics & Probability SC Mathematics GA 398KQ UT WOS:000262731400011 ER PT J AU Cady, B Nathan, NR Michaelson, JS Golshan, M Smith, BL AF Cady, B. Nathan, N. R. Michaelson, J. S. Golshan, M. Smith, B. L. TI Matched Pair Analyses of Stage IV Breast Cancer with or Without Resection of Primary Breast Site SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID PRIMARY TUMOR; SURGICAL ONCOLOGY; IMPROVE SURVIVAL; REGISTRY DATA; METASTASES; CARCINOMA; SURGERY; THERAPY; DISEASE; BENEFIT AB Background: Reports demonstrate improved survival of stage IV breast cancer patients with primary cancer resection. This may result from selection for surgery, rather than biological processes. Methods: We performed matched-pair analysis that minimized potential bias in selecting surgery for primary cancer. Chart review was also performed of 5-year survivors to assess selection bias affecting breast surgery. Results: 19,464 breast cancer patients were identified; 808 (4.2%) were stage IV: 622 were analyzed after eliminating wrong diagnoses or staging, and limiting patients to Massachusetts residents. Matched-pair analysis narrowed or eliminated apparent survival benefit associated with primary site surgery in several comparisons. When the impact of the sequence of systemic and surgical treatments was studied in stage IV patients, 90% 2-year survival occurred in patients receiving chemotherapy first, in contrast to receiving chemotherapy simultaneously with or after surgery, suggesting selection for delayed surgery after excellent response to initial chemotherapy. In bone metastases, the 2-year survival advantage occurred with chemotherapy before surgery; no difference in survival with or without surgery occurred when these treatments were simultaneous. Among 5-year survivors, frequency of primary site surgery after excellent response to systemic therapy, breast surgery in stage III patients incorrectly classified as stage IV, and frequency of oligo metastases all indicated selection bias. Conclusions: Case selection bias in primary breast cancer resection in state IV patients may explain most, if not all, the apparent survival advantage of such surgery. C1 [Cady, B.; Nathan, N. R.; Michaelson, J. S.; Golshan, M.; Smith, B. L.] Harvard Univ, Sch Med, Dept Surg,Gillette Ctr Breast Canc, Massachusetts Gen Hosp,Div Surg Oncol, Boston, MA 02115 USA. [Cady, B.] Cambridge Hosp, Cambridge, MA 02139 USA. [Nathan, N. R.] Harvard Univ, Cambridge, MA 02138 USA. [Michaelson, J. S.] Harvard Univ, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA. [Golshan, M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg,Div Surg Oncol, Boston, MA 02115 USA. RP Cady, B (reprint author), Harvard Univ, Sch Med, Dept Surg,Gillette Ctr Breast Canc, Massachusetts Gen Hosp,Div Surg Oncol, Boston, MA 02115 USA. EM bcady123@comcast.net NR 37 TC 54 Z9 58 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD DEC PY 2008 VL 15 IS 12 BP 3384 EP 3395 DI 10.1245/s10434-008-0085-x PG 12 WC Oncology; Surgery SC Oncology; Surgery GA 382PH UT WOS:000261617400010 PM 18726129 ER PT J AU Kay, J AF Kay, J. TI Nephrogenic systemic fibrosis: a gadolinium-associated fibrosing disorder in patients with renal dysfunction SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID CONTRAST AGENTS; DERMOPATHY; INVOLVEMENT; DIALYSIS; FAILURE; SKIN; GADODIAMIDE; EXPOSURE; DISEASE; TRIGGER AB Nephrogenic systemic fibrosis (NSF) is a debilitating fibrosing disorder that develops in patients with underlying kidney disease following exposure to gadolinium-containing contrast agents. NSF presents with cutaneous hyperpigmentation and induration and joint contractures, but fibrosis may also develop in other organs. NSF has been observed in up to 18% of patients receiving chronic haemodialysis and also may occur in individuals with stages 3 and 4 chronic kidney disease and, occasionally, in individuals who had experienced acute renal failure. Mortality is increased significantly among individuals with NSF. Although no medical treatment has been proved to be universally effective in patients with NSF, imatinib mesylate shows potential as a therapeutic agent and is currently being studied in these patients. C1 [Kay, J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Kay, J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Kay, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Yawkey 2-174,55 Fruit St, Boston, MA 02114 USA. EM jkay@partners.org OI Kay, Jonathan/0000-0002-8970-4260 NR 35 TC 29 Z9 30 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD DEC PY 2008 VL 67 SU 3 BP 66 EP 69 DI 10.1136/ard.2008.102475 PG 4 WC Rheumatology SC Rheumatology GA 375YH UT WOS:000261149200012 ER PT J AU Molloy, ES Singhal, AB Calabrese, LH AF Molloy, E. S. Singhal, A. B. Calabrese, L. H. TI Tumour-like mass lesion: an under-recognised presentation of primary angiitis of the central nervous system SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; GIANT-CELL ARTERITIS; GRANULOMATOUS-ANGIITIS; HODGKINS-DISEASE; BRAIN-TUMOR; VASCULITIS; BIOPSY; PATIENT AB Objective: To describe the occurrence of mass lesions (ML) in primary angiitis of the central nervous system (PACNS) and assess the utility of diagnostic testing and treatment. Methods: We examined the case records of the Cleveland Clinic ( CC), Massachusetts General Hospital (MGH), and the English language medical literature, for biopsy-proven PACNS cases presenting as a solitary ML. Relevant clinical variables were extracted and analysed with JMP software. Results: We identified a total of 38 ML: eight of 202 (4.0%) patients with CC/MGH and 30 of 535 (5.6%) patients with PACNS identified from the medical literature. A higher percentage (13 of 45; 29%) was seen in the amyloid-related angiitis subset. Poorer outcomes were reported in the amyloid group, with five deaths. Of the non-amyloid group, better outcomes were seen in the group treated with corticosteroids and cyclophosphamide as compared with the group treated with corticosteroids alone. Conclusions: Although rare, PACNS should be considered in the differential diagnosis of ML; greater awareness of this manifestation may facilitate more prompt diagnosis and treatment. Biopsy evidence of angiitis is required for diagnosis; specimens should routinely be stained for amyloid. While excision of the lesion may be curative, aggressive immunosuppressive therapy is associated with favourable outcomes and may obviate the need for surgery. C1 [Molloy, E. S.] Cleveland Clin, Dept Rheumat & Immunol Dis, Ctr Vasculitis Care & Res, Cleveland, OH 44195 USA. [Singhal, A. B.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Molloy, ES (reprint author), Cleveland Clin, Dept Rheumat & Immunol Dis, Ctr Vasculitis Care & Res, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM molloye@ccf.org FU NIH-NINDS [R01NS051412, P50NS051343, R01NS38477, P01NS035611] FX ABS: NIH-NINDS R01NS051412; P50NS051343; R01NS38477; P01NS035611 NR 34 TC 37 Z9 38 U1 1 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD DEC PY 2008 VL 67 IS 12 BP 1732 EP 1735 DI 10.1136/ard.2008.096800 PG 4 WC Rheumatology SC Rheumatology GA 371VC UT WOS:000260858800013 PM 18625623 ER PT J AU Aminova, LR Siddiq, A Ratan, RR AF Aminova, Leila R. Siddiq, Ambreena Ratan, Rajiv R. TI Antioxidants, HIF prolyl hydroxylase inhibitors or short interfering RNAs to BNIP3 or PUMA, can prevent prodeath effects of the transcriptional activator, HIF-1 alpha, in a mouse hippocampal neuronal SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; STRESS-INDUCED APOPTOSIS; CELL-DEATH; GLYCOLYTIC-ENZYMES; FACTOR 1-ALPHA; PROTEIN BNIP3; UP-REGULATION; FACTOR-I; EXPRESSION; STABILIZATION AB Hypoxia-inducible factor (HIF) is a transcriptional activator that promotes death or survival in neurons. The regulators and targets of HIF-1 alpha-mediated death remain unclear. We found that prodeath effects of HIF-1 are not attributable to an imbalance in HIF-1 alpha and HIF-1 alpha expression. Rather, the synergistic death caused by oxidative stress and by overexpression of an oxygen-resistant HIF-VP16 in neuroblasts was attributable to transcriptional upregulation of BH3-only prodeath proteins, PUMA or BNIP3. By contrast, overexpression of BNIP3 was not sufficient to potentiate oxidative death. As acidosis is known to activate BNIP3-mediated death, we examined other secondary stresses, such as oxidants or prolyl hydroxylase activity are necessary for exposing the prodeath functions of HIF in neurons. Antioxidants or prolyl hydroxylase inhibition prevented potentiation of death by HIF-1 alpha. Together, these studies suggest that antioxidants and PHD inhibitors abrogate the ability of HIF-mediated transactivation of BH3-only proteins to potentiate oxidative death in normoxia. The findings offer strategies for minimizing the prodeath effects of HIF-1 in neurologic conditions associated with hypoxia and oxidative stress, such as stroke and spinal cord injury. C1 [Aminova, Leila R.] Univ Illinois, Dept Microbiol, Urbana, IL 61802 USA. [Aminova, Leila R.; Siddiq, Ambreena; Ratan, Rajiv R.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Aminova, Leila R.; Siddiq, Ambreena; Ratan, Rajiv R.] BIDMC, Boston, MA USA. [Siddiq, Ambreena; Ratan, Rajiv R.] Cornell Univ, Dept Neurol & Neurosci, Weill Med Coll, Ithaca, NY USA. [Siddiq, Ambreena; Ratan, Rajiv R.] Burke Rehabil Hosp, White Plains, NY USA. [Siddiq, Ambreena; Ratan, Rajiv R.] Cornell Med Res Inst, White Plains, NY USA. RP Aminova, LR (reprint author), Univ Illinois, Dept Microbiol, 601 S Goodwin Ave,CLSL,B128, Urbana, IL 61802 USA. EM aminova@life.uiuc.edu FU New York State Department of Health Center of Research Excellence in Spinal Cord Injury [CO19772]; Adelson Foundation; NIH [RO1NS 40591, RO1NS 46239, RO1NS37060] FX This study was financially supported by New York State Department of Health Center of Research Excellence in Spinal Cord Injury (CO19772), Adelson Foundation, NIH RO1 (NS 40591, NS 46239, and NS37060). NR 31 TC 27 Z9 27 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD DEC PY 2008 VL 10 IS 12 BP 1989 EP 1998 DI 10.1089/ars.2008.2039 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 352XA UT WOS:000259529500001 PM 18774900 ER PT J AU Kazantsev, AG Kolchinsky, AM AF Kazantsev, Aleksey G. Kolchinsky, Alexander M. TI Central Role of alpha-Synuclein Oligomers in Neurodegeneration in Parkinson Disease SO ARCHIVES OF NEUROLOGY LA English DT Article ID SUBSTANTIA-NIGRA; SIRTUINS; METABOLITES; MODEL AB Selective death of nigrostriatal neurons, which leads to Parkinson disease, is explained by misfolding of brain protein alpha-synuclein. Herein, we review the data supporting this concept, propose a scheme of events leading to synuclein-induced neuronal death, and discuss protein deacetylase sirtuins as new potential therapeutic targets involved in this process. C1 [Kazantsev, Aleksey G.] Harvard Univ, Dept Neurol, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Med Sch, Charlestown, MA 02129 USA. [Kolchinsky, Alexander M.] Hlth Front Line Ltd, Champaign, IL USA. RP Kazantsev, AG (reprint author), Harvard Univ, Dept Neurol, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis,Med Sch, Bldg 114,3300 16th St, Charlestown, MA 02129 USA. EM akazantsev@partners.org NR 17 TC 31 Z9 35 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 2008 VL 65 IS 12 BP 1577 EP 1581 DI 10.1001/archneur.65.12.1577 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 380RO UT WOS:000261483100003 PM 19064744 ER PT J AU Dorsey, ER Shoulson, I Leavitt, B Ross, C Beck, CA de Blieck, EA Greenamyre, JT Hersch, SM Kieburtz, K Marder, K McCallum, C Moskowitz, C Oakes, D Rosenblatt, A Shinaman, A Frucht, S Marder, K Moskowitz, C Margolis, R Corey-Bloom, J Hersch, SM Mook, L Shannon, K Jaglin, J Sanchez-Ramos, J Dure, LS Guttman, M Feigin, A Shannon, B Anderson, KE Racette, BA Higgins, D Agarwal, P Seeberger, L Montellano, S Kostyk, S Seward, A Nance, M Raymond, LA Decolongon, J Suchowersky, O Beglinger, L Paulson, H Como, P Barbano, R Zimmerman, C Wojcieszek, J Jog, M Horn, C Colcher, A Geschwind, MD Dubinsky, RM Martin, W Wieler, M LeDoux, MS Harrison, MB Morgan, JC Dill, B Singer, C Quesada, M Kartha, N Wernette, K Frank, S Fernandez, H Jennings, D Kelsey, T Hunter, C Beck, C Bourgeois, K de Blieck, EA Deuel, L McCallum, C McMullen, N Oakes, D Ross, V Rumfola, L Watts, A Weaver, C Winebrenner, T Tariot, PN Watts, A AF Dorsey, E. R. Shoulson, I. Leavitt, B. Ross, C. Beck, C. A. de Blieck, E. A. Greenamyre, J. T. Hersch, S. M. Kieburtz, K. Marder, K. McCallum, C. Moskowitz, C. Oakes, D. Rosenblatt, A. Shinaman, A. Frucht, S. Marder, K. Moskowitz, C. Margolis, R. Corey-Bloom, J. Hersch, S. M. Mook, L. Shannon, K. Jaglin, J. Sanchez-Ramos, J. Dure, L. S. Guttman, M. Feigin, A. Shannon, B. Anderson, K. E. Racette, B. A. Higgins, D. Agarwal, P. Seeberger, L. Montellano, S. Kostyk, S. Seward, A. Nance, M. Raymond, L. A. Decolongon, J. Suchowersky, O. Beglinger, L. Paulson, H. Como, P. Barbano, R. Zimmerman, C. Wojcieszek, J. Jog, M. Horn, C. Colcher, A. Geschwind, M. D. Dubinsky, R. M. Martin, W. Wieler, M. LeDoux, M. S. Harrison, M. B. Morgan, J. C. Dill, B. Singer, C. Quesada, M. Kartha, N. Wernette, K. Frank, S. Fernandez, H. Jennings, D. Kelsey, T. Hunter, C. Beck, C. Bourgeois, K. de Blieck, E. A. Deuel, L. McCallum, C. McMullen, N. Oakes, D. Ross, V. Rumfola, L. Watts, A. Weaver, C. Winebrenner, T. Tariot, P. N. Watts, A. CA Huntington Study Grp TREND-HD Inve TI Randomized Controlled Trial of Ethyl-Eicosapentaenoic Acid in Huntington Disease The TREND-HD Study SO ARCHIVES OF NEUROLOGY LA English DT Article ID PLACEBO-CONTROLLED TRIAL; BETA-OXIDATION; RATING-SCALE; INHIBITION; TESTS; EPA AB Objective: To determine whether ethyl-eicosapentaenoic acid (ethyl-EPA), an omega-3 fatty acid, improves the motor features of Huntington disease. Design: Six-monthmulticenter, randomized, double-blind, placebo-controlled trial followed by a 6-month open-label phase without disclosing initial treatment assignments. Setting: Forty-one research sites in the United States and Canada. Patients: Three hundred sixteen adults with Huntington disease, enriched for a population with shorter trinucleotide (cytosine-adenine-guanine) repeat length expansions. Interventions: Random assignment to placebo or ethyl-EPA, 1 g twice a day, followed by open-label treatment with ethyl-EPA. Main Outcome Measures: Six-month change in the Total Motor Score 4 component of the Unified Huntington's Disease Rating Scale analyzed for all research participants and those with shorter cytosine-adenine-guanine repeat length expansions (< 45). Results: At 6 months, the Total Motor Score 4 point change for patients receiving ethyl-EPA did not differ from that for those receiving placebo. No differences were found in measures of function, cognition, or global impression. Before public disclosure of the 6-month placebo-controlled results, 192 individuals completed the open-label phase. The Total Motor Score 4 change did not worsen for those who received active treatment for 12 continuous months compared with those who received active treatment for only 6 months (2.0-point worsening; P=.02). Conclusion: Ethyl-EPA was not beneficial in patients with Huntington disease during 6 months of placebo-controlled evaluation. C1 [Frucht, S.; Marder, K.; Moskowitz, C.] Columbia Univ, Med Ctr, New York, NY USA. [Margolis, R.] Johns Hopkins Univ, Baltimore, MD USA. [Corey-Bloom, J.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Hersch, S. M.; Mook, L.] Massachusetts Gen Hosp, Charlestown, MA USA. [Shannon, K.; Jaglin, J.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Sanchez-Ramos, J.] Univ S Florida, Tampa, FL USA. [Dure, L. S.] Univ Alabama Birmingham, Birmingham, AL USA. [Guttman, M.] Ctr Movement Disorders, Markham, ON, Canada. [Feigin, A.; Shannon, B.] N Shore Long Isl Jewish Hlth Syst, Manhasset, NY USA. [Anderson, K. E.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Racette, B. A.] Washington Univ, St Louis, MO USA. [Higgins, D.] Albany Med Coll, Albany, NY 12208 USA. [Agarwal, P.; Seeberger, L.; Montellano, S.] Colorado Neurol Inst, Englewood, CO USA. [Kostyk, S.; Seward, A.] Ohio State Univ, Columbus, OH 43210 USA. [Nance, M.] Struthers Parkinsons Ctr, Golden Valley, MN USA. [Raymond, L. A.; Decolongon, J.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Suchowersky, O.] Univ Calgary, Calgary, AB, Canada. [Beglinger, L.; Paulson, H.] Univ Iowa, Iowa City, IA USA. [Wojcieszek, J.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Jog, M.; Horn, C.] London Hlth Sci Ctr, London, ON, Canada. [Colcher, A.] Univ Penn, Philadelphia, PA 19104 USA. [Geschwind, M. D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Dubinsky, R. M.] Univ Kansas, Med Ctr, Kansas City, KS USA. [Martin, W.; Wieler, M.] Univ Alberta, Edmonton, AB, Canada. [LeDoux, M. S.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Harrison, M. B.] Univ Virginia, Charlottesville, VA USA. [Morgan, J. C.; Dill, B.] Med Coll Georgia, Augusta, GA 30912 USA. [Singer, C.; Quesada, M.] Univ Miami, Miami, FL USA. [Kartha, N.; Wernette, K.] Univ Michigan, Ann Arbor, MI 48109 USA. [Frank, S.] Boston Univ, Boston, MA 02215 USA. [Fernandez, H.] Univ Florida, Gainesville, FL USA. [Jennings, D.; Kelsey, T.] Inst Neurodegenerat Disorders, New Haven, CT USA. [Hunter, C.] Baylor Coll Med, Houston, TX 77030 USA. [Tariot, P. N.] Banner Alzheimers Dis Ctr, Phoenix, AZ USA. [Dorsey, E. R.] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14620 USA. RP Dorsey, ER (reprint author), Univ Rochester, Med Ctr, Dept Neurol, 1351 Mt Hope Blvd,Ste 223, Rochester, NY 14620 USA. EM ray.dorsey@ctcc.rochester.edu RI Greenamyre, J. Timothy/B-4049-2011; Raymond, Lynn/A-6664-2010; LeDoux, Mark/I-1390-2013; Sanchez-Ramos, Juan/A-1188-2009 OI Raymond, Lynn/0000-0002-8610-1042; LeDoux, Mark/0000-0002-1748-3390; Sanchez-Ramos, Juan/0000-0002-3391-7857 FU University of Rochester FX This study was funded by a grant from Amarin Neuroscience to the University of Rochester and in turn through subcontracts to the participating research sites. NR 13 TC 39 Z9 39 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9942 EI 1538-3687 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 2008 VL 65 IS 12 BP 1582 EP 1589 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 380RO UT WOS:000261483100004 ER PT J AU Rasper, M Kesari, S AF Rasper, Michael Kesari, Santosh TI Burkitt Lymphoma Presenting as a Rapidly Evolving Cavernous Sinus Syndrome SO ARCHIVES OF NEUROLOGY LA English DT Editorial Material C1 [Kesari, Santosh] Dana Farber Inst, Ctr Neurooncol, Boston, MA 02115 USA. RP Kesari, S (reprint author), Dana Farber Inst, Ctr Neurooncol, Room SW460,44 Binney St, Boston, MA 02115 USA. EM skesari@partners.org RI Kesari, Santosh/E-8461-2013 NR 3 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 2008 VL 65 IS 12 BP 1668 EP 1668 DI 10.1001/archneur.65.12.1668 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 380RO UT WOS:000261483100019 PM 19064758 ER PT J AU Ecoiffier, T El Annan, J Rashid, S Schaumberg, D Dana, R AF Ecoiffier, Tatiana El Annan, Jaafar Rashid, Saadia Schaumberg, Debra Dana, Reza TI Modulation of Integrin alpha(4)beta(1) (VLA-4) in Dry Eye Disease SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID SJOGRENS-SYNDROME; ADHESION MOLECULES; OCULAR SURFACE; CELLS; CYTOKINES; PATHWAY; UVEITIS; MODEL; GAMMA AB Objective: To study the effect of topical application of very late antigen 4 (VLA-4) small-molecule antagonist (anti-VLA-4 sm) in a mouse model of dry eye disease. Methods: Anti-VLA-4 sm (or control vehicle) was applied topically to mice placed in a controlled-environment chamber. Corneal fluorescein staining and conjunctival T-cell enumeration were performed in the different treatment groups. Real-time polymerase chain reaction was used to quantify expression of inflammatory cytokines in the cornea and conjunctiva. Results: Dry eye syndrome induced increased corneal fluorescein staining, corneal and conjunctival tumor necrosis factor alpha messenger RNA expression, and T-cell infiltration into the conjunctiva. Very late antigen 4 blockade significantly decreased corneal fluorescein staining compared with the untreated dry eye disease and control vehicle-treated groups (P<.001 and P=.02, respectively). In addition, VLA-4 blockade was associated with a significant decrease in conjunctival T-cell numbers (P<.001 vs control vehicle-treated group) and tumor necrosis factor-alpha transcript levels in the cornea (P=.04 vs control vehicle-treated group) and conjunctiva (P=.048 vs control vehicle-treated group). Conclusion: Application of topical anti-VLA-4 sm led to a significant decrease in dry eye signs and suppression of inflammatory changes at the cellular and molecular levels. C1 [Ecoiffier, Tatiana; El Annan, Jaafar; Rashid, Saadia; Schaumberg, Debra; Dana, Reza] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [Ecoiffier, Tatiana; El Annan, Jaafar; Rashid, Saadia; Schaumberg, Debra; Dana, Reza] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Schaumberg, Debra] Brigham & Womens Hosp, Div Ophthalm Epidemiol, Boston, MA 02115 USA. [Dana, Reza] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Dana, R (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM reza.dana@schepens.harvard.edu FU Biogen Idec, Inc FX This study was supported by a research grant from Biogen Idec, Inc, to Dr Dana. NR 31 TC 32 Z9 33 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2008 VL 126 IS 12 BP 1695 EP 1699 DI 10.1001/archopht.126.12.1695 PG 5 WC Ophthalmology SC Ophthalmology GA 380RA UT WOS:000261481700012 PM 19064851 ER PT J AU Nathan, DM AF Nathan, David M. CA Diabet Control & Complications TI Prolonged Effect of Intensive Therapy on the Risk of Retinopathy Complications in Patients With Type 1 Diabetes Mellitus 10 Years After the Diabetes Control and Complications Trial SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID PROGRESSION; INTERVENTIONS; EPIDEMIOLOGY; NEPHROPATHY; GLYCATION; COHORT AB Objective: To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. Methods: Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. Results: After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P<.001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P<.001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. Conclusion: The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. C1 [Nathan, David M.] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. RP Nathan, DM (reprint author), Massachusetts Gen Hosp, Diabet Unit, Bulfinch 408,55 Fruit St, Boston, MA 02114 USA. EM dnathan@partners.org OI Shamoon, Harry/0000-0002-5014-5211; orchard, trevor/0000-0001-9552-3215; Lachin, John/0000-0001-9838-2841; Paterson, Andrew/0000-0002-9169-118X FU Division of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; General Clinical Research Centers Program; National Center for Research Resources; Genentech, Inc FX DCCT/EDIC is sponsored through research contracts from the Division of Diabetes, Endocrinology, and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health. Additional support is provided by the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health, and by Genentech, Inc, through a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases. NR 27 TC 50 Z9 51 U1 0 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9950 EI 1538-3601 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2008 VL 126 IS 12 BP 1707 EP 1715 PG 9 WC Ophthalmology SC Ophthalmology GA 380RA UT WOS:000261481700014 PM 19064853 ER PT J AU Radulovic, M Schilero, GJ Wecht, JM Weir, JP Spungen, AM Bauman, WA Lesser, M AF Radulovic, Miroslav Schilero, Gregory J. Wecht, Jill M. Weir, Joseph P. Spungen, Ann M. Bauman, William A. Lesser, Marvin TI Airflow Obstruction and Reversibility in Spinal Cord Injury: Evidence for Functional Sympathetic Innervation SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE Anticholinergic agents; Plethysmography; whole body; Pulmonary function tests; Rehabilitation; Spinal cord injuries; Spirometry ID FORCED OSCILLATION TECHNIQUE; HEALTHY NONSMOKING ADULTS; LOWER RESPIRATORY-TRACT; PULMONARY-FUNCTION; ESSENTIAL HYPERHIDROSIS; AIRWAYS OBSTRUCTION; SMOOTH-MUSCLE; SPIROMETRY; NERVES; PLETHYSMOGRAPHY AB Objectives: The first objective was to assess group differences for specific airway conductance (sGaw) among subjects with tetraplegia, high paraplegia (HP: T2-T6), and low paraplegia (LP: T10-L4). The second objective was to determine the significance of responsiveness to ipratropium bromide (IB) by the assessment of the inherent variability of baseline measurements for impulse oscillation (IOS), body plethysmography, and spirometry. Design: Prospective cross-sectional intervention study. Setting: James J. Peters Veterans Administration Medical Center. Participants: Subjects (N=43): 12 with tetraplegia (C4-8), 11 with HP, 11 with LP, and 9 controls. Interventions: Not applicable. Main Outcome Measures: Measurement of IOS, body plethysmography, and spirometry parameters at baseline and 30 minutes after IB. Results: Baseline sGaw was significantly lower in tetraplegia (0.14 +/- 0.03) compared with HP (0.19 +/- 0.05) and LP (0.19 +/- 0.04) patients. By use of minimal difference to evaluate IB responsiveness in tetraplegia, 4 of 12 and 12 of 12 subjects had significant increases in forced expiratory volume in I second and sGaw, respectively, whereas I I of 12 and 10 of 12 subjects had significant decreases in respiratory resistances measured at 5 and 20Hz (R5 and R20), respectively. Conclusions: The finding of group differences for baseline sGaw supports the hypothesis that human lung contains functional sympathetic innervation. Body plethysmography and IOS were comparable in detecting IB-induced bronchodilation in tetraplegia and significantly more sensitive than spirometry. C1 [Radulovic, Miroslav; Schilero, Gregory J.; Wecht, Jill M.; Spungen, Ann M.; Bauman, William A.; Lesser, Marvin] James J Peters VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, Bronx, NY 10468 USA. [Radulovic, Miroslav; Schilero, Gregory J.; Wecht, Jill M.; Spungen, Ann M.; Bauman, William A.] James J Peters VA Med Ctr, Vet Affairs Rehabil Res & Dev Serv, Bronx, NY 10468 USA. [Radulovic, Miroslav; Schilero, Gregory J.; Wecht, Jill M.; Spungen, Ann M.; Bauman, William A.] James J Peters VA Med Ctr, Dept Med, Bronx, NY 10468 USA. [Spungen, Ann M.; Bauman, William A.] James J Peters VA Med Ctr, Spinal Cord Injury Serv, Bronx, NY 10468 USA. [Schilero, Gregory J.; Wecht, Jill M.; Spungen, Ann M.; Bauman, William A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Wecht, Jill M.; Spungen, Ann M.; Bauman, William A.] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. [Weir, Joseph P.] Des Moines Univ, Osteopath Med Ctr, Des Moines, IA USA. RP Radulovic, M (reprint author), James J Peters VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, Room 1E-02,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM Miroslav.Radulovic@va.gov FU Veterans Administration Rehabilitation Research and Development Center of Excellence [B4162C] FX Supported by the Veterans Administration Rehabilitation Research and Development Center of Excellence (grant no. B4162C). NR 35 TC 13 Z9 13 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 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD DEC PY 2008 VL 89 IS 12 BP 2349 EP 2353 DI 10.1016/j.apmr.2008.06.011 PG 5 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 385GY UT WOS:000261803900017 PM 19061747 ER PT J AU Antonacci, AC Lam, S Lavarias, V Homel, P Eavey, RD AF Antonacci, Anthony C. Lam, Steven Lavarias, Valentina Homel, Peter Eavey, Roland D. TI Benchmarking Surgical Incident Reports Using a Database and a Triage System to Reduce Adverse Outcomes SO ARCHIVES OF SURGERY LA English DT Article ID PATIENT SAFETY EVENT; TRANSFUSION MEDICINE; TAXONOMY; SURGERY; CLASSIFICATION; QUALITY; ERRORS; ROOM AB Objective: To study the profile of incidents affecting quality outcomes after surgery by developing a usable operating room and perioperative clinical incident report database and a functional electronic classification, triage, and reporting system. Previously, incident reports after surgery were handled on an individual, episodic basis, which limited the ability to perceive actuarial patterns and meaningfully improve outcomes. Design, Setting, and Participants: Clinical incident reports were experientially generated in the second largest health care system in New York City. Data were entered into a functional classification system organized into 16 categories, and weekly triage meetings were held to electronically review and report summaries on 40 to 60 incident reports per week. System development and deployment reviewed 1041 reports after 19 693 operative procedures. During the next 4 years, 3819 additional reports were generated from 83 988 operative procedures and were reported electronically to the appropriate departments. Main Outcome Measures: Number of incident reports generated annually. Results: A significant decrease in volume-adjusted clinical incident reports occurred ( from 53 to 39 reports per 1000 procedures) from 2001 to 2005 ( P < .001). Reductions in incident reports were observed for ambulatory conversions ( 74% reduction), wasted implants ( 65%), skin breakdown ( 64%), complications in the operating room ( 42%), laparoscopic conversions ( 32%), and cancellations ( 23%) as a result of data-focused process and clinical interventions. Six of 16 categories of incident reports accounted for more than 88% of all incident reports. Conclusion: These data suggest that effective review, communication, and summary feedback of clinical incident reports can produce a statistically significant decrease in adverse outcomes. C1 [Antonacci, Anthony C.] Cornell Univ, Weill Med Coll, Dept Surg, New York, NY 10021 USA. [Antonacci, Anthony C.] Christ Hosp, Dept Med Affairs & Qual Improvement, Jersey City, NJ 07024 USA. [Lam, Steven] Lenox Hill Hosp, Dept Surg, New York, NY 10021 USA. [Antonacci, Anthony C.; Lavarias, Valentina] Beth Israel Deaconess Med Ctr, Dept Surg, New York, NY 10003 USA. [Homel, Peter] Beth Israel Deaconess Med Ctr, Dept Pain Management & Palliat Care, New York, NY 10003 USA. [Eavey, Roland D.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Pediat Otolaryngol Serv, Boston, MA 02114 USA. [Eavey, Roland D.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Antonacci, AC (reprint author), Christ Hosp, Dept Med Affairs & Qual Improvement, 176 Palisade Ave, Jersey City, NJ 07024 USA. EM aantonacci@gmail.com NR 24 TC 3 Z9 3 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD DEC PY 2008 VL 143 IS 12 BP 1192 EP 1197 PG 6 WC Surgery SC Surgery GA 384JO UT WOS:000261741300011 PM 19075171 ER PT J AU Leen, LLS Filipe, C Billon, A Garmy-Susini, B Jalvy, S Robbesyn, F Daret, D Allieres, C Rittling, SR Werner, N Nickenig, G Deutsch, U Duplaa, C Dufourcq, P Lenfant, FO Desgranges, C Arnal, JF Gadeau, AP AF Leen, Laetitia Lam Shang Filipe, Cedric Billon, Audrey Garmy-Susini, Barbara Jalvy, Sandra Robbesyn, Fanny Daret, Daniele Allieres, Cecile Rittling, Susan R. Werner, Nikos Nickenig, Georg Deutsch, Urban Duplaa, Cecile Dufourcq, Pascale Lenfant, Francoise Desgranges, Claude Arnal, Jean-Francois Gadeau, Alain-Pierre TI Estrogen-Stimulated Endothelial Repair Requires Osteopontin SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE endothelium; endothelial cells; hormone; bone marrow cells; wound healing; osteopontin ID SECRETED PHOSPHOPROTEIN-1 OSTEOPONTIN; SMOOTH-MUSCLE-CELLS; RAT CAROTID-ARTERY; IN-VITRO; ACCELERATES REENDOTHELIALIZATION; RECEPTOR-ALPHA; NEOINTIMAL FORMATION; GENE-EXPRESSION; LOCAL-DELIVERY; BONE AB Objective - Estradiol (E-2) is known to accelerate reendothelialization and thus prevent intimal thickening and in-stent restenosis after angioplasty. Transplantation experiments with ER alpha(-/-) mice have previously shown that E-2 acts through local and bone marrow cell compartments to enhance endothelial healing. However, the downstream mechanisms induced by E-2 to mediate endothelial repair are still poorly understood. Methods and Results - We show here that after endovascular carotid artery injury, E-2-enhanced endothelial repair is lost in osteopontin-deficient mice (OPN-/-). Transplantation of OPN-/- bone marrow into wild- type lethally irradiated mice, and vice versa, suggested that osteopontin plays a crucial role in both the local and the bone marrow actions of E-2. In the vascular compartment, using transgenic mice expressing doxycyclin regulatable-osteopontin, we show that endothelial cell specific osteopontin overexpression mimics E-2-enhanced endothelial cell migration and proliferation in the regenerating endothelium. In the bone marrow cell compartment, we demonstrate that E-2 enhances bone marrow - derived mononuclear cell adhesion to regenerating endothelium in vivo, and that this effect is dependent on osteopontin. Conclusions - We demonstrate here that E-2 acceleration of the endothelial repair requires osteopontin, both for bone marrow-derived cell recruitment and for endothelial cell migration and proliferation. (Arterioscler Thromb Vasc Biol. 2008;28:2131-2136.) C1 [Leen, Laetitia Lam Shang; Jalvy, Sandra; Robbesyn, Fanny; Daret, Daniele; Allieres, Cecile; Duplaa, Cecile; Dufourcq, Pascale; Desgranges, Claude; Gadeau, Alain-Pierre] INSERM, U828, F-33600 Pessac, France. [Leen, Laetitia Lam Shang; Jalvy, Sandra; Robbesyn, Fanny; Daret, Daniele; Allieres, Cecile; Duplaa, Cecile; Dufourcq, Pascale; Desgranges, Claude; Gadeau, Alain-Pierre] Univ Bordeaux Victor Segalen, IFR4, Bordeaux, France. [Filipe, Cedric; Billon, Audrey; Garmy-Susini, Barbara; Lenfant, Francoise; Arnal, Jean-Francois] Fac Med Toulouse, INSERM, U858, F-31073 Toulouse, France. [Filipe, Cedric; Billon, Audrey; Garmy-Susini, Barbara; Lenfant, Francoise; Arnal, Jean-Francois] Univ Toulouse Paul Sabatier, CHU Toulouse Rangueil, I2MR, Toulouse, France. [Rittling, Susan R.] Harvard Univ, Forsyth Dent Inst, Boston, MA 02115 USA. [Werner, Nikos; Nickenig, Georg] Univ Bonn, Med Klin & Poliklin 2, D-5300 Bonn, Germany. [Deutsch, Urban] Univ Bern, Theodor Kocher Inst, CH-3012 Bern, Switzerland. RP Gadeau, AP (reprint author), INSERM, U828, Ave Haut Leveque, F-33600 Pessac, France. EM alain.gadeau@inserm.fr RI Garmy-Susini, Barbara/B-9735-2014; Dufourcq, Pascale/A-2665-2012 FU Conseil Regional d'Aquitaine; Communaute de Travail des Pyrenees, ANR [A05109GS]; Fondation de France; European Vascular Genomics Network; European Community [LSHM-CT-2003-503254]; French Research Ministry and the Aquitaine Region FX This study was supported by grants from Conseil Regional d'Aquitaine (action inter-regionale Aquitaine Midi Pyrenees), Communaute de Travail des Pyrenees, ANR (A05109GS), Fondation de France (program sante), and the European Vascular Genomics Network (www.evgn.org), a Network of Excellence supported by the European Community's sixth Framework Programme for Research Priority "Life sciences, genomics and biotechnology for health" (contract LSHM-CT-2003-503254). L.L.S.L. and F.R. were recipients of fellowships from the French Research Ministry and the Aquitaine Region, respectively. NR 42 TC 14 Z9 17 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD DEC PY 2008 VL 28 IS 12 BP 2131 EP U54 DI 10.1161/ATVBAHA.108.167965 PG 18 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 374GG UT WOS:000261031200009 PM 18772499 ER PT J AU Andersen, B Colburn, K Richard, W Green, L AF Andersen, Bradley Colburn, Keith Richard, Weisbart Green, Lora TI Cellular Penetration and Localization of the Anti-guanosine Antibody 4h2 SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Andersen, Bradley; Colburn, Keith; Green, Lora] LLUMC, Redlands, CA USA. [Richard, Weisbart] Vet Affairs Greater Los Angeles Hlth Syst, Sepulveda, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD DEC PY 2008 VL 58 IS 12 BP 3983 EP 3984 PG 2 WC Rheumatology SC Rheumatology GA 382EI UT WOS:000261587500070 ER PT J AU Silva, F Seo, P Schroeder, D Stone, JH Merkel, PA Spiera, R Hoffman, GS Sebastian, JK Davis, JC St Clair, EW McCune, IJ Ytterberg, SR Specks, U AF Silva, Francisco Seo, Philip Schroeder, Darrell Stone, John H. Merkel, Peter A. Spiera, Robert Hoffman, Gary S. Sebastian, Jodi K. Davis, John C. St Clair, E. William McCune, In Joseph Ytterberg, Steven R. Specks, Ulrich TI Association of Solid Malignancies and Treatment with Etanercept in Patients with Wegener's Granulomatosis: Long-term data from a Multicenter Longitudinal Cohort. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Silva, Francisco; Schroeder, Darrell; Ytterberg, Steven R.; Specks, Ulrich] Mayo Clin, Rochester, MN USA. [Seo, Philip] Johns Hopkins Univ, Baltimore, MD USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Merkel, Peter A.; Sebastian, Jodi K.] Boston Univ, Boston, MA 02215 USA. [Spiera, Robert] Hosp Special Surg, New York, NY 10021 USA. [Hoffman, Gary S.] Cleveland Clin, Cleveland, OH 44106 USA. [Davis, John C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [St Clair, E. William] Duke Univ, Durham, NC USA. [McCune, In Joseph] Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD DEC PY 2008 VL 58 IS 12 BP 3998 EP 3998 PG 1 WC Rheumatology SC Rheumatology GA 382EI UT WOS:000261587500106 ER PT J AU Desai, SP Januzzi, JL Pande, AN Pomerantsev, EV Resnic, FS Fossel, AH Chibnik, LB Solomon, DH AF Desai, Sonali P. Januzzi, James L. Pande, Ashvin N. Pomerantsev, Eugene V. Resnic, Frederic S. Fossel, Anne H. Chibnik, Lori B. Solomon, Daniel H. TI Comparison of Coronary Artery Disease among Rheumatoid Arthritis Patients and Matched Controls Undergoing Percutaneous Coronary Intervention. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Desai, Sonali P.; Resnic, Frederic S.; Fossel, Anne H.; Chibnik, Lori B.; Solomon, Daniel H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Januzzi, James L.; Pomerantsev, Eugene V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pande, Ashvin N.] Caritas St Elizabeths Med Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD DEC PY 2008 VL 58 IS 12 BP 4002 EP 4003 PG 2 WC Rheumatology SC Rheumatology GA 382EI UT WOS:000261587500118 ER PT J AU Vogt, DS Proctor, SP King, DW King, LA Vasterling, JJ AF Vogt, Dawne S. Proctor, Susan P. King, Daniel W. King, Lynda A. Vasterling, Jennifer J. TI Validation of Scales From the Deployment Risk and Resilience Inventory in a Sample of Operation Iraqi Freedom Veterans SO ASSESSMENT LA English DT Article DE war-zone exposure; military deployments; veterans; Operation Iraqi Freedom; psychometric evaluation ID POSTTRAUMATIC-STRESS-DISORDER; MALE VIETNAM VETERANS; MENTAL-HEALTH PROBLEMS; WAR-ZONE STRESSORS; LIFE-EVENTS; PSYCHOLOGICAL-ASSESSMENT; MILITARY PERSONNEL; CONSTRUCT-VALIDITY; MEDICAL OUTCOMES; NATIONAL SAMPLE AB The Deployment Risk and Resilience Inventory (DRRI) is a suite of scales that can be used to assess deployment-related factors implicated in the health and well-being of military veterans. Although initial evidence for the reliability and validity of DRRI scales based on Gulf War veteran samples is encouraging, evidence with respect to a more contemporary cohort of Operation Iraqi Freedom (OIF) veterans is not available. Therefore, the primary goal of the present study was to validate scales from the DRRI in a large sample of OIF army personnel diversified in occupational and demographic characteristics. In general, results supported the use of these DRRI scales in this population. Internal consistency reliability estimates were quite strong. Additionally, support was obtained for criterion-related validity, as demonstrated by associations with mental and physical health measures, and discriminative validity, as demonstrated by differences between key military subgroups. C1 [Vogt, Dawne S.] Boston Univ, Natl Ctr PTSD, Womens Hlth Sci Div, VA Boston Healthcare Syst,Dept Psychiat,Sch Med, Boston, MA 02215 USA. [King, Lynda A.] Boston Univ, Natl Ctr PTSD, Womens Hlth Sci Div, VA Boston Healthcare Syst,Dept Psychol, Boston, MA 02215 USA. [King, Daniel W.] Boston Univ, Natl Ctr PTSD, VA Boston Healthcare Syst, Behav Sci Div,Dept Psychol, Boston, MA 02215 USA. [Vasterling, Jennifer J.] Boston Univ, Natl Ctr PTSD, VA Boston Healthcare Syst, Behav Sci Div,Dept Psychiat,Sch Med,Psychol Serv, Boston, MA 02215 USA. [Proctor, Susan P.] Boston Univ, VA Boston Healthcare Syst, Dept Environm Hlth,Sch Publ Hlth,Res Serv, USA,Res Inst Environm Med,Mil Performance Div, Boston, MA 02215 USA. RP Vogt, DS (reprint author), VA Boston Healthcare Syst 116B5, Womens Hlth Sci Div, 150 S Huntington Ave, Boston, MA 02130 USA. EM dawne.vogt@va.gov NR 67 TC 35 Z9 35 U1 3 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1073-1911 J9 ASSESSMENT JI Assessment PD DEC PY 2008 VL 15 IS 4 BP 381 EP 403 DI 10.1177/1073191108316030 PG 13 WC Psychology, Clinical SC Psychology GA 373TN UT WOS:000260996500001 ER PT J AU Stone, RM AF Stone, Richard M. TI Are new agents really making a difference in MDS? SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE myelodysplastic syndromes; lenalidomide; azacitidine; decitabine ID ACUTE MYELOID-LEUKEMIA; FAMESYLTRANSFERASE INHIBITOR TIPIFARNIB; RISK MYELODYSPLASTIC SYNDROME; TRANS-RETINOIC ACID; PHASE-III; CELL TRANSPLANTATION; APLASTIC-ANEMIA; BONE-MARROW; GROUP-B; LENALIDOMIDE AB Myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow stem cell disorders characterized by dysplastic hypercellular marrows with peripheral cytopenias. The Leukemia & Lymphoma Society estimates the annual US incidence of MDS is at least 12,000. MDS occurs primarily in people over 60 years old. The pathophysiology of most subtypes of MDS is poorly understood. Treating MDS remains a challenge despite the availability of new agents, such as lenalidomide, azacitidine, and decitabine. Whether these drugs have made a real difference in treating this group of diseases remains controversial. C1 [Stone, Richard M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Stone, Richard M.] Dana Farber Canc Inst, Adult Leukemia Program, Boston, MA 02115 USA. RP Stone, RM (reprint author), Harvard Univ, Sch Med, 44 Binney St, Boston, MA 02115 USA. EM rstone@partners.org NR 33 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 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD DEC PY 2008 VL 21 IS 4 BP 639 EP 646 DI 10.1016/j.beha.2008.06.004 PG 8 WC Hematology SC Hematology GA 386JL UT WOS:000261879400006 PM 19041603 ER PT J AU Rogers, JT Bush, AI Cho, HH Smith, DH Thomson, AM Friedlich, AL Lahiri, DK Leedman, PJ Huang, XD Cahill, CM AF Rogers, Jack T. Bush, Ashley I. Cho, Hyan-Hee Smith, Deborah H. Thomson, Andrew M. Friedlich, Avi L. Lahiri, Deboni K. Leedman, Peter J. Huang, Xudong Cahill, Catherine M. TI Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article DE amyloid precursor protein (APP); copper; ferritin; iron; oxidative stress; zinc ID HEMOCHROMATOSIS GENE HFE; RESPONSIVE ELEMENT; 5'-UNTRANSLATED REGION; POLY(C)-BINDING PROTEINS; H-FERRITIN; IN-VIVO; BETA; METAL; DESFERRIOXAMINE; CELLS AB The essential metals iron, zinc and copper deposit near the A beta (amyloid p-peptide) plaques in the brain cortex of AD (Alzheimer's disease) patients. Plaque-associated iron and zinc are in neurotoxic excess at 1 mM concentrations. APP (amyloid precursor protein) is a single transmembrane metalloprotein cleaved to generate the 40-42-amino-acid A beta s, which exhibit metal-catalysed neurotoxicity. in health, ubiquitous APP is cleaved in a non-amyloidogenic pathway within its A beta domain to release the neuroprotective APP ectodomain, APP(s). To adapt and counteract metal-catalysed oxidative stress, as during reperfusion from stroke, iron and cytokines induce the translation of both APP and ferritin (an iron storage protein) by similar mechanisms. We reported that APP was regulated at the translational level by active IL (interleukin)-1 (IL-1-responsive acute box) and IRE (iron-responsive element) RNA stem-loops in the S' untranslated region of APP mRNA. The APP IRE is homologous with the canonical IRE RNA stem-loop that binds the iron regulatory proteins (IRP1 and IRP2) to control intracellular iron homoeostasis by modulating ferritin mRNA translation and transferrin receptor mRNA stability. The APP IRE interacts with IRP1 (cytoplasmic cis-aconitase), whereas the canonical H-ferritin IRE RNA stem-loop binds to IRIP2 in neural cell lines, and in human brain cortex tissue and in human blood lysates. The same constellation of RNA-binding proteins [IRP1/IRP2/poly(C) binding protein] control ferritin and APP translation with implications for the biology of metals in AD. C1 [Rogers, Jack T.; Cho, Hyan-Hee; Friedlich, Avi L.; Huang, Xudong; Cahill, Catherine M.] Massachusetts Gen Hosp, Neurochem Lab, Dept Psychiat, Charlestown, MA 02129 USA. [Bush, Ashley I.] Mental Hlth Res Inst Victoria, Parkville, Vic 3052, Australia. [Smith, Deborah H.] Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06510 USA. [Thomson, Andrew M.] Genome Inst Singapore, Singapore 138672, Singapore. [Lahiri, Deboni K.] Indiana Univ, Sch Med, Dept Psychiat & Med & Mol Genet, Inst Psychiat Res, Indianapolis, IN 46202 USA. [Leedman, Peter J.] Univ Western Australia, Lab Canc Med, Med Res Ctr, Western Australian Inst Med Res, Perth, WA 6009, Australia. [Leedman, Peter J.] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia. [Huang, Xudong] Brigham & Womens Hosp, Dept Radiol, Conjugate & Med Chem Lab, Boston, MA 02115 USA. [Huang, Xudong] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Rogers, JT (reprint author), Massachusetts Gen Hosp, Neurochem Lab, Dept Psychiat, Charlestown, MA 02129 USA. EM jrogers@partners.org RI Leedman, Peter/O-4044-2014; Bush, Ashley/A-1186-2007 OI Bush, Ashley/0000-0001-8259-9069 FU NIA NIH HHS [R01 AG018379, R01 AG018379-09, R01 AG018884, R01 AG018884-07] NR 46 TC 55 Z9 56 U1 3 U2 13 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD DEC PY 2008 VL 36 BP 1282 EP 1287 DI 10.1042/BST0361282 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 384MP UT WOS:000261749200037 PM 19021541 ER PT J AU Takahashi, K AF Takahashi, Kazue TI Lessons learned from murine models of mannose-binding lectin deficiency SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article DE IgM; innate immunity; mannose-binding lectin (MBL); mannose-binding lectin-associated serine protease (MASP); murine model; pathogen ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; RA-REACTIVE FACTOR; SERINE-PROTEASE; STAPHYLOCOCCUS-AUREUS; PATTERN-RECOGNITION; BACTERICIDAL FACTOR; COMPLEMENT PATHWAY; REPERFUSION INJURY; INNATE IMMUNITY; GENE AB MBL (mannose-binding lectin) is a pattern recognition molecule and a component of innate immunity, the first line of the host defence system against foreign bodies and pathogens. MBL deficiency is common in humans and has been associated with immunodeficiency. We have generated mouse models of MBL deficiency in order to explore the molecular mechanisms of MBL function in disease and health. in addition to confirming findings from human clinical research, these model studies have uncovered unexpected roles of MBL and evidence of its interaction with other molecules of the innate immune system. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Programs Dev Immunol, Boston, MA 02114 USA. RP Takahashi, K (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Programs Dev Immunol, 55 Fruit St,GRJ1402, Boston, MA 02114 USA. EM ktakahashi1@partners.org NR 35 TC 8 Z9 13 U1 0 U2 2 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD DEC PY 2008 VL 36 BP 1487 EP 1490 DI 10.1042/BST0361487 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 384MP UT WOS:000261749200077 PM 19021581 ER PT J AU Devaraj, NK Weissleder, R Hilderbrand, SA AF Devaraj, Neal K. Weissleder, Ralph Hilderbrand, Scott A. TI Tetrazine-Based Cycloadditions: Application to Pretargeted Live Cell Imaging SO BIOCONJUGATE CHEMISTRY LA English DT Article ID DIELS-ALDER REACTIONS; FREE CLICK CHEMISTRY; COPPER-FREE; BIOCONJUGATION; REACTIVITY; ANTIBODIES; LIGATION AB Bioorthogonal tetrazine cycloadditions have been applied to live cell labeling. Tetrazines react irreversibly with the strained dienophile norbornene forming dihydropyrazine products and dinitrogen. The reaction is high yielding, selective, and fast in aqueous media. Her2/neu receptors on live human breast cancer cells were targeted with a monoclonal antibody modified with a norbornene. Tetrazines conjugated to a near-infrared fluorochrome selectively and rapidly label the pretargeted antibody in the presence of serum. These findings indicate that this chemistry is suitable for in vitro labeling experiments, and suggests that it may prove a useful strategy for in vivo pretargeted imaging under numerous modalities. C1 [Devaraj, Neal K.; Weissleder, Ralph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Weissleder, Ralph; Hilderbrand, Scott A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Boston, MA 02129 USA. RP Devaraj, NK (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM Scott_Hilderbrand@hms.harvard.edu RI Devaraj, Neal/B-4712-2014 FU NIH [U01-HL080731, T32 - CA 79443] FX The authors would like to thank Drs. Fangwei Shao and Jered Haun for their assistance in the preparation of this manuscript. This research was supported in part by NIH grants U01-HL080731 and T32 - CA 79443. NR 23 TC 320 Z9 322 U1 8 U2 149 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD DEC PY 2008 VL 19 IS 12 BP 2297 EP 2299 DI 10.1021/bc8004446 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 384TT UT WOS:000261767800002 PM 19053305 ER PT J AU Shao, FW Weissleder, R Hilderbrand, SA AF Shao, Fangwei Weissleder, Ralph Hilderbrand, Scott A. TI Monofunctional Carbocyanine Dyes for Bio- and Bioorthogonal Conjugation SO BIOCONJUGATE CHEMISTRY LA English DT Article ID INFRARED FLUORESCENT-PROBES; HEPTAMETHINE CYANINE DYES; IN-VIVO; SUCCINIMIDYL ESTERS; LABELING REAGENTS; CLICK CHEMISTRY; FLUOROCHROMES; CHROMOPHORE; TUMORS AB A facile synthetic route to prepare monofunctional carbocyanine dyes for biological application is developed. Three pentamethine carbocyanine dyes have been successfully modified with a variety of functional groups such as: carboxylic acids, azides, or alkynes. The new dyes are characterized by strong NIR fluorescence emission, high extinction coefficients and good quantum yields. The azide and alkyne dyes have potential utility as components in bioorthogonal labeling schemes via [2 + 3] dipolar cycloaddition "click" reactions. The application of one derivative, CyAM-5 alkyne, for bioorthogonal labeling is demonstrated. Fluorescence microscopy shows coupling of CyAM-5 alkyne to Chinese hamster ovary (CHO) cells preincubated with azide modified glycans. C1 [Shao, Fangwei] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Syst Biol, Charlestown, MA 02129 USA. RP Shao, FW (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Room 5404,Bldg 149,13th St, Charlestown, MA 02129 USA. EM scott_Hilderbrand@hms.harvard.edu RI Shao, Fangwei/B-7026-2011 FU NIH [1-U01-HL080731] FX This work is supported by NIH grant 1-U01-HL080731. We thank Dr. Neal Devaraj for helpful discussion on click chemistry. NR 22 TC 23 Z9 23 U1 2 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD DEC PY 2008 VL 19 IS 12 BP 2487 EP 2491 DI 10.1021/bc800417b PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 384TT UT WOS:000261767800026 PM 19053316 ER PT J AU Hingorani, SR Seidel, K Lindner, A Aneia, T Schoch, G McDonald, G AF Hingorani, Sangeeta R. Seidel, Kristy Lindner, Armando Aneia, Tia Schoch, Gary McDonald, George TI Albuminuria in Hematopoietic Cell Transplantation Patients: Prevalence, Clinical Associations, and Impact on Survival SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE chronic kidney disease; graft-versus-host disease; albuminuria; proteinuria; mortality; hematopoietic cell transplant ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; CARDIOVASCULAR RISK-FACTORS; URINARY ALBUMIN; NEPHROTIC SYNDROME; RENAL-FUNCTION; FAILURE; MICROALBUMINURIA; POPULATION; EXCRETION AB Chronic kidney disease (CKD) is common after hematopoietic cell transplantation (HCT). We prospectively measured the urinary albumin:creatinine ratio (ACR) in 142 patients. Total (intact) monomeric albumin was determined by liquid chromatography of untreated urine samples collected weekly to day 100 after HCT Albuminuria was defined as ACR (mg/g creatinine) > 30; proteinuria, as ACR > 300. Cox and logistic regression analyses evaluated ACR as a risk factor for clinical events. The prevalence of albuminuria was 37% at baseline, 64% at day 100, and 50% at 1 year. Proteinuria occurred in 4% of patients at baseline, in 15% at day 100, and in 4% at 1 year. Characteristics associated with albuminuria include age, sex, donor type, hypertension, and sinusoidal obstruction syndrome (SOS). Albuminuria was associated with an increased risk of acute graft-versus-host disease (aGVHD) and bacteremia, but not acute kidney injury (AKI). Albuminuria at day 100 was associated with CKD at 1 year (odds ratio = 4.0; 95% confidence interval [CI] = 1.1 to 14.6). Nonrelapse mortality (NRM) risk was elevated (hazard ratio = 6.8; 95% CI = 1.1 to 41.5) in patients with overt proteinuria at day 100. Albuminuria occurs frequently after HCT and is correlated with aGVHD, bacteremia, hypertension, and progression of renal disease. Proteinuria at day 100 is associated with an 6-fold increased risk of NRM by 1 year after HCT. C1 [Hingorani, Sangeeta R.; Seidel, Kristy; Aneia, Tia] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Lindner, Armando; McDonald, George] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Schoch, Gary; McDonald, George] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Lindner, Armando] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Hingorani, SR (reprint author), Childrens Hosp & Reg Med Ctr, 4800 Sand Point Way NE,A-7931, Seattle, WA 98105 USA. EM sangeeta.hingorani@seattlechildrens.org FU National Institutes of Health (NIH) [M01-RR-00037, CA18029]; National Institute of Diabetes and Digestive and Kidney Diseases [K23 DK63038]; American Society of Nephrology/Renal Physicians Association Health Scholars; National Kidney Foundation Young Investigators FX This research was supported by National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases Grant K23 DK63038, an American Society of Nephrology/Renal Physicians Association Health Scholars Grant, and a National Kidney Foundation Young Investigators Grant (to S.H.) and NIH Grants M01-RR-00037 (to the University of V Washington General Clinical Research Center) and CA18029 (to G.B.M.). NR 30 TC 26 Z9 26 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2008 VL 14 IS 12 BP 1365 EP 1372 DI 10.1016/j.bbmt.2008.09.015 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 384OR UT WOS:000261754600006 PM 19041058 ER PT J AU Mani, G Johnson, DM Marton, D Feldman, MD Patel, D Ayon, AA Agrawal, CM AF Mani, Gopinath Johnson, Dave M. Marton, Denes Feldman, Marc D. Patel, Devang Ayon, Arturo A. Agrawal, C. Mauli TI Drug delivery from gold and titanium surfaces using self-assembled monolayers SO BIOMATERIALS LA English DT Article DE Drug-eluting stents; Drug delivery; Self-assembled monolayers; Surface modification ID CORONARY-ARTERY-DISEASE; SIROLIMUS-ELUTING STENT; NATIVE-OXIDE SURFACE; BALLOON ANGIOPLASTY; AQUEOUS-SOLUTION; PHOSPHONIC ACID; THROMBOSIS; METAL; FLUORESCENCE; BINDING AB Currently available drug-eluting stents (DES) use polymers for coating and releasing drugs. increasing evidence suggests that inflammatory and hypersensitive reactions are caused by such polymer coatings. This study focused on developing new techniques for delivering drugs directly from metal implant surfaces. Hydroxyl-terminated self-assembled monolayers (SAMs) were coated on Au and Ti surfaces. Therapeutic self-assembled monolayers (TSAMs) were prepared by chemically attaching the model drug, flufenamic acid, to SAM coated metal surfaces. Three different methods of esterification (acid chloride esterification, dry heat esterification, and direct esterification) were explored to attach flufenamic acid to SAMs. TSAMs were characterized using X-ray photoelectron spectroscopy, fluorescence microscopy, atomic force microscopy, and contact angle goniometry. These techniques collectively confirmed the attachment of drug onto SAM coated metal surfaces. In vitro drug release was investigated by immersing TSAM coated metal specimens in tris-buffered saline (TBS) at 37 degrees C for 28 days. TBS was analyzed at 1, 3, 7,14, 21, and 28 days for the amount of drug eluted using high performance liquid chromatography. Large data scatter was observed for the release profiles of TSAMs prepared by acid chloride esterification. TSAMs prepared by dry heat and direct esterification methods showed an initial burst release of the drug followed by a sustained slow release for up to 2 weeks. Thus, this study suggests the potential for using self-assembled monolayers as an alternate system for delivering drugs from coronary stents and other metal implants. C1 [Mani, Gopinath; Johnson, Dave M.; Marton, Denes; Feldman, Marc D.; Ayon, Arturo A.; Agrawal, C. Mauli] Univ Texas San Antonio, Dept Biomed Engn, Coll Engn, San Antonio, TX 78249 USA. [Johnson, Dave M.] Univ Texas San Antonio, Coll Sci, Dept Chem, San Antonio, TX 78249 USA. [Marton, Denes] Univ Texas Hlth Sci Ctr San Antonio, Sch Med, Dept Radiol, San Antonio, TX 78229 USA. [Feldman, Marc D.; Patel, Devang] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Cardiol, San Antonio, TX 78229 USA. [Feldman, Marc D.] Dept Vet Affairs S Texas Hlth Care Syst, San Antonio, TX 78229 USA. RP Agrawal, CM (reprint author), Univ Texas San Antonio, Dept Biomed Engn, Coll Engn, 1 UTSA Circle, San Antonio, TX 78249 USA. EM mauli.agrawal@utsa.edu RI Ayon, Arturo/C-7544-2009; Marton, Denes/E-7759-2010 NR 59 TC 58 Z9 58 U1 3 U2 30 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD DEC PY 2008 VL 29 IS 34 BP 4561 EP 4573 DI 10.1016/j.biomaterials.2008.08.014 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 368KH UT WOS:000260619500011 PM 18790530 ER PT J AU Carraro, A Hsu, WM Kulig, KM Cheung, WS Miller, ML Weinberg, EJ Swart, EF Kaazempur-Mofrad, M Borenstein, JT Vacanti, JP Neville, C AF Carraro, Amedeo Hsu, Wen-Ming Kulig, Katherine M. Cheung, Wing S. Miller, Mark L. Weinberg, Eli J. Swart, Eric F. Kaazempur-Mofrad, Mohammad Borenstein, Jeffrey T. Vacanti, Joseph P. Neville, Craig TI In vitro analysis of a hepatic device with intrinsic microvascular-based channels SO BIOMEDICAL MICRODEVICES LA English DT Article DE tissue engineering; hepatocytes; liver; microfabrication ID BIOARTIFICIAL LIVER; MICROFLUIDIC DEVICES; POLY(DIMETHYLSILOXANE); HEPATOCYTES; RAT; BIOREACTOR; CULTURE; FAILURE; FLOW AB A novel microfluidics-based bilayer device with a discrete parenchymal chamber modeled upon hepatic organ architecture is described. The microfluidics network was designed using computational models to provide appropriate flow behavior based on physiological data from human microvasculature. Patterned silicon wafer molds were used to generate films with the vascular-based microfluidics network design and parenchymal chamber by soft lithography. The assembled device harbors hepatocytes behind a nanoporous membrane that permits transport of metabolites and small proteins while protecting them from the effects of shear stress. The device can sustain both human hepatoma cells and primary rat hepatocytes by continuous in vitro perfusion of medium, allowing proliferation and maintaining hepatic functions such as serum protein synthesis and metabolism. The design and fabrication processes are scalable, enabling the device concept to serve as both a platform technology for drug discovery and toxicity, and for the continuing development of an improved liver-assist device. C1 [Carraro, Amedeo; Hsu, Wen-Ming; Kulig, Katherine M.; Cheung, Wing S.; Vacanti, Joseph P.; Neville, Craig] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Carraro, Amedeo; Hsu, Wen-Ming; Kulig, Katherine M.; Cheung, Wing S.; Vacanti, Joseph P.; Neville, Craig] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Carraro, Amedeo] Univ Padua, Sch Med, Dept Surg & Gastroenterol Sci, Padua, Italy. [Hsu, Wen-Ming] Natl Taiwan Univ Hosp, Dept Surg, Taipei 100, Taiwan. [Miller, Mark L.; Swart, Eric F.; Vacanti, Joseph P.; Neville, Craig] Harvard Univ, Sch Med, Boston, MA USA. [Weinberg, Eli J.; Borenstein, Jeffrey T.] Charles Stark Draper Lab Inc, Ctr Biomed Engn, Cambridge, MA 02139 USA. [Kaazempur-Mofrad, Mohammad] Univ Calif Berkeley, Dept Bioengn, Berkeley, CA 94720 USA. RP Neville, C (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, 185 Cambridge St,CPZN-4809, Boston, MA 02114 USA. EM neville@helix.mgh.harvard.edu OI HSU, WEN-MING/0000-0002-5145-9538 FU Integration of Medicine and Innovative Technology [US Army DAMD17-02-20006] FX Support from the Center for Integration of Medicine and Innovative Technology (US Army DAMD17-02-20006) is gratefully acknowledged. We thank Dr. Irina Pomerantseva for critically reading of the manuscript. NR 26 TC 93 Z9 95 U1 3 U2 24 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1387-2176 J9 BIOMED MICRODEVICES JI Biomed. Microdevices PD DEC PY 2008 VL 10 IS 6 BP 795 EP 805 DI 10.1007/s10544-008-9194-3 PG 11 WC Engineering, Biomedical; Nanoscience & Nanotechnology SC Engineering; Science & Technology - Other Topics GA 348YQ UT WOS:000259246400004 PM 18604585 ER PT J AU Li, Y Tiwari, RC AF Li, Yi Tiwari, Ram C. TI Comparing Trends in Cancer Rates Across Overlapping Regions SO BIOMETRICS LA English DT Article DE Age-adjusted cancer rates; Annual percent change (APC); Hypothesis testing; Pitman asymptotic relative efficiency (ARE); Surveillance; Trends ID REGRESSION AB Monitoring and comparing trends in cancer rates across geographic regions or over different time periods have been major tasks of the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) Program as it profiles healthcare quality as well as decides healthcare resource allocations within a spatial-temporal framework. A fundamental difficulty, however, arises when such comparisons have to be made for regions or time intervals that overlap, for example, comparing the change in trends of mortality rates in a local area (e. g., the mortality rate of breast cancer in California) with a more global level (i.e., the national mortality rate of breast cancer). In view of sparsity of available methodologies, this article develops a simple corrected Z-test that accounts for such overlapping. The performance of the proposed test over the two-sample "pooled" t-test that assumes independence across comparison groups is assessed via the Pitman asymptotic relative efficiency as well as Monte Carlo simulations and applications to the SEER cancer data. The proposed test will be important for the SEER*STAT software, maintained by the NCI, for the analysis of the SEER data. C1 [Li, Yi] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Li, Yi] Dana Farber Canc Inst, Boston, MA 02115 USA. [Tiwari, Ram C.] NCI, Stat Res & Applicat Branch, Bethesda, MD 20892 USA. RP Li, Y (reprint author), Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. EM yili@jimmy.harvard.edu; tiwarir@mail.nih.gov FU NCI FX The authors would like to thank the editor, the associate editor, and an anonymous referee for insightful suggestions that improved the original manuscript. The authors thank Steve Scoppa and Joe Zou of Information Management Services (IMS), Inc., the company that provides biomedical computing support to the NCI, for their valuable contributions. The authors also thank Dr Rocky Feuer for carefully reading an early draft of this work and for many insightful suggestions. NR 8 TC 3 Z9 3 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2008 VL 64 IS 4 BP 1280 EP 1286 DI 10.1111/j.1541-0420.2008.01002.x PG 7 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 374OV UT WOS:000261054500033 PM 18371122 ER PT J AU Deckersbach, T Rauch, SL Buhlmann, U Ostacher, MJ Beucke, JC Nierenberg, AA Sachs, G Dougherty, DD AF Deckersbach, Thilo Rauch, Scott L. Buhlmann, Ulrike Ostacher, Michael J. Beucke, Jan-Carl Nierenberg, Andrew A. Sachs, Gary Dougherty, Darin D. TI An fMRI investigation of working memory and sadness in females with bipolar disorder: a brief report SO BIPOLAR DISORDERS LA English DT Article DE bipolar disorder; fMRI; functional magnetic resonance imaging; sadness; working memory ID ANTERIOR CINGULATE CORTEX; DORSOLATERAL PREFRONTAL CORTEX; POSITRON-EMISSION-TOMOGRAPHY; OBSESSIVE-COMPULSIVE DISORDER; MENSTRUAL-CYCLE; EUTHYMIC PATIENTS; MAJOR DEPRESSION; NEUROPSYCHOLOGICAL FUNCTION; COGNITIVE DYSFUNCTIONS; EXECUTIVE PROCESSES AB Functional magnetic resonance imaging (fMRI) studies have documented abnormalities in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex in bipolar disorder in the context of working memory tasks. It is increasingly recognized that DLPFC regions play a role in mood regulation and the integration of emotion and cognition. The purpose of the present study was to investigate with fMRI the interaction between acute sadness and working memory functioning in individuals with bipolar disorder. Nine depressed individuals with DSM-IV bipolar I disorder (BP-I) and 17 healthy control participants matched for age, gender, education, and IQ completed a 2-back working memory paradigm under no mood induction, neutral state, or acute sadness conditions while undergoing fMRI scanning. Functional MRI data were analyzed with SPM2 using a random-effects model. Behaviorally, BP-I subjects performed equally well as control participants on the 2-back working memory paradigm. Compared to control participants, individuals with BP-I were characterized by more sadness-specific activation increases in the left DLPFC (BA 9/46) and left dorsal anterior cingulate (dACC). Our study documents sadness-specific abnormalities in the left DLPFC and dACC in bipolar disorder that suggest difficulties in the integration of emotion (sadness) and cognition. These preliminary findings require further corroboration with larger sample sizes of medication-free subjects. C1 [Deckersbach, Thilo; Rauch, Scott L.; Buhlmann, Ulrike; Ostacher, Michael J.; Beucke, Jan-Carl; Nierenberg, Andrew A.; Sachs, Gary; Dougherty, Darin D.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Deckersbach, Thilo; Rauch, Scott L.; Buhlmann, Ulrike; Ostacher, Michael J.; Beucke, Jan-Carl; Nierenberg, Andrew A.; Sachs, Gary; Dougherty, Darin D.] Harvard Univ, Sch Med, Boston, MA USA. [Rauch, Scott L.] McLean Hosp, Belmont, MA 02178 USA. [Rauch, Scott L.] Harvard Univ, Sch Med, Belmont, MA 02178 USA. [Beucke, Jan-Carl] Humboldt Univ, Dept Psychol, Berlin, Germany. RP Deckersbach, T (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 149-2628,Bldg 149,13th St,2nd Floor, Charlestown, MA 02129 USA. EM tdeckersbach@partners.org OI Ostacher, Michael/0000-0003-0353-7535 NR 84 TC 27 Z9 27 U1 2 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD DEC PY 2008 VL 10 IS 8 BP 928 EP 942 DI 10.1111/j.1399-5618.2008.00633.x PG 15 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 374OU UT WOS:000261054400009 PM 19594508 ER PT J AU Mandeville, JA Neto, BS Vanni, AJ Smith, GL Rieger-Christ, KM Zeheb, R Loda, M Libertino, JA Summerhayes, IC AF Mandeville, Jessica A. Neto, Brasil Silva Vanni, Alex J. Smith, Gjanje L. Rieger-Christ, Kimberly M. Zeheb, Ron Loda, Massimo Libertino, John A. Summerhayes, Ian C. TI P-cadherin as a prognostic indicator and a modulator of migratory behaviour in bladder carcinoma cells SO BJU INTERNATIONAL LA English DT Article DE P-cadherin; bladder cancer; migration ID BREAST-CANCER CELLS; GAMMA-CATENIN EXPRESSION; RHO-FAMILY GTPASES; N-CADHERIN; PROMOTES MOTILITY; CLASSIC CADHERINS; INVASION; TUMORS; BETA; PROGRESSION AB To identify changes associated with P-cadherin expression in bladder cancer and evaluate the potential role of such events in determining the clinical outcome and cell behaviour, as the function of P-cadherin in normal epithelium is unknown, as is its potential role in neoplastic progression in different cancers. In all, 536 bladder tumour specimens from 408 patients were assembled in seven tissue microarrays. Paraffin sections from each array were processed for immunohistochemistry to assess the expression of P-cadherin. The expression of P-cadherin was forced using lipofectin, followed by an assessment of migration and invasion potential using standard in vitro assays. The absence of P-cadherin staining was associated with muscle-invasive disease, grade 3 (P < 0.001) and nodal disease (P = 0.009). Similar results were obtained when considering cytoplasmic and unrestricted localization of P-cadherin (P < 0.001), except for nodal involvement. The group with cytoplasmic location of P-cadherin showed a shorter cancer-specific survival than the group with membrane location of P-cadherin (P = 0.03). Forced expression of P-cadherin in EJ and UM-UC-3 cells, that constitutively lack P-cadherin expression, resulted in modulation of catenin expression and enhanced migration of EJ and UM-UC-3/P-cadherin transfectants (> 200%). These results showed that loss of expression, cytoplasmic relocation or unrestricted tissue location of P-cadherin was associated with a poor clinical outcome and prognosis in bladder cancer. From the in vitro work it is evident that P-cadherin plays a role in regulating the migration potential of bladder carcinoma cells. C1 [Neto, Brasil Silva; Rieger-Christ, Kimberly M.; Summerhayes, Ian C.] Lahey Clin Fdn, Robert E Wise MD Res & Educ Inst, Cell & Mol Biol Lab, Burlington, MA 01805 USA. [Mandeville, Jessica A.; Neto, Brasil Silva; Vanni, Alex J.; Smith, Gjanje L.; Rieger-Christ, Kimberly M.; Libertino, John A.; Summerhayes, Ian C.] Lahey Clin Fdn, Dept Urol, Burlington, MA USA. [Zeheb, Ron] Lahey Clin Fdn, Dept Pathol, Burlington, MA USA. [Loda, Massimo] Dana Farber Canc Ctr, Dept Pathol, Boston, MA USA. RP Summerhayes, IC (reprint author), Lahey Clin Fdn, Robert E Wise MD Res & Educ Inst, Cell & Mol Biol Lab, 31 Mall Rd, Burlington, MA 01805 USA. EM Ian.C.Summerhayes@lahey.org FU R. E. Wise Research and Education Institute; CAPES/Brazil FX This work was supported by a grant from the R. E. Wise Research and Education Institute. B. Silva Neto M. D. was sponsored by CAPES/Brazil. NR 31 TC 23 Z9 23 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-4096 J9 BJU INT JI BJU Int. PD DEC PY 2008 VL 102 IS 11 BP 1707 EP 1714 DI 10.1111/j.1464-410X.2008.08115.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 375TD UT WOS:000261135300041 PM 18990147 ER PT J AU Jaffe, ES Harris, NL Stein, H Isaacson, PG AF Jaffe, Elaine S. Harris, Nancy Lee Stein, Harald Isaacson, Peter G. TI Classification of lymphoid neoplasms: the microscope as a tool for disease discovery SO BLOOD LA English DT Review ID B-CELL LYMPHOMA; REED-STERNBERG CELLS; NON-HODGKINS-LYMPHOMAS; IMMUNOGLOBULIN-GENE REARRANGEMENTS; HEALTH-ORGANIZATION CLASSIFICATION; PRIMARY FOLLICULAR LYMPHOMA; POLYMERASE CHAIN-REACTION; MALIGNANT-LYMPHOMA; HELICOBACTER-PYLORI; BURKITTS-LYMPHOMA AB In the past 50 years, we have witnessed explosive growth in the understanding of normal and neoplastic lymphoid cells. B-cell, T-cell, and natural killer (NK)-cell neoplasms in many respects recapitulate normal stages of lymphoid cell differentiation and function, so that they can be to some extent classified according to the corresponding normal stage. Likewise, the molecular mechanisms involved the pathogenesis of lymphomas and lymphoid leukemias are often based on the physiology of the lymphoid cells, capitalizing on deregulated normal physiology by harnessing the promoters of genes essential for lymphocyte function. The clinical manifestations of lymphomas likewise reflect the normal function of lymphoid cells in vivo. The multiparameter approach to classification adopted by the World Health Organization (WHO) classification has been validated in international studies as being highly reproducible, and enhancing the interpretation of clinical and translational studies. In addition, accurate and precise classification of disease entities facilitates the discovery of the molecular basis of lymphoid neoplasms in the basic science laboratory. (Blood. 2008;112:4384-4399) C1 [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Harris, Nancy Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Stein, Harald] Charite Univ Med Berlin, Inst Pathol, D-13353 Berlin, Germany. [Isaacson, Peter G.] UCL, Sch Med, Dept Histopathol, London W1N 8AA, England. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bldg 10,Room 2B 42,10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov NR 175 TC 167 Z9 182 U1 1 U2 12 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 1 PY 2008 VL 112 IS 12 BP 4384 EP 4399 DI 10.1182/blood-2008-07-077982 PG 16 WC Hematology SC Hematology GA 376XT UT WOS:000261217000010 PM 19029456 ER PT J AU Cutler, C Stevenson, K Kim, HT Richardson, P Ho, VT Linden, E Revta, C Ebert, R Warren, D Choi, S Koreth, J Armand, P Alyea, E Carter, S Horowitz, M Antin, JH Soiffer, R AF Cutler, Corey Stevenson, Kristen Kim, Haesook T. Richardson, Paul Ho, Vincent T. Linden, Erica Revta, Carolyn Ebert, Ruth Warren, Diane Choi, Sung Koreth, John Armand, Philippe Alyea, Edwin Carter, Shelly Horowitz, Mary Antin, Joseph H. Soiffer, Robert TI Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; VASCULAR SMOOTH-MUSCLE; RENAL-TRANSPLANTATION; THROMBOTIC MICROANGIOPATHY; DECREASED INCIDENCE; DOSE METHOTREXATE; GVHD PROPHYLAXIS; PROGENITOR CELLS; ORAL BUSULFAN; IN-VITRO AB Sirolimus is an effective agent used in graft-versus-host disease (GVHD) prophylaxis after allogeneic transplantation. It also has antiproliferative effects on vascular endothelium when used to coat coronary artery stents. We noted an excess of veno-occlusive disease (VOD) in a clinical trial, and retrospectively reviewed the records of 488 patients to determine the association between sirolimus and VOD. When used with cyclophosphamide/total body irradiation (Cy/TBI) conditioning, sirolimus is associated with an increased incidence of VOD (OR 2.35, P = .005). The concomitant use of methotrexate further increased this rate (OR 3.23, P < .001), while sirolimus without methotrexate was not associated with an increased risk of VOD (OR 1.55, P = .33). Mortality after VOD diagnosis was unaffected, and overall treatment-related mortality was lowest when sirolimus was used without methotrexate. Similar findings were noted in matched, related, and unrelated as well as mismatched donor subgroups. When used with busulfan-based conditioning, sirolimus use was associated with an even higher rate of VOD (OR 8.8, P = .008). Our findings suggest that sirolimus use is associated with VOD after TBI-based transplantation when used with methotrexate after transplantation. Sirolimus-based GVHD prophylaxis without methotrexate is associated with the greatest overall survival. Myeloablative doses of busulfan should not be used with sirolimus-based immunosuppression. (Blood. 2008;112:4425-4431) C1 [Cutler, Corey; Richardson, Paul; Ho, Vincent T.; Linden, Erica; Revta, Carolyn; Ebert, Ruth; Warren, Diane; Koreth, John; Armand, Philippe; Alyea, Edwin; Antin, Joseph H.; Soiffer, Robert] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Cutler, Corey; Choi, Sung; Carter, Shelly; Horowitz, Mary; Antin, Joseph H.; Soiffer, Robert] Blood & Marrow Transplant Clin Trials Network, Rockville, MD USA. [Stevenson, Kristen; Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Choi, Sung] Univ Michigan, Med Ctr, Ann Arbor, MI USA. [Carter, Shelly] EMMES Corp, Rockville, MD USA. [Horowitz, Mary] Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI USA. RP Cutler, C (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,D1B13, Boston, MA 02115 USA. EM corey_cutler@dfci.harvard.edu FU National Heart, Lung, and Blood Institute [PO1 HL070149, U01 HL69249] FX This work was supported in part by National Heart, Lung, and Blood Institute grants PO1 HL070149 and U01 HL69249. C. C. is supported by the Stem Cell Cyclists of the Pan-Mass Challenge. NR 49 TC 71 Z9 75 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 DEC 1 PY 2008 VL 112 IS 12 BP 4425 EP 4431 DI 10.1182/blood-2008-07-169342 PG 7 WC Hematology SC Hematology GA 376XT UT WOS:000261217000015 PM 18776081 ER PT J AU Treon, SP Soumerai, JD Branagan, AR Hunter, ZR Patterson, CJ Ioakimidis, L Briccetti, FM Pasmantier, M Zimbler, H Cooper, RB Moore, M Hill, J Rauch, A Garbo, L Chu, L Chua, C Nantel, SH Lovett, DR Boedeker, H Sonneborn, H Howard, J Musto, P Ciccarelli, BT Hatjiharissi, E Anderson, KC AF Treon, Steven P. Soumerai, Jacob D. Branagan, Andrew R. Hunter, Zachary R. Patterson, Christopher J. Ioakimidis, Leukothea Briccetti, Frederick M. Pasmantier, Mark Zimbler, Harvey Cooper, Robert B. Moore, Maria Hill, John, II Rauch, Alan Garbo, Lawrence Chu, Luis Chua, Cynthia Nantel, Stephen H. Lovett, David R. Boedeker, Hans Sonneborn, Henry Howard, John Musto, Paul Ciccarelli, Bryan T. Hatjiharissi, Evdoxia Anderson, Kenneth C. TI Thalidomide and rituximab in Waldenstrom macroglobulinemia SO BLOOD LA English DT Article ID ANTIBODY-MEDIATED IMMUNOTHERAPY; CONSENSUS PANEL RECOMMENDATIONS; ANTI-CD20 MONOCLONAL-ANTIBODY; 2ND INTERNATIONAL WORKSHOP; COOPERATIVE-ONCOLOGY-GROUP; NON-HODGKINS-LYMPHOMA; CLINICAL ACTIVITY; THERAPY; COMBINATION; DEXAMETHASONE AB Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Waldenstrom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m(2) per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n = 1), partial response (n = 15), and major response (n = 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P = .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie, <= 200 mg/day) should be considered given the high frequency of treatment-related neuropathy in this patient population. This trial is registered at www. clinicaltrials.gov as #NCT00142116. (Blood. 2008;112:4452-4457) C1 [Treon, Steven P.; Soumerai, Jacob D.; Branagan, Andrew R.; Hunter, Zachary R.; Patterson, Christopher J.; Ioakimidis, Leukothea; Ciccarelli, Bryan T.; Hatjiharissi, Evdoxia] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Treon, Steven P.; Hatjiharissi, Evdoxia; Anderson, Kenneth C.] Harvard Univ, Sch Med, Boston, MA USA. [Briccetti, Frederick M.] New Hampshire Hematol Oncol, Concord, NH USA. [Pasmantier, Mark] New York Presbyterian Hosp, Weill Med Coll, New York, NY USA. [Cooper, Robert B.] Danbury Hosp, Praxair Canc Ctr, Danbury, CT USA. [Moore, Maria] Pk Ridge Hosp, Hendersonville, NC USA. [Zimbler, Harvey] Berkshire Hematol Oncol, Pittsfield, MA USA. [Hill, John, II] Hendersonville Hematol Oncol, Hendersonville, NC USA. [Rauch, Alan; Garbo, Lawrence] New York Oncol Hematol, Albany, NY USA. [Chu, Luis] Florida Canc Specialists, Sarasota, FL USA. [Chua, Cynthia] Oncol Hematol Care, Cincinnati, OH USA. [Nantel, Stephen H.] Vancouver Gen Hosp, British Columbia Canc Agcy, Vancouver, BC, Canada. [Lovett, David R.] Cape Cod Hosp, Hyannis, MA USA. [Boedeker, Hans] Bridgton Hosp, Bridgton, ME USA. [Sonneborn, Henry] Seacoast Canc Ctr, Portsmouth, NH USA. [Howard, John] Virginia Oncol Associates, Norfolk, VA USA. [Musto, Paul] Commonwealth Hematol Oncol, Quincy, MA USA. [Hatjiharissi, Evdoxia] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 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.harvard.edu RI Hunter, Zachary/H-3018-2013 OI Hunter, Zachary/0000-0002-1689-1691 FU Peter and Helen Bing Fund; Research Fund for Waldenstrom at the Dana-Farber Cancer Institute; National Institutes of Health Career Development Award [K23CA087977-03] FX This work was supported by the Peter and Helen Bing Fund for Waldenstrom Macroglobulinemia at the Dana-Farber Cancer Institute, the Research Fund for Waldenstrom at the Dana-Farber Cancer Institute, and a National Institutes of Health Career Development Award (K23CA087977-03) (S.P.T.). NR 38 TC 67 Z9 71 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 DEC 1 PY 2008 VL 112 IS 12 BP 4452 EP 4457 DI 10.1182/blood-2008-04-150854 PG 6 WC Hematology SC Hematology GA 376XT UT WOS:000261217000019 PM 18713945 ER PT J AU Ho, AW Hatjiharissi, E Ciccarelli, BT Branagan, AR Hunter, ZR Leleu, X Tournilhac, O Xu, L O'Connor, K Manning, RJ Santos, DD Chemaly, M Patterson, CJ Soumerai, JD Munshi, NC McEarchern, JA Law, CL Grewal, IS Treon, SP AF Ho, Allen W. Hatjiharissi, Evdoxia Ciccarelli, Bryan T. Branagan, Andrew R. Hunter, Zachary R. Leleu, Xavier Tournilhac, Olivier Xu, Lian O'Connor, Kelly Manning, Robert J. Santos, Daniel Ditzel Chemaly, Mariana Patterson, Christopher J. Soumerai, Jacob D. Munshi, Nikhil C. McEarchern, Julie A. Law, Che-Leung Grewal, Iqbal S. Treon, Steven P. TI CD27-CD70 interactions in the pathogenesis of Waldenstrom macroglobulinemia SO BLOOD LA English DT Article ID MAST-CELLS; SOLUBLE CD27; INTERNATIONAL WORKSHOP; HODGKINS-LYMPHOMA; B-CELLS; ACTIVATION; EXPRESSION; RECOMMENDATIONS; CLASSIFICATION; APOPTOSIS AB Waldenstrom macroglobulinemia (WM) is a B-cell malignancy characterized by an IgM monoclonal gammopathy and bone marrow (BM) infiltration with lymphoplasmacytic cells (LPCs). Excess mast cells (MCs) are commonly present in WM, and provide growth and survival signals to LPCs through several TNF family ligands (CD40L, a proliferation-inducing ligand [APRIL], and B-lymphocyte stimulator factor [BLYS]). As part of these studies, we demonstrated that WM LPCs secrete soluble CD27 (sCD27), which is elevated in patients with WM (P < .001 vs healthy donors), and serves as a faithful marker of disease. Importantly, sCD27 stimulated expression of CD40L on 10 of 10 BM MC samples and APRIL on 4 of 10 BM MC samples obtained from patients with WM as well as on LAD2 MCs. Moreover, the SGN-70 humanized monoclonal antibody, which binds to CD70 (the receptor-ligand partner of CD27), abrogated sCD27 mediated up-regulation of CD40L and APRIL on WM MCs. Last, treatment of severe combined immunodeficiency-human (SCID-hu) mice with established WM using the SGN-70 antibody blocked disease progression in 12 of 12 mice, whereas disease progressed in all 5 untreated mice. The results of these studies demonstrate a functional role for sCD27 in WM pathogenesis, along with its utility as a surrogate marker of disease and a target in the treatment of WM. (Blood. 2008; 112: 4683-4689) C1 [Ho, Allen W.; Hatjiharissi, Evdoxia; Ciccarelli, Bryan T.; Branagan, Andrew R.; Hunter, Zachary R.; Leleu, Xavier; Tournilhac, Olivier; Xu, Lian; O'Connor, Kelly; Manning, Robert J.; Santos, Daniel Ditzel; Chemaly, Mariana; Patterson, Christopher J.; Soumerai, Jacob D.; Treon, Steven P.] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02115 USA. [Hatjiharissi, Evdoxia; Leleu, Xavier; Tournilhac, Olivier; Santos, Daniel Ditzel; Munshi, Nikhil C.; Treon, Steven P.] Harvard Univ, Sch Med, Boston, MA USA. [Munshi, Nikhil C.] Jerome Lipper Multiple Myeloma Ctr, Boston, MA USA. [Munshi, Nikhil C.] Vet Adm Med Ctr W Roxbury, Boston, MA 02132 USA. [McEarchern, Julie A.; Law, Che-Leung; Grewal, Iqbal S.] Seattle Genet, Dept Preclin Therapeut, Bothell, WA USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, M548,44 Binney St, Boston, MA 02115 USA. EM steven_treon@dfci.harvard.edu RI Ho, Allen/B-3017-2011; Hunter, Zachary/H-3018-2013 OI Hunter, Zachary/0000-0002-1689-1691 FU Peter and Helen Bing Fund; Edward and Linda Nelson Fund; Bailey Family Fund; National Institutes of Health [K23CA087977-03] FX This work was supported by the Peter and Helen Bing Fund for Waldenstrom macroglobulinemia, the Edward and Linda Nelson Fund for Translational Studies in WM, the Bailey Family Fund at the Dana-Farber Cancer Institute, and a National Institutes of Health Career Development Award (K23CA087977-03) to S. P. T. NR 39 TC 35 Z9 35 U1 1 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 DEC 1 PY 2008 VL 112 IS 12 BP 4683 EP 4689 DI 10.1182/blood-2007-04-084525 PG 7 WC Hematology SC Hematology GA 376XT UT WOS:000261217000046 PM 18216294 ER PT J AU McDowell, JE Dyckman, KA Austin, BP Clementz, BA AF McDowell, Jennifer E. Dyckman, Kara A. Austin, Benjamin P. Clementz, Brett A. TI Neurophysiology and neuroanatomy of reflexive and volitional saccades: Evidence from studies of humans SO BRAIN AND COGNITION LA English DT Review DE Electroencephalography (EEG); Functional magnetic resonance imaging (fMRI); Magnecoencephlography (MEG); Prosaccades; Antisaccades; Express saccades; Ocular motor delayed response; Saccade sequences; Predictive saccadic tracking ID FRONTAL EYE-FIELD; VISUALLY-GUIDED SACCADES; SPATIAL WORKING-MEMORY; EVENT-RELATED FMRI; POSITRON-EMISSION-TOMOGRAPHY; POSTERIOR PARIETAL CORTEX; ANTERIOR CINGULATE CORTEX; DORSOLATERAL PREFRONTAL CORTEX; INDEPENDENT COMPONENT ANALYSIS; SUPPLEMENTARY MOTOR AREA AB This review provides a summary of the contributions made by human functional neuroimaging studies to the understanding of neural correlates of saccadic control. The generation of simple visually guided saccades (redirections of gaze to a visual stimulus or pro-saccades) and more complex volitional saccades require similar basic neural circuitry with additional neural regions supporting requisite higher level processes. The saccadic system has been studied extensively in non-human (e.g., single-unit recordings) and human (e.g., lesions and neuroimaging) primates. Considerable knowledge of this system's functional neuroanatomy makes it useful for investigating models of cognitive control. The network involved in pro-saccade generation (by definition largely exogenously-driven) includes subcortical (striatum, thalamus, superior colliculus, and cerebellar vermis) and cortical (primary Visual, extrastriate, and parietal cortices, and frontal and supplementary eye fields) Structures. Activation in these regions is also observed during endogenously-driven voluntary saccades (e.g., anti-saccades, ocular motor delayed response or memory saccades, predictive tracking tasks and anticipatory saccades, and saccade sequencing), all of which require complex cognitive processes like inhibition and working memory. These additional requirements are supported by changes in neural activity in basic saccade circuitry and by recruitment of additional neural regions (Such as prefrontal and anterior cingulate cortices). Activity in visual cortex is modulated as a function of task demands and may predict the type of saccade to be generated, perhaps via top-down control mechanisms. Neuroimaging studies Suggest two foci of activation within FEF - medial and lateral - which may correspond to volitional and reflexive demands, respectively. Future research on saccade control Could usefully (i) delineate important anatomical subdivisions that underlie functional differences, (ii) evaluate functional connectivity of anatomical regions supporting saccade generation using methods Such as ICA and structural equation modeling, (iii) investigate how context affects behavior and brain activity, and (iv) use multi-modal neuroimaging to maximize spatial and temporal resolution. (C) 2008 Elsevier Inc. All rights reserved. C1 [McDowell, Jennifer E.; Austin, Benjamin P.; Clementz, Brett A.] Univ Georgia, Dept Psychol & Neurosci, Bioimaging Res Ctr, Athens, GA 30602 USA. [Dyckman, Kara A.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. RP McDowell, JE (reprint author), Univ Georgia, Dept Psychol & Neurosci, Bioimaging Res Ctr, Psychol Bldg, Athens, GA 30602 USA. EM jemcd@uga.edu FU National Institute of Health [MH57886, MH001852] FX The authors thank Dr. Jazmin Camchong, Michael Amlung and Friederike Meyer for their contributions. This was funded in part by grants from the National Institute of Health (MH57886 and MH001852). NR 244 TC 161 Z9 166 U1 6 U2 29 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 EI 1090-2147 J9 BRAIN COGNITION JI Brain Cogn. PD DEC PY 2008 VL 68 IS 3 BP 255 EP 270 DI 10.1016/j.bandc.2008.08.016 PG 16 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 382UO UT WOS:000261631100005 PM 18835656 ER PT J AU Prigerson, HG Maciejewski, PK AF Prigerson, Holly G. Maciejewski, Paul K. TI Grief and acceptance as opposite sides of the same coin: setting a research agenda to study peaceful acceptance of loss SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID TRAUMATIC GRIEF; DEATH; CANCER; SCALE C1 [Prigerson, Holly G.] Dana Farber Canc Inst, Brigham & Womens Hosp, Ctr Psychooncol & Palliat Care Res, Dept Psychiat, Boston, MA 02115 USA. [Prigerson, Holly G.] Harvard Univ, Sch Med, Ctr Palliat Care, Boston, MA USA. [Maciejewski, Paul K.] Yale Univ, Sch Med, Dept Psychiat & Womens Hlth Res, New Haven, CT USA. RP Prigerson, HG (reprint author), Dana Farber Canc Inst, Brigham & Womens Hosp, Ctr Psychooncol & Palliat Care Res, Dept Psychiat, Suite 530,44 Binney St, Boston, MA 02115 USA. EM holly_prigerson@dfci.harvard.edu NR 18 TC 27 Z9 28 U1 3 U2 10 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD DEC PY 2008 VL 193 IS 6 BP 435 EP 437 DI 10.1192/bjp.bp.108.053157 PG 3 WC Psychiatry SC Psychiatry GA 381ZO UT WOS:000261574600001 PM 19043142 ER PT J AU Kochinski, S Smith, SR Baity, MR Hilsenroth, MJ AF Kochinski, Sivan Smith, Steven R. Baity, Matthew R. Hilsenroth, Mark J. TI Rorschach correlates of adolescent self-mutilation SO BULLETIN OF THE MENNINGER CLINIC LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-Personality-Assessment CY 2006 CL San Diego, CA SP Soc Personal Assessment ID SEXUAL HOMICIDE PERPETRATORS; PERCEPTUAL-THINKING INDEX; COMPREHENSIVE SYSTEM; INTERRATER RELIABILITY; AGGRESSION VARIABLES; NONVIOLENT PEDOPHILES; RESPONSE-FREQUENCY; OBJECT RELATIONS; INKBLOT METHOD; DATA SETS AB The present study examined various Rorschach variables of aggression, dysphoric affect, and disordered thinking in relation to self-mutilation in samples of self-mutilating (SM; n = 16) and nonself-mutilating (N-SM; n = 26) adolescent inpatients. Categorical comparisons indicated that SM patients had significantly higher mean scores for Aggressive Past (AgPast), but not for Aggressive Content (AgC), Aggressive Movement (AG), Morbid Content(MOR), Inanimate Movement (m), Sum Shading(SumY), and the Perceptual-Thinking Index(PTI), than N-SM patients. Additionally, logistic regression results suggested that PTI and AgPast were the most robust predictors of group membership. The authors propose that self-mutilating adolescents may struggle with internally directed aggression and victimized sense of self that, when coupled with disordered thinking, significantly predicts self-mutilation. C1 [Kochinski, Sivan; Smith, Steven R.] Univ Calif Santa Barbara, Dept Counseling, Sch Psychol, Santa Barbara, CA 93106 USA. [Baity, Matthew R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Baity, Matthew R.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Hilsenroth, Mark J.] Adelphi Univ, Garden City, NY 11530 USA. RP Kochinski, S (reprint author), Univ Calif Santa Barbara, Dept Counseling, Sch Psychol, 1110 Phelps Hill, Santa Barbara, CA 93106 USA. EM sba-razan@education.ucsb.edu NR 72 TC 5 Z9 5 U1 0 U2 6 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0025-9284 J9 B MENNINGER CLIN JI Bull. Menninger Clin. PD WIN PY 2008 VL 72 IS 1 BP 54 EP 77 DI 10.1521/bumc.2008.72.1.54 PG 24 WC Psychiatry; Psychology, Psychoanalysis SC Psychiatry; Psychology GA 295UM UT WOS:000255499400004 PM 18419244 ER PT J AU Murphy, CD Lee, JM Drohan, B Euhus, DM Kopans, DB Gadd, MA Rafferty, EA Specht, MC Smith, BL Hughes, KS AF Murphy, Colleen D. Lee, Janie M. Drohan, Brian Euhus, David M. Kopans, Daniel B. Gadd, Michele A. Rafferty, Elizabeth A. Specht, Michelle C. Smith, Barbara L. Hughes, Kevin S. TI The American Cancer Society Guidelines for Breast Screening With Magnetic Resonance Imaging An Argument for Genetic Testing SO CANCER LA English DT Article DE breast magnetic resonance imaging; breast cancer screening; breast neoplasm; BRCAPRO ID HIGH-RISK; MUTATION CARRIERS; BRCA2 MUTATION; WOMEN; MRI; SUSCEPTIBILITY; SURVEILLANCE; MAMMOGRAPHY AB BACKGROUND. The American Cancer Society (ACS) guidelines for screening with breast magnetic resonance imaging (MRI) recommend MRI for women who have a lifetime risk >= 20% of developing breast cancer. Genetic testing for breast cancer gene (BRCA) mutations is offered to women who have a risk >= 10% of carrying a mutation. The objectives of the current study were 1) to identify the number of women in a breast cancer screening population who had >= 20% lifetime breast cancer risk and, thus, were candidates for screening MRI; and 2) to determine the number of women who had >= 10% risk of BRCA mutation yet had <20% lifetime risk of breast cancer and, thus, may not have been identified as candidates for MRI screening. METHODS. From 2003 to 2005, women who underwent screening mammography completed a self-administered questionnaire regarding breast cancer risk factors. For each patient, the lifetime breast cancer risk and the risk of BRCA mutation was determined by using the computerized BRCAPRO breast cancer risk-assessment model. RESULTS. Of 18,190 women, 78 (0.43%) had >= 20% lifetime risk of breast cancer, all of whom had >= 10% risk of carrying a BRCA mutation. An additional 374 women (2.06%) had <20% lifetime breast cancer risk but >= 10% risk of mutation. Overall, there were 183 (1%) predicted mutation carriers, 27 women (0.15%) who had >= 20% lifetime risk of breast cancer, and 62 women (0.34%) who had >= 10% risk of mutation but <20% lifetime breast cancer risk. CONCLUSIONS. The ACS guidelines for breast MRI screening may systematically exclude MRI screening for many women who have a substantial risk for BRCA mutation. The current results demonstrated a need for greater awareness of breast cancer risk factors in the screening mammography population, so that high-risk women can be identified and given access to genetic testing and counseling regarding all risk-reducing interventions. Cancer 2008;113:3116-20. (C) 2008 American Cancer Society. C1 [Murphy, Colleen D.; Gadd, Michele A.; Specht, Michelle C.; Smith, Barbara L.; Hughes, Kevin S.] Massachusetts Gen Hosp, Avon Comprehens Breast Evaluat Ctr, Div Surg Oncol, Dept Surg, Boston, MA 02114 USA. [Lee, Janie M.; Kopans, Daniel B.; Rafferty, Elizabeth A.] Massachusetts Gen Hosp, Dept Radiol, Div Breast Imaging, Boston, MA 02114 USA. [Drohan, Brian] Univ Massachusetts Lowell, Dept Biomed Engn, Lowell, MA USA. [Euhus, David M.] Univ Texas SW Med Ctr Dallas, Div Surg Oncol, Dallas, TX 75390 USA. RP Hughes, KS (reprint author), Massachusetts Gen Hosp, Avon Comprehens Breast Evaluat Ctr, Div Surg Oncol, Dept Surg, 55 Fruit St,Yawkey 7, Boston, MA 02114 USA. EM kshughes@partners.org OI Hughes, Kevin/0000-0003-4084-6484 FU NCI NIH HHS [K07 CA128816] NR 12 TC 11 Z9 11 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 1 PY 2008 VL 113 IS 11 BP 3116 EP 3120 DI 10.1002/cncr.23913 PG 5 WC Oncology SC Oncology GA 373MS UT WOS:000260976600010 PM 18932252 ER PT J AU Nguyen, PL Chen, MH Catalona, WJ Alexander, BM Roehl, KA Loeb, S D'Amico, AV AF Nguyen, Paul L. Chen, Ming-Hui Catalona, William J. Alexander, Brian M. Roehl, Kimberly A. Loeb, Stacy D'Amico, Anthony V. TI Biochemical Recurrence After Radical Prostatectomy for Prevalent Versus Incident Cases of Prostate Cancer Implications for Management SO CANCER LA English DT Article DE incident cancer; initial screening; prevalent cancer; prostate-specific antigen; survival; prostate cancer; prostatectomy; serial screening ID PREOPERATIVE PSA VELOCITY; SCREENING TRIAL; UNITED-STATES; ANTIGEN ERA; DEATH AB BACKGROUND. Among screened populations, it is unknown whether men with prostate cancer (PC) diagnosed at the initial screening (prevalent cases) have a different outcome than men who are diagnosed at subsequent screenings (incident cases) after adjusting for known prognostic factors. METHODS. The current study cohort was comprised of 1923 men from a prospective PC screening study who underwent radical prostatectomy (RP) between September 19, 1989 and May 22, 2002. Cox regression multivariate analysis was used to determine whether having prevalent PC versus incident PC was associated with the time to prostate-specific antigen (PSA) failure after RP after adjusting for PSA level, Gleason score, clinical tumor (T) classification, and year of RP. RESULTS. men with prevalent PC had higher PSA levels (P < .001) and more advanced clinical T classification (P < .001) than men with incident PC. After a median follow-up of 6.1 years, factors that were associated with a significantly shorter time to PSA failure after RP were prevalent PC (adjusted hazard ratio [AHR], 1.8; 95% confidence interval [95% CI], 1.3-2.6; P = .0005), baseline PSA (AHR, 1.07; 95%CI, 1.04-1.09; P < .001), Gleason 7 disease (AHR, 2.5; 95% CI, 1.9-3.3; P < .001), Gleason 8 to 10 disease (AHR, 2.3; 95%CI, 1.5-3.5; P < .001), and the year of RP (AHR, 0.92; 95%CI, 0.86-0.97; P = .003). Men with prevalent PC also had worse outcomes after adjusting for their more advanced pathologic features. CONCLUSIONS. After adjusting for known prognostic factors, men with prevalent PC had a poorer outcome after RP than men with incident PC. The authors believe that this finding should be taken into consideration when weighing the risk of recurrence and treatment options for men who are diagnosed with PC on their initial screening. Cancer 2008; 113:3146-52. (C) 2008 American Cancer Society. C1 [Nguyen, Paul L.; Alexander, Brian M.] Harvard Univ, Sch Med, Radiat Oncol Program, Boston, MA USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Catalona, William J.] NW Feinberg Sch Med, Dept Urol, Chicago, IL USA. [Roehl, Kimberly A.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Loeb, Stacy] Johns Hopkins Univ Hosp, Dept Urol, Baltimore, MD 21287 USA. [D'Amico, Anthony V.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nguyen, PL (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, Harvard Radiat Oncol Program, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu OI Loeb, Stacy/0000-0003-3933-9207 FU Beckman Coulter FX William Catalona's research is supported in part by Beckman Coulter, a manufacturer of prostate-specific antigen tests. NR 23 TC 11 Z9 11 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 1 PY 2008 VL 113 IS 11 BP 3146 EP 3152 DI 10.1002/cncr.23926 PG 7 WC Oncology SC Oncology GA 373MS UT WOS:000260976600014 PM 18932254 ER PT J AU Kho, ME Lepisto, EM Niland, JC Friedberg, JW LaCasce, AS Weeks, JC AF Kho, Michelle E. Lepisto, Eva M. Niland, Joyce C. Friedberg, Jonathan W. LaCasce, Ann S. Weeks, Jane C. TI Reliability of Staging, Prognosis, and Comorbidity Data Collection in the National Comprehensive Cancer Network (NCCN) Non-Hodgkin Lymphoma (NHL) Multicenter Outcomes Database SO CANCER LA English DT Article DE observer variation; research personnel; quality assurance; National Comprehensive Cancer Network; lymphoma; Charlson comorbidity index ID INTENSIVE-CARE; APACHE-II; INDEX AB BACKGROUND. Clinical trials and outcomes studies often rely on nonphysicians to abstract complex data from medical records, but the reliability of these data are rarely assessed. METHODS. We used standardized charts of patients with non-Hodgkin lymphoma to assess the reliability of key clinical data elements abstracted by 6 clinical research associates (CRAs), 3 project staff, and 3 medical oncologists. We assessed reliability on 5 variables: MD-reported and rater-determined disease stage; International Prognostic Index (IPI; low-low intermediate, intermediate-high, high); Charlson comorbidity index score; and presence of any item from the Charlson index. Intraclass correlation coefficients (ICCs) of 0-0.20 were indicative of "slight", 0.21-0.40 indicated "fair", 0.41-0.60 indicated "moderate", 0.61-0.80 "substantial" and >0.80 "almost perfect" reliability. RESULTS. By outcome, the ICC (95% confidence interval) values for MD-reported stage, rater-determined stage, and IPI were 0.86 (0.67, 0.94), 0.82 (0.59, 0.93), and 0.80 (0.55, 0.92), respectively. In contrast, the ICC (95% confidence interval) of the Charlson score, or presence of any Charlson comorbidity item was 0.47 (0.03, 0.75) and 0.61 (0.23, 0.83), respectively. Reliability varied by rater group; no rater group was consistently more reliable than others. CONCLUSIONS. Trained CRAs abstracted key clinical variables with a very high degree of reliability, and performed at a level similar to study trainers and oncologists. Elements of the Charlson index were less reliable than other data types, possibly because of inherent ambiguity in the index itself. Cancer 2008; 113:3209-12. (C) 2008 American Cancer Society. C1 [Kho, Michelle E.; LaCasce, Ann S.; Weeks, Jane C.] Dana Farber Canc Inst, Dept Med Oncol, Ctr Outcomes & Populat Res, Boston, MA 02115 USA. [Kho, Michelle E.] McMaster Univ, Dept Clin Epidemiol & Biostat, Program Hlth Res Methodol, Hamilton, ON, Canada. [Lepisto, Eva M.] Natl Comprehens Canc Network, Ft Washington, PA USA. [Niland, Joyce C.] City Hope Comprehens Canc Ctr, Div Informat Sci, Duarte, CA USA. [Friedberg, Jonathan W.] Univ Rochester, Dept Hematol Oncol, Rochester, NY USA. RP Weeks, JC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Ctr Outcomes & Populat Res, 44 Binney St, Boston, MA 02115 USA. EM jane_weeks@dfci.harvard.edu FU National Comprehensive Cancer Network; Canadian Institutes of Health Research Fellowship Award; US National Cancer Institute [CA-102216] FX The following centers contributed patient charts to this study: City of Hope Cancer Center, Duarte, CA; Dana-Farber Cancer Institute, Boston, MA; Fox Chase Cancer Center, Philadelphia, PA; University of Texas MID Anderson Cancer Center, Houston, TX; Roswell Park Cancer Institute, Buffalo, NY. The authors would like to thank the following people for their contributions to this project: all of the study participants, Janet Files, Sarah Walsh, and Janet Nikowitz for administrative and organizational assistance; Anna terVeer for assistance with development of the dataset; Layla Rouse and Monir Corona for assistance with development of the study database; and the NCCN NHL Disease-Specific Executive committee for helpful comments and suggestions throughout this study. The National Comprehensive Cancer Network funded this study. Michelle Kho is funded by a Canadian Institutes of Health Research Fellowship Award through the Clinical Research Initiative. Jonathan Friedberg is supported by a career development award from the US National Cancer Institute (CA-102216). NR 16 TC 9 Z9 9 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 1 PY 2008 VL 113 IS 11 BP 3209 EP 3212 DI 10.1002/cncr.23911 PG 4 WC Oncology SC Oncology GA 373MS UT WOS:000260976600022 PM 18855918 ER PT J AU Raina, D Ahmad, R Chen, DS Kumar, S Kharbanda, S Kufe, D AF Raina, Deepak Ahmad, Rehan Chen, Dongshu Kumar, Shailendra Kharbanda, Surender Kufe, Donald TI MUC1 oncoprotein suppresses activation of the ARF-MDM2-p53 pathway SO CANCER BIOLOGY & THERAPY LA English DT Article DE MUC1; ARF; MDM2; p53; HIPK2; INK4 ID CARCINOMA-ASSOCIATED ANTIGEN; BETA-CATENIN; DNA-DAMAGE; APOPTOTIC RESPONSE; C-ABL; GENE-TRANSCRIPTION; SURVIVAL RESPONSE; OXIDATIVE STRESS; TYROSINE KINASE; INK4/ARF LOCUS AB The MUC1 oncoprotein interacts with the c-Abl tyrosine kinase and blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage. Mutation of the MUC1 cytoplasmic domain at Tyr-60 disrupts the MUC1-c-Abl interaction. The present results demonstrate that the MUC1(Y60F) mutant is a potent inducer of the ARF tumor suppressor. MUC1(Y60F) induces transcription of the ARF locus by a c-Abl-dependent mechanism that promotes CUL-4A-mediated nuclear export of the replication protein Cdc6. The functional significance of these findings is that MUC1(Y60F)-induced ARF expression and thereby inhibition of MDM2 results in the upregulation of p53 and the homeodomain interacting protein kinase 2 (HIPK2) serine/threonine kinase. HIPK2-mediated phosphorylation of p53 on Ser-46 was further associated with a shift from expression of the cell cycle arrest-related p21 gene to the apoptosis-related PUMA gene. We also show that the MUC1(Y60F) mutant functions as dominant negative inhibitor of tumorigenicity. These findings indicate that the oncogenic function of MUC1 is conferred by suppressing activation of the ARF-MDM2-p53 pathway. C1 [Raina, Deepak; Ahmad, Rehan; Chen, Dongshu; Kumar, Shailendra; Kharbanda, Surender; Kufe, Donald] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM donald_kufe@dfci.harvard.edu FU National Cancer Institute [CA97098, CA42802] FX This work was supported by Grants CA97098 and CA42802 awarded by the National Cancer Institute. The authors thank Gordon Peters, London Research Institute, U. K., for the ARF-luciferase construct and Bert Vogelstein, Johns Hopkins Oncology Center, Baltimore for the PUMA-luciferase vector. The authors acknowledge Kamal Chauhan for technical support. NR 54 TC 16 Z9 17 U1 1 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD DEC PY 2008 VL 7 IS 12 BP 1959 EP 1967 DI 10.4161/cbt.7.12.6956 PG 9 WC Oncology SC Oncology GA 392RA UT WOS:000262318700017 PM 18981727 ER PT J AU Emmons, K Puleo, E McNeill, L Bennett, G Chan, S Syngal, S AF Emmons, Karen Puleo, Elaine McNeill, Lorna H. Bennett, Gary Chan, Sophia Syngal, Sapna TI Colorectal cancer screening awareness and intentions among low income, sociodemographically diverse adults under age 50 SO CANCER CAUSES & CONTROL LA English DT Article DE CRC Screening; Disparities; Family history ID UNITED-STATES; WORKING-CLASS; HEALTHY DIRECTIONS; FAMILY-HISTORY; SOCIAL-CLASS; POPULATIONS; DISPARITIES; PREDICTORS; PREVENTION; GUIDELINES AB Colorectal cancer (CRC) screening rates in the US are suboptimal, particularly among lower income and racial/ethnically diverse groups. If specific populations have limited awareness of screening when they reach age 50, there may be delays in screening adoption. This study investigated sociodemographic and social contextual factors associated with awareness of CRC and intentions to be screened at age 50 among 692 low income, racial, and ethnic minority adults living in low income housing. The majority of respondents (62%) were between ages 30 and 49, and 94% had some form of health insurance (e.g., Medicaid). About 70% reported having heard about CRC screening; 66% reported intentions to be screened at age 50. In multivariable analyses, screening awareness was associated with age and education. Immigrants who had English as a second language had lower awareness. Females tended to have higher awareness if they had private insurance; there were no differences among males. Multivariable analyses found that screening intentions were higher among men, those with more role responsibilities, more role conflicts, and higher levels of social cohesion. It is important to identify opportunities for maximizing screening uptake among those who become age-eligible for screening if we are to make a significant impact on CRC disparities. C1 [Emmons, Karen; McNeill, Lorna H.; Bennett, Gary] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Puleo, Elaine] Univ Massachusetts, Amherst, MA 01003 USA. [Chan, Sophia] Univ Hong Kong, Hong Kong, Hong Kong, Peoples R China. [Syngal, Sapna] Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Emmons, K (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St, Boston, MA 02115 USA. EM Karen_M_Emmons@dfci.harvard.edu FU National Cancer Institute [5R01CA098864, 3R01CA098864-02S1]; Dana-Farber Cancer Institute; Liberty Mutual and the Patterson Fellowship Fund; DF/HCC; Harvard School of Public Health; Dana-Farber/Harvard Cancer Center FX This research was supported by grant 5R01CA098864 from the National Cancer Institute, support to the Dana-Farber Cancer Institute by Liberty Mutual and the Patterson Fellowship Fund, and support from the DF/HCC and Harvard School of Public Health for the Yerby Fellowship Training Program (LH). G. G. Bennett is also supported by an award from the Dana-Farber/Harvard Cancer Center and by grant 3R01CA098864-02S1 from the National Cancer Institute. NR 49 TC 11 Z9 11 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 2008 VL 19 IS 10 BP 1031 EP 1041 DI 10.1007/s10552-008-9167-0 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 370MM UT WOS:000260766300003 PM 18478340 ER PT J AU Tse, D Zhai, RH Zhou, W Heist, R Asomaning, K Su, L Lynch, T Wain, J Christiani, D Liu, G AF Tse, Darren Zhai, Rihong Zhou, Wei Heist, Rebecca S. Asomaning, Kofi Su, Li Lynch, Thomas J. Wain, John C. Christiani, David C. Liu, Geoffrey TI Polymorphisms of the NER pathway genes, ERCC1 and XPD are associated with esophageal adenocarcinoma risk SO CANCER CAUSES & CONTROL LA English DT Article DE DNA repair; Esophageal cancer; Adenocarcinoma; Polymorphism; Nucleotide excision pathway ID DNA-REPAIR GENES; LUNG-CANCER PATIENTS; SQUAMOUS-CELL CARCINOMA; CHINESE POPULATION; BREAST-CANCER; BARRETTS-ESOPHAGUS; UNITED-STATES; XRCC1; CAPACITY; SUSCEPTIBILITY AB Functional variation in DNA repair capacity through single nucleotide polymorphisms (SNPs) of key repair genes is associated with a higher risk of developing various types of cancer. Studies have focused on the nucleotide excision repair (NER) and base excision repair (BER) pathways. We investigated whether variant alleles in seven SNPs within these pathways increased the risk of esophageal adenocarcinoma. DNA was extracted from prospectively collected blood specimens. The samples were genotyped for SNPs in NER genes (XPD Lys751Gln, XPD Asp312Asn, ERCC1 8092C/A, and ERCC1 118C/T), and BER genes (XRCC1 Arg399Gln, APE1 Asp148Glu, and hOGG1 Ser326Cys). The presence of variant alleles was correlated with risk of esophageal adenocarcinoma both individually and jointly. Variant alleles in NER SNPs XPD Lys751Gln (AOR = 1.50, 95% CI 1.1-2.0), ERCC1 8092 C/A (AOR = 1.44, 95% CI 1.1-1.9), and ERCC1 118C/T (AOR = 1.42, 95% CI 1.0-1.9) were individually associated with esophageal adenocarcinoma risk. An increasing number of variant alleles in NER SNPs showed a significant trend with esophageal adenocarcinoma risk (p = 0.007). The presence of variant alleles in NER genes increases risk of esophageal adenocarcinoma. There is evidence of an additive role for SNPs along a common DNA repair pathway. Future larger studies of esophageal adenocarcinoma etiology should evaluate entire biological pathways. C1 [Liu, Geoffrey] Ontario Canc Inst, Princess Margaret Hosp, Dept Med Oncol, Toronto, ON M5G 2M9, Canada. [Tse, Darren; Liu, Geoffrey] Ontario Canc Inst, Princess Margaret Hosp, Dept Appl Mol Oncol, Toronto, ON M5G 2M9, Canada. [Zhai, Rihong; Zhou, Wei; Heist, Rebecca S.; Asomaning, Kofi; Su, Li; Christiani, David C.; Liu, Geoffrey] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Heist, Rebecca S.; Lynch, Thomas J.; Christiani, David C.; Liu, Geoffrey] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Wain, John C.] Sunnybrook Hlth Sci Ctr, Toronto Sunnybrook Reg Canc Ctr, Toronto, ON M4N 3M5, Canada. RP Liu, G (reprint author), Ontario Canc Inst, Princess Margaret Hosp, Dept Med Oncol, 610 Univ Ave,Suite 7-124, Toronto, ON M5G 2M9, Canada. EM geoffrey.liu@uhn.on.ca RI Liu, Geoffrey/N-4421-2016 FU Wharton Research Fund; Kevin Jackson Memorial Fund [R03-CA109193, R01-CA109193, R01-CA074386] FX We would like to thank Peggy Suen, Andrea Shafer, Richard Rivera-Massa, Lucy-Ann Principe, and Fei-Fei Liu for their help. This research was supported by: Alan B. Brown Chain of Molecular Genomics, The Wharton Research Fund, Kevin Jackson Memorial Fund (R03-CA109193, R01-CA109193, R01-CA074386). NR 45 TC 55 Z9 63 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 2008 VL 19 IS 10 BP 1077 EP 1083 DI 10.1007/s10552-008-9171-4 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 370MM UT WOS:000260766300007 PM 18478337 ER PT J AU Stoffel, EM Turgeon, K Stockwell, DH Normolle, DP Tuck, M Marcon, NE Baron, JA Bresalier, RS Arber, N Ruffin, MT Syngal, S Brenner, DE AF Stoffel, Elena M. Turgeon, Kim Stockwell, David H. Normolle, Daniel P. Tuck, MissyK. Marcon, Norman E. Baron, John A. Bresalier, Robert S. Arber, Nadir Ruffin, Mack T. Syngal, Sapna Brenner, Dean E. CA GLNE-EDRN TI Chromoendoscopy Detects More Adenomas than Colonoscopy Using Intensive Inspection without Dye Spraying SO CANCER PREVENTION RESEARCH LA English DT Article ID ULCERATIVE-COLITI