FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Waters, KM Stram, DO Hassanein, MT Le Marchand, L Wilkens, LR Maskarinec, G Monroe, KR Kolonel, LN Altshuler, D Henderson, BE Haiman, CA AF Waters, Kevin M. Stram, Daniel O. Hassanein, Mohamed T. Le Marchand, Loic Wilkens, Lynne R. Maskarinec, Gertraud Monroe, Kristine R. Kolonel, Laurence N. Altshuler, David Henderson, Brian E. Haiman, Christopher A. TI Consistent Association of Type 2 Diabetes Risk Variants Found in Europeans in Diverse Racial and Ethnic Groups SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; PROSTATE-CANCER RISK; MULTIETHNIC COHORT; COMMON VARIANTS; LOCI; SUSCEPTIBILITY; POPULATION; CDKAL1; KCNQ1; POLYMORPHISMS AB It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be population-specific, as the causal mutations arose after the migrations that established different populations around the world. We selected 19 common variants found to be reproducibly associated to T2D risk in European populations and studied them in a large multiethnic case-control study (6,142 cases and 7,403 controls) among men and women from 5 racial/ethnic groups (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In analysis pooled across ethnic groups, the allelic associations were in the same direction as the original report for all 19 variants, and 14 of the 19 were significantly associated with risk. In summing the number of risk alleles for each individual, the per-allele associations were highly statistically significant (P < 10(-4)) and similar in all populations (odds ratios 1.09-1.12) except in Japanese Americans the estimated effect per allele was larger than in the other populations (1.20; P-het = 3.8x10(-4)). We did not observe ethnic differences in the distribution of risk that would explain the increased prevalence of type 2 diabetes in these groups as compared to European Americans. The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding "synthetic associations'' of rare mutations in T2D. C1 [Waters, Kevin M.; Stram, Daniel O.; Hassanein, Mohamed T.; Monroe, Kristine R.; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Le Marchand, Loic; Wilkens, Lynne R.; Maskarinec, Gertraud; Kolonel, Laurence N.] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA. [Altshuler, David] Massachusetts Inst Technol & Harvard, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Altshuler, David] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. RP Waters, KM (reprint author), Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. EM kwaters@usc.edu; haiman@usc.edu RI Altshuler, David/A-4476-2009 OI Altshuler, David/0000-0002-7250-4107 FU National Cancer Institute [CA63464, CA54281, 1U01HG004802] FX The Multiethnic Cohort Study was supported by National Cancer Institute grants CA63464, CA54281, and 1U01HG004802. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 66 Z9 66 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2010 VL 6 IS 8 AR e1001078 DI 10.1371/journal.pgen.1001078 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 644NG UT WOS:000281383800033 ER PT J AU Gandhi, RT Zheng, L Bosch, RJ Chan, ES Margolis, DM Read, S Kallungal, B Palmer, S Medvik, K Lederman, MM Alatrakchi, N Jacobson, JM Wiegand, A Kearney, M Coffin, JM Mellors, JW Eron, JJ AF Gandhi, Rajesh T. Zheng, Lu Bosch, Ronald J. Chan, Ellen S. Margolis, David M. Read, Sarah Kallungal, Beatrice Palmer, Sarah Medvik, Kathy Lederman, Michael M. Alatrakchi, Nadia Jacobson, Jeffrey M. Wiegand, Ann Kearney, Mary Coffin, John M. Mellors, John W. Eron, Joseph J. CA AIDS Clinical Trials Grp TI The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial SO PLOS MEDICINE LA English DT Article ID IMMUNODEFICIENCY; SUBPOPULATIONS; REPLICATION; SUPPRESSION; ACTIVATION; RECOVERY; PLASMA; BLOOD; RNA AB Background: Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients. Methods and Findings: Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median -0.2 and -0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus -44 cells/mm(3), p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood. Conclusion: In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection. C1 [Gandhi, Rajesh T.] Massachusetts Gen Hosp & Ragon Inst, Boston, MA USA. [Zheng, Lu; Bosch, Ronald J.; Chan, Ellen S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Margolis, David M.; Eron, Joseph J.] Univ N Carolina, Chapel Hill, NC USA. [Read, Sarah] NIAID, Bethesda, MD 20892 USA. [Kallungal, Beatrice] Social & Sci Syst, Silver Spring, MD USA. [Palmer, Sarah] Karolinska Inst, Stockholm, Sweden. [Medvik, Kathy; Lederman, Michael M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Alatrakchi, Nadia] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Jacobson, Jeffrey M.] Drexel Univ, Philadelphia, PA 19104 USA. [Wiegand, Ann; Kearney, Mary] NCI, Frederick, MD 21701 USA. [Coffin, John M.] Tufts Univ, Boston, MA 02111 USA. [Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA USA. RP Gandhi, RT (reprint author), Massachusetts Gen Hosp & Ragon Inst, Boston, MA USA. EM rgandhi@partners.org OI Margolis, David/0000-0001-5714-0002 FU National Institute of Allergy and Infectious Diseases [U01AI068636, AI 068634]; National Institutes of Health [5U01A1068636-04, 25XS119]; F.M. Kirby Foundation; Merck Sharp Dohme, Corp; CTU [5UO1 AI069502-03, AI 069501, AI69423-03, U01 AI069452, 1U01AI069472, AI069556, AI 069494-01, AI069495, AI069471, AI069532, AI-27665, AI069434, AI069419, U01 AI069472-04, AI069424, AI069450, AI69511-02, 5U01 AI069484, AI069470]; CFAR [AI50410]; CTSA [RR025747]; GCRC [M01 RR-00032, RR025780, 5-MO1 RR00044]; CTSC [RR024996] FX The project was supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases. The project was also supported by a grant from the National Institute of Allergy and Infectious Diseases to the Statistical and Data Analysis Center (AI 068634). In addition, JWM was supported by the following National Institutes of Health grants: 5U01A1068636-04 and NIH 25XS119. JMC was a research professor of the American Cancer Society, with support from the F.M. Kirby Foundation. The content is solely the responsibility of the authors and does not represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The study was also supported by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme, Corp. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme, Corp.; We would like to thank all the members of the ACTG 5244 team, including Randi Leavitt, Barbara Philpotts, Betty A. Donoval, Robert Levaro, Ana Martinez, Lisa M. Demeter, Richard D'Aquila, and Carla Pettinelli. We would like to express our special appreciation to Jennifer Janik for her excellent work as the study data manager and to Heather Springer and Amy Jennings for their outstanding work on coordinating the laboratory data for the study. We gratefully acknowledge the hard work of the study staff at all the ACTG sites who screened and enrolled participants in this trial: Annie Luetkemeyer, MD and Joann Volinski, RN- UCSF, San Francisco General Hospital ( Site 801) CTU Grant # 5UO1 AI069502-03; MetroHealth ( Site 2503) CTU Grant # AI 069501; David Currin RN and Cheryl Marcus RN, BSN -University of North Carolina AIDS Clinical Trials Unit ( Site 3201) CTU Grant # AI69423-03, CFAR Grant # AI50410, CTSA Grant # RR025747; Melinda Robertson, RN and Rebecca Creamer- Alabama Therapeutics CRS ( Site 5801) CTU Grant # U01 AI069452, GCRC Grant # M01 RR-00032; Amy Sbrolla, R. N. and Nicole Burgett-Yandow, R. N., B. S. N.-Harvard Massachusetts General Hospital ( Site 101) CTU Grant# 1U01AI069472; Jane Norris, PA-C and Sandra Valle, PA-C-Stanford University ( Site 501) CTU Grant # AI069556; Deborah McMahon, MD and Sally McNulty, BA, RN - University of Pittsburgh ( Site 1001) CTU Grant # AI 069494-01; Teresa Spitz, RN, CCRC and Judy Frain, RN, BSN-Washington University in St. Louis ( Site 2101) CTU Grant # AI069495; Babafemi Taiwo, M. B. B. S., M. D. and Karen Coleman, R. N.-Northwestern University ( Site 2701) CTU Grant # AI069471; HIV Prevention & Treatment CRS ( Site 30329); Margarita Vasquez, RN and Judith A. Aberg, M. D.-New York University/NYC HHC at Bellevue Hospital Center ( Site 401) CTU Grant # AI069532, AI-27665; University of Washington, Seattle ( Site 1401) CTU Grant # AI069434; Todd Stroberg, R. N., and Valery Hughes N. P.-Cornell CTU ( Site 7804) CTU Grant # AI069419 CTSC# RR024996; Mary Albrecht, MD and Amanda Youmans, RN, ANP -Beth Israel Deaconess (Partners/Harvard) ( Site 103) CTU Grant # U01 AI069472-04; Harbor UCLA Medical Center ( Site 603) CTU Grant # AI069424; M. Graham Ray, R. N., M. S. N. and Steven C. Johnson, M. D. -Colorado ACTU ( Site 6101) CTU Grant #AI069450 and GCRC Grant # RR025780; Amneris Luque MD and Mary Adams, RN- University of Rochester ( Site 1101) CTU Grant # AI69511-02 ( as of 2/12/08), GCRC Grant # 5-MO1 RR00044; Nathan M. Thielman, MD and Martha Silberman, RN- Duke University Medical Center ( Site 1601) CTU Grant # 5U01 AI069484; Harlem Family Health Center ( Site 31483) CTU Grant # AI069470. Finally, we would like to thank all the patients who participated in this study. NR 21 TC 131 Z9 131 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD AUG PY 2010 VL 7 IS 8 AR e1000321 DI 10.1371/journal.pmed.1000321 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 645KV UT WOS:000281456500008 ER PT J AU Sanchez, CJ Shivshankar, P Stol, K Trakhtenbroit, S Sullam, PM Sauer, K Hermans, PWM Orihuela, CJ AF Sanchez, Carlos J. Shivshankar, Pooja Stol, Kim Trakhtenbroit, Samuel Sullam, Paul M. Sauer, Karin Hermans, Peter W. M. Orihuela, Carlos J. TI The Pneumococcal Serine-Rich Repeat Protein Is an Intra-Species Bacterial Adhesin That Promotes Bacterial Aggregation In Vivo and in Biofilms SO PLOS PATHOGENS LA English DT Article ID STREPTOCOCCUS-PNEUMONIAE VIRULENCE; SURFACE GLYCOPROTEINS GSPB; FIMBRIA-ASSOCIATED ADHESIN; STAPHYLOCOCCUS-AUREUS; EXTRACELLULAR DNA; INVASIVE DISEASE; MIDDLE-EAR; BINDING; GORDONII; CELLS AB The Pneumococcal serine-rich repeat protein (PsrP) is a pathogenicity island encoded adhesin that has been positively correlated with the ability of Streptococcus pneumoniae to cause invasive disease. Previous studies have shown that PsrP mediates bacterial attachment to Keratin 10 (K10) on the surface of lung cells through amino acids 273-341 located in the Basic Region (BR) domain. In this study we determined that the BR domain of PsrP also mediates an intra-species interaction that promotes the formation of large bacterial aggregates in the nasopharynx and lungs of infected mice as well as in continuous flow-through models of mature biofilms. Using numerous methods, including complementation of mutants with BR domain deficient constructs, fluorescent microscopy with Cy3-labeled recombinant (r) BR, Far Western blotting of bacterial lysates, co-immunoprecipitation with rBR, and growth of biofilms in the presence of antibodies and competitive peptides, we determined that the BR domain, in particular amino acids 122-166 of PsrP, promoted bacterial aggregation and that antibodies against the BR domain were neutralizing. Using similar methodologies, we also determined that SraP and GspB, the Serine-rich repeat proteins (SRRPs) of Staphylococcus aureus and Streptococcus gordonii, respectively, also promoted bacterial aggregation and that their Non-repeat domains bound to their respective SRRPs. This is the first report to show the presence of biofilm-like structures in the lungs of animals infected with S. pneumoniae and show that SRRPs have dual roles as host and bacterial adhesins. These studies suggest that recombinant Non-repeat domains of SRRPs (i.e. BR for S. pneumoniae) may be useful as vaccine antigens to protect against Gram-positive bacteria that cause infection. C1 [Sanchez, Carlos J.; Shivshankar, Pooja; Trakhtenbroit, Samuel; Orihuela, Carlos J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Stol, Kim; Hermans, Peter W. M.] Radboud Univ Nijmegen, Med Ctr, Lab Pediat Infect Dis, NL-6525 ED Nijmegen, Netherlands. [Sullam, Paul M.] San Francisco VA Med Ctr, Div Infect Dis, San Francisco, CA USA. [Sullam, Paul M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Sauer, Karin] SUNY Binghamton, Dept Biol Sci, Binghamton, NY USA. RP Sanchez, CJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. EM orihuela@uthscsa.edu RI Hermans, Peter/F-4655-2010; Hermans, Peter/H-8042-2014 FU NIDCR [DE14318]; EC; NIH [AI41513, AI057433, AI078972]; VA FX CJS is supported through the NIDCR DE14318 for the COSTAR program. KS is funded by the EC Sixth Framework Program (OMVac project). PS is supported by the VA Merit Review Program and by NIH grants AI41513 and AI057433. For CJO this work was supported by the NIH grant AI078972. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 70 Z9 71 U1 2 U2 27 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2010 VL 6 IS 8 AR e1001044 DI 10.1371/journal.ppat.1001044 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 644SM UT WOS:000281399900017 PM 20714350 ER PT J AU Vingadassalom, D Campellone, KG Brady, MJ Skehan, B Battle, SE Robbins, D Kapoor, A Hecht, G Snapper, SB Leong, JM AF Vingadassalom, Didier Campellone, Kenneth G. Brady, Michael J. Skehan, Brian Battle, Scott E. Robbins, Douglas Kapoor, Archana Hecht, Gail Snapper, Scott B. Leong, John M. TI Enterohemorrhagic E. coli Requires N-WASP for Efficient Type III Translocation but Not for EspF(U)-Mediated Actin Pedestal Formation SO PLOS PATHOGENS LA English DT Article ID ENTEROPATHOGENIC ESCHERICHIA-COLI; ARP2/3 COMPLEX; YERSINIA-PSEUDOTUBERCULOSIS; INTESTINAL COLONIZATION; SECRETION SYSTEM; EFFECTORS TIR; HOST-CELLS; PROTEIN; NCK; ESPF(U) AB Upon infection of mammalian cells, enterohemorrhagic E. coli (EHEC) O157:H7 utilizes a type III secretion system to translocate the effectors Tir and EspF(U) (aka TccP) that trigger the formation of F-actin-rich 'pedestals' beneath bound bacteria. EspF(U) is localized to the plasma membrane by Tir and binds the nucleation-promoting factor N-WASP, which in turn activates the Arp2/3 actin assembly complex. Although N-WASP has been shown to be required for EHEC pedestal formation, the precise steps in the process that it influences have not been determined. We found that N-WASP and actin assembly promote EHEC-mediated translocation of Tir and EspF(U) into mammalian host cells. When we utilized the related pathogen enteropathogenic E. coli to enhance type III translocation of EHEC Tir and EspF(U), we found surprisingly that actin pedestals were generated on N-WASP-deficient cells. Similar to pedestal formation on wild type cells, Tir and EspF(U) were the only bacterial effectors required for pedestal formation, and the EspF(U) sequences required to interact with N-WASP were found to also be essential to stimulate this alternate actin assembly pathway. In the absence of N-WASP, the Arp2/3 complex was both recruited to sites of bacterial attachment and required for actin assembly. Our results indicate that actin assembly facilitates type III translocation, and reveal that EspF(U), presumably by recruiting an alternate host factor that can signal to the Arp2/3 complex, exhibits remarkable versatility in its strategies for stimulating actin polymerization. C1 [Vingadassalom, Didier; Campellone, Kenneth G.; Brady, Michael J.; Skehan, Brian; Robbins, Douglas; Leong, John M.] Univ Massachusetts, Sch Med, Dept Mol Genet & Microbiol, Worcester, MA 01655 USA. [Battle, Scott E.; Hecht, Gail] Univ Illinois, Sect Digest Dis & Nutr, Chicago, IL USA. [Kapoor, Archana; Snapper, Scott B.] Massachusetts Gen Hosp, Dept Med & Immunol, Boston, MA 02114 USA. RP Vingadassalom, D (reprint author), Univ Massachusetts, Sch Med, Dept Mol Genet & Microbiol, Worcester, MA 01655 USA. EM John.Leong@umassmed.edu FU National Institutes of Health (NIH) [R01-AI46454, R01-DK058964, P01-DK050694, 5R01-AI052354, 5P01-HL59561] FX This work was supported by National Institutes of Health (NIH) grants R01-AI46454 to J.M.L., R01-DK058964 and P01-DK050694 to G. H., and 5R01-AI052354 and 5P01-HL59561 to S. B. S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 22 Z9 22 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD AUG PY 2010 VL 6 IS 8 AR e1001056 DI 10.1371/journal.ppat.1001056 PG 16 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 644SM UT WOS:000281399900029 PM 20808845 ER PT J AU Carlson, BA Yoo, MH Shrimali, RK Irons, R Gladyshev, VN Hatfield, DL Park, JM AF Carlson, Bradley A. Yoo, Min-Hyuk Shrimali, Rajeev K. Irons, Robert Gladyshev, Vadim N. Hatfield, Dolph L. Park, Jin Mo TI Session 2: Micronutrients and the immune system Role of selenium-containing proteins in T-cell and macrophage function SO PROCEEDINGS OF THE NUTRITION SOCIETY LA English DT Article; Proceedings Paper CT 3rd International Immunonutrition Workshop CY OCT, 2009 CL Girona, SPAIN DE Macrophage; Selenium; Selenocysteine; T-cells ID HYDROPEROXIDE GLUTATHIONE-PEROXIDASE; GENE-EXPRESSION; KAPPA-B; SELENOPROTEINS; SELENOCYSTEINE; ACTIVATION; MECHANISMS; INFECTION; RESPONSES; MICE AB Selenium (Se) has been known for many years to have played a role in boosting the immune function, but the manner in which this element acts at the molecular level in host defence and inflammatory diseases is poorly understood. To elucidate the role of Se-containing proteins in the immune function, we knocked out the expression of this protein class in T-cells or macrophages of mice by targeting the removal of the selenocysteine tRNA gene using loxP-Cre technology. Mice with selenoprotein-less T-cells manifested reduced pools of mature and functional T-cells in lymphoid tissues and an impairment in T-cell-dependent antibody responses. Furthermore, selenoprotein deficiency in T-cells led to an inability of these cells to suppress reactive oxygen species production, which in turn affected their ability to proliferate in response to T-cell receptor stimulation. Selenoprotein-less macrophages, on the other hand, manifested mostly normal inflammatory responses, but this deficiency resulted in an altered regulation in extracellular matrix-related gene expression and a diminished migration of macrophages in a protein gel matrix. These observations provided novel insights into the role of selenoproteins in the immune function and tissue homeostasis. C1 [Carlson, Bradley A.; Yoo, Min-Hyuk; Shrimali, Rajeev K.; Irons, Robert; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,Natl Inst Hlth, Bethesda, MD 20892 USA. [Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. [Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Park, Jin Mo] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Carlson, BA (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,Natl Inst Hlth, Bethesda, MD 20892 USA. EM carlsonb@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013 FU Intramural NIH HHS; NCI NIH HHS [R01 CA080946-10, R01 CA080946]; NIA NIH HHS [R01 AG021518-09, R01 AG021518]; NIGMS NIH HHS [R01 GM065204-09, R01 GM065204, R01 GM061603-10, R01 GM061603] NR 41 TC 31 Z9 34 U1 0 U2 10 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0029-6651 J9 P NUTR SOC JI Proc. Nutr. Soc. PD AUG PY 2010 VL 69 IS 3 BP 300 EP 310 DI 10.1017/S002966511000176X PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 632QC UT WOS:000280439600006 PM 20576203 ER PT J AU Hicken, BL Plowhead, A AF Hicken, Bret L. Plowhead, Angela TI A Model for Home-Based Psychology From the Veterans Health Administration SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article DE home care; psychology and home based primary care; therapy; assessment; homebound ID CORONARY-ARTERY-BYPASS; FAMILY-THERAPY; IN-HOME; ANTIRETROVIRAL THERAPY; CARE; SERVICES; DEPRESSION; PROGRAM; REHABILITATION; INTERVENTION AB The changing healthcare environment is creating opportunities for psychologists to practice in non-traditional settings. This paper describes a Veterans Health Administration (VA) initiative to integrate psychologists into its Home Based Primary Care (HBPC) program. As psychologists new to HBPC are learning, the home offers opportunities and challenges not routinely encountered in the traditional office setting. Home-based psychology offers improved access to mental health services, more effective treatment planning, and more accurate assessments in an underserved patient population. Psychologists practicing in this setting also encounter challenges in dealing with patient confidentiality, distractions, role confusion and boundaries, time management, safety, and professional competency. The VA experience is an instructive case example for psychologists considering this growing field of practice. This paper offers lessons learned from this VA initiative and discusses strategies for dealing with potential challenges. C1 [Hicken, Bret L.] George E Wahlen VA Med Ctr, Salt Lake City, UT USA. [Plowhead, Angela] Portland VA Med Ctr, Portland, OR USA. RP Hicken, BL (reprint author), VA Salt Lake City Hlth Care Syst, VA Rural Hlth Resource Ctr Western Reg, 500 Foothill Dr 182,SLC, Salt Lake City, UT 84148 USA. EM bret.hicken@va.gov NR 37 TC 8 Z9 8 U1 1 U2 2 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7028 J9 PROF PSYCHOL-RES PR JI Prof. Psychol.-Res. Pract. PD AUG PY 2010 VL 41 IS 4 BP 340 EP 346 DI 10.1037/a0020431 PG 7 WC Psychology, Multidisciplinary SC Psychology GA 642LF UT WOS:000281214300010 ER PT J AU Otis, JD Gregor, K Hardway, C Morrison, J Scioli, E Sanderson, K AF Otis, John D. Gregor, Kristin Hardway, Christina Morrison, Jay Scioli, Erica Sanderson, Kristen TI An Examination of the Co-Morbidity Between Chronic Pain and Posttraumatic Stress Disorder on US Veterans SO PSYCHOLOGICAL SERVICES LA English DT Article DE pain; Veterans; military personnel; posttraumatic stress disorder; wounds and injuries ID LOW-BACK-PAIN; PSYCHOMETRIC PROPERTIES; MUTUAL MAINTENANCE; DISABILITY; QUESTIONNAIRE; REPLICATION; INVENTORY; SYMPTOMS; DISTRESS; HEALTH AB The purpose of this study was to assess the comorbidity between chronic pain and posttraumatic stress disorder (PTSD) and examine the extent to which PTSD is associated with changes in the multidimensional experience of pain in a sample of Veterans with chronic pain. It was hypothesized that Veterans with comorbid chronic pain and PTSD would report significantly higher scores on measures of pain intensity, pain behaviors, pain-related disability, and affective distress than Veterans with pain alone. Data were obtained from 149 Veterans who completed self-report questionnaires as part of their participation in a Psychology Pain Management program at a northeastern Department of Veterans Affairs health care facility. Analyses indicated that 49% of the sample met criteria for PTSD. A multivariate analysis of covariance was conducted with age, sex, pain duration, and depressive symptom severity as covariates. In partial support of our hypothesis, the presence of PTSD was found to contribute significantly to measures of affective distress, even after controlling for the effects of depressive symptom severity. The implications of these data are discussed. C1 [Otis, John D.; Gregor, Kristin; Morrison, Jay; Scioli, Erica; Sanderson, Kristen] VA Boston Healthcare Syst, Boston, MA 02130 USA. [Hardway, Christina] Merrimack Coll, Dept Psychol, N Andover, MA 01845 USA. RP Otis, JD (reprint author), VA Boston Healthcare Syst, 150 S Huntington Ave, Boston, MA 02130 USA. EM john.otis@va.gov NR 30 TC 17 Z9 17 U1 1 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1541-1559 EI 1939-148X J9 PSYCHOL SERV JI Psychol. Serv. PD AUG PY 2010 VL 7 IS 3 BP 126 EP 135 DI 10.1037/a0020512 PG 10 WC Psychology, Clinical SC Psychology GA 789QG UT WOS:000292529800003 ER PT J AU Vranceanu, AM Ring, D AF Vranceanu, A. M. Ring, D. TI Psychological factors predict disability after musculoskeletal trauma SO PSYCHOLOGY & HEALTH LA English DT Meeting Abstract C1 [Vranceanu, A. M.; Ring, D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0887-0446 EI 1476-8321 J9 PSYCHOL HEALTH JI Psychol. Health PD AUG 1 PY 2010 VL 25 SU 1 SI SI BP 97 EP 97 PG 1 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA 238AU UT WOS:000325913600208 ER PT J AU Vranceanu, AM Safren, S Ring, D AF Vranceanu, A. M. Safren, S. Ring, D. TI Cognitive behavioural therapy for non-specific arm pain: Results from a pilot SO PSYCHOLOGY & HEALTH LA English DT Meeting Abstract C1 [Vranceanu, A. M.; Safren, S.; Ring, D.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0887-0446 EI 1476-8321 J9 PSYCHOL HEALTH JI Psychol. Health PD AUG 1 PY 2010 VL 25 SU 1 SI SI BP 366 EP 366 PG 1 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA 238AU UT WOS:000325913600874 ER PT J AU Danz, MS Rubenstein, LV Hempel, S Foy, R Suttorp, M Farmer, MM Shekelle, PG AF Danz, M. S. Rubenstein, L. V. Hempel, S. Foy, R. Suttorp, M. Farmer, M. M. Shekelle, P. G. TI Identifying quality improvement intervention evaluations: is consensus achievable? SO QUALITY & SAFETY IN HEALTH CARE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; HEALTH-CARE; FRAMEWORK AB Background The diversity of quality improvement interventions (QIIs) has impeded the use of evidence review to advance quality improvement activities. An agreed-upon framework for identifying QII articles would facilitate evidence review and consensus around best practices. Aim To adapt and test evidence review methods for identifying empirical QII evaluations that would be suitable for assessing QII effectiveness, impact or success. Design Literature search with measurement of multilevel inter-rater agreement and review of disagreement. Methods Ten journals (2005-2007) were searched electronically and the output was screened based on title and abstract. Three pairs of reviewers then independently rated 22 articles, randomly selected from the screened list. Kappa statistics and percentage agreement were assessed. 12 stakeholders in quality improvement, including QII experts and journal editors, rated and discussed publications about which reviewers disagreed. Results The level of agreement among reviewers for identifying empirical evaluations of QII development, implementation or results was 73% (with a paradoxically low kappa of 0.041). Discussion by raters and stakeholders regarding how to improve agreement focused on three controversial article selection issues: no data on patient health, provider behaviour or process of care outcomes; no evidence for adaptation of an intervention to a local context; and a design using only observational methods, as correlational analyses, with no comparison group. Conclusion The level of reviewer agreement was only moderate. Reliable identification of relevant articles is an initial step in assessing published evidence. Advancement in quality improvement will depend on the theory-and consensus-based development and testing of a generalizable framework for identifying QII evaluations. C1 [Danz, M. S.; Rubenstein, L. V.; Hempel, S.; Suttorp, M.; Shekelle, P. G.] RAND Corp, Santa Monica, CA 90407 USA. [Danz, M. S.; Rubenstein, L. V.; Farmer, M. M.; Shekelle, P. G.] Vet Affairs Greater Los Angeles Healthcare Syst, North Hills, CA USA. [Foy, R.] Univ Leeds, Leeds Inst Hlth Sci, Leeds, W Yorkshire, England. RP Danz, MS (reprint author), RAND Corp, Santa Monica, CA 90407 USA. EM mjsdanz@gmail.com FU Robert Wood Johnson (RWJ) Foundation [65113] FX Robert Wood Johnson (RWJ) Foundation under a grant to LVR (grant ID 65113: Advancing the science of continuous quality improvement: A framework for identifying, classifying and evaluating continuous quality improvement studies). NR 18 TC 13 Z9 13 U1 1 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1475-3898 J9 QUAL SAF HEALTH CARE JI Qual. Saf. Health Care PD AUG PY 2010 VL 19 IS 4 BP 279 EP 283 DI 10.1136/qshc.2009.036475 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 688TB UT WOS:000284875300007 PM 20630931 ER PT J AU McLoud, TC AF McLoud, Theresa C. TI Trends in Radiologic Training: National and International Implications SO RADIOLOGY LA English DT Article ID CERTIFICATION; CHALLENGES C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP McLoud, TC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM tmcloud@partners.org NR 10 TC 5 Z9 5 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2010 VL 256 IS 2 BP 343 EP 347 DI 10.1148/radiol.10091429 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 630KO UT WOS:000280272100004 PM 20656829 ER PT J AU Sangwaiya, MJ Boland, GWL Cronin, CG Blake, MA Halpern, EF Hahn, PF AF Sangwaiya, Minal J. Boland, Giles W. L. Cronin, Carmel G. Blake, Michael A. Halpern, Elkan F. Hahn, Peter F. TI Incidental Adrenal Lesions: Accuracy of Characterization with Contrast-enhanced Washout Multidetector CT-10-minute Delayed Imaging Protocol Revisited in a Large Patient Cohort SO RADIOLOGY LA English DT Article ID F-18-FDG PET/CT; CT PROTOCOL; MASSES; ADENOMAS; NONADENOMAS; MALIGNANCY; BENIGN AB Purpose: To reassess the accuracy of the 10-minute delayed scan to differentiate both lipid-rich and lipid-poor lesions in a large cohort of patients. Materials and Methods: This HIPAA-compliant retrospective study had institutional review board approval; the need for informed consent was waived. A multidetector computed tomography (CT) adrenal protocol (unenhanced, dynamic contrast material-enhanced, and 10-minute delayed CT) was used in 314 consecutive patients (201 women, 113 men; mean age, 63.6 years) for the period from January 2006 through February 2009. The mean adrenal attenuation during all three CT phases was measured by two readers, and the relative percentage washout (RPW) and absolute percentage washout (APW) values were calculated. APW and RPW receiver operating characteristic (ROC) analysis was performed to evaluate the strength of the tests. Results: There were 323 adrenal lesions (213 left, 110 right) consisting of 307 adenomas and 16 nonadenomas. The sensitivity, specificity, and accuracy for the RPW test at a washout threshold of 50% were 55.7%, 100%, and 57.9%, respectively; at 40% were 76.9%, 93.7%, and 77.7%; and at 35% were 81.4%, 93.7%, and 82.0%. The sensitivity, specificity, and accuracy for the APW test at a 60% threshold were 52.1%, 93.3%, and 54.0%, respectively; at 55% were 62.5%, 93.3%, and 64.0%; and at 50% were 71.3%, 80.0%, and 71.7%. Areas under the ROC curve were 0.85 (95% confidence interval: 0.75, 0.95) and 0.91 (95% confidence interval: 0.85, 0.97) for the APW and RPW tests, respectively, to detect adenomatous disease. Conclusion: The 10-minute delayed adrenal enhancement washout test has reduced sensitivity for the characterization of adrenal adenomas compared with results from prior studies. (C) RSNA, 2010 C1 [Sangwaiya, Minal J.; Boland, Giles W. L.; Cronin, Carmel G.; Blake, Michael A.; Halpern, Elkan F.; Hahn, Peter F.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Boland, GWL (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM gboland@partners.org NR 21 TC 39 Z9 44 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2010 VL 256 IS 2 BP 504 EP 510 DI 10.1148/radiol.10091386 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 630KO UT WOS:000280272100021 PM 20656838 ER PT J AU Sepahdari, AR Aakalu, VK Setabutr, P Shiehmorteza, M Naheedy, JH Mafee, MF AF Sepahdari, Ali R. Aakalu, Vinay K. Setabutr, Pete Shiehmorteza, Masoud Naheedy, John H. Mafee, Mahmood F. TI Indeterminate Orbital Masses: Restricted Diffusion at MR Imaging with Echo-planar Diffusion-weighted Imaging Predicts Malignancy SO RADIOLOGY LA English DT Article ID NECK LESIONS; HEAD; LYMPHOMA; TUMORS; DIFFERENTIATION; COEFFICIENT; EXPERIENCE; BENIGN; BRAIN AB Purpose: To determine whether magnetic resonance (MR) imaging with diffusion-weighted (DW) imaging can help discriminate between radiologically indeterminate benign and malignant orbital masses and to identify optimal apparent diffusion coefficient (ADC) thresholds for such discrimination. Materials and Methods: Informed consent was waived for this HIPAA-compliant institutional review board-approved retrospective study. Forty-seven orbital masses imaged with echo-planar DW imaging were identified in 47 patients (25 female patients, 22 male patients; average age, 35 years). A fellowship-trained orbital surgeon determined reference-standard diagnoses on the basis of chart review, and a neuroradiology fellow and senior neuroradiologist who were blinded to the diagnoses selected a region of interest for each lesion by consensus. ADC was calculated from signal intensity on DW images obtained with b = 1000 and b = 0 sec/mm(2). Lesion ADC was also compared with that of normal-appearing white matter (ADC ratio). The Student t test was used to compare groups. Receiver operating characteristic analysis was performed. Intraobserver agreement was assessed with a repeat data collection. Results: Malignant lesions had lower ADCs than benign lesions, irrespective of patient age (P < .02) and in adults specifically (P < .05). Lymphomas had lower ADCs than pseudo-tumors (P < .001). An ADC of less than 1.0 x 10(-3) mm(2)/sec and an ADC ratio of less than 1.2 were optimal for predicting malignancy (sensitivity, 63% for both; specificity, 84% and 90%, respectively; and accuracy, 77% and 81%, respectively). Lymphoma was differentiated from pseudotumor with 100% accuracy (in 16 of 16 cases) by using these values. Infiltrative lesions that were hypointense on T2-weighted images were better characterized with DW imaging than lesions that were hyperintense or well defined. Conclusion: Echo-planar DW MR imaging can help characterize indeterminate orbital masses. (C) RSNA, 2010 C1 [Sepahdari, Ali R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Aakalu, Vinay K.; Setabutr, Pete] Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL USA. [Shiehmorteza, Masoud; Naheedy, John H.; Mafee, Mahmood F.] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. RP Sepahdari, AR (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,Gray 273A, Boston, MA 02114 USA. EM alisepahdari@gmail.com NR 23 TC 34 Z9 38 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2010 VL 256 IS 2 BP 554 EP 564 DI 10.1148/radiol.10091956 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 630KO UT WOS:000280272100027 PM 20656840 ER PT J AU Politi, LS Forghani, R Godi, C Resti, AG Ponzoni, M Bianchi, S Iadanza, A Ambrosi, A Falini, A Ferreri, AJM Curtin, HD Scotti, G AF Politi, Letterio S. Forghani, Reza Godi, Claudia Resti, Antonio G. Ponzoni, Maurilio Bianchi, Stefania Iadanza, Antonella Ambrosi, Alessandro Falini, Andrea Ferreri, Andres J. M. Curtin, Hugh D. Scotti, Giuseppe TI Ocular Adnexal Lymphoma: Diffusion-weighted MR Imaging for Differential Diagnosis and Therapeutic Monitoring SO RADIOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; MALT LYMPHOMA; ACUTE STROKE; ORBIT; COEFFICIENT; DISORDERS; BIOMARKER; PERFUSION; LESIONS; GLIOMA AB Purpose: To describe the magnetic resonance (MR) imaging and diffusion-weighted (DW) imaging features of ocular adnexal lymphomas (OALs), to determine the diagnostic accuracy of apparent diffusion coefficient (ADC) for discriminating OALs from other orbital mass lesions, and to assess whether variations in ADC constitute a reliable biomarker of OAL response to therapy. Materials and Methods: Institutional ethical committee approval and informed consent were obtained. In this prospective study, 114 white subjects (65 females and 49 males) were enrolled. Thirty-eight patients with histopathologically proved OAL underwent serial MR and DW imaging examination of the orbits. ADCs of OALs were compared with those of normal orbital structures, obtained in 18 healthy volunteers, and other orbital mass lesions, prospectively acquired in 58 patients (20 primary non-OAL neoplasms, 15 vascular benign lesions, 12 inflammatory lesions, 11 metastases). Interval change in ADC of OALs before and after treatment was analyzed in 29 patients. Analysis of covariance and a paired t test were used for statistical analysis. Results: Baseline ADCs in OALs were lower than those in normal structures and other orbital diseases (P < .001). An ADC threshold of 775 x 10(-6) mm(2)/sec resulted in 96% sensitivity, 93% specificity, 88% positive predictive value, 98.2% negative predictive value, and 94.4% accuracy in OAL diagnosis. Following appropriate treatment, 10 (34%) of 29 patients showed OAL volumetric reduction, accompanied (n = 7) or preceded (n = 3) by an increase in ADC (P = .005). Conversely, a further reduction of ADC was observed in the seven patients who experienced disease progression (P < .05). Conclusion: ADC permits accurate diagnosis of OALs. Interval change in ADC after therapy represents a helpful tool for predicting therapeutic response. (C) RSNA, 2010 C1 [Politi, Letterio S.; Godi, Claudia; Iadanza, Antonella; Falini, Andrea; Scotti, Giuseppe] Ist Sci San Raffaele, Dept Neuroradiol, I-20132 Milan, Italy. [Politi, Letterio S.; Godi, Claudia; Scotti, Giuseppe] Ist Sci San Raffaele, Neuroradiol Res Unit, I-20132 Milan, Italy. [Resti, Antonio G.; Bianchi, Stefania] Ist Sci San Raffaele, Dept Ophthalmol, I-20132 Milan, Italy. [Ponzoni, Maurilio] Ist Sci San Raffaele, Pathol Unit, I-20132 Milan, Italy. [Ponzoni, Maurilio; Ferreri, Andres J. M.] Ist Sci San Raffaele, Unit Lymphoid Malignancies, Med Oncol Unit, Dept Oncol, I-20132 Milan, Italy. [Iadanza, Antonella; Falini, Andrea] Ist Sci San Raffaele, Funct Neuroimaging Unit, I-20132 Milan, Italy. [Forghani, Reza] Massachusetts Gen Hosp, Div Neuroradiol, Boston, MA 02114 USA. [Ambrosi, Alessandro] San Raffaele Univ, Univ Ctr Biomed Sci, CUSSB, Milan, Italy. [Curtin, Hugh D.] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. RP Politi, LS (reprint author), Ist Sci San Raffaele, Dept Neuroradiol, Via Olgettina 60, I-20132 Milan, Italy. EM politi.letterio@hsr.it RI Ferreri, Andres Jose Maria/A-6662-2013; ambrosi, alessandro/H-4424-2011; OI Ferreri, Andres Jose Maria/0000-0001-9606-6124; ambrosi, alessandro/0000-0003-1976-5663; Iadanza, Antonella/0000-0001-6421-6984; falini, andrea/0000-0002-1461-8755; Politi, Letterio Salvatore/0000-0002-6190-6688 NR 33 TC 30 Z9 37 U1 0 U2 2 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2010 VL 256 IS 2 BP 565 EP 574 DI 10.1148/radiol.10100086 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 630KO UT WOS:000280272100028 PM 20656841 ER PT J AU Catalano, OA Choy, G Zhu, A Hahn, PF Sahani, DV AF Catalano, Onofrio A. Choy, Garry Zhu, Andrew Hahn, Peter F. Sahani, Dushyant V. TI Limited Value of Diffusion-weighted MR Imaging for Differentiating Bland from Malignant Portal Venous Thrombi Response SO RADIOLOGY LA English DT Letter C1 [Catalano, Onofrio A.; Choy, Garry; Hahn, Peter F.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Abdominal & Intervent Radiol, Boston, MA 02114 USA. [Zhu, Andrew] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Catalano, OA (reprint author), Massachusetts Gen Hosp, Dept Abdominal & Intervent Radiol, 55 Fruit St,WHT 270, Boston, MA 02114 USA. EM dsahani@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2010 VL 256 IS 2 BP 674 EP 674 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 630KO UT WOS:000280272100046 ER PT J AU Gudzenko, V Bittner, EA Schmidt, UH AF Gudzenko, Vadym Bittner, Edward A. Schmidt, Ulrich H. TI Emergency Airway Management SO RESPIRATORY CARE LA English DT Article DE airway management; intubation; intensive care unit; ICU; hypoxemia; respiratory failure ID RAPID-SEQUENCE INDUCTION; CRITICALLY-ILL PATIENTS; SUCCINYLCHOLINE-INDUCED HYPERKALEMIA; RESPIRATORY-DISTRESS-SYNDROME; ANESTHESIOLOGISTS-TASK-FORCE; IMPOSSIBLE MASK VENTILATION; RANDOMIZED CONTROLLED-TRIAL; ACUTE LUNG INJURY; TRACHEAL INTUBATION; CRICOID PRESSURE AB Emergency airway management is associated with a high complication rate. Evaluating the patient prior to airway management is important to identify patients with increased risk of failed airways. Pre-oxygenation of critically ill patients is less effective in comparison to less sick patients. Induction agents are often required, but most induction agents are associated with hypotension during emergency intubation. Use of muscle relaxants is controversial for emergency intubation, but they are commonly used in the emergency department. Supervision of emergency airway management by attending physicians significantly decreases complications. Standardized algorithms may increase the success of emergency intubation. Attention should be paid to cardiopulmonary stability in the immediate post-intubation period. C1 [Gudzenko, Vadym; Bittner, Edward A.; Schmidt, Ulrich H.] Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Management, Boston, MA 02114 USA. RP Schmidt, UH (reprint author), Massachusetts Gen Hosp, Dept Anesthesiol Crit Care & Pain Management, Gray Bigelow 444,55 Fruit St, Boston, MA 02114 USA. EM uschmidt@partners.org NR 92 TC 9 Z9 10 U1 0 U2 1 PU DAEDALUS ENTERPRISES INC PI IRVING PA 9425 N MAC ARTHUR BLVD, STE 100, IRVING, TX 75063-4706 USA SN 0020-1324 EI 1943-3654 J9 RESP CARE JI Respir. Care PD AUG PY 2010 VL 55 IS 8 BP 1026 EP 1035 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 641LQ UT WOS:000281128100004 PM 20667150 ER PT J AU Elenko, MP Szostak, JW van Oijen, AM AF Elenko, Mark P. Szostak, Jack W. van Oijen, Antoine M. TI Single-molecule binding experiments on long time scales SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article ID REFLECTION FLUORESCENCE MICROSCOPY; LIGAND; LOCALIZATION; SURFACES; APTAMERS; BIOLOGY AB We describe an approach for performing single-molecule binding experiments on time scales from hours to days, allowing for the observation of slower kinetics than have been previously investigated by single-molecule techniques. Total internal reflection fluorescence microscopy is used to image the binding of labeled ligand to molecules specifically coupled to the surface of an optically transparent flow cell. Long-duration experiments are enabled by ensuring sufficient positional, chemical, thermal, and image stability. Principal components of this experimental stability include illumination timing, solution replacement, and chemical treatment of solution to reduce photodamage and photobleaching; and autofocusing to correct for spatial drift. (C) 2010 American Institute of Physics. [doi:10.1063/1.3473936] C1 [Elenko, Mark P.] Harvard Univ, Sch Med, Program Biol & Biomed Sci, Boston, MA 02115 USA. [Szostak, Jack W.] Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. [Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [van Oijen, Antoine M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP van Oijen, AM (reprint author), Univ Groningen, Zernike Inst Adv Mat, NL-9700 AB Groningen, Netherlands. EM antoine_van_oijen@hms.harvard.edu OI van Oijen, Antoine/0000-0002-1794-5161 FU Howard Hughes Medical Institute NR 29 TC 7 Z9 7 U1 0 U2 9 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0034-6748 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD AUG PY 2010 VL 81 IS 8 AR 083705 DI 10.1063/1.3473936 PG 9 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA 651DZ UT WOS:000281906100017 PM 20815611 ER PT J AU Gonzalo, N Tearney, GJ Serruys, PW van Soest, G Okamura, T Garcia-Garcia, HM van Geuns, RJ van der Ent, M Ligthart, J Bouma, BE Regar, E AF Gonzalo, Nieves Tearney, Guillermo J. Serruys, Patrick W. van Soest, Gijs Okamura, Takayuki Garcia-Garcia, Hector M. Jan van Geuns, Robert van der Ent, Martin Ligthart, Jurgen Bouma, Brett E. Regar, Evelyn TI Second-Generation Optical Coherence Tomography in Clinical Practice. High-Speed Data Acquisition Is Highly Reproducible in Patients Undergoing Percutaneous Coronary Intervention SO REVISTA ESPANOLA DE CARDIOLOGIA LA Spanish DT Article DE Optical coherence tomography; Reproducibility; Stent assessment; Atherosclerotic plaque ID INCOMPLETE STENT APPOSITION; IN-VIVO; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC PLAQUE; MYOCARDIAL-INFARCTION; ELUTING STENTS; COVERAGE; THROMBOSIS; MORPHOLOGY; ADVANTAGE AB Introduction and objectives. The development of second-generation optical coherence tomography (i.e. Fourier domain optical coherence tomography, FD-OCT) has made it possible to perform high speed pullbacks during image acquisition without the need for transient occlusion of the coronary artery. The objective of this study was to assess the reproducibility of FD-OCT systems for characterizing plaque and evaluating stent implantation in patients undergoing a percutaneous coronary intervention. Methods. The study included 45 patients scheduled for percutaneous coronary intervention who were enrolled between May and December 2008. Image acquisition was performed by FD-OCT using a non-occlusive technique and employing pullback speeds ranging from 5 to 20 mm/s. Interstudy, interobserver and intraobserver reproducibility of plaque characterization and stent analysis were assessed. Results. Fourier domain imaging was successfully performed in all patients (n=45). The average flush rate was 3 +/- 0.4 mL/s and the contrast volume per pullback was 16.1 +/- 3.5 mL. The mean pullback duration and length were 3.2 +/- 1.2 s and 53.3 +/- 12.4 mm, respectively. The interstudy reproducibility for visualizing edge dissection, tissue prolapse, intrastent dissection and malapposition was excellent (kappa=1). The kappa values for interstudy, interobserver and intraobserver agreement on plaque characterization were 0.92, 0.82 and 0.95, respectively. Conclusions. A second-generation OCT system (i.e. FD-OCT) involving high-speed data acquisition demonstrated good interstudy, interobserver and intraobserver reproducibility for characterizing plaque and evaluating stent implantation in patients undergoing a percutaneous coronary intervention. C1 [Gonzalo, Nieves; Serruys, Patrick W.; van Soest, Gijs; Okamura, Takayuki; Garcia-Garcia, Hector M.; Jan van Geuns, Robert; van der Ent, Martin; Ligthart, Jurgen; Regar, Evelyn] Erasmus Univ, Ctr Thorax, NL-3015 CE Rotterdam, Paises Bajos, Netherlands. [Tearney, Guillermo J.; Bouma, Brett E.] Massachusetts Gen Hosp, Ctr Wellman Fotomed, Boston, MA 02114 USA. RP Regar, E (reprint author), Erasmus Univ, Ctr Thorax, Bd 585,S Gravendijkwal 230, NL-3015 CE Rotterdam, Paises Bajos, Netherlands. EM e.regar@erasmusmc.nl RI van Soest, Gijs/B-4881-2008 NR 34 TC 30 Z9 34 U1 0 U2 0 PU EDICIONES DOYMA S A PI BARCELONA PA TRAV DE GRACIA 17-21, 08021 BARCELONA, SPAIN SN 0300-8932 J9 REV ESP CARDIOL JI Rev. Esp. Cardiol. PD AUG PY 2010 VL 63 IS 8 BP 893 EP 903 DI 10.1016/S0300-8932(10)70201-3 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 632ZF UT WOS:000280468000004 PM 20738934 ER PT J AU Herrero-Garibi, J Cruz-Gonzalez, I Parejo-Diaz, P Jang, IK AF Herrero-Garibi, Jesus Cruz-Gonzalez, Ignacio Parejo-Diaz, Patricia Jang, Ik-Kyung TI Optical Coherence Tomography: Its Value in Intravascular Diagnosis Today SO REVISTA ESPANOLA DE CARDIOLOGIA LA Spanish DT Review DE Atherosclerotic plaque; Imaging; Angiography; Optical coherence tomography ID SIROLIMUS-ELUTING STENTS; CORONARY PLAQUE CHARACTERISTICS; ACUTE MYOCARDIAL-INFARCTION; RABBIT CAROTID MODEL; BARE METAL STENTS; NEOINTIMAL COVERAGE; ATHEROSCLEROTIC PLAQUES; ROTATIONAL ATHERECTOMY; VULNERABLE PLAQUE; STATIN THERAPY AB Optical coherence tomography is a recently developed high-resolution intravascular diagnostic technique. Initially, it was mainly used for characterizing atherosclerotic plaque because it served a number of functions, from identifying plaque with high lipid content to detecting macrophage accumulation, both of which are associated with plaque instability. Currently, there is growing interest in the value of optical coherence tomography in the area of coronary intervention, where the technique offers significant advantages over more widespread intravascular diagnostic techniques such as intravascular ultrasound: its higher resolution means that the vessel lumen diameter can be measured more precisely, periprocedural complications such microdissection of the coronary artery can be detected, stent apposition relative to the vessel wall can be optimized, neointimal hyperplasia can be detected after stent implantation, and neointimal thickness can be measured. It would therefore appear to be a very useful technique for interventional cardiologists. This review article considers the technical details of the technique and its applications, and compares it with other intravascular diagnostic techniques. C1 [Jang, Ik-Kyung] Massachusetts Gen Hosp, Div Cardiol, Serv Cardiol, Fac Med Harvard, Boston, MA 02114 USA. [Herrero-Garibi, Jesus; Cruz-Gonzalez, Ignacio] Hosp Univ Salamanca, Serv Cardiol, Salamanca, Spain. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, Serv Cardiol, Fac Med Harvard, Gray Bigelow 800,55 Fruit St, Boston, MA 02114 USA. EM ijang@partners.org NR 74 TC 5 Z9 8 U1 0 U2 3 PU EDICIONES DOYMA S A PI BARCELONA PA TRAV DE GRACIA 17-21, 08021 BARCELONA, SPAIN SN 0300-8932 J9 REV ESP CARDIOL JI Rev. Esp. Cardiol. PD AUG PY 2010 VL 63 IS 8 BP 951 EP 962 DI 10.1016/S0300-8932(10)70207-4 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 632ZF UT WOS:000280468000010 PM 20738940 ER PT J AU Gaffo, AL AF Gaffo, Angelo L. TI Diagnostic Approach to ANCA-associated Vasculitides SO RHEUMATIC DISEASE CLINICS OF NORTH AMERICA LA English DT Article DE ANCA; Anti-neutrophil cytoplasmic antibody; Vasculitis; Diagnosis; Differential diagnosis ID CHURG-STRAUSS-SYNDROME; ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; MIDLINE DESTRUCTIVE LESIONS; RHEUMATOLOGY 1990 CRITERIA; AUTOANTIBODY-ASSOCIATED GLOMERULONEPHRITIS; INTERNATIONAL CONSENSUS STATEMENT; LIMITED WEGENERS-GRANULOMATOSIS; NERVOUS-SYSTEM INVOLVEMENT; HUMAN NEUTROPHIL ELASTASE; OPEN LUNG BIOPSIES AB Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) include Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Given their rarity, protean clinical manifestations, imperfect diagnostic tests, and wide differential diagnosis, they pose a diagnostic challenge even to experienced clinicians. This article describes diagnostic approaches for patients suspected of having one of the ANCA-associated vasculitides. The clinical findings at presentation, the role of laboratory and imaging tests, and the importance of tissue diagnosis are presented. In each section, issues relevant to the differential diagnosis of AAV are discussed C1 [Gaffo, Angelo L.] Univ Alabama, Div Clin Immunol & Rheumatol, Birmingham, AL 35233 USA. [Gaffo, Angelo L.] Birmingham VA Med Ctr, Birmingham, AL 35233 USA. RP Gaffo, AL (reprint author), Univ Alabama, Div Clin Immunol & Rheumatol, 700 S 19th St, Birmingham, AL 35233 USA. NR 101 TC 9 Z9 11 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 0889-857X J9 RHEUM DIS CLIN N AM JI Rheum. Dis. Clin. North Am. PD AUG PY 2010 VL 36 IS 3 BP 491 EP + DI 10.1016/j.rdc.2010.05.009 PG 17 WC Rheumatology SC Rheumatology GA 649AL UT WOS:000281737300006 PM 20688246 ER PT J AU Rajasekhar, A Clancy, CJ AF Rajasekhar, Anita Clancy, Cornelius J. TI Meningitis due to group C Streptococcus: A case report and review of the literature SO SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID LANCEFIELD GROUP-C; EQUI SUBSPECIES EQUI; BACTERIAL-MENINGITIS; ZOOEPIDEMICUS MENINGITIS; SERIOUS INFECTION; BACTEREMIA; ADULTS; SECONDARY; OUTBREAK; HORSE AB Group C streptococci (GCS) are common causes of veterinary diseases and may colonize humans. Human diseases due to GCS are uncommon and generally occur in the elderly and persons exposed to animals or animal products. We report a case of Streptococcus equi subsp. zooepidemicus meningitis in a horse trainer and review 36 cases of GCS meningitis reported in the literature. The median age was 48 y and the majority of patients were previously healthy. Thirty-one percent (11/36) of the reported cases followed equine exposure and 19% (7/36) ingestion of dairy products. Sixty-seven percent (24/36) were found to have concomitant bacteraemia. The case fatality rate was 31% (11/36), and 28% (7/25) of survivors were reported to have residual neurological impairments. At least 4 days of antibiotics were typically required before symptoms improved. Isolates were generally susceptible to beta-lactams. In conclusion, it is important to consider GCS in the differential of bacterial meningitis, in particular in elderly patients exposed to horses or dairy products. Beta-lactams are first-line therapy, but outcomes are poor. C1 [Clancy, Cornelius J.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. [Clancy, Cornelius J.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. [Rajasekhar, Anita] Univ Florida, Dept Med, Gainesville, FL USA. RP Clancy, CJ (reprint author), Univ Pittsburgh, Dept Med, 930 Scaife Hall, Pittsburgh, PA 15260 USA. EM cjc76@pitt.edu NR 37 TC 5 Z9 6 U1 0 U2 2 PU TAYLOR & FRANCIS AS PI OSLO PA KARL JOHANS GATE 5, NO-0154 OSLO, NORWAY SN 0036-5548 J9 SCAND J INFECT DIS JI Scand. J. Infect. Dis. PD AUG PY 2010 VL 42 IS 8 BP 571 EP 578 DI 10.3109/00365541003754428 PG 8 WC Infectious Diseases SC Infectious Diseases GA 640HR UT WOS:000281041300002 PM 20632899 ER PT J AU Ventura, J Reise, SP Keefe, RSE Baade, LE Gold, JM Green, MF Kern, RS Mesholam-Gately, R Nuechterlein, KH Seidman, LJ Bilder, RM AF Ventura, Joseph Reise, Steven P. Keefe, Richard S. E. Baade, Lyle E. Gold, James M. Green, Michael F. Kern, Robert S. Mesholam-Gately, Raquelle Nuechterlein, Keith H. Seidman, Larry J. Bilder, Robert M. TI The Cognitive Assessment Interview (CAI): Development and validation of an empirically derived, brief interview-based measure of cognition SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Cognitive assessment; Schizophrenia Item response theory; Unidimensionality; Intermediate outcomes; Functional outcome ID CLINICAL-TRIALS; RATING-SCALE; SCHIZOPHRENIA; PERFORMANCE; RELIABILITY; DYSFUNCTION; VALIDITY; BATTERY AB Background: Practical, reliable "real world" measures of cognition are needed to supplement neurocognitive performance data to evaluate possible efficacy of new drugs targeting cognitive deficits associated with schizophrenia. Because interview-based measures of cognition offer one possible approach, data from the MATRICS initiative (n = 176) were used to examine the psychometric properties of the Schizophrenia Cognition Rating Scale (SCoRS) and the Clinical Global Impression of Cognition in Schizophrenia (CGI-CogS). Method: We used classical test theory methods and item response theory to derive the 10-item Cognitive Assessment Interview (CAI) from the SCoRS and CGI-CogS ("parent instruments"). Sources of information for CAI ratings included the patient and an informant. Validity analyses examined the relationship between the CAI and objective measures of cognitive functioning, intermediate measures of cognition, and functional outcome. Results: The rater's score from the newly derived CAI (10 items) correlate highly (r=.87) with those from the combined set of the SCoRS and CGI-CogS (41 items). Both the patient (r=.82) and the informant (r=.95) data were highly correlated with the rater's score. The CAI was modestly correlated with objectively measured neurocognition (r=-.32), functional capacity (r=-.44), and functional outcome (r=-.32), which was comparable to the parent instruments. Conclusions: The CAI allows for expert judgment in evaluating a patient's cognitive functioning and was modestly correlated with neurocognitive functioning, functional capacity, and functional outcome. The CAI is a brief, repeatable, and potentially valuable tool for rating cognition in schizophrenia patients who are participating in clinical trials. (C) 2010 Elsevier B.V. All rights reserved. C1 [Ventura, Joseph] Univ Calif Los Angeles, Dept Psychiat, Semel Inst Neurosci & Human Behav, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Reise, Steven P.; Nuechterlein, Keith H.; Bilder, Robert M.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Keefe, Richard S. E.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. [Baade, Lyle E.] Univ Kansas, Sch Med, Wichita, KS 67214 USA. [Gold, James M.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Green, Michael F.; Kern, Robert S.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Mesholam-Gately, Raquelle; Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Massachusetts Mental Hlth Ctr, Publ Psychiat Div,Med Sch, Boston, MA 02215 USA. RP Ventura, J (reprint author), Univ Calif Los Angeles, Dept Psychiat, Semel Inst Neurosci & Human Behav, David Geffen Sch Med, 300 Med Plaza,Room 2243, Los Angeles, CA 90095 USA. EM jventura@ucla.edu RI Bilder, Robert/A-8894-2008 OI Bilder, Robert/0000-0001-5085-7852 FU Pfizer, Inc.; NIMH [1R21MH073971, N01MH22006]; National Institute of Mental Health [MH37705, P50 MH066286] FX This research was supported by an investigator initiated grant from Pfizer, Inc., and from an NIMH grant 1R21MH073971 that were awarded to Joseph Ventura, Ph.D. Funding for the MATRICS Initiative was provided through contract N01MH22006 from NIMH to the University of California, Los Angeles, Dr. Marder, Principal Investigator; Dr. Green, Co-principal investigator; Dr. Fenton, Project Officer. Funding for MATRICS PASS came from an option (Dr. Green, principal investigator; Dr. Nuechterlein, co-principal investigator) to the NIMH MATRICS Initiative. This research was also supported in part by National Institute of Mental Health Grants MH37705 (P.I: Keith H. Nuechterlein, Ph.D.), and P50 MH066286 (PI: Keith H. Nuechterlein, Ph.D.). NR 21 TC 27 Z9 27 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2010 VL 121 IS 1-3 BP 24 EP 31 DI 10.1016/j.schres.2010.04.016 PG 8 WC Psychiatry SC Psychiatry GA 640SW UT WOS:000281073700003 PM 20542412 ER PT J AU Dickey, CC Morocz, IA Minney, D Niznikiewicz, MA Voglmaier, MM Panych, LP Khan, U Zacks, R Terry, DP Shenton, ME McCarley, RW AF Dickey, Chandlee C. Morocz, Istvan A. Minney, Daniel Niznikiewicz, Margaret A. Voglmaier, Martina M. Panych, Lawrence P. Khan, Usman Zacks, Rayna Terry, Douglas P. Shenton, Martha E. McCarley, Robert W. TI Factors in sensory processing of prosody in schizotypal personality disorder: An fMRI experiment SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizotypal personality disorder; Schizophrenia; Prosody; Social cognition; Superior temporal gyrus; fMRI; Attention; Superior temporal sulcus ID SUPERIOR TEMPORAL GYRUS; EMOTIONAL PROSODY; SOCIAL COGNITION; AFFECT RECOGNITION; IMPAIRED PERCEPTION; HOMOVANILLIC-ACID; PROFILE ANALYSIS; RIGHT-HEMISPHERE; NEURAL RESPONSE; FACIAL AFFECT AB Introduction: Persons diagnosed with schizophrenia demonstrate deficits in prosody recognition. To examine prosody along the schizophrenia spectrum, antipsychotic-naive schizotypa I personality disorder (SPD) subjects and healthy control subjects were compared. It was hypothesized that SPD subjects would perform more poorly: with cognitive and demographic factors contributing to the poor performance. The superior temporal gyrus (STG) was selected as the region-of-interest (ROI) given its known abnormalities in SPD and its important role in the processing of prosody. Methods: SPD and healthy comparison (HC) subjects were matched on age, IQ and parental social-economic status (PSES). Cognitive measures included the Speech Sound Perception Test (SSPT) to examine phonological processing (SPD = 68, HC = 74) and the Verbal Fluency task to examine executive functioning (SPD = 129, HC = 138). The main experiment was a novel fMRI task of prosody identification using semantically neutral sentences spoken with emotional prosody (SPD = 16, HC=13). Finally, volumetric measurement of the superior temporal sulcus (STS), a key region for processing prosody, and partially overlapping with the STG, was performed (SPD=30, HC=30). Results: Phonological processing and executive functioning were both impaired in SPD subjects compared with HC subjects. Contrary to the prediction, SPD subjects, as a group, were similar to HC subjects in terms of correctly indentifying the emotion conveyed and reaction time. Within the SPD group, prosody identification accuracy was influenced by executive functioning, IQ and perhaps PSES, relationships not found with HC subjects. Phonological perception aided prosody identification in both diagnostic groups. As expected, both groups activated the STG while performing the prosody identification task. However, SPD subjects may have been less "efficient" in their recruitment of STG neurons. Finally, SPD subjects demonstrated a trend toward smaller STS volumes on the left, particularly the lower bank. Conclusions: These data suggest that subtle differences between SPD and controls in phonological processing, executive functioning, IQ and possibly PSES, contributed to difficulty in processing prosody for some SPD subjects. Published by Elsevier B.V. C1 [Dickey, Chandlee C.] VA Boston Healthcare Syst, Serious Mental Illness Program, Brockton, MA 02301 USA. [Dickey, Chandlee C.; Niznikiewicz, Margaret A.; Voglmaier, Martina M.; Zacks, Rayna; Shenton, Martha E.; McCarley, Robert W.] VA Boston Healthcare Syst, Neurosci Lab, Brockton, MA 02301 USA. [Dickey, Chandlee C.; Minney, Daniel; Niznikiewicz, Margaret A.; Khan, Usman; Terry, Douglas P.; Shenton, Martha E.] Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Boston, MA 02215 USA. [Morocz, Istvan A.; Panych, Lawrence P.] Brigham & Womens Hosp, Dept Radiol, Med Phys Grp, Boston, MA 02215 USA. [Voglmaier, Martina M.] Cambridge Hlth Alliance, Cambridge, MA 02139 USA. RP Dickey, CC (reprint author), VA Boston Healthcare Syst, Serious Mental Illness Program, Psychiat 116A-7,940 Belmont St, Brockton, MA 02301 USA. EM chandlee_dickey@hms.harvard.edu; pisti@bwh.harvard.edu; daniel.minney@gmail.com; Margaret_niznikiewicz@hms.harvard.edu; Martina_voglmaier@hms.harvard.edu; panych@bwh.harvard.edu; usman@bwh.harvard.edu; Rayna_zacks@hms.harvard.edu; dougt@bwh.harvard.edu; Shenton@bwh.harvard.edu; Robert_mccarley@hms.harvard.edu RI McCarley, Robert/N-5562-2014 OI McCarley, Robert/0000-0001-5705-7495 FU Department of Veterans Affairs; NIMH [R21MH077979]; National Institute of Mental Health [RO1 MH52807] FX The project described was supported by the Department of Veterans Affairs and by NIMH Award Numbers R21MH077979 (CCD) and RO1 MH52807 (RWM) from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health, the National Institutes of Health, or the Department of Veterans Affairs. NR 111 TC 10 Z9 10 U1 3 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2010 VL 121 IS 1-3 BP 75 EP 89 DI 10.1016/j.schres.2010.03.008 PG 15 WC Psychiatry SC Psychiatry GA 640SW UT WOS:000281073700009 PM 20362418 ER PT J AU Fujimura, R AF Fujimura, Robert TI Shock and Age SO SCIENTIST LA English DT Letter C1 VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. RP Fujimura, R (reprint author), VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. EM fujimr@u.washington.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU SCIENTIST INC PI PHILADELPHIA PA 400 MARKET ST, STE 1250, PHILADELPHIA, PA 19106 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD AUG PY 2010 VL 24 IS 8 BP 15 EP 15 PG 1 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 629SE UT WOS:000280219200007 ER PT J AU Kreslavsky, T von Boehmer, H AF Kreslavsky, Taras von Boehmer, Harald TI gamma delta TCR ligands and lineage commitment SO SEMINARS IN IMMUNOLOGY LA English DT Review DE gamma delta T cells; TCR ligands; Lineage commitment; Agonist selection ID T-CELL-RECEPTOR; ALPHA-BETA; THYMOCYTE DEVELOPMENT; POSITIVE SELECTION; ADULT MICE; NK-CELLS; RECOGNITION; ANTIGEN; FATE; SUBSET AB Two major T lymphocyte lineages - alpha beta and gamma delta T cells - develop in the thymus from common precursors. Differentiation of both lineages requires signals coming from TCRs. Development of alpha beta T cells is driven at early stages by signaling from the pre-TCR, most likely in a ligand-independent fashion, and later - by signals delivered by alpha beta TCRs binding to their ligands - classical or non-classical MHC molecules. gamma delta lineage cells likewise require TCR signaling for their differentiation. Recent work from several groups suggests that TCR signaling not only ensures the developmental progression towards alpha beta and gamma delta lineages but that signal strength instructs lineage fate: weaker TCR signal results in alpha beta and stronger-in gamma delta lineage commitment. However, as most gamma delta TCRs remain orphan receptors, it is still debated whether strong signals from gamma delta TCRs in development are generated in a ligand-dependent manner (as in the case of alpha beta TCRs), ligand-independent manner (as for pre-TCR) or both. Here we summarize evidence supporting a possible role for ligands in gamma delta T cell lineage commitment and the generation of gamma delta sublineages. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Kreslavsky, Taras; von Boehmer, Harald] Dana Farber Canc Inst, Lab Lymphocyte Biol Canc Immunol & AIDS, Boston, MA 02115 USA. RP von Boehmer, H (reprint author), Dana Farber Canc Inst, Lab Lymphocyte Biol Canc Immunol & AIDS, 44 Binney St,Smith 736, Boston, MA 02115 USA. EM Harald_Von_Boehmer@dfci.harvard.edu FU National Institutes of Health [R01 A145846, R01 A151378] FX We thank Michael Gleimer and Diana Alvarez Arias for critical reading and helpful discussion of this review. These studies were supported by National Institutes of Health Grants R01 A145846 and R01 A151378. NR 94 TC 17 Z9 17 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD AUG PY 2010 VL 22 IS 4 BP 214 EP 221 DI 10.1016/j.smim.2010.04.001 PG 8 WC Immunology SC Immunology GA 631XG UT WOS:000280383400005 PM 20447836 ER PT J AU Cooper, JB AF Cooper, Jeffrey B. TI Using Simulation to Teach and Study Healthcare Handoffs SO SIMULATION IN HEALTHCARE LA English DT Editorial Material C1 [Cooper, Jeffrey B.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Cooper, Jeffrey B.] Harvard Univ, Sch Med, Boston, MA USA. RP Cooper, JB (reprint author), Ctr Med Simulat, 65 Landsdowne St,Rm 144, Cambridge, MA 02139 USA. EM jcooper@partners.org NR 11 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1559-2332 J9 SIMUL HEALTHC JI Simul. Healthc. PD AUG PY 2010 VL 5 IS 4 BP 191 EP 192 DI 10.1097/SIH.0b013e3181eab91c PG 2 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 641GG UT WOS:000281112200001 PM 20703145 ER PT J AU Bredella, MA AF Bredella, Miriam A. TI Perspective: the bone-fat connection SO SKELETAL RADIOLOGY LA English DT Editorial Material ID PROTON MR SPECTROSCOPY; X-RAY ABSORPTIOMETRY; MARROW FAT; ENHANCES OSTEOGENESIS; CELLS; WOMEN; AGE C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Bredella, MA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Yawkey 6E,55 Fruit St, Boston, MA 02114 USA. EM mbredella@partners.org NR 18 TC 9 Z9 9 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD AUG PY 2010 VL 39 IS 8 BP 729 EP 731 DI 10.1007/s00256-010-0936-y PG 3 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 620FT UT WOS:000279485200001 PM 20473494 ER PT J AU Levine, AC Adusumilli, J Landrigan, CP AF Levine, Adam C. Adusumilli, Josna Landrigan, Christopher P. TI Effects of Reducing or Eliminating Resident Work Shifts over 16 Hours: A Systematic Review SO SLEEP LA English DT Review DE Sleep deprivation; resident physicians; patient safety; occupational safety; work hour limits; extended shifts; systematic review; Institute of Medicine ID INTERNAL-MEDICINE RESIDENTS; GENERAL-SURGERY RESIDENTS; TOTAL SLEEP-DEPRIVATION; DUTY HOURS; GYNECOLOGY RESIDENCY; EMERGENCY EXPERIENCE; SENIOR RESIDENTS; HOURS MANDATES; PERFORMANCE; IMPACT AB Study Objectives: The Institute of Medicine (IOM) has called for the elimination of resident work shifts exceeding 16 hours without sleep. We sought to comprehensively evaluate the effects of eliminating or reducing shifts over 16 hours. Design and Outcome Measures: We performed a systematic review of published and unpublished studies (1950-2008) to synthesize data on all intervention studies that have reduced or eliminated U.S. residents' extended shifts. A total of 2,984 citations were identified initially, which were independently reviewed by two authors to determine their eligibility for inclusion. All outcomes relevant to quality of life, education, and safety were collected. Study quality was rated using the U.S. Preventive Services Task Force methodology. Measurements and Results: Twenty-three studies met inclusion criteria (kappa = 0.88 [95% Cl, 0.77-0.94] for inclusion decisions). Following reduction or elimination of extended shifts, 8 of 8 studies measuring resident quality of life found improvements. Four of 14 studies that assessed educational outcomes found improvements, 9 found no significant changes, and one found education worsened. Seven of 11 identified statistically significant improvements in patient safety or quality of care; no studies found that safety or care quality worsened. Conclusions: In a systematic review, we found that reduction or elimination of resident work shifts exceeding 16 hours did not adversely affect resident education, and was associated with improvements in patient safety and resident quality of life in most studies. Further multi-center studies are needed to substantiate these findings, and definitively measure the effects of eliminating extended shifts on patient outcomes. C1 [Adusumilli, Josna; Landrigan, Christopher P.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Sleep Med,Dept Med,Harvard Work Hours Hlth &, Boston, MA 02115 USA. [Levine, Adam C.] Harvard Univ, Sch Med, Brigham & Womens & Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Landrigan, Christopher P.] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Gen Pediat,Dept Med, Boston, MA 02115 USA. RP Landrigan, CP (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Sleep Med,Dept Med,Harvard Work Hours Hlth &, 75 Francis St, Boston, MA 02115 USA. EM clandrigan@partners.org FU Cephalon FX This was not an industry supported study. Dr. Landrigan has consulted for AxDev on a study that was supported by a grant to AxDev from Cephalon and has consulted for Vital Issues in Medicine. The other authors have indicated no financial conflicts of interest. NR 60 TC 36 Z9 37 U1 1 U2 4 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 EI 1550-9109 J9 SLEEP JI Sleep PD AUG 1 PY 2010 VL 33 IS 8 BP 1043 EP 1053 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 632NZ UT WOS:000280432700007 PM 20815185 ER PT J AU Randhawa, K Smethurst, P Hoo, GWS AF Randhawa, Kanwal Smethurst, Peter Hoo, Guy W. Soo TI Nine-Year Progression of Untreated Pulmonary Mycobacterium szulgai Infection SO SOUTHERN MEDICAL JOURNAL LA English DT Article DE clarithromycin; Mycobacterium szulgai; nontuberculous mycobacterium ID UNUSUAL PATHOGEN; LUNG AB A 58-year-old man was seen with complaints of fevers, night sweats, weight loss, and multiple bilateral cavitary lung lesions. Mycobacterium szulgai with nearly identical antibiograms grew from separate sputum specimens 9 years apart. He was treated with a combination of clarithromycin and ethambutol with clinical, microbiologic, and radiographic resolution of disease. This is the longest untreated case of documented Mycobacterium szulgai infection reported, and offers a glimpse of its natural history when left untreated. Despite an infrequent isolation (<0.5% of cases), it is a pathogenic organism which warrants treatment. C1 VA Greater Angeles Healthcare Syst, W Los Angeles Vet Affairs Med Ctr, Pulm & Crit Care Sect, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Hoo, GWS (reprint author), W Los Angeles Vet Affairs Med Ctr, Pulm & Crit Care Sect 111Q, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Guy.soohoo@va.gov NR 12 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0038-4348 J9 SOUTH MED J JI South.Med.J. PD AUG PY 2010 VL 103 IS 8 BP 828 EP 830 DI 10.1097/SMJ.0b013e3181e6cc26 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 703FU UT WOS:000285964600022 PM 20622732 ER PT J AU Schoenfeld, AJ Hornicek, FJ Pedlow, FX Kobayashi, W Garcia, RT DeLaney, TF Springfield, D Mankin, HJ Schwab, JH AF Schoenfeld, Andrew J. Hornicek, Francis J. Pedlow, Francis X. Kobayashi, Wendy Garcia, Ronald T. DeLaney, Thomas F. Springfield, Dempsey Mankin, Henry J. Schwab, Joseph H. TI Osteosarcoma of the spine: experience in 26 patients treated at the Massachusetts General Hospital SO SPINE JOURNAL LA English DT Article DE Osteosarcoma; Spine; En bloc resection; Radiation; Outcomes ID BONE-TUMOR REGISTRY; PRIMARY OSTEOGENIC-SARCOMA; EN-BLOC SPONDYLECTOMY; TELANGIECTATIC OSTEOSARCOMA; RADIOTHERAPY; RESECTION; COLUMN AB BACKGROUND CONTEXT: Because of the low incidence, treatment recommendations for spinal osteosarcoma are guided by the results of small series and case reports. Many include patients who presented for treatment over the course of three to four decades. PURPOSE: The goal of this investigation was to report the treatments, results, and overall survivorship of 26 patients treated for osteosarcoma of the spine at a single institution. STUDY DESIGN: Retrospective prognostic series (Level III evidence). PATIENT SAMPLE: Twenty-six patients treated at a single center for osteosarcoma of the spine over a 26-year period. OUTCOME MEASURES: Estimation of patient survival, local recurrence, and the presence of metastatic disease. METHODS: We performed a retrospective review of cases of osteosarcoma involving the spine treated at our institution between 1982 and 2008. Medical charts, radiology reports, pathology reports, and operative notes were reviewed for all patients. Available imaging studies were also reviewed. The log-rank test was used to compare baseline differences between groups. Survivorship analysis was performed using Kaplan-Meier methodology. The effect of Paget osteosarcoma, type of resection, presence of local recurrence, tumor size, surgical margins, and metastases on overall survival were also investigated using the log-rank test. RESULTS: Twenty-six patients were included for review in this study. Twenty individuals were treated surgically, and 24 were treated with radiation with a mean dose of 62.2 Gy (range 20-84.7 Gy). Twenty-five patients received chemotherapy. Of those treated surgically, seven received en bloc resection. The median overall survival for all patients in our series was 29.5 months (standard error 14.7, 95% confidence interval 0.6-58). Local recurrence developed in 7 patients (27%), and metastasis occurred in 16 individuals (62%). Patients with Paget osteosarcoma had worse overall survival (p<.001). CONCLUSIONS: Results presented here confirm a poor prognosis for patients with spinal osteosarcoma. Although combination therapies, including surgery, chemotherapy, and high-dose radiation, achieve adequate short-term survival, the 5-year mortality rate remains high. Published by Elsevier Inc. C1 [Schoenfeld, Andrew J.; Hornicek, Francis J.; Pedlow, Francis X.; Garcia, Ronald T.; Springfield, Dempsey; Mankin, Henry J.; Schwab, Joseph H.] Harvard Univ, Sch Med, Dept Orthopaed Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kobayashi, Wendy; DeLaney, Thomas F.] Harvard Univ, Sch Med, Dept Radiat Oncol, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Schoenfeld, AJ (reprint author), Harvard Univ, Sch Med, Dept Orthopaed Surg, Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM ajschoen@neoucom.edu OI Schoenfeld, Andrew/0000-0002-3691-1215 FU PharmaMar; Stephan L Harris Chordoma Center; Sarcoma Foundation; Centecor Corporation; Zimmer Corporation; Johnson Johnson; DePuy; Synthes Spine; Globus; Medtronic; AO Spine Fellowship FX FJH (consulting, Stryker Corporation; speaking and/or teaching arrangements, Stryker Corporation; trips/travel, Stryker Corporation; scientific advisory board, Chordoma Foundation, Desmoid Tumor Research Foundation, American Association Tissue Banks; research support: staff and/or materials, PharmaMar, Stephan L Harris Chordoma Center, Sarcoma Foundation, Centecor Corporation; grants, PharmaMar, Stephan L Harris Chordoma Center, Sarcoma Foundation, Centecor Corporation; fellowship support, Zimmer Corporation); TFD (speaking and/or teaching arrangement, IBA Proton Therapy); DS (stock ownership, including options and warrants, Johnson & Johnson; research support: staff and/or materials, Stryker; fellowship support, Zimmer); JHS (research support: staff and/or materials, DePuy, Synthes Spine, Globus, Medtronic; fellowship support, AO Spine Fellowship). NR 32 TC 19 Z9 21 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1529-9430 J9 SPINE J JI Spine Journal PD AUG PY 2010 VL 10 IS 8 BP 708 EP 714 DI 10.1016/j.spinee.2010.05.017 PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 636QJ UT WOS:000280753300007 PM 20650409 ER PT J AU Trowbridge, JJ Guezguez, B Moon, RT Bhatia, M AF Trowbridge, Jennifer J. Guezguez, Borhane Moon, Randall T. Bhatia, Mickie TI Wnt3a Activates Dormant c-Kit(-) Bone Marrow-Derived Cells with Short-Term Multilineage Hematopoietic Reconstitution Capacity SO STEM CELLS LA English DT Article DE Adult haematopoietic stem cells; c-Kit; Cell cycle; Hematopoietic stem cell transplantation; Wnt; Cell signaling; CFC ID STEM-CELLS; SELF-RENEWAL; IN-VIVO; LYMPHOID PROGENITORS; REGENERATION; RECEPTORS; DIFFERENTIATION; PROTEINS; PATHWAY; MICE AB Quiescent cells lacking expression of mature lineage makers and the c-Kit receptor reside in adult bone marrow. Despite their phenotypic similarity to hematopoietic stem cells, these Lin(-)Sca-1(+)c-Kit(-) cells lack myeloid and erythroid potential and long-term hematopoietic repopulating capacity, whereas, recent studies have functionally demonstrated that the Lin(-)Sca-1(+)c-Kit(-) population contains early lymphoid-committed progenitors. Examining the role of Wnt signaling in regulation of this population, we found that c-Kit(-) cells express diverse Wnt receptors and proliferate upon Wnt pathway activation in vitro and in vivo. Stimulation with Wnt3a, but not Wnt5a or Wnt11, promoted c-Kit(-) cells to give rise to myeloid and erythroid progenitors with robust self-renewal capacity measured by clonal replating. In addition, Wnt3a-stimulated c-Kit(-) cells gave rise to all hematopoietic lineages (lymphoid, myeloid, and erythroid) upon transplant into the liver of newborn recipient mice. Our study reveals that Wnt3a activates unique cell fate decisions of dormant c-Kit(-) that promotes short-term multilineage reconstitution capacity in vivo, thereby revealing a unique role for Wnt activation in hematopoiesis. Overall, our results highlight the potential of utilizing signaling molecules known to have instructive roles in regeneration to discover cell subsets residing in adult organisms with unexploited regenerative capacity. STEM CELLS 2010; 28: 1379-1389 C1 [Trowbridge, Jennifer J.; Guezguez, Borhane; Bhatia, Mickie] McMaster Univ, McMaster Stem Cell & Canc Res Inst, Michael G DeGroote Sch Med, Hamilton, ON L8N 3Z5, Canada. [Trowbridge, Jennifer J.; Guezguez, Borhane; Bhatia, Mickie] McMaster Univ, Dept Biochem & Biomed Studies, Hamilton, ON L8N 3Z5, Canada. [Trowbridge, Jennifer J.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Trowbridge, Jennifer J.] Childrens Hosp, Dept Hematol Oncol, Boston, MA 02115 USA. [Moon, Randall T.] Univ Washington, Sch Med, Dept Pharmacol, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Moon, Randall T.] Univ Washington, Sch Med, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. RP Bhatia, M (reprint author), McMaster Univ, McMaster Stem Cell & Canc Res Inst, Michael G DeGroote Sch Med, 1,200 Main St W,MDCL 5029, Hamilton, ON L8N 3Z5, Canada. EM mbhatia@mcmaster.ca RI Moon, Randall/B-1743-2014 OI Moon, Randall/0000-0002-9352-1408 FU Canadian Institutes of Health Research (CIHR); NIH [P01 GM069983]; Ontario Research Fund (ORF); Canada Research Chair in Stem Cell Biology and Regenerative Medicine; National Cancer Institute of Canada (NCIC); Leukemia and Lymphoma Society FX We thank E. Szabo, K. Vijayaragavan, K. Levac, D. Goodale, A. Fiebig, and T. Wynder for technical assistance, D. Sheerar and M. Levadoux-Martin for FACS sorting, A. Kohn for Wnt11-producing L cells, and J.W. Snow for critical review of the article. This work was supported by a research grant from the Canadian Institutes of Health Research (CIHR), NIH P01 GM069983 to R. T. M., Ontario Research Fund (ORF), Canada Research Chair in Stem Cell Biology and Regenerative Medicine to M. B., and fellowship awards from the National Cancer Institute of Canada (NCIC) and Leukemia and Lymphoma Society (LLS) to J.J.T. R. T. M. is an investigator of the HHMI. J.J.T. is currently affiliated with the Department of Pediatric Oncology, Dana-Farber Cancer Institute and Department of Hematology/Oncology, Children's Hospital Boston, Boston, MA. NR 43 TC 16 Z9 17 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD AUG PY 2010 VL 28 IS 8 BP 1379 EP 1389 DI 10.1002/stem.457 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 646TP UT WOS:000281566200008 PM 20521329 ER PT J AU Payne, CJ Gallagher, SJ Foreman, O Dannenberg, JH Depinho, RA Braun, RE AF Payne, Christopher J. Gallagher, Shannon J. Foreman, Oded Dannenberg, Jan Hermen Depinho, Ronald A. Braun, Robert E. TI Sin3a Is Required by Sertoli Cells to Establish a Niche for Undifferentiated Spermatogonia, Germ Cell Tumors, and Spermatid Elongation SO STEM CELLS LA English DT Article DE Germline; Stem cell niche; Sertoli cells; Germ cell tumor; Spermatogenesis ID HEMATOPOIETIC STEM-CELL; SELF-RENEWAL; TESTICULAR TERATOMAS; EXPRESSING SPERMATOGONIA; TRANSCRIPTIONAL CONTROL; MOUSE TESTIS; MICE; RECEPTOR; ADULT; GENE AB Microenvironments support the maintenance of stem cells and the growth of tumors through largely unknown mechanisms. While cell-autonomous chromatin modifications have emerged as important determinants for self-renewal and differentiation of stem cells, a role for non-cell autonomous epigenetic contributions is not well established. Here, we genetically ablated the chromatin modifier Swi-independent 3a (Sin3a) in fetal Sertoli cells, which partly comprise the niche for male germline stem cells, and investigated its impact on spermatogenic cell fate and teratoma formation in vivo. Sertoli cell-specific Sin3a deletion resulted in the formation of few undifferentiated spermatogonia after birth while initially maintaining spermatogenic differentiation. Stem cell-associated markers Plzf, Gfra1, and Oct4 were downregulated in the mutant fetal gonad, while Sertoli cell markers Steel and Gdnf, which support germ cells, were not diminished. Following birth, markers of differentiating spermatogonia, Kit and Sohlh2, exhibited normal levels, but chemokine-signaling molecules chemokine (C-X-C motif) ligand 12 (CXCL12)/stromal cell-derived factor 1 (SDF1) and chemokine (C-X-C motif) receptor 4 (CXCR4), expressed in Sertoli cells and germ cells, respectively, were not detected. In the juvenile, mutant testes exhibited a progressive loss of differentiating spermatogonia and a block in spermatid elongation, followed by extensive germ cell degeneration. Sertoli cell-specific Sin3a deletion also suppressed teratoma formation by fetal germ cells in an in vivo transplantation assay. We conclude that the epigenome of Sertoli cells influences the establishment of a niche for germline stem cells as well as for tumor initiating cells. STEM CELLS 2010; 28: 1424-1434 C1 [Payne, Christopher J.; Gallagher, Shannon J.] Northwestern Univ, Feinberg Sch Med, Human Mol Genet Program, Childrens Mem Res Ctr, Chicago, IL 60614 USA. [Payne, Christopher J.; Foreman, Oded; Braun, Robert E.] Jackson Lab, Bar Harbor, ME 04609 USA. [Payne, Christopher J.; Gallagher, Shannon J.] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60614 USA. [Dannenberg, Jan Hermen] Netherlands Canc Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands. [Depinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci,Dept Med Oncol, Boston, MA 02115 USA. [Depinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci,Dept Med, Boston, MA 02115 USA. [Depinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Belfer Inst Appl Canc Sci,Dept Genet, Boston, MA 02115 USA. RP Payne, CJ (reprint author), Northwestern Univ, Feinberg Sch Med, Human Mol Genet Program, Childrens Mem Res Ctr, 2300 Childrens Plaza,Box 211, Chicago, IL 60614 USA. EM c-payne@northwestern.edu FU Eunice Kennedy Shriver National Institute of Child Health & Human Development [K99/R00 HD055330]; Damon Runyon Cancer Research Foundation; Dutch Cancer Society; Robert A. and Renee E. Belfer Foundation; NIH; Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health [5K99HD055330-02, 5U54HD042454-08] FX We thank Kevin Kane, Andree Lapierre, and The Jackson Laboratory Surgical Services Staff for providing their expertise and technical skills to the testicular transplant assays. George Enders provided the gift of anti-GCNA1 antibody. C.J.P. is the recipient of an NIH Pathway-to-Independence Award from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (K99/R00 HD055330). J.-H.D. is supported by grants from the Damon Runyon Cancer Research Foundation and the Dutch Cancer Society (KWF). R. A. D. is supported by the Robert A. and Renee E. Belfer Foundation. This work was supported by NIH grants to C.J.P. and R. E. B. We acknowledge the following grant support from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health: 5K99HD055330-02 to C.J.P. and 5U54HD042454-08 to R.E.B. NR 45 TC 33 Z9 36 U1 0 U2 5 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD AUG PY 2010 VL 28 IS 8 BP 1424 EP 1434 DI 10.1002/stem.464 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 646TP UT WOS:000281566200012 PM 20572009 ER PT J AU Hankey, GJ Hacke, W Easton, JD Johnston, SC Mas, JL Brennan, DM Bhatt, DL Fox, KAA Topol, EJ AF Hankey, Graeme J. Hacke, Werner Easton, J. Donald Johnston, S. Claiborne Mas, Jean-Louis Brennan, Danielle M. Bhatt, Deepak L. Fox, Keith A. A. Topol, Eric J. CA CHARISMA Trial Investigators TI Effect of Clopidogrel on the Rate and Functional Severity of Stroke Among High Vascular Risk Patients A Prespecified Substudy of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Trial SO STROKE LA English DT Article DE antiplatelet therapy; cerebrovascular disease/stroke; infarction; stroke prevention; stroke severity ID DISABILITY; PREVENTION; PREDICTORS; RECOVERY; ASPIRIN AB Background and Purpose-Disabling stroke is costly and considered by some patients a fate worse than death. We aimed to determine whether clopidogrel reduces the rate and functional severity of stroke among high vascular risk patients, including patients with previous transient ischemic attack or ischemic stroke, who were enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial. Methods-We randomly assigned 15 603 high vascular risk patients to receive clopidogrel (75 mg daily) or placebo in addition to background acetylsalicylic acid and followed them for a median of 28 months. The main outcome of this prespecified substudy was the functional severity of stroke outcome events as measured by the modified Rankin Scale (mRS) score at 3 months after the stroke outcome. Results-During follow-up, 436 (2.8%) patients had a definite adjudicated stroke and a follow-up assessment of the mRS at 3 months poststroke, of whom 202 had been randomly assigned clopidogrel and 234 placebo (relative risk reduction 14%, 95% CI: -4% to 29%, P=0.12). There was no significant difference between the mean mRS scores at 3 months after stroke among patients assigned clopidogrel compared with placebo (mean mRS 3.6 [SD 2.4] clopidogrel versus 3.3 [SD 2.1] placebo; P=0.15). There was also no significant difference between the various categories of the mRS score at 3 months after stroke among patients assigned to clopidogrel compared with placebo. Among 4320 patients with a qualifying diagnosis of transient ischemic attack or ischemic stroke, 233 (5.4%) experienced a stroke during follow-up, of whom 103 were randomly assigned clopidogrel and 130 placebo (relative risk reduction 20%, 95% CI: -3% to 38%). There was no significant difference between the mean mRS scores at 3 months after stroke among patients with a qualifying transient ischemic attack or ischemic stroke who were assigned clopidogrel compared with placebo (3.4 [SD 2.1] clopidogrel versus 3.3 [SD 1.9] placebo; P=0.48). Conclusion-The addition of clopidogrel to acetylsalicylic acid did not significantly alter the rate and functional severity of stroke outcome events among high vascular risk patients enrolled in the CHARISMA trial. (Stroke. 2010;41:16791683.) C1 [Hankey, Graeme J.] Royal Perth Hosp, Stroke Unit, Dept Neurol, Perth, WA 6000, Australia. [Hacke, Werner] Dept Neurol, Heidelberg, Germany. [Easton, J. Donald] Brown Univ, Providence, RI 02912 USA. [Johnston, S. Claiborne] UCSF Neurol, San Francisco, CA USA. [Mas, Jean-Louis] Hop St Anne, Serv Neurol, F-75674 Paris, France. [Brennan, Danielle M.] Cleveland Clin, Cleveland, OH 44106 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm Edinburgh NHS Trust, Edinburgh, Midlothian, Scotland. [Topol, Eric J.] Scripps Hlth & Scripps Translat Sci Inst, La Jolla, CA USA. RP Hankey, GJ (reprint author), Royal Perth Hosp, Stroke Unit, Dept Neurol, 197 Wellington St, Perth, WA 6000, Australia. EM gjhankey@cyllene.uwa.edu.au RI Walker, Philip/F-3034-2010; Hankey, Graeme /H-4968-2014; OI Hankey, Graeme /0000-0002-6044-7328; Topol, Eric/0000-0002-1478-4729 FU Sanofi-Aventis; Bristol-Myers Squibb FX The CHARISMA trial was sponsored and funded by Sanofi-Aventis and Bristol-Myers Squibb. NR 7 TC 11 Z9 12 U1 5 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2010 VL 41 IS 8 BP 1679 EP 1683 DI 10.1161/STROKEAHA.110.586727 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 631EZ UT WOS:000280330700017 PM 20595658 ER PT J AU Yoo, AJ Barak, ER Copen, WA Kamalian, S Gharai, LR Pervez, MA Schwamm, LH Gonzalez, RG Schaefer, PW AF Yoo, Albert J. Barak, Elizabeth R. Copen, William A. Kamalian, Shahmir Gharai, Leila Rezai Pervez, Muhammad A. Schwamm, Lee H. Gonzalez, R. Gilberto Schaefer, Pamela W. TI Combining Acute Diffusion-Weighted Imaging and Mean Transmit Time Lesion Volumes With National Institutes of Health Stroke Scale Score Improves the Prediction of Acute Stroke Outcome SO STROKE LA English DT Article DE cerebral infarction; diffusion MRI; perfusion MRI ID ACUTE ISCHEMIC-STROKE; TISSUE-PLASMINOGEN ACTIVATOR; CLINICAL-DIFFUSION; INTRAVENOUS THROMBOLYSIS; MISMATCH; PERFUSION; SELECTION; THERAPY; TRIALS; RECANALIZATION AB Background and Purpose-The purpose of this study was to determine whether acute diffusion-weighted imaging (DWI) and mean transit time (MTT) lesion volumes and presenting National Institutes of Health Stroke Scale (NIHSS) can identify patients with acute ischemic stroke who will have a high probability of good and poor outcomes. Methods-Fifty-four patients with acute ischemic stroke who had MRI within 9 hours of symptom onset and 3-month follow-up with modified Rankin scale were evaluated. Acute DWI and MTT lesion volumes and baseline NIHSS scores were calculated. Clinical outcomes were considered good if the modified Rankin Scale was 0 to 2. Results-The 33 of 54 (61%) patients with good outcomes had significantly smaller DWI lesion volumes (P=0.0001), smaller MTT lesion volumes (P < 0.0001), and lower NIHSS scores (P < 0.0001) compared with those with poor outcomes. Receiver operating characteristic curves for DWI, MTT, and NIHSS relative to poor outcome had areas under the curve of 0.889, 0.854, and 0.930, respectively, which were not significantly different. DWI and MTT lesion volumes predicted outcome better than mismatch volume or percentage mismatch. All patients with a DWI volume > 72 mL (13 of 54) and an NIHSS score > 20 (6 of 54) had poor outcomes. All patients with an MTT volume of < 47 mL (16 of 54) and an NIHSS score < 8 (17 of 54) had good outcomes. Combining clinical and imaging thresholds improved prognostic yield (70%) over clinical (43%) or imaging (54%) thresholds alone (P=0.01). Conclusions-Combining quantitative DWI and MTT with NIHSS predicts good and poor outcomes with high probability and is superior to NIHSS alone. (Stroke. 2010;41:1728-1735.) C1 [Schaefer, Pamela W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Neuroradiol,Dept Radiol, Boston, MA 02114 USA. RP Schaefer, PW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Neuroradiol,Dept Radiol, Gray 241 G,55 Fruit St, Boston, MA 02114 USA. EM pschaefer@partners.org OI Kamalian, Shahmir/0000-0002-9640-8144; Schwamm, Lee/0000-0003-0592-9145 FU Penumbra, Inc.; National Institutes of Health FX A.J.Y. has received research funding from Penumbra, Inc. L.H.S. is on the medical advisory board of CoAxia, Inc. R.G.G. has received a research grant from the National Institutes of Health. NR 29 TC 51 Z9 55 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2010 VL 41 IS 8 BP 1728 EP 1735 DI 10.1161/STROKEAHA.110.582874 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 631EZ UT WOS:000280330700025 PM 20595665 ER PT J AU Atochin, DN Yuzawa, I Li, QA Rauwerdink, KM Malhotra, R Chang, JL Brouckaert, P Ayata, C Moskowitz, MA Bloch, KD Huang, PL Buys, ES AF Atochin, Dmitriy N. Yuzawa, Izumi Li, Qian Rauwerdink, Kristen M. Malhotra, Rajeev Chang, Junlei Brouckaert, Peter Ayata, Cenk Moskowitz, Michael A. Bloch, Kenneth D. Huang, Paul L. Buys, Emmanuel S. TI Soluble Guanylate Cyclase alpha 1 beta 1 Limits Stroke Size and Attenuates Neurological Injury SO STROKE LA English DT Article DE cerebral ischemia; gene knockout mice; mouse models ID CEREBRAL-BLOOD-FLOW; NITRIC-OXIDE; MICE DEFICIENT; CGMP; SYSTEM; BRAIN AB Background and Purpose-Nitric oxide mediates endothelium-dependent vasodilation, modulates cerebral blood flow, and determines stroke outcome. Nitric oxide signals in part by stimulating soluble guanylate cyclase (sGC) to synthesize cGMP. To study the role of sGC in stroke injury, we compared the outcome of cerebral ischemia and reperfusion in mice deficient in the alpha(1) subunit of sGC (sGC alpha(-/-)(1)) with that in wild-type mice. Methods-Blood pressure, cerebrovascular anatomy, and vasoreactivity of pressurized carotid arteries were compared in both mouse genotypes. Cerebral blood flow was measured before and during middle cerebral artery occlusion and reperfusion. We then assessed neurological deficit and infarct volume after 1 hour of occlusion and 23 hours of reperfusion and after 24 hours of occlusion. Results-Blood pressure and cerebrovascular anatomy were similar between genotypes. We found that vasodilation of carotid arteries in response to acetylcholine or sodium nitroprusside was diminished in sGC alpha(-/-)(1) compared with wild-type mice. Cerebral blood flow deficits did not differ between the genotypes during occlusion, but during reperfusion, cerebral blood flow was 45% less in sGC alpha(-/-)(1) mice. Infarct volumes and neurological deficits were similar after 24 hours of occlusion in both genotypes. After 1 hour of ischemia and 23 hours of reperfusion, infarct volumes were 2-fold larger and neurological deficits were worse in sGC alpha(-/-)(1) than in the wild-type mice. Conclusion-sGC alpha(1) deficiency impairs vascular reactivity to nitric oxide and is associated with incomplete reperfusion, larger infarct size, and worse neurological damage, suggesting that cGMP generated by sGC alpha(1)beta(1) is protective in ischemic stroke. (Stroke. 2010; 41: 1815-1819.) C1 [Atochin, Dmitriy N.; Li, Qian; Malhotra, Rajeev; Chang, Junlei; Bloch, Kenneth D.; Huang, Paul L.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Atochin, Dmitriy N.; Li, Qian; Malhotra, Rajeev; Chang, Junlei; Bloch, Kenneth D.; Huang, Paul L.] Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA 02129 USA. [Yuzawa, Izumi; Ayata, Cenk; Moskowitz, Michael A.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Rauwerdink, Kristen M.; Bloch, Kenneth D.; Buys, Emmanuel S.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Anesthesia Ctr Crit Care Res, Charlestown, MA 02129 USA. [Brouckaert, Peter] Univ Ghent VIB, Flanders Inst Biotechnol, Dept Med Mol Biol, Ghent, Belgium. [Brouckaert, Peter] Univ Ghent, Dept Mol Biol, B-9000 Ghent, Belgium. RP Atochin, DN (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 E 13th St, Charlestown, MA 02129 USA. EM atochin@cvrc.mgh.harvard.edu RI Chang, Junlei/P-8782-2014; Atochin, Dmitriy/Q-3150-2016 FU American Heart Association [0835344N]; National Institutes of Health [T32-HL007208, P01-NS055104, P50-NS010828, R01-NS033335]; Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO-Vlaanderen); Geconcerteerde Onderzoeksacties FX This study was supported by an American Heart Association Scientist Development Grant 0835344N (D.N.A.), National Institutes of Health grant T32-HL007208 (R. M.), grants from the Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO-Vlaanderen) and the Geconcerteerde Onderzoeksacties (P. B.), and National Institutes of Health grants P01-NS055104 (C. A.), P50-NS010828 (M. A. M.), and R01-NS033335 (P. L. H.). NR 20 TC 15 Z9 15 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2010 VL 41 IS 8 BP 1815 EP 1819 DI 10.1161/STROKEAHA.109.577635 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 631EZ UT WOS:000280330700037 PM 20595671 ER PT J AU Ingraham, AM Cohen, ME Bilimoria, KY Raval, MV Ko, CY Nathens, AB Hall, BL AF Ingraham, Angela M. Cohen, Mark E. Bilimoria, Karl Y. Raval, Mehul V. Ko, Clifford Y. Nathens, Avery B. Hall, Bruce L. TI Comparison of 30-day outcomes after emergency general surgery procedures: Potential for targeted improvement SO SURGERY LA English DT Article ID LAPAROSCOPIC CHOLECYSTECTOMY; SURGICAL CARE; RISK-FACTORS; COLECTOMY; QUALITY; PATIENT; PROGRAM; APPENDICITIS; MANAGEMENT; NATIONWIDE AB Background. Patients who undergo emergency operations represent a high-risk population and have been shown to have a high risk of poor outcomes Little Is known, however; about the variability in the quality of emergency general surgical care across hospitals or within hospitals across different procedures. The objectives of this study were to identify risk factors associated with. adverse events, to compare 30-day outcomes after 3 common emergency general surgery procedures within and across hospitals, and thus, to determine whether the quality of emergency surgical cam is procedure-dependent or intrinsic to oilier aspects of the hospital environment. Methods. Patients who underwent emergency appendectomy, cholecystectomy, or colorectal resection at 95 hospitals that submitted at least 20 of each procedure were identified in the 2005-2008 American College of Surgeons National Surgical Quality Improvement Project database. Outcomes of interest included 30-day overall moridity and serious morbidity/mortality Step-wise logistic regression generated patient-level piedicted probabilities of an outcome. Based on the expected probabilities, observed to expected (O/E) ratios for each outcome, after each of the 3 procedures, were calculated for each hospital. Hospitals were divided into terciles based on O/E ratios. The agreement on hospital outcomes performance for overall morbidity and serious morbidity/mortality after appendectomy, cholecystectomy, and colorectal resection was assessed using weighted kappa statistics. Results. Of the 30,788 appendectomies, 1,984 (6.44%) patients had any morbidity, and 1,140 (3 70%) patients had a serious morbidity or died Of the 5,824 cholecystectomies, 503 (8.64%) patients had any morbidity, and 371 (6.37%) patients had a serious morbidity or died Of the 8,990 colorectal resections, 4,202 (46 74%) patients had any morbidity, and 3,736 (41.56%) patients had a serious morbidity or died For overall morbidity, O/E ratios for appendectomy ranged from 0 26 to 2 36, O/E ratios for cholecystectomy ranged from 0 to 3.04, O/E ratios for colorectal resection ranged from. 0.45 to 1.51. For serious morbidity/mortality, O/E ratios for appendectomy ranged from 0.23 to 2.54; O/E ratios for choloystectomy ranged from 0 to 4 28, O/E ratios for colorectal resection ranged from 0.59 to 1.75 Associations of risk-adjusted hospital outcomes based on tercile rank between procedures demonstrated slight but significant agreement for both overall morbidity (weighted kappa between 0 20 and 0 22) and serious.morbidity/mortality (weighted kappa. bet won 0 18 and 0 22) Despite this, 7 (7.4%) hospitals for overall morbidity and 9 (9.5 %) hospitals for serious morbidity/modality were rated in the highest (best) tercile for all procedures. Eight (8.4%) hospitals for overall morbidity and 8 (8 4%) hospitals for serious.morbidity/mortality were rated in the lowest tercile for all procedures Conclusion. Emergency general surgery procedures, particularly colorectal resections, were associated with substantial 30-day overall morbidity and serious morbidity/mortality. Most hospitals did not have consistent risk-adjusted outcomes across all 3 procedures, but for a substantive minority of institutions (7-10%), good or had performance was generalizable across procedures. Individual hospitals should examine then pocedure-specific outcomes after emergency general surge?), operations to focus quality improvement initiatives appropriately. (Singer), 2010;148.217-38.) C1 [Ingraham, Angela M.; Cohen, Mark E.; Raval, Mehul V.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL 60611 USA. [Ingraham, Angela M.] Univ Cincinnati, Coll Med, Dept Surg, Cincinnati, OH 45267 USA. [Bilimoria, Karl Y.; Raval, Mehul V.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Nathens, Avery B.] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Div Surg & Trauma, Toronto, ON M5B 1W8, Canada. [Hall, Bruce L.] John Cochran Vet Affairs Med Ctr, Dept Surg, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Hall, Bruce L.] Barnes Jewish Hosp, St Louis, MO 63110 USA. [Hall, Bruce L.] Washington Univ, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, John M Olin Sch Business, St Louis, MO 63130 USA. RP Ingraham, AM (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, 633 N St Clau St,Floor 22NE, Chicago, IL 60611 USA. OI Raval, Mehul/0000-0002-1527-2661 NR 31 TC 39 Z9 39 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD AUG PY 2010 VL 148 IS 2 BP 217 EP 238 DI 10.1016/j.surg.2010.05.009 PG 22 WC Surgery SC Surgery GA 632OE UT WOS:000280433200009 PM 20633727 ER PT J AU Li, YQ Liu, BL Fukudome, EY Kochanek, AR Finkelstein, RA Chong, W Jin, GA Lu, J deMoya, MA Velmahos, GC Alm, HB AF Li, Yongqing Liu, Baoling Fukudome, Eugene Y. Kochanek, Ashley R. Finkelstein, Robert A. Chong, Wei Jin, Guang Lu, Jennifer deMoya, Marc A. Velmahos, George C. Alm, Hasan B. TI Surviving lethal septic shock without fluid resuscitation in a rodent model SO SURGERY LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; NF-KAPPA-B; TOLL-LIKE RECEPTOR-4; CARDIAC HISTONES; ACETYLATION; STAT1; TRANSCRIPTION; HEMORRHAGE; STRATEGIES; ACID AB Background. We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase before a lethal dose of lipopolysaccharide (LPS) improves survival in mice The purpose of the present study was to determine whether SAHA treatment would attenuate LPS-induced shock and improve survival when given postinsult in a rodent model Methods. C57BL/6J mice were intrapentoneally (IP) injected with LPS (30 mg/kg), and 2 hours later randomized into 2 groups. (1) vehicle animals (n = 10) received dimethyl sulfoxide (DMSO) solution only, and (2) SA HA animals (11 = 10) were given SA HA (50 mg/kg, IP) in DMSO solution. Survival was monitored over the next 7 days In a second study, LPS-injected mice were treated with either DMSO or SAHA as described, and normal (sham) animals served as controls Lungs were harvested at 4, 6, and 8 hours after LPS injection for analysts of gene expression In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA post-treatment on LPS-induced inflammation using enzyme-linked immunosorbent assay. Results. All LPS-injected mice that received the vehicle agent alone died within 24 hours, whereas the SAHA-treated animals displayed a significant improvement in 1 week survival (80% vs 0%, P < .001) LPS insult significantly enhanced gene expression of MyD88, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and was associated with an increased protein secretion of TXT-alpha and IL-6 into the cell culture medium. In contrast, SAHA treatment significantly attenuated all of these LPS-related alterations. Conclusion. We report for the first time that administration of SAHA (50 mg/kg IP) after a lethal dose of LP,S significantly improves long-term survival, and attenuates expression of the proinflammatory mediators TAT-a and IL-6. Furthermore, our data suggest that the anti-inflammatory effects of,SA may be due to downregulation of the MyD88-dependent pathway, and decreased expression of associated proinflammatory genes (Surgery 2010:148:246-54.) C1 [Li, Yongqing; Liu, Baoling; Fukudome, Eugene Y.; Kochanek, Ashley R.; Finkelstein, Robert A.; Chong, Wei; Jin, Guang; Lu, Jennifer; deMoya, Marc A.; Velmahos, George C.; Alm, Hasan B.] Harvard Univ, Div Trauma Emergency Surg & Surg Crit Care, Dept Surg, Massachusetts Gen Hosp,Sch Med, Boston, MA 02114 USA. [Finkelstein, Robert A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Pediat Crit Care Med,Dept Pediat, Boston, MA 02114 USA. RP Alm, HB (reprint author), Harvard Univ, Div Trauma Emergency Surg & Surg Crit Care, Dept Surg, Massachusetts Gen Hosp,Sch Med, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. FU NIGMS NIH HHS [R01 GM084127] NR 28 TC 31 Z9 35 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD AUG PY 2010 VL 148 IS 2 BP 246 EP 254 DI 10.1016/j.surg.2010.05.003 PG 9 WC Surgery SC Surgery GA 632OE UT WOS:000280433200011 PM 20561658 ER PT J AU Poultsides, GA Zhu, AX Choti, MA Pawlik, TM AF Poultsides, George A. Zhu, Andrew X. Choti, Michael A. Pawlik, Timothy M. TI Intrahepatic Cholangiocarcinoma SO SURGICAL CLINICS OF NORTH AMERICA LA English DT Article DE Peripheral cholangiocarcinoma; Biliary cancer; Liver cancer; Liver resection; Hepatectomy ID LONG-TERM SURVIVAL; TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION; UNRESECTABLE HEPATOCELLULAR-CARCINOMA; SINGLE-INSTITUTION EXPERIENCE; POSITRON-EMISSION-TOMOGRAPHY; RANDOMIZED CONTROLLED TRIAL; SEER DATABASE ANALYSIS; LYMPH-NODE METASTASES; PRIMARY LIVER-CANCER; BILIARY-TRACT AB Intrahepatic cholangiocarcinoma (ICC) is a primary cancer of the bile ducts, arising from malignant transformation of the epithelial cells that line the biliary apparatus ICC is relatively uncommon, but its incidence is on the increase ICC is frequently discovered as an incidental, indeterminate liver mass Surgical resection of ICC represents the only potentially curative therapeutic option. The role of routine hilar lymphadenectomy is controversial, but should be considered to optimize staging Although adjuvant chemotherapy and radiotherapy is probably not supported by current data, each should strongly be considered in patients with lymph node metastasis or an R1 resection. For those patients with inoperable disease, locoregional therapy with transarterial chemoembolization can be considered C1 [Choti, Michael A.; Pawlik, Timothy M.] Johns Hopkins Med Inst, Dept Surg, Div Surg Oncol, Baltimore, MD 21287 USA. [Zhu, Andrew X.] Massachusetts Gen Hosp, Liver Canc Res Program, Dept Surg, Boston, MA 02114 USA. [Zhu, Andrew X.] Massachusetts Gen Hosp, Ctr Canc, Div Med Oncol, Dept Med, Boston, MA 02114 USA. [Poultsides, George A.] Stanford Univ, Sch Med, Div Surg Oncol, Dept Surg, Stanford, CA 94305 USA. RP Pawlik, TM (reprint author), Johns Hopkins Med Inst, Dept Surg, Div Surg Oncol, 600 N Wolfe St,Harvey 611, Baltimore, MD 21287 USA. NR 88 TC 41 Z9 48 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0039-6109 J9 SURG CLIN N AM JI Surg. Clin.-North Am. PD AUG PY 2010 VL 90 IS 4 BP 817 EP + DI 10.1016/j.suc.2010.04.011 PG 22 WC Surgery SC Surgery GA 639PA UT WOS:000280985500015 PM 20637950 ER PT J AU Sylla, P Sohn, DK Cizginer, S Konuk, Y Turner, BG Gee, DW Willingham, FF Hsu, M Mino-Kenudson, M Brugge, WR Rattner, DW AF Sylla, Patricia Sohn, Dae Kyung Cizginer, Sevdenur Konuk, Yusuf Turner, Brian G. Gee, Denise W. Willingham, Field F. Hsu, Maylee Mino-Kenudson, Mari Brugge, William R. Rattner, David W. TI Survival study of natural orifice translumenal endoscopic surgery for rectosigmoid resection using transanal endoscopic microsurgery with or without transgastric endoscopic assistance in a swine model SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-American-Gastrointestinal-and-Endoscopic-Surgeons (SAGES) CY APR 22-25, 2009 CL Phoenix, AZ SP Soc Amer Gastrointestinal & Endoscop Surg DE Colorectal resection; NOTES; Survival; TEM; Transanal endoscopic microsurgery; Transgastric access ID PORCINE MODEL; PROTOTYPE AB The feasibility of transanal rectosigmoid resection with transanal endoscopic microsurgery (TEM) was previously demonstrated in a swine nonsurvival model in which transgastric endoscopic assistance also was shown to extend the length of colon mobilized transanally. A 2-week survival study evaluating transanal endoscopic rectosigmoid resection with stapled colorectal anastomosis was conducted with swine using the transanal approach alone (TEM group, n = 10) or a transanal approach combined with transgastric endoscopic assistance (TEM + TG group, n = 10). Gastrotomies were created using a needleknife and balloon dilation, then closed using prototype T-tags. Outcomes were evaluated and compared between the groups using Student's t-test and Fisher's exact test. Relative to the TEM group, the average length of rectosigmoid mobilized in the TEM + TG group was 15.6 versus 10.5 cm (p < 0.0005), the length of the resected specimen was 9 versus 6.2 cm (p < 0.0005), and the mean operative time was 254.5 versus 97.5 min (p < 0.0005). Intraoperatively, no organ injury or major bleeding was noted. Two T-tag misfires occurred during gastrotomy closure and four small staple line defects requiring transanal repair including one in the TEM group and three in the TEM + TG group (p = 0.2). Postoperatively, there was no mortality, and the animals gained an average of 3.4 lb. Two major complications (10%) were identified at necropsy in the TEM + TG group including an intraabdominal abscess and an abdominal wall hematoma related to T-tag misfire. Gastrotomy closure sites and colorectal anastomoses were all grossly healed, with adhesions noted in 60 and 70% and microabscesses in 50 and 20% of the gastrotomy sites and colorectal anastomoses, respectively. Natural orifice translumenal endoscopic surgery (NOTES) for rectosigmoid resection using TEM with or without transgastric endoscopic assistance is feasible and associated with low morbidity in a porcine survival model. Transgastric assistance significantly prolongs the operative time but extends the length of the rectosigmoid mobilized transanally, with a nonsignificant increase in complication rates related to gastrotomy creation. C1 [Sylla, Patricia; Konuk, Yusuf; Gee, Denise W.; Rattner, David W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. [Cizginer, Sevdenur; Turner, Brian G.; Willingham, Field F.; Brugge, William R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Gastroenterol,Dept Med, Boston, MA 02114 USA. [Hsu, Maylee; Mino-Kenudson, Mari] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Sohn, Dae Kyung] Natl Canc Ctr, Res Inst & Hosp, Ctr Colorectal Canc, Goyang, South Korea. RP Sylla, P (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, 15 Parkman St,WACC 460, Boston, MA 02114 USA. EM psylla@partners.org OI Willingham, Field/0000-0002-7071-3001 NR 14 TC 37 Z9 42 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 J9 SURG ENDOSC JI Surg. Endosc. PD AUG PY 2010 VL 24 IS 8 BP 2022 EP 2030 DI 10.1007/s00464-010-0898-0 PG 9 WC Surgery SC Surgery GA 620GZ UT WOS:000279488400036 PM 20174948 ER PT J AU Defeo, EM Cheng, LL AF DeFeo, Elita M. Cheng, Leo L. TI Characterizing Human Cancer Metabolomics with ex vivo H-1 HRMAS MRS SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article DE Magnetic resonance spectroscopy; Magic angle spinning; Metabolomics; diagnosis; Lung; Breast; Prostate; Brain; Colorectal; Cervical; Cancer; Clinical application ID MAGNETIC-RESONANCE-SPECTROSCOPY; BRAIN-TUMOR BIOPSIES; MAS NMR-SPECTROSCOPY; HR-MAS; PROSTATE-CANCER; CLINICAL-APPLICATIONS; INTACT TISSUE; PROTON NMR; RESOLUTION; QUANTIFICATION AB Publications of proton high resolution magic angle spinning (H-1 HRMAS) magnetic resonance spectroscopy (MRS) and its role in identification of metabolic markers for human cancer reported between 2005 and 2009 are reviewed according the anatomic sites of cancer: lung, breast, prostate, brain, colorectal, and cervical. Limited and insufficient screening options for the general public have indicated a need for more advanced tests that can identify and locate cancer at an early stage. H-1 HRMAS MRS is a valuable tool that can elucidate relevant biological metabolite information that is being used to distinguish cancer from benign tissue, and even classify types of tumors. Researchers are working to translate this ex vivo spectroscopy information into an in vivo system that could be implemented in cancer clinics. For instance, in the case of lung cancer, the goal is to identify the at risk population through a simple blood test, which would be the first level of screening. From these tests, patients identified as at risk will be able to undergo further non-invasive radiological testing for diagnostic purposes. Not only will this ex vivo technology become a valuable diagnostic tool, it will also provide a way to monitor treatments on an individual basis so they can be adjusted accordingly for the best possible outcome. C1 [DeFeo, Elita M.; Cheng, Leo L.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Cheng, Leo L.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Cheng, LL (reprint author), Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM cheng@nmr.mgh.harvard.edu FU NIH [CA115746, CA115746-04S2, CA141139]; MGH A.A. Martinos Center for Biomedical Imaging FX Authors acknowledge partial support by NIH grants CA115746 (LLC), CA115746-04S2 (LLC), CA141139 (LLC), and MGH A.A. Martinos Center for Biomedical Imaging. NR 47 TC 12 Z9 13 U1 2 U2 21 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 1533-0346 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD AUG PY 2010 VL 9 IS 4 BP 381 EP 391 PG 11 WC Oncology SC Oncology GA 633JA UT WOS:000280496800008 PM 20626203 ER PT J AU Galofre, JC Haber, RS Mitchell, AA Pessah, R Davies, TF AF Galofre, Juan C. Haber, Richard S. Mitchell, Adele A. Pessah, Rachel Davies, Terry F. TI Increased Postpartum Thyroxine Replacement in Hashimoto's Thyroiditis SO THYROID LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; SUBCLINICAL HYPOTHYROIDISM; LEVOTHYROXINE REQUIREMENTS; PEROXIDASE ANTIBODIES; FOLLOW-UP; PREGNANCY; WOMEN; DYSFUNCTION; DISEASE; IMMUNOLOGY AB Background: The thyroidal response of pregnant patients with established Hashimoto's thyroiditis remains poorly described. The aim of this study was to determine the impact of pregnancy on Hashimoto's thyroiditis as revealed by changes in postpregnancy levothyroxine requirements. Methods: We performed a retrospective study of 799 hypothyroid patients in a university hospital. We reviewed the clinical records and selected a group of well-documented pregnant (n = 34) and nonpregnant (n 32) hypothyroid women for study. We reviewed levothyroxine intake and serum thyrotropin (TSH) levels during three consecutive 9-month time intervals that were immediately before, during, and after pregnancy. We compared the percent change in levothyroxine dose between the prepregnancy level and each trimester during and after pregnancy. Results: There were two patterns of levothyroxine supplementation during gestation. In pattern 1 (n 11) there was either no change or a single levothyroxine dose increase with no subsequent changes in each trimester (T1 = T2 = T3). In pattern 2 (n 18), multistep levothyroxine dose increases were required throughout pregnancy (T1< T2< T3) to maintain desired TSH levels (< 2.0 mU/L). Women with pattern 2 had mean TSH levels during gestation that differed significantly from pattern 1 (2.8 +/- 0.5 vs. 1.3 +/- 0.1 mU/L respectively; p<0.03). Further, in multivariate logistic regression, women with pattern 2 were 62 times more likely than women with pattern 1 to have a levothyroxine dose at least 20% above baseline at 3 months postpartum (p - 0.04). Conclusions: We showed that >50% of hypothyroid women with Hashimoto's thyroiditis experienced an increase in levothyroxine requirements in the postpartum compared to pregestational doses. This pattern of enhanced levothyroxine need was most likely dependent on the preexisting thyroid functional reserve and postpartum progression of autoimmune destruction. C1 [Galofre, Juan C.; Davies, Terry F.] Mt Sinai Hosp, Mt Sinai Sch Med, Thyroid Res Unit, James J Peters VA Med Ctr, New York, NY 10029 USA. [Galofre, Juan C.] Univ Navarra, Clin Univ, Dept Endocrinol, E-31080 Pamplona, Spain. [Haber, Richard S.; Pessah, Rachel; Davies, Terry F.] Mt Sinai Hosp, Mt Sinai Sch Med, Dept Med, James J Peters VA Med Ctr, New York, NY 10029 USA. [Mitchell, Adele A.] Mt Sinai Hosp, Mt Sinai Sch Med, Dept Genet & Genom Sci, James J Peters VA Med Ctr, New York, NY 10029 USA. RP Davies, TF (reprint author), Mt Sinai Med Ctr, Dept Med, Box 1055,1 Gustave L Levy Pl, New York, NY 10029 USA. EM terry.davies@mssm.edu FU NIDDKD [DK069713]; VA; David Owen Segal Fund; Clinica Universitaria, University of Navarra FX This study was supported in part by grants from NIDDKD (DK069713), the VA Merit Award Program, and the David Owen Segal Fund (Dr. Davies) and the Clinica Universitaria, University of Navarra (Dr. Galofre). NR 33 TC 5 Z9 6 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD AUG PY 2010 VL 20 IS 8 BP 901 EP 908 DI 10.1089/thy.2009.0391 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 634KF UT WOS:000280579000011 PM 20615129 ER PT J AU Hjortnaes, J Gottlieb, D Figueiredo, JL Melero-Martin, J Kohler, RH Bischoff, J Weissleder, R Mayer, JE Aikawa, E AF Hjortnaes, Jesper Gottlieb, Danielle Figueiredo, Jose-Luiz Melero-Martin, Juan Kohler, Rainer H. Bischoff, Joyce Weissleder, Ralph Mayer, John E. Aikawa, Elena TI Intravital Molecular Imaging of Small-Diameter Tissue-Engineered Vascular Grafts in Mice: A Feasibility Study SO TISSUE ENGINEERING PART C-METHODS LA English DT Article ID UTILIZING PULMONARY VENTRICLE; ENDOTHELIAL PROGENITOR CELLS; LATE FOLLOW-UP; IN-VIVO; MOUSE MODEL; MATRIX METALLOPROTEINASES; ARTERY CONDUITS; HEART-VALVES; STEM-CELLS; DISEASE AB Objectives: Creating functional small-diameter tissue-engineered blood vessels has not been successful to date. Moreover, the processes underlying the in vivo remodeling of these grafts and the fate of cells seeded onto scaffolds remain unclear. Here we addressed these unmet scientific needs by using intravital molecular imaging to monitor the development of tissue-engineered vascular grafts (TEVG) implanted in mouse carotid artery. Methods and Results: Green fluorescent protein-labeled human bone marrow-derived mesenchymal stem cells and cord blood-derived endothelial progenitor cells were seeded on polyglycolic acid-poly-L-lactic acid scaffolds to construct small-caliber TEVG that were subsequently implanted in the carotid artery position of nude mice (n = 9). Mice were injected with near-infrared agents and imaged using intravital fluorescence microscope at 0, 7, and 35 days to validate in vivo the TEVG remodeling capability (Prosense680; VisEn, Woburn, MA) and patency (Angiosense750; VisEn). Imaging coregistered strong proteolytic activity and blood flow through anastomoses at both 7 and 35 days postimplantation. In addition, image analyses showed green fluorescent protein signal produced from mesenchymal stem cell up to 35 days postimplantation. Comprehensive correlative histopathological analyses corroborated intravital imaging findings. Conclusions: Multispectral imaging offers simultaneous characterization of in vivo remodeling enzyme activity, functionality, and cell fate of viable small-caliber TEVG. C1 [Hjortnaes, Jesper; Figueiredo, Jose-Luiz; Kohler, Rainer H.; Weissleder, Ralph; Aikawa, Elena] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Boston, MA USA. [Gottlieb, Danielle; Melero-Martin, Juan; Bischoff, Joyce; Mayer, John E.] Harvard Univ, Sch Med, Childrens Hosp, Boston, MA USA. RP Aikawa, E (reprint author), Harvard Univ, Sch Med, Ctr Mol Imaging Res, Massachusetts Gen Hosp, 149 13th St,Room 5420, Charlestown, MA 02129 USA. EM eaikawa@partners.org OI Bischoff, Joyce/0000-0002-6367-1974 FU Wijck-Casper-Stam Foundation; U.S. Army [W81XWH-05-1-0115]; AHA [0835460N] FX This study was supported in part by Wijck-Casper-Stam Foundation (J.H.), U.S. Army Medical Research and Materiel Command (W81XWH-05-1-0115) (J.B.), and AHA 0835460N (E.A.). The authors would like to thank Yoshiko Iwamoto for excellent histological technique, Dr. Soo-Young Kang for assistance with the retroviral transfection of the cells, and David Martin (Tepha) for providing P4HB-based scaffold samples. NR 44 TC 15 Z9 16 U1 0 U2 3 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3384 J9 TISSUE ENG PART C-ME JI Tissue Eng. Part C-Methods PD AUG PY 2010 VL 16 IS 4 BP 597 EP 607 DI 10.1089/ten.tec.2009.0466 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 629VN UT WOS:000280228300005 PM 19751103 ER PT J AU Stowell, CP AF Stowell, Christopher P. TI Effects of storage on the biology and clinical efficacy of the banked red blood cell SO TRANSFUSION AND APHERESIS SCIENCE LA English DT Editorial Material ID VERSUS-HOST-DISEASE; OXYGEN DELIVERY; NITRIC-OXIDE; TRANSFUSION; TRIAL; SHOCK; MICROCIRCULATION; SURGERY; SEPSIS; UPDATE C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Blood Transfus Serv,Dept Pathol, Boston, MA 02114 USA. RP Stowell, CP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Blood Transfus Serv,Dept Pathol, GRJ 148,55 Fruit St, Boston, MA 02114 USA. EM cstowell@partners.org NR 31 TC 7 Z9 7 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1473-0502 J9 TRANSFUS APHER SCI JI Transfus. Apher. Sci. PD AUG PY 2010 VL 43 IS 1 BP 45 EP 47 DI 10.1016/j.transci.2010.05.015 PG 3 WC Hematology SC Hematology GA 644PR UT WOS:000281392400010 PM 20554477 ER PT J AU Steiner, ME Assmann, SF Levy, JH Marshall, J Pulkrabek, S Sloan, SR Triulzi, D Stowell, CP AF Steiner, M. E. Assmann, S. F. Levy, J. H. Marshall, J. Pulkrabek, S. Sloan, S. R. Triulzi, D. Stowell, C. P. TI Addressing the question of the effect of RBC storage on clinical outcomes: The Red Cell Storage Duration Study (RECESS) (Section 7) SO TRANSFUSION AND APHERESIS SCIENCE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; MULTIPLE ORGAN DYSFUNCTION; CARDIAC SURGICAL-PATIENTS; FAILURE ASSESSMENT SCORE; BLOOD-CELLS; TRANSFUSION STRATEGIES; DOUBLE-BLIND; SURGERY; CARE; VALIDATION AB The question of whether storage of red blood cells (RBCs) alters their capacity to deliver oxygen and affects patient outcomes remains in a state of clinical equipoise. Studies of the changes which occur while RBCs are stored have led to several physiologically plausible hypotheses that these changes impair RBC function when the units are transfused. Although there is some evidence of this effect in vivo from animal model experiments, the results of several largely retrospective patient studies have not been consistent. Some studies have shown an association between worse clinical outcomes and transfusion of RBC which have been stored for longer periods of time, while others have found no effect. Three multicenter, randomized, controlled trials have been developed to address this important, but currently unanswered, question. Two clinical trials, one in low birth weight neonates and the other in intensive care unit patients, are enrolling subjects in Canada (the Age of Red Blood Cells in Premature Infants; the Age of Blood Study). The third trial, which is being developed in the United States, is the Red Cell Storage Duration Study (RECESS). This is a multicenter, randomized, controlled trial in which patients undergoing complex cardiac surgical procedures who are likely to require RBC transfusion will be randomized to receive RBC units stored for either 10 or fewer days or 21 or more days. Randomization will only occur if the blood bank has enough units of RBC of both storage times to meet the crossmatch request; hence, subjects randomized to the >= 21 day arm will receive RBC of the same storage time as they would have following standard inventory practice of "oldest units out first". The primary outcome is the change in the Multiple Organ Dysfunction Score (MODS), a composite measure of multiorgan dysfunction, by day 7. Secondary outcomes include the change in the MODS by day 28, all-cause mortality, and several composite and single measures of specific organ system function. The estimated total sample size required will be 1434 evaluable subjects (717 per arm). The RECESS trial is registered through the US National Institutes of Health (clinicaltrials.gov) as NCT00991341. Crown Copyright (C) 2010 Published by Elsevier Ltd. All rights reserved. C1 [Stowell, C. P.] Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA. [Sloan, S. R.; Stowell, C. P.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. [Triulzi, D.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA. [Sloan, S. R.] Childrens Hosp Boston, Dept Lab Med, Boston, MA USA. [Sloan, S. R.] Childrens Hosp Boston, Joint Program Transfus Med, Boston, MA USA. [Marshall, J.] Univ Toronto, Dept Surg, Toronto, ON M5S 1A1, Canada. [Levy, J. H.] Emory Univ Hosp, Dept Anesthesiol, Atlanta, GA USA. [Assmann, S. F.] New England Res Inst, Watertown, MA USA. [Steiner, M. E.; Pulkrabek, S.] Univ Minnesota, Dept Pediat Hematol Oncol, Minneapolis, MN 55455 USA. [Steiner, M. E.; Pulkrabek, S.] Univ Minnesota, Dept Pediat Pulm Crit Care, Minneapolis, MN 55455 USA. RP Stowell, CP (reprint author), Massachusetts Gen Hosp, Blood Transfus Serv, GRJ 148,55 Fruit St, Boston, MA 02114 USA. EM cstowell@partners.org FU NHLBI NIH HHS [U01 HL072033, U01 HL072033-07, U01 HL072072-08, U01 HL072191-08, U01 HL072268, U01 HL072274-08, U01 HL072283-08, U01 HL072289-08, U01 HL072290-08, U01 HL072291, U01 HL072299-07, U01 HL072331-08, U01 HL072346-08, U01 HL072355-08, U01 HL072331, U01 HL072028-08, U01 HL072196-08, U01 HL072248-08, U01 HL072268-08, U01 HL072283, U01 HL072289, U01 HL072291-08, U01 HL072305-08, U01 HL072359, U01 HL072359-07] NR 40 TC 87 Z9 90 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1473-0502 J9 TRANSFUS APHER SCI JI Transfus. Apher. Sci. PD AUG PY 2010 VL 43 IS 1 BP 107 EP 116 DI 10.1016/j.transci.2010.05.014 PG 10 WC Hematology SC Hematology GA 644PR UT WOS:000281392400016 PM 20655807 ER PT J AU Sun, HY Singh, N AF Sun, H. -Y. Singh, N. TI Should intravesical Bacillus Calmette-Guerin be employed in transplant recipients with bladder carcinoma? SO TRANSPLANT INFECTIOUS DISEASE LA English DT Article DE transplant; bladder carcinoma; pro-inflammatory; responses; Bacillus Calmette-Guerin; BCG ID PHASE-III TRIAL; KIDNEY-TRANSPLANTATION; BCG IMMUNOTHERAPY; MYCOBACTERIUM-BOVIS; IN-SITU; IMMUNOSUPPRESSIVE DRUGS; EUROPEAN ORGANIZATION; IMMUNE-RESPONSES; CANCER INCIDENCE; MESSENGER-RNA AB Bacillus Calmette-Guerin (BCG) exerts its antitumor activity through induction of pro-inflammatory cytokines, while immunosuppressive agents prevent organ rejection by suppressing pro-inflammatory and promoting anti-inflammatory responses. Thus, in the setting of transplant populations, the use of intravesical BCG for bladder cancer has the possibility of either promoting allograft rejection or being rendered ineffective by the action of immunosuppressive agents that block pro-inflammatory responses. We discuss the potential immunologic interactions between BCG and immunosuppression, and review relevant outcomes in renal transplant recipients with bladder cancer receiving intravesical BCG. C1 [Sun, H. -Y.; Singh, N.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Sun, H. -Y.] Natl Taiwan Univ, Coll Med, Dept Internal Med, Natl Taiwan Univ Hosp, Taipei, Taiwan. [Singh, N.] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. RP Singh, N (reprint author), VA Med Ctr, Infect Dis Sect, Univ Dr C, Pittsburgh, PA 15240 USA. EM nis5@pitt.edu OI SUN, HSIN-YUN/0000-0003-0074-7721 NR 51 TC 7 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-2273 J9 TRANSPL INFECT DIS JI Transpl. Infect. Dis. PD AUG PY 2010 VL 12 IS 4 BP 358 EP 362 DI 10.1111/j.1399-3062.2010.00506.x PG 5 WC Immunology; Infectious Diseases; Transplantation SC Immunology; Infectious Diseases; Transplantation GA 640ON UT WOS:000281061000012 PM 20412534 ER PT J AU Ciruela, F Vilardaga, JP Fernandez-Duenas, V AF Ciruela, Francisco Vilardaga, Jean-Pierre Fernandez-Duenas, Victor TI Lighting up multiprotein complexes: lessons from GPCR oligomerization SO TRENDS IN BIOTECHNOLOGY LA English DT Review ID PROTEIN-COUPLED RECEPTORS; RESONANCE ENERGY-TRANSFER; BIMOLECULAR FLUORESCENCE COMPLEMENTATION; ADENOSINE A(2A) RECEPTORS; HIGHER-ORDER OLIGOMERS; MOLECULES IN-VIVO; LIVING CELLS; QUANTITATIVE ASSESSMENT; SPECTROSCOPIC RULER; PLASMA-MEMBRANE AB Spatiotemporal characterization of protein protein interactions (PPIs) is essential in determining the molecular mechanisms of intracellular signaling processes. In this review, we discuss how new methodological strategies derived from non-invasive fluorescence- and luminescence-based approaches (FRET, BRET, BiFC and BiLC), when applied to the study of G protein-coupled receptor (GPCR) oligomerization, can be used to detect specific PPIs in live cells. These technologies alone or in concert with complementary methods (SRET, BRET or BiFC, and SNAP-tag or TR-FRET) can be extremely powerful approaches for PPI visualization, even between more than two proteins. Here we provide a comprehensive update on all the biotechnological aspects, including the strengths and weaknesses, of new fluorescence- and luminescence-based methodologies, with a specific focus on their application for studying PPIs. C1 [Ciruela, Francisco; Fernandez-Duenas, Victor] IDIBELL Univ Barcelona, Unitat Farmacol, Dept Patol & Terapeut Expt, Fac Med, Barcelona 08907, Spain. [Vilardaga, Jean-Pierre] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Lab GPCR Biol, Pittsburgh, PA 15261 USA. [Vilardaga, Jean-Pierre] Massachusetts Gen Hosp, Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Vilardaga, Jean-Pierre] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Ciruela, F (reprint author), IDIBELL Univ Barcelona, Unitat Farmacol, Dept Patol & Terapeut Expt, Fac Med, Barcelona 08907, Spain. EM fciruela@ub.edu RI Ciruela, Francisco/A-5096-2013; OI Ciruela, Francisco/0000-0003-0832-3739; Fernandez Duenas, Victor/0000-0001-7834-2965 FU Ministerio de Ciencia e Innovacion [SAF2008-01462, CSD2008-00005]; National Institutes of Health [DK087688] FX This work was supported by grants SAF2008-01462 and Consolider-Ingenio CSD2008-00005 from Ministerio de Ciencia e Innovacion (to F.C.) and a start-up package from the Department of Pharmacology and Chemical Biology, University of Pittsburgh and by the National Institutes of Health grants DK087688 (J.-P.V.). F.C. and V.F.D. belong to the Neuropharmacology and Pain accredited research group (Generalitat de Catalunya, 2009 SGR 232). We thank Benjamin Torrejon and Esther Castano from the Scientific and Technical Services (SCT)-Bellvitge Campus of the University of Barcelona for technical assistance. NR 86 TC 55 Z9 56 U1 3 U2 23 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0167-7799 J9 TRENDS BIOTECHNOL JI Trends Biotechnol. PD AUG PY 2010 VL 28 IS 8 BP 407 EP 415 DI 10.1016/j.tibtech.2010.05.002 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 638NY UT WOS:000280902800003 PM 20542584 ER PT J AU Schlenner, SM Rodewald, HR AF Schlenner, Susan M. Rodewald, Hans-Reimer TI Early T cell development and the pitfalls of potential SO TRENDS IN IMMUNOLOGY LA English DT Review ID COMMON LYMPHOID PROGENITORS; EMBRYONIC STEM-CELLS; DELTA-LIKE 4; BONE-MARROW; DENDRITIC CELLS; IN-VIVO; HEMATOPOIETIC PROGENITORS; THYMIC MICROENVIRONMENT; LINEAGE PROGENITORS; IMMATURE THYMOCYTES AB The long-standing model for hematopoiesis, which features a dichotomy into separate lymphoid and myeloid branches, predicts that progenitor T cells arise from a lymphocyte-restricted pathway. However, experiments that have detected myeloid potential in progenitor T cells have been reported as evidence to question this model. Mapping physiological differentiation pathways has now led to opposite conclusions, by showing that T cells and thymic myeloid cells have distinct origins and that, in vivo, T cell progenitors lack significant potential for myeloid lineages including dendritic cells. Here, we review the underlying experiments that have led to such fundamentally different conclusions. The current controversy might reflect a need to distinguish between cell fates that are possible experimentally from physiological fate choices, to build a map of immunological differentiation pathways. C1 [Rodewald, Hans-Reimer] German Canc Res Ctr, Dept Cellular Immunol, D-69120 Heidelberg, Germany. [Schlenner, Susan M.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Rodewald, Hans-Reimer] Univ Ulm, Inst Immunol, D-89081 Ulm, Germany. RP Rodewald, HR (reprint author), German Canc Res Ctr, Dept Cellular Immunol, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM hans-reimer.rodewald@uni-ulm.de FU DFG [Schl-1897/1-1]; DFG through SFB [497-B5]; KFO [142-P8]; European Community [FP7/2007-2013, 233074] FX We thank Hans Jorg Febling for collaborations on underlying fate mapping studies, and Carmen Blum, Hans Jorg Fehling, Thorsten Feyerabend and Vera Martins for critical reading of the manuscript. SMS is supported by a fellowship from the DFG (Schl-1897/1-1). HRR is supported by the DFG through SFB 497-B5 and KFO 142-P8, and receives funding from the European Research Council under the European Community's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no. 233074. NR 96 TC 31 Z9 31 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD AUG PY 2010 VL 31 IS 8 BP 303 EP 310 DI 10.1016/j.it.2010.06.002 PG 8 WC Immunology SC Immunology GA 642BH UT WOS:000281177300003 PM 20634137 ER PT J AU Kimberly, HH Murray, A Mennicke, M Liteplo, A Lew, J Bohan, JS Tyer-Viola, L Ahn, R Burke, T Noble, VE AF Kimberly, Heidi Harbison Murray, Alice Mennicke, Maria Liteplo, Andrew Lew, Jason Bohan, J. Stephen Tyer-Viola, Lynda Ahn, Roy Burke, Thomas Noble, Vicki E. TI FOCUSED MATERNAL ULTRASOUND BY MIDWIVES IN RURAL ZAMBIA SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE International ultrasound; Ultrasound curriculum; Obstetric ultrasound; Imaging technology; Ultrasound in developing countries ID CARE AB Point-of-care ultrasound is being increasingly implemented in resource-poor settings in an ad hoc fashion. We developed a focused maternal ultrasound-training program for midwives in a rural health district in Zambia. Four hundred forty-one scans were recorded by 21 midwives during the 6-month study period. In 74 scans (17%), the ultrasound findings prompted a change in clinical decision-making. Eight of the midwives were evaluated with a 14-question observed structured clinical examination (OSCE) and demonstrated a slight overall improvement with mean scores at 2 and 6 months of 10.0/14 (71%) and 11.6/14 (83%), respectively. Our pilot project demonstrates that midwives in rural Zambia can be trained to perform basic obstetric ultrasound and that it impacts clinical decision-making. Ultrasound skills were retained over the study period. More data is necessary to determine whether the introduction of ultrasound ultimately improves outcomes of pregnant women in rural Zambia. (E-mail: hkimberly@partners.org) (C) 2010 World Federation for Ultrasound in Medicine & Biology. C1 [Kimberly, Heidi Harbison; Mennicke, Maria; Bohan, J. Stephen] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Murray, Alice] New Royal Infirm, Dept Emergency Med, Edinburgh, Midlothian, Scotland. [Lew, Jason; Tyer-Viola, Lynda; Ahn, Roy; Burke, Thomas] Massachusetts Gen Hosp, Dept Emergency Med, Div Global Hlth & Human Rights, Boston, MA 02114 USA. [Tyer-Viola, Lynda] Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. RP Kimberly, HH (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St, Boston, MA 02115 USA. EM hkimberly@partners.org NR 14 TC 22 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-5629 J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD AUG PY 2010 VL 36 IS 8 BP 1267 EP 1272 DI 10.1016/j.ultrasmedbio.2010.05.017 PG 6 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 643VR UT WOS:000281328200010 PM 20691916 ER PT J AU Johnson, NB Johnson, MM Selig, MK Nielsen, GP AF Johnson, N. B. Johnson, M. M. Selig, M. K. Nielsen, G. P. TI Use of Electron Microscopy in Core Biopsy Diagnosis of Oncocytic Renal Tumors SO ULTRASTRUCTURAL PATHOLOGY LA English DT Article DE biopsy; chromophobe; kidney; oncocytic tumor; oncocytoma ID FINE-NEEDLE-ASPIRATION; CELL-CARCINOMA; DIFFERENTIAL-DIAGNOSIS; MORPHOLOGIC FEATURES; UTILITY; MASSES; EXPRESSION; NEOPLASMS; SPECIMENS; ABLATION AB The distinction between oncocytoma and chromophobe renal cell carcinoma, important clinically, may be challenging, especially as the tissue sample size decreases. Ancillary studies can be helpful, although subject to interpretation and sample variability. The aim of this study was to examine the value of electron microscopy in differentiating between oncocytoma and chromophobe renal cell carcinoma on formalin fixed paraffin embedded needle core biopsies. Twenty renal needle core biopsies were evaluated. Despite formalin fixation and paraffin embedding, the classic ultrastructural features of these neoplasms were retained, revealing 80% sensitivity and 100% specificity by initial work-up. C1 [Nielsen, G. P.] Massachusetts Gen Hosp, Pathol Serv, Dept Pathol, Boston, MA 02114 USA. [Johnson, N. B.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. RP Nielsen, GP (reprint author), Massachusetts Gen Hosp, Pathol Serv, Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM gnielsen@partners.org NR 26 TC 6 Z9 6 U1 0 U2 2 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0191-3123 J9 ULTRASTRUCT PATHOL JI Ultrastruct. Pathol. PD AUG PY 2010 VL 34 IS 4 BP 189 EP 194 DI 10.3109/01913121003725713 PG 6 WC Microscopy; Pathology SC Microscopy; Pathology GA 660LK UT WOS:000282644000001 PM 20594037 ER PT J AU Clemens, JQ Calhoun, EA Litwin, MS Walker-Corkery, E Markossian, T Kusek, JW McNaughton-Collins, M AF Clemens, J. Quentin Calhoun, Elizabeth A. Litwin, Mark S. Walker-Corkery, Elizabeth Markossian, Talar Kusek, John W. McNaughton-Collins, Mary CA Urologic Pelvic Pain Collaborative TI A Survey of Primary Care Physician Practices in the Diagnosis and Management of Women With Interstitial Cystitis/Painful Bladder Syndrome SO UROLOGY LA English DT Article ID SYNDROME/INTERSTITIAL CYSTITIS; PREVALENCE; POPULATION; SYMPTOMS; TIME; PAIN; MEN AB OBJECTIVES To describe the practice patterns among primary care physicians' (PCPs) managing patients with symptoms suggestive of interstitial cystitis/painful bladder syndrome (IC/PBS). METHODS We developed a clinical vignette describing a woman with typical IC/PBS symptoms to elicit questions about etiology, management strategies, and familiarity with this syndrome. We mailed the questionnaire to 556 PCPs, including academicians and community physicians, in Boston, Los Angeles, and Chicago. RESULTS We received 290 completed questionnaires (response rate, 52%). Nineteen percent of respondents reported they had "never" seen a patient like the one described in the vignette. Two-thirds of respondents correctly identified the hallmark symptom of IC/PBS (bladder pain/pressure). Regarding etiology, 90% correctly indicated that IC/PBS was a noninfectious disease, 76% correctly reported that it was not caused by a sexually transmitted infection, and 61% correctly indicated that it was not caused by a psychiatric illness. Common treatments included antibiotics and nonsteroidal anti-inflammatory agents. Referrals were often made to a specialist. CONCLUSIONS Although most PCPs indicate familiarity with IC/PBS, they manage the condition infrequently. They also appear to have significant knowledge deficits about the clinical characteristics of IC/PBS, and they indicate variable practice patterns in the diagnosis and treatment of the condition. Educational efforts directed at PCPs will likely improve the care of patients with IC/PBS. UROLOGY 76: 323-329, 2010. (C) 2010 Elsevier Inc. All rights reserved. C1 [Clemens, J. Quentin] Univ Michigan, Med Ctr, Dept Urol, Ann Arbor, MI 48109 USA. Univ Illinois, Sch Publ Hlth, Chicago, IL USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Hlth Serv, Los Angeles, CA 90095 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Clemens, JQ (reprint author), Univ Michigan, Med Ctr, Dept Urol, 1500 Med Ctr Dr,Taubman Ctr 3875, Ann Arbor, MI 48109 USA. EM qclemens@umich.edu FU National Institutes of Health [U01 DK65187, DK 65277, DK 65257] FX This research was funded by grants (U01 DK65187, DK 65277, and DK 65257) from the National Institutes of Health. NR 16 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD AUG PY 2010 VL 76 IS 2 BP 323 EP 328 DI 10.1016/j.urology.2009.12.047 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 638BR UT WOS:000280865300023 PM 20303575 ER PT J AU Vickers, MM Choueiri, TK Rogers, M Percy, A Finch, D Zama, I Cheng, TN North, S Knox, JJ Kollmannsberger, C McDermott, DF Rini, BI Heng, DY AF Vickers, Michael M. Choueiri, Toni K. Rogers, Miranda Percy, Andrew Finch, Daygen Zama, Ivan Cheng, Tina North, Scott Knox, Jennifer J. Kollmannsberger, Christian McDermott, David F. Rini, Brian I. Heng, Daniel Y. TI Clinical Outcome in Metastatic Renal Cell Carcinoma Patients After Failure of Initial Vascular Endothelial Growth Factor-Targeted Therapy SO UROLOGY LA English DT Article ID PHASE-III TRIAL; INTERFERON-ALPHA; DOUBLE-BLIND; SUNITINIB; SORAFENIB; TEMSIROLIMUS; EFFICACY AB OBJECTIVES To characterize and evaluate the efficacy of second-line therapy in patients who had progressed on initial anti-vascular endothelial growth factor (VEGF) therapy. METHODS Between 2005 and 2007, patients with mRCC who received second-line therapy after 1st-line VEGF-targeted therapy were identified across 7 cancer centers. RESULTS A total of 645 mRCC patients received first-line VEGF-targeted therapy, of which 216 patients received second-line VEGF-targeted therapy (sunitinib, n = 93; sorafenib, n = 80; bevacizumab, n = 11; axitinib, n = 8) or mammalian target of rapamycin (mTOR)-inhibiting agents (temsirolimus, n = 21; everolimus, n = 3). On multivariate analysis, a higher baseline Karnofsky performance status score before first-line therapy predicted which patients were more likely to receive second-line therapy (P < .0001). The median time to treatment failure of second-line therapy was 4.9 months for anti-VEGF therapy and 2.5 months for mTOR inhibitors (P = .014) (HR: 0.52, CI: 0.29-0.91 and HR: 0.495, CI: 0.27-0.9 after adjusting for Memorial Sloan-Kettering Cancer Center prognostic factors and histology, respectively). Overall survival from start of second-line therapy was not significantly different (14.2 vs 10.6 months respectively; P = .38). CONCLUSIONS Baseline Karnofsky performance status is an independent predictor of receiving second-line targeted therapy. Patients who receive a second-line anti-VEGF drug appear to have a similar overall survival to those who receive a second-line anti-mTOR drug. UROLOGY 76: 430-435, 2010. (C) 2010 Elsevier Inc. C1 [Heng, Daniel Y.] Univ Calgary, Dept Oncol, Tom Baker Canc Ctr, Calgary, AB T2N 4N2, Canada. Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Dept Oncol, Boston, MA 02215 USA. BC Canc Agcy, Dept Med Oncol, Vancouver, BC, Canada. Cleveland Clin, Taussig Canc Ctr, Dept Solid Tumor Oncol, Cleveland, OH 44106 USA. Univ Alberta, Cross Canc Inst, Dept Oncol, Edmonton, AB, Canada. Princess Margaret Hosp, Dept Med Oncol & Hematol, Toronto, ON M4X 1K9, Canada. RP Heng, DY (reprint author), Univ Calgary, Dept Oncol, Tom Baker Canc Ctr, 1331-29th St NW, Calgary, AB T2N 4N2, Canada. EM Daniel.Heng@albertahealthservices.ca NR 19 TC 49 Z9 51 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 EI 1527-9995 J9 UROLOGY JI Urology PD AUG PY 2010 VL 76 IS 2 BP 430 EP 434 DI 10.1016/j.urology.2009.12.031 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 638BR UT WOS:000280865300057 PM 20223508 ER PT J AU Vickers, MM Heng, DY Choueiri, TK Rini, BI AF Vickers, Michael M. Heng, Daniel Y. Choueiri, Toni K. Rini, Brian I. TI Clinical Outcome in Metastatic Renal Cell Carcinoma Patients After Failure of Initial Vascular Endothelial Growth Factor-Targeted Therapy REPLY SO UROLOGY LA English DT Editorial Material ID SUNITINIB C1 [Vickers, Michael M.; Heng, Daniel Y.] Tom Baker Canc Clin, Calgary, AB, Canada. [Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Rini, Brian I.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. RP Vickers, MM (reprint author), Tom Baker Canc Clin, Calgary, AB, Canada. NR 6 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD AUG PY 2010 VL 76 IS 2 BP 435 EP 435 DI 10.1016/j.urology.2009.12.028 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 638BR UT WOS:000280865300059 ER PT J AU Suarez, C Zeymer, U Limbourg, T Baumgartner, I Cacoub, P Poldermans, D Rother, J Bhatt, DL Steg, PG AF Suarez, Carmen Zeymer, Uwe Limbourg, Tobias Baumgartner, Iris Cacoub, Patrice Poldermans, Don Roether, Joachim Bhatt, Deepak L. Steg, Ph Gabriel CA REACH Registry Investigators TI Influence of polyvascular disease on cardiovascular event rates. Insights from the REACH Registry SO VASCULAR MEDICINE LA English DT Article DE atherothrombotic disease; cerebrovascular disease; coronary artery disease; peripheral arterial disease; polyvascular disease ID PERIPHERAL ARTERIAL-DISEASE; ANKLE-BRACHIAL INDEX; ATHEROTHROMBOSIS; PREVALENCE; MORTALITY; SURGERY; ASSOCIATION; OUTPATIENTS; GUIDELINES; MANAGEMENT AB Cardiovascular event rates have been shown to increase substantially with the number of symptomatic disease locations. We sought to assess the risk profile, management and subsequent event rates of polyvascular disease patients. Consecutive outpatients were assessed for atherosclerotic risk factors and medications in the REACH Registry. A total of 19,117 symptomatic patients in Europe completed a 2-year follow-up: 77.2% with single arterial bed disease (coronary artery or cerebrovascular or peripheral arterial disease) and 22.8% with polyvascular disease (>= 1 disease location). Polyvascular disease patients were older (68.5 +/- 9.4 vs 66.3 +/- 9.9 years, p < 0.0001), more often current or former smokers (64.9% vs 58.7%, p < 0.0001), and more often suffered from hypertension (59.5% vs 46.6%, p < 0.0001) and diabetes (34.5% vs 25.9%, p < 0.0001) than single arterial bed disease patients. Despite more intense medical therapy, risk factors (smoking, hypertension, low fasting glucose, and low fasting total cholesterol) were less often controlled in polyvascular disease patients. This was associated with substantially more events over 2 years compared with single arterial bed disease patients (cMACCE [cardiovascular death/non-fatal stroke/non-fatal MI] odds ratio, 1.63 [95% CI, 1.45-1.83], p < 0.0001). In conclusion, polyvascular disease patients have more cardiovascular risk factors, and the prognosis for these patients is significantly worse than for patients with single arterial bed disease. This suggests a need to improve detection and consequent medical treatment of polyvascular disease. C1 [Suarez, Carmen] Hop Univ Princesa, Dept Internal Med, Madrid 28006, Spain. [Zeymer, Uwe; Limbourg, Tobias] Univ Heidelberg, Inst Herzinfarktforsch Ludwigshafen, Ludwigshafen, Germany. [Baumgartner, Iris] Univ Hosp, Inselspital, Div Clin & Intervent Angiol, Swiss Cardiovasc Ctr, Bern, Switzerland. [Cacoub, Patrice] Univ Paris 06, Hop La Pitie Salpetriere, AP HP, Paris, France. [Poldermans, Don] Erasmus MC, Rotterdam, Netherlands. [Roether, Joachim] Hannover Med Sch, Johannes Wesling Klinikum Minden, D-3000 Hannover, Germany. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Steg, Ph Gabriel] Univ Paris 07, INSERM, U698, Paris, France. RP Suarez, C (reprint author), Hop Univ Princesa, Dept Internal Med, Diego Leon 62, Madrid 28006, Spain. EM csuarez.hlpr@salud.madrid.org OI ELISAF, MOSES/0000-0003-0505-078X FU sanofi-aventis (Paris, France); Bristol-Myers Squibb (Princeton, NJ, USA); Waksman Foundation (Tokyo, Japan) FX The REACH Registry is sponsored by sanofi-aventis (Paris, France), Bristol-Myers Squibb (Princeton, NJ, USA), and the Waksman Foundation (Tokyo, Japan). The REACH Registry is endorsed by the World Heart Federation. A complete list of REACH investigators is accessible online at www.reachregistry.org. The REACH Registry enforces a no ghost-writing policy. This manuscript was written and edited by the authors, who take full responsibility for its content. The first draft was written by Dr Carmen Suarez. We thank Deborah Burrage, PhD, for her assistance with coordinating revisions and providing editorial help in preparing this manuscript including editing, checking content and language, formatting, referencing and preparing tables and figures, and Tobias Limbourg for his support with statistical analyses. The Institut fur Herzinfarktforschung Ludwigshafen verified all statistical analyses. NR 24 TC 17 Z9 19 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD AUG PY 2010 VL 15 IS 4 BP 259 EP 265 DI 10.1177/1358863X10373299 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 640VB UT WOS:000281080700002 PM 20724374 ER PT J AU Cadosch, D Schlett, CL Gautschi, OP Frei, HC Filgueira, L AF Cadosch, D. Schlett, C. L. Gautschi, O. P. Frei, H. C. Filgueira, L. TI Metal Ions: Important Co-Players in Aseptic Loosening SO ZEITSCHRIFT FUR ORTHOPADIE UND UNFALLCHIRURGIE LA German DT Article DE aseptic loosening; immunoreactivity; biocorrosion; osteolysis; metal ions, metal implants ID IN-VITRO; HIP-REPLACEMENT; OSTEOLYSIS; OSTEOCLASTS; PARTICLES; DEGRADATION; CHEMOKINES; PROSTHESES; MIGRATION; DIAGNOSIS AB Aim: The aims of this review were to discuss the different mechanisms of biocorrosion of orthopaedic metal implants in the human body, as well as the effects of the released metal ions on bone metabolism and the immune system in regard to their involvement in the pathophysiological mechanisms of aseptic loosening and metal hypersensitivity. Implant failure due to aseptic loosening is thought to occur in about 10-15% of cases. Methods: A review of the literature (using PubMed with the search terms: biocorrosion, metal ions and bone metabolism) was performed. Additionally, we discuss our research results in the field of aseptic loosening. Results: Despite a great effort in developing new implants, metal devices used in orthopaedic and trauma surgery remain prone to biocorrosion by several mechanisms including the direct corrosion by osteoclasts, leading to the production of significant amounts of wear particles and metal ions. In addition to the well documented increased osteolytic activity caused by large (in the nanometer range) wear particles, increasing evidence strongly suggests that the released metal ions contribute to the pathophysiological mechanism of aseptic loosening. Metal ions stimulate both the immune system and bone metabolism through a series of direct and indirect pathways leading to an increased osteolytic activity at the bone-implant interface. Conclusion: To date, revision surgery remains the only option for the treatment of a failed orthopaedic implant caused by aseptic loosening. A better understanding of the complex pathophysiological mechanisms (including the effects caused by the released metal ions) of aseptic loosening may have a significant potential in developing novel implants and therapies in order to reduce the incidence of this complication. C1 [Cadosch, D.] Kantonsspital Winterthur, Chirurg Klin, CH-8401 Winterthur, Switzerland. [Cadosch, D.] Univ Spital Zurich, Unfallchirurg Klin, Zurich, Switzerland. [Schlett, C. L.] Massachusetts Gen Hosp, Cardiac CT MR PET Imaging Program, Boston, MA 02114 USA. [Gautschi, O. P.] Kantonsspital St Gallen, Neurochirurg Klin, St Gallen, Switzerland. [Filgueira, L.] Univ Western Australia, Sch Anat & Human Biol, Crawley, Australia. RP Cadosch, D (reprint author), Kantonsspital Winterthur, Chirurg Klin, Brauerstr 15, CH-8401 Winterthur, Switzerland. EM dcadosch@gmx.net RI Filgueira, Luis/B-6492-2008 NR 27 TC 4 Z9 4 U1 0 U2 8 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1864-6697 J9 Z ORTHOP UNFALLCHIR JI Z. Orthop. Unfallchir. PD AUG PY 2010 VL 148 IS 4 BP 393 EP 397 DI 10.1055/s-0030-1250108 PG 5 WC Orthopedics SC Orthopedics GA 645MU UT WOS:000281465300003 PM 20714980 ER PT J AU Lok, JJ Bosch, RJ Benson, CA Collier, AC Robbins, GK Shafer, RW Hughes, MD AF Lok, Judith J. Bosch, Ronald J. Benson, Constance A. Collier, Ann C. Robbins, Gregory K. Shafer, Robert W. Hughes, Michael D. CA ALLRT Team TI Long-term increase in CD4(+) T-cell counts during combination antiretroviral therapy for HIV-1 infection SO AIDS LA English DT Article DE antiretroviral therapy; HIV/AIDS; long-term CD4(+) T-cell count; loss to follow-up; observational data ID SEQUENTIAL 3-DRUG REGIMENS; BASE-LINE; INITIAL THERAPY; VIROLOGICAL SUPPRESSION; HIV-1-INFECTED PATIENTS; COLLABORATIVE ANALYSIS; IMMUNE RECONSTITUTION; VIRAL SUPPRESSION; RANDOMIZED-TRIAL; OUTCOMES AB Objective: To inform guidelines concerning when to initiate combination antiretroviral therapy (ART), we investigated whether CD4(+) T-cell counts (CD4 cell counts) continue to increase over long periods of time on ART. Losses-to-follow-up and some patients discontinuing ART at higher CD4 cell counts hamper such evaluation, but novel statistical methods can help address these issues. We estimated the long-term CD4 cell count trajectory accounting for losses-to-follow-up and treatment discontinuations. Design: The study population included 898 US patients first initiating ART in a randomized trial (AIDS Clinical Trials Group 384); 575 were subsequently prospectively followed in an observational study (AIDS Clinical Trials Group Longitudinal Linked Randomized Trials). Methods: Inverse probability of censoring weighting statistical methods were used to estimate the CD4 cell count trajectory accounting for losses-to-follow-up and ART discontinuations, overall and for pretreatment CD4 cell count categories (<= 200, 201-350, 351-500, and > 500 cells/mu l). Results: Median CD4 cell count increased from 270 cells/mu l pre-ART to an estimated 556 cells/mu l at 3 and 532 cells/mu l at 7 years after starting ART in analyses ignoring treatment discontinuations, and to 570 and 640 cells/mu l, respectively, had all patients continuedART. However, even hadARTbeen continued, an estimated 25, 9, 3, and2% of patients with pretreatment CD4 cell counts of 200 or less, 201 -350, 351 -500, and more than 500 cells/mu l would have had CD4 cell counts of 350 cells/mu l or less after 7 years. Conclusion: If patients remain on ART, CD4 cell counts increase in most patients for at least 7 years. However, the substantial percentage of patients starting therapy at low CD4 cell counts who still had low CD4 cell counts after 7 years provides support for ART initiation at higher CD4 cell counts. (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Lok, Judith J.; Bosch, Ronald J.; Hughes, Michael D.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Benson, Constance A.] Univ Calif San Diego, San Diego, CA 92103 USA. [Collier, Ann C.] Univ Washington, Sch Med, Seattle, WA USA. [Robbins, Gregory K.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02115 USA. [Shafer, Robert W.] Stanford Univ, Dept Med, Div Infect Dis, Stanford, CA 94305 USA. RP Lok, JJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Ctr Biostat AIDS Res, 655 Huntington Ave Bldg 2,Room 409, Boston, MA 02115 USA. EM jlok@hsph.harvard.edu RI Robbins, Gregory/F-7988-2011 FU NIAID [AI 38858, AI 68636, AI 069434, AI 069472, AI 062435, AI069474, AI27664, AI69432]; Statistical and Data Management Center [AI 38855, AI 68634]; National Institute of Health [NIAID R01 AI 51164, AI 024643, NIH- R01- GM48704]; CTU [AI069472]; CFAR [P30 AI060354 A0104]; Boston Medical Center ACTG CRS; GCRC [RR00096]; University of Cincinnati, Judith Feinberg, MD [AI25879, AI69501] FX We are indebted to the patients who volunteered for ACTG 384 and subsequently to ALLRT, the ACTG sites, and the ACTG 384 and ALLRT study teams. We also want to thank Joe Eron for productive discussions and Andrea Rotnitzky for her valuable insights into inverse probability weighting. This study was supported in part by the ACTG funded by the National Institute of Allergy and Infectious Diseases (NIAID; AI 38858, AI 68636, AI 069434, AI 069472, and AI 062435), the Statistical and Data Management Center (AI 38855 and AI 68634), and the National Institute of Health (NIAID R01 AI 51164, AI 024643, and NIH- R01- GM48704).; This work was also supported by the NIAID grant numbers AI069474, AI27664, and AI69432. We would like to thank the ACTG 384 and ALLRT participants and acknowledge the following persons and institutions who participated in the conduct of this study: Massachusetts General Hospital, Amy Sbrolla, BSN, RN and Nicole Burgett-Yandow, BSN, RN; Beth Israel Deaconess Medical Center (BIDMC) CRS, Mary Albrecht, MD and Neah Kim, MSN, FNP-C, CTU grant number AI069472, CFAR grant number, P30 AI060354 A0104; Boston Medical Center ACTG CRS, Paul R. Skolnik, MD; Betsy Adams, RN, CTU grant number 5U01AI069472, GCRC grant number M01-RR00533; Brigham and Women's Hospital, Paul Sax, MD and Joanne Delaney RN, CTU grant number AI069472; Johns Hopkins University, Denice Jones and Ilene Wiggins, RN, CTU grant number AI-69465, GCRC grant number RR-00052; NYU/NYC HHC at Bellevue, Janet Forcht, RN and Richardson St. Louis, CTU grant numbers AI27665 and AI69532, GCRC Grant RR00096; Mount Sinai Medical Center; Stanford University, Sandra Valle, PA-C & Jane Norris, PA-C, CTU grant number UOI-A1069556; San Mateo County AIDS Program; Santa Clara Valley Medical Center; Willow Clinic; UCLA School of Medicine, Judith Currier, MD, MSc and Eric Daar, MD, CTU grant number AI069424; Harbor-UCLA Medical Center; University of California, San Diego Antiviral Res, Susan Cahill, RNand Linda Meixner, RN, CTU grant number AI069432; San Francisco General Hospital, C. Bradley Hare, MD and Diane Havlir, MD, CTU grant number AI69502; Marin County Department of Health; University of Miami, Hector H. Bolivar, MD and Margaret A. Fischl, MD, CTU grant numbers AI27675 and AI69477; University of Pittsburgh, Deborah McMahon, MD and Barbara Rutecki, MSN, MPH, CTU grant number AI69494; Georgetown University, Princy Kumar, MD and Karyn Hawkins, RN; University of Rochester Medical Center, Jane Reid, RNc, MS, ANP and Mary Adams, RN, MPH, CTU grant numbers AI27658 and AI69511, GCRC grant number RR00044; SUNY- Buffalo, Erie County Med Ctr, Gene Morse PharmD, CTU: AI069511-02, CRC: 5-MO1 RR00044; McCree McCuller Wellness Center, Nyef El-Daher MD, CTU: AI069511- 02, CRC: 5-MO1 RR00044; AIDS Community Health Center, Christine Hurley RN and Roberto Corales DO, CTU: AI069511-02, CRC: 5-MO1 RR00044; University of Southern California, Fred R. Sattler, MD and Frances Marie Canchola, RN, CTU grant numbers AI27673 and AI69428; University of Washington (Seattle), Sheryl S. Storey, PA-C and Shelia Dunaway, MD, CTU grant number AI069434, CTU grant number AI27664; University of Minnesota, Henry H. Balfour, Jr and Christine Fietzer, CTU grant number AI27661; Hennepin County Medical Ctr, Keith Henry, MD and Bette Bordenave, RN; University of Iowa Hospitals and Clinics; University of Nebraska Med. Ctr., Susan Swindells, MBBS and Frances Van Meter, APRN, CTU grant number AI27661; Duke University Medical Center, Gary M. Cox, MD and Martha Silberman, RN, CTU grant number 1U01-AI069484; Washington University (St. Louis), Mark Rodriguez RN BSN and Ge-Youl Kim, RN, BSN, CTU grant UO1 AI069495; St. Louis Connect Care; Ohio State University, Michael F.; Para, MD and Diane Gochnour, RN, CTU grant number AI069474; University of Cincinnati, Judith Feinberg, MD and Jenifer Baer, RN, CTU grant number AI-069513; Case Western Reserve University, Benigno Rodriguez, MD, MSc and Barbara Philpotts, RN, BSN, CTU grant numbers AI25879 and AI69501; MetroHealth CRS; Cleveland Clinic; Indiana University, Mitchell Goldman, MD and Beth Zwickl, NP, CTU grant number AI25859-19, GCRC grant number RR000750; Methodist Hospital of Indiana; Wishard emorial Hospital; Northwestern University, Robert L. Murphy, MD and Baiba Berzins, MPH, CTU grant number AI69471; Rush University Medical Center in Chicago, Beverly E. Sha, MD and Janice Fritsche, MS, APRN, CTU grant number U01 AI069471; Cook County Hospital Core Center, Oluwatoyin Adeyemi, MD and Joanne Despotes, RN, MPH; Beth Israel Medical Center, Donna Mildvan, MD and Gwendolyn Costantini, FNP, CTU grant number AI46370; The Miriam Hospital, Karen T. Tashima, MD, Pamela Poethke, RN, BSN, and Katherine Wright and Kim Raposa, CTU grant numbers AI46381 and AI69472; University of North Carolina, David Ragan, RN and Joseph J. Eron Jr, MD, CTU grant number U01 AI069423, CFAR grant number P30AI050410(-11), GCRC grant number M01 RR000046-48; Moses H. Cone Hospital, Kim Epperson, RN and Timothy Lane, MD; Carolinas Medical Center; Wake County Human Services, David Currin, RNand Kristine Patterson, MD; Vanderbilt University, Michael Morgan, FNP, Brenda Jackson, RN, Vicki Bailey, RN and Janet Nicotera, RN, BSN, CTUgrant number AI069439; University of Texas, Southwestern Medical Center, Philip Keiser, MD and Tianna Petersen, MS, CTU grant number AI46376; University of California, Davis Medical Center, Melissa Schreiber, PA and Abby Olusanya, NP, CTU grant number AI38858-09S1; UC Davis Medical Center; University of Maryland, Institute of Human Virology, Charles Davis, MD and Onyinye Erondu, RN, CTU grant number AI69447; University of Hawaii, Nancy Hanks, RN and Lorna Nagamine, RN, CTU grant number AI34853; Puerto Rico-AIDS Clinical Trial Unit PR-ACTU), Jorge L Santana, MD and Santiago Marrero, MD, CTU grant number Al69415; University of Alabama at Birmingham, Michael Saag, MDand Kerry Upton, RN, CTU grant number AI069452, GCRC grant number M01-RR00032; Emory University, The Ponce de Leon Center, Jeffrey Lennox, MD and Carlos del Rio, MD, CTU grant number AI69418, CFAR grant number AI50409; University of Colorado Health Sciences Center, Denver, Beverly Putnam, MSN and Cathi Basler, MSN, CTU grant number AI069450, GCRC grant number RR00051, CFAR grant number AI054907; University of Pennsylvania, Philadelphia, Harvey Friedman, MD and Rosemarie Kappes, MPH, UO1-AI 032783-14 and AI69467, CFAR grant number 5-P30-AI-045008-09; Presbyterian Medical Center; University of Texas, Galveston, William A. O'Brien, MD and Gerianne Casey, RN, CTU grant number AI32782; Aaron Diamond AIDS Research Center; Columbia University, Jolene Noel Connor, RN, RNC and Madeline Torres, RN, RNC, CTU grant number AI069470, GCRC grant number RR024156; Weill Medical College, Valery Hughes, FNP and Todd Stroberg, RN, GCRC grant number RR00047; Cornell University CRS; Emory University Comprehensive Hemophilia Program, James Paul Steinberg, MD; Tulane University, Cindy Leissinger, MD.; M. D. H. is a paid member of Data and Safety Monitoring Boards for Boehringer-Ingelheim, Medicines Development Ltd., Pfizer, and Tibotec. These companies are all manufacturers or developers of ART or other therapy for HIV infection. In the last year and currently, C. A. B. has served on advisory boards for GlaxoSmithKline and Merck, and served on a Data and Safety Monitoring Board for Achillion, A. C. C. receives research support from Merck & Co. and Schering-Plough, has served on advisory boards for GlaxoSmithKline and Pfizer, is a member of a Data and Safety Monitoring Board for Merck & Co., and owns stock in Abbott Laboratories and Bristol Myers Squibb. In the last year, G. K. R. was a consultant for Johnson and Johnson. NR 42 TC 39 Z9 40 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 31 PY 2010 VL 24 IS 12 BP 1867 EP 1876 DI 10.1097/QAD.0b013e32833adbcf PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 622WT UT WOS:000279697400008 PM 20467286 ER PT J AU Williams, K Seiss, K Beamon, J Pereyra, F Rosenberg, ES Walker, BD Yu, XG Lichterfeld, M AF Williams, Katie Seiss, Katherine Beamon, Jill Pereyra, Florencia Rosenberg, Eric S. Walker, Bruce D. Yu, Xu G. Lichterfeld, Mathias TI Epigenetic regulation of telomerase expression in HIV-1-specific CD8(+) T cells SO AIDS LA English DT Article ID CATALYTIC SUBUNIT HTERT; DNA METHYLATION; HIV-1 INFECTION; GENE PROMOTER; IDENTIFICATION; NONPROGRESSORS; CLONING; LINES AB Telomerase activity in HIV-1-specific CD8(+) T cells from controllers contributes to the maintenance of highly functional cytotoxic T cell responses against HIV-1. Here, we show that high expression of telomerase in controllers is associated with hypermethylation at the distal and hypomethylation at the proximal human telomerase catalytic subunit promoter, whereas HIV-1-specific CD8(+) T cells from progressors showed an inverse pattern with distal promoter hypomethylation and proximal promoter hypermethylation. These data suggest distinct epigenetic signatures in HIV-1-specific T cells in progressors and controllers. C1 [Rosenberg, Eric S.; Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Williams, Katie; Seiss, Katherine; Beamon, Jill; Pereyra, Florencia; Walker, Bruce D.; Yu, Xu G.] MIT, Ragon Inst MGH, Boston, MA USA. RP Lichterfeld, M (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Cox 5, Boston, MA 02114 USA. EM mlichterfeld@partners.org FU Doris Duke Clinical Scientist Development Award; NIH [R01 AI078799]; Harvard University Center for AIDS Research FX This work was supported by the Doris Duke Clinical Scientist Development Award (to M. L. and X.G.Y.), NIH R01 AI078799 (X.G.Y.), and a Feasibility Grant from the Harvard University Center for AIDS Research (to M. L.). X.G.Y. and M. L. have contributed to research idea, study concept and writing of manuscript. K. W., K. S., J.B. have contributed to performance of PCR assays and data analysis. F. P. and B. D. W. have contributed to PBMC samples. E. S. R. and B. D. W. have contributed to discussion and review of manuscript. NR 16 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 31 PY 2010 VL 24 IS 12 BP 1964 EP 1966 DI 10.1097/QAD.0b013e32833c7170 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 622WT UT WOS:000279697400022 PM 20588158 ER PT J AU Fang, R Barbera, AJ Xu, YF Rutenberg, M Leonor, T Bi, Q Lan, F Mei, PC Yuan, GC Lian, C Peng, JM Cheng, DM Sui, GC Kaiser, UB Shi, Y Shi, YG AF Fang, Rui Barbera, Andrew J. Xu, Yufei Rutenberg, Michael Leonor, Thiago Bi, Qing Lan, Fei Mei, Pinchao Yuan, Guo-Cheng Lian, Christine Peng, Junmin Cheng, Dongmei Sui, Guangchao Kaiser, Ursula B. Shi, Yang Shi, Yujiang Geno TI Human LSD2/KDM1b/AOF1 Regulates Gene Transcription by Modulating Intragenic H3K4me2 Methylation SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-II; HISTONE METHYLATION; P-TEFB; DEMETHYLASE ACTIVITY; TARGET GENES; HUMAN GENOME; PWWP DOMAIN; S-POMBE; LSD1; CHROMATIN AB Dynamic histone H3K4 methylation is an important epigenetic component of transcriptional regulation. However, most of our current understanding of this histone mark is confined to the regulation of transcriptional initiation. We now show that human LSD2/KDM1b/AOF1, the human homolog of LSD1, is an H3K4me1/2 demethylase that specifically regulates histone H3K4 methylation within intragenic regions of its target genes. Genome-wide mapping reveals that LSD2 associates predominantly with the gene bodies of actively transcribed genes, but is markedly absent from promoters. Depletion of endogenous LSD2 results in an increase of H3K4me2 as well as a decrease of H3K9me2 at LSD2-binding sites and a consequent dysregulation of target gene transcription. Furthermore, characterization of the LSD2 complex reveals that LSD2 forms active complexes with euchromatic histone methyltransferases G9a and NSD3 as well as cellular factors involved in transcription elongation. These data provide a possible molecular mechanism linking LSD2 to transcriptional regulation after initiation. C1 [Fang, Rui; Barbera, Andrew J.; Xu, Yufei; Rutenberg, Michael; Leonor, Thiago; Bi, Qing; Mei, Pinchao; Lian, Christine; Kaiser, Ursula B.; Shi, Yujiang Geno] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Dept Med, Boston, MA 02115 USA. [Fang, Rui; Barbera, Andrew J.; Xu, Yufei; Rutenberg, Michael; Leonor, Thiago; Bi, Qing; Mei, Pinchao; Lian, Christine; Kaiser, Ursula B.; Shi, Yujiang Geno] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Dept BCMP, Boston, MA 02115 USA. [Lan, Fei; Shi, Yang] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Yuan, Guo-Cheng] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Peng, Junmin; Cheng, Dongmei] Emory Univ, Dept Human Genet, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA. [Sui, Guangchao] Wake Forest Univ, Dept Canc Biol, Sch Med, Winston Salem, NC 27157 USA. RP Shi, YG (reprint author), Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Dept Med, 221 Longwood Ave, Boston, MA 02115 USA. EM yujiang_shi@hms.harvard.edu RI XU, YUFEI/F-6550-2011; OI Mei, Pinchao/0000-0002-1564-0372 FU NIH [GM078458, DK077036]; NIH NRSA [T32HL007609, F32GM86021] FX This work was supported by NIH grants GM078458 and DK077036 to Y.G.S. and NIH NRSA Postdoctoral Fellowships T32HL007609 to R.F. and F32GM86021 to A.B. Y.G.S. is a PEW scholar. We thank Chun-Xiang Liu (SABioscience) for technical support with DNA methylation studies and Matthew Simon and Karim-Jean Armache for providing MLA nucleosomes. We also thank Stephen Sugrue, Stephen Buratowski, David Ciccone, and Taiping Chen for helpful discussion and critical reading of the manuscript. NR 43 TC 81 Z9 84 U1 0 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 30 PY 2010 VL 39 IS 2 BP 222 EP 233 DI 10.1016/j.molcel.2010.07.008 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 634IR UT WOS:000280574800009 PM 20670891 ER PT J AU Huang, M Kim, JM Shiotani, B Yang, KL Zou, L D'Andrea, AD AF Huang, Min Kim, Jung Min Shiotani, Bunsyo Yang, Kailin Zou, Lee D'Andrea, Alan D. TI The FANCM/FAAP24 Complex Is Required for the DNA Interstrand Crosslink-Induced Checkpoint Response SO MOLECULAR CELL LA English DT Article ID REPLICATION-PROTEIN-A; ANEMIA CORE COMPLEX; COMPLEMENTATION GROUP-M; FANCONI-ANEMIA; S-PHASE; FANCD2 MONOUBIQUITINATION; DAMAGE RESPONSE; BLOOMS-SYNDROME; ATR; PATHWAY AB Cells from Fanconi anemia (FA) patients are extremely sensitive to DNA interstrand crosslinking (ICL) agents, but the molecular basis of the hypersensitivity remains to be explored. FANCM (FA complementation group M), and its binding partner, FAAP24, anchor the multisubunit FA core complex to chromatin after DNA damage and may contribute to ICL-specific cellular response. Here we show that the FANCM/FAAP24 complex is specifically required for the recruitment of replication protein A (RPA) to ICL-stalled replication forks. ICL-induced RPA foci formation requires the DNA-binding activity of FAAP24 but not the DNA translocase activity of FANCM. Furthermore, FANCM/FAAP24-dependent RPA foci formation is required for efficient ATR-mediated checkpoint activation in response to ICL. Therefore, we propose that FANCM/FAAP24 plays a role in ICL-induced checkpoint activation through regulating RPA recruiment at ICL-stalled replication forks. C1 [Huang, Min; Kim, Jung Min; Yang, Kailin; D'Andrea, Alan D.] Harvard Univ, Dept Radiat Oncol, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. [Shiotani, Bunsyo; Zou, Lee] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Zou, Lee] Harvard Univ, Dept Pathol, Sch Med, Boston, MA 02115 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Dept Radiat Oncol, Dana Farber Canc Inst, Sch Med, Boston, MA 02115 USA. EM alan_dandrea@dfci.harvard.edu RI Yang, Kailin/D-7966-2013; Yang, Kailin/L-2205-2013; OI Yang, Kailin/0000-0001-5968-6738; huang, min/0000-0001-6735-1612 FU National Institutes of Health (NIH) [P01CA092584, RO1DK43889, RO1HL52725] FX We would like to thank Andrew J. Deans and Stephen C. West for providing the FANCM siRNAmir and wild-type FANCM- and K117R FANCM-corrected FANCM siRNAmir HEK293 Flip-in cells; and James A. Borowiec for the Myc-RPA2-WT, Myc-RPA2-D4, and Myc-RPA2-A9 plasmids. We thank Patricia A. Stuckert and Jason T. Tsichlis for technical assistance. We also thank Dipanjan Chowdhury, Clark C. Chen, Johannes Walter, Brendan D. Price, and the members of the D'Andrea laboratory for helpful discussions. K.Y. is a Harvard University Presidential Scholar. This work was supported by National Institutes of Health (NIH) grants P01CA092584, RO1DK43889, and RO1HL52725 to A.D.D. NR 47 TC 56 Z9 58 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 30 PY 2010 VL 39 IS 2 BP 259 EP 268 DI 10.1016/j.molcel.2010.07.005 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 634IR UT WOS:000280574800012 PM 20670894 ER PT J AU Samad, OA Liu, Y Yang, FC Kramer, I Arber, S Ma, QF AF Samad, Omar Abdel Liu, Yang Yang, Fu-Chia Kramer, Ina Arber, Silvia Ma, Qiufu TI Characterization of two Runx1-dependent nociceptor differentiation programs necessary for inflammatory versus neuropathic pain SO MOLECULAR PAIN LA English DT Article ID DORSAL-ROOT GANGLION; SENSORY NEURONS; MOLECULAR-MECHANISMS; GENE DELETION; RECEPTOR; COLD; CHANNELS; MICE; CELL; HYPERALGESIA AB Background: The cellular and molecular programs that control specific types of pain are poorly understood. We reported previously that the runt domain transcription factor Runx1 is initially expressed in most nociceptors and controls sensory neuron phenotypes necessary for inflammatory and neuropathic pain. Results: Here we show that expression of Runx1-dependent ion channels and receptors is distributed into two nociceptor populations that are distinguished by persistent or transient Runx1 expression. Conditional mutation of Runx1 at perinatal stages leads to preferential impairment of Runx1-persistent nociceptors and a selective defect in inflammatory pain. Conversely, constitutive Runx1 expression in Runx1-transient nociceptors leads to an impairment of Runx1-transient nociceptors and a selective deficit in neuropathic pain. Notably, the subdivision of Runx1-persistent and Runx1-transient nociceptors does not follow the classical nociceptor subdivision into IB4(+) nonpeptidergic and IB4(-) peptidergic populations. Conclusion: Altogether, we have uncovered two distinct Runx1-dependent nociceptor differentiation programs that are permissive for inflammatory versus neuropathic pain. These studies lend support to a transcription factor-based distinction of neuronal classes necessary for inflammatory versus neuropathic pain. C1 [Samad, Omar Abdel; Liu, Yang; Yang, Fu-Chia; Ma, Qiufu] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Samad, Omar Abdel; Liu, Yang; Yang, Fu-Chia; Ma, Qiufu] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Kramer, Ina; Arber, Silvia] Univ Basel, Biozentrum, Dept Cell Biol, CH-4056 Basel, Switzerland. [Kramer, Ina; Arber, Silvia] Friedrich Miescher Inst, CH-4002 Basel, Switzerland. RP Ma, QF (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 1 Jimmy Fund Way, Boston, MA 02115 USA. EM qiufu_ma@dfci.harvard.edu RI samad, omar/K-1921-2012 FU NIH (NINDS) [5T32NS007473-09, 5P01NS047572]; NIH from NIDCR [1R01DE018025] FX We thank Drs. Gary Gilliland and Nancy Speck for the Runx1 conditional knockout mice, Dr. Rohini Kuner for the Nav1.8Cre mice, and Dr. Tom Jessell for the Runx1 antibody. We thank Drs. Clifford Woolf, Tarek Samad, Ru-Rong Ji, and Gary J. Brenner for technical assistance in performing surgeries and measuring pain behaviors and for their critical reading of this manuscript. The work is supported by the NIH training grant to FY (NINDS: 5T32NS007473-09), and the NIH grants from NIDCR (1R01DE018025) and NINDS (5P01NS047572) to QM. QM is a Claudia Adams Barr Scholar. NR 42 TC 22 Z9 22 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD JUL 30 PY 2010 VL 6 AR 45 DI 10.1186/1744-8069-6-45 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 658JI UT WOS:000282485900001 ER PT J AU Poorkaj, P Raskind, WH Leverenz, JB Matsushita, M Zabetian, CP Samii, A Kim, S Gazi, N Nutt, JG John, W Yearout, D Greenup, JL Steinbart, EJ Bird, TD AF Poorkaj, Parvoneh Raskind, Wendy H. Leverenz, James B. Matsushita, Mark Zabetian, Cyrus P. Samii, Ali Kim, Sophia Gazi, Nayiry Nutt, John G. John, Wolff Yearout, Dora Greenup, J. Lynne Steinbart, Ellen J. Bird, Thomas D. TI A Novel X-Linked Four-Repeat Tauopathy with Parkinsonism and Spasticity SO MOVEMENT DISORDERS LA English DT Article DE genetic linkage; Parkinson's disease/Parkinsonism; X-linked Parkinsonism; X-linked spastic paraparesis; tauopathy ID WIDE LINKAGE ANALYSIS; DYSTONIA-PARKINSONISM; CORTICOBASAL DEGENERATION; PYRAMIDAL SYNDROME; FRAGILE-X; DISEASE; GENE; SUSCEPTIBILITY; ASSOCIATION; MUTATIONS AB The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X-linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four-repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two-point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LOD(max) score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an similar to 20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at-risk males. To reduce the possibility of a false-positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X-linked parkinsonian syndrome with variable spasticity and four-repeat tau pathology, and defined a novel candidate gene locus spanning similar to 28 Mb from Xp11.2-Xq13.3. (C) 2010 Movement Disorder Society C1 [Poorkaj, Parvoneh; Raskind, Wendy H.; Leverenz, James B.; Kim, Sophia; Gazi, Nayiry; Greenup, J. Lynne] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Poorkaj, Parvoneh; Raskind, Wendy H.; Matsushita, Mark; John, Wolff; Bird, Thomas D.] Univ Washington, Dept Med, Seattle, WA USA. [Raskind, Wendy H.; Leverenz, James B.] Vet Affairs Puget Sound Hlth Care Syst, VISN Mental Illness Res Educ & Clin Ctr 20, Seattle, WA USA. [Leverenz, James B.; Zabetian, Cyrus P.; Samii, Ali; Yearout, Dora; Steinbart, Ellen J.; Bird, Thomas D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Leverenz, James B.; Zabetian, Cyrus P.; Samii, Ali] Vet Affairs Puget Sound Hlth Care Syst, Parkinsons Dis Res Educ & Clin Ctr, Seattle, WA USA. [Nutt, John G.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR USA. [Zabetian, Cyrus P.; Yearout, Dora; Bird, Thomas D.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. RP Poorkaj, P (reprint author), Univ Washington, Dept Psychiat & Behav Sci, Box 356560,1959 NE Pacific St, Seattle, WA 98195 USA. EM pips@uw.edu OI Zabetian, Cyrus/0000-0002-7739-4306 FU Department of Veterans Affairs; University of Washington; Mary Gates Research Scholarship; UW Royalty Research; NICHD; MA; NHGRI; Morris Udall and Alzheimer's Centers; NIH; P Disease Foundation; American Parkinson Disease Association; Northwest Collaborative Care; VA Parkinson Disease Research, Education, and Clinical Center (PADRECC); NIH-NINDS; Schering-Plough Research; VA Merit FX This work was supported, in part, by funds from the Department of Veterans Affairs (T.D.B., P.P., W.R., J.W., A.S., J.N.), a University of Washington Royalty Research Fund grant (P.P.), and a Mary Gates Research Scholarship (S.K.). We are grateful to the members of the family who participated in this research. We wish to thank Lisa M. Tisch, BS, for contributing to this study.; P. Poorkaj: Grants: UW Royalty Research grant; Employment: University of Washington. W. H. Raskind: Grants: NICHD, MA, NHGRI; Employment: University of Washington; Royalties: Athena Diagnostics, Inc. J. B. Leverenz: Consultancies: Novartis, Noven, Forest; Grants: Morris Udall and Alzheimer's Centers, NIH; Employment: Department of Veteran's Affairs. M. Matsushita: Employment: University of Washington. C. P. Zabetian: Honoraria: Oregon Health and Science University, American Parkinson Disease Association; Grants: Department of Veteran's Affairs, NIH, P Disease Foundation, American Parkinson Disease Association, Northwest Collaborative Care; Employment: Department of Veteran's Affairs. A. Samii: Honoraria: Boerhinger-Ingelheim, Teva, Ipsen Pharmaceuticals; Grants: Partial salary support from VA Parkinson Disease Research, Education, and Clinical Center (PADRECC) grant; Employment: University of Washington. S. Kim: Employment: Medical student. N. Gazi: Employment: Dental Student. J. G. Nutt: Advisory Boards: Xenoport, Impax, Neurogen, Synosia; Honoraria: Novartis; Grants: NIH-NINDS: Employment: OHSU and Portland VAH; Contracts: Schering-Plough Research. J. Wolff: Employment: University of Washington. D. Yearout: Employment: University of Washington. J. L. Greenup: Employment: University of Washington. E. J. Steinbart: Employment: University of Washington. T. D. Bird: Honoraria: American Academy of Neurology; Grants: VA Merit; Employment: Department of Veteran's Affairs; Royalties: Athena Diagnostics, Inc. NR 35 TC 5 Z9 5 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL 30 PY 2010 VL 25 IS 10 BP 1409 EP 1417 DI 10.1002/mds.23085 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 636QI UT WOS:000280753200011 PM 20629132 ER PT J AU Ahn, AC Park, M Shaw, JR McManus, CA Kaptchuk, TJ Langevin, HM AF Ahn, Andrew C. Park, Min Shaw, Jessica R. McManus, Claire A. Kaptchuk, Ted J. Langevin, Helene M. TI Electrical Impedance of Acupuncture Meridians: The Relevance of Subcutaneous Collagenous Bands SO PLOS ONE LA English DT Article ID HYPODERMICALLY INJECTED TC-99M; LAPLACE PLANE ANALYSIS; CONNECTIVE-TISSUE; RADIOACTIVE PATHWAYS; TRIGGER POINTS; INVASION; MECHANISMS; ULTRASOUND; NETWORK; HUMANS AB Background: The scientific basis for acupuncture meridians is unknown. Past studies have suggested that acupuncture meridians are physiologically characterized by low electrical impedance and anatomically associated with connective tissue planes. We are interested in seeing whether acupuncture meridians are associated with lower electrical impedance and whether ultrasound-derived measures-specifically echogenic collagenous bands - can account for these impedance differences. Methods/Results: In 28 healthy subjects, we assessed electrical impedance of skin and underlying subcutaneous connective tissue using a four needle-electrode approach. The impedances were obtained at 10 kHz and 100 kHz frequencies and at three body sites - upper arm (Large Intestine meridian), thigh (Liver), and lower leg (Bladder). Meridian locations were determined by acupuncturists. Ultrasound images were obtained to characterize the anatomical features at each measured site. We found significantly reduced electrical impedance at the Large Intestine meridian compared to adjacent control for both frequencies. No significant decrease in impedance was found at the Liver or Bladder meridian. Greater subcutaneous echogenic densities were significantly associated with reduced impedances in both within-site (meridian vs. adjacent control) and between-site (arm vs. thigh vs. lower leg) analyses. This relationship remained significant in multivariable analyses which also accounted for gender, needle penetration depth, subcutaneous layer thickness, and other ultrasound-derived measures. Conclusion/Significance: Collagenous bands, represented by increased ultrasound echogenicity, are significantly associated with lower electrical impedance and may account for reduced impedances previously reported at acupuncture meridians. This finding may provide important insights into the nature of acupuncture meridians and the relevance of collagen in bioelectrical measurements. C1 [Ahn, Andrew C.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ahn, Andrew C.; Kaptchuk, Ted J.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Park, Min] P Pro Korea Co Ltd, Seoul, South Korea. [Shaw, Jessica R.] AltThera Hlth, Boston, MA USA. [McManus, Claire A.] Spaulding Rehabil Hosp, Dept Res & Training, Boston, MA USA. [Kaptchuk, Ted J.] Harvard Univ, Sch Med, Div Res & Educ Complementary & Integrat Med Thera, Boston, MA USA. [Langevin, Helene M.] Univ Vermont, Dept Neurol, Burlington, VT USA. RP Ahn, AC (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. EM aahn1@partners.org FU National Center for Complementary Alternative Medicine (NCCAM) [K23-AT003238, P30AT005895, K24-AT004095]; Clinical Translational Science Award [UL1RR025758]; Bernard Osher Foundation; Beth Israel Deaconess Medical Center from the National Center for Research Resources FX This research was supported by grant number K23-AT003238, P30AT005895, and K24-AT004095 of the National Center for Complementary Alternative Medicine (NCCAM) and supported in part by a gift from The Bernard Osher Foundation. The project described was supported by Clinical Translational Science Award UL1RR025758 to Harvard University and Beth Israel Deaconess Medical Center from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Complementary Alternative Medicine or the National Center for Research Resources or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 23 Z9 27 U1 0 U2 18 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 JUL 30 PY 2010 VL 5 IS 7 AR e11907 DI 10.1371/journal.pone.0011907 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 633QZ UT WOS:000280520300021 PM 20689594 ER PT J AU Butler, KL Ambravaneswaran, V Agrawal, N Bilodeau, M Toner, M Tompkins, RG Fagan, S Irimia, D AF Butler, Kathryn L. Ambravaneswaran, Vijayakrishnan Agrawal, Nitin Bilodeau, Maryelizabeth Toner, Mehmet Tompkins, Ronald G. Fagan, Shawn Irimia, Daniel TI Burn Injury Reduces Neutrophil Directional Migration Speed in Microfluidic Devices SO PLOS ONE LA English DT Article ID LEUKOCYTE CHEMOTAXIS INVITRO; POLYMORPHONUCLEAR LEUKOCYTES; CELL-MIGRATION; GRADIENT GENERATOR; THERMAL-INJURY; EARLY EXCISION; ORGAN FAILURE; INFECTION; COMPLEMENT; EXPRESSION AB Thermal injury triggers a fulminant inflammatory cascade that heralds shock, end-organ failure, and ultimately sepsis and death. Emerging evidence points to a critical role for the innate immune system, and several studies had documented concurrent impairment in neutrophil chemotaxis with these post-burn inflammatory changes. While a few studies suggest that a link between neutrophil motility and patient mortality might exist, so far, cumbersome assays have prohibited exploration of the prognostic and diagnostic significance of chemotaxis after burn injury. To address this need, we developed a microfluidic device that is simple to operate and allows for precise and robust measurements of chemotaxis speed and persistence characteristics at single-cell resolution. Using this assay, we established a reference set of migration speed values for neutrophils from healthy subjects. Comparisons with samples from burn patients revealed impaired directional migration speed starting as early as 24 hours after burn injury, reaching a minimum at 72-120 hours, correlated to the size of the burn injury and potentially serving as an early indicator for concurrent infections. Further characterization of neutrophil chemotaxis using this new assay may have important diagnostic implications not only for burn patients but also for patients afflicted by other diseases that compromise neutrophil functions. C1 [Butler, Kathryn L.; Agrawal, Nitin; Bilodeau, Maryelizabeth; Toner, Mehmet; Tompkins, Ronald G.; Fagan, Shawn; Irimia, Daniel] Shriners Hosp Children, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. [Butler, Kathryn L.; Ambravaneswaran, Vijayakrishnan; Agrawal, Nitin; Bilodeau, Maryelizabeth; Toner, Mehmet; Tompkins, Ronald G.; Fagan, Shawn; Irimia, Daniel] Harvard Univ, Sch Med, Boston, MA USA. [Ambravaneswaran, Vijayakrishnan; Agrawal, Nitin; Toner, Mehmet; Irimia, Daniel] Shriners Hosp Children, Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, BioMEMS Resource Ctr, Boston, MA USA. RP Butler, KL (reprint author), Shriners Hosp Children, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. EM dirimia@hms.harvard.edu OI Irimia, Daniel/0000-0001-7347-2082 FU National Institutes of Health [R01M092804]; Shriners Hospitals for Children FX This work was supported in part by funds from the National Institutes of Health (R01M092804) and the Shriners Hospitals for Children. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 68 TC 46 Z9 47 U1 1 U2 15 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 JUL 30 PY 2010 VL 5 IS 7 AR e11921 DI 10.1371/journal.pone.0011921 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 633QZ UT WOS:000280520300030 PM 20689600 ER PT J AU Kim, T Park, JK Kim, HJ Chung, JH Kim, JW AF Kim, Tae Park, Jin Kyung Kim, Hak-Jae Chung, Joo-Ho Kim, Jong Woo TI Association of histone deacetylase genes with schizophrenia in Korean population SO PSYCHIATRY RESEARCH LA English DT Article DE Case-control study; Histone deacetylase; Schizophrenia; Single-nucleotide polymorphism; Genetic association ID CHROMATIN ULTRASTRUCTURE; RELIABILITY; METHYLATION; SPECIFICITY; NEUTROPHILS; INHIBITORS; SYMPTOMS; PROTEINS; COMPLEX; ILLNESS AB Histone deacetylases (HDACs) are pivotal enzymes in the epigenetic modification or regulatory mechanisms of gene transcription. Based on previous assertions that the pathophysiology of schizophrenia is associated with epigenetics, we hypothesized that polymorphisms of HDAC genes might be related to schizophrenia. We recruited 278 patients with schizophrenia and 234 normal controls from a Korean population. Clinical information of the group with schizophrenia was obtained from medical records, the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and the Operational Criteria Checklist (OPCRIT). Three single-nucleotide polymorphisms (SNFs) in HDAC genes were selected, including rs2530223 of HDAC3, rs1063639 of HDAC4. and rs1555048 of HDAC10. For the analysis of genetic data, SNPStats. SNPAnalyzer, and Helixtree programs were used. In the present study, rs1063639 of the HDAC4 gene showed associations with schizophrenia in the codominant and dominant models. In the analysis of clinical phenotypes, smoking status was associated with rs2530223 of HDAC3 in the codominant and recessive models. The results suggest that HDAC3 and HDAC4 genes might play a role in the pathophysiology of schizophrenia in a Korean population. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Kim, Tae] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Neurosci Lab, Boston, MA 02132 USA. [Park, Jin Kyung] Kyung Hee Univ, Dept Psychiat, EW Neo Med Ctr, Seoul, South Korea. [Kim, Hak-Jae; Chung, Joo-Ho] Kyung Hee Univ, Coll Med, Kohwang Med Res Inst, Seoul, South Korea. [Kim, Jong Woo] Kyung Hee Univ Hosp, Dept Neuropsychiat, Seoul 130702, South Korea. RP Kim, JW (reprint author), Soonchunhyang Univ, Soonchunhyang Med Res Inst, Coll Med, Chunan, South Korea. EM psyjongwoo@freechal.com FU Graduate School, Kyung Hee University, Republic of Korea FX This work was supported by a 2007 Graduate Research Scholarship to T.K. from the Graduate School, Kyung Hee University, Republic of Korea. NR 30 TC 23 Z9 23 U1 0 U2 0 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 JUL 30 PY 2010 VL 178 IS 2 BP 266 EP 269 DI 10.1016/j.psychres.2009.05.007 PG 4 WC Psychiatry SC Psychiatry GA 626TC UT WOS:000279988900008 PM 20471694 ER PT J AU Makris, N Seidman, LJ Ahern, T Kennedy, DN Caviness, VS Tsuang, MT Goldstein, JM AF Makris, Nikolaos Seidman, Larry J. Ahern, Todd Kennedy, David N. Caviness, Verne S. Tsuang, Ming T. Goldstein, Jill M. TI White matter volume abnormalities and associations with symptomatology in schizophrenia SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Schizophrenia; MRI-volumetry; White matter; Cingulum; Temporal white matter; Symptoms ID ANTERIOR CINGULATE CORTEX; CORPUS-CALLOSUM SIZE; LEFT-RIGHT ASYMMETRY; TOPOGRAPHIC PARCELLATION; CEREBRAL LATERALIZATION; BIOLOGICAL MECHANISMS; MORPHOMETRIC-ANALYSIS; TEMPORAL-LOBE; HUMAN BRAIN; VULNERABILITY INDICATOR AB The cerebral white matter (WM) is critically involved in many bio-behavioral functions impaired in schizophrenia. However, the specific neural systems underlying symptomatology in schizophrenia are not well known. By comparing the volume of all brain fiber systems between chronic patients with DSM-III-R schizophrenia (n = 88) and matched healthy community controls (n = 40), we found that a set of a priori WM regions of local and distal associative fiber systems was significantly different in patients with schizophrenia. There were significant positive correlations between volumes (larger) in anterior callosal, cingulate and temporal deep WM regions (related to distal connections) with positive symptoms, such as hallucinations, delusions and bizarre behavior, and significant negative correlation between volumes (smaller) in occipital and paralimbic superficial WM (related to local connections) and posterior callosal fiber systems with higher negative symptoms, such as alogia. Furthermore, the temporal sagittal system showed significant rightward asymmetry between patients and controls. These observations suggest a pattern of volume WM alterations associated with symptomatology in schizophrenia that may be related in part to predisposition to schizophrenia. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Makris, Nikolaos; Seidman, Larry J.; Kennedy, David N.; Caviness, Verne S.; Goldstein, Jill M.] Massachusetts Gen Hosp, Athinoula A Martinos Imaging Ctr, Dept Neurol Psychiat & Radiol, Ctr Morphometr Anal, Boston, MA 02114 USA. [Makris, Nikolaos; Seidman, Larry J.; Goldstein, Jill M.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Makris, Nikolaos; Kennedy, David N.; Caviness, Verne S.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Beth Israel Deaconess Hosp BIDMC, Boston, MA 02115 USA. [Seidman, Larry J.] BIDMC, Commonwealth Res Ctr, MMHC Publ Psychiat Div, Boston, MA USA. [Ahern, Todd] Emory Univ, Dept Neurosci, Atlanta, GA 30322 USA. [Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, Inst Behav Genom, La Jolla, CA 92093 USA. [Tsuang, Ming T.] San Diego VA Healthcare Syst, San Diego, CA USA. [Goldstein, Jill M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Goldstein, Jill M.] Brigham & Womens Hosp, Connors Ctr Womens Hlth & Gender Biol, Boston, MA 02115 USA. RP Goldstein, JM (reprint author), Brigham & Womens Hosp, Div Womens Hlth, 1 Brigham Circle,1620 Tremont St, Boston, MA 02120 USA. EM jill_goldstein@hms.harvard.edu RI Kennedy, David/H-3627-2012 FU National Association for Research in Schizophrenia and Depression (NARSAD); National Institute of Mental Health [RO1 MH56956]; Stanley Medical Research Institute; Fairway Trust FX We thank the following people for their contributions to this project: Camille McPherson, Jason Tourville, Heather Sanders, Sean McInerney, Matthew Albaugh, and Joseph Normandin. Preparation of this article was supported primarily by the National Association for Research in Schizophrenia and Depression (NARSAD) to Dr. Nikos Makris and the National Institute of Mental Health RO1 MH56956 to Dr. Jill M. Goldstein. In addition, subjects and technical assistance (respectively) were acquired with significant support from the NARSAD and Stanley Medical Research Institute to Dr. Larry J. Seidman and the Fairway Trust to Dr. David Kennedy. We also thank Lisa Cushman-Daly for manuscript preparation. NR 92 TC 25 Z9 27 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JUL 30 PY 2010 VL 183 IS 1 BP 21 EP 29 DI 10.1016/j.pscychresns.2010.04.016 PG 9 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 627IV UT WOS:000280033600002 PM 20538438 ER PT J AU Rickles, RJ Pierce, LT Giordano, TP Tam, WF McMillin, DW Delmore, J Laubach, JP Borisy, AA Richardson, PG Lee, MS AF Rickles, Richard J. Pierce, Laura T. Giordano, Thomas P., III Tam, Winnie F. McMillin, Douglas W. Delmore, Jake Laubach, Jacob P. Borisy, Alexis A. Richardson, Paul G. Lee, Margaret S. TI Adenosine A2A receptor agonists and PDE inhibitors: a synergistic multitarget mechanism discovered through systematic combination screening in B-cell malignancies SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; GLUCOCORTICOID-INDUCED APOPTOSIS; MULTIPLE-MYELOMA; MULTICOMPONENT THERAPEUTICS; DRUG; DEXAMETHASONE; PREDNISONE; BORTEZOMIB; MELPHALAN; LYMPHOMA AB Using a combination high-throughput screening technology, multiple classes of drugs and targeted agents were identified that synergize with dexamethasone (Dex) in multiple myeloma (MM) cells. Performing combination screening with these enhancers, we discovered an unexpected synergistic interaction between adenosine receptor agonists and phosphodiesterase (PDE) inhibitors that displays substantial activity in a panel of MM and diffuse large B-cell lymphoma (DLBCL) cell lines and tumor cells from MM patients. We have used selective adenosine receptor agonists, antagonists, and PDE inhibitors as well as small interfering RNAs targeting specific molecular isoforms of these proteins to dissect the molecular mechanism of this synergy. The adenosine A2A receptor and PDE2, 3, 4, and 7 are important for activity. Drug combinations induce cyclic AMP (cAMP) accumulation and up-regulate PDE4B. We also observe rigorous mathematical synergy in 3-way combinations containing A2A agonists, PDE inhibitors, and Dex at multiple concentrations and ratios. Taken together, these data suggest that A2A agonist/PDE inhibitor combinations may be attractive as an adjunctive to clinical glucocorticoid containing regiments for patients with MM or DLBCL and confer benefit in both glucocorticoid-sensitive and -resistant populations. (Blood. 2010; 116(4): 593-602) C1 [Rickles, Richard J.; Pierce, Laura T.; Giordano, Thomas P., III; Tam, Winnie F.; Borisy, Alexis A.; Lee, Margaret S.] CombinatoRx Inc, Cambridge, MA 02142 USA. [McMillin, Douglas W.; Delmore, Jake; Laubach, Jacob P.; Richardson, Paul G.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. RP Rickles, RJ (reprint author), CombinatoRx Inc, 245 1st St, Cambridge, MA 02142 USA. EM rrickles@combinatorx.com FU Millennium Pharmaceuticals FX R.J.R., L. T. P., T. P. G., W. F. T., A. A. B., and M. S. L. performed this work while employees at CombinatoRx. P. G. R. is on the advisory committee for Millennium Pharmaceuticals and Celgene and receives funding from Millennium Pharmaceuticals. The remaining authors declare no competing financial interests. NR 27 TC 12 Z9 14 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 29 PY 2010 VL 116 IS 4 BP 593 EP 602 DI 10.1182/blood-2009-11-252668 PG 10 WC Hematology SC Hematology GA 633KZ UT WOS:000280502800015 PM 20382846 ER PT J AU Moskowitz, MA Lo, EH Iadecola, C AF Moskowitz, Michael A. Lo, Eng H. Iadecola, Costantino TI The Science of Stroke: Mechanisms in Search of Treatments SO NEURON LA English DT Review ID FOCAL CEREBRAL-ISCHEMIA; TISSUE-PLASMINOGEN ACTIVATOR; NEURONAL CELL-DEATH; PLURIPOTENT STEM-CELLS; RANDOMIZED CONTROLLED-TRIALS; NMDA RECEPTOR ACTIVATION; WHITE-MATTER LESIONS; BRAIN VASCULAR CELLS; NITRIC-OXIDE; ALZHEIMERS-DISEASE AB This review focuses on mechanisms and emerging concepts that drive the science of stroke in a therapeutic direction. Once considered exclusively a disorder of blood vessels, growing evidence has led to the realization that the biological processes underlying stroke are driven by the interaction of neurons, glia, vascular cells, and matrix components, which actively participate in mechanisms of tissue injury and repair. As new targets are identified, new opportunities emerge that build on an appreciation of acute cellular events acting in a broader context of ongoing destructive, protective, and reparative processes. The burden of disease is great, and its magnitude widens as a role for blood vessels and stroke in vascular and nonvascular dementias becomes more clearly established. This review then poses a number of fundamental questions, the answers to which may generate new directions for research and possibly new treatments that could reduce the impact of this enormous economic and societal burden. C1 [Moskowitz, Michael A.; Lo, Eng H.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Moskowitz, Michael A.; Lo, Eng H.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Iadecola, Costantino] Weill Cornell Med Coll, Div Neurobiol, New York, NY 10065 USA. RP Moskowitz, MA (reprint author), Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. EM moskowitz@helix.mgh.harvard.edu FU NINDS NIH HHS [R01 NS034179, R01 NS034179-16, R01 NS037853] NR 228 TC 571 Z9 595 U1 12 U2 137 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 29 PY 2010 VL 67 IS 2 BP 181 EP 198 DI 10.1016/j.neuron.2010.07.002 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 632WZ UT WOS:000280461500005 PM 20670828 ER PT J AU Kantoff, PW Higano, CS Shore, ND Berger, ER Small, EJ Penson, DF Redfern, CH Ferrari, AC Dreicer, R Sims, RB Xu, Y Frohlich, MW Schellhammer, PF Ahmed, T Amin, A Arseneau, J Barth, N Bernstein, G Bracken, B Burch, P Caggiano, V Chin, J Chodak, G Chu, F Corman, J Curti, B Dawson, N Deeken, JF Dubernet, T Fishman, M Flanigan, R Gailani, F Garbo, L Gardner, T Gelmann, E George, D Godfrey, T Gomella, L Guerra, M Hall, S Hanson, J Israeli, R Jancis, E Jewett, MAS Kassabian, V Katz, J Klotz, L Koeneman, K Koh, H Kratzke, R Lance, R Lech, J Leichman, L Lemon, R Liang, J Libertino, J Lilly, M Malik, I Martin, SE McCaffrey, J McLeod, D McNeel, D Miles, B Murdock, M Nabhan, C Nemunaitis, J Notter, D Pantuck, A Perrotte, P Pessis, D Petrylak, D Polikoff, J Pommerville, P Ramanathan, S Rarick, M Richards, J Rifkin, R Rohatgi, N Rosenbluth, R Santucci, R Sayegh, A Seigne, J Shapira, I Shedhadeh, N Shepherd, D Sridhar, S Stephenson, R Teigland, C Thaker, N Vacirca, J Villa, L Vogelzang, N Wertheim, M Wolff, JH Wurzel, R Yang, C Young, J AF Kantoff, Philip W. Higano, Celestia S. Shore, Neal D. Berger, E. Roy Small, Eric J. Penson, David F. Redfern, Charles H. Ferrari, Anna C. Dreicer, Robert Sims, Robert B. Xu, Yi Frohlich, Mark W. Schellhammer, Paul F. Ahmed, T. Amin, A. Arseneau, J. Barth, N. Bernstein, G. Bracken, B. Burch, P. Caggiano, V. Chin, J. Chodak, G. Chu, F. Corman, J. Curti, B. Dawson, N. Deeken, J. F. Dubernet, T. Fishman, M. Flanigan, R. Gailani, F. Garbo, L. Gardner, T. Gelmann, E. George, D. Godfrey, T. Gomella, L. Guerra, M. Hall, S. Hanson, J. Israeli, R. Jancis, E. Jewett, M. A. S. Kassabian, V. Katz, J. Klotz, L. Koeneman, K. Koh, H. Kratzke, R. Lance, R. Lech, J. Leichman, L. Lemon, R. Liang, J. Libertino, J. Lilly, M. Malik, I. Martin, S. E. McCaffrey, J. McLeod, D. McNeel, D. Miles, B. Murdock, M. Nabhan, C. Nemunaitis, J. Notter, D. Pantuck, A. Perrotte, P. Pessis, D. Petrylak, D. Polikoff, J. Pommerville, P. Ramanathan, S. Rarick, M. Richards, J. Rifkin, R. Rohatgi, N. Rosenbluth, R. Santucci, R. Sayegh, A. Seigne, J. Shapira, I. Shedhadeh, N. Shepherd, D. Sridhar, S. Stephenson, R. Teigland, C. Thaker, N. Vacirca, J. Villa, L., Jr. Vogelzang, N. Wertheim, M. Wolff, J. H. Wurzel, R. Yang, C. Young, J. CA IMPACT Study Investigators TI Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MITOXANTRONE PLUS PREDNISONE; RANDOMIZED CONTROLLED-TRIAL; SURROGATE MARKER; DENDRITIC CELLS; CLINICAL-TRIALS; PHASE-III; SURVIVAL; MEN; DOCETAXEL; LEUKEMIA AB Background: Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer. Methods: In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase. Results: In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P=0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P=0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P=0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache. Conclusions: The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.) N Engl J Med 2010;363:411-22. C1 [Kantoff, Philip W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Higano, Celestia S.] Univ Washington, Sch Med, Seattle, WA USA. [Shore, Neal D.] Carolina Urol Res Ctr, Myrtle Beach, SC USA. [Berger, E. Roy] SUNY Stony Brook, Sch Med, Stony Brook, NY 11794 USA. [Small, Eric J.] Univ Calif San Francisco, Urol Oncol Program, San Francisco, CA 94143 USA. [Penson, David F.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Redfern, Charles H.] Sharp Healthcare, San Diego, CA USA. [Ferrari, Anna C.] NYU, Ctr Clin Canc, Langone Med Ctr, New York, NY USA. [Dreicer, Robert] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Sims, Robert B.; Xu, Yi; Frohlich, Mark W.] Dendreon Corp, Seattle, WA USA. [Schellhammer, Paul F.] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. RP Kantoff, PW (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 44 Binney St,Dana 1230, Boston, MA 02115 USA. EM philip_kantoff@dfci.harvard.edu FU Dendreon FX Supported by Dendreon. NR 32 TC 2044 Z9 2114 U1 31 U2 200 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 29 PY 2010 VL 363 IS 5 BP 411 EP 422 DI 10.1056/NEJMoa1001294 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 632GS UT WOS:000280411300005 PM 20818862 ER PT J AU Bazari, H Attar, EC Dahl, DM Uppot, RN Colvin, RB AF Bazari, Hasan Attar, Eyal C. Dahl, Douglas M. Uppot, Raul N. Colvin, Robert B. TI Case 23-2010: A 49-Year-Old Man with Erythrocytosis, Perinephric Fluid Collections, and Renal Failure. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NEPHROTIC SYNDROME; LYMPHANGIECTASIA; LYMPHANGIOMATOSIS; SECONDARY; CYSTS; CT; INSUFFICIENCY; POLYCYTHEMIA; DIAGNOSIS; DISEASE C1 [Bazari, Hasan] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Attar, Eyal C.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Dahl, Douglas M.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Uppot, Raul N.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Colvin, Robert B.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Bazari, Hasan; Attar, Eyal C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Dahl, Douglas M.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Uppot, Raul N.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Colvin, Robert B.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Bazari, H (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 39 TC 7 Z9 7 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 JUL 29 PY 2010 VL 363 IS 5 BP 463 EP 475 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 632GS UT WOS:000280411300012 PM 20818867 ER PT J AU Chiang, WC Geel, TM Altintas, MM Sever, S Ruiters, MHJ Reiser, J AF Chiang, Wen Chih Geel, Tessa M. Altintas, Mehmet M. Sever, Sanja Ruiters, Marcel H. J. Reiser, Jochen TI Establishment of Protein Delivery Systems Targeting Podocytes SO PLOS ONE LA English DT Article ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; GLOMERULAR PROTEIN; NEPHROTIC SYNDROME; TRPC6; CELLS AB Background: Podocytes are uniquely structured cells that are critical to the kidney filtration barrier. Their anatomic location on the outer side of the glomerular capillaries expose podocytes to large quantities of both plasma and urinary components and thus are reachable for drug delivery. Recent years have made clear that interference with podocyte-specific disease pathways can modulate glomerular function and influence severity and progression of glomerular disease. Methodology/Principal Findings: Here, we describe studies that show efficient transport of proteins into the mammalian cells mouse 3T3 fibroblasts and podocytes, utilizing an approach termed profection. We are using synthetic lipid structures that allow the safe packing of proteins or antibodies resulting in the subsequent delivery of protein into the cell. The uptake of lipid coated protein is facilitated by the intrinsic characteristic of cells such as podocytes to engulf particles that are physiologically retained in the extracellular matrix. Profection of the restriction enzyme MunI in 3T3 mouse fibroblasts caused an increase in DNA degradation. Moreover, purified proteins such as beta-galactosidase and the large GTPase dynamin could be profected into podocytes using two different profection reagents with the success rate of 95-100%. The delivered b-galactosidase enzyme was properly folded and able to cleave its substrate X-gal in podocytes. Diseased podocytes are also potential recipients of protein cargo as we also delivered fluorophore labeled IgG into puromycin treated podocytes. We are currently optimizing our protocol for in vivo profection. Conclusions: Protein transfer is developing as an exciting tool to study and target highly differentiated cells such as podocytes. C1 [Chiang, Wen Chih; Sever, Sanja; Reiser, Jochen] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Chiang, Wen Chih] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Geel, Tessa M.] Univ Groningen, Inst Drug Explorat GUIDE, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Groningen, Netherlands. [Altintas, Mehmet M.; Reiser, Jochen] Univ Miami, Leonard Miller Sch Med, Div Nephrol & Hypertens, Miami, FL USA. [Ruiters, Marcel H. J.] Synvolux Therapeut BV, Groningen, Netherlands. RP Chiang, WC (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. EM jreiser@med.miami.edu OI Altintas, Mehmet/0000-0002-1871-6985 FU National Taiwan University Hospital; National Health Research Institute in Taiwan; Nephrology & Hypertension Division of the University of Miami; US National Institutes of Health (NIH) [DK073495, T32DK007540]; National Health Research Institute, Taiwan FX WC was sponsored by National Taiwan University Hospital and National Health Research Institute in Taiwan as well as by Divisional funds of the Nephrology & Hypertension Division of the University of Miami. JR is supported by the US National Institutes of Health (NIH) grant DK073495. MMA was supported by NIH training grant T32DK007540. MHJR is part of a commercial funder for this research. TMG also received materials from Synvolux Therapeutics to perform parts of the described experiments. The funders contributed the study design, data collection and analysis.; Wen Chih Chiang is a recipient of National Health Research Institute Physician Scientist Award, Taiwan. The authors thank Prof. V. Siksnys, Institute of Biotechnology, Vilnius, Lithuania for providing MunI. NR 19 TC 7 Z9 7 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 29 PY 2010 VL 5 IS 7 AR e11837 DI 10.1371/journal.pone.0011837 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 633QY UT WOS:000280520200010 PM 20686602 ER PT J AU Duan, ZF Ji, DN Weinstein, EJ Liu, XZ Susa, M Choy, E Yang, C Mankin, H Hornicek, FJ AF Duan, Zhenfeng Ji, Diana Weinstein, Edward J. Liu, Xianzhe Susa, Michiro Choy, Edwin Yang, Cao Mankin, Henry Hornicek, Francis J. TI Lentiviral shRNA screen of human kinases identifies PLK1 as a potential therapeutic target for osteosarcoma SO CANCER LETTERS LA English DT Article DE shRNA; PLK1; Osteosarcoma ID POLO-LIKE KINASE; SMALL INTERFERING RNA; OVARIAN-CANCER CELLS; BREAST-CANCER; MAMMALIAN-CELLS; DOWN-REGULATION; EXPRESSION; RESISTANCE; INHIBITION; GROWTH AB We describe an optimized systematic screen of known kinases using osteosarcoma cell lines (KHOS and U-2OS) and a lentiviral-based short hairpin RNA (shRNA) human kinase library. CellTiter 96 (R) AQueous One Solution Cell Proliferation Assay was used to measure cell growth and survival. We identified several kinases, including human polo-like kinase (PLK1), which inhibit cell growth and induce apoptosis in osteosarcoma cells when knocked down. cDNA rescue and synthetic siRNA assays confirm that the observed phenotypic changes result from the loss of PLK1 gene expression. Furthermore, a small molecule inhibitor to PLK1 inhibited osteosarcoma cell growth and induced apoptosis. Western blot analysis confirmed that PLK1 is highly expressed and activated in several osteosarcoma cell lines as well as in resected tumor samples. Immunohistochemistry analysis showed that patients with high PLK1 tumor expression levels correlated with significantly shorter survival than patients with lower levels of tumor PLK1 expression. These results demonstrate the capability and feasibility of a high-throughput screen with a large collection of lentiviral kinases and its effectiveness in identifying potential drug targets. The development of more potent inhibitors that target PLK1 may open doors to a new range of anti-cancer strategies in osteosarcoma. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Duan, Zhenfeng; Liu, Xianzhe; Susa, Michiro; Choy, Edwin; Yang, Cao; Mankin, Henry; Hornicek, Francis J.] Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Ji, Diana; Weinstein, Edward J.] Sigma Aldrich Corp, Res Biotechnol, St Louis, MO 63103 USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. EM zduan@partners.org RI Susa, Michiro/L-2291-2013; OI Choy, Edwin/0000-0001-9896-8084 NR 48 TC 35 Z9 36 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JUL 28 PY 2010 VL 293 IS 2 BP 220 EP 229 DI 10.1016/j.canlet.2010.01.014 PG 10 WC Oncology SC Oncology GA 608QI UT WOS:000278600400011 PM 20144850 ER PT J AU Barua, S Linton, RS Gamboa, J Banerjee, I Yarmush, ML Rege, K AF Barua, Sutapa Linton, Rebecca S. Gamboa, Jennifer Banerjee, Ipsita Yarmush, Martin L. Rege, Kaushal TI Lytic peptide-mediated sensitization of TRAIL-resistant prostate cancer cells to death receptor agonists SO CANCER LETTERS LA English DT Article DE Lytic peptides; TRAIL; Death receptors; Combination treatments; Prostate cancer ID APOPTOSIS-INDUCING LIGAND; IN-VIVO; CASPASE-8 EXPRESSION; ANTIMICROBIAL PEPTIDES; AMPHIPATHIC PEPTIDE; IONIZING-RADIATION; TARGETED ABLATION; CARCINOMA-CELLS; TUMOR-CELLS; MECHANISMS AB Tumor Necrosis Factor-a Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptors (DR) 4 and 5 have attracted significant attention in recent years due to their ability to selectively induce apoptosis in malignant cells while demonstrating little cytotoxicity in normal cells. Although these candidates are promising in cancer therapy, a number of tumor cells are resistant to TRAIL-mediated apoptosis. We describe the use of a cationic amphipathic lytic peptide, KLA (single letter sequence HHHHHKLAK-LAKKLAKLAKC), for the chemosensitization of TRAIL-resistant LNCaP and PC3-PSMA human prostate cancer cells to DR agonistic antibodies. 'Single-agent' treatment with DR agonistic antibodies did not result in loss of viability of these cells confirming the resistance of these cells. However, the combination treatment of KLA followed by DR agonists resulted in greater cell death compared to the individual treatments acting alone, indicating synergistic action between the two components of the combination treatment. The combination of lytic peptide and DR agonists resulted in a significant increase in activated caspase-3 cleavage and cytochrome-C protein levels in cells, indicating a role for the caspase-mediated apoptotic pathway. In addition, KLA treatment also resulted in increased localization of DR5 and lipid rafts in LNCaP cells. Our results demonstrate, for the first time, that lytic peptides can be employed for sensitizing TRAIL-resistant prostate cancer cells to DR-mediated apoptosis resulting in novel combination treatments for the ablation of advanced cancer cells. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Yarmush, Martin L.; Rege, Kaushal] Arizona State Univ, Biol Design Program, Tempe, AZ 85287 USA. [Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. [Banerjee, Ipsita; Yarmush, Martin L.] Harvard Univ, Shriners Hosp Children, Massachusetts Gen Hosp, Ctr Engn Med CEM,Med Sch, Boston, MA 02114 USA. RP Yarmush, ML (reprint author), Arizona State Univ, Biol Design Program, 501 E Tyler Mall ECG 303, Tempe, AZ 85287 USA. EM ireis@sbi.org; Kaushal.rege@asu.edu FU NIH [5R21CA131891-02]; ASU; NSF NIRT [DMI 0303950]; NASA/NIAC FX We thank Gertrude Gunset and Dr. Michel Sadelain at the Memorial Sloan Cancer Center, New York, NY for PC3-PSMA cells. We also thank Dr. Roger Johnson and Professor Deirdre Meldrum, Dean Ira A. Fulton School of Engineering and Director of the Center for Ecogenomics at the Biodesign Institute at ASU for access to the confocal microscope. This work was supported NIH (5R21CA131891-02) and start-up funds from ASU to KR and an NSF NIRT (DMI 0303950) grant and a NASA/NIAC grant to MLY. The authors are thankful to Kevin Nikitczuk and Z Larkin Kelley for their excellent technical assistance and to Dr. Zaki Megeed and Suraj J. Patel for insightful technical discussions. NR 53 TC 5 Z9 5 U1 2 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD JUL 28 PY 2010 VL 293 IS 2 BP 240 EP 253 DI 10.1016/j.canlet.2010.01.012 PG 14 WC Oncology SC Oncology GA 608QI UT WOS:000278600400013 PM 20347216 ER PT J AU Ramos-Casals, M Tzioufas, AG Stone, JH Siso, A Bosch, X AF Ramos-Casals, Manuel Tzioufas, Athanasios G. Stone, John H. Siso, Antoni Bosch, Xavier TI Treatment of Primary Sjogren Syndrome A Systematic Review SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID PLACEBO-CONTROLLED TRIAL; DRY EYE DISEASE; NONPRESERVED METHYLPREDNISOLONE THERAPY; PILOT CLINICAL-TRIAL; DOUBLE-BLIND; KERATOCONJUNCTIVITIS SICCA; OPHTHALMIC EMULSION; RITUXIMAB TREATMENT; HYDROXYCHLOROQUINE TREATMENT; TOPICAL CYCLOSPORINE AB Context A variety of topical and systemic drugs are available to treat primary Sjogren syndrome, although no evidence-based therapeutic guidelines are currently available. Objective To summarize evidence on primary Sjogren syndrome drug therapy from randomized controlled trials. Data Sources We searched MEDLINE and EMBASE for articles on drug therapy for primary Sjogren syndrome published between January 1, 1986, and April 30, 2010. Study Selection Controlled trials of topical and systemic drugs including adult patients with primary Sjogren syndrome were selected as the primary information source. Results The search strategy yielded 37 trials. A placebo-controlled trial found significant improvement in the Schirmer and corneal staining scores, blurred vision, and artificial tear use in patients treated with topical ocular 0.05% cyclosporine. Three placebo-controlled trials found that pilocarpine was associated with improvements in dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs 26%). Two placebo-controlled trials found that cevimeline was associated with improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye (39%-72% vs 24%-30%). Small trials (<20 patients) found no significant improvement in sicca outcomes for oral prednisone or hydroxychloroquine and limited benefits for immunosuppressive agents (azathioprine and cyclosporine). A large trial found limited benefits for oral interferon alfa-2a. Two placebo-controlled trials of infliximab and etanercept did not achieve the primary outcome (a composite visual analog scale measuring joint pain, fatigue, and dryness); neither did 2 small trials (<30 patients) testing rituximab, although significant results were observed in some secondary outcomes and improvement compared with baseline. Conclusions In primary Sjogren syndrome, evidence from controlled trials suggests benefits for pilocarpine and cevimeline for sicca features and topical cyclosporine for moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown clinical efficacy, and larger controlled trials are needed to establish the efficacy of rituximab. JAMA. 2010; 304(4): 452-460 C1 [Ramos-Casals, Manuel] Hosp Clin Barcelona, Dept Autoimmune Dis, Josep Font Lab Autoimmune Dis,IDIBAPS, Sjogren Syndrome Res Grp AGAUR, E-08036 Barcelona, Spain. [Bosch, Xavier] Hosp Clin Barcelona, Dept Internal Med, Inst Clin Med & Dermatol, E-08036 Barcelona, Spain. [Tzioufas, Athanasios G.] Univ Athens, Sch Med, Dept Pathophysiol, GR-11527 Athens, Greece. [Stone, John H.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. [Siso, Antoni] GESCLINIC, Primary Care Ctr Les Corts, IDIBAPS, Primary Care Res Grp, Barcelona, Spain. RP Ramos-Casals, M (reprint author), Hosp Clin Barcelona, Dept Autoimmune Dis, Josep Font Lab Autoimmune Dis,IDIBAPS, Sjogren Syndrome Res Grp AGAUR, C Villarroel 170, E-08036 Barcelona, Spain. EM mramos@clinic.ub.es OI Ramos-Casals, Manuel/0000-0001-5709-6734; Siso Almirall, Antoni/0000-0001-9832-2689 FU La Marato de TV3 [071810]; Fondo de Investigaciones Sanitarias [080103] FX This study was supported by grants from La Marato de TV3 (071810) and Fondo de Investigaciones Sanitarias (080103). NR 74 TC 128 Z9 135 U1 1 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 28 PY 2010 VL 304 IS 4 BP 452 EP 460 DI 10.1001/jama.2010.1014 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 631MA UT WOS:000280350100029 PM 20664046 ER PT J AU Singh, H Graber, M AF Singh, Hardeep Graber, Mark TI Reducing Diagnostic Error Through Medical Home-Based Primary Care Reform SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID SAFETY C1 [Singh, Hardeep] Baylor Coll Med, Houston VA Hlth Serv Res & Dev Serv Ctr Excellenc, Houston, TX 77030 USA. [Singh, Hardeep] Baylor Coll Med, Ctr Inquiry Improve Outpatient Safety Effect Elec, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Singh, Hardeep] Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Graber, Mark] Northport VA Med Ctr, Northport, NY USA. [Graber, Mark] SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA. RP Singh, H (reprint author), VA Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hardeeps@bcm.tmc.edu FU AHRQ HHS [1R1 3HS018321-01, R18 HS 17820]; NCI NIH HHS [K23CA125585, K23 CA125585, K23 CA125585-05] NR 9 TC 24 Z9 24 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 28 PY 2010 VL 304 IS 4 BP 463 EP 464 DI 10.1001/jama.2010.1035 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 631MA UT WOS:000280350100031 PM 20664048 ER PT J AU Kramer, MA Eden, UT Kolaczyk, ED Zepeda, R Eskandar, EN Cash, SS AF Kramer, Mark A. Eden, Uri T. Kolaczyk, Eric D. Zepeda, Rodrigo Eskandar, Emad N. Cash, Sydney S. TI Coalescence and Fragmentation of Cortical Networks during Focal Seizures SO JOURNAL OF NEUROSCIENCE LA English DT Article ID GRAPH-THEORETICAL ANALYSIS; TEMPORAL-LOBE EPILEPSY; SMALL-WORLD NETWORKS; IN-VITRO; MEASURING SYNCHRONIZATION; INTRACRANIAL EEG; COMPLEX NETWORKS; BRAIN; ONSET; NEOCORTEX AB Epileptic seizures reflect a pathological brain state characterized by specific clinical and electrical manifestations. The proposed mechanisms are heterogeneous but united by the supposition that epileptic activity is hypersynchronous across multiple scales, yet principled and quantitative analyses of seizure dynamics across space and throughout the entire ictal period are rare. To more completely explore spatiotemporal interactions during seizures, we examined electrocorticogram data from a population of male and female human patients with epilepsy and from these data constructed dynamic network representations using statistically robust measures. We found that these networks evolved through a distinct topological progression during the seizure. Surprisingly, the overall synchronization changed only weakly, whereas the topology changed dramatically in organization. A large subnetwork dominated the network architecture at seizure onset and preceding termination but, between, fractured into smaller groups. Common network characteristics appeared consistently for a population of subjects, and, for each subject, similar networks appeared from seizure to seizure. These results suggest that, at the macroscopic spatial scale, epilepsy is not so much a manifestation of hypersynchrony but instead of network reorganization. C1 [Kramer, Mark A.; Eden, Uri T.; Kolaczyk, Eric D.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Zepeda, Rodrigo; Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Eskandar, Emad N.; Cash, Sydney S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Kramer, MA (reprint author), Boston Univ, Dept Math & Stat, 111 Cummington St, Boston, MA 02215 USA. EM mak@bu.edu RI Kramer, Mark/A-1291-2014 FU Burroughs Wellcome Fund; National Science Foundation [IIS-0643995, IOB 0645886]; Office of Naval Research [N00014-06-1-0096]; National Eye Institute [R01EY017658]; National Institute on Drug Abuse [R01NS063249]; Howard Hughes Medical Institute; Klingenstein Foundation; American Epilepsy Foundation; Rappaport Foundation; National Institute of Neurological Disorders and Stroke [R01 NS062092] FX M. A. K. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. U. T. E. was supported by National Science Foundation Grant IIS-0643995. E. D. K. was supported by Office of Naval Research Award N00014-06-1-0096. E. E. was supported by National Eye Institute Grant R01EY017658, National Institute on Drug Abuse Grant R01NS063249, National Science Foundation Grant IOB 0645886, the Howard Hughes Medical Institute, and the Klingenstein Foundation. S. S. C. was supported by funds from an American Epilepsy Foundation-Grass/Morison Fellowship, the Rappaport Foundation, and National Institute of Neurological Disorders and Stroke Grant R01 NS062092. We thank Matt Bianchi, Corey Keller, Caroline Raclin, M. O. Shafi, Kevin Staley, and M. Brandon Westover for comments on previous versions of this manuscript, Hemant Bokil for assistance implementing the coherence analysis, and Alex Chan and Andrew Dykstra for assistance in visualization of the data as well as comments on this manuscript. NR 59 TC 94 Z9 94 U1 0 U2 13 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 28 PY 2010 VL 30 IS 30 BP 10076 EP 10085 DI 10.1523/JNEUROSCI.6309-09.2010 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 633LF UT WOS:000280503500015 PM 20668192 ER PT J AU Mulley, AG AF Mulley, Albert G. TI Improving productivity in the NHS SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material C1 Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Mulley, AG (reprint author), Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. EM amulley@partners.org NR 8 TC 11 Z9 11 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD JUL 27 PY 2010 VL 341 AR c3965 DI 10.1136/bmj.c3965 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 634GX UT WOS:000280569900004 PM 20663837 ER PT J AU Gottlieb, DJ Yenokyan, G Newman, AB O'Connor, GT Punjabi, NM Quan, SF Redline, S Resnick, HE Tong, EK Diener-West, M Shahar, E AF Gottlieb, Daniel J. Yenokyan, Gayane Newman, Anne B. O'Connor, George T. Punjabi, Naresh M. Quan, Stuart F. Redline, Susan Resnick, Helaine E. Tong, Elisa K. Diener-West, Marie Shahar, Eyal TI Prospective Study of Obstructive Sleep Apnea and Incident Coronary Heart Disease and Heart Failure The Sleep Heart Health Study SO CIRCULATION LA English DT Article DE epidemiology; sleep apnea; coronary disease; heart failure ID POSITIVE AIRWAY PRESSURE; HIGH BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; ARTERY-DISEASE; MYOCARDIAL-INFARCTION; ATHEROSCLEROSIS RISK; AMERICAN-INDIANS; FOLLOW-UP; MEN; WOMEN AB Background-Clinic-based observational studies in men have reported that obstructive sleep apnea is associated with an increased incidence of coronary heart disease. The objective of this study was to assess the relation of obstructive sleep apnea to incident coronary heart disease and heart failure in a general community sample of adult men and women. Methods and Results-A total of 1927 men and 2495 women >= 40 years of age and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed up for a median of 8.7 years in this prospective longitudinal epidemiological study. After adjustment for multiple risk factors, obstructive sleep apnea was a significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) only in men <= 70 years of age (adjusted hazard ratio 1.10 [95% confidence interval 1.00 to 1.21] per 10-unit increase in apnea-hypopnea index [AHI]) but not in older men or in women of any age. Among men 40 to 70 years old, those with AHI >= 30 were 68% more likely to develop coronary heart disease than those with AHI <5. Obstructive sleep apnea predicted incident heart failure in men but not in women (adjusted hazard ratio 1.13 [95% confidence interval 1.02 to 1.26] per 10-unit increase in AHI). Men with AHI >= 30 were 58% more likely to develop heart failure than those with AHI <5. Conclusions-Obstructive sleep apnea is associated with an increased risk of incident heart failure in communitydwelling middle- aged and older men; its association with incident coronary heart disease in this sample is equivocal. (Circulation. 2010; 122:352-360.) C1 [Gottlieb, Daniel J.] VA Boston Healthcare Syst, Boston, MA USA. [Gottlieb, Daniel J.; O'Connor, George T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Yenokyan, Gayane; Punjabi, Naresh M.; Diener-West, Marie] Johns Hopkins Univ, Baltimore, MD USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Quan, Stuart F.] Harvard Univ, Sch Med, Boston, MA USA. [Redline, Susan] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Resnick, Helaine E.] Georgetown Univ, Amer Assoc Homes, Washington, DC USA. [Resnick, Helaine E.] Georgetown Univ, Serv Aging, Washington, DC USA. [Tong, Elisa K.] Univ Calif Davis, Davis, CA 95616 USA. [Quan, Stuart F.; Shahar, Eyal] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. RP Gottlieb, DJ (reprint author), Boston Univ, Sch Med, 715 Albany St R304, Boston, MA 02118 USA. EM gottlieb@bu.edu RI Max, Mad/E-5238-2010; Newman, Anne/C-6408-2013; OI Max, Mad/0000-0001-6966-6829; Newman, Anne/0000-0002-0106-1150; O'Connor, George/0000-0002-6476-3926; Yenokyan, Gayane/0000-0003-1482-5612 FU National Heart, Lung, and Blood Institute [U01HL53940]; University of Washington [U01HL53941]; Boston University [U01HL53941]; University of Arizona [U01HL53938]; University of California, Davis [U01HL53916]; University of Minnesota [U01HL53934]; New York University [U01HL53931]; Johns Hopkins University [U01HL53937, U01HL64360]; Case Western Reserve University [U01HL63463]; Missouri Breaks Research [U01HL63429]; ResMed, Inc FX This work was supported by National Heart, Lung, and Blood Institute cooperative agreements U01HL53940 (University of Washington), U01HL53941 (Boston University), U01HL53938 (University of Arizona), U01HL53916 (University of California, Davis), U01HL53934 (University of Minnesota), U01HL53931 (New York University), U01HL53937 and U01HL64360 (Johns Hopkins University), U01HL63463 (Case Western Reserve University), and U01HL63429 (Missouri Breaks Research).; Dr Punjabi has received research support from ResMed, Inc, for multicenter clinical trials of CPAP in individuals with type 2 diabetes mellitus with sleep apnea and has received travel support and honoraria for continuing medical education lectures or symposia sponsored by Respironics and ResMed Inc. Dr Redline receives CPAP equipment from Philips-Respironics for use in National Institutes of Health- and foundation-supported clinical trials and has been nominated to serve as the first incumbent of an endowed professorship donated to the Harvard Medical School by Dr Peter Farrell, the founder and Board Chairman of ResMed Inc, through a charitable remainder trust instrument. The remaining authors report no conflicts. NR 46 TC 427 Z9 439 U1 3 U2 25 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 27 PY 2010 VL 122 IS 4 BP 352 EP 360 DI 10.1161/CIRCULATIONAHA.109.901801 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 631CN UT WOS:000280324300006 PM 20625114 ER PT J AU Wiviott, SD Antman, EM Braunwald, E AF Wiviott, Stephen D. Antman, Elliott M. Braunwald, Eugene TI Prasugrel SO CIRCULATION LA English DT Article DE anticoagulants; platelet aggregation inhibitors; platelets; thrombosis ID PERCUTANEOUS CORONARY INTERVENTION; OPTIMIZING PLATELET INHIBITION; ST-SEGMENT ELEVATION; TRITON-TIMI 38; ASSOCIATION TASK-FORCE; ACUTE MYOCARDIAL-INFARCTION; ORAL ANTIPLATELET THERAPY; ASSESS IMPROVEMENT; STENT THROMBOSIS; PRACTICE GUIDELINES C1 [Wiviott, Stephen D.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Wiviott, SD (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Dept Med, 350 Longwood Ave, Boston, MA 02115 USA. EM swiviott@partners.org FU Daiichi Sankyo; Eli Lilly; Sanofi-Aventis; Merck; Schering Plough; Bristol-Myers Squibb/Sanofi-Aventis FX The JUMBO-TIMI 26, TRITON-TIMI 38, and PRINCIPLE-TIMI 44 trials were supported by Daiichi Sankyo Co, Ltd, and Eli Lilly and Co. Drs Wiviott, Antman, and Braunwald report receiving research grants from Daiichi Sankyo, Eli Lilly, Sanofi-Aventis, Merck, and Schering Plough. In addition, Dr Wiviott reports receiving consulting fees or paid advisory fees from Bristol-Myers Squibb/Sanofi-Aventis, and AstraZeneca and lecture fees from Eli Lilly, Daiichi Sankyo, AstraZeneca, Novartis; Dr Braunwald, consulting fees or paid advisory board fees from Daiichi Sankyo and Sanofi-Aventis and lecture fees from Eli Lilly and Sanofi-Aventis; and Dr Antman, consulting fees or paid advisory board fees from Sanofi-Aventis and lecture fees from Eli Lilly and Sanofi-Aventis. For all lectures, the speakers were in complete control of the content. NR 55 TC 57 Z9 58 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 27 PY 2010 VL 122 IS 4 BP 394 EP U133 DI 10.1161/CIRCULATIONAHA.109.921502 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 631CN UT WOS:000280324300011 PM 20660815 ER PT J AU Peacock, WF Braunwald, E Abraham, W Albert, N Burnett, J Christenson, R Collins, S Diercks, D Fonarow, G Hollander, J Kellerman, A Gheorghiade, M Kirk, D Levy, P Maisel, A Massie, BM O'Connor, C Pang, P Shah, M Sopko, G Stevenson, L Storrow, A Teerlink, J AF Peacock, W. Frank Braunwald, Eugene Abraham, William Albert, Nancy Burnett, John Christenson, Rob Collins, Sean Diercks, Deborah Fonarow, Greg Hollander, Judd Kellerman, Art Gheorghiade, Mihai Kirk, Doug Levy, Phil Maisel, Alan Massie, Barry M. O'Connor, Christopher Pang, Peter Shah, Monica Sopko, George Stevenson, Lynne Storrow, Alan Teerlink, John TI National Heart, Lung, and Blood Institute Working Group on Emergency Department Management of Acute Heart Failure Research Challenges and Opportunities SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE emergency medicine; heart failure; research ID IN-HOSPITAL MORTALITY; NATRIURETIC PEPTIDE; PRACTICE GUIDELINES; CARDIAC TROPONIN; RATE-VARIABILITY; ACUTE DYSPNEA; DIAGNOSIS; TRIAL; READMISSION; ASSOCIATION AB This paper details the substance and recommendations arising from a meeting convened by the National Heart, Lung, and Blood Institute in August 2009, to assess the challenges and opportunities of emergency department management of acute heart failure syndrome (AHFS). The assembled faculty represented a large cross section of medical professionals spanning the medical management continuum of patients presenting with acute heart failure and included heart failure cardiologists, emergency physicians, laboratory medicine specialists, nurses, and bench scientists. Their recommendations include proposals regarding the design and conduct of emergency department-based clinical trials, suggestions regarding the development of improved methods for early detection and monitoring of AHFS, and potential needs for expanding translational and applied AHFS focused research and biotechnology. We anticipate that this review will serve as a starting point for future investigations across the spectrum of funding sources. (J Am Coll Cardiol 2010;56:343-51) (c) 2010 by the American College of Cardiology Foundation C1 [Peacock, W. Frank; Albert, Nancy] Cleveland Clin, Emergency Med Inst, Cleveland, OH 44195 USA. [Braunwald, Eugene] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Burnett, John] Mayo Fdn, Rochester, MN USA. [Abraham, William] Ohio State Univ, Columbus, OH 43210 USA. [Christenson, Rob] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Collins, Sean] Univ Cincinnati, Cincinnati, OH USA. [Diercks, Deborah; Kirk, Doug] Univ Calif, Davis Med Ctr, Sacramento, CA USA. [Fonarow, Greg] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Hollander, Judd] Univ Penn, Philadelphia, PA 19104 USA. [Kellerman, Art] Emory Sch Med, Atlanta, GA USA. [Gheorghiade, Mihai; Pang, Peter] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Levy, Phil] Wayne State Univ, Sch Med, Detroit, MI USA. [Maisel, Alan] Univ Calif San Diego, San Diego, CA 92103 USA. [Massie, Barry M.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Massie, Barry M.; Teerlink, John] San Francisco VA Med Ctr, San Francisco, CA USA. [Shah, Monica; Sopko, George] NHLBI, Bethesda, MD 20892 USA. [O'Connor, Christopher] Duke Univ, Durham, NC USA. [Stevenson, Lynne] Harvard Univ, Sch Med, Boston, MA USA. [Storrow, Alan] Vanderbilt Univ, Nashville, TN USA. RP Peacock, WF (reprint author), Cleveland Clin, Emergency Med Inst, Desk E-19,9500 Euclid Ave, Cleveland, OH 44195 USA. EM Peacocw@ccf.org RI Max, Mad/E-5238-2010; Teerlink, John/D-2986-2012; OI Max, Mad/0000-0001-6966-6829; Hollander, Judd/0000-0002-1318-2785 FU National Heart, Lung, and Blood Institute FX Vanderbilt University, Nash ville, Tennessee. The meeting that this manuscript was derived from was completely and solely supported by the National Heart, Lung, and Blood Institute. For full author disclosures, please see the end of this paper. Jay Cohn, MD, served as Guest Editor for this paper. NR 56 TC 35 Z9 35 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 27 PY 2010 VL 56 IS 5 BP 343 EP 351 DI 10.1016/j.jacc.2010.03.051 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 628IH UT WOS:000280109400001 PM 20650354 ER PT J AU Heidenreich, PA Sahay, A Kapoor, JR Pham, MX Massie, B AF Heidenreich, Paul A. Sahay, Anju Kapoor, John R. Pham, Michael X. Massie, Barry TI Divergent Trends in Survival and Readmission Following a Hospitalization for Heart Failure in the Veterans Affairs Health Care System 2002 to 2006 SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE heart failure; quality of care; outcomes assessment ID LONG-TERM TRENDS; EJECTION FRACTION; BETA-BLOCKERS; POPULATION; MORTALITY; OUTCOMES; ADMISSIONS; PROGNOSIS; INDEX AB Objectives This study sought to determine recent trends over time in heart failure hospitalization, patient characteristics, treatment, rehospitalization, and mortality within the Veterans Affairs health care system. Background Use of recommended therapies for heart failure has increased in the U.S. However, it is unclear to what extent hospitalization rates and the associated mortality have improved. Methods We compared rates of hospitalization for heart failure, 30-day rehospitalization for heart failure, and 30-day mortality following discharge from 2002 to 2006 in the Veterans Affairs Health Care System. Odds ratios for outcome were adjusted for patient diagnoses within the past year, laboratory data, and for clustering of patients within hospitals. Results We identified 50,125 patients with a first hospitalization for heart failure from 2002 to 2006. Mean age did not change (70 years), but increases were noted for most comorbidities (mean Charlson score increased from 1.72 to 1.89, p < 0.0001). Heart failure admission rates remained constant at about 5 per 1,000 veterans. Mortality at 30 days decreased (7.1% to 5.0%, p < 0.0001), whereas rehospitalization for heart failure at 30 days increased (5.6% to 6.1%, p = 0.11). After adjustment for patient characteristics, the odds ratio for rehospitalization in 2006 (vs. 2002) was 0.54 (95% confidence interval [CI]: 0.47 to 0.61) for mortality, but 1.21 (95% CI: 1.04 to 1.41) for heart failure rehospitalization at 30 days. Conclusions Recent mortality and rehospitalization rates in the Veterans Affairs Health Care System have trended in opposite directions. These results have implications for using rehospitalization as a measure of quality of care. (J Am Coll Cardiol 2010;56:362-8) (c) 2010 by the American College of Cardiology Foundation C1 [Heidenreich, Paul A.; Sahay, Anju; Pham, Michael X.] Palo Alto VA Hlth Care Syst, Palo Alto, CA 94304 USA. [Heidenreich, Paul A.; Kapoor, John R.; Pham, Michael X.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Massie, Barry] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Massie, Barry] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP Heidenreich, PA (reprint author), Palo Alto VA Hlth Care Syst, 111C Cardiol,3801 Miranda Ave, Palo Alto, CA 94304 USA. EM heiden@stanford.edu RI Max, Mad/E-5238-2010; OI Max, Mad/0000-0001-6966-6829; Heidenreich, Paul/0000-0001-7730-8490 FU Veterans Affairs Health Services Research Development Office [CHF QUERI-04-326] FX Department of Medicine, University of California at San Francisco, San Francisco, California. Supported by grants from the Veterans Affairs Health Services Research Development Office (CHF QUERI-04-326). Views expressed are those of the authors and not necessarily those of the Department of Veterans Affairs or other affiliated organizations. NR 24 TC 74 Z9 74 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 27 PY 2010 VL 56 IS 5 BP 362 EP 368 DI 10.1016/j.jacc.2010.02.053 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 628IH UT WOS:000280109400003 PM 20650356 ER PT J AU Utskarpen, A Massol, R van Deurs, B Lauvrak, SU Kirchhausen, T Sandvig, K AF Utskarpen, Audrun Massol, Ramiro van Deurs, Bo Lauvrak, Silje Ugland Kirchhausen, Tomas Sandvig, Kirsten TI Shiga Toxin Increases Formation of Clathrin-Coated Pits through Syk Kinase SO PLOS ONE LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; RETROGRADE TRANSPORT; PLASMA-MEMBRANE; ACTIVATION; RECEPTOR; BINDING; INTERNALIZATION; PROTEIN; CELLS; TRAFFICKING AB Clathrin-dependent endocytosis is a main entry mechanism for the glycolipid-binding Shiga toxin (Stx), although clathrin-independent pathways are also involved. Binding of Stx to its receptor Gb3 not only is essential for Stx retrograde transport to the endoplasmic reticulum and toxicity but also activates signaling through the tyrosine kinase Syk. We previously described that Syk activity is important for Stx entry, but it remained unclear how this kinase modulates endocytosis of Stx. Here we characterized the effects of Stx and Syk on clathrin-coated pit formation. We found that acute treatment with Stx results in an increase in the number of clathrin-coated profiles as determined by electron microscopy and on the number of structures containing the endocytic AP-2 adaptor at the plasma membrane determined by live-cell spinning disk confocal imaging. These responses to Stx require functional Syk activity. We propose that a signaling pathway mediated by Syk and modulated by Stx leads to an increased number of endocytic clathrin-coated structures, thus providing a possible mechanism by which Stx enhances its own endocytosis. C1 [Utskarpen, Audrun; Lauvrak, Silje Ugland; Sandvig, Kirsten] Univ Oslo, Ctr Canc Biomed, Fac Div Norwegian Radium Hosp, Oslo, Norway. [Utskarpen, Audrun; Lauvrak, Silje Ugland; Sandvig, Kirsten] Oslo Univ Hosp, Norwegian Radium Hosp, Inst Canc Res, Dept Biochem, Oslo, Norway. [Utskarpen, Audrun; Sandvig, Kirsten] Univ Oslo, Dept Mol Biosci, Oslo, Norway. [Massol, Ramiro] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Massol, Ramiro] Harvard Univ, Sch Med, Childrens Hospital Boston, Boston, MA 02115 USA. [van Deurs, Bo] Univ Copenhagen, Panum Inst, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark. [Kirchhausen, Tomas] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. [Kirchhausen, Tomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA. RP Utskarpen, A (reprint author), Univ Oslo, Ctr Canc Biomed, Fac Div Norwegian Radium Hosp, Oslo, Norway. EM kirchhausen@crystal.harvard.edu; ksandvig@radium.uio.no FU Norwegian Cancer Society; Rikshospitalet University Hospital; Norwegian Research Council; University of Oslo; EMBO (European Molecular Biology Organization); National Institutes of Health [GM075252]; Harvard Digestive Diseases Center National Institutes of Health [P30 DK034854]; Danish Medical Research Council; Danish Cancer Society; NERCE [U54 A1057159] FX Financial support was received from the Norwegian Cancer Society, Rikshospitalet University Hospital, the Norwegian Research Council, and the University of Oslo (AU, KS, SL). AU received an EMBO (European Molecular Biology Organization) short-term fellowship. The work was supported in part by a National Institutes of Health grant GM075252 (TK) and a NERCE grant U54 A1057159 (TK), a grant (P30 DK034854) from the Harvard Digestive Diseases Center National Institutes of Health (RM), and the Danish Medical Research Council and the Danish Cancer Society (BvD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 28 TC 17 Z9 17 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 JUL 27 PY 2010 VL 5 IS 7 AR e10944 DI 10.1371/journal.pone.0010944 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 631TQ UT WOS:000280371800001 PM 20668539 ER PT J AU Hoffman, RM Zeliadt, SB AF Hoffman, Richard M. Zeliadt, Steven B. TI The Cautionary Tale of PSA Testing SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID PROSTATE-SPECIFIC ANTIGEN; TREATMENT DECISIONS; CANCER; MORTALITY; OUTCOMES; TRIAL; MEN C1 [Hoffman, Richard M.] New Mexico VA Hlth Care Syst, Med Serv, Albuquerque, NM USA. [Hoffman, Richard M.] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Zeliadt, Steven B.] Univ Washington, Hlth Serv Res & Dev Ctr Excellence, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Zeliadt, Steven B.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. RP Hoffman, RM (reprint author), 1501 San Pedro Dr SE,Mail Stop 111, Albuquerque, NM 87108 USA. EM rhoffman@unm.edu NR 18 TC 5 Z9 5 U1 0 U2 0 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 JUL 26 PY 2010 VL 170 IS 14 BP 1262 EP 1263 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 631LD UT WOS:000280347400012 PM 20660847 ER PT J AU Tutt, A Robson, M Garber, JE Domchek, SM Audeh, MW Weitzel, JN Friedlander, M Arun, B Loman, N Schmutzler, RK Wardley, A Mitchell, G Earl, H Wickens, M Carmichael, J AF Tutt, Andrew Robson, Mark Garber, Judy E. Domchek, Susan M. Audeh, M. William Weitzel, Jeffrey N. Friedlander, Michael Arun, Banu Loman, Niklas Schmutzler, Rita K. Wardley, Andrew Mitchell, Gillian Earl, Helena Wickens, Mark Carmichael, James TI Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial SO LANCET LA English DT Article ID HOMOLOGY-DIRECTED REPAIR; WILD-TYPE ALLELE; DNA-REPAIR; OVARIAN-CANCER; MUTANT-CELLS; PHASE-II; TUMORS; CARRIERS; RESISTANCE; THERAPY AB Background Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. Methods Women (aged years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. Findings Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). Interpretation The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. C1 [Tutt, Andrew] Kings Coll London, Sch Med, Breakthrough Breast Canc Res Unit, London SE1 9RT, England. [Robson, Mark] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Domchek, Susan M.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Audeh, M. William] Cedars Sinai Med Ctr, Samuel Oschin Canc Inst, Los Angeles, CA 90048 USA. [Weitzel, Jeffrey N.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Friedlander, Michael] Prince Wales Canc Ctr, Sydney, NSW, Australia. [Arun, Banu] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Loman, Niklas] Lund Univ, Skane Univ Hosp, Dept Oncol, Lund, Sweden. [Schmutzler, Rita K.] Univ Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, Ctr Integrated Oncol, Cologne, Germany. [Wardley, Andrew] Christie Hosp NHS Fdn Trust, Manchester, Lancs, England. [Mitchell, Gillian] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Earl, Helena] Univ Cambridge, Dept Oncol, Cambridge, England. [Earl, Helena] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England. [Wickens, Mark; Carmichael, James] AstraZeneca, Macclesfield, Cheshire, England. RP Tutt, A (reprint author), Kings Coll London, Sch Med, Breakthrough Breast Canc Res Unit, 3rd Floor,Bermondsey Wing,Guys Hosp Campus, London SE1 9RT, England. EM andrew.tutt@icr.ac.uk RI friedlander, michael/G-3490-2013; Wardley, ANdrew/N-8135-2015; OI friedlander, michael/0000-0002-6488-0604; Wardley, ANdrew/0000-0002-9639-0888; Robson, Mark/0000-0002-3109-1692; Earl, Helena/0000-0003-1549-8094 FU AstraZeneca FX AT has received a payment from the Institute of Cancer Research Rewards to inventors programme for work on use of PARP inhibitors to target BRCA1-associated and BRCA2-associated cancers; and support for travel to investigators' meetings and an honorarium, funded by AstraZeneca, for an academic lecture. MR has received research grants, support for travel to investigators' meetings and funding for patient payment to undertake study from AstraZeneca, and has received honoraria as a clinical advisory board member for Pfizer. JEG has received funding support for the trial and is a co-investigator for clinical trials for a PARP inhibitor. SMD has received funding support for the trial and for travel to investigators' meetings. MWA has received honoraria for consultancy from AstraZeneca and Myriad Genetics. MF has received honoraria as a clinical advisory board member and support for travel to meetings from AstraZeneca. BA has received a grant from AstraZeneca for a research study. NL has received funding support for the conduct of the trial. RKS has received funding support for the conduct of the trial and for travel to investigators' meetings. AW has received speaking honoraria (including speakers' bureau) and research funding from AstraZeneca. GM has received support for travel to investigators' meetings and funding for patient payment to undertake study from AstraZeneca. MW and JC are employees of AstraZeneca, and JC holds AstraZeneca stock options. JNW and HE declare that they have no conflicts of interest. NR 41 TC 772 Z9 795 U1 22 U2 124 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 24 PY 2010 VL 376 IS 9737 BP 235 EP 244 DI 10.1016/S0140-6736(10)60892-6 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 632VM UT WOS:000280457200032 PM 20609467 ER PT J AU Audeh, MW Carmichael, J Penson, RT Friedlander, M Powell, B Bell-McGuinn, KM Scott, C Weitzel, JN Oaknin, A Loman, N Lu, K Schmutzler, RK Matulonis, U Wickens, M Tutt, A AF Audeh, M. William Carmichael, James Penson, Richard T. Friedlander, Michael Powell, Bethan Bell-McGuinn, Katherine M. Scott, Clare Weitzel, Jeffrey N. Oaknin, Ana Loman, Niklas Lu, Karen Schmutzler, Rita K. Matulonis, Ursula Wickens, Mark Tutt, Andrew TI Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial SO LANCET LA English DT Article ID HOMOLOGY-DIRECTED REPAIR; MUTANT-CELLS; DNA-REPAIR; TUMORS; THERAPY; SENSITIVITY; DELETION; AZD2281; BREAKS; DEFECT AB Background Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations. Methods In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged >= 18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494442. Findings Patients had been given a median of three (range 1-16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20-51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4-31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2,14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%1; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4). Interpretation Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer. C1 [Audeh, M. William] Cedars Sinai Med Ctr, Samuel Oschin Canc Inst, Los Angeles, CA 90048 USA. [Carmichael, James; Wickens, Mark] AstraZeneca, Macclesfield, Cheshire, England. [Penson, Richard T.; Matulonis, Ursula] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Penson, Richard T.; Matulonis, Ursula] Dana Farber Canc Inst, Boston, MA 02115 USA. [Friedlander, Michael] Prince Wales Canc Ctr, Sydney, NSW, Australia. [Powell, Bethan] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Bell-McGuinn, Katherine M.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Scott, Clare] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia. [Scott, Clare] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Weitzel, Jeffrey N.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Oaknin, Ana] Hosp Gen Valle Hebron, Barcelona, Spain. [Loman, Niklas] Lund Univ, Skane Univ Hosp, Dept Oncol, Lund, Sweden. [Lu, Karen] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Schmutzler, Rita K.] Univ Cologne, Ctr Familial Breast, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, Ovarian Canc, Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, Ctr Integrated Oncol, Cologne, Germany. [Tutt, Andrew] Kings Coll London, Breakthrough Breast Canc Res Unit, Sch Med, London WC2R 2LS, England. RP Audeh, MW (reprint author), Cedars Sinai Med Ctr, Samuel Oschin Canc Inst, Los Angeles, CA 90048 USA. EM william.audeh@cshs.org RI friedlander, michael/G-3490-2013 OI friedlander, michael/0000-0002-6488-0604 FU AstraZeneca FX MWA has received honoraria for consultancy from AstraZeneca and Myriad Genetic Laboratories, and funding support for travel to investigators' meetings from AstraZeneca and to advisory board meetings from Myriad Genetic Laboratories. RTP has received honoraria and funding support for travel to investigators' meetings from AstraZeneca, and RTP's institution has received grants from AstraZeneca. ME has received honoraria as a clinical advisory board member and funding support for travel to investigators' meetings from AstraZeneca. BP's institution has received funding support for patient care, and BP has received funding support for travel to an investigators' meeting from AstraZeneca. KMB's institution has received study grants, and KMB has received funding support for travel to investigators' meetings from AstraZeneca. CS has received funding support for travel to investigators' meetings from AstraZeneca. N1:s institution has received funding support for the conduct of the study and travel to investigators' meetings from AstraZeneca, and NL has received honoraria for lectures to patient groups that were organised and funded by AstraZeneca. RKS's institution has received fees to cover study expenses, and RKS has received funding support for travel to investigators' meetings from AstraZeneca. UM's institution has received fees to cover study expenses, and UM has received funding support for travel to investigators' meetings from AstraZeneca. MW and JC are employees of AstraZeneca, and JC has AstraZeneca stock options. AT has received a payment from the UK Institute of Cancer Research's rewards to inventors programme for work on use of PARP inhibitors to target cancers associated with BRCA1 and BRCA2 mutations, and has received funding support for travel to investigators' meetings and an honorarium for an academic lecture from AstraZeneca. AO, KL, and JNW declare that they have no conflicts of interest. NR 28 TC 592 Z9 612 U1 6 U2 54 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUL 24 PY 2010 VL 376 IS 9737 BP 245 EP 251 DI 10.1016/S0140-6736(10)60893-8 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 632VM UT WOS:000280457200033 PM 20609468 ER PT J AU Pekary, AE Sattin, A Blood, J AF Pekary, A. E. Sattin, Albert Blood, James TI Rapid modulation of TRH and TRH-like peptide release in rat brain and peripheral tissues by leptin SO BRAIN RESEARCH LA English DT Article DE Leptin; TRH-like peptide; Rat; Limbic system ID HORMONE TRH; MOOD DISORDERS; RECEPTOR; DEPRESSION; SEIZURES; TESTIS; ANTIDEPRESSANT; CEREBELLUM; EXPRESSION; EPIDIDYMIS AB Leptin is not only a feedback modulator of feeding and energy expenditure but also regulates reproductive functions, CNS development and mood. Obesity and major depression are growing public health concerns which may derive, in part, from disregulation of leptin feedback at the level of the hypothalamic feeding centers and mood regulators within the limbic system. Identifying downstream mediators of leptin action may provide therapeutic opportunities. We and others have previously reported that thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH(2)) and TRH-like peptides (pGlu-X-Pro-NH(2), where "X" can be any amino acid residue) have neuroprotective, antidepressant, anti-epileptic, analeptic, anti-ataxic, and anorectic properties. For this reason, young, adult male Sprague-Dawley rats were injected ip with 1 mg/kg rat leptin and peptide and protein levels were measured in brain and peripheral tissues at 0, 0.5, 1 and 2 h later. Eleven brain regions: pyriform cortex (PYR), entorhinal cortex (ENT), cerebellum (CBL), nucleus accumbens (NA), frontal cortex (FCX), amygdala (AY), posterior cingulate (PCNG), striatum (STR), hippocampus (HC), medulla oblongata (MED) and anterior cingulate (ACNG) and five peripheral tissues (adrenals, testes, epididymis, pancreas and prostate) were analyzed. TRH and six TRH-like peptide levels in STR fell by 0.5 h consistent with leptin-induced release of these peptides: STR (7 down arrow). Significant changes in TRH and TRH-like peptide levels for other brain regions were: CBL (5 down arrow), ENT (5 down arrow), HC (4 down arrow), AY (4 down arrow), FCX (3 down arrow), and ACNG (1 down arrow). The rapid modulation of TRH and TRH-like peptide release combined with their similarity in behavioral, neuroendocrine, immunomodulatory, metabolic and steroidogenic effects to that of leptin is consistent with these peptides participating in downstream signaling. Published by Elsevier B.V. C1 [Pekary, A. E.; Sattin, Albert; Blood, James] VA Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. [Sattin, Albert] VA Greater Los Angeles Healthcare Syst, Psychiat Serv, Los Angeles, CA 90073 USA. [Pekary, A. E.] VA Greater Los Angeles Healthcare Syst, Ctr Ulcer Res & Educ, Los Angeles, CA 90073 USA. [Sattin, Albert] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90073 USA. [Sattin, Albert] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90073 USA. [Pekary, A. E.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90073 USA. RP Pekary, AE (reprint author), VA Greater Los Angeles Healthcare Syst, Res Serv, Bldg 114,Rm 229,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Eugene.Pekary@va.gov FU Department of Veterans Affairs; Pekary Family Trust FX This work was supported by the Department of Veterans Affairs Medical Research funds (AEP and AS) and the Pekary Family Trust. NR 51 TC 10 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 23 PY 2010 VL 1345 BP 9 EP 18 DI 10.1016/j.brainres.2010.05.039 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 635KZ UT WOS:000280655400002 PM 20546704 ER PT J AU Irie, HY Shrestha, Y Selfors, LM Frye, F Iida, N Wang, ZG Zou, LH Yao, J Lu, YL Epstein, CB Natesan, S Richardson, AL Polyak, K Mills, GB Hahn, WC Brugge, JS AF Irie, Hanna Y. Shrestha, Yashaswi Selfors, Laura M. Frye, Fabianne Iida, Naoko Wang, Zhigang Zou, Lihua Yao, Jun Lu, Yiling Epstein, Charles B. Natesan, Sridaran Richardson, Andrea L. Polyak, Kornelia Mills, Gordon B. Hahn, William C. Brugge, Joan S. TI PTK6 Regulates IGF-1-Induced Anchorage-Independent Survival SO PLOS ONE LA English DT Article ID MAMMARY EPITHELIAL-CELLS; BRK TYROSINE KINASE; BREAST-CANCER CELLS; LONG-TERM SURVIVAL; FACTOR-I RECEPTOR; GROWTH-FACTOR; IGF-I; OVARIAN-CANCER; EXPRESSION; ANOIKIS AB Background: Proteins that are required for anchorage-independent survival of tumor cells represent attractive targets for therapeutic intervention since this property is believed to be critical for survival of tumor cells displaced from their natural niches. Anchorage-independent survival is induced by growth factor receptor hyperactivation in many cell types. We aimed to identify molecules that critically regulate IGF-1-induced anchorage-independent survival. Methods and Results: We conducted a high-throughput siRNA screen and identified PTK6 as a critical component of IGF-1 receptor (IGF-1R)-induced anchorage-independent survival of mammary epithelial cells. PTK6 downregulation induces apoptosis of breast and ovarian cancer cells deprived of matrix attachment, whereas its overexpression enhances survival. Reverse-phase protein arrays and subsequent analyses revealed that PTK6 forms a complex with IGF-1R and the adaptor protein IRS-1, and modulates anchorage-independent survival by regulating IGF-1R expression and phosphorylation. PTK6 is highly expressed not only in the previously reported Her2(+) breast cancer subtype, but also in high grade ER(+), Luminal B tumors and high expression is associated with adverse outcomes. Conclusions: These findings highlight PTK6 as a critical regulator of anchorage-independent survival of breast and ovarian tumor cells via modulation of IGF-1 receptor signaling, thus supporting PTK6 as a potential therapeutic target for multiple tumor types. The combined genomic and proteomic approaches in this report provide an effective strategy for identifying oncogenes and their mechanism of action. C1 [Irie, Hanna Y.; Selfors, Laura M.; Frye, Fabianne; Iida, Naoko; Hahn, William C.; Brugge, Joan S.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Irie, Hanna Y.; Shrestha, Yashaswi; Yao, Jun; Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Wang, Zhigang; Zou, Lihua; Richardson, Andrea L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Lu, Yiling; Mills, Gordon B.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. [Epstein, Charles B.; Natesan, Sridaran] Sanofi Aventis, Cambridge, MA USA. [Epstein, Charles B.; Hahn, William C.] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA. RP Irie, HY (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. EM Joan_Brugge@hms.harvard.edu FU National Institutes of Health (NIH) [CA105134, 5K08 CA107231]; Sanofi-Aventis FX The work was supported by National Institutes of Health (NIH) grant CA105134, a grant from Sanofi-Aventis, and a gift from Lee Jeans through the Entertainment Industry Foundation to JSB. HYI was supported by 5K08 CA107231 (NIH), the Terri Brodeur Breast Cancer Research Foundation and a Development Pilot Award from the SPORE in Breast Cancer (NIH P50 CA089393). YS was supported by a fellowship from the Department of Defense (DoD) (W81XWH-08-1-0767), and WH was supported by W81XWH-07-1-0408 (DoD) and R33 CA128625 (NIH/National Cancer Institute [NCI]). GBM and YL were supported by the Kleberg Center for Molecular Markers, P30 CA1667 and P01CA099031. ZW was supported by a grant from the Breast Cancer Research Foundation. JY, KP and LZ were supported by the Specialized Programs of Research Excellence (SPORE) in Breast Cancer (NIH P50 CA089393). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 32 Z9 32 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 JUL 23 PY 2010 VL 5 IS 7 AR e11729 DI 10.1371/journal.pone.0011729 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 630AQ UT WOS:000280243800009 PM 20668531 ER PT J AU Koh, YS Koo, JE Biswas, A Kobayashi, KS AF Koh, Young-Sang Koo, Jung-Eun Biswas, Amlan Kobayashi, Koichi S. TI MyD88-Dependent Signaling Contributes to Host Defense against Ehrlichial Infection SO PLOS ONE LA English DT Article ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; LEGIONELLA-PNEUMOPHILA INFECTION; OUTER-MEMBRANE PROTEIN; TOLL-LIKE RECEPTOR-3; NF-KAPPA-B; MONOCYTOTROPIC EHRLICHIOSIS; ANIMAL-MODEL; BACTERIAL PEPTIDOGLYCAN; PATHOGEN RECOGNITION; ADAPTIVE IMMUNITY AB The ehrlichiae are small Gram-negative obligate intracellular bacteria in the family Anaplasmataceae. Ehrlichial infection in an accidental host may result in fatal diseases such as human monocytotropic ehrlichiosis, an emerging, tick-borne disease. Although the role of adaptive immune responses in the protection against ehrlichiosis has been well studied, the mechanism by which the innate immune system is activated is not fully understood. Using Ehrlichia muris as a model organism, we show here that MyD88-dependent signaling pathways play a pivotal role in the host defense against ehrlichial infection. Upon E. muris infection, MyD88-deficient mice had significantly impaired clearance of E. muris, as well as decreased inflammation, characterized by reduced splenomegaly and recruitment of macrophages and neutrophils. Furthermore, MyD88-deficient mice produced markedly lower levels of IL-12, which correlated well with an impaired Th1 immune response. In vitro, dendritic cells, but not macrophages, efficiently produced IL-12 upon E. muris infection through a MyD88-dependent mechanism. Therefore, MyD88-dependent signaling is required for controlling ehrlichial infection by playing an essential role in the immediate activation of the innate immune system and inflammatory cytokine production, as well as in the activation of the adaptive immune system at a later stage by providing for optimal Th1 immune responses. C1 [Koh, Young-Sang; Biswas, Amlan; Kobayashi, Koichi S.] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Koh, Young-Sang; Biswas, Amlan; Kobayashi, Koichi S.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Koh, Young-Sang; Koo, Jung-Eun] Cheju Natl Univ, Sch Med, Dept Microbiol, Cheju, Jeju Do, South Korea. [Koh, Young-Sang; Koo, Jung-Eun] Cheju Natl Univ, Sch Med, Brain Korea Program 21, Cheju, Jeju Do, South Korea. RP Koh, YS (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. EM Koichi_Kobayashi@dfci.harvard.edu FU NIH [R01DK074738]; Cancer Research Institute; Claudia Adams Barr Award; Korea Research Foundation [KRF-2008-313-C00807] FX This work was supported by a grant from the NIH (R01DK074738) to KSK. KSK is a recipient of the Investigator Award from the Cancer Research Institute and the Claudia Adams Barr Award, and YSK is a recipient of and was supported by the Korea Research Foundation Grant (KRF-2008-313-C00807). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 67 TC 15 Z9 15 U1 0 U2 0 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 JUL 23 PY 2010 VL 5 IS 7 AR e11758 DI 10.1371/journal.pone.0011758 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 630AQ UT WOS:000280243800027 PM 20668698 ER PT J AU Minamishima, YA Kaelin, WG AF Minamishima, Yoji Andrew Kaelin, William G., Jr. TI Reactivation of Hepatic EPO Synthesis in Mice After PHD Loss SO SCIENCE LA English DT Article ID INACTIVATION; ERYTHROPOIESIS; FAILURE C1 [Kaelin, William G., Jr.] Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Kaelin, WG (reprint author), Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA. EM william_kaelin@dfci.harvard.edu RI Minamishima, Yoji/E-5380-2010 OI Minamishima, Yoji/0000-0001-7995-9318 FU Howard Hughes Medical Institute; NCI NIH HHS [R01 CA068490] NR 8 TC 73 Z9 74 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 23 PY 2010 VL 329 IS 5990 BP 407 EP 407 DI 10.1126/science.1192811 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 629KJ UT WOS:000280196500028 PM 20651146 ER PT J AU Mangone, M Manoharan, AP Thierry-Mieg, D Thierry-Mieg, J Han, T Mackowiak, SD Mis, E Zegar, C Gutwein, MR Khivansara, V Attie, O Chen, K Salehi-Ashtiani, K Vidal, M Harkins, TT Bouffard, P Suzuki, Y Sugano, S Kohara, Y Rajewsky, N Piano, F Gunsalus, KC Kim, JK AF Mangone, Marco Manoharan, Arun Prasad Thierry-Mieg, Danielle Thierry-Mieg, Jean Han, Ting Mackowiak, Sebastian D. Mis, Emily Zegar, Charles Gutwein, Michelle R. Khivansara, Vishal Attie, Oliver Chen, Kevin Salehi-Ashtiani, Kourosh Vidal, Marc Harkins, Timothy T. Bouffard, Pascal Suzuki, Yutaka Sugano, Sumio Kohara, Yuji Rajewsky, Nikolaus Piano, Fabio Gunsalus, Kristin C. Kim, John K. TI The Landscape of C. elegans 3 ' UTRs SO SCIENCE LA English DT Article ID HISTONE MESSENGER-RNA; CAENORHABDITIS-ELEGANS; GENOME; TRANSCRIPTOME; MECHANISMS; EXPRESSION; WORMBASE; RESOURCE; BIOLOGY; PROTEIN AB Three-prime untranslated regions (3'UTRs) of metazoan messenger RNAs (mRNAs) contain numerous regulatory elements, yet remain largely uncharacterized. Using polyA capture, 3' rapid amplification of complementary DNA (cDNA) ends, full-length cDNAs, and RNA-seq, we defined similar to 26,000 distinct 3'UTRs in Caenorhabditis elegans for similar to 85% of the 18,328 experimentally supported protein-coding genes and revised similar to 40% of gene models. Alternative 3'UTR isoforms are frequent, often differentially expressed during development. Average 3'UTR length decreases with animal age. Surprisingly, no polyadenylation signal (PAS) was detected for 13% of polyadenylation sites, predominantly among shorter alternative isoforms. Trans-spliced (versus non-trans-spliced) mRNAs possess longer 3'UTRs and frequently contain no PAS or variant PAS. We identified conserved 3'UTR motifs, isoform-specific predicted microRNA target sites, and polyadenylation of most histone genes. Our data reveal a rich complexity of 3'UTRs, both genome-wide and throughout development. C1 [Mangone, Marco; Mis, Emily; Zegar, Charles; Gutwein, Michelle R.; Attie, Oliver; Chen, Kevin; Piano, Fabio; Gunsalus, Kristin C.] NYU, Dept Biol, Ctr Genom & Syst Biol, New York, NY 10003 USA. [Manoharan, Arun Prasad; Han, Ting; Khivansara, Vishal; Kim, John K.] Univ Michigan, Dept Human Genet, Inst Life Sci, Ann Arbor, MI 48109 USA. [Thierry-Mieg, Danielle; Thierry-Mieg, Jean] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Mackowiak, Sebastian D.; Chen, Kevin; Rajewsky, Nikolaus] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. [Salehi-Ashtiani, Kourosh; Vidal, Marc] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Salehi-Ashtiani, Kourosh; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Salehi-Ashtiani, Kourosh; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Harkins, Timothy T.] Roche Appl Sci, Indianapolis, IN 46250 USA. [Bouffard, Pascal] Roche Appl Sci, Life Sci 454, Branford, CT 06405 USA. [Suzuki, Yutaka; Sugano, Sumio] Univ Tokyo, Grad Sch Frontier Sci, Dept Med Genome Sci, Tokyo 1088639, Japan. [Kohara, Yuji] Natl Inst Genet, Ctr Genet Resource Informat, Genome Biol Lab, Mishima, Shizuoka 4118540, Japan. [Piano, Fabio; Gunsalus, Kristin C.] NYU, Abu Dhabi, U Arab Emirates. RP Piano, F (reprint author), NYU, Dept Biol, Ctr Genom & Syst Biol, 1009 Silver Ctr, New York, NY 10003 USA. EM fp1@nyu.edu; kcg1@nyu.edu; jnkim@umich.edu RI THIERRY-MIEG, Jean/F-1975-2017; OI THIERRY-MIEG, Jean/0000-0002-0396-6789; Salehi-Ashtiani, Kourosh/0000-0002-6521-5243; Mangone, Marco/0000-0001-7551-8793 FU NIH [U01-HG004276, R00HG004515, R01GM088565]; Ministry of Education, Culture, Sports, Science and Technology of Japan; Muscular Dystrophy Association; Pew Charitable Trusts; DFCI Strategic Initiative; Helmholtz-Alliance on Systems Biology (Max Delbruck Centrum Systems Biology Network); NIH; National Library of Medicine FX This work was supported in part by grants from NIH (U01-HG004276) to F. P., K. C. G., J.K.K., and N.R.; NIH grant (R00HG004515) to K. C.; Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan to Y.K., S.S., and Y.S.; NIH (R01GM088565), Muscular Dystrophy Association and the Pew Charitable Trusts to J.K.K.; a gift from the Ellison Foundation to M. V. and Institute Sponsored Research funds from the DFCI Strategic Initiative in support of the CCSB; the Helmholtz-Alliance on Systems Biology (Max Delbruck Centrum Systems Biology Network) to S. D. M.; and the Intramural Research Program of NIH, National Library of Medicine to J.T.-M. and D. T.-M. We thank J. V. Moran, T. Blumenthal, A. Billi, D. Mecenas, and B. Bargmann for discussions; T. Shin'I and Exelixis for C. elegans cDNA traces; and, for technical assistance, T. Nawy and B. Brown (statistical analysis); R. Sachidanandam, R. Lyons, and S. Genik (deep sequencing); P. MacMenamin and D. Schaub (3'UTRome database); M. Morris (data submission); and L. Huang (stage analysis). 3'UTRome data sets are available from NCBI Trace Archive, dbEST, Sequence Read Archive, Gene Expression Omnibus, and modENCODE (8). See supporting online materials and methods for details. Annotations are displayed at NCBI AceView (www.aceview.org) (9) and www.UTRome.org (12). NR 23 TC 137 Z9 140 U1 3 U2 23 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 23 PY 2010 VL 329 IS 5990 BP 432 EP 435 DI 10.1126/science.1191244 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 629KJ UT WOS:000280196500035 PM 20522740 ER PT J AU Marks, DI Wang, T Perez, WS Antin, JH Copelan, E Gale, RP George, B Gupta, V Halter, J Khoury, HJ Klumpp, TR Lazarus, HM Lewis, VA McCarthy, P Rizzieri, DA Sabloff, M Szer, J Tallman, MS Weisdorf, DJ AF Marks, David I. Wang, Tao Perez, Waleska S. Antin, Joseph H. Copelan, Edward Gale, Robert Peter George, Biju Gupta, Vikas Halter, Joerg Khoury, H. Jean Klumpp, Thomas R. Lazarus, Hillard M. Lewis, Victor A. McCarthy, Philip Rizzieri, David A. Sabloff, Mitchell Szer, Jeff Tallman, Martin S. Weisdorf, Daniel J. TI The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first and second complete remission SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; INTERNATIONAL BLOOD; GRAFT; RISK; SURVIVAL; RELAPSE AB We examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m(2) or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL. (Blood. 2010; 116(3): 366-374) C1 [Weisdorf, Daniel J.] Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA. [Marks, David I.] Univ Hosp Bristol NHS Trust, Bristol, Avon, England. [Wang, Tao; Perez, Waleska S.] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA. [Antin, Joseph H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Copelan, Edward] Cleveland Clin Fdn, Cleveland, OH USA. [Gale, Robert Peter] Hoechst Celanese Corp, Summit, NJ 07901 USA. [George, Biju] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Gupta, Vikas] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Halter, Joerg] Kantonsspital Basel, Basel, Switzerland. [Khoury, H. Jean] Emory Univ Hosp, Atlanta, GA 30322 USA. [Klumpp, Thomas R.] Temple Univ, Jeanes Hosp, Philadelphia, PA 19122 USA. [Lazarus, Hillard M.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Lewis, Victor A.] Alberta Childrens Prov Gen Hosp, Calgary, AB T2T 5C7, Canada. [McCarthy, Philip] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Rizzieri, David A.] Duke Univ, Med Ctr, Durham, NC USA. [Sabloff, Mitchell] Ottawa Hosp, Blood & Marrow Transplant Program, Ottawa, ON, Canada. [Szer, Jeff] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Tallman, Martin S.] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. RP Weisdorf, DJ (reprint author), Univ Minnesota, Med Ctr, 420 Delaware St SE,MMC 480, Minneapolis, MN 55455 USA. EM weisd001@umn.edu RI Halter, Joerg/C-9487-2012; OI Szer, Jeff/0000-0001-6783-2301 FU National Cancer Institute; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases [U24-CA76518]; National Cancer Institute [5U01HL069294]; Health Resources and Services Administration [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen Inc FX The CIBMTR is supported by the National Cancer Institute, the National Heart, Lung and Blood Institute, and the National Institute of Allergy and Infectious Diseases (Public Health Service Grant/Cooperative Agreement U24-CA76518); the National Heart, Lung and Blood Institute and National Cancer Institute (Grant/Cooperative-Agreement 5U01HL069294); the Health Resources and Services Administration (contract HHSH234200637015C); the Office of Naval Research (grants N00014-06-1-0704 and N00014-08-1-0058); and AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen Inc; anonymous donation to the Medical College of Wisconsin; Astellas Pharma US Inc; Baxter International Inc; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical Inc; Biovitrum AB; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix GmbH; Centers for Disease Control and Prevention; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc; CytoTherm; DOR BioPharma Inc; Dynal Biotech, an Invitrogen Company; Eisai Inc; Enzon Pharmaceuticals Inc; European Group for Blood and Marrow Transplantation; Gamida Cell Ltd; GE Healthcare; Genentech Inc; Genzyme Corporation; Histogenetics Inc; HKS Medical Information Systems; Hospira Inc; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery Co Ltd; Leukemia & Lymphoma Society; Merck & Company; Medical College of Wisconsin; MGI Pharma Inc; Michigan Community Blood Centers; Millennium Pharmaceuticals Inc; Miller Pharmacal Group; Milliman USA Inc; Miltenyi Biotec Inc; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics Inc; Otsuka America Pharmaceutical Inc; Pall Life Sciences; Pfizer Inc; Saladax Biomedical Inc; Schering Corporation; Society for Healthcare Epidemiology of America; Stem-Cyte Inc; StemSoft Software Inc; SysmexAmerica Inc; Teva Pharmaceutical Industries; THERAKOS Inc; Thermogenesis Corporation; Vidacare Corporation; Vion Pharmaceuticals Inc; ViraCor Laboratories; ViroPharma Inc; and Wellpoint Inc. NR 24 TC 85 Z9 88 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 JUL 22 PY 2010 VL 116 IS 3 BP 366 EP 374 DI 10.1182/blood-2010-01-264077 PG 9 WC Hematology SC Hematology GA 629JL UT WOS:000280192300012 PM 20404137 ER PT J AU Choi, JH Banks, AS Estall, JL Kajimura, S Bostrom, P Laznik, D Ruas, JL Chalmers, MJ Kamenecka, TM Bluher, M Griffin, PR Spiegelman, BM AF Choi, Jang Hyun Banks, Alexander S. Estall, Jennifer L. Kajimura, Shingo Bostroem, Pontus Laznik, Dina Ruas, Jorge L. Chalmers, Michael J. Kamenecka, Theodore M. Blueher, Matthias Griffin, Patrick R. Spiegelman, Bruce M. TI Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPAR gamma by Cdk5 SO NATURE LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; INSULIN-RESISTANCE; LIGAND-BINDING; ADIPOSE-TISSUE; OLIGONUCLEOTIDE ARRAYS; EXPRESSION; ADIPOGENESIS; HORMONE; THIAZOLIDINEDIONES; STIMULATION AB Obesity induced in mice by high-fat feeding activates the protein kinase Cdk5 (cyclin-dependent kinase 5) in adipose tissues. This results in phosphorylation of the nuclear receptor PPAR gamma (peroxisome proliferator-activated receptor c), a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPAR gamma does not alter its adipogenic capacity, but leads to dysregulation of a large number of genes whose expression is altered in obesity, including a reduction in the expression of the insulin-sensitizing adipokine, adiponectin. The phosphorylation of PPAR gamma by Cdk5 is blocked by anti-diabetic PPAR gamma ligands, such as rosiglitazone and MRL24. This inhibition works both in vivo and in vitro, and is completely independent of classical receptor transcriptional agonism. Similarly, inhibition of PPAR gamma phosphorylation in obese patients by rosiglitazone is very tightly associated with the anti-diabetic effects of this drug. All these findings strongly suggest that Cdk5-mediated phosphorylation of PPAR gamma may be involved in the pathogenesis of insulin-resistance, and present an opportunity for development of an improved generation of anti-diabetic drugs through PPAR gamma. C1 [Choi, Jang Hyun; Banks, Alexander S.; Estall, Jennifer L.; Kajimura, Shingo; Bostroem, Pontus; Laznik, Dina; Ruas, Jorge L.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Choi, Jang Hyun; Banks, Alexander S.; Estall, Jennifer L.; Kajimura, Shingo; Bostroem, Pontus; Laznik, Dina; Ruas, Jorge L.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Metab & Chron Dis, Boston, MA 02115 USA. [Choi, Jang Hyun; Banks, Alexander S.; Estall, Jennifer L.; Kajimura, Shingo; Bostroem, Pontus; Laznik, Dina; Ruas, Jorge L.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Chalmers, Michael J.; Kamenecka, Theodore M.; Griffin, Patrick R.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA. [Blueher, Matthias] Univ Leipzig, Dept Med, Leipzig, Germany. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu RI Choi, Jang Hyun/B-3055-2012; Banks, Alexander/B-4832-2012; OI Banks, Alexander/0000-0003-1787-6925; Ruas, Jorge/0000-0002-1110-2606 FU NIH [DK31405, DK087853]; Deutsche Forschungsgemeinschaft (DFG); N National Institute of Mental Health [U54-MH084512]; NIH National Institute of General Medical Sciences [R01-GM084041]; Clinical Research group [KFO 152, BL 833/1-1] FX We thank V. Mootha for help with the analysis of microarray data and for critical comments. We thank M. Kirschner for a critical reading of the manuscript and for comments. We are grateful to R. Gupta and P. Cohen for critical comments on the manuscript. J.H.C., A.S.B., J.L.E., P.B., D.L., J.L.R. and B.M.S are supported by NIH DK31405. S.K. is supported by NIH grant DK087853. M.B. is supported by a grant from Deutsche Forschungsgemeinschaft (DFG) and the Clinical Research group 'Atherobesity' KFO 152 (project BL 833/1-1). P.R.G., M.J.C. and T.M.K. are supported in part by the by the Intramural Research Program of the N National Institute of Mental Health (P.R.G., M.J.C., T.M.K., U54-MH084512; H. Rosen Principal Investigator) and by the NIH National Institute of General Medical Sciences (P.R.G. and M.J.C., R01-GM084041). NR 46 TC 356 Z9 372 U1 10 U2 60 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 22 PY 2010 VL 466 IS 7305 BP 451 EP U1 DI 10.1038/nature09291 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 628SJ UT WOS:000280141200027 PM 20651683 ER PT J AU Qi, HH Sarkissian, M Hu, GQ Wang, ZB Bhattacharjee, A Gordon, DB Gonzales, M Lan, F Ongusaha, PP Huarte, M Yaghi, NK Lim, H Garcia, BA Brizuela, L Zhao, KJ Roberts, TM Shi, Y AF Qi, Hank H. Sarkissian, Madathia Hu, Gang-Qing Wang, Zhibin Bhattacharjee, Arindam Gordon, D. Benjamin Gonzales, Michelle Lan, Fei Ongusaha, Pat P. Huarte, Maite Yaghi, Nasser K. Lim, Huijun Garcia, Benjamin A. Brizuela, Leonardo Zhao, Keji Roberts, Thomas M. Shi, Yang TI Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development SO NATURE LA English DT Article ID LINKED MENTAL-RETARDATION; STRUCTURAL INSIGHTS; NERVOUS-SYSTEM; HUMAN GENOME; CELL-CYCLE; GENES; TRANSCRIPTION; CHROMATIN; METHYLATION; FAMILY AB X-linked mental retardation (XLMR) is a complex human disease that causes intellectual disability(1). Causal mutations have been found in approximately 90 X-linked genes(2); however, molecular and biological functions of many of these genetically defined XLMR genes remain unknown. PHF8 (PHD (plant homeo domain) finger protein 8) is a JmjC domain-containing protein and its mutations have been found in patients with XLMR and craniofacial deformities. Here we provide multiple lines of evidence establishing PHF8 as the first mono-methyl histone H4 lysine 20 (H4K20me1) demethylase, with additional activities towards histone H3K9me1 and me2. PHF8 is located around the transcription start sites (TSS) of similar to 7,000 RefSeq genes and in gene bodies and intergenic regions (non-TSS). PHF8 depletion resulted in upregulation of H4K20me1 and H3K9me1 at the TSS and H3K9me2 in the non-TSS sites, respectively, demonstrating differential substrate specificities at different target locations. PHF8 positively regulates gene expression, which is dependent on its H3K4me3-binding PHD and catalytic domains. Importantly, patient mutations significantly compromised PHF8 catalytic function. PHF8 regulates cell survival in the zebrafish brain and jaw development, thus providing a potentially relevant biological context for understanding the clinical symptoms associated with PHF8 patients. Lastly, genetic and molecular evidence supports a model whereby PHF8 regulates zebrafish neuronal cell survival and jaw development in part by directly regulating the expression of the homeodomain transcription factor MSX1/MSXB, which functions downstream of multiple signalling and developmental pathways(3). Our findings indicate that an imbalance of histone methylation dynamics has a critical role in XLMR. C1 [Qi, Hank H.; Lan, Fei; Huarte, Maite; Yaghi, Nasser K.; Lim, Huijun; Shi, Yang] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Qi, Hank H.; Lim, Huijun; Shi, Yang] Childrens Hosp, Dept Med, Div Newborn Med, Boston, MA 02115 USA. [Sarkissian, Madathia; Roberts, Thomas M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Hu, Gang-Qing; Wang, Zhibin; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Bhattacharjee, Arindam; Gordon, D. Benjamin; Brizuela, Leonardo] Agilent Technol, Santa Clara, CA 95051 USA. [Gonzales, Michelle; Garcia, Benjamin A.] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. [Ongusaha, Pat P.] Brigham & Womens Hosp, Vasc Med Res Unit, Cambridge, MA 02139 USA. [Ongusaha, Pat P.] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. RP Shi, Y (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM Thomas_Roberts@dfci.harvard.edu; yshi@hms.harvard.edu RI HU, GANGQING/K-5849-2012; Huarte, Maite/J-6903-2014 OI Huarte, Maite/0000-0003-3753-6493 FU Ruth L. Kirschstein-National Service [T32 NS007473, T32 CA09031-32]; Harvard SHURP; Agency for Science, Technology and Research (A*STAR); National Science Foundation [CBET-0941143]; NIH [GM 071004, NCI118487, CA50661]; Ellison Foundation FX We thank Shi laboratory members for helpful discussions and N. Mosammaparast and S. Chen for providing the nucleosomes. We thank G. Rosenfeld for sharing unpublished PHF8 results, and G. Rosenfeld, A. Schier and P. Hinds for discussions. H.H.Q. is a recipient of Ruth L. Kirschstein-National Service Research Award (T32 NS007473 and T32 CA09031-32). N.K.Y. was supported by Harvard SHURP (Summer Honors Undergraduate Research Program). H.L. is a recipient of the Agency for Science, Technology and Research (A*STAR) National Science Scholarship. This work was supported by grants from the National Science Foundation (CBET-0941143) to B.A.G.; NIH (GM 071004 and NCI118487) to Y. S.; a Senior Scholar Grant from the Ellison Foundation, and an NIH PO1 grant (CA50661) to T.M.R. NR 39 TC 130 Z9 137 U1 3 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 22 PY 2010 VL 466 IS 7305 BP 503 EP U11 DI 10.1038/nature09261 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 628SJ UT WOS:000280141200039 PM 20622853 ER PT J AU Greenberg, SM Rapalino, O Frosch, MP AF Greenberg, Steven M. Rapalino, Otto Frosch, Matthew P. TI A Woman with Dementia and a Seizure Inflammatory cerebral amyloid angiopathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; WHITE-MATTER LESIONS; ALZHEIMER-DISEASE; PRIMARY ANGIITIS; REVERSIBLE LEUKOENCEPHALOPATHY; MICROBLEEDS; MRI; ENCEPHALOPATHY; DIAGNOSIS; INFARCTS C1 [Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Rapalino, Otto] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Frosch, Matthew P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Greenberg, Steven M.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Rapalino, Otto] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Frosch, Matthew P.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 33 TC 5 Z9 5 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 JUL 22 PY 2010 VL 363 IS 4 BP 373 EP 381 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 628RU UT WOS:000280139300013 PM 20660406 ER PT J AU Wolpert, HA AF Wolpert, Howard A. TI Continuous Glucose Monitoring - Coming of Age SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Joslin Diabet Ctr, Sect Adult Diabet, Boston, MA 02215 USA. RP Wolpert, HA (reprint author), Joslin Diabet Ctr, Sect Adult Diabet, Boston, MA 02215 USA. NR 9 TC 11 Z9 11 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 JUL 22 PY 2010 VL 363 IS 4 BP 383 EP 384 DI 10.1056/NEJMe1006098 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 628RU UT WOS:000280139300014 PM 20587584 ER PT J AU Barker, FG Cahill, DP AF Barker, Fred G., II Cahill, Daniel P. TI A Woman with Weakness and a Mass in the Brain REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Barker, Fred G., II; Cahill, Daniel P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Barker, FG (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 22 PY 2010 VL 363 IS 4 BP 395 EP 396 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 628RU UT WOS:000280139300025 ER PT J AU Yu, F Deng, H Yao, H Liu, Q Su, F Song, E AF Yu, F. Deng, H. Yao, H. Liu, Q. Su, F. Song, E. TI Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells SO ONCOGENE LA English DT Article DE microRNA; cancer stem cell; breast cancer; Ubc9; ITGB3 ID CANCER STEM-CELLS; IN-VITRO PROPAGATION; EXPRESSION; UBC9; MECHANISMS; INTEGRINS; ANOIKIS AB Accumulating evidence indicates that a sub-population of cancer cells with stem-like properties, termed tumor-initiating cells (T-ICs), exist in many different kinds of malignancies, which have a pivotal role in tumorigenesis, tumor progression, metastasis and post-treatment relapse. However, how the stem-like properties of T-ICs are regulated remains obscure. Our previous study showed that reduction of let-7 microRNA ( miRNA) in breast tumor-initiating cells (BT-ICs) contributes to the maintenance of their self-renewal capacity and undifferentiated status. In this study we show the effect of mir-30 reduction on the stem-like features of BT-ICs. Similar to let-7, mir-30 is reduced in BT-ICs, and the protein level of Ubc9 (ubiquitin-conjugating enzyme 9) and ITGB3 ( integrin b3), the target genes of mir-30, is markedly upregulated. Enforced constitutive expression of mir-30 in BT-ICs inhibits their self-renewal capacity by reducing Ubc9, and induces apoptosis through silencing ITGB3. On the contrary, blocking the miRNA with a specific antisense oligonucleotide (ASO) in differentiated breast cancer cells revived their self-renewal capacity. Furthermore, ectopic expression of mir-30 in BT-IC xenografts reduces tumorigenesis and lung metastasis in nonobese diabetic/severe combined immunodeficient mice, whereas blocking mir-30 expression enhances tumorigenesis and metastasis. Together, our data suggest mir-30 as one of the important miRNAs in regulating the stem-like features of T-ICs. Oncogene ( 2010) 29, 4194-4204; doi: 10.1038/onc.2010.167; published online 24 May 2010 C1 [Yu, F.; Deng, H.; Liu, Q.; Su, F.; Song, E.] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Breast Surg, Guangzhou 510120, Guangdong, Peoples R China. [Yao, H.] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Med Oncol, Guangzhou 510120, Guangdong, Peoples R China. [Liu, Q.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Song, E.] Sun Yat Sen Univ, Sch Life Sci, Guangzhou 510120, Guangdong, Peoples R China. RP Song, E (reprint author), Sun Yat Sen Univ, Affiliated Hosp 2, Dept Breast Surg, 107 Yanjiang W Rd, Guangzhou 510120, Guangdong, Peoples R China. EM songerwei02@yahoo.com.cn FU Natural Science Foundation of China [30921140312, 30830110, 30772550, 30973396, 30525022, 30671930, 30973505]; Ministry of Science and Technology of China [2010CB912800, 2009CB521706, 2005CB724605]; Natural Science Foundation of Guangdong Province [8251008901000011] FX This work was supported by the Natural Science Foundation of China Grant (30921140312, 30830110, 30772550, 30973396, 30525022, 30671930, 30973505), 973 (2010CB912800, 2009CB521706, 2005CB724605) Projects from the Ministry of Science and Technology of China, and Natural Science Foundation of Guangdong Province (8251008901000011). NR 24 TC 158 Z9 173 U1 2 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 22 PY 2010 VL 29 IS 29 BP 4194 EP 4204 DI 10.1038/onc.2010.167 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 628VL UT WOS:000280151500007 PM 20498642 ER PT J AU Lo, J You, SM Liebau, J Lee, H Grinspoon, S AF Lo, Janet You, Sung Min Liebau, James Lee, Hang Grinspoon, Steven TI Effects of Low-Dose Growth Hormone Withdrawal in Patients With HIV SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID ACCUMULATION C1 [Lo, Janet; You, Sung Min; Liebau, James; Grinspoon, Steven] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. [Lee, Hang] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Lo, J (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NCRR NIH HHS [M01 RR01066, 1 UL1 RR025758, M01 RR001066, UL1 RR025758]; NHLBI NIH HHS [K23 HL092792]; NIDDK NIH HHS [P30 DK040561-15, R01 DK63639, K24 DK064545, P30 DK040561, R01 DK063639] NR 3 TC 6 Z9 6 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 21 PY 2010 VL 304 IS 3 BP 272 EP 274 DI 10.1001/jama.2010.989 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 628HV UT WOS:000280107500016 PM 20639560 ER PT J AU Thompson, MA Aberg, JA Cahn, P Montaner, JSG Rizzardini, G Telenti, A Gatell, JM Gunthard, HF Hammer, SM Hirsch, MS Jacobsen, DM Reiss, P Richman, DD Volberding, PA Yeni, P Schooley, RT AF Thompson, Melanie A. Aberg, Judith A. Cahn, Pedro Montaner, Julio S. G. Rizzardini, Giuliano Telenti, Amalio Gatell, Jose M. Guenthard, Huldrych F. Hammer, Scott M. Hirsch, Martin S. Jacobsen, Donna M. Reiss, Peter Richman, Douglas D. Volberding, Paul A. Yeni, Patrick Schooley, Robert T. TI Antiretroviral Treatment of Adult HIV Infection 2010 Recommendations of the International AIDS Society-USA Panel SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID NAIVE HIV-1-INFECTED PATIENTS; HEPATITIS-B-VIRUS; TWICE-DAILY LOPINAVIR/RITONAVIR; ONCE-DAILY ATAZANAVIR/RITONAVIR; OPTIMIZED BACKGROUND THERAPY; EARLY VIROLOGICAL FAILURE; DRUG-RESISTANCE; MYOCARDIAL-INFARCTION; COLLABORATIVE ANALYSIS; DAILY DARUNAVIR/RITONAVIR AB Context Recent data regarding the consequences of untreated human immunodeficiency virus (HIV) infection and the expansion of treatment choices for antiretroviral-naive and antiretroviral-experienced patients warrant an update of the International AIDS Society-USA guidelines for the use of antiretroviral therapy in adults with HIV infection. Objectives To provide updated recommendations for management of HIV-infected adults, using antiretroviral drugs and laboratory monitoring tools available in the international, developed-world setting. This report provides guidelines for when to initiate antiretroviral therapy, selection of appropriate initial regimens, patient monitoring, when to change therapy, and what regimens to use when changing. Data Sources and Study Selection A panel with expertise in HIV research and clinical care reviewed relevant data published or presented at selected scientific conferences since the last panel report through April 2010. Data were identified through a PubMed search, review of scientific conference abstracts, and requests to antiretroviral drug manufacturers for updated clinical trials and adverse event data. Data Extraction and Synthesis New evidence was reviewed by the panel. Recommendations were drafted by section writing committees and reviewed and edited by the entire panel. The quality and strength of the evidence were rated and recommendations were made by full panel consensus. Conclusions Patient readiness for treatment should be confirmed before initiation of antiretroviral treatment. Therapy is recommended for asymptomatic patients with a CD4 cell count <= 500/mu L, for all symptomatic patients, and those with specific conditions and comorbidities. Therapy should be considered for asymptomatic patients with CD4 cell count >500/mu L. Components of the initial and subsequent regimens must be individualized, particularly in the context of concurrent conditions. Patients receiving antiretroviral treatment should be monitored regularly; treatment failure should be detected and managed early, with the goal of therapy, even in heavily pretreated patients, being HIV-1 RNA suppression below commercially available assay quantification limits. JAMA. 2010;304(3):321-333 www.jama.com C1 [Thompson, Melanie A.] AIDS Res Consortium Atlanta, Atlanta, GA USA. [Richman, Douglas D.; Schooley, Robert T.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Aberg, Judith A.] NYU, Sch Med, New York, NY USA. [Cahn, Pedro] Univ Buenos Aires, Sch Med, Hosp Juan Fernandez, RA-1053 Buenos Aires, DF, Argentina. [Cahn, Pedro] Univ Buenos Aires, Fdn Huesped, RA-1053 Buenos Aires, DF, Argentina. [Gatell, Jose M.] Univ Barcelona, Hosp Clin IDIBAPS, Barcelona, Spain. [Guenthard, Huldrych F.] Univ Zurich, Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, Zurich, Switzerland. [Hammer, Scott M.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Hirsch, Martin S.] Harvard Univ, Sch Med, Boston, MA USA. [Jacobsen, Donna M.] Int AIDS Soc USA, San Francisco, CA USA. [Montaner, Julio S. G.] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Montaner, Julio S. G.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Reiss, Peter] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Richman, Douglas D.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Rizzardini, Giuliano] Luigi Sacco Hosp, Milan, Italy. [Telenti, Amalio] Univ Lausanne Hosp, Lausanne, Switzerland. [Volberding, Paul A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Volberding, Paul A.] San Francisco VA Med Ctr, San Francisco, CA USA. [Yeni, Patrick] Hop Bichat Claude Bernard, F-75877 Paris 18, France. [Yeni, Patrick] Xavier Bichat Med Sch, Paris, France. RP Thompson, MA (reprint author), 131 Ponce de Leon Ave NE,Ste 130, Atlanta, GA 30308 USA. EM drmt@mindspring.com RI gunthard, huldrych/F-1724-2011; Infektiologie, USZ/A-6921-2011; Rizzardini, Giuliano/K-9458-2016 OI gunthard, huldrych/0000-0002-1142-6723; Rizzardini, Giuliano/0000-0002-5183-7818 FU Abbott Laboratories; Avexa; Boehringer Ingelheim Pharmaceuticals; Bristol-Myers Squibb; GlaxoSmithKline; Gilead Sciences; GeoVax; Katketsuken; Koronis Pharmaceuticals; Merck Research Laboratories; Myriad; Ora-Sure; Pfizer; Progenics Pharmaceuticals; Roche Laboratories; Roche Molecular Systems; Serono; Theratechnologies Tibotec Therapeutics; Tobira Therapeutics; Trimeris; VaxGen; GlaxoSmithKline Italy; International AIDS Society-USA; ViiV Healthcare FX Dr Thompson reported receiving research grants awarded to AIDS Research Consortium of Atlanta from Abbott Laboratories, Avexa, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Sciences, GeoVax, Katketsuken, Koronis Pharmaceuticals, Merck Research Laboratories, Myriad, Ora-Sure, Panacos Pharmaceuticals (now Myriad), Pfizer, Progenics Pharmaceuticals, Roche Laboratories, Roche Molecular Systems, Serono, Theratechnologies Tibotec Therapeutics, Tobira Therapeutics, Trimeris, and VaxGen; has served on the scientific advisory boards or as a clinical trial design consultant for Chimerix, GeoVax, GlaxoSmithKline, Panacos Pharmaceuticals, Progenics Pharmaceuticals, and Tibotec Therapeutics; has received honoraria for scientific lectures from GlaxoSmithKline and Serono; and has served on data and safety monitoring boards for Tibotec Therapeutics. Dr Aberg reported serving as a scientific advisor to Abbott Laboratories, Boehringer Ingelheim Pharmaceutical, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Theratechnologies, Tibotec Therapeutics, and ViiV Healthcare; has received grants and research support from Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Schering-Plough, Theratechnologies, Tibotec Therapeutics, Virco Lab, and Wyeth; and has received honoraria from Abbott Laboratories, Bristol-Myers Squibb, and Gilead Sciences. Dr Cahn reported serving on the advisory boards for Avexa, Gilead Sciences, GlaxoSmithKline, Myriad Genetics, Merck, Pfizer, Pharmasset, ScheringPlough, and Tibotec Therapeutics; has served as an investigator for Avexa, Boehringer Ingelheim Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Pharmasset, Roche Laboratories, ScheringPlough, and Tibotec Therapeutics; and has received honoraria for speaking engagements from Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Merck, Pfizer, and Tibotec Therapeutics. Dr Montaner reported receiving research grants from, and served as an ad hoc advisor or consultant to, Abbott Laboratories, Argos Therapeutics, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Cato Research Canada, ConjuChem Biotech, Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche, Johnson& Johnson, Merck Canada, Merck Frosst Laboratories, Pfizer Canada, Serono, Theratechnologies, and Tibotec Pharmaceuticals and has served on an endpoint adjudication committee for Schering-Plough. Dr Rizzardini reported receiving research grants from Gilead Sciences and Merck Sharp& Dohme. Dr Telenti reported receiving research grants or honoraria for lectures from Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, and GlaxoSmithKline. Dr Gatell reported receiving research grants or honoraria for serving on advisory boards or for lectures from Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharpe & Dohme, Pfizer, GlaxoSmithKline, Roche Laboratories, Theratechnologies, Tibotec Therapeutics, Tobira Therapeutics, and Virco Lab. Dr Gunthard reported serving as a consultant and medical advisor for Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Pfizer, Tibotec Therapeutics, and ViiV Healthcare and has received unrestricted research and educational grants from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp& Dohme, and Pfizer.; Dr Hammer reported serving on a scientific or clinical advisory boards for Merck, Progenics Pharmaceuticals, TaiMed Biologics, TibotecTherapeutics, and Wyeth; has received clinical research contracts from Merck; and has served on data and safety monitoring boards and committees for Bristol-Myers Squibb and on the board of directors of SIGA Pharmaceuticals. Dr Hirsch reported serving on data and safety monitoring boards for Merck and TaiMed Biologics. Dr Reiss reported serving as a scientific advisor to Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Theratechnologies, Tibotec Therapeutics, and Tobira Therapeutics; has served on data and safety monitoring boards and endpoint adjudication committees for Tibotec Therapeutics; has received honoraria for speaking engagements at scientific conferences from Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Theratechnologies; and has received research support from Gilead Sciences, ViiV Healthcare, and Boehringer Ingelheim Pharmaceuticals. Dr Richman reported being a consultant to Anadys Pharmaceuticals, Biota, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Chimerix, GenProbe, Gilead Sciences, Idenix Pharmaceuticals, Koronis Pharmaceuticals, Merck, Monogram Biosciences, Myriad Genetics, Pfizer, Roche, Theraclone Sciences, and Tobira Therapeutics; has served on an endpoint adjudication committee for Schering-Plough; has been the recipient of a research grant from Merck; and has been a stock options holder of Chimerix and Idenix Pharmaceuticals. Dr Volberding reported serving on data and safety monitoring boards for Merck and TaiMed Biologics and on an endpoint adjudication committee for Schering-Plough; has provided paid expert testimony for commercial firms; has served on scientific or clinical advisory boards for Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Pfizer, and Tobira Therapeutics; and has been the recipient of service grants for, or held contracts from, GlaxoSmithKline Italy. Dr Yeni reported receiving scientific grants from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Pfizer, Merck, and Roche Laboratories. Dr Schooley reported serving as a consultant to Achillion Pharmaceuticals, Anadys Pharmaceuticals, Ardea Biosciences, Gilead Sciences, GlaxoSmithKline, Inhibitex, iTherX, Johnson & Johnson, LabCorp, Merck, Myriad Biosciences, Pfizer, TaiMed Biologics, Tanox, Tobira Therapeutics, Vertex Pharmaceuticals, and Vical; has received grants from Gilead Sciences and Pfizer; and has stock options for Achillion Pharmaceuticals.; This work was funded by the International AIDS Society-USA. Panel members serve in volunteer capacities (ie, are not compensated). No private sector or government funding was used to support the effort. The International AIDS Society-USA has received grants for selected CME activities (unrelated to guidelines development) from Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche Laboratories, Tibotec Therapeutics, and ViiV Healthcare. Grants are pooled such that no single company supports any single effort. NR 146 TC 582 Z9 600 U1 4 U2 55 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 21 PY 2010 VL 304 IS 3 BP 321 EP 333 DI 10.1001/jama.2010.1004 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 628HV UT WOS:000280107500022 PM 20639566 ER PT J AU Chiao, EY Dezube, BJ Krown, SE Wachsman, W Brock, MV Giordano, TP Mitsuyasu, R Pantanowitz, L AF Chiao, Elizabeth Y. Dezube, Bruce J. Krown, Susan E. Wachsman, William Brock, Malcolm V. Giordano, Thomas P. Mitsuyasu, Ronald Pantanowitz, Liron TI Time for Oncologists to Opt In for Routine Opt-Out HIV Testing? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; AIDS-RELATED MALIGNANCIES; SQUAMOUS-CELL CARCINOMA; HEALTH-CARE SETTINGS; LUNG-CANCER; INFECTED PATIENTS; UNITED-STATES; ANAL CANCER; DEFINING CANCERS AB Human immunodeficiency virus (HIV)-infected individuals are at high risk of malignancies. However, it is not currently the standard of care to routinely test cancer patients for HIV. In 2006, the Centers for Disease Control and Prevention recommended HIV testing in all health care settings, calling for standard nontargeted "opt-out" HIV screening. For a variety of reasons, routine opt-out HIV testing is still not widely used in the United States. Although many barriers to routine opt-out HIV testing have been addressed, such opt-out HIV testing continues to be conducted primarily in venues that target specific patient populations such as pregnant women. Although opt-out testing has been piloted in emergency departments, less emphasis has been placed on opt-out HIV testing in other clinical settings. In this article, the background, rationale, and evidence for supporting opt-out HIV testing as routine care for cancer patients are presented. In addition, evidence is discussed for the potential of opt-out HIV testing to improve clinical outcomes by facilitating appropriate HIV management during cancer treatment for individuals who are found to be HIV positive. JAMA. 2010;304(3):334-339 www.jama.com C1 [Chiao, Elizabeth Y.; Giordano, Thomas P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Chiao, Elizabeth Y.; Giordano, Thomas P.] Dept Vet Affairs Med Ctr, Houston, TX USA. [Dezube, Bruce J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Hematol Oncol, Boston, MA 02215 USA. [Krown, Susan E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Wachsman, William] Univ Calif San Diego, Med Ctr, San Diego, CA 92103 USA. [Brock, Malcolm V.] Johns Hopkins Med Ctr, Baltimore, MD USA. [Mitsuyasu, Ronald] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles Ctr Clin AIDS Res & Educ, Los Angeles, CA 90095 USA. [Pantanowitz, Liron] Tufts Univ, Sch Med, Baystate Med Ctr, Dept Pathol, Springfield, MA 01199 USA. RP Chiao, EY (reprint author), Michael E DeBakey VA Med Ctr 152, Houston VA Hlth Serv Res & Dev, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM echiao@bcm.edu FU National Cancer Institute [UO1 CA 121947]; Houston VA Health Services Research and Development Center of Excellence [HFP90-020]; National Cancer Institute, National Institutes of Health [K23CA124318] FX This material is based on work supported by National Cancer Institute grant UO1 CA 121947 to the AIDS Malignancy Consortium. This work was also supported in part by the Houston VA Health Services Research and Development Center of Excellence (grant HFP90-020). Dr Chiao received support from the National Cancer Institute, National Institutes of Health, grant K23CA124318. NR 50 TC 20 Z9 20 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 21 PY 2010 VL 304 IS 3 BP 334 EP 339 DI 10.1001/jama.2010.752 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 628HV UT WOS:000280107500023 PM 20639567 ER PT J AU Buscher, AL Giordano, TP AF Buscher, April L. Giordano, Thomas P. TI Gaps in Knowledge in Caring for HIV Survivors Long-term SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID UNITED-STATES; POPULATION C1 Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Michael E DeBakey VA Med Ctr, Hlth Serv Res & Dev Ctr Excellence, Houston, TX USA. RP Giordano, TP (reprint author), Michael E DeBakey VA Med Ctr 152, Hlth Serv Res & Dev Ctr Excellence, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM tpg@bcm.tmc.edu NR 9 TC 7 Z9 7 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 21 PY 2010 VL 304 IS 3 BP 340 EP 341 DI 10.1001/jama.2010.870 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 628HV UT WOS:000280107500024 PM 20639568 ER PT J AU Bayomy, AF Aubin, PM Sangeorzan, BJ Ledoux, WR AF Bayomy, Ahmad F. Aubin, Patrick M. Sangeorzan, Bruce J. Ledoux, William R. TI Arthrodesis of the First Metatarsophalangeal Joint: A Robotic Cadaver Study of the Dorsiflexion Angle SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID HALLUX-RIGIDUS; PLANTAR PRESSURE; PLATE FIXATION; GAIT ANALYSIS; OSTEOARTHRITIS; VALGUS; ARTHRITIS AB Background: Arthrodesis of the first metatarsophalangeal joint is indicated for severe osteoarthritis or as a revision of failed treatment for hallux valgus. The literature suggests that an optimum fused dorsiflexion angle is between 20 degrees and 25 degrees from the axis of the first metatarsal. The purpose of this study was to investigate the relationship between dorsiflexion angle and plantar pressure in the postoperative gait. We assumed that there is a fused dorsiflexion angle at which pressures are minimized under the hallux and the first metatarsal head. Methods: Six cadaver foot specimens underwent incremental changes in simulated fused metatarsophalangeal joint dorsiflexion angle followed by dynamic gait simulation. A robotic gait simulator performed at 50% of body weight and one-fifteenth of physiologic velocity. In vitro tibial kinematics and tendon forces were based on normative in vivo gait and electromyographic data and were manually tuned to match the in vitro ground reaction force and tendon force behavior. Regression lines were calculated for peak pressure and pressure-time integral under the hallux and the metatarsal head by dorsiflexion angle. Results: Peak pressure and pressure-time integral under the hallux were negatively correlated with dorsiflexion angle (p < 0.004), while peak pressure and pressure-time integral under the metatarsal head were positively correlated with dorsiflexion angle (p < 0.004). The intersection of the regression lines that represented the angle at which peak pressure and pressure-time integral were minimized was 24.7 degrees for peak pressure and 21.3 degrees for pressure-time integral. Conclusions: Our findings support the hypothesis that an angle-pressure relationship exists following arthrodesis of the first metatarsophalangeal joint and that it is inversely related for the hallux and the metatarsal head. Our results encompass the suggested range of 20 degrees to 25 degrees. Clinical Relevance: This investigation provides a basis for assessing clinical decisions surrounding operative technique and hardware utilization that may improve gait, quality of life, and functional performance in patients undergoing operative treatment of osteoarthritis of the first metatarsophalangeal joint. C1 [Bayomy, Ahmad F.; Aubin, Patrick M.; Sangeorzan, Bruce J.; Ledoux, William R.] VA Puget Sound Hlth Care Syst, Ctr Excellence Limb Loss Prevent & Prosthet Engn, Rehabil Res & Dev Serv, Dept Vet Affairs, Seattle, WA 98108 USA. Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. RP Bayomy, AF (reprint author), VA Puget Sound Hlth Care Syst, Ctr Excellence Limb Loss Prevent & Prosthet Engn, Rehabil Res & Dev Serv, Dept Vet Affairs, MS 151,1660 S Columbian Way, Seattle, WA 98108 USA. EM wrledoux@u.washington.edu RI Ledoux, William/K-6815-2015 OI Ledoux, William/0000-0003-4982-7714 FU Department of Veterans Affairs Rehabilitation Research and Development Service [A2661C, A4843C]; University of Washington FX In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants of less than $10,000 from the Department of Veterans Affairs Rehabilitation Research and Development Service (#A2661C and #A4843C) and the University of Washington Medical Student Research Training Program. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. NR 30 TC 13 Z9 14 U1 2 U2 3 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD JUL 21 PY 2010 VL 92A IS 8 BP 1754 EP 1764 DI 10.2106/JBJS.I.00984 PG 11 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 629RE UT WOS:000280216600009 PM 20660239 ER PT J AU Coleman, JE Nahmani, M Gavornik, JP Haslinger, R Heynen, AJ Erisir, A Bear, MF AF Coleman, Jason E. Nahmani, Marc Gavornik, Jeffrey P. Haslinger, Robert Heynen, Arnold J. Erisir, Alev Bear, Mark F. TI Rapid Structural Remodeling of Thalamocortical Synapses Parallels Experience-Dependent Functional Plasticity in Mouse Primary Visual Cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article ID OCULAR DOMINANCE PLASTICITY; LONG-TERM DEPRESSION; MONOCULAR DEPRIVATION; NMDA RECEPTOR; DENDRITIC SPINES; CEREBRAL-CORTEX; GENICULOCORTICAL AFFERENTS; POSTNATAL-DEVELOPMENT; HIPPOCAMPAL-NEURONS; VESICULAR GLUTAMATE AB Monocular lid closure (MC) causes a profound shift in the ocular dominance ( OD) of neurons in primary visual cortex (V1). Anatomical studies in both cat and mouse V1 suggest that large-scale structural rearrangements of eye-specific thalamocortical (TC) axons in response to MC occur much more slowly than the shift in OD. Consequently, there has been considerable debate as to whether the plasticity of TC synapses, which transmit competing visual information from each eye to V1, contributes to the early functional consequences of MC or is simply a feature of long-term deprivation. Here, we used quantitative immuno-electron microscopy to examine the possibility that alterations of TC synapses occur rapidly enough to impact OD after brief MC. The effect of short-term deprivation on TC synaptic structure was examined in male C57BL/6 mice that underwent 3 and 7 d of MC or monocular retinal inactivation (MI) with tetrodotoxin. The data show that 3 d of MC is sufficient to induce substantial remodeling of TC synapses. In contrast, 3 d of MI, which alters TC activity but does not shift OD, does not significantly affect the structure of TC synapses. Our results support the hypothesis that the rapid plasticity of TC synapses is a key step in the sequence of events that shift OD in visual cortex. C1 [Nahmani, Marc; Erisir, Alev] Univ Virginia, Dept Psychol, Charlottesville, VA 22904 USA. [Coleman, Jason E.; Gavornik, Jeffrey P.; Heynen, Arnold J.; Bear, Mark F.] MIT, Howard Hughes Med Inst, Picower Inst Learning & Memory, Cambridge, MA 02142 USA. [Haslinger, Robert; Bear, Mark F.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02142 USA. [Haslinger, Robert] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Erisir, A (reprint author), Univ Virginia, Dept Psychol, 102 Gilmer Hall,POB 400400, Charlottesville, VA 22904 USA. EM erisir@virginia.edu; mbear@mit.edu RI Erisir, Alev/A-5952-2014 OI Nahmani, Marc/0000-0002-5840-2462; Erisir, Alev/0000-0002-7538-7911 FU National Institutes of Health [F31NS059189, K25NS052422, RO1EY12138, RO1EYO12309] FX This research was supported by National Institutes of Health Grants F31NS059189 (M.N.), K25NS052422 (R.H.), RO1EY12138 (A.E.), and partly by RO1EYO12309 (M.F.B.). We thank Sam Cooke, Mikhail Frenkel, Lena Khibnik, Monica Linden, and Marshall Hussain Shuler for helpful discussions and comments. We also thank Suzanne Meagher, Kathleen Oram, Bonnie Shepard, Erik Sklar, and Vivian Tang for administrative and technical support. NR 60 TC 38 Z9 38 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 21 PY 2010 VL 30 IS 29 BP 9670 EP 9682 DI 10.1523/JNEUROSCI.1248-10.2010 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 629NL UT WOS:000280206500004 PM 20660250 ER PT J AU Lee, SH Kim, PJ Ahn, YY Jeong, H AF Lee, Sang Hoon Kim, Pan-Jun Ahn, Yong-Yeol Jeong, Hawoong TI Googling Social Interactions: Web Search Engine Based Social Network Construction SO PLOS ONE LA English DT Article ID COMMUNITY STRUCTURE; WEIGHTED NETWORKS; COMPLEX NETWORKS; SYSTEMS; STATES AB Social network analysis has long been an untiring topic of sociology. However, until the era of information technology, the availability of data, mainly collected by the traditional method of personal survey, was highly limited and prevented large-scale analysis. Recently, the exploding amount of automatically generated data has completely changed the pattern of research. For instance, the enormous amount of data from so-called high-throughput biological experiments has introduced a systematic or network viewpoint to traditional biology. Then, is "high-throughput'' sociological data generation possible? Google, which has become one of the most influential symbols of the new Internet paradigm within the last ten years, might provide torrents of data sources for such study in this (now and forthcoming) digital era. We investigate social networks between people by extracting information on the Web and introduce new tools of analysis of such networks in the context of statistical physics of complex systems or socio-physics. As a concrete and illustrative example, the members of the 109th United States Senate are analyzed and it is demonstrated that the methods of construction and analysis are applicable to various other weighted networks. C1 [Lee, Sang Hoon; Jeong, Hawoong] Korea Adv Inst Sci & Technol, Dept Phys, Taejon 305701, South Korea. [Kim, Pan-Jun] Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA. [Ahn, Yong-Yeol] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Ahn, Yong-Yeol] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Ahn, Yong-Yeol] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Jeong, Hawoong] Korea Adv Inst Sci & Technol, Inst BioCentury, Taejon 305701, South Korea. RP Lee, SH (reprint author), Korea Adv Inst Sci & Technol, Dept Phys, Taejon 305701, South Korea. EM hjeong@kaist.edu RI Lee, Sang Hoon/C-6327-2011; Jeong, Hawoong/C-1587-2011; Jeong, Hawoong/A-2469-2009 OI Jeong, Hawoong/0000-0002-2491-8620 FU NAP of Korea Research Council of Fundamental Science Technology FX This work was supported by NAP of Korea Research Council of Fundamental Science & Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 21 Z9 21 U1 2 U2 15 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 JUL 21 PY 2010 VL 5 IS 7 AR e11233 DI 10.1371/journal.pone.0011233 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 629KQ UT WOS:000280197500001 PM 20657762 ER PT J AU Siddappa, NB Watkins, JD Wassermann, KJ Song, RJ Wang, W Kramer, VG Lakhashe, S Santosuosso, M Poznansky, MC Novembre, FJ Villinger, F Else, JG Montefiori, DC Rasmussen, RA Ruprecht, RM AF Siddappa, Nagadenahalli B. Watkins, Jennifer D. Wassermann, Klemens J. Song, Ruijiang Wang, Wendy Kramer, Victor G. Lakhashe, Samir Santosuosso, Michael Poznansky, Mark C. Novembre, Francis J. Villinger, Francois Else, James G. Montefiori, David C. Rasmussen, Robert A. Ruprecht, Ruth M. TI R5 Clade C SHIV Strains with Tier 1 or 2 Neutralization Sensitivity: Tools to Dissect Env Evolution and to Develop AIDS Vaccines in Primate Models SO PLOS ONE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL DEPLETION; GP120 ENVELOPE GLYCOPROTEIN; ACUTE HIV-1 INFECTION; PASSAGED IN-VIVO; ANTIBODY-RESPONSE; TYPE-1 GP120; GASTROINTESTINAL-TRACT; LINKED GLYCOSYLATION; RHESUS-MONKEYS AB Background: HIV-1 clade C (HIV-C) predominates worldwide, and anti-HIV-C vaccines are urgently needed. Neutralizing antibody (nAb) responses are considered important but have proved difficult to elicit. Although some current immunogens elicit antibodies that neutralize highly neutralization-sensitive (tier 1) HIV strains, most circulating HIVs exhibiting a less sensitive (tier 2) phenotype are not neutralized. Thus, both tier 1 and 2 viruses are needed for vaccine discovery in nonhuman primate models. Methodology/Principal Findings: We constructed a tier 1 simian-human immunodeficiency virus, SHIV-1157ipEL, by inserting an "early,'' recently transmitted HIV-C env into the SHIV-1157ipd3N4 backbone [ 1] encoding a "late'' form of the same env, which had evolved in a SHIV-infected rhesus monkey (RM) with AIDS. SHIV-1157ipEL was rapidly passaged to yield SHIV-1157ipEL-p, which remained exclusively R5-tropic and had a tier 1 phenotype, in contrast to "late'' SHIV-1157ipd3N4 (tier 2). After 5 weekly low-dose intrarectal exposures, SHIV-1157ipEL-p systemically infected 16 out of 17 RM with high peak viral RNA loads and depleted gut CD4(+) T cells. SHIV-1157ipEL-p and SHIV-1157ipd3N4 env genes diverge mostly in V1/V2. Molecular modeling revealed a possible mechanism for the increased neutralization resistance of SHIV-1157ipd3N4 Env: V2 loops hindering access to the CD4 binding site, shown experimentally with nAb b12. Similar mutations have been linked to decreased neutralization sensitivity in HIV-C strains isolated from humans over time, indicating parallel HIV-C Env evolution in humans and RM. Conclusions/Significance: SHIV-1157ipEL-p, the first tier 1 R5 clade C SHIV, and SHIV-1157ipd3N4, its tier 2 counterpart, represent biologically relevant tools for anti-HIV-C vaccine development in primates. C1 [Siddappa, Nagadenahalli B.; Watkins, Jennifer D.; Wassermann, Klemens J.; Song, Ruijiang; Wang, Wendy; Kramer, Victor G.; Lakhashe, Samir; Rasmussen, Robert A.; Ruprecht, Ruth M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Siddappa, Nagadenahalli B.; Watkins, Jennifer D.; Song, Ruijiang; Lakhashe, Samir; Santosuosso, Michael; Poznansky, Mark C.; Rasmussen, Robert A.; Ruprecht, Ruth M.] Harvard Univ, Sch Med, Boston, MA USA. [Santosuosso, Michael; Poznansky, Mark C.] Massachusetts Gen Hosp E, Partners AIDS Res Ctr & Infect Dis Med, Charlestown, MA USA. [Novembre, Francis J.; Villinger, Francois; Else, James G.] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. [Novembre, Francis J.] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Villinger, Francois; Else, James G.] Emory Univ, Div Pathol & Lab Med, Atlanta, GA 30322 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Siddappa, NB (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM ruth_ruprecht@dfci.harvard.edu RI Lakhashe, Samir/F-1150-2014; OI Byrareddy, Siddappa /0000-0002-7423-1763 FU National Institutes of Health [P01 AI048240, R01 DE012937, R01 DE016013]; [RR-00165] FX This work was supported by National Institutes of Health grants P01 AI048240, R01 DE012937, and R01 DE016013 to R. M. R. Base grant RR-00165 provided support to the Yerkes National Primate Research Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 27 Z9 27 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 21 PY 2010 VL 5 IS 7 AR e11689 DI 10.1371/journal.pone.0011689 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 629KQ UT WOS:000280197500028 PM 20657739 ER PT J AU Segal, S Gelfand, BJ Hurwitz, S Berkowitz, L Ashley, SW Nadel, ES Katz, JT AF Segal, Scott Gelfand, Brian J. Hurwitz, Shelley Berkowitz, Lori Ashley, Stanley W. Nadel, Eric S. Katz, Joel T. TI Plagiarism in Residency Application Essays SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SUBSEQUENT DISCIPLINARY ACTION; RESEARCH PUBLICATIONS; MISREPRESENTATION; STUDENTS AB Background: Anecdotal reports suggest that some residency application essays contain plagiarized content. Objective: To determine the prevalence of plagiarism in a large cohort of residency application essays. Design: Retrospective cohort study. Setting: 4975 application essays submitted to residency programs at a single large academic medical center between 1 September 2005 and 22 March 2007. Measurements: Specialized software was used to compare residency application essays with a database of Internet pages, published works, and previously submitted essays and the percentage of the submission matching another source was calculated. A match of more than 10% to an existing work was defined as evidence of plagiarism. Results: Evidence of plagiarism was found in 5.2% (95% CI, 4.6% to 5.9%) of essays. The essays of non-U.S. citizens were more likely to demonstrate evidence of plagiarism. Other characteristics associated with the prevalence of plagiarism included medical school location outside the United States and Canada; previous residency or fellowship; lack of research experience, volunteer experience, or publications; a low United States Medical Licensing Examination Step 1 score; and nonmembership in the Alpha Omega Alpha Honor Medical Society. Limitations: The software database is probably incomplete, the 10%-match threshold for defining plagiarism has not been statistically validated, and the study was confined to applicants to 1 institution. Evidence of matching content in an essay cannot be used to infer the applicant's intent and is not sensitive to variations in the cultural context of copying in some societies. Conclusion: Evidence of plagiarism in residency application essays is more common in international applicants but was found in those by applicants to all specialty programs, from all medical school types, and even among applicants with significant academic honors. C1 [Segal, Scott] Harvard Univ, Dept Anesthesiol Perioperat & Pain Med, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Segal, S (reprint author), Harvard Univ, Dept Anesthesiol Perioperat & Pain Med, Sch Med, Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM bsegal@partners.org NR 32 TC 25 Z9 26 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 20 PY 2010 VL 153 IS 2 BP 112 EP W44 DI 10.7326/0003-4819-153-2-201007200-00007 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 628DU UT WOS:000280095400006 PM 20643991 ER PT J AU Berger, JS Bhatt, DL Steinhubl, SR Shao, M Lincoff, AM Steg, PG Montalescot, G Hacke, W Fox, KA Topol, EJ Berger, PB AF Berger, Jeffrey S. Bhatt, Deepak L. Steinhubl, Steven R. Shao, Mingyuan Lincoff, A. Michael Steg, P. Gabriel Montalescot, Gilles Hacke, Werner Fox, Keith A. Topol, Eric J. Berger, Peter B. CA CHARISMA Investigators TI Response to Letter Regarding Article, "Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease" SO CIRCULATION LA English DT Letter C1 [Berger, Jeffrey S.] NYU, Sch Med, New York, NY 10016 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Steinhubl, Steven R.] Med Co, Zurich, Switzerland. [Shao, Mingyuan; Lincoff, A. Michael] Cleveland Clin, Cleveland, OH 44106 USA. [Steg, P. Gabriel] Univ Paris, INSERM, U698, F-75252 Paris, France. [Montalescot, Gilles] CHU Pitie Salpetriere, Inst Cardiol, Paris, France. [Hacke, Werner] Univ Heidelberg, Heidelberg, Germany. [Fox, Keith A.] Univ & Royal Infirm Edinburgh, Edinburgh, Midlothian, Scotland. [Topol, Eric J.] Scripps Clin, La Jolla, CA 92037 USA. [Berger, Peter B.] Geisinger Med Ctr, Danville, PA 17822 USA. RP Berger, JS (reprint author), NYU, Sch Med, New York, NY 10016 USA. RI Walker, Philip/F-3034-2010; OI Topol, Eric/0000-0002-1478-4729 NR 2 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 20 PY 2010 VL 122 IS 3 BP E395 EP E395 DI 10.1161/CIRCULATIONAHA.110.951814 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 628FB UT WOS:000280098900015 ER PT J AU Xia, Q Wang, SB Kozanek, M Passias, P Wood, K Li, GA AF Xia, Qun Wang, Shaobai Kozanek, Michal Passias, Peter Wood, Kirkham Li, Guoan TI In-vivo motion characteristics of lumbar vertebrae in sagittal and transverse planes SO JOURNAL OF BIOMECHANICS LA English DT Article DE Lumbar spine; in-vivo; Spine kinematics; Range of motion; Center of rotation; Total disc replacement; Dynamic fusion ID TOTAL DISC REPLACEMENT; INVESTIGATIONAL DEVICE EXEMPTION; CARTILAGE CONTACT DEFORMATION; CHARITE(TM) ARTIFICIAL DISC; AXIAL ROTATION; INSTANTANEOUS AXIS; FOLLOW-UP; CLINICAL-OUTCOMES; FINITE-ELEMENT; SPINE AB Lumbar vertebrae are complicated in structure and function. The purpose of this study was to investigate the in-vivo motion characteristics of different portions of the lumbar vertebrae during functional activities. Motion of L2, L3 and L4 was reproduced using a combined dual fluoroscopic and MR imaging technique during flexion-extension and left-right twisting of the trunk. The ranges of motion (ROM) of the proximal vertebra with respect to the distal one at 3 representative locations: the center of the vertebral body, the center of the spinal canal and the tip of the spinous process were measured. Centers of rotation (COR) of the vertebrae were then determined by calculation of the points of zero motion in 2D sagittal and transverse planes. During flexion-extension, the center of the vertebral body moved less than 0.6 mm, while the tip of the spinous process moved less than 7.5 mm in the sagittal plane. The CORs of both L23 (L2 with respect to L3) and 134 were located inside the vertebral body, at a distance about one-third the length of the vertebral body from the posterior edge. During left-right twisting, the center of the vertebral body moved less than 1.0 mm, while the tip of the spinous process moved less than 1.6 mm in the transverse plane. The CORs of both L23 and L34 were located approximately 30 mm anterior to the front edge of the vertebral body. The results of this study may be used to define the ideal locations for surgical placement of the disc prosthesis, thus help improve the prosthesis design and surgical treatment of various pathological conditions. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Xia, Qun; Wang, Shaobai; Kozanek, Michal; Passias, Peter; Wood, Kirkham; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, Boston, MA 02114 USA. [Xia, Qun] Tianjin Orthopaed Hosp, Tianjin, Peoples R China. [Wang, Shaobai] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org FU NASS; ECOR Formulaic Bridge Funds; Department of Orthopaedic Surgery, Massachusetts General Hospital/Harvard Medical School FX Support from NASS Grant, ECOR Formulaic Bridge Funds and the Department of Orthopaedic Surgery, Massachusetts General Hospital/Harvard Medical School was greatly appreciated. NR 41 TC 22 Z9 27 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD JUL 20 PY 2010 VL 43 IS 10 BP 1905 EP 1909 DI 10.1016/j.jbiomech.2010.03.023 PG 5 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 630YR UT WOS:000280313300009 PM 20381051 ER PT J AU Malin, JL Diamant, AL Leake, B Liu, YH Thind, A Kahn, KL Schneider, EC Epstein, AM Maly, RC AF Malin, Jennifer L. Diamant, Allison L. Leake, Barbara Liu, Yihang Thind, Amardeep Kahn, Katherine L. Schneider, Eric C. Epstein, Arnold M. Maly, Rose C. TI Quality of Care for Breast Cancer for Uninsured Women in California Under the Breast and Cervical Cancer Prevention Treatment Act SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INSURANCE STATUS; UNITED-STATES; LOW-INCOME; STAGE; IMPLEMENTATION; DISPARITIES; SURVIVAL; OUTCOMES; SOCIETY; IMPACT AB Purpose The objective of this study was to evaluate the quality of care provided to uninsured women with breast cancer who received treatment through the Breast and Cervical Cancer Prevention Treatment Program (BCCTP). Methods Participants included women with stage I to III breast cancer (n = 658) from a consecutive sample of women 18 years or older who received coverage through the California BCCTP between February 2003 and September 2005 who consented to a survey and medical record review (61% response rate). Quality of breast cancer care was evaluated using 29 evidence-based quality measures developed for the National Initiative for Cancer Care Quality (NICCQ). NICCQ, a largely insured cohort of women diagnosed with stage I to III breast cancer in 1998, was used to benchmark the results. Results Twenty-three percent of women presented with stage III disease compared with fewer than 10% nationally. Patients received 93% of recommended care (95% CI, 92% to 93%). Adherence to recommended care within domains ranged from 87% for post-treatment surveillance (95% CI, 84% to 90%) to 97% for diagnostic evaluation (95% CI, 96% to 97%). Compared to the NICCQ cohort, adherence to quality measures was as good or better for the BCCPT cohort in all domains except post-treatment surveillance. Conclusion The BCCTP has made important inroads in providing poor, uninsured women with access to high quality care when faced with the diagnosis of breast cancer; however, many present at an advanced stage, which is associated with worse outcomes. C1 Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. RAND Corp, Santa Monica, CA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02115 USA. Univ Western Ontario, Schulich Sch Med, London, ON, Canada. RP Malin, JL (reprint author), VA Greater Los Angeles Healthcare Syst, Div Hematol Oncol 111 H, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM jennifer.malin@va.gov OI Schneider, Eric/0000-0002-1132-5084 FU American Cancer Society [TURSG-02-081]; California Breast Cancer Research Program [7PB-0070]; National Cancer Institute [R01CA119197-0181] FX Supported by Grant No. TURSG-02-081 from the American Cancer Society, Grant No. 7PB-0070 from the California Breast Cancer Research Program, and Grant No. R01CA119197-0181 from the National Cancer Institute. NR 27 TC 8 Z9 8 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 JUL 20 PY 2010 VL 28 IS 21 BP 3479 EP 3484 DI 10.1200/JCO.2009.27.7491 PG 6 WC Oncology SC Oncology GA 626YE UT WOS:000280003700013 PM 20530279 ER PT J AU Hezel, AF Deshpande, V Zhu, AX AF Hezel, Aram F. Deshpande, Vikram Zhu, Andrew X. TI Genetics of Biliary Tract Cancers and Emerging Targeted Therapies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID GROWTH-FACTOR-RECEPTOR; BILE-DUCT CANCER; INTRAHEPATIC CHOLANGIOCELLULAR CARCINOMA; INTRADUCTAL PAPILLARY NEOPLASM; PHASE-II TRIAL; K-RAS; GALLBLADDER CARCINOMA; INTRAEPITHELIAL NEOPLASIA; HEPATOCELLULAR-CARCINOMA; BETA-CATENIN AB Biliary tract cancers (BTC), which encompass intra-and extrahepatic cholangiocarcinomas and gallbladder carcinomas, are a genetically diverse collection of cancers. Evidence suggests distinct models of molecular and pathologic progression, and a growing body of genetics data points to a heterogeneous collection of underlying mutations in key oncogenes and tumor suppressor genes. Although tumor genetics have been used to tailor individual treatment regimens and guide clinical decision making in other cancers, these principles have not been applied in BTC. Recent clinical trials with targeted therapies seem promising, although the relationships between subsets of patients with positive responses to therapy and tumor genetics remain unexplored. Here, we summarize the molecular pathogenesis and genetics of BTCs and animal modeling and relate these to recent and ongoing clinical trials with targeted agents. C1 [Hezel, Aram F.] Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. RP Hezel, AF (reprint author), Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. EM Aram_Hezel@URMC.Rochester.edu FU Howard Hughes Medical Institute; NIHK08 Career Development Award FX Supported by a Howard Hughes Medical Institute Early Career Development Award (A.F.H.) and NIHK08 Career Development Award (A.F.H.). NR 116 TC 89 Z9 90 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 JUL 20 PY 2010 VL 28 IS 21 BP 3531 EP 3540 DI 10.1200/JCO.2009.27.4787 PG 10 WC Oncology SC Oncology GA 626YE UT WOS:000280003700020 PM 20547994 ER PT J AU Roe, MT Messenger, JC Weintraub, WS Cannon, CP Fonarow, GC Dai, D Chen, AY Klein, LW Masoudi, FA McKay, C Hewitt, K Brindis, RG Peterson, ED Rumsfeld, JS AF Roe, Matthew T. Messenger, John C. Weintraub, William S. Cannon, Christopher P. Fonarow, Gregg C. Dai, David Chen, Anita Y. Klein, Lloyd W. Masoudi, Frederick A. McKay, Charles Hewitt, Kathleen Brindis, Ralph G. Peterson, Eric D. Rumsfeld, John S. TI Treatments, Trends, and Outcomes of Acute Myocardial Infarction and Percutaneous Coronary Intervention SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute myocardial infarction; percutaneous coronary intervention; NCDR ID QUALITY-OF-CARE; ST-ELEVATION; PERFORMANCE; IMPLEMENTATION; BIVALIRUDIN; ASSOCIATION; MORTALITY; REGISTRY; CRUSADE; NETWORK C1 [Roe, Matthew T.; Dai, David; Chen, Anita Y.; Peterson, Eric D.] Duke Univ Med Ctr, Duke Clin Res Inst, Durham, NC 27705 USA. [Messenger, John C.; Masoudi, Frederick A.; Rumsfeld, John S.] Univ Colorado Denver, Aurora, CO USA. [Weintraub, William S.] Christiana Care Hlth Syst, Newark, DE USA. [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA. [Klein, Lloyd W.] Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. [Masoudi, Frederick A.] Denver Hlth Med Ctr, Denver, CO USA. [McKay, Charles] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Hewitt, Kathleen] Natl Cardiovasc Data Registry, Washington, DC USA. [Brindis, Ralph G.] No Calif Kaiser Permanente, San Francisco, CA USA. [Rumsfeld, John S.] Denver Vet Affairs Med Ctr, Denver, CO USA. RP Roe, MT (reprint author), Duke Univ Med Ctr, Duke Clin Res Inst, 2400 Pratt St,Room 7035, Durham, NC 27705 USA. EM matthew.roe@duke.edu FU Merck/Schering-Plough Corporation; Bristol-Myers Squibb/Sanofi Pharmaceutical; Eli Lilly; Bristol-Myers Squibb; Sanofi-Aventis; Merck/Schering-Plough; GlaxoSmithKline; Novartis; AstraZeneca; Accumetrics; Intekrin Therapeutics; Merck; Takeda; ACCF; Oklahoma Foundation for Medical Quality; Lilly; Johnson Johnson FX Denver Veterans Affairs Medical Center, Denver, Colorado. The NCDR ACTION Registry GWTG is a program of the American College of Cardiology and the American Heart Association that receives funding from the Merck/Schering-Plough Corporation and Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership. The CathPCI registry does not receive external funding. For complete author disclosures, please see the end of this paper.; Dr. Roe has received research funding from Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, and Merck/Schering-Plough; and consulting fees/honoraria from GlaxoSmithKline, Novartis, Eli Lilly, Bristol-Myers Squibb, Sanofi-Aventis, Merck/Schering-Plough, and AstraZeneca. Dr. Messenger is a Principal Investigator for the Resolute substudy, Medtronic Co. Dr. Cannon has received research grants/support from Accumetrics, AstraZeneca, GlaxoSmithKline, Intekrin Therapeutics, Merck, and Takeda; is on the advisory board of Bristol-Myers Squibb/Sanofi, Novartis, and Alnylam; and is a clincal advisor with equity in Automedics Medical Systems. Dr. Fonarow has received honoraria from Merck and Bristol-Myers Squibb/Sanofi. Dr. Klein is on the Speakers' Bureau of Pfizer, Lilly, and Daiichi-Sankyo. Dr. Masoudi has contracts with the ACCF and the Oklahoma Foundation for Medical Quality. Dr. McKay is an ACC-NCDR Senior Medical Officer. Dr. Peterson has received research support from Bristol-Myers Squibb/Sanofi, Merck/Schering-Plough, Lilly, and Johnson & Johnson. Dr. Rumsfeld is the Chief Science Officer for the NCDR. NR 22 TC 173 Z9 185 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 20 PY 2010 VL 56 IS 4 BP 254 EP 263 DI 10.1016/j.jacc.2010.05.008 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 628IG UT WOS:000280109300002 PM 20633817 ER PT J AU Mikheeva, SA Mikheev, AM Petit, A Beyer, R Oxford, RG Khorasani, L Maxwell, JP Glackin, CA Wakimoto, H Gonzalez-Herrero, I Sanchez-Garcia, I Silber, JR Horner, PJ Rostomily, RC AF Mikheeva, Svetlana A. Mikheev, Andrei M. Petit, Audrey Beyer, Richard Oxford, Robert G. Khorasani, Leila Maxwell, John-Patrick Glackin, Carlotta A. Wakimoto, Hiroaki Gonzalez-Herrero, Ines Sanchez-Garcia, Isidro Silber, John R. Horner, Philip J. Rostomily, Robert C. TI TWIST1 promotes invasion through mesenchymal change in human glioblastoma SO MOLECULAR CANCER LA English DT Article ID STEM-CELLS; BREAST-CANCER; GLIOMA INVASION; TUMOR INVASION; E-CADHERIN; EXPRESSION; TRANSITION; TRANSCRIPTION; BRAIN; MIGRATION AB Background: Tumor cell invasion into adjacent normal brain is a mesenchymal feature of GBM and a major factor contributing to their dismal outcomes. Therefore, better understandings of mechanisms that promote mesenchymal change in GBM are of great clinical importance to address invasion. We previously showed that the bHLH transcription factor TWIST1 which orchestrates carcinoma metastasis through an epithelial mesenchymal transition (EMT) is upregulated in GBM and promotes invasion of the SF767 GBM cell line in vitro. Results: To further define TWIST1 functions in GBM we tested the impact of TWIST1 over-expression on invasion in vivo and its impact on gene expression. We found that TWIST1 significantly increased SNB19 and T98G cell line invasion in orthotopic xenotransplants and increased expression of genes in functional categories associated with adhesion, extracellular matrix proteins, cell motility and locomotion, cell migration and actin cytoskeleton organization. Consistent with this TWIST1 reduced cell aggregation, promoted actin cytoskeletal re-organization and enhanced migration and adhesion to fibronectin substrates. Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. Distinct from carcinoma EMT, TWIST1 did not generate an E-to N-cadherin " switch" in GBM cell lines. The clinical relevance of putative TWIST target genes SNAI2 and fibroblast activation protein alpha (FAP) identified in vitro was confirmed by their highly correlated expression with TWIST1 in 39 human tumors. The potential therapeutic importance of inhibiting TWIST1 was also shown through a decrease in cell invasion in vitro and growth of GBM stem cells. Conclusions: Together these studies demonstrated that TWIST1 enhances GBM invasion in concert with mesenchymal change not involving the canonical cadherin switch of carcinoma EMT. Given the recent recognition that mesenchymal change in GBMs is associated with increased malignancy, these findings support the potential therapeutic importance of strategies to subvert TWIST1-mediated mesenchymal change. C1 [Mikheeva, Svetlana A.; Mikheev, Andrei M.; Petit, Audrey; Oxford, Robert G.; Khorasani, Leila; Maxwell, John-Patrick; Silber, John R.; Horner, Philip J.; Rostomily, Robert C.] Univ Washington, Sch Med, Dept Neurol Surg, Seattle, WA 98195 USA. [Mikheeva, Svetlana A.; Mikheev, Andrei M.; Petit, Audrey; Horner, Philip J.; Rostomily, Robert C.] Univ Washington, Sch Med, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. [Glackin, Carlotta A.] Beckman Res Inst City Hope, Div Mol Med, Duarte, CA 91010 USA. [Wakimoto, Hiroaki] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurosurg Lab, Boston, MA 02114 USA. [Gonzalez-Herrero, Ines; Sanchez-Garcia, Isidro] Univ Salamanca, CSIC, IBMCC, Expt Therapeut & Translat Oncol Program, Salamanca 37007, Spain. [Mikheev, Andrei M.] Petrov Res Inst Oncol, St Petersburg 197758, Russia. RP Rostomily, RC (reprint author), Univ Washington, Sch Med, Dept Neurol Surg, Seattle, WA 98195 USA. EM rosto@u.washington.edu RI IBSAL, Secretaria/H-3719-2011; Gonzalez, Ines/G-8546-2015; OI Gonzalez, Ines/0000-0003-1142-4362; SANCHEZ-GARCIA, ISIDRO/0000-0001-6989-9905 FU NIH/NINDS [T32-NS-0007144]; University of Washington Institutional Bridge; FEDER; MICINN [SAF2009-08803]; Junta de Castilla y Leon [CSI13A08, GR15]; MEC OncoBIO Consolider-Ingenio [CSD2007-0017]; Sandra Ibarra Foundation; NIH [R01 CA109335-04A1] FX We acknowledge Rosemary Kimmel for her expert editorial assistance, J. Barber for the help with statistical analysis, Drs Jing Zhang, Eduardo Mendez and Daniel Silbergeld for critical review of the manuscript, Theo Bammler and Frederico Farin of the UW CHDD Genomics Core for assistance with microarray studies, Glen MacDonald of the CHDD Cellular Morphology Core for assistance with development of whole brain tumor imaging techniques, Drs Daniel L Silbergeld, Alexander M Spence, Jason Rockhill, and Maciej Mrugala whose clinical efforts made this work possible. This research was funded in part through an NIH/NINDS T32-NS-0007144 Clinical Neuroscience Training Grant (RO, LK, JM) and a University of Washington Institutional Bridge Funding Grant (RCR, AKM). Research in ISG group is supported partially by FEDER and by MICINN (SAF2009-08803), Junta de Castilla y Leon (CSI13A08 and proyecto Biomedicina 2009-2010), MEC OncoBIO Consolider-Ingenio 2010 (Ref. CSD2007-0017), Sandra Ibarra Foundation, NIH grant (R01 CA109335-04A1) and by Group of Excellence Grant (GR15) from Junta de Castilla y Leon. There are no conflicts of interest. NR 55 TC 101 Z9 104 U1 3 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD JUL 20 PY 2010 VL 9 AR 194 DI 10.1186/1476-4598-9-194 PG 18 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 657ZL UT WOS:000282458000001 PM 20646316 ER PT J AU Ryan, JA Brunelle, JK Letai, A AF Ryan, Jeremy A. Brunelle, Joslyn K. Letai, Anthony TI Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4(+) CD8(+) thymocytes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE BCL-21; BIM; negative selection ID BCL-2 FAMILY-MEMBERS; T-CELL DEVELOPMENT; CYTOCHROME-C; MEMBRANE PERMEABILIZATION; BH3 DOMAINS; BAX; DEATH; PROTEINS; SURVIVAL; BIM AB It is well established that CD4(+) CD8(+) thymocytes are more sensitive to myriad death stimuli than CD4(+) or CD8(+) single positive (SP) thymocytes. The mechanism behind this hypersensitivity to apoptosis of CD4(+) CD8(+) thymocytes is not understood. To test whether the difference lay in the apoptotic preset of mitochondria, established by the BCL-2 family of proteins, we developed a method, FACS-based BH3 profiling. Using this tool, we could discriminate thymocyte subpopulations and demonstrate that mitochondria in double positive (DP) thymocytes are more primed for death than those in single positive counterparts. Loss of proapoptotic BIM, known to cause autoimmunity, also causes loss of "priming." Priming is a phenotype with physiologic consequences, which can be measured at the single-cell level in complex samples using FACS-based BH3 profiling. C1 [Ryan, Jeremy A.; Brunelle, Joslyn K.; Letai, Anthony] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Letai, Anthony] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Letai, A (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM anthony_letai@dfci.harvard.edu FU National Institutes of Health [R01CA129974] FX We thank John Daley for sharing FACS machine expertise, Joe Opferman and Nick Souders for advice, and Glenn Dranoff for very helpful critical comments. A.L. and J.A.R. gratefully acknowledge support from National Institutes of Health Grant R01CA129974. A.L. is a Leukemia and Lymphoma Society scholar. NR 34 TC 57 Z9 57 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 20 PY 2010 VL 107 IS 29 BP 12895 EP 12900 DI 10.1073/pnas.0914878107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 628TJ UT WOS:000280144500036 PM 20615979 ER PT J AU Koh, AS Kingston, RE Benoist, C Mathis, D AF Koh, Andrew S. Kingston, Robert E. Benoist, Christophe Mathis, Diane TI Global relevance of Aire binding to hypomethylated lysine-4 of histone-3 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromatin; epigenetic; T cells; thymus; immunological tolerance ID PHD FINGER; AUTOIMMUNE REGULATOR; IMMUNOLOGICAL-TOLERANCE; H3; TRANSCRIPTION; METHYLATION; DNMT3L; RECOGNITION; CHROMATIN; CELLS AB Aire promotes the ectopic expression of a repertoire of peripheral-tissue antigens (PTAs) in thymic medullary epithelial cells (MECs) to mediate deletional tolerance and thereby prevent autoimmunity. Binding of hypomethylated histone 3 (H3)-tails by Aire's plant homeodomain (PHD) finger is essential for Aire function in cultured cell models, prompting speculation that Aire-PHD:H3-tail interactions underlie targeting of Aire to weakly transcribed loci. To evaluate the role of Aire's PHD finger in MECs on a global scale in vivo, we complemented Aire-deficient mice with a mutant of Aire that inhibits its binding to hypomethylated H3K4 residues. Although the range of Aire-targeted genes was largely unaffected in these mice, the D299A mutation caused a global dampening of Aire's transcriptional impact, resulting in an autoimmune disease similar in profile to that of their Aire-deficient counterparts. To test whether a low H3K4 methylation state is sufficient for Aire targeting, we overexpressed an H3K4-specific demethylase in an Aire-dependent cultured cell system, and determined its capacity to extend Aire's transcriptional footprint. The range and magnitude of Aire-regulated genes was largely unaffected, the only genes additionally induced by Aire in this context being those already accessed for repression. In short, Aire's H3-binding module is necessary for Aire-mediated regulation of gene expression and central tolerance induction, but this influence is unlikely to reflect a targeting mechanism solely based on the recognition of hypomethylated H3K4 residues. C1 [Koh, Andrew S.; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Koh, Andrew S.; Kingston, Robert E.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Koh, Andrew S.; Kingston, Robert E.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Benoist, C (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM cbdm@hms.harvard.edu FU Manipulated NOD Mouse Core of the Juvenille Diabetes Research Foundation Center at Harvard Medical School; National Institutes of Health [RO1 DK60027, RO1 GM079641]; Ruth L. Kirschstein predoctoral fellowship [T32 DK07260] FX We thank Drs. Yang Shi and Shigeki Iwase (Department of Pathology, Harvard Medical School, Boston, MA) for reagents, and Matthew Simon and Adam Matthews for insightful discussions. We also thank Kristen Leatherbee, Scott Davis, Kimie Hattori, and John Stockton for technical assistance. This work was supported by the Manipulated NOD Mouse Core of the Juvenille Diabetes Research Foundation Center at Harvard Medical School, and by National Institutes of Health Grants RO1 DK60027 (to D.M. and C.B.), RO1 GM079641 (to R.E.K.), and a Ruth L. Kirschstein predoctoral fellowship, National Research Service Award T32 DK07260 (to A.S.K.). NR 32 TC 26 Z9 27 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 JUL 20 PY 2010 VL 107 IS 29 BP 13016 EP 13021 DI 10.1073/pnas.1004436107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 628TJ UT WOS:000280144500057 PM 20615959 ER PT J AU Haramati, S Chapnik, E Sztainberg, Y Eilam, R Zwang, R Gershoni, N McGlinn, E Heiser, PW Wills, AM Wirguin, I Rubin, LL Misawa, H Tabin, CJ Brown, R Chen, A Hornstein, E AF Haramati, Sharon Chapnik, Elik Sztainberg, Yehezkel Eilam, Raya Zwang, Raaya Gershoni, Noga McGlinn, Edwina Heiser, Patrick W. Wills, Anne-Marie Wirguin, Itzhak Rubin, Lee L. Misawa, Hidemi Tabin, Clifford J. Brown, Robert, Jr. Chen, Alon Hornstein, Eran TI miRNA malfunction causes spinal motor neuron disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ALS; Dicer; microRNA; motor neuron; neurodegeneration ID AMYOTROPHIC-LATERAL-SCLEROSIS; HEAVY NEUROFILAMENT SUBUNIT; RNA-BINDING PROTEIN; MUSCULAR-ATROPHY; MESSENGER-RNA; INTERMEDIATE-FILAMENTS; MICROPROCESSOR COMPLEX; TRANSGENIC MICE; SELECTIVE LOSS; MOUSE MODEL AB Defective RNA metabolism is an emerging mechanism involved in ALS pathogenesis and possibly in other neurodegenerative disorders. Here, we show that microRNA (miRNA) activity is essential for long-term survival of postmitotic spinal motor neurons (SMNs) in vivo. Thus, mice that do not process miRNA in SMNs exhibit hallmarks of spinal muscular atrophy (SMA), including sclerosis of the spinal cord ventral horns, aberrant end plate architecture, and myofiber atrophy with signs of denervation. Furthermore, a neurofilament heavy subunit previously implicated in motor neuron degeneration is specifically up-regulated in miRNA-deficient SMNs. We demonstrate that the heavy neurofilament subunit is a target of miR-9, a miRNA that is specifically down-regulated in a genetic model of SMA. These data provide evidence for miRNA function in SMN diseases and emphasize the potential role of miR-9-based regulatory mechanisms in adult neurons and neurodegenerative states. C1 [McGlinn, Edwina; Tabin, Clifford J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Haramati, Sharon; Sztainberg, Yehezkel; Zwang, Raaya; Chen, Alon] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. [Chapnik, Elik; Gershoni, Noga; Hornstein, Eran] Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. [Eilam, Raya] Weizmann Inst Sci, Dept Vet Resources, IL-76100 Rehovot, Israel. [Sztainberg, Yehezkel] Bar Ilan Univ, Leslie & Susan Gonda Goldschmied Multidisciplinar, IL-52900 Ramat Gan, Israel. [Heiser, Patrick W.; Rubin, Lee L.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Wills, Anne-Marie] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Wirguin, Itzhak] Ben Gurion Univ Negev, Soroka Med Ctr, Dept Neurol, IL-91352 Beer Sheva, Israel. [Misawa, Hidemi] Keio Univ, Dept Pharmacol, Fac Pharm, Tokyo 1608582, Japan. [Brown, Robert, Jr.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. RP Tabin, CJ (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. EM tabin@genetics.med.harvard.edu; alon.chen@weizmann.ac.il; eran.hornstein@weizmann.ac.il RI HORNSTEIN, ERAN/K-1340-2012; OI HORNSTEIN, ERAN/0000-0002-5534-1924; McGlinn, Edwina/0000-0002-1829-986X FU Israel Science Foundation; Britain-Israel Research and Academic Partnership; Nella and Leon Benoziyo Center for Neurological Disease; Estate of Flourence Blau; Wolfson Family Charitable Trust for miRNA; Israel Ministry of Health; Nella and Leon Benoziyo Center for Neurosciences; Spinal Muscular Atrophy Foundation; Harvard Stem Cell Institute FX We thank Menachem Segal, Eithan Galun, Avraham Yaron, and Yoram Groner for feedback on the work; Mike Fainzilber and Benny Shilo for remarks on the manuscript; Tali Zimmerman and Judith Chermesh for mouse husbandry; Dena Leshkowitz and Ester Feldmesser for statistics; and Cherill Banks for editorial assistance. E. H. is the incumbent of the Helen and Milton A. Kimmelman Career Development Chair. A.C. is the incumbent of the Philip Harris and Gerald Ronson Career Development Chair. This work was supported by research grants (to E.H.) from the Israel Science Foundation Legacy program, Britain-Israel Research and Academic Partnership, Nella and Leon Benoziyo Center for Neurological Disease, Estate of Flourence Blau, and Wolfson Family Charitable Trust for miRNA and by research grants (to A.C.) from the Israel Science Foundation, Israel Ministry of Health, Nella and Leon Benoziyo Center for Neurosciences, Roberto and Renata Ruhman, Mr. and Mrs. Mike Kahn, Mr. Jorge David Ashkenazi, and Mr. and Mrs. Barry Wolfe. Work at the lab of L.L.R. is supported by the Spinal Muscular Atrophy Foundation and by the Harvard Stem Cell Institute. NR 73 TC 121 Z9 128 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 JUL 20 PY 2010 VL 107 IS 29 BP 13111 EP 13116 DI 10.1073/pnas.1006151107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 628TJ UT WOS:000280144500073 PM 20616011 ER PT J AU Lee, BY Popovich, MJ Ye, TA Bailey, RR Ufberg, PJ Wiringa, AE Muder, RR AF Lee, Bruce Y. Popovich, Michael J. Ye Tian Bailey, Rachel R. Ufberg, Paul J. Wiringa, Ann E. Muder, Robert R. TI The potential value of Clostridium difficile vaccine: An economic computer simulation model SO VACCINE LA English DT Article DE Clostridium difficile; Vaccine; Economics; Computer simulation ID IMMUNE-RESPONSE; TOXIN-A; COLITIS; DIARRHEA; DISEASE; VANCOMYCIN; METRONIDAZOLE; IMMUNIZATION; INFECTION; TRIAL AB Efforts are currently underway to develop a vaccine against Clostridium difficile infection (CDI). We developed two decision analytic Monte Carlo computer simulation models: (1) an Initial Prevention Model depicting the decision whether to administer C. difficile vaccine to patients at-risk for CDI and (2) a Recurrence Prevention Model depicting the decision whether to administer C. difficile vaccine to prevent CDI recurrence. Our results suggest that a C. difficile vaccine could be cost-effective over a wide range of C. difficile risk, vaccine costs, and vaccine efficacies especially, when being used post-CDI treatment to prevent recurrent disease. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Lee, Bruce Y.; Popovich, Michael J.; Ye Tian; Bailey, Rachel R.; Ufberg, Paul J.; Wiringa, Ann E.] Univ Pittsburgh, Publ Hlth Computat & Operat Res Grp PHICOR, Pittsburgh, PA 15213 USA. [Lee, Bruce Y.; Popovich, Michael J.; Ye Tian; Bailey, Rachel R.; Ufberg, Paul J.; Wiringa, Ann E.] Univ Pittsburgh, Dept Biomed Informat, Pittsburgh, PA 15213 USA. [Lee, Bruce Y.; Popovich, Michael J.; Ye Tian; Bailey, Rachel R.; Ufberg, Paul J.; Wiringa, Ann E.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. [Muder, Robert R.] Univ Pittsburgh, Div Infect Dis, VA Pittsburgh Hlth Syst, Pittsburgh, PA 15213 USA. RP Lee, BY (reprint author), Univ Pittsburgh, Publ Hlth Computat & Operat Res Grp PHICOR, 200 Meyran Ave,Suite 200, Pittsburgh, PA 15213 USA. EM BYL1@pitt.edu OI Slayton, Rachel/0000-0003-4699-8040 FU National Institute of General Medical Sciences Models of Infectious Disease Agent Study (MIDAS) [1U54GM088491-0109]; Pennsylvania Department of Health; Bill and Melinda Gates Foundation FX This study was supported by the National Institute of General Medical Sciences Models of Infectious Disease Agent Study (MIDAS) grant 1U54GM088491-0109, the Pennsylvania Department of Health, and the Vaccine Modeling Initiative (VMI), funded by the Bill and Melinda Gates Foundation. 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. NR 55 TC 29 Z9 29 U1 1 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 JUL 19 PY 2010 VL 28 IS 32 BP 5245 EP 5253 DI 10.1016/j.vaccine.2010.05.062 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 639QF UT WOS:000280988600015 PM 20541582 ER PT J AU Wang, TJ Zhang, F Richards, JB Kestenbaum, B van Meurs, JB Berry, D Kiel, DP Streeten, EA Ohlsson, C Koller, DL Peltonen, L Cooper, JD O'Reilly, PF Houston, DK Glazer, NL Vandenput, L Peacock, M Shi, J Rivadeneira, F McCarthy, MI Anneli, P de Boer, IH Mangino, M Kato, B Smyth, DJ Booth, SL Jacques, PF Burke, GL Goodarzi, M Cheung, CL Wolf, M Rice, K Goltzman, D Hidiroglou, N Ladouceur, M Wareham, NJ Hocking, LJ Hart, D Arden, NK Cooper, C Malik, S Fraser, WD Hartikainen, AL Zhai, GJ Macdonald, HM Forouhi, NG Loos, RJF Reid, DM Hakim, A Dennison, E Liu, YM Power, C Stevens, HE Jaana, L Vasan, RS Soranzo, N Bojunga, J Psaty, BM Lorentzon, M Foroud, T Harris, TB Hofman, A Jonsson, JO Cauley, JA Uitterlinden, AG Gibson, Q Jarvelin, MR Karasik, D Siscovick, DS Econs, MJ Kritchevsky, SB Florez, JC Todd, JA Dupuis, J Hypponen, E Spector, TD AF Wang, Thomas J. Zhang, Feng Richards, J. Brent Kestenbaum, Bryan van Meurs, Joyce B. Berry, Diane Kiel, Douglas P. Streeten, Elizabeth A. Ohlsson, Claes Koller, Daniel L. Peltonen, Leena Cooper, Jason D. O'Reilly, Paul F. Houston, Denise K. Glazer, Nicole L. Vandenput, Liesbeth Peacock, Munro Shi, Julia Rivadeneira, Fernando McCarthy, Mark I. Anneli, Pouta de Boer, Ian H. Mangino, Massimo Kato, Bernet Smyth, Deborah J. Booth, Sarah L. Jacques, Paul F. Burke, Greg L. Goodarzi, Mark Cheung, Ching-Lung Wolf, Myles Rice, Kenneth Goltzman, David Hidiroglou, Nick Ladouceur, Martin Wareham, Nicholas J. Hocking, Lynne J. Hart, Deborah Arden, Nigel K. Cooper, Cyrus Malik, Suneil Fraser, William D. Hartikainen, Anna-Liisa Zhai, Guangju Macdonald, Helen M. Forouhi, Nita G. Loos, Ruth J. F. Reid, David M. Hakim, Alan Dennison, Elaine Liu, Yongmei Power, Chris Stevens, Helen E. Jaana, Laitinen Vasan, Ramachandran S. Soranzo, Nicole Bojunga, Joerg Psaty, Bruce M. Lorentzon, Mattias Foroud, Tatiana Harris, Tamara B. Hofman, Albert Jonsson, John-Olov Cauley, Jane A. Uitterlinden, Andre G. Gibson, Quince Jarvelin, Marjo-Riitta Karasik, David Siscovick, David S. Econs, Michael J. Kritchevsky, Stephen B. Florez, Jose C. Todd, John A. Dupuis, Josee Hyppoenen, Elina Spector, Timothy D. TI Common genetic determinants of vitamin D insufficiency: a genome-wide association study SO LANCET LA English DT Article ID D-BINDING PROTEIN; RANDOMIZED CONTROLLED-TRIALS; LEMLI-OPITZ-SYNDROME; D DEFICIENCY; SERUM 25-HYDROXYVITAMIN-D; PLASMA-CONCENTRATIONS; D SUPPLEMENTATION; CANCER RISK; METAANALYSIS; CALCIUM AB Background Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. Methods We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Findings Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-22) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2-16, p=1.0x10(-26)) compared with those in the lowest quartile. Interpretation Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. C1 [Wang, Thomas J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kiel, Douglas P.; Cheung, Ching-Lung; Karasik, David] Hebrew SeniorLife, Inst Aging Res, Genet Epidemiol Program, Boston, MA USA. [Wang, Thomas J.; Florez, Jose C.] Harvard Univ, Sch Med, Boston, MA USA. [Wang, Thomas J.; Kiel, Douglas P.; Vasan, Ramachandran S.; Dupuis, Josee] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Zhang, Feng; Mangino, Massimo; Kato, Bernet; Hart, Deborah; Zhai, Guangju; Soranzo, Nicole; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Richards, J. Brent; Ladouceur, Martin] McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada. [Goltzman, David] McGill Univ, Ctr Hlth, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent; Goltzman, David; Ladouceur, Martin] McGill Univ, Dept Med, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent; Ladouceur, Martin] McGill Univ, Dept Human Genet, Montreal, PQ H3T 1E2, Canada. [Richards, J. Brent; Ladouceur, Martin] McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ H3T 1E2, Canada. [Kestenbaum, Bryan; de Boer, Ian H.] Univ Washington, Harborview Med Ctr, Kidney Res Inst, Div Nephrol, Seattle, WA 98104 USA. [Glazer, Nicole L.; Rice, Kenneth; Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Med, Seattle, WA 98104 USA. [Glazer, Nicole L.; Rice, Kenneth; Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA. [Psaty, Bruce M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98104 USA. [van Meurs, Joyce B.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Gibson, Quince] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Hofman, Albert; Uitterlinden, Andre G.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC, Dept Klin Genet, Rotterdam, Netherlands. [van Meurs, Joyce B.; Rivadeneira, Fernando; Hofman, Albert; Uitterlinden, Andre G.] NGI, Sponsored NCHA, Rotterdam, Netherlands. [Berry, Diane; Power, Chris; Hyppoenen, Elina] UCL, Inst Child Hlth, MRC Ctr Epidemiol Child Hlth, London, England. [Berry, Diane; Power, Chris; Hyppoenen, Elina] Ctr Paediat Epidemiol & Biostat, London, England. [Streeten, Elizabeth A.; Shi, Julia] Univ Maryland, Sch Med, Div Endocrinol, Baltimore, MD 21201 USA. [Ohlsson, Claes; Vandenput, Liesbeth; Lorentzon, Mattias] Univ Gothenburg, Inst Med, Dept Internal Med, Sahlgrenska Acad, Gothenburg, Sweden. [Jonsson, John-Olov] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden. [Koller, Daniel L.; Peacock, Munro; Foroud, Tatiana; Econs, Michael J.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Peltonen, Leena; Soranzo, Nicole] Wellcome Trust Sanger Inst, Hinxton, England. [Peltonen, Leena] Univ Helsinki, Helsinki, Finland. [Peltonen, Leena] Inst Mol Med Finland, Natl Inst Hlth & Welf, Helsinki, Finland. [Cooper, Jason D.; Smyth, Deborah J.; Stevens, Helen E.; Todd, John A.] Univ Cambridge, JDRF WT Diabet & Inflammat Lab, Cambridge, England. [O'Reilly, Paul F.; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, Fac Med, London, England. [Houston, Denise K.; Liu, Yongmei; Kritchevsky, Stephen B.] Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Burke, Greg L.] Wake Forest Univ, Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [McCarthy, Mark I.] Univ Oxford, OCDEM, Oxford, England. [McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Arden, Nigel K.; Cooper, Cyrus] Univ Oxford, NIHR Musculoskeletal Biomed Res Unit, Oxford, England. [McCarthy, Mark I.] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England. [Anneli, Pouta; Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Oulu, Finland. [Booth, Sarah L.; Jacques, Paul F.] Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer USDA, Boston, MA 02111 USA. [Goodarzi, Mark] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Wolf, Myles] Univ Miami, Miller Sch Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. [Cheung, Ching-Lung] ASTAR, Genome Inst Singapore Computat & Math Biol, Singapore, Singapore. [Hidiroglou, Nick] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Wareham, Nicholas J.; Forouhi, Nita G.; Loos, Ruth J. F.] Addenbrookes Hosp, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England. [Hocking, Lynne J.; Macdonald, Helen M.; Reid, David M.] Univ Aberdeen, Div Appl Med, Bone & Musculoskeletal Res Programme, Aberdeen, Scotland. [Arden, Nigel K.; Cooper, Cyrus; Dennison, Elaine] Univ Southampton, MRC Epidemiol Resource Ctr, Southampton, Hants, England. [Malik, Suneil] Publ Hlth Agcy Canada, Off Biotechnol Genom & Populat Hlth, Toronto, ON, Canada. [Fraser, William D.] Univ Liverpool, Unit Clin Chem, Sch Clin Sci, Liverpool L69 3BX, Merseyside, England. [Hartikainen, Anna-Liisa] Univ Oulu, Dept Obstet & Gynaecol, Oulu, Finland. [Jaana, Laitinen; Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Hakim, Alan] Whipps Cross Univ Hosp, Dept Rheumatol, London, England. [Jaana, Laitinen] Finnish Inst Occupat Hlth, Oulu, Finland. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Div Prevent Med, Boston, MA 02118 USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Bojunga, Joerg] Klinikum Johann Wolfgang Goethe Univ, Frankfurt, Germany. [Harris, Tamara B.] NIA, NIH, Bethesda, MD 20892 USA. [Cauley, Jane A.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. RP Spector, TD (reprint author), Kings Coll London, Dept Twin Res & Genet Epidemiol, St Thomas Hosp Campus,1st Floor S Wing Block 4,We, London SE1 7EH, England. EM tjwang@partners.org; e.hypponen@ich.ucl.ac.uk; tim.spector@kcl.ac.uk RI CHEUNG, Ching-Lung/C-2529-2012; Spector, Tim/F-6533-2012; Rice, Kenneth/A-4150-2013; Hypponen, Elina/B-2596-2014; Rivadeneira, Fernando/O-5385-2015; Osborne, Nicholas/N-4915-2015; mangino, massimo/F-5134-2011; OI Dupuis, Josee/0000-0003-2871-3603; Kritchevsky, Stephen/0000-0003-3336-6781; Kiel, Douglas/0000-0001-8474-0310; Karasik, David/0000-0002-8826-0530; Forouhi, Nita/0000-0002-5041-248X; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Vandenput, Liesbeth/0000-0002-1712-6131; Cauley, Jane A/0000-0003-0752-4408; Cheung, Ching Lung/0000-0002-6233-9144; Hocking, Lynne J/0000-0002-2414-2826; Ramachandran, Vasan/0000-0001-7357-5970; Rice, Kenneth/0000-0001-5779-4495; Hypponen, Elina/0000-0003-3670-9399; Rivadeneira, Fernando/0000-0001-9435-9441; Osborne, Nicholas/0000-0002-6700-2284; mangino, massimo/0000-0002-2167-7470; Soranzo, Nicole/0000-0003-1095-3852; smyth, deborah/0000-0002-6330-2669 FU Novartis; Roche; Amgen; NIH/NHLBI [N01-HC-25195]; American Heart Association; US Department of Agriculture, Agricultural Research Service [58-1950-7-707]; National Institute of Aging [AG14759]; National Institute of Arthritis, Musculoskeletal, and Skin Diseases; National Institute on Aging [R01 AR/AG 41398]; Affymetrix Inc [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Wellcome Trust; Arthritis Research Campaign; European Community [FP7/2007-2013, HEALTH-F2-2008-201865-GEFOS, 200800, OA /(FP7/2007-2013), HEALTH-F4-2007-201413, QLG2-CT-2002-01254]; UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre; Biotechnology and Biological Sciences Research Council [G20234]; National Eye Institute (NEI) via an NIH/Center for Inherited Disease Research (CIDR); Netherlands Organization of Scientific Research (NWO) [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015: RIDE2]; Netherlands Genomics Initiative/NWO [050-060-810]; European Commission [HEALTH-F2-2008-201865-GEFOS, HEALTH-F2-2008-00-TREAT-OA]; Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development; Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission; Municipality of Rotterdam FX TJW has served on the scientific advisory board of Diasorin. DKH has received honoraria from Abbott Nutrition. MW has received consultancy fees, honoraria, and speakers' fees from Abbott and Genzyme. DMR has acted as a consultant for Novartis, Roche, Pfizer, Amgen, Shire, Merck, and Servier, has received speakers' fees from Novartis, Roche, and Amgen, and owns stock in GlaxoSmithKline and Astra Zeneca. ML(2) has received lecture fees from Novartis and Sanofi-Aventis. All other authors declare that they have no conflicts of interest.; Framingham Heart Study The Framingham Heart Study of the National Heart, Lung and Blood Institute (NHLBI) of the US National Institutes of Health (NIH) and Boston University School of Medicine is supported by the NIH/NHLBI contract N01-HC-25195. The present study received support from the American Heart Association, the US Department of Agriculture, Agricultural Research Service (under Cooperative Agreement No 58-1950-7-707), and the National Institute of Aging (AG14759). DK was supported by a grant from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases and the National Institute on Aging (R01 AR/AG 41398). The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource project. This work was partly supported by a contract with Affymetrix Inc for genotyping services (Contract No N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis, which is funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Twins UK and Chingford The study was funded by the Wellcome Trust, Arthritis Research Campaign, European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F2-2008-201865-GEFOS and Seventh Framework Programme grant 200800 Treat OA /(FP7/2007-2013), ENGAGE project grant agreement HEALTH-F4-2007-201413, and the FP.5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from the UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. TDS is an NIHR senior investigator. The project also received support from a Biotechnology and Biological Sciences Research Council project grant. (G20234). The authors acknowledge the funding and support of the National Eye Institute (NEI) via an NIH/Center for Inherited Disease Research (CIDR) genotyping project. We thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, quality control, and genotyping; Le Centre National de Genotypage, France, for genotyping; Duke University, NC, USA, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki. Genotyping was also done by CIDR as part of an NEI/NIH project grant. The Rotterdam Study This study was funded by the Netherlands Organization of Scientific Research (NWO) Investments (175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015: RIDE2), the Netherlands Genomics Initiative/NWO project 050-060-810, and the European Commission (HEALTH-F2-2008-201865-GEFOS, and HEALTH-F2-2008-00-TREAT-OA). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We thank the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. NR 34 TC 616 Z9 631 U1 3 U2 49 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUL 17 PY 2010 VL 376 IS 9736 BP 180 EP 188 DI 10.1016/S0140-6736(10)60588-0 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 630YP UT WOS:000280313100025 PM 20541252 ER PT J AU Heilig, EA Xia, WM Shen, J Kelleher, RJ AF Heilig, Elizabeth A. Xia, Weiming Shen, Jie Kelleher, Raymond J., III TI A Presenilin-1 Mutation Identified in Familial Alzheimer Disease with Cotton Wool Plaques Causes a Nearly Complete Loss of gamma-Secretase Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMYLOID PRECURSOR PROTEIN; TERMINAL PAL MOTIF; A-BETA; SPASTIC PARAPARESIS; TRANSGENIC MICE; CAENORHABDITIS-ELEGANS; INTRACELLULAR DOMAINS; CATALYTIC SITE; APP; DEPOSITION AB Mutations in presenilin-1 and presenilin-2 (PS1 and PS2) are the most common cause of familial Alzheimer disease. PS1 and PS2 are the presumptive catalytic components of the multisub-unit gamma-secretase complex, which proteolyzes a number of type I transmembrane proteins, including the amyloid precursor protein (APP) and Notch. APP processing by gamma-secretase produces beta-amyloid peptides (A beta 40 and A beta 42) that accumulate in the Alzheimer disease brain. Here we identify a pathogenic L435F mutation in PS1 in two affected siblings with early-onset familial Alzheimer disease characterized by deposition of cerebral cotton wool plaques. The L435F mutation resides in a conserved C-terminal PAL sequence implicated in active site conformation and catalytic activity. The impact of PS1 mutations in and around the PAL motif on gamma-secretase activity was assessed by expression of mutant PS1 in mouse embryo fibroblasts lacking endogenous PS1 and PS2. Surprisingly, the L435F mutation caused a nearly complete loss of gamma-secretase activity, including > 90% reductions in the generation of A beta 40, A beta 42, and the APP and Notch intracellular domains. Two nonpathogenic PS1 mutations, P433L and L435R, caused essentially complete loss of gamma-secretase activity, whereas two previously identified pathogenic PS1 mutations, P436Q and P436S, caused partial loss of function with substantial reductions in production of A beta 40, A beta 42, and the APP and Notch intracellular domains. These results argue against overproduction of A beta 42 as an essential property of presenilin proteins bearing pathogenic mutations. Rather, our findings provide support for the hypothesis that pathogenic mutations cause a general loss of presenilin function. C1 [Heilig, Elizabeth A.; Kelleher, Raymond J., III] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Heilig, Elizabeth A.; Kelleher, Raymond J., III] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Xia, Weiming; Shen, Jie] Brigham & Womens Hosp, Dept Neurol, Ctr Neurol Dis, Boston, MA 02115 USA. [Heilig, Elizabeth A.; Xia, Weiming; Shen, Jie; Kelleher, Raymond J., III] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Heilig, Elizabeth A.; Xia, Weiming; Shen, Jie; Kelleher, Raymond J., III] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Kelleher, RJ (reprint author), MGH Simches Res Ctr, CPZN 6234,185 Cambridge St, Boston, MA 02114 USA. EM kelleher@helix.mgh.harvard.edu RI xia, weiming/E-5465-2016 OI xia, weiming/0000-0002-7463-3295 FU Alzheimer's Association; National Institutes of Health (NINDS) [R01 NS41783]; National Institutes of Health Training [T32 AG000222-18] FX This work was supported, in whole or in part, by grants from the Alzheimer's Association (to J.S. and R.J.K.) and by National Institutes of Health Grant R01 NS41783 (NINDS; to J.S.).; Supported by National Institutes of Health Training Grant T32 AG000222-18. NR 58 TC 30 Z9 32 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 16 PY 2010 VL 285 IS 29 BP 22350 EP 22359 DI 10.1074/jbc.M110.116962 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 622YF UT WOS:000279702200048 PM 20460383 ER PT J AU Orkin, SH Higgs, DR AF Orkin, Stuart H. Higgs, Douglas R. TI MEDICINE Sickle Cell Disease at 100 Years SO SCIENCE LA English DT Editorial Material ID FETAL-HEMOGLOBIN; BETA-THALASSEMIA; RISK-FACTORS; ANEMIA; BCL11A; EXPRESSION; BURDEN C1 [Orkin, Stuart H.] Childrens Hosp, Boston, MA 02115 USA. [Orkin, Stuart H.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA 02115 USA. [Higgs, Douglas R.] John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford 0X3 9DS, England. RP Orkin, SH (reprint author), Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu FU Howard Hughes Medical Institute; NHLBI NIH HHS [R01 HL032259] NR 21 TC 19 Z9 20 U1 0 U2 7 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 16 PY 2010 VL 329 IS 5989 BP 291 EP 292 DI 10.1126/science.1194035 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 625VW UT WOS:000279925900030 PM 20647458 ER PT J AU Kao, KK Fink, MP AF Kao, Kenneth K. Fink, Mitchell P. TI The biochemical basis for the anti-inflammatory and cytoprotective actions of ethyl pyruvate and related compounds SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE ROS; Inflammation; NF-kappaB; Glyoxalase; Janus-associated kinase ID NF-KAPPA-B; SEVERE ACUTE-PANCREATITIS; ISCHEMIA-REPERFUSION INJURY; WIDE THERAPEUTIC WINDOW; HUMAN ENDOTHELIAL-CELLS; DIRECTLY TARGETING P65; DISTANT ORGAN INJURY; HEMORRHAGIC-SHOCK; IMPROVES SURVIVAL; OXIDATIVE STRESS AB Pyruvate is an important metabolic intermediate, and also is an effective scavenger of hydrogen peroxide and other reactive oxygen species (ROS). Pharmacological administration of pyruvate has been shown to improve organ function in animal models of oxidant-mediated cellular injury. However, pyruvate is relatively unstable in aqueous solutions, which could limit the therapeutic potential of this compound. Ethyl pyruvate (EP), a simple derivative of pyruvic acid, is also an ROS scavenger, but seems to exert pharmacological effects, such as suppression of inflammation, which are at least quantitatively different and in some instances are qualitatively distinct from those exerted by pyruvate anion. Treatment with EP has been shown to improve survival and/or ameliorate organ dysfunction in a wide variety of pre-clinical models of acute illnesses, such as severe sepsis, acute pancreatitis and stroke. Using other animal models, some studies have demonstrated that more prolonged treatment with EP can ameliorate inflammatory bowel disease or slow the rate of growth of malignant tumors. In a clinical trial of patients undergoing cardiac surgery, treatment with EP was shown to be safe, but it failed to improve outcome. The true therapeutic potential of EP and related compounds remains to be elucidated. In this review, some of the biochemical mechanisms, which might be responsible for the pharmacological effects of EP, are discussed. Published by Elsevier Inc. C1 [Kao, Kenneth K.; Fink, Mitchell P.] VA Greater Angeles Hlth Care Syst, Dept Surg, Los Angeles, CA USA. [Kao, Kenneth K.; Fink, Mitchell P.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Fink, Mitchell P.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Los Angeles, CA 90095 USA. RP Fink, MP (reprint author), VA Greater Los Angeles UCLA, Dept Surg, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM Mitchell.Fink@va.gov RI Ji, Haofeng/G-6206-2012 NR 104 TC 84 Z9 87 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JUL 15 PY 2010 VL 80 IS 2 BP 151 EP 159 DI 10.1016/j.bcp.2010.03.007 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 599UN UT WOS:000277939300001 PM 20230800 ER PT J AU Baumgartner, C Lewis, GD Netzer, M Pfeifer, B Gerszten, RE AF Baumgartner, Christian Lewis, Gregory D. Netzer, Michael Pfeifer, Bernhard Gerszten, Robert E. TI A new data mining approach for profiling and categorizing kinetic patterns of metabolic biomarkers after myocardial injury SO BIOINFORMATICS LA English DT Article ID FEATURE-SELECTION TECHNIQUES; MASS-SPECTROMETRY; DISCOVERY; BIOINFORMATICS; ISCHEMIA; DISEASE; HYPOXANTHINE; INFARCTION; ALGORITHM; XANTHINE AB Motivation: The discovery of new and unexpected biomarkers in cardiovascular disease is a highly data-driven process that requires the complementary power of modern metabolite profiling technologies, bioinformatics and biostatistics. Clinical biomarkers of early myocardial injury are lacking. A prospective biomarker cohort study was carried out to identify, categorize and profile kinetic patterns of early metabolic biomarkers of planned myocardial infarction (PMI) and spontaneous (SMI) myocardial infarction. We applied a targeted mass spectrometry (MS)-based metabolite profiling platform to serial blood samples drawn from carefully phenotyped patients undergoing alcohol septal ablation for hypertrophic obstructive cardiomyopathy serving as a human model of PMI. Patients with SMI and patients undergoing catheterization without induction of myocardial infarction served as positive and negative controls to assess generalizability of markers identified in PMI. Results: To identify metabolites of high predictive value in tandem mass spectrometry data, we introduced a new feature selection method for the categorization of metabolic signatures into three classes of weak, moderate and strong predictors, which can be easily applied to both paired and unpaired samples. Our paradigm outperformed standard null-hypothesis significance testing and other popular methods for feature selection in terms of the area under the receiver operating curve and the product of sensitivity and specificity. Our results emphasize that this new method was able to identify, classify and validate alterations of levels in multiple metabolites participating in pathways associated with myocardial injury as early as 10 min after PMI. C1 [Baumgartner, Christian; Netzer, Michael; Pfeifer, Bernhard] Univ Hlth Sci Med Informat & Technol UMIT, Inst Elect Elect & Bioengn, Res Grp Clin Bioinformat, A-6060 Hall In Tirol, Austria. [Lewis, Gregory D.; Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Lewis, Gregory D.; Gerszten, Robert E.] Harvard Univ, Sch Med, Donald W Reynolds Cardiovasc Clin Res Ctr Atheros, Boston, MA USA. [Lewis, Gregory D.; Gerszten, Robert E.] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Baumgartner, C (reprint author), Univ Hlth Sci Med Informat & Technol UMIT, Inst Elect Elect & Bioengn, Res Grp Clin Bioinformat, A-6060 Hall In Tirol, Austria. EM christian.baumgartner@umit.at FU Austrian Genome Program GEN-AU; NIH [K23HL091106, R01 HL072872, U01HL083141, R01DK081572]; Donald W. Reynolds Foundation; Foundation Leducq; American Heart Association; Established Investigator Award FX Austrian Genome Program GEN-AU, project 'Bioinformatics Integration Network' (to C.B. and M.N.); NIH (K23HL091106 to G.D.L. and R01 HL072872, U01HL083141 and R01DK081572 to R.E.G.); the Donald W. Reynolds Foundation (to R.E.G.); Foundation Leducq (to R.E.G.); American Heart Association Fellow-to-Faculty Award (to G.D.L.); Established Investigator Award (to R.E.G.). NR 30 TC 14 Z9 16 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUL 15 PY 2010 VL 26 IS 14 BP 1745 EP 1751 DI 10.1093/bioinformatics/btq254 PG 7 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 620BQ UT WOS:000279474400010 PM 20483816 ER PT J AU Beaver, JE Tasan, M Gibbons, FD Tian, WD Hughes, TR Roth, FP AF Beaver, John E. Tasan, Murat Gibbons, Francis D. Tian, Weidong Hughes, Timothy R. Roth, Frederick P. TI FuncBase: a resource for quantitative gene function annotation SO BIOINFORMATICS LA English DT Article ID MUS-MUSCULUS; PREDICTION; ASSOCIATION AB Computational gene function prediction can serve to focus experimental resources on high-priority experimental tasks. FuncBase is a web resource for viewing quantitative machine learning-based gene function annotations. Quantitative annotations of genes, including fungal and mammalian genes, with Gene Ontology terms are accompanied by a community feedback system. Evidence underlying function annotations is shown. For example, a custom Cytoscape viewer shows functional linkage graphs relevant to the gene or function of interest. FuncBase provides links to external resources, and may be accessed directly or via links from species-specific databases. C1 [Beaver, John E.; Tasan, Murat; Gibbons, Francis D.; Tian, Weidong; Roth, Frederick P.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Hughes, Timothy R.] Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada. [Hughes, Timothy R.] Univ Toronto, Banting & Best Dept Med Res, Toronto, ON M5S 3E1, Canada. [Roth, Frederick P.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. RP Roth, FP (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RI Roth, Frederick/H-6308-2011; OI Roth, Frederick/0000-0002-6628-649X FU National Institues of Health [NS054052, NS035611, HL081341, HG001715, HG004233, HG003224]; Canadian Institute for Advanced Research Fellowship FX National Institues of Health (grants NS054052, NS035611, HL081341, HG001715, HG004233 and HG003224); A Canadian Institute for Advanced Research Fellowship (to F. P. R.). NR 13 TC 11 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUL 15 PY 2010 VL 26 IS 14 BP 1806 EP 1807 DI 10.1093/bioinformatics/btq265 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 620BQ UT WOS:000279474400028 PM 20495000 ER PT J AU Deng, XM Nagle, A Wu, T Sakata, T Henson, K Chen, Z Kuhen, K Plouffe, D Winzeler, E Adrian, F Tuntland, T Chang, J Simerson, S Howard, S Ek, J Isbell, J Tully, DC Chatterjee, AK Gray, NS AF Deng, Xianming Nagle, Advait Wu, Tao Sakata, Tomoyo Henson, Kerstin Chen, Zhong Kuhen, Kelli Plouffe, David Winzeler, Elizabeth Adrian, Francisco Tuntland, Tove Chang, Jonathan Simerson, Susan Howard, Steven Ek, Jared Isbell, John Tully, David C. Chatterjee, Arnab K. Gray, Nathanael S. TI Discovery of novel 1H-imidazol-2-yl-pyrimidine-4,6-diamines as potential antimalarials SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE 1H-Imidazol-2-yl-pyrimidine-4,6-diamines; Antimalarial ID RESISTANCE; MALARIA; KINASE AB A novel family of 1H-imidazol-2-yl-pyrimidine-4,6-diamines has been identified with potent activity against the erythrocyte-stage of Plasmodium falciparum (Pf), the most common causative agent of malaria. A systematic SAR study resulted in the identification of compound 40 which exhibits good potency against both wild-type and drug resistant parasites and exhibits good in vivo pharmacokinetic properties. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Deng, Xianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Deng, Xianming; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Nagle, Advait; Wu, Tao; Sakata, Tomoyo; Henson, Kerstin; Chen, Zhong; Kuhen, Kelli; Plouffe, David; Winzeler, Elizabeth; Adrian, Francisco; Tuntland, Tove; Chang, Jonathan; Simerson, Susan; Howard, Steven; Ek, Jared; Isbell, John; Tully, David C.; Chatterjee, Arnab K.] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. RP Gray, NS (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 250 Longwood Ave,SGM 628, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu OI Tuntland, Tove/0000-0001-5831-1723; Winzeler, Elizabeth/0000-0002-4049-2113 FU Novartis Research Foundation; Biomedical Primate Research Center; Swiss Tropical Institute; Wellcome Trust; Medicines for Malaria Venture FX This work was supported by a joint grant to the Genomics Institute of the Novartis Research Foundation, the Biomedical Primate Research Center, the Swiss Tropical Institute and the Novartis Institute for the Tropical Diseases from Wellcome Trust and Medicines for Malaria Venture. NR 12 TC 17 Z9 17 U1 0 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 JUL 15 PY 2010 VL 20 IS 14 BP 4027 EP 4031 DI 10.1016/j.bmcl.2010.05.095 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 617CQ UT WOS:000279258800006 PM 20610151 ER PT J AU Deng, XM Lim, SM Zhang, JM Gray, NS AF Deng, Xianming Lim, Sang Min Zhang, Jianming Gray, Nathanael S. TI Broad spectrum alkynyl inhibitors of T315I Bcr-Abl SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Kinase inhibitors; T315I Bcr-Ab1 ID INACTIVE KINASE CONFORMATIONS; SELECTIVE INHIBITOR; TYROSINE KINASE; IMATINIB; RESISTANCE; LEUKEMIA; MUTATION; DESIGN; AMN107; MUTANT AB A series of alkyne-containing type II inhibitors with potent inhibitory activity of T315I Bcr-Abl has been identified. The most active compound 4 exhibits an EC(50) of less than 1 nM against wild-type Bcr-Abl and an EC50 of 10 nM against T315I mutant but is broadly active against a number of other kinases. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Deng, Xianming; Lim, Sang Min; Zhang, Jianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Deng, Xianming; Lim, Sang Min; Zhang, Jianming; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Lim, Sang Min] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. RP Gray, NS (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 250 Longwood Ave,SGM 628, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu FU NIH [R01 CA130876-02] FX This work was supported by the NIH, R01 CA130876-02. We thank Ambit Biosciences for technical support in the compound selectivity pro. ling. The kinase dendrogram was adapted and reproduced with permission from Cell Signaling Technology, Inc. (http://www.cellsignal.com). NR 19 TC 15 Z9 15 U1 0 U2 7 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 JUL 15 PY 2010 VL 20 IS 14 BP 4196 EP 4200 DI 10.1016/j.bmcl.2010.05.043 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 617CQ UT WOS:000279258800046 PM 20541934 ER PT J AU de Jong, JLO Davidson, AJ Wang, YA Palis, J Opara, P Pugach, E Daley, GQ Zon, LI AF de Jong, Jill L. O. Davidson, Alan J. Wang, Yuan Palis, James Opara, Praise Pugach, Emily Daley, George Q. Zon, Leonard I. TI Interaction of retinoic acid and scl controls primitive blood development SO BLOOD LA English DT Article ID EMBRYONIC STEM-CELL; HOX GENE-EXPRESSION; YOLK-SAC; HEMATOPOIETIC PROGENITORS; DEFINITIVE HEMATOPOIESIS; CDX GENES; ZEBRAFISH; MOUSE; VASCULOGENESIS; EMBRYOGENESIS AB Hematopoietic development during embryogenesis involves the interaction of extrinsic signaling pathways coupled to an intrinsic cell fate that is regulated by cell-specific transcription factors. Retinoic acid (RA) has been linked to stem cell self-renewal in adults and also participates in yolk sac blood island formation. Here, we demonstrate that RA decreases gata1 expression and blocks primitive hematopoiesis in zebrafish (Danio rerio) embryos, while increasing expression of the vascular marker, fli1. Treatment with an inhibitor of RA biosynthesis or a retinoic acid receptor antagonist increases gata1(+) erythroid progenitors in the posterior mesoderm of wild-type embryos and anemic cdx4(-/-) mutants, indicating a link between the cdx-hox signaling pathway and RA. Overexpression of scl, a DNA binding protein necessary for hematopoietic development, rescues the block of hematopoiesis induced by RA. We show that these effects of RA and RA pathway inhibitors are conserved during primitive hematopoiesis in murine yolk sac explant cultures and embryonic stem cell assays. Taken together, these data indicate that RA inhibits the commitment of mesodermal cells to hematopoietic fates, functioning downstream of cdx4 and upstream of scl. Our studies establish a new connection between RA and scl during development that may participate in stem cell self-renewal and hematopoietic differentiation. (Blood. 2010; 116(2): 201-209) C1 [de Jong, Jill L. O.; Wang, Yuan; Opara, Praise; Pugach, Emily; Daley, George Q.; Zon, Leonard I.] Childrens Hosp Boston, Stem Cell Program, Boston, MA USA. [de Jong, Jill L. O.; Wang, Yuan; Opara, Praise; Pugach, Emily; Daley, George Q.; Zon, Leonard I.] Childrens Hosp Boston, Div Hematol Oncol, Boston, MA USA. [de Jong, Jill L. O.; Wang, Yuan; Opara, Praise; Pugach, Emily; Daley, George Q.; Zon, Leonard I.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. [Davidson, Alan J.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA USA. [Palis, James] Univ Rochester, Dept Pediat, Rochester, NY 14627 USA. RP Zon, LI (reprint author), HHMI Childrens Hosp, 300 Longwood Ave,Karp 7, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu FU National Institutes of Health [5K08DK074595, DK09361, 2R01HL048801-15A2]; Howard Hughes Medical Institute FX This work was supported by National Institutes of Health grants (5K08DK074595, J.L.O.d.J.; DK09361, J.P.; and 2R01HL048801-15A2, L.I.Z.), and by the Howard Hughes Medical Institute (G. Q. D. and L.I.Z.). NR 43 TC 16 Z9 16 U1 0 U2 7 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 JUL 15 PY 2010 VL 116 IS 2 BP 201 EP 209 DI 10.1182/blood-2009-10-249557 PG 9 WC Hematology SC Hematology GA 626HA UT WOS:000279955800010 PM 20410509 ER PT J AU Wasif, N Bentrem, DJ Farrell, JJ Ko, CY Hines, OJ Reber, HA Tomlinson, JS AF Wasif, Nabil Bentrem, David J. Farrell, James J. Ko, Clifford Y. Hines, Oscar J. Reber, Howard A. Tomlinson, James S. TI Invasive Intraductal Papillary Mucinous Neoplasm Versus Sporadic Pancreatic Adenocarcinoma A Stage-Matched Comparison of Outcomes SO CANCER LA English DT Article DE intraductal papillary mucinous neoplasm; pancreatic cancer; stage-matched; survival; outcomes ID ADDITIONAL PRIMARY CANCERS; INSTITUTIONAL EXPERIENCE; DUCTAL ADENOCARCINOMA; UPDATED EXPERIENCE; SURGICAL RESECTION; SURVIVAL; PROGNOSIS; PREDICTORS; CARCINOMA; MUCUS AB BACKGROUND: Although invasive intraductal papillary mucinous neoplasm (IPMN) of the pancreas is thought to be more indolent than sporadic pancreatic adenocarcinoma (PAC), the natural history remains poorly defined. The authors compared survival and identify prognostic factors after resection for invasive IPMN versus stage-matched PAC. METHODS: The Surveillance, Epidemiology, and End Results database (1991-2005) was used to identify 729 patients with invasive IPMN and 8082 patients with PAC who underwent surgical resection. RESULTS: Patients with resected invasive IPMN experienced improved overall survival when compared with resected PAC (median survival, 21 vs 14 months; P < .001). Stratification by nodal status demonstrated no difference in survival among lymph node-positive patients; however, median survival of resected, lymph node-negative, invasive IPMN was significantly improved compared with lymph node-negative PAC (34 vs 18 months; P < .001). On multivariate analysis, PAC histology was an adverse predictor of overall survival (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.15-1.50) compared with invasive IPMN. For patients with invasive IPMN, positive lymph nodes (HR, 1.98; 95% CI, 1.50-2.60), high tumor grade (HR, 1.74; 95% CI, 1.31-2.31), tumor size >2 cm (HR, 1.50; 95% CI, 1.04-2.19), and age >66 years (HR, 1.33; 95% CI, 1.03-1.73) were adverse predictors of survival. CONCLUSIONS: Although lymph node-negative invasive IPMN showed improved survival after resection compared with lymph node-negative PAC, the natural history of lymph node-positive invasive IPMN mimicked that of lymph node-positive PAC. The authors also identified adverse predictors of survival in invasive IPMN to guide discussions regarding use of adjuvant therapies and prognosis after resection of invasive IPMN. Cancer 2010;116:3369-77. (C) 2010 American Cancer Society. C1 [Tomlinson, James S.] Univ Calif Los Angeles, Div Surg Oncol, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Wasif, Nabil] St Johns Hlth Ctr, John Wayne Canc Inst, Santa Monica, CA USA. [Bentrem, David J.] Northwestern Univ, Dept Surg, Jesse Brown VA Med Ctr, Chicago, IL 60611 USA. [Farrell, James J.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Ko, Clifford Y.; Tomlinson, James S.] Greater Los Angeles VA Med Ctr, Dept Surg, Los Angeles, CA USA. RP Tomlinson, JS (reprint author), Univ Calif Los Angeles, Div Surg Oncol, David Geffen Sch Med, Dept Surg, Box 951782,54-139A CHS,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM jtomlinson@mednet.ucla.edu FU National Cancer Institute [CA090848]; Rod Fasone Memorial Cancer Fund (Indianapolis, Ind); Henry L. Guenther Foundation (Los Angeles, Calif); William Randolph Hearst Foundation (San Francisco, Calif); Davidow Charitable Fund (Los Angeles, Calif) FX Supported by grant CA090848 from the National Cancer Institute and by funding from the Rod Fasone Memorial Cancer Fund (Indianapolis, Ind), the Henry L. Guenther Foundation (Los Angeles, Calif), the William Randolph Hearst Foundation (San Francisco, Calif), the Davidow Charitable Fund (Los Angeles, Calif), and Mrs. Ruth Well (Los Angeles, Calif). NR 36 TC 44 Z9 46 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2010 VL 116 IS 14 BP 3369 EP 3377 DI 10.1002/cncr.25070 PG 9 WC Oncology SC Oncology GA 623PM UT WOS:000279754300011 PM 20564064 ER PT J AU Wray, J Williamson, EA Chester, S Farrington, J Sterk, R Weinstock, DM Jasin, M Lee, SH Nickoloff, JA Hromas, R AF Wray, Justin Williamson, Elizabeth A. Chester, Sean Farrington, Jacqueline Sterk, Rosa Weinstock, David M. Jasin, Maria Lee, Suk-Hee Nickoloff, Jac A. Hromas, Robert TI The transposase domain protein Metnase/SETMAR suppresses chromosomal translocations SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID STRAND BREAK REPAIR; SETMAR PROTEIN; DNA-REPAIR; MECHANISMS; LEUKEMIA; CELLS; DECATENATION; INTEGRATION; ELEMENT; GENE AB Chromosomal translocations are common in leukemia, but little is known about their mechanism. Metnase (also termed SETMAR) is a fusion of a histone methylase and transposase protein that arose specifically in primates. Transposases were thought to be extinct in primates because they would mediate deleterious DNA movement. In primates, Metnase interacts with DNA Ligase IV (Lig IV) and promotes nonhomologous end-joining (NHEJ) DNA repair. We show here that the primate-specific protein Metnase can also enhance NHEJ in murine cells and can also interact with murine Lig IV, indicating that it integrated into the preexisting NHEJ pathway after its development in primates. Significantly, expressing Metnase in murine cells significantly reduces chromosomal translocations. We propose that the fusion of the histone methylase SET domain and the transposase domain in the anthropoid lineage to form primate Metnase promotes accurate intrachromosomal NHEJ and thereby suppresses interchromosomal translocations. Metnase may have been selected for because it has a function opposing transposases and may thus play a key role in suppressing translocations that underlie oncogenicity. (C) 2010 Elsevier Inc. All rights reserved. C1 [Wray, Justin; Williamson, Elizabeth A.; Chester, Sean; Farrington, Jacqueline; Sterk, Rosa; Hromas, Robert] Univ New Mexico, Dept Med, Hlth Sci Ctr, Div Hematol Oncol,Canc Res & Treatment Ctr, Albuquerque, NM 87131 USA. [Weinstock, David M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Weinstock, David M.; Jasin, Maria] Mem Sloan Kettering Canc Ctr, Dept Dev Biol, New York, NY 10065 USA. [Lee, Suk-Hee] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Nickoloff, Jac A.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. RP Hromas, R (reprint author), Univ New Mexico, Dept Med, Hlth Sci Ctr, Div Hematol Oncol,Canc Res & Treatment Ctr, Albuquerque, NM 87131 USA. EM rhromas@salud.unm.edu FU National Institutes of Health (NIH) [CA92111, T32 DK0075-20, CA 100862, HL093606, CA139429, CA140442]; U.S. Army [DAMD17-00-1-0295]; Walther Cancer Institute; IU Simon Cancer Center FX S.-H.L. was supported by National Institutes of Health (NIH) grant CA92111 and the U.S. Army (DAMD17-00-1-0295), B.D.B. was supported by an NIH predoctoral training grant (T32 DK0075-20), the Walther Cancer Institute, and the IU Simon Cancer Center, J.A.N. was supported by NIH grant CA 100862, and R.H. was supported by NIH grants HL093606, CA139429, and CA140442. NR 22 TC 14 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD JUL 15 PY 2010 VL 200 IS 2 BP 184 EP 190 DI 10.1016/j.cancergencyto.2010.04.011 PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 618RN UT WOS:000279373500017 PM 20620605 ER PT J AU Duda, DG Jain, RK AF Duda, Dan G. Jain, Rakesh K. TI Premetastatic Lung "Niche": Is Vascular Endothelial Growth Factor Receptor 1 Activation Required? SO CANCER RESEARCH LA English DT Review ID MYELOID CELLS; METASTASIS FORMATION; CANCER DEVELOPMENT; TUMOR; VEGF; ANGIOGENESIS; MEDIATOR; FLT1 AB Inflammatory pathways may mediate preparation of the "metastatic soil" in the lungs. Some of these pathways-activation and/or the recruitment of certain inflammatory cells-might depend on vascular endothelial growth factor receptor 1 (VEGFR1) activity. Thus, blocking the activity of VEGFR1 (or the interaction with its ligands) has emerged as a potential antimetastasis strategy to target not only angiogenesis and cancer cell survival and migration, but also the recruitment of tumor growth-promoting bone marrow-derived cells (BMDC). However, inhibition of VEGFR1 activity by blocking antibodies or by genetic deletion of the tyrosine kinase domain neither prevented nor changed the rate of spontaneous metastasis formation after surgical removal of primary tumors. Thus, development of VEGFR1-targeted agents should be pursued in selected tumors (e.g., by identifying cancers that depend on VEGFR1 signaling for survival) or in specific combination therapies. Preventing metastasis will likely require identification and blockade of additional or alternative proinflammatory pathways that mediate the priming of the metastatic soil and the growth of micrometastases. Cancer Res; 70(14);5670-3. (C)2010 AACR. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Steele Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Duda, DG (reprint author), Cox 734,100 Blossom St, Boston, MA 02114 USA. EM duda@steele.mgh.harvard.edu; jain@steele.mgh.harvard.edu FU NIH [P01-CA80124, R01-CA115767, R01-CA85140, R01-CA126642, T32-CA73479, R21-CA139168]; AstraZeneca; Dyax FX R. K. Jain: commercial research grant, AstraZeneca and Dyax; consultant/advisory board, AstraZeneca, Dyax, Millennium, Regeneron, Genzyme, Morphosys, and SynDevRx; speaker honorarium, Genzyme and Alnylam. D. G. Duda disclosed no potential conflicts of interest.; NIH grants P01-CA80124, R01-CA115767, R01-CA85140, R01-CA126642, T32-CA73479, and R21-CA139168. NR 23 TC 21 Z9 21 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2010 VL 70 IS 14 BP 5670 EP 5673 DI 10.1158/0008-5472.CAN-10-0119 PG 4 WC Oncology SC Oncology GA 626GV UT WOS:000279955300002 PM 20587530 ER PT J AU Miron, A Varadi, M Carrasco, D Li, HL Luongo, L Kim, HJ Park, SY Cho, EY Lewis, G Kehoe, S Iglehart, JD Dillon, D Allred, DC Macconaill, L Gelman, R Polyak, K AF Miron, Alexander Varadi, Maria Carrasco, Daniel Li, Hailun Luongo, Lauren Kim, Hee Jung Park, So Yeon Cho, Eun Yoon Lewis, Gretchen Kehoe, Sarah Iglehart, J. Dirk Dillon, Deborah Allred, D. Craig Macconaill, Laura Gelman, Rebecca Polyak, Kornelia TI PIK3CA Mutations in In situ and Invasive Breast Carcinomas SO CANCER RESEARCH LA English DT Article ID CANCER; GENE; PI3K AB The PIK3 signaling pathway has been identified as one of the most important and most frequently mutated pathways in breast cancer. Somatic mutations in the catalytic subunit of PIK3CA have been found in a significant fraction of breast carcinomas, and it has been proposed that mutant PIK3CA plays a role in tumor initiation. However, the majority of primary human tumors analyzed for genetic alterations in PIK3CA have been invasive breast carcinomas and the frequency of PIK3CA mutations in preinvasive lesions has not been explored. To investigate this, we sequenced exons 9 and 20 of PIK3CA in pure ductal carcinoma in situ ( DCIS), DCIS adjacent to invasive carcinoma, and invasive ductal breast carcinomas. In a subset of cases, both in situ and invasive areas were analyzed from the same tumor. We found that the frequency of PIK3CA mutations was essentially the same (similar to 30%) in all three histologic groups. In some cases, in situ and invasive areas of the same tumor were discordant for PIK3CA status, and in two cases in which multiple invasive and adjacent in situ areas within the same tumor were analyzed independently, we detected intratumor heterogeneity for PIK3CA mutations. Our results suggest that mutation of PIK3CA is an early event in breast cancer that is more likely to play a role in breast tumor initiation than in invasive progression, although a potential role for exon 9 mutations in the progression of a subset of DCIS cases cannot be excluded. Cancer Res; 70(14); 5674-8. (C)2010 AACR. C1 [Miron, Alexander; Lewis, Gretchen; Iglehart, J. Dirk; Polyak, Kornelia] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Varadi, Maria; Carrasco, Daniel; Kim, Hee Jung; Polyak, Kornelia] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Li, Hailun; Gelman, Rebecca] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Luongo, Lauren; Kehoe, Sarah; Macconaill, Laura; Polyak, Kornelia] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Kim, Hee Jung; Iglehart, J. Dirk; Dillon, Deborah; Gelman, Rebecca] Harvard Univ, Sch Med, Boston, MA USA. [Dillon, Deborah] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Gelman, Rebecca] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Park, So Yeon] Seoul Natl Univ, Coll Med, Dept Pathol, Songnam, Gyeonggi, South Korea. [Park, So Yeon] Bundang Hosp, Songnam, Gyeonggi, South Korea. [Cho, Eun Yoon] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul, South Korea. [Allred, D. Craig] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. RP Polyak, K (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St D740C, Boston, MA 02115 USA. EM Kornelia_Polyak@dfci.harvard.edu RI Park, So Yeon/A-2621-2012; Seoul National University, Pathology/B-6702-2012 FU Dana-Farber/Harvard Cancer Center [CA89393]; Novartis FX K. Polyak: commercial research grant and consultant, Novartis. The other authors disclosed no potential conflicts of interest.; National Cancer Institute Specialized Program in Research Excellence in Breast Cancer at Dana-Farber/Harvard Cancer Center (CA89393) grant (A. Miron, J.D. Iglehart, D. Dillon, R. Gelman, and K. Polyak). NR 17 TC 64 Z9 65 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2010 VL 70 IS 14 BP 5674 EP 5678 DI 10.1158/0008-5472.CAN-08-2660 PG 5 WC Oncology SC Oncology GA 626GV UT WOS:000279955300003 PM 20551053 ER PT J AU Kozin, SV Kamoun, WS Huang, YH Dawson, MR Jain, RK Duda, DG AF Kozin, Sergey V. Kamoun, Walid S. Huang, Yuhui Dawson, Michelle R. Jain, Rakesh K. Duda, Dan G. TI Recruitment of Myeloid but not Endothelial Precursor Cells Facilitates Tumor Regrowth after Local Irradiation SO CANCER RESEARCH LA English DT Article ID PROGENITOR CELLS; STEM-CELLS; ANGIOGENESIS; THERAPY; REVASCULARIZATION; VASCULOGENESIS; MOBILIZATION; RADIOTHERAPY; POPULATION; RADIATION AB Tumor neovascularization and growth might be promoted by the recruitment of bone marrow-derived cells (BMDC), which include endothelial precursor cells and "vascular modulatory" myelomonocytic (CD11b+) cells. BMDCs may also drive tumor regrowth after certain chemotherapeutic and vascular disruption treatments. In this study, we evaluated the role of BMDC recruitment in breast and lung carcinoma xenograft models after local irradiation (LI). We depleted the bone marrow by including whole-body irradiation (WBI) of 6 Gy as part of a total tumor dose of 21 Gy, and compared the growth delay with the one achieved after LI of 21 Gy. In both models, the inclusion of WBI induced longer tumor growth delays. Moreover, WBI increased lung tumor control probability by LI. Exogenous delivery of BMDCs from radiation-naive donors partially abrogated the WBI effect. Myeloid BMDCs, primarily macrophages, rapidly accumulated in tumors after LI. Intratumoral expression of stromal-derived factor 1 alpha (SDF-1 alpha), a chemokine that promotes tissue retention of BMDCs, was noted 2 days after LI. Conversely, treatment with an inhibitor of SDF-1 alpha receptor CXCR4 (AMD3100) with LI significantly delayed tumor regrowth. However, when administered starting from 5 days post-LI, AMD3100 treatment was ineffective. Lastly, with restorative bone marrow transplantation of Tie2-GFP-labeled BMDC population, we observed an increased number of monocytes but not endothelial precursor cells in tumors that recurred following LI. Our results suggest that an increase in intratumoral SDF-1 alpha triggered by LI recruits myelomonocytes/macrophages which promotes tumor regrowth. Cancer Res; 70(14); 5679-85. (C)2010 AACR. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Steele Lab Tumor Biol, COX 734,100 Blossom St, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu RI Huang, Yuhui/E-5046-2010; OI Huang, Yuhui/0000-0002-6226-2028; Huang, Yuhui/0000-0003-1985-3575 FU AstraZeneca; Dyax; NIH [R01-CA115767, P01-CA80124, R01-CA126642, R21-CA139168] FX R. K. Jain: commercial research grant, AstraZeneca and Dyax; honoraria, Genzyme and Alnylam; ownership interest, SynDevRx; consultant/advisory board, AstraZeneca, Dyax, Genzyme, Regeneron, and SynDevRx. The other authors disclosed no potential conflicts of interest.; NIH grant R01-CA115767 (R. K. Jain) and partially by NIH grants P01-CA80124 and R01-CA126642 (R. K. Jain), and R21-CA139168 (D. G. Duda). NR 21 TC 108 Z9 110 U1 2 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2010 VL 70 IS 14 BP 5679 EP 5685 DI 10.1158/0008-5472.CAN-09-4446 PG 7 WC Oncology SC Oncology GA 626GV UT WOS:000279955300004 PM 20631066 ER PT J AU Turke, AB Engelman, JA AF Turke, Alexa B. Engelman, Jeffrey A. TI PIKing the Right Patient SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID DUAL PI3K/MTOR INHIBITOR; BREAST-CANCER CELLS; ANTITUMOR-ACTIVITY; PI3K; HER2; MEK; NVP-BEZ235; APOPTOSIS; MUTATIONS; INDUCTION AB HER2 amplification and PIK3CA mutation were validated as biomarkers for sensitivity to the single-agent phosphoinositide 3-kinase (PI3K) inhibitor, GDC-0941, in breast cancer models. A novel expression profile was developed to identify other breast cancers sensitive to PI3K inhibitors. These expression studies highlighted feedback networks connecting TORC1, PI3K, and mitogen-activated protein kinase (MAPK) pathways, and underscored the potential for combination therapies. Clin Cancer Res; 16(14); 3523-5. (C) 2010 AACR. C1 [Turke, Alexa B.; Engelman, Jeffrey A.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. RP Engelman, JA (reprint author), Massachusetts Gen Hosp, Ctr Canc, CNY 149,13th St, Charlestown, MA 02129 USA. EM jengelman@partners.org NR 13 TC 12 Z9 12 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2010 VL 16 IS 14 BP 3523 EP 3525 DI 10.1158/1078-0432.CCR-10-1201 PG 3 WC Oncology SC Oncology GA 625NW UT WOS:000279903100001 PM 20538763 ER PT J AU Mayer, EL Krop, IE AF Mayer, Erica L. Krop, Ian E. TI Advances in Targeting Src in the Treatment of Breast Cancer and Other Solid Malignancies SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; SRC/ABL KINASE INHIBITOR; RESISTANT PROSTATE-CANCER; CELL LUNG-CANCER; C-SRC; FAMILY KINASES; DASATINIB BMS-354825; FACTOR RECEPTOR; IN-VIVO; ANDROGEN RECEPTOR AB Src, a membrane-associated nonreceptor tyrosine kinase, plays a crucial role in the coordination and facilitation of cell-signaling pathways controlling a wide range of cellular functions, including growth, survival, invasion, adhesion, and migration. Deregulation and increased activity of Src has been observed in multiple human malignancies, prompting the development of specific inhibitors of Src. In preclinical studies, Src inhibitors show antitumor effects in multiple solid tumor types. Recently completed early-phase trials using the inhibitors dasatinib and bosutinib have suggested modest activity as monotherapy in breast and prostate cancer, with potentially greater activity in combination regimens. Given the interaction between Src and the estrogen receptor, ongoing trials are exploring combinations with endocrine therapy. The relationship between Src and the vascular endothelial growth factor receptor also justifies investigation of combinations with angiogenesis inhibitors. Future trials will continue to explore the contribution of Src inhibition with both chemotherapy and targeted agents. Clin Cancer Res; 16(14); 3526-32. (C) 2010 AACR. C1 [Mayer, Erica L.; Krop, Ian E.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Mayer, EL (reprint author), Dana Farber Canc Inst, Mayer 2,44 Binney St, Boston, MA 02115 USA. EM emayer@partners.org NR 70 TC 85 Z9 87 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2010 VL 16 IS 14 BP 3526 EP 3532 DI 10.1158/1078-0432.CCR-09-1834 PG 7 WC Oncology SC Oncology GA 625NW UT WOS:000279903100002 PM 20634194 ER PT J AU Chae, SS Kamoun, WS Farrar, CT Kirkpatrick, ND Niemeyer, E de Graaf, AMA Sorensen, AG Munn, LL Jain, RK Fukumura, D AF Chae, Sung-Suk Kamoun, Walid S. Farrar, Christian T. Kirkpatrick, Nathaniel D. Niemeyer, Elisabeth de Graaf, Annemarie M. A. Sorensen, A. Gregory Munn, Lance L. Jain, Rakesh K. Fukumura, Dai TI Angiopoietin-2 Interferes with Anti-VEGFR2-Induced Vessel Normalization and Survival Benefit in Mice Bearing Gliomas SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ANTIANGIOGENIC THERAPY; TUMOR-GROWTH; KINASE INHIBITOR; VEGF; OVEREXPRESSION; DEXAMETHASONE; ANGIOGENESIS; PERMEABILITY; VASCULATURE AB Purpose: In brain tumors, cerebral edema is a significant source of morbidity and mortality. Recent studies have shown that inhibition of vascular endothelial growth factor (VEGF) signaling induces transient vascular normalization and reduces cerebral edema, resulting in a modest survival benefit in glioblastoma patients. During anti-VEGF treatment, circulating levels of angiopoietin (Ang)-2 remained high after an initial minor reduction. It is not known, however, whether Ang-2 can modulate anti-VEGF treatment of glioblastoma. Here, we used an orthotopic glioma model to test the hypothesis that Ang-2 is an additional target for improving the efficacy of current anti-VEGF therapies in glioma patients. Experimental Design: To recapitulate high levels of Ang-2 in glioblastoma patients during anti-VEGF treatment, Ang-2 was ectopically expressed in U87 glioma cells. Animal survival and tumor growth were assessed to determine the effects of Ang-2 and anti-VEGF receptor 2 (VEGFR2) treatment. We also monitored morphologic and functional vascular changes using multiphoton laser scanning microscopy and immunohistochemistry. Results: Ectopic expression of Ang-2 had no effect on vascular permeability, tumor growth, or survival, although it resulted in higher vascular density, with dilated vessels and reduced mural cell coverage. On the other hand, when combined with anti-VEGFR2 treatment, Ang-2 destabilized vessels without affecting vessel regression and compromised the survival benefit of VEGFR2 inhibition by increasing vascular permeability. VEGFR2 inhibition normalized tumor vasculature whereas ectopic expression of Ang-2 diminished the beneficial effects of VEGFR2 blockade by inhibiting vessel normalization. Conclusion: Cancer treatment regimens combining anti-VEGF and anti-Ang-2 agents may be an effective strategy to improve the efficacy of current anti-VEGF therapies. Clin Cancer Res; 16(14); 3618-27. (c) 2010 AACR. C1 [Chae, Sung-Suk; Kamoun, Walid S.; Kirkpatrick, Nathaniel D.; Niemeyer, Elisabeth; de Graaf, Annemarie M. A.; Munn, Lance L.; Jain, Rakesh K.; Fukumura, Dai] Massachusetts Gen Hosp, Edwin L Steele Lab, Dept Radiat Oncol, Boston, MA 02114 USA. [Farrar, Christian T.; Sorensen, A. Gregory] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Farrar, Christian T.; Sorensen, A. Gregory] Harvard Univ, Sch Med, Boston, MA USA. [Niemeyer, Elisabeth] Univ Lubeck, Klin Strahlentherapie, UK SH Campus Luebeck, Lubeck, Germany. RP Fukumura, D (reprint author), Massachusetts Gen Hosp, Edwin L Steele Lab, Dept Radiat Oncol, 100 Blossom St,COX-736, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu; dai@steele.mgh.harvard.edu RI Munn, Lance/L-3950-2016 OI Munn, Lance/0000-0003-0698-7232 FU US National Cancer Institute [R01-CA96915, R01-CA85140, R01-CA115767, R01-CA126642, P01-CA80124]; NIH [T32-CA073479]; Suzan G. Komen FX Grant Support US National Cancer Institute grants R01-CA96915 (D. Fukumura), and R01-CA85140, R01-CA115767, R01-CA126642 and P01-CA80124 (R.K. Jain). N.D. Kirkpatrick was supported by an NIH training grant (T32-CA073479). W.S. Kamoun was supported by a Suzan G. Komen postdoctoral fellowship. NR 28 TC 61 Z9 63 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2010 VL 16 IS 14 BP 3618 EP 3627 DI 10.1158/1078-0432.CCR-09-3073 PG 10 WC Oncology SC Oncology GA 625NW UT WOS:000279903100011 PM 20501615 ER PT J AU Cho, DC Cohen, MB Panka, DJ Collins, M Ghebremichael, M Atkins, MB Signoretti, S Mier, JW AF Cho, Daniel C. Cohen, Matthew B. Panka, David J. Collins, Michael Ghebremichael, Musie Atkins, Michael B. Signoretti, Sabina Mier, James W. TI The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID PHOSPHATIDYLINOSITOL 3-KINASE/MAMMALIAN TARGET; INITIATION-FACTOR 4E; MAMMALIAN TARGET; PATHOLOGICAL ANGIOGENESIS; TUMOR SUPPRESSION; CANCER-THERAPY; HIF-ALPHA; IN-VIVO; PHOSPHORYLATION; TRANSLATION AB Purpose: Inhibitors of TORC1 have been shown to be active in patients with metastatic renal cell carcinoma (RCC). As the phosphatidylinositol 3-kinase (PI3K) pathway activates numerous other kinases, transcription factors, and proteins associated with cell growth and survival besides mammalian target of rapamycin (mTOR), disruption of this pathway upstream of mTOR may be more effective than inhibition of TORC1 alone. Experimental Design: To investigate this possibility, the dual PI3K/mTOR inhibitor NVP-BEZ235 was compared with rapamycin in RCC cell lines and xenografts generated from 786-O and A498 cells. Results: Treatment of RCC cell lines with NVP-BEZ235 in vitro resulted in the nuclear translocation of p27, greater reduction in tumor cell proliferation, and more complete suppression of Akt, Mnk-1, eIF4E, and 4EBP-1 phosphorylation and cyclin D1 and hypoxia-inducible factor 2 alpha (HIF2 alpha) expression than that achieved with rapamycin. The reduction of HIF2a levels correlated with reduced HIF activity as determined by luciferase assay. NVP-BEZ235 induced growth arrest in both the 786-O and A498 xenografts that was associated with inhibition of Akt and S6 phosphorylation as well as the induction of apoptosis and reduction in markers of tumor cell proliferation. In contrast, rapamycin induced only minimal growth retardation. Conclusion: Dual inhibition of PI3K/mTOR with NVP-BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more effectively than inhibition of TORC1 alone. These results provide the rationale for the clinical assessment of agents such as NVP-BEZ235 in patients with advanced RCC. Clin Cancer Res; 16(14); 3628-38. (c) 2010 AACR. C1 [Cho, Daniel C.; Cohen, Matthew B.; Panka, David J.; Atkins, Michael B.; Mier, James W.] Beth Israel Deaconess Med Ctr, Div Hematol & Oncol, Boston, MA 02215 USA. [Collins, Michael; Signoretti, Sabina] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ghebremichael, Musie] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. RP Cho, DC (reprint author), Beth Israel Deaconess Med Ctr, Div Hematol & Oncol, 330 Brookline Ave,MASCO 4, Boston, MA 02215 USA. EM dcho1@bidmc.harvard.edu FU NIH [2P50CA101942, 1K08CA142890] FX Grant Support NIH Grant 2P50CA101942, 1K08CA142890. NR 35 TC 118 Z9 123 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 15 PY 2010 VL 16 IS 14 BP 3628 EP 3638 DI 10.1158/1078-0432.CCR-09-3022 PG 11 WC Oncology SC Oncology GA 625NW UT WOS:000279903100012 PM 20606035 ER PT J AU Julg, B Pereyra, F Buzon, MJ Piechocka-Trocha, A Clark, MJ Baker, BM Lian, J Miura, T Martinez-Picado, J Addo, MM Walker, BD AF Julg, B. Pereyra, F. Buzon, M. J. Piechocka-Trocha, A. Clark, M. J. Baker, B. M. Lian, J. Miura, T. Martinez-Picado, J. Addo, M. M. Walker, B. D. TI Infrequent Recovery of HIV from but Robust Exogenous Infection of Activated CD4(+) T Cells in HIV Elite Controllers SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; REPLICATION CAPACITY; VIRAL REPLICATION; EX-VIVO; TYPE-1; LYMPHOCYTES; SUPPRESSORS; VIREMIA; ABSENCE AB Background. Human immunodeficiency virus (HIV) elite controllers are able to control infection with HIV-1 spontaneously to undetectable levels in the absence of antiretroviral therapy, but the mechanisms leading to this phenotype are poorly understood. Although low frequencies of HIV-infected peripheral CD4(+) T cells have been reported in this group, it remains unclear to what extent these are due to viral attenuation, active immune containment, or intracellular host factors that restrict virus replication. Methods. We assessed proviral DNA levels, autologous viral growth from and infectability of in vitro activated, CD8(+) T cell-depleted CD4(+) T cells from HIV elite controllers (mean viral load, <50 copies/mL), viremic controllers (mean viral load, <2000 copies/mL), chronic progressors, and individuals receiving highly active antiretroviral therapy. Results. Although we successfully detected autologous virus production in ex vivo activated CD4(+) T cells from all chronic progressors and from most of the viremic controllers, we were able to measure robust autologous viral replication in only 2 of 14 elite controllers subjected to the same protocol. In vitro activated autologous CD4(+) T cells from elite controllers, however, supported infection with both X4 and R5 tropic HIV strains at comparable levels to those in CD4(+) T cells from HIV-uninfected subjects. Proviral DNA levels were the lowest in elite controllers, suggesting that extremely low frequencies of infected cells contribute to difficulty in isolation of virus. Conclusions. These data indicate that elite control is not due to inability of activated CD4(+) T cells to support HIV infection, but the relative contributions of host and viral factors that account for maintenance of low-level infection remain to be determined. C1 [Julg, B.; Pereyra, F.; Piechocka-Trocha, A.; Clark, M. J.; Baker, B. M.; Lian, J.; Miura, T.; Addo, M. M.; Walker, B. D.] Massachusetts Gen Hosp, Ragon Inst, MIT, Boston, MA 02114 USA. [Julg, B.; Pereyra, F.; Piechocka-Trocha, A.; Clark, M. J.; Baker, B. M.; Lian, J.; Miura, T.; Addo, M. M.; Walker, B. D.] Harvard Univ, Boston, MA 02115 USA. [Piechocka-Trocha, A.; Miura, T.; Walker, B. D.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Buzon, M. J.; Martinez-Picado, J.] Hosp Badalona Germans Trias & Pujol, IrsiCaixa Fdn, Badalona, Spain. [Martinez-Picado, J.] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain. [Miura, T.] Univ Tokyo, Inst Med Sci, Tokyo, Japan. RP Walker, BD (reprint author), Massachusetts Gen Hosp, Ragon Inst, MIT, 149 13th St, Charlestown, MA 02129 USA. EM bwalker@partners.org RI Martinez-Picado, Javier/G-5507-2012; Buzon, Maria J/G-8286-2015 OI Martinez-Picado, Javier/0000-0002-4916-2129; Buzon, Maria J/0000-0003-4427-9413 FU National Institutes of Health [RO1 AI030914]; Bill and Melinda Gates Foundation; Centers for AIDS Research FX National Institutes of Health (RO1 AI030914 to B. D. W.), Bill and Melinda Gates Foundation, and Centers for AIDS Research. NR 27 TC 55 Z9 56 U1 4 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 15 PY 2010 VL 51 IS 2 BP 233 EP 238 DI 10.1086/653677 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 612UQ UT WOS:000278929900016 PM 20550452 ER PT J AU Seaman, ME Contino, G Bardeesy, N Kelly, KA AF Seaman, Marc E. Contino, Gianmarco Bardeesy, Nabeel Kelly, Kimberly A. TI Molecular imaging agents: impact on diagnosis and therapeutics in oncology SO EXPERT REVIEWS IN MOLECULAR MEDICINE LA English DT Review ID NF-KAPPA-B; POSITRON-EMISSION-TOMOGRAPHY; ENDOTHELIAL GROWTH-FACTOR; METASTATIC BREAST-CANCER; MONOCLONAL-ANTIBODY; TUMOR ANGIOGENESIS; COLORECTAL-CANCER; DRUG PENETRATION; GENE-TRANSFER; BRAIN-TUMORS AB Imaging has become a crucial tool in oncology throughout the course of disease detection and management, and is an integral part of clinical trials. Anatomical and functional imaging led the way, providing valuable information used in the diagnosis of disease, including data regarding the size and location of the tumour and on physiological processes such as blood flow and perfusion. As understanding of cancer pathogenesis has advanced through the identification of genetic, biochemical and cellular alterations in evolving tumours, emphasis has been put on developing methods to detect and serially monitor such alterations. This class of approaches is referred to as molecular imaging. Molecular imaging offers the potential for increasingly sensitive and specific visualisation and quantification of biological processes at the cellular and molecular level. These approaches have become established as essential tools for cancer research, early cancer detection and staging, and monitoring and predicting response to targeted therapies. Here, we discuss recent advances in the development of molecular imaging agents and their implementation in basic cancer research as well as in more rationalised approaches to cancer care. C1 [Seaman, Marc E.; Kelly, Kimberly A.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22908 USA. [Contino, Gianmarco; Bardeesy, Nabeel] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. [Contino, Gianmarco; Bardeesy, Nabeel] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Contino, Gianmarco] European Inst Oncol, Div Gen Surg, Milan, Italy. [Contino, Gianmarco] Univ Milan, Milan, Italy. RP Kelly, KA (reprint author), Univ Virginia, Dept Biomed Engn, Box 800759 Hlth Syst, Charlottesville, VA 22908 USA. EM kak3x@eservices.virginia.edu OI Contino, Gianmarco/0000-0001-5874-0405 FU Johnson & Johnson Corporate Office of Science and Technology; Wallace H. Coulter Foundation; NCI [RO1 CA137071]; Harvard Cancer Center; American-Italian Cancer Foundation; Fondazione Umberto Verones; [R01 CA133557]; [P01 CA117969] FX K.K. is funded by Johnson & Johnson Corporate Office of Science and Technology, and Wallace H. Coulter Foundation; K. K., M. S. and N.B. are funded by NCI RO1 CA137071; N.B. is supported by R01 CA133557, P01 CA117969 and the Harvard Cancer Center GI SPORE; G. C. is supported by an American-Italian Cancer Foundation Post-Doctoral Research Fellowship and a grant from the Fondazione Umberto Verones. The authors thank the peer reviewers for their consideration and thoughtful suggestions. NR 89 TC 9 Z9 10 U1 1 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1462-3994 J9 EXPERT REV MOL MED JI Expert Rev. Mol. Med. PD JUL 15 PY 2010 VL 12 AR e20 DI 10.1017/S1462399410001511 PG 20 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 651VZ UT WOS:000281956600001 PM 20633310 ER PT J AU Yoon, JC Ng, A Kim, BH Bianco, A Xavier, RJ Elledge, SJ AF Yoon, John C. Ng, Aylwin Kim, Brian H. Bianco, Antonio Xavier, Ramnik J. Elledge, Stephen J. TI Wnt signaling regulates mitochondrial physiology and insulin sensitivity SO GENES & DEVELOPMENT LA English DT Article DE RNAi screen; mitochondria; Wnt signaling; IRS-1 ID RECEPTOR SUBSTRATE-1; BETA-CATENIN; C-MYC; DISEASES; GENES; PATHWAY; CANCER; IDENTIFICATION; DYSFUNCTION; BIOGENESIS AB Mitochondria serve a critical role in physiology and disease. The genetic basis of mitochondrial regulation in mammalian cells has not yet been detailed. We performed a large-scale RNAi screen to systematically identify genes that affect mitochondrial abundance and function. This screen revealed previously unrecognized roles for >150 proteins in mitochondrial regulation. We report that increased Wnt signals are a potent activator of mitochondrial biogenesis and reactive oxygen species (ROS) generation, leading to DNA damage and acceleration of cellular senescence in primary cells. The signaling protein insulin receptor substrate-1 (IRS-1), shown here to be a transcriptional target of Wnt, is induced in this setting. The increased level of IRS-1 drives activation of mitochondrial biogenesis; furthermore, in insulin-responsive cell types, it enhances insulin signaling, raising the possibility that Wnt proteins may be used to modulate glucose homeostasis. Our results identify a key component of the mitochondrial regulatory apparatus with a potentially important link to metabolic and degenerative disorders. C1 [Yoon, John C.; Elledge, Stephen J.] Harvard Univ, Sch Med, Dept Genet, Howard Hughes Med Inst,Div Genet,Brigham & Womens, Boston, MA 02115 USA. [Yoon, John C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Diabet Unit, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Kim, Brian H.; Bianco, Antonio] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Thyroid,Dept Med, Boston, MA 02115 USA. RP Elledge, SJ (reprint author), Harvard Univ, Sch Med, Dept Genet, Howard Hughes Med Inst,Div Genet,Brigham & Womens, Boston, MA 02115 USA. EM selledge@genetics.med.harvard.edu RI Bianco, Antonio/A-4965-2008 OI Bianco, Antonio/0000-0001-7737-6813 FU Damon Runyon Cancer Research Foundation; Crohn's and Colitis Foundation of America; NIH; CMRC FX We thank J. Cunningham, P. Puigserver, and members of the Elledge laboratory for advice and discussions; M. Rosene and Y. Leng for technical assistance; and the ICCB and the EM Core for assistance with the siRNA library and electron microscopy, respectively. This work was supported by a fellowship from the Damon Runyon Cancer Research Foundation awarded to J. C. Y.; a fellowship from the Crohn's and Colitis Foundation of America to A.N.; NIH career development grants to J. C. Y. and B. H. K.; NIH research grants to A. B., R. J. X., and S. J. E.; and a CMRC grant to S. J. E. S. J. E. is an Investigator with the Howard Hughes Medical Institute. NR 41 TC 99 Z9 100 U1 2 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 15 PY 2010 VL 24 IS 14 BP 1507 EP 1518 DI 10.1101/gad.1924910 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 626BS UT WOS:000279941500008 PM 20634317 ER PT J AU Hu, B Lefort, K Qiu, W Nguyen, BC Rajaram, RD Castillo, E He, FL Chen, YP Angel, P Brisken, C Dotto, GP AF Hu, Bing Lefort, Karine Qiu, Wenying Nguyen, Bach-Cuc Rajaram, Renuga Devi Castillo, Einar He, Fenglei Chen, Yiping Angel, Peter Brisken, Cathrin Dotto, G. Paolo TI Control of hair follicle cell fate by underlying mesenchyme through a CSL-Wnt5a-FoxN1 regulatory axis SO GENES & DEVELOPMENT LA English DT Article DE Notch; Wnt; ROR2; FoxN1; epithelial-mesenchymal interactions ID RECEPTOR TYROSINE KINASE; TERMINAL DIFFERENTIATION; STEM-CELLS; TRANSCRIPTIONAL PROGRAM; C-JUN; NOTCH; GENE; EXPRESSION; WNT5A; KERATINOCYTES AB Epithelial-mesenchymal interactions are key to skin morphogenesis and homeostasis. We report that maintenance of the hair follicle keratinocyte cell fate is defective in mice with mesenchymal deletion of the CSL/RBP-J kappa gene, the effector of "canonical'' Notch signaling. Hair follicle reconstitution assays demonstrate that this can be attributed to an intrinsic defect of dermal papilla cells. Similar consequences on hair follicle differentiation result from deletion of Wnt5a, a specific dermal papilla signature gene that we found to be under direct Notch/CSL control in these cells. Functional rescue experiments establish Wnt5a as an essential downstream mediator of Notch-CSL signaling, impinging on expression in the keratinocyte compartment of FoxN1, a gene with a key hair follicle regulatory function. Thus, Notch/CSL signaling plays a unique function in control of hair follicle differentiation by the underlying mesenchyme, with Wnt5a signaling and FoxN1 as mediators. C1 [Hu, Bing; Lefort, Karine; Qiu, Wenying; Castillo, Einar; Dotto, G. Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Nguyen, Bach-Cuc; Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Rajaram, Renuga Devi; Brisken, Cathrin] Ecole Polytech Fed Lausanne, Swiss Inst Expt Canc Res, CH-1066 Epalinges, Switzerland. [He, Fenglei; Chen, Yiping] Tulane Univ, Dept Cell & Mol Biol, New Orleans, LA 70118 USA. [Angel, Peter] German Canc Res Ctr, D-69120 Heidelberg, Germany. RP Dotto, GP (reprint author), Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. EM paolo.dotto@unil.ch RI He, Fenglei/F-2523-2010 FU Swiss National Foundation, Oncosuisse [02361-02-2009]; European Union [LSHB-CT-2005-019067]; NIH [AR39190, AR054856] FX We thank Dr. T. Honjo (Kyoto University, Kyoto, Japan) for generously providing the RBP-J kappaloxP/loxP mice, Dr. M. Okabe (Osaka University, Suita, Japan) for the C57BL/6-Tg(Act-EGFP) transgenic strain, Dr. T. T. Sun (New York University, NY, USA) for his gift of antibodies, Dr. D. M. Prowse (Cancer Research UK, London, UK) for the pBabepuroFoxN1-ER construct, Dr. U. Just (Christian-Albrechts-University of Kiel, Germany) for the rNERT-neo and rneo plasmids, and Dr. C. Missero for careful reading of the manuscript. This work was supported by grants from the Swiss National Foundation, Oncosuisse (Grant 02361-02-2009), the European Union (Epistem, Sixth Framework Program, LSHB-CT-2005-019067), and the NIH (Grants AR39190 and AR054856) to G. P. D. NR 51 TC 45 Z9 46 U1 0 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 15 PY 2010 VL 24 IS 14 BP 1519 EP 1532 DI 10.1101/gad.1886910 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 626BS UT WOS:000279941500009 PM 20634318 ER PT J AU Nguyen, PL Chen, MH Beard, CJ Suh, WW Renshaw, AA Loffredo, M McMahon, E Kantoff, PW D'Amico, AV AF Nguyen, Paul L. Chen, Ming-Hui Beard, Clair J. Suh, W. Warren Renshaw, Andrew A. Loffredo, Marian McMahon, Elizabeth Kantoff, Philip W. D'Amico, Anthony V. TI RADIATION WITH OR WITHOUT 6 MONTHS OF ANDROGEN SUPPRESSION THERAPY IN INTERMEDIATE- AND HIGH-RISK CLINICALLY LOCALIZED PROSTATE CANCER: A POSTRANDOMIZATION ANALYSIS BY RISK GROUP SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol DE Prostate cancer; Risk groups; Intermediate risk; High risk; Comorbidity; Androgen suppression therapy; Radiation; Randomized trial ID RANDOMIZED CONTROLLED-TRIAL; DEPRIVATION THERAPY; CARDIOVASCULAR MORTALITY; RADIOTHERAPY; ADENOCARCINOMA AB Purpose: Six months of androgen suppression therapy (AST) plus radiation (RT) prolongs survival vs. RT alone in men with unfavorable risk localized prostate cancer (PCa), but it is unknown if this benefit applies to all risk subgroups and, in particular, the intermediate-risk group. Methods and Materials: Among 206 men with stages T1b to T2b PCa and either a prostate-specific antigen level of >10 or a Gleason score of >= 7 or MRI evidence of T3 disease randomized to receive 70 Gy of RT with or without 6 months of AST, Cox multivariable analysis was used to assess the impact of AST on overall survival in intermediate- and high-risk localized PCa, adjusting for age, Adult Comorbidity Evaluation 27 comorbidity score, interaction between comorbidity and treatment, and known prognostic factors. Survival estimates were compared using a two-sided log-rank test. Results: After an 8.2-year median follow-up, 74 men died. Compared to treatment with AST plus RT, treatment with RT alone was associated with an increased risk of death in intermediate-risk (adjusted hazard ratio, 3.0 [95% confidence interval, 1.3-7.2]; p = 0.01) and high-risk PCa (adjusted hazard ratio, 3.3 [95% confidence interval, 0.94-11.3]; p = 0.06). The survival benefit of adding AST was restricted to men with no or mild comorbidity in both the intermediate-risk (90.9% vs. 85.8% survival, respectively, at 7 years for AST plus RT vs. RT alone; p = 0.009) and high-risk (88.9% vs. 51.2% survival, respectively, at 7 years for AST plus RT vs. RT alone; p = 0.007) subgroups. Conclusions: In men with localized PCa who have no or mild comorbidity, adding 6 months of AST to RT was associated with improved survival for those with both intermediate-risk and high-risk disease, but in men with moderate to severe comorbidity, no benefit was observed in either risk group. (C) 2010 Elsevier Inc. C1 [Nguyen, Paul L.; Beard, Clair J.; Suh, W. Warren; Loffredo, Marian; McMahon, Elizabeth; D'Amico, Anthony V.] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Nguyen, Paul L.; Beard, Clair J.; Suh, W. Warren; Loffredo, Marian; McMahon, Elizabeth; Kantoff, Philip W.; D'Amico, Anthony V.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [Renshaw, Andrew A.] Baptist Hosp Miami, Dept Pathol, Miami, FL USA. [Kantoff, Philip W.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Nguyen, Paul L.; Beard, Clair J.; Suh, W. Warren; Kantoff, Philip W.; D'Amico, Anthony V.] Harvard Univ, Sch Med, Boston, MA USA. RP Nguyen, PL (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, 75 Francis St, Boston, MA 02115 USA. EM pnguyen@LROC.harvard.edu NR 18 TC 25 Z9 25 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2010 VL 77 IS 4 BP 1046 EP 1052 DI 10.1016/j.ijrobp.2009.06.038 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 620HJ UT WOS:000279489500012 PM 19864082 ER PT J AU MacDonald, SM Harisinghani, MG Katkar, A Napolitano, B Wolfgang, J Taghian, AG AF MacDonald, Shannon M. Harisinghani, Mukesh G. Katkar, Amol Napolitano, Brian Wolfgang, John Taghian, Alphonse G. TI NANOPARTICLE-ENHANCED MRI TO EVALUATE RADIATION DELIVERY TO THE REGIONAL LYMPHATICS FOR PATIENTS WITH BREAST CANCER SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and Oncology CY SEP 21-25, 2008 CL Boston, MA SP Amer Soc Therapeut Radiol & Oncol DE Breast cancer; radiation planning; nanoparticle; nodal mapping; lymphatic delineation ID INTENSITY-MODULATED RADIOTHERAPY; NODE METASTASES; POSTOPERATIVE RADIOTHERAPY; PSYCHOLOGICAL MORBIDITY; ADJUVANT CHEMOTHERAPY; AXILLARY DISSECTION; RANDOMIZED-TRIAL; RISK; IRRADIATION; THERAPY AB Purpose: At present, radiation (RT) fields are based largely, and often solely, on bony anatomy. Recent efforts have been taken to better define lymphatic regions for RT planning. Lymphotrophic nanoparticle-enhanced MRI (LN-MRI) allows for accurate identification of malignant and benign lymph nodes. We sought to evaluate RT delivery to lymphatics for breast cancer using LN-MRI. Methods and Materials: Twenty-three patients with breast cancer underwent LN-MRI. MRIs were anatomically registered to a reference CT; benign and malignant lymph nodes were contoured. Standard RT fields were planned and dose calculated to prescribe 45-50 Gy. Lymphatic regions were contoured on CT. Coverage of LN-MRI lymph nodes by RT fields and contoured lymphatics were assessed. Results: Eighty-one percent of all lymph nodes defined by LN-MRI were covered by the 45-Gy isodose line; 82% of malignant and 79% of benign. The 50-Gy isodose line only encompassed 60% of LN-MRI defined lymph nodes-64% of malignant and 59% of benign. For nodal volumes contoured in the absence of a margin, 86% of actual lymph nodes were within contoured volumes. When a 5-mm expansion was added, 99% were included. Conclusions: LN-MRI is a useful tool to delineate the location of breast regional lymphatics. These results suggest less than desired coverage of lymph nodes using standard RT fields and that a margin may be advisable when defining nodal volumes by CT. The use of IMRT and RT in lieu of surgery makes accurate definition of the location of breast regional lymphatics of paramount importance. (C) 2010 Elsevier Inc. C1 [MacDonald, Shannon M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP MacDonald, SM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Cox 340,100 Blossom St, Boston, MA 02114 USA. EM smacdonald@partners.org NR 29 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2010 VL 77 IS 4 BP 1098 EP 1104 DI 10.1016/j.ijrobp.2009.06.002 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 620HJ UT WOS:000279489500020 PM 19836160 ER PT J AU Miyamoto, DT Mamon, HJ Ryan, DP Willett, CG Ancukiewicz, M Kobayashi, WK Blaszkowsky, L Fernandez-del Castillo, C Hong, TS AF Miyamoto, David T. Mamon, Harvey J. Ryan, David P. Willett, Christopher G. Ancukiewicz, Marek Kobayashi, Wendy K. Blaszkowsky, Lawrence Fernandez-del Castillo, Carlos Hong, Theodore S. TI OUTCOMES AND TOLERABILITY OF CHEMORADIATION THERAPY FOR PANCREATIC CANCER PATIENTS AGED 75 YEARS OR OLDER SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Pancreatic cancer; Elderly; Chemoradiation; Radiation; Toxicity ID RANDOMIZED CONTROLLED-TRIAL; PHASE-III TRIAL; ADJUVANT RADIOTHERAPY; PERIAMPULLARY REGION; CURATIVE RESECTION; COOPERATIVE GROUP; 5-FLUOROURACIL; CHEMOTHERAPY; CHEMORADIOTHERAPY; COMORBIDITY AB Purpose: To review the outcomes and tolerability of full-dose chemoradiation in elderly patients aged 75 years or older with localized pancreatic cancer. Methods and Materials: We retrospectively reviewed patients aged 75 years or older with nonmetastatic pancreatic cancer treated with chemoradiation therapy at two institutions from 2002 to 2007. Patients were analyzed for treatment toxicity, local recurrences, distant metastases, and survival. Results: A total of 42 patients with a median age of 78 years (range, 75-90 years) who received chemoradiation therapy for pancreatic cancer were identified. Of the patients, 24 had locally advanced disease treated with definitive chemoradiation, and 18 had disease treated with surgery and chemoradiation. Before chemoradiotherapy, the mean Eastern Cooperative Oncology Group performance status was 1.0 +/- 0.8, and the mean 6-month weight loss was 5.3 +/- 3.8 kg. The mean radiation dose delivered was 48.1 +/- 9.2 Gy. All patients received fluoropyrimidine-based chemotherapy concurrently with radiotherapy. In all, 8 patients (19%) were hospitalized, 7 (17%) had an emergency room visit, 15(36%) required a radiation treatment break, 3(7%) required a chemotherapy break, 9(21%) did not complete therapy, and 22 (49%) had at least one of these adverse events. The most common toxicities were nausea, pain, and failure to thrive. Median overall survival was 8.6 months (95% confidence interval, 7.2-13.1) in patients who received definitive chemoradiation therapy and 20.6 months (95% confidence interval, 9.5-infinity) in patients who underwent resection and chemoradiation therapy. Conclusions: In this dataset of very elderly patients with pancreatic cancer and good Eastern Cooperative Oncology Group performance status, outcomes after chemoradiotherapy were similar to those among historic controls for patients with locally advanced and resected pancreatic cancer, although many patients experienced substantial treatment-related toxicity. (C) 2010 Elsevier Inc. C1 [Ancukiewicz, Marek; Kobayashi, Wendy K.; Hong, Theodore S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Ryan, David P.; Blaszkowsky, Lawrence] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Fernandez-del Castillo, Carlos] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Miyamoto, David T.] Harvard Univ, Sch Med, Harvard Radiat Oncol Program, Boston, MA USA. [Mamon, Harvey J.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Willett, Christopher G.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC USA. RP Hong, TS (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 3, Boston, MA 02114 USA. EM tshong1@partners.org NR 18 TC 14 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2010 VL 77 IS 4 BP 1171 EP 1177 DI 10.1016/j.ijobp.2009.06.020 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 620HJ UT WOS:000279489500031 PM 19800182 ER PT J AU Zhang, ZX Shek, K Wang, SA Huang, XY Lau, A Yin, ZQ Sun, HT Liu, WH Garcia, B Rittling, S Jevnikar, AM AF Zhang, Zhu-Xu Shek, Kelvin Wang, Shuang Huang, Xuyan Lau, Arthur Yin, Ziqin Sun, Hongtao Liu, Weihua Garcia, Bertha Rittling, Susan Jevnikar, Anthony M. TI Osteopontin Expressed in Tubular Epithelial Cells Regulates NK Cell-Mediated Kidney Ischemia Reperfusion Injury SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACUTE-RENAL-FAILURE; T-CELL; UP-REGULATION; MACROPHAGE INFILTRATION; INTERSTITIAL FIBROSIS; ANGIOTENSIN-II; IFN-GAMMA; MICE; APOPTOSIS; ISCHEMIA/REPERFUSION AB Renal ischemia reperfusion injury (IRI) occurs after reduced renal blood flow and is a major cause of acute injury in both native and transplanted kidneys. Studies have shown diverse cell types in both the innate and the adaptive immune systems participate in kidney IRI as dendritic cells, macrophages, neutrophils, B cells, CD4(+) NK(+) cells, and CD4(+) T cells all contribute to this form of injury. Recently, we have found that NK cells induce apoptosis in tubular epithelial cells (TECs) and also contribute to renal IRI. However, the mechanism of NK cell migration and activation during kidney IRI remains unknown. In this study, we have identified that kidney TECs express a high level of osteopontin (OPN) in vitro and in vivo. C57BL/6 OPN-deficient mice have reduced NK cell infiltration with less tissue damage compared with wild-type C57BL/6 mice after ischemia. OPN can directly activate NK cells to mediate TEC apoptotic death and can also regulate chemotaxis of NK cells to TECs. Taken together, our study's results indicate that OPN expression by TECs is an important factor in initial inflammatory responses that involves NK cells activity in kidney IRI. Inhibiting OPN expression at an early stage of IRI may be protective and preserve kidney function after transplantation. The Journal of Immunology, 2010, 185: 967-973. C1 [Zhang, Zhu-Xu; Wang, Shuang; Huang, Xuyan; Lau, Arthur; Yin, Ziqin; Sun, Hongtao; Liu, Weihua; Garcia, Bertha; Jevnikar, Anthony M.] Univ Western Ontario, Multiorgan Transplant Program, London Hlth Sci Ctr, London, ON N6A 5A5, Canada. [Zhang, Zhu-Xu; Garcia, Bertha; Jevnikar, Anthony M.] Univ Western Ontario, Dept Med, London, ON N6A 5A5, Canada. [Zhang, Zhu-Xu; Lau, Arthur; Garcia, Bertha; Jevnikar, Anthony M.] Univ Western Ontario, Dept Pathol, London, ON N6A 5A5, Canada. [Shek, Kelvin; Jevnikar, Anthony M.] Univ Western Ontario, Dept Microbiol & Immunol, London, ON N6A 5A5, Canada. [Zhang, Zhu-Xu; Wang, Shuang; Huang, Xuyan; Yin, Ziqin; Sun, Hongtao; Liu, Weihua; Garcia, Bertha; Jevnikar, Anthony M.] Lawson Hlth Res Inst, London, ON, Canada. [Rittling, Susan] Forsyth Inst, Dept Cytokine Biol, Boston, MA 02115 USA. RP Zhang, ZX (reprint author), Univ Western Ontario, Dept Med, Univ Hosp, C9-116,339 Windermere Rd, London, ON N6A 5A5, Canada. EM zhuxu.zhang@lhsc.on.ca; jevnikar@uwo.ca FU Canadian Institutes of Health Research; Kidney Foundation of Canada; Heart and Stroke Foundation of Canada; London Health Sciences Centre, London, Ontario, Canada; Wyeth-CIHR Chair in Transplantation FX This work was supported by the Canadian Institutes of Health Research (A.M.J.), the Kidney Foundation of Canada (Z.X.Z.), the Heart and Stroke Foundation of Canada (Z.X.Z.), and the Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada. A.M.J. is also supported as the Wyeth-CIHR Chair in Transplantation. NR 53 TC 29 Z9 31 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2010 VL 185 IS 2 BP 967 EP 973 DI 10.4049/jimmunol.0903245 PG 7 WC Immunology SC Immunology GA 622PH UT WOS:000279675200023 PM 20548025 ER PT J AU Crowe, SR Ash, LL Engler, RJM Ballard, JD Harley, JB Farris, AD James, JA AF Crowe, Sherry R. Ash, Linda L. Engler, Renata J. M. Ballard, Jimmy D. Harley, John B. Farris, A. Darise James, Judith A. TI Select Human Anthrax Protective Antigen Epitope-Specific Antibodies Provide Protection from Lethal Toxin Challenge SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; BACILLUS-ANTHRACIS; MONOCLONAL-ANTIBODIES; NEUTRALIZING ANTIBODIES; INHALATIONAL ANTHRAX; PASSIVE PROTECTION; IMMUNE-RESPONSES; GUINEA-PIGS; IN-VITRO; VACCINE AB Bacillus anthracis remains a serious bioterrorism concern, and the currently licensed vaccine remains an incomplete solution for population protection from inhalation anthrax and has been associated with concerns regarding efficacy and safety. Thus, understanding how to generate long-lasting protective immunity with reduced immunizations or provide protection through postexposure immunotherapeutics are long-sought goals. Through evaluation of a large military cohort, we characterized the levels of antibodies against protective antigen and found that over half of anthrax vaccinees had low serum levels of in vitro toxin neutralization capacity. Using solid-phase epitope mapping and confirmatory assays, we identified several neutralization-associated humoral epitopes and demonstrated that select antipeptide responses mediated protection in vitro. Finally, passively transferred antibodies specific for select epitopes provided protection in an in vivo lethal toxin mouse model. Identification of these antigenic regions has important implications for vaccine design and the development of directed immunotherapeutics. C1 [Crowe, Sherry R.; Ash, Linda L.; Harley, John B.; Farris, A. Darise; James, Judith A.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Ballard, Jimmy D.; Harley, John B.; Farris, A. Darise; James, Judith A.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Harley, John B.] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK USA. [Engler, Renata J. M.] Walter Reed Army Med Ctr, Vaccine Healthcare Ctr Network, Washington, DC 20307 USA. RP James, JA (reprint author), Clin Immunol Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM jamesj@omrf.org FU National Institute of Allergy and Infectious Diseases [U19AI062629]; National Center for Research Resources [P20RR15577]; Walter Reed Army Medical Center Vaccine Healthcare Centers Network and Allergy-Immunology Department FX National Institute of Allergy and Infectious Diseases (grant U19AI062629); National Center for Research Resources (grant P20RR15577); Walter Reed Army Medical Center Vaccine Healthcare Centers Network and Allergy-Immunology Department (local protocol development and management). NR 47 TC 20 Z9 20 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 15 PY 2010 VL 202 IS 2 BP 251 EP 260 DI 10.1086/653495 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 612VL UT WOS:000278932900010 PM 20533877 ER PT J AU Shahi, P Gulshan, K Naar, AM Moye-Rowley, WS AF Shahi, Puja Gulshan, Kailash Naeaer, Anders M. Moye-Rowley, W. Scott TI Differential Roles of Transcriptional Mediator Subunits in Regulation of Multidrug Resistance Gene Expression in Saccharomyces cerevisiae SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID BINDING CASSETTE TRANSPORTER; PLEIOTROPIC DRUG-RESISTANCE; POLYMERASE-II HOLOENZYME; PLASMA-MEMBRANE; MITOCHONDRIAL DYSFUNCTION; GENOME-WIDE; YEAST; PROTEIN; COMPLEX; PATHWAY AB The multiprotein transcriptional Mediator complex provides a key link between RNA polymerase II and upstream transcriptional activator proteins. Previous work has established that the multidrug resistance transcription factors Pdr1 and Pdr3 interact with the Mediator component Med15/Gal11 to drive normal levels of expression of the ATP-binding cassette transporter-encoding gene PDR5 in Saccharomyces cerevisiae. PDR5 transcription is induced upon loss of the mitochondrial genome (rho(0) cells) and here we provide evidence that this rho(0) induction is Med15 independent. A search through other known Mediator components determined that Med12/Srb8, a member of the CDK8 Mediator submodule, is required for rho(0) activation of PDR5 transcription. The CDK8 submodule contains the cyclin C homologue (CycC/Srb11), cyclin-dependent kinase Cdk8/Srb10, and the large Med13/Srb9 protein. Loss of these other proteins did not lead to the same block in PDR5 induction. Chromatin immunoprecipitation analyses demonstrated that Med15 is associated with the PDR5 promoter in both rho(+) and rho(0), whereas Med12 recruitment to this target promoter is highly responsive to loss of the mitochondrial genome. Coimmunoprecipitation experiments revealed that association of Pdr3 with Med12 can only be detected in rho(0) cells. These experiments uncover the unique importance of Med12 in activated transcription of PDR5 seen in rho(0) cells. C1 [Shahi, Puja; Gulshan, Kailash; Moye-Rowley, W. Scott] Univ Iowa, Carver Coll Med, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA. [Naeaer, Anders M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Cell Biol,Canc Ctr, Charlestown, MA 02129 USA. RP Moye-Rowley, WS (reprint author), Univ Iowa, Carver Coll Med, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA. EM scott-moye-rowley@uiowa.edu OI Moye-Rowley, Scott/0000-0002-7163-1120 FU National Institutes of Health [GM49825] FX This work was supported by National Institutes of Health Grant GM49825. NR 51 TC 22 Z9 22 U1 1 U2 7 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL 15 PY 2010 VL 21 IS 14 BP 2469 EP 2482 DI 10.1091/mbc.E09-10-0899 PG 14 WC Cell Biology SC Cell Biology GA 624PY UT WOS:000279833100010 PM 20505076 ER PT J AU Rosenthal, E Brennan, L Xie, S Hurtig, H Milber, J Weintraub, D Karlawish, J Siderowf, A AF Rosenthal, Emily Brennan, Laura Xie, Sharon Hurtig, Howard Milber, Joshua Weintraub, Daniel Karlawish, Jason Siderowf, Andrew TI Association Between Cognition and Function in Patients With Parkinson Disease With and Without Dementia SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; cognitive impairment; ADL ID MENTAL-STATE-EXAMINATION; SCREENING TOOL; RATING-SCALE; IMPAIRMENT; DISABILITY; SCORE AB Patients with Parkinson's disease (PD) often have cognitive deficits from the time of diagnosis. Except in patients with dementia, the impact of cognitive symptoms on daily function is not well documented. This study had two objectives: (I) to determine the functional significance of cognitive deficits in nondemented patients with PD and (2) to assess the sensitivity of two measures of global cognitive abilities to identify individuals with impaired ADL function. One hundred eleven subjects with PD and a range of cognitive abilities were included. Of these, 20 were diagnosed with PDD. All subjects were assessed with the Mattis Dementia Rating Scale to two (DRS-2) and the Mini-Mental State Examination (MMSE). ADL function was reported by an informant using the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL). The ability of the DRS-2 and MMSE to capture the impact of cognitive impairment on ADL function was assessed in the entire cohort and in subsets of nondemented individuals. After adjustment for covariates, cognition as measured by the DRS-2 was strongly related to ADL function in the entire cohort (partial correlation coefficient = 0.55, P < 0.001). The association remained strong when only nondemented subjects were included (r = 0.42, P < 0.001). The DRS-2 was significantly more accurate than the MMSE, particularly for detecting milder degrees of ADL impairment (ROC area = 0.87 vs. 0.75, P = 0.0008). Cognition is associated with impairment in ADL function, even in nondemented patients with PD. However, sensitive cognitive assessment measures may be needed to identify these functionally relevant impairments. (C) 2010 Movement Disorder Society C1 [Rosenthal, Emily; Brennan, Laura; Hurtig, Howard; Milber, Joshua; Siderowf, Andrew] Univ Penn, Dept Neurol, Sch Med, Div Geriatr, Philadelphia, PA 19107 USA. [Xie, Sharon] Univ Penn, Dept Biostat, Sch Med, Div Geriatr, Philadelphia, PA 19107 USA. [Weintraub, Daniel] Univ Penn, Dept Psychiat, Sch Med, Div Geriatr, Philadelphia, PA 19107 USA. [Weintraub, Daniel] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Karlawish, Jason] Univ Penn, Dept Med & Med Eth, Sch Med, Div Geriatr, Philadelphia, PA 19107 USA. RP Siderowf, A (reprint author), Univ Penn, Dept Neurol, Sch Med, Div Geriatr, 330 S 9th St,2nd Floor, Philadelphia, PA 19107 USA. EM andrew.siderowf@uphs.upenn.edu FU NINDS NIH HHS [P50 NS053488-030001, P50 NS053488-01A20001, P50 NS053488-020001] NR 28 TC 56 Z9 56 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL 15 PY 2010 VL 25 IS 9 BP 1170 EP 1176 DI 10.1002/mds.23073 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 636YN UT WOS:000280781500009 PM 20310053 ER PT J AU Ku, S Glass, GA AF Ku, Stephen Glass, Graham A. TI Age of Parkinson's Disease Onset as a Predictor for the Development of Dyskinesia SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; dyskinesia; age of onset ID MOTOR FLUCTUATIONS; DOPAMINE AGONISTS; INITIAL TREATMENT; LEVODOPA; PRAMIPEXOLE; ROPINIROLE; THERAPY; TRIAL; RISK AB The risk of developing levodopa-associated dyskinesia is known to vary inversely with the age of Parkinson's disease onset. This study quantifies dyskinesia risks for different Parkinson's onset ages in a patient population treated at the Parkinson's Disease Research, Education, and Clinical Center at the San Francisco Veterans Affairs Medical Center. Medical records were reviewed to determine age of Parkinson's onset, medication history, and dyskinesia onset. Dyskinesia risks were determined by using Kaplan-Meier analysis. Cox proportional hazard models were used to compare age groups and to perform multivariate modeling. This study included 109 patients with Parkinson's, 105 of whom had onset of symptoms after 1989. At 5 years of levodopa treatment, the dyskinesia risk for patients with onset age 40-49 was 70%, decreasing to 42% for onset ages 50-59, 33% for onset ages 60-69, and 24% for onset ages 70-79. Pairwise comparisons between the 40-49 age group and the other age groups were statistically significant in time-to-event models. After 5 years of levodopa treatment, dyskinesia risks became uniformly high regardless of age of onset. These results suggest it is appropriate to use different baseline dyskinesia risks in clinical decision-making for patients on the basis of their ages of onset. However, the most significant difference occurs between ages 40-49 and ages 50-79, and if more than 5 years of levodopa therapy are anticipated, dyskinesia risk may have less utility when deciding upon Parkinson's therapy. Drug studies for Parkinson's disease should also take age of Parkinson's onset into account when analyzing dyskinesia outcomes. (C) 2010 Movement Disorder Society C1 [Glass, Graham A.] Univ Calif San Francisco, UCSF Med Ctr, Dept Neurol, San Francisco, CA 94143 USA. [Ku, Stephen] Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. [Ku, Stephen; Glass, Graham A.] San Francisco VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, San Francisco, CA USA. RP Glass, GA (reprint author), Univ Calif San Francisco, UCSF Med Ctr, Dept Neurol, San Francisco, CA 94143 USA. EM graham.glass@ucsf.edu FU NIH/NCRR UCSF-CTSI [UL1 RR024131]; University of California, San Francisco School of Medicine; Allergan, Inc; Movement Disorders Society FX This project was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Additional support was provided by the University of California, San Francisco School of Medicine Quarterly Research Fellowship. Honoraria: Dr. Glass has received $8,000 in compensation from Allergan Inc. for speakers bureau participation. Grants: Stephen Ku has received two University of California, San Francisco (UCSF) School of Medicine Quarterly Research Fellowships and a UCSF Pathways to Careers in Clinical and Translational Research Program Quarterly Fellowship. UCSF has received unrestricted educational grants from Allergan, Inc in the last 12 months. Expert Testimony: Dr. Glass has provided legal guidance and received compensation in sum amounting to less than $10,000. He has not testified. Employment: Stephen Ku has been employed by the Asian & Pacific Islander Health Parity Coalition, leading a hepatitis B community education program. Other: Stephen Ku has received a Movement Disorders Society travel grant and a UCSF School of Medicine travel grant. NR 17 TC 18 Z9 22 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL 15 PY 2010 VL 25 IS 9 BP 1177 EP 1182 DI 10.1002/mds.23068 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 636YN UT WOS:000280781500010 PM 20310028 ER PT J AU Franceschini, MA Radhakrishnan, H Thakur, K Wu, WC Ruvinskaya, S Carp, SA Boas, DA AF Franceschini, Maria Angela Radhakrishnan, Harsha Thakur, Kiran Wu, Weicheng Ruvinskaya, Svetlana Carp, Stefan A. Boas, David A. TI The effect of different anesthetics on neurovascular coupling SO NEUROIMAGE LA English DT Article ID CEREBRAL-BLOOD-FLOW; RAT SOMATOSENSORY CORTEX; NEAR-INFRARED SPECTROSCOPY; DIFFUSE OPTICAL TOMOGRAPHY; ACTIVITY-DEPENDENT INCREASES; FUNCTIONAL BRAIN ACTIVATION; EVOKED-POTENTIALS; HEMODYNAMIC-RESPONSE; NEURONAL-ACTIVITY; BARREL CORTEX AB To date, the majority of neurovascular coupling studies focused on the thalamic afferents' activity in layer IV and the corresponding large spiking activity as responsible for functional hyperemia. This paper highlights the role of the secondary and late cortico-cortical transmission in neurovascular coupling. Simultaneous scalp electroencephalography (EEG) and diffuse optical imaging (DOI) measurements were obtained during multiple conditions of event-related electrical forepaw stimulation in 33 male Sprague-Dawley rats divided into 6 groups depending on the maintaining anesthetic - alpha-chloralose, pentobarbital, ketamine-xylazine, fentanyl-droperidol, isoflurane, or propofol. The somatosensory evoked potentials (SEP) were decomposed into four components and the question of which best predicts the hemodynamic responses was investigated. Results of the linear regression analysis show that the hemodynamic response is best correlated with the secondary and late cortico-cortical transmissions and not with the initial thalamic input activity in layer IV. Baseline cerebral blood flow (CBF) interacts with neural activity and influences the evoked hemodynamic responses. Finally, neurovascular coupling appears to be the same across all anesthetics used. (C) 2010 Elsevier Inc. All rights reserved. C1 [Franceschini, Maria Angela; Radhakrishnan, Harsha; Thakur, Kiran; Wu, Weicheng; Ruvinskaya, Svetlana; Carp, Stefan A.; Boas, David A.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Franceschini, MA (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 13th St,Bldg 149,Rm 2301, Charlestown, MA 02129 USA. EM mari@nmr.mgh.harvard.edu RI Radhakrishnan, Harsha/K-5557-2012 FU US National Institutes of Health (NIH) [R01-EB001954, R01-EB006385] FX We would like to thank Anna Devor, Ellen Grant and John Marota for valuable discussions and Gary Boas for careful editing of the manuscript. This research is supported by the US National Institutes of Health (NIH) grants R01-EB001954 and R01-EB006385. NR 99 TC 62 Z9 62 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2010 VL 51 IS 4 BP 1367 EP 1377 DI 10.1016/j.neuroimage.2010.03.060 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 601EV UT WOS:000278042000009 PM 20350606 ER PT J AU Stone, JH Merkel, PA Spiera, R Seo, P Langford, CA Hoffman, GS Kallenberg, CGM Clair, EWS Turkiewicz, A Tchao, NK Webber, L Ding, L Sejismundo, LP Mieras, K Weitzenkamp, D Ikle, D Seyfert-Margolis, V Mueller, M Brunetta, P Allen, NB Fervenza, FC Geetha, D Keogh, KA Kissin, EY Monach, PA Peikert, T Stegeman, C Ytterberg, SR Specks, U AF Stone, John H. Merkel, Peter A. Spiera, Robert Seo, Philip Langford, Carol A. Hoffman, Gary S. Kallenberg, Cees G. M. Clair, E. William St. Turkiewicz, Anthony Tchao, Nadia K. Webber, Lisa Ding, Linna Sejismundo, Lourdes P. Mieras, Kathleen Weitzenkamp, David Ikle, David Seyfert-Margolis, Vicki Mueller, Mark Brunetta, Paul Allen, Nancy B. Fervenza, Fernando C. Geetha, Duvuru Keogh, Karina A. Kissin, Eugene Y. Monach, Paul A. Peikert, Tobias Stegeman, Coen Ytterberg, Steven R. Specks, Ulrich CA RAVE-ITN Res Grp TI Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ANTIBODY-ASSOCIATED VASCULITIS; GRANULOMATOSIS ETANERCEPT TRIAL; WEGENERS-GRANULOMATOSIS; RANDOMIZED-TRIAL; SYSTEMIC VASCULITIDES; CELL-ACTIVATION; B-CELLS; THERAPY; INDUCTION; REMISSION AB Background: Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. Methods: We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. Results: Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. Conclusions: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.) N Engl J Med 2010;363:221-32. C1 [Specks, Ulrich] Mayo Clin & Mayo Fdn, Div Pulm & Crit Care Med, Rochester, MN 55905 USA. [Stone, John H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Merkel, Peter A.; Kissin, Eugene Y.; Monach, Paul A.] Boston Univ, Med Ctr, Boston, MA USA. [Spiera, Robert] Hosp Special Surg, New York, NY 10021 USA. [Seo, Philip; Sejismundo, Lourdes P.; Geetha, Duvuru] Johns Hopkins Univ, Baltimore, MD USA. [Langford, Carol A.; Hoffman, Gary S.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Kallenberg, Cees G. M.; Stegeman, Coen] Univ Groningen, Groningen, Netherlands. [Clair, E. William St.; Allen, Nancy B.] Duke Univ, Durham, NC USA. [Turkiewicz, Anthony] Univ Alabama, Birmingham, AL USA. [Tchao, Nadia K.; Seyfert-Margolis, Vicki; Mueller, Mark] Immune Tolerance Network, Bethesda, MD USA. [Webber, Lisa; Ding, Linna] NIAID, Bethesda, MD 20892 USA. [Seyfert-Margolis, Vicki] US FDA, Rockville, MD 20857 USA. [Brunetta, Paul] Genentech Inc, San Francisco, CA 94080 USA. [Weitzenkamp, David; Ikle, David] Rho, Raleigh, NC USA. RP Specks, U (reprint author), Mayo Clin & Mayo Fdn, Div Pulm & Crit Care Med, Rochester, MN 55905 USA. EM specks.ulrich@mayo.edu OI Carey, John/0000-0001-7292-2328 FU National Institute of Allergy and Infectious Diseases [N01-AI-15416, ITN021AI]; Mayo Clinic and Foundation; National Center for Research Resources (NCRR) [RR024150-01, RR025005, K24 AR049185, K23 AR052820]; Boston University; National Institutes of Health [RR 025771, M01 RR00533, K24 AR02224]; Arthritis Foundation FX Supported by a grant from the National Institute of Allergy and Infectious Diseases to the Immune Tolerance Network (N01-AI-15416; protocol no. ITN021AI). Genentech and Biogen provided the study medications and partial funding. At the Mayo Clinic and Foundation, the trial was supported by a Clinical and Translational Science Award from the National Center for Research Resources (NCRR) (RR024150-01); at Johns Hopkins University, by grants from the NCRR (RR025005) and career development awards (K24 AR049185, to Dr. Stone, and K23 AR052820, to Dr. Seo); and at Boston University, by a Clinical and Translational Science Award (RR 025771), grants from the National Institutes of Health (M01 RR00533) and a career development award (K24 AR02224, to Dr. Merkel), and an Arthritis Foundation Investigator Award (to Dr. Monach). Enzyme-linked immunosorbent assay kits for antineutrophil cytoplasmic antibody were provided by Euroimmun (Lubeck, Germany). NR 35 TC 748 Z9 784 U1 2 U2 32 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 15 PY 2010 VL 363 IS 3 BP 221 EP 232 DI 10.1056/NEJMoa0909905 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 625AR UT WOS:000279864200005 PM 20647199 ER PT J AU Greer, DM Styer, AK Toth, TL Kindregan, CP Romero, JM AF Greer, David M. Styer, Aaron K. Toth, Thomas L. Kindregan, Charles P. Romero, Javier M. TI Case 21-2010: A Request for Retrieval of Oocytes from a 36-Year-Old Woman with Anoxic Brain Injury. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SPERM RETRIEVAL; CRYOPRESERVATION; DEATH; REPRODUCTION; PRESERVATION; TECHNOLOGY; FERTILITY; TISSUE; STATE; IVF C1 [Greer, David M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Styer, Aaron K.; Toth, Thomas L.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Romero, Javier M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Greer, David M.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Styer, Aaron K.; Toth, Thomas L.] Harvard Univ, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Romero, Javier M.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Kindregan, Charles P.] Suffolk Univ, Sch Law, Boston, MA 02114 USA. RP Greer, DM (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NR 28 TC 5 Z9 5 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 15 PY 2010 VL 363 IS 3 BP 276 EP 283 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 625AR UT WOS:000279864200012 PM 20647203 ER PT J AU Allen, S Wilson, MW Watkins, A Billups, C Qaddoumi, I Haik, BH Rodriguez-Galindo, C AF Allen, Steven Wilson, Matthew W. Watkins, Amy Billups, Catherine Qaddoumi, Ibrahim Haik, Barrett H. Rodriguez-Galindo, Carlos TI Comparison of Two Methods for Carboplatin Dosing in Children With Retinoblastoma SO PEDIATRIC BLOOD & CANCER LA English DT Article DE carboplatin; glomerular filtration rate; retinoblastoma ID GLOMERULAR-FILTRATION RATE; SERUM CREATININE LEVEL; GERM-CELL TUMORS; RENAL-FUNCTION; INTRAOCULAR RETINOBLASTOMA; SOLID TUMORS; PHASE-I; PATIENT CHARACTERISTICS; PROSPECTIVE VALIDATION; FOCAL THERAPY AB Background. Carboplatin is the most effective drug in retinoblastoma but systemic clearance is variable in young patients. While most regimens use a flat close, individualized targeting may provide a more adjusted systemic exposure. Patients and Methods. We compared carboplatin closes between two groups of children, with retinoblastoma that were treated using a flat dose of 560 mg/m(2) or a targeted AUC of 6.5 using a modified Calvert formula. Results. Ninety-eight patients with retinoblastoma received a total of 576 cycles of carboplatin (median 8 cycles). Fifty patients (51%) received a fixed dose per m(2), 32 (33%) received a dose based on AUC, 1 patient received fixed close per kilogram, and in 15 patients a combination AUC and fixed doses was used. The median cumulative carboplatin dose (mg/m(2)) for patients who received eight cycles using fixed per m(2) closing was 2151.8 (range, 1414.2-2852.0), compared to 1104.1 for nine patients who received eight cycles using Calvert closing (range, 779.0-1992.7) (P<0.001). For cycles given using AUC, the median percentage of the hypothetical fixed per m2 close was 70% (range, 48-134%). Younger patients had larger differences. Patients receiving carboplatin based on fixed per m2 dosing were 3.0 times more likely to have a platelet transfusion (95% confidence interval, 1.3-7.3). Conclusions. Carboplatin administration needs to consider the changes in renal function occurring during the first months of life. The use of a targeted AUC provides the most accurate method; however, mg per kg of body weight dosing is a very reliable alternative method. Pediatr Blood Cancer 2010;55:47-54. (C) 2010 Wiley-Liss, Inc. C1 [Allen, Steven; Qaddoumi, Ibrahim; Rodriguez-Galindo, Carlos] St Jude Childrens Hosp, Dept Oncol, Memphis, TN 38105 USA. [Wilson, Matthew W.; Haik, Barrett H.] St Jude Childrens Hosp, Dept Surg, Memphis, TN 38105 USA. [Wilson, Matthew W.; Haik, Barrett H.] Univ Tennessee, Ctr Hlth Sci, Hamilton Eye Inst, Dept Ophthalmol, Memphis, TN 38163 USA. [Watkins, Amy; Billups, Catherine] St Jude Childrens Hosp, Dept Biostat, Memphis, TN 38105 USA. [Qaddoumi, Ibrahim; Rodriguez-Galindo, Carlos] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. RP Rodriguez-Galindo, C (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM carlos_rodriguez-galindo@dfci.harvard.edu FU American Lebanese Associated Charities (ALSAC) [P30-CA23099, CA21765]; Research to Prevent Blindness, New York; St Giles Foundation, New York FX Grant sponsor: American Lebanese Associated Charities (ALSAC); Grant numbers: P30-CA23099, CA21765; Grant sponsor: Research to Prevent Blindness, New York; Grant sponsor: St Giles Foundation, New York. NR 43 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL 15 PY 2010 VL 55 IS 1 BP 47 EP 54 DI 10.1002/pbc.22467 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 601BJ UT WOS:000278032700014 PM 20486170 ER PT J AU Sun, HY Forrest, G Gupta, KL Aguado, JM Lortholary, O Julia, MB Safdar, N Patel, R Kusne, S Singh, N AF Sun, Hsin-Yun Forrest, Graeme Gupta, Krishan L. Aguado, Jose M. Lortholary, Olivier Blanes Julia, Marino Safdar, Nasia Patel, Robin Kusne, Shimon Singh, Nina TI Rhino-Orbital-Cerebral Zygomycosis in Solid Organ Transplant Recipients SO TRANSPLANTATION LA English DT Article DE Zygomycosis; Solid organ transplant; Rhino-orbital-cerebral ID LIPOSOMAL AMPHOTERICIN-B; RENAL-ALLOGRAFT RECIPIENT; CENTRAL-NERVOUS-SYSTEM; INVASIVE FUNGAL-INFECTIONS; RHINOCEREBRAL MUCORMYCOSIS; KIDNEY-TRANSPLANTATION; LIPID COMPLEX; CUNNINGHAMELLA-BERTHOLLETIAE; CRYPTOCOCCAL MENINGITIS; CARDIAC TRANSPLANTATION AB Background. Rhino-orbital-cerebral disease is a significant manifestation of zygomycosis in solid organ transplant (SOT) recipients. However, its characteristics and outcome are not well addressed. Methods. SOT recipients with zygomycosis as per the European Organization for Research and Treatment in Cancer and the Mycoses Study Group criteria in a cohort study at our centers published previously and those identified with a PubMed search from the 1950s to November 2009 were studied. Patients with mycosis involving the sinuses, orbits, or central nervous system (CNS) were included. Results. Patients comprised a total of 90 SOT recipients with rhino-orbital-cerebral zygomycosis, including 13 in our cohort and 77 in the literature. CNS disease occurred in 57% (51 of 90). Overall mortality was 52.3% (46 of 88), and the mortality in patients with CNS disease was 73.5% (36 of 49). In logistic regression analysis, older age (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.04-1.21, P=0.002) was associated with a higher mortality rate, whereas lipid formulations of amphotericin B compared with amphotericin B deoxycholate (OR 0.09, 95% CI 0.02-0.50, P=0.006) and surgery (OR 0.12, 95% CI 0.01-0.94, P=0.043) were independently associated with an improved survival even when controlled for CNS involvement and the era of diagnosis of disease. Conclusions. Rhino-orbital-cerebral zygomycosis, particularly CNS disease, is associated with substantial mortality rate in SOT recipients. Older age is a significant risk factor for mortality, whereas lipid formulations of amphotericin B and surgery improved outcomes. C1 [Sun, Hsin-Yun; Singh, Nina] VA Pittsburgh Healthcare Syst, Dept Med, Div Infect Dis, Pittsburgh, PA USA. [Sun, Hsin-Yun] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. [Sun, Hsin-Yun] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Forrest, Graeme] Univ Maryland, Dept Med, Div Infect Dis, Baltimore, MD 21201 USA. [Gupta, Krishan L.] Postgrad Inst Med Educ & Res, Dept Nephrol, Chandigarh 160012, India. [Gupta, Krishan L.] Postgrad Inst Med Educ & Res, Dept Pathol, Chandigarh 160012, India. [Aguado, Jose M.] Hosp Octubre, Unidad Enfermedades Infecciosas, Infect Dis Unit, Madrid, Spain. [Lortholary, Olivier] Univ Paris 05, Hop Necker Enfants Malad, Dept Immunol Infect Dis & Hematol, Ctr Infectiol Necker Pasteur, Paris, France. [Lortholary, Olivier] Inst Pasteur, Ctr Natl Reference Mycol & Antifong, Paris, France. [Blanes Julia, Marino] Hosp Univ La Fe, Infect Dis Unit, Valencia, Spain. [Safdar, Nasia] Univ Wisconsin, Dept Med, Infect Dis Sect, Madison, WI USA. [Patel, Robin] Mayo Clin, Div Clin Microbiol, Rochester, MN USA. [Patel, Robin] Mayo Clin, Div Infect Dis, Rochester, MN USA. [Kusne, Shimon] Mayo Clin, Div Infect Dis & Transplantat Med, Scottsdale, AZ USA. [Singh, Nina] Univ Pittsburgh, Pittsburgh, PA USA. RP Singh, N (reprint author), VA Med Ctr, Infect Dis Sect, Univ Dr C, Pittsburgh, PA 15240 USA. EM nis5@pitt.edu OI SUN, HSIN-YUN/0000-0003-0074-7721 FU Pfizer; Schering Plough; Astellas FX N.S. has received grant support from Pfizer and Schering Plough. G.F. has received grant support from Astellas. Other authors declare no conflicts of interest.; This work was in part supported by Schering Plough (N.S.). NR 83 TC 33 Z9 33 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2010 VL 90 IS 1 BP 85 EP 92 DI 10.1097/TP.0b013e3181dde8fc PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 622ES UT WOS:000279644400012 PM 20626095 ER PT J AU Talcott, JA Zietman, AL AF Talcott, James A. Zietman, Anthony L. TI Conventional and High-Dose Radiation in Treating Early Prostate Cancer Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID RANDOMIZED-TRIAL; ADENOCARCINOMA; THERAPY C1 [Talcott, James A.; Zietman, Anthony L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Talcott, JA (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jtalcott@partners.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 14 PY 2010 VL 304 IS 2 BP 155 EP 155 DI 10.1001/jama.2010.928 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 624IN UT WOS:000279811000013 ER PT J AU O'Hare, AM Rodriguez, RA Hailpern, SM Larson, EB Tamura, MK AF O'Hare, Ann M. Rodriguez, Rudolph A. Hailpern, Susan M. Larson, Eric B. Tamura, Manjula Kurella TI Regional Variation in Health Care Intensity and Treatment Practices for End-stage Renal Disease in Older Adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID OF-LIFE CARE; DECISION-MAKING; NATIONAL-SURVEY; UNITED-STATES; DIALYSIS; POPULATION AB Context An increasing number of older adults are being treated for end-stage renal disease (ESRD) with long-term dialysis. Objectives To determine how ESRD treatment practices for older adults vary across regions with differing end-of-life intensity of care. Design, Setting, and Participants Retrospective observational study using a national ESRD registry to identify a cohort of 41 420 adults (of white or black race), aged 65 years or older, who started long-term dialysis or received a kidney transplant between June 1, 2005, and May 31, 2006. Regional end-of-life intensity of care was defined using an index from the Dartmouth Atlas of Healthcare. Main Outcome Measures Incidence of treated ESRD (dialysis or transplant), preparedness for ESRD (under the care of a nephrologist, having a fistula [vs graft or catheter] at time of hemodialysis initiation), and end-of-life care practices. Results Among whites, the incidence of ESRD was progressively higher in regions with greater intensity of care and this trend was most pronounced at older ages. Among blacks, a similar relationship was present only at advanced ages (men aged >= 80 years and women aged >= 85 years). Patients living in regions in the highest compared with lowest quintile of end-of-life intensity of care were less likely to be under the care of a nephrologist before the onset of ESRD (62.3% [95% confidence interval {CI}, 61.3%-63.3%] vs 71.1% [95% CI, 69.9%-72.2%], respectively) and less likely to have a fistula (vs graft or catheter) at the time of hemodialysis initiation (11.2% [95% CI, 10.6%-11.8%] vs 16.9% [95% CI, 15.9%-17.8%]). Among patients who died within 2 years of ESRD onset (n=21 190), those living in regions in the highest compared with lowest quintile of end-of-life intensity of care were less likely to have discontinued dialysis before death (22.2% [95% CI, 21.1%-23.4%] vs 44.3% [95% CI, 42.5%-46.1%], respectively), less likely to have received hospice care (20.7% [95% CI, 19.5%-21.9%] vs 33.5% [95% CI, 31.7%-35.4%]), and more likely to have died in the hospital (67.8% [95% CI, 66.5%-69.1%] vs 50.3% [95% CI, 48.5%-52.1%]). These differences persisted in adjusted analyses. Conclusion There are pronounced regional differences in treatment practices for ESRD in older adults that are not explained by differences in patient characteristics. JAMA. 2010; 304(2): 180-186 www.jama.com C1 [O'Hare, Ann M.; Rodriguez, Rudolph A.] VA Puget Sound Healthcare Syst, Dept Med, Seattle, WA 98108 USA. [O'Hare, Ann M.] VA Puget Sound Healthcare Syst, HSR&D Ctr Excellence, Seattle, WA 98108 USA. [O'Hare, Ann M.; Rodriguez, Rudolph A.; Larson, Eric B.] Univ Washington, Dept Med, Seattle, WA USA. [Larson, Eric B.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Tamura, Manjula Kurella] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. [Tamura, Manjula Kurella] VA Palo Alto Healthcare Syst, Dept Med, Palo Alto, CA USA. RP O'Hare, AM (reprint author), VA Puget Sound Healthcare Syst, Dept Med, 111J Nephrol,1660 S Columbian Way, Seattle, WA 98108 USA. EM Ann.OHare@va.gov RI Kurella Tamura, Manjula/C-8284-2014 OI Kurella Tamura, Manjula/0000-0001-5227-2479 FU Beeson Career Development Award [K23AG28980, K23AG028952]; National Institutes of Health; Satellite Research; Amgen; American Society of Nephrology; Association of Subspecialty Professors; University of California, San Francisco FX Dr O'Hare reported receiving royalties from UpToDate, an honorarium from the Japanese Society for Foot Care, and a Career Development Award from the Department of Veterans Affairs' Health Services Research and Development Service and serving as the principal investigator on an interagency agreement between the Centers for Disease Control and Prevention and the VA Puget Sound Healthcare System. Dr Hailpern reported being employed by LipoScience (Raleigh, North Carolina) during the time frame that she was working on this study but her work on the project was completed during her free time and was not part of her work for the company. Dr Larson reported receiving research support from the National Institutes of Health, royalties from UpToDate, Springer, and Elsevier, and speaker honoraria from universities and other nonprofit organizations. Dr Kurella Tamura reported receiving research funding from Satellite Research, Amgen, a Junior Development Award in Geriatric Nephrology from the American Society of Nephrology and Association of Subspecialty Professors, and an intramural grant from the University of California, San Francisco. The financial disclosures listed herein for Drs O'Hare and Kurella Tamura are for the last 5 years.; Dr O'Hare is supported by Beeson Career Development Award K23AG28980. Dr Kurella Tamura is supported by Beeson Career Development Award K23AG028952. NR 13 TC 75 Z9 75 U1 2 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 14 PY 2010 VL 304 IS 2 BP 180 EP 186 DI 10.1001/jama.2010.924 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 624IN UT WOS:000279811000024 PM 20628131 ER PT J AU DesRoches, CM Rao, SR Fromson, JA Birnbaum, RJ Iezzoni, L Vogeli, C Campbell, EG AF DesRoches, Catherine M. Rao, Sowmya R. Fromson, John A. Birnbaum, Robert J. Iezzoni, Lisa Vogeli, Christine Campbell, Eric G. TI Physicians' Perceptions, Preparedness for Reporting, and Experiences Related to Impaired and Incompetent Colleagues SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MEDICAL PROFESSIONALISM; SOCIAL-CONTRACT; NATIONAL-SURVEY AB Context Peer monitoring and reporting are the primary mechanisms for identifying physicians who are impaired or otherwise incompetent to practice, but data suggest that the rate of such reporting is lower than it should be. Objective To understand physicians' beliefs, preparedness, and actual experiences related to colleagues who are impaired or incompetent to practice medicine. Design, Setting, and Participants Nationally representative survey of 2938 eligible physicians practicing in the United States in 2009 in anesthesiology, cardiology, family practice, general surgery, internal medicine, pediatrics, and psychiatry. Overall, 1891 physicians (64.4%) responded. Main Outcome Measures Beliefs about and preparedness for reporting and experiences with colleagues who practice medicine while impaired or who are incompetent in their medical practice. Results Sixty-four percent (n=1120) of surveyed physicians agreed with the professional commitment to report physicians who are significantly impaired or otherwise incompetent to practice. Nonetheless, only 69% (n=1208) of physicians reported being prepared to effectively deal with impaired colleagues in their medical practice, and 64% (n=1126) reported being so prepared to deal with incompetent colleagues. Seventeen percent (n=309) of physicians had direct personal knowledge of a physician colleague who was incompetent to practice medicine in their hospital, group, or practice. Of those with this knowledge, 67% (n=204) reported this colleague to the relevant authority. Underrepresented minorities and graduates of non-US medical schools were less likely than their counterparts to report, and physicians working in hospitals or medical schools were most likely to report. The most frequently cited reason for taking no action was the belief that someone else was taking care of the problem (19% [n=58]), followed by the belief that nothing would happen as a result of the report (15% [n=46]) and fear of retribution (12% [n=36]). Conclusion Overall, physicians support the professional commitment to report all instances of impaired or incompetent colleagues in their medical practice to a relevant authority; however, when faced with these situations, many do not report. JAMA. 2010; 304(2): 187-193 www.jama.com C1 [DesRoches, Catherine M.; Rao, Sowmya R.; Iezzoni, Lisa; Vogeli, Christine; Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Rao, Sowmya R.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Fromson, John A.; Birnbaum, Robert J.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP DesRoches, CM (reprint author), Massachusetts Gen Hosp, Mongan Inst Hlth Policy, 50 Staniford St,Ste 900, Boston, MA 02114 USA. EM cdesroches@partners.org FU Institute on Medicine FX This study, which is the second in the series, was supported by a grant from the Institute on Medicine as a Profession. NR 17 TC 55 Z9 56 U1 1 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 14 PY 2010 VL 304 IS 2 BP 187 EP 193 DI 10.1001/jama.2010.921 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 624IN UT WOS:000279811000025 PM 20628132 ER PT J AU Milad, MR Zeidan, MA Contero, A Pitman, RK Klibanski, A Rauch, SL Goldstein, JM AF Milad, M. R. Zeidan, M. A. Contero, A. Pitman, R. K. Klibanski, A. Rauch, S. L. Goldstein, J. M. TI THE INFLUENCE OF GONADAL HORMONES ON CONDITIONED FEAR EXTINCTION IN HEALTHY HUMANS SO NEUROSCIENCE LA English DT Article DE estrogen; progesterone; sex difference; fear; menstrual cycle; learning and memory ID POSTTRAUMATIC-STRESS-DISORDER; ESTROGEN-RECEPTOR-BETA; PREMENSTRUAL DYSPHORIC DISORDER; ENHANCES COGNITIVE PERFORMANCE; MENSTRUAL-CYCLE; SEX-DIFFERENCES; ANXIETY DISORDERS; PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; MEMORY AB Recent rodent studies suggest that gonadal hormones influence extinction of conditioned fear. Here we investigated sex differences in, and the influence of estradiol and progesterone on, fear extinction in healthy humans. Men and women underwent a two-day paradigm in which fear conditioning and extinction learning took place on day 1 and extinction recall was tested on day 2. Visual cues were used as the conditioned stimuli and a mild electric shock was used as the unconditioned stimulus. Skin conductance was recorded throughout the experiment and used to measure conditioned responses (CRs). Blood samples were obtained from all women to measure estradiol and progesterone levels. We found that higher estradiol during extinction learning enhanced subsequent extinction recall but had no effects on fear acquisition or extinction learning itself. Sex differences were only observed during acquisition, with men exhibiting significantly higher CRs. After dividing women into low- and high-estradiol groups, men showed comparable extinction recall to high-estradiol women, and both of these groups showed higher extinction recall than low-estradiol women. Therefore, sex differences in extinction memory emerged only after taking into account women's estradiol levels. Lower estradiol may impair extinction consolidation in women. These findings could have practical applications in the treatment of anxiety disorders through cognitive and behavioral therapies. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Milad, M. R.; Zeidan, M. A.; Contero, A.; Pitman, R. K.; Rauch, S. L.; Goldstein, J. M.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. [Milad, M. R.; Zeidan, M. A.; Contero, A.; Pitman, R. K.; Rauch, S. L.; Goldstein, J. M.] Harvard Univ, Sch Med, Charlestown, MA USA. [Klibanski, A.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Rauch, S. L.] McLean Hosp, Belmont, MA 02178 USA. [Goldstein, J. M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Goldstein, J. M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Goldstein, J. M.] Connors Ctr Womens Hlth & Gender Biol, Boston, MA USA. RP Milad, MR (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. EM milad@nmr.mgh.harvard.edu FU National Institute of Mental Health [K01MH080346]; Harvard Clinical and Translational Science Center from the National Center for Research Resources [1UL1 RR025758-01] FX The work was supported by a grant from the National Institute of Mental Health (K01MH080346) to M.R.M. The project described was also supported by Grant 1UL1 RR025758-01, Harvard Clinical and Translational Science Center from the National Center for Research Resources, and ORWH-NIMH P50 MH082679 (JMG, P.I.) for JMG's time. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 50 TC 109 Z9 112 U1 4 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUL 14 PY 2010 VL 168 IS 3 BP 652 EP 658 DI 10.1016/j.neuroscience.2010.04.030 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 608UM UT WOS:000278611500007 PM 20412837 ER PT J AU Seetharaman, SV Winkler, DD Taylor, AB Cao, XH Whitson, LJ Doucette, PA Valentine, JS Schirf, V Demeler, B Carroll, MC Culotta, VC Hart, PJ AF Seetharaman, Sai V. Winkler, Duane D. Taylor, Alexander B. Cao, Xiaohang Whitson, Lisa J. Doucette, Peter A. Valentine, Joan S. Schirf, Virgil Demeler, Borries Carroll, Mark C. Culotta, Valeria C. Hart, P. John TI Disrupted Zinc-Binding Sites in Structures of Pathogenic SOD1 Variants D124V and H80R SO BIOCHEMISTRY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; HUMAN SUPEROXIDE-DISMUTASE; MOTOR-NEURON DEGENERATION; COPPER CHAPERONE CCS; CU,ZN-SUPEROXIDE DISMUTASE; BIOPHYSICAL PROPERTIES; ALS; DISULFIDE; ACTIVATION; CYSTEINE-111 AB Mutations in human copper-zinc superoxide dismutase (SOD1) cause an inherited form of the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we present structures of the pathogenic SOD1 variants D124V and H80R, both of which demonstrate compromised zinc-binding sites. The disruption of the zinc-binding sites in H80R SOD1 leads to conformational changes in loop elements, permitting non-native SOD1-SOD1 interactions that mediate the assembly of these proteins into higher-order filamentous arrays. Analytical ultracentrifugation sedimentation velocity experiments indicate that these SOD1 variants are more prone to monomerization than the wild-type enzyme. Although D124V and H80R SOD1 proteins appear to have fully functional copper-binding sites, inductively coupled plasma mass spectrometery (ICP-MS) and anomalous scattering X-ray diffraction analyses reveal that zinc (not copper) occupies the copper-binding sites in these variants. The absence of copper in these proteins, together with the results of covalent thiol modification experiments in yeast strains with and without the gene encoding the copper chaperone for SOD1 (CCS), suggests that CCS may not fully act on newly translated forms of these polypeptides. Overall, these findings lend support to the hypothesis that immature mutant SOD1 species contribute to toxicity in SOD1-linked ALS. C1 [Seetharaman, Sai V.; Winkler, Duane D.; Taylor, Alexander B.; Cao, Xiaohang; Whitson, Lisa J.; Schirf, Virgil; Demeler, Borries; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Seetharaman, Sai V.; Winkler, Duane D.; Taylor, Alexander B.; Cao, Xiaohang; Whitson, Lisa J.; Hart, P. John] Univ Texas Hlth Sci Ctr San Antonio, Xray Crystallog Core Lab, San Antonio, TX 78229 USA. [Doucette, Peter A.; Valentine, Joan S.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Carroll, Mark C.; Culotta, Valeria C.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. [Hart, P. John] S Texas Vet Hlth Care Syst, Dept Vet Affairs, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. RP Hart, PJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. EM pjhart@biochem.uthscsa.edu FU National Institutes of Health [NS39112, RR022200, NS049134, GM50016]; National Science Foundation [TG-MCB070038]; Johns Hopkins University NIEHS center; American Foundation for Aging Research; Judith and Jean Pape Adams Charitable Foundation; William and Ella Owens Medical Research Foundation; Texas Advanced Computing Center at The University of Texas; Bioinformatics Core Facility at The University of Texas Health Science Center FX This work was supported by National Institutes of Health Grants NS39112 (P.J.H.), RR022200 (B.D.), NS049134 (J.S.V.), and GM50016 (V.C.C.), National Science Foundation Grant TG-MCB070038 (B.D.), and the Johns Hopkins University NIEHS center (V.C.C.). D.D.W. and L.J.W. were supported in part by an American Foundation for Aging Research predoctoral fellowship. X.C. and S.V.S. were supported in part by the Judith and Jean Pape Adams Charitable Foundation and the William and Ella Owens Medical Research Foundation.; We acknowledge the support provided by the staff at the Texas Advanced Computing Center at The University of Texas and by Jeremy Mann at the Bioinformatics Core Facility at The University of Texas Health Science Center. Support for the X-ray Crystallography Core Laboratory and the Center for Analytical Ultracentrifugation of Macromolecular Assemblies by The University of Texas Health Science Center Executive Research Committee and the San Antonio Cancer Institute is also gratefully acknowledged NR 57 TC 22 Z9 22 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 13 PY 2010 VL 49 IS 27 BP 5714 EP 5725 DI 10.1021/bi100314n PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 618XL UT WOS:000279389300010 PM 20515040 ER PT J AU Zaman, MS Chen, Y Deng, G Shahryari, V Suh, SO Saini, S Majid, S Liu, J Khatri, G Tanaka, Y Dahiya, R AF Zaman, M. S. Chen, Y. Deng, G. Shahryari, V. Suh, S. O. Saini, S. Majid, S. Liu, J. Khatri, G. Tanaka, Y. Dahiya, R. TI The functional significance of microRNA-145 in prostate cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE miR145; prostate; cell growth; apoptosis; TNFSF10 ID HISTONE DEACETYLASE INHIBITORS; CARCINOMA-CELL-LINES; HUMAN BREAST-CANCER; CYCLE ARREST; EXPRESSION; APOPTOSIS; PROTEIN; LIGAND; CHEMOPREVENTION; ADENOCARCINOMA AB BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in numerous cellular processes. Recent studies have shown aberrant expression of miRNAs in prostate cancer tissues and cell lines. On the basis of miRNA microarray data, we found that miR-145 is significantly downregulated in prostate cancer. METHODS AND RESULTS: We investigated the expression and functional significance of miR-145 in prostate cancer. The expression of miR-145 was low in all the prostate cell lines tested (PC3, LNCaP and DU145) compared with the normal cell line, PWR-1E, and in cancerous regions of human prostate tissue when compared with the matched adjacent normal. Overexpression of miR-145 in PC3-transfected cells resulted in increased apoptosis and an increase in cells in the G2/M phase, as detected by flow cytometry. Investigation of the mechanisms of inactivation of miR-145 through epigenetic pathways revealed significant DNA methylation of the miR-145 promoter region in prostate cancer cell lines. Microarray analyses of miR-145-overexpressing PC3 cells showed upregulation of the pro-apoptotic gene TNFSF10, which was confirmed by real-time PCR and western analysis. CONCLUSION: One of the genes significantly upregulated by miR-145 overexpression is the proapoptotic gene TNFSF10. Therefore, modulation of miR-145 may be an important therapeutic approach for the management of prostate cancer. British Journal of Cancer (2010) 103, 256-264. doi: 10.1038/sj.bjc.6605742 www.bjcancer.com Published online 29 June 2010 (C) 2010 Cancer Research UK C1 [Zaman, M. S.; Chen, Y.; Deng, G.; Shahryari, V.; Suh, S. O.; Saini, S.; Majid, S.; Liu, J.; Khatri, G.; Tanaka, Y.; Dahiya, R.] San Francisco VA Med Ctr, Dept Urol, San Francisco, CA USA. [Zaman, M. S.; Chen, Y.; Deng, G.; Shahryari, V.; Suh, S. O.; Saini, S.; Majid, S.; Liu, J.; Khatri, G.; Tanaka, Y.; Dahiya, R.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Dahiya, R (reprint author), San Francisco VA Med Ctr, Dept Urol, San Francisco, CA USA. EM rdahiya@urology.ucsf.edu RI Jackson, Benjamin/C-4297-2012; Chen, Yi /J-4807-2012 FU NIH [RO1CA111470] FX We thank Dr Roger Erickson for support and assistance with the preparation of the article. This study was supported by the NIH Grant RO1CA111470 (to the principal investigator, Dr R Dahiya). NR 50 TC 84 Z9 90 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 13 PY 2010 VL 103 IS 2 BP 256 EP 264 DI 10.1038/sj.bjc.6605742 PG 9 WC Oncology SC Oncology GA 625JV UT WOS:000279892300015 PM 20588276 ER PT J AU Whittaker, S Martin, M Marais, R AF Whittaker, Steven Martin, Matthew Marais, Richard TI All Roads Lead to the Ribosome SO CANCER CELL LA English DT Editorial Material ID TRANSLATIONAL CONTROL; INHIBITOR; MTOR AB In this issue of Cancer Cell, She et al. show that in cancer cells a protein called 4E-BP1 is a key integrator of protein synthesis downstream of the ERK and AKT signaling pathways, providing an intriguing rationale for why their simultaneous targeting could enhance therapeutic efficacy. C1 [Martin, Matthew; Marais, Richard] Inst Canc Res, London SW3 6JB, England. [Whittaker, Steven] Dana Farber Canc Inst, Boston, MA 02115 USA. [Whittaker, Steven] Broad Inst, Cambridge Ctr 7, Cambridge, MA 02142 USA. RP Marais, R (reprint author), Inst Canc Res, 237 Fulham Rd, London SW3 6JB, England. EM richard.marais@icr.ac.uk OI Marais, Richard/0000-0001-7484-4183 NR 9 TC 1 Z9 1 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 JUL 13 PY 2010 VL 18 IS 1 BP 5 EP 6 DI 10.1016/j.ccr.2010.06.008 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 627IG UT WOS:000280032100003 PM 20609347 ER PT J AU Park, JM Fisher, DE AF Park, Jin Mo Fisher, David E. TI Testimony from the Bedside: From Coley's Toxins to Targeted Immunotherapy SO CANCER CELL LA English DT Editorial Material ID CTLA-4; ANTIBODIES; BLOCKADE AB A new clinical study reported in the New England Journal of Medicine unveils the long-awaited outcome of anti-CTLA-4 therapy for melanoma. It provides grounds for continued enthusiasm for cancer immunotherapy, deepens our thoughts on underlying mechanisms, and suggests exciting next steps. C1 [Park, Jin Mo; Fisher, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr,Dept Dermatol, Boston, MA 02114 USA. RP Fisher, DE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cutaneous Biol Res Ctr,Dept Dermatol, Boston, MA 02114 USA. EM dfisher3@partners.org FU NIAMS NIH HHS [R01 AR043369] NR 9 TC 4 Z9 4 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUL 13 PY 2010 VL 18 IS 1 BP 9 EP 10 DI 10.1016/j.ccr.2010.06.010 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 627IG UT WOS:000280032100005 PM 20609349 ER PT J AU Freedman, JE Larson, MG Tanriverdi, K O'Donnell, CJ Morin, K Hakanson, AS Vasan, RS Johnson, AD Iafrati, MD Benjamin, EJ AF Freedman, Jane E. Larson, Martin G. Tanriverdi, Kahraman O'Donnell, Christopher J. Morin, Kristine Hakanson, Amanda S. Vasan, Ramachandran S. Johnson, Andrew D. Iafrati, Mark D. Benjamin, Emelia J. TI Relation of Platelet and Leukocyte Inflammatory Transcripts to Body Mass Index in the Framingham Heart Study SO CIRCULATION LA English DT Article DE genes; epidemiology; leukocytes; platelets ID GENE-EXPRESSION PROFILES; GENOME-WIDE ASSOCIATION; PERIPHERAL-BLOOD; CELLS; PATTERNS; DISEASES; HUMANS; AORTA AB Background-Although many genetic epidemiology and biomarker studies have been conducted to examine associations of genetic variants and circulating proteins with cardiovascular disease and risk factors, there has been little study of gene expression or transcriptomics. Quantitative differences in the abundance of transcripts has been demonstrated in malignancies, but gene expression from a large community-based cohort examining risk of cardiovascular disease has never been reported. Methods and Results-On the basis of preliminary microarray data and previously suggested genes from the literature, we measured expression of 48 genes by high-throughput quantitative reverse-transcriptase polymerase chain reaction in 1846 participants of the Framingham Offspring cohort from RNA derived from isolated platelets and leukocytes. A multivariable stepwise regression model was used to assess clinical correlates of quantitative RNA expression. For specific inflammatory platelet-derived transcripts, including ICAM1, IFNG, IL1R1, IL6, MPO, COX2, TNF, TLR2, and TLR4, there were significant associations with higher body mass index (BMI). Compared with platelets, fewer leukocyte-derived transcripts were associated with BMI or other cardiovascular risk factors. Select transcripts were found to be highly heritable, including GPIBA and COX1. Almost uniformly, heritable transcripts were not those associated with BMI. Conclusions-Inflammatory transcripts derived from platelets, particularly those part of the nuclear factor kappa B pathway, are associated with BMI, whereas others are heritable. This is the first study, using a large community-based cohort, to demonstrate clinical correlates of gene expression and is consistent with the hypothesis that specific peripheral-blood transcripts play a role in the pathogenesis of coronary heart disease and its risk factors. (Circulation. 2010; 122: 119-129.) C1 [Freedman, Jane E.] Boston Univ, Sch Med, Dept Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Math & Stat, Boston, MA 02118 USA. [Hakanson, Amanda S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Iafrati, Mark D.] Tufts Med Ctr, Div Vasc Surg, Boston, MA USA. [Larson, Martin G.; O'Donnell, Christopher J.; Hakanson, Amanda S.; Vasan, Ramachandran S.; Johnson, Andrew D.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Freedman, JE (reprint author), Boston Univ, Sch Med, Dept Med, Whitaker Cardiovasc Inst, 700 Albany St,W-507, Boston, MA 02118 USA. EM freedmaj@bu.edu RI Johnson, Andrew/G-6520-2013; OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU [N01-HC 25195]; [HL087201]; [HL092577-01A1]; [HL076784]; [AG028321] FX The Framingham Heart Study is supported by N01-HC 25195; this work was also supported by HL087201 (Dr Freedman) and HL092577-01A1, HL076784, and AG028321 (Dr Benjamin). NR 33 TC 58 Z9 62 U1 0 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 JUL 13 PY 2010 VL 122 IS 2 BP 119 EP U52 DI 10.1161/CIRCULATIONAHA.109.928192 PG 25 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 624FI UT WOS:000279801700004 PM 20606121 ER PT J AU Rigotti, N Pipe, A Benowitz, N Arteaga, C Garza, D Tonstad, S Samuels, L AF Rigotti, Nancy Pipe, Andrew Benowitz, Neal Arteaga, Carmen Garza, Dahlia Tonstad, Serena Samuels, Larry TI A randomized Trial of Varenicline for Smoking Cessation in Patients with Cardiovascular Disease: Analysis of Efficacy by Baseline Characteristics SO CIRCULATION LA English DT Meeting Abstract CT World Congress of Cardiology Scientific Sessions CY JUN 16-19, 2010 CL Beijing, PEOPLES R CHINA C1 [Rigotti, Nancy] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Rigotti, Nancy] Harvard Univ, Sch Med, Boston, MA USA. [Pipe, Andrew] Univ Ottawa, Inst Heart, Ottawa, ON K1N 6N5, Canada. [Benowitz, Neal] Univ Calif San Francisco, Dept Med & Biopharmaceut Sci, San Francisco, CA 94143 USA. [Arteaga, Carmen; Garza, Dahlia] Pfizer Inc, New York, NY USA. [Tonstad, Serena] Ullevaal Univ Hosp, Dept Prevent Cardiol, Oslo, Norway. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 13 PY 2010 VL 122 IS 2 MA P929 BP E275 EP E275 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 624FI UT WOS:000279801703136 ER PT J AU Wright, J Fiocchi, F Kehoe, K Mitchell, K Thrutchley, D Breeding, T Gupte, S Buchanan, D Spertus, J Rumsfeld, J AF Wright, Janet Fiocchi, Fran Kehoe, Katie Mitchell, Kristi Thrutchley, Duane Breeding, Tracie Gupte, Sunil Buchanan, Donna Spertus, John Rumsfeld, John TI Building Quality Improvement from the Ground Up: Lessons from the Design and Implementation of the IC3 Program National Practice-Based Quality Improvement Program SO CIRCULATION LA English DT Meeting Abstract CT World Congress of Cardiology Scientific Sessions CY JUN 16-19, 2010 CL Beijing, PEOPLES R CHINA C1 [Wright, Janet; Fiocchi, Fran; Kehoe, Katie; Mitchell, Kristi; Gupte, Sunil] Amer Coll Cardiol, Washington, DC USA. [Thrutchley, Duane; Breeding, Tracie; Buchanan, Donna; Spertus, John] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Rumsfeld, John] Denver VA Med Ctr, Denver, CO USA. NR 0 TC 0 Z9 0 U1 0 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 JUL 13 PY 2010 VL 122 IS 2 MA 0347 BP E84 EP E84 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 624FI UT WOS:000279801701315 ER PT J AU Sasaki, Y Gold, J Watanabe, T AF Sasaki, Yuka Gold, Joshua Watanabe, Takeo TI Perceptual Learning: Cortical Changes When Cats Learn a New Trick SO CURRENT BIOLOGY LA English DT Editorial Material ID PRIMARY VISUAL-CORTEX; TEXTURE-DISCRIMINATION; V1 NEURONS; AREA C1 [Sasaki, Yuka] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Sasaki, Yuka] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Gold, Joshua] Univ Penn, Dept Neurosci, Philadelphia, PA 19104 USA. [Watanabe, Takeo] Boston Univ, Dept Psychol, Boston, MA 02215 USA. RP Sasaki, Y (reprint author), Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. EM takeo@bu.edu FU NEI NIH HHS [R01 EY019466] NR 17 TC 3 Z9 3 U1 1 U2 6 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 JUL 13 PY 2010 VL 20 IS 13 BP R557 EP R558 DI 10.1016/j.cub.2010.05.004 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 627FG UT WOS:000280024300012 PM 20619806 ER PT J AU Tamplin, OJ Zon, LI AF Tamplin, Owen J. Zon, Leonard I. TI Blood Flow: Metalloproteases Cut Loose in Primitive Erythrocytes SO CURRENT BIOLOGY LA English DT Editorial Material ID AORTIC ENDOTHELIUM; YOLK-SAC; EMBRYO PROPER; MOUSE; HEMATOPOIESIS; ZEBRAFISH C1 [Tamplin, Owen J.] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Tamplin, OJ (reprint author), Childrens Hosp, Stem Cell Program, 300 Longwood Ave,Karp 7, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu RI Tamplin, Owen/C-1617-2014 OI Tamplin, Owen/0000-0001-9146-4860 NR 15 TC 2 Z9 2 U1 0 U2 2 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 JUL 13 PY 2010 VL 20 IS 13 BP R561 EP R562 DI 10.1016/j.cub.2010.05.014 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 627FG UT WOS:000280024300014 PM 20619808 ER PT J AU Shave, R Baggish, A George, K Wood, M Scharhag, J Whyte, G Gaze, D Thompson, PD AF Shave, Rob Baggish, Aaron George, Keith Wood, Malissa Scharhag, Jurgen Whyte, Gregory Gaze, David Thompson, Paul D. TI Exercise-Induced Cardiac Troponin Elevation Evidence, Mechanisms, and Implications SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE cardiac biomarkers; cardiac damage; exercise; troponin ID ACUTE MYOCARDIAL-INFARCTION; BRAIN NATRIURETIC PEPTIDE; KINASE-MB-ISOENZYME; PREDICTING ELECTROCARDIOGRAPHIC ABNORMALITIES; SIGNAL-AVERAGED ELECTROCARDIOGRAPHY; PROLONGED STRENUOUS EXERCISE; ULTRA-ENDURANCE EXERCISE; ACUTE CORONARY SYNDROMES; BLUNT CHEST TRAUMA; MARATHON RUNNERS AB Regular physical exercise is recommended for the primary prevention of cardiovascular disease. Although the high prevalence of physical inactivity remains a formidable public health issue, participation in exercise programs and recreational sporting events, such as marathons and triathlons, is on the rise. Although regular exercise training reduces cardiovascular disease risk, recent studies have documented elevations in cardiac troponin (cTn) consistent with cardiac damage after bouts of exercise in apparently healthy individuals. At present, the prevalence, mechanism(s), and clinical significance of exercise-induced cTn release remains incompletely understood. This paper will review the biochemistry, prevalence, potential mechanisms, and management of patients with exercise-induced cTn elevations. (J Am Coll Cardiol 2010; 56: 169-76) (C) 2010 by the American College of Cardiology Foundation C1 [Shave, Rob; Gaze, David] Brunel Univ, Uxbridge UB8 3PH, Middx, England. [Baggish, Aaron; Wood, Malissa] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [George, Keith; Whyte, Gregory] Liverpool John Moores Univ, Liverpool L3 5UX, Merseyside, England. [Scharhag, Jurgen] Univ Potsdam, Ctr Sports Med, Potsdam, Germany. [Gaze, David] St Georges Healthcare NHS Trust, London, England. [Thompson, Paul D.] Hartford Hosp, Henry Low Heart Ctr, Hartford, CT 06115 USA. RP Shave, R (reprint author), Univ Wales Inst Cardiff, Sch Sport, Cyncoed Campus,Cyncoed Rd, Cardiff CF23 6XD, S Glam, Wales. EM rshave@uwic.ac.uk OI Shave, Rob/0000-0002-0283-037X NR 73 TC 133 Z9 136 U1 1 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 13 PY 2010 VL 56 IS 3 BP 169 EP 176 DI 10.1016/j.jacc.2010.03.037 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 620SO UT WOS:000279520200001 PM 20620736 ER PT J AU Pijls, NHJ Fearon, WF Tonino, PAL Siebert, U Ikeno, F Bornschein, B van't Veer, M Klauss, V Manoharan, G Engstrom, T Oldroyd, KG Lee, PNV MacCarthy, PA De Bruyne, B AF Pijls, Nico H. J. Fearon, William F. Tonino, Pim A. L. Siebert, Uwe Ikeno, Fumiaki Bornschein, Bernhard van't Veer, Marcel Klauss, Volker Manoharan, Ganesh Engstrom, Thomas Oldroyd, Keith G. Lee, Peter N. Ver MacCarthy, Philip A. De Bruyne, Bernard CA FAME Study Investigators TI Fractional Flow Reserve Versus Angiography for Guiding Percutaneous Coronary Intervention in Patients With Multivessel Coronary Artery Disease 2-Year Follow-Up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE fractional flow reserve; multivessel coronary artery disease; drug-eluting stents; percutaneous coronary intervention; coronary pressure; pressure wire ID OPTIMAL MEDICAL THERAPY; DRUG-ELUTING STENTS; FUNCTIONAL SEVERITY; CLINICAL-OUTCOMES; PCI; STENOSES AB Objectives The purpose of this study was to investigate the 2-year outcome of percutaneous coronary intervention (PCI) guided by fractional flow reserve (FFR) in patients with multivessel coronary artery disease (CAD). Background In patients with multivessel CAD undergoing PCI, coronary angiography is the standard method for guiding stent placement. The FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study showed that routine FFR in addition to angiography improves outcomes of PCI at 1 year. It is unknown if these favorable results are maintained at 2 years of follow-up. Methods At 20 U.S. and European medical centers, 1,005 patients with multivessel CAD were randomly assigned to PCI with drug-eluting stents guided by angiography alone or guided by FFR measurements. Before randomization, lesions requiring PCI were identified based on their angiographic appearance. Patients randomized to angiography-guided PCI underwent stenting of all indicated lesions, whereas those randomized to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was <= 0.80. Results The number of indicated lesions was 2.7 +/- 0.9 in the angiography-guided group and 2.8 +/- 1.0 in the FFR-guided group (p = 0.34). The number of stents used was 2.7 +/- 1.2 and 1.9 +/- 1.3, respectively (p < 0.001). The 2-year rates of mortality or myocardial infarction were 12.9% in the angiography-guided group and 8.4% in the FFR-guided group (p = 0.02). Rates of PCI or coronary artery bypass surgery were 12.7% and 10.6%, respectively (p = 0.30). Combined rates of death, nonfatal myocardial infarction, and revascularization were 22.4% and 17.9%, respectively (p = 0.08). For lesions deferred on the basis of FFR >0.80, the rate of myocardial infarction was 0.2 % and the rate of revascularization was 3.2 % after 2 years. Conclusions Routine measurement of FFR in patients with multivessel CAD undergoing PCI with drug-eluting stents significantly reduces mortality and myocardial infarction at 2 years when compared with standard angiography-guided PCI. (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation [FAME]; NCT00267774) (J Am Coll Cardiol 2010; 56: 177-84) (C) 2010 by the American College of Cardiology Foundation C1 [Pijls, Nico H. J.] Catharina Hosp, Dept Cardiol, NL-5623 EJ Eindhoven, Netherlands. [Fearon, William F.; Ikeno, Fumiaki] Stanford Univ, Med Ctr, Stanford, CA 94305 USA. [Fearon, William F.; Ikeno, Fumiaki] Palo Alto VA Hlth Care Syst, Stanford, CA USA. [Siebert, Uwe; Bornschein, Bernhard] Univ Hlth Sci Med Informat & Technol, Hall In Tirol, Austria. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Klauss, Volker] Univ Hosp, Med Poliklin, Munich, Germany. [Manoharan, Ganesh] Royal Victoria Hosp, Ctr Heart, Belfast BT12 6BA, Antrim, North Ireland. [Engstrom, Thomas] Rigshosp, DK-2100 Copenhagen, Denmark. [Oldroyd, Keith G.] Golden Jubilee Natl Hosp, Glasgow, Lanark, Scotland. [Lee, Peter N. Ver] NE Cardiol Associates, Bangor, ME USA. [Lee, Peter N. Ver] Eastern Maine Med Ctr, Bangor, ME USA. [MacCarthy, Philip A.] Kings Coll Hosp London, London, England. [De Bruyne, Bernard] Cardiovasc Ctr Aalst, Aalst, Belgium. RP Pijls, NHJ (reprint author), Catharina Hosp, Dept Cardiol, Michelangelolaan 2, NL-5623 EJ Eindhoven, Netherlands. EM nico.pijls@inter.nl.net RI 刘, 李陆/H-8469-2015; OI Engstrom, Thomas/0000-0001-5436-9194 FU St. Jude Medical; Biosensors; Boston Scientific; Meijer Lavino Foundation for Cardiac Research FX Dr. Pijls reports receiving an institutional research grant for the Catharina Hospital Eindhoven from St. Jude Medical. Dr. Oldroyd reports receiving speaker fees from Biosensors and Boston Scientific. Dr. Ver Lee reports receiving lecture fees from and is on the Speakers' Bureau of St. Jude Medical. Dr. De Bruyne reports receiving research grants from The Meijer Lavino Foundation for Cardiac Research. NR 18 TC 378 Z9 420 U1 4 U2 31 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 13 PY 2010 VL 56 IS 3 BP 177 EP 184 DI 10.1016/j.jacc.2010.04.012 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 620SO UT WOS:000279520200002 PM 20537493 ER PT J AU Marselli, L Thorne, J Dahiya, S Sgroi, DC Sharma, A Bonner-Weir, S Marchetti, P Weir, GC AF Marselli, Lorella Thorne, Jeffrey Dahiya, Sonika Sgroi, Dennis C. Sharma, Arun Bonner-Weir, Susan Marchetti, Piero Weir, Gordon C. TI Gene Expression Profiles of Beta-Cell Enriched Tissue Obtained by Laser Capture Microdissection from Subjects with Type 2 Diabetes SO PLOS ONE LA English DT Article ID PANCREATIC-ISLETS; INSULIN-SECRETION; ENDOPLASMIC-RETICULUM; GLUCOSE-TOLERANCE; TRANSCRIPTIONAL REGULATION; CHRONIC HYPERGLYCEMIA; GROWTH-REGULATION; PROTEIN; APOPTOSIS; STRESS AB Background: Changes in gene expression in pancreatic beta-cells from type 2 diabetes (T2D) should provide insights into their abnormal insulin secretion and turnover. Methodology/Principal Findings: Frozen sections were obtained from cadaver pancreases of 10 control and 10 T2D human subjects. Beta-cell enriched samples were obtained by laser capture microdissection (LCM). RNA was extracted, amplified and subjected to microarray analysis. Further analysis was performed with DNA-Chip Analyzer (dChip) and Gene Set Enrichment Analysis (GSEA) software. There were changes in expression of genes linked to glucotoxicity. Evidence of oxidative stress was provided by upregulation of several metallothionein genes. There were few changes in the major genes associated with cell cycle, apoptosis or endoplasmic reticulum stress. There was differential expression of genes associated with pancreatic regeneration, most notably upregulation of members of the regenerating islet gene (REG) family and metalloproteinase 7 (MMP7). Some of the genes found in GWAS studies to be related to T2D were also found to be differentially expressed. IGF2BP2, TSPAN8, and HNF1B (TCF2) were upregulated while JAZF1 and SLC30A8 were downregulated. Conclusions/Significance: This study made possible by LCM has identified many novel changes in gene expression that enhance understanding of the pathogenesis of T2D. C1 [Marselli, Lorella; Thorne, Jeffrey; Sharma, Arun; Bonner-Weir, Susan; Weir, Gordon C.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol,Res Div, Boston, MA 02115 USA. [Marselli, Lorella; Thorne, Jeffrey; Sharma, Arun; Bonner-Weir, Susan; Weir, Gordon C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Dahiya, Sonika; Sgroi, Dennis C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02115 USA. [Marchetti, Piero] Univ Pisa, Dept Endocrinol & Metab, Sect Endocrinol & Metab Organ Transplantat, Pisa, Italy. RP Marselli, L (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol,Res Div, Boston, MA 02115 USA. EM gordon.weir@joslin.harvard.edu RI Marchetti, Piero/J-7439-2013; OI Marchetti, Piero/0000-0003-4907-0635; Bonner-Weir, Susan/0000-0003-4682-0656 FU American Diabetes Association; Juvenile Diabetes Research Foundation; National Institutes of Health, Advanced Microscopy, Bioinformatics, and Genomics Cores of Joslin Diabetes and Endocrinology Research Center [RO1 DK66056, P30 DK36836]; Diabetes Research and Wellness Foundation; European Community FX This study was supported by grants from the American Diabetes Association, the Juvenile Diabetes Research Foundation, the National Institutes of Health (RO1 DK66056 and P30 DK36836 - the Advanced Microscopy, Bioinformatics, and Genomics Cores of Joslin Diabetes and Endocrinology Research Center), the Diabetes Research and Wellness Foundation and the European Community (EURODIA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 79 TC 82 Z9 84 U1 2 U2 14 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 JUL 13 PY 2010 VL 5 IS 7 AR e11499 DI 10.1371/journal.pone.0011499 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 624MG UT WOS:000279822300003 PM 20644627 ER PT J AU Mauney, JR Ramachandran, A Yu, RN Daley, GQ Adam, RM Estrada, CR AF Mauney, Joshua R. Ramachandran, Aruna Yu, Richard N. Daley, George Q. Adam, Rosalyn M. Estrada, Carlos R. TI All-Trans Retinoic Acid Directs Urothelial Specification of Murine Embryonic Stem Cells via GATA4/6 Signaling Mechanisms SO PLOS ONE LA English DT Article ID SMOOTH-MUSCLE-CELLS; TRANSCRIPTION FACTOR GATA6; GENE-EXPRESSION; MOLECULAR-MECHANISMS; EXTERNAL GENITALIA; STROMAL CELLS; GUT ENDODERM; DIFFERENTIATION; BLADDER; MOUSE AB The urinary bladder and associated tract are lined by the urothelium, a transitional epithelium that acts as a specialized permeability barrier that protects the underlying tissue from urine via expression of a highly specific group of proteins known as the uroplakins (UP). To date, our understanding of the developmental processes responsible for urothelial differentiation has been hampered due to the lack of suitable models. In this study, we describe a novel in vitro cell culture system for derivation of urothelial cells from murine embryonic stem cells (ESCs) following cultivation on collagen matrices in the presence all trans retinoic acid (RA). Upon stimulation with micromolar concentrations of RA, ESCs significantly downregulated the pluripotency factor OCT-4 but markedly upregulated UP1A, UP1B, UP2, UP3A, and UP3B mRNA levels in comparison to naive ESCs and spontaneously differentiating controls. Pan-UP protein expression was associated with both p63- and cytokeratin 20-positive cells in discrete aggregating populations of ESCs following 9 and 14 days of RA stimulation. Analysis of endodermal transcription factors such as GATA4 and GATA6 revealed significant upregulation and nuclear enrichment in RA-treated UP2-GFP+ populations. GATA4-/- and GATA6-/- transgenic ESC lines revealed substantial attenuation of RA-mediated UP expression in comparison to wild type controls. In addition, EMSA analysis revealed that RA treatment induced formation of transcriptional complexes containing GATA4/6 on both UP1B and UP2 promoter fragments containing putative GATA factor binding sites. Collectively, these data suggest that RA mediates ESC specification toward a urothelial lineage via GATA4/6-dependent processes. C1 [Mauney, Joshua R.; Ramachandran, Aruna; Yu, Richard N.; Adam, Rosalyn M.; Estrada, Carlos R.] Childrens Hosp, Urol Dis Res Ctr, Boston, MA 02115 USA. [Mauney, Joshua R.; Ramachandran, Aruna; Yu, Richard N.; Adam, Rosalyn M.; Estrada, Carlos R.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Daley, George Q.] Harvard Stem Cell Inst, Boston, MA USA. [Daley, George Q.] Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA USA. RP Mauney, JR (reprint author), Childrens Hosp, Urol Dis Res Ctr, 300 Longwood Ave, Boston, MA 02115 USA. EM rosalyn.adam@childrens.harvard.edu; carlos.estrada@childrens.harvard.edu RI Estrada, Carlos/H-2199-2015 OI Estrada, Carlos/0000-0003-0586-9832 FU Children's Hospital Boston, Office of Sponsored Programs Support for Pilot Studies (Estrada); National Institutes of Health (NIH), NIDDK [P50 DK065298-06]; Harvard Catalyst/Harvard Clinical and Translational Science Center, Estrada [UL1 RR025758-01] FX This work was supported by grants from Children's Hospital Boston, Office of Sponsored Programs Support for Pilot Studies (Estrada) and the National Institutes of Health (NIH), NIDDK P50 DK065298-06 (Freeman). This work was also conducted with support from the Faculty Career Development Award program of the Harvard Catalyst/Harvard Clinical and Translational Science Center (Award # UL1 RR025758-01, Estrada). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources or the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 26 Z9 27 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 13 PY 2010 VL 5 IS 7 AR e11513 DI 10.1371/journal.pone.0011513 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 624MG UT WOS:000279822300004 PM 20644631 ER PT J AU Paraskar, AS Soni, S Chin, KT Chaudhuri, P Muto, KW Berkowitz, J Handlogten, MW Alves, NJ Bilgicer, B Dinulescu, DM Mashelkar, RA Sengupta, S AF Paraskar, Abhimanyu S. Soni, Shivani Chin, Kenneth T. Chaudhuri, Padmaparna Muto, Katherine W. Berkowitz, Julia Handlogten, Michael W. Alves, Nathan J. Bilgicer, Basar Dinulescu, Daniela M. Mashelkar, Raghunath A. Sengupta, Shiladitya TI Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemotherapy; nanomedicine; cancer ID HUMAN TUMOR XENOGRAFT; K-RAS; CANCER; DNA; PERMEABILITY; CARBOPLATIN; MUTATIONS; LIPOSOMES; DELIVERY; MODELS AB Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 + 0.16 mu M) comparable to that of free cisplatin (3.87 +/- 0.37 mu M), and superior to carboplatin (14.75 +/- 0.38 mu M). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer. C1 [Mashelkar, Raghunath A.] Natl Chem Lab, Pune 411008, Maharashtra, India. [Paraskar, Abhimanyu S.; Soni, Shivani; Chaudhuri, Padmaparna; Sengupta, Shiladitya] Brigham & Womens Hosp, Dept Med, Cambridge, MA 02139 USA. [Paraskar, Abhimanyu S.; Soni, Shivani; Chaudhuri, Padmaparna; Dinulescu, Daniela M.; Sengupta, Shiladitya] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chin, Kenneth T.; Muto, Katherine W.; Berkowitz, Julia; Dinulescu, Daniela M.; Sengupta, Shiladitya] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Handlogten, Michael W.; Alves, Nathan J.; Bilgicer, Basar] Univ Notre Dame, Notre Dame, IN 46556 USA. [Sengupta, Shiladitya] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Sengupta, Shiladitya] Indo US Joint Ctr Nanobiotechnol, Cambridge, MA 02139 USA. [Sengupta, Shiladitya] Dana Farber Canc Inst, Brookline, MA 02445 USA. [Sengupta, Shiladitya] Translat Hlth Sci & Technol Inst, New Delhi 110067, India. RP Mashelkar, RA (reprint author), Natl Chem Lab, Pune 411008, Maharashtra, India. EM ram@ncl.res.in; ssengupta2@partners.org RI Alves, Nathan/E-8033-2012; Handlogten, Michael/J-8958-2012 FU US Department of Defense (DOD) [W81XWH-07-1-0482]; National Institutes of Health [R01 (1R01CA135242-01A2)]; Burroughs-Wellcome Foundation; Harvard Ovarian Cancer Spore Award; Canary Fund; Mary Kay Ash Foundation; V Foundation for Cancer Research FX S. Sengupta is supported by US Department of Defense (DOD) Breast Cancer Research Program (BCRP) Era of Hope Scholar Award W81XWH-07-1-0482, a DOD Collaborative Innovator Grant, and National Institutes of Health Grant R01 (1R01CA135242-01A2). A. P. is supported by a DOD BCRP postdoctoral fellowship award. D. M. D. is supported by the Burroughs-Wellcome Foundation, a Harvard Ovarian Cancer Spore Award, the Canary Fund, the Mary Kay Ash Foundation, and the V Foundation for Cancer Research Scholar award. NR 32 TC 63 Z9 64 U1 7 U2 34 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 13 PY 2010 VL 107 IS 28 BP 12435 EP 12440 DI 10.1073/pnas.1007026107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 624TD UT WOS:000279843200010 PM 20616005 ER PT J AU Bradner, JE Mak, R Tanguturi, SK Mazitschek, R Haggarty, SJ Ross, K Chang, CY Bosco, J West, N Morse, E Lin, K Shen, JP Kwiatkowski, NP Gheldof, N Dekker, J DeAngelo, DJ Carr, SA Schreiber, SL Golub, TR Ebert, BL AF Bradner, James E. Mak, Raymond Tanguturi, Shyam K. Mazitschek, Ralph Haggarty, Stephen J. Ross, Kenneth Chang, Cindy Y. Bosco, Jocelyn West, Nathan Morse, Elizabeth Lin, Katherine Shen, John Paul Kwiatkowski, Nicholas P. Gheldof, Nele Dekker, Job DeAngelo, Daniel J. Carr, Steven A. Schreiber, Stuart L. Golub, Todd R. Ebert, Benjamin L. TI Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE histone; acetylation; hemoglobinopathies; chromatin ID FETAL-HEMOGLOBIN PRODUCTION; CHROMOSOME CONFORMATION; EXPRESSION; HYDROXYUREA; BCL11A; INHIBITORS; ANEMIA; DIFFERENTIATION; INDUCTION; CRISES AB The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease. C1 [Bradner, James E.; Mak, Raymond; Tanguturi, Shyam K.; Mazitschek, Ralph; Haggarty, Stephen J.; Ross, Kenneth; Chang, Cindy Y.; Bosco, Jocelyn; West, Nathan; Morse, Elizabeth; Shen, John Paul; Kwiatkowski, Nicholas P.; Carr, Steven A.; Schreiber, Stuart L.; Golub, Todd R.; Ebert, Benjamin L.] Harvard & Massachusetts Inst Technol, Broad Inst, Cambridge, MA 02142 USA. [Bradner, James E.; West, Nathan; Morse, Elizabeth; DeAngelo, Daniel J.; Golub, Todd R.; Ebert, Benjamin L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lin, Katherine; Ebert, Benjamin L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Gheldof, Nele; Dekker, Job] Univ Massachusetts, Sch Med, Worcester, MA 01655 USA. [Schreiber, Stuart L.] Harvard Univ, Cambridge, MA 02138 USA. [Schreiber, Stuart L.; Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Ebert, Benjamin L.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Schreiber, SL (reprint author), Harvard & Massachusetts Inst Technol, Broad Inst, Cambridge, MA 02142 USA. EM stuart_schreiber@harvard.edu; golub@broadinstitute.org; bebert@partners.org RI Mazitschek, Ralph/E-3741-2013; OI Mazitschek, Ralph/0000-0002-1105-689X; Tanguturi, Shyam/0000-0001-6479-1946; Haggarty, Stephen J./0000-0002-7872-168X; Shen, John Paul/0000-0003-4588-2775 FU National Institutes of Health (NIH) [5R01 HG003945]; Burroughs-Wellcome; NIH [1K08CA128972, GM38627, HG003143]; American Society of Hematology (ASH); Burroughs-Wellcome Foundation FX We thank Edward Greenberg, David Peck, and Veronica Saenz-Vash for technical assistance and Gretchen Jones and Rachel Murphy for assistance with figure preparation. We thank Peter Atadja and Martha Li for assistance with the LBH-589 clinical data and funding of the clinical trial. This work was funded by National Institutes of Health (NIH) Grant 5R01 HG003945 and the Burroughs-Wellcome Fund (Career Awards for Medical Sciences) (to B.L.E.); NIH Grant 1K08CA128972, the American Society of Hematology (ASH Scholar Award), and the Burroughs-Wellcome Foundation (Career Awards for Medical Sciences) (to J.E.B.); NIH Grant GM38627 (to S.L.S.); and NIH Grant HG003143 (to J.D.). T.R.G. and S.L.S. are investigators of The Howard Hughes Medical Institute. NR 34 TC 83 Z9 84 U1 3 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 13 PY 2010 VL 107 IS 28 BP 12617 EP 12622 DI 10.1073/pnas.1006774107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 624TD UT WOS:000279843200041 PM 20616024 ER PT J AU Chang, AN Walter, LC AF Chang, Anna Walter, Louise C. TI Recognizing Dementia as a Terminal Illness in Nursing Home Residents SO ARCHIVES OF INTERNAL MEDICINE LA English DT Editorial Material ID CARE C1 [Chang, Anna] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA 94121 USA. San Francisco VA Med Ctr, San Francisco, CA 94121 USA. RP Chang, AN (reprint author), Univ Calif San Francisco, Dept Med, Div Geriatr, 4150 Clement St,Box 181G, San Francisco, CA 94121 USA. EM Anna.Chang2@va.gov FU NCI NIH HHS [1R01CA134425-01] NR 11 TC 5 Z9 5 U1 0 U2 5 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 JUL 12 PY 2010 VL 170 IS 13 BP 1107 EP 1109 DI 10.1001/archinternmed.2010.166 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 624DY UT WOS:000279797700004 PM 20625014 ER PT J AU Balasubramanian, S Mani, SK Kasiganesan, H Baicu, CC Kuppuswamy, D AF Balasubramanian, Sundaravadivel Mani, Santhosh K. Kasiganesan, Harinath Baicu, Catalin C. Kuppuswamy, Dhandapani TI Hypertrophic Stimulation Increases beta-actin Dynamics in Adult Feline Cardiomyocytes SO PLOS ONE LA English DT Article ID OVERLOAD CARDIAC-HYPERTROPHY; CYTOPLASMIC GAMMA-ACTIN; FOCAL COMPLEX-FORMATION; PRESSURE-OVERLOAD; SKELETAL-MUSCLE; C-SRC; INTEGRIN; EXPRESSION; HEART; MYOCARDIUM AB The myocardium responds to hemodynamic stress through cellular growth and organ hypertrophy. The impact of cytoskeletal elements on this process, however, is not fully understood. While alpha-actin in cardiomyocytes governs muscle contraction in combination with the myosin motor, the exact role of beta-actin has not been established. We hypothesized that in adult cardiomyocytes, as in non-myocytes, beta-actin can facilitate cytoskeletal rearrangement within cytoskeletal structures such as Z-discs. Using a feline right ventricular pressure overload (RVPO) model, we measured the level and distribution of beta-actin in normal and pressure overloaded myocardium. Resulting data demonstrated enriched levels of beta-actin and enhanced translocation to the Triton-insoluble cytoskeletal and membrane skeletal complexes. In addition, RVPO in vivo and in vitro hypertrophic stimulation with endothelin (ET) or insulin in isolated adult cardiomyocytes enhanced the content of polymerized fraction (F-actin) of beta-actin. To determine the localization and dynamics of beta-actin, we adenovirally expressed GFP-tagged beta-actin in isolated adult cardiomyocytes. The ectopically expressed beta-actin-GFP localized to the Z-discs, costameres, and cell termini. Fluorescence recovery after photobleaching (FRAP) measurements of beta-actin dynamics revealed that beta-actin at the Z-discs is constantly being exchanged with beta-actin from cytoplasmic pools and that this exchange is faster upon hypertrophic stimulation with ET or insulin. In addition, in electrically stimulated isolated adult cardiomyocytes, while beta-actin overexpression improved cardiomyocyte contractility, immunoneutralization of beta-actin resulted in a reduced contractility suggesting that beta-actin could be important for the contractile function of adult cardiomyocytes. These studies demonstrate the presence and dynamics of beta-actin in the adult cardiomyocyte and reinforce its usefulness in measuring cardiac cytoskeletal rearrangement during hypertrophic stimulation. C1 [Balasubramanian, Sundaravadivel; Mani, Santhosh K.; Kasiganesan, Harinath; Baicu, Catalin C.; Kuppuswamy, Dhandapani] Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Med, Div Cardiol, Charleston, SC 29425 USA. [Kuppuswamy, Dhandapani] Vet Affairs Med Ctr, Ralph H Johnson Dept, Charleston, SC 29403 USA. RP Balasubramanian, S (reprint author), Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Med, Div Cardiol, Charleston, SC 29425 USA. EM balasubr@musc.edu FU National Institutes of Health (NIH) [RHL092124A] FX This study was supported by National Institutes of Health (NIH) grant RHL092124A (to D.K). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 11 Z9 11 U1 0 U2 0 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 JUL 12 PY 2010 VL 5 IS 7 AR e11470 DI 10.1371/journal.pone.0011470 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 623XV UT WOS:000279781600003 PM 20635003 ER PT J AU Molander, RC Yonker, JA Krahn, DD AF Molander, Rachel C. Yonker, James A. Krahn, Dean D. TI Age-Related Changes in Drinking Patterns From Mid- to Older Age: Results From the Wisconsin Longitudinal Study SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol; Aging; Longitudinal; Drinking Behavior ID NATIONAL EPIDEMIOLOGIC SURVEY; LIFE-COURSE VARIATION; ALCOHOL-CONSUMPTION; UNITED-STATES; SWEDISH WOMEN; HEALTH; RETIREMENT; BEHAVIORS; MEN; MORTALITY AB Background: Drinking has generally been shown to decline with age in older adults. However, results vary depending on the measure of alcohol consumption used and the study population. The goals of this study were to (i) describe changes in drinking in a current cohort of older adults using a variety of measures of drinking and (ii) examine a number of different possible predictors of change. Methods: This is a longitudinal study of a community-based sample surveyed at 2 time points, ages 53 and 64 years. We estimated a series of logistic regressions to predict change and stability in drinking categories of nondrinking, moderate drinking, and heavy drinking. Linear regressions were used to predict change in past-month drinking days, past-month average drinks per drinking day, and past-month total drinks. Results: From age 53 to 64, average drinks per drinking day and heavy drinking decreased. Frequency of drinking increased for men and women, and total drinks per month increased for men. The most consistent predictors of drinking changes were gender, health, and education. Other factors predicted drinking change but were not consistent across drinking measures including: adolescent IQ, income, lifetime history of alcohol-related problems, religious service attendance, depression, debt, and changes in employment. Conclusions: Heavy drinking decreases with age, but we may see more frequent moderate drinking with current and upcoming cohorts of older adults. Components of quantity and frequency of drinking change differently. Composite measures of total alcohol consumption may not be adequate for describing relevant changes in drinking over time. A number of factors predicted patterns of change in drinking and warrant further exploration. C1 [Molander, Rachel C.; Krahn, Dean D.] Univ Wisconsin, Sch Med, Dept Psychiat, Madison, WI 53719 USA. [Yonker, James A.] Univ Wisconsin, Dept Sociol, Ctr Demog & Ecol, Madison, WI 53719 USA. [Yonker, James A.; Krahn, Dean D.] Univ Wisconsin, Ctr Demog Hlth & Aging, Madison, WI 53719 USA. [Krahn, Dean D.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Molander, RC (reprint author), Univ Wisconsin, Sch Med, Dept Psychiat, 3001 Res Pk Rd, Madison, WI 53719 USA. EM r.molander@hosp.wisc.edu RI Yonker, James/J-6561-2014 OI Yonker, James/0000-0002-9483-8511 FU National Institute on Aging [R01 AG-9775, P01 AG-21079]; William Vilas Estate Trust; Graduate School of the University of Wisconsin-Madison; National Institute of Child Health and Human Development FX The research reported herein was supported by the National Institute on Aging (R01 AG-9775 and P01 AG-21079), by the William Vilas Estate Trust, and by the Graduate School of the University of Wisconsin-Madison. Computation was carried out using facilities of the Center for Demography and Ecology at the University of Wisconsin-Madison, which are supported by Center and Training Grants from the National Institute of Child Health and Human Development and the National Institute on Aging. NR 46 TC 29 Z9 29 U1 6 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 EI 1530-0277 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL 10 PY 2010 VL 34 IS 7 BP 1182 EP 1192 DI 10.1111/j.1530-0277.2010.01195.x PG 11 WC Substance Abuse SC Substance Abuse GA 615GM UT WOS:000279122600007 PM 20477774 ER PT J AU Williams, EC Palfai, T Cheng, DM Samet, JH Bradley, KA Koepsell, TD Wickizer, TM Heagerty, PJ Saitz, R AF Williams, Emily C. Palfai, Tibor Cheng, Debbie M. Samet, Jeffrey H. Bradley, Katharine A. Koepsell, Thomas D. Wickizer, Thomas M. Heagerty, Patrick J. Saitz, Richard TI Physical Health and Drinking Among Medical Inpatients With Unhealthy Alcohol Use: A Prospective Study1 SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Hospital-Based Brief Intervention; Physical Health; Readiness to Change; Unhealthy Alcohol Use; Alcohol Dependence ID PRIMARY-CARE PATIENTS; RANDOMIZED CONTROLLED-TRIAL; BRIEF INTERVENTION; UNITED-STATES; SUBSTANCE-ABUSE; HEAVY DRINKERS; USE DISORDERS; LIVER-TRANSPLANTATION; FOLLOW-UP; CONSUMPTION AB Objective: Unhealthy alcohol use is common in medical inpatients, and hospitalization has been hypothesized to serve as a "teachable moment" that could motivate patients to decrease drinking, but studies of hospital-based brief interventions have often not found decreases. Evaluating associations between physical health and subsequent drinking among medical inpatients with unhealthy alcohol use could inform refinement of hospital-based brief interventions by identifying an important foundation on which to build them. We tested associations between poor physical health and drinking after hospitalization and whether associations varied by alcohol dependence status and readiness to change. Methods: Participants were medical inpatients who screened positive for unhealthy alcohol use and consented to participate in a randomized trial of brief intervention (n = 341). Five measures of physical health were independent variables. Outcomes were abstinence and the number of heavy drinking days (HDDs) reported in the 30 days prior to interviews 3 months after hospitalization. Separate regression models were fit to evaluate each independent variable controlling for age, gender, randomization group, and baseline alcohol use. Interactions between each independent variable and alcohol dependence and readiness to change were tested. Stratified models were fit when significant interactions were identified. Results: Among all participants, measures of physical health were not significantly associated with either abstinence or number of HDDs at 3 months. Having an alcohol-attributable principal admitting diagnosis was significantly associated with fewer HDDs in patients who were nondependent [adjusted incidence rate ratio (aIRR) 0.10, 95% CI 0.03-0.32] or who had low alcohol problem perception (aIRR 0.36, 95% CI 0.13-0.99) at hospital admission. No significant association between alcohol-attributable principal admitting diagnosis and number of HDDs was identified for participants with alcohol dependence or high problem perception. Conclusions: Among medical inpatients with nondependent unhealthy alcohol use and those who do not view their drinking as problematic, alcohol-attributable illness may catalyze decreased drinking. Brief interventions that highlight alcohol-related illness might be more successful. C1 [Williams, Emily C.; Bradley, Katharine A.] VA Hlth Serv Res & Dev, Seattle, WA USA. [Bradley, Katharine A.] Univ Washington, Dept Med, Seattle, WA USA. [Williams, Emily C.; Bradley, Katharine A.; Koepsell, Thomas D.; Wickizer, Thomas M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Koepsell, Thomas D.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Heagerty, Patrick J.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Boston Med Ctr, Gen Internal Med Sect, Clin Addict Res & Educ CARE Unit, Boston, MA USA. [Palfai, Tibor; Cheng, Debbie M.; Samet, Jeffrey H.; Saitz, Richard] Boston Univ, Sch Med, Boston, MA 02118 USA. [Palfai, Tibor] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Cheng, Debbie M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Saitz, Richard] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Samet, Jeffrey H.] Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. RP Williams, EC (reprint author), VA Puget Sound Hlth Care Syst, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM emily.williams3@va.gov FU NIAAA [R01-AA 12617]; VA Puget Sound Health Care System, Seattle, Washington FX Views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, the University of Washington, or Boston University. Preliminary versions of this work were presented at the 2007 meeting of the International Network on Brief Interventions for Alcohol Problems and the 2008 Research Society on Alcoholism annual meeting, as well as included in the dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy from the University of Washington (ECW). This study was supported by NIAAA grant R01-AA 12617 (Saitz, PI), and the material presented here is the result of work supported by resources from the VA Puget Sound Health Care System, Seattle, Washington. NR 65 TC 12 Z9 12 U1 3 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUL 10 PY 2010 VL 34 IS 7 BP 1257 EP 1265 DI 10.1111/j.1530-0277.2010.01203.x PG 9 WC Substance Abuse SC Substance Abuse GA 615GM UT WOS:000279122600015 PM 20477765 ER PT J AU Siegel, MD Prigerson, HG AF Siegel, Mark D. Prigerson, Holly G. TI The Perception Gap Race, Religion, and Prognosis in the ICU SO CHEST LA English DT Editorial Material ID OF-LIFE CARE; CARDIOPULMONARY-RESUSCITATION; ADVANCED CANCER; FAMILY-MEMBERS; MEDICAL-CARE; NEAR-DEATH; END; PERSPECTIVES; ISSUES C1 [Siegel, Mark D.] Yale Univ, Sch Med, Pulm & Crit Care Sect, Dept Internal Med, New Haven, CT 06520 USA. [Prigerson, Holly G.] Harvard Univ, Brigham & Womens Hosp, Dept Psychiat, Sch Med, Boston, MA 02115 USA. [Prigerson, Holly G.] Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. RP Siegel, MD (reprint author), Yale Univ, Sch Med, Pulm & Crit Care Sect, Dept Internal Med, 333 Cedar St,LCI 105,POB 208057, New Haven, CT 06520 USA. EM mark.siegel@yale.edu NR 16 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUL 10 PY 2010 VL 138 IS 1 BP 8 EP 9 DI 10.1378/chest.10-0454 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 625MX UT WOS:000279900500003 PM 20605808 ER PT J AU O'Donnell, CR Bankier, AA Stiebellehner, L Reilly, JJ Brown, R Loring, SH AF O'Donnell, Carl R. Bankier, Alexander A. Stiebellehner, Leopold Reilly, John J. Brown, Robert Loring, Stephen H. TI Lung Volumes in COPD Not Only the Total Lung Capacity Response SO CHEST LA English DT Letter ID DISEASE C1 [O'Donnell, Carl R.] Beth Israel Deaconess Med Ctr, Dept Pulm & Crit Care Med, Boston, MA USA. [Bankier, Alexander A.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA USA. [Loring, Stephen H.] Beth Israel Deaconess Med Ctr, Dept Anesthesia & Crit Care, Boston, MA USA. [Stiebellehner, Leopold] Med Univ Vienna, Dept Pulmonol, Vienna, Austria. [Reilly, John J.] Univ Pittsburgh, Div Pulm & Crit Care Med, Pittsburgh, PA USA. [Brown, Robert] Massachusetts Gen Hosp, Pulm & Crit Care Med Unit, Boston, MA 02114 USA. RP O'Donnell, CR (reprint author), Beth Israel Deaconess Med Ctr, Div Pulm Crit Care & Sleep Med, E Dana 717,330 Brookline Ave, Boston, MA 02215 USA. EM codonne1@bidmc.harvard.edu RI Reilly, John/H-8755-2012 NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUL 10 PY 2010 VL 138 IS 1 BP 233 EP 234 DI 10.1378/chest.10-1008 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 625MX UT WOS:000279900500040 ER PT J AU Ogale, S Lee, TA Sullivan, SD AF Ogale, Sarika Lee, Todd A. Sullivan, Sean D. TI Safety of Ipratropium Bromide Response SO CHEST LA English DT Letter ID BETA-AGONISTS; COPD C1 [Ogale, Sarika; Sullivan, Sean D.] Univ Washington, Dept Pharm, Seattle, WA 98195 USA. [Lee, Todd A.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Ctr Management Complex Chron Care, Hines, IL 60141 USA. Univ Illinois, Ctr Pharmacoecon Res, Dept Pharm Practice, Chicago, IL USA. RP Lee, TA (reprint author), Edward Hines Jr VA Hosp 151 H, 5000 S 5th Ave, Hines, IL 60141 USA. EM todd.lee@va.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUL 10 PY 2010 VL 138 IS 1 BP 235 EP 236 DI 10.1378/chest.10-0403 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 625MX UT WOS:000279900500043 ER PT J AU Ng, K Schrag, D AF Ng, Kimmie Schrag, Deborah TI Microsatellite Instability and Adjuvant Fluorouracil Chemotherapy: A Mismatch? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID METASTATIC COLORECTAL-CANCER; III COLON-CANCER; HMLH1 PROMOTER; STAGE-II; OXALIPLATIN; LEUCOVORIN; IRINOTECAN; THERAPY; MUTATIONS; SURVIVAL C1 [Ng, Kimmie; Schrag, Deborah] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ng, K (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 42 TC 20 Z9 21 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 JUL 10 PY 2010 VL 28 IS 20 BP 3207 EP 3210 DI 10.1200/JCO.2010.28.9314 PG 4 WC Oncology SC Oncology GA 622CW UT WOS:000279637600001 PM 20498398 ER PT J AU McLeod, HL Sargent, DJ Marsh, S Green, EM King, CR Fuchs, CS Ramanathan, RK Williamson, SK Findlay, BP Thibodeau, SN Grothey, A Morton, RF Goldberg, RM AF McLeod, Howard L. Sargent, Daniel J. Marsh, Sharon Green, Erin M. King, Cristi R. Fuchs, Charles S. Ramanathan, Ramesh K. Williamson, Stephen K. Findlay, Brian P. Thibodeau, Stephen N. Grothey, Axel Morton, Roscoe F. Goldberg, Richard M. TI Pharmacogenetic Predictors of Adverse Events and Response to Chemotherapy in Metastatic Colorectal Cancer: Results From North American Gastrointestinal Intergroup Trial N9741 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID FLUOROURACIL PLUS LEUCOVORIN; RANDOMIZED CONTROLLED-TRIAL; III COLON-CANCER; ADJUVANT TREATMENT; CLINICAL-PRACTICE; DRUG-THERAPY; IRINOTECAN; OXALIPLATIN; WARFARIN; POLYMORPHISMS AB Purpose With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets. Patients and Methods Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing. Results All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study. Conclusion This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical. C1 [McLeod, Howard L.] Univ N Carolina, Inst Pharmacogenom & Individualized Therapy, Chapel Hill, NC 27599 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Washington Univ, Sch Med, St Louis, MO USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Natl Canc Inst Canada, St Catharines, ON, Canada. Iowa Oncol Res Assoc, Community Clin Oncol Program, Des Moines, IA USA. RP McLeod, HL (reprint author), Univ N Carolina, Inst Pharmacogenom & Individualized Therapy, Campus Box 7361, Chapel Hill, NC 27599 USA. EM hmcleod@unc.edu RI Goldberg , Richard/M-1311-2013; OI Sargent, Daniel/0000-0002-2684-4741 FU Public Health Service [CA-25224, CA-37404, CA-32102, CA-38926, CA-21115, CA-35101, CA-77202]; National Institutes of Health [R21-CA102461, U01-GM63340] FX Supported in part by Public Health Service Grants No. CA-25224, CA-37404, CA-32102, CA-38926, CA-21115, CA-35101, and CA-77202. The North American Gastrointestinal Intergroup N9741 genetic analysis was supported by National Institutes of Health Grants No. R21-CA102461 and U01-GM63340. NR 26 TC 102 Z9 107 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2010 VL 28 IS 20 BP 3227 EP 3233 DI 10.1200/JCO.2009.21.7943 PG 7 WC Oncology SC Oncology GA 622CW UT WOS:000279637600006 PM 20530282 ER PT J AU Singh, H Hirani, K Kadiyala, H Rudomiotov, O Davis, T Khan, MM Wahls, TL AF Singh, Hardeep Hirani, Kamal Kadiyala, Himabindu Rudomiotov, Olga Davis, Traber Khan, Myrna M. Wahls, Terry L. TI Characteristics and Predictors of Missed Opportunities in Lung Cancer Diagnosis: An Electronic Health Record-Based Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DELAYED DIAGNOSIS; BREAST-CANCER; INFORMATION-TECHNOLOGY; MALPRACTICE CLAIMS; COLORECTAL-CANCER; UNITED-STATES; PRIMARY-CARE; FOLLOW-UP; TIME; PATIENT AB Purpose Understanding delays in cancer diagnosis requires detailed information about timely recognition and follow-up of signs and symptoms. This information has been difficult to ascertain from paper-based records. We used an integrated electronic health record (EHR) to identify characteristics and predictors of missed opportunities for earlier diagnosis of lung cancer. Methods Using a retrospective cohort design, we evaluated 587 patients of primary lung cancer at two tertiary care facilities. Two physicians independently reviewed each case, and disagreements were resolved by consensus. Type I missed opportunities were defined as failure to recognize predefined clinical clues (ie, no documented follow-up) within 7 days. Type II missed opportunities were defined as failure to complete a requested follow-up action within 30 days. Results Reviewers identified missed opportunities in 222 (37.8%) of 587 patients. Median time to diagnosis in cases with and without missed opportunities was 132 days and 19 days, respectively (P < .001). Abnormal chest x-ray was the clue most frequently associated with type I missed opportunities (62%). Follow-up on abnormal chest x-ray (odds ratio [OR], 2.07; 95% CI, 1.04 to 4.13) and completion of first needle biopsy (OR, 3.02; 95% CI, 1.76 to 5.18) were associated with type II missed opportunities. Patient adherence contributed to 44% of patients with missed opportunities. Conclusion Preventable delays in lung cancer diagnosis arose mostly from failure to recognize documented abnormal imaging results and failure to complete key diagnostic procedures in a timely manner. Potential solutions include EHR-based strategies to improve recognition of abnormal imaging and track patients with suspected cancers. C1 Michael E DeBakey VA Med Ctr, Houston Vet Affairs Hlth Serv Res & Dev Ctr Excel, Houston, TX USA. Baylor Coll Med, Dept Med, Sect Hlth Serv Res, Houston, TX 77030 USA. Iowa City Vet Adm Med Ctr, Iowa City, IA USA. Univ Iowa, Carver Coll Med, Iowa City, IA USA. RP Singh, H (reprint author), VA Med Ctr, 152,2002 Holcombe Blvd, Houston, TX 77030 USA. EM hardeeps@bcm.edu OI Davis Giardina, Traber/0000-0002-9184-6524 FU National Institutes of Health [K23CA125585]; Houston Veterans Administration Health Services Research and Development Center of Excellence [HFP90-020] FX Supported by K23 Career Development Award No. K23CA125585 from the National Institutes of Health (H.S.) and in part by the Houston Veterans Administration Health Services Research and Development Center of Excellence (HFP90-020). NR 58 TC 41 Z9 41 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 JUL 10 PY 2010 VL 28 IS 20 BP 3307 EP 3315 DI 10.1200/JCO.2009.25.6636 PG 9 WC Oncology SC Oncology GA 622CW UT WOS:000279637600017 PM 20530272 ER PT J AU Balboni, TA Balboni, MJ Prigerson, HG AF Balboni, Tracy A. Balboni, Michael J. Prigerson, Holly G. TI Spiritual Care in Patients With Advanced Cancer: What Does It Imply? - Reply to HWM van Laarhoven et al SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID MEDICAL-CARE; NEAR-DEATH; ASSOCIATIONS C1 [Balboni, Tracy A.; Balboni, Michael J.; Prigerson, Holly G.] Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. [Balboni, Michael J.] Boston Univ, Boston, MA 02215 USA. [Prigerson, Holly G.] Harvard Univ, Sch Med, Ctr Palliat Care, Boston, MA USA. RP Balboni, TA (reprint author), Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. NR 6 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 JUL 10 PY 2010 VL 28 IS 20 BP E333 EP E333 DI 10.1200/JCO.2010.28.5536 PG 1 WC Oncology SC Oncology GA 622CW UT WOS:000279637600031 ER PT J AU Fujii, T Fuchs, BC Yamada, S Lauwers, GY Kulu, Y Goodwin, JM Lanuti, M Tanabe, KK AF Fujii, Tsutomu Fuchs, Bryan C. Yamada, Suguru Lauwers, Gregory Y. Kulu, Yakup Goodwin, Jonathan M. Lanuti, Michael Tanabe, Kenneth K. TI Mouse model of carbon tetrachloride induced liver fibrosis: Histopathological changes and expression of CD133 and epidermal growth factor SO BMC GASTROENTEROLOGY LA English DT Article ID HEPATIC STELLATE CELLS; HEPATOCELLULAR-CARCINOMA; FACTOR RECEPTOR; STEM/PROGENITOR CELLS; FACTOR-ALPHA; RAT-LIVER; CIRRHOSIS; REGENERATION; MICE; HEPATOCYTES AB Background: In the setting of chronic liver injury in humans, epidermal growth factor (EGF) and EGF receptor (EGFR) are up-regulated and have been proposed to have vital roles in both liver regeneration and development of hepatocellular carcinoma (HCC). Chronic liver injury also leads to hepatic stellate cell (HSC) differentiation and a novel subpopulation of HSCs which express CD133 and exhibit properties of progenitor cells has been described in rats. The carbon tetrachloride (CCl(4))-induced mouse model has been historically relied upon to study liver injury and regeneration. We exposed mice to CCl(4) to assess whether EGF and CD133+ HSCs are up-regulated in chronically injured liver. Methods: CCl(4) in olive oil was administered to strain A/J mice three times per week by oral gavage. Results: Multiple well-differentiated HCCs were found in all livers after 15 weeks of CCl(4) treatment. Notably, HCCs developed within the setting of fibrosis and not cirrhosis. CD133 was dramatically up-regulated after CCl(4) treatment, and increased expression of desmin and glial fibrillary acidic protein, representative markers of HSCs, was also observed. EGF expression significantly decreased, contrary to observations in humans, whereas the expression of amphiregulin, another EGFR ligand, was significantly increased. Conclusions: Species-specific differences exist with respect to the histopathological and molecular pathogenesis of chronic liver disease. CCl(4)-induced chronic liver injury in A/J mice has important differences compared to human cirrhosis leading to HCC. C1 [Fujii, Tsutomu; Fuchs, Bryan C.; Yamada, Suguru; Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA 02114 USA. [Fujii, Tsutomu; Fuchs, Bryan C.; Yamada, Suguru; Lauwers, Gregory Y.; Kulu, Yakup; Goodwin, Jonathan M.; Lanuti, Michael; Tanabe, Kenneth K.] Harvard Univ, Sch Med, Boston, MA USA. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Ctr Canc, Dept Pathol, Boston, MA USA. [Goodwin, Jonathan M.; Lanuti, Michael] Massachusetts Gen Hosp, Ctr Canc, Div Thorac Surg, Boston, MA USA. RP Tanabe, KK (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA 02114 USA. EM ktanabe@partners.org RI Fujii, Tsutomu/M-4838-2014 FU U.S. National Institute of Health (NIH) [2R01CA076183]; Deutsche Forschungsgemeinschaft; Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery; Aid for Cancer Research; NIH [1K01CA140861] FX This work was supported by the U.S. National Institute of Health (NIH) grant 2R01CA076183 (KKT), Deutsche Forschungsgemeinschaft (YK), the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery (BCF), Aid for Cancer Research (BCF) and NIH grant 1K01CA140861 (BCF). NR 42 TC 61 Z9 66 U1 1 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-230X J9 BMC GASTROENTEROL JI BMC Gastroenterol. PD JUL 9 PY 2010 VL 10 AR 79 DI 10.1186/1471-230X-10-79 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 661ZQ UT WOS:000282774200002 PM 20618941 ER PT J AU Bai, XY Kim, J Yang, ZA Jurynec, MJ Akie, TE Lee, J LeBlanc, J Sessa, A Jiang, H DiBiase, A Zhou, Y Grunwald, DJ Lin, S Cantor, AB Orkin, SH Zon, LI AF Bai, Xiaoying Kim, Jonghwan Yang, Zhongan Jurynec, Michael J. Akie, Thomas E. Lee, Joseph LeBlanc, Jocelyn Sessa, Anna Jiang, Hong DiBiase, Anthony Zhou, Yi Grunwald, David J. Lin, Shuo Cantor, Alan B. Orkin, Stuart H. Zon, Leonard I. TI TIF1 gamma Controls Erythroid Cell Fate by Regulating Transcription Elongation SO CELL LA English DT Article ID RNA-POLYMERASE-II; P-TEFB; IN-VIVO; PAF1 COMPLEX; ZEBRAFISH; HEMATOPOIESIS; EMBRYO; GATA-1; DOMAIN; GENES AB Recent genome-wide studies have demonstrated that pausing of RNA polymerase II (Pol II) occurred on many vertebrate genes. By genetic studies in the zebrafish tif1 gamma mutant moonshine we found that loss of function of Pol II-associated factors PAF or DSIF rescued erythroid gene transcription in tif1 gamma-deficient animals. Biochemical analysis established physical interactions among TIF1 gamma, the blood-specific SCL transcription complex, and the positive elongation factors p-TEFb and FACT. Chromatin immunoprecipitation assays in human CD34(+) cells supported a TIF1 gamma-dependent recruitment of positive elongation factors to erythroid genes to promote transcription elongation by counteracting Pol II pausing. Our study establishes a mechanism for regulating tissue cell fate and differentiation through transcription elongation. C1 [Bai, Xiaoying; Kim, Jonghwan; Lee, Joseph; LeBlanc, Jocelyn; Sessa, Anna; DiBiase, Anthony; Zhou, Yi; Orkin, Stuart H.; Zon, Leonard I.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Bai, Xiaoying; Lee, Joseph; LeBlanc, Jocelyn; Sessa, Anna; DiBiase, Anthony; Zhou, Yi; Zon, Leonard I.] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Bai, Xiaoying; Kim, Jonghwan; Akie, Thomas E.; Lee, Joseph; LeBlanc, Jocelyn; Sessa, Anna; DiBiase, Anthony; Zhou, Yi; Cantor, Alan B.; Orkin, Stuart H.; Zon, Leonard I.] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Div Hematol Oncol,Childrens Hosp Boston, Boston, MA 02115 USA. [Kim, Jonghwan; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Yang, Zhongan; Jiang, Hong; Lin, Shuo] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. [Jurynec, Michael J.; Grunwald, David J.] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. RP Zon, LI (reprint author), Howard Hughes Med Inst, Boston, MA 02115 USA. EM zon@enders.tch.harvard.edu FU National Institutes of Health [5PO1HL32262-28, 5R37 DK55381-010] FX We thank Drs. H. Chen, S. Guo, S. Takada, E.H. Bresnick, and S.J. Brandt for providing regents, Y. Huang, A. Chen, and R. Mathieu for technical assistance. We are grateful to Drs. T.V. Bowman, C. Ceol, and R. White for helpful discussion and critical comments. This study was supported by National Institutes of Health grants 5PO1HL32262-28 and 5R37 DK55381-010. X. Bai and J. Kim are Howard Hughes Medical Institute (HHMI) research fellows. L.I. Zon and S.H. Orkin are HHMI investigators. L.I.Z. is a founder and stock holder of Fate, Inc. and a scientific advisor for Stemgent. NR 51 TC 113 Z9 117 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 9 PY 2010 VL 142 IS 1 BP 133 EP 143 DI 10.1016/j.cell.2010.05.028 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 622CU UT WOS:000279637300019 PM 20603019 ER PT J AU Braunwald, E AF Braunwald, Eugene TI Sir James W. Black, MD, FRS 1924-2010 In Memoriam SO CIRCULATION RESEARCH LA English DT Biographical-Item C1 [Braunwald, Eugene] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Braunwald, Eugene] Brigham & Womens Hosp, Div Cardiovasc, Dept Med, Boston, MA 02115 USA. [Braunwald, Eugene] Harvard Univ, Sch Med, Boston, MA USA. RP Braunwald, E (reprint author), Brigham & Womens Hosp, TIMI Study Grp, 75 Francis St, Boston, MA 02115 USA. EM ebraunwald@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 9 PY 2010 VL 107 IS 1 BP 3 EP 5 DI 10.1161/CIRCRESAHA.110.226118 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 622GJ UT WOS:000279649000001 ER PT J AU Smogorzewska, A Desetty, R Saito, TT Schlabach, M Lach, FP Sowa, ME Clark, AB Kunkel, TA Harper, JW Colaiacovo, MP Elledge, SJ AF Smogorzewska, Agata Desetty, Rohini Saito, Takamune T. Schlabach, Michael Lach, Francis P. Sowa, Mathew E. Clark, Alan B. Kunkel, Thomas A. Harper, J. Wade Colaiacovo, Monica P. Elledge, Stephen J. TI A Genetic Screen Identifies FAN1, a Fanconi Anemia-Associated Nuclease Necessary for DNA Interstrand Crosslink Repair SO MOLECULAR CELL LA English DT Article ID HOLLIDAY JUNCTION RESOLVASES; CANCER SUSCEPTIBILITY GENE; FANCD2 MONOUBIQUITINATION; CAENORHABDITIS-ELEGANS; DAMAGE RESPONSE; STRAND BREAKS; RECOMBINATION; PATHWAY; PROTEIN; PHOSPHORYLATION AB The Fanconi anemia (FA) pathway is responsible for interstrand crosslink repair. At the heart of this pathway is the FANCI-FAND2 (ID) complex, which, upon ubiquitination by the FA core complex, travels to sites of damage to coordinate repair that includes nucleolytic modification of the DNA surrounding the lesion and translesion synthesis. How the ID complex regulates these events is unknown. Here we describe a shRNA screen that led to the identification of two nucleases necessary for crosslink repair, FAN1 (KIAA1018) and EXDL2. FAN1 colocalizes at sites of DNA damage with the ID complex in a manner dependent on FAN1's ubiquitin-binding domain (UBZ), the ID complex, and monoubiquitination of FANCD2. FAN1 possesses intrinsic 5'-3' exonuclease activity and endonuclease activity that cleaves nicked and branched structures. We propose that FAN1 is a repair nuclease that is recruited to sites of crosslink damage in part through binding the ubiquitinated ID complex through its UBZ domain. C1 [Smogorzewska, Agata; Schlabach, Michael; Elledge, Stephen J.] Harvard Univ, Sch Med,Brigham & Womens Hosp, Howard Hughes Med Inst, Dept Genet,Dept Med,Div Genet, Boston, MA 02115 USA. [Smogorzewska, Agata] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Smogorzewska, Agata; Desetty, Rohini; Lach, Francis P.] Rockefeller Univ, Lab Genome Maintenance, New York, NY 10065 USA. [Sowa, Mathew E.; Harper, J. Wade] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Genet Mol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Smogorzewska, A (reprint author), Harvard Univ, Sch Med,Brigham & Womens Hosp, Howard Hughes Med Inst, Dept Genet,Dept Med,Div Genet, Boston, MA 02115 USA. EM asmogorzewska@rockefeller.edu; selledge@genetics.med.harvard.edu RI Smogorzewska, Agata/B-8891-2011; Saito, Takamune/G-2294-2014 OI Saito, Takamune/0000-0002-4447-4115 FU National Institutes of Health (NIH) [R01GM072551]; CMCR [1U19A1067751-01]; Giovanni Armenise-Harvard Foundation; Division of Intramural Research of the National Institute of Environmental Health Sciences, NIH [Z01 ES065089]; Burroughs Wellcome Fund; [T32CA09216] FX We thank Jen Svendsen and members of the Elledge lab for protocols and discussion. Special thanks to Alberto Ciccia for insightful suggestions and comments. This work is supported by grants from the National Institutes of Health (NIH) and CMCR grant #1U19A1067751-01 to S.J.E., NIH grant R01GM072551 and a Giovanni Armenise-Harvard Foundation award to M.P.C., a NIH grant to J.W.H., and Project Z01 ES065089 to T.A.K., in the Division of Intramural Research of the National Institute of Environmental Health Sciences, NIH. A.S. was supported by T32CA09216 to the Pathology Department at the Massachusetts General Hospital and by Burroughs Wellcome Fund Career Award for Medical Scientists and is an Irma T. Hirschl scholar. S.J.E. is an investigator of the Howard Hughes Medical Institute. NR 52 TC 174 Z9 187 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 9 PY 2010 VL 39 IS 1 BP 36 EP 47 DI 10.1016/j.molcel.2010.06.023 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 628RT UT WOS:000280139200006 PM 20603073 ER PT J AU Fadini, GP Maruyama, S Ozaki, T Taguchi, A Meigs, J Dimmeler, S Zeiher, AM de Kreutzenberg, S Avogaro, A Nickenig, G Schmidt-Lucke, C Werner, N AF Fadini, Gian Paolo Maruyama, Shoichi Ozaki, Takenori Taguchi, Akihiko Meigs, James Dimmeler, Stefanie Zeiher, Andreas M. de Kreutzenberg, Saula Avogaro, Angelo Nickenig, Georg Schmidt-Lucke, Caroline Werner, Nikos TI Circulating Progenitor Cell Count for Cardiovascular Risk Stratification: A Pooled Analysis SO PLOS ONE LA English DT Article ID C-REACTIVE PROTEIN; MULTIPLE BIOMARKERS; NATURAL-HISTORY; METABOLIC SYNDROME; PERIPHERAL-BLOOD; VASCULAR REPAIR; EVENTS; PREDICTION; DISEASE; ATHEROSCLEROSIS AB Background: Circulating progenitor cells (CPC) contribute to the homeostasis of the vessel wall, and a reduced CPC count predicts cardiovascular morbidity and mortality. We tested the hypothesis that CPC count improves cardiovascular risk stratification and that this is modulated by low-grade inflammation. Methodology/Principal Findings: We pooled data from 4 longitudinal studies, including a total of 1,057 patients having CPC determined and major adverse cardiovascular events (MACE) collected. We recorded cardiovascular risk factors and high-sensitive C-reactive protein (hsCRP) level. Risk estimates were derived from Cox proportional hazard analyses. CPC count and/or hsCRP level were added to a reference model including age, sex, cardiovascular risk factors, prevalent CVD, chronic renal failure (CRF) and medications. The sample was composed of high-risk individuals, as 76.3% had prevalent CVD and 31.6% had CRF. There were 331 (31.3%) incident MACE during an average 1.7 +/- 1.1 year follow-up time. CPC count was independently associated with incident MACE even after correction for hsCRP. According to C-statistics, models including CPC yielded a non-significant improvement in accuracy of MACE prediction. However, the integrated discrimination improvement index (IDI) showed better performance of models including CPC compared to the reference model and models including hsCRP in identifying MACE. CPC count also yielded significant net reclassification improvements (NRI) for CV death, non-fatal AMI and other CV events. The effect of CPC was independent of hsCRP, but there was a significant more-than-additive interaction between low CPC count and raised hsCRP level in predicting incident MACE. Conclusions/Significance: In high risk individuals, a reduced CPC count helps identifying more patients at higher risk of MACE over the short term, especially in combination with a raised hsCRP level. C1 [Fadini, Gian Paolo; de Kreutzenberg, Saula; Avogaro, Angelo] Univ Padua, Sch Med, Dept Clin & Expt Med, Padua, Italy. [Maruyama, Shoichi; Ozaki, Takenori] Nagoya Univ, Grad Sch Med, Dept Nephrol, Nagoya, Aichi 4648601, Japan. [Taguchi, Akihiko] Natl Cardiovasc Ctr, Dept Cerebrovasc Dis, Osaka, Japan. [Meigs, James] Harvard Univ, Sch Med, Boston, MA USA. [Meigs, James] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Dimmeler, Stefanie; Zeiher, Andreas M.] Goethe Univ Frankfurt, Frankfurt, Germany. [Nickenig, Georg; Werner, Nikos] Univ Hosp Bonn, Dept Internal Med 2, Div Cardiol Pneumol & Angiol, Bonn, Germany. [Schmidt-Lucke, Caroline] Charite, Dept Cardiol & Pneumol, D-13353 Berlin, Germany. RP Fadini, GP (reprint author), Univ Padua, Sch Med, Dept Clin & Expt Med, Padua, Italy. EM gianpaolofadini@hotmail.com OI FADINI, GIAN PAOLO/0000-0002-6510-2097 NR 46 TC 66 Z9 70 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 9 PY 2010 VL 5 IS 7 AR e11488 DI 10.1371/journal.pone.0011488 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 623CM UT WOS:000279715300005 PM 20634884 ER PT J AU Kang, J Yoo, J Lee, S Tang, WL Aguilar, B Ramu, S Choi, I Otu, HH Shin, JW Dotto, GP Koh, CJ Detmar, M Hong, YK AF Kang, Jinjoo Yoo, Jaehyuk Lee, Sunju Tang, Wanli Aguilar, Berenice Ramu, Swapnika Choi, Inho Otu, Hasan H. Shin, Jay W. Dotto, G. Paolo Koh, Chester J. Detmar, Michael Hong, Young-Kwon TI An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells SO BLOOD LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; GROWTH-FACTOR; TRANSCRIPTION FACTOR; COUP-TFII; GENE-EXPRESSION; KAPOSI-SARCOMA; CANCER CELLS; NOTCH STATUS; IN-VITRO; DIFFERENTIATION AB Arteriovenous-lymphatic endothelial cell fates are specified by the master regulators, namely, Notch, COUP-TFII, and Prox1. Whereas Notch is expressed in the arteries and COUP-TFII in the veins, the lymphatics express all 3 cell fate regulators. Previous studies show that lymphatic endothelial cell (LEC) fate is highly plastic and reversible, raising a new concept that all 3 endothelial cell fates may coreside in LECs and a subtle alteration can result in a reprogramming of LEC fate. We provide a molecular basis verifying this concept by identifying a cross-control mechanism among these cell fate regulators. We found that Notch signal down-regulates Prox1 and COUP-TFII through Hey1 and Hey2 and that activated Notch receptor suppresses the lymphatic phenotypes and induces the arterial cell fate. On the contrary, Prox1 and COUP-TFII attenuate vascular endothelial growth factor signaling, known to induce Notch, by repressing vascular endothelial growth factor receptor-2 and neuropilin-1. We show that previously reported podoplanin-based LEC heterogeneity is associated with differential expression of Notch1 in human cutaneous lymphatics. We propose that the expression of the 3 cell fate regulators is controlled by an exquisite feedback mechanism working in LECs and that LEC fate is a consequence of the Prox1-directed lymphatic equilibrium among the cell fate regulators. (Blood. 2010; 116(1): 140-150) C1 [Kang, Jinjoo; Yoo, Jaehyuk; Lee, Sunju; Tang, Wanli; Aguilar, Berenice; Ramu, Swapnika; Choi, Inho; Hong, Young-Kwon] Univ So Calif, Dept Surg, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA 90033 USA. [Kang, Jinjoo; Yoo, Jaehyuk; Lee, Sunju; Tang, Wanli; Aguilar, Berenice; Ramu, Swapnika; Choi, Inho; Hong, Young-Kwon] Univ So Calif, Dept Biochem & Mol Biol, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA 90033 USA. [Otu, Hasan H.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Otu, Hasan H.] Yeditepe Univ, Dept Genet & Bioengn, Istanbul, Turkey. [Shin, Jay W.; Detmar, Michael] Swiss Fed Inst Technol, Inst Pharmaceut Sci, Zurich, Switzerland. [Dotto, G. Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Koh, Chester J.] Childrens Hosp Los Angeles, Div Pediat Urol, Los Angeles, CA 90027 USA. RP Hong, YK (reprint author), Univ So Calif, Dept Surg, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, 1450 Biggy St,NRT6501,Mail Code 9601, Los Angeles, CA 90033 USA. EM young.hong@usc.edu OI Otu, Hasan/0000-0002-9253-8152 FU National Institutes of Health/National Cancer Institute [CA69184, CA92644]; American Cancer Society; American Heart Association; March of Dimes Foundation; National Institutes of Health/National Heart, Lung, and Blood Institute; [1R21HL082643]; [1R01HD059762] FX This work was supported by the National Institutes of Health/National Cancer Institute (grants CA69184 and CA92644; M. D.); and the American Cancer Society, the American Heart Association, the March of Dimes Foundation, and the National Institutes of Health/National Heart, Lung, and Blood Institute (1R21HL082643 and 1R01HD059762; Y.-K.H.). NR 53 TC 47 Z9 47 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 8 PY 2010 VL 116 IS 1 BP 140 EP 150 DI 10.1182/blood-2009-11-252270 PG 11 WC Hematology SC Hematology GA 622DX UT WOS:000279641400021 PM 20351309 ER PT J AU Surolia, I Pirnie, SP Chellappa, V Taylor, KN Cariappa, A Moya, J Liu, H Bell, DW Driscoll, DR Diederichs, S Haider, K Netravali, I Le, S Elia, R Dow, E Lee, A Freudenberg, J De Jager, PL Chretien, Y Varki, A MacDonald, ME Gillis, T Behrens, TW Bloch, D Collier, D Korzenik, J Podolsky, DK Hafler, D Murali, M Sands, B Stone, JH Gregersen, PK Pillai, S AF Surolia, Ira Pirnie, Stephan P. Chellappa, Vasant Taylor, Kendra N. Cariappa, Annaiah Moya, Jesse Liu, Haoyuan Bell, Daphne W. Driscoll, David R. Diederichs, Sven Haider, Khaleda Netravali, Ilka Le, Sheila Elia, Roberto Dow, Ethan Lee, Annette Freudenberg, Jan De Jager, Philip L. Chretien, Yves Varki, Ajit MacDonald, Marcy E. Gillis, Tammy Behrens, Timothy W. Bloch, Donald Collier, Deborah Korzenik, Joshua Podolsky, Daniel K. Hafler, David Murali, Mandakolathur Sands, Bruce Stone, John H. Gregersen, Peter K. Pillai, Shiv TI Functionally defective germline variants of sialic acid acetylesterase in autoimmunity SO NATURE LA English DT Article ID MUTATIONS; DISEASE; MARKER AB Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulates B lymphocyte antigen receptor signalling and is required for the maintenance of immunological tolerance in mice(1,2). Heterozygous loss-of-function germline rare variants and a homozygous defective polymorphic variant of SIAE were identified in 24/923 subjects of European origin with relatively common autoimmune disorders and in 2/648 controls of European origin. All heterozygous loss-of-function SIAE mutations tested were capable of functioning in a dominant negative manner. Ahomozygous secretion-defective polymorphic variant of SIAE was catalytically active, lacked the ability to function in a dominant negative manner, and was seen in eight autoimmune subjects but in no control subjects. The odds ratio for inheriting defective SIAE alleles was 8.6 in all autoimmune subjects, 8.3 in subjects with rheumatoid arthritis, and 7.9 in subjects with type I diabetes. Functionally defective SIAE rare and polymorphic variants represent a strong genetic link to susceptibility in relatively common human autoimmune disorders. C1 [Surolia, Ira; Pirnie, Stephan P.; Chellappa, Vasant; Taylor, Kendra N.; Cariappa, Annaiah; Moya, Jesse; Liu, Haoyuan; Bell, Daphne W.; Driscoll, David R.; Diederichs, Sven; Haider, Khaleda; Netravali, Ilka; Le, Sheila; Elia, Roberto; Dow, Ethan; Pillai, Shiv] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Lee, Annette; Freudenberg, Jan; Gregersen, Peter K.] N Shore LIJ Hlth Syst, Feinstein Inst Med Res, Manhasset, NY 11030 USA. [De Jager, Philip L.; Hafler, David] Brigham & Womens Hosp, Ctr Neurol Dis, Div Mol Immunol, Boston, MA 02115 USA. [De Jager, Philip L.; Hafler, David] Partners Ctr Personalized Genet Med, Boston, MA 02115 USA. [De Jager, Philip L.; Hafler, David] Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [De Jager, Philip L.; Hafler, David] MIT, Cambridge, MA 02142 USA. [Chretien, Yves] Harvard Univ, Dept Stat, Cambridge, MA 02138 USA. [Varki, Ajit] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Varki, Ajit] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. [MacDonald, Marcy E.; Gillis, Tammy] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. [Behrens, Timothy W.] Genentech Inc, San Francisco, CA 94080 USA. [Bloch, Donald; Collier, Deborah; Stone, John H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Rheumatol, Boston, MA 02114 USA. [Korzenik, Joshua; Podolsky, Daniel K.; Sands, Bruce] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Murali, Mandakolathur] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Clin Immunol Lab, Boston, MA 02114 USA. RP Pillai, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. EM pillai@helix.mgh.harvard.edu RI Diederichs, Sven/J-6237-2012 OI Diederichs, Sven/0000-0001-7901-4752 FU Alliance for Lupus Research; Center for the Study of Inflammatory Bowel Disease at MGH; NIH [AI 064930, AI 076505, AR 058481, NS 32765]; NIH for NARAC [AR 044422, AR 022263]; MADGC [AI 068759] FX We thank M. Cohen for coordinating the recall of inflammatory bowel disease patients, and K. Pedrick and E. Chung for their contributions. These studies were supported by grants from the Alliance for Lupus Research, the Center for the Study of Inflammatory Bowel Disease at MGH, and the NIH (AI 064930, AI 076505, and AR 058481) to S. P. and a grant to M.E.M. (NS 32765). P.K.G. acknowledges NIH support for NARAC (AR 044422 and AR 022263) and MADGC (AI 068759). The NIDDK is acknowledged for making samples available from the EDIC collection of its DNA repository. D. W. B. acknowledges the Intramural program of the National Human Genome Research Institute at NIH. NR 16 TC 88 Z9 93 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 8 PY 2010 VL 466 IS 7303 BP 243 EP U118 DI 10.1038/nature09115 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 621LR UT WOS:000279580800038 PM 20555325 ER PT J AU Basaria, S Coviello, AD Travison, TG Storer, TW Farwell, WR Jette, AM Eder, R Tennstedt, S Ulloor, J Zhang, AQ Choong, K Lakshman, KM Mazer, NA Miciek, R Krasnoff, J Elmi, A Knapp, PE Brooks, B Appleman, E Aggarwal, S Bhasin, G Hede-Brierley, L Bhatia, A Collins, L LeBrasseur, N Fiore, LD Bhasin, S AF Basaria, Shehzad Coviello, Andrea D. Travison, Thomas G. Storer, Thomas W. Farwell, Wildon R. Jette, Alan M. Eder, Richard Tennstedt, Sharon Ulloor, Jagadish Zhang, Anqi Choong, Karen Lakshman, Kishore M. Mazer, Norman A. Miciek, Renee Krasnoff, Joanne Elmi, Ayan Knapp, Philip E. Brooks, Brad Appleman, Erica Aggarwal, Sheetal Bhasin, Geeta Hede-Brierley, Leif Bhatia, Ashmeet Collins, Lauren LeBrasseur, Nathan Fiore, Louis D. Bhasin, Shalender TI Adverse Events Associated with Testosterone Administration SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; ANABOLIC-ANDROGENIC STEROIDS; PLACEBO-CONTROLLED TRIALS; OLDER MEN; MUSCLE STRENGTH; CARDIOVASCULAR-DISEASE; PHYSICAL FUNCTION; BODY-COMPOSITION; SKELETAL-MUSCLE; DOUBLE-BLIND AB BACKGROUND Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. METHODS Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. RESULTS A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. CONCLUSIONS In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.) C1 [Basaria, Shehzad; Coviello, Andrea D.; Travison, Thomas G.; Storer, Thomas W.; Eder, Richard; Ulloor, Jagadish; Zhang, Anqi; Choong, Karen; Lakshman, Kishore M.; Mazer, Norman A.; Miciek, Renee; Krasnoff, Joanne; Elmi, Ayan; Knapp, Philip E.; Brooks, Brad; Appleman, Erica; Aggarwal, Sheetal; Bhasin, Geeta; Hede-Brierley, Leif; Bhatia, Ashmeet; Collins, Lauren; LeBrasseur, Nathan; Bhasin, Shalender] Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. [Basaria, Shehzad; Coviello, Andrea D.; Travison, Thomas G.; Storer, Thomas W.; Eder, Richard; Ulloor, Jagadish; Zhang, Anqi; Choong, Karen; Lakshman, Kishore M.; Mazer, Norman A.; Miciek, Renee; Krasnoff, Joanne; Elmi, Ayan; Knapp, Philip E.; Brooks, Brad; Appleman, Erica; Aggarwal, Sheetal; Bhasin, Geeta; Hede-Brierley, Leif; Bhatia, Ashmeet; Collins, Lauren; LeBrasseur, Nathan; Bhasin, Shalender] Boston Med Ctr, Boston, MA USA. [Travison, Thomas G.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Jette, Alan M.] Boston Univ, Sch Publ Hlth, Hlth & Disabil Res Inst, Boston, MA 02118 USA. [Farwell, Wildon R.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Farwell, Wildon R.] Harvard Univ, Sch Med, Boston, MA USA. [Farwell, Wildon R.; Fiore, Louis D.] VA Boston Healthcare Syst, Jamaica Plain, MA USA. [Tennstedt, Sharon] New England Res Inst, Watertown, MA 02172 USA. RP Bhasin, S (reprint author), Boston Univ, Sch Med, Sect Endocrinol Diabet & Nutr, 670 Albany St, Boston, MA 02118 USA. EM bhasin@bu.edu OI Jette, Alan/0000-0002-2117-9973; LeBrasseur, Nathan/0000-0002-2002-0418 FU National Institutes on Aging [1UO1AG14369]; Boston Claude D. Pepper Older Americans Independence Center [5P30AG031679]; Boston University Clinical and Translational Science Institute [1UL1RR025771]; Novartis; GlaxoSmithKline; Solvay Pharmaceuticals; Merck; Ligand Pharmaceuticals; Lipocine and Solvay Pharmaceuticals FX Supported primarily by the National Institutes on Aging under a cooperative agreement (1UO1AG14369). Additional support was provided by grants from the Boston Claude D. Pepper Older Americans Independence Center (5P30AG031679) and the Boston University Clinical and Translational Science Institute (1UL1RR025771). A part of the work was supported by the resources and facilities of the Veterans Affairs Boston Healthcare System. Testosterone and placebo gel for the study were provided by Auxilium Pharmaceuticals, Norristown, PA.; Dr. Bhasin reports receiving consulting fees and payments for travel or accommodation expenses from Novartis and GlaxoSmithKline and grant support from Solvay Pharmaceuticals, Merck, and Ligand Pharmaceuticals; Dr. Coviello, receiving compensation from Endo Pharmaceuticals for participation in a 1-day discussion group; Dr. Mazer, receiving consulting fees from Lipocine and Solvay Pharmaceuticals and a fee for expert testimony from Watson Laboratories and being a full-time employee of Hoffmann-La Roche Pharmaceuticals; and Dr. Tennstedt, receiving grant support from Auxilium for data analysis. No other potential conflict of interest relevant to this article was reported. NR 55 TC 567 Z9 582 U1 10 U2 50 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 8 PY 2010 VL 363 IS 2 BP 109 EP 122 DI 10.1056/NEJMoa1000485 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 621JY UT WOS:000279574100004 PM 20592293 ER PT J AU Utz, AL Schaefer, PW Snuderl, M AF Utz, Andrea L. Schaefer, Pamela W. Snuderl, Matija TI Case 20-2010: A 32-Year-Old Woman with Oligomenorrhea and Infertility Differential Diagnosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID POLYCYSTIC-OVARY-SYNDROME; PITUITARY-ADENOMAS; MANAGEMENT; PROLIFERATION; EXPRESSION; CONSENSUS; CRITERIA; WOMEN C1 [Utz, Andrea L.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Schaefer, Pamela W.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Snuderl, Matija] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Utz, Andrea L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Schaefer, Pamela W.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Snuderl, Matija] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Utz, Andrea L.] Vanderbilt Univ, Med Ctr, Pituitary Ctr, Nashville, TN USA. RP Utz, AL (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. NR 17 TC 0 Z9 0 U1 0 U2 6 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 8 PY 2010 VL 363 IS 2 BP 178 EP 186 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 621JY UT WOS:000279574100012 PM 20647214 ER PT J AU Ramadori, G Fujikawa, T Fukuda, M Anderson, J Morgan, DA Mostoslavsky, R Stuart, RC Perello, M Vianna, CR Nillni, EA Rahmouni, K Coppari, R AF Ramadori, Giorgio Fujikawa, Teppei Fukuda, Makoto Anderson, Jason Morgan, Donald A. Mostoslavsky, Raul Stuart, Ronald C. Perello, Mario Vianna, Claudia R. Nillni, Eduardo A. Rahmouni, Kamal Coppari, Roberto TI SIRT1 Deacetylase in POMC Neurons Is Required for Homeostatic Defenses against Diet-Induced Obesity SO CELL METABOLISM LA English DT Article ID REGULATES FOOD-INTAKE; HYPOTHALAMIC PROOPIOMELANOCORTIN NEURONS; CENTRAL MELANOCORTIN SYSTEM; ENERGY-BALANCE; ADIPOSE-TISSUE; WEIGHT HOMEOSTASIS; AGRP NEURONS; LEPTIN; RECEPTOR; GLUCOSE AB Feeding on high-calorie (HC) diets induces serious metabolic imbalances, including obesity. Understanding the mechanisms against excessive body weight gain is critical for developing effective anti-obesity strategies. Here we show that lack of nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase SIRT1 in pro-opiomelanocortin (POMC) neurons causes hypersensitivity to diet-induced obesity due to reduced energy expenditure. The ability of leptin to properly engage the phosphoinositide 3-kinase (PI3K) signaling in POMC neurons and elicit remodeling of perigonadal white adipose tissue (WAT) is severely compromised in mutant mice. Also, electrophysiological and histomorphomolecular analyses indicate a selective reduction in sympathetic nerve activity and brown-fat-like characteristics in perigonadal WAT of mutant mice, suggesting a physiologically important role for POMC neurons in controlling this visceral fat depot. In summary, our results provide direct genetic evidence that SIRT1 in POMC neurons is required for normal autonomic adaptations against diet-induced obesity. C1 [Ramadori, Giorgio; Fujikawa, Teppei; Fukuda, Makoto; Anderson, Jason; Perello, Mario; Vianna, Claudia R.; Coppari, Roberto] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Hypothalam Res, Dallas, TX 75390 USA. [Morgan, Donald A.; Rahmouni, Kamal] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. [Mostoslavsky, Raul] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Canc Ctr, Boston, MA 02115 USA. [Stuart, Ronald C.; Nillni, Eduardo A.] Brown Univ, Rhode Isl Hosp, Warren Alpert Med Sch, Providence, RI 02903 USA. RP Coppari, R (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, Div Hypothalam Res, Dallas, TX 75390 USA. EM roberto.coppari@utsouthwestern.edu RI Fukuda, Makoto/C-9745-2009; vianna, claudia /I-4991-2012; Morgan, Donald/L-6907-2013; Coppari, Roberto/B-4799-2014; Fukuda, Makoto/I-7915-2014; OI Fukuda, Makoto/0000-0003-0112-9925; Fukuda, Makoto/0000-0003-0112-9925; Fujikawa, Teppei/0000-0002-4056-0526 FU Mouse Metabolic Phenotyping Core at UTSW Medical Center [PL1 DK081182-01, 1UL1RR024923-01]; Department of Internal Medicine/Division of Hypothalamic Research; UTSW Medical Center; American Heart Association; National Institute of Health [DK080836, DK58148] FX We thank Wenhao Li and Kristen Wertz for technical assistance, Dr. Joyce Repa (UTSW Medical Center, USA) for quantitative real-time PCR primers, Dr. Yoshiyuki Horio (Sapporo Medical School, Japan) for the SIRT1 antisera, Dr. Frederick Alt (Harvard Medical School, USA) for the Cre-conditional Sirt1 null mice, Dr. Aktar All and Laura Brule for metabolic assessments at the Mouse Metabolic Phenotyping Core at UTSW Medical Center (supported by PL1 DK081182-01 and 1UL1RR024923-01), and Drs. Joel K. Elmquist (UTSW Medical Center, USA) and Bradford B. Lowell (Harvard Medical School, USA) for helpful discussions and careful reading of the manuscript. This work was supported by the Department of Internal Medicine/Division of Hypothalamic Research, UTSW Medical Center (start-up to R.C.), the American Heart Association (Scientist Development Grant to R.C. and Postdoctoral Fellowship to G.R.), and by National Institute of Health Grants (DK080836 to R.C. and DK58148 to E.A.N.). NR 62 TC 90 Z9 94 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JUL 7 PY 2010 VL 12 IS 1 BP 78 EP 87 DI 10.1016/j.cmet.2010.05.010 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 623PI UT WOS:000279753900011 PM 20620997 ER PT J AU Xu, Y Hill, JW Fukuda, M Gautron, L Sohn, JW Kim, KW Lee, CE Choi, MJ Lauzon, DA Dhillon, H Lowell, BB Zigman, JM Zhao, JJ Elmquist, JK AF Xu, Yong Hill, Jennifer W. Fukuda, Makoto Gautron, Laurent Sohn, Jong-Woo Kim, Ki-Woo Lee, Charlotte E. Choi, Michelle J. Lauzon, Danielle A. Dhillon, Harveen Lowell, Bradford B. Zigman, Jeffrey M. Zhao, Jean J. Elmquist, Joel K. TI PI3K Signaling in the Ventromedial Hypothalamic Nucleus Is Required for Normal Energy Homeostasis SO CELL METABOLISM LA English DT Article ID BROWN ADIPOSE-TISSUE; DIET-INDUCED OBESITY; STEROIDOGENIC FACTOR-1; METABOLIC SYNDROME; BODY-WEIGHT; LEPTIN RESISTANCE; SF1 NEURONS; RATS; RECEPTOR; MICE AB Phosphatidyl inositol 3-kinase (PI3K) signaling in the hypothalamus has been implicated in the regulation of energy homeostasis, but the critical brain sites where this intracellular signal integrates various metabolic cues to regulate food intake and energy expenditure are unknown. Here, we show that mice with reduced PI3K activity in the ventromedial hypothalamic nucleus (VMH) are more sensitive to high-fat diet-induced obesity due to reduced energy expenditure. In addition, inhibition of PI3K in the VMH impaired the ability to alter energy expenditure in response to acute high-fat diet feeding and food deprivation. Furthermore, the acute anorexigenic effects induced by exogenous leptin were blunted in the mutant mice. Collectively, our results indicate that PI3K activity in VMH neurons plays a physiologically relevant role in the regulation of energy expenditure. C1 [Zhao, Jean J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Zhao, Jean J.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Xu, Yong; Hill, Jennifer W.; Fukuda, Makoto; Gautron, Laurent; Sohn, Jong-Woo; Kim, Ki-Woo; Lee, Charlotte E.; Choi, Michelle J.; Lauzon, Danielle A.; Zigman, Jeffrey M.; Elmquist, Joel K.] Univ Texas SW Med Ctr Dallas, Div Hypothalam Res, Dept Internal Med, Dallas, TX 75390 USA. [Xu, Yong; Hill, Jennifer W.; Fukuda, Makoto; Gautron, Laurent; Sohn, Jong-Woo; Kim, Ki-Woo; Lee, Charlotte E.; Choi, Michelle J.; Lauzon, Danielle A.; Zigman, Jeffrey M.; Elmquist, Joel K.] Harvard Univ, Sch Med, Dept Pharmacol, Boston, MA 02115 USA. [Dhillon, Harveen; Lowell, Bradford B.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA. [Hill, Jennifer W.] Univ Toledo, Coll Med, Dept Physiol & Pharmacol, Ctr Diabet & Endocrine Res, Toledo, OH 43614 USA. RP Zhao, JJ (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM jean_zhao@dfci.harvard.edu; joel.elmquist@utsouthwestern.edu RI Fukuda, Makoto/C-9745-2009; Sohn, Jong Woo/D-6700-2014; Fukuda, Makoto/I-7915-2014 OI Fukuda, Makoto/0000-0003-0112-9925; Fukuda, Makoto/0000-0003-0112-9925 FU NIH [PL1 DK081182, UL1 RR024923, K99 DK085330, 1F320K066972, R01DK071051, RL1 DK081185, R37DK53301, R01DK071320, R01CA134502-01]; Canadian Institute of Health Research; UTSW Medical Center; V Foundation; ADA [1-07-RA-41]; ADA Smith Family Foundation FX We would like to thank the Mouse Metabolic Phenotyping Core at UTSW Medical Center (supported by NIH PL1 DK081182 and UL1 RR024923). This work was supported by grants from Canadian Institute of Health Research (Y.X.) and the NIH (K99 DK085330 to Y.X.; 1F320K066972 to J.W.H.; R01DK071051 to B.B.L.; RL1 DK081185, R37DK53301, and R01DK071320 to J.K.E.; and R01CA134502-01 to J.J.Z.); by UTSW Medical Center Disease-Oriented Clinical Scholars Program (J.M.Z.); by the V Foundation (J.J.Z.); by an ADA research grant (1-07-RA-41 to J.K.E. and L.G.); and by an ADA Smith Family Foundation Pinnacle Program Award to J.K.E. NR 42 TC 55 Z9 55 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JUL 7 PY 2010 VL 12 IS 1 BP 88 EP 95 DI 10.1016/j.cmet.2010.05.002 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 623PI UT WOS:000279753900012 PM 20620998 ER PT J AU Garber, JE Halabi, S Tolaney, SM Kaplan, E Archer, L Atkins, JN Edge, S Shapiro, CL Dressler, L Paskett, EM Kimmick, G Orcutt, J Scalzo, A Winer, E Levine, E Shahab, N Berliner, N AF Garber, Judy E. Halabi, Susan Tolaney, Sara M. Kaplan, Ellen Archer, Laura Atkins, James N. Edge, Stephen Shapiro, Charles L. Dressler, Lynn Paskett, Electra M. Kimmick, Gretchen Orcutt, James Scalzo, Anthony Winer, Eric Levine, Ellis Shahab, Nasir Berliner, Nancy CA Cancer Leukemia Grp B TI Factor V Leiden Mutation and Thromboembolism Risk in Women Receiving Adjuvant Tamoxifen for Breast Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ACTIVATED PROTEIN-C; BOWEL PROJECT P-1; VENOUS THROMBOSIS; PREVENTION TRIAL; RANDOMIZED-TRIALS; VEIN-THROMBOSIS; FOLLOW-UP; THERAPY; PROTHROMBIN; RESISTANCE AB Background Tamoxifen use has been associated with increased risk of thromboembolic events (TEs) in women with breast cancer and women at high risk for the disease. Factor V Leiden (FVL) is the most common inherited clotting factor mutation and also confers increased thrombosis risk. We investigated whether FVL was associated with TE risk in women with early-stage breast cancer who took adjuvant tamoxifen. Methods A case-control study was conducted among 34 Cancer and Leukemia Group B (CALGB) institutions. We matched each of 124 women who had experienced a documented TE while taking adjuvant tamoxifen for breast cancer (but who were not necessarily on a CALGB treatment trial) to two control subjects (women who took adjuvant tamoxifen but did not experience TE) by age at diagnosis (+/- 5 years). DNA from blood was analyzed for FVL mutations. Conditional logistic regression was used to estimate odds ratios (ORs) and to evaluate other potential factors associated with TE and tamoxifen use. All P values are based on two-sided tests. Results FVL mutations were identified in 23 (18.5%) case and 12 (4.8%) control subjects (OR = 4.66, 95% confidence interval = 2.14 to 10.14, P < .001). In the multivariable model, FVL mutation was associated with TE (OR = 4.73, 95% confidence interval = 2.10 to 10.68, P < .001). Other statistically significant factors associated with TE risk were personal history of TE and smoking. Conclusions Among women taking adjuvant tamoxifen for early-stage breast cancer, those who had a TE were nearly five times more likely to carry a FVL mutation than those who did not have a TE. Postmenopausal women should be evaluated for the FVL mutation before prescription of adjuvant tamoxifen if a positive test would alter therapeutic decision making. C1 [Garber, Judy E.; Tolaney, Sara M.; Winer, Eric] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Halabi, Susan] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. [Halabi, Susan; Kaplan, Ellen; Archer, Laura] Duke Univ, CALGB Stat Ctr, Durham, NC USA. [Atkins, James N.; Orcutt, James] SE Canc Control Consortium Inc, CCOP, Winston Salem, NC USA. [Edge, Stephen] Roswell Pk Canc Inst, Dept Surg, Buffalo, NY 14263 USA. [Levine, Ellis] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Shapiro, Charles L.] Ohio State Univ, James Canc Ctr, Div Med Oncol, Columbus, OH 43210 USA. [Paskett, Electra M.] Ohio State Univ, Coll Publ Hlth, Div Epidemiol, Columbus, OH 43210 USA. [Dressler, Lynn] Univ N Carolina, Inst Pharmacogen & Individualized Therapy, Eshelman Sch Pharm, Chapel Hill, NC USA. [Kimmick, Gretchen] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA. [Kimmick, Gretchen] Wake Forest Univ, Bowman Gray Sch Med, Dept Hematol & Oncol, Winston Salem, NC USA. [Scalzo, Anthony] SUNY Upstate Med Ctr, Syracuse, NY USA. [Shahab, Nasir] Univ Missouri, Div Med Oncol, Ellis Fischel Canc Ctr, Columbia, MO USA. [Berliner, Nancy] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Berliner, Nancy] Yale Univ, Sch Med, Div Hematol, New Haven, CT USA. RP Garber, JE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,Smith 209, Boston, MA 02115 USA. EM judy_garber@dfci.harvard.edu FU National Cancer Institute [CA31946, CA37447, CA33601]; Donaghue Foundation; Susan G. Komen for the Cure Foundation [9634]; Astra Zeneca; [CA45418]; [CA32291]; [CA47577]; [CA77597]; [CA45389]; [CA35113]; [CA12449]; [CA03927]; [CA04457]; [CA02599]; [CA45808]; [CA21060]; [CA77658]; [CA60138]; [CA41287]; [CA47642]; [CA12046]; [CA77406] FX The research for CALGB 9872 was supported, in part, by grants from the National Cancer Institute (CA31946 and CA37447) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman) and to the CALGB Statistical Center (Stephen George, PhD, CA33601) and from the Donaghue Foundation and Susan G. Komen for the Cure Foundation (9634) to N.B.; G. Kimmick reports associations with Astra Zeneca and Pfizer and support from Astra Zeneca.; The following institutions participated in this study: Christiana Care Health Services, Inc. CCOP, Wilmington, DE (Stephen Grubbs, MD, supported by CA45418); Dana-Farber Cancer Institute, Boston, MA (Eric P. Winer, MD, supported by CA32291); Duke University Medical Center, Durham, NC (Jeffrey Crawford, MD, supported by CA47577); Georgetown University Medical Center, Washington, DC (Minetta C. Liu, MD, supported by CA77597); Hematology-Oncology Associates of Central New York CCOP, Syracuse, NY (Jeffrey Kirshner, MD, supported by CA45389); Illinois Oncology Research Association, Peoria, IL (John W. Kugler, MD, supported by CA35113); Massachusetts General Hospital, Boston, MA (Jeffrey W. Clark, MD, supported by CA12449); Medical University of South Carolina, Charleston, SC (Mark Green, MD, supported by CA03927); Mount Sinai School of Medicine, New York, NY (Lewis R. Silverman, MD, supported by CA04457); Roswell Park Cancer Institute, Buffalo, NY (Ellis Levine, MD, supported by CA02599); Southeast Cancer Control Consortium, Inc. CCOP, Goldsboro, NC (James N. Atkins, MD, supported by CA45808); State University of New York Upstate Medical University, Syracuse, NY (Stephen L. Graziano, MD, supported by CA21060); The Ohio State University Medical Center, Columbus, OH (Clara D Bloomfield, MD, supported by CA77658); University of California at San Francisco, San Francisco, CA (Alan P. Venook, MD, supported by CA60138); University of Chicago, Chicago, IL (Gini Fleming, MD, supported by CA41287); University of Iowa, Iowa City, IA (Daniel A. Vaena, MD, supported by CA47642); University of Missouri/Ellis Fischel Cancer Center, Columbia, MO (Michael C Perry, MD, supported by CA12046); University of Vermont, Burlington, VT (Hyman B. Muss, MD, supported by CA77406); Wake Forest University School of Medicine, Winston-Salem, NC (David D Hurd, MD, supported by CA03927). NR 41 TC 24 Z9 24 U1 0 U2 7 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 JUL 7 PY 2010 VL 102 IS 13 BP 942 EP 949 DI 10.1093/jnci/djq211 PG 8 WC Oncology SC Oncology GA 625VU UT WOS:000279925600008 PM 20554945 ER PT J AU Dehghani, N Cash, SS Chen, CC Hagler, DJ Huang, MX Dale, AM Halgren, E AF Dehghani, Nima Cash, Sydney S. Chen, Chih C. Hagler, Donald J., Jr. Huang, Mingxiong Dale, Anders M. Halgren, Eric TI Divergent Cortical Generators of MEG and EEG during Human Sleep Spindles Suggested by Distributed Source Modeling SO PLOS ONE LA English DT Article ID SURFACE-BASED ANALYSIS; HIGH-RESOLUTION; BRAIN ACTIVITY; PREFRONTAL CORTEX; COORDINATE SYSTEM; OSCILLATIONS; MAGNETOENCEPHALOGRAPHY; LOCALIZATION; ELECTROENCEPHALOGRAM; RECONSTRUCTION AB Background: Sleep spindles are similar to 1-second bursts of 10-15 Hz activity, occurring during normal stage 2 sleep. In animals, sleep spindles can be synchronous across multiple cortical and thalamic locations, suggesting a distributed stable phase-locked generating system. The high synchrony of spindles across scalp EEG sites suggests that this may also be true in humans. However, prior MEG studies suggest multiple and varying generators. Methodology/Principal Findings: We recorded 306 channels of MEG simultaneously with 60 channels of EEG during naturally occurring spindles of stage 2 sleep in 7 healthy subjects. High-resolution structural MRI was obtained in each subject, to define the shells for a boundary element forward solution and to reconstruct the cortex providing the solution space for a noise-normalized minimum norm source estimation procedure. Integrated across the entire duration of all spindles, sources estimated from EEG and MEG are similar, diffuse and widespread, including all lobes from both hemispheres. However, the locations, phase and amplitude of sources simultaneously estimated from MEG versus EEG are highly distinct during the same spindles. Specifically, the sources estimated from EEG are highly synchronous across the cortex, whereas those from MEG rapidly shift in phase, hemisphere, and the location within the hemisphere. Conclusions/Significance: The heterogeneity of MEG sources implies that multiple generators are active during human sleep spindles. If the source modeling is correct, then EEG spindles are generated by a different, diffusely synchronous system. Animal studies have identified two thalamo-cortical systems, core and matrix, that produce focal or diffuse activation and thus could underlie MEG and EEG spindles, respectively. Alternatively, EEG spindles could reflect overlap at the sensors of the same sources as are seen from the MEG. Although our results generally match human intracranial recordings, additional improvements are possible and simultaneous intra-and extra-cranial measures are needed to test their accuracy. C1 [Dehghani, Nima; Hagler, Donald J., Jr.; Huang, Mingxiong; Dale, Anders M.; Halgren, Eric] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. [Dehghani, Nima; Cash, Sydney S.; Chen, Chih C.] Harvard Univ, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. [Dehghani, Nima] CNRS, UNIC, Lab Computat Neurosci, Gif Sur Yvette, France. [Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Chen, Chih C.] Natl Taiwan Univ Hosp, Dept Neurol, Taipei, Taiwan. [Dale, Anders M.; Halgren, Eric] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. RP Dehghani, N (reprint author), Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA. EM ehalgren@ucsd.edu OI Dehghani, Nima/0000-0003-2032-8903 FU National Institutes of Health (NIH) [EB009282, NS18741, NS44623] FX This work was supported by National Institutes of Health (NIH) grants EB009282, NS18741, and NS44623. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 19 Z9 20 U1 1 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 JUL 7 PY 2010 VL 5 IS 7 AR e11454 DI 10.1371/journal.pone.0011454 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 621OQ UT WOS:000279589300005 PM 20628643 ER PT J AU Mamtani, M Matsubara, T Shimizu, C Furukawa, S Akagi, T Onouchi, Y Hata, A Fujino, A He, WJ Ahuja, SK Burns, JC AF Mamtani, Manju Matsubara, Tomoyo Shimizu, Chisato Furukawa, Susumu Akagi, Teiji Onouchi, Yoshihiro Hata, Akira Fujino, Akihiro He, Weijing Ahuja, Sunil K. Burns, Jane C. TI Association of CCR2-CCR5 Haplotypes and CCL3L1 Copy Number with Kawasaki Disease, Coronary Artery Lesions, and IVIG Responses in Japanese Children SO PLOS ONE LA English DT Article ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; GAMMA-GLOBULIN THERAPY; INTRAVENOUS IMMUNOGLOBULIN TREATMENT; MACROPHAGE INFLAMMATORY PROTEIN-1; CONTAINING SEGMENTAL DUPLICATIONS; RECEPTOR GENE POLYMORPHISMS; RISK-FACTORS; AUTOIMMUNE-DISEASES; HUMAN GENOME; SUSCEPTIBILITY AB Background: The etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown. Methodology/Principal Findings: We used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., or. four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR) = 2.25, p = 0.004 and OR = 6.26, p = 0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR = 0.21, p = 0.026) and CAL development (OR = 0.44, p = 0.071). Conclusions/Significance: The CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG. C1 [Mamtani, Manju; He, Weijing; Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Mamtani, Manju; He, Weijing; Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Vet Adm Ctr AIDS & HIV Infect 1, San Antonio, TX 78229 USA. [Matsubara, Tomoyo] Juntendo Univ, Grad Sch Med, Dept Pediat, Chiba, Japan. [Shimizu, Chisato; Burns, Jane C.] Univ Calif San Diego, Sch Med, Rady Childrens Hosp, Dept Pediat, La Jolla, CA 92093 USA. [Furukawa, Susumu] Yamaguchi Univ, Grad Sch Med, Dept Pediat, Yamaguchi, Japan. [Akagi, Teiji] Okayama Univ Hosp, Pediat Cardiac Care Unit, Okayama, Japan. [Onouchi, Yoshihiro] RIKEN, Ctr Genom Med, Lab Cardiovasc Dis, Kanagawa, Japan. [Hata, Akira] Chiba Univ, Dept Publ Hlth, Grad Sch Med, Chiba, Japan. [Fujino, Akihiro] Natl Ctr Child Hlth & Dev, Dept Surg, Tokyo, Japan. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Microbiol & Immunol, San Antonio, TX 78229 USA. [Ahuja, Sunil K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. RP Mamtani, M (reprint author), Univ Texas Hlth Sci Ctr San Antonio, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. EM ahujas@uthscsa.edu RI Burns, Jane/J-6167-2015; Shimizu, Chisato/J-6516-2015 FU National Institutes of Health, National Heart, Lung, Blood Institute [HL074864, HL69413]; Max and Minnie Tomerlin Voelcker Fund; Burroughs Wellcome Clinical Scientist Award in Translational Research; Doris Duke Distinguished Clinical Scientist Award FX This work was supported in part by grants from the National Institutes of Health, National Heart, Lung, Blood Institute, HL074864 and HL69413 awarded to JCB. This work was also supported by the Voelcker Senior Scholar Award from The Max and Minnie Tomerlin Voelcker Fund awarded to SKA. SKA is also supported by a Burroughs Wellcome Clinical Scientist Award in Translational Research, and the Doris Duke Distinguished Clinical Scientist Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 59 TC 9 Z9 12 U1 1 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 JUL 7 PY 2010 VL 5 IS 7 AR e11458 DI 10.1371/journal.pone.0011458 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 621OQ UT WOS:000279589300006 PM 20628649 ER PT J AU Jena, AB Goldman, DP Kamdar, A Lakdawalla, DN Lu, Y AF Jena, Anupam B. Goldman, Dana P. Kamdar, Amee Lakdawalla, Darius N. Lu, Yang TI Sexually Transmitted Diseases Among Users of Erectile Dysfunction Drugs: Analysis of Claims Data SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID UNITED-STATES; SILDENAFIL USE; RISK BEHAVIORS; HIV-INFECTION; SAN-FRANCISCO; OLDER-PEOPLE; MEN; ATTITUDES; VIAGRA; ADULTS AB Background: Pharmacologic treatments for erectile dysfunction (ED) have gained popularity among middle-aged and older men. Increased sexual activity among those who use these drugs raises concerns about sexually transmitted diseases (STDs). Objective: To examine the rates of STDs in men who use and do not use ED drugs. Design: Retrospective cohort study. Setting: Database of claims from 1997 to 2006 for 1 410 806 men older than age 40 years with private, employer-based insurance from 44 large companies. Patients: 33 968 men with at least 1 filled prescription for an ED drug and 1 376 838 patients with no prescription. Measurements: STD prevalence among users and nonusers of ED drugs. Results: Users of ED drugs had higher rates of STDs than nonusers the year before initiating ED drug therapy (214 vs. 106 annually per 100 000 persons; P = 0.003) and the year after (105 vs. 65; P = 0.004). After adjustment for age and other comorbid conditions, users of ED drugs had an odds ratio (OR) for an STD of 2.80 (95% CI, 2.10 to 3.75) in the year before initiating drug therapy; the OR was 2.65 (CI, 1.84 to 3.81) in the year after. These differences were largely due to infections with HIV. The OR for HIV infection was 3.32 (CI, 2.38 to 4.36) in the year before and 3.19 (CI, 2.11 to 4.83) in the year after an ED drug prescription was filled. Significant changes in STD rates from the year before to the year after the first ED drug prescription was filled were not documented (adjusted OR for STD for users before vs. after the first ED drug prescription was filled, 0.96 [CI, 0.87 to 1.06]). Limitation: Selection bias precludes conclusions about whether use of ED treatments directly leads to increases in STDs. Conclusion: Men who use ED drugs have higher rates of STDs, particularly HIV infection, both in the year before and after use of these drugs. The observed association between ED drug use and STDs may have more to do with the types of patients using ED drugs rather than a direct effect of ED drug availability on STD rates. Counseling about safe sexual practices and screening for STDs should accompany the prescription of ED drugs. C1 Harvard Univ, Sch Med, Boston, MA USA. Univ So Calif, Los Angeles, CA USA. Univ Chicago, Booth Grad Sch Business, Chicago, IL 60637 USA. RAND Corp, Santa Monica, CA USA. RP Jena, AB (reprint author), Massachusetts Gen Hosp, Dept Med, Wang Ambulatory Care Ctr, 15 Parkman St, Boston, MA 02114 USA. EM jena.anupam@mgh.harvard.edu RI Lakdawalla, Darius/B-4409-2011; OI Lu, Yang/0000-0003-2905-7302; Lakdawalla, Darius/0000-0001-5934-8042 FU RAND Roybal Center; National Institutes of Health; Agency for Healthcare Research and Quality; Bing Center for Health Economics; RAND Roybal Center for Health Policy Simulation [P30AG024968]; National Institutes of Health [5 T32 GM07281]; Agency for Healthcare Research and Quality through a University of California, Los Angeles [T32 HS 000046]; National Institute for Child Health and Human Development [1R01HD054877] FX Primary Funding Source: RAND Roybal Center, National Institutes of Health, and Agency for Healthcare Research and Quality.; By the Bing Center for Health Economics and RAND Roybal Center for Health Policy Simulation (grant P30AG024968), a National Institutes of Health Medical Scientist National Research Award (grant 5 T32 GM07281 to Dr. Jena), the Agency for Healthcare Research and Quality through a University of California, Los Angeles/RAND Training Grant (grant T32 HS 000046 to Dr. Jena), and the National Institute for Child Health and Human Development (grant 1R01HD054877 to Dr. Jena). NR 30 TC 32 Z9 33 U1 0 U2 10 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 6 PY 2010 VL 153 IS 1 BP 1 EP + DI 10.7326/0003-4819-153-1-201007060-00003 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 620GS UT WOS:000279487700001 PM 20621899 ER PT J AU Baggish, AL AF Baggish, Aaron L. TI Should Electrocardiography Be Used in Cardiovascular Screening of High School Athletes? RESPONSE SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Baggish, AL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 6 PY 2010 VL 153 IS 1 BP 64 EP 65 DI 10.7326/0003-4819-153-1-201007060-00028 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 620GS UT WOS:000279487700025 ER PT J AU Mukherjee, R Rivers, WT Ruddy, JM Matthews, RG Koval, CN Plyler, RA Chang, EI Patel, RK Kern, CB Stroud, RE Spinale, FG AF Mukherjee, Rupak Rivers, William T. Ruddy, Jean Marie Matthews, Robert G. Koval, Christine N. Plyler, Rebecca A. Chang, Eileen I. Patel, Risha K. Kern, Christine B. Stroud, Robert E. Spinale, Francis G. TI Long-Term Localized High-Frequency Electric Stimulation Within the Myocardial Infarct Effects on Matrix Metalloproteinases and Regional Remodeling SO CIRCULATION LA English DT Article DE extracellular matrix; myocardial infarction; remodeling; matrix metalloproteinases ID INHIBITION; FIBROBLASTS; FAILURE; IDENTIFICATION; REPERFUSION; INDUCTION; ISCHEMIA; ABLATION; CULTURE; TISSUE AB Background-Disruption of the balance between matrix metalloproteinases (MMP) and MMP inhibitors (TIMPs) within a myocardial infarct (MI) contributes to left ventricular wall thinning and changes in regional stiffness at the MI region. This study tested the hypothesis that a targeted regional approach through localized high-frequency stimulation (LHFS) using low-amplitude electric pulses instituted within a formed MI scar would alter MMP/TIMP levels and prevent MI thinning. Methods and Results-At 3 weeks after MI, pigs were randomized for LHFS (n=7; 240 bpm, 0.8 V, 0.05-ms pulses) or were left unstimulated (UNSTIM; n=10). At 4 weeks after MI, left ventricular wall thickness (echocardiography; 0.89 +/- 0.07 versus 0.67 +/- 0.08 cm; P<0.05) and regional stiffness (piezoelectric crystals; 14.70 +/- 2.08 versus 9.11 +/- 1.24; P<0.05) were higher with LHFS than in UNSTIM. In vivo interstitial MMP activity (fluorescent substrate cleavage; 943 +/- 59 versus 1210 +/- 72 U; P<0.05) in the MI region was lower with LHFS than in UNSTIM. In the MI region, MMP-2 levels were lower and TIMP-1 and collagen levels were higher with LHFS than in UNSTIM (all P<0.05). Transforming growth factor-beta receptor 1 and phosphorylated SMAD-2/3 levels within the MI region were higher with LHFS than in UNSTIM. Electric stimulation (4 Hz) of isolated fibroblasts resulted in reduced MMP-2 and MT1-MMP levels but increased TIMP-1 levels compared with unstimulated fibroblasts. Conclusions-These unique findings demonstrate that LHFS of the MI region altered left ventricular wall thickness and material properties, likely as a result of reduced regional MMP activity. Thus, LHFS may provide a novel means to favorably modify left ventricular remodeling after MI. (Circulation. 2010;122:20-32.) C1 [Mukherjee, Rupak; Rivers, William T.; Ruddy, Jean Marie; Matthews, Robert G.; Koval, Christine N.; Plyler, Rebecca A.; Chang, Eileen I.; Patel, Risha K.; Stroud, Robert E.; Spinale, Francis G.] Med Univ S Carolina, Div Cardiothorac Surg, Charleston, SC 29425 USA. [Kern, Christine B.] Med Univ S Carolina, Dept Regenerat Med & Cell Biol, Charleston, SC 29425 USA. [Spinale, Francis G.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Mukherjee, R (reprint author), Med Univ S Carolina, Div Cardiothorac Surg, Strom Thurmond Res Bldg,770 MUSC Complex,Suite 62, Charleston, SC 29425 USA. EM mukherr@musc.edu OI Chang, Eileen/0000-0002-3444-7260 FU National Heart, Lung, and Blood Institute [HL-45024, HL-97012, PO1-48788]; Veterans Administration Merit Award FX This study was supported in part by National Heart, Lung, and Blood Institute grants HL-45024, HL-97012, and PO1-48788 and a Veterans Administration Merit Award (Dr Spinale). NR 36 TC 7 Z9 7 U1 1 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 JUL 6 PY 2010 VL 122 IS 1 BP 20 EP U64 DI 10.1161/CIRCULATIONAHA.110.936872 PG 18 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 621FL UT WOS:000279560800005 PM 20566951 ER PT J AU Buck, AW Fowler, VG Yongsunthon, R Liu, J DiBartola, AC Que, YA Moreillon, P Lower, SK AF Buck, Andrew W. Fowler, Vance G., Jr. Yongsunthon, Ruchirej Liu, Jie DiBartola, Alex C. Que, Yok-Ai Moreillon, Philippe Lower, Steven K. TI Bonds between Fibronectin and Fibronectin-Binding Proteins on Staphylococcus aureus and Lactococcus lactis SO LANGMUIR LA English DT Article ID ATOMIC-FORCE MICROSCOPY; SHEWANELLA-ONEIDENSIS MR-1; SURFACE PROTEIN; NUCLEOTIDE-SEQUENCE; LIVING BACTERIUM; CLUMPING FACTOR; SINGLE PROTEIN; LIVE DIATOM; INFECTIONS; EXPRESSION AB Bacterial cell-wall-associated fibronectin binding proteins A and B (FnBPA and FnBPA) form bonds with host fibronectin. This binding reaction is often the initial step in prosthetic device infections. Atomic force microscopy was used to evaluate binding interactions between a fibronectin-coated probe and laboratory-derived Staphylococcus mucus that are (i) defective in both FnBPA and FnBPB (fnbA fnbB double mutant, DU5883), (ii) capable of expressing only FnBPA (fnbA double mutant complemented with pFNBA4), or (iii) capable of expressing only FnBPB (fnbA fnbB double mutant complemented with pFNBB4). These experiments were repeated using Lactococcus lactis constructs expressing fnbA and fnbB genes from S. aureus. A distinct force signature was observed for those bacteria that expressed FnBPA or FnBPB. Analysis of this force signature with the biomechanical wormlike chain model suggests that parallel bonds form between fibronectin and FnBPs on a bacterium. The strength and covalence of bonds were evaluated via nonlinear regression of force profiles. Binding events were more frequent (p < 0.01) for S. mucus. expressing FnBPA or FnBPB than for the S. mucus double mutant. The binding force, frequency, and profile were similar between the FnBPA and FnBPB expressing strains of S. aureus. The absence of both FnBPs from the surface of S. amens removed its ability to form a detectable bond with fibronectin. By contrast, ectopic expression of FnBPA or FnBPB on the surface of L. lactis conferred fibronectin binding characteristics similar to those of S. amens. These measurements demonstrate that fibronectin-binding adhesins FnBPA and FnBPB are necessary and sufficient for the binding of S. aureus to prosthetic devices that are coated with host fibronectin. C1 [Lower, Steven K.] Ohio State Univ, Mendenhall Lab 275, Columbus, OH 43210 USA. [Buck, Andrew W.; Fowler, Vance G., Jr.] Duke Univ, Med Ctr, Durham, NC USA. [Fowler, Vance G., Jr.] Duke Clin Res Inst, Durham, NC USA. [Que, Yok-Ai] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Moreillon, Philippe] Univ Lausanne, Lausanne, Switzerland. RP Lower, SK (reprint author), Ohio State Univ, Mendenhall Lab 275, 125 S Oval Mall, Columbus, OH 43210 USA. EM Lower.9@osu.edu RI Lower, Steven/A-2440-2008 OI Lower, Steven/0000-0001-9796-0830 FU National Institutes of Health (NHLBI) [HL086593]; National Science Foundation [0745808]; Swiss National Foundation [PASMP3-123226]; Foederatio Medicorum Helveticae; SICPA foundation FX Timothy Foster kindly supplied the S. aureus strains used in these experiments. We thank the anonymous reviewers for their constructive comments. This work was supported by Grant HL086593 from the National Institutes of Health (NHLBI) and Grant 0745808 from the National Science Foundation. Y.-A.Q was supported by fellowships from the Swiss National Foundation (PASMP3-123226), the Foederatio Medicorum Helveticae, and the SICPA foundation. S.K.L. acknowledges the contributions of J. Tak. NR 68 TC 17 Z9 17 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD JUL 6 PY 2010 VL 26 IS 13 BP 10764 EP 10770 DI 10.1021/la100549u PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 616VX UT WOS:000279239900051 PM 20218549 ER PT J AU Volakakis, N Kadkhodaei, B Joodmardi, E Wallis, K Panman, L Silvaggi, J Spiegelman, BM Perlmann, T AF Volakakis, Nikolaos Kadkhodaei, Banafsheh Joodmardi, Eliza Wallis, Karin Panman, Lia Silvaggi, Jessica Spiegelman, Bruce M. Perlmann, Thomas TI NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE excitotoxicity; kainic acid; oxidative stress ID ELEMENT-BINDING PROTEIN; NEURONAL CELL-DEATH; TRANSCRIPTION FACTORS; HIPPOCAMPAL-NEURONS; SIGNALING PATHWAY; MOUSE-BRAIN; RAT-BRAIN; IN-VITRO; EXPRESSION; ISCHEMIA AB Induced expression of neuroprotective genes is essential for maintaining neuronal integrity after stressful insults to the brain. Here we show that NR4A nuclear orphan receptors are induced after excitotoxic and oxidative stress in neurons, up-regulate neuroprotective genes, and increase neuronal survival. Moreover, we show that NR4A proteins are induced by cAMP response element binding protein (CREB) in neurons exposed to stressful insults and that they function as mediators of CREB-induced neuronal survival. Animals with null mutations in three of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes, and increased vulnerability in the hippocampus after treatment with kainic acid. We also demonstrate that NR4A and the transcriptional coactivator PGC-1 alpha independently regulate distinct CREB-dependent neuroprotective gene programs. These data identify NR4A nuclear orphan receptors as essential mediators of neuroprotection after exposure to neuropathological stress. C1 [Silvaggi, Jessica; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Cell Biol, Boston, MA 02115 USA. [Volakakis, Nikolaos; Kadkhodaei, Banafsheh; Joodmardi, Eliza; Panman, Lia; Perlmann, Thomas] Ludwig Inst Canc Res, S-17177 Stockholm, Sweden. [Volakakis, Nikolaos; Kadkhodaei, Banafsheh; Wallis, Karin; Perlmann, Thomas] Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden. RP Spiegelman, BM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Cell Biol, 44 Binney St, Boston, MA 02115 USA. EM bruce_spiegelman@dfci.harvard.edu; thomas.perlmann@licr.ki.se FU Alexander S. Onassis Public Benefit Foundation; Swedish Research Council; Knut and Alice Wallenberg Foundation; Swedish Agency for Innovation Systems (VINNOVA); National Institutes of Health; National Heart, Lung, and Blood Institute [R01 HL085593] FX We thank the Bjorn Vennstrom laboratory at Karolinska Institute (Stockholm, Sweden) for providing resources. N.V. was supported by a scholarship from the Alexander S. Onassis Public Benefit Foundation. This work was supported by the Swedish Research Council via the Linnaeus Center in Developmental Biology for Regenerative Medicine (T.P.), the Knut and Alice Wallenberg Foundation (T.P.), the Swedish Agency for Innovation Systems (VINNOVA) (T.P.), and a grant from the National Institutes of Health (to B.M.S.) (National Heart, Lung, and Blood Institute Grant R01 HL085593). NR 39 TC 54 Z9 56 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 6 PY 2010 VL 107 IS 27 BP 12317 EP 12322 DI 10.1073/pnas.1007088107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 621JI UT WOS:000279572100050 PM 20566846 ER PT J AU Merkenschlager, M von Boehmer, H AF Merkenschlager, Matthias von Boehmer, Harald TI PI3 kinase signalling blocks Foxp3 expression by sequestering Foxo factors SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Review ID REGULATORY T-CELLS; TRANSCRIPTION FACTOR FOXP3; RETINOIC-ACID; DNA METHYLATION; GENE-EXPRESSION; REG-CELLS; IN-VIVO; DIFFERENTIATION; RECEPTOR; MTOR AB Expression of the regulatory T (T reg) cell-associated transcription factor Foxp3 can be induced by signals from the T cell receptor (TCR), interleukin-2 (IL-2), and transforming growth factor (TGF)-beta. These signals are integrated by a network involving phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB; here referred to as Akt), and the mammalian target of rapamycin (mTOR). New studies show that the Foxo proteins Foxo1 and Foxo3a, which are inactivated by Akt, drive Foxp3 expression. These studies therefore explain the negative regulation of Foxp3 by PI3K signaling, and add Foxo proteins to the growing list of nuclear factors capable of modulating Foxp3 expression. C1 [Merkenschlager, Matthias] Univ London Imperial Coll Sci Technol & Med, Lymphocyte Dev Grp, MRC, Ctr Clin Sci, London W12 0NN, England. [von Boehmer, Harald] Dana Farber Canc Inst, Lab Lymphocyte Biol, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Merkenschlager, M (reprint author), Univ London Imperial Coll Sci Technol & Med, Lymphocyte Dev Grp, MRC, Ctr Clin Sci, London W12 0NN, England. EM matthias.merkenschlager@csc.mrc.ac.uk; Harald_von_Boehmer@dfci.harvard.edu OI Merkenschlager, Matthias/0000-0003-2889-3288 FU Medical Research Council, UK; National Institutes of Health [R37 AI 53102] FX Related work in the authors' laboratories is supported by the Medical Research Council, UK (M. Merkenschlager) and National Institutes of Health grant R37 AI 53102 (H. von Boehmer). NR 45 TC 78 Z9 79 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 5 PY 2010 VL 207 IS 7 BP 1347 EP 1350 DI 10.1084/jem.20101156 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 619XX UT WOS:000279464700001 PM 20603315 ER PT J AU Zha, S Bassing, CH Sanda, T Brush, JW Patel, H Goff, PH Murphy, MM Tepsuporn, S Gatti, RA Look, AT Alt, FW AF Zha, Shan Bassing, Craig H. Sanda, Takaomi Brush, James W. Patel, Harin Goff, Peter H. Murphy, Michael M. Tepsuporn, Suprawee Gatti, Richard A. Look, A. Thomas Alt, Frederick W. TI ATM-deficient thymic lymphoma is associated with aberrant tcrd rearrangement and gene amplification SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; T-CELL LEUKEMIA; ATAXIA-TELANGIECTASIA; V(D)J RECOMBINATION; CHROMOSOME BREAKS; ALPHA/DELTA LOCUS; ALPHA-BETA; DNA BREAKS; B-CELLS; TRANSLOCATIONS AB Ataxia telangiectasia mutated (ATM) deficiency predisposes humans and mice to T lineage lymphomas with recurrent chromosome 14 translocations involving the T cell receptor alpha/delta (Tcra/d) locus. Such translocations have been thought to result from aberrant repair of DNA double-strand breaks (DSBs) during Tcra locus V(D)J recombination, and to require the Tcra enhancer (E.) for Tcra rearrangement or expression of the translocated oncogene. We now show that, in addition to the known chromosome 14 translocation, ATM-deficient mouse thymic lymphomas routinely contain a centromeric fragment of chromosome 14 that spans up to the 5' boundary of the Tcra/d locus, at which position a 500-kb or larger region centromeric to Tcra/d is routinely amplified. In addition, they routinely contain a large deletion of the telomeric end of one copy of chromosome 12. In contrast to prior expectations, the recurrent translocations and amplifications involve VD)J recombination-initiated breaks in the Tcrd locus, as opposed to the Tcra locus, and arise independently of the E alpha. Overall, our studies reveal previously unexpected mechanisms that contribute to the oncogenic transformation of ATM-deficient T lineage cells. C1 [Zha, Shan; Bassing, Craig H.; Brush, James W.; Patel, Harin; Goff, Peter H.; Murphy, Michael M.; Tepsuporn, Suprawee; Alt, Frederick W.] Childrens Hosp, Howard Hughes Med Inst, Immune Dis Inst, Boston, MA 02115 USA. [Sanda, Takaomi; Look, A. Thomas] Harvard Univ, Sch Med, Dana Faber Canc Inst, Boston, MA 02115 USA. [Gatti, Richard A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol, Los Angeles, CA 90095 USA. [Gatti, Richard A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Lab Med, Los Angeles, CA 90095 USA. RP Alt, FW (reprint author), Childrens Hosp, Howard Hughes Med Inst, Immune Dis Inst, Boston, MA 02115 USA. EM sz2296@columbia.edu; alt@enders.tch.harvard.edu FU Leukemia and Lymphoma Society of American SCOR [7391-07]; National Institutes of Health [RO1 AI020047, CA109901, R01 CA125195] FX This work was supported by Leukemia and Lymphoma Society of American SCOR grant 7391-07 and National Institutes of Health RO1 AI020047 to F. W. Alt, National Institutes of Health CA109901 to F. W. Alt and A. T. Look, and National Institutes of Health R01 CA125195 to C.H. Bassing. F.W. Alt is an investigator of the Howard Hughes Medical Institute and S. Zha was a fellow and is now a special fellow of the Leukemia and Lymphomas Society of America. NR 46 TC 43 Z9 43 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 5 PY 2010 VL 207 IS 7 BP 1369 EP 1380 DI 10.1084/jem.20100285 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 619XX UT WOS:000279464700004 PM 20566716 ER PT J AU Harada, Y Harada, Y Elly, C Ying, G Paik, JH DePinho, RA Liu, YC AF Harada, Yohsuke Harada, Yasuyo Elly, Chris Ying, Ge Paik, Ji-Hye DePinho, Ronald A. Liu, Yun-Cai TI Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ANERGY INDUCTION; ACTIVATION; MTOR; AKT; PROTEOLYSIS; DEFICIENCY; MECHANISMS; SURVIVAL; RECEPTOR; NFAT AB The transcription factor Foxp3 is essential for optimal regulatory T (T reg) cell development and function. Here, we show that CD4(+) T cells from Cbl-b RING finger mutant knockin or Cbl-b-deficient mice show impaired TGF-beta-induced Foxp3 expression. These T cells display augmented Foxo3a phosphorylation, but normal TGF-beta signaling. Expression of Foxo3a rescues Foxp3 expression in Cbl-b-deficient T cells, and Foxo3a deficiency results in defective TGF-beta-driven Foxp3 induction. A Foxo3a-binding motif is present in a proximal region of the Foxp3 promoter, and is required for Foxo3a association. Foxo1 exerts similar effects as Foxo3a on Foxp3 expression. This study reveals that Foxo factors promote transcription of the Foxp3 gene in induced T reg cells, and thus provides new mechanistic insight into Foxo-mediated T cell regulation. C1 [Harada, Yohsuke; Harada, Yasuyo; Elly, Chris; Ying, Ge; Liu, Yun-Cai] La Jolla Inst Allergy & Immunol, Div Cell Biol, La Jolla, CA 92037 USA. [Paik, Ji-Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Liu, YC (reprint author), La Jolla Inst Allergy & Immunol, Div Cell Biol, La Jolla, CA 92037 USA. EM yuncail@liai.org FU National Institutes of Health FX This work is supported by grants from National Institutes of Health to Y-C. Liu. NR 40 TC 136 Z9 143 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 JUL 5 PY 2010 VL 207 IS 7 BP 1381 EP 1391 DI 10.1084/jem.20100004 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 619XX UT WOS:000279464700005 PM 20439537 ER PT J AU Walter, JE Rucci, F Patrizi, L Recher, M Regenass, S Paganini, T Keszei, M Pessach, I Lang, PA Poliani, PL Giliani, S Al-Herz, W Cowan, MJ Puck, JM Bleesing, J Niehues, T Schuetz, C Malech, H DeRavin, SS Facchetti, F Gennery, AR Andersson, E Kamani, NR Sekiguchi, J Alenezi, HM Chinen, J Dbaibo, G ElGhazali, G Fontana, A Pasic, S Detre, C Terhorst, C Alt, FW Notarangelo, LD AF Walter, Jolan E. Rucci, Francesca Patrizi, Laura Recher, Mike Regenass, Stephan Paganini, Tiziana Keszei, Marton Pessach, Itai Lang, Philipp A. Poliani, Pietro Luigi Giliani, Silvia Al-Herz, Waleed Cowan, Morton J. Puck, Jennifer M. Bleesing, Jack Niehues, Tim Schuetz, Catharina Malech, Harry DeRavin, Suk See Facchetti, Fabio Gennery, Andrew R. Andersson, Emma Kamani, Naynesh R. Sekiguchi, JoAnn Alenezi, Hamid M. Chinen, Javier Dbaibo, Ghassan ElGhazali, Gehad Fontana, Adriano Pasic, Srdjan Detre, Cynthia Terhorst, Cox Alt, Frederick W. Notarangelo, Luigi D. TI Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CLASS-SWITCH RECOMBINATION; OMENN-SYNDROME; V(D)J RECOMBINATION; BONE-MARROW; T-CELLS; HOMEOSTATIC PROLIFERATION; LYMPHOCYTE DEVELOPMENT; POSITIVE SELECTION; ESCAPE TOLERANCE; MURINE MODEL AB The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro-B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP-keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4(+) T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell-activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations. C1 [Walter, Jolan E.; Rucci, Francesca; Patrizi, Laura; Recher, Mike; Pessach, Itai; Andersson, Emma; Notarangelo, Luigi D.] Harvard Univ, Childrens Hosp, Div Immunol, Sch Med, Boston, MA 02115 USA. [Walter, Jolan E.; Rucci, Francesca; Patrizi, Laura; Recher, Mike; Pessach, Itai; Andersson, Emma; Notarangelo, Luigi D.] Harvard Univ, Childrens Hosp, Manton Ctr Orphan Dis Res, Sch Med, Boston, MA 02115 USA. [Keszei, Marton; Detre, Cynthia; Terhorst, Cox] Harvard Univ, Sch Med, Div Immunol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Regenass, Stephan; Fontana, Adriano] Univ Zurich Hosp, Div Clin Immunol, CH-8091 Zurich, Switzerland. [Paganini, Tiziana; Giliani, Silvia] Univ Brescia, Pediat Clin, Nocivelli Inst Mol Med, I-25123 Brescia, Italy. [Poliani, Pietro Luigi; Facchetti, Fabio] Univ Brescia, Dept Pathol, I-25123 Brescia, Italy. [Lang, Philipp A.] Univ Toronto, Dept Immunol, Ontario Canc Inst, Campbell Inst Breast Canc Res, Toronto, ON M5G 2M9, Canada. [Al-Herz, Waleed; Alenezi, Hamid M.] Al Sabah Hosp, Dept Pediat, Allergy & Clin Immunol Unit, Kuwait 70459, Kuwait. [Cowan, Morton J.; Puck, Jennifer M.] Univ Calif San Francisco, Dept Pediat, Sch Med, San Francisco, CA 94143 USA. [Cowan, Morton J.; Puck, Jennifer M.] UCSF Childrens Hosp, San Francisco, CA 94143 USA. [Bleesing, Jack] Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. [Niehues, Tim] Univ Dusseldorf, Helios Klinikum Krefeld Acad Hosp, Ctr Child Hlth & Adolescence, D-02151 Dusseldorf, Germany. [Schuetz, Catharina] Univ Hosp Ulm, Dept Pediat & Adolescent Med, D-89070 Ulm, Germany. [Malech, Harry; DeRavin, Suk See] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Gennery, Andrew R.] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Kamani, Naynesh R.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. [Sekiguchi, JoAnn] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Chinen, Javier] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Sect Allergy & Immunol, Houston, TX 77030 USA. [Dbaibo, Ghassan] Amer Univ Beirut, Dept Pediat & Adolescent Med, Beirut 11072020, Lebanon. [ElGhazali, Gehad] King Fahad Med City, Fac Med, Dept Immunol, Riyadh 11525, Saudi Arabia. [Pasic, Srdjan] Mother & Child Hlth Inst Serbia, Dept Pediat Immunol, Belgrade 11070, Serbia. RP Notarangelo, LD (reprint author), Harvard Univ, Childrens Hosp, Div Immunol, Sch Med, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu; luigi.notarangelo@childrens.harvard.edu RI Facchetti, Fabio/E-7190-2010; Poliani, Pietro Luigi/E-8145-2010; Keszei, Marton/F-3295-2014; Notarangelo, Luigi/F-9718-2016; OI Facchetti, Fabio/0000-0003-4975-2388; Poliani, Pietro Luigi/0000-0002-5662-8978; Keszei, Marton/0000-0002-1158-2179; Notarangelo, Luigi/0000-0002-8335-0262; Sekiguchi, JoAnn/0000-0002-7178-4258; Malech, Harry/0000-0001-5874-5775 FU National Institutes of Health [P01 AI076210-01A1, U54AI082973-01, AI063058]; American Academy of Allergy, Asthma and Immunology, American Thoracic Society; GlaxoSmithKline; Manton Foundation; Dubai Harvard Foundation for Medical Research; Jeffrey Model Diagnostic Center for Primary Immunodeficiencies at Children's Hospital Boston, Fondazione CARIPLO; University of California; San Francisco Jeffrey Model Diagnostic Center for Primary Immunodeficiencies; Swiss National Science Foundation (SNF/SSMBS) [PASMP3-127678/1] FX This work was partially contributed to by the National Institutes of Health Grants P01 AI076210-01A1 (to L.D. Notarangelo, F.W. Alt, and C. Terhorst), U54AI082973-01 (to M.J. Cowan, J.M. Puck, and L.D. Notarangelo) and AI063058 (to J. Sekiguchi), the 2008 Fellows Career Development Award by the American Academy of Allergy, Asthma and Immunology, American Thoracic Society and GlaxoSmithKline (to J.E. Walter), the Manton Foundation, the Dubai Harvard Foundation for Medical Research, the Jeffrey Model Diagnostic Center for Primary Immunodeficiencies at Children's Hospital Boston, Fondazione CARIPLO (to P.L. Poliani), and the University of California, San Francisco Jeffrey Model Diagnostic Center for Primary Immunodeficiencies. M. Recher was supported by grant PASMP3-127678/1 from the Swiss National Science Foundation (SNF/SSMBS). NR 77 TC 42 Z9 43 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 5 PY 2010 VL 207 IS 7 BP 1541 EP 1554 DI 10.1084/jem.20091927 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 619XX UT WOS:000279464700017 PM 20547827 ER PT J AU Kim, KH Burns, JA Bernstein, JJ Maguluri, GN Park, BH de Boer, JF AF Kim, Ki Hean Burns, James A. Bernstein, Jonathan J. Maguluri, Gopi N. Park, B. Hyle de Boer, Johannes F. TI In vivo 3D human vocal fold imaging with polarization sensitive optical coherence tomography and a MEMS scanning catheter SO OPTICS EXPRESS LA English DT Article ID NERVE-FIBER LAYER; BIREFRINGENCE; COLLAGEN AB We present in-vivo 3D human vocal fold images with polarization sensitive optical coherence tomography (PS-OCT). Characterizing the extent and location of vocal fold lesions provides useful information in guiding surgeons during phonomicrosurgery. Previous studies showed that PS-OCT imaging can distinguish vocal fold lesions from normal tissue, but these studies were limited to 2D cross-sectional imaging and were susceptible to sampling error. In-vivo 3D endoscopic imaging was performed by using a recently developed 2-axis MEMS scanning catheter and a spectral domain OCT (SD-OCT), running at 18.5 frames/s. Imaging was performed in the operating room with patients under general anesthesia and 3D images were acquired either by 2D scanning of the scanner on the sites of interest or by combining 1D scanning and manual sliding to capture whole length of the vocal fold. Vocal fold scar, polyps, nodules, papilloma and malignant lesions were imaged and characteristics of individual lesions were analyzed in terms of spatial distribution and variation of tissue structure and birefringence. The 3D large sectional PS-OCT imaging showed that the spatial extent of vocal fold lesions can be found non-invasively with good contrast from normal tissue. (C) 2010 Optical Society of America C1 [Kim, Ki Hean] Pohang Univ Sci & Technol, Dept Mech Engn & Integrat Biosci & Biotechnol, Pohang 790784, Gyeongbuk, South Korea. [Burns, James A.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Bernstein, Jonathan J.] Charles Stark Draper Lab, Cambridge, MA 02139 USA. [Maguluri, Gopi N.; de Boer, Johannes F.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Park, B. Hyle] Univ Calif Riverside, Dept Bioengn, Riverside, CA 92521 USA. [de Boer, Johannes F.] Vrije Univ Amsterdam, Dept Phys & Astron, Inst Lasers Life & Biophoton Amsterdam, NL-1081 HV Amsterdam, Netherlands. RP Kim, KH (reprint author), Pohang Univ Sci & Technol, Dept Mech Engn & Integrat Biosci & Biotechnol, San 31 Hyoja Dong, Pohang 790784, Gyeongbuk, South Korea. EM jfdeboer@few.vu.nl RI de Boer, Johannes/B-7590-2012 OI de Boer, Johannes/0000-0003-1253-4950 FU POSTECH Basic Science Research Institute; Korean Science Foundation [4.0004598, 4.0004533]; National Institute of Health [R01 RR19768]; Dutch Science Foundation [FOM 09NIG03]; Department of the US Army [W81XWH-07-2-0011] FX This research was supported in part by the POSTECH Basic Science Research Institute Grant, the Korean Science Foundation Grant (4.0004598), the World Class University Program of Korean Science Foundation (4.0004533), the National Institute of Health (R01 RR19768), the Dutch Science Foundation (FOM 09NIG03), and by the Department of the US Army(W81XWH-07-2-0011). The content of the information does not necessarily reflect the position or the policy of the US Government, and no official endorsement should be inferred. NR 22 TC 19 Z9 20 U1 2 U2 15 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JUL 5 PY 2010 VL 18 IS 14 BP 14644 EP 14653 DI 10.1364/OE.18.014644 PG 10 WC Optics SC Optics GA 622DN UT WOS:000279639900036 PM 20639950 ER PT J AU Volberding, PA Deeks, SG AF Volberding, Paul A. Deeks, Steven G. TI Antiretroviral therapy and management of HIV infection SO LANCET LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; RANDOMIZED CONTROLLED-TRIAL; AIDS-DEFINING MALIGNANCIES; SOCIETY-USA PANEL; TERM-FOLLOW-UP; DRUG-RESISTANCE; VIRAL LOAD; IMMUNE ACTIVATION; HIV-1-INFECTED PATIENTS AB Antiretroviral therapy of HIV infection has changed a uniformly fatal into a potentially chronic disease. There are now 17 drugs in common use for HIV treatment. Patients who can access and adhere to combination therapy should be able to achieve durable, potentially lifelong suppression of HIV replication. Despite the unquestioned success of antiretroviral therapy, limitations persist. Treatment success needs strict lifelong drug adherence. Although the widely used drugs are generally well tolerated, most have some short-term toxic effects and all have the potential for both known and unknown long-term toxic effects. Drug and administration costs limit treatment in resource-poor regions, and are a growing concern even in resource rich settings. Finally, complete or near complete control of viral replication does not fully restore health. Long-term treated patients who are on an otherwise effective regimen often show persistent immune dysfunction and have higher than expected risk for various non-AIDS-related complications, including heart, bone, liver, kidney, and neurocognitive diseases. C1 [Volberding, Paul A.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Med, San Francisco, CA 94121 USA. RP Volberding, PA (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Med, 4150 Clement St, San Francisco, CA 94121 USA. EM paul.volberding@va.gov FU UCSF-Gladstone Institute of Virology and Immunology Centers for AIDS Research [PO AI027763]; NIH [AI087145, AI069994] FX This work was supported in part by the UCSF-Gladstone Institute of Virology and Immunology Centers for AIDS Research (PO AI027763) (PAV, SGD). Additional support was provided by the NIH (AI087145, AI069994) (SGD). We thank Warner Greene for permission to use figure 1, John C W Carroll for assistance with graphic design, and Pam Derish for copy editing assistance. NR 146 TC 173 Z9 174 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUL 3 PY 2010 VL 376 IS 9734 BP 49 EP 62 DI 10.1016/S0140-6736(10)60676-9 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 624SR UT WOS:000279841600024 PM 20609987 ER PT J AU Wang, YY Hai, T Liu, ZC Zhou, SY Lv, Z Ding, CH Liu, L Niu, YY Zhao, XY Tong, M Wang, L Jouneau, A Zhang, X Ji, WZ Zhou, Q AF Wang, Yingying Hai, Tang Liu, Zichuan Zhou, Shuya Lv, Zhuo Ding, Chenhui Liu, Lei Niu, Yuyu Zhao, Xiaoyang Tong, Man Wang, Liu Jouneau, Alice Zhang, Xun Ji, Weizhi Zhou, Qi TI HSPC117 deficiency in cloned embryos causes placental abnormality and fetal death SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Nuclear transfer; Mouse embryo; HSPC117; Placenta; Implantation ID ADULT SOMATIC-CELLS; NUCLEAR TRANSFER; MOUSE CLONES; ES CELLS; CLONING; BLASTOCYSTS; GENERATION; OCT4 AB Somatic cell nuclear transfer (SCNT) has been successfully used in many species to produce live cloned offspring, albeit with low efficiency. The low frequency of successful development has usually been ascribed to incomplete or inappropriate reprogramming of the transferred nuclear genome. Elucidating the genetic differences between normal fertilized and cloned embryos is key to understand the low efficiency of SCNT. Here, we show that expression of HSPC117, which encodes a hypothetical protein of unknown function, was absent or very low in cloned mouse blastocysts. To investigate the role of HSPC117 in embryo development, we knocked-down this gene in normal fertilized embryos using RNA interference. We assessed the post-implantation survival of HSPC117 knock-down embryos at 3 stages: E9 (prior to placenta formation); E12 (after the placenta was fully functional) and E19 (post-natal). Our results show that, although siRNA-treated in vivo fertilized/produced (IVP) embryos could develop to the blastocyst stage and implanted without any difference from control embryos, the knock-down embryos showed substantial fetal death, accompanied by placental blood clotting, at E12. Furthermore, comparison of HSPC117 expression in placentas of nuclear transfer (NT), intracytoplasmic sperm injection (ICSI) and IVP embryos confirmed that HSPC117 deficiency correlates well with failures in embryo development: all NT embryos with a fetus, as well as IVP and ICSI embryos, had normal placental HSPC117 expression while those NT embryos showing reduced or no expression of HSPC117 failed to form a fetus. In conclusion, we show that HSPC117 is an important gene for post-implantation development of embryos, and that HSPC117 deficiency leads to fetal abnormalities after implantation, especially following placental formation. We suggest that defects in HSPC117 expression may be an important contributing factor to loss of cloned NT embryos in vivo. (C) 2010 Elsevier Inc. All rights reserved. C1 [Wang, Yingying; Niu, Yuyu; Ji, Weizhi] Chinese Acad Sci, Dept Reprod & Dev, Kunming Inst Zool, Kunming 650223, Peoples R China. [Wang, Yingying; Niu, Yuyu; Ji, Weizhi] Chinese Acad Sci, Kunming Primate Res Ctr, Kunming 650223, Peoples R China. [Wang, Yingying; Hai, Tang; Liu, Zichuan; Zhou, Shuya; Lv, Zhuo; Ding, Chenhui; Liu, Lei; Zhao, Xiaoyang; Tong, Man; Wang, Liu; Zhou, Qi] Chinese Acad Sci, State Key Lab Reprod Biol, Inst Zool, Beijing 100080, Peoples R China. [Wang, Yingying; Hai, Tang; Liu, Zichuan; Zhou, Shuya; Lv, Zhuo; Zhao, Xiaoyang; Tong, Man] Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China. [Jouneau, Alice] INRA, UMR 1198, ENVA, CNRS,FRE 2857, F-78350 Jouy En Josas, France. [Zhang, Xun] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Zhang, Xun] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Ji, WZ (reprint author), Chinese Acad Sci, Dept Reprod & Dev, Kunming Inst Zool, Kunming 650223, Peoples R China. EM wji@mail.kiz.ac.cn; qzhou@ioz.ac.cn RI Lu, Zhuo/D-4517-2014; OI ZHAO, Xiao-Yang/0000-0003-2544-8293 FU China National Basic Research Program [2006CB701501]; National Key Scientific Program [2006CB944003] FX We are grateful to Nathalie Beaujean (INRA) for many discussions and to Brendan Cormack (Johns Hopkins University School of Medicine) for comments and modification of this manuscript. This study was supported in part by grants from the China National Basic Research Program 2006CB701501 and grants from The National Key Scientific Program 2006CB944003. NR 21 TC 6 Z9 10 U1 2 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 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 2 PY 2010 VL 397 IS 3 BP 407 EP 412 DI 10.1016/j.bbrc.2010.05.105 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 626OF UT WOS:000279974600007 PM 20510672 ER PT J AU Polo, JM Hochedlinger, K AF Polo, Jose M. Hochedlinger, Konrad TI When Fibroblasts MET iPSCs SO CELL STEM CELL LA English DT Editorial Material ID PLURIPOTENT STEM-CELLS; GENERATION AB Two independent studies by Li et al. (2010) and Samavarchi-Tehrani et al. (2010) in this issue of Cell Stem Cell suggest that a mesenchymal-to-epithelial transition is a critical initiating event during the derivation of induced pluripotent stem cells (iPSCs) from fibroblasts, indicating remarkable similarities between cellular reprogramming, development, and cancer. C1 [Polo, Jose M.; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Howard Hughes Med Inst, Boston, MA 02114 USA. [Polo, Jose M.; Hochedlinger, Konrad] Ctr Regenerat Med, Boston, MA 02114 USA. [Polo, Jose M.; Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Polo, Jose M.; Hochedlinger, Konrad] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Polo, Jose M.; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. RP Hochedlinger, K (reprint author), Massachusetts Gen Hosp, Ctr Canc, Howard Hughes Med Inst, 185 Cambridge St, Boston, MA 02114 USA. EM khochedlinger@helix.mgh.harvard.edu OI Polo, Jose M/0000-0002-2531-778X NR 10 TC 36 Z9 38 U1 0 U2 5 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 JUL 2 PY 2010 VL 7 IS 1 BP 5 EP 6 DI 10.1016/j.stem.2010.05.018 PG 2 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 629TJ UT WOS:000280222300003 PM 20621040 ER PT J AU Loh, YH Hartung, O Li, H Guo, CG Sahalie, JM Manos, PD Urbach, A Heffner, GC Grskovic, M Vigneault, F Lensch, MW Park, IH Agarwal, S Church, GM Collins, JJ Irion, S Daley, GQ AF Loh, Yuin-Han Hartung, Odelya Li, Hu Guo, Chunguang Sahalie, Julie M. Manos, Philip D. Urbach, Achia Heffner, Garrett C. Grskovic, Marica Vigneault, Francois Lensch, M. William Park, In-Hyun Agarwal, Suneet Church, George M. Collins, James J. Irion, Stefan Daley, George Q. TI Reprogramming of T Cells from Human Peripheral Blood SO CELL STEM CELL LA English DT Article ID PLURIPOTENT STEM-CELLS; HUMAN SOMATIC-CELLS; HUMAN CORD BLOOD; DEFINED FACTORS; GENERATION; FIBROBLASTS; EXPRESSION; INDUCTION C1 [Grskovic, Marica; Irion, Stefan] iPierian Inc, San Francisco, CA 94080 USA. [Loh, Yuin-Han; Hartung, Odelya; Sahalie, Julie M.; Manos, Philip D.; Urbach, Achia; Heffner, Garrett C.; Lensch, M. William; Park, In-Hyun; Agarwal, Suneet; Daley, George Q.] Childrens Hosp, Div Pediat Hematol Oncol, Stem Cell Transplantat Program, Boston, MA 02115 USA. [Loh, Yuin-Han; Hartung, Odelya; Sahalie, Julie M.; Manos, Philip D.; Urbach, Achia; Heffner, Garrett C.; Lensch, M. William; Park, In-Hyun; Agarwal, Suneet; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Loh, Yuin-Han; Hartung, Odelya; Sahalie, Julie M.; Manos, Philip D.; Urbach, Achia; Heffner, Garrett C.; Lensch, M. William; Park, In-Hyun; Agarwal, Suneet; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Loh, Yuin-Han; Hartung, Odelya; Sahalie, Julie M.; Manos, Philip D.; Urbach, Achia; Heffner, Garrett C.; Lensch, M. William; Park, In-Hyun; Agarwal, Suneet; Daley, George Q.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Li, Hu; Collins, James J.] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Li, Hu; Collins, James J.] Boston Univ, Ctr BioDynam, Boston, MA 02215 USA. [Li, Hu; Collins, James J.] Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02115 USA. [Guo, Chunguang; Lensch, M. William; Collins, James J.; Daley, George Q.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Guo, Chunguang] Harvard Univ, Sch Med, Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA. [Guo, Chunguang; Vigneault, Francois; Church, George M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Daley, George Q.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Daley, George Q.] Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. RP Irion, S (reprint author), iPierian Inc, San Francisco, CA 94080 USA. EM stefanirion@ipierian.com; george.daley@childrens.harvard.edu RI Loh, Yuin-Han/E-1096-2014 OI Loh, Yuin-Han/0000-0002-4715-6454 FU National Institutes of Health (NIH) [RL1DE019021]; Howard Hughes Medical Institute; SysCODE (Systems-based Consortium for Organ Design Engineering); Agency of Science, Technology, and Research (A*Star); Institute of Medical Biology, Singapore FX This research was funded by grants from the National Institutes of Health (NIH) and the Howard Hughes Medical Institute to G.Q.D. J.J.C. is supported by SysCODE (Systems-based Consortium for Organ Design & Engineering), NIH grant # RL1DE019021. Y.-H.L. is supported by the overseas fellowship from Agency of Science, Technology, and Research (A*Star) and the Institute of Medical Biology, Singapore. We are grateful to Ann M. Mullally, Anupama Narla, Benjamin L. Ebert, Lars U.W. Muller, Axel Schambach, and Stelios Andreadis for technical assistances. We acknowledge Sabine Loewer for helpful discussions and critical comments on the manuscript. G.Q.D. is a member of the Scientific Advisory Board of iPierian, Inc. M.G. and S.I. are employed by iPierian, Inc., a biotechnology company using iPSCs for drug discovery. NR 22 TC 130 Z9 142 U1 2 U2 22 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 JUL 2 PY 2010 VL 7 IS 1 BP 15 EP 19 DI 10.1016/j.stem.2010.06.004 PG 5 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 629TJ UT WOS:000280222300007 PM 20621044 ER PT J AU Taylor, PL Barker, RA Blume, KG Cattaneo, E Colman, A Deng, H Edgar, H Fox, IJ Gerstle, C Goldstein, LSB High, KA Lyall, A Parkman, R Pitossi, FJ Prentice, ED Rooke, HM Sipp, DA Srivastava, A Stayn, S Steinberg, GK Wagers, AJ Weissman, IL AF Taylor, Patrick L. Barker, Roger A. Blume, Karl G. Cattaneo, Elena Colman, Alan Deng, Hongkui Edgar, Harold Fox, Ira J. Gerstle, Claude Goldstein, Lawrence S. B. High, Katherine A. Lyall, Andrew Parkman, Robertson Pitossi, Fernando J. Prentice, Ernest D. Rooke, Heather M. Sipp, Douglas A. Srivastava, Alok Stayn, Susan Steinberg, Gary K. Wagers, Amy J. Weissman, Irving L. TI Patients Beware: Commercialized Stem Cell Treatments on the Web SO CELL STEM CELL LA English DT News Item ID ISSCR GUIDELINES AB A report by the International Society for Stem Cell Research (ISSCR)'s Task Force on Unproven Stem Cell Treatments outlines development of resources for patients, their families, and physicians seeking information on stem cell treatments. C1 [Rooke, Heather M.] Int Soc Stem Cell Res, Boston, MA 02115 USA. [Taylor, Patrick L.] Childrens Hosp, Boston, MA 02115 USA. [Barker, Roger A.] Univ Cambridge, Dept Clin Neurosci, Cambridge Ctr Brain Repair, Cambridge CB2 2PY, England. [Blume, Karl G.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Cattaneo, Elena] Univ Milan, I-20133 Milan, Italy. [Colman, Alan] ASTAR Singapore Stem Cell Consortium, Singapore 138648, Singapore. [Deng, Hongkui] Peking Univ, Beijing 100871, Peoples R China. [Edgar, Harold] Columbia Law Sch, New York, NY 10027 USA. [Fox, Ira J.] UPMC, Childrens Hosp Pittsburgh, McGowan Inst Regenerat Med, Pittsburgh, PA 15201 USA. [Goldstein, Lawrence S. B.] Univ Calif San Diego, La Jolla, CA 92093 USA. [High, Katherine A.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Lyall, Andrew] Stem Cell Network, Ottawa, ON K1H 8L6, Canada. [Parkman, Robertson] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Pitossi, Fernando J.] Fdn Inst Leloir IIBBA CONICET, RA-1405 Buenos Aires, DF, Argentina. [Prentice, Ernest D.] Univ Nebraska Med Ctr, Omaha, NE 68198 USA. [Sipp, Douglas A.] RIKEN, Ctr Dev Biol, Chuo Ku, Kobe, Hyogo 6500047, Japan. [Srivastava, Alok] Christian Med Coll & Hosp, Vellore 632004, Tamil Nadu, India. [Wagers, Amy J.] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Rooke, HM (reprint author), Int Soc Stem Cell Res, Boston, MA 02115 USA. RI Sipp, Douglas/C-9218-2017; OI Sipp, Douglas/0000-0002-5979-0938; CATTANEO, ELENA/0000-0002-0755-4917 NR 10 TC 21 Z9 22 U1 0 U2 4 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 JUL 2 PY 2010 VL 7 IS 1 BP 43 EP 49 DI 10.1016/j.stem.2010.06.001 PG 7 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 629TJ UT WOS:000280222300012 PM 20621049 ER PT J AU Curtis, SJ Sinkevicius, KW Li, DA Lau, AN Roach, RR Zamponi, R Woolfenden, AE Kirsch, DG Wong, KK Kim, CF AF Curtis, Stephen J. Sinkevicius, Kerstin W. Li, Danan Lau, Allison N. Roach, Rebecca R. Zamponi, Raffaella Woolfenden, Amber E. Kirsch, David G. Wong, Kwok-Kin Kim, Carla F. TI Primary Tumor Genotype Is an Important Determinant in Identification of Lung Cancer Propagating Cells SO CELL STEM CELL LA English DT Article ID ADULT-MOUSE LUNG; STEM-CELLS; INITIATING CELLS; MARKER; MEDULLOBLASTOMA; HETEROGENEITY; EXPRESSION; MUTATIONS; HIERARCHY; MODEL AB Successful cancer therapy requires the elimination or incapacitation of all tumor cells capable of regenerating a tumor. Therapeutic advances therefore necessitate the characterization of the cells that are able to propagate a tumor in vivo. We show an important link between tumor genotype and isolation of tumor-propagating cells (TPCs). Three mouse models of the most common form of human lung cancer each had TPCs with a unique cell-surface phenotype. The cell-surface marker Sca1 did not enrich for TPCs in tumors initiated with oncogenic Kras, and only Sca1-negative cells propagated EGFR mutant tumors. In contrast, Sca1-positive cells were enriched for tumor-propagating activity in Kras tumors with p53 deficiency. Primary tumors that differ in genotype at just one locus can therefore have tumor-propagating cell populations with distinct markers. Our studies show that the genotype of tumor samples must be considered in studies to identify, characterize, and target tumor-propagating cells. C1 [Curtis, Stephen J.; Sinkevicius, Kerstin W.; Lau, Allison N.; Roach, Rebecca R.; Zamponi, Raffaella; Kim, Carla F.] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Curtis, Stephen J.; Sinkevicius, Kerstin W.; Lau, Allison N.; Roach, Rebecca R.; Zamponi, Raffaella; Kim, Carla F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Curtis, Stephen J.; Sinkevicius, Kerstin W.; Lau, Allison N.; Roach, Rebecca R.; Zamponi, Raffaella; Kim, Carla F.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Li, Danan; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Li, Danan; Wong, Kwok-Kin] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Li, Danan; Wong, Kwok-Kin] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA 02115 USA. [Woolfenden, Amber E.] Novartis Inst BioMed Res Inc, Cambridge, MA 02139 USA. [Kirsch, David G.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27708 USA. [Kirsch, David G.] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27708 USA. RP Kim, CF (reprint author), Childrens Hosp, Stem Cell Program, 300 Longwood Ave, Boston, MA 02115 USA. EM carla.kim@childrens.harvard.edu OI wong, kwok kin/0000-0001-6323-235X FU DoD, Air Force Office of Scientific Research [32 CFR 168a]; American Cancer Society [PF-09-121-01-DDC]; Dana Farber Harvard Cancer Center Lung Cancer [P50 CA090578, R01 AG2400401, R01 CA122794, R01 CA140594]; V Foundation, American Cancer Society [RSG-08-082-01-MGO]; Harvard Stem Cell Institute; NIH/NCI [2P50CA090578]; Lung Cancer Alliance FX We thank S. Lawrence, K. Mercer, E. Jackson, A. Dooley, S. Perera, the DFCI, CHB HemOnc, MIT FACS facilities, and members of the Kim Lab for technical assistance and discussions; E. Passegue for cell cycle protocol; R. Bronson for histopathology; T. Jacks for mouse strains and helpful discussions; and G. Evan, S. Ryeom, L. Zon, C. Cepko, S. Elledge, S. Armstrong, H. Hock, and K. Cichowski for critical reading. This work was supported by a DoD, Air Force Office of Scientific Research, National Defense Science and Engineering Graduate Fellowship, 32 CFR 168a (to S.J.C.), PF-09-121-01-DDC from the American Cancer Society (to K.W.S.), Dana Farber Harvard Cancer Center Lung Cancer SPORE grant P50 CA090578, R01 AG2400401, R01 CA122794, and R01 CA140594 (to K-K.W.), the V Foundation, American Cancer Society Research Scholar Grant #RSG-08-082-01-MGO, the Harvard Stem Cell Institute, NIH/NCI 2P50CA090578, and The Lung Cancer Alliance (to C.F.K.). We apologize for not citing primary references because of space constraints. NR 27 TC 76 Z9 81 U1 0 U2 9 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 JUL 2 PY 2010 VL 7 IS 1 BP 127 EP 133 DI 10.1016/j.stem.2010.05.021 PG 7 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 629TJ UT WOS:000280222300019 PM 20621056 ER PT J AU Jiang, XF Xu, Y Price, BD AF Jiang, Xiaofeng Xu, Ye Price, Brendan D. TI Acetylation of H2AX on lysine 36 plays a key role in the DNA double-strand break repair pathway SO FEBS LETTERS LA English DT Article DE H2AX; Acetylation; Chromatin; DNA double-strand break; Histone acetyltransferase; IR ID HISTONE ACETYLTRANSFERASE; GENOMIC STABILITY; DAMAGE RESPONSE; CHROMATIN; PHOSPHORYLATION; ACTIVATION; TIP60; ATM; H3; LINKS AB Phosphorylation of H2AX functions to recruit DNA repair complexes to sites of DNA damage. Here, we report that H2AX is constitutively acetylated on lysine 36 (H2AXK36Ac) by the CBP/p300 acetyltransferases. H2AXK36Ac is required for cells to survive exposure to ionizing radiation; however, H2AXK36Ac levels are not increased by DNA damage. Further, acetylation of H2AX did not affect phosphorylation of H2AX or the formation of DNA damage foci. Finally, cells with a double mutation in both the H2AX acetylation and phosphorylation sites were more radiosensitive than cells containing individual mutations. H2AXK36Ac is therefore a novel, constitutive histone modification located within the histone core region which regulates radiation sensitivity independently of H2AX phosphorylation. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved. C1 [Jiang, Xiaofeng; Xu, Ye; Price, Brendan D.] Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, Boston, MA 02115 USA. RP Price, BD (reprint author), Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Stabil & DNA Repair, JF516,44 Binney St, Boston, MA 02115 USA. EM brendan_price@dfci.harvard.edu FU NCI [CA64585, CA93602]; DOD FX We thank members of the Price laboratory, Anyong Xie and Ralph Scully for valuable discussions and sharing unpublished data; X. Yang and Q. Liu for providing HAT constructs; J. Chen for MDC1 antibody and A. Nussenzweig for H2AX-/- MEF cells. Supported by grants from the NCI (CA64585 and CA93602) and the DOD Breast Cancer Program to BDP. NR 23 TC 16 Z9 17 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 2 PY 2010 VL 584 IS 13 BP 2926 EP 2930 DI 10.1016/j.febslet.2010.05.017 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 609LF UT WOS:000278657200035 PM 20488183 ER PT J AU Vest, RS O'Leary, H Coultrap, SJ Kindy, MS Bayer, KU AF Vest, Rebekah S. O'Leary, Heather Coultrap, Steven J. Kindy, Mark S. Bayer, K. Ulrich TI Effective Post-insult Neuroprotection by a Novel Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Inhibitor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID D-ASPARTATE RECEPTOR; INDUCED CELL-DEATH; TISSUE-PLASMINOGEN ACTIVATOR; ISCHEMIC BRAIN-DAMAGE; NMDA RECEPTOR; GLUTAMATE NEUROTOXICITY; HIPPOCAMPAL-NEURONS; CEREBRAL-ISCHEMIA; SELF-ASSOCIATION; GLUCOSE DEPRIVATION AB Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is a major mediator of physiological glutamate signaling involved in higher brain functions. Here, we show CaMKII involvement in pathological glutamate signaling relevant in stroke. The novel inhibitor tatCN21 was neuroprotective even when added hours after glutamate insults. By contrast, the "traditional" inhibitor KN93 attenuated excitotoxicity only when present during the insult. Both inhibitors efficiently blocked Ca2+/CaM-stimulated CaMKII activity, CaMKII interaction with NR2B and aggregation of CaMKII holoenzymes. However, only tatCN21 but not KN93 blocked the Ca2+-independent "autonomous" activity generated by Thr-286 autophosphorylation, the hallmark feature of CaMKII regulation. Mutational analysis further validated autonomous CaMKII activity as the drug target crucial for post-insult neuroprotection. Overexpression of CaMKII wild type but not the autonomy-deficient T286A mutant significantly increased glutamate-induced neuronal death. Maybe most importantly, tatCN21 also significantly reduced infarct size in a mouse stroke model (middle cerebral arterial occlusion) when injected (1 mg/kg intravenously) 1 h after onset of arterial occlusion. Together, these data demonstrate that inhibition of autonomous CaMKII activity provides a promising therapeutic avenue for post-insult neuro-protection after stroke. C1 Univ Colorado, Denver Sch Med, Dept Pharmacol, Aurora, CO 80045 USA. [Kindy, Mark S.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Kindy, Mark S.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. EM ulli.bayer@ucdenver.edu FU National Institutes of Health [P30NS048154, F31NS061584, T32GM007635]; Veterans Affairs Merit Review; State of Colorado TTO BDEGP; University of Colorado, Denver [P20RR017677-08, R01NS052644] FX This work was supported, in whole or in part, by National Institutes of Health Grants P30NS048154 (University of Colorado, Denver, center grant), P20RR017677-08, and R01NS052644 (to K. U. B.). This work was also supported by Veterans Affairs Merit Review (to M. S. K.) and State of Colorado TTO BDEGP. The University of Colorado is currently seeking patent protection for tatCN21 and its uses.; Supported by National Institutes of Health Training Grant F31NS061584.; Supported by National Institutes of Health Training Grant T32GM007635. NR 72 TC 44 Z9 44 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 2 PY 2010 VL 285 IS 27 BP 20675 EP 20682 DI 10.1074/jbc.M109.088617 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 616SH UT WOS:000279228600031 PM 20424167 ER PT J AU Kim, YW Kutchukian, PS Verdine, GL AF Kim, Young-Woo Kutchukian, Peter S. Verdine, Gregory L. TI Introduction of All-Hydrocarbon i,i+3 Staples into alpha-Helices via Ring-Closing Olefin Metathesis SO ORGANIC LETTERS LA English DT Article ID HYDROGEN-BOND SURROGATE; PEPTIDES; CONFORMATION; ACTIVATION; PROTEINS; MODEL AB The introduction of all-hydrocarbon i,i+3 staples into alpha-helical peptide scaffolds via ring-closing olefin metathesis (RCM) between two alpha-methyl,alpha-pentenylglycine residues incorporated at i and i+3 positions, which lie on the same face of the helix, has been investigated. The reactions were found to be highly dependent upon the side-chain stereochemistry of the amino acids undergoing RCM. The i,i+3 stapling system established here provides a potentially useful alternative to the well-established i,i+4 stapling system now in widespread use. C1 [Verdine, Gregory L.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02115 USA. RP Verdine, GL (reprint author), Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. EM gregory_verdine@harvard.edu RI Kutchukian, Peter/A-9826-2016 OI Kutchukian, Peter/0000-0002-5684-1971 FU Harvard & Dana-Farber Program in Cancer Chemical Biology; NSF FX We thank Tom Grossmann (Harvard University) for assistance with MALDI TOF/TOF analysis. This research was supported by the Harvard & Dana-Farber Program in Cancer Chemical Biology and an NSF graduate research fellowship (to P.S.K.). NR 25 TC 60 Z9 60 U1 3 U2 18 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD JUL 2 PY 2010 VL 12 IS 13 BP 3046 EP 3049 DI 10.1021/ol1010449 PG 4 WC Chemistry, Organic SC Chemistry GA 614OR UT WOS:000279070100040 PM 20527740 ER PT J AU Li, STT Paterniti, DA Co, JPT West, DC AF Li, Su-Ting T. Paterniti, Debora A. Co, John Patrick T. West, Daniel C. TI Successful Self-Directed Lifelong Learning in Medicine: A Conceptual Model Derived From Qualitative Analysis of a National Survey of Pediatric Residents SO ACADEMIC MEDICINE LA English DT Article ID PHYSICIAN CHARTER; PROFESSIONALISM; MILLENNIUM; EDUCATION AB Purpose Self-directed lifelong learning is integral to medical professionalism, yet how best to encourage its development during clinically intensive training is unknown. The authors develop a model for successful self-directed learning by analyzing qualitative data from a national survey of residents. Method Pediatric and medicine/pediatric residents at 46 training programs completed a Web-based survey in 2008-2009. Self-reported barriers to and strategies for achieving self-directed learning goals were systematically analyzed through inductive iterative review. Results A total of 992 out of 1,739 (57%) residents responded. Barriers to achieving self-directed learning goals were categorized into difficulty with personal reflection, environmental strain, competing demands, difficulty with goal generation, and problems with plan development and implementation. Strategies for achieving learning goals included creating goals that were important (relevant to the learner and prioritized by the learner as important to achieve), specific (with broad goals broken down into incremental steps and a specific plan for each step), measurable, accountable (with reminder and tracking systems and building in internal and external accountability), realistic (achievable goals which utilize existing opportunities and constant self-adjustment), and included a timeline for completing the goal (and incorporating the goal into their daily routine). Conclusions On the basis of the data, the authors propose a conceptual model for self-directed lifelong learning involving creation of learning goals and plan development based on individual reflection and self-assessment, and continual revision of goals and/or plans based on degree of goal attainment. This model could be broadly applicable throughout medical education. C1 [Li, Su-Ting T.] Univ Calif Davis, Dept Pediat, Sacramento, CA 95817 USA. [Paterniti, Debora A.] Univ Calif Davis, Dept Internal Med, Ctr Healthcare Policy & Res, Sacramento, CA 95817 USA. [Paterniti, Debora A.] Univ Calif Davis, Dept Sociol, Ctr Healthcare Policy & Res, Sacramento, CA 95817 USA. [Co, John Patrick T.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Massachusetts Gen Hosp,Off Grad Med Educ, Boston, MA 02115 USA. [West, Daniel C.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. RP Li, STT (reprint author), 2516 Stockton Blvd, Sacramento, CA 95817 USA. EM su-ting.li@ucdmc.ucdavis.edu OI Li, Su-Ting/0000-0002-9104-912X FU Association of Pediatric Program Directors FX This study was funded in part by a Special Projects grant from the Association of Pediatric Program Directors. NR 16 TC 27 Z9 27 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD JUL PY 2010 VL 85 IS 7 BP 1229 EP 1236 DI 10.1097/ACM.0b013e3181e1931c PG 8 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 618TK UT WOS:000279378400028 PM 20592521 ER PT J AU Stille, C Turchi, RM Antonelli, R Cabana, MD Cheng, TL Laraque, D Perrin, J AF Stille, Christopher Turchi, Renee M. Antonelli, Richard Cabana, Michael D. Cheng, Tina L. Laraque, Danielle Perrin, James CA Acad Pediat Assoc Task Force Famil TI The Family-Centered Medical Home: Specific Considerations for Child Health Research and Policy SO ACADEMIC PEDIATRICS LA English DT Article ID YOUNG-ADULTS; CARE; DEFINITION; PROMOTION; DISPARITIES; PREVENTION; FRAMEWORK; NEEDS; 1ST C1 [Stille, Christopher] Univ Massachusetts, Sch Med, Div Gen Pediat, Worcester, MA 01655 USA. [Turchi, Renee M.] St Christophers Hosp Children, Dept Pediat, Special Programs, Philadelphia, PA 19133 USA. [Turchi, Renee M.] Drexel Univ, Sch Publ Hlth, Dept Community Hlth & Prevent, Philadelphia, PA 19104 USA. [Antonelli, Richard] Harvard Univ, Sch Med, Childrens Hosp Boston, Integrated Care Org, Boston, MA USA. [Cabana, Michael D.] Univ Calif San Francisco, Philip R Lee Inst Hlth Policy Studies, Div Gen Pediat, San Francisco, CA 94143 USA. [Cheng, Tina L.] Johns Hopkins Univ, Div Gen Pediat & Adolescent Med, Baltimore, MD USA. [Laraque, Danielle] Mt Sinai Sch Med, Dept Pediat, Div Gen Pediat, New York, NY USA. [Perrin, James] Harvard Univ, Sch Med, MassGen Hosp Children, Ctr Child & Adolescent Hlth Policy, Boston, MA USA. RP Stille, C (reprint author), Univ Massachusetts, Sch Med, Div Gen Pediat, Benedict A3-125,55 Lake Ave N, Worcester, MA 01655 USA. EM christopher.stille@umassmemorial.org OI Stille, Christopher/0000-0001-9192-6818 NR 36 TC 39 Z9 39 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1876-2859 J9 ACAD PEDIATR JI Acad. Pediatr. PD JUL-AUG PY 2010 VL 10 IS 4 BP 211 EP 217 PG 7 WC Pediatrics SC Pediatrics GA 627WG UT WOS:000280074000001 PM 20605546 ER PT J AU Aboul-Fotouh, F Asghar-Ali, AA AF Aboul-Fotouh, Frieda Asghar-Ali, Ali Abbas TI Therapy 101: A Psychotherapy Curriculum for Medical Students SO ACADEMIC PSYCHIATRY LA English DT Article AB Objective: This pilot project, designed and taught by a resident, created a curriculum to introduce medical students to the practice of psychotherapy. Medical students who are knowledgeable about psychotherapy can become physicians who are able to refer patients to psychotherapeutic treatments. A search of the literature did not identify a curriculum that introduced psychotherapy, its applications, and evidence for its use. Methods: The authors worked closely with a faculty mentor to create a course that fulfilled a perceived need for more psychotherapy teaching of medical students. "Therapy 101: An Introduction to Psychotherapy" is a 6-hour curriculum that employs creative teaching techniques such as video clips from TV shows, role play, and recordings of therapy sessions. The series was evaluated using a multiple-choice pre/postcourse test with questions on psychotherapy, written feedback, and perceived knowledge of psychotherapy. Results: The scores from the pre/postcourse test measuring the students' knowledge of psychotherapy did not change significantly. However, students' self-rating of knowledge greatly increased after the series. Written feedback showed substantial enthusiasm for the course. Conclusion: Students can benefit from a short and engaging curriculum on psychotherapy. "Therapy 101" was very well accepted by students and has been integrated into the curriculum for students in the mental health pathway. Medical students may benefit from more exposure to psychotherapy as taught by a resident. C1 [Asghar-Ali, Ali Abbas] Michael E DeBakey VA Med Ctr, Houston, TX 77030 USA. Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Aboul-Fotouh, Frieda] Harvard Massachusetts Gen Hosp, Boston, MA USA. RP Asghar-Ali, AA (reprint author), Michael E DeBakey VA Med Ctr, 2002 Holcombe Blvd,MHCL 116, Houston, TX 77030 USA. EM asgharal@bcm.edu NR 21 TC 4 Z9 4 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1042-9670 J9 ACAD PSYCHIATR JI Acad. Psych. PD JUL-AUG PY 2010 VL 34 IS 4 BP 248 EP 252 PG 5 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA 615DS UT WOS:000279113900002 PM 20576980 ER PT J AU Rudolph, JL Schreiber, KA Culley, DJ McGlinchey, RE Crosby, G Levitsky, S Marcantonio, ER AF Rudolph, J. L. Schreiber, K. A. Culley, D. J. McGlinchey, R. E. Crosby, G. Levitsky, S. Marcantonio, E. R. TI Measurement of post-operative cognitive dysfunction after cardiac surgery: a systematic review SO ACTA ANAESTHESIOLOGICA SCANDINAVICA LA English DT Review ID CORONARY-ARTERY-BYPASS; QUALITY-OF-LIFE; PROSPECTIVE RANDOMIZED-TRIAL; HIGH-RISK PATIENTS; LONGER HOSPITAL STAY; CARDIOPULMONARY BYPASS; GRAFT-SURGERY; ON-PUMP; NEUROCOGNITIVE OUTCOMES; FOLLOW-UP AB Post-operative cognitive dysfunction (POCD) is a decline in cognitive function from pre-operative levels, which has been frequently described after cardiac surgery. The purpose of this study was to examine the variability in the measurement and definitions for POCD using the framework of a 1995 Consensus Statement on measurement of POCD. Electronic medical literature databases were searched for the intersection of the search terms 'thoracic surgery' and 'cognition, dementia, and neuropsychological test.' Abstracts were reviewed independently by two reviewers. English articles with > 50 participants published since 1995 that performed pre-operative and post-operative psychometric testing in patients undergoing cardiac surgery were reviewed. Data relevant to the measurement and definition of POCD were abstracted and compared with the recommendations of the Consensus Statement. Sixty-two studies of POCD in patients undergoing cardiac surgery were identified. Of these studies, the recommended neuropsychological tests were carried out in less than half of the studies. The cognitive domains measured most frequently were attention (n=56; 93%) and memory (n=57; 95%); motor skills were measured less frequently (n=36; 60%). Additionally, less than half of the studies examined anxiety and depression, performed neurological exam, or accounted for learning. Four definitions of POCD emerged: per cent decline (n=15), standard deviation decline (n=14), factor analysis (n=13), and analysis of performance on individual tests (n=12). There is marked variability in the measurement and definition of POCD. This heterogeneity may impede progress by reducing the ability to compare studies on the causes and treatment of POCD. C1 [Rudolph, J. L.] Harvard Univ, Brigham & Womens Hosp, Sch Med,Div Aging, Geriatr Res Educ & Clin Ctr,VA Boston Healthcare, Boston, MA 02130 USA. [Schreiber, K. A.] Loyola Univ Chicago, Stritch Sch Med, Maywood, IL USA. [Culley, D. J.; Crosby, G.] Harvard Univ, Brigham & Womens Hosp, Dept Anesthesiol, Sch Med, Boston, MA 02130 USA. [Levitsky, S.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiothorac Surg, Boston, MA 02130 USA. [Marcantonio, E. R.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gen Med, Boston, MA 02130 USA. [Marcantonio, E. R.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Primary Care & Gerontol, Boston, MA 02130 USA. RP Rudolph, JL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med,Div Aging, Geriatr Res Educ & Clin Ctr,VA Boston Healthcare, 150 S Huntington Ave, Boston, MA 02130 USA. EM jrudolph@partners.org RI McGlinchey, Regina/R-1971-2016 FU VA Rehabilitation Research and Development Career Development Award; NIH [AG026781, AG029861, AG027549, AG030618, AG028189, AG008812] FX Conflict of interest: The authors have no financial conflict of interest to declare. Financial disclosure: Dr Rudolph is supported by a VA Rehabilitation Research and Development Career Development Award. Additional support for this award was provided by NIH grants (AG026781, AG029861, AG027549, AG030618, AG028189, and AG008812). NR 91 TC 73 Z9 82 U1 3 U2 21 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-5172 J9 ACTA ANAESTH SCAND JI Acta Anaesthesiol. Scand. PD JUL PY 2010 VL 54 IS 6 BP 663 EP 677 DI 10.1111/j.1399-6576.2010.02236.x PG 15 WC Anesthesiology SC Anesthesiology GA 604QA UT WOS:000278292400002 PM 20397979 ER PT J AU Honings, J Gaissert, HA van der Heijden, HFM Verhagen, AFTM Kaanders, JHAM Marres, HAM AF Honings, Jimmie Gaissert, Henning A. van der Heijden, Henricus F. M. Verhagen, Ad F. T. M. Kaanders, Johannes H. A. M. Marres, Henri A. M. TI Clinical aspects and treatment of primary tracheal malignancies SO ACTA OTO-LARYNGOLOGICA LA English DT Review DE Tracheal neoplasms; treatment of tracheal cancer; diagnostic protocol; staging guideline; treatment algorithm ID SQUAMOUS-CELL CARCINOMA; TUMORS; EXPERIENCE; RESECTION; CANCER; NEOPLASMS; NATIONWIDE; SURVIVAL; FINLAND; CARINA AB Conclusions: Selecting patients that are candidates for surgical treatment is important in the work-up of patients with tracheal cancer. Toward this goal, centralization of care concerning tracheal tumors is advised. Centralization may increase long-term survival and decrease operative morbidity and mortality even further. Objective: Primary tracheal tumors pose a diagnostic and therapeutic challenge for the physician when confronted with this mostly malignant tumor. Diagnosis is often delayed for months or years due to its aspecific and asthma-mimicking symptoms. Knowledge from retrospective series is limited and few clinicians have gained experience with this tumor. The available literature on the diagnosis and management of this group of tumors is reviewed to summarize the available knowledge about these uncommon tumors. New diagnostic, staging, and treatment guidelines are proposed. Methods: PubMed was searched for English publications from 1960. The available literature was reviewed and summarized. Results: Surgical resection and primary reconstruction is the best curative treatment modality available at present. In centers of experience, more than half of all patients with tracheal cancer may be candidates for surgical resection, although in population-based studies this treatment is applied in only 10-25% of patients. C1 [Honings, Jimmie; Marres, Henri A. M.] Radboud Univ Nijmegen, Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, NL-6500 HB Nijmegen, Netherlands. [Gaissert, Henning A.] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. [Gaissert, Henning A.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Gaissert, Henning A.] Harvard Univ, Sch Med, Boston, MA USA. [van der Heijden, Henricus F. M.] Radboud Univ Nijmegen, Med Ctr, Dept Pulm Dis, NL-6500 HB Nijmegen, Netherlands. [Verhagen, Ad F. T. M.] Radboud Univ Nijmegen, Med Ctr, Dept Cardiothorac Surg, NL-6500 HB Nijmegen, Netherlands. [Kaanders, Johannes H. A. M.] Radboud Univ Nijmegen, Med Ctr, Dept Radiat Oncol, NL-6500 HB Nijmegen, Netherlands. RP Honings, J (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Otorhinolaryngol Head & Neck Surg, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM j.honings@kno.umcn.nl RI van der Heijden, H.F.M. (Erik)/D-3774-2009; Kaanders, Hans/A-7432-2014; Marres, H.A.M./H-8071-2014; Verhagen, A.F.T.M./L-4709-2015; Honings, Jimmie/B-3639-2016 OI van der Heijden, H.F.M. (Erik)/0000-0003-3596-518X; Honings, Jimmie/0000-0001-5077-3472 NR 30 TC 13 Z9 13 U1 1 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0001-6489 J9 ACTA OTO-LARYNGOL JI Acta Oto-Laryngol. PD JUL PY 2010 VL 130 IS 7 BP 763 EP 772 DI 10.3109/00016480903403005 PG 10 WC Otorhinolaryngology SC Otorhinolaryngology GA 647LL UT WOS:000281619900002 PM 20569185 ER PT J AU Pastor, R Kamens, HM McKinnon, CS Ford, MM Phillips, TJ AF Pastor, Raul Kamens, Helen M. McKinnon, Carrie S. Ford, Matthew M. Phillips, Tamara J. TI Repeated ethanol administration modifies the temporal structure of sucrose intake patterns in mice: effects associated with behavioral sensitization SO ADDICTION BIOLOGY LA English DT Article DE Addiction; alcohol; behavioral sensitization; GABA(B) receptor; motivation; sucrose ID CROSS-SENSITIZATION; NUCLEUS-ACCUMBENS; INCENTIVE-SENSITIZATION; DOPAMINE TRANSMISSION; EATING-DISORDERS; SACCHARIN INTAKE; D-AMPHETAMINE; ANIMAL-MODEL; COCAINE; ADDICTION AB Neuroadaptations supporting behavioral sensitization to abused drugs are suggested to underlie pathological, excessive motivation toward drugs and drug-associated stimuli. Drug-induced sensitization has also been linked to increased appetitive responses for non-drug, natural reinforcers. The present research investigated whether ethanol (EtOH)-induced neural changes, inferred from psychomotor sensitization, can modify consumption and intake dynamics for the natural reinforcer, sucrose. The effects of EtOH-induced sensitization in mice on the temporal structure of sucrose intake patterns were measured using a lickometer system. After sensitization, sucrose intake dynamics were measured for 1 hour daily for 7 days and indicated more rapid initial approach and consumption of sucrose in EtOH-sensitized groups; animals showed a shorter latency to the first intake bout and an increased number of sucrose bottle licks during the initial 15 minutes of the 1-hour sessions. This effect was associated with increased frequency and size of bouts. For the total 1-hour session, sucrose intake and bout dynamics were not different between groups, indicating a change in patterns of sucrose intake but not total consumption. When sensitization was prevented by the gamma-aminobutyric acid B receptor agonist, baclofen, the increased rate of approach and consumption of sucrose were also prevented. Thus, EtOH-induced sensitization, and not the mere exposure to EtOH, was associated with changes in sucrose intake patterns. These data are consistent with current literature suggesting an enhancing effect of drug-induced sensitization on motivational processes involved in reinforcement. C1 [Pastor, Raul] Univ Jaume 1, Area Psicobiol, Castellon de La Plana 12071, Spain. [Pastor, Raul; Kamens, Helen M.; McKinnon, Carrie S.; Ford, Matthew M.; Phillips, Tamara J.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA. [Pastor, Raul; Kamens, Helen M.; McKinnon, Carrie S.; Ford, Matthew M.; Phillips, Tamara J.] Portland Alcohol Res Ctr, Portland, OR USA. [Phillips, Tamara J.] Portland VA Med Ctr, Res Serv, Portland, OR USA. RP Pastor, R (reprint author), Univ Jaume 1, Area Psicobiol, Ave Sos Baynat S-N, Castellon de La Plana 12071, Spain. EM raul.pastor@uji.es OI Kamens, Helen/0000-0001-5085-8847; Ford, Matthew/0000-0002-1204-1980 FU Department of Veterans Affairs; NIH/NIAAA [P60 AA010760] FX This study is supported by a grant from the Department of Veterans Affairs and by NIH/NIAAA grant P60 AA010760. We thank Dr. Sarah E. Holstein, Na Li and Sue Burkhart-Kasch for their technical assistance, and Dr. Amanda L. Sharpe for assistance with the lickometer apparatus. NR 64 TC 10 Z9 10 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD JUL PY 2010 VL 15 IS 3 BP 324 EP 335 DI 10.1111/j.1369-1600.2010.00229.x PG 12 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 606AX UT WOS:000278393800009 PM 20624153 ER PT J AU Sadow, PM Hunt, JL AF Sadow, Peter M. Hunt, Jennifer L. TI Mixed Medullary-follicular-derived Carcinomas of the Thyroid Gland SO ADVANCES IN ANATOMIC PATHOLOGY LA English DT Review DE medullary thyroid carcinoma; follicular carcinoma; papillary carcinoma; collission tumor; mixed tumor; c-cell tumors ID OF-THE-LITERATURE; PAPILLARY CARCINOMA; PROGNOSTIC-FACTORS; COLLISION TUMOR; FOLLOW-UP; CANCER; SURVIVAL; COMPONENTS; DIAGNOSIS; FEATURES AB Tumors of the thyroid are subclassified based on the cell of origin and commonly include follicular-derived tumors and C-cell-derived tumors. The most common follicular-derived tumors are papillary carcinoma and follicular carcinoma, whereas the malignant C-cell-derived tumor is medullary thyroid carcinoma. Rare cases in the literature describe patients who have follicular-derived and C-cell-derived tumors in the same thyroid gland. These can be synchronous but anatomically separate carcinomas, or they can show some mixing of the 2 components. The mixture may be at an interface, as in collision tumors, or can be throughout the entire lesion, as in true mixed medullary-follicular-derived carcinomas. The clinical, histologic, and molecular features of these mixed tumors and the classification guidelines are reviewed. C1 [Sadow, Peter M.; Hunt, Jennifer L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Hunt, JL (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren 202,55 Fruit St, Boston, MA 02114 USA. EM Jhunt5@partners.org NR 34 TC 6 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-4109 J9 ADV ANAT PATHOL JI Adv. Anat. Pathol. PD JUL PY 2010 VL 17 IS 4 BP 282 EP 285 DI 10.1097/PAP.0b013e3181e4ab3e PG 4 WC Pathology SC Pathology GA 616ZA UT WOS:000279249200006 PM 20574174 ER PT J AU Weinstein, JR Anderson, S AF Weinstein, Jessica R. Anderson, Sharon TI The Aging Kidney: Physiological Changes SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Aging; Glomerular filtration rate; Renin-angiotensin system; Nitric oxide; Gender ID RENIN-ANGIOTENSIN SYSTEM; NITRIC-OXIDE SYNTHASE; RENAL-DISEASE; GLOMERULAR HYPERTENSION; VASCULAR-DISEASE; AGE; RAT; INJURY; HUMANS; RISK AB Age-associated loss of kidney function has been recognized for decades. With aging, many subjects exhibit progressive decreases in glomerular filtration rate and renal blood flow, with wide variability among individuals. The fall in glomerular filtration rate is because of reductions in the glomerular capillary plasma flow rate and the glomerular capillary ultrafiltration coefficient. In addition, a primary reduction in afferent arteriolar resistance is associated with an increase in glomerular capillary hydraulic pressure. These hemodynamic changes occur in concert with structural changes, including loss of renal mass; hyalinization of afferent arterioles and in some cases, development of aglomerular arterioles; an increase in the percentage of sclerotic glomeruli; and tubulointerstitial fibrosis. Aging is associated with altered activity and responsiveness to vasoactive stimuli, such that responses to vasoconstrictor stimuli are enhanced, whereas vasodilatory responses are impaired. Changes in the activity of the renin-angiotensin and nitric oxide systems appear to be particularly important, as is the modulating effect of gender. These changes may predispose the older kidney to acute kidney injury, including normotensive ischemic nephropathy, as well as progressive chronic kidney disease. (C) 2010 by the National Kidney Foundation, Inc. All rights reserved. C1 [Anderson, Sharon] Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, Portland, OR 97239 USA. Portland VA Med Ctr, Med Serv, Portland, OR USA. RP Anderson, S (reprint author), Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, OHSU Nephrol PP 262,3314 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM anderssh@ohsu.edu FU NTH [AG 14699]; AHRQ [HS 017582] FX This work was supported, in part, by a grant from the NTH (AG 14699), and by a training grant from the AHRQ (to J.W., HS 017582). NR 61 TC 82 Z9 87 U1 2 U2 12 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1548-5595 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD JUL PY 2010 VL 17 IS 4 BP 302 EP 307 DI 10.1053/j.ackd.2010.05.002 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 624GD UT WOS:000279804000004 PM 20610357 ER PT J AU Fischer, MJ O'Hare, AM AF Fischer, Michael J. O'Hare, Ann M. TI Epidemiology of Hypertension in the Elderly With Chronic Kidney Disease SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Geriatrics; Blood pressure; Aged; Chronic kidney failure ID BLOOD-PRESSURE CONTROL; NUTRITION EXAMINATION SURVEY; EVALUATION PROGRAM KEEP; 3RD NATIONAL-HEALTH; STAGE RENAL-DISEASE; UNITED-STATES; SYSTOLIC HYPERTENSION; PREVALENCE; MANAGEMENT; RISK AB As the population of the United States ages, the prevalence of age-related chronic conditions such as hypertension and chronic kidney disease (CKD) will also increase. Available studies in nationally representative samples and select outpatient populations indicate that hypertension is very common in older adults with CKD, and despite the use of medication it is often poorly controlled. Generally, less than one-third of the elderly patients with CKD achieve a level of blood pressure control consistent with that of the current guideline recommendations. However, limited evidence is available from observational studies and clinical trials to inform management of hypertension in the elderly population with CKD. The available published data suggest that the relationship between clinical outcomes and the treatment of hypertension among older adults with CKD is complex and distinct from that of their younger counterparts. Larger and more robust analyses are needed for a better understanding of the association between hypertension, its treatment, and clinical events in elderly patients with CKD. Published by Elsevier Inc. on behalf of the National Kidney Foundation. C1 Univ Illinois, Med Ctr, Jesse Brown VA Med Ctr, Chicago, IL USA. Edward Hines Jr VA Hosp, Ctr Management Complex Chron Care, Hines, IL 60141 USA. Univ Washington, VA Puget Sound Healthcare Syst, Seattle, WA 98195 USA. RP Fischer, MJ (reprint author), Hines VA Hosp, Ctr Management Complex Chron Care, 5000 S 5th Ave 151H, Hines, IL 60141 USA. EM fischerm@uic.edu FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service; National Institutes of Health [K23AG28980] FX Support and Financial Disclosure Declaration: The authors received funding support for this research project from: Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (VA HSR&D Career Development Award-M. Fischer) and the National Institutes of Health (K23AG28980-A. O'Hare). The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or Health Services Research and Development Service. NR 55 TC 8 Z9 8 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1548-5595 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD JUL PY 2010 VL 17 IS 4 BP 329 EP 340 DI 10.1053/j.ackd.2010.05.003 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 624GD UT WOS:000279804000007 PM 20610360 ER PT J AU Pinkerton, SD Bogart, LM Howerton, D Snyder, S Becker, K Asch, SM AF Pinkerton, Steven D. Bogart, Laura M. Howerton, Devery Snyder, Susan Becker, Kirsten Asch, Steven M. TI Cost of Rapid HIV Testing at 45 US Hospitals SO AIDS PATIENT CARE AND STDS LA English DT Article ID UNITED-STATES; EMERGENCY; SETTINGS AB In 2006, the United States Centers for Disease Control and Prevention (CDC) recommended expanded and routine use of single-session rapid HIV tests in all health care settings to increase the proportion of persons who learn their HIV status. Limited empiric information is available regarding the costs of rapid testing and pre- and posttest counseling in health care settings. We surveyed 45 U. S. hospitals during 2005 through 2006 to assess the costs associated with rapid testing and counseling. Cost analyses were conducted from the provider (hospital) perspective, and results were expressed in year 2006 U. S. dollars. The mean per-test cost of rapid HIV testing and counseling was $48.07 for an HIV-negative test and $64.17 for a preliminary-positive test. Pre- and posttest counseling costs accounted for 38.4% of the total cost of rapid testing for HIV-negative patients. Counseling costs were significantly correlated with overall test costs. Many hospitals contained overall test costs by limiting time spent in pre- and posttest counseling or by using lower-paid personnel for counseling activities or both. Counseling costs constituted a significant proportion of the overall costs of rapid testing and counseling activities at study hospitals. Our data provide useful baseline data before implementation of the CDC's 2006 recommendations. Costs can be reduced by limiting time spent in pre- and posttest counseling or by using lower-paid personnel for counseling activities or both. C1 [Pinkerton, Steven D.] Med Coll Wisconsin, Dept Psychiat & Behav Med, Ctr AIDS Intervent Res, Milwaukee, WI 53202 USA. [Bogart, Laura M.; Becker, Kirsten; Asch, Steven M.] RAND Corp, Hlth Program, Santa Monica, CA USA. [Bogart, Laura M.] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA USA. [Howerton, Devery] Ctr Dis Control & Prevent, Lab Practice Evaluat, Div Lab Syst, Atlanta, GA USA. [Howerton, Devery] Ctr Dis Control & Prevent, Genom Branch, Div Lab Syst, Atlanta, GA USA. [Snyder, Susan; Asch, Steven M.] VA Greater Los Angeles Healthcare Network, Los Angeles, CA USA. [Asch, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Pinkerton, SD (reprint author), Med Coll Wisconsin, Dept Psychiat & Behav Med, Ctr AIDS Intervent Res, 2071 N Summit Ave, Milwaukee, WI 53202 USA. EM pinkrton@mcw.edu FU Centers for Disease Control and Prevention (CDC) [U65/CCU924523-01]; National Institute of Mental Health (NIMH) [P30-MH52776] FX This study was supported by grants U65/CCU924523-01 from the Centers for Disease Control and Prevention (CDC) and P30-MH52776 from the National Institute of Mental Health (NIMH). The findings and conclusions presented here are those of the authors and do not necessarily represent the views of the CDC or NIH. NR 10 TC 9 Z9 9 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD JUL PY 2010 VL 24 IS 7 BP 409 EP 413 DI 10.1089/apc.2009.0348 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 629UF UT WOS:000280224500002 PM 20578906 ER PT J AU Saha, S Jacobs, EA Moore, RD Beach, MC AF Saha, Somnath Jacobs, Elizabeth A. Moore, Richard D. Beach, Mary Catherine TI Trust in Physicians and Racial Disparities in HIV Care SO AIDS PATIENT CARE AND STDS LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; AFRICAN-AMERICANS; CONSPIRACY BELIEFS; MEDICATION ADHERENCE; INFECTED PATIENTS; EQUAL ACCESS; HEALTH-CARE; RACE/ETHNICITY; INSTRUMENTS; GOVERNMENT AB Mistrust among African Americans is often considered a potential source of racial disparities in HIV care. We sought to determine whether greater trust in one's provider among African-American patients mitigates racial disparities. We analyzed data from 1,104 African-American and 201 white patients participating in a cohort study at an urban, academic HIV clinic between 2005 and 2008. African Americans expressed lower levels of trust in their providers than did white patients (8.9 vs. 9.4 on a 0-10 scale; p<0.001). African Americans were also less likely than whites to be receiving antiretroviral therapy (ART) when eligible (85% vs. 92%; p = 0.02), to report complete ART adherence over the prior 3 days (83% vs. 89%; p = 0.005), and to have a suppressed viral load (40% vs. 47%; p = 0.04). Trust in one's provider was not associated with receiving ART or with viral suppression but was significantly associated with adherence. African Americans who expressed less than complete trust in their providers (0-9 of 10) had lower ART adherence than did whites (adjusted OR, 0.40; 95% CI, 0.25-0.66). For African Americans who expressed complete trust in their providers (10 of 10), the racial disparity in adherence was less prominent but still substantial (adjusted OR, 0.59; 95% CI, 0.36-0.95). Trust did not affect disparities in receipt of ART or viral suppression. Our findings suggest that enhancing trust in patient-provider relationships for African-American patients may help reduce disparities in ART adherence and the outcomes associated with improved adherence. C1 [Saha, Somnath] Oregon Hlth & Sci Univ, Div Gen Internal Med & Geriatr, Gen Internal Med Sect, Portland VA Med Ctr, Portland, OR 97239 USA. [Jacobs, Elizabeth A.] John H Stroger Jr Hosp Cook Cty, Div Gen Internal Med, Chicago, IL USA. [Jacobs, Elizabeth A.] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Moore, Richard D.; Beach, Mary Catherine] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. RP Saha, S (reprint author), Oregon Hlth & Sci Univ, Div Gen Internal Med & Geriatr, Gen Internal Med Sect, Portland VA Med Ctr, 3710 SW US Vet Hosp Rd P3HSRD, Portland, OR 97239 USA. EM sahas@ohsu.edu FU NIMH NIH HHS [R34 MH089279] NR 32 TC 40 Z9 40 U1 2 U2 9 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD JUL PY 2010 VL 24 IS 7 BP 415 EP 420 DI 10.1089/apc.2009.0288 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 629UF UT WOS:000280224500003 PM 20578909 ER PT J AU Haber, MM Hunt, B Freston, JW Peura, DA Kovacs, TO Atkinson, S Hisada, M AF Haber, M. M. Hunt, B. Freston, J. W. Peura, D. A. Kovacs, T. O. Atkinson, S. Hisada, M. TI Changes of gastric histology in patients with erosive oesophagitis receiving long-term lansoprazole maintenance therapy SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID GASTROESOPHAGEAL-REFLUX DISEASE; HELICOBACTER-PYLORI INFECTION; PROTON-PUMP INHIBITORS; 20 MG; INTESTINAL METAPLASIA; DOSE LANSOPRAZOLE; CONTROLLED TRIAL; DOUBLE-BLIND; OMEPRAZOLE; SAFETY AB Background Changes in gastric histology associated with long-term maintenance therapy with lansoprazole for erosive oesophagitis have not been well described. Aim To evaluate the effect on gastric histology of long-term dose-titrated lansoprazole administered as maintenance therapy for up to 82 months in patients with erosive oesophagitis. Methods Sequential gastric biopsy specimens were obtained for evaluation of histological changes and Helicobacter pylori infection status. Results Active and chronic inflammation improved from baseline to final visit in a majority of patients receiving long-term therapy with lansoprazole, irrespective of baseline H. pylori infection status. Reductions in active inflammation in the gastric body and antrum were seen in 53% (17/32) and 67% (20/30) of H. pylori-positive patients, respectively, and in 88% (7/8) and 86% (12/14) of H. pylori-negative patients, respectively. Reductions in chronic inflammation in the gastric body and antrum were seen in 38% (12/32) and 47% (15/32) of H. pylori-positive patients, respectively, and in 58% (70/121) and 57% (68/120) of H. pylori-negative patients, respectively. No clinically meaningful increases in hyperplasia, dysplasia, neoplasia, intestinal metaplasia or atrophy were observed during the follow-up period. Conclusions Lansoprazole administered as maintenance therapy for up to 6 years in patients with erosive oesophagitis demonstrated gastric mucosal safety and was well tolerated. Aliment Pharmacol Ther 2010; 32: 83-96 C1 [Hunt, B.; Atkinson, S.; Hisada, M.] Takeda Global Res & Dev Ctr Inc, Deerfield, IL 60015 USA. [Haber, M. M.] Drexel Univ, Coll Med, Dept Pathol, Philadelphia, PA 19104 USA. [Freston, J. W.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Peura, D. A.] Univ Virginia Hlth Syst, Div Gastroenterol & Hepatol, Charlottesville, VA USA. [Kovacs, T. O.] CURE Clin, VA Greater Healthcare Syst, Los Angeles, CA USA. RP Hisada, M (reprint author), Takeda Global Res & Dev Ctr Inc, 1 Takeda Pkwy, Deerfield, IL 60015 USA. EM michie.hisada@tgrd.com FU TGRD [M94-140]; Takeda Pharmaceuticals North America, Inc FX Declaration of personal interests: Dr Haber has served as a consultant for Takeda Global Research & Development Center, Inc. (TGRD), Deerfield, IL, USA [TAP Pharmaceutical Products Inc., is now a part of TGRD]. Dr Peura has served as a consultant for Takeda Global Research & Development Center, Inc. and as a member of the speaker's bureau for Takeda Pharmaceuticals North America, Inc. Dr Freston has served as a consultant for Takeda Global Research & Development Center, Inc, AstraZeneca, Takeda Pharmaceuticals North America, Inc., Glaxo-SmithKline, and EnteroMedics Inc. Dr Kovacs confirms that he has no conflicts of interest or disclosures. Dr Hisada, Ms. Hunt, and Dr Atkinson are employees of Takeda Global Research & Development Center, Inc. Declaration of funding interests: This study (M94-140) was funded in full by TGRD. Writing support was provided by Gill Gummer and Rx Communications (UK), and funded by Takeda Pharmaceuticals North America, Inc. The authors would like to thank the M94-140 investigators for participating in the study. Regrettably, Dr Haber passed away on Oct 4 after having overseen completion of this manuscript. NR 33 TC 6 Z9 6 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JUL 1 PY 2010 VL 32 IS 1 BP 83 EP 96 DI 10.1111/j.1365-2036.2010.04310.x PG 14 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 606AY UT WOS:000278393900010 PM 20345509 ER PT J AU Patil, SU Long, AA AF Patil, Sarita U. Long, Aidan A. TI The usefulness of biomarkers of airway inflammation in managing asthma SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article; Proceedings Paper CT Eastern Allergy Conference CY MAY 02, 2009 CL Palm Beach, FL DE Airway hyperresponsiveness; asthma; biomarker; exhaled breath condensate; exhaled nitric oxide; mannitol; sputum eosinophils ID EXHALED NITRIC-OXIDE; RANDOMIZED CONTROLLED-TRIAL; EOSINOPHIL CATIONIC PROTEIN; SPUTUM CELL COUNTS; ADENOSINE 5'-MONOPHOSPHATE; BRONCHIAL HYPERRESPONSIVENESS; INHALED CORTICOSTEROIDS; ALLERGEN AVOIDANCE; BASEMENT-MEMBRANE; BREATH CONDENSATE AB The goal of managing asthma is to maintain disease control. Current approaches to assessment of control do not include measurement of airway inflammation. This study was designed to assess the usefulness of biomarkers of airway inflammation in guiding asthma management decisions. A literature review was performed. Bronchial biopsy is a direct measure of airway inflammation but not practical for routine use. Enumeration of sputum eosinophils is very useful in guiding changes in controller medication to decrease asthma exacerbations, whereas measurement of exhaled nitric oxide has not proven to be useful in this regard. Serial measurement of airway hyperreactivity as a guide to asthma management yields inconclusive results. Use of indirect stimuli for bronchial challenge offers both practical and theoretical advantages in the assessment of airway hyperreactivity. Data on the analysis of exhaled breath condensate have not yet been studied adequately in guiding management decisions. Enumeration of sputum cell counts appears to be the most useful biomarker of airway inflammation in guiding asthma management decisions. Combined approaches using simple methods of measuring airway hyperreactivity and obtaining sputum samples hold promise for the future, particularly if rapid analysis of cellular products in sputum can be developed. (Allergy Asthma Proc 31:259-268, 2010; doi:10.2500/aap.2010.31.3350) C1 [Patil, Sarita U.; Long, Aidan A.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Long, AA (reprint author), Harvard Univ, Fac Med, DRAI, COX 201,5 Fruit St, Boston, MA 02114 USA. EM aalong@partners.org NR 72 TC 10 Z9 14 U1 0 U2 3 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD JUL-AUG PY 2010 VL 31 IS 4 BP 259 EP 268 DI 10.2500/aap.2010.31.3350 PG 10 WC Allergy SC Allergy GA 648KL UT WOS:000281692400001 PM 20819317 ER PT J AU Amirzadeh, A Verma, P Lee, S Klaustermeyer, W AF Amirzadeh, Ali Verma, Prashant Lee, Sabrina Klaustermeyer, William TI Epinephrine auto-injector use and demographics in a Veterans Administration population SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article; Proceedings Paper CT 66th Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology CY FEB 26-MAR 02, 2010 CL New Orleans, LA SP Amer Acad Allergy, Asthma & Immunol DE Anaphylaxis; demographics; epinephrine; EpiPen; quality control; twinject; use; veteran ID ANAPHYLAXIS AB The epinephrine auto-injector has been widely used over a long period of time. Certain aspects of this therapy and demographic data, however, have not been well studied. This study investigates patient use and understanding of epinephrine auto-injector use. As part of an ongoing quality assurance program, we evaluated 66 patients who had been given an epinephrine auto-injector and followed in the Allergy and Immunology Clinics at the West Los Angeles Veterans Medical Center. Data analyzed included patient demographics, medical indications for epinephrine auto-injector prescriptions, and the patient's understanding and use of the device. The mean age of our patients was 50 years. There were 44 men (66.7%) and 22 women (33%). Twenty-three patients were prescribed epinephrine auto-injector for adverse food reactions. Ninety-two percent (92%) of the patients knew how to use their epinephrine auto-injector properly, however, only 58% carried their device with them consistently. Of the patients, 91% understood why the auto-injector was prescribed. Of the total patients prescribed epinephrine auto-injector, 79% refilled their medication before the 1 year expiratidn date. Only 12% of the patients studied had required the use of their auto-injector. Most patients knew how and when to administer their epinephrine auto-injector. Despite detailed instructions in a specialty clinic only a slight majority carried it consistently. These data clearly indicate that further patient education or other measures are needed to improve compliance and effective use. (Allergy Asthma Proc 31:304-307, 2010; doi: 10.2500/aap.2010.31.3351) C1 [Amirzadeh, Ali; Verma, Prashant; Lee, Sabrina; Klaustermeyer, William] Univ Calif Los Angeles, Dept Med, Div Allergy & Immunol, Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Amirzadeh, A (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Dept Allergy & Immunol IIIR, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM aliamirzadeh@gmail.com NR 9 TC 3 Z9 3 U1 0 U2 0 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD JUL-AUG PY 2010 VL 31 IS 4 BP 304 EP 307 DI 10.2500/aap.2010.31.3351 PG 4 WC Allergy SC Allergy GA 648KL UT WOS:000281692400006 PM 20819320 ER PT J AU Banerji, A Rudders, SA Corel, B Garth, AM Clark, S Camargo, CA AF Banerji, Aleena Rudders, Susan A. Corel, Blanka Garth, Alisha M. Clark, Sunday Camargo, Carlos A., Jr. TI Repeat epinephrine treatments for food-related allergic reactions that present to the emergency department SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article DE Adult; allergy; anaphylaxis; antihistamines; atopy; emergency department; epinephrine; food allergy; risk factors; steroids; treatment ID INDUCED ANAPHYLAXIS; MANAGEMENT; COMMUNITY AB To date, there are sparse data on epinephrine treatment for food-related anaphylaxis in adults. We sought to establish the frequency of more than one epinephrine treatment for adult patients who present with food-related anaphylaxis to the emergency department (ED). We performed a chart review, at two academic centers, of all adults presenting to the ED for food allergy (ICD9CM codes 693.1, 995.0, 995.1, 995.3, 995.7, 995.60-995.69, 558.3, 692.5, and 708.X) between January 1, 2001 and December 31, 2006. We focused on causative foods; treatments, including the number of epinephrine treatments given before and during the ED visit; and disposition. Through random sampling and appropriate weighting, the 486 reviewed cases represented a study cohort of 1286 patients. The median age was 36 years and the cohort was 62% women. Shellfish (23%), peanuts (12%), tree nuts (14%), and fish (14%) provoked the allergic reaction most commonly. Most patients (62%; 95% confidence interval [CI], 57-68%) met criteria for food-related anaphylaxis. In the ED, anaphylaxis patients received epinephrine (18%), antihistamines (91%), corticosteroids (81%), and inhaled albuterol (19%). Overall, 17% (95% CI, 9-25%) of patients with food-related anaphylaxis given epinephrine received >1 dose over the course of their reaction. Among anaphylaxis patients admitted to the hospital, only 10% included anaphylaxis in the discharge diagnosis. At ED discharge (82% of patients), 18% were referred to an allergist and 39% were prescribed self-injectable epinephrine. Among ED patients with food-related anaphylaxis treated with epinephrine, 17% were given >1 dose. This study supports the recommendation that patients at risk for food-related anaphylaxis should carry 2 doses of epinephrine. (Allergy Asthma Proc 31:308-316, 2010; doi: 10.2500/aap.2010.31.3375) C1 [Banerji, Aleena; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Dept Med, Boston, MA 02114 USA. [Corel, Blanka; Garth, Alisha M.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Rudders, Susan A.] Childrens Hosp, Div Allergy & Immunol, Boston, MA 02115 USA. [Clark, Sunday] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. RP Banerji, A (reprint author), Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Dept Med, 55 Fruit St,Cox 201, Boston, MA 02114 USA. EM abanerji@partners.org FU Dey FX C. Camargo has consulted for Dey (Napa, California); this project was partly supported by an investigator-initiated research grant to C. Camargo from Dey NR 18 TC 26 Z9 26 U1 0 U2 5 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD JUL-AUG PY 2010 VL 31 IS 4 BP 308 EP 316 DI 10.2500/aap.2010.31.3375 PG 9 WC Allergy SC Allergy GA 648KL UT WOS:000281692400007 PM 20819321 ER PT J AU Serrano-Pozo, A Vega, GL Lutjohann, D Locascio, JJ Tennis, MK Deng, A Atri, A Hyman, BT Irizarry, MC Growdon, JH AF Serrano-Pozo, Alberto Vega, Gloria L. Luetjohann, Dieter Locascio, Joseph J. Tennis, Marsha K. Deng, Amy Atri, Alireza Hyman, Bradley T. Irizarry, Michael C. Growdon, John H. TI Effects of Simvastatin on Cholesterol Metabolism and Alzheimer Disease Biomarkers SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE Alzheimer disease; simvastatin; cholesterol; biomarker ID AMYLOID PRECURSOR PROTEIN; TRANSGENIC MOUSE MODEL; LIPID-LOWERING AGENTS; REDUCTASE INHIBITORS; PLASMA-LEVELS; STATIN USE; COGNITIVE IMPAIRMENT; CEREBROSPINAL-FLUID; INCIDENT DEMENTIA; CONTROLLED TRIAL AB Preclinical and epidemiologic studies suggest a protective effect of statins on Alzheimer disease (AD). Experimental evidence indicates that some statins can cross the blood-brain barrier, alter brain cholesterol metabolism, and may ultimately decrease the production of amyloid-beta (A beta) peptide. Despite these promising leads, clinical trials have yielded inconsistent results regarding the benefits of statin treatment in AD. Seeking to detect a biological signal of statins effect on AD, we conducted a 12-week open-label trial with simvastatin 40 mg/d and then 80 mg/d in 12 patients with AD or amnestic mild cognitive impairment and hypercholesterolemia. We quantified cholesterol precursors and metabolites and AD biomarkers of A beta and tau in both plasma and cerebrospinal fluid at baseline and after the 12-week treatment period. We found a modest but significant inhibition of brain cholesterol biosynthesis after simvastatin treatment, as indexed by a decrease of cerebrospinal fluid lathosterol and plasma 24S-hydroxycholesterol. Despite this effect, there were no changes in AD biomarkers. Our findings indicate that simvastatin treatment can affect brain cholesterol metabolism within 12 weeks, but did not alter molecular indices of AD pathology during this short-term treatment. C1 [Serrano-Pozo, Alberto; Locascio, Joseph J.; Tennis, Marsha K.; Deng, Amy; Atri, Alireza; Hyman, Bradley T.; Irizarry, Michael C.; Growdon, John H.] Massachusetts Gen Hosp, Memory Disorders Unit, Dept Neurol, Boston, MA 02114 USA. [Serrano-Pozo, Alberto; Locascio, Joseph J.; Tennis, Marsha K.; Deng, Amy; Atri, Alireza; Hyman, Bradley T.; Irizarry, Michael C.; Growdon, John H.] Massachusetts Gen Hosp, Massachusetts Alzheimers Dis Res Ctr, Boston, MA 02114 USA. [Serrano-Pozo, Alberto; Locascio, Joseph J.; Atri, Alireza; Hyman, Bradley T.; Growdon, John H.] Harvard Univ, Sch Med, Boston, MA USA. [Atri, Alireza] Vet Adm Bedford Med Ctr, Educ & Clin Ctr, Ctr Translat Cognit Neurosci & Geriatr Res, Bedford, MA USA. [Vega, Gloria L.] Univ Texas SW Med Ctr Dallas, Ctr Human Nutr, Dept Clin Nutr, Dallas, TX 75390 USA. [Luetjohann, Dieter] Univ Bonn, Inst Clin Chem & Pharmacol, D-5300 Bonn, Germany. [Serrano-Pozo, Alberto] Hosp Univ Virgen Rocio, IBiS, Neurol Serv, Seville 41013, Spain. RP Growdon, JH (reprint author), Massachusetts Gen Hosp, Memory Disorders Unit, Dept Neurol, 15 Parkman St,WACC 715, Boston, MA 02114 USA. EM growdon@helix.mgh.harvard.edu RI SERRANO-POZO, ALBERTO/F-5119-2013; OI Atri, Alireza/0000-0003-4405-6973; SERRANO-POZO, ALBERTO/0000-0003-0899-7530 FU Instituto de Salud Carlos III-Fondo de Investigacion Sanitaria, Ministerio de Ciencia e Innovacion, Madrid, Spain [CM06/00161]; Moss Heart Foundation FX Dr Serrano-Pozo was funded by a Research Fellowship from the Instituto de Salud Carlos III-Fondo de Investigacion Sanitaria (CM06/00161, Ministerio de Ciencia e Innovacion, Madrid, Spain). Dr Vega received support from the Moss Heart Foundation. NR 61 TC 25 Z9 25 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2010 VL 24 IS 3 BP 220 EP 226 DI 10.1097/WAD.0b013e3181d61fea PG 7 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 643PJ UT WOS:000281310200002 PM 20473136 ER PT J AU Sano, M Egelko, S Ferris, S Kaye, J Hayes, TL Mundt, JC Donohue, M Walter, S Sun, S Sauceda-Cerda, L AF Sano, Mary Egelko, Susan Ferris, Steven Kaye, Jeffrey Hayes, Tamara L. Mundt, James C. Donohue, Michael Walter, Sarah Sun, Shelly Sauceda-Cerda, Luis TI Pilot Study to Show the Feasibility of a Multicenter Trial of Home-based Assessment of People Over 75 Years Old SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE alzheimer disease; prevention trials; home-based assessment ID PREVENTION INSTRUMENT PROJECT; MILD COGNITIVE IMPAIRMENT; CLINICAL-TRIALS; NEUROPSYCHOLOGICAL ASSESSMENT; ALZHEIMER-DISEASE; DEPRESSION; INVENTORY; DEMENTIA; SCALE AB This report describes a pilot study to evaluate feasibility of new home-based assessment technologies applicable to clinical trials for prevention of cognitive loss and Alzheimer disease. Methods: Community-dwelling nondemented individuals >= 75 years old were recruited and randomized to 1 of 3 assessment methodologies: (1) mail-in questionnaire/ live telephone interviews (MIP); (2) automated telephone with interactive voice recognition (IVR); and (3) internet-based computer Kiosk (KIO). Brief versions of cognitive and noncognitive outcomes were adapted to the different methodologies and administered at baseline and 1-month. An Efficiency measure, consisting of direct staff-to-participant time required to complete assessments, was also compared across arms. Results: Forty-eight out of 60 screened participants were randomized. The dropout rate across arms from randomization through 1-month was different: 33% for KIO, 25% for IVR, and 0% for MIP (Fisher Exact Test P = 0.04). Nearly all participants who completed baseline also completed 1-month assessment (38 out of 39). The 1-way ANOVA across arms for total staff-to-participant direct contact time (ie, training, baseline, and 1-month) was significant: F (2,33) = 4.588; P = 0.017, with lowest overall direct time in minutes for IVR (Mn - 44.4; SD = 21.5), followed by MIP (Mn = 74.9; SD = 29.9), followed by KIO (Mn = 129.4; SD = 117.0). Conclusions: In this sample of older individuals, a higher dropout rate occurred in those assigned to the high-technology assessment techniques; however, once participants had completed baseline in all 3 arms, they continued participation through 1 month. High-technology home-based assessment methods, which do not require live testers, began to emerge as more time-efficient over the brief time of this pilot, despite initial time-intensive participant training. C1 [Sano, Mary; Egelko, Susan] Mt Sinai Sch Med, New York, NY 10029 USA. [Ferris, Steven] NYU, Sch Med, New York, NY USA. [Sano, Mary; Egelko, Susan] James J Peters VAMC, Bronx, NY USA. [Ferris, Steven] Nathan S Kline Inst Psychiat Res, Orangeburg, NY USA. [Kaye, Jeffrey; Hayes, Tamara L.; Sauceda-Cerda, Luis] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Mundt, James C.] Healthcare Technol Syst, Madison, WI USA. [Donohue, Michael; Walter, Sarah; Sun, Shelly] UCSD, La Jolla, CA USA. RP Sano, M (reprint author), Mt Sinai Sch Med, New York, NY 10029 USA. EM mary.sano@mssm.edu OI Kaye, Jeffrey/0000-0002-9971-3478; Ferris, Steven/0000-0001-8641-6223 FU NIA [U01AG10483, P50AG005138, P30AG008051, P30AG024978, P30-AG024978, P30-AG08017]; Intel Corporation FX Supported by these NIA grants: U01AG10483, P50AG005138, P30AG008051, and P30AG024978. Development of the Kiosk and MedTracker was supported in part by grants from NIA (P30-AG024978; P30-AG08017) and Intel Corporation. NR 26 TC 4 Z9 4 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2010 VL 24 IS 3 BP 256 EP 263 DI 10.1097/WAD.0b013e3181d7109f PG 8 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 643PJ UT WOS:000281310200007 PM 20592583 ER PT J AU Leonardi, S Rao, SV Harrington, RA Bhatt, DL Gibson, CM Roe, MT Kochman, J Huber, K Zeymer, U Madan, M Gretler, DD McClure, MW Paynter, GE Thompson, V Welsh, RC AF Leonardi, Sergio Rao, Sunil V. Harrington, Robert A. Bhatt, Deepak L. Gibson, C. Michael Roe, Matthew T. Kochman, Janusz Huber, Kurt Zeymer, Uwe Madan, Mina Gretler, Daniel D. McClure, Matthew W. Paynter, Gayle E. Thompson, Vivian Welsh, Robert C. TI Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI) SO AMERICAN HEART JOURNAL LA English DT Article ID OF-FUNCTION POLYMORPHISM; ST-SEGMENT ELEVATION; MYOCARDIAL-INFARCTION; ANTIPLATELET THERAPY; PLATELET INHIBITION; ACTIVE METABOLITE; ASPIRIN; EVENTS; CANGRELOR; RESPONSIVENESS AB Despite current dual-antiplatelet therapy with aspirin and clopidogrel, adverse clinical events continue to occur during and after percutaneous coronary intervention (PCI). The failure of clopidogrel to provide optimal protection may be related to delayed onset of action, interpatient variability in its effect, and an insufficient level of platelet inhibition. Furthermore, the irreversible binding of clopidogrel to the P2Y(12) receptor for the life span of the platelet is associated with increased bleeding risk especially during urgent or emergency surgery. Novel antiplatelet agents are required to improve management of patients undergoing PCI. Elinogrel is a potent, direct-acting (ie, non-prodrug), selective, competitive, and reversible P2Y(12) inhibitor available in both intravenous and oral formulations. The INNOVATE-PCI study is a phase 2 randomized, double-blind, clopidogrel-controlled trial to evaluate the safety, tolerability, and preliminary efficacy of this novel antiplatelet agent in patients undergoing nonurgent PCI. (Am Heart J 2010; 160: 65-72.) C1 [Leonardi, Sergio] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27705 USA. [Leonardi, Sergio] Fdn IRCCS Policlin San Matteo, Dept Cardiol, Pavia, Italy. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Gibson, C. Michael] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Kochman, Janusz] Med Univ Warsaw, Chair & Dept Cardiol 1, Warsaw, Poland. [Huber, Kurt] Wilhelminen Hosp, Dept Med 3, Vienna, Austria. [Zeymer, Uwe] Inst Herzinfarktforsch Ludwigshafen, Ludwigshafen, Germany. [Madan, Mina] Sunnybrook Hlth Sci Ctr, Schulich Heart Ctr, Toronto, ON M4N 3M5, Canada. [Madan, Mina] Univ Toronto, Toronto, ON, Canada. [Gretler, Daniel D.; McClure, Matthew W.] Portola Pharmaceut Inc, San Francisco, CA USA. [Welsh, Robert C.] Mazankowski Alberta Heart Inst, Edmonton, AB, Canada. [Welsh, Robert C.] Univ Alberta, Edmonton, AB, Canada. RP Leonardi, S (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, 2400 Pratt St, Durham, NC 27705 USA. EM sergio.leonardi@duke.edu FU Astra Zeneca; Bristol-Myers Squibb; Eisai; Ethicon; Heartscape; Sanofi Aventis; Medicines Company; Eli Lilly FX D. L. B.: research grants from Astra Zeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis, and The Medicines Company. U. Z.: research grants from Bristol-Myers Squibb, Sanofi Aventis, The Medicines Company, and Eli Lilly. NR 28 TC 48 Z9 52 U1 0 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 JUL PY 2010 VL 160 IS 1 BP 65 EP 72 DI 10.1016/j.ahj.2010.04.008 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 619OV UT WOS:000279440400011 PM 20598974 ER PT J AU Spatz, ES Ross, JS Desai, MM Canavan, ME Krumholz, HM AF Spatz, Erica S. Ross, Joseph S. Desai, Mayur M. Canavan, Maureen E. Krumholz, Harlan M. TI Beyond insurance coverage: Usual source of care in the treatment of hypertension and hypercholesterolemia. Data from the 2003-2006 National Health and Nutrition Examination Survey SO AMERICAN HEART JOURNAL LA English DT Article ID IMPROVING PRIMARY-CARE; CHRONIC ILLNESS; UNITED-STATES; CARDIOVASCULAR-DISEASE; CHOLESTEROL TREATMENT; US ADULTS; SERVICES; ACCESS; RISK; OUTCOMES AB Background Expanding insurance coverage, while necessary, may not be sufficient to ensure high-quality care for adults with cardiovascular disease. We sought to examine the association between having a usual source of care (USOC) and receiving medication treatment of hypertension and hypercholesterolemia. Methods Using the 2003-2006 National Health and Nutrition Examination Survey, we categorized USOC (a place to go when sick or need medical advice) and insurance status in adults >= 35 years old with an indication for medication treatment of hypertension (n = 3,142) and hypercholesterolemia (n = 1,134), determined using the Joint National Committee 7 and Adult Treatment Panel III recommendations, respectively. Multivariable logistic regression modeling was used to determine the independent effect of USOC on receiving treatment of hypertension and hypercholesterolemia, controlling for age, sex, race/ethnicity, insurance status, and comorbidities. Separate multivariable models were examined stratified by insurance status. Results Among subjects with an indication for treatment of hypertension and hypercholesterolemia, 32.4% and 42.0% were untreated, respectively. When compared with adults with a USOC, adults without a USOC were more likely to be untreated for hypertension (adjusted prevalence ratio [aPR] 2.43, 95% CI 1.88-2.85) and hypercholesterolemia (aPR 1.79, 95% CI 1.31-2.13). In stratified analyses among subjects with insurance, no USOC remained associated with being untreated (hypertension, aPR 2.58, 95% CI 1.88-3.08; hypercholesterolemia, aPR 1.65, 95% CI 0.97-2.18). Conclusions Absence of a USOC was associated with being untreated for hypertension and hypercholesterolemia, even among individuals with insurance, suggesting that efforts to improve chronic disease management should also facilitate access to a regular source of care. (Am Heart J 2010; 160: 115-21.) C1 [Spatz, Erica S.; Krumholz, Harlan M.] Yale Univ, Sch Med, Robert Wood Johnson Clin Scholars Program, New Haven, CT 06520 USA. [Ross, Joseph S.] Mt Sinai Sch Med, Dept Geriatr & Palliat Med, New York, NY USA. [Ross, Joseph S.] James J Peters VA Med Ctr, HSR&D Res Enhancement Award Program, Bronx, NY USA. [Ross, Joseph S.] James J Peters VA Med Ctr, Geriatr Res Educ & Clin Ctr, Bronx, NY USA. [Desai, Mayur M.; Canavan, Maureen E.] Yale Univ, Sch Publ Hlth, Div Chron Dis Epidemiol, New Haven, CT 06520 USA. [Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Med, Sect Cardiolovasc Med, New Haven, CT 06520 USA. [Krumholz, Harlan M.] Yale Univ, Sch Epidemiol & Publ Hlth, Sect Hlth Policy & Adm, New Haven, CT 06520 USA. [Krumholz, Harlan M.] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. RP Spatz, ES (reprint author), Yale Univ, Sch Med, Robert Wood Johnson Clin Scholars Program, 333 Cedar St,SHM IE 61, New Haven, CT 06520 USA. EM erica.spatz@yale.edu FU NIA NIH HHS [K08 AG032886-02, K08 AG032886] NR 41 TC 14 Z9 14 U1 0 U2 5 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 JUL PY 2010 VL 160 IS 1 BP 115 EP 121 DI 10.1016/j.ahj.2010.04.013 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 619OV UT WOS:000279440400018 PM 20598981 ER PT J AU Donohue, JM Zhang, YT Lave, JR Gellad, WF Men, A Perera, S Hanlon, JT AF Donohue, Julie M. Zhang, Yuting Lave, Judith R. Gellad, Walid F. Men, Aiju Perera, Subashan Hanlon, Joseph T. TI The Medicare drug benefit (Part D) and treatment of heart failure in older adults SO AMERICAN HEART JOURNAL LA English DT Article ID RANDOMIZED-TRIAL; ELDERLY-PATIENTS; BETA-BLOCKERS; ADHERENCE; THERAPY; NONADHERENCE; MORTALITY; OUTCOMES; COST AB Background Adherence to pharmacotherapy for heart failure is poor among older adults in part because of high prescription drug costs. We examined the impact of improvements in drug coverage under Medicare Part D on utilization of, and adherence to, medications for heart failure in older adults. Methods We used a quasi-experimental approach to analyze pharmacy claims for 6,950 individuals aged >= 65 years with heart failure enrolled in a Medicare managed care organization 2 years before and after Part D's implementation. We compared prescription fill patterns among individuals who moved from limited (quarterly benefits caps of $150 or $350) or no drug coverage to Part D in 2006 with those who had generous employer-sponsored coverage throughout the study period. Results Individuals who previously lacked drug coverage filled approximately 6 more heart failure prescriptions annually after Part D (adjusted ratio of prescription counts = 1.36, 95% CI 1.29-1.44, P < .0001 relative to the comparison group). Those previously lacking drug coverage were more likely to fill prescriptions for an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker plus a beta-blocker after Part D (adjusted ratio of odds ratios = 1.73, 95% CI 1.42-2.10, P < .0001) and more likely to be adherent to such pharmacotherapy (adjusted ratio of odds ratios = 2.95, 95% CI 1.85-4.69, P < .0001) relative to the comparison group. Conclusions Medicare Part D was associated with improved access to medications and adherence to pharmacotherapy in older adults with heart failure. (Am Heart J 2010; 160: 159-65.) C1 [Donohue, Julie M.; Zhang, Yuting; Lave, Judith R.; Men, Aiju] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, Pittsburgh, PA 15261 USA. [Gellad, Walid F.] Univ Pittsburgh, Dept Med Gen Internal Med, Pittsburgh, PA 15261 USA. [Gellad, Walid F.; Hanlon, Joseph T.] Pittsburgh Vet Affairs Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Gellad, Walid F.] RAND Corp, Pittsburgh, PA USA. [Perera, Subashan] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Perera, Subashan; Hanlon, Joseph T.] Univ Pittsburgh, Dept Geriatr Med, Pittsburgh, PA 15261 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Sch Pharm, Dept Pharm, Pittsburgh, PA 15261 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Sch Pharm, Dept Therapeut, Pittsburgh, PA 15261 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Clin & Translat Sci Inst, Pittsburgh, PA 15261 USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Donohue, JM (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Hlth Policy & Management, 130 DeSoto St,Crabtree Hall A613, Pittsburgh, PA 15261 USA. EM jdonohue@pitt.edu RI Max, Mad/E-5238-2010; Perera, Subashan/D-7603-2014; OI Max, Mad/0000-0001-6966-6829; Donohue, Julie/0000-0003-2418-6017; Zhang, Yuting/0000-0002-6460-6779 FU NCATS NIH HHS [KL2 TR000146]; NCRR NIH HHS [KL2 RR024154, KL2 RR024154-04, 05 KL2 RR024154-04]; NIA NIH HHS [P30 AG024827] NR 28 TC 19 Z9 19 U1 1 U2 4 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 JUL PY 2010 VL 160 IS 1 BP 159 EP 165 DI 10.1016/j.ahj.2010.04.023 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 619OV UT WOS:000279440400024 PM 20598987 ER PT J AU Shao, YH Croitor, SK Moreyra, AE Wilson, AC Kostis, WJ Cosgrove, NM Kostis, JB AF Shao, Yu-Hsuan Croitor, Sherryl K. Moreyra, Abel E. Wilson, Alan C. Kostis, William J. Cosgrove, Nora M. Kostis, John B. CA MIDAS Study Grp MIDAS II TI Comparison of Hospital Versus Out of Hospital Coronary Death Rates in Women and Men SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; SEX-DIFFERENCES; HEART-DISEASE; CASE-FATALITY; GENDER-DIFFERENCES; METABOLIC SYNDROME; POPULATION; MORTALITY; SURVIVAL; MONICA AB Young women hospitalized with acute myocardial infarction (MI) have greater in-hospital mortality than young men. However, the reasons for this difference have not been well characterized. We analyzed the data from 423,067 patients (247,701 men and 175,366 women) who were discharged with the diagnosis of MI from nonfederal hospitals in New Jersey and 355,569 coronary heart disease (CHD) deaths in New Jersey from 1990 to 2004 in 4 age strata: 35 to 54, 55 to 64, 65 to 74 and >= 75 years. Of the patients hospitalized for MI, young (35 to 54 years) women had greater in-hospital mortality than young men (5.2% vs 2.5%, adjusted odds ratio 1.64, 95% confidence interval 1.48 to 1.81, p <0.0001). However, in a community-wide analysis, when the total out-of-hospital CHD deaths in New Jersey were examined, young women had a lower out-of-hospital death rate than young men (11 vs 55/100,000). Statewide, young women were 4 times less likely to be hospitalized for MI (78 vs 297/100,000, relative risk 0.26), but they were only 1/2 as likely to die from MI in the hospital (7 vs 17/100,000, relative risk 0.41). Thus, women had a greater odds ratio for in-hospital mortality but a lower odds ratio for out-of-hospital CHD death than men. In conclusion, the greater in-hospital mortality of young women hospitalized for MI compared to young men could be explained in part by the finding that young men were more likely to have out-of-hospital CHD death. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:26-30) C1 [Shao, Yu-Hsuan; Moreyra, Abel E.; Wilson, Alan C.; Cosgrove, Nora M.; Kostis, John B.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. [Croitor, Sherryl K.] St Lukes Roosevelt Hosp, New York, NY 10025 USA. [Kostis, William J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kostis, JB (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. EM kostis@umdnj.edu NR 27 TC 3 Z9 4 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 1 PY 2010 VL 106 IS 1 BP 26 EP 30 DI 10.1016/j.amjcard.2010.02.013 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 622JX UT WOS:000279659700005 PM 20609642 ER PT J AU Avelar, E Durst, R Rosito, GA Thangaroopan, M Kumar, S Tournoux, F Chan, RC Hung, J Hoffmann, U Abbara, S Brady, T Cury, RC AF Avelar, Erick Durst, Ronen Rosito, Guido A. Thangaroopan, Molly Kumar, Simi Tournoux, Francois Chan, Raymond C. Hung, Judy Hoffmann, Udo Abbara, Suhny Brady, Thomas Cury, Ricardo C. TI Comparison of the Accuracy of Multidetector Computed Tomography Versus Two-Dimensional Echocardiography to Measure Left Atrial Volume SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID TIME 3-DIMENSIONAL ECHOCARDIOGRAPHY; SIZE AB Left atrial (LA) volume is an important prognostic factor in cardiovascular disease. Multidetector computed tomography (MDCT) is an emerging cardiac imaging modality; however, its accuracy in measuring the LA volume has not been well studied. The aim of our study was to determine the accuracy of MDCT in quantifying the LA volume. A total of 48 patients underwent MDCT and 2-dimensional (2D) echocardiography (2DE) on the same day. The area length and Simpson's methods were used to obtain the 2D echocardiographic LA volume. The LA volume assessment by MDCT was obtained using the modified Simpson's method. Four artificial phantoms were created, and their true volume was assessed by an independent observer using both imaging modalities. The correlation between the LA volume by MDCT and 2DE was significant (r = 0.68). The mean 2D echocardiographic LA volume was lower than the LA volume obtained with MDCT (2DE 79 +/- 37 vs MDCT 103 +/- 32, p <0.05). In the phantom experiment, the volume obtained using MDCT and 2DE correlated significantly with the true volume (r = 0.97, p <0.05 vs r = 0.96, p <0.05, respectively). However, the mean 2D echocardiographic phantom volume was 16% lower than the true volume (2DE, Simpson's method 53 +/- 24 vs the true volume 61 +/- 24, p <0.05). The mean volume calculated using MDCT did not differ from the true volume (MDCT 60 +/- 21 vs true volume 61 +/- 24, p = NS). 2DE appeared to systematically underestimate the LA volume compared to phantom and cardiac MDCT, suggesting that different normal cutoff values should be used for each modality. In conclusion, LA volume quantification using MDCT is an accurate and feasible method. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:104-109) C1 [Avelar, Erick] Univ Connecticut, Ctr Hlth, Dept Cardiol, Farmington, CT USA. [Avelar, Erick; Durst, Ronen; Tournoux, Francois; Hung, Judy] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Rosito, Guido A.; Thangaroopan, Molly; Hoffmann, Udo; Abbara, Suhny; Brady, Thomas; Cury, Ricardo C.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Rosito, Guido A.] Univ Fed Ciencias Saude Porto Alegre, Porto Alegre, RS, Brazil. [Kumar, Simi] Univ Connecticut, Ctr Hlth, Dept Internal Med, Farmington, CT USA. [Chan, Raymond C.] Philips Res N Amer, Clin Sites Res, New York, NY USA. [Cury, Ricardo C.] Baptist Hosp Miami, Cardiovasc MR & CT Program, Miami, FL USA. [Cury, Ricardo C.] Baptist Cardiac & Vasc Inst, Miami, FL USA. RP Avelar, E (reprint author), Univ Connecticut, Ctr Hlth, Dept Cardiol, Farmington, CT USA. EM eavelar@uchc.edu NR 14 TC 20 Z9 21 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 JUL 1 PY 2010 VL 106 IS 1 BP 104 EP 109 DI 10.1016/j.amjcard.2010.02.021 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 622JX UT WOS:000279659700019 PM 20609656 ER PT J AU Agoston, ES Robinson, SF Mehra, KK Birch, C Semmel, D Mirkovic, J Haddad, RI Posner, MR Kindelberger, D Krane, JF Brodsky, J Crum, CP AF Agoston, Elin S. Robinson, Stephen F. Mehra, Karishma K. Birch, Chandler Semmel, Dana Mirkovic, Jelena Haddad, Robert I. Posner, Marshall R. Kindelberger, David Krane, Jeffrey F. Brodsky, Joshua Crum, Christopher P. TI Polymerase Chain Reaction Detection of HPV in Squamous Carcinoma of the Oropharynx SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Polymerase chain reaction; In situ hybridization; Human papillomavirus; Oropharynx; Squamous cell carcinoma; Molecular diagnostics ID HUMAN-PAPILLOMAVIRUS TYPE-16; ONCOGENIC HUMAN-PAPILLOMAVIRUS; CELL-CYCLE ARREST; NECK-CANCER; TONSILLAR CARCINOMA; P16(INK4A) EXPRESSION; CONSENSUS PRIMERS; CERVICAL-CANCER; PALATINE TONSIL; ORAL-CAVITY AB Human papillomavirus (HPV) testing is routinely performed on oropharyngeal carcinomas. We compared the Access Genetics (Minneapolis, MN) polymerase chain reaction (PCR) assay (AGPCR), DNA-DNA in situ hybridization (ISH; Ventana, Tucson, AZ), and HP V-16 E7 PCR amplification in consecutively accessioned oropharyngeal cancers. We tested 126 cases by both PCR methods; 102 were positive by either for a maximum positive rate (MPR) of 81.0%. Relative to the MPR, the sensitivities of AGPCR and E7 PCR were 90.2% and 72.5%, respectively. Of 17 AGPCR+ cases tested by ISH, 14/14 unequivocally positive/negative were concordant. All cases (97/97) positive by either PCR assay were positive for p16. There was no relationship between level of histologic differentiation and HPV status. ISH and AGPCR have comparable performance for the detection of HP V in orophatyngeal carcinomas. PCR is a suitable and economical assay that is comparable to ISH in sensitivity and may provide logistical advantages relative to ISH for assessing HPV status in orophatyngeal malignancies. However, it is imperative that appropriate sensitivity controls be in place for such assays. C1 [Agoston, Elin S.; Mehra, Karishma K.; Birch, Chandler; Semmel, Dana; Kindelberger, David; Krane, Jeffrey F.; Brodsky, Joshua; Crum, Christopher P.] Brigham & Womens Hosp, Div Womens & Perinatal Pathol, Dept Pathol, Boston, MA 02115 USA. [Haddad, Robert I.; Posner, Marshall R.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Med Oncol, Head & Neck Oncol Program, Boston, MA 02115 USA. [Haddad, Robert I.; Posner, Marshall R.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Robinson, Stephen F.] Boston Univ, Boston, MA 02215 USA. [Mirkovic, Jelena] Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Crum, CP (reprint author), Brigham & Womens Hosp, Div Womens & Perinatal Pathol, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RI Mirkovic, Jelena/A-6253-2013 NR 46 TC 20 Z9 20 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JUL PY 2010 VL 134 IS 1 BP 36 EP 41 DI 10.1309/AJCP1AAWXE5JJCLZ PG 6 WC Pathology SC Pathology GA 613IM UT WOS:000278972600006 PM 20551264 ER PT J AU Mahalingam, M Hoang, MP AF Mahalingam, Meera Hoang, Mai P. TI D2-40 Expression in Primary Scarring and Nonscarring Alopecia SO AMERICAN JOURNAL OF DERMATOPATHOLOGY LA English DT Article DE alopecia; scarring; nonscarring; D2-40 ID BULGE REGION; PODOPLANIN; MARKER; CARCINOMAS; NESTIN; CELLS; SKIN AB The pathogenesis of scarring alopecia is believed to be related to damage to stem cells within, and outside the confines of, the follicular bulge region. Scattered reports indicate that D2-40, a monoclonal antibody that specifically detects a fixation-resistant epitope on podoplanin, highlights the basal cell layer of the outer root sheath. Given this, we sought to ascertain involvement of the same in a total of 52 cases of alopecia (33 scarring and 19 nonscarring). D2-40 expression, noted in the peripheral layer of the outer root sheath (above and below attachment of the pilar muscle), was similar in 24/33 (73%) and increased in 9/33 (27%) in the infundibular region of cases of scarring alopecia in comparison to its expression in 17/19 (90%; no expression noted in the other 2) of cases of nonscarring alopecia. The absence of a unifying diagnosis in entities demonstrating an increase precludes any correlation from being made regarding D2-40 expression and histologic diagnosis. However, more recently, podoplanin has been shown to be a novel Fos target gene in some skin cancers. Thus, from a scientific perspective, involvement of Fos-dependent transcription mechanisms in the etiopathogenesis of select scarring alopecias does not seem entirely unreasonable although studies defining the role of the Fos-podoplanin axis in development of the normal hair follicle are required before a definitive conclusion can be drawn. C1 [Mahalingam, Meera] Boston Univ, Sch Med, Dermatopathol Sect, Dept Dermatol, Boston, MA 02118 USA. [Hoang, Mai P.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hoang, Mai P.] Harvard Univ, Sch Med, Boston, MA USA. RP Mahalingam, M (reprint author), Boston Univ, Sch Med, Dermatopathol Sect, Dept Dermatol, 609 Albany St,J-301, Boston, MA 02118 USA. EM mmahalin@bu.edu OI Mahalingam, Meera/0000-0002-2800-9985 NR 13 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0193-1091 J9 AM J DERMATOPATH JI Am. J. Dermatopathol. PD JUL PY 2010 VL 32 IS 5 BP 427 EP 431 DI 10.1097/DAD.0b013e3181c34242 PG 5 WC Dermatology SC Dermatology GA 614VG UT WOS:000279087300002 PM 20414092 ER PT J AU Barg, FK Mavandadi, S Givens, JL Knott, K Zubritsky, C Oslin, DW AF Barg, Frances K. Mavandadi, Shahrzad Givens, Jane L. Knott, Kathryn Zubritsky, Cynthia Oslin, David W. TI When Late-Life Depression Improves: What Do Older Patients Say About Their Treatment? SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Depression intervention; patient perception; intervention attributes; older adults; patient-centered care ID GERIATRIC DEPRESSION; PRIMARY-CARE; RANDOMIZED-TRIAL; MIXED-METHODS; PRISM-E; ADULTS; SCALE; PREFERENCES; DISABILITY; COMMUNITY AB Introduction: Experts speculate about the mechanisms through which depression interventions operate. However, little is known about what patients think are the "active ingredients" in depression treatment. Given the importance of patient-centered care, understanding this dimension of the provider-intervention-patient interaction provides a missing piece to designing interventions that are congruent with patients' beliefs and preferences about treatment initiation, treatment adherence, and treatment maintenance. Methods: The authors used a parallel mixed methods design to identify a purposive sample of 24 older adults with depression who participated in either an integrated care or an enhanced referral model of depression treatment. Open-ended semistructured interviews were used to identify patient perceptions about the benefits of depression treatment during the study. Quantitative assessments of depression status were made at the completion of participation in the treatment study and 6 months postparticipation. Results: Twelve of 24 participants achieved remission of their depression symptoms, with the remainder showing no improvement or a partial response to treatment. Participants who achieved and sustained a remission of their depression symptoms (N = 7) attributed their improvement to clear psychoeducational support with their depression care providers and described an ability to affect the outcome of their treatment. Participants who improved but then relapsed described their treatment in vague terms, referring to social aspects of participation. Participants who did not achieve remission ascribed recognition and treatment of their depression to forces outside themselves and described few details about their treatment. Conclusion: Clinicians should consider patient perceptions of the benefits of depression treatment as they discuss and implement therapeutic interventions with depressed older adults. (Am J Geriatr Psychiatry 2010; 18: 596-605) C1 [Barg, Frances K.; Knott, Kathryn] Univ Penn, Dept Family Med & Community Hlth, Philadelphia, PA 19104 USA. [Barg, Frances K.] Univ Penn, Dept Anthropol, Philadelphia, PA 19104 USA. [Mavandadi, Shahrzad; Oslin, David W.] Philadelphia Vet Affairs Med Ctr, MIRECC, Philadelphia, PA USA. [Givens, Jane L.] Harvard Univ, Sch Med, Inst Aging Res, Boston, MA USA. [Oslin, David W.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. RP Barg, FK (reprint author), Univ Penn, Dept Family Med & Community Hlth, 2 Gates HUP,3400 Spruce St, Philadelphia, PA 19104 USA. EM bargf@uphs.upenn.edu FU Advanced Center for Intervention and Services Research; NIH/NIMH; P30-MH066270; Substance Abuse and Mental Health Services Administration (SAMHSA); Center for Mental Health Services (CMHS); Center for Substance Abuse Treatment (CSAT); Center for Substance Abuse and Prevention (CSAP); Department of Veterans Affairs (VA); Health Resources and Services Administration (HRSA); Centers for Medicare and Medicaid Services (CMS) FX This work was supported by the Advanced Center for Intervention and Services Research, NIH/NIMH, P30-MH066270, Oslin, PI. PRISM-E was a collaborative research study funded by the Substance Abuse and Mental Health Services Administration (SAMHSA), including its three centers: Center for Mental Health Services (CMHS), Center for Substance Abuse Treatment (CSAT), and the Center for Substance Abuse and Prevention (CSAP). Additional support and funding was provided by the Department of Veterans Affairs (VA), the Health Resources and Services Administration (HRSA), and the Centers for Medicare and Medicaid Services (CMS). NR 34 TC 2 Z9 2 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JUL PY 2010 VL 18 IS 7 BP 596 EP 605 DI 10.1097/JGP.0b013e3181b7f0f9 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 615WP UT WOS:000279169100005 PM 20593539 ER PT J AU Sultzer, DL Melrose, RJ Harwood, DG Campa, O Mandelkern, MA AF Sultzer, David L. Melrose, Rebecca J. Harwood, Dylan G. Campa, Olivia Mandelkern, Mark A. TI Effect of Memantine Treatment on Regional Cortical Metabolism in Alzheimer's Disease SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Alzheimer's disease; PET; therapeutics; memantine ID NEUROBEHAVIORAL RATING-SCALE; CEREBRAL GLUCOSE-METABOLISM; LONGITUDINAL PET EVALUATION; DEMENTIA; MODERATE; CORTEX; TRIAL; HYPOMETABOLISM; RIVASTIGMINE; PROGRESSION AB Objectives: Cortical systems involved in the response to medication treatment for Alzheimer's disease (AD) are poorly understood. Preclinical studies have demonstrated the effect of memantine on neuroreceptors and cell physiology, although the impact of treatment on cortical activity in vivo is not known. Design: (18)F-fluorodeoxyglucose positron emission tomography (PET) imaging and clinical assessment before and after open-label memantine treatment. Participants/Setting: Seventeen outpatients with probable AD on stable cholinesterase inhibitor medication. Intervention: Memantine up to 10 mg twice daily for 10 weeks. Measurements: Voxel-based analyses of change in cortical metabolic activity; Mattis Dementia Rating Scale (DRS), and Neurobehavioral Rating Scale (NRS). Results: Mean age was 81 years; mean Mini-Mental State Examination score was 19.4. Compared with baseline, metabolic activity was significantly higher after 10 weeks memantine treatment in two cortical regions bilaterally: the inferior temporal gyrus (BA 20) and the angular gyrus/supramarginal gyrus (BA 39, 40). There was no significant relationship between change in DRS score and change in cortical metabolism, although change in NRS score was associated with the extent of metabolic change in the right parietal and temporal cortex. Conclusion: Metabolic activity in bilateral inferior parietal and temporal cortex increases during 10 weeks of memantine treatment in patients with AD. PET imaging can reveal functional effects of medications on neural activity and may help to define critical mechanisms involved in drug treatment. (Am J Geriatr Psychiatry 2010; 18: 606-614) C1 [Sultzer, David L.; Melrose, Rebecca J.; Harwood, Dylan G.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Sultzer, David L.; Melrose, Rebecca J.; Harwood, Dylan G.; Campa, Olivia] VA Greater Los Angeles Healthcare Syst, Psychiat & Mental Hlth Serv, Irvine, CA USA. [Mandelkern, Mark A.] VA Greater Los Angeles Healthcare Syst, Nucl Med Serv, Irvine, CA USA. [Mandelkern, Mark A.] Univ Calif Irvine, Dept Phys, Irvine, CA 92717 USA. RP Sultzer, DL (reprint author), 3 South,116AE,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM dsultzer@ucla.edu FU Forest Research Institute; Department of Veterans Affairs; Eli Lilly; Astra Zeneca FX This work was supported by Forest Research Institute and the Department of Veterans Affairs.; Dr. Sultzer reports receiving consultation fees from Eli Lilly and Astra Zeneca. NR 37 TC 5 Z9 5 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JUL PY 2010 VL 18 IS 7 BP 606 EP 614 DI 10.1097/JGP.0b013e3181ca3a4e PG 9 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 615WP UT WOS:000279169100006 PM 20220580 ER PT J AU Castellone, DD Van Cott, EM AF Castellone, Donna D. Van Cott, Elizabeth M. TI Reply to "A comment on laboratory monitoring of new anticoagulants" SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter C1 [Castellone, Donna D.] Siemens Healthcare Diagnost, Tarrytown, NY USA. [Van Cott, Elizabeth M.] Massachusetts Gen Hosp, Dept Pathol, Coagulat Lab, Boston, MA 02114 USA. RP Castellone, DD (reprint author), Siemens Healthcare Diagnost, Tarrytown, NY USA. NR 1 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 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD JUL PY 2010 VL 85 IS 7 BP 546 EP 546 DI 10.1002/ajh.21718 PG 1 WC Hematology SC Hematology GA 620NI UT WOS:000279506200027 ER PT J AU Spiegel, BMR Bolus, R Desai, AA Zager, P Parker, T Moran, J Bolus, S Solomon, MD Khawar, O Gitlin, M Sul, H Talley, J Nissenson, A AF Spiegel, Brennan M. R. Bolus, Roger Desai, Amar A. Zager, Philip Parker, Tom Moran, John Bolus, Sally Solomon, Matthew D. Khawar, Osman Gitlin, Matthew Sul, Hack Talley, Jennifer Nissenson, Allen TI Dialysis Practices That Distinguish Top-Versus Bottom-Performing Facilities by Hemoglobin Outcomes SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Dialysis; anemia; best practice; outcomes ID INCIDENT HEMODIALYSIS-PATIENTS; ANEMIA MANAGEMENT; MORTALITY; ASSOCIATION; MORBIDITY; ADEQUACY AB Background: Because there is wide variation in outcomes across dialysis facilities, it is possible that top-performing units use practices not shared by others. The Identifying Best Practices in Dialysis (IBPiD) Study seeks to identify practices that distinguish top-from bottom-performing facilities by key outcomes, including achievement of recommended hemoglobin targets. Study Design: Observational study with cross-sectional study ascertainment of predictors and outcomes. Predictors: Facility dialysis practices ascertained using practice surveys of dialysis staff who indicated their level of agreement that each practice occurs in their facility (1-6 on a Likert scale). Setting & Participants: 423 personnel in 90 dialysis facilities from 1 for-profit and 2 not-for-profit dialysis organizations. Outcomes: Percentage of patients per month per facility with hemoglobin levels of 11-12 g/dL. We divided facilities by median into top-versus bottom-performing groups and compared mean scores for each practice using t tests. We report practices that were statistically significant and achieved at least a medium effect size (ES) >= 0.4. Results: 17 of 155 tested predictors were significant. Achievement of hemoglobin level targets was related most strongly to the use of chairside computers (ES, 0.8 [95% CI, 0.4-1.4]), extent/quality of educational videos (ES, 0.6 [95% CI, 0.2-1.1]), frequency of calling per diem staff if short staffed (ES, 0.6 [95% CI, 0.21-1.1]), policy that nurses pass written competency examinations before hire (ES, 0.6 [95% CI, 0.2-1.0]), and technician cannulation mastery (ES, 0.6 [95% CI, 0.2-1.1]). Limitations: This is a cross-sectional study that can address only associations, not causations. Future research should measure the longitudinal predictive value of these practices. Conclusions: High-performing facilities report more effective education programs, better staff management, higher staff competency, and higher use of chairside computers, a potential marker of information technology proficiency. This suggests that hemoglobin level management is enhanced by processes reflecting a coordinated multidisciplinary environment. Am J Kidney Dis 56:86-94. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use. C1 [Spiegel, Brennan M. R.] Univ Calif Los Angeles, VA Ctr Outcomes Res & Educ, VA Greater Los Angeles Healthcare Syst, David Geffen Sch Med,Dept Med, Los Angeles, CA 90073 USA. [Desai, Amar A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Desai, Amar A.; Solomon, Matthew D.] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. [Zager, Philip] DCI, Nashville, TN USA. [Parker, Tom] Renal Ventures Managements LLC, Lakewood, CO USA. [Moran, John] Satellite Healthcare, Mountain View, CA USA. [Gitlin, Matthew] Amgen Inc, Thousand Oaks, CA 91320 USA. [Nissenson, Allen] DaVita Inc, Segundo, CA USA. RP Spiegel, BMR (reprint author), Univ Calif Los Angeles, VA Ctr Outcomes Res & Educ, VA Greater Los Angeles Healthcare Syst, David Geffen Sch Med,Dept Med, 11301 Wilshire Blvd,Bldg 115,Rm 215, Los Angeles, CA 90073 USA. EM bspiegel@mednet.ucla.edu FU Renal Physicians Association; American Nephrology Nurses Association; Amgen Inc FX This study was endorsed and supported by the Renal Physicians Association and American Nephrology Nurses Association. Special thanks to the participating dialysis organizations: Dialysis Clinic Inc, Renal Ventures Management LLC, and Satellite Healthcare. The opinions and assertions contained herein are the sole views of the authors and are not to be construed as official or as reflecting the views of the Department of Veteran Affairs.; Dr Spiegel, as the Principal Investigator of this investigator-initiated study, received a research grant from Amgen Inc, which markets erythropoiesis-stimulating agents. Dr Spiegel maintained full control over all aspects of the study design, implementation, data collection, data analysis, data interpretation, and manuscript preparation; he had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of data analysis. Dr Gitlin is an employee of Amgen Inc. The other authors declare that they have no relevant financial interests. NR 18 TC 8 Z9 8 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD JUL PY 2010 VL 56 IS 1 BP 86 EP 94 DI 10.1053/j.ajkd.2010.02.346 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 614OQ UT WOS:000279070000015 PM 20493604 ER PT J AU Lee, BY Wiringa, AE Bailey, RR Goyal, V Lewis, GJ Tsui, BYK Smith, KJ Muder, RR AF Lee, Bruce Y. Wiringa, Ann E. Bailey, Rachel R. Goyal, Vishal Lewis, G. Jonathan Tsui, Becky Y. K. Smith, Kenneth J. Muder, Robert R. TI Screening Cardiac Surgery Patients for MRSA: An Economic Computer Model SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; STERNAL WOUND-INFECTION; HOSPITAL-ACQUIRED INFECTION; SURGICAL SITE INFECTION; METHICILLIN-RESISTANT; NASAL CARRIAGE; INTRANASAL MUPIROCIN; POSTSTERNOTOMY MEDIASTINITIS; CLINICAL-FEATURES; HEART-SURGERY AB Objective: To estimate the economic value of preoperative methicillin-resistant Staphylococcus aureus (MRSA) screening and decolonization for cardiac surgery patients. Study Design: Monte Carlo decision-analytic computer simulation model. Methods: We developed a computer simulation model representing the decision of whether to perform preoperative MRSA screening and decolonizing those patients with a positive MRSA culture. Sensitivity analyses varied key input parameters including MRSA colonization prevalence, decolonization success rates, the number of surveillance sites, and screening/ decolonization costs. Separate analyses estimated the incremental cost-effectiveness ratio (ICER) of the screening and decolonization strategy from the third-party payer and hospital perspectives. Results: Even when MRSA colonization prevalence and decolonization success rate were as low as 1% and 25%, respectively, the ICER of implementing routine surveillance was well under $ 15,000 per quality-adjusted life-year from both the third-party payer and hospital perspectives. The surveillance strategy was economically dominant (less costly and more effective than no testing) for most scenarios explored. Conclusions: Our results suggest that routine preoperative MRSA screening of cardiac surgery patients could provide substantial economic value to third-party payers and hospitals over a wide range of MRSA colonization prevalence levels, decolonization success rates, and surveillance costs. Healthcare administrators, infection control specialists, and surgeons can compare their local conditions with our study's benchmarks to make decisions about whether to implement preoperative MRSA testing. Third-party payers may want to consider covering such a strategy. (Am J Manag Care. 2010; 16(7): e163-e173) C1 [Lee, Bruce Y.; Wiringa, Ann E.; Bailey, Rachel R.; Goyal, Vishal; Lewis, G. Jonathan; Tsui, Becky Y. K.] Univ Pittsburgh, Dept Biomed Informat, Pittsburgh, PA 15213 USA. [Lee, Bruce Y.; Wiringa, Ann E.; Bailey, Rachel R.; Goyal, Vishal; Lewis, G. Jonathan; Tsui, Becky Y. K.; Smith, Kenneth J.] Univ Pittsburgh, Sect Decis Sci & Clin Syst Modeling, Pittsburgh, PA 15213 USA. [Lee, Bruce Y.; Wiringa, Ann E.; Bailey, Rachel R.; Goyal, Vishal; Lewis, G. Jonathan; Tsui, Becky Y. K.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Muder, Robert R.] VA Pittsburgh Hlth Care Syst, Div Infect Dis, Pittsburgh, PA USA. RP Lee, BY (reprint author), Univ Pittsburgh, Dept Biomed Informat, 200 Meyran Ave,Ste 200, Pittsburgh, PA 15213 USA. EM byl1@pitt.edu FU National Institute of General Medical Sciences Models of Infectious Agent Study (MIDAS) [1U54GM088491-0109] FX This research was supported by National Institute of General Medical Sciences Models of Infectious Agent Study (MIDAS) Grant 1U54GM088491-0109. 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. NR 71 TC 11 Z9 11 U1 0 U2 1 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD JUL PY 2010 VL 16 IS 7 BP E163 EP E173 PG 11 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 635DR UT WOS:000280636300009 PM 20645662 ER PT J AU Holmes, LB AF Holmes, Lewis B. TI Karoly Mehes: Pioneer in the Study of Minor Anomalies. A Good and Creative Friend Remembered SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Biographical-Item C1 MassGen Hosp Children, Genet Unit, Boston, MA 02114 USA. RP Holmes, LB (reprint author), MassGen Hosp Children, Genet Unit, 175 Cambridge St,5th Floor CPZS 5, Boston, MA 02114 USA. EM holmes.lewis@mgh.harvard.edu NR 1 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 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL PY 2010 VL 152A IS 7 BP 1617 EP 1620 DI 10.1002/ajmg.a.33436 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 628JG UT WOS:000280115000005 PM 20583186 ER PT J AU Wisniowiecka-Kowalnik, B Nesteruk, M Peters, SU Xia, ZL Cooper, ML Savage, S Amato, RS Bader, P Browning, MF Haun, CL Duda, AW Cheung, SW Stankiewicz, P AF Wisniowiecka-Kowalnik, Barbara Nesteruk, Monika Peters, Sarika U. Xia, Zhilian Cooper, M. Lance Savage, Sarah Amato, R. Stephen Bader, Patricia Browning, Marsha F. Haun, Christa L. Duda, Andrew Walter, III Cheung, Sau Wai Stankiewicz, Pawel TI Intragenic Rearrangements in NRXN1 in Three Families With Autism Spectrum Disorder, Developmental Delay, and Speech Delay SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE NRXN1; ASD; developmental delay; array CGH; copy-number variation ID STRUCTURAL VARIANTS; GENES; SCHIZOPHRENIA; MICRODELETIONS; ABNORMALITIES; ARCHITECTURE; ASSOCIATION; DISRUPTION; MECHANISM; GENETICS AB NRXN1 is highly expressed in brain and has been shown recently to be associated with ASD, schizophrenia, cognitive and behavioral abnormalities, and alcohol and nicotine dependence. We present three families, in whom we identified intragenic rearrangements within NRXN1 using a clinical targeted oligonucleotide array CGH. An similar to 380 kb deletion was identified in a woman with Asperger syndrome, anxiety, and depression and in all four of her children affected with autism, anxiety, developmental delay, and speech delay but not in an unaffected child. An similar to 180 kb tandem duplication was found in a patient with autistic disorder and cognitive delays, and in his mother and younger brother who have speech delay. An similar to 330 kb tandem duplication was identified in a patient with autistic features. As predicted by conceptual translation, all three genomic rearrangements led to the premature truncation of NRXN1. Our data support previous observations that NRXN1 may be pathogenic in a wide variety of psychiatric diseases, including autism spectrum disorder, global developmental delay, anxiety, and depression. (C) 2010 Wiley-Liss, Inc. C1 [Wisniowiecka-Kowalnik, Barbara; Nesteruk, Monika; Peters, Sarika U.; Xia, Zhilian; Cooper, M. Lance; Cheung, Sau Wai; Stankiewicz, Pawel] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Wisniowiecka-Kowalnik, Barbara; Nesteruk, Monika; Stankiewicz, Pawel] Inst Mother & Child Hlth, Dept Med Genet, Warsaw, Poland. [Savage, Sarah; Amato, R. Stephen] Eastern Maine Med Ctr, Bangor, ME USA. [Bader, Patricia] Parkview Mem Hosp, Dept Cytogenet, Ft Wayne, IN USA. [Browning, Marsha F.; Haun, Christa L.; Duda, Andrew Walter, III] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Duda, Andrew Walter, III] Autism Consortium, Boston, MA USA. RP Stankiewicz, P (reprint author), Baylor Coll Med, Dept Mol & Human Genet, 1 Baylor Plaza,Rm R809, Houston, TX 77030 USA. EM pawels@bcm.edu FU Polish Ministry of Science and Higher Education [R13-0005-04/2008] FX Grant sponsor: Polish Ministry of Science and Higher Education; Grant number: R13-0005-04/2008. NR 35 TC 34 Z9 37 U1 1 U2 9 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 JUL PY 2010 VL 153B IS 5 BP 983 EP 993 DI 10.1002/ajmg.b.31064 PG 11 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 617CZ UT WOS:000279259700001 PM 20162629 ER PT J AU Marchani, EE Bird, TD Steinbart, EJ Rosenthal, E Yu, CE Schellenberg, GD Wijsman, EM AF Marchani, Elizabeth E. Bird, Thomas D. Steinbart, Ellen J. Rosenthal, Elisabeth Yu, Chang-En Schellenberg, Gerard D. Wijsman, Ellen M. TI Evidence for Three Loci Modifying Age-at-Onset of Alzheimer's Disease in Early-Onset PS epsilon N2 Families SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE genome-scan; modifier scan; quantitative trait; complex disease; dementia ID GENOME-WIDE ASSOCIATION; SERUM-AMYLOID-P; NEUROTROPHIC FACTOR BDNF; MONTE-CARLO SEGREGATION; POPULATION-BASED SAMPLE; LINKAGE ANALYSIS; APOLIPOPROTEIN-E; DUTCH POPULATION; OLIGOGENIC SEGREGATION; COMMUNITY POPULATION AB Families with early-onset Alzheimer's disease (AD) sharing a single PSEN2 mutation exhibit a wide range of age-at-onset, suggesting that modifier loci segregate within these families. While APOE is known to be an age-at-onset modifier, it does not explain all of this variation. We performed a genome scan within nine such families for loci influencing age-at-onset, while simultaneously controlling for variation in the primary PSEN2 mutation (N141I) and APOE. We found significant evidence of linkage between age-at-onset and chromosome 1q23.3 (P< 0.001) when analysis included all families, and to chromosomes 1q23.3 (P G 0.001), 17p13.2 (P=0.0002), 7q33 (P=0.017), and 11p14.2 (P = 0.017) in a single large pedigree. Simultaneous analysis of these four chromosomes maintained strong evidence of linkage to chromosomes 1q23.3 and 17p13.2 when all families were analyzed, and to chromosomes 1q23.3, 7q33, and 17p13.2 within the same single pedigree. Inclusion of major gene covariates proved essential to detect these linkage signals, as all linkage signals dissipated when PSEN2 and APOE were excluded from the model. The four chromosomal regions with evidence of linkage all coincide with previous linkage signals, associated SNPs, and/or candidate genes identified in independent AD study populations. This study establishes several candidate regions for further analysis and is consistent with an oligogenic model of AD risk and age-at-onset. More generally, this study also demonstrates the value of searching for modifier loci in existing datasets previously used to identify primary causal variants for complex disease traits. (C) 2010 Wiley-Liss, Inc. C1 [Marchani, Elizabeth E.; Bird, Thomas D.; Rosenthal, Elisabeth; Wijsman, Ellen M.] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Bird, Thomas D.; Steinbart, Ellen J.; Yu, Chang-En] Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Bird, Thomas D.; Steinbart, Ellen J.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Yu, Chang-En] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA 98195 USA. [Schellenberg, Gerard D.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Wijsman, Ellen M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Wijsman, Ellen M.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. RP Wijsman, EM (reprint author), Univ Washington, Dept Med, Div Med Genet, Box 357720, Seattle, WA 98195 USA. EM wijsman@u.washington.edu FU Veterans Affairs Research Funds; National Institute of Health (NIH) [AG05136, AG00258, GM46255] FX Grant sponsor: Veterans Affairs Research Funds; Grant sponsor: National Institute of Health (NIH); Grant numbers: AG05136, AG00258, GM46255. NR 96 TC 12 Z9 12 U1 1 U2 2 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 JUL PY 2010 VL 153B IS 5 BP 1031 EP 1041 DI 10.1002/ajmg.b.31072 PG 11 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 617CZ UT WOS:000279259700006 PM 20333730 ER PT J AU Kostis, WJ Chan, AT Dunn, JM Henrikson, CA AF Kostis, William J. Chan, Angel T. Dunn, Justin M. Henrikson, Charles A. TI The Long and the Short of It SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID SYNCHRONIZATION; DISSOCIATION C1 [Kostis, William J.; Chan, Angel T.; Dunn, Justin M.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Henrikson, Charles A.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. RP Kostis, WJ (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. EM wkostis@partners.org NR 7 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD JUL PY 2010 VL 123 IS 7 BP 606 EP 608 DI 10.1016/j.amjmed.2010.02.008 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 614NT UT WOS:000279067100010 PM 20609683 ER PT J AU Chong, CR AF Chong, Curtis R. TI An Unnecessary Death in Zambia SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Chong, Curtis R.] Massachusetts Gen Hosp, Dept Internal Med Housestaff, Boston, MA 02114 USA. [Chong, Curtis R.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Chong, CR (reprint author), Massachusetts Gen Hosp, Dept Internal Med Housestaff, 55 Fruit St,GRB 740, Boston, MA 02114 USA. EM crchong@post.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD JUL PY 2010 VL 123 IS 7 BP 669 EP 669 DI 10.1016/j.amjmed.2009.12.033 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 614NT UT WOS:000279067100021 PM 20609692 ER PT J AU Bakris, GL Basile, JN Giles, TD Taylor, AA AF Bakris, George L. Basile, Jan N. Giles, Thomas D. Taylor, Addison A. TI The Role of Nitric Oxide in Improving Endothelial Function and Cardiovascular Health: Focus on Nebivolol SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE beta-Blockers; Endothelial function; Hypertension; Nebivolol; Nitric oxide; Vasodilating beta-blockers ID DEPENDENT VASCULAR RELAXATION; CENTRAL AORTIC PRESSURE; ESSENTIAL-HYPERTENSION; BLOOD-PRESSURE; BETA-BLOCKERS; ERECTILE DYSFUNCTION; INSULIN-RESISTANCE; RANDOMIZED-TRIAL; HEART-FAILURE; ATENOLOL AB Although beta-blockers have been endorsed by guidelines committees for the treatment of patients with hypertension, particularly those with significant CVD and high CVD risk, there are concerns about conventional beta-blockers related to poorer clinical outcomes compared with other classes of antihypertensive agents, as well as deleterious effects on quality of life and lipid and carbohydrate metabolism. beta-Blockers comprise a heterogeneous group of antihypertensive agents, including nonselective agents, cardioselective, nonvasodilating agents, and vasodilating agents that either combine beta-nonselectivity with alpha-blockade or possess cardioselectivity without alpha-blockade. The pharmacologic, mechanistic, and hemodynamic differences between conventional, nonvasodilating beta-blockers and vasodilating beta-blockers are discussed in this review, with a focus on the cardioselective vasodilating beta-blocker nebivolol. These differences may have important clinical implications, particularly in the treatment of complicated hypertension, such as that associated with patients with diabetes or the cardiometabolic syndrome, elderly patients, and African American patients, suggesting that mechanism of action may be an important consideration when choosing a beta-blocker. (C) 2010 Published by Elsevier Inc. . The American Journal of Medicine (2010) 123, S2-S8 C1 [Bakris, George L.] Univ Chicago, Med Ctr, Dept Med, Hypertens Dis Unit, Chicago, IL 60637 USA. [Basile, Jan N.] Med Univ S Carolina, Coll Med, Seinsheimer Cardiovasc Hlth Program, Charleston, SC 29425 USA. [Basile, Jan N.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Giles, Thomas D.] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Taylor, Addison A.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Taylor, Addison A.] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. [Taylor, Addison A.] Baylor Coll Med, Dept Mol Physiol, Houston, TX 77030 USA. RP Giles, TD (reprint author), 109 Holly Dr, Metairie, LA 70005 USA. EM tgiles4@cox.net FU CVRx, Inc.; Forest Laboratories, Inc.; GlaxoSmithKline; Novartis AG; Abbott Laboratories; Bristol-Myers Squibb Company; Forest Research Institute, Inc.; Merck Co., Inc.; Pfizer Inc; sanofi-aventis FX The authors who contributed to this article have disclosed the following industry relationships:; George L. Bakris, MD, has worked as a consultant to Abbott Laboratories, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Boehringer Ingelheim, CVRx, Inc., Forest Laboratories, Inc., Gilead Sciences, Inc., GlaxoSmithKline, Merck & Co., Inc., Novartis AG, Takeda Pharmaceuticals North America, Inc., and Walgreen Co.; and has received research/grant support from CVRx, Inc., Forest Laboratories, Inc., and GlaxoSmithKline.; Thomas D. Giles, MD, has worked as a consultant to Bristol-Myers Squibb Company, Daiichi-Sankyo Co. Ltd, Forest Laboratories, Inc., NicOx, Novartis AG, and sanofi-aventis; has received honoraria from Bristol-Myers Squibb Company, Daiichi-Sankyo Co. Ltd, Forest Laboratories Inc., NicOx, Novartis AG, and sanofi-aventis; and has received research/grant support from Forest Laboratories, Inc. and Novartis AG.; Addison A. Taylor, MD, PhD, is a member of the Speakers' Bureaus of Abbott Laboratories, Boehringer Ingelheim, Forest Laboratories, Inc., GlaxoSmithKline, Merck & Co., Inc., and Novartis AG; has worked as a consultant to Abbott Laboratories, Boehringer Ingelheim, Forest Laboratories, Inc., GlaxoSmithKline, Merck & Co., Inc., and Novartis AG; has served on the advisory boards of Abbott Laboratories, Boehringer Ingelheim, Forest Laboratories, Inc., GlaxoSmithKline, Merck & Co., Inc., and Novartis AG; and has received research/grant support from Abbott Laboratories, Bristol-Myers Squibb Company, Forest Research Institute, Inc. (a subsidiary of Forest Laboratories, Inc.), Merck & Co., Inc., Novartis AG, Pfizer Inc, and sanofi-aventis. NR 41 TC 8 Z9 8 U1 0 U2 2 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 JUL PY 2010 VL 123 IS 7 SU 1 BP S2 EP S8 DI 10.1016/j.amjmed.2010.04.012 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 614NO UT WOS:000279066500002 PM 20609695 ER PT J AU Basile, JN AF Basile, Jan N. TI One Size Does Not Fit All: The Role of Vasodilating beta-Blockers in Controlling Hypertension as a Means of Reducing Cardiovascular and Stroke Risk SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE beta-Blockers; Efficacy; Hypertension; Nebivolol; Tolerability; Vasodilating beta-blockers ID RANDOMIZED CONTROLLED-TRIAL; BLOOD-PRESSURE; 1ST-LINE THERAPY; HEART-FAILURE; NITRIC-OXIDE; NEBIVOLOL; METOPROLOL; ATENOLOL; CARVEDILOL; PREVENTION AB beta-Blockers have played a key role in the management of hypertension-related cardiovascular disease for decades, and continue to be recommended as a mainstay of therapy in national guidelines statements. Recent data have shown less optimal reductions in total mortality, CVD mortality, and CVD events with beta-blockers compared with renin-angiotensin system-blocking agents or calcium channel blockers. The beta-blocker class, however, spans a wide range of agents, and the growing concern about the risk-benefit profile of beta-blockers should not be generalized to later-generation vasodilating beta-blockers such as carvedilol and nebivolol. A growing database from hypertension studies confirms the clinical efficacy and safety of vasodilating beta-blockers, and outcome studies indicate that these agents can play an important role in global CVD reduction in patients with hypertensive or ischemic heart failure. (C) 2010 Elsevier Inc. All rights reserved. . The American Journal of Medicine (2010) 123, S9- S15 C1 [Basile, Jan N.] Med Univ S Carolina, Coll Med, Seinsheimer Cardiovasc Hlth Program, Charleston, SC 29425 USA. [Basile, Jan N.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. RP Basile, JN (reprint author), Med Univ S Carolina, Coll Med, Seinsheimer Cardiovasc Hlth Program, 171 Ashley Ave, Charleston, SC 29425 USA. EM basilejn@musc.edu FU National Heart, Lung, and Blood Institute (NHLBI) FX Dr. Basile is supported by the National Heart, Lung, and Blood Institute (NHLBI) through funding for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the Systolic Blood Pressure Intervention Trial (SPRINT). NR 39 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD JUL PY 2010 VL 123 IS 7 SU 1 BP S9 EP S15 DI 10.1016/j.amjmed.2010.04.013 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 614NO UT WOS:000279066500003 PM 20609697 ER PT J AU Fonseca, VA Zinman, B Nauck, MA Goldfine, AB Plutzky, J AF Fonseca, Vivian A. Zinman, Bernard Nauck, Michael A. Goldfine, Allison B. Plutzky, Jorge TI Confronting the Type 2 Diabetes Epidemic: the Emerging Role of Incretin-Based Therapies SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Incretin-based therapies; Glucagon-like peptide-1 receptor agonists; Dipeptydl peptidase-4 inhibitors; Type 2 diabetes ID GLUCAGON-LIKE PEPTIDE-1; AMERICAN-HEART-ASSOCIATION; BLOOD-GLUCOSE IMPROVES; DRUG-NAIVE PATIENTS; GLYCEMIC CONTROL; EXENATIDE EXENDIN-4; MYOCARDIAL-INFARCTION; ACUTE-PANCREATITIS; INSULIN-SECRETION; TREATED PATIENTS AB This report highlights a roundtable discussion that occurred during the annual meeting of the International Diabetes Federation (IDF) in November 2009, in Montreal, Quebec, Canada. Participants included Bernard Zinman, MD, Michael A. Nauck, MD, PhD, Jorge Plutzky, MD, and Allison B. Goldfine, MD. The roundtable was chaired by Vivian A. Fonseca, MD. Among the topics discussed were the burden of type 2 diabetes mellitus and the importance of "appropriate therapy," which includes not only managing glycemia but also the management of concomitant risk factors such as hypertension and dyslipidemia. The discussants also identified issues that remain to be resolved, such as determining the nature of first-line therapy (e. g., should initial dual-agent therapy be encouraged?) and agreeing upon the most appropriate agent to be combined with metformin, which is the current standard of care. Among the new treatments discussed for type 2 diabetes were the analogues of the incretin hormones glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), namely, the GLP-1 receptor agonists-as well as the inhibitors of dipeptidyl peptidase-4 (DPP-4), the enzyme that regulates the bioactivity of the endogenous incretin hormones. These agents have some interesting advantages; not only do they effectively lower glucose, but they also have demonstrated beneficial metabolic and cardiovascular effects. Particularly with respect to the GIP and GLP-1, weight loss, blood pressure reductions, and beta-cell function improvements have been observed in clinical trials. What remains to be determined, by means of additional clinical experience and perhaps additional head-to-head trials, are the long-term benefits of GLP-1 receptor agonists and DPP-4 inhibitors and the sorts of roles these 2 classes of agents may play in the type 2 diabetes therapeutic continuum. C1 [Fonseca, Vivian A.] Tulane Univ, Hlth Sci Ctr, Endocrinol Sect, New Orleans, LA 70118 USA. [Zinman, Bernard] Univ Toronto, Toronto, ON, Canada. [Zinman, Bernard] Mt Sinai Hosp, Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Nauck, Michael A.] Ctr Diabet, Diabet Zentrum Bad Lauterberg, Bad Lauterberg Im Harz, Germany. [Goldfine, Allison B.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Plutzky, Jorge] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Fonseca, VA (reprint author), Tulane Univ, Hlth Sci Ctr, Endocrinol Sect, New Orleans, LA 70118 USA. RI Zinman, Bernard/E-7266-2013 FU AstraZeneca; Daiichi Sankyo Co. Ltd.; Eli Lilly and Company; GlaxoSmithKline; Novartis Pharmaceuticals Corp.; Novo Nordisk A/S; Pfizer Inc; sanofi-aventis; Takeda Pharmaceuticals North America, Inc. FX Vivian A. Fonseca, MD, has received research/grant support (to Tulane University) from AstraZeneca, Daiichi Sankyo Co. Ltd., Eli Lilly and Company, GlaxoSmithKline, Novartis Pharmaceuticals Corp., Novo Nordisk A/S, Pfizer Inc, sanofi-aventis, and Takeda Pharmaceuticals North America, Inc.; and has received honoraria from Daiichi Sankyo Co. Ltd., Eli Lilly and Company, GlaxoSmithKline, Novartis Pharmaceuticals Corp., Novo Nordisk A/S, sanofi-aventis, and Takeda Pharmaceuticals North America, Inc.; Allison B. Goldfine, MD, serves on the advisory board of Tethys Bioscience, Inc.; has worked as a site investigator for Daiichi Sankyo Co. Ltd. and Eli Lilly and Company; has received in-kind research support from Caraco Pharmaceutical Laboratories, Ltd., LifeScan, Inc. (a Johnson & Johnson company), Medtronic, Inc., and Mercodia AB; and has received honoraria for consulting from CV Therapeutics (a subsidiary of Gilead Sciences), Daiichi Sankyo Co. Ltd., Merck & Co., Inc., and Novo Nordisk A/S. NR 63 TC 18 Z9 19 U1 1 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 JUL PY 2010 VL 123 IS 7 BP S2 EP S10 DI 10.1016/j.amjmed.2010.04.002 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 614NT UT WOS:000279067100031 PM 20609666 ER PT J AU Saul, N Maryniuk, MD AF Saul, Nora Maryniuk, Melinda D. TI USING THE GLYCEMIC INDEX IN DIABETES MANAGEMENT SO AMERICAN JOURNAL OF NURSING LA English DT Article ID MONOUNSATURATED FAT DIET; TYPE-2; WEIGHT C1 [Saul, Nora] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Saul, N (reprint author), Joslin Diabet Ctr, Boston, MA 02215 USA. EM nora.saul@joslin.harvard.edu NR 8 TC 0 Z9 1 U1 1 U2 1 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 JUL PY 2010 VL 110 IS 7 BP 68 EP 69 DI 10.1097/01.NAJ.0000383944.98887.0d PG 2 WC Nursing SC Nursing GA 622WG UT WOS:000279696100021 PM 20574213 ER PT J AU Lin, HW Richmon, JD Emerick, KS de Venecia, RK Zeitels, SM Faquin, WC Lin, DT AF Lin, Harrison W. Richmon, Jeremy D. Emerick, Kevin S. de Venecia, Ronald K. Zeitels, Steven M. Faquin, William C. Lin, Derrick T. TI Malignant transformation of a highly aggressive human papillomavirus type 11-associated recurrent respiratory papillomatosis SO AMERICAN JOURNAL OF OTOLARYNGOLOGY LA English DT Article; Proceedings Paper CT Combined Sections Meeting of the Southern/Middle Triological-Society CY JAN 08-11, 2009 CL Bonita Springs, FL SP Triol Soc ID VACUUM-ASSISTED CLOSURE AB Objective: The objective is to present an uncommon case of squamous cell carcinoma (SCC) arising from extensive recurrent respiratory papillomatosis (RRP) involving the upper and lower airway and temporal bone. Study Design: This is a case report and a review of the literature. Methods: We describe a case of a 24-year old woman with a history of human papillomavirus (HPV) type 11 since childhood originating in the larynx and trachea, then progressing to involve the distal pulmonary alveoli and right middle ear through the eustachian tube. Papillomatous growth was treated with multiple surgeries including laser cytoreduction of laryngotracheal papillomatosis and radical mastoidectomy, followed by a trial of chemotherapy. Despite this aggressive treatment regimen, papillomatous growth progressed with recurrence in the right eustachian tube, middle ear, and mastoid eventually extending to involve the calvaria and scalp. Results: The patient underwent a composite resection of involved tissues, including the scalp, auricle, and lateral temporal bone, with reconstruction using a latissimus dorsi free flap. Final pathologic analysis revealed an extensive infiltrative well-differentiated SCC arising from the papilloma. A review of the literature on aggressive respiratory papillomatosis suggests that malignant transformation of juvenile-onset RRP occurs exclusively in cases positive for HPV-11. Conclusions: We report an unusual case of SCC originating from extensive RRP involving the airway, temporal bone, and scalp and describe the medical and surgical management. Although the incidence of juvenile-onset RRP transformation to SCC is very low, the presence of HPV-11 as a risk factor for malignant transformation of RRP is becoming evident. (C) 2010 Elsevier Inc. All rights reserved. C1 [Lin, Harrison W.; Emerick, Kevin S.; de Venecia, Ronald K.; Lin, Derrick T.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. [Lin, Harrison W.; Emerick, Kevin S.; de Venecia, Ronald K.; Lin, Derrick T.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Richmon, Jeremy D.] Johns Hopkins Univ, Dept Otolaryngol Head & Neck Surg, Baltimore, MD USA. [Zeitels, Steven M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Surg, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02115 USA. [Faquin, William C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Lin, HW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, 243 Charles St, Boston, MA 02114 USA. EM harrison_lin@meei.harvard.edu NR 8 TC 21 Z9 22 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0196-0709 J9 AM J OTOLARYNG JI Am. J. Otolaryngol. PD JUL-AUG PY 2010 VL 31 IS 4 BP 291 EP 296 DI 10.1016/j.amjoto.2009.02.019 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA 624UR UT WOS:000279847700017 PM 20015762 ER PT J AU Xie, F Sun, DW Schering, A Nakao, S Zandi, S Liu, P Hafezi-Moghadam, A AF Xie, Fang Sun, Dawei Schering, Alexander Nakao, Shintaro Zandi, Souska Liu, Ping Hafezi-Moghadam, Ali TI Novel Molecular Imaging Approach for Subclinical Detection of lritis and Evaluation of Therapeutic Success SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ENDOTOXIN-INDUCED UVEITIS; SELECTIN GLYCOPROTEIN LIGAND-1; ROLLING IN-VIVO; ENDOTHELIAL INJURY; CELLS; MIGRATION; ADHESION; DISEASE; MODEL; IRIS AB There is an urgent need for early diagnosis in medicine, whereupon effective treatments could prevent irreversible tissue damage. Acute anterior chamber inflammation is the most common form of uveitis and a major cause of vision loss. The proximity of the iris vasculature to the light-permeable cornea and its involvement in ocular inflammation make it an ideal target for noninvasive molecular imaging. To accomplish this, carboxylated fluorescent microspheres (MSs) were conjugated with recombinant P-selectin glycoprotein ligand-1 and systemically injected in endotoxin-induced uveitic animals. MS adhesion in the microcirculation of the anterior and posterior chamber was visualized by intravital microscopy and scanning laser ophthalinoscopy. In iritic animals, significantly higher numbers of recombinant P-selectin glycoprotein ligand-1-conjugated MSs adhered to the endothelium (P = 0.03) matching the increase in leukocyte adhesion. Conjugated MSs specifically interacted with firmly adhering leukocytes, allowing quantification of the endogenous immune response. Topical eye drop treatment with dexamethasone (P < 0.01) or cyclosporine A (P < 0.01) significantly lowered MS adhesion in iris vessels. Surprisingly, topical dexamethasone significantly reduced MS interaction in the fundus vessels (P < 0.01), while cyclosporine A did not. In vivo MS accumulation preceded clinical signs of anterior uveitis and leukocyte adhesion in iris vasculature. This work introduces noninvasive subclinical detection of endothelial injury in the iris vasculature, providing a unique opportunity for quantifying vascular injury and immune response in vivo. (Am J Pathol 2010, 177:39-48; DOI: 10.2353/ajpath.2010.100007) C1 [Xie, Fang; Sun, Dawei; Schering, Alexander; Nakao, Shintaro; Zandi, Souska; Hafezi-Moghadam, Ali] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Xie, Fang; Sun, Dawei; Schering, Alexander; Nakao, Shintaro; Zandi, Souska; Hafezi-Moghadam, Ali] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Xie, Fang; Liu, Ping] Harbin Med Coll, Affiliated Hosp 1, Dept Ophthalmol, Harbin, Peoples R China. [Sun, Dawei] Harbin Med Coll, Affiliated Hosp 2, Harbin, Peoples R China. RP Hafezi-Moghadam, A (reprint author), Angiogenesis Lab, 325 Cambridge St,3rd Floor, Boston, MA 02114 USA. EM ali_hafezi-moghadam@meei.harvard.edu FU NIH [A1050775]; American Health Assistance Foundation; Science & Technology project of Heilongjiang Province, China [GB06C40104]; Malaysian Palm Oil Board FX Supported by NIH grants A1050775 (A.H.-M.), American Health Assistance Foundation (A.H.-M.), a Science & Technology project of Heilongjiang Province, China (GB06C40104 to D.S.), and the Malaysian Palm Oil Board (A.H.-M.). NR 21 TC 9 Z9 9 U1 0 U2 2 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 JUL PY 2010 VL 177 IS 1 BP 39 EP 48 DI 10.2353/ajpath.2010.100007 PG 10 WC Pathology SC Pathology GA 624GM UT WOS:000279805100008 PM 20581051 ER PT J AU Yoon, SO Zhang, X Freedman, AS Zahrieh, D Lossos, IS Li, L Choi, YS AF Yoon, Sun-Ok Zhang, Xin Freedman, Arnold S. Zahrieh, David Lossos, Izidore S. Li, Li Choi, Yong Sung TI Down-Regulation of CD9 Expression and its Correlation to Tumor Progression in B Lymphomas SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID FOLLICULAR DENDRITIC CELLS; MULTIPLE-MYELOMA CELLS; COLON-CARCINOMA CELLS; HUMAN BREAST-CANCER; PROTEIN-1 MRP-1/CD9; GENE-EXPRESSION; LUNG-CANCER; MONOCLONAL-ANTIBODY; TETRASPANIN CD9; DECREASED EXPRESSION AB Histological transformation, a pivotal event in the natural history of cancers including lymphomas, is typically associated with more aggressive clinical behavior. L3055, a B lymphoma cell line of germinal center (GC) origin, is dependent on follicular dendritic cells (FDCs) for survival and proliferation, similar to GC-B cells. However, L3055 cells become less FDC-dependent after prolonged culture, which is analogous to transformation in vivo. Comparison of two L3055 subclones (i.e., the FDC-dependent indolent clone 12 and the FDC-independent aggressive clone 33) by DNA microarray revealed that CD9 was the most differentially expressed gene (P = 0.05). L3055-12 expresses high levels of CD9 while L3055-33 does not. Reduced levels or loss of CD9 expression is also observed in other CD9-positive B lymphoma cell lines. The resultant CD9-negative cells grow faster than CD9-positive cells due to their greater resistance to apoptosis. Furthermore CD9-negative cells are less dependent on FDCs for their survival and growth compared with CD9-positive cells. CD9 down-regulation in B lymphomas appears to be controlled epigenetically, mainly through histone modifications. These findings imply that CD9 is inversely correlated with B lymphoma progression, and CD9 inactivation may play an important role in B lymphoma transformation. (Am J Pathol 2010, 177:377-386; DOI: 10.2353/ajpath.2010.100048) C1 [Yoon, Sun-Ok; Zhang, Xin; Li, Li; Choi, Yong Sung] Ochsner Clin Fdn, Cellular Immunol Lab, New Orleans, LA 70121 USA. [Freedman, Arnold S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zahrieh, David] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Zahrieh, David] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Computat Biol, Boston, MA 02115 USA. [Lossos, Izidore S.] Univ Miami, Dept Med, Div Hematol Oncol, Miami, FL USA. [Lossos, Izidore S.] Univ Miami, Dept Mol & Cellular Pharmacol, Miami, FL USA. RP Choi, YS (reprint author), Ochsner Clin Fdn, Cellular Immunol Lab, 1514 Jefferson Highway, New Orleans, LA 70121 USA. EM ychoi@ochsner.org FU National Institutes of Health [R01CA121039]; Norman Hirshfield Foundation FX Supported by National Institutes of Health grant R01CA121039 to Y.S.C. and Norman Hirshfield Foundation to A.S.F. NR 60 TC 8 Z9 8 U1 0 U2 5 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 JUL PY 2010 VL 177 IS 1 BP 377 EP 386 DI 10.2353/ajpath.2010.100048 PG 10 WC Pathology SC Pathology GA 624GM UT WOS:000279805100039 PM 20566742 ER PT J AU Benedettini, E Sholl, LM Peyton, M Reilly, J Ware, C Davis, L Vena, N Bailey, D Yeap, BY Fiorentino, M Ligon, AH Pan, BS Richon, V Minna, JD Gazdar, AF Draetta, G Bosari, S Chirieac, LR Lutterbach, B Loda, M AF Benedettini, Elisa Sholl, Lynette M. Peyton, Michael Reilly, John Ware, Christopher Davis, Lenora Vena, Natalie Bailey, Dyane Yeap, Beow Y. Fiorentino, Michelangelo Ligon, Azra H. Pan, Bo-Sheng Richon, Victoria Minna, John D. Gazdar, Adi F. Draetta, Giulio Bosari, Silvano Chirieac, Lucian R. Lutterbach, Bart Loda, Massimo TI Met Activation in Non-Small Cell Lung Cancer Is Associated with de Novo Resistance to EGFR Inhibitors and the Development of Brain Metastasis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CHEMOTHERAPY-NAIVE PATIENTS; HEPATOCYTE GROWTH-FACTOR; PHASE-II; SOMATIC MUTATIONS; TYROSINE KINASE; GEFITINIB RESISTANCE; C-MET; AMPLIFICATION; THERAPY; CARCINOMA AB Most non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations respond to tyrosine kinase inhibitor (TKI) therapy. However, about 30% exhibit primary resistance to EGFR TKI therapy. Here we report that Met protein expression and phosphorylation were associated with primary resistance to EGFR TKI therapy in NSCLC patients harboring EGFR mutations, implicating Met as a de novo mechanism of resistance. In a separate patient cohort, Met expression and phosphorylation were also associated with development of NSCLC brain metastasis and were selectively enriched in brain metastases relative to paired primary lung tumors. A similar metastasis-specific activation of Met occurred in vitro in the isogenous cell lines H2073 and H1993, which are derived from the primary lung tumor and a metastasis respectively, from the same patient. We conclude that Met activation is found in NSCLC before EGFR-targeted therapy and is associated with both primary resistance to EGFR inhibitor therapy and with the development of metastases. If confirmed in larger cohorts, our analysis suggests that patient tumors harboring both Met activation and EGFR mutation could potentially benefit from early intervention with a combination of EGFR and Met inhibitors. (Am J Pathol 2010, 177:415-423; DOI: 10.2353/ajpath.2010.090863) C1 [Reilly, John; Davis, Lenora; Pan, Bo-Sheng; Lutterbach, Bart] Merck Res Labs, Boston, MA 02115 USA. [Benedettini, Elisa; Fiorentino, Michelangelo; Loda, Massimo] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ware, Christopher; Vena, Natalie; Bailey, Dyane; Ligon, Azra H.; Loda, Massimo] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Draetta, Giulio] Dana Farber Canc Inst, Ctr Appl Canc Sci, Boston, MA 02115 USA. [Benedettini, Elisa; Bosari, Silvano] Univ Milan, AOS Paolo & Fdn IRCCS Ca Granda, Dept Med Surg & Dent, Div Pathol,Osped Maggiore Policlin, Milan, Italy. [Sholl, Lynette M.; Ligon, Azra H.; Chirieac, Lucian R.; Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Sholl, Lynette M.; Yeap, Beow Y.; Ligon, Azra H.; Chirieac, Lucian R.; Loda, Massimo] Harvard Univ, Sch Med, Boston, MA USA. [Peyton, Michael; Gazdar, Adi F.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Peyton, Michael; Gazdar, Adi F.] Univ Texas SW Med Ctr Dallas, Simmons Canc Ctr, Dallas, TX 75390 USA. [Minna, John D.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Minna, John D.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. [Gazdar, Adi F.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Richon, Victoria] Epizyme Inc, Boston, MA USA. [Loda, Massimo] Harvard Univ, Broad Inst, Boston, MA 02115 USA. [Loda, Massimo] MIT, Broad Inst, Boston, MA USA. RP Lutterbach, B (reprint author), Merck Res Labs, Boston, MA 02115 USA. EM Bart_lutterbach@merck.com RI Peyton, Michael/A-8728-2008; Bosari, Silvano/K-7744-2016 OI Bosari, Silvano/0000-0002-9744-6951 FU Lung Cancer Specialized Program of Research Excellence (SPORE) [2P50 CA090578-06, P50CA70907]; University of Milan, Italy FX Supported by Lung Cancer Specialized Program of Research Excellence (SPORE) 2P50 CA090578-06 (to M.L., L.C., B.Y.Y.) and SPORE P50CA70907 (to J.D.M. and A.G.). M.L. is a Novartis Investigator. E.B. is supported by a Ph.D. Program fellowship in Molecular Medicine, University of Milan, Italy. NR 34 TC 76 Z9 77 U1 0 U2 8 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 JUL PY 2010 VL 177 IS 1 BP 415 EP 423 DI 10.2353/ajpath.2010.090863 PG 9 WC Pathology SC Pathology GA 624GM UT WOS:000279805100042 PM 20489150 ER PT J AU Stolzmann, KL Gagnon, DR Brown, R Tun, CG Garshick, E AF Stolzmann, Kelly L. Gagnon, David R. Brown, Robert Tun, Carlos G. Garshick, Eric TI Risk Factors for Chest Illness in Chronic Spinal Cord Injury A Prospective Study SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Spinal Cord Injury; Chest Illness; Pulmonary Function; Morbidity ID RESPIRATORY ILLNESS; PULMONARY-FUNCTION; PERSISTENT WHEEZE; VETERANS; STANDARDIZATION; POPULATION; SPIROMETRY; DISORDERS; MORTALITY; VISITS AB Stolzmann KL, Gagnon DR, Brown R, Tun CG, Garshick E: Risk factors for chest illness in chronic spinal cord injury: A prospective study. Am J Phys Med Rehabil 2010; 89: 576-583. Objective: Chest illnesses commonly cause morbidity in persons with chronic spinal cord injury. Risk factors remain poorly characterized because previous studies have not accounted for factors other than spinal cord injury. Design: Between 1994 and 2005, 403 participants completed a respiratory questionnaire and underwent spirometry. Participants were contacted at a median of 1.7 yrs [interquartile range: 1.3-2.5 yrs] apart over a mean (SD) of 5.1 +/- 3.0 yrs and asked to report chest illnesses that had resulted in time off work, spent indoors, or in bed since prior contact. Results: In 97 participants, there were 247 chest illnesses (0.12/person-year) with 54 hospitalizations (22%). Spinal cord injury level, completeness of injury, and duration of injury were not associated with illness risk. Adjusting for age and smoking history, any wheeze (relative risk = 1.92; 95% confidence interval: 1.19, 3.08), pneumonia or bronchitis since spinal cord injury (relative risk = 2.29; 95% confidence interval: 1.40, 3.75), and physician-diagnosed chronic obstructive pulmonary disease (relative risk = 2.17; 95% confidence interval: 1.08, 4.37) were associated with a greater risk of chest illness. Each percent-predicted decrease in forced expiratory volume in 1 sec was associated with a 1.2% increase in risk of chest illness (P = 0.030). Conclusions: In chronic spinal cord injury, chest illness resulting in time spent away from usual activities was not related to the level or completeness of spinal cord injury but was related to reduced pulmonary function, wheeze, chronic obstructive pulmonary disease, a history of pneumonia and bronchitis, and smoking. C1 [Stolzmann, Kelly L.; Gagnon, David R.; Tun, Carlos G.; Garshick, Eric] VA Boston Healthcare Syst, Dept Vet Affairs, Res & Dev Serv, Boston, MA USA. [Stolzmann, Kelly L.] Harvard Univ, Sch Med, VA Boston, Programs Res, Boston, MA USA. [Gagnon, David R.] Boston Univ, Sch Publ Hlth, VA Boston Healthcare Syst, VA Cooperat Studies Program,Dept Biostat, Boston, MA USA. [Brown, Robert] Massachusetts Gen Hosp, Pulm & Crit Care Med Unit, Boston, MA 02114 USA. [Brown, Robert] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Tun, Carlos G.] VA Boston Healthcare Syst, Rehabil Med Serv, Boston, MA USA. [Garshick, Eric] VA Boston Healthcare Syst, Pulm & Crit Care Med Sect, Med Serv, Boston, MA USA. [Garshick, Eric] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Garshick, E (reprint author), VA Boston Healthcare Syst, Pulm & Crit Care Med Sect, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. OI Gagnon, David/0000-0002-6367-3179 FU Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service [B6618R]; Massachusetts Veterans Epidemiology Research and Information Center, Cooperative Studies Program, Department of Veterans Affairs; National Institute of Child Health and Human Development [RO1 HD042141] FX This study was supported by the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service [Merit Review Grant B6618R]; the Massachusetts Veterans Epidemiology Research and Information Center, Cooperative Studies Program, Department of Veterans Affairs; and National Institute of Child Health and Human Development [RO1 HD042141]. This study was presented at a poster presentation session at the American Thoracic Society Conference in Toronto, Canada, May 19, 2008. Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States Government. NR 23 TC 13 Z9 13 U1 0 U2 0 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 JUL PY 2010 VL 89 IS 7 BP 576 EP 583 DI 10.1097/PHM.0b013e3181ddca8e PG 8 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 613IP UT WOS:000278972900008 PM 20463565 ER PT J AU Zhao, T Li, JA Chen, AF AF Zhao, Ting Li, Jian Chen, Alex F. TI MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1 SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article ID CALORIE RESTRICTION; DOWN-REGULATION; EMERGING ROLES; GROWTH ARREST; MIR-34A; SIRT1; EXPRESSION; CANCER; DYSFUNCTION; PHENOTYPE AB Zhao T, Li J, Chen AF. MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. Am J Physiol Endocrinol Metab 299: E110-E116, 2010. First published April 27, 2010; doi:10.1152/ajpendo.00192.2010.-Endothelial progenitor cells (EPCs) play an important role in angiogenesis, which is essential for numerous physiological processes as well as tumor growth. Several microRNAs (miRNAs) have been reported to be involved in angiogenesis. MiR-34a, recently reported as a tumor suppressor, has been found to target silent information regulator 1 (Sirt1), leading to cell cycle arrest or apoptosis. However, the role of miR-34a in EPC-mediated angiogenesis was unknown. The present study tested the hypothesis that miR-34a inhibits EPC-mediated angiogenesis by inducing senescence via suppressing Sirt1. Bone marrow-derived EPCs from adult male Spraque-Dawley rats were used. Results of flow cytometry showed that EPCs after 7 days of culture expressed both stem cell markers CD34 and CD133 and endothelial cell markers VEGFR-2 (flk-1) and VE-cadherin. MiR-34a was expressed in normal EPCs, and overexpression of miR-34a via its mimic transfection significantly increased its expression and impaired in vitro EPC angiogenesis. MiR-34a overexpression led to a significantly increased EPC senescence, paralleled with an similar to 40% Sirt1 reduction. Furthermore, knockdown of Sirt1 by its siRNA resulted in diminished EPC angiogenesis and increased senescence. Finally, overexpression of miR-34a increased the level of Sirt1 effector-acetylated forkhead box O transcription factors 1 (FoxO1), an effect mimicked in EPCs following Sirt1 knockdown. In conclusion, miR-34a impairs EPC-mediated angiogenesis by induction of senescence via inhibiting Sirt1. C1 [Chen, Alex F.] Univ Pittsburgh, Sch Med, Dept Surg, Vasc Med Inst,VA Vasc Surg Res, Pittsburgh, PA 15240 USA. [Zhao, Ting; Chen, Alex F.] Univ Pittsburgh, Sch Med, McGowan Inst Regenerat Med, Pittsburgh, PA 15240 USA. [Zhao, Ting; Chen, Alex F.] Vet Affairs Pittsburgh Healthcare Syst, Vasc Surg Res, Pittsburgh, PA USA. [Zhao, Ting; Li, Jian] Chinese Acad Med Sci, Beijing Inst Geriatr, Beijing 100037, Peoples R China. [Zhao, Ting; Li, Jian] Peking Union Med Coll, Beijing 100021, Peoples R China. RP Chen, AF (reprint author), Univ Pittsburgh, Sch Med, Dept Surg, Vasc Med Inst,VA Vasc Surg Res, 2W109 151L-U,VAPHS,Univ Dr, Pittsburgh, PA 15240 USA. EM chena5@upmc.edu FU National Institute of General Medical Sciences [R01-GM-077352]; American Diabetes Association Research [7-08-RA-23]; National Basic Research Program of China [2006CB503910]; National High-Tech Research and Development Program of China [2006AA 02A 408] FX This work was supported by National Institute of General Medical Sciences Grant R01-GM-077352, American Diabetes Association Research Award 7-08-RA-23 (to Dr. A. F. Chen), and grants from National Basic Research Program of China (2006CB503910) and National High-Tech Research and Development Program of China (2006AA 02A 408; to Dr. J. Li). NR 41 TC 152 Z9 164 U1 0 U2 14 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUL PY 2010 VL 299 IS 1 BP E110 EP E116 DI 10.1152/ajpendo.00192.2010 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 609MH UT WOS:000278660200015 PM 20424141 ER PT J AU Beck, PL Ihara, E Hirota, SA MacDonald, JA Meng, D Nanthakumar, NN Podolsky, DK Xavier, RJ AF Beck, P. L. Ihara, E. Hirota, S. A. MacDonald, J. A. Meng, D. Nanthakumar, N. N. Podolsky, D. K. Xavier, R. J. TI Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3 SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE trefoil factor family 3 ID SODIUM-INDUCED COLITIS; MIGRATION-INHIBITORY FACTOR; ALPHA(1,3)FUCOSYLTRANSFERASE FUC-TVII; PLATELET P-SELECTIN; BOWEL-DISEASE; ULCERATIVE-COLITIS; CROHNS-DISEASE; MONOCLONAL-ANTIBODY; ADHESION MOLECULES; IMMUNE-RESPONSE AB Beck P, Ihara E, Hirota SA, MacDonald J, Meng D, Nanthakumar N, Podolsky D, Xavier R. Exploring the interplay of barrier function and leukocyte recruitment in intestinal inflammation by targeting fucosyltransferase VII and trefoil factor 3. Am J Physiol Gastrointest Liver Physiol 299: G43-G53, 2010. First published March 18, 2010; doi:10.1152/ajpgi.00228.2009.-Intestinal mucosal integrity is dependent on epithelial function and a regulated immune response to injury. Fucosyltransferase VII (Fuc-TVII) is an essential enzyme required for the expression of the functional ligand for E- and P-selectin. Trefoil factor 3 (TFF3) is involved in both protecting the intestinal epithelium against injury as well as aiding in wound repair following injury. The aim of the present study was to assess the interplay between barrier function and leukocyte recruitment in intestinal inflammation. More specifically, we aimed to examine how targeted disruption of Fuc-TVII either in wild-type or TFF3(-/-) mice would alter their susceptibility to colonic injury. TFF3 and Fuc-TVII double-knockout mice (TFF3/Fuc-TVII(-/-) mice) were generated by mating TFF3(-/-) and Fuc-TVII(-/-) mice. Colitis was induced by administration of dextran sodium sulfate (DSS) (2.5% wt/vol) in the drinking water. Changes in baseline body weight, diarrhea, and fecal blood were assessed daily. Upon euthanasia, extents of colonic inflammation were assessed macroscopically, microscopically, and through quantification of myeloperoxidase (MPO) activity. Colonic lymphocyte subpopulations were assessed at 6 days after administration of DSS by flow cytometry and immunohistochemistry. No baseline intestinal inflammation was found in TFF3/Fuc-TVII(-/-), TFF3(-/-), Fuc-TVII(-/-), or wild-type mice. Loss of Fuc-TVII resulted in a reduction in disease severity whereas TFF3(-/-) mice were markedly more susceptible to DSS-induced colitis. Remarkably, the loss of Fuc-TVII in TFF3(-/-) mice markedly decreased the severity of DSS-induced colitis as evidenced by reduced weight loss, diarrhea, decreased colonic MPO levels and improved survival. Furthermore, the loss of TFF3 resulted in increased severity of spontaneous colitis in IL-2/beta-microglobulin-deficient mice. These studies highlight the importance of the interplay between factors involved in the innate immune response, mucosal barrier function, and genes involved in regulating leukocyte recruitment and other aspects of the immune response. C1 [Beck, P. L.] Univ Calgary, Hlth Sci Ctr, Div Gastroenterol, Gastrointestinal Res Grp,Fac Med, Calgary, AB T2N 4N1, Canada. [Meng, D.; Nanthakumar, N. N.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, R. J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Xavier, R. J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Podolsky, D. K.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Beck, PL (reprint author), Univ Calgary, Hlth Sci Ctr, Div Gastroenterol, Gastrointestinal Res Grp,Fac Med, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. EM plbeck@ucalgary.ca OI MacDonald, Justin/0000-0002-9238-8473; Ihara, Eikichi/0000-0002-7070-6610 FU Crohn's and Colitis Foundation of Canada; National Institutes of Health [HD12437, DK70260, HD059126]; Canadian Association of Gastroenterology/Canadian Institutes of Health Research; Canada Research Chair; [DK043351]; [DK83756] FX This research was funded by a grant-in-aid from the Crohn's and Colitis Foundation of Canada to P. L. Beck. This work was partially supported by National Institutes of Health grants (HD12437, DK70260, and HD059126) to N. N. Nanthakumar. R. J. Xavier is supported by DK043351 and DK83756. P. L. Beck is an Alberta Heritage Foundation for Medical Research (AHFMR) Scholar. E. Ihara and S. A. Hirota are recipients of Canadian Association of Gastroenterology/Canadian Institutes of Health Research fellowships. J. A. MacDonald is an AHFMR Senior Scholar and recipient of a Canada Research Chair (Tier II). NR 51 TC 10 Z9 10 U1 0 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 JUL PY 2010 VL 299 IS 1 BP G43 EP G53 DI 10.1152/ajpgi.00228.2009 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 611DZ UT WOS:000278792600004 PM 20299601 ER PT J AU Haworth, RA Potter, KT Russell, DC AF Haworth, Robert A. Potter, Katherine T. Russell, Douglas C. TI Role of arachidonic acid, lipoxygenase, and mitochondrial depolarization in reperfusion arrhythmias SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE mitochondria; ischemia; reperfusion; reactive oxygen species; anion channels ID CA-2&-INDUCED MEMBRANE TRANSITION; ACUTE MYOCARDIAL-INFARCTION; FREE-FATTY-ACIDS; RAT HEART-CELLS; PERMEABILITY TRANSITION; INDUCED CARDIOPROTECTION; UNCOUPLING PROTEINS; LIPID-PEROXIDATION; CARDIAC MYOCYTES; ANION CHANNEL AB Haworth RA, Potter KT, Russell DC. Role of arachidonic acid, lipoxygenase, and mitochondrial depolarization in reperfusion arrhythmias. Am J Physiol Heart Circ Physiol 299: H165-H174, 2010. First published April 30, 2010; doi:10.1152/ajpheart.00906.2009.-We have sought evidence that arachidonic acid (AA) induces mitochondrial depolarization in isolated myocytes by a lipoxygenase (LOX)-dependent mechanism and that such depolarization might contribute to arrhythmogenesis following ischemia-reperfusion injury. A method was developed for measuring mitochondrial depolarization in isolated adult rat myocytes in suspension, using tetramethylrhodamine ethyl ester. The addition of AA to myocytes resulted in mitochondrial depolarization that was inhibited by the LOX inhibitor baicalein, by the reactive oxygen species (ROS) scavenger mercaptoproprionylglycine, and by the anion channel inhibitor diisothiocyanatostilbene-disulfonic acid (DIDS). AA induced mitochondrial uncoupling and mitochondrial ATPase activity in myocytes, but both were insensitive to baicalein. We conclude that the metabolic effect of AA in myocytes puts mitochondria into an energetically compromised state where membrane potential is easily changed by the DIDS-sensitive LOX/ROS-mediated opening of an inner membrane anion channel. In an in vivo anesthetized rat model of coronary artery occlusion, baicalein was found to strongly inhibit arrhythmias induced by ischemia-reperfusion injury. Arrhythmias following ischemia-reperfusion injury have been previously associated with DIDS-sensitive ROS-mediated mitochondrial depolarization, and free fatty acids including AA were previously found to accumulate during such injury. We therefore conclude that arrhythmias following ischemia-reperfusion injury might originate from mitochondrial depolarization mediated by LOX and AA. C1 [Haworth, Robert A.] Univ Wisconsin, Dept Surg, Ctr Clin Sci, Madison, WI 53792 USA. [Potter, Katherine T.; Russell, Douglas C.] Univ Wisconsin, Div Cardiovasc Med, Ctr Clin Sci, Madison, WI 53792 USA. [Russell, Douglas C.] William S Middleton Mem Vet Adm Med Ctr, Med Serv, Cardiol Sect, Madison, WI USA. RP Haworth, RA (reprint author), Univ Wisconsin, Dept Surg, Ctr Clin Sci, 600 Highland Ave, Madison, WI 53792 USA. EM haworth@surgery.wisc.edu FU William S. Middleton Memorial Veterans Hospital (Madison, WI); American Heart Association [0650147Z]; Cardiothoracic Division of the Department of Surgery FX This work was supported with resources from and the use of the facilities at the William S. Middleton Memorial Veterans Hospital (Madison, WI). This work was supported by an American Heart Association Grant-in-Aid 0650147Z (to R. A. Haworth) and by the Cardiothoracic Division of the Department of Surgery. NR 52 TC 6 Z9 8 U1 1 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 JUL PY 2010 VL 299 IS 1 BP H165 EP H174 DI 10.1152/ajpheart.00906.2009 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 612HT UT WOS:000278888400022 PM 20435853 ER PT J AU Jones, JA Ruddy, JM Bouges, S Zavadzkas, JA Brinsa, TA Stroud, RE Mukherjee, R Spinale, FG Ikonomidis, JS AF Jones, Jeffrey A. Ruddy, Jean Marie Bouges, Shenikqua Zavadzkas, Juozas A. Brinsa, Theresa A. Stroud, Robert E. Mukherjee, Rupak Spinale, Francis G. Ikonomidis, John S. TI Alterations in membrane type-1 matrix metalloproteinase abundance after the induction of thoracic aortic aneurysm in a murine model SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE fibroblast; vascular remodeling; extracellular matrix; microbubble contrast ID TISSUE INHIBITOR; GENE-EXPRESSION; MT1-MMP; MATRIX-METALLOPROTEINASE-2; LOCALIZATION; INFLAMMATION; DEGRADATION; DEFICIENCY; ACTIVATION; FIBRILLIN AB Jones JA, Ruddy JM, Bouges S, Zavadzkas JA, Brinsa TA, Stroud RE, Mukherjee R, Spinale FG, Ikonomidis JS. Alterations in membrane type-1 matrix metalloproteinase abundance after the induction of thoracic aortic aneurysm in a murine model. Am J Physiol Heart Circ Physiol 299: H114-H124, 2010. First published April 23, 2010; doi:10.1152/ajpheart.00028.2010.-Thoracic aortic aneurysms (TAAs) develop as a result of dysregulated extracellular matrix remodeling mediated by several matrix metalloproteinases (MMPs). Membrane type-1 MMP (MT1-MMP) is the prototypical member of a unique family of membrane-bound MMPs, possessing multiple substrates and functions. The present study tested the hypothesis that MT1-MMP expression, abundance, and activity would be elevated during TAA development and that this protease is produced primarily by mesenchymal cells within the thoracic aorta. Descending thoracic aortas were harvested from C57BL/6J mice at multiple time points (2, 4, 8, and 16 wk, n = 15 each) post-TAA induction (0.5M CaCl(2), 15 min) and compared with reference controls (n = 15). The expression and abundance of MT1-MMP, MMP-2, and tissue inhibitor of metalloproteinase (TIMP)-2 were assessed by quantitative PCR and immunoblot analysis. MT1-MMP activity was determined by fluorescent peptide assay. MT1-MMP was localized within the aortic wall by immunohistochemistry. MT1-MMP abundance and localization in live animals (8 wk post-TAA induction vs. control) was determined by microultrasound imaging with an MT1-MMP-targeted microbubble contrast agent. Aortic diameter was increased 172 +/- 7% at 16 wk post-TAA induction (P < 0.05). MT1-MMP and MMP-2 mRNA levels were elevated at 2 wk post-TAA induction (P < 0.05). MT1-MMP protein abundance increased progressively to a maximum of 178 +/- 26% at 16 wk post-TAA induction, whereas MMP-2 and TIMP-2 peaked at 2 wk post-TAA induction (526 +/- 93% and 376 +/- 48%, respectively, P < 0.05). MT1-MMP colocalized with fibroblasts, and MT1-MMP-targeted contrast binding was elevated in 8-wk TAA-induced mice versus control mice (217 +/- 53% vs. 81 +/- 8%, P < 0.05). In conclusion, these novel results suggest that MT1-MMP plays a dynamic multifunctional role in TAA development and, therefore, may provide a significant target for therapeutic strategies. C1 [Jones, Jeffrey A.; Ruddy, Jean Marie; Bouges, Shenikqua; Zavadzkas, Juozas A.; Brinsa, Theresa A.; Stroud, Robert E.; Mukherjee, Rupak; Spinale, Francis G.; Ikonomidis, John S.] Med Univ S Carolina, Dept Surg, Div Cardiothorac Surg Res, Charleston, SC 29425 USA. [Jones, Jeffrey A.; Spinale, Francis G.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Ikonomidis, JS (reprint author), Med Univ S Carolina, Div Cardiothorac Surg, Dept Surg, 114 Doughty St,Ste 625, Charleston, SC 29425 USA. EM wilburnm@musc.edu FU Department of Veterans Affairs Career Development Award CDA-2; Merit Award; National Heart, Lung, and Blood Institute [HL-075488-05] FX This work was supported by Department of Veterans Affairs Career Development Award CDA-2 (to J. A. Jones) and a Merit Award (to F. G. Spinale) and by National Heart, Lung, and Blood Institute Grant HL-075488-05 (to J. S. Ikonomidis). NR 41 TC 8 Z9 10 U1 1 U2 4 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 JUL PY 2010 VL 299 IS 1 BP H114 EP H124 DI 10.1152/ajpheart.00028.2010 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 612HT UT WOS:000278888400017 PM 20418476 ER PT J AU Mukherjee, R Zavadzkas, JA Rivers, WT McLean, JE Chang, EI Bouges, S Matthews, RG Koval, CN Stroud, RE Spinale, FG AF Mukherjee, Rupak Zavadzkas, Juozas A. Rivers, William T. McLean, Julie E. Chang, Eileen I. Bouges, Shenikqua Matthews, Robert G. Koval, Christine N. Stroud, Robert E. Spinale, Francis G. TI Short-term disruption in regional left ventricular electrical conduction patterns increases interstitial matrix metalloproteinase activity SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE myocardium; interstitium ID MYOCARDIAL-INFARCTION; ATRIAL-FIBRILLATION; HEART; INDUCTION AB Mukherjee R, Zavadzkas JA, Rivers WT, McLean JE, Chang EI, Bouges S, Matthews RG, Koval CN, Stroud RE, Spinale FG. Short-term disruption in regional left ventricular electrical conduction patterns increases interstitial matrix metalloproteinase activity. Am J Physiol Heart Circ Physiol 299: H217-H224, 2010. First published May 14, 2010; doi: 10.1152/ajpheart.00065.2010.-Increased matrix metalloproteinase (MMP) abundance occurs with adverse left ventricular (LV) remodeling in a number of cardiac disease states, including those induced by long-standing arrhythmias. However, whether regionally contained aberrant electrical activation of the LV, with consequent dyskinesia, alters interstitial MMP activation remained unknown. Electrical activation of the LV of pigs (n = 10, 30-35 kg) was achieved by pacing (150 beats/min) at left atrial and LV sites such that normal atrioventricular activation (60 min) was followed by regional early LV activation for 60 min within 1.5 cm of the paced site and restoration of normal atrioventricular pacing for 120 min. Regional shortening (piezoelectric crystals) and interstitial MMP activity (microdialysis with MMP fluorogenic substrate) at the LV pacing site and a remote LV site were monitored at 30-min intervals. During aberrant electrical stimulation, interstitial MMP activity at the paced site was increased (122 +/- 4%) compared with the remote region (100%, P < 0.05). Restoration of atrioventricular pacing after the 60-min period of aberrant electrical activation normalized segmental shortening (8.5 +/- 0.4%), but MMP activity remained elevated (121 +/- 6%, P , 0.05). This study demonstrates that despite the restoration of mechanical function, disturbances in electrical conduction, in and of itself, can cause acute increases in regional in vivo MMP activation and, therefore, contribute to myocardial remodeling. C1 [Mukherjee, Rupak; Zavadzkas, Juozas A.; Rivers, William T.; McLean, Julie E.; Chang, Eileen I.; Bouges, Shenikqua; Matthews, Robert G.; Koval, Christine N.; Stroud, Robert E.; Spinale, Francis G.] Med Univ S Carolina, Div Cardiothorac Surg, Charleston, SC 29425 USA. [Spinale, Francis G.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Mukherjee, R (reprint author), Med Univ S Carolina, Div Cardiothorac Surg, Strom Thurmond Res Bldg,770 MUSC Complex,Suite 6, Charleston, SC 29425 USA. EM mukherr@musc.edu OI Chang, Eileen/0000-0002-3444-7260 FU National Heart, Lung, and Blood Institute [HL-45024, HL-97012, PO1-48788]; Veterans Affairs Merit Award FX This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-45024, HL-97012, and PO1-48788 and by a Veterans Affairs Merit Award. NR 22 TC 2 Z9 2 U1 0 U2 2 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 JUL PY 2010 VL 299 IS 1 BP H217 EP H224 DI 10.1152/ajpheart.00065.2010 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 612HT UT WOS:000278888400028 PM 20472759 ER PT J AU Baggett, TP O'Connell, JJ Singer, DE Rigotti, NA AF Baggett, Travis P. O'Connell, James J. Singer, Daniel E. Rigotti, Nancy A. TI The Unmet Health Care Needs of Homeless Adults: A National Study SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID NUTRITION EXAMINATION SURVEY; NEW-YORK-CITY; MEDICAL-CARE; URBAN HOMELESS; FOOD INSUFFICIENCY; UNITED-STATES; HOUSED POOR; RISK-FACTORS; LOS-ANGELES; SERVICE USE AB Objectives. We assessed the prevalence and predictors of past-year unmet needs for 5 types of health care services in a national sample of homeless adults. Methods. We analyzed data from 966 adult respondents to the 2003 Health Care for the Homeless User Survey, a sample representing more than 436000 individuals nationally. Using multivariable logistic regression, we determined the independent predictors of each type of unmet need. Results. Seventy-three percent of the respondents reported at least one unmet health need, including an inability to obtain needed medical or surgical care (32%), prescription medications (36%), mental health care (21%), eyeglasses (41%), and dental care (41%). In multivariable analyses, significant predictors of unmet needs included food insufficiency, out-of-home placement as a minor, vision impairment, and lack of health insurance. Individuals who had been employed in the past year were more likely than those who had not to be uninsured and to have unmet needs for medical care and prescription medications. Conclusions. This national sample of homeless adults reported substantial unmet needs for multiple types of health care. Expansion of health insurance may improve health care access for homeless adults, but addressing the unique challenges inherent to homelessness will also be required. (Am J Public Health. 2010;100:1326-1333. doi:10.2105/AJPH.2009.180109) C1 [Baggett, Travis P.; O'Connell, James J.; Singer, Daniel E.; Rigotti, Nancy A.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Baggett, Travis P.; Singer, Daniel E.; Rigotti, Nancy A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [O'Connell, James J.] Boston Hlth Care Homeless Program, Boston, MA USA. RP Baggett, TP (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM tbaggett@partners.org FU Department of Health and Human Services [T32HP10251] FX This study was funded by a grant from the Health Resources and Services Administration of the Department of Health and Human Services (T32HP10251) to support the Harvard Medical School Fellowship in General Medicine and Primary Care. NR 76 TC 105 Z9 106 U1 6 U2 32 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JUL PY 2010 VL 100 IS 7 BP 1326 EP 1333 DI 10.2105/AJPH.2009.180109 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 610SO UT WOS:000278756000032 PM 20466953 ER PT J AU Shi, J Hang, JQ Mehta, AJ Zhang, HX Dai, HL Su, L Eisen, EA Christiani, DC AF Shi, Jing Hang, Jing-qing Mehta, Amar J. Zhang, Hong-xi Dai, He-lian Su, Li Eisen, Ellen A. Christiani, David C. TI Long-term Effects of Work Cessation on Respiratory Health of Textile Workers A 25-Year Follow-up Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE respiratory disease; environmental health; cotton textile workers; endotoxin exposure; occupational health ID COTTON DUST EXPOSURE; LUNG-FUNCTION DECLINE; REPUBLIC-OF-CHINA; PULMONARY-FUNCTION; BACTERIAL-ENDOTOXIN; SYMPTOMS; SMOKING; RESPONSES; DISEASE AB Rationale The degree to which chronic respiratory health effects caused by exposures to cotton dust and endotoxin is reversible after cessation of textile work is unknown. Objectives: To investigate changes in lung function and respiratory symptoms after cessation of textile work and to determine whether past exposure to cotton dust and endotoxin or smoking history modify the associations. Methods: We performed a prospective cohort study consisting of 447 cotton textile workers exposed to cotton dust and 472 unexposed silk textile workers, with a 25-year follow-up. Spirometry testing and respiratory questionnaires were conducted at 5-year intervals. Generalized estimated equations were used to model the average 5-year change in FEV(1) and odds ratios of respiratory symptom prevalence. Measurements and Main Results: Years since cessation of textile work was positively associated with 11.3 ml/yr and 5.6 ml/yr gains in 5-year FEV(1) change for cotton and silk workers, respectively. Among male cotton workers, smokers gained more FEV(1) per year after cessation of exposure than did nonsmokers, and the risk of symptoms of chronic bronchitis and byssinosis was larger for smoking than for nonsmoking male cotton workers. Conclusions: Cessation of textile work was significantly associated with improvement in lung function and respiratory symptoms. The positive effect of work cessation was greater for cotton workers than for silk workers. For cotton workers, the improvement in lung function loss after cessation of textile work was greater among smokers, but no differences were observed for silk workers. C1 [Shi, Jing; Mehta, Amar J.; Su, Li; Eisen, Ellen A.; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Environm & Occupat Med & Epidemiol Program, Dept Environm Hlth, Boston, MA 02115 USA. [Shi, Jing] Univ Sci & Technol Beijing, Sch Civil & Environm Engn, Beijing 100083, Peoples R China. [Hang, Jing-qing; Zhang, Hong-xi; Dai, He-lian] Shanghai Putuo Dist Peoples Hosp, Shanghai, Peoples R China. [Eisen, Ellen A.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Christiani, David C.] Harvard Univ, Dept Med, Sch Med, Boston, MA 02115 USA. [Christiani, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit, Boston, MA 02115 USA. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Environm & Occupat Med & Epidemiol Program, Dept Environm Hlth, 665 Huntington Ave,Bldg 1-1407, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu FU NIOSH [R01 OH02421]; NIH [ES00002] FX Supported by NIOSH grant R01 OH02421 and NIH grant ES00002. NR 28 TC 6 Z9 6 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL PY 2010 VL 182 IS 2 BP 200 EP 206 DI 10.1164/rccm.200903-0329OC PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 629NN UT WOS:000280206700011 PM 20339150 ER PT J AU Redline, S Yenokyan, G Gottlieb, DJ Shahar, E O'Connor, GT Resnick, HE Diener-West, M Sanders, MH Wolf, PA Geraghty, EM Ali, T Lebowitz, M Punjabi, NM AF Redline, Susan Yenokyan, Gayane Gottlieb, Daniel J. Shahar, Eyal O'Connor, George T. Resnick, Helaine E. Diener-West, Marie Sanders, Mark H. Wolf, Philip A. Geraghty, Estella M. Ali, Tauqeer Lebowitz, Michael Punjabi, Naresh M. TI Obstructive Sleep Apnea-Hypopnea and Incident Stroke The Sleep Heart Health Study SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE sleep apnea; stroke; epidemiology ID POSITIVE AIRWAY PRESSURE; ISCHEMIC-STROKE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; NOCTURNAL ARRHYTHMIAS; INTERMITTENT HYPOXIA; ASSOCIATION; ATHEROSCLEROSIS; HEMODYNAMICS; COMMUNITIES AB Rationale Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population. Objectives: To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea. Methods: Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea hypopnea index (OAHI) and outcome was incident ischemic stroke. Measurements and Main Results: A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest ANI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1-7.4). In the mild to moderate range (OAHI, 5-25), each one-unit increase in AN! in men was estimated to increase stroke risk by 6% (95% confidence interval, 2-10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25. Conclusions: The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials. C1 [Redline, Susan] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Yenokyan, Gayane; Diener-West, Marie] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Punjabi, Naresh M.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Gottlieb, Daniel J.; O'Connor, George T.; Wolf, Philip A.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Gottlieb, Daniel J.] VA Boston Healthcare Syst, Boston, MA USA. [Shahar, Eyal] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Div Epidemiol & Biostat, Tucson, AZ USA. [Resnick, Helaine E.] Georgetown Univ, Amer Assoc Homes & Serv Aging, Washington, DC USA. [Resnick, Helaine E.] Georgetown Univ, Dept Med, Washington, DC USA. [Sanders, Mark H.] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Geraghty, Estella M.; Ali, Tauqeer] Univ Calif Davis, Div Gen Internal Med, Davis, CA 95616 USA. Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. [Lebowitz, Michael] Univ Arizona, Coll Med, Dept Med, Tucson, AZ USA. RP Redline, S (reprint author), Brigham & Womens Hosp, 221 Longwood Ave, Boston, MA 02115 USA. EM susan.redline@gmail.com OI O'Connor, George/0000-0002-6476-3926; Yenokyan, Gayane/0000-0003-1482-5612 FU National Heart, Lung and Blood Institute, University of Washington [U01HL53940]; Boston University [U01HL53941]; University of Arizona [U01HL53938]; University of California, Davis [U01HL53916]; University of Minnesota [U01HL53934]; New York University [U01HL53931]; Johns Hopkins University [U01HL53937, U01HL64360]; Case Western Reserve University [U01HL63463]; Missouri Breaks Research [U01HL63429] FX Supported by National Heart, Lung and Blood Institute cooperative agreements U01HL53940 (University of Washington), U01HL53941 (Boston University), U01HL53938 (University of Arizona), U01HL53916 (University of California, Davis), U01HL53934 (University of Minnesota), U01HL53931 (New York University), U01HL53937 and U01HL64360 (Johns Hopkins University), U01HL63463 (Case Western Reserve University), and U01HL63429 (Missouri Breaks Research). NR 35 TC 375 Z9 389 U1 1 U2 20 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL PY 2010 VL 182 IS 2 BP 269 EP 277 DI 10.1164/rccm.200911-1746OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 629NN UT WOS:000280206700019 PM 20339144 ER PT J AU Kambadakone, AR Prakash, P Hahn, PF Sahani, DV AF Kambadakone, Avinash R. Prakash, Priyanka Hahn, Peter F. Sahani, Dushyant V. TI Low-Dose CT Examinations in Crohn's Disease: Impact on Image Quality, Diagnostic Performance, and Radiation Dose SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE Crohn's disease; MDCT; noise index; radiation dose ID INFLAMMATORY-BOWEL-DISEASE; TUBE CURRENT MODULATION; NOISE-REDUCTION FILTERS; MULTIDETECTOR CT; FOLLOW-THROUGH; CAPSULE ENDOSCOPY; ABDOMINAL CT; ENTEROGRAPHY; EXPOSURE; EPIDEMIOLOGY AB OBJECTIVE. The objective of this study was to evaluate the image quality and diagnostic performance of simulated low-dose MDCT examinations in patients with Crohn's disease. MATERIALS AND METHODS. Thirty-five MDCT examinations from 25 patients (14 males and 11 females; age range, 16-86 years) with known or suspected Crohn's disease were retrospectively evaluated. The MDCT images (5 mm thickness) were modified by artificially introducing noise using volume CT noise simulation software to simulate low-dose MDCT data acquired with noise indexes (NIs) of 18-35. The 175 MDCT image data sets generated were then randomized and reviewed by two readers to assess the subjective image quality and diagnostic accuracy for confidently detecting Crohn's disease findings on a 5-point scale (1, definitely absent; 5, definitely present). The image quality, diagnostic performance, and radiation dose from the original MDCT examinations served as a reference standard for comparison. RESULTS. The simulated low-dose CT images with elevated NIs of 18-25 yielded optimal image quality and concordant diagnostic accuracy with standard-dose scans with a mean baseline volume CT dose index of 16 +/- 3.34 (SD) mGy (image quality score, 4-4.9 vs 4.95, respectively; p = 0.4). Images simulating NIs of 30-35 were considered degraded because of excessive image noise and presented lower diagnostic performance (range of image quality score, 3-3.6; weighted. = 0.25-0.37; p < 0.001). Diagnostic performance and reader confidence for the determination of Crohn's disease manifestations in cases in which the reference standard was positive were higher at NIs of = 25 compared with NI of 30 (reader confidence score, 4.5 vs 3.6, respectively; p < 0.05) and an NI of 35 (3.2, p < 0.05). Compared with the standard-dose examination, a 31-64% reduction in radiation dose was estimated for NI levels of 18-25, which corresponds to image noise of 19-27 HU in subcutaneous fat. CONCLUSION. Processed MDCT images with the introduction of noise to simulate low-dose MDCT examinations with NI levels of 18-25 allows substantial dose reduction for CT examinations in Crohn's disease without compromising diagnostic information. C1 [Kambadakone, Avinash R.; Prakash, Priyanka; Hahn, Peter F.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent Radiol, Dept Radiol, Boston, MA 02114 USA. RP Sahani, DV (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent Radiol, Dept Radiol, 55 Fruit St,White Bldg 270, Boston, MA 02114 USA. EM dsahani@partners.org NR 48 TC 42 Z9 45 U1 0 U2 5 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 JUL PY 2010 VL 195 IS 1 BP 78 EP 88 DI 10.2214/AJR.09.3420 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 613RQ UT WOS:000278998200011 PM 20566800 ER PT J AU Lin, A Harris, M Zalis, M AF Lin, Abraham Harris, Mitchell Zalis, Michael TI Initial Observations of Electronic Medical Record Usage During CT and MRI Interpretation: Frequency of Use and Impact on Workflow SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE data search; electronic medical record; time efficiency; workflow ID UNITED-STATES; 2004 ACMI; ADOPTION; SYSTEMS; TRENDS AB OBJECTIVE. Electronic medical record (EMR) systems permit integration of contextual nonimaging EMR data into examination interpretation; however, the extra effort required to search and review these nonradiologic data are not well characterized. We assessed the gross frequency and pattern of EMR usage in the interpretation of diagnostic CT and MRI examinations. SUBJECTS AND METHODS. We defined nonradiologic EMR data as laboratory data, nonimaging specialty report, clinical note, and administrative data not available on PACS. For abdominal, neuroradiologic, and musculoskeletal CT and MRI, we prospectively recorded the time required for image analysis (including prior imaging studies and their reports), nonradiologic EMR use, and initial report drafting by fellows and staff in randomized sessions. We assessed EMR use as a fraction of work activity and according to technique, sub-specialty, inpatient status, and radiologist experience. RESULTS. We observed 372 CT and MRI interpretations by 33 radiologists. For CT, radiologists used the EMR in 34% of abdominal, 57% of neuroradiologic, and 38% of musculoskeletal interpretations. For MRI, EMR was used in 73% of abdominal, 56% of neuroradiologic, and 33% of musculoskeletal interpretations. For CT, EMR usage comprised 18%, 14%, and 18% of diagnostic effort (image analysis plus EMR use) for abdominal, neuroradiologic, and musculoskeletal interpretations, respectively; for MRI, EMR usage comprised 21%, 16%, and 15% of diagnostic effort for abdominal, neuroradiologic, and musculoskeletal interpretations, respectively. Frequency of EMR use was significantly greater for neuroradiology CT and abdominal MRI (p < 0.05, Fisher's test). EMR usage was not consistently related to inpatient status for CT or radiologist experience. CONCLUSION. For CT and MRI interpretation, EMR usage is frequent and comprises a significant fraction of diagnostic effort. C1 [Lin, Abraham; Harris, Mitchell; Zalis, Michael] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Zalis, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, 25 New Chardon St,Ste 400A, Boston, MA 02114 USA. EM mzalis@mgh.harvard.edu FU American Cancer Society; GE Healthcare FX M. Zalis has received support from the American Cancer Society (research scholar grant) and GE Healthcare (investigator initiated research grant). NR 12 TC 10 Z9 10 U1 4 U2 4 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 JUL PY 2010 VL 195 IS 1 BP 188 EP 193 DI 10.2214/AJR.09.2946 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 613RQ UT WOS:000278998200026 PM 20566815 ER PT J AU Cronin, CG Prakash, P Blake, MA AF Cronin, Carmel G. Prakash, Priyanka Blake, Michael A. TI Oral and IV Contrast Agents for the CT Portion of PET/CT SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review DE contrast material; IV contrast agents; oral contrast agents; PET/CT; small bowel ID EMISSION-TOMOGRAPHY; ENHANCED CT; FDG-PET/CT; NONENHANCED CT; RECTAL-CANCER; PROTOCOLS; IMPACT C1 [Cronin, Carmel G.; Prakash, Priyanka; Blake, Michael A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Cronin, Carmel G.; Prakash, Priyanka; Blake, Michael A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Blake, MA (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM mblake2@partners.org NR 15 TC 11 Z9 11 U1 0 U2 4 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 JUL PY 2010 VL 195 IS 1 BP W5 EP W13 DI 10.2214/AJR.09.3844 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 613RQ UT WOS:000278998200040 PM 20566780 ER PT J AU Seon, JK Gadikota, HR Wu, JL Sutton, K Gill, TJ Li, GA AF Seon, Jong Keun Gadikota, Hemanth R. Wu, Jia-Lin Sutton, Karen Gill, Thomas J. Li, Guoan TI Comparison of Single- and Double-Bundle Anterior Cruciate Ligament Reconstructions in Restoration of Knee Kinematics and Anterior Cruciate Ligament Forces SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article DE anterior cruciate ligament; reconstruction; single bundle; double bundle; kinematics ID ANATOMIC DOUBLE-BUNDLE; FEMORAL TUNNEL PLACEMENT; IN-SITU FORCES; BIOMECHANICAL ANALYSIS; ACL; STABILITY; GRAFT; TENSION; DEFICIENCY; ROTATION AB Background: Anterior cruciate ligament (ACL) deficiency alters 6 degrees of freedom knee kinematics, yet only anterior translation and internal rotation have been the primary measures in previous studies. Purpose: To compare the 6 degrees of freedom knee kinematics and the graft forces after single- and double-bundle ACL reconstructions under various external loading conditions. Study Design: Controlled laboratory study. Methods: Ten human cadaveric knees were tested with a robotic testing system under 4 conditions: intact, ACL deficient, single-bundle reconstructed with a quadrupled hamstring tendon graft, and double-bundle reconstructed with 2 looped hamstring tendon grafts. Knee kinematics and forces of the ACL or ACL graft in each knee were measured under 3 loading conditions: an anterior tibial load of 134 N, a simulated quadriceps muscle load of 400 N, and combined tibial torques (10 N.m valgus and 5 N.m internal tibial torques) at 0 degrees, 15 degrees, 30 degrees, 60 degrees, and 90 degrees of knee flexion. Results: The double-bundle reconstruction restored the anterior and medial laxities closer to the intact knee than the single-bundle reconstruction. However, the internal rotation of the tibia under the simulated quadriceps muscle load was significantly decreased when compared with the intact knee after both reconstructions, more so after double-bundle reconstruction (P<.05). The entire graft force of the double-bundle reconstruction was more similar to that of the intact ACL than that of the single-bundle reconstruction. However, the posterolateral bundle graft in the double-bundle reconstructed knee was overloaded as compared with the intact posterolateral bundle. Conclusion: The double-bundle reconstruction can better restore the normal anterior-posterior and medial-lateral laxities than the single-bundle reconstruction can, but an overloading of the posterolateral bundle graft can occur in a double-bundle reconstructed knee. C1 [Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, Boston, MA 02114 USA. [Seon, Jong Keun; Gadikota, Hemanth R.; Wu, Jia-Lin; Sutton, Karen; Gill, Thomas J.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Seon, Jong Keun] Chonnam Natl Univ, Hwasun Hosp, Dept Orthopaed, Jeonnam, South Korea. [Wu, Jia-Lin] Triserv Gen Hosp, Natl Def Med Ctr, Dept Orthopaed Surg, Taipei, Taiwan. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org FU National Institutes of Health [R01AR055612]; Department of Orthopaedic Surgery of Massachusetts General Hospital; DePuy Mitek, Raynham, Massachusetts FX One or more authors has declared a potential conflict of interest: Support was received from the National Institutes of Health (R01AR055612), the Department of Orthopaedic Surgery of Massachusetts General Hospital, and DePuy Mitek, Raynham, Massachusetts. NR 34 TC 31 Z9 35 U1 0 U2 4 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 JUL PY 2010 VL 38 IS 7 BP 1359 EP 1367 DI 10.1177/0363546510361494 PG 9 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 617TH UT WOS:000279304200007 PM 20392968 ER PT J AU Wu, JL Hosseini, A Kozanek, M Gadikota, HR Gill, TJ Li, GA AF Wu, Jia-Lin Hosseini, Ali Kozanek, Michal Gadikota, Hemanth R. Gill, Thomas J. Li, Guoan TI Kinematics of the Anterior Cruciate Ligament During Gait SO AMERICAN JOURNAL OF SPORTS MEDICINE LA English DT Article DE in vivo knee kinematics; gait; anterior cruciate ligament (ACL); ACL bundles ID IN-SITU FORCES; STRAIN BEHAVIOR; KNEE-JOINT; POSTEROLATERAL BUNDLES; ANATOMIC RECONSTRUCTION; VIVO KINEMATICS; NORMAL WALKING; TIBIAL LOADS; FLEXION; REHABILITATION AB Background: The function of the anteromedial (AM) and posterolateral (PL) bundles of the anterior cruciate ligament (ACL) during gait has not been reported. Hypothesis: The AM and PL bundles have distinct functional behavior during the stance phase of treadmill gait. Study Design: Descriptive laboratory study. Methods: Three-dimensional models of the knee were created by magnetic resonance images from 8 healthy subjects. The contour of the 2 bundle attachments were constructed on each model. Each bundle was represented by a straight line connecting its tibial and femoral attachment centroids. Next, the knee kinematics during the stance phase of gait was determined with a dual fluoroscopic imaging system. The relative elongation, sagittal plane elevation, coronal plane elevation, and transverse plane deviation of the 2 bundles were measured directly from heel strike to toe-off. Results: At heel strike, the AM and PL bundles had first peak elongation of 9% +/- 7% and 9% +/- 13%, respectively. At 50% progress of the stance phase, both bundles were maximally elongated, 12% +/- 7% for the AM bundle and 13% +/- 15% for the PL bundle. No significant difference was found for each bundle between 40% and 60% of the stance phase (P>.05). With increasing knee flexion, the sagittal plane and coronal plane elevations of the 2 bundles decreased, whereas the deviation angles increased. Conclusion: Both bundles are anisometric and function in a similar manner during the stance phase of gait. They were maximally elongated throughout the midstance where they were stretched maximally to resist anterior tibial translation. C1 [Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, Boston, MA 02114 USA. [Wu, Jia-Lin; Hosseini, Ali; Kozanek, Michal; Gadikota, Hemanth R.; Gill, Thomas J.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Wu, Jia-Lin] Triserv Gen Hosp, Natl Def Med Ctr, Dept Orthopaed Surg, Taipei, Taiwan. [Hosseini, Ali] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. RP Li, GA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab,Dept Orthopaed Surg, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org FU National Institutes of Health [AR 052408, AR051078] FX One or more authors has declared a potential conflict of interest: The authors gratefully acknowledge the support of the National Institutes of Health grants AR 052408 and AR051078. NR 46 TC 22 Z9 25 U1 1 U2 5 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 JUL PY 2010 VL 38 IS 7 BP 1475 EP 1482 DI 10.1177/0363546510364240 PG 8 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 617TH UT WOS:000279304200023 PM 20442323 ER PT J AU Kaafarani, HMA Smith, TS Neumayer, L Berger, DH DePalma, RG Itani, KMF AF Kaafarani, Haytham M. A. Smith, Tracy Schifftner Neumayer, Leigh Berger, David H. DePalma, Ralph G. Itani, Kamal M. F. TI Trends, outcomes, and predictors of open and conversion to open cholecystectomy in Veterans Health Administration hospitals SO AMERICAN JOURNAL OF SURGERY LA English DT Article DE Laparoscopic cholecystectomy; Open cholecystectomy; Conversion rate; Surgical outcomes; Mortality; Morbidity; Predictors; Secular trends; Quality of care ID 30-DAY POSTOPERATIVE MORTALITY; UNIVERSITY MEDICAL-CENTERS; AFFAIRS SURGICAL RISK; LAPAROSCOPIC CHOLECYSTECTOMY; ACUTE CHOLECYSTITIS; QUALITY; CARE; MORBIDITY; IMPROVEMENT; EXPERIENCE AB BACKGROUND: Laparoscopic cholecystectomy (LC) accounts for more than 85% of cholecystectomies. Factors prompting open cholecystectomy (OC) or conversion from LC to OC (CONY) are not completely understood. METHODS: Prospectively collected data from the National Surgical Quality Improvement Program (NSQIP) were combined with administrative data to identify patients undergoing cholecystectomy from October 2005 to October 2008. Three cohorts were defined: LC, OC, and CONV. Using logistic hierarchical modeling, we identified predictors of the choice of OC and the decision to CONV. RESULTS: A total of 11,669 patients underwent cholecystectomy at 117 VA hospitals, including 9,530 LC (81.7%). While the rate of conversion from LC to OC remained stable over the study period (9.0% overall), the percentage of OC decreased from 11.5% in 2006 to 10.1% in 2007 and 8.9% in 2008 (P = .0002). Compared with LC, the OC cohort had more comorbidities (35 of 41 preoperative characteristics, all P < .05), a higher 30-day. morbidity rate (18.7% vs 4.8%. P < .0001), and a higher 30-day mortality rate (2.4% vs .4%, P < .0001). American Society of Anesthesiologist (ASA) class, patient comorbidities (eg, ascites, bleeding disorders, pneumonia) and functional status predicted a choice of OC. Age, preoperative albumin, previous abdominal surgery and emergency status predicted OC and CONV (all P < .05). A higher hospital conversion rate was independently predictive of OC (odds ratio [1% rate increase]: 1.05 [1.02-1.07]; P = .0004). CONCLUSION: In the last 3 years, there has been a trend towards performing fewer OCs in VA hospitals. More patient comorbidities and higher hospital-level conversion rates are predictive of the choice to perform or convert to OC. Published by Elsevier Inc. C1 [Kaafarani, Haytham M. A.; Itani, Kamal M. F.] VA Boston Healthcare Syst, Dept Surg, W Roxbury, MA USA. [Smith, Tracy Schifftner] Eastern Colorado Healthcare Syst, Dept Vet Affairs, Denver, CO USA. [Neumayer, Leigh] VA Salt Lake City Hlth Care Syst, Dept Surg, Salt Lake City, UT USA. [Berger, David H.] Michael E DeBakey VA Med Ctr, Dept Surg, Houston, TX USA. [DePalma, Ralph G.] Dept Vet Affairs Cent Off, Patient Care Serv, Washington, DC USA. RP Itani, KMF (reprint author), VA Boston Healthcare Syst, Dept Surg, W Roxbury, MA USA. EM kitani@med.va.gov NR 28 TC 39 Z9 40 U1 2 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 J9 AM J SURG JI Am. J. Surg. PD JUL PY 2010 VL 200 IS 1 BP 32 EP 40 DI 10.1016/j.amjsurg.2009.08.020 PG 9 WC Surgery SC Surgery GA 635ZU UT WOS:000280697900006 PM 20637334 ER PT J AU Mekel, M Nucera, C Hodin, RA Parangi, S AF Mekel, Michal Nucera, Carmelo Hodin, Richard A. Parangi, Sareh TI Surgical implications of B-Raf(V600E) mutation in fine-needle aspiration of thyroid nodules SO AMERICAN JOURNAL OF SURGERY LA English DT Review DE B-Raf; Fine-needle aspiration biopsy; Thyroid nodules; Papillary thyroid cancer ID LYMPH-NODE METASTASES; BRAF V600E MUTATION; BRAF(V600E) MUTATION; PAPILLARY CARCINOMAS; B-RAF; HUMAN CANCER; CLINICAL-IMPLICATIONS; BIOPSY SPECIMENS; HOT-SPOT; DIAGNOSIS AB BACKGROUND: Management of patients with thyroid nodules is based on establishing an accurate diagnosis; however, differentiating benign from malignant lesions preoperatively is not always possible using current cytological techniques. Novel molecular testing on cytological material could lead to clearer treatment algorithms. B-Raf(V600E) mutation is the most common genetic alteration in thyroid cancer, specifically found in papillary thyroid cancer (PTC), and usually reported to be associated with aggressive disease. DATA SOURCE: A literature search using PubMed identified all the pertinent literature on the identification and utilization of the B-Raf(V600E) mutation in thyroid cancer. CONCLUSIONS: The utility of using B-Raf mutation testing for nodules with indeterminate cytology is limited since many of those nodules (benign and malignant) do not harbor B-Raf mutations. However, when the pathologist sees cytological features suspicious for PTC, B-Raf(V600E) mutation analysis may enhance the assessment of preoperative risks for PTC, directing a more aggressive initial surgical management when appropriate. (C) 2010 Elsevier Inc. All rights reserved. C1 [Mekel, Michal; Nucera, Carmelo; Hodin, Richard A.; Parangi, Sareh] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Surg Unit,Thyroid Canc Res Lab, Boston, MA 02115 USA. RP Parangi, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Surg Unit,Thyroid Canc Res Lab, Boston, MA 02115 USA. EM sparangi@partners.org FU American Physicians Fellowship for Medicine in Israel; Rambam-Health Care Campus, Israel; American Friends of Rambam; Israel Medical Association; Israel Cancer Association FX Dr Mekel is a recipient of fellowship grant from the American Physicians Fellowship for Medicine in Israel. Dr Mekel is also supported in part by Rambam-Health Care Campus, Israel, the American Friends of Rambam, Israel Medical Association and the Israel Cancer Association. NR 65 TC 13 Z9 14 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 J9 AM J SURG JI Am. J. Surg. PD JUL PY 2010 VL 200 IS 1 BP 136 EP 143 DI 10.1016/j.amjsurg.2009.08.029 PG 8 WC Surgery SC Surgery GA 635ZU UT WOS:000280697900023 PM 20637346 ER PT J AU Colvin, RB AF Colvin, R. B. TI Dimensions of Antibody-Mediated Rejection SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material ID ALLOGRAFT-REJECTION; CARDIAC ALLOGRAFTS; C4D; ALLOANTIBODY; LIVER C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Colvin, RB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM colvin@helix.mgh.harvard.edu FU NHLBI NIH HHS [P01 HL018646]; NIAID NIH HHS [U19 AI066705, U19 AI102405] NR 12 TC 18 Z9 18 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 JUL PY 2010 VL 10 IS 7 BP 1509 EP 1510 DI 10.1111/j.1600-6143.2010.03172.x PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 615SD UT WOS:000279155900007 PM 20642676 ER PT J AU Meije, Y Tonjes, RR Fishman, JA AF Meije, Y. Toenjes, R. R. Fishman, J. A. TI Retroviral Restriction Factors and Infectious Risk in Xenotransplantation SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Review DE Donor infection; ethics; HIV infection; posttransplant infection; retroviruses and xenotransplantation; xenotransplantation ID PORCINE ENDOGENOUS RETROVIRUS; TO-BABOON XENOTRANSPLANTATION; CROSS-SPECIES TRANSMISSION; MINIATURE SWINE; HUMAN-CELLS; LYMPHOTROPIC HERPESVIRUS; HUMAN TRIM5-ALPHA; HUMAN APOBEC3G; PIG; RECOMBINANT AB The clinical application of xenotransplantation poses immunologic, ethical, and microbiologic challenges. Significant progress has been made in the investigation of each of these areas. Among concerns regarding infectious risks for human xenograft recipients is the identification in swine of infectious agents including porcine endogenous retroviruses (PERV) that are capable of replication in some human cell lines. PERV replication has, however, been difficult to demonstrate in primate-derived cell lines and in preclinical studies of non-human primates receiving porcine xenografts. Endogenous 'retroviral restriction factors' are intracellular proteins and components of the innate immune system that act at various steps in retroviral replication. Recent studies suggest that some of these factors may have applications in the management of endogenous retroviruses in xenotransplantation. The risks of PERV infection and the potential role of retroviral restriction factors in xenotransplantation are reviewed in detail. C1 [Fishman, J. A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Fishman, J. A.] Harvard Univ, Sch Med, Boston, MA USA. [Toenjes, R. R.] Paul Ehrlich Inst, D-6070 Langen, Germany. [Meije, Y.] Hosp Univ 12 Octubre, Infect Dis Unit, Madrid, Spain. RP Fishman, JA (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. EM jfishman@partners.org FU Public Health Services [NIH-NIAID PO1-AI45897]; Spanish Infectious Disease and Clinical Microbiology Society (SEIMC) FX This study was supported by Public Health Services grant NIH-NIAID PO1-AI45897. YM has been supported with a grant from Spanish Infectious Disease and Clinical Microbiology Society (SEIMC). NR 40 TC 18 Z9 19 U1 2 U2 27 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 JUL PY 2010 VL 10 IS 7 BP 1511 EP 1516 DI 10.1111/j.1600-6143.2010.03146.x PG 6 WC Surgery; Transplantation SC Surgery; Transplantation GA 615SD UT WOS:000279155900008 PM 20642677 ER PT J AU Wilens, TE Martelon, MK Kruesi, MJP Parcell, T Westerberg, D Schillinger, M Gignac, M Biederman, J AF Wilens, Timothy E. Martelon, M. K. Kruesi, M. J. P. Parcell, T. Westerberg, D. Schillinger, M. Gignac, M. Biederman, J. TI Does Conduct Disorder Mediate the Development of Substance Use Disorders in Adolescents with Bipolar Disorder? A Case-Control Family Study SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Meeting Abstract C1 [Wilens, Timothy E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD JUL-AUG PY 2010 VL 19 IS 4 MA 13 BP 372 EP 373 PG 2 WC Substance Abuse SC Substance Abuse GA 612QA UT WOS:000278914700024 ER PT J AU Wilens, TE Martelon, M Wozniak, J Monuteaux, M Evans, M Parcell, T Biederman, J AF Wilens, Timothy E. Martelon, M. Wozniak, J. Monuteaux, M. Evans, M. Parcell, T. Biederman, J. TI Maternal Cigarette Smoking and Substance Use Disorders during Pregnancy and Offspring Bipolar Disorder SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Meeting Abstract C1 [Wilens, Timothy E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD JUL-AUG PY 2010 VL 19 IS 4 MA 12 BP 372 EP 372 PG 1 WC Substance Abuse SC Substance Abuse GA 612QA UT WOS:000278914700023 ER PT J AU Wilens, TE Prince, JB Waxmonsky, J Doyle, R Spencer, T Martelon, MK Evans, M AF Wilens, Timothy E. Prince, J. B. Waxmonsky, J. Doyle, R. Spencer, T. Martelon, M. K. Evans, M. TI Open Trial of Sustained Release Bupropion in Adults with ADHD plus Substance Use Disorders SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Meeting Abstract C1 [Wilens, Timothy E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD JUL-AUG PY 2010 VL 19 IS 4 MA 14 BP 373 EP 373 PG 1 WC Substance Abuse SC Substance Abuse GA 612QA UT WOS:000278914700025 ER PT J AU Kelly, JF Kane, MT Mograss, L AF Kelly, John F. Kane, M. T. Mograss, L. TI Adapting and Implementing Evidence-Based Practices in Young Adults with Substance Use Disorder: A Pilot Study SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Meeting Abstract C1 [Kelly, John F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kelly, John F.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD JUL-AUG PY 2010 VL 19 IS 4 MA 22 BP 375 EP 376 PG 2 WC Substance Abuse SC Substance Abuse GA 612QA UT WOS:000278914700031 ER PT J AU Smith, DZ Pulas, T Renner, JA AF Smith, D. Zach Pulas, T. Renner, J. A., Jr. TI Mislabeled, Misdosed, and Contaminated: A Meta-Analysis of Black Market Anabolic Steroids SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Meeting Abstract C1 [Smith, D. Zach] Boston Med Ctr, Boston, MA USA. [Smith, D. Zach] Boston VA Healthcare Syst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD JUL-AUG PY 2010 VL 19 IS 4 MA 26 BP 377 EP 377 PG 1 WC Substance Abuse SC Substance Abuse GA 612QA UT WOS:000278914700034 ER PT J AU Batki, SL Dimmock, JA Ploutz-Snyder, R Carey, KB Maisto, SA Meszaros, ZS Cavallerano, MB Canfield, K Leontieva, L AF Batki, Steven L. Dimmock, J. A. Ploutz-Snyder, R. Carey, K. B. Maisto, S. A. Meszaros, Z. S. Cavallerano, M. B. Canfield, K. Leontieva, L. TI Nonalcohol Substance Use in Alcohol-Dependent Patients with Schizophrenia or Schizoaffective Disorder SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Meeting Abstract C1 [Batki, Steven L.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Batki, Steven L.] San Francisco VA Med Ctr, San Francisco, CA USA. [Batki, Steven L.] SUNY Upstate Med Univ Syracuse, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD JUL-AUG PY 2010 VL 19 IS 4 MA 32 BP 378 EP 379 PG 2 WC Substance Abuse SC Substance Abuse GA 612QA UT WOS:000278914700039 ER PT J AU Snyder, CW Vandromme, MJ Tyra, SL Hawn, MT AF Snyder, Christopher W. Vandromme, Marianne J. Tyra, Sharon L. Hawn, Mary T. TI Retention of Colonoscopy Skills after Virtual Reality Simulator Training by Independent and Proctored Methods SO AMERICAN SURGEON LA English DT Article; Proceedings Paper CT Annual Scientific Meeting and Postgraduate Course Program of the Southeastern-Surgical-Congress CY FEB 20-23, 2010 CL Savannah, GA ID SURGICAL SKILLS; OPERATING-ROOM; PROFICIENCY AB Virtual reality (VR) simulators may enhance surgical resident colonoscopy skills, but the duration of skill retention and the effects of different simulator training methods are unknown. Medical students participating in a randomized trial of independent (automated simulator feedback only) versus proctored (human expert feedback plus simulator feedback) simulator training performed a standardized VR colonoscopy scenario at baseline, at the end of training (posttraining), and after a median 4.5 months without practice (retention). Performances were scored on a 10-point scale based on expert proficiency criteria and compared for the independent and proctored groups. Thirteen trainees (8 proctored, 5 independent) were included. Performance at retention testing was significantly better than baseline (median score 10 vs 5, P < 0.0001), and no different from posttraining (median score 10 vs 10, P = 0.19). Score changes from baseline to retention and from posttraining to retention were no different for the proctored and independent groups. Overinsufflation and excessive force were the most common reasons for nonproficiency at retention. After proficiency-based VR simulator training, colonoscopy skills are retained for several months, regardless of whether an independent or proctored approach is used. Error avoidance skills may not be retained as well as speed and efficiency skills. C1 [Snyder, Christopher W.; Vandromme, Marianne J.; Tyra, Sharon L.; Hawn, Mary T.] Univ Alabama, Dept Surg, Sect Gastrointestinal Surg, Birmingham, AL 35294 USA. [Hawn, Mary T.] Birmingham Vet Affairs Med Ctr, Ctr Surg Med Acute Care Res & Transit, Birmingham, AL USA. RP Hawn, MT (reprint author), Univ Alabama, Dept Surg, Sect Gastrointestinal Surg, 1922 7th Ave S,KB 428, Birmingham, AL 35294 USA. EM mhawn@uab.edu NR 14 TC 15 Z9 15 U1 1 U2 2 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 JUL PY 2010 VL 76 IS 7 BP 743 EP 746 PG 4 WC Surgery SC Surgery GA 619GF UT WOS:000279416500017 PM 20698383 ER PT J AU Shapiro, LE Alfille, PH Sandberg, WS AF Shapiro, Laurie E. Alfille, Paul H. Sandberg, Warren S. TI Robots with a Social Memory SO ANESTHESIA AND ANALGESIA LA English DT Editorial Material C1 [Shapiro, Laurie E.; Alfille, Paul H.; Sandberg, Warren S.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Shapiro, Laurie E.; Alfille, Paul H.; Sandberg, Warren S.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Sandberg, WS (reprint author), Vanderbilt Univ, Med Ctr, Dept Anesthesiol, 1211 21st Ave S,722 MAB, Nashville, TN 37212 USA. EM warren.sandberg@vanderbilt.edu OI Sandberg, Warren/0000-0002-9246-777X NR 4 TC 5 Z9 5 U1 0 U2 0 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 JUL PY 2010 VL 111 IS 1 BP 19 EP 20 DI 10.1213/ANE.0b013e3181e1d6b8 PG 2 WC Anesthesiology SC Anesthesiology GA 617LF UT WOS:000279281500008 PM 20576964 ER PT J AU Hung, YC Suzuki, S Huang, CJ Chen, CC Pan, YY Wang, CF Srinavasan, V Gerner, P AF Hung, Yu-Chun Suzuki, Suzuko Huang, Chun-Jen Chen, Chien-Chuan Pan, Yu-Yen Wang, Chi-Fei Srinavasan, Venkatesh Gerner, Peter TI Resiniferatoxin Combined with Antidepressants Preferentially Prolongs Sensory/Nociceptive Block in Rat Sciatic Nerve SO ANESTHESIA AND ANALGESIA LA English DT Article ID LOCAL-ANESTHETICS; PERINEURAL RESINIFERATOXIN; CAPSAICIN RECEPTOR; TRICYCLIC ANTIDEPRESSANTS; SODIUM-CHANNELS; ION-CHANNEL; IN-VITRO; AMITRIPTYLINE; PAIN; PREVENTS AB BACKGROUND: Current techniques of peripheral nerve block have major limitations, including lack of differentiation between motor and sensory fibers and potential toxicity of local anesthetics. Recent studies have suggested that a nociceptive-selective nerve block can be achieved via a transient receptor potential vanilloid type 1 activator (capsaicin) along with local anesthetics. We hypothesized that the combination of potent transient receptor potential vanilloid type 1 agonist resiniferatoxin (RTX) and selected antidepressants (amitriptyline, doxepin, and fluoxetine, also potent sodium channel blockers) would produce prolonged and predominantly sensory nerve block. METHODS: Rats were anesthetized with isoflurane, and 0.2 mL of amitriptyline, doxepin, or fluoxetine was deposited next to the surgically exposed sciatic nerves (n = 8 per group). Some animals received a second injection containing RTX (n = 8 per group). The effect of nerve block was assessed by neurobehavioral tests of the motor function (extensor postural thrust) and the nocifensive reaction (mechanical pinch). RESULTS: A single application of RTX produced nociceptive-selective sciatic nerve block, whereas antidepressants produced nociceptive and motor block. The combined administration of RTX and antidepressant resulted in a predominantly nociceptive nerve block. Compared with antidepressants or RTX alone, the combination prolonged the nociceptive nerve block more than the motor block. CONCLUSIONS: The combined application of RTX and antidepressants produced a markedly prolonged nociceptive peripheral nerve block in rat sciatic nerves compared with either agent alone. However, the 2-drug regimen also elicited prolonged blockade of the motor function, although disproportionately less compared with the nociceptive modality, suggesting the existence of nontransient receptor potential vanilloid type 1 mediated mechanisms. The mechanisms through which RTX affects nociceptive signal transduction/transmission have yet to be fully elucidated. (Anesth Analg 2010;111:207-13) C1 [Hung, Yu-Chun; Chen, Chien-Chuan; Pan, Yu-Yen] Mackay Mem Hosp, Dept Anesthesiol, Taipei 10449, Taiwan. [Hung, Yu-Chun; Chen, Chien-Chuan] Mackay Med Nursing & Management Coll, Taipei, Taiwan. [Suzuki, Suzuko; Wang, Chi-Fei; Gerner, Peter] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Huang, Chun-Jen] Buddhist Tzu Chi Gen Hosp, Taipei Branch, Taipei, Taiwan. [Srinavasan, Venkatesh] Harvard Univ, Sch Med, Dept Anesthesiol, VA Boston Healthcare Syst, Boston, MA USA. RP Hung, YC (reprint author), Mackay Mem Hosp, Dept Anesthesiol, 92 Sec 2,Zhongshan N Rd, Taipei 10449, Taiwan. EM yuchun51@ms22.hinet.net FU National Science Council, Taiwan [NSC97-2314-B-195-005-MY3]; Mackay Memorial Hospital, Taiwan [MMH9714]; National Institutes of Health, Bethesda, MD [GM64051] FX Supported by the National Science Council, Taiwan (research grant no. NSC97-2314-B-195-005-MY3 to Y-CH), Mackay Memorial Hospital, Taiwan (research grant no. MMH9714 to Y-CH), and the National Institutes of Health, Bethesda, MD (research grant no. GM64051 to PG). NR 26 TC 0 Z9 2 U1 0 U2 0 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 JUL PY 2010 VL 111 IS 1 BP 207 EP 213 DI 10.1213/ANE.0b013e3181e0cc90 PG 7 WC Anesthesiology SC Anesthesiology GA 617LF UT WOS:000279281500036 PM 20519419 ER PT J AU Krodel, DJ Bittner, EA Abdulnour, R Brown, R Eikermann, M AF Krodel, David J. Bittner, Edward A. Abdulnour, Raja Brown, Robert Eikermann, Matthias TI Case Scenario: Acute Postoperative Negative Pressure Pulmonary Edema SO ANESTHESIOLOGY LA English DT Article ID UPPER AIRWAY-OBSTRUCTION; RESPIRATORY-DISTRESS-SYNDROME; LUNG FLUID BALANCE; NEUROMUSCULAR BLOCKADE; CYCLIC STRETCH; BARRIER; STRESS; INJURY; CAPILLARIES; VENTILATION C1 [Krodel, David J.; Bittner, Edward A.; Abdulnour, Raja; Brown, Robert; Eikermann, Matthias] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Eikermann, M (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St, Boston, MA 02114 USA. EM meikermann@partners.org NR 41 TC 26 Z9 27 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 JUL PY 2010 VL 113 IS 1 BP 200 EP 207 DI 10.1097/ALN.0b013e3181e32e68 PG 8 WC Anesthesiology SC Anesthesiology GA 616XM UT WOS:000279244800022 PM 20526178 ER PT J AU Rudders, SA Banerji, A Katzman, DP Clark, S Camargo, CA AF Rudders, Susan A. Banerji, Aleena Katzman, Daniel P. Clark, Sunday Camargo, Carlos A., Jr. TI Multiple epinephrine doses for stinging insect hypersensitivity reactions treated in the emergency department SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID HYMENOPTERA VENOM ALLERGY; FOOD-INDUCED ANAPHYLAXIS; NATURAL-HISTORY; UNITED-STATES; CHILDREN; EPIDEMIOLOGY; VISITS; IMMUNOTHERAPY; SENSITIVITY; MULTICENTER AB Background: Data are sparse on epinephrine treatment for stinging insect hypersensitivity (SIH) reactions. Objective: To establish the frequency of receiving more than 1 dose of epinephrine in patients presenting to the emergency department (ED) with SIH reactions. Methods: We performed a medical record review of all 153 patients with SIH reactions presenting to 3 EDs in Boston, Massachusetts, between January 1, 2001, and December 31, 2006. Patients were identified by International Classification of Diseases, Ninth Revision (ICD-9) codes (989.5, 995.0, and 995.3). We focused on clinical presentations and treatments, including epinephrine treatments given before and during the ED visit. Results: The cohort was 54% male, with a median age of 33 years. Bees were the most frequently reported triggering insect (74%). A total of 59% of patients experienced large local reactions, whereas 36% had systemic reactions (10% cutaneous systemic and 26% anaphylaxis). The remaining 5% presented with normal local reactions to insect stings. Among patients with systemic reactions, 82% were stung within 3 hours of arrival at the ED. Most (60%) received treatments before arrival at the ED, including 26% who received epinephrine. While in the ED, these patients received antihistamines (76%), systemic corticosteroids (55%), and epinephrine (9%). Overall, 35% of patients with systemic reactions received epinephrine, and among this subset, 16% received more than 1 dose. Most patients with systemic reactions (67%) were discharged to home. At ED discharge, 68% received a prescription for self-injectable epinephrine, but only 11% had documentation of referral to an allergist. Conclusions: Among patients with systemic SIH reactions who received epinephrine, 16% received a second dose. Physicians should consider prescribing 2 doses of self-injectable epinephrine for patients at risk for systemic SIH reactions. Ann Allergy Asthma Immunol. 2010; 105: 85-93. C1 [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, EMNet Coordinating Ctr, Dept Emergency Med, Boston, MA 02114 USA. [Rudders, Susan A.] Childrens Hosp, Div Allergy & Immunol, Boston, MA 02115 USA. [Banerji, Aleena; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Dept Med, Boston, MA 02114 USA. [Clark, Sunday] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. RP Camargo, CA (reprint author), Massachusetts Gen Hosp, EMNet Coordinating Ctr, Dept Emergency Med, 326 Cambridge St,Suite 410, Boston, MA 02114 USA. EM ccamargo@partners.org FU National Institutes of Health [NRSA T32-AI-007512]; Dey Pharma FX Dr Rudders is supported by National Institutes of Health training grant NRSA T32-AI-007512. Dr Camargo is principal investigator of an investigator-initiated research grant from Dey Pharma that partly supported the present study. NR 34 TC 21 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1081-1206 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD JUL PY 2010 VL 105 IS 1 BP 85 EP 93 DI 10.1016/j.anai.2010.05.004 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 701PE UT WOS:000285832100014 PM 20642208 ER PT J AU Bergmann, AK Grace, RF Neufeld, EJ AF Bergmann, Anke K. Grace, Rachael F. Neufeld, Ellis J. TI Genetic studies in pediatric ITP: outlook, feasibility, and requirements SO ANNALS OF HEMATOLOGY LA English DT Article; Proceedings Paper CT 3rd Intercontinental-Cooperative-ITP-Study-Group Expert Meeting CY SEP 03-05, 2009 CL Basel, SWITZERLAND SP Intercontinental Cooperat ITP Study Grp DE GWAS; Immune thrombocytopenic purpura; Registries; Cohort studies ID IDIOPATHIC THROMBOCYTOPENIC PURPURA; ASSOCIATION ANALYSES; POLYMORPHISMS; CHILDHOOD; CHILDREN; ADULTS; IMMUNOGLOBULIN; PATHOGENESIS; FREQUENCIES; GUIDELINES AB The genomic revolution in medicine has not escaped attention of clinicians and scientists involved in medical management and research studies of immune thrombocytopenic purpura (ITP). In principle, ITP biology and care will benefit greatly from modern methods to understand the patterns of gene expression and genetic markers associated with fundamental parameters of the disease including predictors of remission, risk factors for severity, determinants of response to various therapies, and possibly biological sub-types. However, applying modern genetics to ITP carries severe challenges: (a) Achieving adequate sample sizes is a fundamental problem because ITP is rare (and in pediatric ITP, chronic cases constitute only about one fourth of the total); (b) familial transmission of childhood ITP is so rare that a convincing pedigree requires consideration of other immunologic or hematologic disorders; (iii) ITP is probably biologically heterogeneous, based on clinical observations, immunological studies, and animal models. Here we review the advantages and disadvantages of potential genetic approaches. Sufficient information is available to set reasonable bounds on which genetic analyses of ITP are feasible and how they are most likely to be accomplished. The highest priority is for accurate phenotypes to compare to genetic analyses. Several registries worldwide hold promise for accomplishing this goal. C1 [Bergmann, Anke K.; Grace, Rachael F.; Neufeld, Ellis J.] Childrens Hosp, Div Hematol & Oncol, Boston, MA 02115 USA. [Grace, Rachael F.; Neufeld, Ellis J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bergmann, Anke K.; Grace, Rachael F.; Neufeld, Ellis J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Neufeld, EJ (reprint author), Childrens Hosp, Div Hematol & Oncol, 300 Longwood Ave Karp 08210, Boston, MA 02115 USA. EM ellis.neufeld@childrens.harvard.edu RI Neufeld, Ellis/F-9331-2011; OI Grace, Fergal/0000-0002-3144-5999 FU NCRR NIH HHS [KL2 RR025757, 1KL2RR025757-0 1]; NHLBI NIH HHS [K24 HL004184, K24 HL004184-09, K24-HL004184] NR 36 TC 19 Z9 20 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-5555 J9 ANN HEMATOL JI Ann. Hematol. PD JUL PY 2010 VL 89 SU 1 BP S95 EP S103 DI 10.1007/s00277-009-0865-9 PG 9 WC Hematology SC Hematology GA 622RE UT WOS:000279682100017 PM 20309691 ER PT J AU Burstein, R Jakubowski, M Garcia-Nicas, E Kainz, V Bajwa, Z Hargreaves, R Becerra, L Borsook, D AF Burstein, Rami Jakubowski, Moshe Garcia-Nicas, Esther Kainz, Vanessa Bajwa, Zahid Hargreaves, Richard Becerra, Lino Borsook, David TI Thalamic Sensitization Transforms Localized Pain into Widespread Allodynia SO ANNALS OF NEUROLOGY LA English DT Article ID STEM TRIGEMINAL NEURONS; MIDDLE MENINGEAL ARTERY; BRAIN-STEM; SAGITTAL SINUS; FUNCTIONAL-PROPERTIES; CHEMICAL-STIMULATION; CUTANEOUS ALLODYNIA; NOCICEPTIVE NEURONS; POSTERIOR THALAMUS; MIGRAINE HEADACHE AB Objective: Focal somatic pain can evolve into widespread hypersensitivity to nonpainful and painful skin stimuli (allodynia and hyperalgesia, respectively). We hypothesized that transformation of headache into whole-body allodynia/hyperalgesia during a migraine attack is mediated by sensitization of thalamic neurons that process converging sensory impulses from the cranial meninges and extracephalic skin. Methods: Extracephalic allodynia was assessed using single unit recording of thalamic trigeminovascular neurons in rats and contrast analysis of blood oxygenation level-dependent (BOLD) signals registered in functional magnetic resonance imaging (fMRI) scans of patients exhibiting extracephalic allodynia. Results: Sensory neurons in the rat posterior thalamus that were activated and sensitized by chemical stimulation of the cranial dura exhibited long-lasting hyperexcitability to innocuous (brush, pressure) and noxious (pinch, heat) stimulation of the paws. Innocuous, extracephalic skin stimuli that did not produce neuronal firing at baseline (eg, brush) became as effective as noxious stimuli (eg, pinch) in eliciting large bouts of neuronal firing after sensitization was established. In migraine patients, fMRI assessment of BOLD signals showed that brush and heat stimulation at the skin of the dorsum of the hand produced larger BOLD responses in the posterior thalamus of subjects undergoing a migraine attack with extracephalic allodynia than the corresponding responses registered when the same patients were free of migraine and allodynia. Interpretation: We propose that the spreading of multimodal allodynia and hyperalgesia beyond the locus of migraine headache is mediated by sensitized thalamic neurons that process nociceptive information from the cranial meninges together with sensory information from the skin of the scalp, face, body, and limbs. ANN NEUROL 2010;68:81-91 C1 [Burstein, Rami; Jakubowski, Moshe; Garcia-Nicas, Esther; Kainz, Vanessa; Bajwa, Zahid] Beth Israel Deaconess Med Ctr, Dept Anesthesia & Crit Care, Boston, MA 02215 USA. [Burstein, Rami] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. [Hargreaves, Richard] Merck Res Labs, West Point, PA USA. [Becerra, Lino] Harvard Univ, McLean Hosp, Sch Med, PAIN Grp,Dept Psychiat, Belmont, MA 02178 USA. [Becerra, Lino; Borsook, David] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Becerra, Lino; Borsook, David] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Burstein, R (reprint author), Beth Israel Deaconess Med Ctr, Dept Anesthesia & Crit Care, CLS 649,330 Brookline Ave, Boston, MA 02215 USA. EM rburstei@bidmc.harvard.edu FU National Institute of Neurological Disorders and Stroke (NINDS) [NS-051484, NS-056195, K24 064050]; Merck Co. [25791] FX This research was supported by National Institute of Neurological Disorders and Stroke (NINDS) grants NS-051484 (R.B.), NS-056195 (D.B., R.B., L.B.), K24 064050 (D.B.), and by a Merck & Co. Investigator-Initiated Studies Program grant #25791 (D.B.) NR 55 TC 117 Z9 122 U1 1 U2 5 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 JUL PY 2010 VL 68 IS 1 BP 81 EP 91 DI 10.1002/ana.21994 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 618MY UT WOS:000279361000011 PM 20582997 ER PT J AU Ticozzi, N LeClerc, AL Keagle, PJ Glass, JD Wills, AM van Blitterswijk, M Bosco, DA Rodriguez-Leyva, I Gellera, C Ratti, A Taroni, F McKenna-Yasek, D Sapp, PC Silani, V Furlong, CE Brown, RH Landers, JE AF Ticozzi, Nicola LeClerc, Ashley Lyn Keagle, Pamela J. Glass, Jonathan D. Wills, Anne-Marie van Blitterswijk, Marka Bosco, Daryl A. Rodriguez-Leyva, Ildefonso Gellera, Cinzia Ratti, Antonia Taroni, Franco McKenna-Yasek, Diane Sapp, Peter C. Silani, Vincenzo Furlong, Clement E. Brown, Robert H., Jr. Landers, John E. TI Paraoxonase Gene Mutations in Amyotrophic Lateral Sclerosis SO ANNALS OF NEUROLOGY LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; SPORADIC ALS; CLUSTER POLYMORPHISMS; COLORECTAL ADENOMAS; RARE VARIANTS; PON1; SUSCEPTIBILITY; PROTEIN; IDENTIFICATION; PROMOTER AB Three clustered, homologous paraoxonase genes (PON1, PON2, and PON3) have roles in preventing lipid oxidation and detoxifying organophosphates. Recent reports describe a genetic association between the PON genes and sporadic amyotrophic lateral sclerosis (ALS). We now report that in genomic DNA from individuals with familial and sporadic ALS, we have identified at least 7 PON gene mutations that are predicted to alter PON function. ANN NEUROL 2010;68:102-107 C1 [Ticozzi, Nicola; LeClerc, Ashley Lyn; Keagle, Pamela J.; Bosco, Daryl A.; McKenna-Yasek, Diane; Sapp, Peter C.; Brown, Robert H., Jr.; Landers, John E.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01605 USA. [Ticozzi, Nicola; Ratti, Antonia; Silani, Vincenzo] Univ Studi Milano, Dept Neurol, Milan, Italy. [Ticozzi, Nicola; Ratti, Antonia; Silani, Vincenzo] Univ Studi Milano, Neurosci Lab, Dino Ferrari Ctr, IRCCS Ist Auxol Italiano, Milan, Italy. [Glass, Jonathan D.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Wills, Anne-Marie] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Rodriguez-Leyva, Ildefonso] Univ Autonoma San Luis Potosi, Fac Med, San Luis Potosi, Mexico. [Gellera, Cinzia; Taroni, Franco] IRCCS Carlo Besta Neurol Inst, Unit Genet Neurodegenerat & Metab Dis, Milan, Italy. [Sapp, Peter C.] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Sapp, Peter C.] MIT, Dept Biol, Cambridge, MA USA. [Furlong, Clement E.] Univ Washington, Div Med Genet, Dept Med, Seattle, WA 98195 USA. [Furlong, Clement E.] Univ Washington, Dept Gen Sci, Seattle, WA USA. RP Landers, JE (reprint author), Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01605 USA. EM john.landers@umassmed.edu RI van Blitterswijk, Marka/H-7274-2012; Ticozzi, Nicola/K-8094-2016; GELLERA, CINZIA/J-7887-2016; OI van Blitterswijk, Marka/0000-0002-3054-7053; Ticozzi, Nicola/0000-0001-5963-7426; GELLERA, CINZIA/0000-0002-3582-665X; Silani, Vincenzo/0000-0002-7698-3854 FU ALS Therapy Alliance; Angel Fund; Pierre L. de Bourgknecht ALS Research Foundation; Al-Athel ALS Research Foundation; ALS Family Charitable Foundation; Packard Center for ALS Research; American Academy of Neurology Foundation/ALS Association; National Institute of Neurological Disorders and Stroke [IRO1NS050557-03]; NIH National Institute of Environmental Health Sciences [RO1ES09883-04A2]; Italian Ministry of Health [ex Art.56, n.533F/N1, RF2007/INN644440]; Peviani family FX This study was supported by the ALS Therapy Alliance, Project ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation, the Packard Center for ALS Research (J.D.G.), American Academy of Neurology Foundation/ALS Association (A.-M.W.), the National Institute of Neurological Disorders and Stroke (IRO1NS050557-03 to R.H.B.), the NIH National Institute of Environmental Health Sciences (RO1ES09883-04A2 to C.E.F.), the Italian Ministry of Health (Malattie Neurodegenerative, ex Art.56, n.533F/N1, N.T., VS., A.R.), the Peviani family (N.T., V.S.), and the Italian Ministry of Health (grant RF2007/INN644440, F.T., C.G.). NR 25 TC 28 Z9 28 U1 0 U2 1 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 JUL PY 2010 VL 68 IS 1 BP 102 EP 107 DI 10.1002/ana.21993 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 618MY UT WOS:000279361000013 PM 20582942 ER PT J AU Oaklander, AL Fields, HL AF Oaklander, Anne Louise Fields, Howard L. TI Does Body Mass Index Increase Risk of Hemorrhagic Stroke? Reply SO ANNALS OF NEUROLOGY LA English DT Letter ID REGIONAL PAIN SYNDROME; SYNDROME TYPE-I; DYSTONIA C1 [Oaklander, Anne Louise] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Oaklander, Anne Louise] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. [Fields, Howard L.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Oaklander, AL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. NR 9 TC 1 Z9 2 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 JUL PY 2010 VL 68 IS 1 BP 116 EP 117 DI 10.1002/ana.22084 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 618MY UT WOS:000279361000019 PM 20583223 ER PT J AU Wu, WC Smith, TS Henderson, WG Eaton, CB Poses, RM Uttley, G Mor, V Sharma, SC Vezeridis, M Khuri, SF Friedmann, PD AF Wu, Wen-Chih Smith, Tracy S. Henderson, William G. Eaton, Charles B. Poses, Roy M. Uttley, Georgette Mor, Vincent Sharma, Satish C. Vezeridis, Michael Khuri, Shukri F. Friedmann, Peter D. TI Operative Blood Loss, Blood Transfusion, and 30-Day Mortality in Older Patients After Major Noncardiac Surgery SO ANNALS OF SURGERY LA English DT Article ID AFFAIRS SURGICAL RISK; POSTOPERATIVE MORTALITY; CELL TRANSFUSIONS; HEMOGLOBIN-LEVEL; MORBIDITY; ANEMIA; CARE; ADJUSTMENT; QUALITY; GENDER AB Objective: Anemia and operative blood loss are common in the elderly, but evidence is lacking on whether intraoperative blood transfusions can reduce the risk of postoperative death. Methods: We analyzed retrospective data from 239,286 patients 65 years of older who underwent major noncardiac surgery in 1997 to 2004 at veteran hospitals nationwide. Propensity-score matching was used to adjust for differences between patients who received intraoperative blood transfusions (9.4%) and those who did not, and data were used to determine the association between intraoperative blood transfusion and 30-day postoperative mortality. Results: After propensity-score matching, intraoperative blood transfusion was associated with mortality risk reductions in patients with preoperative hematocrit levels of <24% (odds ratio: 0.60, 95% CI: 0.41-0.87), and in patients with hematocrit of 30% or greater when there is substantial (500999 mL) blood loss (odds ratio: 0.35, 95% CI: 0.22-0.56 for hematocrit levels between 30%-35.9% and 0.78, 95% CI: 0.62-0.97 for hematocrit levels of 36% or greater). When operative blood loss was <500 mL, transfusion was not associated with mortality reductions for patients with hematocrit levels of 24% or greater, and conferred increased mortality risks in patients with preoperative hematocrit levels between 30% to 35.9% (odds ratio 1.29, 95% CI: 1.04-1.60). Conclusions: Intraoperative blood transfusion is associated with a lower 30- day postoperative mortality among elderly patients undergoing major noncardiac surgery if there is substantial operative blood loss or low preoperative hematocrit levels (<24%). Transfusion is associated with increased mortality risks for those with preoperative hematocrit levels between 30% and 35.9% and <500 mL of blood loss. C1 [Wu, Wen-Chih; Friedmann, Peter D.] Brown Univ, Providence Vet Affairs Med Ctr, Res Enhancement Award Program, Providence, RI 02912 USA. [Wu, Wen-Chih; Friedmann, Peter D.] Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. [Wu, Wen-Chih; Poses, Roy M.; Sharma, Satish C.; Friedmann, Peter D.] Alpert Med Sch, Dept Med, Providence, RI USA. [Wu, Wen-Chih; Mor, Vincent; Sharma, Satish C.] Brown Univ, Providence Vet Affairs Med Ctr, Med Serv, Providence, RI 02912 USA. [Smith, Tracy S.] Denver VA Med Ctr, NSQIP Denver Data Anal Ctr, Denver, CO USA. [Henderson, William G.] Univ Colorado, Hlth Outcomes Program, Denver, CO 80202 USA. [Henderson, William G.] Denver VA Med Ctr, Denver, CO USA. [Eaton, Charles B.] Brown Univ, Alpert Med Sch, Dept Family Med, Providence, RI 02912 USA. [Eaton, Charles B.] Brown Univ, Mem Hosp Rhode Isl, Ctr Primary Care & Prevent, Providence, RI 02912 USA. [Vezeridis, Michael] Brown Univ, Alpert Med Sch, Dept Surg, Providence, RI 02912 USA. [Vezeridis, Michael] Brown Univ, Providence Vet Affairs Med Ctr, Surg Serv, Providence, RI 02912 USA. [Uttley, Georgette] QCMetrix Inc, Waltham, MA USA. [Khuri, Shukri F.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Khuri, Shukri F.] VA Boston Healthcare Syst, Surg Serv, Boston, MA 02115 USA. RP Wu, WC (reprint author), 830 Chalkstone Ave, Providence, RI 02908 USA. EM Wen-Chih.Wu@va.gov FU Department of Veterans Affairs Health Services Research & Development Service [IIR 04-313, REA 08-263] FX Supported by Merit Review Award # IIR 04-313 and Research Enhancement Award Program (REAP), award REA 08-263, from the Department of Veterans Affairs Health Services Research & Development Service. Support includes research time and data access for Dr. Wu, Dr. Henderson and Tracy S Smith, and consultant fees for Dr. Eaton and Dr. Poses. NR 36 TC 83 Z9 85 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD JUL PY 2010 VL 252 IS 1 BP 11 EP 17 DI 10.1097/SLA.0b013e3181e3e43f PG 7 WC Surgery SC Surgery GA 612RW UT WOS:000278921200004 PM 20505504 ER PT J AU Fink, AS Prochazka, AV Henderson, WG Bartenfeld, D Nyirenda, C Webb, A Berger, DH Itani, K Whitehill, T Edwards, J Wilson, M Karsonovich, C Parmelee, P AF Fink, Aaron S. Prochazka, Allan V. Henderson, William G. Bartenfeld, Debra Nyirenda, Carsie Webb, Alexandra Berger, David H. Itani, Kamal Whitehill, Thomas Edwards, James Wilson, Mark Karsonovich, Cynthia Parmelee, Patricia TI Enhancement of Surgical Informed Consent by Addition of Repeat Back A Multicenter, Randomized Controlled Clinical Trial SO ANNALS OF SURGERY LA English DT Article ID HEALTH LITERACY; PHYSICIAN COMMUNICATION; SHORT-FORM; PATIENT; ANXIETY; SCALE; CARE; SATISFACTION; STRATEGIES; MANAGEMENT AB Objective: In this randomized, controlled, unblinded trial, we sought to test Repeat Back's (RB) effect on comprehension following informed consent discussions. Summary Background Data: RB has been suggested as a method to improve patient comprehension when obtaining informed consent. In this technique, patients are asked to recount what they have been told in the informed consent discussion. Despite preliminary data, this practice has not been evaluated in any large scale study. Methods: This study was conducted in 7 Veterans Health Administration Medical Centers where informed consent is obtained using iMedConsent, the VA's computer based platform. Patients scheduled for elective surgeries were randomized to RB (a module added to the iMedConsent package) or standard iMedConsent (no RB). Comprehension was tested after the informed consent using procedure-specific questionnaires. Time stamps in the iMedConsent program estimated the time spent completing the informed consent process. Provider and patient satisfaction were measured using 5-point Likert scales. Statistical comparisons of groups were performed using t-tests and chi(2) tests. Results: A total of 575 patients were enrolled. In the RB group, providers spent 2.6 minutes longer (P < 0.0001) obtaining informed consent. The mean comprehension score was significantly higher in the RB group (71.4%) versus the no RB group (68.2%, P = 0.03); the effect was greatest in carotid endarterectomy patients (RB = 73.4% vs. no RB = 67.7%, P = 0.02). Quality of decision making was rated similarly. Providers were neutral to slightly favorable regarding RB. Conclusions: RB implemented within an electronic informed consent system improved patient comprehension. The additional time required was acceptable to providers. RB should be considered as an enhancement to surgical informed consent. C1 [Fink, Aaron S.; Bartenfeld, Debra; Webb, Alexandra] VAMC Atlanta, Surg Serv, Decatur, GA 30033 USA. [Fink, Aaron S.; Webb, Alexandra] Emory Univ, Sch Med, Dept Surg, Atlanta, GA 30322 USA. [Prochazka, Allan V.] Denver VAMC, Surg Serv, Denver, CO USA. [Prochazka, Allan V.; Henderson, William G.; Nyirenda, Carsie] Univ Colorado, Hlth Outcomes Program, Denver, CO 80202 USA. [Berger, David H.] Baylor Coll Med, Michael Bakey Dept Surg, Houston, TX 77030 USA. [Berger, David H.] Michael DeBakey VAMC, Houston, TX USA. [Itani, Kamal] Harvard Univ, Sch Med, Boston, MA USA. [Itani, Kamal] Boston Univ, Dept Surg, Boston, MA 02215 USA. [Itani, Kamal] Boston VAMC, Boston, MA USA. [Whitehill, Thomas] Univ Colorado, Dept Surg, Denver, CO 80202 USA. [Edwards, James] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. [Edwards, James] Portland VA Med Ctr, Portland, OR USA. [Wilson, Mark] Pittsburgh VAMC, Pittsburgh, PA USA. [Wilson, Mark] Univ Pittsburgh, Med Ctr, Dept Surg, Pittsburgh, PA USA. [Karsonovich, Cynthia] Tampa VAMC, Tampa, FL USA. [Karsonovich, Cynthia] Univ S Florida, Dept Surg, Tampa, FL 33620 USA. [Parmelee, Patricia] Univ Alabama, Dept Psychol, Tuscaloosa, AL 35487 USA. RP Fink, AS (reprint author), VAMC Atlanta, Surg Serv, 112,1670 Clairmont Rd, Decatur, GA 30033 USA. EM aaron.fink@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [IAF 05-308-01] FX Supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service (Project no. IAF 05-308-01). NR 39 TC 35 Z9 35 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD JUL PY 2010 VL 252 IS 1 BP 27 EP 36 DI 10.1097/SLA.0b013e3181e3ec61 PG 10 WC Surgery SC Surgery GA 612RW UT WOS:000278921200007 PM 20562609 ER PT J AU Bilimoria, KY Cohen, ME Ingraham, AM Bentrem, DJ Richards, K Hall, BL Ko, CY AF Bilimoria, Karl Y. Cohen, Mark E. Ingraham, Angela M. Bentrem, David J. Richards, Karen Hall, Bruce L. Ko, Clifford Y. TI Effect of Postdischarge Morbidity and Mortality on Comparisons of Hospital Surgical Quality SO ANNALS OF SURGERY LA English DT Article ID ADMINISTRATIVE DATA; HEALTH-CARE; IMPROVEMENT PROGRAM; RISK ADJUSTMENT; WOUND-INFECTION; PATIENT SAFETY; OF-CARE; SURGERY; DATABASES; OUTCOMES AB Background: Hospitals increasingly rely on surgical quality assessment programs that require considerable resources to capture outcomes after hospital discharge. However, it is unclear whether capturing postdischarge complications and deaths is important. Our objectives were (1) to determine the frequency of postdischarge complications and deaths and (2) to determine whether hospital rankings change with inclusion of postdischarge outcomes. Methods: From 181 hospitals participating in the American College of Surgeon's National Surgical Quality Improvement Program, 329,951 patients were identified (2006-2007). Mortality and 19 complications within 30 days of the index operation were categorized as occurring before or after discharge. Risk-adjusted hospital rankings were compared based on whether only predischarge (inpatient) versus both pre- and postdischarge (inpatient and outpatient within 30 days of operation) morbidity and mortality were included. Results: Postdischarge complications accounted for 32.9% of all complications. Certain complications occurred frequently after discharge: surgical site infections (66.0%), urinary tract infections (39.4%), pulmonary embolisms (42.2%), and deep venous thromboses (34.5%). Of all patients experiencing complications, 39.7% had only postdischarge complications. Of 5827 postoperative deaths, 23.6% occurred after discharge. Hospital quality rankings changed when postdischarge outcomes were excluded versus included for morbidity (median hospital rank change: 16 ranks; interquartile range, 7-36) and mortality (median hospital rank change: 14 ranks; interquartile range, 6-29), and there was disagreement in outlier status designations depending on whether postdischarge events were included (morbidity: kappa = 0.546; mortality: kappa = 0.507). Conclusions: A substantial proportion of postoperative complications and deaths occur after hospital discharge. Inclusion of postdischarge events considerably affects hospital quality rankings and outlier status designations. Quality improvement programs and research that do not consider postdischarge outcomes may offer incomplete information to hospitals, payers, providers, and patients. C1 [Bilimoria, Karl Y.; Cohen, Mark E.; Ingraham, Angela M.; Richards, Karen] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL 60611 USA. [Bilimoria, Karl Y.; Bentrem, David J.] Northwestern Univ, Dept Surg, Feinberg Sch Med, Chicago, IL 60611 USA. [Hall, Bruce L.] John Cochran Vet Affairs Med Ctr, Dept Surg, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Sch Med, Dept Surg, St Louis & Barnes Jewish Hosp, St Louis, MO 63110 USA. [Hall, Bruce L.] Washington Univ, Ctr Hlth Policy, St Louis, MO 63110 USA. [Hall, Bruce L.] Washington Univ, John M Olin Sch Business, St Louis, MO 63110 USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Bilimoria, KY (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, 633 N St Clair St,22nd Floor, Chicago, IL 60611 USA. EM kbilimoria@facs.org FU Northwestern University; Illinois Division of the American Cancer Society; Barnum Foundation FX Supported by a Priority Grant from Northwestern University and by a grant from the Illinois Division of the American Cancer Society and the Barnum Foundation (to D.J.B.). NR 50 TC 60 Z9 61 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD JUL PY 2010 VL 252 IS 1 BP 183 EP 190 DI 10.1097/SLA.0b013e3181e4846e PG 8 WC Surgery SC Surgery GA 612RW UT WOS:000278921200028 PM 20531000 ER PT J AU Javid, S Segara, D Lotfi, P Raza, S Golshan, M AF Javid, Sara Segara, Davendra Lotfi, Parisa Raza, Sughra Golshan, Mehra TI Can Breast MRI Predict Axillary Lymph Node Metastasis in Women Undergoing Neoadjuvant Chemotherapy SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID PREOPERATIVE CHEMOTHERAPY; CANCER PATIENTS; MONITORING RESPONSE; BIOPSY; DISSECTION; MORBIDITY; TRIAL; ULTRASONOGRAPHY; MAMMOGRAPHY; TOMOGRAPHY AB Axillary lymph node status provides important staging information. We sought to evaluate the predictive value of breast magnetic resonance imaging (MRI) in detecting axillary lymph node metastases prior to initiation of neoadjuvant chemotherapy (NAC) and in detecting residual lymph node metastases after NAC in women found to be node positive prior to NAC. Women underwent breast MRI with axillary evaluation prior to initiation of NAC and again after completion of NAC. Pathologic confirmation of lymph node status was confirmed by sentinel lymph node biopsy (SLNB), image-guided axillary fine-needle aspiration (FNA)/core biopsy, or axillary lymph node dissection. We evaluated the sensitivity, specificity, and negative and positive predictive values of MRI in detecting axillary node involvement. Seventy-four women completed NAC and underwent surgery. Sensitivity of MRI in detecting axillary node involvement prior to NAC was 64.7% and specificity was 100%, with positive and negative predictive values of MRI of 100% and 77.8%, respectively. Sensitivity and specificity of MRI to identify residual pathologic axillary lymph node disease following NAC were 85.7% and 89%, respectively, while the positive and negative predictive values were 92% and 80.9%, respectively. Breast MRI has moderate sensitivity and high specificity for predicting axillary lymph node status prior to NAC. In patients found to be node positive prior to NAC, MRI was able to predict with moderate sensitivity and specificity whether residual nodal disease was present. The accuracy of MRI is not adequate to obviate either the need for staging by sentinel node biopsy or the need for completion axillary dissection in women determined to be node positive prior to NAC. C1 [Javid, Sara; Segara, Davendra; Golshan, Mehra] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Raza, Sughra] Harvard Univ, Brigham & Womens Hosp, Dept Radiol, Sch Med, Boston, MA 02115 USA. [Javid, Sara; Segara, Davendra; Golshan, Mehra] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Lotfi, Parisa] Harvard Univ, Sch Med, Faulkner Hosp, Boston, MA 02115 USA. RP Javid, S (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM MGOLSHAN@PARTNERS.ORG NR 28 TC 20 Z9 23 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 JUL PY 2010 VL 17 IS 7 BP 1841 EP 1846 DI 10.1245/s10434-010-0934-2 PG 6 WC Oncology; Surgery SC Oncology; Surgery GA 613ZN UT WOS:000279024200018 PM 20143266 ER PT J AU Wasif, N Maggard, MA Ko, CY Giuliano, AE AF Wasif, Nabil Maggard, Melinda A. Ko, Clifford Y. Giuliano, Armando E. TI Invasive Lobular vs. Ductal Breast Cancer: A Stage-Matched Comparison of Outcomes SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article; Proceedings Paper CT Breast Cancer Symposium of the American-Society-of-Clinical-Oncology CY OCT 08-10, 2009 CL San Francisco, CA SP Amer Soc Clin Oncol ID SURGICAL ADJUVANT BREAST; CLINICAL-TRIALS; RECEPTOR STATUS; E-CADHERIN; CARCINOMA; THERAPY; CHEMOTHERAPY; SURVIVAL; FEATURES; DIAGNOSIS AB Invasive lobular breast cancer (ILC) is less common than invasive ductal breast cancer (IDC), more difficult to detect mammographically, and usually diagnosed at a later stage. Does delayed diagnosis of ILC affect survival? We used a national registry to compare outcomes of patients with stage-matched ILC and IDC. Query of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) tumor registry identified 263,408 women diagnosed with IDC or ILC between 1993 and 2003. Survival of patients matched by T and N stage was compared using Kaplan-Meier curves and log-rank analysis. When compared with IDC, ILC was more likely to be > 2 cm (43.1 vs. 32.6%; P < 0.001), lymph node positive (36.8 vs. 34.4%; P < 0.001), and ER positive (93.1 vs. 75.6%; P < 0.001). The 5-year disease-specific survival (DSS) was significantly better for patients with ILC than for those with IDC, before (90 vs. 88%; P < 0.001) and after matching for stage T1N0 (98 vs. 96%; P < 0.001), T2N0 (94 vs. 88%; P < 0.001), and T3N0 (92 vs. 83%, P < 0.001). The 5-year DSS for patients with nodal metastasis of ILC vs. IDC was 89% vs. 88% (P = NS) for stage T1N1, 81 vs. 73% (P < 0.001) for T2N1, and 72 vs. 56% (P < 0.001) for T3N1. Multivariate analysis identified a 14% survival benefit for ILC (hazard ratio 0.86, 95% confidence interval 0.80-0.92). Stage-matched prognosis is better for patients with ILC than for those with IDC. Our findings support a different biology for ILC and are important for counseling and risk stratification. C1 [Wasif, Nabil; Giuliano, Armando E.] St Johns Hlth Ctr, John Wayne Canc Inst, Santa Monica, CA USA. [Maggard, Melinda A.; Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Wasif, Nabil] Mayo Clin, Dept Surg, Scottsdale, AZ USA. [Ko, Clifford Y.] Greater Los Angeles VA Healthcare Syst, Dept Surg, Los Angeles, CA USA. RP Wasif, N (reprint author), St Johns Hlth Ctr, John Wayne Canc Inst, Santa Monica, CA USA. EM giulianoa@jwci.org NR 34 TC 60 Z9 62 U1 1 U2 2 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 JUL PY 2010 VL 17 IS 7 BP 1862 EP 1869 DI 10.1245/s10434-010-0953-z PG 8 WC Oncology; Surgery SC Oncology; Surgery GA 613ZN UT WOS:000279024200021 PM 20162457 ER PT J AU Miriovsky, BJ Michaud, K Thiele, GM O'Dell, JR Cannon, GW Kerr, G Richards, JS Johnson, D Caplan, L Reimold, A Hooker, R Mikuls, TR AF Miriovsky, Benjamin J. Michaud, Kaleb Thiele, Geoffrey M. O'Dell, James R. Cannon, Grant W. Kerr, Gail Richards, J. Steuart Johnson, Dannette Caplan, Liron Reimold, Andreas Hooker, Roderick Mikuls, Ted R. TI Anti-CCP antibody and rheumatoid factor concentrations predict greater disease activity in men with rheumatoid arthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID CYCLIC CITRULLINATED PEPTIDE; PROTEIN ANTIBODIES; PROSPECTIVE COHORT; ASSOCIATION; PROGRESSION; HEALTH; VALIDATION; PHENOTYPE; CRITERIA; WOMEN AB Objective To examine associations of anti-cyclic citrullinated peptide (aCCP) antibody and rheumatoid factor (RF) concentrations with future disease activity in men with rheumatoid arthritis (RA). Methods Outcome measures were examined in male US veterans with RA and included (1) proportion of observations in remission (disease activity score (DAS28) <= 2.6); (2) remission for >= 3 consecutive months; and (3) area under the curve (AUC) for DAS28. The associations of autoantibody concentration (per 100 unit increments) with outcomes were examined using multivariate regression. Results 826 men with RA were included in the analysis; the mean (SD) age was 65 (10.5) years and follow-up was for 2.6 (1.3) years. Most were aCCP (75%) and RF (80%) positive. After multivariate adjustment, aCCP (OR 0.93; 95% CI 0.89 to 0.96) and RF concentrations (OR 0.92; 95% CI 0.90 to 0.94) were associated with a lower odds of remission, a lower proportion of observation in remission (p=0.017 and p=0.002, respectively) and greater AUC DAS28 (p=0.092 and p=0.007, respectively). Among patients with discordant autoantibody status, higher concentrations of both aCCP and RF trended towards an inverse association with remission (OR 0.93; 95% CI 0.83 to 1.05 and OR 0.80; 95% CI 0.59 to 1.10, respectively). Conclusions Higher aCCP concentrations (particularly in RF-positive patients) are associated with increased disease activity in US veterans with RA, indicating that aCCP concentration is predictive of future disease outcomes in men. C1 [Miriovsky, Benjamin J.; Michaud, Kaleb; Thiele, Geoffrey M.; O'Dell, James R.; Mikuls, Ted R.] Omaha VAMC, Omaha, NE USA. [Miriovsky, Benjamin J.; Michaud, Kaleb; Thiele, Geoffrey M.; O'Dell, James R.; Mikuls, Ted R.] Nebraska Arthrit Outcomes Res Ctr, Omaha, NE USA. [Cannon, Grant W.] George E Wahlen VAMC, Salt Lake City, UT USA. [Kerr, Gail; Richards, J. Steuart] VAMC, Washington, DC USA. [Johnson, Dannette] Jackson VAMC, Jackson, MS USA. [Caplan, Liron] Denver VAMC, Denver, CO USA. [Reimold, Andreas; Hooker, Roderick] Dallas VAMC, Dallas, TX USA. RP Mikuls, TR (reprint author), Univ Nebraska, Med Ctr, Dept Internal Med, Sect Rheumatol & Immunol, 986270 Nebraska Med Ctr, Omaha, NE 68198 USA. EM tmikuls@unmc.edu OI Thiele, Geoffrey/0000-0001-5688-8596 FU American College of Rheumatology (ACR) Research and Education Foundation; NIH/NIAMS [R03 AR054539]; Veterans Health Administration (VHA); Abbott Laboratories; Bristol-Myers Squibb; NIAMS [K23 AR050004]; VHA (VA Merit); VA HSRD FX BJM was supported by the Ephraim P Engleman Endowed Resident Reseach Preceptorship from the American College of Rheumatology (ACR) Research and Education Foundation. This work was funded by a grant from NIH/NIAMS (R03 AR054539, PI TRM). The VARA Registry has received research support from the Health Services Research & Development (HSR&D) Program of the Veterans Health Administration (VHA) in addition to unrestricted research funds from Abbott Laboratories and Bristol-Myers Squibb. TRM receives research support from NIAMS (K23 AR050004) and the VHA (VA Merit). LC is supported by a VA HSR&D Career Development Award. NR 27 TC 29 Z9 30 U1 0 U2 0 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 JUL PY 2010 VL 69 IS 7 BP 1292 EP 1297 DI 10.1136/ard.2009.122739 PG 6 WC Rheumatology SC Rheumatology GA 622MD UT WOS:000279667000008 PM 20439294 ER PT J AU Jaff, MR Cahill, KE Yu, AP Birnbaum, HG Engelhart, LM AF Jaff, Michael R. Cahill, Kevin E. Yu, Andrew P. Birnbaum, Howard G. Engelhart, Luella M. TI Clinical Outcomes and Medical Care Costs Among Medicare Beneficiaries Receiving Therapy for Peripheral Arterial Disease SO ANNALS OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT International Symposium on Endovascular Therapy CY JAN 20-24, 2008 CL Hollywood, FL ID NATIONAL-HEALTH; CO-MORBIDITY; POPULATION; PREVALENCE; CLAUDICATION; METAANALYSIS; OLDER AB Background: Peripheral arterial disease (PAD) is a common disorder with multiple options for treatment, ranging from medical interventions, surgical revascularization, and endovascular therapy. Despite the explosive advances in endovascular therapy, cost-effective methods of care have not been well defined. We analyze therapeutic strategies, outcomes, and medical cost of treatment among Medicare patients with PAD. Methods and Results: Patients who underwent therapy for PAD were identified from a 5% random sample of Medicare beneficiaries from Medicare Standard Analytic Files for the period 1999-2005. Clinical outcomes (death, amputation, new clinical symptoms related to PAD) and direct medical costs were examined by chosen revascularization options (endovascular, surgical, and combinations). One-year PAD prevalence increased steadily from 8.2% in 1999 to 9.5% in 2005. The risk-adjusted time to first post-treatment clinical outcome was lowest in those treated with "percutaneous transluminal angioplasty (PTA) or atherectomy and stents" (HR, 0.829; 95% CI, 0.793-0.865; p < 0.001) and stents only (HR, 0.904; 95% CI, 0.848-0.963; p = 0.002) compared with PTA alone. The lowest per patient risk-adjusted costs during the quarter of the first observed treatment were associated with "PTA and stents" ($15,197), and stents only ($15,867). Risk-adjusted costs for surgical procedures (bypass and endarterectomy) were $27,021 during the same period. Diabetes was present in 61.7% of the PAD population and was associated with higher risks of clinical events and higher medical costs compared with PAD patients without diabetes. Conclusion: The clinical and economic burden of PAD in the Medicare population is substantial, and the interventions used to treat PAD are associated with differences in clinical and economic outcomes. Prospective cost-effectiveness analyses should be included in future PAD therapy trials to inform payers and providers of the relative value of available treatment options. C1 [Jaff, Michael R.] Massachusetts Gen Hosp, Vasc Ctr, Boston, MA 02114 USA. [Cahill, Kevin E.; Yu, Andrew P.; Birnbaum, Howard G.] Anal Grp Inc, Boston, MA USA. [Engelhart, Luella M.] DePuy Inc, Raynham, MA USA. RP Jaff, MR (reprint author), Harvard Univ, Sch Med, 55 Fruit St,GB 832, Boston, MA 02114 USA. EM mjaff@partners.org NR 17 TC 30 Z9 30 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-5096 J9 ANN VASC SURG JI Ann. Vasc. Surg. PD JUL PY 2010 VL 24 IS 5 BP 577 EP 587 DI 10.1016/j.avsg.2010.03.015 PG 11 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 611MP UT WOS:000278819800002 PM 20579582 ER PT J AU Garcia, S Murray, STN Moritz, TE Pierpont, G Goldman, S Larsen, GC Littooy, F Ward, HB McFalls, EO AF Garcia, Santiago Murray, Sara T. N. Moritz, Thomas E. Pierpont, Gordon Goldman, Steven Larsen, Greg C. Littooy, Fred Ward, Herbert B. McFalls, Edward O. TI Culprit Coronary Lesions Requiring Percutaneous Coronary Intervention After Vascular Surgery Often Arise From In-Stent Restenosis of Bare Metal Stents SO ANNALS OF VASCULAR SURGERY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; PERIPHERAL ARTERIAL-DISEASE; ELEVATED HOMOCYSTEINE LEVELS; ENDOTHELIAL DYSFUNCTION; REVASCULARIZATION; MORTALITY; ASSOCIATION; EVENTS; RISK AB Background: The natural history of coronary artery disease (CAD) after vascular surgery is poorly defined. The aim of this study was to determine the temporal change of coronary artery lesions requiring revascularization with a percutaneous coronary intervention (PCI) after elective vascular surgery and to determine the utility of preoperative biomarkers on predicting those patients at risk for new coronary lesions. Methods: The Coronary Artery Revascularization Prophylaxis Trial tested the long-term survival benefit of coronary artery revascularization before elective vascular surgery. Among randomized patients who subsequently required PCI after surgery, the stenosis of the culprit lesion from the follow-up angiogram was compared with the preoperative vessel stenosis at the identical site on the baseline angiogram. Results: A total of 30 patients underwent PCI for progressive symptoms at a median of 11.5 (interquartiles: 4.5-18.5) months postsurgery. Of 30 patients, 16 (53%) had nonobstructive CAD preoperatively (group 1) with a stenosis that increased from 17 +/- 6% to 91 +/- 2% (P < 0.01) and 14 (47%) had severe CAD at the culprit site preoperatively (group 2), with a stenosis that increased 89 +/- 2% (P = 0.15). The only biomarker that was an identifier of early coronary artery lesion formation in group 1 compared with group 2 patients was a higher baseline homocysteine level (14.6 +/- 1.4 vs. 10.6 +/- 0.7 mg/dL; P = 0.02). Conclusions: Culprit coronary artery lesions requiring PCI after an elective vascular operation often arise from in-stent restenosis. Therapies that either stabilize existing plaques or prevent restenosis, particularly among patients with elevated homocysteine levels, have the greatest promise for improving postoperative outcomes. C1 [Garcia, Santiago; Murray, Sara T. N.; Pierpont, Gordon; McFalls, Edward O.] Univ Minnesota, Div Cardiol, Minneapolis, MN USA. [Garcia, Santiago; Murray, Sara T. N.; Pierpont, Gordon; Ward, Herbert B.; McFalls, Edward O.] Minneapolis VA Med Ctr, Minneapolis, MN USA. [Ward, Herbert B.] Univ Minnesota, Div Cardiothorac Surg, Minneapolis, MN USA. [Moritz, Thomas E.] Cooperat Studies Program Coordinating Ctr, Hines, IL USA. [Littooy, Fred] VA Med Ctr Hines, Div Vasc Surg, Hines, IL USA. [Goldman, Steven] So Arizona VA Healthcare Syst, Div Cardiol, Tucson, AZ USA. [Goldman, Steven] Univ Arizona, Sarver Heart Ctr, Tucson, AZ USA. [Larsen, Greg C.] Portland VA Med Ctr, Div Cardiol, Portland, OR USA. RP McFalls, EO (reprint author), VA Med Ctr, Div Cardiol, 1 Vet Dr, Minneapolis, MN 55417 USA. EM mcfal001@umn.edu FU Department of Veterans Affairs Office of Research and Development FX Supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development. NR 23 TC 0 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-5096 J9 ANN VASC SURG JI Ann. Vasc. Surg. PD JUL PY 2010 VL 24 IS 5 BP 596 EP 601 DI 10.1016/j.avsg.2010.03.006 PG 6 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 611MP UT WOS:000278819800004 PM 20579583 ER PT J AU Reslan, OM Ebaugh, JL Raffetto, JD AF Reslan, Ossama M. Ebaugh, James L. Raffetto, Joseph D. TI Bilateral Asymptomatic Extracranial Carotid Artery Aneurysms SO ANNALS OF VASCULAR SURGERY LA English DT Article ID SURGICAL-TREATMENT; EXPERIENCE; MANAGEMENT; REPAIR AB Aneurysms of the extracranial carotid arteries are rare and account for 0.4-1% of all arterial aneurysms and about 4% of all peripheral arterial aneurysms. Causes include atherosclerosis, fibromuscular dysplasia, trauma (penetrating and blunt cervical trauma and hyperextension of the neck), iatrogenic lesions, infection, congenital defects, and irradiation arteritis. Atherosclerosis is responsible for 46-70% of all carotid artery aneurysms. The most frequent site of carotid artery aneurysms is the common carotid artery, particularly at its bifurcation and proximal internal carotid artery (ICA). The middle and distal portions of the ICA are the next most common sites. Aneurysms at the point of bifurcation are usually fusiform, whereas those located in the middle and distal portions of the ICA are usually saccular. This uncommon but interesting vascular disorder usually presents as a parapharyngeal pulsatile mass. It can be partially or completely thrombosed and thereby cause embolization or compression of neurovascular structures, with ruptures and ischemic events as other complications. Surgical treatment of extracranial carotid aneurysms is required in most cases, to avert disastrous consequences. Conservative management of extracranial ICA aneurysms has resulted in a mortality rate of nearly 71%. Nonoperative treatment is generally indicated in young patients who have nonpenetrating traumatic and spontaneously dissecting aneurysms. However, when anticoagulation therapy fails or when persistent neurologic symptoms or progressive expansion of the aneurysm occurs, surgical repair is indicated. C1 [Reslan, Ossama M.] Amer Univ Beirut, Dept Surg, Beirut, Lebanon. [Ebaugh, James L.; Raffetto, Joseph D.] VA Boston HCS, Dept Surg & Vasc Surg, W Roxbury, MA 02132 USA. [Ebaugh, James L.; Raffetto, Joseph D.] Brigham & Womens Hosp, Dept Surg & Vasc Surg, Boston, MA 02115 USA. [Ebaugh, James L.; Raffetto, Joseph D.] Harvard Univ, Sch Med, Dept Surg & Vasc Surg, Boston, MA 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 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0890-5096 J9 ANN VASC SURG JI Ann. Vasc. Surg. PD JUL PY 2010 VL 24 IS 5 AR 691.e11 DI 10.1016/j.avsg.2010.02.004 PG 6 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 611MP UT WOS:000278819800021 PM 20409683 ER PT J AU Sabbaghian, MS Rothberger, G Alongi, AP Gagner, JP Goldberg, JD Rolnitzky, L Chiriboga, L Hajdu, CH Zagzag, D Basch, R Shamamian, P AF Sabbaghian, M. Shirin Rothberger, Gary Alongi, Alexandra P. Gagner, Jean-Pierre Goldberg, Judith D. Rolnitzky, Linda Chiriboga, Luis Hajdu, Cristina H. Zagzag, David Basch, Ross Shamamian, Peter TI Levels of Elevated Circulating Endothelial Cell Decline after Tumor Resection in Patients with Pancreatic Ductal Adenocarcinoma SO ANTICANCER RESEARCH LA English DT Article DE Pancreatic cancer; endothelial cells; neovascularization; angiogenesis; placental growth factor ID PROGENITOR CELLS; GROWTH-FACTOR; COLORECTAL-CANCER; ANGIOGENESIS; NEOVASCULARIZATION; VASCULOGENESIS; MARKER; PRECURSORS; VEGF AB Aim: To evaluate circulating endothelial lineage cells (ELCs) as biomarkers of tumor neovascularization in patients with pancreatic ductal adenocarcinoma (PDAC). Materials and Methods: ELCs were isolated from the peripheral blood of patients with PDAC (n=14) or controls (n=17) before and after tumor resection/surgery and quantified using flow cytometry. Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were detected in tumor using immunohistochemistry and in plasma using an ELISA technique. Results: Circulating ELC levels were increased in patients with PDAC compared to controls. After PDAC resection, ELC levels declined. ELC level increases were associated with cancer recurrence. VEGF and PlGF were identified in cancer cells and exocrine pancreas cells. Only PlGF was detected in tumor-associated inflammatory cells. Plasma levels of PlGF were higher in patients with PDAC compared to controls. Conclusion: Circulating ELCs are a potential biomarker of PDAC neovascularization, and PlGF may be an important target in treatment of PDAC. C1 [Shamamian, Peter] Ralph H Johnson Vet Affairs Med Ctr, Surg Serv 112, Surg Serv, Charleston, SC 29401 USA. [Sabbaghian, M. Shirin; Rothberger, Gary; Alongi, Alexandra P.; Gagner, Jean-Pierre] NYU, Sch Med, Dept Surg, SA Localio Lab, New York, NY 10016 USA. [Goldberg, Judith D.; Rolnitzky, Linda] NYU, Sch Med, Div Biostat, New York, NY 10016 USA. [Chiriboga, Luis; Hajdu, Cristina H.; Zagzag, David; Basch, Ross] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Zagzag, David; Basch, Ross] NYU, Ctr Canc, New York, NY 10016 USA. [Shamamian, Peter] Med Univ S Carolina, Dept Surg, Charleston, SC 29425 USA. RP Shamamian, P (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Surg Serv 112, Surg Serv, 109 Bee St, Charleston, SC 29401 USA. EM shamamia@musc.edu OI Chiriboga, Luis/0000-0002-2028-6873 FU S. Arthur Localio Professorship Fund; New York University Cancer Institute FX This work was supported, in part, by the S. Arthur Localio Professorship Fund and by a Translational Research Pilot Project Grant from the New York University Cancer Institute. NR 21 TC 7 Z9 7 U1 0 U2 3 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JUL PY 2010 VL 30 IS 7 BP 2911 EP 2917 PG 7 WC Oncology SC Oncology GA 637DQ UT WOS:000280796400061 PM 20683032 ER PT J AU Xu, Y Morse, LR da Silva, RAB Odgren, PR Sasaki, H Stashenko, P Battaglino, RA AF Xu, Yan Morse, Leslie R. da Silva, Raquel Assed Bezerra Odgren, Paul R. Sasaki, Hajime Stashenko, Philip Battaglino, Ricardo A. TI PAMM: A Redox Regulatory Protein That Modulates Osteoclast Differentiation SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID BONE-MINERAL DENSITY; NF-KAPPA-B; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; TRANSCRIPTION FACTORS; FREE-RADICALS; ANTIOXIDANT; WOMEN; THIOREDOXIN; NHA-OC/NHA2 AB The central role of reactive oxygen species (ROS) in osteoclast differentiation and in bone homeostasis prompted us to characterize the redox regulatory system of osteoclasts. In this report, we describe the expression and functional characterization of PAMM, a CXXC motif-containing peroxiredoxin 2-like protein expressed in bone marrow monocytes on stimulation with M-CSF and RANKL. Expression of wild-type (but not C to G mutants of the CXXC domain) PAMM in HEK293 cells results in an increased GSH/GSSG ratio, indicating a shift toward a more reduced environment. Expression of PAMM in RAW264.7 monocytes protected cells from hydrogen peroxide-induced oxidative stress, indicating that PAMM regulates cellular redox status. RANKL stimulation of RAW 264.7 cells caused a decrease in the GSH/GSSG ratio (reflecting a complementary increase in ROS). In addition, RANKL-induced osteoclast formation requires phosphorylation and translocation of NF-kappa B and c-Jun. In stably transfected RAW 264.7 cells, PAMM overexpression prevented the reduction of GSH/GSSG induced by RANKL. Concurrently, PAMM expression completely abolished RANKL-induced p100 NF-kappa B and c-Jun activation, as well as osteoclast formation. We conclude that PAMM is a redox regulatory protein that modulates osteoclast differentiation in vitro. PAMM expression may affect bone resorption in vivo and help to maintain bone mass. Antioxid. Redox Signal. 13, 27-37. C1 [Xu, Yan; Sasaki, Hajime; Stashenko, Philip; Battaglino, Ricardo A.] Harvard Univ, Sch Med, Dept Cytokine Biol, Forsyth Inst, Boston, MA USA. [Morse, Leslie R.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. [da Silva, Raquel Assed Bezerra] Univ Sao Paulo, Sch Dent Ribeirao Preto, Dept Pediat Clin Prevent & Community Dent, Sao Paulo, Brazil. [Odgren, Paul R.] Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01655 USA. RP Battaglino, RA (reprint author), 140 Fenway, Boston, MA 02115 USA. EM rbattaglino@forsyth.org RI Morse, Leslie/C-9442-2015; battaglino, ricardo/D-2892-2015; Bezerra da Silva, Raquel /M-8655-2016 OI Morse, Leslie/0000-0002-7426-6341; Bezerra da Silva, Raquel /0000-0002-0230-1347 FU NIH/NICHD [K12 HD001097-08]; US NIDCR [RO1 DE07444] FX We thank Ms Justine Dobeck for technical assistance and Subbiah Yoganathan for expertise with animal experimentation. The work was supported by grant K12 HD001097-08 to LRM from NIH/NICHD, and grant RO1 DE07444 to PRO from the US NIDCR. Opinions expressed are those of the authors and do not necessarily represent those of the US NIH. NR 32 TC 14 Z9 18 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUL PY 2010 VL 13 IS 1 BP 27 EP 37 DI 10.1089/ars.2009.2886 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 599LT UT WOS:000277915000003 PM 19951071 ER PT J AU Lee, J Kim, Y Yun, HS Kim, JG Oh, S Kim, SH AF Lee, Jin Kim, Younghoon Yun, Hyun Sun Kim, Jong Gun Oh, Sejong Kim, Sae Hun TI Genetic and Proteomic Analysis of Factors Affecting Serum Cholesterol Reduction by Lactobacillus acidophilus A4 SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID MAJOR FACILITATOR SUPERFAMILY; CARBON CATABOLITE REPRESSION; COVALENTLY BOUND FLAVIN; BACILLUS-SUBTILIS; 3BETA-HYDROXYSTEROID OXIDASE; STREPTOCOCCUS-PNEUMONIAE; ENTEROCOCCUS-FAECALIS; LACTOCOCCUS-LACTIS; METABOLIC SYNDROME; ESCHERICHIA-COLI AB This article identifies novel factors involved in cholesterol reduction by probiotic bacteria, which were identified using genetic and proteomic approaches. Approximately 600 Lactobacillus acidophilus A4 mutants were created by random mutagenesis. The cholesterol-reducing ability of each mutant was determined and verified using two different methods: the o-phthalaldehyde assay and gas chromatographic analysis (GC). Among screened mutants, strain BA9 showed a dramatically diminished ability to reduce cholesterol, as demonstrated by a 7.7% reduction rate, while the parent strain had a more than 50% reduction rate. The transposon insertion site was mapped using inverse PCR (I-PCR), and it was determined using bioinformatic methods that the deleted region contained the Streptococcus thermophilus catabolite control protein A gene (ccpA). In addition, we have shown using two-dimensional gel electrophoresis (2-DE) that several proteins, including a transcription regulator, FMN-binding protein, major facilitator superfamily permease, glycogen phosphorylase, the YknV protein, and fructose/tagatose bisphosphate aldolase, were strongly regulated by the ccpA gene. In addition, in vivo experiments investigating ccpA function were conducted with rats. Rats fed wild-type L. acidophilus A4 showed a greater than 20% reduction in total serum cholesterol, but rats fed BA9 mutant L. acidophilus showed only an approximately 10% reduction in cholesterol. These results provide important insights into the mechanism by which these lactic acid bacteria reduce cholesterol. C1 [Lee, Jin; Yun, Hyun Sun; Kim, Sae Hun] Korea Univ, Div Food Biosci & Technol, Seoul 136701, South Korea. [Kim, Jong Gun] Korea Univ, Div Biotechnol, Seoul 136701, South Korea. [Kim, Younghoon] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Kim, Younghoon] Harvard Univ, Sch Med, Boston, MA 02214 USA. [Oh, Sejong] Chonnam Natl Univ, Dept Anim Sci, Inst Agr Sci & Technol, Kwangju, South Korea. RP Kim, SH (reprint author), Korea Univ, Div Food Biosci & Technol, 1,5-Ka Anam Dong, Seoul 136701, South Korea. EM saehkim@korea.ac.kr FU Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea [108141-3]; South Korean government (MEST) [20090083882] FX This study was supported by the Technology Development Program for Agriculture and Forestry, Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea (108141-3), and a Korea Science and Engineering Foundation (KOSEF) grant funded by the South Korean government (MEST) (20090083882). NR 61 TC 16 Z9 17 U1 1 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUL PY 2010 VL 76 IS 14 BP 4829 EP 4835 DI 10.1128/AEM.02892-09 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 621UX UT WOS:000279611500030 PM 20495044 ER PT J AU Morganroth, PA Kreider, ME Okawa, J Taylor, L Werth, VP AF Morganroth, Pamela A. Kreider, Mary Elizabeth Okawa, Joyce Taylor, Lynne Werth, Victoria P. TI Interstitial Lung Disease in Classic and Skin-Predominant Dermatomyositis A Retrospective Study With Screening Recommendations SO ARCHIVES OF DERMATOLOGY LA English DT Article ID CLINICALLY AMYOPATHIC DERMATOMYOSITIS; CONNECTIVE-TISSUE DISEASE; PULMONARY-FUNCTION TESTS; MYCOPHENOLATE-MOFETIL; RHEUMATOID-ARTHRITIS; POLYMYOSITIS; POLYMYOSITIS/DERMATOMYOSITIS; METHOTREXATE; SCLERODERMA; THERAPY AB Objectives: (1) To determine the prevalence of interstitial lung disease (ILD) and isolated low diffusing capacity for carbon monoxide (DLCO) in a large cohort of outpatients with dermatomyositis. (2) To compare the pulmonary abnormalities of patients with classic dermatomyositis and those with skin-predominant dermatomyositis. Design: Retrospective cohort study. Setting: University hospital outpatient dermatology referral center. Patients: Medical records of 91 outpatients with adult-onset dermatomyositis seen between May 26, 2006, and May 25, 2009, were reviewed. Main Outcome Measures: Presence of ILD on thin-slice chest computed tomographic (CT) scans and DLCO. Results: Of the 71 patients with dermatomyositis who had CT or DLCO data, 16 of 17 (23%; 95% confidence interval [CI], 13%-33%) had ILD as defined by CT results. All patients with ILD had a reduced DLCO, and the ILD prevalence was not different between patients with skin-predominant dermatomyositis (10 of 35 [29%]) and those with classic dermatomyositis (6 of 36 [17%]) (P=.27). Eighteen of 71 patients with dermatomyositis (25%; 95% CI, 15%-36%) (7 of 35 [20%] with skin-predominant dermatomyositis; 11 of 36 [31%] with classic dermatomyositis; P=.41) had a low DLCO in the absence of CT findings showing ILD. The prevalence of malignant disease was higher in patients with classic dermatomyositis than in those with skin-predominant dermatomyositis (P=.02), and no patients with skin-predominant dermatomyositis had internal malignant disease. Conclusions: Radiologic ILD and isolated DLCO reductions, which may signify early ILD or pulmonary hypertension, are common in dermatology outpatients with both classic and skin-predominant dermatomyositis. Because DLCO testing is both inexpensive and sensitive for pulmonary disease, it may be appropriate to screen all patients with dermatomyositis with serial DLCO measurements and base further testing on DLCO results. C1 [Morganroth, Pamela A.; Okawa, Joyce; Werth, Victoria P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Morganroth, Pamela A.; Kreider, Mary Elizabeth; Okawa, Joyce; Werth, Victoria P.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Kreider, Mary Elizabeth] Univ Penn, Div Pulm Med, Philadelphia, PA 19104 USA. [Taylor, Lynne] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Morganroth, Pamela A.; Okawa, Joyce; Werth, Victoria P.] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. RP Werth, VP (reprint author), Hosp Univ Penn, Dept Dermatol, PCAM, Ste 1-330S,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM werth@mail.med.upenn.edu FU Department of Veterans Health Administration; Office of Research Development; Biomedical Laboratory Research and Development; National Institutes of Health (NIH) [K24-AR 02207]; National Institute of Arthritis; Musculoskeletal and Skin Diseases (NIH) [5T32-AR007465-26] FX This study was supported in part by a Merit Review grant from the Department of Veterans Health Administration, Office of Research Development, Biomedical Laboratory Research and Development, and by the National Institutes of Health (NIH K24-AR 02207) to Dr Werth. The Dermatology Research Training Grant from the National Institutes of Health, National Institute of Arthritis, and Musculoskeletal and Skin Diseases (NIH 5T32-AR007465-26) provided support for Dr Morganroth. NR 29 TC 26 Z9 26 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JUL PY 2010 VL 146 IS 7 BP 729 EP 738 PG 10 WC Dermatology SC Dermatology GA 628BC UT WOS:000280088100005 PM 20644033 ER PT J AU Klein, R Rosenbach, M Kim, EJ Kim, B Werth, VP Dunham, J AF Klein, Rachel Rosenbach, Misha Kim, Ellen J. Kim, Brian Werth, Victoria P. Dunham, Jonathan TI Tumor Necrosis Factor Inhibitor-Associated Dermatomyositis SO ARCHIVES OF DERMATOLOGY LA English DT Article ID TNF-TARGETED THERAPIES; FACTOR-ALPHA; RHEUMATOID-ARTHRITIS; INFLAMMATORY MYOPATHIES; ANTIBODY; AUTOIMMUNITY; ETANERCEPT; ACTIVATION; MECHANISMS; RECEPTORS AB Background: Dermatomyositis is an autoimmune disease of unknown etiology characterized by inflammation of the skin and muscles. Several medications have been implicated in the development of dermatomyositis; however, the disease has rarely been linked to the use of tumor necrosis factor (TNF) inhibitors. We report 4 cases of dermatomyositis that developed or were exacerbated by exposure to the TNF inhibitors etanercept and adalimumab. Observation: Four patients with symptoms of inflammatory arthritis were treated with TNF inhibitors for a duration ranging from 2 months to 2 years. All 4 patients developed symptoms consistent with dermatomyositis, including inflammatory rash and muscle weakness. Their symptoms persisted after discontinuation of the treatment with the TNF inhibitors but responded to treatment with corticosteroids and immunosuppressive medications. Conclusions: Tumor necrosis factor inhibitors have been associated with the onset of a number of autoimmune disorders, most commonly vasculitis and a lupuslike syndrome. Rarely have they been associated with dermatomyositis. The 4 cases reported herein indicate that TNF inhibitor use can be associated with either induction or exacerbation of dermatomyositis. C1 [Dunham, Jonathan] Univ Penn, Sch Med, Dept Med, Perelman Ctr Adv Med,Div Rheumatol, Philadelphia, PA 19104 USA. [Klein, Rachel; Rosenbach, Misha; Kim, Ellen J.; Kim, Brian; Werth, Victoria P.] Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. [Werth, Victoria P.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Dunham, J (reprint author), Univ Penn, Sch Med, Dept Med, Perelman Ctr Adv Med,Div Rheumatol, 1st Floor S Pavil,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM Jonathan.Dunham@uphs.upenn.edu FU NIAMS NIH HHS [K24 AR002207, K24 AR002207-07] NR 23 TC 50 Z9 55 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JUL PY 2010 VL 146 IS 7 BP 780 EP 784 PG 5 WC Dermatology SC Dermatology GA 628BC UT WOS:000280088100014 PM 20644041 ER PT J AU Lerner, EA Yosipovitch, G AF Lerner, Ethan A. Yosipovitch, Gil TI A Tribute to Walter Shelley, a Pioneer Itch Researcher (1917-2009) SO ARCHIVES OF DERMATOLOGY LA English DT Biographical-Item C1 [Lerner, Ethan A.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Yosipovitch, Gil] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. RP Lerner, EA (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. EM elerner@partners.org FU NIAMS NIH HHS [R01 AR042005] NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JUL PY 2010 VL 146 IS 7 BP 788 EP 788 PG 1 WC Dermatology SC Dermatology GA 628BC UT WOS:000280088100016 PM 20644043 ER PT J AU Goyal, S Chauhan, SK El Annan, J Nallasamy, N Zhang, QA Dana, R AF Goyal, Sunali Chauhan, Sunil K. El Annan, Jaafar Nallasamy, Nambi Zhang, Qiang Dana, Reza TI Evidence of Corneal Lymphangiogenesis in Dry Eye Disease A Potential Link to Adaptive Immunity? SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR-3; MACROPHAGES; CELLS; HEMANGIOGENESIS; SJOGRENS; VEGFR-3; TH17 AB Objective: To determine the effect of desiccating stress on corneal angiogenic responses in dry eye disease (DED) using a murine model. Methods: Dry eye was induced in murine eyes using high-flow desiccated air. Corneas were double stained with CD31 (panendothelial marker) and LYVE-1 (lymphatic endothelial marker). Real-time polymerase chain reaction was performed to quantify expression of vascular endothelial growth factors (VEGF-A, VEGF-C, and VEGF-D) and their receptors (VEGFR-2 and VEGFR-3) in the cornea on days 6, 10, and 14. Enumeration of CD11b(+)/LYVE-1(+) monocytic cells was performed in corneas with DED on clay 14. Flow cytometric evaluation of the draining lymph nodes in normal mice and mice with DED was performed to determine whether DED is associated with homing of mature (major histocompatibility complex class II(hi)) antigen-presenting cells to the lymphoid compartment. Results: Lymphatic vessels unaccompanied by blood vessels were seen growing toward the center of corneas with DED. Significant increases in lymphatic area (P<.001) and lymphatic caliber (P<.02) were seen on day 14 of disease. Lymphangiogenic-specific VEGF-D and VEGFR-3 levels increased earliest on day 6 followed by increased VEGF-C, VEGF-A, and VEGFR-2 levels. Increased recruitment of CD11b(+)/LYVE-1(+) monocytic cells to the cornea and homing of mature CD11b(+) antigen-presenting cells to the draining lymph nodes were also associated with DED. Conclusion: Low-grade inflammation associated with DED is an inducer of lymphangiogenesis without accompanying hemangiogenesis. C1 [Goyal, Sunali; Chauhan, Sunil K.; El Annan, Jaafar; Zhang, Qiang; Dana, Reza] Schepens Eye Res Inst, Boston, MA 02114 USA. [Goyal, Sunali; Chauhan, Sunil K.; El Annan, Jaafar; Nallasamy, Nambi; Zhang, Qiang; Dana, Reza] Harvard Univ, Sch Med, Boston, MA USA. [Dana, Reza] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Dana, R (reprint author), Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM reza.dana@schepens.harvard.edu FU NEI NIH HHS [R01 EY020889, R01 EY020889-02] NR 28 TC 39 Z9 40 U1 2 U2 3 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 JUL PY 2010 VL 128 IS 7 BP 819 EP 824 PG 6 WC Ophthalmology SC Ophthalmology GA 625DB UT WOS:000279871900002 PM 20625040 ER PT J AU Pineda, R Denevich, S Lee, WC Waycaster, C Pashos, CL AF Pineda, Roberto Denevich, Svetlana Lee, Won Chan Waycaster, Curtis Pashos, Chris L. TI Economic Evaluation of Toric Intraocular Lens A Short- and Long-term Decision Analytic Model SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID CATARACT-SURGERY; ASTIGMATISM CORRECTION; COST-UTILITY AB Objective: To assess the economic value of improved uncorrected visual acuity among patients with cataract and preexisting astigmatism treated with toric intraocular lenses (IOLs) compared with conventional monofocal IOLs. Methods: We developed a decision analytic model of hypothetical patients with preexisting astigmatism. We examined costs and outcomes among patients 65 years and older with cataract and preexisting astigmatism (1.5-3.0 diopters) who were receiving either toric or conventional IOLs with and without intraoperative refractive correction (IRC). Data were obtained from the literature and from a survey of 60 US ophthalmologists. Total medical costs of bilateral treatment were calculated for the first posttreatment year and remaining lifetime. Cost-effectiveness and cost-utility outcomes were computed. Future costs and utilities were discounted by 3%. Results: A larger proportion of patients receiving toric IOLs achieved distance vision spectacle independence (67%) and uncorrected visual acuity of 20/25 or better OU (53%) compared with conventional IOLs with (63% and 48%, respectively) or without IRC (53% and 44%, respectively), resulting in fewer future vision corrections. Toric IOLs provided an additional 10.20 quality-adjusted life years (QALYs) compared with conventional IOLs with (10.14 QALYs) and without IRC (10.10 QALYs). Higher first-year costs of the toric IOL ($5739) compared with the conventional IOL with ($5635) or without ($4687) IRC were offset by lifetime cost savings of $34 per patient, $393 per patient achieving uncorrected visual acuity of 20/25 or better, and $349 per QALY compared with the conventional IOL without IRC. Conclusions: Toric IOLs reduce lifetime economic costs by reducing the need for glasses or contact lenses following cataract removal. These results can inform physicians and patients regarding the value of toric IOLs in the treatment of cataract and preexisting astigmatism. C1 [Pineda, Roberto] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Denevich, Svetlana; Pashos, Chris L.] Abt Biopharma Solut Inc, Hlth Econ Res & Qual Life Evaluat Serv, Lexington, MA USA. [Lee, Won Chan] Abt Biopharma Solut Inc, Hlth Econ Res & Qual Life Evaluat Serv, Bethesda, MD USA. [Waycaster, Curtis] Alcon Labs Inc, Ft Worth, TX 76101 USA. RP Pashos, CL (reprint author), United Biosource Corp, Ctr Hlth Econ Epidemiol & Sci Policy, 430 Bedford St,Ste 300, Lexington, MA 02420 USA. EM chris.pashos@unitedbiosource.com FU Alcon Laboratories, Inc; Alcon Labs, Fort Worth, Texas FX Dr Pineda received financial support from Alcon Laboratories, Inc, as a consultant. Dr Waycaster is an employee of Alcon Labs. When this research was conducted, Drs Denevich, Lee, and Pashos were employees of Abt Bio-Pharma Solutions, Inc, an independent research organization, which is now part of United BioSource Corporation.; Funding for this research was provided by Alcon Labs, Fort Worth, Texas. NR 21 TC 8 Z9 8 U1 0 U2 3 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 JUL PY 2010 VL 128 IS 7 BP 834 EP 840 PG 7 WC Ophthalmology SC Ophthalmology GA 625DB UT WOS:000279871900004 PM 20625042 ER PT J AU Kim, IK Lane, AM Gragoudas, ES AF Kim, Ivana K. Lane, Anne Marie Gragoudas, Evangelos S. TI Survival in Patients With Presymptomatic Diagnosis of Metastatic Uveal Melanoma SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID LIVER METASTASES AB Objective: To determine if patients diagnosed as having metastatic uveal melanoma before the onset of symptoms experience more favorable survival outcomes than patients diagnosed after the onset of symptoms. Methods: A retrospective cohort study was performed among 90 patients who were diagnosed as having metastatic uveal melanoma after proton beam irradiation by routine surveillance testing (asymptomatic group) compared with 259 patients who were diagnosed as having metastatic uveal melanoma after development of symptoms (symptomatic group). The median survival times and cumulative rates of melanoma-related death after diagnosis of metastasis were compared between the 2 groups. Results: No differences were noted between groups in known prognostic factors for melanoma-related death, including age and tumor size. Cumulative rates of melanoma-related death were higher for patients in the symptomatic group vs the asymptomatic group (P<.001, log-rank test) owing to differences in mortality observed in the first year after diagnosis of metastasis (87.8% vs 68.5%). By the second year after diagnosis of metastasis, cumulative rates had reached 90% or higher in both groups. The median time to melanoma-related death after primary tumor diagnosis was 40.6 months in the asymptomatic group vs 45.1 months in the symptomatic group (P=.61). Conclusion: Presymptomatic detection of metastatic uveal melanoma by routine surveillance testing seems to confer a survival advantage only in the first year after diagnosis of metastasis, which is likely because of lead-time bias. C1 [Kim, Ivana K.; Lane, Anne Marie; Gragoudas, Evangelos S.] Harvard Univ, Retina Serv, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Sch Med, Boston, MA 02114 USA. RP Kim, IK (reprint author), Harvard Univ, Retina Serv, Massachusetts Eye & Ear Infirm, Dept Ophthalmol,Sch Med, 243 Charles St, Boston, MA 02114 USA. EM ivana_kim@meei.harvard.edu FU Research to Prevent Blindness; Massachusetts Eye and Ear Infirmary Melanoma Research Fund FX This study was supported in part by the Research to Prevent Blindness (Dr Kim) and Massachusetts Eye and Ear Infirmary Melanoma Research Fund (Dr Gragoudas). NR 15 TC 17 Z9 18 U1 0 U2 1 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 JUL PY 2010 VL 128 IS 7 BP 871 EP 875 PG 5 WC Ophthalmology SC Ophthalmology GA 625DB UT WOS:000279871900010 PM 20625048 ER PT J AU Wiggs, JL AF Wiggs, Janey L. TI Genotypes Need Phenotypes SO ARCHIVES OF OPHTHALMOLOGY LA English DT Editorial Material ID MACULAR DEGENERATION; DBGAP DATABASE; OPHTHALMOLOGY; GENOME; ERA C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. RP Wiggs, JL (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM janey_wiggs@meei.harvard.edu NR 10 TC 6 Z9 6 U1 0 U2 1 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 JUL PY 2010 VL 128 IS 7 BP 934 EP 935 PG 2 WC Ophthalmology SC Ophthalmology GA 625DB UT WOS:000279871900022 PM 20625059 ER PT J AU Jakobiec, FA Stacy, RC Mehta, M Fay, A AF Jakobiec, Frederick A. Stacy, Rebecca C. Mehta, Manisha Fay, Aaron TI IgG4-Positive Dacryoadenitis and Kuttner Submandibular Sclerosing Inflammatory Tumor SO ARCHIVES OF OPHTHALMOLOGY LA English DT Letter ID DISEASE; SIALADENITIS; LYMPHOMA C1 [Jakobiec, Frederick A.; Stacy, Rebecca C.; Mehta, Manisha] Massachusetts Eye & Ear Infirm, Cogan Eye Pathol Lab, Boston, MA 02114 USA. [Fay, Aaron] Massachusetts Eye & Ear Infirm, Div Ophthalm Plast & Reconstruct Surg, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Massachusetts Eye & Ear Infirm, Cogan Eye Pathol Lab, 243 Charles St,Ste 321, Boston, MA 02114 USA. EM fred_jakobiec@meei.harvard.edu NR 12 TC 5 Z9 5 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 JUL PY 2010 VL 128 IS 7 BP 942 EP 944 PG 3 WC Ophthalmology SC Ophthalmology GA 625DB UT WOS:000279871900025 PM 20625062 ER PT J AU Brigger, MT Ashland, JE Hartnick, C AF Brigger, Matthew T. Ashland, Jean E. Hartnick, Christopher TI Injection Pharyngoplasty With Calcium Hydroxylapatite for Velopharyngeal Insufficiency Patient Selection and Technique SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article ID VOCAL FOLD AUGMENTATION; CLEFT-PALATE SPEAKERS; COMPETENCE; SPHINCTER AB Objective: To identify children who may benefit from calcium hydroxylapatite (CaHA) injection pharyngoplasty for symptomatic velopharyngeal insufficiency (VPI). Design: Retrospective review of children with VPI who underwent injection pharyngoplasty with CaHA. Setting: Multidisciplinary pediatric aerodigestive center. Patients: Children with symptomatic VPI as defined by abnormal speech associated with subjective and objective measures of hypernasality. Intervention: Posterior pharyngeal wall augmentation with injectable CaHA. Main Outcome Measure: Nasalence scores recorded as number of standard deviations (SDs) from normalized scores, and perceptual scoring recorded as standardized weighted score and caretaker satisfaction from direct report. Results: Twelve children who had undergone injection pharyngoplasty with CaHA were identified. Of the 12 children, 8 demonstrated success at 3 months as defined by nasalence (<1 SD above normal nasalance scores), perceptual scoring (decrease in weighted score), and overall caretaker satisfaction. Four children were followed up for more than 24 months and continued to demonstrate stable success. The 4 children who failed the procedure all failed before the 3-month evaluation and demonstrated increased baseline severity of VPI as defined by increased preoperative nasalence scores (5.25 SD vs 2.4 SD above normalized scores), perceptual scores (weighted score, 4.25 vs 3.85), and characteristic nasendoscopy findings of a broad-based velopharyngeal gap or unilateral adynamism. Three of the 4 treatment failures occurred early in the senior author's (C.J.H.) experience with the technique. Conclusions: Injection pharyngoplasty with CaHA is a useful adjunct in the treatment of children with mild VPI. Efficacy and safety have been demonstrated more than 24 months after injection. Patient selection and operative technique are critical to the success of the procedure. Success is seen most often in children with mild VPI and small well-defined velopharyngeal gaps consistent with touch closure. C1 [Brigger, Matthew T.] USN, Dept Otolaryngol Head & Neck Surg, San Diego Med Ctr, San Diego, CA 92134 USA. [Ashland, Jean E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Speech Language & Swallowing Disorders, Boston, MA USA. [Hartnick, Christopher] Harvard Univ, Sch Med, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. RP Brigger, MT (reprint author), USN, Dept Otolaryngol Head & Neck Surg, San Diego Med Ctr, 34800 Bob Wilson Dr, San Diego, CA 92134 USA. EM matt.brigger@alumni.vanderbilt.edu NR 16 TC 16 Z9 16 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD JUL PY 2010 VL 136 IS 7 BP 666 EP 670 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 625WA UT WOS:000279926300003 PM 20644060 ER PT J AU Jung, D Cunnane, ME Cunningham, MJ AF Jung, David Cunnane, Mary E. Cunningham, Michael J. TI Radiology Quiz Case 2 Juvenile nasopharyngeal angiofibroma (JNA), Radkowski grade 1b SO ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Editorial Material ID FOLLOW-UP; RADIATION C1 [Jung, David; Cunningham, Michael J.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Cunnane, Mary E.] Harvard Univ, Sch Med, Boston, MA USA. RP Jung, D (reprint author), Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. NR 10 TC 0 Z9 0 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0886-4470 J9 ARCH OTOLARYNGOL JI Arch. Otolaryngol. Head Neck Surg. PD JUL PY 2010 VL 136 IS 7 BP 741 EP 743 PG 3 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 625WA UT WOS:000279926300019 PM 20644076 ER PT J AU Fallon, MA Wilbur, DC Prasad, M AF Fallon, Margaret A. Wilbur, David C. Prasad, Manju TI Ovarian Frozen Section Diagnosis Use of Whole-Slide Imaging Shows Excellent Correlation Between Virtual Slide and Original Interpretations in a Large Series of Cases SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT 97th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY MAR 01-07, 2008 CL Denver, CO SP US & Canadian Acad Pathol ID ACCURACY; TUMORS AB Context.-Whole-slide images (WSI) are a tool for remote interpretation, archiving, and teaching. Ovarian frozen sections (FS) are common and hence determination of the operating characteristics of the interpretation of these specimens using WSI is important. Objectives.-To test the reproducibility and accuracy of ovarian FS interpretation using WSI, as compared with routine analog interpretation, to understand the technology limits and unique interpretive pitfalls. Design.-A sequential series of ovarian FS slides, representative of routine practice, were converted to WSI. Whole-slide images were examined by 2 pathologists, masked to all prior results. Correlation characteristics among the WSI, the original, and the final interpretations were analyzed. Results.-A total of 52 cases, consisting of 71 FS slides, were included; 34 cases (65%) were benign, and 18 cases (35%) were malignant, borderline, and of uncertain potential (9 [17%], 7 [13%], and 2 [4%] of 52 cases, respectively). The correlation between WSI and FS interpretations was 96% (50 of 52) for each pathologist for benign versus malignant, borderline, and uncertain entities. Each pathologist undercalled 2 borderline malignant cases (4%) as benign cysts on WSI. There were no overcalls of benign cases. Specific issues within the benign and malignant groups involved endometriosis versus hemorrhagic corpora lutea, and granulosa cell tumor versus carcinoma, respectively. Conclusions.-The correlation between original FS and WSI interpretations was very high. The few discordant cases represent recognized differential diagnostic issues. Ability to examine gross pathology and real-time consultation with surgeons might be expected to improve performance. Ovarian FS diagnosis by WSI is accurate and reproducible, and thus, remote interpretation, teaching, and digital archiving of ovarian FS specimens by this method can be reliable. (Arch Pathol Lab Med. 2010;134:1020-1023) C1 [Wilbur, David C.] Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Fallon, Margaret A.; Prasad, Manju] Univ Massachusetts, Dept Pathol, Worcester, MA 01605 USA. [Wilbur, David C.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Wilbur, DC (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St, Boston, MA 02114 USA. EM dwilbur@partners.org NR 9 TC 18 Z9 18 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JUL PY 2010 VL 134 IS 7 BP 1020 EP 1023 PG 4 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 622BQ UT WOS:000279633900016 PM 20586631 ER PT J AU Krause, DS Spitzer, TR Stowell, CP AF Krause, Daniela S. Spitzer, Thomas R. Stowell, Christopher P. TI The Concentration of CD44 Is Increased in Hematopoietic Stem Cell Grafts of Patients With Acute Myeloid Leukemia, Plasma Cell Myeloma, and Non-Hodgkin Lymphoma SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; AUTOLOGOUS BONE-MARROW; SOLUBLE CD44; B-CELL; BREAST-CANCER; CARCINOMA-CELLS; HYALURONIC-ACID; POTENTIAL USE; TUMOR-GROWTH; SERUM AB Context.-In autologous hematopoietic stem cell transplantation (autoHSCT), malignant cells remaining in the graft may reengraft leading to relapse of the original disease. CD44 is known to play a role in the engraftment of leukemia-initiating cells and is shed from the surface of malignant cells. Soluble CD44 is a cleaved fragment, which is found in the serum of patients with metastasized epithelial and hematologic malignancies and in some other cancers, and has been demonstrated to be correlated with clinical outcome. Objectives.-To investigate (1) a possible correlation between the concentration of CD44 in an autoHSCT graft and the type of hematologic malignancy and (2) a possible correlation between the concentration of CD44 in the autoHSCT graft with clinical outcome after autoHSCT. Design.-We measured CD44 in 157 hematopoietic stem cell grafts from patients with hematologic malignancies and from 43 healthy donors by enzyme-linked immunosorbent assay. Results.-Levels of CD44 were almost 2-fold higher in the patients' grafts. Highest levels were found in the grafts of patients with acute myeloid leukemia, diffuse large B-cell lymphoma, and plasma cell myeloma, congruent with known CD44 expression levels in these malignancies. The survival advantage among patients with CD44 levels less than 22 000 ng/mL was highly statistically significant. Conclusion.-These results show that CD44 levels in an autoHSCT graft may be linked to clinical outcome after autoHSCT. (Arch Pathol Lab Med. 2010;134:1033-1038) C1 [Krause, Daniela S.; Stowell, Christopher P.] Massachusetts Gen Hosp, Dept Pathol, Blood Transfus Serv, Boston, MA 02114 USA. [Spitzer, Thomas R.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. RP Stowell, CP (reprint author), Massachusetts Gen Hosp, Dept Pathol, Blood Transfus Serv, 55 Fruit St, Boston, MA 02114 USA. EM cstowell@partners.org NR 36 TC 14 Z9 15 U1 0 U2 3 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD JUL PY 2010 VL 134 IS 7 BP 1033 EP 1038 PG 6 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 622BQ UT WOS:000279633900019 PM 20586634 ER PT J AU Shen, SQ Shin, JJ Strle, K McHugh, G Li, X Glickstein, LJ Drouin, EE Steere, AC AF Shen, Shiqian Shin, Junghee J. Strle, Klemen McHugh, Gail Li, Xin Glickstein, Lisa J. Drouin, Elise E. Steere, Allen C. TI Treg Cell Numbers and Function in Patients With Antibiotic-Refractory or Antibiotic-Responsive Lyme Arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID REGULATORY T-CELLS; TNF-ALPHA THERAPY; RHEUMATOID-ARTHRITIS; BORRELIA-BURGDORFERI; SYNOVIAL-FLUID; PERIPHERAL-BLOOD; DISEASE SEVERITY; INFLAMMATION; RESISTANT; CYTOKINES AB Objective. In a murine model of antibiotic-refractory Lyme arthritis, the numbers of Treg cells are dramatically reduced. The aim of this study was to examine Treg cell numbers and function in patients with antibiotic-refractory Lyme arthritis. Methods. CD4+ T cell subsets were enumerated in the peripheral blood (PB) and synovial fluid (SF) of 12 patients with antibiotic-refractory arthritis and 6 patients with antibiotic-responsive arthritis. Treg cell function was examined using Borrelia-specific and nonspecific Treg cell proliferation assays. Results. In both patient groups, interferon-gamma positive Th1 cells in SF were abundant and enriched (similar to 50% of CD4+ T cells). In patients with antibiotic-refractory arthritis, the median percentages of FoxP3-positive Treg cells were significantly higher in SF than in PB (12% versus 6%; P = 0.03) or in SF from patients with antibiotic-responsive arthritis (12% versus 5%; P = 0.04). Moreover, in the antibiotic-refractory group, a higher percentage of Treg cells in SF correlated with a shorter duration until resolution of arthritis (r = -0.74, P = 0.006). In contrast, patients with fewer Treg cells had suboptimal responses to disease-modifying antirheumatic drugs and a longer duration of arthritis after antibiotic treatment, and they often required synovectomies for arthritis resolution. In each group, Treg cells in SF dampened Borrelia burgdorferi-specific proliferative responses, and in 2 patients with antibiotic-refractory arthritis, Treg cells were functional in nonspecific suppression assays. Conclusion. Treg cells were functional in patients with antibiotic-refractory arthritis, and in some patients, higher numbers of these cells in SF appeared to participate in arthritis resolution. However, as in the murine model, patients with antibiotic-refractory arthritis and lower numbers of Treg cells seemed unable to achieve resolution of synovial inflammation. C1 [Steere, Allen C.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Steere, AC (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, 55 Fruit St,CNY149-8301, Boston, MA 02114 USA. EM asteere@partners.org RI Li, Xin/E-3505-2011 FU NIH [AR-20358, AR-007258]; English, Bonter, Mitchell Foundation; Eshe Fund; Lyme/Arthritis Research Fund at Massachusetts General Hospital; Lillian B. Davey Foundation; Walter J. and Lille A. Berbecker Foundation; Arthritis Foundation; Massachusetts General Hospital FX Supported by the NIH (grant AR-20358), the English, Bonter, Mitchell Foundation, the Eshe Fund, and the Lyme/Arthritis Research Fund at Massachusetts General Hospital. Dr. Shen's work was supported by a scholarship from the Lillian B. Davey Foundation. Dr. Shin's work was supported by an NIH training grant (AR-007258) and a scholarship from the Walter J. and Lille A. Berbecker Foundation. Dr. Strle's work was supported by a scholarship from the Walter J. and Lille A. Berbecker Foundation. Dr. Li's work was supported by the Arthritis Foundation and a Claflin Distinguished Scholar Award from Massachusetts General Hospital. NR 44 TC 26 Z9 26 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-US JI Arthritis Rheum. PD JUL PY 2010 VL 62 IS 7 BP 2127 EP 2137 DI 10.1002/art.27468 PG 11 WC Rheumatology SC Rheumatology GA 661VM UT WOS:000282758500033 PM 20506317 ER PT J AU Katerberg, H Delucchi, KL Stewart, SE Lochner, C Denys, DAJP Stack, DE Andresen, JM Grant, JE Kim, SW Williams, KA den Boer, JA van Balkom, AJLM Smit, JH van Oppen, P Polman, A Jenike, MA Stein, DJ Mathews, CA Cath, DC AF Katerberg, Hilga Delucchi, Kevin L. Stewart, S. Evelyn Lochner, Christine Denys, Damiaan A. J. P. Stack, Denise E. Andresen, J. Michael Grant, J. E. Kim, Suck W. Williams, Kyle A. den Boer, Johan A. van Balkom, Anton J. L. M. Smit, Johannes H. van Oppen, Patricia Polman, Annemiek Jenike, Michael A. Stein, Dan J. Mathews, Carol A. Cath, Danielle C. TI Symptom Dimensions in OCD: Item-Level Factor Analysis and Heritability Estimates SO BEHAVIOR GENETICS LA English DT Article DE OCD; Factor analysis; Heritability; Symptom dimensions; Y-BOCS; Genetic; Severity; Onset ID OBSESSIVE-COMPULSIVE DISORDER; INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; FACTOR-ANALYZED SYMPTOM; COLLABORATIVE GENETICS; QUANTITATIVE-TRAIT; YBOCS DIMENSIONS; SEX-DIFFERENCES; SIBLING PAIRS; DSM-IV; SCALE AB To reduce the phenotypic heterogeneity of obsessive-compulsive disorder (OCD) for genetic, clinical and translational studies, numerous factor analyses of the Yale-Brown Obsessive Compulsive Scale checklist (YBOCS-CL) have been conducted. Results of these analyses have been inconsistent, likely as a consequence of small sample sizes and variable methodologies. Furthermore, data concerning the heritability of the factors are limited. Item and category-level factor analyses of YBOCS-CL items from 1224 OCD subjects were followed by heritability analyses in 52 OCD-affected multigenerational families. Item-level analyses indicated that a five factor model: (1) taboo, (2) contamination/cleaning, (3) doubts, (4) superstitions/rituals, and (5) symmetry/hoarding provided the best fit, followed by a one-factor solution. All 5 factors as well as the one-factor solution were found to be heritable. Bivariate analyses indicated that the taboo and doubts factor, and the contamination and symmetry/hoarding factor share genetic influences. Contamination and symmetry/hoarding show shared genetic variance with symptom severity. Nearly all factors showed shared environmental variance with each other and with symptom severity. These results support the utility of both OCD diagnosis and symptom dimensions in genetic research and clinical contexts. Both shared and unique genetic influences underlie susceptibility to OCD and its symptom dimensions. C1 [Cath, Danielle C.] Univ Utrecht, Altrecht Outpatient Anxiety Serv, Dept Clin & Hlth Psychol, NL-3551 DC Utrecht, Netherlands. [Stein, Dan J.] Univ Cape Town, Dept Psychiat, ZA-7925 Cape Town, South Africa. [van Balkom, Anton J. L. M.; Smit, Johannes H.; van Oppen, Patricia] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Williams, Kyle A.] Univ Minnesota, Dept Neurol, Minneapolis, MI USA. [Kim, Suck W.] Univ Minnesota, Dept Psychiat, Minneapolis, MI USA. [Grant, J. E.] Univ Minnesota, Sch Med, Dept Psychiat, Minneapolis, MN 55455 USA. [Andresen, J. Michael] MIT, Cambridge, MA 02139 USA. [Denys, Damiaan A. J. P.] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands. [Lochner, Christine; Stein, Dan J.] Univ Stellenbosch, Dept Psychiat, MRC Unit Anxiety & Stress Disorders, ZA-7600 Stellenbosch, South Africa. [Stewart, S. Evelyn; Stack, Denise E.; Jenike, Michael A.] McLean Hosp, Obsess Compuls Disorder Inst, Belmont, MA 02178 USA. [Stewart, S. Evelyn] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Psychiat & Neurodev Genet Unit, Boston, MA USA. [Stewart, S. Evelyn; Jenike, Michael A.] Massachusetts Gen Hosp, Pediat Obsess Compuls Disorder Clin, Boston, MA 02114 USA. [Delucchi, Kevin L.; Mathews, Carol A.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Katerberg, Hilga; van Balkom, Anton J. L. M.; Smit, Johannes H.; van Oppen, Patricia] GGZ Buitenamstel, Amsterdam, Netherlands. [Katerberg, Hilga; den Boer, Johan A.; Polman, Annemiek] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. RP Cath, DC (reprint author), Univ Utrecht, Altrecht Outpatient Anxiety Serv, Dept Clin & Hlth Psychol, Mimosastr 2-4, NL-3551 DC Utrecht, Netherlands. EM dcath@xs4all.nl RI Stein, Dan/A-1752-2008; OI Stein, Dan/0000-0001-7218-7810; Stewart, S. Evelyn/0000-0002-0994-6383 FU Obsessive-Compulsive Foundation (Boston, USA); Tourette Syndrome Association (Bayside, New York); Anxiety Disorders Association of America (Boston, USA); American Academy of Child and Adolescent Psychiatry (USA); NARSAD (New York, USA) FX This work was supported in part by the Obsessive-Compulsive Foundation (Boston, USA), the Tourette Syndrome Association (Bayside, New York), the Anxiety Disorders Association of America (Boston, USA), the American Academy of Child and Adolescent Psychiatry (USA) and NARSAD (New York, USA). NR 55 TC 56 Z9 58 U1 4 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD JUL PY 2010 VL 40 IS 4 BP 505 EP 517 DI 10.1007/s10519-010-9339-z PG 13 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 612KP UT WOS:000278897500008 PM 20361247 ER PT J AU Chasson, GS Buhlmann, U Tolin, DF Rao, SR Reese, HE Rowley, T Welsh, KS Wilhelm, S AF Chasson, Gregory S. Buhlmann, Ulrike Tolin, David F. Rao, Sowmya R. Reese, Hannah E. Rowley, Theresa Welsh, Kaitlyn S. Wilhelm, Sabine TI Need for speed: Evaluating slopes of OCD recovery in behavior therapy enhanced with D-cycloserine SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE Obsessive-Compulsive Disorder; D-Cycloserine; Exposure and response prevention; OCD treatment; Behavior therapy ID OBSESSIVE-COMPULSIVE DISORDER; EXPOSURE THERAPY; SCALE; AUGMENTATION; PREVENTION; EXTINCTION; INTERVIEW; FEAR AB Evidence suggests that the antibiotic D-cycloserine (DCS) enhances the treatment effects of exposure and response prevention (ERP) for Obsessive Compulsive Disorder (OCD). Further, evidence suggests that the effects of DCS diminish partway through treatment, but it is unclear to what extent. In an effort to evaluate these issues, the current study re-analyzes data from a 10-session randomized controlled trial of ERP + DCS versus ERP + placebo in a sample of 22 adults with OCD. We analyzed repeated-measures mixed models with random slopes and intercepts across different intervals: sessions 1-10, 1-5, and 6-10. The results indicate that the course of ERP was 2.3 times faster over the full 10 sessions for the DCS compared to the placebo group, and nearly six times quicker in the first half of ERP. Further interpretation of the results suggests that DCS does not amplify the effects of ERP, but instead initiates treatment effects sooner in treatment. In addition, DCS does not necessarily lose its effect over repeated use, but instead may exhaust its maximum utility after effectively jump-starting ERR Ultimately, DCS may provide a means for curtailing treatment costs, decreasing treatment dropout and refusal rates, and enhancing access to care. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Wilhelm, Sabine] Harvard Univ, Massachusetts Gen Hosp, Sch Med, OCD & Related Disorders Program, Boston, MA 02114 USA. [Buhlmann, Ulrike] Humboldt Univ, D-1086 Berlin, Germany. [Tolin, David F.] Yale Univ, Sch Med, Inst Living, New Haven, CT 06520 USA. RP Wilhelm, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, OCD & Related Disorders Program, 185 Simches Res Bldg,Floor 2, Boston, MA 02114 USA. EM wilhelm@psych.mgh.harvard.edu NR 21 TC 49 Z9 52 U1 3 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 J9 BEHAV RES THER JI Behav. Res. Ther. PD JUL PY 2010 VL 48 IS 7 BP 675 EP 679 DI 10.1016/j.brat.2010.03.007 PG 5 WC Psychology, Clinical SC Psychology GA 614FW UT WOS:000279041800013 PM 20362975 ER PT J AU Jessen, N Koh, HJ Folmes, CD Wagg, C Fujii, N Lofgren, B Wolf, CM Berul, CI Hirshman, MF Lopaschuk, GD Goodyear, LJ AF Jessen, Niels Koh, Ho-Jin Folmes, Clifford D. Wagg, Cory Fujii, Nobuharu Lofgren, Bo Wolf, Cordula M. Berul, Charles I. Hirshman, Michael F. Lopaschuk, Gary D. Goodyear, Laurie J. TI Ablation of LKB1 in the heart leads to energy deprivation and impaired cardiac function SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Cardiac function; LKB1; AMP-activated protein kinase; mTOR ID ACTIVATED PROTEIN-KINASE; FATTY-ACID OXIDATION; ACETYL-COA CARBOXYLASE; SKELETAL-MUSCLE; GLUCOSE-UPTAKE; CONTRACTILE FUNCTION; ISCHEMIC HEARTS; FAILING HEART; CELL-GROWTH; MALONYL-COA AB Energy deprivation in the myocardium is associated with impaired heart function and increased morbidity. LKB1 is a kinase that is required for activation of AMP-activated protein kinase (AMPK) as well as 13 AMPK-related protein kinases. AMPK stimulates ATP production during ischemia and prevents post-ischemic dysfunction. We used the Cre-Lox system to generate mice where LKB1 was selectively knocked out in cardiomyocytes and muscle cells (LKB1-KO) to assess the role of LKB1 on cardiac function in these mice. Heart rates of LKB1-KO mice were reduced and ventricle diameter was increased. Ex vivo, cardiac function was impaired during aerobic perfusion of isolated working hearts, and recovery of function after ischemia was reduced. Although oxidative metabolism and mitochondrial function were normal, the AMP/ATP ratio was increased in LKB1-KO hearts. This was associated with a complete ablation of AMPK alpha 2 activity, and a stimulation of signaling through the mammalian target of rapamycin. Our results establish a critical role for LKB1 for normal cardiac function under both aerobic conditions and during recovery after ischemia. Ablation of LKB1 leads to a decreased cardiac efficiency despite normal mitochondrial oxidative metabolism. (C) 2010 Elsevier B.V. All rights reserved. C1 [Goodyear, Laurie J.] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. [Jessen, Niels] Univ Aarhus, Dept Pharmacol, Aarhus, Denmark. [Folmes, Clifford D.; Wagg, Cory; Lopaschuk, Gary D.] Univ Alberta, Fac Med & Dent, Mazankowski Alberta Heart Inst, Cardiovasc Res Grp, Edmonton, AB, Canada. [Wolf, Cordula M.; Berul, Charles I.] Harvard Univ, Childrens Hosp, Sch Med, Dept Cardiol, Boston, MA 02115 USA. RP Goodyear, LJ (reprint author), Joslin Diabet Ctr, Sect Integrat Physiol & Metab, 1 Joslin Pl, Boston, MA 02215 USA. EM laurie.goodyear@joslin.harvard.edu RI Jessen, Niels/E-1731-2011; Fujii, Nobuharu/J-2724-2014; OI Fujii, Nobuharu/0000-0002-0974-3033; Jessen, Niels/0000-0001-5613-7274 FU National Institute of Health [DK068626, AR45670]; Danish Agency for Science Technology and Innovation [271-07-0719]; Canadian Institutes of Health Research FX This work was supported by National Institute of Health grants to LJG (grant numbers: DK068626 and AR45670). Additional funds to support this work were provided by the Danish Agency for Science Technology and Innovation to N Jessen (grant number: 271-07-0719), and from a Canadian Institutes of Health Research grant to G. Lopaschuk. The authors thank C.R. Kahn and R.A. DePinho for providing the MCK-Cre and foxed LKB1 mice. We also thank N. Mukai for excellent technical assistance and Dr. Ding An for valuable scientific input. NR 34 TC 24 Z9 25 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD JUL-AUG PY 2010 VL 1802 IS 7-8 BP 593 EP 600 DI 10.1016/j.bbadis.2010.04.008 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 622HI UT WOS:000279651600002 PM 20441792 ER PT J AU Contreras, MA Ries, WL Shanmugarajan, S Arboleda, G Singh, I Singh, AK AF Contreras, Miguel Agustin Ries, William Louis Shanmugarajan, Srinivasan Arboleda, Gonzalo Singh, Inderjit Singh, Avtar Kaur TI Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Galactosylsphingosine; Insulin-like growth factor-1; Krabbe disease; Lysosomal disorders; Osteopenia; Psychosine; Twitcher mice ID GLOBOID-CELL LEUKODYSTROPHY; PSYCHOSINE-INDUCED APOPTOSIS; TANDEM MASS-SPECTROMETRY; I IGF-I; SPHINGOSINE 1-PHOSPHATE; MOLECULAR-MECHANISM; STORAGE DISEASE; MUTANT TWITCHER; MOUSE; HORMONE AB Krabbe disease is an inherited lysosomal disorder in which galactosylsphingosine (psychosine) accumulates mainly in the central nervous system. To gain insight into the possible mechanism(s) that may be participating in the inhibition of the postnatal somatic growth described in the animal model of this disease (twitcher mouse, twi), we studied their femora. This study reports that twi femora are smaller than of those of wild type (wt), and present with abnormality of marrow cellularity, bone deposition (osteoblastic function), and osteoclastic activity. Furthermore, lipidomic analysis indicates altered sphingolipid homeostasis, but without significant changes in the levels of sphingolipid-derived intermediates of cell death (ceramide) or the levels of the osteoclast-osteoblast coupling factor (sphingosine-1-phosphate). However, there was significant accumulation of psychosine in the femora of adult twi animals as compared to wt, without induction of tumor necrosis factor-alpha or interleukin-6. Analysis of insulin-like growth factor-1 (IGF-1) plasma levels, a liver secreted hormone known to play a role in bone growth, indicated a drastic reduction in twi animals when compared to wt. To identify the cause of the decrease, we examined the IGF-1 mRNA expression and protein levels in the liver. The results indicated a significant reduction of IGF-1 mRNA as well as protein levels in the liver from twi as compared to wt littermates. Our data suggest that a combination of endogenous (psychosine) and endocrine (IGF-1) factors play a role in the inhibition of postnatal bone growth in twi mice; and further suggest that derangements of liver function may be contributing, at least in part, to this alteration. (C) 2010 Elsevier B.V. All rights reserved. C1 [Contreras, Miguel Agustin; Ries, William Louis; Shanmugarajan, Srinivasan; Arboleda, Gonzalo; Singh, Inderjit] Med Univ S Carolina, Darby Childrens Res Inst, Dept Pediat, Charleston, SC 29425 USA. [Singh, Avtar Kaur] Ralph H Johnson Vet Adm Med Ctr, Dept Pathol & Lab Med, Charleston, SC USA. RP Singh, AK (reprint author), Med Univ S Carolina, Darby Childrens Res Inst 516, 173 Ashley Ave, Charleston, SC 29425 USA. EM gharboledab@unal.edu.co; avtar.singh@med.va.gov FU National Center for Research Resources [C06 RR018823, C06 RR015455]; National Institutes of Health [NS-22576, NS-34741, NS-37766, NS-40810, AG-25307] FX The authors would like to thank Ms. Joyce Bryan, Dr. Narender Nath and the members of the Lipidomics Core Facility of the Medical University of South Carolina for the excellent technical assistance. This work was supported by Grants from the Extramural Research Facilities Program of the National Center for Research Resources (C06 RR018823 and C06 RR015455) and from the National Institutes of Health (NS-22576, NS-34741, NS-37766, NS-40810 and AG-25307). NR 73 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 EI 0006-3002 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD JUL-AUG PY 2010 VL 1802 IS 7-8 BP 601 EP 608 DI 10.1016/j.bbadis.2010.04.006 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 622HI UT WOS:000279651600003 PM 20441793 ER PT J AU Kim, J Amante, DJ Moody, JP Edgerly, CK Bordiuk, OL Smith, K Matson, SA Matson, WR Scherzer, CR Rosas, HD Hersch, SM Ferrante, RJ AF Kim, Jinho Amante, Daniel J. Moody, Jennifer P. Edgerly, Christina K. Bordiuk, Olivia L. Smith, Karen Matson, Samantha A. Matson, Wayne R. Scherzer, Clemens R. Rosas, H. Diana Hersch, Steven M. Ferrante, Robert J. TI Reduced creatine kinase as a central and peripheral biomarker in Huntington's disease SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE Biomarker; Creatine kinase; Huntington's disease; Energetic defects; Blood buffy coat ID INCREASED OXIDATIVE DAMAGE; AMYOTROPHIC-LATERAL-SCLEROSIS; DEFICIENCY SYNDROMES; TRANSGENIC MICE; COENZYME Q(10); MOUSE MODEL; BRAIN; GAMT; DNA; MECHANISMS AB A major goal of current clinical research in Huntington's disease (HD) has been to identify preclinical and manifest disease biomarkers, as these may improve both diagnosis and the power for therapeutic trials. Although the underlying biochemical alterations and the mechanisms of neuronal degeneration remain unknown, energy metabolism defects in HD have been chronicled for many years. We report that the brain isoenzyme of creatine kinase (CK-BB), an enzyme important in buffering energy stores, was significantly reduced in presymptomatic and manifest disease in brain and blood buffy coat specimens in HD mice and HD patients. Brain CK-BB levels were significantly reduced in R6/2 mice by similar to 18% to similar to 68% from 21 to 91 days of age, while blood CK-BB levels were decreased by similar to 14% to similar to 44% during the same disease duration. Similar findings in CK-BB levels were observed in the 140 CAG mice from 4 to 12 months of age, but not at the earliest time point, 2 months of age. Consistent with the HD mice, there was a grade-dependent loss of brain CK-BB that worsened with disease severity in HD patients from similar to 28% to similar to 63%, as compared to non-diseased control patients. In addition, CK-BB blood buffy coat levels were significantly reduced in both premanifest and symptomatic HD patients by similar to 23% and similar to 39%, respectively. The correlation of CK-BB as a disease biomarker in both CNS and peripheral tissues from HD mice and HD patients may provide a powerful means to assess disease progression and to predict the potential magnitude of therapeutic benefit in this disorder. Published by Elsevier B.V. C1 [Kim, Jinho; Amante, Daniel J.; Moody, Jennifer P.; Edgerly, Christina K.; Bordiuk, Olivia L.; Smith, Karen; Matson, Samantha A.; Matson, Wayne R.; Ferrante, Robert J.] New England Vet Adm VISN 1, Geriatr Res Educ Clin Ctr, Bedford, MA 01730 USA. [Kim, Jinho; Amante, Daniel J.; Smith, Karen; Ferrante, Robert J.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Kim, Jinho; Amante, Daniel J.; Smith, Karen; Ferrante, Robert J.] Boston Univ, Sch Med, Dept Lab Med & Pathol, Boston, MA 02118 USA. [Kim, Jinho; Amante, Daniel J.; Smith, Karen; Ferrante, Robert J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Scherzer, Clemens R.] Brigham & Womens Hosp, Ctr Neurol Dis, Cambridge, MA 02139 USA. [Scherzer, Clemens R.] Harvard Univ, Sch Med, Cambridge, MA 02139 USA. [Rosas, H. Diana; Hersch, Steven M.] Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. [Rosas, H. Diana; Hersch, Steven M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Rosas, H. Diana; Hersch, Steven M.] Massachusetts Gen Hosp, Mass Gen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. RP Ferrante, RJ (reprint author), New England Vet Adm VISN 1, Geriatr Res Educ Clin Ctr, Bedford, MA 01730 USA. EM rjferr@bu.edu RI Hartman, Jessica/N-3210-2016 FU National Institutes of Health [NS045806, U01AT000613, NS058793]; Veterans Administration [VISN 1]; New England HDSA Center of Excellence; CHDI Foundation FX We wish to thank Dr. Ann McKee for donating brain tissue specimens from the Boston University Alzheimer's Disease Brain Bank (NIA P30AG13846). This work was supported by National Institutes of Health Grants NS045806 (RJF and SMH), U01AT000613 (SMH) and NS058793 (SMH, HDR, CRS, WRM, RJF), the Veterans Administration VISN 1 (RJF and WRM), the New England HDSA Center of Excellence (SMH and HDR), and the CHDI Foundation (RJF). NR 52 TC 22 Z9 23 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD JUL-AUG PY 2010 VL 1802 IS 7-8 BP 673 EP 681 DI 10.1016/j.bbadis.2010.05.001 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 622HI UT WOS:000279651600010 PM 20460152 ER PT J AU Reiner, T Kohler, RH Liew, CW Hill, JA Gaglia, J Kulkarni, RN Weissleder, R AF Reiner, Thomas Kohler, Rainer H. Liew, Chong Wee Hill, Jonathan A. Gaglia, Jason Kulkarni, Rohit N. Weissleder, Ralph TI Near-Infrared Fluorescent Probe for Imaging of Pancreatic beta Cells SO BIOCONJUGATE CHEMISTRY LA English DT Article ID MASS; MOUSE; RECEPTOR; EXPRESSION; ISLETS; MODEL; RAT AB The ability to image and ultimately quantitate beta-cell mass in vivo will likely have far reaching implications in the study of diabetes biology, in the monitoring of disease progression or response to treatment, and for drug development. Here, using animal models, we report on the synthesis, characterization, and intravital microscopic imaging properties of a near-infrared fluorescent exendin-4 analogue with specificity for the GLP-1 receptor on beta cells (E4(K12)-FI). The agent demonstrated subnanomolar EC(50) binding concentrations, with high specificity and binding that could be inhibited by GLP-1R agonists. Following intravenous administration to mice, pancreatic islets were readily distinguishable from exocrine pancreas, achieving target-to-background ratios within the pancreas of 6:1, as measured by intravital microscopy. Serial imaging revealed rapid accumulation kinetics (with initial signal within the islets detectable within 3 min and peak fluorescence within 20 min of injection), making this an ideal agent for in vivo imaging. C1 [Reiner, Thomas; Kohler, Rainer H.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Liew, Chong Wee; Hill, Jonathan A.; Gaglia, Jason; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Dept Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Hill, Jonathan A.; Gaglia, Jason] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, 185 Cambridge St,CPZN 5206, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu OI Gaglia, Jason/0000-0003-2904-312X; Reiner, Thomas/0000-0002-7819-5480 FU NIH [P01 A154904, 1201 67536, U24 CA092782, 1RL9EB008539-01]; Canadian Institutes of Health Research; Canadian Diabetes Association; Deutsche Akademie der Naturforscher Leopolina (German Academy of Sciences Leopoldina) FX We would especially like to thank Christophe Benoist and Diane Mathis for many helpful discussions. We acknowledge the help of George Holz for providing reagents, Yoshiko Iwamoto for histology and Rostic Gorbatov for surgery. The work was supported in part by NIH Grants P01 A154904, 1201 67536, U24 CA092782, an NIH Interdisciplinary training grant (1RL9EB008539-01) (SysCODE) for C.W.L., fellowships from the Canadian Institutes of Health Research and the Canadian Diabetes Association for J.A.H. and a grant from the Deutsche Akademie der Naturforscher Leopolina (German Academy of Sciences Leopoldina) to T.R. NR 33 TC 22 Z9 23 U1 0 U2 11 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 JUL PY 2010 VL 21 IS 7 BP 1362 EP 1368 DI 10.1021/bc100184w PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 627GS UT WOS:000280028100028 PM 20583828 ER PT J AU Lee, J Cohen, MS Engel, SA Glahn, D Nuechterlein, KH Wynn, JK Green, MF AF Lee, Junghee Cohen, Mark S. Engel, Stephen A. Glahn, David Nuechterlein, Keith H. Wynn, Jonathan K. Green, Michael F. TI Regional Brain Activity During Early Visual Perception in Unaffected Siblings of Schizophrenia Patients SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Backward masking; early visual perception; lateral occipital complex; schizophrenia; unaffected siblings ID BACKWARD-MASKING PERFORMANCE; INFORMATION-PROCESSING DEFICITS; MULTIPLE TRIAL TYPES; EVENT-RELATED FMRI; FUNCTIONAL MRI; SEPARATING PROCESSES; OCCIPITAL CORTEX; BIPOLAR DISORDER; ATTENTION; AWARENESS AB Background: Visual masking paradigms assess the early part of visual information processing, which may reflect vulnerability measures for schizophrenia. We examined the neural substrates of visual backward performance in unaffected sibling of schizophrenia patients using functional magnetic resonance imaging (fMRI). Methods: Twenty-one unaffected siblings of schizophrenia patients and 19 healthy controls performed a backward masking task and three functional localizer tasks to identify three visual processing regions of interest (ROI): lateral occipital complex (LO), the motion-sensitive area, and retinotopic areas. In the masking task, we systematically manipulated stimulus onset asynchronies (SOAs). We analyzed fMRI data in two complementary ways: 1) an ROI approach for three visual areas, and 2) a whole-brain analysis. Results: The groups did not differ in behavioral performance. For ROI analysis, both groups increased activation as SOAs increased in LO. Groups did not differ in activation levels of the three ROIs. For whole-brain analysis, controls increased activation as a function of SOAs, compared with siblings in several regions (i.e., anterior cingulate cortex, posterior cingulate cortex, inferior prefrontal cortex, inferior parietal lobule). Conclusions: The study found: 1) area LO showed sensitivity to the masking effect in both groups; 2) siblings did not differ from controls in activation of LO; and 3) groups differed significantly in several brain regions outside visual processing areas that have been related to attentional or re-entrant processes. These findings suggest that LO dysfunction may be a disease indicator rather than a risk indicator for schizophrenia. C1 [Lee, Junghee; Cohen, Mark S.; Nuechterlein, Keith H.; Wynn, Jonathan K.; Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Lee, Junghee; Wynn, Jonathan K.; Green, Michael F.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Engel, Stephen A.] Univ Minnesota, Calif Dept Psychol, Minneapolis, MN USA. [Glahn, David] Yale Univ, Sch Med, Olin Neuropsychiat Res Ctr, Inst Living, New Haven, CT USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Nuechterlein, Keith H.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. RP Lee, J (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, 300 Med Plaza,Suite 2200, Los Angeles, CA 90095 USA. EM jungheelee@ucla.edu RI Lee, Junghee/C-5226-2014; Wynn, Jonathan/H-3749-2014; Cohen, Mark/C-6610-2011 OI Lee, Junghee/0000-0001-9567-8700; Wynn, Jonathan/0000-0002-1763-8540; Cohen, Mark/0000-0001-6731-4053 FU National Institutes of Mental Health [MH43292, MH065707] FX Support for this study came from National Institutes of Mental Health Grant Nos. MH43292 and MH065707 (principal investigator: Michael F. Green, Ph.D.). We thank Poorang Non, Alex Korb, and Alisa Malin for assistance in data collection. NR 63 TC 10 Z9 10 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 1 PY 2010 VL 68 IS 1 BP 78 EP 85 DI 10.1016/j.biopsych.2010.03.028 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 616KH UT WOS:000279207800010 PM 20494338 ER PT J AU Palomo, M Diaz-Ricart, M Carbo, C Rovira, M Fernandez-Aviles, F Martine, C Ghita, G Escolar, G Carreras, E AF Palomo, Marta Diaz-Ricart, Maribel Carbo, Carla Rovira, Montserrat Fernandez-Aviles, Francesc Martine, Carmen Ghita, Gabriela Escolar, Gines Carreras, Enric TI Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: Role of the Conditioning Regimen and the Type of Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Endothelial dysfuntion; Inflammation markers; Hematopoietic stem cell transplantation ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; SINUSOIDAL OBSTRUCTION SYNDROME; VON-WILLEBRAND-FACTOR; NECROSIS-FACTOR-ALPHA; ADHESION MOLECULES; ACTIVATION; RECEPTORS; DAMAGE; COMPLICATIONS AB There is endothelial activation and damage in hematopoietic stem cell transplantation (HSCT). The impact of the conditioning and type of HSCT on endothelial dysfunction in the early phases of HSCT has been evaluated. Plasma samples were obtained before and at different times after autologous and allogeneic HSCT with and without early complications. Changes in soluble markers of endothelial damage (VWF, ADAMTS-13, sVCAM-1, sICAM-1, and sTNFRI) were measured. There were changes in all markers evaluated that followed different patterns in auto and allo settings. For VWF and sTNRI, progressive increases from day Pre to day 14 and to day 21 were observed in the auto and the allo group, respectively. ADAMTS-13 activity correlated inversely with VWF levels. Levels of sVCAM-1 decreased until day 7, and raised significantly to day 14 and to day 21 in the auto and the allo HSCT, respectively. No significant changes were detected for sICAM-1. Our results confirm that there is endothelial damage at the early phases of HSCT, apparently induced by the consecutive effects of the conditioning, the proinflammatory agents used during transplantation, the translocation of endotoxins across the damaged gastrointestinal tract, and the engraftment. However, the comparative analysis between patients with and without complications suggests that none of these markers has diagnostic or prognostic value. Biol Blood Marrow Transplant 16: 985-993 (2010) (C) 2010 American Society for Blood and Marrow Transplantation C1 [Palomo, Marta; Diaz-Ricart, Maribel; Escolar, Gines] Univ Barcelona, Hosp Clin, Hemotherapy Hemostasis Dept,Ctr Diagnost Biomed, Inst Invest Biomed August Pi i Sunyer, E-08036 Barcelona, Spain. [Carbo, Carla] Harvard Univ, Sch Med, Dept Pathol, Immune Dis Inst, Boston, MA 02115 USA. [Rovira, Montserrat; Fernandez-Aviles, Francesc; Martine, Carmen; Ghita, Gabriela; Carreras, Enric] Univ Barcelona, Hosp Clin, Stem Cell Transplantat Unit,Hematol Dept, Inst Invest Biomed August Pi i Sunyer, E-08036 Barcelona, Spain. RP Palomo, M (reprint author), Univ Barcelona, Hosp Clin, Hemotherapy Hemostasis Dept,Ctr Diagnost Biomed, Inst Invest Biomed August Pi i Sunyer, Villarroel 170, E-08036 Barcelona, Spain. EM palomo_marta@hotmail.com OI DIAZ-RICART, MARIBEL/0000-0003-1122-0052 FU Fondo de Investigaciones de la Seguridad Social (FIS) [PI060260, PI080156]; German Jose Carreras Leukaemia Foundation [R 07/41v, SGR2005-00952]; Ministerio de Ciencia y Tecnologia [SAF2006-08003]; Red HERACLES, Instituto de Salud Carlos III [RD06/0009/1003] FX This work has been partially supported by grants FIS PI060260 and FIS PI080156 (Fondo de Investigaciones de la Seguridad Social), German Jose Carreras Leukaemia Foundation (R 07/41v), SGR2005-00952 (Generalitat de Catalunya), SAF2006-08003 (Ministerio de Ciencia y Tecnologia), and RD06/0009/1003 (Red HERACLES, Instituto de Salud Carlos III). We thank Fulgencio Navalon, Jose M. Rodriguez, Patricia Molina, and Marc Pino for their technical assistance in this study. NR 37 TC 34 Z9 35 U1 0 U2 4 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 JUL PY 2010 VL 16 IS 7 BP 985 EP 993 DI 10.1016/j.bbmt.2010.02.008 PG 9 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 618PG UT WOS:000279367500011 PM 20167280 ER PT J AU Richardson, PG Soiffer, RJ Antin, JH Uno, H Jin, ZZ Kurtzberg, J Martin, PL Steinbach, G Murray, KF Vogelsang, GB Chen, AR Krishnan, A Kernan, NA Avigan, DE Spitzer, TR Shulman, HM Di Salvo, DN Revta, C Warren, D Momtaz, P Bradwin, G Wei, LJ Iacobelli, M McDonald, GB Guinan, EC AF Richardson, Paul G. Soiffer, Robert J. Antin, Joseph H. Uno, Hajime Jin, Zhezhen Kurtzberg, Joanne Martin, Paul L. Steinbach, Gideon Murray, Karen F. Vogelsang, Georgia B. Chen, Allen R. Krishnan, Amrita Kernan, Nancy A. Avigan, David E. Spitzer, Thomas R. Shulman, Howard M. Di Salvo, Donald N. Revta, Carolyn Warren, Diane Momtaz, Parisa Bradwin, Gary Wei, L. J. Iacobelli, Massimo McDonald, George B. Guinan, Eva C. TI Defibrotide for the Treatment of Severe Hepatic Veno-Occlusive Disease and Multiorgan Failure after Stem Cell Transplantation: A Multicenter, Randomized, Dose-Finding Trial SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Defibrotide; Severe Veno-Occlusive Disease; Multi-organ failure; Dose-Finding Study ID BONE-MARROW-TRANSPLANTATION; SINUSOIDAL OBSTRUCTION SYNDROME; VENO-OCCLUSIVE DISEASE; HIGH-RISK POPULATION; PEDIATRIC STEM; ENDOTHELIAL-CELLS; COMPASSIONATE-USE; SIGNIFICANT TOXICITY; CONTINUOUS-INFUSION; PROPHYLACTIC USE AB Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type I (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD. Biol Blood Marrow Transplant 16: 1005-1017 (2010) (C) 2010 American Society for Blood and Marrow Transplantation C1 [Richardson, Paul G.; Soiffer, Robert J.; Antin, Joseph H.; Avigan, David E.; Spitzer, Thomas R.; Revta, Carolyn; Warren, Diane; Momtaz, Parisa] Massachusetts Gen Hosp, Beth Israel Deaconess Med Ctr, Dana Farber Canc Inst, Ctr Hematol Oncol,Dept Adult Oncol, Boston, MA 02115 USA. [Bradwin, Gary] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Uno, Hajime] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Jin, Zhezhen] Columbia Univ, Dept Biostat, New York, NY USA. [Kurtzberg, Joanne; Martin, Paul L.] Duke Univ, Med Ctr, Durham, NC USA. [Steinbach, Gideon; Shulman, Howard M.; McDonald, George B.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Murray, Karen F.] Seattle Childrens Hosp, Seattle, WA USA. [Vogelsang, Georgia B.; Chen, Allen R.] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Krishnan, Amrita] City Hope Canc Ctr, Duarte, CA USA. [Kernan, Nancy A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Di Salvo, Donald N.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiol, Boston, MA 02115 USA. [Di Salvo, Donald N.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wei, L. J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Iacobelli, Massimo] Gentium SpA, Villa Guardia, Como, Italy. [Guinan, Eva C.] Childrens Hosp, Dept Pediat, Dana Farber Canc Inst, Boston, MA 02115 USA. [Guinan, Eva C.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. RP Richardson, PG (reprint author), Massachusetts Gen Hosp, Beth Israel Deaconess Med Ctr, Dana Farber Canc Inst, Ctr Hematol Oncol,Dept Adult Oncol, 44 Binney St,Dana 1B02, Boston, MA 02115 USA. EM paul_richardson@dfci.harvard.edu OI Kernan, Nancy/0000-0003-1417-1823 FU Gentium SpA; Orphan Drug Products [FDR-001667]; Richard Corman Multiple Myeloma Research Fund FX We thank Colleen Didas, Caroline Harvey, the nurses, clinical research coordinators, research pharmacists, and especially the patients and families involved in the trial for their participation. We also thank Krishna Menon, PhD, for his assistance with pharmacokinetic studies, Nader Rifai, PhD (Children's Hospital of Boston) for his contribution on biomarkers, and Nicole Carreau, Steve Hill, and Claire Chapman for their editorial assistance with the manuscript. Funding for this assistance was provided in part by Gentium SpA. This study was supported in part by research funding from Gentium SpA, by Orphan Drug Products Grant FDR-001667, and by the the Richard Corman Multiple Myeloma Research Fund. NR 52 TC 85 Z9 94 U1 0 U2 2 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 JUL PY 2010 VL 16 IS 7 BP 1005 EP 1017 DI 10.1016/j.bbmt.2010.02.009 PG 13 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 618PG UT WOS:000279367500013 PM 20167278 ER PT J AU Ballen, KK Cutler, C Yeap, BY McAfee, SL Dey, BR Attar, EC Chen, YB Haspel, RL Liney, D Koreth, J Ho, V Alyea, EP Soiffer, RJ Spitzer, TR Antin, JH AF Ballen, Karen K. Cutler, Corey Yeap, Beow Y. McAfee, Steven L. Dey, Bimalangshu R. Attar, Eyal C. Chen, Yi-Bin Haspel, Richard L. Liney, Deborah Koreth, John Ho, Vincent Alyea, Edwin P. Soiffer, Robert J. Spitzer, Thomas R. Antin, Joseph H. TI Donor-Derived Second Hematologic Malignancies after Cord Blood Transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Cord blood; Second cancer ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; SEVERE APLASTIC-ANEMIA; LYMPHOPROLIFERATIVE DISORDERS; SOLID CANCERS; SINGLE-INSTITUTE; EBV REACTIVATION; UNRELATED DONORS; COMPETING RISK AB Double umbilical cord blood transplantation (UCBT) with a reduced-intensity conditioning regimen is an effective strategy for adult patients without a matched donor. The risk of second malignancies in these patients has not yet been established, however. In the present study, 98 adults with a hematologic malignancy underwent double UCBT. Seventy patients received a reduced-intensity conditioning regimen of fludarabine 30 mg/m(2)/day for 6 days, melphalan 100 mg/m(2)/day for 1 day, and rabbit antithymocyte globulin 1.5 mg/kg/day for 4 days, and 28 patients received a myeloablative total body radiation containing conditioning regimen. Sixty-three patients received sirolimus-based graft-versus-host disease (GVHD) prophylaxis, and 35 patients received non sirolimus-based GVHD prophylaxis. The median patient age was 48 years (range, 19-67 years). Eighteen patients developed a second malignancy at a median of 134 days after transplantation. Sixteen patients had lymphoma, and 2 patients had myelodysplasic syndrome/myeloproliferative disorder (MDS/MPD). Sixteen of these second malignancies (both cases of MDS/MPD and 14 of the lymphomas) were donor-derived; the origins of the others were not determined. GVHD prophylaxis, HLA matching, primary disease, age, total nucleated cell dose, and CD34(+) cell dose were not associated with a higher rate of second malignancy. Second myelogenous malignancies of donor origin occur after double UCBT, suggesting that a search for donor origin should be performed in all patients with suspected relapse. Biol Blood Marrow Transplant 16: 1025-1031 (2010) (C) 2010 American Society for Blood and Marrow Transplantation C1 [Ballen, Karen K.] Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Boston, MA 02114 USA. Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. RP Ballen, KK (reprint author), Massachusetts Gen Hosp, Dept Med, Div Hematol Oncol, Suite 118, Boston, MA 02114 USA. EM Kballen@partners.org FU National Heart, Lung and Blood Institute [U54HL081030, PO1 CA142106]; Genzyme FX This work was supported in part by National Heart, Lung and Blood Institute Grant U54HL081030 and PO1 CA142106. Yi-Bin Chen is a Special Fellow in Clinical Research of the Leukemia Lymphoma Society.; Thomas R. Spitzer has received consulting fees from Genzyme. NR 44 TC 20 Z9 21 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 JUL PY 2010 VL 16 IS 7 BP 1025 EP 1031 DI 10.1016/j.bbmt.2010.02.014 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 618PG UT WOS:000279367500015 PM 20178854 ER PT J AU Mani, G Macias, CE Feldman, MD Marton, D Oh, S Agrawal, CM AF Mani, Gopinath Macias, Celia E. Feldman, Marc D. Marton, Denes Oh, Sunho Agrawal, C. Mauli TI Delivery of paclitaxel from cobalt-chromium alloy surfaces without polymeric carriers SO BIOMATERIALS LA English DT Article DE Drug-eluting stents; Drug delivery; Cobalt-Chromium alloy; Surface treatment; Surface modification ID SELF-ASSEMBLED MONOLAYERS; DRUG-ELUTING STENTS; BALLOON-EXPANDABLE-STENT; CORONARY-ARTERY DISEASE; IN-VITRO CONDITIONS; PORCINE MODEL; TITANIUM SURFACES; NEOINTIMAL HYPERPLASIA; INTIMAL HYPERPLASIA; RESTENOSIS AB Polymer-based carriers are commonly used to deliver drugs from stents. However, adverse responses to polymer coatings have raised serious concerns. This research is focused on delivering drugs from stents without using polymers or any carriers. Paclitaxel (PAT), an anti-restenotic drug, has strong adhesion towards a variety of material surfaces. In this study, we have utilized such natural adhesion property of PAT to attach these molecules directly to cobalt chromium (Co-Cr) alloy, an ultra-thin stent strut material. Four different groups of drug coated specimens were prepared by directly adding PAT to Co-Cr alloy surfaces: Group-A (PAT coated, unheated, and ethanol cleaned): Group-B (PAT coated, heat treated, and ethanol cleaned); Group-C (PAT coated, unheated, and not ethanol cleaned); and Group-D (PAT coated, heat treated and not ethanol cleaned). In vitro drug release of these specimens was investigated using high performance liquid chromatography. Groups A and B showed sustained PAT release for up to 56 days. A simple ethanol cleaning procedure after PAT deposition can remove the loosely bound drug crystals from the alloy surfaces and thereby allowing the remaining strongly bound drug molecules to be released at a sustained rate. The heat treatment after PAT coating further improved the stability of PAT on Co-Cr alloy and allowed the drug to be delivered at a much slower rate, especially during the initial 7 days. The specimens which were not cleaned in ethanol, Groups C and D, showed burst release. PAT coated Co-Cr alloy specimens were thoroughly characterized using scanning electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. These techniques were collectively useful in studying the morphology, distribution, and attachment of PAT molecules on Co-Cr alloy surfaces. Thus, this study suggests the potential for delivering paclitaxel from Co-Cr alloy surfaces without using any carriers. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Mani, Gopinath; Macias, Celia E.; Feldman, Marc D.; Marton, Denes; Oh, Sunho; Agrawal, C. Mauli] Univ Texas San Antonio, Dept Biomed Engn, Coll Engn, San Antonio, TX 78249 USA. [Feldman, Marc D.] 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. [Marton, Denes] Univ Texas Hlth Sci Ctr San Antonio, Dept Radiol, Sch Med, San Antonio, TX 78229 USA. RP Mani, G (reprint author), Univ Texas San Antonio, Dept Biomed Engn, Coll Engn, 1 UTSA Circle, San Antonio, TX 78249 USA. EM Gopinath.Mani@utsa.edu RI Marton, Denes/E-7759-2010 FU NIGMS NIH HHS [R25 GM060655] NR 66 TC 25 Z9 27 U1 0 U2 7 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 JUL PY 2010 VL 31 IS 20 BP 5372 EP 5384 DI 10.1016/j.biomaterials.2010.03.043 PG 13 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 608GP UT WOS:000278571800010 PM 20398928 ER PT J AU Guo, MY Heitjan, DF AF Guo, Mengye Heitjan, Daniel F. TI Multiplicity-calibrated Bayesian hypothesis tests SO BIOSTATISTICS LA English DT Article DE Bayes factor; Bonferroni inequality; Frequentist calibration; Multiplicity ID BONFERRONI PROCEDURE; CLINICAL-TRIALS AB When testing multiple hypotheses simultaneously, there is a need to adjust the levels of the individual tests to effect control of the family-wise error rate (FWER). Standard frequentist adjustments control the error rate but are typically both conservative and oblivious to prior information. We propose a Bayesian testing approach-multiplicity-calibrated Bayesian hypothesis testing-that sets individual critical values to reflect prior information while controlling the FWER via the Bonferroni inequality. If the prior information is specified correctly, in the sense that those null hypotheses considered most likely to be false in fact are false, the power of our method is substantially greater than that of standard frequentist approaches. We illustrate our method using data from a pharmacogenetic trial and a preclinical cancer study. We demonstrate its error rate control and power advantage by simulation. C1 [Guo, Mengye] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02446 USA. [Heitjan, Daniel F.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Guo, MY (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02446 USA. EM mengye@jimmy.harvard.edu FU United States Public Health Service [P50 CA084718, R01 CA063562, R01 CA116723, P20 RR020741] FX The United States Public Health Service (P50 CA084718 from the National Cancer Institute and National Institute on Drug Abuse; R01 CA063562 and R01 CA116723 from the National Cancer Institute; P20 RR020741 from the National Center for Research Resources). NR 27 TC 3 Z9 3 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 EI 1468-4357 J9 BIOSTATISTICS JI Biostatistics PD JUL PY 2010 VL 11 IS 3 BP 473 EP 483 DI 10.1093/biostatistics/kxq012 PG 11 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 609WQ UT WOS:000278689300016 PM 20212321 ER PT J AU Schmidt, BJ Lin-Schmidt, X Chamberlin, A Salehi-Ashtiani, K Papin, JA AF Schmidt, Brian J. Lin-Schmidt, Xiefan Chamberlin, Austin Salehi-Ashtiani, Kourosh Papin, Jason A. TI Metabolic systems analysis to advance algal biotechnology SO BIOTECHNOLOGY JOURNAL LA English DT Review DE Algae; Biofuels; Chlamydomonas reinhardtii; Flux balance analysis; Metabolic network ID ROBUST SYNTHETIC BIOLOGY; FLUX BALANCE ANALYSIS; IN-SILICO; CHLAMYDOMONAS-REINHARDTII; ESCHERICHIA-COLI; MANNHEIMIA-SUCCINICIPRODUCENS; SACCHAROMYCES-CEREVISIAE; BIOETHANOL PRODUCTION; MITOCHONDRIAL-DNA; GENOME SEQUENCE AB Algal fuel sources promise unsurpassed yields in a carbon neutral manner that minimizes resource competition between agriculture and fuel crops. Many challenges must be addressed before algal biofuels can be accepted as a component of the fossil fuel replacement strategy. One significant challenge is that the cost of algal fuel production must become competitive with existing fuel alternatives. Algal biofuel production presents the opportunity to fine-tune microbial metabolic machinery for an optimal blend of biomass constituents and desired fuel molecules. Genome-scale model-driven algal metabolic design promises to facilitate both goals by directing the utilization of metabolites in the complex, interconnected metabolic networks to optimize production of the compounds of interest. Network analysis can direct microbial development efforts towards successful strategies and enable quantitative fine-tuning of the network for optimal product yields while maintaining the robustness of the production microbe. Metabolic modeling yields insights into microbial function, guides experiments by generating testable hypotheses, and enables the refinement of knowledge on the specific organism. While the application of such analytical approaches to algal systems is limited to date, metabolic network analysis can improve understanding of algal metabolic systems and play an important role in expediting the adoption of new biofuel technologies. C1 [Schmidt, Brian J.; Lin-Schmidt, Xiefan; Chamberlin, Austin; Papin, Jason A.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22908 USA. [Salehi-Ashtiani, Kourosh] Harvard Univ, Sch Med, CCSB, Dept Canc Biol, Boston, MA USA. [Salehi-Ashtiani, Kourosh] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Salehi-Ashtiani, Kourosh] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Papin, JA (reprint author), Univ Virginia, Dept Biomed Engn, Box 800759, Charlottesville, VA 22908 USA. EM kourosh_salehi-ashtiani@dfci.harvard.edu; papin@virginia.edu OI Salehi-Ashtiani, Kourosh/0000-0002-6521-5243; Papin, Jason/0000-0002-2769-5805 FU Office of Science (Biological and Environmental Research), US Department of Energy [DE-FG02-07ER64496] FX We would like to thank Ani Manichaikul for insightful discussions into the applications of microalgae-derived biotechnologies. This work was supported by a grant from the Office of Science (Biological and Environmental Research), US Department of Energy, DE-FG02-07ER64496, to J.P. and K.S.-A. NR 91 TC 15 Z9 15 U1 0 U2 24 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1860-6768 J9 BIOTECHNOL J JI Biotechnol. J. PD JUL PY 2010 VL 5 IS 7 BP 660 EP 670 DI 10.1002/biot.201000129 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 634YP UT WOS:000280622500003 PM 20665641 ER PT J AU Abraham, S Sheridan, SD Miller, B Rao, RR AF Abraham, Sheena Sheridan, Steven D. Miller, Bradley Rao, Raj R. TI Stable Propagation of Human Embryonic and Induced Pluripotent Stem Cells on Decellularized Human Substrates SO BIOTECHNOLOGY PROGRESS LA English DT Article DE human pluripotent stem cells; feeder free; acellular substrates ID REAL-TIME PCR; IN-VITRO; UNDIFFERENTIATED GROWTH; HUMAN BLASTOCYSTS; CULTURE-SYSTEM; HUMAN FEEDERS; LINES; DIFFERENTIATION; FIBROBLASTS; DERIVATION AB Human pluripotent stem cells (hPSCs) that include human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) have gained enormous interest as potential sources for regenerative biomedical therapies and model systems for studying early development. Traditionally, mouse embryonic fibroblasts have been used as a supportive feeder layer for the sustained propagation of hPSCs. However, the use of nonhuman-derived feeders presents concerns about the possibility of xenogenic contamination, labor intensiveness, and variability in experimental results in hPSC cultures. Toward addressing some of these concerns, we report the propagation of three different hPSCs on feeder-free extracellular matrix (ECM)-based substrates derived from human fibroblasts. hPSCs propagated in this setting were indistinguishable by multiple criteria, including colony morphology, expression of pluripotency protein markers, trilineage in vitro differentiation, and gene expression patterns, from hPSCs cultured directly on a fibroblast feeder layer. Further, hPSCs maintained a normal karyotype when analyzed after 15 passages in this setting. Development of this ECM-based culture system is a significant advance in hPSC propagation methods as it could serve as a critical component in the development of humanized propagation systems for the production of stable hPSCs and its derivatives for research and therapeutic applications. (C) 2010 American Institute of Chemical Engineers Biotechnol. Prog., 26: 1126-1134, 2010 C1 [Abraham, Sheena; Rao, Raj R.] Virginia Commonwealth Univ, Dept Chem & Life Sci Engn, Richmond, VA 23284 USA. [Sheridan, Steven D.] Harvard Univ, Sch Med, Ctr Human Genet Res, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Miller, Bradley] Univ Virginia, Dept Pathol, Charlottesville, VA 22908 USA. RP Rao, RR (reprint author), Virginia Commonwealth Univ, Dept Chem & Life Sci Engn, Richmond, VA 23284 USA. EM rrrao@vcu.edu FU NSF [0744556]; NIH [T15-HL074303]; VCU Graduate School FX This work was supported in part by funding provided by NSF-CAREER 0744556 (RRR), NIH T15-HL074303 (RRR), and a research grant from the VCU Graduate School (SA). Karyotypic analyses were conducted by Cell Line Genetics (Madison, WI). The authors also thank Dr. Shawn Holt and Dr. Kristoffer Valerie for providing the immortalized human foreskin fibroblasts and immortalized human dermal fibroblasts used in this study. NR 31 TC 8 Z9 8 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 8756-7938 J9 BIOTECHNOL PROGR JI Biotechnol. Prog. PD JUL-AUG PY 2010 VL 26 IS 4 BP 1126 EP 1134 DI 10.1002/btpr.412 PG 9 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 640IP UT WOS:000281045100026 PM 20730767 ER PT J AU Sonpavde, G Sternberg, CN AF Sonpavde, Guru Sternberg, Cora N. TI Neoadjuvant systemic therapy for urological malignancies SO BJU INTERNATIONAL LA English DT Review DE Prostate cancer; bladder cancer; renal cell carcinoma; neoadjuvant therapy; surgery ID RENAL-CELL CARCINOMA; LOCALIZED PROSTATE-CANCER; PHASE-II TRIAL; GEMCITABINE PLUS CISPLATIN; INVASIVE BLADDER-CANCER; ANDROGEN-DEPRIVATION THERAPY; RANDOMIZED CONTROLLED-TRIAL; INDIVIDUAL PATIENT DATA; POSITIVE BREAST-CANCER; RADICAL PROSTATECTOMY AB Neoadjuvant cisplatin-based combined chemotherapy is an established standard for muscle-invasive bladder cancer and pathological complete remission is an excellent intermediate surrogate endpoint for survival. Phase III trials are ongoing to elucidate the role of neoadjuvant combined androgen deprivation and docetaxel-based chemotherapy for localized high-risk prostate cancer. Neoadjuvant therapy with biological agents targeting angiogenesis preceding cytoreductive nephrectomy for metastatic renal cell carcinoma is a novel approach, although ongoing randomized trials are validating this paradigm and attempting to establish the timing and necessity of cytoreductive nephrectomy. Neoadjuvant trials provide a window of opportunity to evaluate and screen novel agents for biological activity by using brief therapy preceding surgery and provide a rationale to further develop the most promising agents in larger trials. The neoadjuvant therapy approach followed by surgery is acceptable and feasible with a wide array of agents in urological cancers and provides a paradigm for evaluating the activity, mechanism of action and resistance to new treatments. Urological cancers are initially characterized by localized presentation in the vast majority of cases, coupled with a substantial risk of distant relapses following surgical resection. Therefore, the paradigm of neoadjuvant therapy preceding surgery may expedite the development of novel systemic agents and improve outcomes. C1 [Sternberg, Cora N.] San Camillo Forlanini Hosp, Dept Med Oncol, Rome, Italy. [Sonpavde, Guru] Baylor Coll Med, Sect Med Oncol, Dept Med, Houston, TX 77030 USA. [Sonpavde, Guru] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Sternberg, CN (reprint author), San Camillo & Forlanini Hosp, Dept Med Oncol, Nuovo Padigl 4,Circonvallaz Gianicolense 87, I-00152 Rome, Italy. EM csternberg@scamilloforlanini.rm.it FU Eli Lilly; Pfizer; Bristol-Myers Squibb; Cytogen; AstraZeneca; Sanofi-Aventis; Cougar Biotech FX Guru Sonpavde receives research support from Eli Lilly, Pfizer, Bristol-Myers Squibb, Cytogen and AstraZeneca and is on the speakers' bureau for Pfizer, Novartis and Sanofi-Aventis.; Cora N. Sternberg has received research support from Eli Lilly, Sanofi-Aventis, Cougar Biotech, and is on the advisory board/consultant for Bayer, Novartis, GlaxoSmithKline and Pfizer. NR 131 TC 16 Z9 20 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 EI 1464-410X J9 BJU INT JI BJU Int. PD JUL PY 2010 VL 106 IS 1 BP 6 EP 22 DI 10.1111/j.1464-410X.2010.09425.x PG 17 WC Urology & Nephrology SC Urology & Nephrology GA 607PA UT WOS:000278516600003 PM 20553475 ER PT J AU Schnabel, RB Baumert, J Barbalic, M Dupuis, J Ellinor, PT Durda, P Dehghan, A Bis, JC Illig, T Morrison, AC Jenny, NS Keaney, JF Gieger, C Tilley, C Yamamoto, JF Khuseyinova, N Heiss, G Doyle, M Blankenberg, S Herder, C Walston, JD Zhu, YY Vasan, RS Klopp, N Boerwinkle, E Larson, MG Psaty, BM Peters, A Ballantyne, CM Witteman, JCM Hoogeveen, RC Benjamin, EJ Koenig, W Tracy, RP AF Schnabel, Renate B. Baumert, Jens Barbalic, Maja Dupuis, Josee Ellinor, Patrick T. Durda, Peter Dehghan, Abbas Bis, Joshua C. Illig, Thomas Morrison, Alanna C. Jenny, Nancy S. Keaney, John F., Jr. Gieger, Christian Tilley, Cathy Yamamoto, Jennifer F. Khuseyinova, Natalie Heiss, Gerardo Doyle, Margaret Blankenberg, Stefan Herder, Christian Walston, Jeremy D. Zhu, Yanyan Vasan, Ramachandran S. Klopp, Norman Boerwinkle, Eric Larson, Martin G. Psaty, Bruce M. Peters, Annette Ballantyne, Christie M. Witteman, Jacqueline C. M. Hoogeveen, Ron C. Benjamin, Emelia J. Koenig, Wolfgang Tracy, Russell P. TI Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators SO BLOOD LA English DT Article ID GENOME-WIDE ASSOCIATION; BLOOD-GROUP; DISEASE; ANTIGEN/RECEPTOR; CELLS; GENE; ATHEROSCLEROSIS; CCR2; IDENTIFICATION; RECRUITMENT AB To identify the genetic basis of circulating concentrations of monocyte chemoattractant protein-1 (MCP-1), we conducted genome-wide association analyses for MCP-1 in 3 independent cohorts (n = 9598). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism, rs12075 (Asp42Gly) in DARC, the gene for Duffy antigen receptor for chemokines, a known vascular reservoir of proinflammatory cytokines (minor allele frequency, 45.6%; P < 1.0 * 10(-323)). This association was supported by family-based genetic linkage at a locus encompassing the DARC gene (genome-wide P = 8.0 * 10(-13)). Asp42Gly accounted for approximately 20% of the variability in serum MCP-1 concentrations and also was associated with serum concentrations of interleukin-8 and RANTES. While exploring a lack of association between this polymorphism and EDTA plasma MCP-1 concentrations (P = .82), we determined that both clotting and exogenous heparan sulfate (unfractionated heparin) released substantial amounts of MCP-1 from Darc. Quantitative immuno-flow cytometry failed to identify meaningful Asp42Gly-associated differences in Darc expression, suggesting that a functional change is responsible for the differential cytokine binding. We conclude that Asp42Gly is a major regulator of erythrocyte Darc-mediated cytokine binding and thereby the circulating concentrations of several proinflammatory cytokines. We have also identified for the first time 2 mechanisms for the release of reservoir chemokines with possible clinical implications. (Blood. 2010; 115(26):5289-5299) C1 [Benjamin, Emelia J.] Boston Univ, Sch Med, Framingham Heart Study,Dept Med, Whitaker Cardiovasc Inst,Sect Prevent Med, Framingham, MA 01702 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Dept Med,Sect Cardiol, Framingham, MA 01702 USA. [Schnabel, Renate B.; Dupuis, Josee; Keaney, John F., Jr.; Yamamoto, Jennifer F.; Vasan, Ramachandran S.; Larson, Martin G.; Benjamin, Emelia J.] NHLBI, Boston, MA USA. [Schnabel, Renate B.; Blankenberg, Stefan] Johannes Gutenberg Univ Mainz, Gutenberg Heart Study, Mainz, Germany. [Baumert, Jens; Illig, Thomas; Gieger, Christian; Klopp, Norman; Peters, Annette] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany. [Barbalic, Maja; Morrison, Alanna C.; Heiss, Gerardo; Boerwinkle, Eric; Ballantyne, Christie M.; Hoogeveen, Ron C.] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Barbalic, Maja; Morrison, Alanna C.; Heiss, Gerardo; Boerwinkle, Eric; Ballantyne, Christie M.; Hoogeveen, Ron C.] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. [Dupuis, Josee; Yamamoto, Jennifer F.; Zhu, Yanyan] Boston Univ, Sch Publ Hlth, Dept Biostat, Framingham, MA 01702 USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Durda, Peter; Jenny, Nancy S.; Tilley, Cathy; Doyle, Margaret; Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Dehghan, Abbas; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Khuseyinova, Natalie; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89081 Ulm, Germany. [Herder, Christian] Univ Dusseldorf, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany. [Walston, Jeremy D.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Walston, Jeremy D.] Johns Hopkins Univ, Johns Hopkins Geriatr Ctr, Baltimore, MD USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Grp Hlth, Seattle, WA 98101 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Framingham, MA 01702 USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Framingham Heart Study,Dept Med, Whitaker Cardiovasc Inst,Sect Prevent Med, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM ronh@bcm.tmc.edu; emelia@bu.edu; wolfgang.koenig@uniklinik-ulm.de; russell.tracy@uvm.edu RI Peters, Annette/A-6117-2011; Schnabel, Renate/F-6527-2014; OI Dupuis, Josee/0000-0003-2871-3603; Benjamin, Emelia/0000-0003-4076-2336; Gieger, Christian/0000-0001-6986-9554; Dehghan, Abbas/0000-0001-6403-016X; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU NCRR NIH HHS [1S10RR163736-01A1, UL1RR025005]; NHGRI NIH HHS [U01HG004402]; NHLBI NIH HHS [2K24HL04334, HL064753, HL076784, HL093328, K24 HL105780, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01 HL077449, R01 HL104156, R01HL086694, R01HL087641, R01HL59367]; NIA NIH HHS [AG028321]; NIDA NIH HHS [R21 DA027021]; NIDDK NIH HHS [DK080739]; NINDS NIH HHS [6R01-NS 17950] NR 46 TC 55 Z9 55 U1 0 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 1 PY 2010 VL 115 IS 26 BP 5289 EP 5299 DI 10.1182/blood-2009-05-221382 PG 11 WC Hematology SC Hematology GA 619MV UT WOS:000279435200005 PM 20040767 ER PT J AU Benita, Y Cao, ZF Giallourakis, C Li, C Gardet, A Xavier, RJ AF Benita, Yair Cao, Zhifang Giallourakis, Cosmas Li, Chun Gardet, Agnes Xavier, Ramnik J. TI Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; MICROARRAY EXPERIMENTS; POSITIVE SELECTION; EXPRESSION; CD4; IDENTIFICATION; COMMITMENT; LYMPHOMA; HYBRIDIZATION; SUPERFAMILY AB The identification of transcriptional regulatory networks, which control tissue-specific development and function, is of central importance to the understanding of lymphocyte biology. To decipher transcriptional networks in T-cell development and differentiation we developed a browsable expression atlas and applied a novel quantitative method to define gene sets most specific to each of the represented cell subsets and tissues. Using this system, body atlas size datasets can be used to examine gene enrichment profiles from a cell/tissue perspective rather than gene perspective, thereby identifying highly enriched genes within a cell type, which are often key to cellular differentiation and function. A systems analysis of transcriptional regulators within T cells during different phases of development and differentiation resulted in the identification of known key regulators and uncharacterized coexpressed regulators. ZBTB25, a BTB-POZ family transcription factor, was identified as a highly T cell-enriched transcription factor. We provide evidence that ZBTB25 functions as a negative regulator of nuclear factor of activated T cells (NF-AT) activation, such that RNA interference mediated knockdown resulted in enhanced activation of target genes. Together, these findings suggest a novel mechanism for NF-AT mediated gene expression and the compendium of expression data provides a quantitative platform to drive exploration of gene expression across a wide range of cell/tissue types. (Blood. 2010; 115(26):5376-5384) C1 [Benita, Yair; Cao, Zhifang; Giallourakis, Cosmas; Li, Chun; Gardet, Agnes; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Benita, Yair; Cao, Zhifang; Giallourakis, Cosmas; Li, Chun; Gardet, Agnes; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA USA. [Giallourakis, Cosmas; Gardet, Agnes; Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Giallourakis, Cosmas; Gardet, Agnes; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. [Xavier, Ramnik J.] Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA USA. RP Xavier, RJ (reprint author), Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, 185 Cambridge St, Boston, MA 02114 USA. EM xavier@molbio.mgh.harvard.edu RI Benita, Yair/E-3094-2012 FU National Institutes of Health [AI062773, DK83756, DK043351] FX R.J.X. is supported by National Institutes of Health grants AI062773, DK83756, and DK043351. A.G. is a fellow of the Crohn's and Colitis Foundation of America. NR 42 TC 62 Z9 64 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 JUL 1 PY 2010 VL 115 IS 26 BP 5376 EP 5384 DI 10.1182/blood-2010-01-263855 PG 9 WC Hematology SC Hematology GA 619MV UT WOS:000279435200014 PM 20410506 ER PT J AU Prabhala, RH Pelluru, D Fulciniti, M Prabhala, HK Nanjappa, P Song, WH Pai, C Amin, S Tai, YT Richardson, PG Ghobrial, IM Treon, SP Daley, JF Anderson, KC Kutok, JL Munshi, NC AF Prabhala, Rao H. Pelluru, Dheeraj Fulciniti, Mariateresa Prabhala, Harsha K. Nanjappa, Puru Song, Weihua Pai, Christine Amin, Samir Tai, Yu-Tzu Richardson, Paul G. Ghobrial, Irene M. Treon, Steven P. Daley, John F. Anderson, Kenneth C. Kutok, Jeffery L. Munshi, Nikhil C. TI Elevated IL-17 produced by T(H)17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma SO BLOOD LA English DT Article ID T-HELPER-CELLS; ROR-GAMMA-T; DENDRITIC CELLS; INNATE IMMUNITY; HOST-DEFENSE; BONE-MARROW; FACTOR-BETA; TH17 CELLS; INTERLEUKIN-17; RECEPTOR AB Elevated cytokines in bone marrow (BM) micro-environment (interleukin-6 [IL-6], transforming growth factor-beta [TGF-beta], and IL-1 beta) may play an important role in observed immune dysfunction in multiple myeloma (MM). As IL-6 and TGF-beta are important for the generation of T-helper 17 (T(H)17) cells, we evaluated and observed a significantly elevated baseline and induced frequency of T(H)17 cells in peripheral blood mononuclear cells (PBMCs) and BM mononuclear cells (BMMCs) from MM patients compared with healthy donors. We observed significant increase in levels of serum IL-17, IL-21, IL-22, and IL-23 in blood and BM in MM compared with healthy donors. We also observed that myeloma PBMCs after T(H)17 polarization significantly induced IL-1 alpha, IL-13, IL-17, and IL-23 production compared with healthy donor PBMCs. We next observed that IL-17 promotes myeloma cell growth and colony formation via IL-17 receptor, adhesion to bone marrow stromal cells (BMSCs) as well as increased growth in vivo in murine xenograft model of human MM. Additionally, we have observed that combination of IL-17 and IL-22 significantly inhibited the production of T(H)1-mediated cytokines, including interferon-gamma (IFN-gamma), by healthy donor PBMCs. In conclusion, IL-17-producing T(H)17 cells play an important role in MM pathobiology and may be an important therapeutic target for anti-MM activity and to improve immune function. (Blood. 2010; 115(26): 5385-5392) C1 [Prabhala, Rao H.; Pelluru, Dheeraj; Fulciniti, Mariateresa; Nanjappa, Puru; Song, Weihua; Amin, Samir; Tai, Yu-Tzu; Richardson, Paul G.; Ghobrial, Irene M.; Treon, Steven P.; Daley, John F.; Anderson, Kenneth C.; Munshi, Nikhil C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Prabhala, Rao H.; Pai, Christine; Munshi, Nikhil C.] Vet Adm Boston Healthcare Syst, W Roxbury, MA USA. [Prabhala, Rao H.; Anderson, Kenneth C.; Kutok, Jeffery L.; Munshi, Nikhil C.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Prabhala, Harsha K.] Univ Virginia, Sch Med, MD PhD Program, Charlottesville, VA 22908 USA. RP Munshi, NC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM rao_prabhala@dfci.harvard.edu; nikhil_munshi@dfci.harvard.edu OI Amin, Samir/0000-0002-3207-9505 FU Department of Veterans Affairs; National Institutes of Health [RO1-124929, P50-100707, PO1-78 378]; Multiple Myeloma Research Foundation FX This work was supported by the Department of Veterans Affairs Merit Review Award (N.C.M.) and National Institutes of Health grants RO1-124929 (N.C.M.), P50-100707, and PO1-78 378 (N.C.M., K.C.A.). This work was also supported by Multiple Myeloma Research Foundation awards to R.H.P. NR 50 TC 119 Z9 141 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 1 PY 2010 VL 115 IS 26 BP 5385 EP 5392 DI 10.1182/blood-2009-10-246660 PG 8 WC Hematology SC Hematology GA 619MV UT WOS:000279435200015 PM 20395418 ER PT J AU Lopaciuk, S Windyga, J Watala, CW Bykowska, K Pietrucha, T Kwiecinski, H Czlonkowska, A Kuczynska-Zardzewialy, A Jackson, AA Carew, JA Bauer, KA AF Lopaciuk, Stanislaw Windyga, Jerzy Watala, Cezary W. Bykowska, Ksenia Pietrucha, Tadeusz Kwiecinski, Hubert Czlonkowska, Anna Kuczynska-Zardzewialy, Arleta Jackson, Audrey A. Carew, Josephine A. Bauer, Kenneth A. TI Polymorphisms in the factor VII gene and ischemic stroke in young adults SO BLOOD COAGULATION & FIBRINOLYSIS LA English DT Article DE coagulation factors; polymorphisms; thrombosis ID COAGULATION-FACTOR-VII; CORONARY-HEART-DISEASE; TISSUE FACTOR; MYOCARDIAL-INFARCTION; INSERTION POLYMORPHISM; 3'-UNTRANSLATED REGION; PROMOTER REGION; FVII GENE; IN-VITRO; PLASMA AB Polymorphic configurations of the coagulation factor VII gene (F7) are associated with plasma levels of FVII antigen (FVII:Ag) and FVII coagulant activity (FVII:C). Our aim was to determine whether F7 polymorphisms influence risk of ischemic stroke in young adults. One hundred and fifty survivors of ischemic stroke before the age of 45 and an equal number of age and sex-matched controls were genotyped for five F7 polymorphisms: the -A670C transversion, -323 decanucleotide insertion (P + 10), the number (which varies between five and eight) of a 37 base pair repeat polymorphisms in intron 7 (IVS7), amino acid substitution R353Q, and R154AA insertion. 353Q, P + 10 and R154AA were demonstrated to associate with significantly decreased plasma FVII: Ag, whereas -670C and IVS7 seven or higher were associated with a tendency towards increased plasma FVII: Ag. The former three polymorphisms were significantly more common in control individuals than in patients, whereas the latter two were significantly more common in patients than in control individuals. The multiple logistic regression analysis revealed that two F7 polymorphisms, S670C and IVS7 seven or higher, are independent risk factors for ischemic stroke in young adult patients. Blood Coagul Fibrinolysis 21:442-447 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Jackson, Audrey A.; Carew, Josephine A.; Bauer, Kenneth A.] VA Boston Healthcare Syst, W Roxbury, MA USA. [Lopaciuk, Stanislaw; Windyga, Jerzy; Bykowska, Ksenia] Inst Hematol & Blood Transfus, Dept Haemostasis & Thrombosis, Warsaw, Poland. [Watala, Cezary W.] Med Univ Lodz, Dept Haemostasis & Haemostat Disorders, Lodz, Poland. [Pietrucha, Tadeusz] Med Univ Lodz, Lab Med Biotechnol, Lodz, Poland. [Kwiecinski, Hubert] Med Univ, Dept Neurol, Warsaw, Poland. [Czlonkowska, Anna] Wolski Hosp, Inst Psychiat & Neurol, Dept Neurol 2, Warsaw, Poland. [Kuczynska-Zardzewialy, Arleta] Wolski Hosp, Dept Neurol, Warsaw, Poland. [Kuczynska-Zardzewialy, Arleta] Wolski Hosp, Stroke Unit, Warsaw, Poland. RP Bauer, KA (reprint author), VA Boston Healthcare Syst 151, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM kbauer@bidmc.harvard.edu FU Institute of Hematology and Transfusion Medicine, Warsaw; Department of Veterans Affairs FX The work was supported by the Institute of Hematology and Transfusion Medicine, Warsaw and by a Department of Veterans Affairs Merit Research Service Award to J.A.C. NR 37 TC 11 Z9 13 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-5235 J9 BLOOD COAGUL FIBRIN JI Blood Coagul. Fibrinolysis PD JUL PY 2010 VL 21 IS 5 BP 442 EP 447 DI 10.1097/MBC.0b013e3283389513 PG 6 WC Hematology SC Hematology GA 619AZ UT WOS:000279400400010 PM 20453637 ER PT J AU Brown, J Lipton, A Cook, R Michaelson, D Coleman, R Saad, F AF Brown, J. Lipton, A. Cook, R. Michaelson, D. Coleman, R. Saad, F. TI Correlations between N-telopeptide of type I collagen with survival and fractures in patients with metastatic bone disease from renal cell carcinoma SO BONE LA English DT Meeting Abstract CT 9th International Meeting on Cancer Induced Bone Disease CY OCT 28-31, 2009 CL Arlington, VA C1 [Brown, J.] Univ Leeds, Leeds, W Yorkshire, England. [Lipton, A.] Penn State Milton S Hershey Med Ctr, Hershey, PA USA. [Cook, R.] Univ Waterloo, Waterloo, ON N2L 3G1, Canada. [Michaelson, D.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Coleman, R.] Univ Sheffield, Weston Pk Hosp, Sheffield, S Yorkshire, England. [Saad, F.] Univ Montreal, Ctr Hosp, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 2010 VL 47 SU 2 BP S312 EP S312 DI 10.1016/j.bone.2010.01.279 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 632SV UT WOS:000280449200099 ER PT J AU Cackowski, FC Anderson, JL Choksi, RJ Patrene, KD Ross, FP Stolz, B Shapiro, SD Windle, JJ Blair, HC Roodman, GD AF Cackowski, F. C. Anderson, J. L. Choksi, R. J. Patrene, K. D. Ross, F. P. Stolz, B. Shapiro, S. D. Windle, J. J. Blair, H. C. Roodman, G. D. TI PTHrP Stimulates Angiogenesis by Means of Osteoclast Derived MMP-9 SO BONE LA English DT Meeting Abstract CT 9th International Meeting on Cancer Induced Bone Disease CY OCT 28-31, 2009 CL Arlington, VA ID HORMONE-RELATED PEPTIDE; PROTEIN C1 [Cackowski, F. C.; Anderson, J. L.; Choksi, R. J.; Patrene, K. D.] Univ Pittsburgh, Dept Med, Div Hematol Oncol, Pittsburgh, PA USA. [Ross, F. P.] Washington Univ, Dept Pathol & Immunol, St Louis, MO USA. [Stolz, B.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA USA. [Shapiro, S. D.] Univ Pittsburgh, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA USA. [Windle, J. J.] Virginia Commonwealth Univ, Richmond, VA USA. [Blair, H. C.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA. [Roodman, G. D.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 2010 VL 47 SU 2 BP S297 EP S298 DI 10.1016/j.bone.2010.01.244 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 632SV UT WOS:000280449200070 ER PT J AU D'Souza, S Shiozawa, Y Galson, DL Taichman, R Roodman, G AF D'Souza, S. Shiozawa, Y. Galson, D. L. Taichman, R. Roodman, G. TI Annexin II and Annexin II Receptor Interactions Enhance Multiple Myeloma Growth in the Bone Marrow Microenvironment SO BONE LA English DT Meeting Abstract CT 9th International Meeting on Cancer Induced Bone Disease CY OCT 28-31, 2009 CL Arlington, VA C1 [D'Souza, S.; Galson, D. L.; Roodman, G.] Univ Pittsburgh, Sch Med, Dept Med, Bone Biol Ctr,UPMC, Pittsburgh, PA USA. [D'Souza, S.; Galson, D. L.; Roodman, G.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Shiozawa, Y.; Taichman, R.] Univ Michigan, Sch Dent, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 2010 VL 47 SU 2 BP S284 EP S285 DI 10.1016/j.bone.2010.01.212 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 632SV UT WOS:000280449200046 ER PT J AU D'Souza, S Del Prete, D Sammut, B Esteve, F Yu, S Xiao, G Galson, DL Roodman, G AF D'Souza, S. Del Prete, D. Sammut, B. Esteve, F. Yu, S. Xiao, G. Galson, D. L. Roodman, G. TI Multiple myeloma cell induction of Gfi-1 in stromal cells suppresses osteoblast differentiation in patients with myeloma SO BONE LA English DT Meeting Abstract CT 9th International Meeting on Cancer Induced Bone Disease CY OCT 28-31, 2009 CL Arlington, VA C1 Univ Pittsburgh, Dept Med, Bone Biol Ctr, UPMC,Sch Med, Pittsburgh, PA USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 2010 VL 47 SU 2 BP S284 EP S284 DI 10.1016/j.bone.2010.01.211 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 632SV UT WOS:000280449200045 ER PT J AU Hatoum, HT Lin, S Smith, MR Guo, A Lipton, A AF Hatoum, H. T. Lin, S. Smith, M. R. Guo, A. Lipton, A. TI Timing of zoledronic acid treatment impacts risk and frequency of skeletal complications and follow-up duration in prostate cancer patients with bone metastasis SO BONE LA English DT Meeting Abstract CT 9th International Meeting on Cancer Induced Bone Disease CY OCT 28-31, 2009 CL Arlington, VA C1 [Hatoum, H. T.] Univ Illinois, Parmacoecon Ctr, Chicago, IL USA. [Smith, M. R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Guo, A.] Novartis Pharmaceut, E Hanover, NJ USA. [Lipton, A.] Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Hershey, PA 17033 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD JUL PY 2010 VL 47 SU 2 BP S309 EP S309 DI 10.1016/j.bone.2010.01.269 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 632SV UT WOS:000280449200093 ER PT J AU Upadhyay, J Maleki, N Potter, J Elman, I Rudrauf, D Knudsen, J Wallin, D Pendse, G McDonald, L Griffin, M Anderson, J Nutile, L Renshaw, P Weiss, R Becerra, L Borsook, D AF Upadhyay, Jaymin Maleki, Nasim Potter, Jennifer Elman, Igor Rudrauf, David Knudsen, Jaime Wallin, Diana Pendse, Gautam McDonald, Leah Griffin, Margaret Anderson, Julie Nutile, Lauren Renshaw, Perry Weiss, Roger Becerra, Lino Borsook, David TI Alterations in brain structure and functional connectivity in prescription opioid-dependent patients SO BRAIN LA English DT Article DE prescription opioids; chronic pain; addiction; functional connectivity; morphology ID HUMAN CEREBRAL-CORTEX; DRUG-ADDICTION; GEOMETRICALLY ACCURATE; METHADONE-MAINTENANCE; COGNITIVE PERFORMANCE; SYNAPTIC PLASTICITY; SPATIAL STATISTICS; NUCLEUS-ACCUMBENS; AMYGDALA VOLUME; MRI AB A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients [(n = 10); from a larger study on prescription opioid dependent patients (n = 133)] and matched healthy individuals (n = 10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function. C1 [Upadhyay, Jaymin; Maleki, Nasim; Knudsen, Jaime; Wallin, Diana; Pendse, Gautam; Anderson, Julie; Nutile, Lauren; Becerra, Lino; Borsook, David] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat,PAIN Grp,Brain Imaging Ctr, Belmont, MA 02478 USA. [Potter, Jennifer; McDonald, Leah; Griffin, Margaret; Weiss, Roger] Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat,Div Alcohol & Drug Abuse, Belmont, MA 02478 USA. [Elman, Igor] Harvard Univ, McLean Hosp, Sch Med, Clin Psychopathol Lab, Belmont, MA 02478 USA. [Rudrauf, David] Univ Iowa, Lab Brain Imaging & Cognit Neurosci, Iowa City, IA 52242 USA. [Renshaw, Perry] Univ Utah, Med Ctr, Inst Brain, Salt Lake City, UT 84112 USA. [Becerra, Lino; Borsook, David] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Becerra, Lino; Borsook, David] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Borsook, D (reprint author), Harvard Univ, McLean Hosp, Sch Med, Dept Psychiat,PAIN Grp,Brain Imaging Ctr, 115 Mill St, Belmont, MA 02478 USA. EM dborsook@partners.org RI Potter, Jennifer/C-6720-2008; OI Potter, Jennifer/0000-0002-7250-4422; Wallin, Diana/0000-0003-4244-0314 FU National Institute on Drug Abuse [U10DA015831, K24 DA022288]; L Herlands Fund; National Institute of Neurological Disorders and Stroke [K24 NS064050] FX Supplemental Grant from National Institute on Drug Abuse U10DA015831 (R. W.); National Institute on Drug Abuse Grant K24 DA022288 (R. W.); L Herlands Fund to D. B. and L. B. (P.A.I.N. Group) and National Institute of Neurological Disorders and Stroke K24 NS064050 (D. B.). NR 87 TC 102 Z9 108 U1 3 U2 21 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD JUL PY 2010 VL 133 BP 2098 EP 2114 DI 10.1093/brain/awq138 PN 7 PG 17 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 620BL UT WOS:000279473900021 PM 20558415 ER PT J AU Propper, RE O'Donnell, LJ Whalen, S Tie, YM Norton, IH Suarez, RO Zollei, L Radmanesh, A Golby, AJ AF Propper, Ruth E. O'Donnell, Lauren J. Whalen, Stephen Tie, Yanmei Norton, Isaiah H. Suarez, Ralph O. Zollei, Lilla Radmanesh, Alireza Golby, Alexandra J. TI A combined fMRI and DTI examination of functional language lateralization and arcuate fasciculus structure: Effects of degree versus direction of hand preference SO BRAIN AND COGNITION LA English DT Article DE Handedness; Language; Arcuate fasciculus; fMRI; DTI ID EYE-MOVEMENTS ENHANCE; PLANUM TEMPORALE; PARS TRIANGULARIS; CORPUS-CALLOSUM; FIBER DENSITY; HUMAN BRAIN; HANDEDNESS; MRI; ASYMMETRY; DOMINANCE AB The present study examined the relationship between hand preference degree and direction, functional language lateralization in Broca's and Wernicke's areas, and structural measures of the arcuate fasciculus. Results revealed an effect of degree of hand preference on arcuate fasciculus structure, such that consistently-handed individuals, regardless of the direction of hand preference, demonstrated the most asymmetric arcuate fasciculus, with larger left versus right arcuate, as measured by DTI. Functional language lateralization in Wernicke's area, measured via fMRI, was related to arcuate fasciculus volume in consistent-left-handers only, and only in people who were not right hemisphere lateralized for language; given the small sample size for this finding, future investigation is warranted. Results suggest handedness degree may be an important variable to investigate in the context of neuroanatomical asymmetries. (C) 2010 Elsevier Inc. All rights reserved. C1 [Propper, Ruth E.] Merrimack Coll, Dept Psychol, N Andover, MA 01845 USA. [Propper, Ruth E.; O'Donnell, Lauren J.; Whalen, Stephen; Tie, Yanmei; Norton, Isaiah H.; Suarez, Ralph O.; Radmanesh, Alireza; Golby, Alexandra J.] Harvard Univ, Brigham & Womens Hosp, Golby Neurosurg Brain Mapping Lab, Sch Med,Dept Neurosurg, Boston, MA 02115 USA. [Propper, Ruth E.; O'Donnell, Lauren J.; Whalen, Stephen; Tie, Yanmei; Norton, Isaiah H.; Suarez, Ralph O.; Radmanesh, Alireza; Golby, Alexandra J.] Harvard Univ, Brigham & Womens Hosp, Golby Neurosurg Brain Mapping Lab, Sch Med,Dept Radiol, Boston, MA 02115 USA. [Zollei, Lilla] Massachusetts Gen Hosp, AA Martinos Ctr, Boston, MA 02114 USA. RP Propper, RE (reprint author), Merrimack Coll, Dept Psychol, 315 Turnpike St, N Andover, MA 01845 USA. EM ruth.propper@merrimack.edu OI Radmanesh, Alireza/0000-0002-8581-2600; O'Donnell, Lauren Jean/0000-0003-0197-7801 FU NIH; NINDS [K08-NS048063-02]; NCRR [U41-RR019703]; Brain Science Foundation; [R25 CA089017-06A2] FX Support for this research was provided by NIH Grants: NINDS, K08-NS048063-02 (AJG); NCRR, U41-RR019703 (AJG); and R25 CA089017-06A2 (LO) and the Brain Science Foundation (AJG). The authors would like to thank Stephen D. Christman, Ph.D., at the University of Toledo, Psychology Department, Toledo, Ohio, for comments and suggestions. NR 49 TC 46 Z9 47 U1 4 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD JUL PY 2010 VL 73 IS 2 BP 85 EP 92 DI 10.1016/j.bandc.2010.03.004 PG 8 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 611EP UT WOS:000278794500002 PM 20378231 ER PT J AU Evans, JR Bosman, JD Brown-Endres, L Yehiely, F Cryns, VL AF Evans, Joseph R. Bosman, Joshua D. Brown-Endres, Lauren Yehiely, Fruma Cryns, Vincent L. TI Induction of the small heat shock protein alpha B-crystallin by genotoxic stress is mediated by p53 and p73 SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE p53; p73; Delta Np73 alpha; TAp73; alpha B-crystallin; DNA damage ID CELL-CYCLE ARREST; WILD-TYPE P53; INDUCED APOPTOSIS; POOR-PROGNOSIS; BREAST-CANCER; FEEDBACK LOOP; IN-VIVO; BINDING-SITE; TARGET GENES; HUMAN TUMORS AB The small heat shock protein alpha B-crystallin is a molecular chaperone that is induced by stress and protects cells by inhibiting protein aggregation and apoptosis. To identify novel transcriptional regulators of the alpha B-crystallin gene, we examined the alpha B-crystallin promoter for conserved transcription factor DNA-binding elements and identified a putative response element for the p53 tumor suppressor protein. Ectopic expression of wild-type p53 induced alpha B-crystallin mRNA and protein with delayed kinetics compared to p21. Additionally, the induction of alpha B-crystallin by genotoxic stress was inhibited by siRNAs targeting p53. Although the p53-dependent transactivation of an alpha B-crystallin promoter luciferase reporter required the putative p53RE, chromatin immunoprecipitation failed to detect p53 binding to the alpha B-crystallin promoter. These results suggested an indirect mechanism of transactivation involving p53 family members p63 or p73. Delta Np73 was dramatically induced by p53 in a TAp73-dependent manner, and silencing p73 suppressed the transcriptional activation of alpha B-crystallin by p53. Moreover, ectopic expression of Delta Np73 alpha (but not other p73 isoforms) increased alpha B-crystallin mRNA levels in the absence of p53. Collectively, our results link the molecular chaperone alpha B-crystallin to the cellular genotoxic stress response via a novel mechanism of transcriptional regulation by p53 and p73. C1 [Evans, Joseph R.; Bosman, Joshua D.; Yehiely, Fruma; Cryns, Vincent L.] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Dept Med,Cell Death Regulat Lab, Chicago, IL 60611 USA. [Evans, Joseph R.; Bosman, Joshua D.; Yehiely, Fruma; Cryns, Vincent L.] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Dept Cell & Mol Biol,Cell Death Regulat Lab, Chicago, IL 60611 USA. [Brown-Endres, Lauren] Massachusetts Gen Hosp, Dept Dermatol, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Brown-Endres, Lauren] Harvard Univ, Sch Med, Charlestown, MA USA. RP Cryns, VL (reprint author), Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Dept Med,Cell Death Regulat Lab, Lurie 4-113,303 E Super St, Chicago, IL 60611 USA. EM v-cryns@northwestern.edu FU NIH [R01CA097198, R21CA125181, T32CA09560]; Breast Cancer Research Foundation FX We are indebted to Dr. Sam Lee (Harvard Medical School) for providing the EJ-p53 cells and Dr. Xinbin Chen (University of California-Davis) for providing p73 plasmids and advice. These studies were supported by NIH grants R01CA097198 (VLC), R21CA125181 (VLC), T32CA09560 (JRE), and by the Breast Cancer Research Foundation (VLC). NR 61 TC 10 Z9 10 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD JUL PY 2010 VL 122 IS 1 BP 159 EP 168 DI 10.1007/s10549-009-0542-7 PG 10 WC Oncology SC Oncology GA 608WD UT WOS:000278615800017 PM 19777343 ER PT J AU Berenson, JR Anderson, KC Audell, RA Boccia, RV Coleman, M Dimopoulos, MA Drake, MT Fonseca, R Harousseau, JL Joshua, D Lonial, S Niesvizky, R Palumbo, A Roodman, GD San-Miguel, JF Singhal, S Weber, DM Zangari, M Wirtschafter, E Yellin, O Kyle, RA AF Berenson, James R. Anderson, Kenneth C. Audell, Robert A. Boccia, Ralph V. Coleman, Morton Dimopoulos, Meletios A. Drake, Matthew T. Fonseca, Rafael Harousseau, Jean-Luc Joshua, Douglas Lonial, Sagar Niesvizky, Ruben Palumbo, Antonio Roodman, G. David San-Miguel, Jesus F. Singhal, Seema Weber, Donna M. Zangari, Maurizio Wirtschafter, Eric Yellin, Ori Kyle, Robert A. TI Monoclonal gammopathy of undetermined significance: a consensus statement SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE monoclonal gammopathy of undetermined significance; fractures; peripheral neuropathy; osteoporosis ID CONTROLLED-TRIAL ALADIN; BONE-MINERAL DENSITY; ALPHA-LIPOIC ACID; VERTEBRAL COMPRESSION FRACTURES; MYELIN-ASSOCIATED GLYCOPROTEIN; PAINFUL DIABETIC NEUROPATHY; PRECEDES MULTIPLE-MYELOMA; ACETYL-L-CARNITINE; PERIPHERAL NEUROPATHY; SIGNIFICANCE MGUS AB P>On February 25, 2009, a panel of international experts on plasma cell dyscrasia and skeletal disease met to discuss monoclonal gammopathy of undetermined significance (MGUS). This non-malignant B-cell disorder is the most common plasma cell dyscrasia and is associated with an increased risk of developing serious B-cell disorders. Individuals with MGUS also have an increased risk of osteoporosis and osteopenia associated with an increased likelihood of developing fractures especially in the vertebral column, peripheral neuropathy and thromboembolic events. The goal of the meeting was to develop a consensus statement regarding the appropriate tests to screen, evaluate and follow-up patients with MGUS. The panel also addressed the identification and treatment of MGUS-related skeletal problems, thromboembolic events and neurological complications. The following consensus statement outlines the conclusions and marks the first time that a consensus statement for the screening and treatment of MGUS has been clearly stated. C1 [Berenson, James R.; Wirtschafter, Eric] Inst Myeloma & Bone Canc Res, W Hollywood, CA 90069 USA. [Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Audell, Robert A.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Boccia, Ralph V.] Ctr Canc & Blood Disorders, Bethesda, MD USA. [Coleman, Morton; Niesvizky, Ruben] New York Presbyterian Hosp, Weill Cornell Med Coll, Div Hematol & Med Oncol, Ctr Lymphoma & Myeloma, New York, NY USA. [Dimopoulos, Meletios A.] Univ Athens, Sch Med, Dept Clin Therapeut, Alexandra Hosp, GR-11527 Athens, Greece. [Drake, Matthew T.] Mayo Clin, Coll Med, Div Endocrinol & Metab, Rochester, MN USA. [Fonseca, Rafael] Mayo Clin Arizona, Scottsdale, AZ USA. [Harousseau, Jean-Luc] Univ Hosp Hotel Dieu, Dept Haematol, Nantes, France. [Joshua, Douglas] Royal Prince Alfred Hosp, Inst Haematol, Camperdown, NSW 2050, Australia. [Lonial, Sagar] Emory Univ, Winship Canc Ctr, Atlanta, GA 30322 USA. [Palumbo, Antonio] Univ Turin, Div Ematol, Turin, Italy. [Roodman, G. David] Vet Affairs Pittsburgh Healthcare Syst, Dept Med Hematol Oncol, Pittsburgh, PA USA. [San-Miguel, Jesus F.] Hosp Univ Salamanca, CIC, IBMCC, USAL,CSIC, Salamanca, Spain. [Singhal, Seema] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Weber, Donna M.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA. [Zangari, Maurizio] Univ Utah, Div Hematol, Blood Marrow Transplant & Myeloma Program, Salt Lake City, UT USA. [Kyle, Robert A.] Mayo Clin, Div Hematol, Rochester, MN USA. RP Berenson, JR (reprint author), Inst Myeloma & Bone Canc Res, 9201 W Sunset Blvd,Suite 300, W Hollywood, CA 90069 USA. EM jberenson@imbcr.org RI IBSAL, Secretaria/H-3719-2011; OI SAN MIGUEL, JESUS/0000-0002-9183-4857 NR 86 TC 47 Z9 47 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUL PY 2010 VL 150 IS 1 BP 28 EP 38 DI 10.1111/j.1365-2141.2010.08207.x PG 11 WC Hematology SC Hematology GA 608XD UT WOS:000278618400004 PM 20507313 ER PT J AU Galor, A Feuer, W Kempen, JH Kacmaz, RO Liesegang, TL Suhler, EB Foster, CS Jabs, DA Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Thorne, JE AF Galor, Anat Feuer, William Kempen, John H. Kacmaz, R. Oktay Liesegang, Teresa L. Suhler, Eric B. Foster, C. Stephen Jabs, Douglas A. Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Thorne, Jennifer E. TI Adverse effects of smoking on patients with ocular inflammation SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article ID CIGARETTE-SMOKING; RISK-FACTORS; EYE DISEASE; THERAPY; UVEITIS; EPIDEMIOLOGY; EPISCLERITIS; PREVALENCE; PREDICTORS; SCLERITIS AB Background To evaluate how smoking affects the time to disease quiescence and time to disease recurrence in patients with ocular inflammation. Methods A retrospective cohort study of patients with ocular inflammation who were followed longitudinally and had smoking information available in the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study database. Results Among 2676 patients with active ocular inflammation, smokers were more likely to have bilateral ocular disease and poorer visual acuity on presentation compared with non-smokers and previous smokers. In a multivariate analysis, there was no statistically significant difference in the time to disease quiescence between groups. However, the median time to recurrence of ocular inflammation was statistically significantly longer for non-smokers (9.4 months) and for previous smokers (10.7 months) than for current smokers (7.8 months) (p=0.02). The RR of ocular inflammation recurrence was higher for smokers than for non-smokers (adjusted HR 1.19, 95% CI 1.03 to 1.37) and tended towards significance in previous smokers (adjusted HR 1.11, 95% CI 0.93 to 1.35). Conclusions Smoking was associated with an increased likelihood of bilateral ocular inflammation and reduced vision upon presentation, and an increased risk of recurrence compared with not smoking. These results suggest that patients with ocular inflammation should be counselled to stop smoking as part of routine management. C1 [Galor, Anat; Feuer, William] Univ Miami, Bascom Palmer Eye Inst, Coral Gables, FL 33124 USA. [Galor, Anat] Univ Penn, Dept Ophthalmol, Miami Vet Adm Med Ctr, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Dept Ophthalmol, Ocular Inflammat Serv, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kacmaz, R. Oktay; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Liesegang, Teresa L.; Suhler, Eric B.; Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Ophthalmol, 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. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY 10029 USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Jabs, Douglas A.; Thorne, Jennifer E.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21205 USA. RP Thorne, JE (reprint author), Wilmer Eye Inst, 550 N Broadway,Suite 700, Baltimore, MD 21287 USA. EM jthorne@jhmi.edu FU National Eye Institute [EY014943]; Bascom Palmer Eye Institute [P30 EY014801]; Research to Prevent Blindness; Paul and Evanina Mackall Foundation; US Department of Veterans' Affairs; National Eye Institute FX This study was supported primarily by National Eye Institute Grant EY014943 (to JHK). Data analysis was supported by core center grant P30 EY014801 (Bascom Palmer Eye Institute), from the National Eye Institute, unrestricted funds from Research to Prevent Blindness, and the Paul and Evanina Mackall Foundation. JHK is a Research to Prevent Blindness James S. Adams Special Scholar Award recipient. DAJ and JTR are Research to Prevent Blindness Senior Scientific Investigator Award recipients. JET is a Research to Prevent Blindness Harrington Special Scholar Award recipient. GAL-C was previously supported by, and RBN continues to be supported by, intramural funds of the National Eye Institute. AG and EBS receive support from the US Department of Veterans' Affairs. NR 23 TC 17 Z9 17 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD JUL PY 2010 VL 94 IS 7 BP 848 EP 853 DI 10.1136/bjo.2009.174466 PG 6 WC Ophthalmology SC Ophthalmology GA 621GR UT WOS:000279564400008 PM 20606023 ER PT J AU Takayesu, JK Nadel, ES Bhatia, K Walls, RM AF Takayesu, James K. Nadel, Eric S. Bhatia, Kriti Walls, Ron M. TI Incorporating simulation into a residency curriculum SO CANADIAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article DE simulation; curriculum; residency; teaching methods; emergency medicine; postgraduate; medical education ID EMERGENCY-MEDICINE; EDUCATION AB The integration of simulation into a medical postgraduate curriculum requires informed implementation in ways that take advantage of simulation's unique ability to facilitate guided application of new knowledge. It requires review of all objectives of the training program to ensure that each of these is mapped to the best possible learning method. To take maximum advantage of the training enhancements made possible by medical simulation, it must be integrated into the learning environment, not simply added on. This requires extensive reorganization of the resident didactic schedule. Simulation planning is supported by clear learning objectives that define the goals of the session, promote learner investment in active participation and allow for structured feedback for individual growth. Teaching to specific objectives using simulation requires an increased time commitment from teaching faculty and careful logistical planning to facilitate flow of learners through a series of simulations in ways that maximize learning. When applied appropriately, simulation offers a unique opportunity for learners to acquire and apply new knowledge under direct supervision in ways that complement the rest of the educational curriculum. In addition, simulation can improve the learning environment and morale of residents, provide additional methods of resident evaluation, and facilitate the introduction of new technologies and procedures into the clinical environment. C1 [Takayesu, James K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02114 USA. [Nadel, Eric S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Harvard Affiliated Emergency Med Residency Progra, Boston, MA 02114 USA. [Bhatia, Kriti; Walls, Ron M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Emergency Med, Boston, MA 02114 USA. RP Takayesu, JK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, 5 Emerson Pl,Rm 108, Boston, MA 02114 USA. EM jtakayesu@partners.org NR 10 TC 3 Z9 3 U1 0 U2 1 PU DECKER PUBL INC PI HAMILTON PA 69 JOHN ST S, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1481-8035 J9 CAN J EMERG MED JI Can. J. Emerg. Med. PD JUL PY 2010 VL 12 IS 4 BP 349 EP 353 PG 5 WC Emergency Medicine SC Emergency Medicine GA 629PN UT WOS:000280212300010 PM 20650029 ER PT J AU Dy, SM Lorenz, KA ONeill, SM Asch, SM Walling, AM Tisnado, D Antonio, AL Malin, JL AF Dy, Sydney M. Lorenz, Karl A. ONeill, Sean M. Asch, Steven M. Walling, Anne M. Tisnado, Diana Antonio, Anna Liza Malin, Jennifer L. TI Cancer Quality-ASSIST Supportive Oncology Quality Indicator Set Feasibility, Reliability, and Validity Testing SO CANCER LA English DT Article DE supportive oncology; quality indicators; pain; dysprea; care planning ID EVIDENCE-BASED RECOMMENDATIONS; HOSPICE CARE; LIFE; PERFORMANCE; END AB BACKGROUND: Although measuring the quality of symptom management and end-of-life care could help provide a basis for improving supportive care for advanced cancer, few quality indicators in this area have been rigorously developed or evaluated. METHODS: The authors conducted a pilot evaluation of a comprehensive set of 92 supportive oncology quality indicators, Cancer Quality-ASSIST, including outpatient and hospital indicators for symptoms commonly related to cancer and its treatment and information and care planning. They operationalized the indicators and developed an electronic abstraction tool and extensive guidelines and training materials. Quality assurance nurses abstracted the medical records for 356 advanced cancer patients in 2 settings: a Veterans Administration hospital and an academic hospital and cancer center. The authors evaluated the indicators' feasibility, inter-rater reliability, and validity. RESULTS: The authors successfully evaluated 78 indicators across the domains; results were similar in the 2 settings. They could not feasibly evaluate 3 indicators because of low prevalence; 22 indicators had significant inter-rater reliability issues, 9 had significant validity issues, and 3 had both reliability and validity issues, leaving a set of 41 indicators most promising for further testing and use in this population, with an overall kappa score of 0.85 for specified care. CONCLUSIONS: Of 92 Cancer Quality-ASSIST quality indicators for symptoms, treatment toxicity, and information and care planning, 41 were sufficiently feasible, reliable, and valid to be used for patients with advanced cancer in these settings. This set of indicators shows promise for describing key supportive care processes in advanced cancer. Cancer 2010;116:3267-75. (C) 2010 American Cancer Society. C1 [Dy, Sydney M.] Johns Hopkins Sch Med, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. [Dy, Sydney M.] Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Dy, Sydney M.] Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21205 USA. [Lorenz, Karl A.; Asch, Steven M.; Malin, Jennifer L.] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, RAND Hlth, Los Angeles, CA 90095 USA. [ONeill, Sean M.] Univ Calif Los Angeles, David Geffen Sch Med, RAND Pardee Grad Sch, Los Angeles, CA 90095 USA. [Walling, Anne M.; Tisnado, Diana] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. [Antonio, Anna Liza] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. RP Dy, SM (reprint author), Johns Hopkins Sch Med, Dept Hlth Policy & Management, Room 609,624 N Broadway, Baltimore, MD 21205 USA. EM sdy@jhsph.edu OI O'Neill, Sean/0000-0001-7759-8942 FU Department of Veterans Affairs, Veterans Health Administration, and Health Services Research and Development Service [SHP 08-196]; Agency for Healthcare Research and Quality [290-2005-00341]; US Department of Health and Human Services FX Supported by the Department of Veterans Affairs, Veterans Health Administration, and Health Services Research and Development Service SHP 08-196, and under Contract No. 290-2005-00341 from the Agency for Healthcare Research and Quality, the US Department of Health and Human Services, as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) program. NR 23 TC 27 Z9 27 U1 0 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 1 PY 2010 VL 116 IS 13 BP 3267 EP 3275 DI 10.1002/cncr.25109 PG 9 WC Oncology SC Oncology GA 616KS UT WOS:000279208900027 PM 20564637 ER PT J AU Annunziata, CM Stavnes, HT Kleinberg, L Berner, A Hernandez, LF Birrer, MJ Steinberg, SM Davidson, B Kohn, EC AF Annunziata, Christina M. Stavnes, Helene Tuft Kleinberg, Lilach Berner, Aasmund Hernandez, Lidia F. Birrer, Michael J. Steinberg, Seth M. Davidson, Ben Kohn, Elise C. TI Nuclear Factor kappa B Transcription Factors Are Coexpressed and Convey a Poor Outcome in Ovarian Cancer SO CANCER LA English DT Article DE nuclear factor kappa B; ovarian cancer; immunohistochemistry; survival; p50; matrix metalloproteinase 9; prognosis ID DOSE-INTENSE PACLITAXEL; PROMOTES TUMOR-GROWTH; INITIAL THERAPY; CARCINOMA; CYCLOPHOSPHAMIDE; ANGIOGENESIS; PROGRESSION; METASTASIS; TRANSITION; EXPRESSION AB BACKGROUND: Recent work has suggested a role for nuclear factor kappa B (NF-kappa B) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-kappa B in ovarian cancer is unknown. The authors hypothesized that the NF-kappa B pathway is over activated in aggressive ovarian cancers. METHODS: The levels of 3 NF-kappa B transcription factors, the activating inhibitors of NF-kappa B (I kappa B) kinases, and the NF-kappa B target matrix metalloproteinase 9 (MMP9) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel, cisplatin, and cyclophosphamide. Associations were made between NF-kappa B pathway proteins and outcome. The validation of coexpression was performed at the gene level in 2 independently collected cohorts of 185 and 153 ovarian cancers. RESULTS: The presence of NF-kappa B proteins in newly diagnosed advanced ovarian cancers was established, and a potential association with overall survival was identified. Transcription factors p65 and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) were coexpressed with I kappa B kinase alpha, 1 component of a key trimolecular regulatory complex. Coexpression of the NF-kappa B machinery suggested activity of NF-kappa B signaling in these ovarian tumors. A significant association of p50 with poor overall survival was observed (P = .02). MMP9 expression had the opposite association, in which patients who had tumors without MMP9 staining had the poorest prognosis (P = .01), and this association held true at the gene expression level in an independently collected cohort of 185 ovarian cancers. CONCLUSIONS: The deregulation of NF-kappa B activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-kappa B pathway may present an opportunity to improve outcome in the subset of women who have pathway activity. Cancer 2010;116:3276-84. (C) 2070 American Cancer Society. C1 [Annunziata, Christina M.; Hernandez, Lidia F.; Kohn, Elise C.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stavnes, Helene Tuft; Kleinberg, Lilach; Berner, Aasmund; Davidson, Ben] Rikshosp Univ Hosp, Div Pathol, Norwegian Radium Hosp, Oslo, Norway. [Birrer, Michael J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Davidson, Ben] Univ Oslo, Fac Div, Radiumhosp Med Fac, Oslo, Norway. RP Annunziata, CM (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM annunzic@mail.nih.gov RI Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU Center for Cancer Research, NCI; Marsha Rivkin Foundation for Ovarian Cancer Research; Norwegian Cancer Society; Health Region of South-Eastern Norway FX Supported by the Intramural Program of the Center for Cancer Research, NCI (Drs. Annunziata and Kohn), the Marsha Rivkin Foundation for Ovarian Cancer Research (Dr. Annunziata), and by grants from the Norwegian Cancer Society and the Health Region of South-Eastern Norway (Dr. Davidson). NR 28 TC 70 Z9 75 U1 2 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD JUL 1 PY 2010 VL 116 IS 13 BP 3276 EP 3284 DI 10.1002/cncr.25190 PG 9 WC Oncology SC Oncology GA 616KS UT WOS:000279208900028 PM 20564628 ER PT J AU Sweeney, CJ Takimoto, C Wood, L Porter, JM Tracewell, WG Darwish, M D'Andrea, DM Remick, SC AF Sweeney, Christopher J. Takimoto, Chris Wood, Leslie Porter, Jennifer M. Tracewell, William G. Darwish, Mona D'Andrea, Denise M. Remick, Scot C. TI A pharmacokinetic and safety study of intravenous arsenic trioxide in adult cancer patients with renal impairment SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Arsenical species; Metabolites; Systemic exposure; Accumulation ID ACUTE PROMYELOCYTIC LEUKEMIA; TOXICITY; MULTICENTER; CELLS AB This study evaluated the pharmacokinetic and safety profiles of arsenic trioxide given twice per week in adult cancer patients with advanced malignancies and varying degrees of renal function. Patients received intravenous arsenic trioxide 0.15 mg/kg twice weekly for 4 weeks, followed by a 2-week rest period. The pharmacokinetic profiles of the pharmacologically active arsenical species, arsenious acid (As(III)), and its metabolites, monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)), were evaluated during the first cycle for 72 h following doses on days 1 and 22. Safety assessments were made at each treatment visit. Twenty patients received an average of 11 doses. Compared with normal renal function, mild to severe renal impairment decreased urinary excretion of As(III) and increased exposure to MMA(V) and DMA(V) 1.4- to 8-fold after multiple dose administration. Only severe renal impairment substantially increased exposure to As(III) (AUC(0-t) increased by 18% after a single dose and 40% after multiple doses). The safety profile of arsenic trioxide after limited treatment on a twice-per-week schedule was comparable across all renal function groups. Renal impairment did increase the systemic exposure to arsenic and its methylated metabolites following standard daily dosing of arsenic trioxide. The data from the limited number of patients with severe renal dysfunction did not suggest that severe renal impairment affected the safety profile of arsenic trioxide in cancer patients who received limited treatment with arsenic trioxide. C1 [Sweeney, Christopher J.; Porter, Jennifer M.] Indiana Univ, Dept Med, Indianapolis, IN 46202 USA. RP Sweeney, CJ (reprint author), Dana Farber Canc Inst, 44 Binney St,Rm 1230, Boston, MA 02115 USA. EM chsweene@iupui.edu FU Cephalon, Inc., Frazer, Pennsylvania; NIH [M01 RR-000080, GCRC M01RR00750] FX The authors gratefully acknowledge the editorial support provided by Bridget O'Keeffe, PhD, and Helix Medical Communications LLC. This study was funded by Cephalon, Inc., Frazer, Pennsylvania with additional support from NIH Grant No. M01 RR-000080 (SR) and NIH Grant GCRC M01RR00750 (CS). NR 20 TC 14 Z9 16 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUL PY 2010 VL 66 IS 2 BP 345 EP 356 DI 10.1007/s00280-009-1169-4 PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 597TV UT WOS:000277785600016 PM 19911123 ER PT J AU Sun, T Lee, GSM Werner, L Pomerantz, M Oh, WK Kantoff, PW Freedman, ML AF Sun, Tong Lee, Gwo-Shu Mary Werner, Lillian Pomerantz, Mark Oh, William K. Kantoff, Philip W. Freedman, Matthew L. TI Inherited Variations in AR, ESR1, and ESR2 Genes Are Not Associated With Prostate Cancer Aggressiveness or With Efficacy of Androgen Deprivation Therapy SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ESTROGEN-RECEPTOR-BETA; RISK; POLYMORPHISMS; PROGRESSION; MORTALITY; COHORT AB Background: Sex steroid hormone receptors mediate essential processes in normal prostate growth and contribute to prostate cancer development. Method: In this study, we investigated the association between common inherited variation of the AR, ESR1, and ESR2 genes and two clinically relevant traits: the risk of developing aggressive prostate cancer and the response to androgen deprivation therapy (ADT) in a hospital-based cohort. A total of 43 tagging single nucleotide polymorphisms covering the loci of AR (n = 4), ESR1 (n = 32), and ESR2 (n = 7) were successfully genotyped in 4,073 prostate cancer cases. Results: None of these single nucleotide polymorphisms were significantly associated with disease aggressiveness as assessed by the D'Amico risk classification, pathologic stage, or the response to ADT. Conclusions: Our results suggest that common genetic variations in AR, ESR1, or ESR2 are not strongly associated with prostate cancer aggressiveness or response to ADT. Impact: Our study did not find convincing evidence of inherited variations in the major receptors for androgens and estrogens and their associations with prostate cancer traits. Cancer Epidemiol Biomarkers Prev; 19(7); 1871-8. (C) 2010 AACR. C1 [Sun, Tong; Lee, Gwo-Shu Mary; Pomerantz, Mark; Oh, William K.; Kantoff, Philip W.; Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Werner, Lillian] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kantoff, PW (reprint author), 44 Binney St D710A, Boston, MA 02115 USA. EM philip_kantoff@dfci.harvard.edu; mfreedman@partners.org RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 FU NCI NIH HHS [2 P50 CA090381-06, P50 CA090381] NR 24 TC 15 Z9 15 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2010 VL 19 IS 7 BP 1871 EP 1878 DI 10.1158/1055-9965.EPI-10-0216 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 621OU UT WOS:000279590100025 PM 20615892 ER PT J AU Valente, SM AF Valente, Sharon M. TI Oncology Nurses' Knowledge of Suicide Evaluation and Prevention SO CANCER NURSING LA English DT Article DE Knowledge; Nurses; Suicide; Suicide prevention ID LONG-TERM; CANCER; RISK; CARE; INTENT AB Background: Cancer patients can present with a risk of suicide, making it important for oncology nurses to be knowledge about the high-risk factors for suicide in this population and to be competent in suicide detection and management. Objective: The aim of this study was to describe oncology nurses' identification of risk factors, knowledge, and skill at suicide evaluation and prevention based on evaluation of a vignette and to describe nurses' assessments and interventions for suicidal patients. Methods: As part of a larger exploratory, national study, clinical oncology nurses (n = 1200) from the Oncology Nurses Society responded to a knowledge survey; a total of 454 evaluable questionnaires (37% response rate) were returned. Results: Nurses reviewed a vignette of a suicidal patient and correctly identified these risk factors: widower (69.8%), wishes he/she were dead (82.8%), and gives away prized possessions (79.6%). Few nurses knew that ethnicity (0.4%), age (13.2%), or sex (16.4%) indicated suicide risk. Nurses incorrectly believed that worrying, crying, and executive position indicated suicide risk (40.6Y42%). Most nurses rated themselves as having little to some skill and knowledge of suicide evaluation. Conclusion: Oncology nurses were able to identify certain behavioral risk factors at acceptable rates but not demographic risk factors. Implications for Practice: Oncology nurses are likely to interact with patients at suicide risk and would benefit from knowledge about behavioral and demographic risk factors that contribute to an oncology patient becoming high risk for suicide. Such knowledge could contribute to overall patient safety. C1 [Valente, Sharon M.] Vet Adm Greater Los Angeles Healthcare Syst, Res & Educ, Los Angeles, CA USA. RP Valente, SM (reprint author), 346 N Bowling Green Way, Los Angeles, CA 90049 USA. EM sharon.valente@va.gov FU Oncology Nurses Society/Bristol FX Funding: Oncology Nurses Society/Bristol. NR 24 TC 3 Z9 3 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0162-220X J9 CANCER NURS JI Cancer Nurs. PD JUL-AUG PY 2010 VL 33 IS 4 BP 290 EP 295 DI 10.1097/NCC.0b013e3181cc4f33 PG 6 WC Oncology; Nursing SC Oncology; Nursing GA 614KZ UT WOS:000279058900005 PM 20467313 ER PT J AU Martin, KJ Fournier, MV Reddy, GPV Pardee, AB AF Martin, Katherine J. Fournier, Marcia V. Reddy, G. Prem Veer Pardee, Arthur B. TI A Need for Basic Research on Fluid-Based Early Detection Biomarkers SO CANCER RESEARCH LA English DT Review ID CIRCULATING NUCLEIC-ACIDS; PERIPHERAL-BLOOD; GENE-EXPRESSION; CANCER; MARKERS; CELLS AB Cancer continues to be a major cause of mortality despite decades of effort and expense. The problem reviewed here is that before many cancers are discovered they have already progressed to become drug resistant or metastatic. Biomarkers found in blood or other body fluids could supplement current clinical indicators to permit earlier detection and thereby reduce cancer mortality. Cancer Res; 70(13); 5203-6. (C) 2010 AACR. C1 [Pardee, Arthur B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Reddy, G. Prem Veer] Henry Ford Hosp, Vattikuti Urol Inst, Detroit, MI 48202 USA. [Martin, Katherine J.; Fournier, Marcia V.] Bioarray Therapeut Inc, Belmont, MA USA. RP Pardee, AB (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Marcia.fournier@yahoo.com; arthur_pardee@dfci.harvard.edu NR 24 TC 22 Z9 22 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2010 VL 70 IS 13 BP 5203 EP 5206 DI 10.1158/0008-5472.CAN-10-0987 PG 4 WC Oncology SC Oncology GA 618ZY UT WOS:000279396800002 PM 20587531 ER PT J AU Boni, A Cogdill, AP Dang, P Udayakumar, D Njauw, CNJ Sloss, CM Ferrone, CR Flaherty, KT Lawrence, DP Fisher, DE Tsao, H Wargo, JA AF Boni, Andrea Cogdill, Alexandria P. Dang, Ping Udayakumar, Durga Njauw, Ching-Ni Jenny Sloss, Callum M. Ferrone, Cristina R. Flaherty, Keith T. Lawrence, Donald P. Fisher, David E. Tsao, Hensin Wargo, Jennifer A. TI Selective BRAF(V600E) Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function SO CANCER RESEARCH LA English DT Article ID THERAPY; CANCER; IMMUNOTHERAPY; EXPRESSION; ANTIGEN; MUTATIONS; KINASE; GENE AB Targeted therapy against the BRAF/mitogen-activated protein kinase (MAPK) pathway is a promising new therapeutic approach for the treatment of melanoma. Treatment with selective BRAF inhibitors results in a high initial response rate but limited duration of response. To counter this, investigators propose combining this therapy with other targeted agents, addressing the issue of redundancy and signaling through different oncogenic pathways. An alternative approach is combining BRAF/MAPK-targeted agents with immunotherapy. Preliminary evidence suggests that oncogenic BRAF (BRAF(V600E)) contributes to immune escape and that blocking its activity via MAPK pathway inhibition leads to increased expression of melanocyte differentiation antigens (MDA). Recognition of MDAs is a critical component of the immunologic response to melanoma, and several forms of immunotherapy capitalize on this recognition. Among the various approaches to inhibiting BRAF/MAPK, broad MAPK pathway inhibition may have deleterious effects on T lymphocyte function. Here, we corroborate the role of oncogenic BRAF in immune evasion by melanoma cells through suppression of MDAs. We show that inhibition of the MAPK pathway with MAPK/extracellular signal-regulated kinase kinase (MEK) inhibitors or a specific inhibitor of BRAF(V600E) in melanoma cell lines and tumor digests results in increased levels of MDAs, which is associated with improved recognition by antigen-specific T lymphocytes. However, treatment with MEK inhibitors impairs T lymphocyte function, whereas T-cell function is preserved after treatment with a specific inhibitor of BRAF(V600E). These findings suggest that immune evasion of melanomas mediated by oncogenic BRAF may be reversed by targeted BRAF inhibition without compromising T-cell function. These findings have important implications for combined kinase-targeted therapy plus immunotherapy for melanoma. Cancer Res; 70(13); 5213-9. (C) 2010 AACR. C1 [Boni, Andrea; Cogdill, Alexandria P.; Dang, Ping; Udayakumar, Durga; Njauw, Ching-Ni Jenny; Sloss, Callum M.; Ferrone, Cristina R.; Flaherty, Keith T.; Lawrence, Donald P.; Fisher, David E.; Tsao, Hensin; Wargo, Jennifer A.] Massachusetts Gen Hosp, Div Surg Oncol Med Oncol & Dermatol, Boston, MA 02114 USA. RP Wargo, JA (reprint author), Massachusetts Gen Hosp, Div Surg Oncol Med Oncol & Dermatol, 55 Fruit St, Boston, MA 02114 USA. EM jwargo@partners.org RI Njauw, Ching-Ni/H-8046-2012; OI Cogdill, Alexandria/0000-0001-8917-9462 FU Massachusetts General Hospital; Schlesinger family. FX Intramural funds from Massachusetts General Hospital and philanthropic support of the Schlesinger family. NR 20 TC 317 Z9 322 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2010 VL 70 IS 13 BP 5213 EP 5219 DI 10.1158/0008-5472.CAN-10-0118 PG 7 WC Oncology SC Oncology GA 618ZY UT WOS:000279396800004 PM 20551059 ER PT J AU Heine, VM Priller, M Ling, J Rowitch, DH Schuller, U AF Heine, Vivi M. Priller, Markus Ling, Jason Rowitch, David H. Schueller, Ulrich TI Dexamethasone Destabilizes Nmyc to Inhibit the Growth of Hedgehog-Associated Medulloblastoma SO CANCER RESEARCH LA English DT Article ID GRANULE NEURON PRECURSORS; N-MYC; PATHWAY; BRAIN; MICE; PROLIFERATION; PROGRESSION; MECHANISM; DEFECTS; CELLS AB Mouse studies indicate that the synthetic glucocorticoid dexamethasone (Dex) impairs the proliferation of granule neuron precursors in the cerebellum, which are transformed to medulloblastoma by activation of Sonic hedgehog (Shh) signaling. Here, we show that Dex treatment also inhibits Shh-induced tumor growth, enhancing the survival of tumor-prone transgenic mice. We found that Nmyc was specifically required in granule cells for Shh-induced tumorigenesis and that Dex acted to reduce Nmyc protein levels. Moreover, we found that Dex-induced destabilization of Nmyc is mediated by activation of glycogen synthase kinase 3 beta, which targets Nmyc for proteasomal degradation. Together, our findings show that Dex antagonizes Shh signaling downstream of Smoothened in medulloblastoma. Cancer Res; 70(13); 5220-5. (C) 2010 AACR. C1 [Rowitch, David H.] Univ Calif San Francisco, Inst Regenerat Med, Dept Pediat, San Francisco, CA 94143 USA. [Heine, Vivi M.; Rowitch, David H.] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Pediat & Neurosurg, San Francisco, CA 94143 USA. [Rowitch, David H.] Univ Calif San Francisco, Div Neonatol, San Francisco, CA 94143 USA. [Ling, Jason] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Priller, Markus; Schueller, Ulrich] Univ Munich, Ctr Neuropathol, Munich, Germany. RP Rowitch, DH (reprint author), Univ Calif San Francisco, Inst Regenerat Med, Dept Pediat, 513 Parnassus Ave, San Francisco, CA 94143 USA. EM rowitchd@peds.ucsf.edu; ulrich.schueller@lmu.de RI Heine, Vivi/F-1741-2011 FU NIH [NS047527]; March of Dimes Foundation; Pediatric Brain Tumor Foundation; Wilhelm-Sander-Stiftung FX NIH grant NS047527 (D.H. Rowitch), the March of Dimes Foundation (D.H. Rowitch), the Pediatric Brain Tumor Foundation (D.H. Rowitch), and the Wilhelm-Sander-Stiftung (U. Schuller). U. Schuller is a member of the Max-Eder-junior-research-program of the German Cancer Aid. D. H. Rowitch is a Howard Hughes Medical Institute Investigator. NR 21 TC 14 Z9 15 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2010 VL 70 IS 13 BP 5220 EP 5225 DI 10.1158/0008-5472.CAN-10-0554 PG 6 WC Oncology SC Oncology GA 618ZY UT WOS:000279396800005 PM 20530674 ER PT J AU Taniguchi, CM Winnay, J Kondo, T Bronson, RT Guimaraes, AR Aleman, JO Luo, J Stephanopoulos, G Weissleder, R Cantley, LC Kahn, CR AF Taniguchi, Cullen M. Winnay, Jonathon Kondo, Tatsuya Bronson, Roderick T. Guimaraes, Alexander R. Aleman, Jose O. Luo, Ji Stephanopoulos, Gregory Weissleder, Ralph Cantley, Lewis C. Kahn, C. Ronald TI The Phosphoinositide 3-Kinase Regulatory Subunit p85 alpha Can Exert Tumor Suppressor Properties through Negative Regulation of Growth Factor Signaling SO CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION PROFILES; HEPATOCELLULAR-CARCINOMA; PROTEIN STABILITY; PHOSPHATIDYLINOSITOL 3'-KINASE; INSULIN-RESISTANCE; CATALYTIC SUBUNIT; PROSTATE-CANCER; BREAST-CANCER; PTEN; PATHWAYS AB Phosphoinositide 3-kinase (PI3K) plays a critical role in tumorigenesis, and the PI3K p85 regulatory subunit exerts both positive and negative effects on signaling. Expression of Pik3r1, the gene encoding p85, is decreased in human prostate, lung, ovarian, bladder, and liver cancers, consistent with the possibility that p85 has tumor suppressor properties. We tested this hypothesis by studying mice with a liver-specific deletion of the Pik3r1 gene. These mice exhibited enhanced insulin and growth factor signaling and progressive changes in hepatic pathology, leading to the development of aggressive hepatocellular carcinomas with pulmonary metastases. Liver tumors that arose exhibited markedly elevated levels of phosphatidylinositol (3,4,5)-trisphosphate, along with Akt activation and decreased PTEN expression, at both the mRNA and protein levels. Together, these results substantiate the concept that the p85 subunit of PI3K has a tumor-suppressive role in the liver and possibly other tissues. Cancer Res; 70(13); 5305-15. (C) 2010 AACR. C1 [Taniguchi, Cullen M.; Winnay, Jonathon; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Bronson, Roderick T.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA. [Luo, Ji; Weissleder, Ralph; Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02215 USA. [Guimaraes, Alexander R.; Weissleder, Ralph] Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, Boston, MA 02114 USA. [Cantley, Lewis C.; Kahn, C. Ronald] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA. [Kondo, Tatsuya] Kumamoto Univ, Grad Sch Med Sci, Dept Metab Med, Kumamoto, Japan. [Aleman, Jose O.; Stephanopoulos, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu RI Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU NIH [DK33201, DK55545]; Joslin Diabetes and Endocrinology Research Center [DK34834, GM41890, CA089021]; Southern Association for Institutional Research [2U24CA092782-07]; American Diabetes Association; Medical Scientist Training Program FX NIH grants DK33201 and DK55545, Joslin Diabetes and Endocrinology Research Center grants DK34834 (C.R. Kahn) and GM41890 and CA089021 (L.C. Cantley), Southern Association for Institutional Research grant 2U24CA092782-07 (R. Weissleder), American Diabetes Association Medical Scholars Award (C.M. Taniguchi), and Medical Scientist Training Program Scholarship (Harvard Medical School). NR 50 TC 47 Z9 51 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2010 VL 70 IS 13 BP 5305 EP 5315 DI 10.1158/0008-5472.CAN-09-3399 PG 11 WC Oncology SC Oncology GA 618ZY UT WOS:000279396800013 PM 20530665 ER PT J AU Liu, CY Wu, MC Chen, F Ter-Minassian, M Asomaning, K Zhai, RH Wang, ZX Su, L Heist, RS Kulke, MH Lin, XH Liu, G Christiani, DC AF Liu, Chen-yu Wu, Michael C. Chen, Feng Ter-Minassian, Monica Asomaning, Kofi Zhai, Rihong Wang, Zhaoxi Su, Li Heist, Rebecca S. Kulke, Matthew H. Lin, Xihong Liu, Geoffrey Christiani, David C. TI A Large-scale genetic association study of esophageal adenocarcinoma risk SO CARCINOGENESIS LA English DT Article ID BARRETTS-ESOPHAGUS; LUNG-CANCER; RHEUMATOID-ARTHRITIS; CASPASE ACTIVATION; UNITED-STATES; POLYMORPHISMS; POPULATION; APOPTOSIS; DISEASE; EPIDEMIOLOGY AB The incidence of esophageal adenocarcinoma (EA) has been increasing rapidly, particularly among white males, over the past few decades in the USA. However, the etiology of EA and the striking male predominance is not fully explained by known risk factors. To identify susceptible genes for EA risk, we conducted a pathway-based candidate gene association study on 335 Caucasian EA cases and 319 Caucasian controls. A total of 1330 single-nucleotide polymorphisms (SNPs) selected from 354 genes were analyzed using an Illumina GoldenGate assay. The genotyped common SNPs include missense and exonic SNPs, SNPs within untranslated regions and 2 kb 5' of the gene, and tagSNPs for genes with little functional information available. Logistic regression adjusted for potential confounders was used to assess the genetic effect of each SNP on EA risk. We also tested gene-gender interactions using the likelihood ratio tests. We found that the genetic variants in the apoptosis pathway were significantly associated with EA risk after correcting for multiple comparisons. SNPs of rs3127075 in Caspase-7 (CASP7) and rs4661636 in Caspase-9 (CASP9) genes that play a critical role in apoptosis were found to be associated with an increased risk of EA. A protective effect of SNP rs572483 in the progesterone receptor (PGR) gene was observed among women carrying the variant G allele [adjusted odds ratio (OR) = 0.19; 95% confidence interval (CI) = 0.08-0.46] but was not observed among men (adjusted OR = 1.38; 95% CI = 0.95-2.00). In conclusion, this study suggests that the genetic variants of CASP7 and CASP9 in the apoptosis pathway may be important predictive markers for EA susceptibility and that PGR in the sex hormone signaling pathway may be associated with the gender differences in EA risk. C1 [Liu, Chen-yu; Chen, Feng; Ter-Minassian, Monica; Asomaning, Kofi; Zhai, Rihong; Wang, Zhaoxi; Su, Li; Heist, Rebecca S.; Liu, Geoffrey; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, Boston, MA 02115 USA. [Wu, Michael C.; Lin, Xihong] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Heist, Rebecca S.; Christiani, David C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. [Kulke, Matthew H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Liu, Geoffrey] Princess Margaret Hosp, Dept Med, Div Med Oncol & Haematol, Toronto, ON M5G 2M9, Canada. [Liu, Geoffrey] Univ Toronto, Ontario Canc Inst, Dept Med Biophys, Div Appl Mol Oncol, Toronto, ON M5G 2M9, Canada. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm & Occupat Med & Epidemiol Program, 665 Huntington Ave,Bldg Room 1401, Boston, MA 02115 USA. EM dchris@hsph.harvard.edu RI Liu, Geoffrey/N-4421-2016; OI LIU, CHEN-YU/0000-0002-4693-5667; Wu, Michael C./0000-0002-3357-6570 FU National Institutes of Health [R01CA109193, R03CA110822, R01CA074386, ES00002]; Canadian Institutes of Health; Kevin Jackson Memorial Fund; Alan B. Brown Chair in Molecular Genomics; National Cancer Institute of Canada; Posluns Family Fund Foundation; Flight Attendant Medical Research Institute [062459]; National Center for Research Resources [U54 RR020278] FX National Institutes of Health (R01CA109193, R03CA110822, R01CA074386, ES00002); Canadian Institutes of Health Research operating grant; Kevin Jackson Memorial Fund; Alan B. Brown Chair in Molecular Genomics; National Cancer Institute of Canada Dorothy Lamont Award; Posluns Family Fund Foundation; Flight Attendant Medical Research Institute Award No. 062459. The Broad Institute Center for Genotyping and Analysis is supported by grant from the National Center for Research Resources (U54 RR020278). NR 56 TC 35 Z9 36 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2010 VL 31 IS 7 BP 1259 EP 1263 DI 10.1093/carcin/bgq092 PG 5 WC Oncology SC Oncology GA 620BD UT WOS:000279473100012 PM 20453000 ER PT J AU Ansel, GM Hopkins, LN Jaff, MR Rubino, P Bacharach, JM Scheinert, D Myla, S Das, T Cremonesi, A AF Ansel, Gary M. Hopkins, L. Nelson Jaff, Michael R. Rubino, Paolo Bacharach, J. Michael Scheinert, Dierk Myla, Subbarao Das, Tony Cremonesi, Alberto CA Investigators Armour Pivotal Trial TI Safety and Effectiveness of the INVATEC MO.MA (R) Proximal Cerebral Protection Device During Carotid Artery Stenting: Results From the ARMOUR Pivotal Trial SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE embolic protection; peripheral vascular disease; carotid stenosis; stroke; high surgical risk; internal carotid artery ID SURGICAL-RISK PATIENTS; FLOW BLOCKAGE; NEUROPROTECTION; EXPERIENCE; REGISTRY; SYSTEM AB Objective: The multicenter ARMOUR (ProxirnAI PRotection with the MO.MA Device DUring CaRotid Stenting) trial evaluated the 30-day safety and effectiveness of the MO.MA (R) Proximal Cerebral Protection Device (Invatec, Roncadelle, Italy) utilized to treat high surgical risk patients undergoing carotid artery stenting (CAS). Background: Distal embolic protection devices (EPD) have been traditionally utilized during CAS. The MO.MA device acts as a balloon occlusion "endovascular clamping" system to achieve cerebral protection prior to crossing the carotid stenosis. Methods: This prospective registry enrolled 262 subjects, 37 roll-in and 225 pivotal subjects evaluated with intention to treat (ITT) from September 2007 to February 2009. Subjects underwent CAS using the MO.MA device. The primary endpoint, myocardial infarction, stroke, or death through 30 days (30-day major adverse cardiac and cerebrovascular events [MACCE]) was compared to a performance goal of 13% derived from trials utilizing distal EPD. Results: For the ITT population, the mean age was 74.7 years with 66.7% of the cohort being male. Symptomatic patients comprised 15.1% and 25.9% were octogenarians. Device success was 98.2% and procedural success was 932%. The 30-day MACCE rate was 2.7% [95% CI (1.0-5.8%)] with a 30-day major stroke rate of 0.9%. No symptomatic patient suffered a stroke during this trial. Conclusions: The ARMOUR trial demonstrated that the MO.MA (R) Proximal Cerebral Protection Device is safe and effective for high surgical risk patients undergoing CAS. The absence of stroke in symptomatic patients is the lowest rate reported in any independently adjudicated prospective multicenter registry trial to date. (C) 2010 Wiley-Liss, Inc. C1 [Ansel, Gary M.] Riverside Methodist Hosp, Dept Cardiol, Columbus, OH 43214 USA. [Hopkins, L. Nelson] SUNY Buffalo, Dept Neurosurg, Buffalo, NY 14260 USA. [Hopkins, L. Nelson] SUNY Buffalo, Dept Radiol, Buffalo, NY 14260 USA. [Hopkins, L. Nelson] Toshiba Stroke Ctr, Buffalo, NY USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Dept Med, Div Cardiol Vasc Med, Vasc Ctr, Boston, MA 02114 USA. [Rubino, Paolo] Clin Montevergine, Invas Cardiol Lab, Mercogliano, Italy. [Bacharach, J. Michael] N Cent Heart Hosp S Dakota, Dept Vasc Med & Peripheral Vasc Intervent, Sioux Falls, SD USA. [Scheinert, Dierk] Park Hosp, Dept Angiol, Leipzig, Germany. [Myla, Subbarao] Hoag Mem Hosp, Dept Cardiovasc Res & Vasc Intervent, Newport Beach, CA USA. [Das, Tony] Texas Hlth Presbyterian Dallas, Dept Cardiol, Dallas, TX USA. [Cremonesi, Alberto] GVM Hosp Care & Res, Intervent Cardioangiol Unit, Cotignola, Italy. RP Ansel, GM (reprint author), Riverside Methodist Hosp, Dept Cardiol, 3705 Olentangy River Rd, Columbus, OH 43214 USA. EM gansel@mocvc.com FU Abbott/Guidant Vascular and WL Gore; Boston Scientific, Cordis Johnson Johnson; Invatec FX Conflict of interest: Dr. Ansel has received speaker's bureau fees and research support from Abbott/Guidant Vascular and WL Gore, and research support from Boston Scientific, Cordis Johnson & Johnson, and Invatec; he also sits on the Boston Scientific, Cordis Johnson & Johnson, Lumen Biomedical, and WL Gore advisory boards. Dr. Hopkins has received research support from Boston Scientific, Cordis Johnson & Johnson, ev3, and Toshiba, and speaker's bureau fees and research support from Abbott; he sits on the Abbott, Access Closure, Bard, Boston Scientific, Cordis Johnson & Johnson, Gore, Lumen Biomedical, Micrus, and Toshiba advisory boards, and claims ownership/financial Interest in AccessClosure, Boston Scientific, and Micrus. Dr. Jaff is a non-compensated consultant for Abbott, Boston Scientific, Medtronic Vascular, and sits on the VIVA Physicians, Inc. board. Drs. Rubino, Bacharach, and My la claim no conflicts of interest. Drs. Scheinert and Das are compensated consultants for Invatec. Dr. Cremonesi has received research grants and consulting and teaching fees from Abbott, Bard, Boston Scientific, Cordis, ev3, Gore, Invatec, and Medtronic. NR 18 TC 89 Z9 97 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD JUL 1 PY 2010 VL 76 IS 1 BP 1 EP 8 DI 10.1002/ccd.22439 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 623PO UT WOS:000279754500001 PM 20222019 ER PT J AU Armstrong, EJ Shunk, KA AF Armstrong, Ehrin J. Shunk, Kendrick A. TI Coronary Guidewire Circumcision During Use of a Gopher Support Catheter: Potential Adverse Interaction with Polymer-Jacketed Wire Design SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE percutaneous coronary intervention; complications adult cath/intervention; angiography; coronary ID ANGIOPLASTY GUIDEWIRE; TRANSCATHETER RETRIEVAL; ATHERECTOMY; EQUIPMENT; REMOVAL AB Support catheters with a threaded, distal tip may be useful for crossing recalcitrant coronary lesions. The interaction between the Gopher support catheter and polymer-coated coronary guidewires may, however, result in circumferential stripping of polymer from the guidewire, with resulting wire damage or fracture. We report two cases of polymer-coated guidewire damage with use of a Gopher support catheter, suggesting that these two devices should not be used together. (C) 2010 Wiley-Liss, Inc. C1 [Shunk, Kendrick A.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, Div Cardiol, San Francisco, CA 94143 USA. RP Shunk, KA (reprint author), San Francisco VA Med Ctr, Cardiol 111C,4150 Clement St, San Francisco, CA 94121 USA. EM kendrick.shunk@va.gov NR 10 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD JUL 1 PY 2010 VL 76 IS 1 BP 112 EP 116 DI 10.1002/ccd.22477 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 623PO UT WOS:000279754500021 PM 20578095 ER PT J AU Diaz, T Cubeddu, RJ Rengifo-Moreno, PA Cruz-Gonzalez, I Solis-Martin, J Buonanno, FS Inglessis, I Palacios, IF AF Diaz, Tulio Cubeddu, Roberto J. Rengifo-Moreno, Pablo A. Cruz-Gonzalez, Ignacio Solis-Martin, Jorge Buonanno, Ferdinando S. Inglessis, Ignacio Palacios, Igor F. TI Management of Residual Shunts After Initial Percutaneous Patent Foramen Ovale Closure: A Single Center Experience With Immediate and Long-Term Follow-Up SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE CHDA, congenital heart disease in adults; PFO, patent foramen; ovale/atrial septal defect; FIST, fistula/shunts ID PRESUMED PARADOXICAL EMBOLISM; TRANSCATHETER CLOSURE; DECOMPRESSION-SICKNESS; THROMBOEMBOLIC EVENTS; CRYPTOGENIC STROKE; DEVICE; OCCLUDER; RISK; DIVERS; PFO AB Background: Moderate-to-large residual shunts following percutaneous patent foramen ovale (PFO) closure are clinically important and associated with recurrent neuro-embolic events. However, their management has not been clearly established in clinical practice. We report our experience in patients of these patients with a prior history of cryptogenic stroke and/or transient ischemic attack (TIA). Methods: All patients undergoing percutaneous PFO closure were routinely screened at six-months for residual shunts using transthoracic 2D echocardiography with antecubital administration of agitated saline contrast and color flow Doppler. Patients with evidence of moderate-to-large residual shunts were selected to undergo reintervention with shunt closure. Post-reintervention follow-up was performed at 24-hr, 30 days, and every six months thereafter. Clinical predictors of the moderate-to-large residual shunts, and the feasibility, safety and long-term efficacy of percutaneous residual shunt closure using a second device implant were examined. Results: Between 1995 and 2007, a total of 424 patients underwent PFO closure. Of these, 5% (21/424) had moderate-to-large residual shunts. Baseline characteristics among patients with moderate-to-large residual shunts and those with only none or small defects (n = 403) were similar. Multivariate analysis identified the 24-hr postprocedure shunt as the only independent predictor of residual shunting at six months. Of the 21 study patients with moderate-to-large residual shunt (mean age, 47 +/- 14), one underwent successful elective surgical repair, while the remaining 20 underwent transcatheter closure using a second device. The technique was successful in 95% (19/20), and all but one patient had complete shunt closure at six months of their percutaneous reintervention. We report no deaths, recurrent strokes or TIAs during the long-term mean follow-up period of 2.9 years. Conclusions: Our study suggests that in patients with moderate-to-large residual PFO shunts, percutaneous reintervention using a second device implant is safe and effective. (C) 2010 Wiley-Liss, Inc. C1 [Diaz, Tulio; Cubeddu, Roberto J.; Rengifo-Moreno, Pablo A.; Cruz-Gonzalez, Ignacio; Solis-Martin, Jorge; Buonanno, Ferdinando S.; Inglessis, Ignacio; Palacios, Igor F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. RP Palacios, IF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. EM ipalacios@partners.org RI IBSAL, Secretaria/H-3719-2011 NR 25 TC 14 Z9 14 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD JUL 1 PY 2010 VL 76 IS 1 BP 145 EP 150 DI 10.1002/ccd.22475 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 623PO UT WOS:000279754500029 PM 20578100 ER PT J AU Vasilyev, A Drummond, IA AF Vasilyev, Aleksandr Drummond, Iain A. TI Fluid flow and guidance of collective cell migration SO CELL ADHESION & MIGRATION LA English DT Article DE collective migration; fluid flow; mechanotransduction; development; kidney; zebrafish AB Collective cell migration is emerging as a significant component of many biological processes including metazoan development, tissue maintenance and repair and tumor progression. Different contexts dictate different mechanisms by which migration is guided and maintained. In vascular endothelia subjected to significant shear stress, fluid flow is utilized to properly orient a migrating group of cells. Recently, we discovered that the developing zebrafish pronephric epithelium undergoes a similar response to luminal fluid flow, which guides pronephric epithelial migration towards the glomerulus. Intratubular migration leads to significant changes in kidney morphology. This novel process provides a powerful in vivo model for further exploration of the mechanisms underlying mechanotransduction and collective migration. C1 [Vasilyev, Aleksandr] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA USA. [Drummond, Iain A.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA USA. RP Vasilyev, A (reprint author), Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA USA. EM avasilyev@partners.org FU NIH [K08DK082782, DK53093, DK71041] FX Authors apologize to those whose work was not directly referenced due to space constraints. This work was supported by NIH grants K08DK082782 to A.V. and DK53093, DK71041 to I.A.D. NR 43 TC 4 Z9 4 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6918 J9 CELL ADHES MIGR JI Celll Adhes. Migr. PD JUL-SEP PY 2010 VL 4 IS 3 BP 353 EP 357 DI 10.4161/cam.4.3.11428 PG 5 WC Cell Biology SC Cell Biology GA V21VJ UT WOS:000208234800006 PM 20234192 ER PT J AU Kong, TQ Xu, DS Tran, M Denker, BM AF Kong, Tianqing Xu, Daosong Mei Tran Denker, Bradley M. TI Regulation of integrin expression by G alpha 12 An additional potential mechanism modulating cell attachment SO CELL ADHESION & MIGRATION LA English DT Article DE G proteins; kidney; extra-cellular matrix; collagen; laminin; gene expression AB Integrins regulate cell attachment and migration through interactions with specific proteins in the extra-cellular matrix. Heterotrimeric G proteins are essential signal transduction proteins that intersect with integrin signaling to regulate fundamental cellular behaviors. Although integrin and G protein signaling often act in concert, how these mechanisms interact in epithelial cells has not been extensively studied. We recently reported G alpha 12 regulation of epithelial cell attachment and migration on collagen-I through alpha 2 beta 1 integrins (Kong et al. Mol Biol Cell 2009). Activated G alpha 12 inhibited alpha 2 beta 1 integrin functions through an inside-out signaling mechanism that involved Rho, Src and protein phosphatases without affecting alpha 2 or beta 1 expression. Activated G alpha 12 prevented tubulogenesis in 3D-MDCK cell cultures and promoted the formation of cystic structures. Herein, we extend these findings to show G alpha 12-stimulated transcriptional changes in integrin expression that affect MDCK cell attachment. Based on results from a microarray with MDCK cells expressing constitutively active G alpha 12 (QL alpha 12), we confirmed with real time PCR that expressing QL alpha 12 led to a 4-fold inhibition of alpha 6 mRNA expression. Cell surface expression and total alpha 6 protein was reduced by FACS and immunofluorescence. QL alpha 12 expressing MDCK cells also revealed less attachment to laminin-5, an alpha 6 integrin ligand. Taken together, G proteins regulate integrins through canonical signaling pathways and potentially regulate integrin expression levels to modulate cellular responses in a variety of pathophysiologic conditions including polycystic kidney disease. C1 [Kong, Tianqing; Mei Tran; Denker, Bradley M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Renal, Boston, MA 02115 USA. [Xu, Daosong] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kong, TQ (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Renal, Boston, MA 02115 USA. EM tkong@rics.bwh.harvard.edu FU NIH [P50 DK074030, RO1GM55223, K01 DK080179] FX Supported by NIH P50 DK074030 B.M.D. Project 1. NIH RO1GM55223 to B.M.D., K01 DK080179 to T.K. We thank members of the Harvard Polycystic Kidney Disease Center and the Denker Laboratory for helpful comments and suggestions. NR 27 TC 2 Z9 2 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6918 J9 CELL ADHES MIGR JI Celll Adhes. Migr. PD JUL-SEP PY 2010 VL 4 IS 3 BP 372 EP 376 DI 10.4161/cam.4.3.11639 PG 5 WC Cell Biology SC Cell Biology GA V21VJ UT WOS:000208234800010 PM 20424510 ER PT J AU Abou-Khalil, R Brack, AS AF Abou-Khalil, Rana Brack, Andrew S. TI Muscle stem cells and reversible quiescence The role of sprouty SO CELL CYCLE LA English DT Article DE Satellite cell; Muscle stem cell; Pax7; Sprouty; Quiescence; Niche; Regeneration ID FIBROBLAST-GROWTH-FACTOR; MYOGENIC SATELLITE CELLS; SKELETAL-MUSCLE; SELF-RENEWAL; PROGENITOR CELLS; GENE-EXPRESSION; RESERVE CELLS; FGF; PAX7; DIFFERENTIATION AB Quiescence is a critical determinant for sustained stem cell function throughout life. Disruption of cellular quiescence leads to loss of the stem cell pool and impaired tissue repair. In adult skeletal muscle, Pax7(+) satellite cells (the muscle stem cells) are capable of self-renewal and differentiation in their endogenous environment during repair. In response to muscle injury, Pax7(+) satellite cells enter the cell cycle; a subpopulation returns to quiescence to fully replenish the satellite cell pool while others contribute to myofiber repair. We demonstrate that Sprouty1 (Spry1), an inhibitor of receptor tyrosine kinase signaling is required for the return to quiescence of the self-renewing Pax7(+) satellite cell pool during repair. The temporal regulation of Spry1 expression during repair and its functional requirement in a subpopulation of cycling Pax7(+) cells during repair ensure that tissue regeneration and re-establishment of the dormant stem cell pool are coordinated. C1 [Abou-Khalil, Rana; Brack, Andrew S.] Harvard Univ, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02115 USA. RP Brack, AS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02115 USA. EM brack.andrew@mgh.harvard.edu NR 76 TC 12 Z9 13 U1 0 U2 7 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD JUL 1 PY 2010 VL 9 IS 13 BP 2575 EP 2580 DI 10.4161/cc.9.13.12149 PG 6 WC Cell Biology SC Cell Biology GA 642IX UT WOS:000281205400031 PM 20581433 ER PT J AU Mullally, WJ Hall, KE AF Mullally, William J. Hall, Kathryn E. TI Hypnic headache secondary to haemangioblastoma of the cerebellum SO CEPHALALGIA LA English DT Article DE hypnic headache; haemangioblastoma; secondary headache AB We report a case of secondary hypnic headache in a patient with a haemangioblastoma of the cerebellum. The number of secondary cases is steadily increasing in the medical literature and magnetic resonance imaging of the brain should be considered mandatory after arriving at a presumptive diagnosis. C1 [Mullally, William J.] Harvard Vanguard Med Associates, Dept Neurol, Boston, MA USA. [Mullally, William J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Hall, Kathryn E.] Massachusetts Gen Hosp, Clin Res Ctr, Boston, MA 02114 USA. RP Mullally, WJ (reprint author), Faulkner Hosp, Brigham & Womens Hosp, HVMA Suite 47,1153 Ctr St, Jamaica Plain, MA 02130 USA. EM williammullally@aol.com NR 12 TC 7 Z9 8 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0333-1024 J9 CEPHALALGIA JI Cephalalgia PD JUL PY 2010 VL 30 IS 7 BP 887 EP 889 DI 10.1177/0333102409352911 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 620WT UT WOS:000279533400017 PM 20647180 ER PT J AU Feng, P Wang, H Feldman, RS Pribitkin, EA Breslin, PAS AF Feng, Pu Wang, Hong Feldman, Roy S. Pribitkin, Edmund A. Breslin, Paul A. S. TI The T Cells in Peripheral Taste Tissue of Healthy Human Adults: Predominant Memory T Cells and Th-1 Cells SO CHEMICAL SENSES LA English DT Article DE lymphocyte subset; memory T cells; regulatory T cells; taste tissue; Th1 cells ID ORAL LICHEN-PLANUS; GAMMA-DELTA; OCULAR SURFACE; INTESTINAL INFLAMMATION; UP-REGULATION; HUMAN NAIVE; EXPRESSION; RECEPTOR; LYMPHOCYTES; CHEMOKINE AB A healthy taste system is important to the maintenance of nutrition and overall quality of life, and taste disorders are associated with many inflammatory states. We previously determined the immune cells in normal human gustatory tissue; they are predominantly dendritic cells and CD4 T cells with a few macrophages and B lymphocytes present. There are, however, few reports of the subtypes of resident lymphocytes in or near taste tissues. The present study further characterized the distribution and population of the major subtypes of T cells in situ within biopsies of healthy human fungiform papillae (FP). Immunohistochemical analyses indicated that T-helper (Th)1 cells (CCR5+) were more predominant in FP than Th2 T cells (CCR4+). CD45RO+ memory T cells were the principal T cells in gustatory tissue, whereas CD45RA+ naive T cells were uncommon. Regarding subcompartments of the tissue, most intraepithelial lymphocytes of FPs were gamma/delta T cells, whereas the major subtype of lymphocytes in the lamina propria were alpha/beta T cells. Regulatory T cells that express CTLA-4 (CD152) and interleukin-2 receptors (IL-2R, CD25) were found at low levels in FP. The T cells stand ready to respond to inflammatory and infectious insults and may play a role in the taste alterations observed during acute and chronic inflammatory states. C1 [Feng, Pu; Wang, Hong; Feldman, Roy S.; Pribitkin, Edmund A.; Breslin, Paul A. S.] Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. [Feldman, Roy S.] Vet Affairs Med Ctr, Dent Serv, Philadelphia, PA USA. [Feldman, Roy S.; Breslin, Paul A. S.] Univ Penn, Sch Dent Med, Philadelphia, PA 19104 USA. [Pribitkin, Edmund A.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Breslin, Paul A. S.] Rutgers State Univ, Dept Nutr Sci, Sch Environm & Biol Sci, New Brunswick, NJ 08903 USA. RP Feng, P (reprint author), Monell Chem Senses Ctr, 3500 Market St, Philadelphia, PA 19104 USA. EM pfeng@monell.org FU National Institutes of Health [DC 02995, P50 DC 06760] FX This work was supported by National Institutes of Health [DC 02995 and P50 DC 06760 to P.A.S.B]. NR 44 TC 4 Z9 4 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0379-864X J9 CHEM SENSES JI Chem. Senses PD JUL PY 2010 VL 35 IS 6 BP 501 EP 509 DI 10.1093/chemse/bjq040 PG 9 WC Behavioral Sciences; Food Science & Technology; Neurosciences; Physiology SC Behavioral Sciences; Food Science & Technology; Neurosciences & Neurology; Physiology GA 613HX UT WOS:000278971100005 PM 20457570 ER PT J AU Seneviratne, SK Truong, QA Bamberg, F Rogers, IS Shapiro, MD Schlett, CL Chae, CU Cury, R Abbara, S Brady, TJ Nagurney, JT Hoffmann, U AF Seneviratne, Sujith K. Truong, Quynh A. Bamberg, Fabian Rogers, Ian S. Shapiro, Michael D. Schlett, Christopher L. Chae, Claudia U. Cury, Ricardo Abbara, Suhny Brady, Thomas J. Nagurney, John T. Hoffmann, Udo TI Incremental Diagnostic Value of Regional Left Ventricular Function Over Coronary Assessment by Cardiac Computed Tomography for the Detection of Acute Coronary Syndrome in Patients With Acute Chest Pain From the ROMICAT Trial SO CIRCULATION-CARDIOVASCULAR IMAGING LA English DT Article DE computed tomography; left ventricular function; acute coronary syndrome; emergency department ID ELEVATION MYOCARDIAL-INFARCTION; EMERGENCY-DEPARTMENT PATIENTS; AMERICAN-HEART-ASSOCIATION; LOW-RISK PATIENTS; MAGNETIC-RESONANCE; UNSTABLE ANGINA; PRACTICAL IMPLEMENTATION; PREDICTIVE INSTRUMENT; CLINICAL CARDIOLOGY; DOSE REDUCTION AB Background-The incremental value of regional left ventricular function (LVF) over coronary assessment to detect acute coronary syndrome (ACS) is uncertain. Methods and Results-We analyzed 356 patients (mean age, 53 +/- 12 years; 62% men) with acute chest pain and inconclusive initial emergency department evaluation. Patients underwent 64-slice contrast-enhanced cardiac computed tomography before hospital admission. Caregivers and patients remained blinded to the results. Regional LVF and presence of coronary atherosclerotic plaque and significant stenosis (>50%) were separately assessed by 2 independent readers. Incremental value of regional LVF to predict ACS was determined in the entire cohort and in subgroups of patients with nonobstructive coronary artery disease, inconclusive assessment for stenosis (defined as inability to exclude significant stenosis due to calcium or motion), and significant stenosis. During their index hospitalization, 31 patients were ultimately diagnosed with ACS (8 myocardial infarction, 22 unstable angina), of which 74% (23 patients) had regional LV dysfunction. Adding regional LVF resulted in a 10% increase in sensitivity to detect ACS by cardiac computed tomography (87%; 95% confidence interval, 70% to 96%) and significantly improved the overall accuracy (c-statistic: 0.88 versus 0.94 and 0.79 versus 0.88, for extent of plaque and presence of stenosis, respectively; both P < 0.03). The diagnostic accuracy of regional LVF for detection of ACS has 89% sensitivity and 86% specificity in patients with significant stenosis (n = 33) and 60% sensitivity and 86% specificity in patients with inconclusive coronary computed tomographic angiography (n = 33). Conclusions-Regional LVF assessment at rest improves diagnostic accuracy for ACS in patients with acute chest pain, especially in those with coronary artery disease and thus may be helpful to guide further management in patients at intermediate risk for ACS. C1 [Seneviratne, Sujith K.; Truong, Quynh A.; Bamberg, Fabian; Rogers, Ian S.; Shapiro, Michael D.; Schlett, Christopher L.; Chae, Claudia U.; Cury, Ricardo; Abbara, Suhny; Brady, Thomas J.; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Nagurney, John T.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, 165 Charles River Plaza,Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org FU National Institutes of Health [R01 HL080053]; National Heart Foundation of New Zealand [1152] FX This work was supported by the National Institutes of Health (R01 HL080053). Dr Seneviratne received support from the National Heart Foundation of New Zealand grant 1152. Drs Rogers, Truong, and Shapiro were supported by the National Institutes of Health grant T32HL076136. NR 48 TC 38 Z9 41 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-9651 J9 CIRC-CARDIOVASC IMAG JI Circ.-Cardiovasc. Imaging PD JUL PY 2010 VL 3 IS 4 BP 375 EP 383 DI 10.1161/CIRCIMAGING.109.892638 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 628UW UT WOS:000280149200005 PM 20484542 ER PT J AU Maddox, TM Ross, C Tavel, HM Lyons, EE Tillquist, M Ho, PM Rumsfeld, JS Margolis, KL O'Connor, PJ Selby, JV Magid, DJ AF Maddox, Thomas M. Ross, Colleen Tavel, Heather M. Lyons, Ella E. Tillquist, Maggie Ho, P. Michael Rumsfeld, John S. Margolis, Karen L. O'Connor, Patrick J. Selby, Joe V. Magid, David J. TI Blood Pressure Trajectories and Associations With Treatment Intensification, Medication Adherence, and Outcomes Among Newly Diagnosed Coronary Artery Disease Patients SO CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES LA English DT Article DE hypertension; epidemiology; health services research; myocardial infarction; mortality ID NONADHERENCE; HYPERTENSION; PREVENTION; CARE AB Background-Blood pressure (BP) control among coronary artery disease patients remains suboptimal in clinical practice, potentially due to gaps in treatment intensification and medication adherence. However, longitudinal studies evaluating these relationships and outcomes are limited. Methods and Results-We assessed BP trajectories among health maintenance organization patients with hypertension and incident coronary artery disease. BP trajectories were modeled over the year after coronary artery disease diagnosis, stratified by target BP goal. Treatment intensification (increase in BP therapies in the setting of an elevated BP), medication adherence (percentage of days covered with BP therapies), and outcomes (all-cause mortality, myocardial infarction, and revascularization) were evaluated in multivariable models: 9569 patients had a <140/90 mm Hg BP target and 12 861 had a <130/80 mm Hg BP target. Within each group, 4 trajectories were identified: good, borderline, improved, and poor control. After adjustment, increasing BP treatment intensity was significantly associated with better BP trajectories in both groups. Medication adherence had inconsistent effects. There were no significant differences in combined outcomes by BP trajectory, but among the diabetes and renal disease cohort, borderline control patients were less likely to have myocardial infarction (odds ratio, 0.61; 95% confidence interval, 0.40-0.93), and good control patients were less likely to have myocardial infarction (odds ratio, 0.53; 95% confidence interval, 0.34-0.84) or a revascularization procedure (odds ratio, 0.66; 95% confidence interval, 0.47-0.93) compared with poor control patients. Conclusions-In this health maintenance organization population, treatment intensification but not medication adherence significantly affects BP trajectories in the year after coronary artery disease diagnosis. Better BP trajectories are associated with lower rates of myocardial infarction and revascularization. (Circ Cardiovasc Qual Outcomes. 2010;3:347-357.) C1 [Maddox, Thomas M.] Univ Colorado Denver, Denver VAMC, Cardiol Sect 111B, Denver, CO 80220 USA. [Ross, Colleen; Tavel, Heather M.; Lyons, Ella E.; Magid, David J.] Kaiser Permanente Colorado, Inst Hlth Res, Denver, CO USA. [Tillquist, Maggie] Univ Colorado Denver, Sch Med, Denver, CO 80220 USA. [Margolis, Karen L.; O'Connor, Patrick J.] Hlth Partners Res Fdn, Minneapolis, MN USA. [Selby, Joe V.] Kaiser Permanente No Calif, Oakland, CA USA. RP Maddox, TM (reprint author), Univ Colorado Denver, Denver VAMC, Cardiol Sect 111B, 1055 Clermont St, Denver, CO 80220 USA. EM thomas.maddox@va.gov FU National Heart Lung and Blood Institute [U19 HL91179-01]; VA Health Services Research and Development FX This study was supported by a grant made to the Cardiovascular Research Network (CVRN) from the National Heart Lung and Blood Institute under cooperative agreement U19 HL91179-01.; Drs Maddox and Ho are supported by VA Health Services Research and Development Career Development Awards. Dr Ho is a consultant for Wellpoint, Inc. NR 17 TC 19 Z9 19 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7713 J9 CIRC-CARDIOVASC QUAL JI Circ.-Cardiovasc. Qual. Outcomes PD JUL PY 2010 VL 3 IS 4 BP 347 EP 357 DI 10.1161/CIRCOUTCOMES.110.957308 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 628NC UT WOS:000280125900004 PM 20488918 ER PT J AU Baggish, AL Weiner, RB Kanayama, G Hudson, JI Picard, MH Hutter, AM Pope, HG AF Baggish, Aaron L. Weiner, Rory B. Kanayama, Gen Hudson, James I. Picard, Michael H. Hutter, Adolph M., Jr. Pope, Harrison G., Jr. TI Long-Term Anabolic-Androgenic Steroid Use Is Associated With Left Ventricular Dysfunction SO CIRCULATION-HEART FAILURE LA English DT Article DE myocardial contraction; mechanics; systole; diastole; anabolic agent ID IDIOPATHIC DILATED CARDIOMYOPATHY; MYOCARDIAL-INFARCTION; CARDIOVASCULAR COMPLICATIONS; TISSUE DOPPLER; HEART-FAILURE; WEIGHT LIFTER; BODY-BUILDERS; CARDIAC DEATH; COCAINE USE; ABUSE AB Background-Although illicit anabolic-androgenic steroid (AAS) use is widespread, the cardiac effects of long-term AAS use remain inadequately characterized. We compared cardiac parameters in weightlifters reporting long-term AAS use to those in otherwise similar weightlifters without prior AAS exposure. Methods and Results-We performed 2D tissue-Doppler and speckle-tracking echocardiography to assess left ventricular (LV) ejection fraction, LV systolic strain, and conventional indices of diastolic function in long-term AAS users (n=12) and otherwise similar AAS nonusers (n=7). AAS users (median [quartile 1, quartile 3] cumulative lifetime AAS exposure, 468 [169, 520] weeks) closely resembled nonusers in age, prior duration of weightlifting, and current intensity of weight training. LV structural parameters were similar between the two groups; however, AAS users had significantly lower LV ejection fraction (50.6% [48.4, 53.6] versus 59.1% [58.0%, 61.7%]; P=0.003 by two-tailed Wilcoxon rank sum test), longitudinal strain (16.9% [14.0%, 19.0%] versus 21.0% [20.2%, 22.9%]; P=0.004), and radial strain (38.3% [28.5%, 43.7%] versus 50.1% [44.3%, 61.8%]; P=0.02). Ten of the 12 AAS users showed LV ejection fractions below the accepted limit of normal (>= 55%). AAS users also demonstrated decreased diastolic function compared to nonusers as evidenced by a markedly lower early peak tissue velocity (7.4 [6.8, 7.9] cm/s versus 9.9 [8.3, 10.5] cm/s; P=0.005) and early-to-late diastolic filling ratio (0.93 [0.88, 1.39] versus 1.80 [1.48, 2.00]; P=0.003). Conclusions-Cardiac dysfunction in long-term AAS users appears to be more severe than previously reported and may be sufficient to increase the risk of heart failure. (Circ Heart Fail. 2010;3:472-476.) C1 [Baggish, Aaron L.; Weiner, Rory B.; Picard, Michael H.; Hutter, Adolph M., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Baggish, Aaron L.; Weiner, Rory B.; Picard, Michael H.; Hutter, Adolph M., Jr.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kanayama, Gen; Hudson, James I.; Pope, Harrison G., Jr.] McLean Hosp, Biol Psychiat Lab, Belmont, MA 02178 USA. [Kanayama, Gen; Hudson, James I.; Pope, Harrison G., Jr.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Baggish, AL (reprint author), Yawkey Ste 5B,55 Fruit St, Boston, MA 02114 USA. EM abaggish@partners.org OI Picard, Michael/0000-0002-9264-3243 FU National Institute on Drug Abuse [DA 016744] FX Supported in part by National Institute on Drug Abuse grant DA 016744 (to Drs Hudson, Kanayama, and Pope). NR 42 TC 58 Z9 59 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3289 EI 1941-3297 J9 CIRC-HEART FAIL JI Circ.-Heart Fail. PD JUL PY 2010 VL 3 IS 4 BP 472 EP U15 DI 10.1161/CIRCHEARTFAILURE.109.931063 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 628KN UT WOS:000280118600002 PM 20424234 ER PT J AU Zadra, G Priolo, C Patnaik, A Loda, M AF Zadra, Giorgia Priolo, Carmen Patnaik, Akash Loda, Massimo TI New Strategies in Prostate Cancer: Targeting Lipogenic Pathways and the Energy Sensor AMPK SO CLINICAL CANCER RESEARCH LA English DT Article ID ACTIVATED PROTEIN-KINASE; FATTY-ACID SYNTHASE; METABOLIC SYNDROME; DIETARY-FAT; JAPANESE POPULATION; INSULIN-RESISTANCE; LKB1-AMPK PATHWAY; DIABETIC-PATIENTS; REDUCED RISK; CELL-GROWTH AB Although the role of metabolic syndrome (MS) and a high fat diet in prostate cancer (PCa) risk is still a matter of intense debate, it is becoming increasingly clear that obesity can cause perturbations in metabolic pathways that contribute to the pathogenesis and progression of PCa. Moreover, prostate epithelial cells per se undergo a series of metabolic changes, including an increase in de novo lipogenesis, during the process of tumor formation. These metabolic alterations, at both the cellular and organismal levels, are intertwined with genetic aberrations necessary for neoplastic transformation. Thus, altered metabolism is currently subject to intense research efforts and might provide preventative and therapeutic opportunities, as well as a platform for biomarker development. In this article, we review evidence that the metabolic sensor 5'-AMP-activated protein kinase (AMPK), which physiologically integrates nutritional and hormonal signals and regulates cell survival and growth-related metabolic pathways to preserve intracellular ATP levels, represents a link between energy homeostasis and cancer. Thus, when AMPK is not activated, as in the setting of MS and obesity, systemic metabolic alterations permissive to the development of PCa are allowed to proceed unchecked. Hence, the use of AMPK activators and inhibitors of key lipogenic enzymes may represent a promising therapeutic strategy for PCa. Clin Cancer Res; 16(13); 3322-8. (C) 2010 AACR. C1 [Zadra, Giorgia; Priolo, Carmen; Loda, Massimo] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med Oncol, Boston, MA 02115 USA. [Patnaik, Akash] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Sch Med, Boston, MA 02115 USA. [Loda, Massimo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Loda, Massimo] Broad Inst, Cambridge, MA USA. RP Loda, M (reprint author), Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med Oncol, 44 Binney St,Dana 1536, Boston, MA 02115 USA. EM massimo_loda@dfci.harvard.edu FU Prostate Cancer Foundation; National Cancer Institute [RO1CA131945, PO1CA89021, P50 CA90381]; Linda and Arthur Gelb Center for Translational Research FX Prostate Cancer Foundation, the National Cancer Institute (RO1CA131945, PO1CA89021, and P50 CA90381), and the Linda and Arthur Gelb Center for Translational Research. NR 65 TC 38 Z9 41 U1 1 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 1 PY 2010 VL 16 IS 13 BP 3322 EP 3328 DI 10.1158/1078-0432.CCR-09-1955 PG 7 WC Oncology SC Oncology GA 619AR UT WOS:000279399200003 PM 20423984 ER PT J AU Eder, JP Shapiro, GI Appleman, LJ Zhu, AX Miles, D Keer, H Cancilla, B Chu, F Hitchcock-Bryan, S Sherman, L McCallum, S Heath, EI Boerner, SA LoRusso, PM AF Eder, Joseph Paul Shapiro, Geoffrey I. Appleman, Leonard J. Zhu, Andrew X. Miles, Dale Keer, Harold Cancilla, Belinda Chu, Felix Hitchcock-Bryan, Suzanne Sherman, Laurie McCallum, Stewart Heath, Elisabeth I. Boerner, Scott A. LoRusso, Patricia M. TI A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2 SO CLINICAL CANCER RESEARCH LA English DT Article ID HEPATOCELLULAR-CARCINOMA; INVASIVE GROWTH; HEPATOCYTE; EXPRESSION; CANCER; ANGIOGENESIS; OPINION; TARGET; CELLS AB Purpose: Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. We conducted a phase I, first-time-in-human, clinical trial using escalating doses of oral foretinib. The primary objectives are to identify a maximum tolerated dose and determine the safety profile of foretinib. Secondary objectives included evaluation of plasma pharmacokinetics, long-term safety after repeated administration, preliminary antitumor activity, and pharmacodynamic activity. Experimental Design: Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard measures exist. All patients received foretinib orally for 5 consecutive days every 14 days. Dose escalation followed a conventional "3+3" design. Results: Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non-dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tumor biopsies at submaximal doses. Conclusions: The recommended dose of foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials. Clin Cancer Res; 16(13); 3507-16. (C) 2010 AACR. C1 [Heath, Elisabeth I.; Boerner, Scott A.; LoRusso, Patricia M.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. [Eder, Joseph Paul; Shapiro, Geoffrey I.; Hitchcock-Bryan, Suzanne] Brigham & Womens Hosp, Early Drug Dev Ctr, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Eder, Joseph Paul; Shapiro, Geoffrey I.; Hitchcock-Bryan, Suzanne] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Zhu, Andrew X.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Appleman, Leonard J.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Miles, Dale; Keer, Harold; Cancilla, Belinda; Chu, Felix] Exelixis Inc, San Francisco, CA USA. [Sherman, Laurie; McCallum, Stewart] GlaxoSmithKline Inc, Collegeville, PA USA. RP LoRusso, PM (reprint author), Wayne State Univ, Karmanos Canc Inst, 4100 John R,Mailcode HW04HO, Detroit, MI 48201 USA. EM lorussop@karmanos.org OI Appleman, Leonard/0000-0003-4951-7388 FU GlaxoSmithKline; Exelixis, Inc. [NCT00742131]; GSK FX GlaxoSmithKline and Exelixis, Inc. (NCT00742131). All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Editorial support in the form copyediting, creation of figures, and formatting for submission was provided by Publication CONNEXION (Newtown, PA) and was funded by GSK. NR 26 TC 110 Z9 111 U1 0 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 1 PY 2010 VL 16 IS 13 BP 3507 EP 3516 DI 10.1158/1078-0432.CCR-10-0574 PG 10 WC Oncology SC Oncology GA 619AR UT WOS:000279399200022 PM 20472683 ER PT J AU Gaxiola, E Eng-Cecena, L Ortiz-Galvan, F Llamas-Lopez, L Rangel-Guerra, R Alcocer-Gamba, MA Bhatt, DL Steg, PG AF Gaxiola, Efrain Eng-Cecena, Luis Ortiz-Galvan, Fernando Llamas-Lopez, Leonardo Rangel-Guerra, Ricardo Alcocer-Gamba, Marco A. Bhatt, Deepak L. Steg, P. Gabriel CA REACH Registry Investigators TI Assessment of Atherothrombosis and Its Treatment in Mexico: First-Year Data of the REACH Registry SO CLINICAL CARDIOLOGY LA English DT Article ID CARDIOVASCULAR RISK-FACTORS; SECONDARY PREVENTION; VASCULAR-DISEASE; HEART-DISEASE; POPULATION; STATISTICS; GUIDELINES; UPDATE AB Background: Atherothrombosis, a generalized and progressive process, is currently a major healthcare problem in Mexico. Methods: The worldwide Reduction of Atherothrombosis for Continued Health (REACH) registry aimed to evaluate risk factors for atherosclerosis, long-term cardiovascular (CV) event rates, and current management of either patients with established symptomatic atherosclerotic disease or asymptomatic subjects with multiple risk factors for atherothrombotic disease. One-year follow-up of the global REACH database was available for 64 977 outpatients. This report includes the Mexican subregistry wherein 62 internists, cardiologists, and neurologists evaluated baseline patient characteristics, risk factors, medications, and CV event rates as primary outcomes at 1-year follow-up. Results: Complete 1-year follow-up data were available for 837 Mexicans. We observed a high prevalence of diabetes (47.1%), hypertension (74.7%), and hypercholesterolemia (57.8%). Antiplatelet, antihypertensive and/or glucose-lowering agents, and lipid-lowering drugs were used in 87.6%, 84.1%, and 61% of patients, respectively. The all-cause mortality rate was 3.3%. The composite outcome CV death/myocardial infarction/stroke/hospitalization for atherothrombotic events was higher in the symptomatic group (14.6%) than in asymptomatic subjects with multiple risk factors (5.1%; P = 0.01), similar to Latin American results of the global REACH report. The highest CV event rate occurred among symptomatic atherothrombotic patients with 3 vascular disease locations (30.2%), followed by those with 2 (21.9%) and a location (13.4%; P = 0.0006). Conclusions: Prevalence of risk factors and CV event rates including hospitalization in Mexican atherothrombotic patients was high despite the current medication use, which suggests it is necessary to have more aggressive risk-factor management. C1 [Gaxiola, Efrain] Jardines Hosp Especialidades, Dept Cardiol, ZC-45040 Zapopan, Jalisco, Mexico. [Llamas-Lopez, Leonardo] Hosp Reg Dr Valentin Gomez Farias, ISSSTE, Dept Neurol, Zapopan, Jalisco, Mexico. [Rangel-Guerra, Ricardo] Hosp Cristus Muguerza Alta Especialidad, Dept Neurol, Monterrey, Nuevo Leon, Mexico. [Alcocer-Gamba, Marco A.] Inst Corazon Queretaro, Dept Cardiol, Queretaro, Mexico. [Bhatt, Deepak L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bhatt, Deepak L.] VA Boston Healthcare Syst, Boston, MA USA. [Steg, P. Gabriel] Univ Paris, Ctr Hosp Bichat Claude Bernard, F-75252 Paris, France. RP Gaxiola, E (reprint author), Jardines Hosp Especialidades, Dept Cardiol, Av Manuel J Clouthier 669, ZC-45040 Zapopan, Jalisco, Mexico. EM gaxiola.efrain@gmail.com FU sanofi-aventis; Bristol-Myers Squibb; Waksman Foundation of Japan (Tokyo, Japan); Pfizer; Eli Lilly; Abbott Labs; Bayer; AstraZeneca; Schering-Plough; Abbott-Biogen Idec; Bayer Schering; Serono; Teva Pharmaceutical Industries; UCB; Bial; Supernus; Roche; Bayer HealthCare; Merck Sharp Dohme; Eisai; Ethicon; Heartscape; The Medicines Company FX The REACH registry is sponsored by sanofi-aventis, Bristol-Myers Squibb, and the Waksman Foundation of Japan (Tokyo, Japan). The REACH registry is endorsed by the World Heart Federation. A complete list of REACH investigators is accessible online at www.reachregistry.org. The REACH registry enforces a no-ghostwriting policy. This manuscript was written and edited by the authors, who take full responsibility for its content. The first draft was written by Dr. Efrain Gaxiola.; Dr. Efrain Gaxiola has received research grants from sanofi-aventis, speaker fees from Pfizer and Eli Lilly, and fees as an advisory board member from Abbott Labs and Pfizer. Dr. Luis Eng-Cecena has received speaker fees from sanofi-aventis, Pfizer, Bayer, and AstraZeneca, and fees as advisory board member from Schering-Plough. Dr. Fernando Ortiz-Galvan has received institutional research grants from sanofi-aventis and Abbott Labs. Dr. Leonardo Llamas-Lopez has received research grants from Bristol-Myers Squibb, Abbott-Biogen Idec, Bayer Schering, Serono, and Teva Pharmaceutical Industries. Dr. Ricardo Rangel-Guerra has received research grants from Bristol-Myers Squibb, UCB, Pfizer, Bial, Supernus, and Roche. Dr. Marco Alcocer-Gamba has received research grants from AstraZeneca, Bristol-Myers Squibb, sanofi-aventis, Bayer HealthCare, Pfizer, and Merck Sharp & Dohme. Dr. Deepak L. Bhatt has received institutional research grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, sanofi-aventis, and The Medicines Company. Dr. P. Gabriel Steg has received research grants from sanofi-aventis (significant); is on the speakers' bureau (all modest) for Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Nycomed, sanofi-aventis, Servier, and The Medicines Company; and is a consultant/advisory board member (all modest) for Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Endotis Pharma, GlaxoSmithKline, Medtronic, Merck Sharp & Dohme, Nycomed, sanofi-aventis, Servier, and The Medicines Company. NR 18 TC 3 Z9 3 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0160-9289 J9 CLIN CARDIOL JI Clin. Cardiol. PD JUL PY 2010 VL 33 IS 7 BP 445 EP 451 DI 10.1002/clc.20800 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 631MP UT WOS:000280351800010 PM 20641123 ER PT J AU Zanni, MV Stanley, TL Makimura, H Chen, CY Grinspoon, SK AF Zanni, Markella V. Stanley, Takara L. Makimura, Hideo Chen, Cindy Y. Grinspoon, Steven K. TI Effects of TNF-alpha antagonism on E-selectin in obese subjects with metabolic dysregulation SO CLINICAL ENDOCRINOLOGY LA English DT Article ID SOLUBLE E-SELECTIN; INTERCELLULAR-ADHESION MOLECULE-1; NF-KAPPA-B; DIABETES-MELLITUS; RHEUMATOID-ARTHRITIS; PSORIATIC-ARTHRITIS; INSULIN-RESISTANCE; CIRCULATING LEVELS; ENDOTHELIAL-CELLS; ATHEROSCLEROSIS AB Objective Endothelial adhesion molecules like E-selectin play an important role in leukocyte recruitment and development of atherosclerotic plaque. E-selectin is increased in obesity, yet little is known regarding the specific factors contributing to elevated E-selectin in obesity and whether tumour necrosis factor alpha (TNF-alpha) increases E-selectin in vivo in this population. The objectives of this study were to: (1) determine the body composition, metabolic and inflammatory factors associated with increased E-selectin and (2) determine the role of TNF-alpha in the physiological regulation of E-selectin by antagonism of TNF-alpha with etanercept among obese subjects. Methods E-selectin levels, body composition, metabolic parameters and inflammatory cytokines were assessed in 51 obese subjects and 37 non-obese healthy controls. Obese subjects were randomized to etanercept 50 mg weekly or placebo for 4 weeks. Changes in E-selectin were compared between treatment groups. Results Obese subjects had higher E-selectin than non-obese controls (47.4 [32.7-58.8] vs. 27.2 [20.3-42.1] ng/ml, obese vs. non-obese, P < 0.0001). E-selectin was significantly associated with multiple body composition measures and metabolic parameters, along with specific measures of TNF-alpha activation, including soluble tumour necrosis factor receptors 1 (P - 0.03) and 2 (P = 0.02). In multivariate modelling, visceral adipose tissue, but not other measures of body composition, remained significantly associated with E-selectin. Among obese subjects, treatment with etanercept significantly decreased E-selectin (-5.7 +/- 8.7 vs. 0.5 +/- 6.0 ng/ml, etanercept vs. placebo, P = 0.005). Conclusions E-selectin is increased in obesity, in relationship to increased visceral adiposity and markers of TNF-alpha activation. TNF-alpha antagonism with etanercept reduces E-selectin in obese subjects, providing evidence that the systemic circulatory release of E-selectin is regulated at least in part by TNF-alpha in obesity. C1 [Grinspoon, Steven K.] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Grinspoon, SK (reprint author), Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU Amgen; NIH [M01-RR-01066, 1 UL1 RR025758-01, K24 DK064545]; National Center for Research Resources; Harvard Clinical and Translational Science Center FX The authors would like to thank the patients for their commitment to the study, as well as the nursing staff of the Massachusetts Institute of Technology Clinical Research Center and the Massachusetts General Hospital Clinical Research Center for their dedicated patient care. Funding was provided by Amgen in the form of an investigator initiated research grant and NIH M01-RR-01066 and 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center, from the National Center for Research Resources. NIH funding also provided by K24 DK064545 to Steven K. Grinspoon. There are no financial conflicts to disclose. Clinical trials.gov identifier is NCT00409318. NR 35 TC 12 Z9 13 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD JUL PY 2010 VL 73 IS 1 BP 48 EP 54 DI 10.1111/j.1365-2265.2009.03741.x PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 612QR UT WOS:000278917100008 PM 19878508 ER PT J AU Jacobson, KR Tierney, DB Jeon, CY Mitnick, CD Murray, MB AF Jacobson, Karen R. Tierney, Dylan B. Jeon, Christie Y. Mitnick, Carole D. Murray, Megan B. TI Treatment Outcomes among Patients with Extensively Drug-Resistant Tuberculosis: Systematic Review and Meta-Analysis SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID HIV-INFECTED PATIENTS; MULTIDRUG-RESISTANT; MYCOBACTERIUM-TUBERCULOSIS; UNITED-STATES; EPIDEMIOLOGY; TB; FLUOROQUINOLONES; MANAGEMENT; PREDICTORS; MUTATIONS AB Background. The treatment of extensively drug-resistant tuberculosis (XDR TB) presents a major challenge. Second-line antimycobacterial drugs are less effective, more toxic, and more costly than first-line agents, and XDR TB strains are, by definition, resistant to the most potent second-line options: the injectable agents and fluoroquinolones. We conducted a meta-analysis to assess XDR TB treatment outcomes and to identify therapeutic approaches associated with favorable responses. Methods. We searched PubMed and EMBASE databases to identify studies conducted through May 2009 that report XDR TB treatment outcomes. Results. The search yielded 13 observational studies covering 560 patients, of whom 43.7% (95% confidence interval, 32.8%-54.5%) experienced favorable outcomes, defined as either cure or treatment completion, and 20.8% (95% confidence interval, 14.2%-27.3%) died. Random effects meta-analysis and meta-regression showed that studies in which a higher proportion of patients received a later-generation fluoroquinolone reported a higher proportion of favorable treatment outcomes (P=.012). Conclusions. This meta-analysis provides the first empirical evidence that the use of later-generation fluoroquinolones for the treatment of XDR TB significantly improves treatment outcomes, even though drug-susceptibility testing demonstrates resistance to a representative fluoroquinolone. These results suggest that the addition of later-generation fluoroquinolones to XDR TB regimens may improve treatment outcomes and should be systematically evaluated in well-designed clinical studies. C1 [Jacobson, Karen R.; Tierney, Dylan B.; Murray, Megan B.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Jeon, Christie Y.; Murray, Megan B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Mitnick, Carole D.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA USA. [Murray, Megan B.] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. RP Jacobson, KR (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St,GRJ5-5, Boston, MA 02114 USA. EM krjacobson@partners.org OI Jacobson, Karen/0000-0003-4239-3685 FU National Institutes of Health FX National Institutes of Health (T32 to K.R.J. and D.B.T.). NR 40 TC 146 Z9 152 U1 2 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2010 VL 51 IS 1 BP 6 EP 14 DI 10.1086/653115 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 605VM UT WOS:000278375100002 PM 20504231 ER PT J AU Fishbain, J Peleg, AY AF Fishbain, Joel Peleg, Anton Y. TI Treatment of Acinetobacter Infections SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID VENTILATOR-ASSOCIATED PNEUMONIA; NEGATIVE BACTERIAL-INFECTIONS; CARBAPENEM-RESISTANT ACINETOBACTER; BAUMANNII-CALCOACETICUS COMPLEX; CRITICALLY-ILL PATIENTS; BLOOD-STREAM INFECTION; PSEUDOMONAS-AERUGINOSA; AMPICILLIN-SULBACTAM; ATTRIBUTABLE MORTALITY; COMBINATION THERAPY AB Acinetobacter baumannii remains an important and difficult-to-treat pathogen whose resistance patterns result in significant challenges for the clinician. Despite the prevalence and interest in A. baumannii infections, there is relatively limited well-controlled scientific data to help the clinician select optimal empirical and subsequent targeted therapy for a variety of infections. We will review the currently available antimicrobial agents and discuss the clinical data supporting the use of the various agents. C1 [Fishbain, Joel] St John Hosp & Med Ctr, Div Infect Dis, Detroit, MI USA. [Peleg, Anton Y.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Peleg, Anton Y.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Peleg, Anton Y.] Alfred Hosp, Melbourne, Vic, Australia. [Peleg, Anton Y.] Monash Univ, Dept Microbiol, Melbourne, Vic 3004, Australia. RP Fishbain, J (reprint author), St John Hosp & Med Ctr, Div Infect Dis, 19251 Mack Ave,Ste 333, Grosse Pointe Woods, MI 48236 USA. EM Joel.Fishbain@stjohn.org OI Peleg, Anton/0000-0002-2296-2126 NR 43 TC 106 Z9 128 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2010 VL 51 IS 1 BP 79 EP 84 DI 10.1086/653120 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 605VM UT WOS:000278375100013 PM 20504234 ER PT J AU Walensky, RP Ciaranello, AL Park, JE Freedberg, KA AF Walensky, Rochelle P. Ciaranello, Andrea L. Park, Ji-Eun Freedberg, Kenneth A. TI Cost-Effectiveness of Laboratory Monitoring in Sub-Saharan Africa: A Review of the Current Literature SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID RESOURCE-LIMITED SETTINGS; ANTIRETROVIRAL THERAPY; POOR SETTINGS; STRATEGIES AB As the global community evaluates the unprecedented investment in the scale-up of human immunodeficiency virus (HIV) therapy and considers future investments in HIV care, it is crucial to identify those HIV interventions that maximize the benefit realized from each dollar spent. The use of laboratory monitoring assays-CD4 cell count and HIV RNA level-in decisions about when to initiate and switch antiretroviral therapy may offer substantial clinical benefit, but their economic value remains controversial. Cost-effectiveness analysis can be used to evaluate the value for money of strategies for HIV care, including alternative approaches to laboratory monitoring. Five published cost-effectiveness analyses address the question of CD4 cell count and HIV RNA level monitoring for HIV-infected patients in Africa, with differing conclusions. We describe the use of cost-effectiveness analysis in resource-limited settings and review the cost-effectiveness literature with regard to monitoring the CD4 cell count and HIV RNA level in Africa, highlighting some of the most critical issues in this debate. C1 [Walensky, Rochelle P.; Park, Ji-Eun; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MA 02114 USA. [Walensky, Rochelle P.; Ciaranello, Andrea L.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Div Infect Dis, Dept Med, Boston, MA 02114 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Harvard Univ Ctr AIDS Res, Boston, MA USA. [Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Walensky, RP (reprint author), Massachusetts Gen Hosp, Div Gen Med, Dept Med, 50 Staniford St,9th Fl, Boston, MA 02114 USA. EM rwalensky@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU National Institute of Allergy and Infectious Diseases [R01 AI058736, K24 AI062476, P30 AI060354, K01 AI078754]; Doris Duke Charitable Foundation; Elizabeth Glaser Pediatric AIDS Foundation FX National Institute of Allergy and Infectious Diseases (R01 AI058736, K24 AI062476, P30 AI060354, K01 AI078754), the Doris Duke Charitable Foundation (Clinical Scientist Development Award), and the Elizabeth Glaser Pediatric AIDS Foundation. NR 29 TC 26 Z9 26 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2010 VL 51 IS 1 BP 85 EP 92 DI 10.1086/653119 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 605VM UT WOS:000278375100014 PM 20482371 ER PT J AU San-juan, D Chiappa, KH Cole, AJ AF San-juan, Daniel Chiappa, Keith H. Cole, Andrew J. TI Propofol and the electroencephalogram SO CLINICAL NEUROPHYSIOLOGY LA English DT Review DE EEG; Electroencephalogram; Propofol; Anesthetics; Sedation ID REFRACTORY STATUS EPILEPTICUS; RAT HIPPOCAMPAL SLICES; SEIZURE-LIKE PHENOMENA; INTENSIVE-CARE UNIT; ELECTROCONVULSIVE-THERAPY; BURST-SUPPRESSION; ANESTHETIC AGENTS; TRACHEAL INTUBATION; BISPECTRAL INDEX; SPECTRAL ENTROPY AB Propofol is an emulsion formulation of 2,6 diisopropylphenol developed in 1975. Widely recognized, it offers beneficial effects compared with other sedative drugs. Propofol is used in several clinical situations including multiple surgical procedures and critical-care medical conditions. Since technological advances over recent years have allowed an ever-increasing number of patients undergoing propofol therapy to be monitored by using continuous digital EEG, it is important to have a complete understanding of the effects of propofol on EEG in diverse clinical scenarios. This paper presents a review of the effects of propofol in electroencephalograms and discusses proconvulsive, anticonvulsive proprieties and the EEG findings in different medical conditions. (C) 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [San-juan, Daniel; Chiappa, Keith H.; Cole, Andrew J.] Massachusetts Gen Hosp, Neurophysiol Serv, Boston, MA 02114 USA. RP San-juan, D (reprint author), MGH Epilepsy Serv, 55 Fruit St, Boston, MA 02114 USA. EM pegaso31@yahoo.com NR 103 TC 27 Z9 28 U1 2 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUL PY 2010 VL 121 IS 7 BP 998 EP 1006 DI 10.1016/j.clinph.2009.12.016 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 603QE UT WOS:000278222300005 PM 20071229 ER PT J AU Kawai, T Cosimi, AB AF Kawai, Tatsuo Cosimi, A. Benedict TI Induction of tolerance in clinical kidney transplantation SO CLINICAL TRANSPLANTATION LA English DT Review ID RENAL-ALLOGRAFT REJECTION; TOTAL LYMPHOID IRRADIATION; RETRACTED ARTICLE. SEE; MONOCLONAL-ANTIBODY; CYNOMOLGUS MONKEYS; NONHUMAN-PRIMATES; MIXED CHIMERISM; BONE-MARROW; LYMPHOHEMATOPOIETIC CHIMERISM; MULTIPLE-MYELOMA AB Induction of donor-specific tolerance has been an ultimate goal in organ transplantation. Although numerous regimens for the induction of allograft tolerance have been developed in rodents, their application to primates has been limited. The approaches that have been successfully applied in primates can be divided into (i) use of total lymphoid irradiation, (ii) costimulatory blockade, (iii) profound depletion of recipient T cells, (iv) infusion of regulatory cells and (v) donor bone marrow (DBM) infusion/transplantation. Among these approaches, successful allograft tolerance has been achieved in clinical kidney transplantation using DBM transplantation. C1 [Kawai, Tatsuo; Cosimi, A. Benedict] Harvard Univ, Transplant Ctr, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kawai, T (reprint author), Harvard Univ, Transplant Ctr, Sch Med, Massachusetts Gen Hosp, Whte 521,55 Fruit St, Boston, MA 02114 USA. EM tatkawai@verizon.net FU NHLBI NIH HHS [P01 HL018646]; NIDDK NIH HHS [U19 DK080652] NR 42 TC 6 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0902-0063 J9 CLIN TRANSPLANT JI Clin. Transplant. PD JUL PY 2010 VL 24 SU 22 BP 2 EP 5 DI 10.1111/j.1399-0012.2010.01268.x PG 4 WC Surgery; Transplantation SC Surgery; Transplantation GA 606CE UT WOS:000278397600002 PM 20590685 ER PT J AU Shimizu, A Yamada, K AF Shimizu, Akira Yamada, Kazuhiko TI Histopathology of xenografts in pig to non-human primate discordant xenotransplantation SO CLINICAL TRANSPLANTATION LA English DT Review DE alpha 1; 3-galactosyltransferase; acute cellular xenograft rejection; acute humoral xenogarft rejection; chronic xenograft rejection; hyperacute rejection; pig; xenotransplantation ID DECAY-ACCELERATING FACTOR; GENE-KNOCKOUT PIGS; THROMBOTIC MICROANGIOPATHY; CARDIAC XENOGRAFTS; NUCLEAR TRANSFER; KO PIGS; REJECTION; BABOONS; TRANSPLANTATION; ACTIVATION AB Xenotransplantation could provide a solution to the critical shortage of organs for transplantation in humans. Swine have been proposed as a suitable donor species. Swine organs, however, when transplanted to primates, are rapidly rejected by hyperacute rejection (HAR) and acute humoral xenograft rejection (AHXR). Both HAR and AHXR are triggered by xenoreactive natural antibodies directed against a specific epitope (galactose alpha 1-3 galactose: Gal) on porcine vascular endothelium. In attempt to prevent HAR and AHXR, alpha 1,3-galactosyltransferase gene knockout (GalT-KO) pigs have been produced. GalT-KO pig organs do not express the Gal epitope (antigen), and it therefore can eliminate the anti-Gal antibody - Gal antigen immunoreaction in xenotransplantation. We reported our initial study of kidney transplantation from GalT-KO miniature swine to baboons with either immunosuppression protocol or with a tolerance inducing protocol. Here, we discussed the pathology of xenografts in GalT-KO pig to non-human primate kidney transplantation. C1 [Shimizu, Akira] Nippon Med Sch, Dept Pathol, Bunkyo Ku, Tokyo 1138602, Japan. [Shimizu, Akira; Yamada, Kazuhiko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA. RP Shimizu, A (reprint author), Nippon Med Sch, Dept Pathol, Bunkyo Ku, 1-1-5 Sendagi, Tokyo 1138602, Japan. EM ashimizu@nms.ac.jp FU Japanese Society for the Promotion of Science [C 18591787, C20591900] FX This research was supported in part by grants from the Japanese Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C 18591787, C20591900). NR 41 TC 7 Z9 7 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0902-0063 J9 CLIN TRANSPLANT JI Clin. Transplant. PD JUL PY 2010 VL 24 SU 22 BP 11 EP 15 DI 10.1111/j.1399-0012.2010.01270.x PG 5 WC Surgery; Transplantation SC Surgery; Transplantation GA 606CE UT WOS:000278397600004 PM 20590687 ER PT J AU Freudenreich, O AF Freudenreich, Oliver TI TARGETED CARE PLANS FOR SCHIZOPHRENIA SO CNS SPECTRUMS LA English DT Article C1 [Freudenreich, Oliver] Harvard Univ, Sch Med, Psychiat, Cambridge, MA 02138 USA. [Freudenreich, Oliver] Massachusetts Gen Hosp, Early Psychosis Program, Boston, MA 02114 USA. RP Freudenreich, O (reprint author), Harvard Univ, Sch Med, Psychiat, Cambridge, MA 02138 USA. NR 27 TC 0 Z9 0 U1 2 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1092-8529 EI 2165-6509 J9 CNS SPECTRUMS JI CNS Spectr. PD JUL PY 2010 VL 15 IS 7 SU 8 BP 6 EP 9 DI 10.1017/S1092852900004284 PG 4 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA V44BR UT WOS:000209725000002 ER PT J AU Nierenberg, AA AF Nierenberg, Andrew A. TI Are We Losing Our Minds? SO CNS SPECTRUMS LA English DT Editorial Material C1 [Nierenberg, Andrew A.] Harvard Univ, Sch Med, Boston, MA USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. RP Nierenberg, AA (reprint author), Harvard Univ, Sch Med, Boston, MA USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1092-8529 EI 2165-6509 J9 CNS SPECTRUMS JI CNS Spectr. PD JUL PY 2010 VL 15 IS 7 BP 416 EP 417 DI 10.1017/S1092852900000341 PG 2 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA V44BQ UT WOS:000209724900001 PM 20625363 ER PT J AU Simon, NM Worthington, JJ Moshier, SJ Marks, EH Hoge, EA Brandes, M Delong, H Pollack, MH AF Simon, Naomi M. Worthington, John J. Moshier, Samantha J. Marks, Elizabeth H. Hoge, Elizabeth A. Brandes, Mina Delong, Hannah Pollack, Mark H. TI Duloxetine for the Treatment of Generalized Social Anxiety Disorder: A Preliminary Randomized Trial of Increased Dose to Optimize Response SO CNS SPECTRUMS LA English DT Article AB Objective:This is the first trial examining duloxetine for generalized social anxiety disorder (GSAD) and the effect of increased dose for those without early remission. Methods: Individuals (n=39) with GSAD received 6 weeks of open-label duloxetine 60 mg/day; those with a Liebowitz Social Anxiety Disorder Scale (LSAS) score >30 at week 6 were randomized in double-blind fashion to an additional 18 weeks of continued duloxetine 60 mg/day or to duloxetine 120 mg/day. Results: Duloxetine was associated with a significant LSAS reduction at week 6 (91.3 [17.7] to 69.8 [28.5], paired t [df]=5.2 [38], P<.0001), and randomized participants overall continued to improve at week 24 (74.6 [23.9] to 60.3 [29.7]; paired t [df]=3.3 [27], P=.0026). Though the increased dose strategy was associated with a moderate effect size (Cohen's d=.57), there was no significant difference at week 24 endpoint in LSAS reduction (20.5 [26.0] versus 7.3 [17.2], t [df]=1.6 [26], P=.13) nor remission (33% versus 8%) for duloxetine with dose increased to 120 mg/day compared to duloxetine continued at 60 mg/day. Overall, 44% (17/39) discontinued prior to week 24. Conclusions:Though with limited power, these data provide preliminary support for the efficacy of duloxetine for GSAD, and suggest continued improvement but limited remission overall at 24 weeks for individuals remaining symptomatic at week 6. These observations warrant further controlled study. C1 [Simon, Naomi M.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Simches Res Bldg,2nd Floor,185 Cambridge St, Boston, MA 02114 USA. [Worthington, John J.; Moshier, Samantha J.; Marks, Elizabeth H.; Hoge, Elizabeth A.; Brandes, Mina; Delong, Hannah; Pollack, Mark H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Simon, NM (reprint author), Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Simches Res Bldg,2nd Floor,185 Cambridge St, Boston, MA 02114 USA. EM nsimon@partners.org RI Hoge, Elizabeth/H-5879-2012 OI Hoge, Elizabeth/0000-0002-5513-2292 FU Eli Lilly; Investigator Initiated Research Study grant FX This study was funded by an Investigator Initiated Research Study grant to Dr. Simon from Eli Lilly. NR 23 TC 3 Z9 3 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1092-8529 EI 2165-6509 J9 CNS SPECTRUMS JI CNS Spectr. PD JUL PY 2010 VL 15 IS 7 BP 436 EP 443 DI 10.1017/S1092852900000365 PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA V44BQ UT WOS:000209724900003 ER PT J AU Katon, W Lin, EHB Von Korff, M Ciechanowski, P Ludman, E Young, B Rutter, C Oliver, M McGregor, M AF Katon, Wayne Lin, Elizabeth H. B. Von Korff, Michael Ciechanowski, Paul Ludman, Evette Young, Bessie Rutter, Carolyn Oliver, Malia McGregor, Mary TI Integrating depression and chronic disease care among patients with diabetes and/or coronary heart disease: The design of the TEAMcare study SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Diabetes; Depression; Coronary heart disease; TEAMcare study ID RANDOMIZED CONTROLLED-TRIAL; LONGER-TERM OUTCOMES; COLLABORATIVE CARE; COST-EFFECTIVENESS; MAJOR DEPRESSION; MYOCARDIAL-INFARCTION; CHRONIC ILLNESS; COMORBID DEPRESSION; MEDICAL ILLNESS; OLDER PATIENTS AB Diabetes and coronary heart disease (CHD) are two of the most prevalent medical illnesses in the US population and comorbid depression occurs in up to 20% of these patients. Guidelines for management of diabetes and CHD overlap for healthy lifestyle and disease-control recommendations. However, the majority of patients with these medical illnesses have been shown to have inadequate control of key risk factors such as blood pressure, LDL cholesterol, or blood sugar. Comorbid depression has been shown to adversely affect self-care of diabetes and CHD, and is associated with an increased risk of complications and mortality. Interventions that have improved quality and outcomes of depression care alone in patients with diabetes and CHD have not demonstrated benefits in self-care, improved disease control or morbidity and mortality. This paper describes the design and development of a new biopsychosocial intervention (TEAMcare) aimed at improving both medical disease control and depression in patients with poor control of diabetes and/or CHD who met the criteria for comorbid depression. A team approach is used with a nurse interventionist who receives weekly psychiatric and primary care physician caseload supervision in order to enhance treatment by the primary care physician. This intervention is being tested in an NIMH-funded randomized controlled trial in a large integrated health plan. (C) 2010 Elsevier Inc. All rights reserved. C1 [Katon, Wayne; Ciechanowski, Paul] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Lin, Elizabeth H. B.; Von Korff, Michael; Ludman, Evette; Rutter, Carolyn; Oliver, Malia; McGregor, Mary] Grp Hlth Res Inst, Seattle, WA USA. [Young, Bessie] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Young, Bessie] Vet Affairs Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA USA. RP Katon, W (reprint author), Univ Washington, Sch Med, Dept Psychiat & Behav Sci, 1959 NE Pacific St,Box 356560, Seattle, WA 98195 USA. EM wkaton@uw.edu FU National Institute of Mental Health [MH41739, K24 MH069741] FX This research was supported by grants from the National Institute of Mental Health to Dr. Katon (MH41739 and K24 MH069741). NR 61 TC 41 Z9 41 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JUL PY 2010 VL 31 IS 4 BP 312 EP 322 DI 10.1016/j.cct.2010.03.009 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 627HX UT WOS:000280031200008 PM 20350619 ER PT J AU Jarrett, RB Thase, ME AF Jarrett, Robin B. Thase, Michael E. TI Comparative efficacy and durability of continuation phase cognitive therapy for preventing recurrent depression: Design of a double-blinded, fluoxetine- and pill placebo-controlled, randomized trial with 2-year follow-up SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Relapse prevention; Recurrent depression; Cognitive therapy; Fluoxetine; Longitudinal follow-up ID PSYCHOMETRIC PROPERTIES; UNIPOLAR DEPRESSION; RELAPSE PREVENTION; RATING-SCALE; PSYCHOTHERAPY; INVENTORY; MOOD; QUALITY; ANTIDEPRESSANTS; PHARMACOTHERAPY AB Background: Major Depressive Disorder (MDD) is highly prevalent and associated with disability and chronicity. Although cognitive therapy (CT) is an effective short-term treatment for MDD, a significant proportion of responders subsequently suffer relapses or recurrences. Purpose: This design prospectively evaluates: 1) a method to discriminate CT-treated responders at lower vs. higher risk for relapse; and 2) the subsequent durability of 8-month continuation phase therapies in randomized higher risk responders followed for an additional 24 months. The primary prediction is: after protocol treatments are stopped, higher risk patients randomly assigned to continuation phase CT (C-CT) will have a lower risk of relapse/ recurrence than those randomized to fluoxetine (FLX). Methods: Outpatients, aged 18 to 70 years, with recurrent MDD received 12-14 weeks of CT provided by 15 experienced therapists from two sites. Responders (i.e., no MOD and 17-item Hamilton Rating Scale for Depression <= 12) were stratified into higher and lower risk groups based on stability of remission during the last 6 weeks of CT. The lower risk group entered follow-up for 32 months; the higher risk group was randomized to 8 months of continuation phase therapy with either C-CT or clinical management plus either double-blinded FLX or pill placebo. Following the continuation phase, higher risk patients were followed by blinded evaluators for 24 months. Results: The trial began in 2000. Enrollment is complete (n = 523). The follow-up continues. Conclusions: The trial evaluates the preventive effects and durability of acute and continuation phase treatments in the largest known sample of CT responders collected worldwide. (C) 2010 Published by Elsevier Inc. C1 [Jarrett, Robin B.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Thase, Michael E.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Thase, Michael E.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Thase, Michael E.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. RP Jarrett, RB (reprint author), Univ Texas SW Med Ctr Dallas, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Robin.Jarrett@UTSouthwestern.edu; Thase@Mail.Med.UPenn.edu FU National Institute of Mental Health [K24-MH001571, R01 MH-58397, R01 MH-69219, R01 MH-58356, R01 MH-69618] FX This report was supported by Grants Number K24-MH001571, R01 MH-58397, R01 MH-69219 (to Robin B. Jarrett, Ph.D.) and R01 MH-58356 and R01 MH-69618 (to Michael E. Thase, M.D.) from the National Institute of Mental Health. We appreciate the support of our NIMH Program Officer, Jane Pearson, Ph.D., throughout this investigation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National institute of Mental Health (NIMH) or the National Institutes of Health (NIH). We also wish to acknowledge the unrestricted support of Eli Lilly and Company, who provided the fluoxetine and matched pill placebo until 2006. Thereafter, study materials were purchased and prepared to appear identical for both sites by the pharmacy at the University of Texas Southwestern Medical Center at Dallas. NR 66 TC 22 Z9 22 U1 4 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JUL PY 2010 VL 31 IS 4 BP 355 EP 377 DI 10.1016/j.cct.2010.04.004 PG 23 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 627HX UT WOS:000280031200012 PM 20451668 ER PT J AU Stoodley, CJ Schmahmann, JD AF Stoodley, Catherine J. Schmahmann, Jeremy D. TI Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing SO CORTEX LA English DT Article DE Cognition; Motor; Limbic; Dysmetria; Imaging; Connections ID VERBAL WORKING-MEMORY; ATAXIA RATING-SCALE; POSITRON-EMISSION-TOMOGRAPHY; ANTERIOR CINGULATE CORTEX; POSTERIOR-FOSSA TUMORS; WORD-STEM COMPLETION; LONG-TERM SEQUELAE; BLOOD-FLOW CHANGES; FUNCTIONAL MRI; RHESUS-MONKEY AB Patients with cerebellar damage often present with the cerebellar motor syndrome of dysmetria, dysarthria and ataxia, yet cerebellar lesions can also result in the cerebellar cognitive affective syndrome (CCAS), including executive, visual spatial, and linguistic impairments, and affective dysregulation. We have hypothesized that there is topographic organization in the human cerebellum such that the anterior lobe and lobule VIII contain the representation of the sensorimotor cerebellum; lobules VI and VII of the posterior lobe comprise the cognitive cerebellum; and the posterior vermis is the anatomical substrate of the limbic cerebellum. Here we analyze anatomical, functional neuroimaging, and clinical data to test this hypothesis. We find converging lines of evidence supporting regional organization of motor, cognitive, and limbic behaviors in the cerebellum. The cerebellar motor syndrome results when lesions involve the anterior lobe and parts of lobule VI, interrupting cerebellar communication with cerebral and spinal motor systems. Cognitive impairments occur when posterior lobe lesions affect lobules VI and VII (including Crus I, Crus II, and lobule VIIB), disrupting cerebellar modulation of cognitive loops with cerebral association cortices. Neuropsychiatric disorders manifest when vermis lesions deprive cerebro-cerebellar-limbic loops of cerebellar input. We consider this functional topography to be a consequence of the differential arrangement of connections of the cerebellum with the spinal cord, brainstem, and cerebral hemispheres, reflecting cerebellar incorporation into the distributed neural circuits subserving movement, cognition, and emotion. These observations provide testable hypotheses for future investigations. (C) 2009 Elsevier Srl. All rights reserved. C1 [Stoodley, Catherine J.] Massachusetts Gen Hosp, Dept Neurol, Ataxia Unit, Cognit Behav Neurol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Stoodley, CJ (reprint author), Massachusetts Gen Hosp, Dept Neurol, Ataxia Unit, Cognit Behav Neurol Unit, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM cstoodley@partners.org RI Stoodley, Catherine/P-2081-2016 OI Stoodley, Catherine/0000-0003-2629-0213 FU Birmingham Foundation; Executive Committee on Research of Massachusetts General Hospital; [R01 MH067980] FX This work was supported in part by R01 MH067980, the Birmingham Foundation, and a Fund for Medical Discovery Award to CJS from the Executive Committee on Research of Massachusetts General Hospital. NR 229 TC 323 Z9 332 U1 8 U2 44 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD JUL-AUG PY 2010 VL 46 IS 7 SI SI BP 831 EP 844 DI 10.1016/j.cortex.2009.11.008 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 614OJ UT WOS:000279069200003 PM 20152963 ER PT J AU Querques, J Kontos, N Freudenreich, O AF Querques, John Kontos, Nicholas Freudenreich, Oliver TI Determination of decision-making capacity: A first step SO CRITICAL CARE MEDICINE LA English DT Letter ID CONSENT C1 [Querques, John; Kontos, Nicholas; Freudenreich, Oliver] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Querques, J (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. NR 3 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUL PY 2010 VL 38 IS 7 BP 1614 EP 1615 DI 10.1097/CCM.0b013e3181db7e6b PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 612RL UT WOS:000278920000025 PM 20562557 ER PT J AU Camargo, CA Sutherland, ER Bailey, W Castro, M Yancey, SW Emmett, AH Stempel, DA AF Camargo, Carlos A., Jr. Sutherland, E. Rand Bailey, William Castro, Mario Yancey, Steven W. Emmett, Amanda H. Stempel, David A. TI Effect of increased body mass index on asthma risk, impairment and response to asthma controller therapy in African Americans SO CURRENT MEDICAL RESEARCH AND OPINION LA English DT Article DE African American; Asthma; Body mass index; Fluticasone propionate; Salmeterol ID AIRWAY HYPERRESPONSIVENESS; OBESITY; WEIGHT; FLUTICASONE; PREVALENCE; SALMETEROL; OVERWEIGHT; WOMEN AB Objective: To explore whether obesity alters the risk, impairment and response to treatment in African Americans with asthma. Methods: The data used for this secondary analysis are from a 1-year study in African American subjects comparing fluticasone propionate/salmeterol 100/50 mu g combination (FSC) and fluticasone propionate 100 mu g (FP). Subjects were retrospectively stratified by body mass index (BMI) <20 [underweight], 20-24.9 [normal weight], 25-29.9 [overweight], 30-34.9 [obese I], 35-39.9 [obese II], and >= 40 [obese III] kg/m(2). Outcomes studied included impairment domains: FEV(1), morning and evening peak expiratory flow (AM and PM PEF), daily albuterol use, daily symptom scores and future risk domain: exacerbations. Clinical trial registration: www.clinicaltrials.gov; NCT00102765 Results: There were 475 subjects evenly distributed between FSC and FP by baseline parameters. There were 207 subjects with a BMI >= 30, including 70 subjects with a BMI >= 40. Baseline BMI >= 40 was associated with numerically lower baseline AM and PM PEF. There was an attenuation of response to both treatments for only PM PEF (p < 0.05). By contrast, subjects with lower degrees of obesity or overweight did not differ from those with normal weight. The total population exacerbation rate was 2-fold greater in obese III subjects (39%) compared with subjects in other BMI categories (16-21%) (p < 0.05). A potential study limitation is the retrospective analysis of existing data. Discussion: Response to treatment was attenuated for PM PEF for subjects with BMI >= 40 and was also associated with an increased rate of asthma exacerbations. C1 [Yancey, Steven W.; Emmett, Amanda H.; Stempel, David A.] GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Sutherland, E. Rand] Natl Jewish Hlth, Denver, CO USA. [Bailey, William] Univ Alabama, Birmingham, AL USA. [Castro, Mario] Washington Univ, Sch Med, St Louis, MO USA. RP Stempel, DA (reprint author), GlaxoSmithKline Inc, 5 Moore Dr,POB 13398, Res Triangle Pk, NC 27709 USA. EM david.a.stempel@gsk.com FU GlaxoSmithKline; AstraZeneca; Dey; Genentech; GSK; Merck; Novartis; Respironics; Schering-Plough; Boehringer-Ingelheim; NIH; CMRO; NovoNordisk FX Funding for this research was provided by GlaxoSmithKline.; C. A. C. has received financial support from a variety of groups for participation in conferences, consulting, and medical research; industry sponsors with an interest in asthma: AstraZeneca, Dey, Genentech, GSK, Merck, Novartis, Respironics, and Schering-Plough. E. R. S. serves as a consultant or advisor to Dey, GlaxoSmithKline and Schering-Plough and has research grants from Boehringer-Ingelheim, NIH and Novartis. W. B. has received research grants from Boehringer-Ingelheim and GlaxoSmithKline; consulted for AstraZeneca and GlaxoSmithKline; and is on the speakers' bureaus of AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, and Pfizer. M. C. has no conflicts to report. S. W. Y., A. H. E. and D. A. S. are employees of GlaxoSmithKline.; Peer reviewers may receive honoraria from CMRO for review work. Peer Reviewer 1 has disclosed that he/she is the recipient of research/grant funding from GSK and AstraZeneca and is a consultant/advisor to GSK, Sepracor, AstraZeneca and NovoNordisk. Peer Reviewer 2 has disclosed no relevant financial relationships.; Part of this work has been previously presented at the Annual Meeting of the American Academy of Allergy Asthma & Immunology; March 13-17, 2009, Washington, DC, USA NR 24 TC 20 Z9 20 U1 0 U2 0 PU LIBRAPHARM/INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4 LQ, ENGLAND SN 0300-7995 J9 CURR MED RES OPIN JI Curr. Med. Res. Opin. PD JUL PY 2010 VL 26 IS 7 BP 1629 EP 1635 DI 10.1185/03007995.2010.483113 PG 7 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 622YW UT WOS:000279704500009 PM 20429821 ER PT J AU Huett, A Goel, G Xavier, RJ AF Huett, Alan Goel, Gautam Xavier, Ramnik J. TI A systems biology viewpoint on autophagy in health and disease SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Article DE autophagy; cancer; inflammatory bowel disease; mitophagy; reactive oxygen species; systems biology ID ENDOPLASMIC-RETICULUM; SELECTIVE AUTOPHAGY; MEDIATED CLEAVAGE; T-LYMPHOCYTES; CELLS; MITOCHONDRIA; ACTIVATION; MITOPHAGY; CYTOPLASM; APOPTOSIS AB Purpose of review The field of autophagy is rapidly expanding to encompass many important areas of cell biology, physiology and disease. Recent discoveries and tools allow the connection of the autophagy pathway to other cellular signals and processes, thus beginning a systematic approach to elucidation of autophagy components, functions and connections. Recent findings We outline recent discoveries illustrating the role of autophagy in Parkinson's disease, inflammatory bowel disease (IBD) and cancer. Recently important details of the mechanisms by which autophagy operates in these contexts have been elucidated. We illustrate how autophagy can be triggered by diverse stimuli and how cell fate is determined by the responses to many signals and stresses. We discuss the known links between autophagy and apoptosis and present a working model of the current interactions between autophagy components, apoptosis and cell cycle control at different stages of autophagic vesicle progression. Summary Autophagy represents not only an essential metabolic process, but a hub which responds to diverse stresses and signals to aid cell survival or control cell fate. There are currently many known links between autophagy and disease states, and the pace of discovery appears to be accelerating. Thus an understanding of autophagy is likely to be crucial to current and future approaches to therapy. Here we give a systems biology view of the autophagy field and how it is being connected to other pathways, such as apoptosis and responses to reactive oxygen damage. C1 [Xavier, Ramnik J.] Harvard Univ, Ctr Computat & Integrat Biol, Richard B Simches Res Ctr, Massachusetts Gen Hosp,Sch Med, Boston, MA 02114 USA. [Huett, Alan; Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit,Ctr Inflammatory Bowel Dis, Boston, MA 02114 USA. [Xavier, Ramnik J.] MIT & Harvard, Broad Inst, Cambridge, MA USA. RP Xavier, RJ (reprint author), Harvard Univ, Ctr Computat & Integrat Biol, Richard B Simches Res Ctr, Massachusetts Gen Hosp,Sch Med, 185 Cambridge St,7th Floor, Boston, MA 02114 USA. EM ahuett@ccib.mgh.harvard.edu; ggoel@ccib.mgh.harvard.edu; xavier@molbio.mgh.harvard.edu NR 38 TC 24 Z9 27 U1 0 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0267-1379 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD JUL PY 2010 VL 26 IS 4 BP 302 EP 309 DI 10.1097/MOG.0b013e32833ae2ed PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 613YO UT WOS:000279021500002 PM 20571384 ER PT J AU Borsook, D Becerra, L AF Borsook, David Becerra, Lino TI Using NMR approaches to drive the search for new CNS therapeutics SO CURRENT OPINION IN INVESTIGATIONAL DRUGS LA English DT Review DE Clinical; CNS; drug development; functional MRI; NMR; pharmacological MRI; preclinical ID STATE FUNCTIONAL CONNECTIVITY; CENTRAL-NERVOUS-SYSTEM; TENSOR-BASED MORPHOMETRY; DRUG DEVELOPMENT; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; NEUROPATHIC PAIN; HUMAN BRAIN; HEALTHY-VOLUNTEERS; COGNITIVE MEASURES AB The use of MRI-based imaging in drug development has received increased interest recently because of the difficulties associated with the development of CNS pharmacotherapies. While not yet routine, there have been significant advances in imaging that allow this technology to be used for evaluating disease state and drug effects. For disease states, both single and longitudinal studies of non-invasive measures may be obtained to provide a read-out of disease processes and, potentially, to predict the disease state and its evolution. In addition, imaging has enabled the development of improved preclinical disease models based on changes in brain circuitry. Pharmacological MRI, the imaging-based evaluation of drug effects, includes measures of direct effects on the brain, as well as the effects of chronic dosing on brain changes and neurochemical changes associated with these brain effects using magnetic resonance spectroscopy. Thus, imaging may become an integrated process in drug development, during both the preclinical and clinical stages. However, validation, the implementation of good clinical practices and regulatory acceptance are hurdles that remain to be overcome. C1 [Borsook, David] Massachusetts Gen Hosp, Pain & Analgesia Imaging Neurosci Grp, Athinoula Martinos Ctr Biomed Imaging, Dept Radiol & Psychiat, Charlestown, MA 02129 USA. Childrens Hosp Boston, Pain & Analgesia Imaging Neurosci Grp, Boston, MA 02115 USA. McLean Hosp, Pain & Analgesia Imaging Neurosci Grp, Brain Imaging Ctr, Belmont, MA 02478 USA. RP Borsook, D (reprint author), Massachusetts Gen Hosp, Pain & Analgesia Imaging Neurosci Grp, Athinoula Martinos Ctr Biomed Imaging, Dept Radiol & Psychiat, 149 13th St, Charlestown, MA 02129 USA. EM dborsook@partners.org FU National Institute of Neurological Disorders and Stroke [K24 NINDS]; L Herlands Pain Research Fund FX David Borsook is supported by the National Institute of Neurological Disorders and Stroke (K24 NINDS), and both David Borsook and Lino Becerra are supported by the L Herlands Pain Research Fund. NR 84 TC 8 Z9 8 U1 0 U2 2 PU THOMSON REUTERS (SCIENTIFIC) LTD PI LONDON PA 77 HATTON GARDEN, LONDON, EC1N 8JS, ENGLAND SN 1472-4472 J9 CURR OPIN INVEST DR JI Curr. Opin. Investig. Drugs PD JUL PY 2010 VL 11 IS 7 BP 771 EP 778 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 614JJ UT WOS:000279053000004 PM 20571972 ER PT J AU Marrari, A Trent, JC George, S AF Marrari, Andrea Trent, Jonathan C. George, Suzanne TI Personalized cancer therapy for gastrointestinal stromal tumor: synergizing tumor genotyping with imatinib plasma levels SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE gastrointestinal stromal tumor; imatinib plasma levels; tumor genotyping ID CHRONIC MYELOID-LEUKEMIA; STANDARD-DOSE IMATINIB; ACTIVATING MUTATIONS; MOLECULAR RESPONSES; DRUG-RESISTANCE; LUNG-CANCER; PHARMACOKINETICS; MESYLATE; STI571; TRIAL AB Purpose of review Imatinib has exceptional activity in controlling gastrointestinal stromal tumor (GIST) due to inhibition of the constitutively active conformation of KIT and platelet-derived growth factor-alpha (PDGFRA), which is commonly seen in this tumor. This review explores the current available data on the correlation between imatinib plasma levels, response to treatment, and the mutational status of KIT and PDGFRA. Recent findings A recent retrospective analysis demonstrated a relationship between imatinib plasma levels and progression-free survival in patients with advanced GIST. Plasma imatinib levels were notably unrelated to the daily administered dose of imatinib in this small series. Prior phase III trials have demonstrated that dose escalation of imatinib may lead to increased disease control in a subset of patients with advanced GIST who progress on standard dose imatinib. Moreover, patients with GIST carrying an exon 9 mutation may benefit from higher doses of imatinib. Summary Current available data suggest a possible correlation between imatinib plasma level and progression-free survival in patients with advanced GIST. A prospective trial is underway to evaluate whether modification of imatinib dose to achieve a target imatinib plasma level will impact patient outcome when compared with standard imatinib dosing (www.clinicaltrials.gov, NCT01031628). C1 [Marrari, Andrea; George, Suzanne] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Trent, Jonathan C.] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX 77030 USA. RP George, S (reprint author), Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, 44 Binney St, Boston, MA 02115 USA. EM sgeorge2@partners.org FU Pfizer; Conticanet (Connective Tissue Cancer Network) FX A. M. received a travel grant from Pfizer. J.T. received honoraria and clinical trial support from Novartis. Laboratory support from Merck. S. G. Advisory Board Novartis and Pfizer; Clinical trial support from Novartis and Pfizer.; Grant support: Conticanet (Connective Tissue Cancer Network) Mobility Program 2009-2010 (A. M.). NR 34 TC 11 Z9 11 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD JUL PY 2010 VL 22 IS 4 BP 336 EP 341 DI 10.1097/CCO.0b013e32833a6b8e PG 6 WC Oncology SC Oncology GA 615QL UT WOS:000279150200008 PM 20489620 ER PT J AU Moshirfar, M Hazin, R Khalifa, YM AF Moshirfar, Majid Hazin, Ribhi Khalifa, Yousuf M. TI Central toxic keratopathy SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article DE central toxic keratopathy; diffuse lamellar keratitis; infectious keratitis; keratitis; laser in situ keratomileusis ID IN-SITU KERATOMILEUSIS; LAMELLAR REFRACTIVE SURGERY; FEMTOSECOND LASER; EPITHELIAL INGROWTH; KERATITIS; LASIK; COMPLICATIONS; KERATECTOMY AB Purpose of review To describe recent evidence from the literature regarding central toxic keratopathy syndrome (CTK). Recent findings CTK describes a rare, self-limited, noninflammatory postsurgical condition that presents with central corneal opacity and a significant hyperopic shift. Although its cause remains uncertain, CTK bears a striking clinical resemblance to other more serious conditions and is, therefore, often misdiagnosed and mismanaged. Despite its noninflammatory nature, the overlapping clinical features CTK shares with other inflammatory and infectious processes have led some to treat CTK with steroids. Recent studies discourage the use of steroids in CTK and recommend allowing the condition to resolve on its own. Summary Although CTK resembles other inflammatory conditions that are responsive to steroids, current studies suggest that steroid administration is contraindicated in CTK and can exacerbate preexisting refractive alterations in patients with the condition. C1 [Moshirfar, Majid] Univ Utah, Sch Med, Dept Ophthalmol & Visual Sci, John A Moran Eye Ctr,Med Ctr Salt Lake City, Salt Lake City, UT 84132 USA. [Hazin, Ribhi] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. [Khalifa, Yousuf M.] Univ Rochester, Sch Med, Flaum Eye Inst, Rochester, NY USA. RP Moshirfar, M (reprint author), Univ Utah, Sch Med, Dept Ophthalmol & Visual Sci, John A Moran Eye Ctr,Med Ctr Salt Lake City, Salt Lake City, UT 84132 USA. EM majid.moshirfar@hsc.utah.edu NR 26 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8738 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD JUL PY 2010 VL 21 IS 4 BP 274 EP 279 DI 10.1097/ICU.0b013e32833a8cb2 PG 6 WC Ophthalmology SC Ophthalmology GA 610DE UT WOS:000278710000007 PM 20531192 ER PT J AU Beghi, M Rosenbaum, JF AF Beghi, Massimiliano Rosenbaum, Jerrold F. TI Risk factors for fatal and nonfatal repetition of suicide attempt: a critical appraisal SO CURRENT OPINION IN PSYCHIATRY LA English DT Article DE repetition; risk factors; self-harm; suicide attempt ID PROGNOSIS AB Purpose of review To perform a critical appraisal of reports on suicide attempts published in 2009, looking for features and predictors of suicidal behavior. Recent findings We searched Psychinfo, Embase, and Pubmed in the period from 1 December 2008 to 31 December 2009 looking for papers on suicide attempt. Rates of suicide attempts are in line with previous data and confirm a north-south gradient in the suicide attempt rate. Previous attempts are the strongest risk factors for further attempt. Moreover, we point out the importance of mood disorders (in particular depression) and personality disorders, unemployment, and a medium age as risk factors. In adolescence, the repetition rate seems to overlap that of the adult population, though the samples are very small. Even in this case, the presence of a previous suicide attempt increases the risk for repeated suicide attempt. By contrast, the role of psychiatric and demographic variables is less clear. Studies on personality disorders confirm that having a personality disorder increases the risk for further attempt, but this correlation is significantly less strong for fatal repetition. In depressed patients, the presence of anxiety perhaps acts as a protective factor. Summary The risk for a suicide attempt is higher for people who had previously attempted. Having a psychiatric diagnosis and more specifically a mood disorder is also a strong predictor for both fatal and nonfatal suicide attempt. C1 [Beghi, Massimiliano] Univ Milano Bicocca, Psychiat Clin, Milan, Italy. [Rosenbaum, Jerrold F.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Beghi, Massimiliano] Salvini Hosp, Dept Psychiat, Rho, Italy. RP Beghi, M (reprint author), Psychosocial Ctr CPS, Via Beatrice Este 28, I-20017 Milan, Italy. EM massibeghi@libero.it NR 27 TC 35 Z9 35 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD JUL PY 2010 VL 23 IS 4 BP 349 EP 355 DI 10.1097/YCO.0b013e32833ad783 PG 7 WC Psychiatry SC Psychiatry GA 607WD UT WOS:000278537100009 PM 20520547 ER PT J AU Klick, JC Hauer, J AF Klick, Jeffrey C. Hauer, Julie TI Pediatric Palliative Care SO CURRENT PROBLEMS IN PEDIATRIC AND ADOLESCENT HEALTH CARE LA English DT Article AB Palliative care has always been a part of the care of children. It includes any intervention that focuses on relieving suffering, slowing the progression of disease, and improving quality of life at any stage of disease. In addition, for even the child with the most unpredictable disease, there are predictable times in this child's life when the child, family, and care team will be suffering in ways that can be mitigated by specific interventions. Rather than defining pediatric palliative care in terms of a patient base, severity of disease, or even a general philosophy of care, palliative care can best be understood as a specific set of tasks directed at mitigating suffering. By understanding these tasks; learning to identify predictable times and settings of suffering; and learning to collaborate with multidisciplinary specialists, use communication skills, and identify clinical resources, the pediatrician can more effectively support children with life-threatening illnesses and their families. In this article, we define palliative care as a focus of care integrated in all phases of life and as a set of interventions aimed at easing suffering associated with life-threatening conditions. We detail an approach to these interventions and discuss how they can be implemented by the pediatrician with the support of specialists in hospice and palliative medicine. We discuss common and predictable times of suffering when these interventions become effective ways to treat suffering and improve quality of life. Finally, we discuss those situations that pediatricians most commonly and intensely interface with palliative care-the care of the child with complex, chronic conditions and severe neurologic impairment (SNI). Curr Probl Pediatr Adolesc Health Care 2010;40:120-151 C1 [Klick, Jeffrey C.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Gen Pediat, Philadelphia, PA 19104 USA. [Hauer, Julie] Dana Farber Canc Inst, Div Pediat Palliat Care, Boston, MA 02115 USA. RP Klick, JC (reprint author), Univ Penn, Childrens Hosp Philadelphia, Sch Med, Div Gen Pediat, Philadelphia, PA 19104 USA. NR 135 TC 20 Z9 24 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1538-5442 J9 CURR PROB PEDIATR AD JI Curr. Probl. Pediatr. Adolesc. Health Care PD JUL PY 2010 VL 40 IS 6 BP 120 EP 151 DI 10.1016/j.cppeds.2010.05.001 PG 32 WC Pediatrics SC Pediatrics GA V26OG UT WOS:000208554300002 PM 20638035 ER PT J AU Quant, EC Drappatz, J Wen, PY Norden, AD AF Quant, Eudocia C. Drappatz, Jan Wen, Patrick Y. Norden, Andrew D. TI Recurrent High-Grade Glioma SO CURRENT TREATMENT OPTIONS IN NEUROLOGY LA English DT Review ID PHASE-II TRIAL; BEVACIZUMAB PLUS IRINOTECAN; MALIGNANT GLIOMAS; GLIOBLASTOMA-MULTIFORME; RESPONSE CRITERIA; CLINICAL-TRIALS; END-POINT; CHEMOTHERAPY; TEMOZOLOMIDE; BRAIN AB Opinions vary on the best treatment options for recurrent high-grade glioma. Some argue that bevacizumab should become standard of care for patients with recurrent glioblastoma, especially in light of recent FDA approval for this indication. However, this opinion is not uniformly accepted. Age, performance status, histology, tumor size and location, O6-methylguanine-DNA methyltransferase (MGMT) methylation status for glioblastoma, 1p/19q status for oligodendroglial tumors, and the number and types of prior therapies are important considerations. In addition, recurrent disease must be distinguished from "pseudoprogression" due to treatment effects. Enrollment in a clinical trial is the optimal choice for most patients with recurrent high-grade glioma after failure of radiation therapy and temozolomide. For patients who are ineligible or do not have access to clinical trials, then either bevacizumab monotherapy or bevacizumab in combination with a second agent such as irinotecan is recommended. Involved-field external beam radiation should be considered for patients with anaplastic gliomas who have not received radiation. For patients with anaplastic astrocytoma who progress after radiotherapy, temozolomide may be used. For patients with anaplastic oligodendroglioma who progress after radiotherapy, PCV chemotherapy and temozolomide are options. Oligodendroglial tumors with 1p/19q deletions are more likely to respond to treatment. In the past, carmustine was commonly used to treat recurrent high-grade glioma, but the utility of carmustine in the modern era is unknown because most studies were performed prior to the widespread use of temozolomide. High-precision re-irradiation such as stereotactic radiosurgery is another option in high-grade glioma, especially for patients with poor bone marrow reserve or inability to tolerate chemotherapy, but there is a paucity of studies with adequate controls. Surgery may be useful as adjuvant treatment for patients with symptoms due to mass effect or for patients requiring definitive histopathology, but it generally should be combined with another treatment modality. Emerging therapies, including dose-intense temozolomide regimens, targeted molecular inhibitors, other antiangiogenic therapies, viral gene therapies, immunotherapies, and convection-enhanced delivery of targeted immunotoxins, are still under investigation. C1 [Norden, Andrew D.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. EM anorden@partners.org FU Exelixis; Angiochem; Schering-Plough; Amgen; Novartis; Boehringer Ingelheim; AstraZeneca; Genentech FX Dr. Jan Drappatz has received consulting fees from Exelixis, Angiochem, and Schering-Plough. Dr. Andrew Norden served on a speaker's bureau for Schering-Plough and an advisory board for Genentech. Dr. Patrick Wen receives research support from Amgen, Novartis, Exelixis, Schering-Plough, Boehringer Ingelheim, AstraZeneca, and Genentech. NR 49 TC 19 Z9 20 U1 0 U2 6 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1092-8480 J9 CURR TREAT OPTION NE JI Curr. Treat. Options Neurol. PD JUL PY 2010 VL 12 IS 4 BP 321 EP 333 DI 10.1007/s11940-010-0078-5 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 607QO UT WOS:000278521600006 PM 20842591 ER PT J AU Kapoor, R Elston, DM AF Kapoor, Roger Elston, Dirk M. TI What's Eating You? Dermacentor Ticks SO CUTIS LA English DT Article ID MOUNTAIN-SPOTTED-FEVER; RICKETTSIA; PARALYSIS; IXODIDAE; ACARI C1 [Elston, Dirk M.] Geisinger Med Ctr, Dept Dermatol, Danville, PA 17822 USA. [Elston, Dirk M.] Geisinger Med Ctr, Dept Lab Med, Danville, PA 17822 USA. [Kapoor, Roger] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Elston, DM (reprint author), Geisinger Med Ctr, Dept Dermatol, 100 N Acad Ave, Danville, PA 17822 USA. NR 15 TC 0 Z9 0 U1 0 U2 0 PU QUADRANT HEALTHCOM INC PI PARSIPPANY PA 7 CENTURY DRIVE, STE 302, PARSIPPANY, NJ 07054-4603 USA SN 0011-4162 J9 CUTIS JI Cutis PD JUL PY 2010 VL 86 IS 1 BP 17 EP 19 PG 3 WC Dermatology SC Dermatology GA 632CD UT WOS:000280396800004 PM 21049761 ER PT J AU Cannizzo, E Bellio, E Sohani, AR Hasserjian, RP Ferry, JA Dorn, ME Sadowski, C Bucci, JJ Carulli, G Preffer, F AF Cannizzo, Elisa Bellio, Emanuele Sohani, Aliyah R. Hasserjian, Robert P. Ferry, Judith A. Dorn, Michelle E. Sadowski, Craig Bucci, Janessa J. Carulli, Giovanni Preffer, Frederic TI Multiparameter Immunophenotyping by Flow Cytometry in Multiple Myeloma: The Diagnostic Utility of Defining Ranges of Normal Antigenic Expression in Comparison to Histology SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE multiple myeloma; flow cytometry; ranges of normal antigenic expression; multiparameter flow cytometry; polyclonal plasma cells' immunophenotype ID MALIGNANT PLASMA-CELLS; MINIMAL RESIDUAL DISEASE; HIGH-DOSE THERAPY; MONOCLONAL GAMMOPATHY; UNDETERMINED SIGNIFICANCE; BONE-MARROW; UNCERTAIN SIGNIFICANCE; PROGNOSTIC-FACTOR; CD117 EXPRESSION; DIFFERENTIATION AB Background: Numerous studies have reported on the immunophenotype of plasma cells (PCs) in monoclonal gammopathy of undetermined significance (MGUS) and in plasma cell myeloma (PCM), but very few have examined the immunophenotype of normal PCs. In this study, an objective definition of normal range of expression for each antigen was found on normal control PCs. Using these new ranges of normal expression (new method) is different from using a static 20% of PCs cut-off for all antigens as described in the literature (traditional method). These newly calculated normal ranges for each antigen were applied to our data, and compared to histologic and immunohistochemical findings. Methods: Bone marrow samples from 46 patients with PC neoplasms and 15 normal controls were studied. A minimum of 100 PC were analyzed for each patient and control sample. An 8-color staining method was applied to study the immunophenotype of PCs, using a BD FACSCanto II. Results: By the new ranges of normality calculated in this study it was determined that different antigens have different level of expression on polyclonal PCs. CD19 correlated with histology by both the traditional and new methods, but had superior correlation by the new method. Conclusions: This report is the first 8-color immunophenotypic study of PCM in which a "range of normal expression" for each antigen is defined. This is a critical step to help distinguish between a normal and neoplastic PC immunophenotype and discern which antigens are of diagnostic importance. (C) 2010 Clinical Cytometry Society C1 [Cannizzo, Elisa; Sohani, Aliyah R.; Hasserjian, Robert P.; Ferry, Judith A.; Dorn, Michelle E.; Sadowski, Craig; Bucci, Janessa J.; Preffer, Frederic] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cannizzo, Elisa; Sohani, Aliyah R.; Hasserjian, Robert P.; Ferry, Judith A.; Dorn, Michelle E.; Sadowski, Craig; Bucci, Janessa J.; Preffer, Frederic] Harvard Univ, Sch Med, Boston, MA USA. [Cannizzo, Elisa; Bellio, Emanuele; Carulli, Giovanni] Univ Pisa, Sect Hematol, Dept Oncol Transplant & Advances Med, Pisa, Italy. RP Cannizzo, E (reprint author), Santa Chiara Hosp, Div Hematol, Via Roma 67, I-56126 Pisa, Italy. EM elisacannizzo@libero.it NR 50 TC 43 Z9 43 U1 1 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD JUL PY 2010 VL 78B IS 4 BP 231 EP 238 DI 10.1002/cyto.b.20517 PG 8 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 620DG UT WOS:000279478600002 PM 20198608 ER PT J AU Britton, JC Stewart, SE Killgore, WDS Rosso, IM Price, LM Gold, AL Pine, DS Wilhelm, S Jenike, MA Rauch, SL AF Britton, Jennifer C. Stewart, S. Evelyn Killgore, William D. S. Rosso, Isabelle M. Price, Lauren M. Gold, Andrea L. Pine, Daniel S. Wilhelm, Sabine Jenike, Michael A. Rauch, Scott L. TI AMYGDALA ACTIVATION IN RESPONSE TO FACIAL EXPRESSIONS IN PEDIATRIC OBSESSIVE-COMPULSIVE DISORDER SO DEPRESSION AND ANXIETY LA English DT Article DE OCD; fMRI; neuroimaging; anxiety disorder; fear; disgust ID GENERALIZED SOCIAL PHOBIA; MEDIAL PREFRONTAL CORTEX; POSTTRAUMATIC-STRESS-DISORDER; POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL GLUCOSE-METABOLISM; BRAIN ACTIVATION; MAJOR DEPRESSION; EMOTIONAL FACES; ANTIDEPRESSANT TREATMENT; SYMPTOM PROVOCATION AB Background: Exaggerated amygdala activation to threatening faces has been detected in adults and children with anxiety disorders, compared to healthy comparison (HC) subjects. However, the profile of amygdala activation in response to facial expressions in obsessive-compulsive disorder (OLD,) may be a distinguishing feature; a prior study found that compared with healthy adults, adults with OCD exhibited less amygdala activation to emotional and neutral faces, relative to fixation [Cannistraro et al. (2004). Biological Psychiatry 56:916-920]. Methods: In the current event-related functional magnetic resonance imaging (fMRI) study, a pediatric OCD sample (N = 12) and a HC sample (N = 17) performed a gender discrimination task while viewing emotional faces (happy, fearful, disgusted) and neutral faces. Results: Compared to the HC group, the OCD group showed less amygdala/hippocampus activation in all emotion and neutral conditions relative to fixation. Conclusions: Like previous reports in adult OCD, pediatric OCD may have a distinct neural profile from other anxiety disorders, with respect to amygdala activation in response to emotional stimuli that are not disorder specific. Depression and Anxiety 27:643-651, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Britton, Jennifer C.; Pine, Daniel S.] NIH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Britton, Jennifer C.; Killgore, William D. S.; Rosso, Isabelle M.; Price, Lauren M.; Gold, Andrea L.; Rauch, Scott L.] McLean Hosp, Brain Imaging Ctr, Belmont, MA 02178 USA. [Stewart, S. Evelyn; Wilhelm, Sabine; Jenike, Michael A.; Rauch, Scott L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Stewart, S. Evelyn] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Gold, Andrea L.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. RP Britton, JC (reprint author), NIH, Mood & Anxiety Disorders Program, 9000 Rockville Pike,Bldg 15K, Bethesda, MD 20892 USA. EM brittonjen@mail.nih.gov RI Britton, Jennifer/J-4501-2013; Stewart, Evelyn/K-6961-2014; OI Gold, Andrea/0000-0003-4447-776X; Killgore, William/0000-0002-5328-0208; Stewart, S. Evelyn/0000-0002-0994-6383 FU David Judah Fund; National Institutes of Health; National Institute of Mental Health FX The authors disclose the following financial relationships within the past 3 years: Contract grant sponsors: David Judah Fund; The Intramural Research Program of the National Institutes of Health and the National Institute of Mental Health. NR 71 TC 23 Z9 23 U1 4 U2 11 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUL PY 2010 VL 27 IS 7 BP 643 EP 651 DI 10.1002/da.20718 PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 622KY UT WOS:000279663900003 PM 20602430 ER PT J AU Norris, RA Moreno-Rodriguez, R Wessels, A Merot, J Bruneval, P Chester, AH Yacoub, MH Hagege, A Slaugenhaupt, SA Aikawa, E Schott, JJ Lardeux, A Harris, BS Williams, LK Richards, A Levine, RA Markwald, RR AF Norris, R. A. Moreno-Rodriguez, R. Wessels, A. Merot, J. Bruneval, P. Chester, A. H. Yacoub, M. H. Hagege, A. Slaugenhaupt, S. A. Aikawa, E. Schott, J. J. Lardeux, A. Harris, B. S. Williams, L. K. Richards, A. Levine, R. A. Markwald, R. R. TI Expression of the Familial Cardiac Valvular Dystrophy Gene, Filamin-A, During Heart Morphogenesis SO DEVELOPMENTAL DYNAMICS LA English DT Article DE filamin; cytoskeleton; valve; epicardial; endothelium; cardiac; morphogenesis; development; cushion; mesenchyme ID MITRAL-VALVE-PROLAPSE; ACTIN-BINDING PROTEIN; MARFAN-SYNDROME; SMOOTH-MUSCLE; AVIAN HEART; CELLS EPDCS; IN-VIVO; INTEGRIN; EPICARDIUM; TENDON AB Myxoid degeneration of the cardiac valves is a common feature in a heterogeneous group of disorders that includes Marfan syndrome and isolated valvular diseases. Mitral valve prolapse is the most common outcome of these and remains one of the most common indications for valvular surgery. While the etiology of the disease is unknown, recent genetic studies have demonstrated that an X-linked form of familial cardiac valvular dystrophy can be attributed to mutations in the Filamin-A gene. Since these inheritable mutations are present from conception, we hypothesize that filamin-A mutations present at the time of valve morphogenesis lead to dysfunction that progresses postnatally to clinically relevant disease. Therefore, by carefully evaluating genetic factors (such as filamin-A) that play a substantial role in MVP, we can elucidate relevant developmental pathways that contribute to its pathogenesis. In order to understand how developmental expression of a mutant protein can lead to valve disease, the spatio-temporal distribution of filamin-A during cardiac morphogenesis must first be characterized. Although previously thought of as a ubiquitously expressed gene, we demonstrate that filamin-A is robustly expressed in non-myocyte cells throughout cardiac morphogenesis including epicardial and endocardial cells, and mesenchymal cells derived by EMT from these two epithelia, as well as mesenchyme of neural crest origin. In postnatal hearts, expression of filamin-A is significantly decreased in the atrioventricular and outflow tract valve leaflets and their suspensory apparatus. Characterization of the temporal and spatial expression pattern of filamin-A during cardiac morphogenesis is a crucial first step in our understanding of how mutations in filamin-A result in clinically relevant valve disease. Developmental Dynamics 239:2118-2127, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Norris, R. A.] Med Univ S Carolina, Cardiovasc Dev Biol Ctr, Dept Regenerat Med & Cell Biol, Childrens Res Inst, Charleston, SC 29425 USA. [Merot, J.; Schott, J. J.; Lardeux, A.] INSERM, UMR 915, Nantes, France. [Merot, J.; Schott, J. J.; Lardeux, A.] CNRS, ERL 3147, Nantes, France. [Merot, J.; Schott, J. J.; Lardeux, A.] Univ Nantes, Fac Med, Nantes, France. [Merot, J.; Schott, J. J.; Lardeux, A.] CHU Nantes, Inst Thorax, F-44035 Nantes 01, France. [Hagege, A.] Hop Europeen Georges Pompidou, AP HP, Dept Cardiol, Paris, France. [Slaugenhaupt, S. A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Levine, R. A.] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Bruneval, P.] Univ Paris 05, INSERM, U970, Paris, France. [Chester, A. H.; Yacoub, M. H.] Univ London Imperial Coll Sci Technol & Med, Heart Sci Ctr, Harefield, Middx, England. [Aikawa, E.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Norris, RA (reprint author), Med Univ S Carolina, Cardiovasc Dev Biol Ctr, Dept Regenerat Med & Cell Biol, Childrens Res Inst, 173 Ashley Ave,606 CRI, Charleston, SC 29425 USA. EM norrisra@musc.edu RI Schott, jean-Jacques/F-8842-2013; MEROT, Jean/D-5741-2015 FU NIH-NHLBI [HL33756, HL084285]; NIH-NCRR [COBRE P20RR016434-07, P20RR016434-09S1]; NSF [FIBRE EF0526854, EPS-0902795]; Foundation Leducq (Paris, France) Transatlantic Mitral Network of Excellence Grantpi [207CVD04]; SC INBRE [5MO1RR001070-28]; AHA [GIA-2060075, AHA-GIA 0835460N]; INSERM [UMR 915, Nantes, F-44035]; CNRS, France FX Grant sponsor: NIH-NHLBI; Grant numbers: HL33756, HL084285; Grant sponsor: NIH-NCRR; Grant numbers: COBRE P20RR016434-07, P20RR016434-09S1; Grant sponsor: NSF; Grant numbers: FIBRE EF0526854, EPS-0902795; Grant sponsor: Foundation Leducq (Paris, France) Transatlantic Mitral Network of Excellence Grantpi; Grant number: 207CVD04; Grant sponsor: SC INBRE; Grant number: 5MO1RR001070-28; Grant sponsor: AHA; Grant numbers: GIA-2060075, AHA-GIA 0835460N.; The authors thank members of the Markwald and Norris labs for critical reading of the manuscript, and Aimee Phelps for excellent technical assistance. This work was sponsored in part by NIH-NHLBI: HL33756 (R.R.M.), NIH-NCRR: COBRE P20RR 016434-07 (R.R.M. and B.S.H.), P20 RR016434-09S1 (R.R.M. and R.A.N.); National Science Foundation: FIBRE EF0526854 and EPS-0902795 (R.R.M. and R.A.N.); the Foundation Leducq (Paris, France) Transatlantic Mitral Network of Excellence grant 07CVD04 (R.A.N., R.R.M., R.A.L., A.H., S.A.S., J.M., J.J.S.); SC INBRE: 5MO1RR 001070-28 (R.A.N.); INSERM, UMR 915, Nantes, F-44035, France (J.M. and J.J.S.); CNRS, ERL3147, Nantes F-44035, France (J.M. and J.J.S.); Universite de Nantes, Faculte de Medecine, l'institut du thorax, Nantes, F-44035, France (J.M. and J.J.S.); CHU Nantes, l'institut du thorax, Nantes, F-44000, France (J.M. and J.J.S.); NIHNCRR-P20 RR016434, NIH-HLBI 1R01-HL084285, AHA-GIA 09GRNT2060075 (A.W.), and AHA-GIA 0835460N (E.A.). NR 56 TC 19 Z9 19 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD JUL PY 2010 VL 239 IS 7 BP 2118 EP 2127 DI 10.1002/dvdy.22346 PG 10 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 622KX UT WOS:000279663800022 PM 20549728 ER PT J AU Borg, R Kuenen, JC Carstensen, B Zheng, H Nathan, DM Heine, RJ Nerup, J Borch-Johnsen, K Witte, DR AF Borg, Rikke Kuenen, Judith C. Carstensen, Bendix Zheng, Hui Nathan, David M. Heine, Robert J. Nerup, Jorn Borch-Johnsen, Knut Witte, Daniel R. CA ADAG Study Grp TI Associations Between Features of Glucose Exposure and A1C The A1C-Derived Average Glucose (ADAG) Study SO DIABETES LA English DT Article ID TYPE-2 DIABETIC-PATIENTS; FASTING PLASMA-GLUCOSE; CARDIOVASCULAR-DISEASE; GLYCEMIC CONTROL; POSTPRANDIAL HYPERGLYCEMIA; METABOLIC CONTROL; FOLLOW-UP; RISK; MORTALITY; HBA(1C) AB OBJECTIVE-Various methods are used to quantify postprandial glycemia or glucose variability, but few have been compared and none are standardized. Our objective was to examine the relationship among common indexes of postprandial glycemia, overall hyperglycemia, glucose variability, and A1C using detailed glucose measures obtained during everyday life and to study which blood glucose values of the day provide the strongest prediction of A1C. RESEARCH DESIGN AND METHODS-In the A1C-Derived Average Glucose (ADAG) study, glucose levels were monitored in 507 participants (268 type 1 diabetic, 159 type 2 diabetic, and 80 nondiabetic subjects) with continuous glucose monitoring (CGM) and frequent self-monitoring of blood glucose (SMBG) during 16 weeks. We calculated several indexes of glycemia and analyzed their intercorrelations. The association between glucose measurements at different times of the day (pre- and postprandial) and A1C was examined using multiple linear regression. RESULTS-Indexes of glucose variability showed strong intercorrelation. Among postprandial indexes, the area under the glucose curve calculated from CGM 2 h after a meal correlated well with the 90-min SMBG postprandial measurements. Fasting blood glucose (FBG) levels were only moderately correlated with indexes of hyperglycemia and average or postprandial glucose levels. Indexes derived with SMBG strongly correlated with those from CGM. Some SMBG time points had a stronger association with Ale than others. Overall, preprandial glucose values had a stronger association with A1C than postprandial values for both diabetes types, particularly for type 2 diabetes. CONCLUSIONS-Indexes of glucose variability and average and postprandial glycemia intercorrelate strongly within each category. Variability indexes are weakly correlated with the other categories, indicating that these measures convey different information. FBG is not a clear indicator of general glycemia. Preprandial glucose values have a larger impact on A1C levels than postprandial values. Diabetes 59:1585-1590, 2010 C1 [Borg, Rikke; Carstensen, Bendix; Nerup, Jorn; Borch-Johnsen, Knut; Witte, Daniel R.] Steno Diabet Ctr, Copenhagen, Denmark. [Kuenen, Judith C.; Heine, Robert J.] Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. [Zheng, Hui; Nathan, David M.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Zheng, Hui; Nathan, David M.] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Zheng, Hui; Nathan, David M.] Harvard Univ, Sch Med, Boston, MA USA. RP Borg, R (reprint author), Steno Diabet Ctr, Copenhagen, Denmark. EM rbrg@steno.dk RI Witte, Daniel/C-1722-2008 OI Witte, Daniel/0000-0002-0769-2922 FU American Diabetes Association; European Association for the Study of Diabetes; Abbott Diabetes Care; Bayer Healthcare; GlaxoSmith-Kline; Sanofi-Aventis Netherlands; Merck Company; Lifescan; Medtronic Minimed; Sehested Hansen Foundation; Clinical Development Foundation at Steno Diabetes Center; Danish Diabetes Association FX The ADAG study is supported by research grants from the American Diabetes Association and European Association for the Study of Diabetes. Financial support was provided by Abbott Diabetes Care, Bayer Healthcare, GlaxoSmith-Kline, Sanofi-Aventis Netherlands, Merck & Company, Lifescan, and Medtronic Minimed. Supplies and equipment were provided by Medtronic Minimed, Lifescan, and Hemocue.; The Steno substudy was supported by research grants from the Sehested Hansen Foundation, the Clinical Development Foundation at Steno Diabetes Center, and the Danish Diabetes Association. NR 31 TC 36 Z9 36 U1 1 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2010 VL 59 IS 7 BP 1585 EP 1590 DI 10.2337/db09-1774 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 621WD UT WOS:000279615100005 PM 20424232 ER PT J AU Davis, RC Castellani, LW Hosseini, M Ben-Zeev, O Mao, HZ Weinstein, MM Jung, DY Jun, JY Kim, JK Lusis, AJ Peterfy, M AF Davis, Richard C. Castellani, Lawrence W. Hosseini, Maryam Ben-Zeev, Osnat Mao, Hui Z. Weinstein, Michael M. Jung, Dae Young Jun, John Y. Kim, Jason K. Lusis, Aldons J. Peterfy, Miklos TI Early Hepatic Insulin Resistance Precedes the Onset of Diabetes in Obese C57BLKS-db/db Mice SO DIABETES LA English DT Article ID LEPTIN RECEPTOR GENE; IN-VIVO; EXPRESSION PROFILES; MOUSE STRAIN; DB/DB MICE; RAT-LIVER; FATTY; MUSCLE; SUSCEPTIBILITY; MUTATIONS AB OBJECTIVE-To identify metabolic derangements contributing to diabetes susceptibility in the leptin receptor-deficient obese C57BLKS/J-db/db (BKS-db) mouse strain. RESEARCH DESIGN AND METHODS-Young BKS-db mice were used to identify metabolic pathways contributing to the development of diabetes. Using the diabetes-resistant B6-db strain as a comparison, in vivo and in vitro approaches were applied to identify metabolic and molecular differences between the two strains. RESULTS-Despite higher plasma insulin levels, BKS-db mice exhibit lower lipogenic gene expression, rate of lipogenesis, hepatic triglyceride and glycogen content, and impaired insulin suppression of gluconeogenic genes. Hepatic insulin receptor substrate (IRS)-1 and IRS-2 expression and insulin-stimulated Akt-phosphorylation are decreased in BKS-db primary hepatocytes. Hyperinsulinemic-euglycemic clamp studies indicate that in contrast to hepatic insulin resistance, skeletal muscle is more insulin sensitive in BKS-db than in B6-db mice. We also demonstrate that elevated plasma triglyceride levels in BKS-db mice are associated with reduced triglyceride clearance due to lower lipase activities. CONCLUSIONS-Our study demonstrates the presence of metabolic derangements in BKS-db before the onset of beta-cell failure and identifies early hepatic insulin resistance as a component of the BKS-db phenotype. We propose that defects in hepatic insulin signaling contribute to the development of diabetes in the BKS-db mouse strain. Diabetes 59:1616-1625, 2010 C1 [Davis, Richard C.; Castellani, Lawrence W.; Hosseini, Maryam; Ben-Zeev, Osnat; Weinstein, Michael M.; Lusis, Aldons J.; Peterfy, Miklos] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Hosseini, Maryam; Ben-Zeev, Osnat; Mao, Hui Z.; Peterfy, Miklos] VA Greater Los Angeles Healthcare Syst, Lipid Res Lab, Los Angeles, CA USA. [Hosseini, Maryam; Mao, Hui Z.; Peterfy, Miklos] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Jung, Dae Young; Kim, Jason K.] Univ Massachusetts, Sch Med, Program Mol Med, Div Endocrinol Metab & Diabet, Worcester, MA USA. [Jung, Dae Young; Jun, John Y.; Kim, Jason K.] Penn State Univ, Sch Med, Dept Cellular & Mol Physiol, Hershey, PA USA. [Kim, Jason K.] Univ Massachusetts, Sch Med, Dept Med, Div Endocrinol Metab & Diabet, Worcester, MA USA. RP Peterfy, M (reprint author), Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. EM mpeterfy@ucla.edu FU National Institutes of Health [DK071673, DK80756]; Cedars-Sinai Medical Center; American Diabetes Association [1-05-RA-96, 7-07-RA-80] FX This work was supported by National Institutes of Health Grants DK071673 and DK80756, the Cedars-Sinai Medical Center, and American Diabetes Association Grants 1-05-RA-96 and 7-07-RA-80. NR 47 TC 32 Z9 33 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2010 VL 59 IS 7 BP 1616 EP 1625 DI 10.2337/db09-0878 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 621WD UT WOS:000279615100009 PM 20393148 ER PT J AU German, JP Wisse, BE Thaler, JP Oh-I, S Sarruf, DA Ogimoto, K Kaiyala, KJ Fischer, JD Matsen, ME Taborsky, GJ Schwartz, MW Morton, GJ AF German, Jonathan P. Wisse, Brent E. Thaler, Joshua P. Oh-I, Shinsuke Sarruf, David A. Ogimoto, Kayoko Kaiyala, Karl J. Fischer, Jonathan D. Matsen, Miles E. Taborsky, Gerald J., Jr. Schwartz, Michael W. Morton, Gregory J. TI Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes SO DIABETES LA English DT Article ID EURODIAB PROSPECTIVE COMPLICATIONS; ENERGY-EXPENDITURE; GENE-EXPRESSION; RISK-FACTORS; TYPE-1; HYPERGLYCEMIA; SENSITIVITY; PLASMA; MICE; RATS AB OBJECTIVE-Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM. RESEARCH DESIGN AND METHODS-Adult male Wistar rats remained nondiabetic or were injected with the beta-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 mu g/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured. RESULTS-Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate-phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM. CONCLUSIONS-We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency. Diabetes 59:1626-1634, 2010 C1 [German, Jonathan P.; Wisse, Brent E.; Thaler, Joshua P.; Oh-I, Shinsuke; Sarruf, David A.; Ogimoto, Kayoko; Fischer, Jonathan D.; Matsen, Miles E.; Schwartz, Michael W.; Morton, Gregory J.] Univ Washington, Dept Med, Diabet & Obes Ctr Excellence, Seattle, WA 98195 USA. [Kaiyala, Karl J.] Univ Washington, Sch Dent, Dept Dent Publ Hlth Sci, Seattle, WA 98195 USA. [Taborsky, Gerald J., Jr.] VA Puget Sound Hlth Care Syst, Dept Vet Affairs Med Ctr, Seattle, WA USA. RP Morton, GJ (reprint author), Univ Washington, Dept Med, Diabet & Obes Ctr Excellence, Seattle, WA 98195 USA. EM gjmorton@u.washington.edu RI Schwartz, Michael/H-9950-2012 FU National Institutes of Health [DK-083042, DK-052989, DK-050154-13]; Clinical Nutrition Research Unit at the University of Washington [DK-035816]; AstraZeneca; American Heart Association FX This work was supported by National Institutes of Health (grants DK-083042 and DK-052989 to M.W.S. and DK-050154-13 to G.J.T.), by the Clinical Nutrition Research Unit (grant DK-035816) at the University of Washington, by research funding from AstraZeneca, and by a Scientist Development Grant from the American Heart Association (to G.J.M.). NR 50 TC 58 Z9 64 U1 1 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2010 VL 59 IS 7 BP 1626 EP 1634 DI 10.2337/db09-1918 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 621WD UT WOS:000279615100010 PM 20424233 ER PT J AU Simon, SR Trinacty, CM Soumerai, SB Piette, JD Meigs, JB Shi, P Ensroth, A Ross-Degnan, D AF Simon, Steven R. Trinacty, Connie Mah Soumerai, Stephen B. Piette, John D. Meigs, James B. Shi, Ping Ensroth, Arthur Ross-Degnan, Dennis TI Improving Diabetes Care Among Patients Overdue for Recommended Testing: A Randomized Controlled Trial of Automated Telephone Outreach SO DIABETES CARE LA English DT Article ID NURSE FOLLOW-UP; OUTCOMES; QUALITY; ADULTS; CALLS AB OBJECTIVE - The study's objective was to assess the effects of automated telephone out-reach with speech recognition (ATO-SR) on diabetes-related testing. RESEARCH DESIGN AND METHODS - We identified 1,200 health plan members who were overdue for diabetes-related testing and randomly allocated 600 to ATO-SR and 600 to usual care (no intervention). The intervention included three interactive calls encouraging recommended testing. The primary outcome was retinopathy testing, since this was the health plan's principal goal. Tests for glycemia, hyperlipidemia, and nephropathy were secondary outcomes. RESULTS - In total, 232 participants (39%) verbally responded to the calls. There was no difference between the intervention and the usual care groups in the primary outcome (adjusted hazard ratio 0.93 [95% CI 0.71-1.221) and no effect of the intervention on any of the secondary outcomes. CONCLUSIONS - Fewer than 40% of the patients randomized to ATO-SR interacted verbally with the system. The intervention had no effect on the study's outcomes. C1 [Simon, Steven R.; Trinacty, Connie Mah; Soumerai, Stephen B.; Shi, Ping; Ross-Degnan, Dennis] Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02115 USA. [Simon, Steven R.; Trinacty, Connie Mah; Soumerai, Stephen B.; Shi, Ping; Ross-Degnan, Dennis] Harvard Pilgrim Hlth Care Inst, Boston, MA USA. [Piette, John D.] Univ Michigan, Ann Arbor VA Med Ctr, Ann Arbor, MI 48109 USA. [Piette, John D.] Univ Michigan, Div Gen Internal Med, Ann Arbor, MI 48109 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Ensroth, Arthur] Harvard Pilgrim Hlth Care, Clin Programs & Qual Measurement, Wellesley, MA USA. RP Simon, SR (reprint author), Harvard Univ, Sch Med, Dept Populat Med, Boston, MA 02115 USA. EM steven_simon@hphc.org FU American Diabetes Association [01-05-JF-40]; Harvard Pilgrim Health Care Institute; Agency for Healthcare Research and Quality [U18HS016970, U18HS010391]; National Institute of Diabetes and Digestive and Kidney Diseases [K24 DK080140] FX This work was supported by a Junior Faculty Career Development Award (01-05-JF-40) from the American Diabetes Association to S.R.S. and by the Harvard Pilgrim Health Care Institute. S.R.S. is an investigator in the Health Information Technology Centers for Research and Education on Therapeutics and is supported by the Agency for Healthcare Research and Quality (Grant U18HS016970). S.B.S. is an investigator in the HMO Research Network Centers for Education and Research on Therapeutics and is supported by the Agency for Healthcare Research and Quality (Grant U18HS010391). J.D.P. is a VA Research Career Scientist. J.B.M. was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant K24 DK080140). NR 8 TC 8 Z9 8 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2010 VL 33 IS 7 BP 1452 EP 1453 DI 10.2337/dc09-2332 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 656SL UT WOS:000282356800009 PM 20357376 ER PT J AU Lee, CC Sharp, SJ Wexler, DJ Adler, AI AF Lee, Cheetin C. Sharp, Stephen J. Wexler, Deborah J. Adler, Amanda I. TI Dietary Intake of Eicosapentaenoic and Docosahexaenoic Acid and Diabetic Nephropathy: Cohort Analysis of the Diabetes Control and Complications Trial SO DIABETES CARE LA English DT Article AB OBJECTIVE - To investigate the association between dietary n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) and the degree and development of albuminuria in type 1 diabetes. RESEARCH DESIGN AND METHODS - We analyzed longitudinal data from 1,436 participants in the Diabetes Control and Complications Trial. We defined the average intake of eicosapentaenoic and docosahexaenoic acid from diet histories. Urinary albumin excretion rates (UAERs) were measured over 24 h; incident albuminuria was considered the first occurrence of an UAER >40 mg/24 h sustained for year in normoalbuminuric individuals. RESULTS - In a mean follow-up of 6.5 years, we observed a lower mean UAER (difference 22.7 mg/24 h [95% CI 1.6-43.8)]) in the top versus the bottom third of dietary n-3 LC-PUFAs, but we found no association with incident albuminuria. CONCLUSIONS - Dietary n-3 LC-PUFAs appear inversely associated with the degree but not with the incidence of albuminuria in type 1 diabetes. These findings require further investigation in prospective studies. C1 [Lee, Cheetin C.; Sharp, Stephen J.; Adler, Amanda I.] Inst Metab Sci, Med Res Council Epidemiol Unit, Cambridge, England. [Wexler, Deborah J.] Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. [Wexler, Deborah J.] Harvard Univ, Sch Med, Boston, MA USA. [Adler, Amanda I.] Addenbrookes Hosp, Wolfson Diabet & Endocrine Clin, Inst Metab Sci, Cambridge, England. RP Adler, AI (reprint author), Inst Metab Sci, Med Res Council Epidemiol Unit, Cambridge, England. EM amanda.adler@addenbrookes.nhs.uk FU NIDDK NIH HHS [K23 DK080228] NR 13 TC 11 Z9 12 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2010 VL 33 IS 7 BP 1454 EP 1456 DI 10.2337/dc09-2245 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 656SL UT WOS:000282356800010 PM 20357378 ER PT J AU Gaziano, JM Cincotta, AH O'Connor, CM Ezrokhi, M Rutty, D Ma, ZJ Scranton, RE AF Gaziano, J. Michael Cincotta, Anthony H. O'Connor, Christopher M. Ezrokhi, Michael Rutty, Dean Ma, Z. J. Scranton, Richard E. TI Randomized Clinical Trial of Quick-Release Bromocriptine Among Patients With Type 2 Diabetes on Overall Safety and Cardiovascular Outcomes SO DIABETES CARE LA English DT Article ID INTENSIVE GLYCEMIC CONTROL; INSULIN-RESISTANCE; MORTALITY; RISK; ROSIGLITAZONE; SULFONYLUREA; METFORMIN; ADVANCE; ACCORD AB OBJECTIVE - Quick-release bromocriptine (bromocriptine-QR), a D2 dopamine receptor agonist, is indicated as a treatment for type 2 diabetes. The Cycloset Safety Trial, a 52-week, randomized, double-blind, multicenter trial, evaluated the overall safety and cardiovascular safety of this novel therapy for type 2 diabetes. RESEARCH DESIGN AND METHODS - A total of 3,095 patients with type 2 diabetes were randomized 2:1 to bromocriptine-QR or placebo in conjunction with the patient's usual diabetes therapy (diet controlled only or up to two antidiabetes medications, including insulin). The all-cause safety end point was the occurrence of any serious adverse event (SAE), with a hazard ratio (HR) noninferiority margin of 1.5. In a prespecified analysis, the frequency of cardiovascular disease (CVD) events defined as a composite of myocardial infarction, stroke, coronary revascularization, and hospitalization for angina or congestive heart failure was evaluated using modified intent-to-treat analysis (clinicaltrials.gov, NCT00377676). RESULTS - In the bromocriptine-QR group, 176 (8.6%) people reported SAEs compared with 98(9.6%) in the placebo group (HR 1.02 [96% one-sided CI 1.27]). Fewer people reported a CVD end point in the bromocriptine-QR group versus the placebo group (37 [1.8%] vs. 32 [3.2%], respecively) (HR 0.60 195% two-sided CI 0.35-0.96]). Nausea was the most commonly reported adverse event in the bromocriptine-QR group. CONCLUSIONS - The frequency of SAEs was comparable between the treatment arms. Compared with patients in the placebo arm, fewer patients taking bromocriptine-QR experienced a cardiovascular end point. C1 [Gaziano, J. Michael; Scranton, Richard E.] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Ctr VA Cooperat Studies Programs, Boston, MA USA. [Gaziano, J. Michael; Scranton, Richard E.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael; Scranton, Richard E.] Harvard Univ, Sch Med, Boston, MA USA. [Cincotta, Anthony H.; Ezrokhi, Michael; Scranton, Richard E.] Verosci LLC, Tiverton, RI USA. [O'Connor, Christopher M.] Duke Clin Res Inst, Durham, NC USA. [Ma, Z. J.] Columbia Univ, Dept Stat, New York, NY USA. RP Gaziano, JM (reprint author), VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Ctr VA Cooperat Studies Programs, Boston, MA USA. EM jmgaziano@partners.org FU National Institutes of Health (National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute on Aging; National Eye Institute); Veteran's Affairs Cooperative Studies Program; Pliva, Inc. (Zagreb, Croatia); VeroScience, LLC (Tiverton, RI); VeroScience, LLC; Wyeth Pharmaceuticals FX J.M.G. has received investigator-initiated federal funding from National Institutes of Health (National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute on Aging; National Eye Institute) and the Veteran's Affairs Cooperative Studies Program.; The study was initially sponsored by Pliva, Inc. (Zagreb, Croatia) in collaboration with VeroScience, LLC (Tiverton, RI), and subsequently by VeroScience, LLC unilaterally. The sponsors were involved in the study design and statistical analysis plan. The writing of this report and the decision to publish was the responsibility of all the study authors. J.M.G. has received nonfederal investigator initiated funding from Amgen and Pliva; has received research support in the form of pills and/or packaging from Wyeth Pharmaceuticals; and has received honoraria from Bayer and McNeil Consumer Products for speaking engagements. A.H.C. and R.E.S. are officers at VeroScience, LLC. C.M.O. served as paid chairman of the Adverse Adjudication Committee for VeroScience, LLC. M.E. is employed by VeroScience, LLC. Z.J.M. has been a paid consultant for VeroScience, LLC. No other potential conflicts of interest relevant to this article were reported. NR 25 TC 87 Z9 91 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2010 VL 33 IS 7 BP 1503 EP 1508 DI 10.2337/dc09-2009 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 656SL UT WOS:000282356800021 PM 20332352 ER PT J AU Chiu, CJ Wray, LA Beverly, EA AF Chiu, Ching-Ju Wray, Linda A. Beverly, Elizabeth A. TI Relationship of glucose regulation to changes in weight: a systematic review and guide to future research SO DIABETES-METABOLISM RESEARCH AND REVIEWS LA English DT Review DE systematic review; diabetes; glucose regulation; weight change ID CENTRAL-NERVOUS-SYSTEM; INCREASED VISCERAL ADIPOSITY; IMPROVED GLYCEMIC CONTROL; POPULATION-BASED SAMPLE; HIGH FASTING INSULIN; BODY-WEIGHT; DIABETES-MELLITUS; PLASMA-INSULIN; FOOD-INTAKE; BLOOD-PRESSURE AB Although weight gain and obesity are risk factors for poor glucose regulation, the relationship, if any, of glucose regulation to changes in weight is not well understood. The purpose of this study was to conduct a systematic review of research examining the relationship of glucose regulation to changes in weight in human-based studies and to provide guidelines for future research in this area. We searched electronic databases and reference sections of relevant articles, including both diabetic and non-diabetic populations, to locate all the literature published before February 2010, and then conducted a systematic review across studies to compare the research designs and findings. The 22 studies meeting our criteria for review generally supported the relationship of glucose regulation to changes in weight. Three studies reported that poor glucose regulation is associated with weight gain; 12 studies concluded that poor glucose regulation is associated with weight loss; 5 showed complex relationships depending on age, sex, or race/ethnicity; and 2 suggested no relationship. The diverse findings may imply that the direction (negative or positive) of the relationship may depend on specific conditions. More research focused on different subpopulations may provide more definitive information supplemental to the current preliminary findings. Recommendations regarding future research in this particular area are provided in the discussion. Copyright (C) 2010 John Wiley & Sons, Ltd. C1 [Chiu, Ching-Ju; Wray, Linda A.] Penn State Univ, Dept Biobehav Hlth, University Pk, PA 16802 USA. [Beverly, Elizabeth A.] Harvard Univ, Sch Med, Joslin Diabet Med Ctr, Boston, MA USA. RP Chiu, CJ (reprint author), Penn State Univ, Dept Biobehav Hlth, 315 HHD E, University Pk, PA 16802 USA. EM cuc197@psu.edu NR 75 TC 5 Z9 5 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1520-7560 J9 DIABETES-METAB RES JI Diabetes-Metab. Res. Rev. PD JUL PY 2010 VL 26 IS 5 BP 323 EP 335 DI 10.1002/dmrr.1095 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 627IY UT WOS:000280033900001 PM 20578206 ER PT J AU Lee, CG Fujimoto, WY Brunzell, JD Kahn, SE McNeely, MJ Leonetti, DL Boyko, EJ AF Lee, Christine G. Fujimoto, Wilfred Y. Brunzell, John D. Kahn, Steven E. McNeely, Marguerite J. Leonetti, Donna L. Boyko, Edward J. TI Intra-abdominal fat accumulation is greatest at younger ages in Japanese-American adults SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Aging; Intra-abdominal fat; Adiposity; Japanese-American; Longitudinal ID IMPAIRED GLUCOSE-TOLERANCE; VISCERAL ADIPOSITY; BODY-COMPOSITION; COMPUTED-TOMOGRAPHY; INSULIN-RESISTANCE; RISK-FACTORS; MEN; WEIGHT; ASSOCIATION; OVERWEIGHT AB Aims: We evaluated whether changes over 10-11 years in weight, subcutaneous abdominal fat (SQAF), and intra-abdominal fat (IAF) differ by age and contrasted age-related adiposity changes by gender. Methods: This is a prospective cohort study of non-diabetic, Japanese-American men and women aged 34-74 years. IAF and SQAF were measured by CT scan at baseline and 10-11-year follow-up visits. Results: The youngest participants gained the most weight, SQAF and IAF over 10-11 years. Older age at baseline was associated with significantly less change in weight (beta-coefficient: -0.19, 95% CI -0.22, -0.15), SQAF (beta-coefficient: -0.07, 95% CI -0.11, -0.02) and IAF (beta-coefficient: -0.74, 95% CI -1.03, -0.45) that persisted even after adjustments for sex, smoking, caloric intake, adiposity at baseline, and change in physical activity. Age was positively correlated with change in SQAF (beta-coefficient: 0.14, 95% CI 0.10, 0.18) and IAF (beta-coefficient: 0.51, 95% CI 0.21, 0.81) in separate models after further adjustment for weight change. Gender did not alter the associations between adiposity change and age. Conclusions: Men and women gained the greatest absolute amount of weight, SQAF, and IAF at younger ages; however, older adults with comparable weight changes had relatively greater fat accumulation within IAF and SQAF depots. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Lee, Christine G.] Oregon Hlth & Sci Univ, Dept Med, Div Endocrinol Diabet Clin Nutr, Portland, OR 97239 USA. [Fujimoto, Wilfred Y.; Brunzell, John D.; Kahn, Steven E.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Kahn, Steven E.; Boyko, Edward J.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [McNeely, Marguerite J.; Boyko, Edward J.] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA USA. [Leonetti, Donna L.] Univ Washington, Dept Anthropol, Seattle, WA 98195 USA. RP Lee, CG (reprint author), Oregon Hlth & Sci Univ, Dept Med, Div Endocrinol Diabet Clin Nutr, 3181 SW Sam Jackson Pk Rd,CR113, Portland, OR 97239 USA. EM leechr@ohsu.edu OI Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health [DK-31170, HL-49293, DK-02654]; Diabetes and Endocrinology Research Center [DK-17047]; Clinical Nutrition Research Unit [DK-35816]; General Clinical Research Center at the University of Washington [RR-00037]; Medical Research Service of the Department of Veterans Affairs FX This work was supported by National Institutes of Health Grants DK-31170, HL-49293, and DK-02654; by facilities and services provided by the Diabetes and Endocrinology Research Center (DK-17047), Clinical Nutrition Research Unit (DK-35816), and the General Clinical Research Center (RR-00037) at the University of Washington, and by the Medical Research Service of the Department of Veterans Affairs. These data have been presented at the following meetings: American Federation for Medical Research Western Regional Meeting, Carmel, CA, January 2009 and 11th Symposium of the International Diabetes Epidemiology Group, Montreal, CAN, October 2009.; All authors have been involved in one or more of the following study activities: design, data collection, data analysis, and manuscript preparation. We are grateful to the King County Japanese-American Community for support and cooperation. NR 26 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD JUL PY 2010 VL 89 IS 1 BP 58 EP 64 DI 10.1016/j.diabres.2010.03.006 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 626GI UT WOS:000279953900009 PM 20392506 ER PT J AU Boyko, EJ Doheny, RA McNeely, MJ Kahn, SE Leonetti, DL Fujimoto, WY AF Boyko, Edward J. Doheny, Rebecca A. McNeely, Marguerite J. Kahn, Steven E. Leonetti, Donna L. Fujimoto, Wilfred Y. TI Latent class analysis of the metabolic syndrome SO DIABETES RESEARCH AND CLINICAL PRACTICE LA English DT Article DE Metabolic syndrome; Latent class analysis; Intra-abdominal fat; Waist circumference; Japanese-American ID INSULIN-RESISTANCE SYNDROME; DIABETES-MELLITUS; ADIPOSE-TISSUE; RISK-FACTORS; SYNDROME-X; DIAGNOSIS; OBESITY; DEFINITION; STATEMENT; MEN AB Attempts to explain the associations among metabolic syndrome (MetS) features using factor analysis to identify unobserved potential causes have resulted in inconsistent findings. We examined whether an unobserved categorical factor explains the associations among MetS features using latent class analysis. A cross-sectional analysis of 499 nondiabetic Japanese-Americans who underwent measurements of fasting blood, waist circumference (WC) and CT-measured intra-abdominal fat (IAF) area was conducted. MetS components were defined by IDF criteria. IAF and fasting serum insulin (FI) were dichotomized at the 75(th) percentile. Latent two- and three-class models were fit that included hypertension, dyslipidemia, hyperglycemia, and either WC, IAF, or FI for a total of six models. A three-class latent model fit the data well, while a two-class model did not. In the three-class model, one latent class was strongly associated with all MetS components, while another was associated with hyperglycemia and hypertension only. IAF was associated with only one latent class. Latent class analysis supports the presence of an unobserved factor linked to the co-occurrence of MetS features. One class of this factor was associated with hypertension and hyperglycemia but not central adiposity or FI, suggesting another pathway for observed MetS features. Published by Elsevier Ireland Ltd. C1 [Boyko, Edward J.; Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Boyko, Edward J.; Doheny, Rebecca A.; McNeely, Marguerite J.] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA USA. [Kahn, Steven E.; Fujimoto, Wilfred Y.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Leonetti, Donna L.] Univ Washington, Dept Anthropol, Seattle, WA 98195 USA. RP Boyko, EJ (reprint author), 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM eboyko@u.washington.edu OI Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health [DK-31170, HL-49293, DK-02654, DK-17047, DK-35816, RR-00037]; Diabetes and Endocrinology Research Center [DK-17047]; Clinical Nutrition Research Unit [DK-35816]; General Clinical Research Center at the University of Washington [RR-00037]; VA Puget Sound Health Care System, Seattle, Washington; King County Japanese-American Community FX Grant Support: National Institutes of Health Grants DK-31170, HL-49293, DK-02654, DK-17047, DK-35816, and RR-00037.; This work was supported by National Institutes of Health Grants DK-31170, HL-49293, and DK-02654; by facilities and services provided by the Diabetes and Endocrinology Research Center (DK-17047), Clinical Nutrition Research Unit (DK-35816), and the General Clinical Research Center (RR-00037) at the University of Washington, and by resources from the VA Puget Sound Health Care System, Seattle, Washington. We are grateful to the King County Japanese-American Community for support and cooperation. NR 26 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-8227 J9 DIABETES RES CLIN PR JI Diabetes Res. Clin. Pract. PD JUL PY 2010 VL 89 IS 1 BP 88 EP 93 DI 10.1016/j.diabres.2010.02.013 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 626GI UT WOS:000279953900013 PM 20211506 ER PT J AU Chase, HP Beck, RW Xing, DY Tamborlane, WV Coffey, J Fox, LA Ives, B Keady, J Kollman, C Laffel, L Ruedy, KJ AF Chase, H. Peter Beck, Roy W. Xing, Dongyuan Tamborlane, William V. Coffey, Julie Fox, Larry A. Ives, Brett Keady, Joyce Kollman, Craig Laffel, Lori Ruedy, Katrina J. TI Continuous Glucose Monitoring in Youth with Type 1 Diabetes: 12-Month Follow-Up of the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Randomized Trial SO DIABETES TECHNOLOGY & THERAPEUTICS LA English DT Article ID INTENSIVE TREATMENT; COMPLICATIONS; MANAGEMENT; MELLITUS; IMPACT AB Background: The use of continuous glucose monitoring (CGM) in the pediatric population is not well characterized. We have evaluated the use of CGM over a 12-month interval in youth with type 1 diabetes (TID) and have provided a description of CGM use. Methods: Eighty subjects 8-17 years old with T1D and baseline hemoglobin A1c (HbA1c) >= 7.0% used CGM as part of a 6-month randomized trial and subsequent 6-month extension study. Outcomes included frequency of CGM use, HbA1c levels, rate of severe hypoglycemia, and a CGM satisfaction scale. Results: Seventy-six (95%) of 80 subjects were using CGM after 6 months (median use = 5.5 days/week) compared with 67 (84%) after 12 months (median use = 4.0 days/week). The 17 subjects using CGM >= 6 days/week in month 12 had substantially greater improvement from baseline in HbA1c than did the 63 subjects using CGM <6 days/week in month 12 (mean change - 0.8 +/- 0.6% vs. +0.1 +/- 0.7%, P < 0.001). They also reported greater satisfaction with use of CGM (P = 0.001). The incidence of severe hypoglycemic events was low during the 12 months of the study irrespective of the amount of CGM use. Conclusions: In youth with T1D, frequency of use decreases over time. Individuals who use CGM on a near-daily basis can have substantial improvement in glycemic control. C1 [Chase, H. Peter; Beck, Roy W.; Xing, Dongyuan; Kollman, Craig; Ruedy, Katrina J.] Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. [Chase, H. Peter] Barbara Davis Ctr, Denver, CO USA. [Tamborlane, William V.; Ives, Brett] Yale Univ, New Haven, CT USA. [Coffey, Julie] Univ Iowa, Iowa City, IA USA. [Fox, Larry A.] Nemours Childrens Clin, Jacksonville, FL USA. [Keady, Joyce; Laffel, Lori] Joslin Diabet Ctr, Boston, MA 02215 USA. RP Chase, HP (reprint author), Jaeb Ctr Hlth Res, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM jdrfapp@jaeb.org FU Juvenile Diabetes Research Foundation, Inc. [22-2006-1107, 22-2006-1117, 22-2006-1112, 22-2006-1123, 01-2006-8031]; Abbott Diabetes Care, Inc.; Medtronic Minimed, Inc.; Abbott Diabetes Care, Inc FX The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group would like to recognize the efforts of the subjects and their families and thank them for their participation. Study funding was provided by the Juvenile Diabetes Research Foundation, Inc. (grant numbers 22-2006-1107, 22-2006-1117, 22-2006-1112, 22-2006-1123, and 01-2006-8031).; The study was designed and conducted by the investigators listed in the Appendix, who collectively wrote the manuscript and vouch for the data. The investigators had complete autonomy to analyze and report the trial results. There were no agreements concerning confidentiality of the data between the Juvenile Diabetes Research Foundation, Inc. and the authors or their institutions. The Jaeb Center for Health Research 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. Continuous glucose monitors and sensors were purchased at a bulk discount price from DexCom, Inc. (San Diego, CA), Medtronic MiniMed, Inc. (Northridge, CA), and Abbott Diabetes Care, Inc. (Alameda, CA.). Home glucose meters and test strips were provided to the study by LifeScan, Inc. (Milpitas, CA) and Abbott Diabetes Care, Inc. The companies had no involvement in the design, conduct, or analysis of the trial or the manuscript preparation. H. P. C. and L. A. F. report having received research supplies from Abbott Diabetes Care, Inc. J. C. reports having received consulting fees from Abbott Diabetes Care, Inc. J. K. reports having received consulting fees from Medtronic Minimed, Inc. C. K. reports having received consulting fees from Medtronic MiniMed, Inc. L. L. reports having received consulting fees and speaker honorarium from Abbott Diabetes Care, Inc. and consulting fees and research funding from Medtronic MiniMed, Inc. W. V. T. reports having received consulting fees from Abbott Diabetes Care, Inc. and consulting fees, a speaker honorarium, and research funding from Medtronic MiniMed, Inc. NR 13 TC 39 Z9 39 U1 1 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1520-9156 EI 1557-8593 J9 DIABETES TECHNOL THE JI Diabetes Technol. Ther. PD JUL PY 2010 VL 12 IS 7 BP 507 EP 515 DI 10.1089/dia.2010.0021 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 619SJ UT WOS:000279450300001 PM 20597824 ER PT J AU Rolandsson, O Palmer, JP AF Rolandsson, O. Palmer, J. P. TI Latent autoimmune diabetes in adults (LADA) is dead: long live autoimmune diabetes! SO DIABETOLOGIA LA English DT Editorial Material DE Aetiology; Autoimmunity; Classification; Type 1 diabetes; Type 2 diabetes ID GLUTAMIC-ACID DECARBOXYLASE; IA-2 AUTOANTIBODIES; GENERAL-POPULATION; INSULIN-RESISTANCE; GAD ANTIBODIES; ISLET PROTEINS; TYPE-1; ONSET; DIAGNOSIS; CHILDREN C1 [Rolandsson, O.] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Palmer, J. P.] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Rolandsson, O (reprint author), Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. EM olov.rolandsson@fammed.umu.se NR 44 TC 29 Z9 31 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD JUL PY 2010 VL 53 IS 7 BP 1250 EP 1253 DI 10.1007/s00125-010-1713-0 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 602DM UT WOS:000278118700002 PM 20336277 ER PT J AU Igoillo-Esteve, M Marselli, L Cunha, DA Ladriere, L Ortis, F Grieco, FA Dotta, F Weir, GC Marchetti, P Eizirik, DL Cnop, M AF Igoillo-Esteve, M. Marselli, L. Cunha, D. A. Ladriere, L. Ortis, F. Grieco, F. A. Dotta, F. Weir, G. C. Marchetti, P. Eizirik, D. L. Cnop, M. TI Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes SO DIABETOLOGIA LA English DT Article DE Chemokine; Cytokine; Endoplasmic reticulum; Fatty acid; Inflammation; Interleukin-1 beta; Islet; Palmitate; Pancreatic beta cell; Type 2 diabetes ID ENDOPLASMIC-RETICULUM STRESS; FREE FATTY-ACIDS; FACTOR-KAPPA-B; LASER CAPTURE MICRODISSECTION; INSULIN GENE-EXPRESSION; OXIDATIVE STRESS; TRANSCRIPTION FACTOR; HIGH GLUCOSE; ER STRESS; GK RAT AB Beta cell failure is a crucial component in the pathogenesis of type 2 diabetes. One of the proposed mechanisms of beta cell failure is local inflammation, but the presence of pancreatic islet inflammation in type 2 diabetes and the mechanisms involved remain under debate. Chemokine and cytokine expression was studied by microarray analysis of laser-capture microdissected islets from pancreases obtained from ten non-diabetic and ten type 2 diabetic donors, and by real-time PCR of human islets exposed to oleate or palmitate at 6 or 28 mmol/l glucose. The cellular source of the chemokines was analysed by immunofluorescence of pancreatic sections from individuals without diabetes and with type 2 diabetes. Microarray analysis of laser-capture microdissected beta cells showed increased chemokine and cytokine expression in type 2 diabetes compared with non-diabetic controls. The inflammatory response in type 2 diabetes was mimicked by exposure of non-diabetic human islets to palmitate, but not to oleate or high glucose, leading to the induction of IL-1 beta, TNF-alpha, IL-6, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL1) and chemokine (C-C motif) ligand 2 (CCL2). Interference with IL-1 beta signalling abolished palmitate-induced cytokine and chemokine expression but failed to prevent lipotoxic human islet cell death. Palmitate activated nuclear factor kappa B (NF-kappa B) in human pancreatic beta and non-beta cells, and chemically induced endoplasmic reticulum stress caused cytokine expression and NF-kappa B activation similar to that occurring with palmitate. Saturated-fatty-acid-induced NF-kappa B activation and endoplasmic reticulum stress may contribute to IL-1 beta production and mild islet inflammation in type 2 diabetes. This inflammatory process does not contribute to lipotoxicity ex vivo, but may lead to local chemokine release. C1 [Igoillo-Esteve, M.; Cunha, D. A.; Ladriere, L.; Ortis, F.; Eizirik, D. L.; Cnop, M.] Univ Libre Bruxelles, Expt Med Lab, B-1070 Brussels, Belgium. [Marselli, L.; Marchetti, P.] Univ Pisa, Dept Endocrinol & Metab, Metab Unit, Pisa, Italy. [Grieco, F. A.; Dotta, F.] Univ Siena, Dept Internal Med Endocrine & Metab Sci & Biochem, I-53100 Siena, Italy. [Grieco, F. A.; Dotta, F.] Umberto Di Mario Fdn, Siena, Italy. [Weir, G. C.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Cnop, M.] Univ Libre Bruxelles, Erasmus Hosp, Div Endocrinol, Brussels, Belgium. RP Cnop, M (reprint author), Univ Libre Bruxelles, Expt Med Lab, CP-618,Route Lennik 808, B-1070 Brussels, Belgium. EM mcnop@ulb.ac.be RI Dotta, Francesco/H-3788-2012; Ortis, Fernanda/K-7917-2014; Marchetti, Piero/J-7439-2013; OI Marchetti, Piero/0000-0003-4907-0635; Cnop, Miriam/0000-0002-5112-1692; Dotta, Francesco/0000-0003-4947-7478 FU European Union; Belgian Program on Interuniversity Poles of Attraction; Fonds National de la Recherche Scientifique (FNRS); Fonds de la Recherche Scientifique Medicale (FRSM); Actions de Recherche Concertes de la Communaute Francaise, Belgium FX We thank G. Vandenbroeck, M. Urbain, J. Schoonheydt and R. Leeman (Laboratory of Experimental Medicine) for expert technical assistance. This work was supported by the European Union (Integrated Project EuroDia in the Framework Programme [ FP] 6 and Collaborative Projects CEED3 and NAIMIT in FP7); the Belgian Program on Interuniversity Poles of Attraction (IUAP P6/ 40); the Fonds National de la Recherche Scientifique (FNRS), Fonds de la Recherche Scientifique Medicale (FRSM) and Actions de Recherche Concertes de la Communaute Francaise, Belgium (M. Cnop and D. L. Eizirik); the Italian Diabetes Research Foundation- FORISID and the Italian Ministry of Health (F. Dotta); the European Association for the Study of Diabetes- European Foundation for the Study of Diabetes GlaxoSmithKline research grant (L. Marselli). NR 55 TC 94 Z9 99 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD JUL PY 2010 VL 53 IS 7 BP 1395 EP 1405 DI 10.1007/s00125-010-1707-y PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 602DM UT WOS:000278118700018 PM 20369226 ER PT J AU Srivastava, S Nadelman, C AF Srivastava, Sucheta Nadelman, Celina TI Synchronous Ipsilateral Warthin Tumor Encased by a Separate Mucoepidermoid Carcinoma of the Parotid Gland: A Case Report and Review of the Literature SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Review DE mucoepidermoid carcinoma; Warthin tumor; chronic sialadenitis; FNA; cytology; ipsilateral synchronous distinct neoplasms; parotid gland ID FINE-NEEDLE-ASPIRATION; MAJOR SALIVARY-GLANDS; CHRONIC SIALADENITIS; PLEOMORPHIC ADENOMA; MULTIPLE TUMORS; BIOPSY; DIAGNOSIS; LESIONS; BENIGN; CYTOLOGY AB Fine-needle aspiration (FNA) is a cost effective and low morbidity procedure in the initial assessment of salivary gland tumors. However, cytological assessment of ipsilateral synchronous tumors (which make up less than 0.3% of all salivary gland neoplasms) may pose diagnostic challenges. Therefore, a wholesome approach, including FNA with clinical and radiological correlation, is of utmost importance. Here, we report a unique case of Warthin tumor encased by a separate high-grade mucoepidermoid carcinoma that was first diagnosed on FNA. Another striking feature seen was the presence of chronic sialadenitis in the surrounding nonneoplastic salivary gland. The presence of two different neoplasms in the background of chronic sialadenitis raises the question of a possible causal relationship. Traditionally, there has been diagnostic difficulty, when dealing with synchronous tumors of the salivary gland and the background of chronic sialadenitis may further complicate the diagnosis. FNA is very helpful and can give important cues to the diagnosis. Diagn. Cytopathol. 2010;38:533-537. (C) 2009 Wiley-Liss, Inc. C1 [Srivastava, Sucheta] LAC USC Med Ctr, Dept Pathol & Lab Med, Pathol Resident PGY 1, Los Angeles, CA 90033 USA. [Nadelman, Celina] W Los Angeles VA Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA USA. RP Srivastava, S (reprint author), LAC USC Med Ctr, Dept Pathol & Lab Med, Pathol Resident PGY 1, Los Angeles, CA 90033 USA. EM sasrivas@usc.edu NR 40 TC 3 Z9 3 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD JUL PY 2010 VL 38 IS 7 BP 533 EP 537 DI 10.1002/dc.21267 PG 5 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 620RM UT WOS:000279517000015 PM 20027619 ER PT J AU Nordenstedt, H White, DL El-Serag, HB AF Nordenstedt, Helena White, Donna L. El-Serag, Hashem B. TI The changing pattern of epidemiology in hepatocellular carcinoma SO DIGESTIVE AND LIVER DISEASE LA English DT Article DE Cirrhosis; Epidemiology; GLOBOCAN; Hepatitis; Liver cancer AB Primary liver cancer (PLC) represents approximately 4% of all new cancer cases diagnosed worldwide. The purpose of this review is to describe some of the latest international patterns in PLC incidence and mortality, as well as to give an overview of the main etiological factors. We used two databases, GLOBOCAN 2002 and the World Health Organization (WHO) mortality database to analyze the incidence and mortality rates for PLC in several regions around the world. The highest age adjusted incidence rates (>20 per 100,000) were reported from countries in Southeast Asia and sub-Saharan Africa that are endemic for HBV infection. Countries in Southern Europe have medium-high incidence rates, while low-incidence areas (<5 per 100,000) include South and Central America, and the rest of Europe. Cirrhosis is present in about 80-90% of HCC patients and is thereby the largest single risk factor. Main risk factors include HBV, HCV, aflatoxin and possibly obesity and diabetes. Together HBV and HCV account for 80-90% of all HCC worldwide. HBV continues to be the major HCC risk factor worldwide, although its importance will most likely decrease during the coming decades due to the widespread use of the HBV vaccine in the newborns. HCV has been the dominant viral cause in HCC in North America, some Western countries and Japan. Obesity and diabetes are increasing at a fast pace throughout the world, and if they are proven to be HCC risk factors, they would account for more HCC cases in the future. (C) 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. C1 [Nordenstedt, Helena] Karolinska Inst, Stockholm, Sweden. [White, Donna L.; El-Serag, Hashem B.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [White, Donna L.; El-Serag, Hashem B.] Baylor Coll Med, Gastroenterol Sect, Houston, TX 77030 USA. [White, Donna L.; El-Serag, Hashem B.] Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. RP El-Serag, HB (reprint author), Michael E DeBakey Vet Affairs Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hasheme@bcm.tmc.edu FU Bayer HealthCare FX The corresponding author has received a fee from Bayer HealthCare for his contribution to this supplement. Bayer HealthCare played no role in the preparation, review, or approval of the manuscript. The co-authors have no conflict of interest to report. NR 55 TC 226 Z9 230 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1590-8658 EI 1878-3562 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD JUL PY 2010 VL 42 SU 3 BP S206 EP S214 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V45NY UT WOS:000209824500001 PM 20547305 ER PT J AU Korsten, MA Spungen, AM Rosman, AR Ancha, HR Post, JB Shaw, S Hunt, KK Williams, R Bauman, WA AF Korsten, M. A. Spungen, A. M. Rosman, A. R. Ancha, H. R. Post, J. B. Shaw, S. Hunt, K. K. Williams, R., III Bauman, W. A. TI A Prospective Assessment of Renal Impairment After Preparation for Colonoscopy: Oral Sodium Phosphate Appears to Be Safe in Well-Hydrated Subjects with Normal Renal Status SO DIGESTIVE DISEASES AND SCIENCES LA English DT Article DE Colonoscopy; Preparation; Efficacy; Kidney failure; PEG; Oral sodium phosphate solution ID CONTRAST-INDUCED NEPHROPATHY; PHOSPHOSODA BOWEL PREPARATION; POLYETHYLENE-GLYCOL SOLUTION; RANDOMIZED CONTROLLED-TRIAL; GLOMERULAR-FILTRATION-RATE; FATAL HYPERPHOSPHATEMIA; SERUM CREATININE; KIDNEY INJURY; FAILURE; QUALITY AB The outcome of colonoscopy is highly dependent upon the quality of bowel cleansing prior to the procedure. Oral sodium phosphate solutions (OSPS) or preparations containing polyethylene glycol (PEG) are generally employed. However, the safety of administering OSPS prior to colonoscopy has been questioned because of the potential for renal failure. To compare rates of renal failure after OSPS and PEG in a randomized, prospective trial and to assess the quality of colonoscopy after these two bowel preparations. Subjects with eGFR a parts per thousand yen 60 ml/min/1.73 m(2) and expressed willingness to adhere to hydration recommendations were randomized to OSPS or PEG solutions. Renal function was assessed 1 week prior to, immediately prior to, and 1 week after colonoscopy. No subject had acute kidney failure after OSPS or PEG. OSPS was associated with significant increases in the serum phosphate and sodium levels and significant decreases in the calcium and potassium levels. These values returned to normal limits in all subjects by 1 week after colonoscopy. The quality of colonic cleansing was superior after OSPS than after PEG (Ottawa score 2.5 +/- A 2.2 vs. 3.5 +/- A 2.3, respectively, P < 0.05). The detection of one or more adenomatous polyps was higher after OSPS than after PEG. Renal failure was not detected after the use of OSPS for colonoscopy preparation in subjects with recently documented normal renal function who were able to consume the required amounts of water after each dose. However, based on the number of subjects studied, the theoretical risk of this complication is still between 0 and 6.3%. Thus, it is appreciated that only a very large prospective trial would have yielded a more accurate estimate of the likelihood of renal compromise after OSPS. Despite this caveat, OSPS has advantages over PEG in terms of the adequacy of colonic visualization and the number of polyps detected. C1 [Korsten, M. A.; Spungen, A. M.; Rosman, A. R.; Ancha, H. R.; Post, J. B.; Shaw, S.; Hunt, K. K.; Williams, R., III; Bauman, W. A.] James J Peters VA Med Ctr, RR&D Ctr Excellence Med Consequences SCI, Bronx, NY USA. [Korsten, M. A.; Rosman, A. R.; Ancha, H. R.; Shaw, S.; Hunt, K. K.] James J Peters VA Med Ctr, GI Program, Bronx, NY USA. [Korsten, M. A.; Rosman, A. R.; Ancha, H. R.; Post, J. B.; Shaw, S.; Hunt, K. K.; Bauman, W. A.] James J Peters VA Med Ctr, Med Serv, Bronx, NY USA. [Korsten, M. A.; Spungen, A. M.; Rosman, A. R.; Post, J. B.; Shaw, S.; Hunt, K. K.; Bauman, W. A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Spungen, A. M.; Bauman, W. A.] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. RP Korsten, MA (reprint author), James J Peters VA Med Ctr, RR&D Ctr Excellence Med Consequences SCI, Bronx, NY USA. EM mark.korsten@va.gov FU Department of Veterans Affairs FX The funds for carrying out this research were provided solely by the Department of Veterans Affairs. No pharmaceutical company involved in the manufacture of purgative products supported this work. NR 48 TC 14 Z9 16 U1 0 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0163-2116 J9 DIGEST DIS SCI JI Dig. Dis. Sci. PD JUL PY 2010 VL 55 IS 7 BP 2021 EP 2029 DI 10.1007/s10620-009-1013-z PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 612LP UT WOS:000278900200029 PM 19834806 ER PT J AU Ellis, C AF Ellis, Charles TI Stroke in young adults SO DISABILITY AND HEALTH JOURNAL LA English DT Article DE Young stroke; Costs; Length of stay ID INTERNATIONAL-CLASSIFICATION; DISEASES; ICD-9-CM AB Background: Stroke among young adults is generally considered a rare event, although few studies have considered national data. Objective: The objective of this paper was to profile stroke in young adults in the United States using a national dataset. Methods: Data from the 2007 Nationwide Inpatient Sample were examined to estimate the number of patients, mean length of stay, mean costs, and discharge disposition of young adults (aged 18-44 y) with a diagnosis of stroke. Results: Estimates indicate that 41,587 (or 4.9%) of individuals experiencing a stroke in 2007 were young adults: 32,438 had an ischemic stroke, 4662 had a subarachnoid hemorrhage, and 4487 had an intracerebral hemorrhage. The average length of stay was 4.7 days for ischemic stroke, 11.6 days for subarachnoid hemorrhage, and 11.2 days for intracerebral hemorrhage. Approximately 5% (2013) of young adults died of stroke. Most young adults were discharged routinely to home at an average cost associated with their hospital stay of $34,886 for ischemic stroke, $146,307 for subarachnoid hemorrhage, and $94,482 for intracerebral hemorrhage. Conclusions: A substantial number of young adults experience stroke in the United States at costs that are higher than those for stroke patients overall. (C) 2010 Elsevier Inc. All rights reserved. C1 [Ellis, Charles] Med Univ S Carolina, Dept Hlth Profess, Charleston, SC 29425 USA. [Ellis, Charles] Ralph H Johnson VA Med Center, Ctr Dis Prevent & Hlth Intervent Diverse Populat, Charleston, SC 29401 USA. RP Ellis, C (reprint author), 77 President St, Charleston, SC USA. EM ellisc@musc.edu FU Center for Disease Prevention and Health Interventions FX This work represents work supported by the use of facilities at the Charleston, SC, Center for Disease Prevention and Health Interventions for Diverse Populations. NR 11 TC 6 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-6574 J9 DISABIL HEALTH J JI Disabil. Health J. PD JUL PY 2010 VL 3 IS 3 BP 222 EP 224 DI 10.1016/j.dhjo.2010.01.001 PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Rehabilitation SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Rehabilitation GA 668QP UT WOS:000283285000010 PM 21122787 ER PT J AU Baldwin, ML Marcus, SC De Simone, J AF Baldwin, Marjorie L. Marcus, Steven C. De Simone, Jeffrey TI Job loss discrimination and former substance use disorders SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Substance use disorders; Job loss; Labor market discrimination ID LABOR-MARKET DISCRIMINATION; ILLICIT DRUG-USE; DSM-IV ALCOHOL; UNITED-STATES; COCAINE USE; DISABILITIES; ABUSE; MEN; EMPLOYMENT; MARIJUANA AB Persons with former alcohol or drug use disorders are protected from labor market discrimination by the Americans with Disabilities Act of 1990. They have been neglected, however, in empirical studies of labor market discrimination following implementation of the Act. We apply econometric techniques used to study other disabled groups to determine if there are significant differences in employment outcomes for persons with and without former substance use disorders and, if so, what part of these differences potentially can be attributed to employer discrimination. There are no significant differences in employment rates between persons with and without former substance use disorders, and among those who are employed no significant differences in rates of full-time employment. But persons with former substance use disorders report significantly higher rates of involuntary job loss within the previous year. Part of the differential remains unexplained after controlling for other factors that affect employment outcomes, suggesting employer discrimination may be one cause of poor job stability among this group. Certain identifiable subgroups with low levels of human capital are particularly susceptible to substance-related discrimination. (c) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Baldwin, Marjorie L.] Arizona State Univ, WP Carey Sch Business, Sch Hlth Management & Policy, Tempe, AZ 85287 USA. [Marcus, Steven C.] Univ Penn, Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Marcus, Steven C.] Univ Penn, Sch Social Policy & Practice, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Marcus, Steven C.] Univ Penn, Leonard Davis Inst Hlth Econ, Ctr Hlth Equ Res Er Promot, Philadelphia, PA 19104 USA. [De Simone, Jeffrey] Univ Texas Arlington, NBER, Arlington, TX 76019 USA. [De Simone, Jeffrey] Univ Texas Arlington, Dept Econ, Arlington, TX 76019 USA. RP Baldwin, ML (reprint author), Arizona State Univ, WP Carey Sch Business, Sch Hlth Management & Policy, Box 874506, Tempe, AZ 85287 USA. EM Marjorie.Baldwin@asu.edu FU National Institute of Drug and Alcohol Abuse (NIDA) [R03 DA019860-01]; Ortho-McNeil Janssen FX This research was supported by grant # R03 DA019860-01 from the National Institute of Drug and Alcohol Abuse (NIDA). NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.; Dr. Marcus has received grants from Ortho-McNeil Janssen and has been a consultant to Eli Lilly and Company, Bristol Myers Squibb, Astra Zeneca, and Pfizer. NR 26 TC 11 Z9 12 U1 2 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2010 VL 110 IS 1-2 BP 1 EP 7 DI 10.1016/j.drugalcdep.2010.01.018 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 621KQ UT WOS:000279577200001 PM 20347233 ER PT J AU Mimiaga, MJ Reisner, SL Fontaine, YM Bland, SE Driscoll, MA Isenberg, D Cranston, K Skeer, MR Mayer, KH AF Mimiaga, Matthew J. Reisner, Sari L. Fontaine, Yves-Michel Bland, Sean E. Driscoll, Maura A. Isenberg, Deborah Cranston, Kevin Skeer, Margie R. Mayer, Kenneth H. TI Walking the line: Stimulant use during sex and HIV risk behavior among Black urban MSM SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Stimulant use; Black; MSM; HIV; Sexual risk behavior ID PLACEBO-CONTROLLED TRIAL; SUBSTANCE USE DISORDERS; AFRICAN-AMERICAN MEN; LOS-ANGELES-COUNTY; METHAMPHETAMINE USE; UNITED-STATES; CONTINGENCY MANAGEMENT; BISEXUAL MEN; CAGE QUESTIONNAIRE; OUTPATIENT TREATMENT AB Background: Although the association of stimulant use to sexual risk taking and HIV transmission has been well documented among white gay men, stimulant use during sex continues to be under-explored among Black men who have sex with men (MSM). Methods: Black MSM (n=197) recruited via modified respondent-driven sampling between January and July 2008 completed an interviewer-administered quantitative assessment and optional HIV counseling and testing. Bivariate logistic regression procedures were employed to examine the association of demographics, sexual risk, and other psychosocial factors with stimulant use (at least monthly during sex in the past 12 months). Variable elimination using the backward selection process was used to fit two separate final multivariable logistic regression models examining stimulant use as the outcome and HIV sexual risk in the past 12 months by gender as the primary predictor: (1) Model 1: HIV sexual risk behavior with a casual male sex partner as a primary, forced predictor; (2) Model 2: HIV sexual risk behavior with a female sex partner as primary, forced predictor. Results: One-third (34%) of Black MSM reported using stimulants monthly or more frequently during sex in the past 12 months. The following factors were independently associated with stimulant use during sex: (1) Model I: unprotected anal sex with a casual male sex partner in the past 12 months (AOR =2.61; 95% CI = 1.06-6.42; p = 0.01), older age (AOR= 1.09; 95% CI =1.05-1.15; p<0.001), erectile dysfunction (ED) medication use monthly or more during sex in the past 12 months (AOR = 7.81; 95% CI = 1.46-41.68; p = 0.02), problematic alcohol use (AOR = 3.31; 95% CI = 1.312-8.38; p = 0.005), and higher HIV treatment optimism (AOR =0.86; 95% CI = 0.76-0.97; p = 0.01). (2) Model 2: unprotected vaginal or anal sex with a female partner in the past 12 months (AOR= 3.54; 95% CI = 1.66-7.56; p = 0.001), older age (AOR = 1.10; 95% CI = 1.05-1.14; p < 0.001), ED use monthly or more during sex in the past 12 months (AOR = 3.70; 95% CI = 1.13-12.13; p = 0.03), clinically significant depressive symptoms (CES-D) at the time of study enrollment (AOR = 3.11; 95% CI = 1.45-6.66; p = 0.004), and supportive condom use norms (AOR = 0.69; 95% CI = 0.49-0.97; p = 0.03). Conclusion: Frequent stimulant use is an important factor in HIV and STD sexual risk among Black MSM, particularly for older men and those with co-occurring psychosocial morbidities. HIV and STD prevention interventions in this population may benefit from addressing the precipitants of stimulant use and sexual risk taking. (c) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Mimiaga, Matthew J.; Reisner, Sari L.; Bland, Sean E.; Skeer, Margie R.; Mayer, Kenneth H.] Fenway Community Hlth, Fenway Inst, Boston, MA USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Mimiaga, Matthew J.; Reisner, Sari L.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Fontaine, Yves-Michel] Columbia Univ, New York, NY USA. [Driscoll, Maura A.; Isenberg, Deborah; Cranston, Kevin] Massachusetts Dept Publ Hlth, Boston, MA USA. [Skeer, Margie R.] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. [Mayer, Kenneth H.] Miriam Hosp, Brown Med Sch, Providence, RI 02906 USA. RP Mimiaga, MJ (reprint author), Fenway Hlth, Fenway Inst, 8th Floor,1340 Boylston St, Boston, MA 02215 USA. EM mmimiaga@fenwayhealth.org FU National Institute on Drug Abuse [R03DA023393] FX This work was funded by the Office of HIV/AIDS, Massachusetts Department of Public Health. Some of the investigator time on this project was support by grant number R03DA023393 from the National Institute on Drug Abuse (PI: M. Mimiaga). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 62 TC 28 Z9 28 U1 3 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2010 VL 110 IS 1-2 BP 30 EP 37 DI 10.1016/j.drugalcdep.2010.01.017 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 621KQ UT WOS:000279577200005 PM 20334986 ER PT J AU Kelly, JF Dow, SJ Yeterian, JD Kahler, CW AF Kelly, John F. Dow, Sarah J. Yeterian, Julie D. Kahler, Christopher W. TI Can 12-step group participation strengthen and extend the benefits of adolescent addiction treatment? A prospective analysis SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Alcoholics Anonymous; Narcotics Anonymous; Self-help; Groups; Adolescent ID SELF-HELP GROUPS; MULTIVARIATE PROCESS MODEL; SUBSTANCE-ABUSE; INPATIENT TREATMENT; CONTINUING CARE; REDUCE DEMAND; ATTENDANCE; OUTCOMES; INVOLVEMENT; SUPPORT AB Background: Despite advances in the development of treatments for adolescents with substance use disorders (SUD), relapse remains common following an index treatment episode. Community continuing care resources, such as Alcoholics Anonymous (AA) and Narcotics Anonymous (NA), have been shown to be helpful and cost-effective recovery resources among adults. However, little is known about the clinical utility and effectiveness of AA/NA for adolescents, despite widespread treatment referrals. Method: Adolescents (N=127; 24% female, 87% White, M age = 16.7 years) enrolled in a naturalistic, prospective study of community outpatient treatment were assessed at intake, and 3 and 6 months later using a battery of standardized and validated measures. Results: Just over one-quarter of youth attended AA/NA meetings during the first 3 months, which was predicted by a goal of abstinence, prior AA/NA attendance, and prior SOD treatment experiences. Controlled multiple regression analyses revealed an independent effect of AA/NA on abstinence, in both contemporaneous and lagged models, which persisted over and above the effects of pre-treatment AA/NA attendance, prior treatment, self-efficacy, abstinence goal, and concomitant outpatient treatment. Conclusions: Results suggest that, similar to findings comparing adult outpatients to inpatients, AA/NA participation is less common among less severe adolescent outpatients. Nonetheless, attendance appears to strengthen and extend the benefits of typical community outpatient treatment. Given the dramatic increase in rates of substance use among same-aged peers in the population at this life-stage, and the relative dearth of abstainers and recovery-specific supports, these resources may provide a concentrated cost-effective social recovery resource for young people. (c) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Kelly, John F.; Dow, Sarah J.; Yeterian, Julie D.] Massachusetts Gen Hosp, Ctr Addict Med, Dept Psychiat, Boston, MA 02114 USA. [Kelly, John F.; Dow, Sarah J.; Yeterian, Julie D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kahler, Christopher W.] Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02903 USA. RP Kelly, JF (reprint author), 60 Staniford St,Suite 120, Boston, MA 02114 USA. EM jkelly11@partners.org FU National Institute of Alcohol Abuse and Alcoholism (NIAAA) [R01015526-01-A4] FX Funding for this study was provided by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) grant R01015526-01-A4. Opinions are those solely of the authors and do not reflect those of the funding agency. NR 47 TC 31 Z9 31 U1 2 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2010 VL 110 IS 1-2 BP 117 EP 125 DI 10.1016/j.drugalcdep.2010.02.019 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 621KQ UT WOS:000279577200016 PM 20338698 ER PT J AU Obika, M Trence, DL AF Obika, Mikako Trence, Dace L. TI COMPARISON OF TYPE 2 DIABETES CARE IN THE UNITED STATES AND JAPAN SO ENDOCRINE PRACTICE LA English DT Editorial Material ID GLUCOSE-TOLERANCE; RISK-FACTORS; MELLITUS; OBESITY; PREVALENCE; MICROALBUMINURIA; SUSCEPTIBILITY; COMPLICATIONS; OVERWEIGHT; ADULTS C1 [Obika, Mikako] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Lab Med, Okayama 7008558, Japan. [Obika, Mikako] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Trence, Dace L.] Univ Washington, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. RP Obika, M (reprint author), Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Lab Med, 2-5-1 Shikata Cho, Okayama 7008558, Japan. EM mika_obika@yahoo.co.jp NR 34 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC CLIN ENDOCRINOL PI JACKSONVILLE PA 1000 RIVERSIDE AVE, STE 205, JACKSONVILLE, FL 32204 USA SN 1530-891X J9 ENDOCR PRACT JI Endocr. Pract. PD JUL-AUG PY 2010 VL 16 IS 4 BP 707 EP 711 DI 10.4158/EP09312.CO PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 642BJ UT WOS:000281177600024 PM 20350922 ER PT J AU Weir, GC Bonner-Weir, S AF Weir, Gordon C. Bonner-Weir, Susan TI Dreams for Type 1 Diabetes: Shutting Off Autoimmunity and Stimulating beta-Cell Regeneration SO ENDOCRINOLOGY LA English DT Editorial Material ID GLUCAGON-LIKE PEPTIDE-1; NOD MICE; COMBINATION THERAPY; RESTORES NORMOGLYCEMIA; NEOGENESIS; TOLERANCE; GROWTH; ONSET; MASS; CD26 C1 [Weir, Gordon C.] Harvard Univ, Sect Islet Cell Biol & Regenerat Med, Sch Med, Res Div,Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Dept Med, Sch Med, Boston, MA 02215 USA. RP Weir, GC (reprint author), Harvard Univ, Sect Islet Cell Biol & Regenerat Med, Sch Med, Res Div,Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM gordon.weir@joslin.harvard.edu NR 22 TC 5 Z9 6 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUL PY 2010 VL 151 IS 7 BP 2971 EP 2973 DI 10.1210/en.2010-0538 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 614IK UT WOS:000279049300001 PM 20570953 ER PT J AU Khodr, CE Clark, S Bokov, AF Richardson, A Strong, R Hurley, DL Phelps, CJ AF Khodr, Christina E. Clark, Sara Bokov, Alex F. Richardson, Arlan Strong, Randy Hurley, David L. Phelps, Carol J. TI Early Postnatal Administration of Growth Hormone Increases Tuberoinfundibular Dopaminergic Neuron Numbers in Ames Dwarf Mice SO ENDOCRINOLOGY LA English DT Article ID TYROSINE-HYDROXYLASE; PROLACTIN GENE; NEUROTROPHIC SIGNALS; TARGETED DISRUPTION; PITUITARY PROLACTIN; CELL-PROLIFERATION; LONG-TERM; ADULT; RAT; DIFFERENTIATION AB Hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons secrete dopamine, which inhibits pituitary prolactin (PRL) secretion. PRL has demonstrated neurotrophic effects on TIDA neuron development in PRL-, GH-, and TSH-deficient Ames (df/df) and Snell (dw/dw) dwarf mice. However, both PRL and PRL receptor knockout mice exhibit normal-sized TIDA neuron numbers, implying GH and/or TSH influence TIDA neuron development. The current study investigated the effect of porcine (p) GH on TIDA neuron development in Ames dwarf hypothalamus. Normal (DF/df) and dwarf mice were treated daily with pGH or saline beginning at 3 d of age for a period of 42 d. After treatment, brains were analyzed using catecholamine histofluorescence, tyrosine hydroxylase immunocytochemistry, and bromodeoxyuridine (BrdU) immunocytochemistry to detect BrdU incorporation. DF/df males and df/df treated with pGH experienced increased (P <= 0.01) weight gain compared with those treated with saline. DF/df had greater (P <= 0.01) TIDA neuron numbers than df/df, regardless of treatment. TIDA neuron number in pGH-treated df/df was greater (P <= 0.01) than in saline-treated df/df. Zona incerta and periventricular dopamine neurons were not affected by treatment or genotype. There was no effect of genotype or treatment on BrdU incorporation in the arcuate nucleus, median eminence, or periventricular region surrounding the third ventricle. Saline-treated df/df experienced decreased (P <= 0.05) dentate gyrus BrdU incorporation compared with saline-treated DF/df. In the lateral ventricle, pGH-treated males had greater BrdU immunoreactivity than pGH-treated females. The results show an effect of pGH on TIDA neuron development, although this effect is less potent than that of PRL, and likely GH-induced preservation of TIDA neurons rather than generation of new TIDA neurons via neurogenesis. (Endocrinology 151: 3277-3285, 2010) C1 [Khodr, Christina E.; Clark, Sara; Hurley, David L.; Phelps, Carol J.] Tulane Univ, Sch Med, Neurosci Program, New Orleans, LA 70112 USA. [Bokov, Alex F.; Richardson, Arlan; Strong, Randy] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. [Richardson, Arlan; Strong, Randy] S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. [Richardson, Arlan] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Bokov, Alex F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. RP Hurley, DL (reprint author), E Tennessee State Univ, Bill Gatton Coll Pharm, Dept Pharmaceut Sci, POB 70594, Johnson City, TN 37614 USA. EM hurleyd@etsu.edu FU Louisiana BORSF Board of Regents; National Science Foundation [IBN-0350537]; Public Health Service [NS25987] FX This work was supported by Louisiana BORSF Board of Regents Support Fund grant (to C.E.K.), National Science Foundation Grant IBN-0350537 (to D.L.H.), and Public Health Service Grant NS25987 (to C.J.P.). NR 49 TC 4 Z9 4 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUL PY 2010 VL 151 IS 7 BP 3277 EP 3285 DI 10.1210/en.2009-1482 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 614IK UT WOS:000279049300031 PM 20463054 ER PT J AU Chu-Shore, CJ Major, P Camposano, S Muzykewicz, D Thiele, EA AF Chu-Shore, Catherine J. Major, Philippe Camposano, Susana Muzykewicz, David Thiele, Elizabeth A. TI The natural history of epilepsy in tuberous sclerosis complex SO EPILEPSIA LA English DT Article DE Epilepsy; Infantile spasms; Outcome; Genetics; Tuberous sclerosis complex ID INFANTILE SPASMS; DIAGNOSTIC-CRITERIA; MUTATIONAL ANALYSIS; SIGNALING PATHWAYS; CHILDREN; TSC2; DISEASE; MTOR AB P>Background: Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease. Methods: A retrospective chart review of all patients with TSC seen between January 2002 and October 2008. Charts were reviewed for a history of infantile spasms (IS), seizure other than IS, refractory epilepsy, Lennox-Gastaut syndrome (LGS), anticonvulsant medication use, ages of seizure onset, last seizure, last clinic visit, clinical seizure phenotype(s), cognitive impairment, and genetic mutation. Results: Two hundred ninety-one patients were included. Among these patients, 37.8% had a history of IS; 85.2% had a history of seizure; 54.1% developed multiple seizure types, not including IS; 63.2% had seizure onset in the first year of life; and 12.1% of adults without a seizure history developed epilepsy. Of epilepsy patients, 62.5% developed refractory epilepsy and 33.5% achieved epilepsy remission; 37.5% of these patients achieved medication freedom. IS was a risk factor for refractory epilepsy (p < 0.0001) and LGS (p < 0.0001). History of seizure, IS, age at seizure onset, and refractory epilepsy each correlated with poor cognitive outcome (p < 0.0001). Epilepsy remission correlated with better cognitive outcome (p < 0.0001). TSC2 was a risk factor for IS and epilepsy; patients without an identified mutation were more likely to achieve remission. Conclusion: Most patients with TSC develop epilepsy and most develop multiple seizure types. Onset typically occurs in the first year of life; however, adults remain at risk. Although refractory epilepsy is common, many patients achieve seizure control. Many features of seizure history are predictive of cognitive and epilepsy outcome. C1 [Chu-Shore, Catherine J.; Major, Philippe; Camposano, Susana; Muzykewicz, David; Thiele, Elizabeth A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Thiele, EA (reprint author), Carol & James Herscot Ctr Tuberous Sclerosis Comp, 175 Cambridge St,Suite 340, Boston, MA 02114 USA. EM ethiele@partners.org FU Carol and James Herscot Center for Tuberous Sclerosis Complex FX This study was supported by the Carol and James Herscot Center for Tuberous Sclerosis Complex. NR 31 TC 139 Z9 145 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD JUL PY 2010 VL 51 IS 7 BP 1236 EP 1241 DI 10.1111/j.1528-1167.2009.02474.x PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 619PG UT WOS:000279441500018 PM 20041940 ER PT J AU Gonzalez-Heydrich, J Whitney, J Waber, D Forbes, P Hsin, O Faraone, SV Dodds, A Rao, S Mrakotsky, C MacMillan, C DeMaso, DR de Moor, C Torres, A Bourgeois, B Biederman, J AF Gonzalez-Heydrich, Joseph Whitney, Jane Waber, Deborah Forbes, Peter Hsin, Olivia Faraone, Stephen V. Dodds, Alice Rao, Sneha Mrakotsky, Christine MacMillan, Carlene DeMaso, David R. de Moor, Carl Torres, Alcy Bourgeois, Blaise Biederman, Joseph TI Adaptive phase I study of OROS methylphenidate treatment of attention deficit hyperactivity disorder with epilepsy SO EPILEPSY & BEHAVIOR LA English DT Article DE Epilepsy; Seizures; Attention deficit hyperactivity disorder; Stimulant; Methylphenidate; OROS methylphenidate; Pharmacotherapy; Childhood seizures ID DEFICIT/HYPERACTIVITY DISORDER; SEMISTRUCTURED INTERVIEW; SEIZURE CLASSIFICATION; PEDIATRIC-PATIENTS; CLINICAL-TRIAL; CHILDREN; ADOLESCENTS; PREVALENCE; EPIDEMIOLOGY; RELIABILITY AB Objective: The goal of this study was to pilot a randomized controlled trial of OROS methylphenidate (OROS-MPH) to treat attention deficit hyperactivity disorder (ADHD) plus epilepsy. Methods: Thirty-three patients, 6-18 years of age, taking antiepileptic drugs and with a last seizure 1-60 months prior were assigned to a maximum daily dose of 18,36, or 54 mg of OROS-MPH in a double-blind placebo-controlled crossover trial. Results: There were no serious adverse events and no carryover effects in the crossover trial. OROS-MPH reduced ADHD symptoms more than did placebo treatment. There were too few seizures during the active (5) and placebo arms (3) to confidently assess seizure risk; however, considering exposure time, we observed an increased daily risk of seizures with increasing dose of OROS-MPH, suggesting that potential safety concerns require further study. Conclusion: A larger study to assess the effect of OROS-MPH on seizure risk is needed. A crossover design including subjects with frequent seizures could maximize power and address high patient heterogeneity and recruitment difficulties. (C) 2010 Elsevier Inc. All rights reserved. C1 [Gonzalez-Heydrich, Joseph] Harvard Univ, Dept Psychiat, Psychopharmacol Program, Childrens Hosp Boston,Sch Med, Boston, MA 02115 USA. [Forbes, Peter; de Moor, Carl] Childrens Hosp Boston, Clin Res Program, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Torres, Alcy; Bourgeois, Blaise] Harvard Univ, Childrens Hosp Boston, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Biederman, Joseph] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Pediat Psychopharmacol Res Unit, Boston, MA 02115 USA. RP Gonzalez-Heydrich, J (reprint author), Harvard Univ, Dept Psychiat, Psychopharmacol Program, Childrens Hosp Boston,Sch Med, Fegan 8, Boston, MA 02115 USA. EM joseph.gonzalez-heydrich@childrens.harvard.edu OI Torres, Alcy/0000-0001-5798-9161; Faraone, Stephen/0000-0002-9217-3982 FU NIMH [K23 MH066835] FX This study was supported by NIMH Grant K23 MH066835. NR 37 TC 27 Z9 29 U1 3 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD JUL PY 2010 VL 18 IS 3 BP 229 EP 237 DI 10.1016/j.yebeh.2010.02.022 PG 9 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA 630FW UT WOS:000280259500015 PM 20493783 ER PT J AU Dudek, FE Ekstrand, JJ Staley, KJ AF Dudek, F. Edward Ekstrand, Jeffrey J. Staley, Kevin J. TI IS NEURONAL DEATH NECESSARY FOR ACQUIRED EPILEPTOGENESIS IN THE IMMATURE BRAIN? SO EPILEPSY CURRENTS LA English DT Review ID PROLONGED FEBRILE SEIZURES; SPONTANEOUS RECURRENT SEIZURES; INDUCED STATUS EPILEPTICUS; TEMPORAL-LOBE EPILEPSY; LONG-TERM; RAT MODEL; HIPPOCAMPAL EXCITABILITY; MESSENGER-RNA; DENTATE GYRUS; INJURY AB A central question concerning acquired epileptogenesis in the immature brain is whether neuronal death is required for the development of epilepsy after a brain insult. Results from three different animal models of brain injury during early development have been used to develop the hypothesis that status epilepticus, prolonged febrile seizures, or hypoxia-induced seizures can lead to chronic epilepsy without the occurrence of neuronal death. This brief review will summarize the evidence supporting the hypothesis in each model and then critique the data and published interpretations. A case will be made that the evidence to date neither rules out the occurrence of neuronal death nor demonstrates that epileptogenesis (i.e., spontaneous recurrent seizures) has actually occurred in these animal models of acquired pediatric epilepsy. We also review evidence for the opposing hypothesis: acquired epileptogenesis in the immature brain requires, or at least often involves, neuronal death. C1 [Dudek, F. Edward] Univ Utah, Sch Med, Dept Physiol, Salt Lake City, UT 84108 USA. [Ekstrand, Jeffrey J.] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT 84108 USA. [Staley, Kevin J.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Dudek, FE (reprint author), Univ Utah, Sch Med, Dept Physiol, 420 Chipeta Way,Suite 1700, Salt Lake City, UT 84108 USA. EM ed.dudek@hsc.utah.edu NR 41 TC 16 Z9 16 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1535-7597 J9 EPILEPSY CURR JI Epilepsy Curr. PD JUL-AUG PY 2010 VL 10 IS 4 BP 95 EP 99 DI 10.1111/j.1535-7511.2010.01369.x PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 652PY UT WOS:000282022800008 PM 20697505 ER PT J AU Selmecki, A Forche, A Berman, J AF Selmecki, Anna Forche, Anja Berman, Judith TI Genomic Plasticity of the Human Fungal Pathogen Candida albicans SO EUKARYOTIC CELL LA English DT Article ID FIELD GEL-ELECTROPHORESIS; CHROMOSOMAL DNA-MOLECULES; REPETITIVE SEQUENCES RPSS; WHITE-OPAQUE TRANSITION; MAJOR REPEAT SEQUENCE; SACCHAROMYCES-CEREVISIAE; GENE-EXPRESSION; AZOLE RESISTANCE; MATING-TYPE; FLUCONAZOLE RESISTANCE AB The genomic plasticity of Candida albicans, a commensal and common opportunistic fungal pathogen, continues to reveal unexpected surprises. Once thought to be asexual, we now know that the organism can generate genetic diversity through several mechanisms, including mating between cells of the opposite or of the same mating type and by a parasexual reduction in chromosome number that can be accompanied by recombination events (2, 12, 14, 53, 77, 115). In addition, dramatic genome changes can appear quite rapidly in mitotic cells propagated in vitro as well as in vivo. The detection of aneuploidy in other fungal pathogens isolated directly from patients (145) and from environmental samples (71) suggests that variations in chromosome organization and copy number are a common mechanism used by pathogenic fungi to rapidly generate diversity in response to stressful growth conditions, including, but not limited to, antifungal drug exposure. Since cancer cells often become polyploid and/or aneuploid, some of the lessons learned from studies of genome plasticity in C. albicans may provide important insights into how these processes occur in higher-eukaryotic cells exposed to stresses such as anticancer drugs. C1 [Berman, Judith] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Selmecki, Anna] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Forche, Anja] Bowdoin Coll, Dept Biol, Brunswick, ME 04011 USA. [Berman, Judith] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. RP Berman, J (reprint author), Univ Minnesota, Dept Genet Cell Biol & Dev, 6-160 Jackson Hall, Minneapolis, MN 55455 USA. EM jberman@umn.edu OI Berman, Judith/0000-0002-8577-0084 FU NIH [NIAID R01AI0624273, NIAID R01AI075096]; Microbial and Plant Genomics Institute of Minnesota Integrative FX This work was supported by NIH NIAID R01AI0624273 and NIAID R01AI075096 to J.B. and by a Microbial and Plant Genomics Institute of Minnesota Integrative Fellowship to A. NR 210 TC 66 Z9 67 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD JUL PY 2010 VL 9 IS 7 BP 991 EP 1008 DI 10.1128/EC.00060-10 PG 18 WC Microbiology; Mycology SC Microbiology; Mycology GA 621ER UT WOS:000279557900002 PM 20495058 ER PT J AU Mowry, SE Tang, C Sadeghi, A Wang, MB AF Mowry, Sarah E. Tang, Christopher Sadeghi, Ahmad Wang, Marilene B. TI Standard chemoradiation versus intensity-modulated chemoradiation: a quality of life assessment in oropharyngeal cancer patients SO EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY LA English DT Article DE IMRT; Chemoradiation; Oropharyngeal cancer; Quality of life ID PHASE-II TRIAL; NECK-CANCER; RADIATION-THERAPY; CONVENTIONAL RADIOTHERAPY; CARCINOMA; HEAD; CHEMOTHERAPY; XEROSTOMIA; SURGERY; HEALTH AB This study is based on the context that many patients with advanced oropharyngeal carcinoma are being treated with primary chemoradiation. The aims of this study are to identify differences in quality of life (QOL) between patients with advanced oropharyngeal cancer following traditional chemoradiation versus chemotherapy with intensity-modulated radiation therapy (CIMRT). This research is designed on a cohort study from an academic tertiary referral center. Fifty patients were identified from an institutional database of patients who had undergone primary chemotherapy and radiation (traditional or IMRT) for advanced oropharyngeal carcinoma. Patients responded via mail using the University of Washington quality of life instrument version 4. Statistical analysis of data was performed using Chi-square and Wilcoxon tests. The results comprise the responses of 17 CRT (57%) and 14 CIMRT (70%) patients. The patients completed the survey between 9 and 44 months following end of treatment. When adjusted for tumor stage and time since treatment, CIMRT patients reported improved appearance (p = 0.05), chewing (p = 0.02), and mood (p = 0.01). There was a trend toward significance for improved activity (p = 0.07), recreation (p = 0.07), and anxiety (p = 0.08). There were no differences between the two groups for saliva, taste, shoulder function, speech, and swallowing. But there was a trend for significance for improved overall QOL in patients who had undergone CIMRT (p = 0.06). In conclusion, CIMRT results in improved QOL for some domains but surprisingly not for swallowing or saliva. Patients undergoing CIMRT also report slightly better QOL overall when compared to patients receiving more traditional forms of radiation therapy. C1 [Mowry, Sarah E.; Tang, Christopher; Wang, Marilene B.] Univ Calif Los Angeles, David Geffen Sch Med, Div Head & Neck Surg, Los Angeles, CA 90095 USA. [Sadeghi, Ahmad] VA Greater Los Angeles Healthcare Syst, Dept Radiat Oncol, Los Angeles, CA USA. [Wang, Marilene B.] VA Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. RP Mowry, SE (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Head & Neck Surg, 62-132 CHS,BOX 951624, Los Angeles, CA 90095 USA. EM Smowry1978@gmail.com NR 17 TC 13 Z9 13 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0937-4477 J9 EUR ARCH OTO-RHINO-L JI Eur. Arch. Oto-Rhino-Laryn. PD JUL PY 2010 VL 267 IS 7 BP 1111 EP 1116 DI 10.1007/s00405-009-1183-5 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA 599UR UT WOS:000277939700015 PM 20039175 ER PT J AU Kuusikko, S Pollock-Wurman, R Ebeling, H Hurtig, T Joskitt, L Mattila, ML Jussila, K Moilanen, I AF Kuusikko, Sanna Pollock-Wurman, Rachel Ebeling, Hanna Hurtig, Tuula Joskitt, Leena Mattila, Marja-Leena Jussila, Katja Moilanen, Irma TI Psychometric evaluation of social phobia and anxiety inventory for children (SPAI-C) and social anxiety scale for children-revised (SASC-R) (vol 18, pg 116, 2009) SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Correction C1 [Kuusikko, Sanna; Pollock-Wurman, Rachel; Ebeling, Hanna; Hurtig, Tuula; Joskitt, Leena; Mattila, Marja-Leena; Jussila, Katja; Moilanen, Irma] Univ Oys, Child Psychiat Clin, Dept Child Psychiat, Oys 90029, Finland. [Kuusikko, Sanna; Pollock-Wurman, Rachel; Ebeling, Hanna; Hurtig, Tuula; Joskitt, Leena; Mattila, Marja-Leena; Jussila, Katja; Moilanen, Irma] Univ Hosp Oulu, Oys 90029, Finland. [Pollock-Wurman, Rachel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Kuusikko, S (reprint author), Univ Oys, Child Psychiat Clin, Dept Child Psychiat, POB 26, Oys 90029, Finland. EM kuusisan@paju.oulu.fi NR 1 TC 0 Z9 0 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD JUL PY 2010 VL 19 IS 7 BP 625 EP 625 DI 10.1007/s00787-010-0100-1 PG 1 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 616FT UT WOS:000279195100011 ER PT J AU Saul, H Partridge, A AF Saul, Helen Partridge, Ann TI Non-adherence: a new epidemic? SO EUROPEAN JOURNAL OF CANCER LA English DT Editorial Material C1 [Partridge, Ann] Harvard Univ, Sch Med, Boston, MA USA. [Partridge, Ann] Dana Farber Canc Inst, Breast Oncol Program, Boston, MA USA. [Partridge, Ann] Dana Farber Canc Inst, Program Young Women Breast Canc, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2010 VL 46 IS 10 BP 1767 EP 1767 PG 1 WC Oncology SC Oncology GA 627JO UT WOS:000280035500013 ER PT J AU Sasaki, T Rodig, SJ Chirieac, LR Janne, PA AF Sasaki, Takaaki Rodig, Scott J. Chirieac, Lucian R. Janne, Pasi A. TI The biology and treatment of EML4-ALK non-small cell lung cancer SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Non-small cell lung carcinoma; Translocation; Kinase inhibitor; Clinical trial ID GROWTH-FACTOR-RECEPTOR; CLINICOPATHOLOGICAL FEATURES; FUSION GENE; ANAPLASTIC LYMPHOMA; TUMOR-SUPPRESSOR; MUTATIONS; ALK; KINASE; KRAS; ADENOCARCINOMA AB The fusion between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK),has recently been identified in a subset of non-small cell lung cancers (NSCLCs). EML4-ALK is most often detected in never smokers with lung cancer and has unique pathologic features. EML4-ALK is oncogenic both in vitro and in vivo and ALK kinase inhibitors are quite effective in pre-clinical model systems. More recently ALK inhibitors have entered clinical development and remarkably clinical efficacy has been observed in NSCLC patients harbouring EML4-ALK translocations. This review will focus on the biology, clinical characteristics, diagnosis and treatment of EML4-ALK NSCLC. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Sasaki, Takaaki; Janne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA. [Sasaki, Takaaki; Janne, Pasi A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Rodig, Scott J.; Chirieac, Lucian R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Janne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Janne, Pasi A.] Harvard Univ, Sch Med, Boston, MA USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, D820,44 Binney St, Boston, MA 02115 USA. EM pjanne@partners.org OI Sasaki, Takaaki/0000-0002-6505-8786 FU National Institutes of Health [R01CA136851] FX This study was supported by the National Institutes of Health R01CA136851 (P.A.J.). NR 43 TC 227 Z9 268 U1 1 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2010 VL 46 IS 10 BP 1773 EP 1780 DI 10.1016/j.ejca.2010.04.002 PG 8 WC Oncology SC Oncology GA 627JO UT WOS:000280035500016 PM 20418096 ER PT J AU Sonnenberg, A AF Sonnenberg, Amnon TI The validity of hospital discharge data Response SO EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Letter C1 [Sonnenberg, Amnon] Portland VA Med Ctr, Portland, OR 97239 USA. [Sonnenberg, Amnon] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. RP Sonnenberg, A (reprint author), Portland VA Med Ctr, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu 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 0954-691X J9 EUR J GASTROEN HEPAT JI Eur. J. Gastroenterol. Hepatol. PD JUL PY 2010 VL 22 IS 7 BP 900 EP 900 DI 10.1097/MEG.0b013e3283349e5e PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 608FZ UT WOS:000278569900026 ER PT J AU Gibson, CM AF Gibson, C. Michael TI Long-term anticoagulation in cardiovascular indications SO EUROPEAN JOURNAL OF HAEMATOLOGY LA English DT Article DE acute coronary syndrome; antithrombotic therapy ID ACUTE CORONARY SYNDROMES; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL; ATRIAL-FIBRILLATION; ANTIPLATELET THERAPY; STROKE PREVENTION; UNSTABLE ANGINA; IN-RANGE; WARFARIN; ASPIRIN AB Despite dual antiplatelet therapy with aspirin and clopidogrel, in the year following hospitalization for an acute coronary syndrome (ACS), patients remain at high risk of death or recurrent myocardial infarction (MI) with an approximately 10% event rate. A recent meta-analysis demonstrated a 40% reduction in the risk of recurrent MI with the use of the anticoagulant warfarin. However, use of warfarin is complicated by the need for monitoring of the prothrombin time, high rates of bleeding, and interactions with a variety of foods and other medications. Novel anticoagulants are in development that offer simpler dosing, do not require monitoring, have fewer drug interactions, and may offer greater efficacy than warfarin in the setting of ACS. Similarly, the vitamin K antagonists (VKAs) have shown clear benefit compared with aspirin or clopidogrel for reducing the incidence of stroke in atrial fibrillation (AF) in patients at higher risk for thromboembolic events and are recommended in patients with CHADS(2) scores >= 2. Despite the proven benefits of warfarin, however, several analyses have shown it to be underused in clinical practice. Novel oral anticoagulants under development could have a tremendous impact on patient care given the societal burden of AF. The key characteristics of an advance in anticoagulation will be efficacy and safety at least comparable to those of warfarin as well as ease of use and cost-effectiveness. C1 [Gibson, C. Michael] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gibson, C. Michael] Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, Boston, MA 02215 USA. RP Gibson, CM (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM mgibson@perfuse.org FU Abbott; Angel Medical Systems; AstraZeneca; Atrium Medical Corporation; Baxter; Bayer; FibroGen; FoldRx; Genentech; HeartScape Technologies; Ikaria; Johnson Johnson; Lantheus Medical Imaging; Portola; sanofi-aventis; Schering-Plough FX He has received research/grant support from Abbott; Angel Medical Systems; AstraZeneca; Atrium Medical Corporation; Baxter; Bayer; FibroGen; FoldRx; Genentech; HeartScape Technologies; Ikaria, Johnson & Johnson; Lantheus Medical Imaging; Portola; sanofi-aventis; and Schering-Plough. NR 33 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0902-4441 J9 EUR J HAEMATOL JI Eur. J. Haematol. PD JUL PY 2010 VL 85 SU 72 BP 20 EP 28 PG 9 WC Hematology SC Hematology GA 612RO UT WOS:000278920400004 ER PT J AU Massie, BM AF Massie, Barry M. TI Is the effect of angiotensin receptor blockade in patients with heart failure modified by treatment with aspirin? The answer is not so clear! SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Editorial Material ID CONVERTING-ENZYME-INHIBITORS; VENTRICULAR SYSTOLIC FUNCTION; ANTIPLATELET THERAPY; RANDOMIZED-TRIAL; CANDESARTAN; WARFARIN; WATCH C1 Univ Calif San Francisco, San Francisco Vet Adm Med Ctr, Cardiol Div 111C, San Francisco, CA 94121 USA. RP Massie, BM (reprint author), Univ Calif San Francisco, San Francisco Vet Adm Med Ctr, Cardiol Div 111C, 4150 Clement St, San Francisco, CA 94121 USA. EM barry.massie@va.gov NR 17 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1388-9842 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD JUL PY 2010 VL 12 IS 7 BP 639 EP 641 DI 10.1093/eurjhf/hfq096 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 616CR UT WOS:000279186300001 PM 20576831 ER PT J AU Domian, IJ Buikema, JW de Boer, RA van der Meer, P AF Domian, Ibrahim J. Buikema, Jan W. de Boer, Rudolf A. van der Meer, Peter TI Stem cells in heart failure SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Editorial Material ID ACUTE MYOCARDIAL-INFARCTION; PROGENITOR CELLS; MONONUCLEAR-CELLS; THERAPY; TRIAL; REGENERATION; MUSCLE; AMI C1 [Buikema, Jan W.; de Boer, Rudolf A.; van der Meer, Peter] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Domian, Ibrahim J.] Harvard Stem Cell Inst, Cambridge, MA USA. [Domian, Ibrahim J.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP van der Meer, P (reprint author), Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. EM p.van.der.meer@thorax.umcg.nl FU NHLBI NIH HHS [K08 HL091209] NR 23 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1388-9842 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD JUL PY 2010 VL 12 IS 7 BP 642 EP 644 DI 10.1093/eurjhf/hfq105 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 616CR UT WOS:000279186300002 PM 20576832 ER PT J AU Winkel, TA Hoeks, SE Schouten, O Zeymer, U Limbourg, T Baumgartner, I Bhatt, DL Steg, PG Goto, S Rother, J Cacoub, PP Verhagen, HJM Bax, JJ Poldermans, D AF Winkel, T. A. Hoeks, S. E. Schouten, O. Zeymer, U. Limbourg, T. Baumgartner, I. Bhatt, D. L. Steg, Ph. G. Goto, S. Roether, J. Cacoub, P. P. Verhagen, H. J. M. Bax, J. J. Poldermans, D. TI Prognosis of Atrial Fibrillation in Patients with Symptomatic Peripheral Arterial Disease: Data from the REduction of Atherothrombosis for Continued Health (REACH) Registry SO EUROPEAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY LA English DT Article DE Atrial fibrillation; Prognosis; REACH Registry ID CLINICAL CLASSIFICATION SCHEMES; RISK-FACTORS; ANTIPLATELET THERAPY; PREDICTING STROKE; PREVALENCE; MANAGEMENT; ANTICOAGULATION; OUTPATIENTS; GUIDELINES; WARFARIN AB Background: Atrial fibrillation (AF) is a significant risk factor for cardiovascular (CV) mortality. This study aims to evaluate the prognostic implication of AF in patients with peripheral arterial disease (PAD). Methods: The International Reduction of Atherothrombosis for Continued Health (REACH) Registry included 23,542 outpatients in Europe with established coronary artery disease, cerebrovascular disease (CVD), PAD and/or >= 3 risk factors. Of these, 3753 patients had symptomatic PAD. CV risk factors were determined at baseline. Study end point was a combination of cardiac death, non-fatal myocardial infarction (MI) and stroke (CV events) during 2 years of follow-up. Cox regression analysis adjusted for age, gender and other risk factors (i.e., congestive heart failure, coronary artery re-vascularisation, coronary artery bypass grafting (CABG), MI, hypertension, stroke, current smoking and diabetes) was used. Results: Of 3753 PAD patients, 392 (10%) were known to have AF. Patients with AF were older and had a higher prevalence of CVD, diabetes and hypertension. Long-term CV mortality occurred in 5.6% of patients with AF and in 1.6% of those without AF (p < 0.001). Multivariable analyses showed that AF was an independent predictor of late CV events (hazard ratio (HR): 1.5; 95% confidence interval (CI): 1.09-2.0). Conclusion: AF is common in European patients with symptomatic PAD and is independently associated with a worse 2-year CV outcome. (C) 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. C1 [Winkel, T. A.; Hoeks, S. E.; Verhagen, H. J. M.; Poldermans, D.] Erasmus MC, Dept Vasc Surg, Erasmus Med Ctr, NL-3015 GD Rotterdam, Netherlands. [Schouten, O.] Reinier Graaf Hosp, Dept Surg, Delft, Netherlands. [Zeymer, U.; Limbourg, T.] Heidelberg Univ, Inst Herzinfarktforsch Ludwigshafen, Ludwigshafen, Germany. [Baumgartner, I.] Univ Hosp, Inselspital, Div Clin & Intervent Angiol, Swiss Cardiovasc Ctr, Bern, Switzerland. [Bhatt, D. L.] VA Boston Healthcare Syst, Boston, MA USA. [Bhatt, D. L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Steg, Ph. G.] Univ Paris 07, INSERM, U698, Ctr Hosp Bichat Claude Bernard,AP HP, Paris, France. [Goto, S.] Tokai Univ, Sch Med, Kanagawa 2591100, Japan. [Roether, J.] Hannover Med Sch, Johannes Wesling Klinikum Minden, D-3000 Hannover, Germany. [Cacoub, P. P.] Univ Paris 06, Hosp La Pitie Salpetriere, AP HP, Paris, France. [Bax, J. J.] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands. RP Poldermans, D (reprint author), Erasmus MC, Dept Vasc Surg, Erasmus Med Ctr, Room H 805,S Gravendijkwal 230, NL-3015 GD Rotterdam, Netherlands. EM d.poldermans@erasmusmc.nl FU Sanofi-Aventis; Bristol-Myers Squibb; Waksman Foundation (Tokyo, Japan); Lijf Et Leven Foundation, Rotterdam, the Netherlands FX The REACH Registry is sponsored by Sanofi-Aventis, Bristol-Myers Squibb and the Waksman Foundation (Tokyo, Japan). Tamara Winkel and Sanne Hoeks were partially supported by the Lijf Et Leven Foundation, Rotterdam, the Netherlands. The REACH Registry is endorsed by the World Heart Federation. A complete list of REACH investigators is accessible online at www.reachregistry.org. The REACH Registry enforces a no ghost-writing policy. This manuscript was written and edited by the authors, who take full responsibility for its content. The first draft was written by Tamara A. Winkel. We thank Deborah Burrage (PhD) for her assistance with coordinating revisions and providing editorial help in preparing this manuscript including editing, checking content and language, formatting, referencing and preparing tables and figures, and Tobias Limbourg for his support with statistical analyses. The Institut fur Herzinfarktforschung Ludwigshafen verified all statistical analyses. NR 33 TC 20 Z9 20 U1 0 U2 4 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1078-5884 EI 1532-2165 J9 EUR J VASC ENDOVASC JI Eur. J. Vasc. Endovasc. Surg. PD JUL PY 2010 VL 40 IS 1 BP 9 EP 16 DI 10.1016/j.ejvs.2010.03.003 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 636HV UT WOS:000280723400002 PM 20385507 ER PT J AU Schlett, CL Kwait, DC Mahabadi, AA Bamberg, F O'Donnell, CJ Fox, CS Hoffmann, U AF Schlett, Christopher L. Kwait, Dylan C. Mahabadi, Amir A. Bamberg, Fabian O'Donnell, Christopher J. Fox, Caroline S. Hoffmann, Udo TI Simple area-based measurement for multidetector computed tomography to predict left ventricular size SO EUROPEAN RADIOLOGY LA English DT Article DE Multidetector computed tomography; Left ventricle; Left ventricular size; Cardio-thoracic ratio; Direct transverse cardiac diameter; Framingham Heart Study ID ACUTE PULMONARY-EMBOLISM; CHRONIC HEART-FAILURE; MYOCARDIAL-INFARCTION; CARDIOTHORACIC RATIO; CHEST-PAIN; MORTALITY; MASS; CT; FRAMINGHAM; SURVIVAL AB Measures of left ventricular (LV) mass and dimensions are independent predictors of morbidity and mortality. We determined whether an axial area-based method by computed tomography (CT) provides an accurate estimate of LV mass and volume. A total of 45 subjects (49% female, 56.0 +/- 12 years) with a wide range of LV geometry underwent contrast-enhanced 64-slice CT. LV mass and volume were derived from 3D data. 2D images were analysed to determine LV area, the direct transverse cardiac diameter (dTCD) and the cardiothoracic ratio (CTR). Furthermore, feasibility was confirmed in 100 Framingham Offspring Cohort subjects. 2D measures of LV area, dTCD and CTR were 47.3 +/- 8 cm(2), 14.7 +/- 1.5 cm and 0.54 +/- 0.05, respectively. 3D-derived LV volume (end-diastolic) and mass were 148.9 +/- 45 cm(3) and 124.2 +/- 34 g, respectively. Excellent inter- and intra-observer agreement were shown for 2D LV area measurements (both intraclass correlation coefficients (ICC) = 0.99, p < 0.0001) and could be confirmed on non-contrast CT. The measured 2D LV area was highly correlated to LV volume, mass and size (r = 0.68; r = 0.73; r = 0.82; all p < 0.0001, respectively). On the other hand, CTR was not correlated to LV volume, mass, size or 2D LV area (all p > 0.27). Compared with traditionally used CTR, LV size can be accurately predicted based on a simple and highly reproducible axial LV area-based measurement. C1 [Schlett, Christopher L.; Kwait, Dylan C.; Mahabadi, Amir A.; Bamberg, Fabian; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Schlett, Christopher L.; Kwait, Dylan C.; Mahabadi, Amir A.; Bamberg, Fabian; Fox, Caroline S.; Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Bamberg, Fabian] Univ Munich, Munich, Germany. [Bamberg, Fabian] Univ Hosp Munich, Dept Clin Radiol, Munich, Germany. [O'Donnell, Christopher J.; Fox, Caroline S.] Natl Heart Lung & Blood Insts Framingham Heart St, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Metab & Diabet, Boston, MA 02115 USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org FU National Heart, Lung and Blood Institute [N01-HC-25195]; National Institute of Health (NIH) [R01 HL080053]; Siemens Medical Solutions; German Federal Ministry of Education and Research; Foundation of German Business, Berlin FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (N01-HC-25195), National Institute of Health (NIH, R01 HL080053), and in part by Siemens Medical Solutions. Christopher Schlett was supported by grants from the German Federal Ministry of Education and Research, and Foundation of German Business, Berlin. NR 29 TC 14 Z9 14 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 J9 EUR RADIOL JI Eur. Radiol. PD JUL PY 2010 VL 20 IS 7 BP 1590 EP 1596 DI 10.1007/s00330-010-1720-z PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 607RA UT WOS:000278522800006 PM 20204649 ER PT J AU Saur, SC Alkadhi, H Stolzmann, P Baumuller, S Leschka, S Scheffel, H Desbiolles, L Fuchs, TJ Szekely, G Cattin, PC AF Saur, Stefan C. Alkadhi, Hatem Stolzmann, Paul Baumueller, Stephan Leschka, Sebastian Scheffel, Hans Desbiolles, Lotus Fuchs, Thomas J. Szekely, Gabor Cattin, Philippe C. TI Effect of reader experience on variability, evaluation time and accuracy of coronary plaque detection with computed tomography coronary angiography SO EUROPEAN RADIOLOGY LA English DT Article DE Coronary plaque; Observer variability; Evaluation time; Reader experience; Computed tomography coronary angiography ID INTRAVASCULAR ULTRASOUND; CT ANGIOGRAPHY; ARTERY; QUANTIFICATION; CALCIFICATION; LESIONS AB To assess the effect of reader experience on variability, evaluation time and accuracy in the detection of coronary artery plaques with computed tomography coronary angiography (CTCA). Three independent, blinded readers with three different experience levels twice labelled 50 retrospectively electrocardiography (ECG)-gated contrast-enhanced dual-source CTCA data sets (15 female, age 67.3 +/- 10.4 years, range 46-86 years) indicating the presence or absence of coronary plaques. The evaluation times for the readings were recorded. Intra- and interobserver variability expressed as kappa statistics and sensitivity, specificity, and negative and positive predictive values were calculated for plaque detection, with a consensus reading of the three readers taken as the standard of reference. A bootstrap method was applied in the statistical analysis to account for clustering. Significant correlations were found between reader experience and, respectively, evaluation times (r = -0.59, p < 0.05) and intraobserver variability (r = 0.73, p < 0.05). The evaluation time significantly differed among the readers (p < 0.05). The observer variability for plaque detection, compared with the consensus, varied between kappa = 0.582 and kappa = 0.802. Variability of plaque detection was significantly smaller (p < 0.05) and more accurate (p < 0.05) for the most experienced reader. Reader experience significantly correlated with observer variability, evaluation time and accuracy of coronary plaque detection at CTCA. C1 [Alkadhi, Hatem; Stolzmann, Paul; Baumueller, Stephan; Leschka, Sebastian; Scheffel, Hans; Desbiolles, Lotus] Univ Zurich Hosp, Inst Diagnost Radiol, CH-8091 Zurich, Switzerland. [Saur, Stefan C.; Szekely, Gabor; Cattin, Philippe C.] ETH, Comp Vis Lab, Zurich, Switzerland. [Alkadhi, Hatem] Massachusetts Gen Hosp, Cardiac MR PET CT Grp, Boston, MA 02114 USA. [Alkadhi, Hatem] Harvard Univ, Sch Med, Boston, MA USA. [Fuchs, Thomas J.] ETH, Dept Comp Sci, Zurich, Switzerland. [Cattin, Philippe C.] Univ Basel, Med Image Anal Ctr, Basel, Switzerland. RP Alkadhi, H (reprint author), Univ Zurich Hosp, Inst Diagnost Radiol, Raemistr 100, CH-8091 Zurich, Switzerland. EM hatem.alkadhi@usz.ch RI Cattin, Philippe/B-1301-2009 FU National Center of Competence in Research, Computer Aided and Image Guided Medical Interventions of the Swiss National Science Foundation FX This research has been supported by the National Center of Competence in Research, Computer Aided and Image Guided Medical Interventions of the Swiss National Science Foundation (http://co-me.ch). NR 28 TC 8 Z9 8 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0938-7994 J9 EUR RADIOL JI Eur. Radiol. PD JUL PY 2010 VL 20 IS 7 BP 1599 EP 1606 DI 10.1007/s00330-009-1709-7 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 607RA UT WOS:000278522800008 PM 20119728 ER PT J AU Li, Y Peng, ZC Xiao, B Houser, CR AF Li, Yi Peng, Zechun Xiao, Bo Houser, Carolyn R. TI Activation of ERK by spontaneous seizures in neural progenitors of the dentate gyrus in a mouse model of epilepsy SO EXPERIMENTAL NEUROLOGY LA English DT Article DE Extracellular signal-regulated kinase (ERK); Hippocampus; Dentate gyrus; Subgranular zone; Neurogenesis; Brain lipid binding protein (BLBP); Spontaneous seizure; Pilocarpine; Epilepsy ID SIGNAL-REGULATED KINASE; ADULT HIPPOCAMPAL NEUROGENESIS; TEMPORAL-LOBE EPILEPSY; GRANULE CELL NEUROGENESIS; STATUS EPILEPTICUS; RAT HIPPOCAMPUS; STEM-CELL; PROTEIN-KINASE; FUNCTIONAL-INTEGRATION; SUBVENTRICULAR ZONE AB Cellular changes that are associated with spontaneous seizures in temporal lobe epilepsy are not well understood but could influence ongoing epilepsy-related processes. In order to identify cell signaling events that could occur at the time of spontaneous seizures, the localization of phosphorylated extracellular signal-regulated kinase (PERK) was studied in a pilocarpine mouse model of epilepsy at very short intervals (1.5-2.5 min) after detection of a spontaneous seizure. Within the hippocampal formation, immunolabeling of pERK was evident in a subpopulation of cells in the subgranular zone (SGZ) of the dentate gyrus at these short intervals. Many of these cells had a long vertical process and resembled radial glia, while others had short processes and were oriented horizontally. Labeling with a series of developmental markers demonstrated that virtually all pERK-labeled cells were neural progenitor cells (NPCs). A high percentage (similar to 80%) of the pERK-labeled cells was labeled with either glial fibrillary acidic protein or brain lipid binding protein, indicating that these cells were radial glia-like NPCs. A smaller percentage of labeled cells expressed NeuroD, suggesting that they were later-developing NPCs that were assuming a neuronal identity. Early expression of pERK was not detected in immature neurons. Double labeling with proliferation markers demonstrated that approximately 30% of pERK-labeled NPCs expressed Mcm2, indicating that they were actively proliferating. Furthermore, virtually all radial glia-like NPCs that were in the proliferative cycle expressed pERK. These findings suggest that spontaneous seizures and associated ERK activation could contribute to the proliferation of radial glia-like NPCs in this epilepsy model. (C) 2010 Elsevier Inc. All rights reserved. C1 [Li, Yi; Peng, Zechun; Houser, Carolyn R.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA. [Li, Yi; Xiao, Bo] Cent S Univ, Xiang Ya Hosp, Dept Neurol, Changsha 410008, Hunan, Peoples R China. [Houser, Carolyn R.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA. [Houser, Carolyn R.] Vet Adm Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA 90073 USA. RP Houser, CR (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, CHS 73-235,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM houser@mednet.ucla.edu FU Veterans Affairs Medical Research; National Institutes of Health [NS046524]; P.R. China Scholarship Council; Ministry of Health, P.R. China [2007(353)] FX This work was supported by Veterans Affairs Medical Research Funds (C.R.H.), National Institutes of Health Grant NS046524 (C.R.H.), a joint PhD program fellowship provided by the P.R. China Scholarship Council (Y. L) and the Ministry of Health Grant 2007(353), P.R. China (B.X.). We thank Christine Huang and Yliana Cetina for expert assistance with tissue preparation. NR 67 TC 19 Z9 20 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUL PY 2010 VL 224 IS 1 SI SI BP 133 EP 145 DI 10.1016/j.expneurol.2010.03.003 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 615IO UT WOS:000279128400016 PM 20226181 ER PT J AU Pino, MS Chung, DC AF Pino, Maria S. Chung, Daniel C. TI Application of molecular diagnostics for the detection of Lynch syndrome SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE genetic testing; immunohistochemistry; Lynch syndrome; microsatellite instability; mismatch repair genes ID NONPOLYPOSIS COLORECTAL-CANCER; DNA MISMATCH-REPAIR; TUMOR MICROSATELLITE INSTABILITY; REVISED BETHESDA GUIDELINES; EGAPP WORKING GROUP; OVARIAN-CANCER; COLON-CANCER; ENDOMETRIAL CARCINOMAS; GENOMIC DELETIONS; MUTATION DETECTION AB Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is the most common hereditary colorectal cancer (CRC) syndrome, accounting for approximately 2-5% of all newly diagnosed cases of CRC. Patients with LS have an increased lifetime risk of colorectal (52.2% in women and 68.7% in men) and endometrial cancer (15-70%), as well as certain extra-colonic cancers. Germline mutations in one of several DNA mismatch repair genes underlie LS. Molecular testing has emerged as an indispensable strategy for the diagnosis of LS. The diagnostic workup of at-risk individuals includes a careful family history evaluation, microsatellite instability, immunohistochemistry and germline DNA analysis. A positive test result can guide clinicians in formulating the appropriate screening, surveillance and management strategies. However, because of the absence of an overt phenotype, such as a diffuse polyposis, it is not always straightforward to recognize LS clinically. C1 [Pino, Maria S.; Chung, Daniel C.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Chung, DC (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 50 Blossom St, Boston, MA 02114 USA. EM dchung@partners.org FU MGH ECOR Fund for Medical Discovery; National Institutes of Health [CA 92594, P50 CA127003]; Kate J and Dorothy L Clapp Fund FX Maria S Pino was supported by the MGH ECOR Fund for Medical Discovery; Daniel C Chung was supported in part by National Institutes of Health CA 92594 and P50 CA127003 and also the Kate J and Dorothy L Clapp Fund. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 126 TC 11 Z9 13 U1 0 U2 5 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD JUL PY 2010 VL 10 IS 5 BP 651 EP 665 DI 10.1586/ERM.10.45 PG 15 WC Pathology SC Pathology GA 629CT UT WOS:000280172700014 PM 20629513 ER PT J AU Jackson, ML Bassett, KL AF Jackson, M. L. Bassett, K. L. TI The natural history of the Charles Bonnet Syndrome. Do the hallucinations go away? SO EYE LA English DT Letter ID VISUAL HALLUCINATIONS C1 [Jackson, M. L.] Harvard Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. [Bassett, K. L.] Univ British Columbia, British Columbia Ctr Epidemiol & Int Ophthalmol, Vancouver, BC V5Z 1M9, Canada. RP Jackson, ML (reprint author), Harvard Dept Ophthalmol, Massachusetts Eye & Ear Infirm, Boston, MA USA. EM Marylou_jackson@meei.harvard.edu NR 2 TC 7 Z9 8 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-222X J9 EYE JI Eye PD JUL PY 2010 VL 24 IS 7 BP 1303 EP 1304 DI 10.1038/eye.2010.12 PG 4 WC Ophthalmology SC Ophthalmology GA 626OT UT WOS:000279976000040 PM 20150924 ER PT J AU Ueda, S Kitazawa, S Ishida, K Nishikawa, Y Matsui, M Matsumoto, H Aoki, T Nozaki, S Takeda, T Tamori, Y Aiba, A Kahn, CR Kataoka, T Satoh, T AF Ueda, Shuji Kitazawa, Sohei Ishida, Kota Nishikawa, Yuki Matsui, Megumi Matsumoto, Hikaru Aoki, Takuji Nozaki, Shinsuke Takeda, Tomoya Tamori, Yoshikazu Aiba, Atsu Kahn, C. Ronald Kataoka, Tohru Satoh, Takaya TI Crucial role of the small GTPase Rac1 in insulin-stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma SO FASEB JOURNAL LA English DT Article DE GLUT4; Akt; AS160; electron microscopy ID LIVING MICE; T-TUBULES; GLUT4; GLUCOSE; CELLS; ACTIN; COMPARTMENTS; ACTIVATION; RESISTANCE; DISRUPTION AB The Rho family GTPase Rac1 has been implicated in the regulation of glucose uptake in myoblast cell lines. However, no evidence for the role of Rac1 has been provided by a mouse model. The purpose of this study is to test the involvement of Rac1 in insulin action in mouse skeletal muscle. Intravenous administration of insulin indeed elicited Rac1 activation in gastrocnemius muscle, suggesting the involvement of Rac1 in this signaling pathway. We then examined whether insulin-stimulated translocation of the facilitative glucose transporter GLUT4 from its storage sites to the skeletal muscle sarcolemma depends on Rac1. We show that ectopic expression of constitutively activated Rac1, as well as intravenous administration of insulin, caused translocation of GLUT4 to the gastrocnemius muscle sarcolemma, as revealed by immunofluorescent staining of a transiently expressed exofacial epitope-tagged GLUT4 reporter. Of particular note, insulin-dependent, but not constitutively activated Rac1-induced, GLUT4 translocation was markedly suppressed in skeletal muscle-specific rac1-knockout mice compared to control mice. Immunogold electron microscopic analysis of endogenous GLUT4 gave similar results. Collectively, we propose a critical role of Rac1 in insulin-dependent GLUT4 translocation to the skeletal muscle sarcolemma, which has heretofore been predicted solely by cell culture studies.-Ueda, S., Kitazawa, S., Ishida, K., Nishikawa, Y., Matsui, M., Matsumoto, H., Aoki, T., Nozaki, S., Takeda, T., Tamori, Y., Aiba, A., Kahn, C. R., Kataoka, T., Satoh, T. Crucial role of the small GTPase Rac1 in insulin-stimulated translocation of glucose transporter 4 to the mouse skeletal muscle sarcolemma. FASEB J. 24, 2254-2261 (2010). www.fasebj.org C1 [Satoh, Takaya] Kobe Univ, Grad Sch Med, Dept Biochem & Mol Biol, Div Mol Biol,Chuo Ku, Kobe, Hyogo 6500017, Japan. [Kitazawa, Sohei] Kobe Univ, Grad Sch Med, Dept Pathol, Div Mol Pathol, Kobe, Hyogo 6500017, Japan. [Tamori, Yoshikazu] Kobe Univ, Grad Sch Med, Dept Internal Med, Div Diabet Metab & Endocrinol, Kobe, Hyogo 6500017, Japan. [Aiba, Atsu] Kobe Univ, Grad Sch Med, Dept Physiol & Cell Biol, Div Mol Genet, Kobe, Hyogo 6500017, Japan. [Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RP Satoh, T (reprint author), Kobe Univ, Grad Sch Med, Dept Biochem & Mol Biol, Div Mol Biol,Chuo Ku, 5-1 Kusunoki Cho, Kobe, Hyogo 6500017, Japan. EM tkysato@med.kobe-u.ac.jp RI Satoh, Takaya/K-2628-2014 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan; Takeda Science Foundation FX The authors are grateful to Jonathan Bogan (Yale University School of Medicine, New Haven, CT, USA), Harvey Lodish (Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA, USA), and Jun-ichi Miyazaki (Osaka University, Osaka, Japan) for plasmid DNAs. The authors also thank Masato Kasuga (International Medical Center of Japan) for critical reading of the manuscript and valuable suggestions and Nobuyuki Takenaka (Kobe University) for technical assistance. This investigation was supported by Grants-in-Aid for Scientific Research on Priority Areas (Systems Genomics and Life Surveyor), Scientific Research (B), the 21st Century COE Program (Center of Excellence for Signal Transduction Disease: Diabetes Mellitus as Model), and the Global COE Program (Global Center for Education and Research in Integrative Membrane Biology) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by a grant from the Takeda Science Foundation. NR 29 TC 51 Z9 51 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2010 VL 24 IS 7 BP 2254 EP 2261 DI 10.1096/fj.09-137380 PG 8 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 618HV UT WOS:000279343600012 PM 20203090 ER PT J AU Sharma, NS Nagrath, D Yarmush, ML AF Sharma, Nripen S. Nagrath, Deepak Yarmush, Martin L. TI Adipocyte-derived basement membrane extract with biological activity: applications in hepatocyte functional augmentation in vitro SO FASEB JOURNAL LA English DT Article DE Adipogel; natural biomaterials; metabolic analysis ID ISOLATED RAT HEPATOCYTES; METABOLIC FLUX ANALYSIS; LONG-TERM CULTURE; EXTRACELLULAR-MATRIX; PROTEIN-SYNTHESIS; AMINO-ACIDS; SANDWICH CONFIGURATION; COLLAGEN SANDWICH; GROWTH-FACTORS; LIVER AB Natural and synthetic biomaterials utilized in tissue engineering applications require a dynamic interplay of complex macromolecular compositions of hydrated extracellular matrices (ECMs) and soluble growth factors. The challenges in utilizing synthetic ECMs is the effective control of temporal and spatial complexity of multiple signal presentation, as compared to natural ECMs that possess the inherent properties of biological recognition, including presentation of receptor-binding ligands, susceptibility to cell-triggered proteolytic degradation, and remodeling. We have developed a murine preadipocyte differentiation system for generating a natural basement membrane extract (Adipogel) comprising ECM proteins (collagen IV, laminin, hyaluronan, and fibronectin) and including relevant growth factors (hepatocyte growth factor, vascular endothelial growth factor, and leukemia inhibitory factor). We have shown the effective utilization of the growth factor-enriched extracellular matrix for enhanced albumin synthesis rate of primary hepatocyte cultures for a period of 10 d as compared to collagen sandwich cultures and comparable or higher function as compared to Matrigel cultures. We have also demonstrated comparable cytochrome P450 1A1 activity for the collagen-Adipogel condition to the collagen double-gel and Matrigel culture conditions. A metabolic analysis revealed that utilization of Adipogel in primary hepatocyte cultures increased serine, glycine, threonine, alanine, tyrosine, valine, methionine, lysine, isoleucine, leucine, phenylalanine, taurine, cysteine, and glucose uptake rates to enhance hepatocyte protein synthesis as compared to collagen double-gel cultures. The demonstrated synthesis, isolation, characterization, and application of Adipogel provide immense potential for tissue engineering and regenerative medicine applications.-Sharma, N. S., Nagrath, D., Yarmush, M. L. Adipocyte-derived basement membrane extract with biological activity: applications in hepatocyte functional augmentation in vitro. FASEB J. 24, 2364-2374 (2010). www.fasebj.org C1 [Sharma, Nripen S.; Yarmush, Martin L.] Shriners Hosp Children, Boston, MA 02114 USA. [Sharma, Nripen S.; Yarmush, Martin L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med,Surg Serv, Boston, MA USA. [Sharma, Nripen S.; Yarmush, Martin L.] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ USA. [Nagrath, Deepak] Rice Univ, Dept Chem & Biomol Engn, Houston, TX USA. RP Yarmush, ML (reprint author), Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org OI Nagrath, Deepak/0000-0002-8999-2282 FU U.S. National Institutes of Health [R01 DK059766, R01 AI063795]; Shriners Hospitals for Children FX This work was supported by U.S. National Institutes of Health grants R01 DK059766 and R01 AI063795, and grants from the Shriners Hospitals for Children. Resources were provided by the BioMEMS Resource Center (P41 EB-002503). The authors declare there are no conflicts of interest. NR 41 TC 10 Z9 10 U1 0 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2010 VL 24 IS 7 BP 2364 EP 2374 DI 10.1096/fj.09-135095 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 618HV UT WOS:000279343600023 PM 20233948 ER PT J AU Noda, K Melhorn, MI Zandi, S Frimmel, S Tayyari, F Hisatomi, T Almulki, L Pronczuk, A Hayes, KC Hafezi-Moghadam, A AF Noda, Kousuke Melhorn, Mark I. Zandi, Souska Frimmel, Sonja Tayyari, Faryan Hisatomi, Toshio Almulki, Lama Pronczuk, Andrzej Hayes, K. C. Hafezi-Moghadam, Ali TI An animal model of spontaneous metabolic syndrome: Nile grass rat SO FASEB JOURNAL LA English DT Article DE type 2 diabetes; nutrition; hypertension; atherosclerosis; dyslipidemia; leptin ID ARVICANTHIS-NILOTICUS; DIURNAL RODENT; ONSET OBESITY; UP-REGULATION; IN-VIVO; ADIPONECTIN; FAT; PATHOPHYSIOLOGY; ASSOCIATIONS; ADIPOCYTES AB Metabolic syndrome (MetS) is a prevalent and complex disease, characterized by the variable coexistence of obesity, dyslipidemia, hyperinsulinaemia, and hypertension. The alarming rise in the prevalence of metabolic disorders makes it imperative to innovate preventive or therapeutic measures for MetS and its complications. However, the elucidation of the pathogenesis of MetS has been hampered by the lack of realistic models. For example, the existing animal models of MetS, i.e., genetically engineered rodents, imitate certain aspects of the disease, while lacking other important components. Defining the natural course of MetS in a spontaneous animal model of the disease would be desirable. Here, we introduce the Nile grass rat (NGR), Arvicanthis niloticus, as a novel model of MetS. Studies of over 1100 NGRs in captivity, fed normal chow, revealed that most of these animals spontaneously develop dyslipidemia (P<0.01), and hyperglycemia (P<0.01) by 1 yr of age. Further characterization showed that the diabetic rats develop liver steatosis, abdominal fat accumulation, nephropathy, atrophy of pancreatic islets of Langerhans, fatty streaks in the aorta, and hypertension (P<0.01). Diabetic NGRs in the early phase of the disease develop hyperinsulinemia, and show a strong inverse correlation between plasma adiponectin and HbA1c levels (P<0.01). These data indicate that the NGR is a valuable, spontaneous model for exploring the etiology and pathophysiology of MetS as well as its various complications.-Noda, K., Melhorn, M.I., Zandi, S., Frimmel, S., Tayyari, F., Hisatomi, T., Almulki, L., Pronczuk, A., Hayes, K.C., Hafezi-Moghadam, A. An animal model of spontaneous metabolic syndrome: Nile grass rat. FASEB J. 24, 2443-2453 (2010). www.fasebj.org C1 [Noda, Kousuke; Melhorn, Mark I.; Zandi, Souska; Frimmel, Sonja; Tayyari, Faryan; Hisatomi, Toshio; Almulki, Lama; Hafezi-Moghadam, Ali] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Angiogenesis Lab, Boston, MA 02114 USA. [Noda, Kousuke; Melhorn, Mark I.; Zandi, Souska; Frimmel, Sonja; Tayyari, Faryan; Hisatomi, Toshio; Almulki, Lama; Hafezi-Moghadam, Ali] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Pronczuk, Andrzej; Hayes, K. C.] Brandeis Univ, Dept Biol, Foster Biomed Res Lab, Waltham, MA 02254 USA. RP Hafezi-Moghadam, A (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Angiogenesis Lab, 325 Cambridge St,3rd Floor, Boston, MA 02114 USA. EM ali_hafezi-moghadam@hms.harvard.edu OI Hisatomi, Toshio/0000-0003-2552-9595; Hafezi-Moghadam, Ali/0000-0002-5336-0697 FU U.S. National Institute of Health [AI050775]; American Health Assistance Foundation; Malaysian Palm Oil Board FX The authors thank Rebecca C. Garland for her help with manuscript preparation and insightful discussions. This work was supported by U.S. National Institute of Health grant AI050775 (A.H.-M.), the American Health Assistance Foundation (A.H.-M.), and the Malaysian Palm Oil Board. NR 32 TC 15 Z9 15 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2010 VL 24 IS 7 BP 2443 EP 2453 DI 10.1096/fj.09-152678 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 618HV UT WOS:000279343600031 PM 20335226 ER PT J AU Wu, F Schweizer, C Rudinskiy, N Taylor, DM Kazantsev, A Luthi-Carter, R Fraering, PC AF Wu, Fang Schweizer, Claude Rudinskiy, Nikita Taylor, David M. Kazantsev, Aleksey Luthi-Carter, Ruth Fraering, Patrick C. TI Novel gamma-secretase inhibitors uncover a common nucleotide-binding site in JAK3, SIRT2, and PS1 SO FASEB JOURNAL LA English DT Article DE Alzheimer's disease; amyloid-beta peptides; presenilin-1; off-target effect; substrate-binding sites ID AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; IDENTIFICATION; DEACETYLASES; KINASE; NICOTINAMIDE; MECHANISM; COMPLEX; DOMAIN; ALPHA AB gamma-Secretase is an intramembrane-cleaving protease responsible for the final proteolytic event in the production of the amyloid-beta peptides (A beta) implicated in Alzheimer's disease ( AD). Inhibition of gamma-secretase activity is thus an attractive therapeutic strategy to slow down the pathogenesis of AD. Drugs often target more than one biomolecule because of conserved 3-dimensional structures in prospective protein binding sites. We have capitalized on this phenomenon of nature to identify new gamma-secretase inhibitors. Here we show that 2-hydroxy naphthyl derivatives, a previously identified subclass of NAD(+) analog inhibitors of sirtuin 2 (SIRT2), are direct gamma-secretase inhibitors. Subsequent structure-activity relationship studies further showed that 2-hydroxy-1-naphthaldehyde is the minimal pharmacophore for gamma-secretase inhibition. In evaluating target protein determinants of inhibition, we identified a common GXG signature nucleotide-binding site (NBS) shared by the gamma-secretase subunit presenilin-1 C-terminal fragment (PS1-CTF), SIRT2, and Janus kinase 3 (JAK3). Because a detailed 3-dimensional structure of gamma-secretase is beyond our knowledge, we took advantage of the known crystal structure of human JAK3 to model the NBS of the PS1-CTF, which includes the catalytic residue D385. Our results suggest that the flexible PS1-CTF 381LGLG384 loop comprises a substrate-docking site capable of recognizing specifically different gamma-secretase substrates.-Wu, F., Schweizer, C., Rudinskiy, N., Taylor, D. M., Kazantsev, A., Luthi-Carter, R., Fraering, P.C. Novel gamma-secretase inhibitors uncover a common nucleotide-binding site in JAK3, SIRT2, and PS1. FASEB J. 24, 2464-2474 (2010). www.fasebj.org C1 [Wu, Fang; Schweizer, Claude; Fraering, Patrick C.] Swiss Fed Inst Technol, Brain Mind Inst, Lab Mol & Cellular Biol Alzheimers Dis, CH-1015 Lausanne, Switzerland. [Rudinskiy, Nikita; Taylor, David M.; Luthi-Carter, Ruth] Swiss Fed Inst Technol, Brain Mind Inst, Lab Funct Neurogenom, CH-1015 Lausanne, Switzerland. Swiss Fed Inst Technol, Sch Life Sci, CH-1015 Lausanne, Switzerland. [Kazantsev, Aleksey] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Massachusetts Gen Inst Neurodegenerat Dis, Charlestown, MA USA. RP Fraering, PC (reprint author), Swiss Fed Inst Technol EPFL, Brain Mind Inst, CH-1015 Lausanne, Switzerland. EM patrick.fraering@epfl.ch RI Wu, Fang/B-1945-2008 OI Wu, Fang/0000-0002-4194-2243 FU Swiss National Science Foundation [310000-116652/1]; National Center for Competence in Research (NCCR); Strauss Foundation FX The authors thank Dr. M.S. Wolfe (Center for Neurological Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA) for the T20 cells, Dr. Helena Karlstrom (Karolinska Institute, Stockholm, Sweden) for the Pen-2 antibody UD-1, L. Aeschbach for excellent technical support, and Dr. J.R. Alattia for helpful discussions. This work was supported by the Swiss National Science Foundation (to P.C.F.; grant 310000-116652/1) and the National Center for Competence in Research (NCCR; Neural Plasticity and Repair; to P.C.F), and the Strauss Foundation (to P.C.F. and C.S.). NR 46 TC 13 Z9 14 U1 0 U2 5 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2010 VL 24 IS 7 BP 2464 EP 2474 DI 10.1096/fj.09-148031 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 618HV UT WOS:000279343600033 PM 20237298 ER PT J AU Xu, RJ Sun, W Jin, JF Obeid, LM Mao, CG AF Xu, Ruijuan Sun, Wei Jin, Junfei Obeid, Lina M. Mao, Cungui TI Role of alkaline ceramidases in the generation of sphingosine and its phosphate in erythrocytes SO FASEB JOURNAL LA English DT Article DE ceramide; erythroid cells; S1P; and S1P lyase ID MOLECULAR-CLONING; NEUTRAL CERAMIDASE; ACID CERAMIDASE; FARBER-DISEASE; SPHINGOSINE-1-PHOSPHATE LYASE; FUNCTIONAL-CHARACTERIZATION; CELLS; GENE; SPHINGOMYELINASE; DIFFERENTIATION AB Plasma sphingosine-1-phosphate (S1P) has been suggested to mainly originate from erythrocytes; however, within the erythrocyte, how sphingosine (SPH) generation-the precursor to S1P-is controlled is unknown. SPH is only generated from the hydrolysis of ceramides via ceramidases. Five human ceramidases have been identified: 1 acid, 1 neutral, and 3 alkaline ceramidases (ACER1, ACER2, and ACER3). Here, we demonstrate that only alkaline ceramidase activity is expressed in erythrocytes and that it is instrumental for SPH generation. Erythrocytes have alkaline but not acid or neutral ceramidase activity on D-e-C(18:1)-ceramide, a common substrate of ceramidases. Not only alkaline ceramidase activity but also the generation of SPH and S1P are increased during erythroid differentiation in K562 erythroleukemic cells. Such SPH and S1P increases were inhibited by the alkaline ceramidase inhibitor D-e-MAPP, suggesting that alkaline ceramidases have a role in the generation of SPH and S1P in erythroid cells. Alkaline ceramidase activity is highly expressed in mouse erythrocytes, and intravenous administration of D-e-MAPP decreased both SPH and S1P in erythrocytes and plasma. Collectively, these results suggest that alkaline ceramidase activity is important for the generation of SPH, the S1P precursor in erythrocytes.-Xu, R., Sun, W., Jin, J., Obeid, L. M., Mao, C. Role of alkaline ceramidases in the generation of sphingosine and its phosphate in erythrocytes. FASEB J. 24, 2507-2515 (2010). www.fasebj.org C1 [Mao, Cungui] Med Univ S Carolina, Dept Med, Div Gen Internal Med, Charleston, SC 29425 USA. [Obeid, Lina M.; Mao, Cungui] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Obeid, Lina M.] Med Univ S Carolina, Ralph H Johnson Vet Adm Hosp, Charleston, SC 29425 USA. RP Mao, CG (reprint author), Med Univ S Carolina, Dept Med, Div Gen Internal Med, 114 Doughty St,Rm 646,STB,POB 250779, Charleston, SC 29425 USA. EM maoc@musc.edu OI obeid, lina/0000-0002-0734-0847 FU U.S. National Institutes of Health [R01CA104834, P20RR017677, GM062887]; Veterans Affairs merit award FX This work was supported by U.S. National Institutes of Health grants R01CA104834 (C.M.), P20RR017677 (C.M.), and GM062887 (L.M.O.), and a Veterans Affairs merit award (L.M.O.). The authors thank Dr. Jennifer Schnellmann for English proofreading and editing of the manuscript. NR 39 TC 20 Z9 20 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD JUL PY 2010 VL 24 IS 7 BP 2507 EP 2515 DI 10.1096/fj.09-153635 PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 618HV UT WOS:000279343600037 PM 20207939 ER PT J AU Partridge, AH Ruddy, KJ Gelber, S Schapira, L Abusief, M Meyer, M Ginsburg, E AF Partridge, Ann H. Ruddy, Kathryn J. Gelber, Shari Schapira, Lidia Abusief, Mary Meyer, Meghan Ginsburg, Elizabeth TI Ovarian reserve in women who remain premenopausal after chemotherapy for early stage breast cancer SO FERTILITY AND STERILITY LA English DT Article DE Ovarian reserve; breast cancer; chemotherapy; premenopausal; fertility ID FOLLICLE-STIMULATING-HORMONE; IN-VITRO FERTILIZATION; MULLERIAN-INHIBITING SUBSTANCE; ADJUVANT CHEMOTHERAPY; CHILDHOOD-CANCER; YOUNG-WOMEN; PREDICTION; TAMOXIFEN; COUNT; METAANALYSIS AB Objective: To compare markers of ovarian reserve between women exposed to cytotoxic chemotherapy for early stage breast cancer and matched controls. Design: Cross-sectional evaluation of markers of ovarian reserve. Setting: Dana-Farber/Brigham and Women's Cancer Center, Massachusetts General Hospital, and Faulkner Hospital in Boston, MA. Patient(s): Breast cancer survivors with continued menses after chemotherapy were compared with age-matched, gravidity-matched controls. Main Outcome Measure(s): Antral follicle count (AFC), anti-Mullerian hormone (AMH), FSH, inhibin B (InB), and E-2 on day 2, 3, or 4 of the menstrual cycle. A Bonferroni correction was performed to correct for multiple comparisons. Result(s): Twenty survivors and 20 controls were evaluated; 50% of survivors were currently on tamoxifen. Median AFC was 6 for survivors and 9.5 for controls. There were significant differences between the two groups in AFC, AMH, and nonsignificant differences in FSH and InB, all indicating better ovarian reserve in controls. The AFC and AMH levels were highly correlated (r = 0.72). Survivors on tamoxifen had lower AFC, AMH, InB, and higher E-2 than nontamoxifen-treated survivors. Conclusion(s): Premenopausal breast cancer survivors have diminished ovarian reserve compared with controls. (Fertil Steril (R) 2010;94:638-44. (C) 2010 by American Society for Reproductive Medicine.) C1 [Partridge, Ann H.; Ruddy, Kathryn J.; Gelber, Shari; Meyer, Meghan; Ginsburg, Elizabeth] Dana Farber Canc Inst, Boston, MA 02115 USA. [Partridge, Ann H.; Ruddy, Kathryn J.; Abusief, Mary; Ginsburg, Elizabeth] Brigham & Womens Hosp, Boston, MA 02115 USA. [Schapira, Lidia] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Schapira, Lidia] Harvard Univ, Sch Med, Boston, MA USA. RP Partridge, AH (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM ahpartridge@partners.org NR 29 TC 80 Z9 82 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUL PY 2010 VL 94 IS 2 BP 638 EP 644 DI 10.1016/j.fertnstert.2009.03.045 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 623RF UT WOS:000279758800034 PM 19409543 ER PT J AU Seminowicz, DA Labus, JS Bueller, JA Tillisch, K Naliboff, BD Bushnell, MC Mayer, EA AF Seminowicz, David A. Labus, Jennifer S. Bueller, Joshua A. Tillisch, Kirsten Naliboff, Bruce D. Bushnell, M. Catherine Mayer, Emeran A. TI Regional Gray Matter Density Changes in Brains of Patients With Irritable Bowel Syndrome SO GASTROENTEROLOGY LA English DT Article DE Neuroimaging; Voxel-Based Morphometry; VBM; Neural ID CHRONIC BACK-PAIN; AUTOMATED 3-D EXTRACTION; VOXEL-BASED MORPHOMETRY; VISCERAL PAIN; MRI DATA; MIGRAINE; FIBROMYALGIA; INTENSITY; CORTEX; REGISTRATION AB BACKGROUND & AIMS: Several studies have examined structural brain changes associated with chronic pain syndromes, including irritable bowel syndrome (IBS), but study sample sizes have been small and heterogeneous. METHODS: We used magnetic resonance imaging-based techniques, voxel-based morphometry, and cortical thickness analysis to examine brain anatomical differences in a relatively large, tightly screened sample of IBS patients (n = 55); we compared data with that from healthy persons (controls; n = 48). RESULTS: IBS was associated with decreased gray matter density (GMD) in widespread areas of the brain, including medial prefrontal and ventrolateral prefrontal cortex, posterior parietal cortex, ventral striatum, and thalamus. Compared with controls, we observed increased GMD in patients with IBS in the pregenual anterior cingulate cortex and the orbitofrontal cortex, as well as trends in the posterior insula/secondary somatosensory cortex, (para) hippocampus, and left dorsolateral prefrontal cortex. In accounting for anxiety and depression, we found that several of the regions involved in affective processing no longer differed between patients with IBS and controls, whereas the differences in prefrontal and posterior parietal cortices remained. The areas of decreased GMD associated with IBS were largely consistent across clinical subgroups, based on predominant bowel habit and pain predominance of symptoms. No overall or regional differences were observed in cortical thickness between patients with IBS and controls. CONCLUSIONS: Changes in density of gray matter among regions involved in cognitive/evaluative functions are specifically observed in patients with IBS, whereas changes in other areas of the brain can be explained by levels of anxiety and depression. C1 [Seminowicz, David A.; Bushnell, M. Catherine] McGill Univ, Alan Edwards Ctr Res Pain, Montreal, PQ H3A 2B2, Canada. [Labus, Jennifer S.; Bueller, Joshua A.; Tillisch, Kirsten; Naliboff, Bruce D.; Mayer, Emeran A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Ctr Neurobiol Stress, Los Angeles, CA 90095 USA. [Labus, Jennifer S.; Bueller, Joshua A.; Tillisch, Kirsten; Naliboff, Bruce D.; Mayer, Emeran A.] VA Greater Angeles Hlth Care Syst, Los Angeles, CA USA. RP Seminowicz, DA (reprint author), McGill Univ, Alan Edwards Ctr Res Pain, Room M-19 Strathcona Anat & Dent,3640 Univ St, Montreal, PQ H3A 2B2, Canada. EM david.seminowicz@mcgill.ca RI Seminowicz, David/F-8732-2015 OI Seminowicz, David/0000-0003-3111-3756 FU Avera Pharmaceuticals; GlaxoSmithKline; National Institutes of Health [DK 64530, AT 00268, DK 48351, DK 073451-01, DK 071626-04, DK 084169-01]; Canadian Institute of Health Research FX E.A.M. has received research support from Avera Pharmaceuticals and GlaxoSmithKline. The remaining authors disclose no conflicts.; This work was supported by National Institutes of Health grants DK 64530 (E. A. M.), AT 00268 (E. A. M.), and DK 48351 (E. A. M.), DK 073451-01 (K. T.), DK 071626-04 (J.S.L.), DK 084169-01 (J.S.L.). D. A. S. was supported by a fellowship from the Canadian Institute of Health Research. NR 53 TC 105 Z9 110 U1 0 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2010 VL 139 IS 1 BP 48 EP U82 DI 10.1053/j.gastro.2010.03.049 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 617ZQ UT WOS:000279321000015 PM 20347816 ER PT J AU Hirota, SA Fines, K Ng, J Traboulsi, D Lee, J Ihara, E Li, Y Willmore, WG Chung, D Scully, MM Louie, T Medlicott, S Lejeune, M Chadee, K Armstrong, G Colgan, SP Muruve, DA MacDonald, JA Beck, PL AF Hirota, Simon A. Fines, Kyla Ng, Jeffrey Traboulsi, Danya Lee, Josh Ihara, Eikichi Li, Yan Willmore, William G. Chung, Daniel Scully, Melanie M. Louie, Thomas Medlicott, Shaun Lejeune, Manigandan Chadee, Kris Armstrong, Glen Colgan, Sean P. Muruve, Daniel A. MacDonald, Justin A. Beck, Paul L. TI Hypoxia-Inducible Factor Signaling Provides Protection in Clostridium difficile-Induced Intestinal Injury SO GASTROENTEROLOGY LA English DT Article DE Vascular Endothelial Growth Factor; Tumor Necrosis Factor; ITF/TFF3; Nitric Oxide Synthase ID EPITHELIAL BARRIER FUNCTION; TOXIN-B; FACTOR-I; COLON-CANCER; CELLS; INHIBITION; INDUCTION; HIF-1; HIF-1-ALPHA; ACTIVATION AB BACKGROUND & AIMS: Clostridium difficile is the leading cause of nosocomial infectious diarrhea. Antibiotic resistance and increased virulence of strains have increased the number of C difficile-related deaths worldwide. The innate host response mechanisms to C difficile are not resolved; we propose that hypoxia-inducible factor (HIF-1) has an innate, protective role in C difficile colitis. We studied the impact of C difficile toxins on the regulation of HIF-1 and evaluated the role of HIF-1 alpha in C difficile-mediated injury/inflammation. METHODS: We assessed HIF-1 alpha mRNA and protein levels and DNA binding in human mucosal biopsy samples and Caco-2 cells following exposure to C difficile toxins. We used the mouse ileal loop model of C difficile toxin-induced intestinal injury. Mice with targeted deletion of HIF-1 alpha in the intestinal epithelium were used to assess the effects of HIF-1 alpha signaling in response to C difficile toxin. RESULTS: Mucosal biopsy specimens and Caco-2 cells exposed to C difficile toxin had a significant increase in HIF-1 alpha transcription and protein levels. Toxin-induced DNA binding was also observed in Caco-2 cells. Toxin-induced HIF-1 alpha accumulation was attenuated by nitric oxide synthase inhibitors. In vivo deletion of intestinal epithelial HIF-1 alpha resulted in more severe, toxin-induced intestinal injury and inflammation. In contrast, stabilization of HIF-1 alpha with dimethyloxallyl glycine attenuated toxin-induced injury and inflammation. This was associated with induction of HIF-1-regulated protective factors (such as vascular endothelial growth factor-alpha, CD73, and intestinal trefoil factor) and down-regulation of proinflammatory molecules such as tumor necrosis factor and Cxcl1. CONCLUSIONS: HIF-1 alpha protects the intestinal mucosa from C difficile toxins. The innate protective actions of HIF-1 alpha in response to C difficile toxins be developed as therapeutics for C difficile-associated disease. C1 [Hirota, Simon A.; Fines, Kyla; Ng, Jeffrey; Li, Yan; Louie, Thomas; Muruve, Daniel A.; Beck, Paul L.] Univ Calgary, Dept Med, Calgary, AB, Canada. [Hirota, Simon A.; Fines, Kyla; Traboulsi, Danya; Lee, Josh; Ihara, Eikichi; MacDonald, Justin A.] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada. [Willmore, William G.] Carleton Univ, Dept Biol, Ottawa, ON K1S 5B6, Canada. [Chung, Daniel] Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Chung, Daniel] Harvard Univ, Sch Med, Boston, MA USA. [Scully, Melanie M.; Colgan, Sean P.] Univ Colorado, Hlth Sci Ctr, Div Gastroenterol, Mucosal Inflammat Program, Denver, CO USA. [Medlicott, Shaun] Univ Calgary, Dept Pathol, Calgary, AB, Canada. [Lejeune, Manigandan; Chadee, Kris; Armstrong, Glen] Univ Calgary, Dept Microbiol & Infect Dis, Calgary, AB, Canada. RP Beck, PL (reprint author), Univ Calgary, Dept Med, Calgary, AB, Canada. EM plbeck@ucalgary.ca OI MacDonald, Justin/0000-0002-9238-8473; Ihara, Eikichi/0000-0002-7070-6610 FU Canadian Association of Gastroenterology/Canadian Institutes of Health Research (CIHR); Canada Research Chair; Alberta Heritage Foundation for Medical Research (AHFMR); National Institutes of Health [DK50189, DE13499, HL60569]; Crohn's and Colitis Foundation of America; CIHR FX Supported by a Canadian Association of Gastroenterology/Canadian Institutes of Health Research (CIHR) postdoctoral fellowship (to S. H.), AHFMR Clinical Investigatorship (to P. L. B.), Canada Research Chair and Alberta Heritage Foundation for Medical Research (AHFMR) Senior Scholar award (to J.A.M.), as well as grants from the National Institutes of Health DK50189, DE13499, and HL60569 (to S. P. C.), and from the Crohn's and Colitis Foundation of America (to S. P. C.) and CIHR (to P. L. B. and J.A.M). NR 29 TC 33 Z9 36 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2010 VL 139 IS 1 BP 259 EP U378 DI 10.1053/j.gastro.2010.03.045 PG 14 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 617ZQ UT WOS:000279321000036 PM 20347817 ER PT J AU Yeh, JM Ho, W Hur, C AF Yeh, Jennifer M. Ho, Wendy Hur, Chin TI Cost-effectiveness of endoscopic surveillance of gastric ulcers to improve survival SO GASTROINTESTINAL ENDOSCOPY LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; FOLLOW-UP; HELICOBACTER-PYLORI; GASTROINTESTINAL-ENDOSCOPY; UNITED-STATES; CANCER; DIAGNOSIS; RISK; COMPLICATIONS; ERADICATION AB Background: Endoscopic surveillance of presumed-benign gastric ulcers may detect missed malignancy, but its impact on long-tern outcomes is uncertain. Objective: To estimate the clinical benefits and cost-effectiveness of follow-up surveillance. Design: State-transition model. Setting: To simulate the clinical course of presumed-benign gastric ulcers, we estimated prevalence and incidence of undetected gastric cancer, surveillance effectiveness, stage-specific disease mortality rates, and costs from clinical studies and databases. Patients: This study involved 60-year-old men diagnosed with presumed-benign gastric ulcers. Intervention: Follow-up endoscopic surveillance. Main Outcome Measurements: Lifetime gastric cancer risk, life expectancy, quality-adjusted life expectancy, lifetime costs, and incremental cost-effectiveness ratios. Results: For a cohort of 60-year-old men with presumed-benign gastric ulcers and a 2.6% prevalence of undetected malignancy, the lifetime gastric cancer risk was 4.4%. Surveillance improved (undiscounted) life expectancy by 10.0 days and increased discounted quality-adjusted life expectancy by 3.4 days at a cost of $146,700 per quality-adjusted life year (QALY). Surveillance cost less than $50,000 per QALY if the undetected gastric cancer prevalence was 6.5%, and it cost less than $100,000 per QALY if the prevalence was greater than 3.5%, endoscopy costs were 40% lower, or the disutility associated with gastric cancer was 30% lower. Probabilistic sensitivity analysis suggested that at a willingness-to-pay threshold of $100,000 per QALY, the probability that surveillance was cost effective was 25.2%. Limitations: Data from multiple sources with varied study designs were used. Conclusion: Endoscopic surveillance of presumed-benign gastric ulcers may improve overall survival. However, unless the prevalence of having undetected malignancy exceeds 6%, surveillance is unlikely to be cost-effective. (Gastrointest Endosc 2010;72:33-43.) C1 [Yeh, Jennifer M.] Harvard Univ, Sch Publ Hlth, Ctr Hlth Decis Sci, Boston, MA 02115 USA. [Ho, Wendy] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Dept Med, Los Angeles, CA 90095 USA. [Hur, Chin] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Hur, Chin] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Yeh, JM (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Hlth Decis Sci, 718 Huntington Ave,2nd Floor, Boston, MA 02115 USA. OI Hur, Chin/0000-0002-2819-7576 FU National Cancer Institute [R25-CA057711] FX All authors disclosed no financial relationships relevant to this publication. Dr. Yeb's work is funded by the National Cancer Institute (R25-CA057711). NR 34 TC 9 Z9 9 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD JUL PY 2010 VL 72 IS 1 BP 33 EP 43 DI 10.1016/j.gie.2010.01.047 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 622TD UT WOS:000279687600007 PM 20430384 ER PT J AU Morasco, BJ Huckans, M Loftis, JM Woodhouse, J Seelye, A Turk, DC Hauser, P AF Morasco, Benjamin J. Huckans, Marilyn Loftis, Jennifer M. Woodhouse, Jonathan Seelye, Adriana Turk, Dennis C. Hauser, Peter TI Predictors of pain intensity and pain functioning in patients with the hepatitis C virus SO GENERAL HOSPITAL PSYCHIATRY LA English DT Article DE Chronic pain; Hepatitis C virus; Depression; Biopsychosocial model ID SUBSTANCE USE DISORDERS; METHADONE-MAINTENANCE; PSYCHIATRIC-DISORDERS; PERSISTENT PAIN; UNITED-STATES; INFECTION; PREVALENCE; DEPRESSION; POPULATION; VETERANS AB Objective: To examine the relationships among biological and psychological variables with pain intensity and pain functioning in patients with the hepatitis C virus (HCV). Methods: Participants were 49 patients with HCV who completed well-validated assessments of pain intensity and pain functioning. Participants also completed measures of psychological functioning, and medical records were reviewed. Results: Thirty-three (67.3%) of 49 participants had a current diagnosis for a pain-related condition. Regression analyses were conducted to examine variables associated with pain intensity and pain functioning. The psychosocial variables, particularly depression severity, accounted for an additional 21% of the variance in average pain intensity (P=.002) and 33% of the variance in pain functioning (P<.001). These results remained significant even after controlling for demographic characteristics, opioid prescription status and disease-related variables. Conclusion: These results provide preliminary support for the role of biological and psychological factors in the development and exacerbation of pain in HCV patients. Future studies should include a more comprehensive assessment of pain-related factors and examine their associations with additional disease-related and biological variables. Developing a better understanding of the factors associated with pain in HCV patients will help to inform future interventions for chronic pain in this patient population. Published by Elsevier Inc. C1 [Morasco, Benjamin J.; Huckans, Marilyn; Loftis, Jennifer M.; Woodhouse, Jonathan; Seelye, Adriana; Hauser, Peter] Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, Portland, OR 97239 USA. [Morasco, Benjamin J.; Huckans, Marilyn; Loftis, Jennifer M.; Woodhouse, Jonathan; Seelye, Adriana; Hauser, Peter] Portland VA Med Ctr, NW Hepatitis C Resource Ctr, Portland, OR 97239 USA. [Morasco, Benjamin J.; Huckans, Marilyn; Loftis, Jennifer M.; Hauser, Peter] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Huckans, Marilyn; Loftis, Jennifer M.; Hauser, Peter] Portland VA Med Ctr, Div Res, Portland, OR 97239 USA. [Woodhouse, Jonathan] George Fox Univ, Dept Psychol, Newberg, OR USA. [Seelye, Adriana] Washington State Univ, Dept Psychol, Pullman, WA 99164 USA. [Turk, Dennis C.] Univ Washington, Sch Med, Dept Anesthesiol & Pain Med, Seattle, WA USA. RP Morasco, BJ (reprint author), Portland VA Med Ctr R&D99, 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM benjamin.morasco@va.gov FU VA Career Development Award; Northwest Health Foundation; National Institute on Drug Abuse [K23DA023467] FX This study was supported in part by a VA Career Development Award and Northwest Health Foundation grant awarded to Dr. Huckans. Dr. Morasco was supported by award K23DA023467 from the National Institute on Drug Abuse. The content of this manuscript is the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs or the National Institute on Drug Abuse. NR 42 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0163-8343 J9 GEN HOSP PSYCHIAT JI Gen. Hosp. Psych. PD JUL-AUG PY 2010 VL 32 IS 4 BP 413 EP 418 DI 10.1016/j.genhosppsych.2010.03.010 PG 6 WC Psychiatry SC Psychiatry GA 631ZQ UT WOS:000280389800009 PM 20633746 ER PT J AU Esposito, F Patsopoulos, NA Cepok, S Kockum, I Leppa, V Booth, DR Heard, RN Stewart, GJ Cox, M Scott, RJ Lechner-Scott, J Goris, A Dobosi, R Dubois, B Rioux, JD Oturai, AB Sondergaard, HB Sellebjerg, F Sorensen, PS Reunanen, M Koivisto, K Cournu-Rebeix, I Fontaine, B Winkelmann, J Gieger, C Infante-Duarte, C Zipp, F Bergamaschi, L Leone, M Bergamaschi, R Cavalla, P Lorentzen, AR Mero, IL Celius, EG Harbo, HF Spurkland, A Comabella, M Brynedal, B Alfredsson, L Bernardinelli, L Robertson, NP Hawkins, CP Barcellos, LF Beecham, G Bush, W Cree, BAC Daly, MJ Ivinson, AJ Aubin, C Compston, A D'Alfonso, S Haines, JL Hauser, SL Hemmer, B Hillert, J McCauley, JL Oksenberg, J Olsson, T Palotie, A Peltonen, L Pericak-Vance, MA Saarela, J Sawcer, SJ Stranger, B Boneschi, FM Comi, G Hafler, DA de Bakker, PIW De Jager, PL AF Esposito, F. Patsopoulos, N. A. Cepok, S. Kockum, I. Leppa, V. Booth, D. R. Heard, R. N. Stewart, G. J. Cox, M. Scott, R. J. Lechner-Scott, J. Goris, A. Dobosi, R. Dubois, B. Rioux, J. D. Oturai, A. B. Sondergaard, H. B. Sellebjerg, F. Sorensen, P. S. Reunanen, M. Koivisto, K. Cournu-Rebeix, I. Fontaine, B. Winkelmann, J. Gieger, C. Infante-Duarte, C. Zipp, F. Bergamaschi, L. Leone, M. Bergamaschi, R. Cavalla, P. Lorentzen, A. R. Mero, I-L Celius, E. G. Harbo, H. F. Spurkland, A. Comabella, M. Brynedal, B. Alfredsson, L. Bernardinelli, L. Robertson, N. P. Hawkins, C. P. Barcellos, L. F. Beecham, G. Bush, W. Cree, B. A. C. Daly, M. J. Ivinson, A. J. Aubin, C. Compston, A. D'Alfonso, S. Haines, J. L. Hauser, S. L. Hemmer, B. Hillert, J. McCauley, J. L. Oksenberg, J. Olsson, T. Palotie, A. Peltonen, L. Pericak-Vance, M. A. Saarela, J. Sawcer, S. J. Stranger, B. Boneschi, F. M. Comi, G. Hafler, D. A. de Bakker, P. I. W. De Jager, P. L. CA IMSGC TI IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci SO GENES AND IMMUNITY LA English DT Article DE multiple sclerosis; susceptibility loci; eQTL ID GENOME-WIDE ASSOCIATION; DIAGNOSTIC-CRITERIA; MCDONALD CRITERIA; GENE-EXPRESSION; DISEASE; RISK; METAANALYSIS; VARIANTS; POLYMORPHISMS; P12(DOC-1) AB A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value = 3.55 x 10(-9)), IL12A (P = 3.08 x 10(-8)) and MPHOSPH9/CDK2AP1 (P = 3.96 x 10(-8)). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P - 1.18 x 10(-5)) and in peripheral blood mononuclear cells from subjects with MS (P - 0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation. Genes and Immunity (2010) 11, 397-405; doi: 10.1038/gene.2010.28; published online 17 June 2010 C1 [Esposito, F.; Boneschi, F. M.; Comi, G.] Ist Sci San Raffaele, Dept Neurol, I-20132 Milan, Italy. [Esposito, F.; Boneschi, F. M.; Comi, G.] Ist Sci San Raffaele, Inst Expt Neurol, I-20132 Milan, Italy. [Patsopoulos, N. A.; Hillert, J.; Stranger, B.; de Bakker, P. I. W.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Patsopoulos, N. A.; Stranger, B.; Hafler, D. A.; de Bakker, P. I. W.; De Jager, P. L.] Harvard Univ, Sch Med, Boston, MA USA. [Patsopoulos, N. A.; De Jager, P. L.] Brigham & Womens Hosp, Dept Neurol, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA. [Cepok, S.; Hemmer, B.] Tech Univ Munich, Klinikum Rechts Isar, D-8000 Munich, Germany. [Kockum, I.; Olsson, T.] Karolinska Inst, Karolinska Univ Hosp, Dept Clin Neurosci, Neuroimmunol Unit, Solna, Sweden. [Kockum, I.; Hillert, J.; Olsson, T.] Karolinska Inst, Karolinska Univ Hosp, Ctr Mol Med, Solna, Sweden. [Leppa, V.; Palotie, A.; Peltonen, L.; Saarela, J.] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland. [Leppa, V.; Palotie, A.; Peltonen, L.; Saarela, J.] Univ Helsinki, FIMM, Helsinki, Finland. [Booth, D. R.; Heard, R. N.; Stewart, G. J.] Univ Sydney, Westmead Hosp, Inst Immunol & Allergy Res, Westmead Millennium Inst, Sydney, NSW 2006, Australia. [Cox, M.; Scott, R. J.; Lechner-Scott, J.] Univ Newcastle, Callaghan, NSW 2308, Australia. [Goris, A.; Dobosi, R.; Dubois, B.] Katholieke Univ Leuven, Sect Expt Neurol, Louvain, Belgium. [Rioux, J. D.] Univ Montreal, Montreal, PQ, Canada. [Rioux, J. D.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Oturai, A. B.; Sondergaard, H. B.; Sellebjerg, F.; Sorensen, P. S.] Copenhagen Univ Hosp, Rigshosp, Danish Multiple Sclerosis Res Ctr, DK-2100 Copenhagen, Denmark. [Reunanen, M.] Oulu Univ Hosp, Dept Neurol, Oulu, Finland. [Koivisto, K.] Cent Hosp Seinajoki, Seinajoki, Finland. [Cournu-Rebeix, I.; Fontaine, B.] INSERM, UMR S975, Paris, France. [Cournu-Rebeix, I.; Fontaine, B.] Univ Paris 06, Ctr Rech Inst Cerveau & Moelle, CNRS 7225, UMR S975, Paris, France. [Cournu-Rebeix, I.; Fontaine, B.] Hop La Pitie Salpetriere, AP HP, Dept Neurol, F-75651 Paris, France. [Winkelmann, J.] Tech Univ Munich, Neurol Klin, Munich, Germany. [Winkelmann, J.] Tech Univ Munich, Inst Humangenet, Munich, Germany. [Winkelmann, J.] Helmholtz Zentrum Munchen, Inst Humangenet, Munich, Germany. [Gieger, C.] Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, Munich, Germany. [Infante-Duarte, C.] Charite, Cecilie Vogt Clin Neurol, D-13353 Berlin, Germany. [Zipp, F.] Johannes Gutenberg Univ Mainz, Univ Med Mainz, Dept Neurol, Mainz, Germany. [Bergamaschi, L.; D'Alfonso, S.] Univ Piemonte Orientale, Interdisciplinary Res Ctr Autoimmune Dis, Novara, Italy. [Bergamaschi, L.; D'Alfonso, S.] Univ Piemonte Orientale, Dept Med Sci, Novara, Italy. [Leone, M.] AOU Maggiore Carita, Neurol Clin, Novara, Italy. [Bergamaschi, R.] IRCCS, Neurol Inst C Mondino, Pavia, Italy. [Cavalla, P.] Osped San Giovanni Battista Torino, Dept Neurol, Turin, Italy. [Lorentzen, A. R.; Harbo, H. F.] Univ Oslo, Ulleval Univ Hosp, Fac Div, Dept Neurol, Oslo, Norway. [Lorentzen, A. R.; Mero, I-L] Oslo Univ Hosp, Rikshosp, Inst Immunol, Oslo, Norway. [Mero, I-L; Celius, E. G.; Harbo, H. F.] Oslo Univ Hosp, Dept Neurol, Oslo, Norway. [Spurkland, A.] Univ Oslo, Inst Basal Med Sci, Oslo, Norway. [Comabella, M.] Hosp Univ Vall Hebron, CEM Cat, Unitat Neuroimmunol Clin, Barcelona, Spain. [Alfredsson, L.; Hillert, J.] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Bernardinelli, L.] Univ Pavia, Dept Appl Sci, I-27100 Pavia, Italy. [Bernardinelli, L.] Univ Cambridge, Stat Lab, Ctr Math Sci, Cambridge CB2 1SB, England. [Robertson, N. P.] Univ Wales Hosp, Dept Neurol, Cardiff CF4 4XW, S Glam, Wales. [Hawkins, C. P.] Keele Univ, Human Genom Res Grp, Stoke On Trent, Staffs, England. [Hawkins, C. P.] Univ Hosp N Staffordshire, Dept Neurol, Stoke On Trent, Staffs, England. [Barcellos, L. F.] Univ Calif Berkeley, Sch Publ Hlth, Div Epidemiol, Berkeley, CA 94720 USA. [Beecham, G.; McCauley, J. L.; Pericak-Vance, M. A.] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA. [Bush, W.; Haines, J. L.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Cree, B. A. C.; Hauser, S. L.; Oksenberg, J.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Daly, M. J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Daly, M. J.; Aubin, C.; Stranger, B.; Hafler, D. A.; de Bakker, P. I. W.; De Jager, P. L.] MIT, Cambridge, MA 02139 USA. [Daly, M. J.; Aubin, C.; Stranger, B.; Hafler, D. A.; de Bakker, P. I. W.; De Jager, P. L.] Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02138 USA. [Ivinson, A. J.] Harvard Univ, Sch Med, Harvard Neurodiscovery Ctr, Boston, MA USA. [Compston, A.; Sawcer, S. J.] Univ Cambridge, Dept Clin Neurosci, Addenbrookes Hosp, Cambridge, England. [Peltonen, L.] Wellcome Trust Sanger Inst, Cambridge, England. [Hafler, D. A.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. RP Esposito, F (reprint author), Ist Sci San Raffaele, Dept Neurol, I-20132 Milan, Italy. RI turton, miranda/F-4682-2011; Haines, Jonathan/C-3374-2012; Martinelli Boneschi, Filippo/H-8592-2012; de Bakker, Paul/B-8730-2009; Saarela, Janna/E-5369-2014; D'Alfonso, Sandra/K-7295-2014; Zipp, Frauke/C-9968-2015; Rioux, John/A-9599-2015; Hauser, Stephen/J-2978-2016; Esposito, Federica/K-6537-2016; OI Spurkland, Anne/0000-0003-4421-0766; de Bakker, Paul/0000-0001-7735-7858; D'Alfonso, Sandra/0000-0002-3983-9925; Zipp, Frauke/0000-0002-1231-1928; Rioux, John/0000-0001-7560-8326; Esposito, Federica/0000-0003-2550-0805; Saarela, Janna/0000-0002-0853-6219; Alfredsson, Lars/0000-0003-1688-6697; Cavalla, Paola/0000-0003-4589-4864; Winkelmann, Juliane/0000-0003-2667-9691; Gieger, Christian/0000-0001-6986-9554; Stranger, Barbara/0000-0001-9021-7331; Leone, Maurizio/0000-0002-6339-5738 FU FISM [2008/R/11]; INSERM; ARSEP; AFM; National Multiple Sclerosis Society; Medical Research Council [G0700061]; Cambridge NIHR Biomedical Research Centre; Swedish Research Council; EU [LSHM-CT-2005-018637]; Bibbi and Niels Jensens Foundation; Montel Williams Foundation; Soderberg Foundation; National MS Society (NMSS); [R01NS049477] FX We are grateful to the patients and the healthy controls for their participation in this study. PLD is a Harry Weaver Neuroscience Scholar Award Recipient of the National MS Society (NMSS). DAH is a Jacob Javits Scholar of NIH. SD is supported by a FISM grant (2008/R/11). BF and IR are authors on behalf of REFGENSEP, a national French clinical and research network funded by INSERM, ARSEP and AFM. The International MS Genetics Consortium is supported by R01NS049477 and by the National Multiple Sclerosis Society. This work was also supported by the Medical Research Council (G0700061) and by the Cambridge NIHR Biomedical Research Centre. The sampling and analysis of the Swedish cohorts have received grant support from The Swedish Research Council, the EU fp6 program neuropromise (LSHM-CT-2005-018637), as well as from the Bibbi and Niels Jensens Foundation, The Montel Williams Foundation and the Soderberg Foundation. NR 43 TC 34 Z9 36 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1466-4879 EI 1476-5470 J9 GENES IMMUN JI Genes Immun. PD JUL PY 2010 VL 11 IS 5 BP 397 EP 405 DI 10.1038/gene.2010.28 PG 9 WC Genetics & Heredity; Immunology SC Genetics & Heredity; Immunology GA 628VC UT WOS:000280150200004 ER PT J AU Landaas, ET Johansson, S Jacobsen, KK Ribases, M Bosch, R Sanchez-Mora, C Jacob, CP Boreatti-Hummer, A Kreiker, S Lesch, KP Kiemeney, LA Kooij, JJS Kan, C Buitelaar, JK Faraone, SV Halmoy, A Ramos-Quiroga, JA Cormand, B Reif, A Franke, B Mick, E Knappskog, PM Haavik, J AF Landaas, E. T. Johansson, S. Jacobsen, K. K. Ribases, M. Bosch, R. Sanchez-Mora, C. Jacob, C. P. Boreatti-Huemmer, A. Kreiker, S. Lesch, K. -P. Kiemeney, L. A. Kooij, J. J. S. Kan, C. Buitelaar, J. K. Faraone, S. V. Halmoy, A. Ramos-Quiroga, J. A. Cormand, B. Reif, A. Franke, B. Mick, E. Knappskog, P. M. Haavik, J. TI An international multicenter association study of the serotonin transporter gene in persistent ADHD SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Adult attention deficit hyperactivity disorder; comorbidity; depression; gender; 5-HTT; 5-HTTLPR; serotonin; SERT; SLC6A4 ID DEFICIT-HYPERACTIVITY-DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; FAMILY-BASED ASSOCIATION; STRESSFUL LIFE EVENTS; ADULT ADHD; POLYMORPHISM 5-HTTLPR; DOPAMINE TRANSPORTER; PERSONALITY-TRAITS; NO ASSOCIATION; HUMAN BRAIN AB Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting children and adults. It has been suggested that gene variants related to serotonin neurotransmission are associated with ADHD. We tested the functional promoter polymorphism 5-HTTLPR and seven single nucleotide polymorphisms in SLC6A4 for association with ADHD in 448 adult ADHD patients and 580 controls from Norway. Replication attempts were performed in a sample of 1454 Caucasian adult ADHD patients and 1302 controls from Germany, Spain, the Netherlands and USA, and a meta-analysis was performed also including a previously published adult ADHD study. We found an association between ADHD and rs140700 [odds ratio (OR ) = 0.67; P = 0.01] and the short (S) allele of the 5-HTTLPR (OR = 1.19; P = 0.06) in the Norwegian sample. Analysis of a possible gender effect suggested that the association might be restricted to females (rs140700: OR = 0.45; P = 0.00084). However, the meta-analysis of 1894 cases and 1878 controls could not confirm the association for rs140700 [OR = 0.85, 95% confidence interval (CI) = 0.67-1.09; P = 0.20]. For 5-HTTLPR, five of six samples showed a slight overrepresentation of the S allele in patients, but meta-analysis refuted a strong effect (OR = 1.10, 95% CI = 1.00-1.21; P = 0.06). Neither marker showed any evidence of differential effects for ADHD subtype, gender or symptoms of depression/anxiety. In conclusion, our results do not support a major role for SLC6A4 common variants in persistent ADHD, although a modest effect of the 5-HTTLPR and a role for rare variants cannot be excluded. C1 [Landaas, E. T.; Johansson, S.; Jacobsen, K. K.; Halmoy, A.; Haavik, J.] Univ Bergen, Dept Biomed, Bergen, Norway. [Landaas, E. T.; Johansson, S.; Jacobsen, K. K.; Knappskog, P. M.] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. [Ribases, M.; Bosch, R.; Sanchez-Mora, C.; Ramos-Quiroga, J. A.] Hosp Univ Vall Hebron, Dept Psychiat, Barcelona, Catalonia, Spain. [Sanchez-Mora, C.] Hosp Univ Vall Hebron, Psychiat Genet Unit, Barcelona, Catalonia, Spain. [Jacob, C. P.; Boreatti-Huemmer, A.; Kreiker, S.; Lesch, K. -P.; Reif, A.] Univ Wurzburg, Dept Psychiat Psychosomat & Psychotherapy, Wurzburg, Germany. [Kreiker, S.] Univ Wurzburg, Dept Child & Adolescent Psychiat Psychosomat & Ps, Wurzburg, Germany. [Kiemeney, L. A.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol Biostat & HTA, NL-6525 ED Nijmegen, Netherlands. [Kooij, J. J. S.] Program Adult ADHD, Psychomed Programs, PsyQ, The Hague, Netherlands. [Kan, C.; Buitelaar, J. K.] Radboud Univ Nijmegen, Med Ctr, Dept Psychiat, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Behav Sci, Syracuse, NY USA. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. [Ramos-Quiroga, J. A.] Univ Autonoma Barcelona, Dept Psychiat & Legal Med, Catalonia, Spain. [Cormand, B.] Univ Barcelona, Dept Genet, Fac Biol, Catalonia, Spain. [Cormand, B.] Biomed Network Res Ctr Rare Dis CIBER ER, Barcelona, Catalonia, Spain. [Cormand, B.] Univ Barcelona, Inst Biomed, Catalonia, Spain. [Franke, B.] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Mick, E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Mick, E.] Harvard Univ, Sch Med, Boston, MA USA. [Haavik, J.] Haukeland Hosp, Div Psychiat, N-5021 Bergen, Norway. RP Haavik, J (reprint author), Univ Bergen, Dept Biomed, Bergen, Norway. EM jan.haavik@biomed.uib.no RI Franke, Barbara/D-4836-2009; Buitelaar, Jan/E-4584-2012; Kiemeney, Lambertus/D-3357-2009; Johansson, Stefan/C-4394-2011; Cormand, Bru/H-5338-2015; Lesch, Klaus-Peter/J-4906-2013; OI Franke, Barbara/0000-0003-4375-6572; Buitelaar, Jan/0000-0001-8288-7757; Kiemeney, Lambertus/0000-0002-2368-1326; Johansson, Stefan/0000-0002-2298-7008; Cormand, Bru/0000-0001-5318-4382; Lesch, Klaus-Peter/0000-0001-8348-153X; Mick, Eric/0000-0001-8505-8145; Ramos-Quiroga, Josep Antoni/0000-0003-1622-0350; Ribases, Marta/0000-0003-1039-1116; Faraone, Stephen/0000-0002-9217-3982; Haavik, Jan/0000-0001-7865-2808 FU Research Council of Norway; Western Norway Regional Health Authority (Helse Vest); Instituto de Salud Carlos III-FIS, Spain [PI040524, PI041267]; Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR [2009SGR-00971]; Ministerio de Ciencia e Innovacion (Spain); Hersenstichting Nederland; DFG [RE1632/1-1, RE1632/1-3, KFO 125, SFB 581, SFB TRR 58]; BMBF [IZKF Wurzburg 01KS9603, IZKF N-27-N]; ECNEWMOOD LSHM-CT-2003-503474 FX We are grateful to all patients and controls for their participation in the study. We thank Paal Borge and Sigrid Erdal for help with genotyping of the Norwegian samples. SNP genotyping of the Norwegian samples was performed at the CIGENE national technology platform supported by the Functional Genomics Program (FUGE) of the Research Council of Norway. We thank Mariana Nogueira and Montse Corrales for their involvement in the clinical assessment in Spain and to M. Dolors Castellar and others from the 'Banc de Sang i Teixits' (Hospital Vall d'Hebron, Barcelona) for their collaboration in the recruitment of control subjects. We thank Remco Makkinje, Marlies Naber and Angelien Heister for help with genotyping in the Netherlands. The Dutch controls were derived from the Nijmegen Biomedical Study. Principal investigators of the Nijmegen Biomedical Study are L.A.L.M. Kiemeney, M. den Heijer, A.L.M. Verbeek, D.W. Swinkels and B. Franke. We thank T. Topner, N. Steigerwald, G. Ortega, N. Doring and J. Auer for excellent technical assistance in Germany. The Norwegian part of the study was supported by the Research Council of Norway and the Western Norway Regional Health Authority (Helse Vest). Financial support for the Spanish part of the study was received from 'Instituto de Salud Carlos III-FIS, Spain' (PI040524, PI041267) and 'Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR' (2009SGR-00971). M.R. is a recipient of a 'Ramon y Cajal' contract from 'Ministerio de Ciencia e Innovacion' (Spain). The Dutch part of the project was supported by the Hersenstichting Nederland (Fonds Psychische Gezondheid). The German part of the study was supported by the DFG (Grant RE1632/1-1 and 1-3 to A.R., KFO 125 to A.R., C.P.J. and K.-P.L.; SFB 581 to K.-P.L., SFB TRR 58 to A.R. and K.-P.L.), BMBF (IZKF Wurzburg 01KS9603 to K.-P.L.; IZKF N-27-N to A.R.) and the EC (NEWMOOD LSHM-CT-2003-503474 to K.P.L.). NR 59 TC 27 Z9 27 U1 2 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUL PY 2010 VL 9 IS 5 BP 449 EP 458 DI 10.1111/j.1601-183X.2010.00567.x PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 619QC UT WOS:000279443700002 PM 20113357 ER PT J AU Manning, AL Longworth, MS Dyson, NJ AF Manning, Amity L. Longworth, Michelle S. Dyson, Nicholas J. TI Loss of pRB causes centromere dysfunction and chromosomal instability SO GENES & DEVELOPMENT LA English DT Article DE Cohesin; condensin; retinoblastoma; merotely; CIN; aneuploid ID MEROTELIC KINETOCHORE ORIENTATION; SISTER-CHROMATID COHESION; MAMMALIAN TISSUE-CELLS; RETINOBLASTOMA PROTEIN; TUMOR-SUPPRESSOR; CLONAL EVOLUTION; HUMAN CANCERS; CONDENSIN-II; PROMOTES ANEUPLOIDY; GENOMIC INSTABILITY AB Chromosome instability (CIN) is a common feature of tumor cells. By monitoring chromosome segregation, we show that depletion of the retinoblastoma protein (pRB) causes rates of missegregation comparable with those seen in CIN tumor cells. The retinoblastoma tumor suppressor is frequently inactivated in human cancers and is best known for its regulation of the G1/S-phase transition. Recent studies have shown that pRB inactivation also slows mitotic progression and promotes aneuploidy, but reasons for these phenotypes are not well understood. Here we describe the underlying mitotic defects of pRB-deficient cells that cause chromosome missegregation. Analysis of mitotic cells reveals that pRB depletion compromises centromeric localization of CAP-D3/condensin II and chromosome cohesion, leading to an increase in intercentromeric distance and deformation of centromeric structure. These defects promote merotelic attachment, resulting in failure of chromosome congression and an increased propensity for lagging chromosomes following mitotic delay. While complete loss of centromere function or chromosome cohesion would have catastrophic consequences, these more moderate defects allow pRB-deficient cells to proliferate but undermine the fidelity of mitosis, leading to whole-chromosome gains and losses. These observations explain an important consequence of RB1 inactivation, and suggest that subtle defects in centromere function are a frequent source of merotely and CIN in cancer. C1 [Dyson, Nicholas J.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Dyson, NJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM dyson@helix.mgh.harvard.edu FU American Cancer Society; Leukemia and Lymphoma Society; Charles King Trust; NIH [R01CA064402, R01GM081607] FX We thank David Pellman for RPE-1 cell lines, Terry Orr-Weaver for the dRad21 antibodies, Anders Naar for help with microscopy, Neil Ganem for critical reading of the manuscript, and Mathew Meyerson, Tanja van Harn, Hein te Riele, and Fred Dick for sharing their unpublished results. A. L. M. is supported by a post-doctoral fellowship from the American Cancer Society; M. S. L. is supported by fellowships from the Leukemia and Lymphoma Society and the Charles King Trust. This work was supported by NIH grants R01CA064402 and R01GM081607 to N.J.D. NR 59 TC 103 Z9 104 U1 0 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2010 VL 24 IS 13 BP 1364 EP 1376 DI 10.1101/gad.1917310 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 619CA UT WOS:000279405000006 PM 20551165 ER PT J AU Walker, AK Yang, FJ Jiang, KR Ji, JY Watts, JL Purushotham, A Boss, O Hirsch, ML Ribich, S Smith, JJ Israelian, K Westphal, CH Rodgers, JT Shioda, T Elson, SL Mulligan, P Najafi-Shoushtari, H Black, JC Thakur, JK Kadyk, LC Whetstine, JR Mostoslavsky, R Puigserver, P Li, XL Dyson, NJ Hart, AC Naar, AM AF Walker, Amy K. Yang, Fajun Jiang, Karen Ji, Jun-Yuan Watts, Jennifer L. Purushotham, Aparna Boss, Olivier Hirsch, Michael L. Ribich, Scott Smith, Jesse J. Israelian, Kristine Westphal, Christoph H. Rodgers, Joseph T. Shioda, Toshi Elson, Sarah L. Mulligan, Peter Najafi-Shoushtari, Hani Black, Josh C. Thakur, Jitendra K. Kadyk, Lisa C. Whetstine, Johnathan R. Mostoslavsky, Raul Puigserver, Pere Li, Xiaoling Dyson, Nicholas J. Hart, Anne C. Naar, Anders M. TI Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP SO GENES & DEVELOPMENT LA English DT Article DE Cholesterol; fasting; lipid; SIRT1; SREBP ID ELEMENT-BINDING PROTEINS; SMALL-MOLECULE ACTIVATORS; CAENORHABDITIS-ELEGANS; CALORIE RESTRICTION; TRANSCRIPTION FACTORS; C-ELEGANS; MITOCHONDRIAL-FUNCTION; PROTEASOME PATHWAY; METABOLIC SYNDROME; GLUCOSE-TOLERANCE AB The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood. Moreover, the evolutionary conservation of fasting regulation of SREBP-dependent programs of gene expression and control of lipid homeostasis has been unclear. We demonstrate here a conserved role for orthologs of the NAD(+)-dependent deacetylase SIRT1 in metazoans in down-regulation of SREBP orthologs during fasting, resulting in inhibition of lipid synthesis and fat storage. Our data reveal that SIRT1 can directly deacetylate SREBP, and modulation of SIRT1 activity results in changes in SREBP ubiquitination, protein stability, and target gene expression. In addition, chemical activators of SIRT1 inhibit SREBP target gene expression in vitro and in vivo, correlating with decreased hepatic lipid and cholesterol levels and attenuated liver steatosis in diet-induced and genetically obese mice. We conclude that SIRT1 orthologs play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis. C1 [Walker, Amy K.; Yang, Fajun; Jiang, Karen; Ji, Jun-Yuan; Shioda, Toshi; Mulligan, Peter; Najafi-Shoushtari, Hani; Black, Josh C.; Thakur, Jitendra K.; Whetstine, Johnathan R.; Mostoslavsky, Raul; Dyson, Nicholas J.; Naar, Anders M.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Yang, Fajun; Rodgers, Joseph T.; Mulligan, Peter; Najafi-Shoushtari, Hani; Thakur, Jitendra K.; Puigserver, Pere; Naar, Anders M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Watts, Jennifer L.] Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. [Purushotham, Aparna; Li, Xiaoling] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Boss, Olivier; Hirsch, Michael L.; Ribich, Scott; Smith, Jesse J.; Israelian, Kristine; Westphal, Christoph H.] GSK Co, Sirtris, Cambridge, MA 02139 USA. [Rodgers, Joseph T.; Puigserver, Pere] Dana Farber Canc Inst, Boston, MA 02115 USA. [Elson, Sarah L.; Kadyk, Lisa C.] Exelixis Inc, San Francisco, CA 94080 USA. RP Naar, AM (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM naar@helix.mgh.harvard.edu RI Black, Joshua/Q-2484-2015; OI Najafi-Shoushtari, Hani/0000-0002-7562-4083 FU NIH National Center for Research Resources (NCRR); Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School; NIH [R01DK07833, R01GM071449, R01GM53203] FX We thank Kent Golic and the Bloomington Drosophila Stock Center for dSir2-null flies, and some nematode strains used in this study were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). We thank J. Ericsson for the mutated SREBP-1a plasmid, David J. Gagne and Nekeya Meade for help with the ob/ob mice, Luisa DeStefano for Drosophila experiments, and Jill C. Milne and Michael R. Jirousek for helpful discussions. This work was supported by The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School and the following grants from NIH: R01DK07833 and R01GM071449 to A.M.N., and R01GM53203 to N.J.D. NR 73 TC 139 Z9 154 U1 1 U2 13 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUL 1 PY 2010 VL 24 IS 13 BP 1403 EP 1417 DI 10.1101/gad.1901210 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 619CA UT WOS:000279405000009 PM 20595232 ER PT J AU Kirby, A Kang, HM Wade, CM Cotsapas, C Kostem, E Han, B Furlotte, N Kang, EY Rivas, M Bogue, MA Frazer, KA Johnson, FM Beilharz, EJ Cox, DR Eskin, E Daly, MJ AF Kirby, Andrew Kang, Hyun Min Wade, Claire M. Cotsapas, Chris Kostem, Emrah Han, Buhm Furlotte, Nick Kang, Eun Yong Rivas, Manuel Bogue, Molly A. Frazer, Kelly A. Johnson, Frank M. Beilharz, Erica J. Cox, David R. Eskin, Eleazar Daly, Mark J. TI Fine Mapping in 94 Inbred Mouse Strains Using a High-Density Haplotype Resource SO GENETICS LA English DT Article ID IN-SILICO; COMPLEX TRAITS; LABORATORY MOUSE; POPULATION-STRUCTURE; PHENOME DATABASE; GENETIC-ANALYSIS; MILLION SNPS; GENOME; ASSOCIATION; MICE AB The genetics of phenotypic variation in inbred mice has for nearly a century provided a primary weapon in the medical research arsenal. A catalog of the genetic variation among inbred mouse strains, however, is required to enable powerful positional cloning and association techniques. A recent whole-genome resequencing study of 15 inbred mouse strains captured a significant fraction of the genetic variation among a limited number of strains, yet the common use of hundreds of inbred strains in medical research motivates the need for a high-density variation map of a larger set of strains. Here we report a dense set of genotypes from 94 inbred mouse strains containing 10.77 million genotypes over 121,433 single nucleotide polymorphisms (SNPs), dispersed at 20-kb intervals on average across the genome, with an average concordance of 99.94% with previous SNP sets. Through pairwise comparisons of the strains, we identified an average of 4.70 distinct segments over 73 classical inbred strains in each region of the genome, suggesting limited genetic diversity between the strains. Combining these data with genotypes of 7570 gap-filling SNPs, we further imputed the untyped or missing genotypes of 94 strains over 8.27 million Perlegen SNPs. The imputation accuracy among classical inbred strains is estimated at 99.7% for the genotypes imputed with high confidence. We demonstrated the utility of these data in high-resolution linkage mapping through power simulations and statistical power analysis and provide guidelines for developing such studies. We also provide a resource of in silico association mapping between the complex traits deposited in the Mouse Phenome Database with our genotypes. We expect that these resources will facilitate effective designs of both human and mouse studies for dissecting the genetic basis of complex traits. C1 [Kostem, Emrah; Han, Buhm; Furlotte, Nick; Kang, Eun Yong; Eskin, Eleazar] Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90095 USA. [Kirby, Andrew; Cotsapas, Chris; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kirby, Andrew; Wade, Claire M.; Cotsapas, Chris; Rivas, Manuel; Daly, Mark J.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Kang, Hyun Min] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Wade, Claire M.] Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. [Cotsapas, Chris; Daly, Mark J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Rivas, Manuel] MIT, Dept Math, Cambridge, MA 02139 USA. [Bogue, Molly A.] Jackson Lab, Bar Harbor, ME 04609 USA. [Frazer, Kelly A.; Beilharz, Erica J.; Cox, David R.] Perlegen Sci, Mountain View, CA 94043 USA. [Johnson, Frank M.] Natl Inst Environm Hlth Sci, Toxicol Operat Branch, Res Triangle Pk, NC 27709 USA. [Eskin, Eleazar] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. RP Eskin, E (reprint author), Univ Calif Los Angeles, Dept Comp Sci, 3532-J Boelter Hall, Los Angeles, CA 90095 USA. EM eeskin@cs.ucla.edu RI Eskin, Eleazar/J-9187-2012; OI Eskin, Eleazar/0000-0003-1149-4758; Wade, Claire/0000-0003-3413-4771; Cotsapas, Chris/0000-0002-7772-5910 FU National Institutes of Health (NIH) [P41-HG003056, K25-HL080079, U01-DA024417, HG00521401, NH084698, MH071984, DA028420]; National Science Foundation [0513612, 0731455, 0729049]; Samsung Scholarship; GlaxoSmithKline; Jackson Laboratory; University of California, Los Angeles; National Toxicology Program [N01-ES-45530]; National Institute of Environmental Health Sciences to Perlegen Sciences FX A. K., C. M. W., C. C., M. R., and M.J.D. were supported by National Institutes of Health (NIH) grant P41-HG003056, which also provided support for the genotyping. H. M. K., E. K., B. H., N.F., E.Y.K, and E. E. were supported by National Science Foundation grants 0513612, 0731455, and 0729049, and NIH grants K25-HL080079 and U01-DA024417. H. M. K. and B. H. were supported by the Samsung Scholarship. H. M. K. was also supported by NIH grants HG00521401 and NH084698 and by GlaxoSmithKline. M. B. was supported by The Jackson Laboratory and by NIH grants MH071984 and DA028420. This research also was supported in part by the University of California, Los Angeles, subcontract of contract N01-ES-45530 from the National Toxicology Program and National Institute of Environmental Health Sciences to Perlegen Sciences. NR 44 TC 55 Z9 55 U1 1 U2 5 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD JUL PY 2010 VL 185 IS 3 BP 1081 EP 1095 DI 10.1534/genetics.110.115014 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 651EE UT WOS:000281906800030 PM 20439770 ER PT J AU Liu, YC Shao, Z Yuan, GC AF Liu, Yingchun Shao, Zhen Yuan, Guo-Cheng TI Prediction of Polycomb target genes in mouse embryonic stem cells SO GENOMICS LA English DT Article DE Polycomb; Epigenetics; Transcription factor sequence motif; ChIP-chip; ChIP-seq; Stem cell; Mouse ID POLYCOMB/TRITHORAX RESPONSE ELEMENTS; DNA-BINDING MOTIF; NONCODING RNAS; DEVELOPMENTAL REGULATORS; TRANSCRIPTIONAL NETWORK; DROSOPHILA-MELANOGASTER; GROUP PROTEIN; CHROMATIN; GENOME; COMPLEX AB Polycomb group (PcG) proteins are important epigenetic regulators, yet the underlying targeting mechanism in mammals is still poorly understood. We have developed a computational approach to predict genome-wide PcG target genes in mouse embryonic stem cells. We use TF binding and motif information as predictors and apply the Bayesian Additive Regression Trees (BART) model for classification. Our model has good prediction accuracy. The performance can be mainly explained by five TF features (Zf5, Tcfcp2l1, Ctcf, E2f1, Myc). Our analysis of H3K27me3 and gene expression data suggests that genomic sequence is highly correlated with the overall PcG target plasticity. We have also compared the PcG target sequence signatures between mouse and Drosophila and found that they are strikingly different. Our predictions may be useful for de novo search for Polycomb response elements (PRE) in mammals. (C) 2010 Elsevier Inc. All rights reserved. C1 [Yuan, Guo-Cheng] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Harvard Univ, Dept Biostat, Boston, MA 02115 USA. RP Yuan, GC (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM gcyuan@jimmy.harvard.edu FU Claudia Adams Barr Award FX We thank Drs. Xiaohua Shen, Jonghwan Kim, Kimberly Glass, Catherine Yan, and Stuart Orkin for helpful discussions. We also thank Drs. Bradley Bernstein, Mythily Ganapathi, Leonie Ringrose, and Marc Rehmsmeier for assistance with data related to the cited publications. This research was supported by a Claudia Adams Barr Award. NR 54 TC 20 Z9 22 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUL PY 2010 VL 96 IS 1 BP 17 EP 26 DI 10.1016/j.ygeno.2010.03.012 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 617TV UT WOS:000279305700003 PM 20353814 ER PT J AU Palumbo, A Larocca, A Genuardi, M Kotwica, K Gay, F Rossi, D Benevolo, G Magarotto, V Cavallo, F Bringhen, S Rus, C Masini, L Iacobelli, M Gaidano, G Mitsiades, C Anderson, K Boccadoro, M Richardson, P AF Palumbo, Antonio Larocca, Alessandra Genuardi, Mariella Kotwica, Katarzyna Gay, Francesca Rossi, Davide Benevolo, Giulia Magarotto, Valeria Cavallo, Federica Bringhen, Sara Rus, Cecilia Masini, Luciano Iacobelli, Massimo Gaidano, Gianluca Mitsiades, Constantine Anderson, Kenneth Boccadoro, Mario Richardson, Paul CA GIMEMA TI Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE melphalan; defibrotide; SCID/NOD mice; multiple myeloma ID RANDOMIZED CONTROLLED-TRIAL; PLUS THALIDOMIDE; ELDERLY-PATIENTS; ORAL MELPHALAN; COMBINATION; BORTEZOMIB; CHEMOTHERAPY AB Background Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen. Design and Methods This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1-4, prednisone at a dose of 1.5 mg/kg also on days 1-4 and thalidomide at a dose of 50-100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1-4 and 1.6, 3.2, or 4.8 g on days 5-35.3 Results Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3-4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient. Conclusions This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1-4 followed by 4.8 g p.o. on days 5-35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs (ClinicalTrials.gov Identifier: NCT00406978). C1 [Palumbo, Antonio; Larocca, Alessandra; Genuardi, Mariella; Kotwica, Katarzyna; Gay, Francesca; Rossi, Davide; Magarotto, Valeria; Cavallo, Federica; Bringhen, Sara; Rus, Cecilia; Boccadoro, Mario] Univ Turin, Div Ematol, Azienda Osped San Giovanni Battista, Osped Molinette, I-10126 Turin, Italy. [Rossi, Davide; Gaidano, Gianluca] Univ Piemonte Orientale, Dipartimento Oncol, Novara, Italy. [Rossi, Davide; Gaidano, Gianluca] Univ Piemonte Orientale, IRCAD, Novara, Italy. [Rossi, Davide; Gaidano, Gianluca] Univ Piemonte Orientale, Div Ematol, Dipartimento Sci Med, Novara, Italy. [Masini, Luciano] UOC Ematol Az Osped SM Nuova, Reggio Emilia, Italy. [Mitsiades, Constantine; Anderson, Kenneth; Richardson, Paul] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. RP Palumbo, A (reprint author), Univ Turin, Div Ematol, Azienda Osped San Giovanni Battista, Osped Molinette, Via Genova 3, I-10126 Turin, Italy. EM appalumbo@yahoo.com OI CAVALLO, Federica/0000-0003-2047-1099 FU Janssen-Cilag; Celgene FX AP has received honoraria from and serves on advisory committees for Celgene and Janssen-Cilag; FG and FC have received honoraria from Celgene; SB has received honoraria from Celgene and Janssen-Cilag; MI serves as scientific director for Gentium; KA was a member of Gentium's Board of Directors until August 2009; MB has received research support from and serves as a consultant on scientific advisory boards for Celgene and Janssen-Cilag; PR has received honoraria for serving on Gentium's advisory committees. NR 26 TC 23 Z9 23 U1 1 U2 7 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD JUL PY 2010 VL 95 IS 7 BP 1144 EP 1149 DI 10.3324/haematol.2009.047913 PG 6 WC Hematology SC Hematology GA 624WT UT WOS:000279853500016 PM 20053869 ER PT J AU Steensma, DP AF Steensma, David P. TI P39/Tsugane cells are a false cell line contaminated with HL-60 cells and are not suitable for mechanistic studies in myelodysplastic syndromes (Retracted Article. See vol 95, pg 1620, 2010) SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Letter C1 Dana Farber Canc Inst, Dept Hematol Malignancies, Luekemia Grp, Boston, MA 02115 USA. RP Steensma, DP (reprint author), Dana Farber Canc Inst, Dept Hematol Malignancies, Luekemia Grp, 44 Binney St,Suite D1B30,Mayer 1B21, Boston, MA 02115 USA. NR 4 TC 2 Z9 2 U1 3 U2 8 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD JUL PY 2010 VL 95 IS 7 BP 1229 EP 1230 DI 10.3324/haematol.2010.022988 PG 2 WC Hematology SC Hematology GA 624WT UT WOS:000279853500030 PM 20421273 ER PT J AU Balboni, MJ Balboni, TA AF Balboni, Michael J. Balboni, Tracy A. TI Reintegrating Care for the Dying, Body and Soul SO HARVARD THEOLOGICAL REVIEW LA English DT Article ID QUALITY-OF-LIFE; ADVANCED CANCER; HEALTH-CARE; NEAR-DEATH; TREATMENT PREFERENCES; MEDICAL-CARE; END; ASSOCIATIONS; PHYSICIANS; DECISIONS C1 [Balboni, Michael J.; Balboni, Tracy A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. RP Balboni, MJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Cambridge, MA 02138 USA. NR 38 TC 6 Z9 6 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0017-8160 J9 HARVARD THEOL REV JI Harv. Theol. Rev. PD JUL PY 2010 VL 103 IS 3 BP 351 EP 364 PG 14 WC Religion SC Religion GA 626WD UT WOS:000279997500006 ER PT J AU Werner, RM Bradlow, ET AF Werner, Rachel M. Bradlow, Eric T. TI Public Reporting On Hospital Process Improvements Is Linked To Better Patient Outcomes SO HEALTH AFFAIRS LA English DT Article ID PAY-FOR-PERFORMANCE; CARE AB The Centers for Medicare and Medicaid Services publicly reports so-called process performance at all U. S. hospitals, such as whether certain recommended treatments are given to specific types of patients. We examined whether hospital performance on key process indicators improved during the three years since this reporting began. We also studied whether or not these changes improved patient outcomes or yielded other quality improvements, such as reduced hospital readmission rates. We found that, from 2004 to 2006, hospital process performance improved and was associated with better patient and quality outcomes. Most notably, for acute myocardial infarction, performance improvements were associated with declines in mortality rates, lengths-of-stay, and readmission rates. Although we cannot conclude that public reporting caused the improvement in processes or outcomes, these results are encouraging, since improving process performance may improve quality more broadly. C1 [Werner, Rachel M.] Ctr Hlth Equ Res, Philadelphia, PA USA. [Werner, Rachel M.] VA Med Ctr, Philadelphia, PA USA. [Werner, Rachel M.; Bradlow, Eric T.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Werner, RM (reprint author), Ctr Hlth Equ Res, Philadelphia, PA USA. EM rwerner@upenn.edu FU Veterans Affairs Health Services Research and Development Career Development Award; Pennsylvania Department of Health FX The authors thank David Asch for comments on an earlier draft of this paper and Janell Olah for research assistance. Rachel Werner is supported by a Veterans Affairs Health Services Research and Development Career Development Award. This project was funded, in part, under a grant from the Pennsylvania Department of Health, which specifically disclaims responsibility for any analyses, interpretations, or conclusions. NR 10 TC 44 Z9 44 U1 2 U2 9 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JUL-AUG PY 2010 VL 29 IS 7 BP 1319 EP 1324 DI 10.1377/hlthaff.2008.0770 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 621EP UT WOS:000279557600008 PM 20606180 ER PT J AU Dixon, RF AF Dixon, Ronald F. TI Enhancing Primary Care Through Online Communication SO HEALTH AFFAIRS LA English DT Article ID ELECTRONIC HEALTH RECORDS; GENERAL MEDICINE PRACTICE; RANDOMIZED-TRIAL; INFORMATION-TECHNOLOGY; DIABETES-MELLITUS; VIRTUAL VISITS; TELEMEDICINE; MANAGEMENT; PHYSICIANS; FAILURE AB The effective delivery of primary care requires more frequent information exchange and communication than the typical office visit allows. Although industry leaders endorse health information technology (IT) to improve health outcomes and reduce costs, there has been less attention devoted to the use of this technology to deliver care. Using Internet-based technologies such as secure messaging, videoconferencing, and remote physiological monitoring can provide information to improve the patient-provider relationship and the quality of health care. Evidence has shown that patients and providers are willing to use these care delivery technologies. However, their success will require integration with electronic health records and payment models that support their implementation and growth. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dixon, RF (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM rdixon@partners.org FU Center for the Integration of Medicine and Innovative Technology FX The author thanks the Center for the Integration of Medicine and Innovative Technology for their support of his research. He also thanks Pamela Fairbrother, Jane Newman, Cheytan Vedvyas, and Elizabeth Ohashi for their assistance in preparing the manuscript. NR 26 TC 22 Z9 22 U1 4 U2 16 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JUL-AUG PY 2010 VL 29 IS 7 BP 1364 EP 1369 DI 10.1377/hlthaff.2010.0110 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 621EP UT WOS:000279557600017 PM 20606189 ER PT J AU Zeitzew, SL AF Zeitzew, Steven L. TI Paying For Health Care That Is Not Cost-Effective SO HEALTH AFFAIRS LA English DT Letter C1 US Dept Vet Affairs, W Los Angeles Healthcare Ctr, Los Angeles, CA USA. RP Zeitzew, SL (reprint author), US Dept Vet Affairs, W Los Angeles Healthcare Ctr, Los Angeles, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JUL-AUG PY 2010 VL 29 IS 7 BP 1417 EP 1417 DI 10.1377/hlthaff.2010.0476 PG 1 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 621EP UT WOS:000279557600031 PM 20606202 ER PT J AU Wolf, EJ Mori, DL AF Wolf, Erika J. Mori, DeAnna L. TI Time to Abandon Small-Sample Cohort Research in Health Psychology? Response SO HEALTH PSYCHOLOGY LA English DT Letter C1 [Wolf, Erika J.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Wolf, Erika J.; Mori, DeAnna L.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. RP Wolf, EJ (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. OI Wolf, Erika/0000-0003-2666-2435 NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 J9 HEALTH PSYCHOL JI Health Psychol. PD JUL PY 2010 VL 29 IS 4 BP 341 EP 342 DI 10.1037/a0020330 PG 2 WC Psychology, Clinical; Psychology SC Psychology GA 631ME UT WOS:000280350600002 ER PT J AU Porthan, K Marjamaa, A Viitasalo, M Vaananen, H Jula, A Toivonen, L Nieminen, MS Newton-Cheh, C Salomaa, V Kontula, K Oikarinen, L AF Porthan, Kimmo Marjamaa, Annukka Viitasalo, Matti Vaananen, Heikki Jula, Antti Toivonen, Lauri Nieminen, Markku S. Newton-Cheh, Christopher Salomaa, Veikko Kontula, Kimmo Oikarinen, Lasse TI Relationship of common candidate gene variants to electrocardiographic T-wave peak to T-wave end interval and T-wave morphology parameters SO HEART RHYTHM LA English DT Article DE Electrocardiography; Epidemiology; Genetics; Genetic polymorphism; Ion channels; Nitric oxide synthase; Repolarization; T wave ID LONG-QT-SYNDROME; MODULATES CARDIAC REPOLARIZATION; TRANSMURAL DISPERSION; CELLULAR BASIS; CARDIOVASCULAR MORTALITY; KCNH2 HERG; POLYMORPHISM; HEART; POPULATION; K897T AB BACKGROUND Single-nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels and nitric oxide synthase-1 adaptor protein (NOS1AP) are associated with electrocardiographic (ECG) QT-interval duration, but the association of these SNPs with new, prognostically important ECG measures of ventricular repolarization is unknown. OBJECTIVE The purpose of this study was to examine the relationship of SNPs to ECG T-wave peak to T-wave end (TPE) interval and T-wave morphology parameters. METHODS We studied 5,890 adults attending the Health 2000 Study, a Finnish epidemiologic survey. TPE interval and four T-wave morphology parameters were measured from digital 12-lead ECGs and related to the seven SNPs showing a phenotypic effect on QT-interval duration in the Health 2000 Study population. RESULTS In multivariable analyses, the KCNH2 K897T minor allele was associated with a 1.2-ms TPE-interval shortening (P = .00005) and the KCNH2 intronic rs3807375 minor allele was associated with a 0.8-ms TPE-interval prolongation (P = .001), whereas the KCNE1 D85N variant had no TPE-interval effect (P = .20). NOS1AP minor alleles (rs2880058, rs4657139, rs10918594, rs10494366) were associated with a shorter TPE interval (effects from 0.5 to 0.8 ms, P from .032 to .002), which resulted from their stronger effects on QT(peak) than QT(end) interval. None of the SNPs showed a consistent association with T-wave morphology parameters. CONCLUSION KCNH2 K897T and rs3807375 as well as the four studied NOS1AP variants have modest effects on ECG TPE interval but are not related to T-wave morphology measures. The previously observed prognostic value of T-wave morphology parameters likely is not based on these SNPs. C1 [Porthan, Kimmo; Viitasalo, Matti; Toivonen, Lauri; Nieminen, Markku S.; Oikarinen, Lasse] Univ Helsinki, Cent Hosp, Dept Cardiol, Helsinki, Finland. [Marjamaa, Annukka] Univ Helsinki, Biomedicum Helsinki, Res Program Mol Med, Helsinki, Finland. [Vaananen, Heikki] Helsinki Univ Technol, Dept Biomed Engn & Computat Sci, FIN-02150 Espoo, Finland. [Jula, Antti] Natl Inst Hlth & Welf, Turku, Finland. [Salomaa, Veikko] Natl Inst Hlth & Welf, Helsinki, Finland. [Kontula, Kimmo] Univ Helsinki, Cent Hosp, Dept Med, Helsinki, Finland. [Newton-Cheh, Christopher] Harvard & MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Porthan, K (reprint author), Univ Helsinki, Cent Hosp, Dept Cardiol, Haartmaninkatu 4,POB 340, Helsinki 00029, Finland. EM kimmo.porthan@fimnet.fi RI Vaananen, Heikki/F-7013-2012 OI Vaananen, Heikki/0000-0001-8649-1047 FU Aarne and Aili Turunen Foundation; Aarne Koskelo Foundation; Finnish Foundation for Cardiovascular Research; Finnish Medical Foundation; Maud Kuistila Memorial Foundation; Orion-Farmos Research Foundation; Paavo and Eila Salonen Foundation; Emil Aaltonen Foundation; NIH [K23 HL080025]; Doris Duke Charitable Foundation; Burroughs Wellcome Fund; Academy of Finland [129494]; Sigrid Juselius Foundation FX Dr. Porthan was supported by grants from the Aarne and Aili Turunen Foundation, the Aarne Koskelo Foundation, the Finnish Foundation for Cardiovascular Research, the Finnish Medical Foundation, the Maud Kuistila Memorial Foundation, the Orion-Farmos Research Foundation, and the Paavo and Eila Salonen Foundation. Dr. Marjamaa was supported by a grant from the Emil Aaltonen Foundation. Drs. Viitasalo and Oikarinen were supported by grants from the Finnish Foundation for Cardiovascular Research. Dr. Newton-Cheh was supported by NIH Grant K23 HL080025, the Doris Duke Charitable Foundation, and the Burroughs Wellcome Fund.; Dr. Salomaa was supported by Grant 129494 from the Academy of Finland and by the Sigrid Juselius Foundation. Dr. Kontula was supported by grants from the Sigrid Juselius Foundation and the Academy of Finland. This work was performed at Helsinki University Central Hospital, Helsinki, Finland. Address reprint requests and correspondence: Dr. Kimmo Porthan, Department of Cardiology, Helsinki University Central Hospital, Haartmaninkatu 4, P.O. Box 340, 00029 HUS, Finland. E-mail address: kimmo. porthan@fimnet.fi. (Received December 5, 2009; accepted March 1, 2010.) NR 35 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2010 VL 7 IS 7 BP 898 EP 903 DI 10.1016/j.hrthm.2010.03.002 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 617VQ UT WOS:000279310400008 PM 20215044 ER PT J AU Milan, DJ Melman, YF Ellinor, PT AF Milan, David J. Melman, Yonathan F. Ellinor, Patrick T. TI Rare ion channel polymorphisms: Separating signal from noise SO HEART RHYTHM LA English DT Editorial Material ID LONG-QT SYNDROME; VARIANTS; SCN5A C1 [Milan, David J.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Milan, David J.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Melman, Yonathan F.] Brigham & Womens Hosp, Div Internal Med, Boston, MA 02115 USA. RP Milan, DJ (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St, Boston, MA 02114 USA. EM dmilan@partners.org FU NIDA NIH HHS [R21 DA026982, R21 DA027021] NR 10 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 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2010 VL 7 IS 7 BP 920 EP 921 DI 10.1016/j.hrthm.2010.05.004 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 617VQ UT WOS:000279310400012 PM 20451667 ER PT J AU Zarraga, IG MacMurdy, K Raitt, M AF Zarraga, Ignatius Gerardo MacMurdy, Karen Raitt, Merritt TI Unusual migration of an abandoned fractured lead SO HEART RHYTHM LA English DT Editorial Material DE Pacemaker lead; Fracture; Migration C1 [Zarraga, Ignatius Gerardo] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [MacMurdy, Karen; Raitt, Merritt] Portland VA Med Ctr, Portland, OR USA. RP Zarraga, IG (reprint author), Oregon Hlth & Sci Univ, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM zarragai@ohsu.edu OI Raitt, Merritt/0000-0001-5638-7732 NR 5 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2010 VL 7 IS 7 BP 1004 EP 1005 DI 10.1016/j.hrthm.2009.10.026 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 617VQ UT WOS:000279310400031 PM 20056497 ER PT J AU Lampert, R Hayes, DL Annas, GJ Farley, MA Goldstein, NE Hamilton, RM Kay, GN Kramer, DB Mueller, PS Padeletti, L Pozuelo, L Schoenfeld, MH Vardas, PE Wiegand, DL Zellner, R AF Lampert, Rachel Hayes, David L. Annas, George J. Farley, Margaret A. Goldstein, Nathan E. Hamilton, Robert M. Kay, G. Neal Kramer, Daniel B. Mueller, Paul S. Padeletti, Luigi Pozuelo, Leo Schoenfeld, Mark H. Vardas, Panos E. Wiegand, Debra L. Zellner, Richard TI HRS Expert Consensus Statement on the Management of Cardiovascular Implantable Electronic Devices (CIEDs) in patients nearing end of life or requesting withdrawal of therapy SO HEART RHYTHM LA English DT Article ID TERMINALLY-ILL PATIENTS; OF-LIFE; CARDIOVERTER-DEFIBRILLATORS; SUSTAINING TREATMENT; PALLIATIVE CARE; HEART-FAILURE; OLDER-ADULTS; TREATMENT PREFERENCES; DECISION-MAKING; HEALTH C1 [Lampert, Rachel; Schoenfeld, Mark H.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Hayes, David L.; Mueller, Paul S.] Mayo Clin, Rochester, MN USA. [Annas, George J.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Farley, Margaret A.] Yale Univ, Sch Divin, New Haven, CT 06520 USA. [Goldstein, Nathan E.] Mt Sinai Sch Med, New York, NY USA. [Goldstein, Nathan E.] James J Peters VA Med Ctr, Bronx, NY USA. [Hamilton, Robert M.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Kay, G. Neal] Univ Alabama, Birmingham, AL USA. [Kramer, Daniel B.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Padeletti, Luigi] Univ Florence, Inst Cardiol, Florence, Italy. [Pozuelo, Leo] Cleveland Clin, Cleveland, OH 44106 USA. [Vardas, Panos E.] Herakl Univ Hosp, Iraklion, Greece. [Wiegand, Debra L.] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. [Zellner, Richard] Case Western Reserve Univ, Bioeth Dept, Cleveland, OH 44106 USA. RP Lampert, R (reprint author), Yale Univ, Sch Med, New Haven, CT 06520 USA. OI Annas, George/0000-0001-5836-7831 NR 107 TC 155 Z9 155 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD JUL PY 2010 VL 7 IS 7 BP 1008 EP 1026 DI 10.1016/j.hrthm.2010.04.033 PG 19 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 617VQ UT WOS:000279310400032 PM 20471915 ER PT J AU Davila, JA Morgan, RO Richardson, PA Du, XL McGlynn, KA El-Serag, HB AF Davila, Jessica A. Morgan, Robert O. Richardson, Peter A. Du, Xianglin L. McGlynn, Katherine A. El-Serag, Hashem B. TI Use of Surveillance for Hepatocellular Carcinoma Among Patients With Cirrhosis in the United States SO HEPATOLOGY LA English DT Article ID PRIMARY LIVER-CANCER; HEPATITIS-C; INCREASING INCIDENCE; VIRAL-HEPATITIS; SURVIVAL; EXPERIENCE; MANAGEMENT; INFECTION; VETERANS; IMPROVE AB Surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is recommended but may not be performed. The extent and determinants of HCC surveillance are unknown. We conducted a population-based United States cohort study of patients over 65 years of age to examine use and determinants of prediagnosis surveillance in patients with HCC who were previously diagnosed with cirrhosis. Patients diagnosed with HCC during 1994-2002 were identified from the linked Surveillance, Epidemiology, and End-Results registry Medicare databases. We identified alpha-fetoprotein (AFP) and ultrasound tests performed for HCC surveillance, and examined factors associated with surveillance. We identified 1,873 HCC patients with a prior diagnosis of cirrhosis. In the 3 years before HCC, 17% received regular surveillance and 38% received inconsistent surveillance. In a subset of 541 patients in whom cirrhosis was recorded for 3 or more years prior to HCC, only 29% received routine surveillance and 33% received inconsistent surveillance. Among all patients who received regular surveillance, approximately 52% received both AFP and ultrasound, 46% received AFP only, and 2% received ultrasound only. Patients receiving regular surveillance were more likely to have lived in urban areas and had higher incomes than those who did not receive surveillance. Before diagnosis, approximately 48% of patients were seen by a gastroenterologist/hepatologist or by a physician with an academic affiliation; they were approximately 4.5-fold and 2.8-fold, respectively, more likely to receive regular surveillance than those seen by a primary care physician only. Geographic variation in surveillance was observed and explained by patient and physician factors. Conclusion: Less than 20% of patients with cirrhosis who developed HCC received regular surveillance. Gastroenterologists/hepatologists or physicians with an academic affiliation are more likely to perform surveillance. (HEPATOLOGY: 2010;52:132-141) C1 [Davila, Jessica A.; Morgan, Robert O.; Richardson, Peter A.; El-Serag, Hashem B.] Houston VA Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Sect Hlth Serv Res, Houston, TX USA. [El-Serag, Hashem B.] Houston VA Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Gastroenterol Sect, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. [Du, Xianglin L.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol, Houston, TX USA. [McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, US Dept HHS, Bethesda, MD 20892 USA. RP Davila, JA (reprint author), Michael E DeBakey VA Med Ctr, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. EM jdavila@bcm.tmc.edu FU American Cancer Society [RSGPB-07-010-01-CPHPS, NCI R01 125487, DK K24 04107]; Houston VA Health Services Research and Development Center of Excellence [HEP90-029] FX Supported in part by grants from the American Cancer Society (RSGPB-07-010-01-CPHPS to J. A. D.; NCI R01 125487 and DK K24 04107 to H. B. E-S.) and the Houston VA Health Services Research and Development Center of Excellence (HEP90-029). NR 38 TC 154 Z9 155 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2010 VL 52 IS 1 BP 132 EP 141 DI 10.1002/hep.23615 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 619DK UT WOS:000279409200015 PM 20578139 ER PT J AU Townson, DH Putnam, AN Sullivan, BT Guo, L Irving-Rodgers, HF AF Townson, David H. Putnam, Amanda N. Sullivan, Brian T. Guo, Lankai Irving-Rodgers, Helen F. TI Expression and distribution of cytokeratin 8/18 intermediate filaments in bovine antral follicles and corpus luteum: An intrinsic mechanism of resistance to apoptosis? SO HISTOLOGY AND HISTOPATHOLOGY LA English DT Article DE Ovary; Apoptosis; Cytoskeleton ID SIMPLE EPITHELIAL-CELLS; ADULT HUMAN OVARY; FAS LIGAND; GRANULOSA-CELLS; RAT OVARY; KERATIN; VIMENTIN; ANTIGEN; DISEASE; ATRESIA AB Apoptosis is a mechanism of cell elimination during follicular atresia and luteal regression. Recent evidence suggests sensitivity to apoptosis in some cell types is partly dependent upon cytokeratin-containing intermediate filaments. Specifically, cytokeratin 8/18 (CK8/18) filaments are thought to impart resistance to apoptosis. Here, cytokeratin filament expression within bovine ovarian follicles and corpora lutea (CL) was characterized and the potential relationship between cell-specific CK8/18 expression and apoptosis explored. Immunoprecipitation and western blot analysis confirmed CK8 associates with CK18 to form CK8/18 heterodimeric filaments within bovine ovarian cells. Immunostaining revealed populations of CK18-positive (CK18+) cells in healthy growing follicles that increased in postovulatory follicles. Atretic follicles at all stages of atresia also contained some CK18+ cells. However, no CK18+ cells were detected in primordial or primary follicles. In CL, developing CL contained a higher proportion of CK18+ cells (similar to 35%, range 30-70%) than mature CL (similar to 16%) and regressing CL (similar to 5%; P<0.05, n = 3-5 CL/stage), suggesting CK8/18 filament expression diminishes over time, as luteal cells become more susceptible to apoptosis. Dual-fluorescence labeling for CK18 and a cell death marker (TUNEL labeling) confirmed this view, demonstrating less death of CK18+ than CK18-luteal cells throughout the estrous cycle (P<0.05). The results indicate differential expression of CK8/18 filaments occurs in cells of bovine ovarian follicles and CL throughout the estrous cycle. The prevalence and cell-specific pattern of cytokeratin expression in these structures is consistent with the concept these filaments might impart resistance to apoptosis in ovarian cells as is seen in other cell types. C1 [Townson, David H.] Univ New Hampshire, Dept Mol Cellular & Biomed Sci, Durham, NH 03824 USA. [Putnam, Amanda N.] First Light Biosci, Bedford, MA USA. [Sullivan, Brian T.] PPD Inc, Waltham, MA USA. [Guo, Lankai] Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. [Irving-Rodgers, Helen F.] Univ Adelaide, Res Ctr Reprod Hlth, Sch Paediat & Reprod Hlth, Adelaide, SA, Australia. RP Townson, DH (reprint author), Univ New Hampshire, Dept Mol Cellular & Biomed Sci, Durham, NH 03824 USA. EM dave.townson@unh.edu RI Irving-Rodgers, Helen/E-3660-2010 FU USDA [200235203-12257, 2007-35203-18074]; National Health and Medical Research Council of Australia FX This work was supported by USDA grants 200235203-12257 (DHT), 2007-35203-18074 (DHT), and the National Health and Medical Research Council of Australia (HIR). It is scientific contribution number 2371 from the New Hampshire Agricultural Experiment Station. The author wishes to thank Jessica A. Cherry, Jennifer J. Forcina, and Amy R. Liptak for their contributions to this manuscript, Dr A. Conley for the donation of CYP17 antibody, and Wendy Bonner for immunohistochemistry of follicles. NR 48 TC 8 Z9 8 U1 0 U2 0 PU F HERNANDEZ PI MURCIA PA PLAZA FUENSANTA 2-7 C, 30008 MURCIA, SPAIN SN 0213-3911 J9 HISTOL HISTOPATHOL JI Histol. Histopath. PD JUL PY 2010 VL 25 IS 7 BP 889 EP 900 PG 12 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 601CM UT WOS:000278035600007 PM 20503177 ER PT J AU Walsh, JE Clark, AM Day, TA Gillespie, MB Young, MRI AF Walsh, Jarrett E. Clark, Anna-Maria Day, Terry A. Gillespie, M. Boyd Young, M. Rita I. TI Use of alpha,25-Dihydroxyvitamin D-3 treatment to stimulate immune infiltration into head and neck squamous cell carcinoma SO HUMAN IMMUNOLOGY LA English DT Article DE Head and neck cancer; Head and neck squamous cell carcinoma; Recurrence; T-cell, vitamin D ID ENDOTHELIAL GROWTH-FACTOR; DENDRITIC CELLS; CANCER PATIENTS; PERIPHERAL-BLOOD; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; MONONUCLEAR-CELL; PROGENITOR CELLS; T-LYMPHOCYTES; CD34(+) CELLS; TUMOR-CELLS AB Prior studies have shown that treatment of head and neck squamous cell carcinoma (HNSCC) patients with 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] reduced intratumoral levels of immune inhibitory CD34(+) progenitor cells while increasing levels of mature progeny dendritic cells. This finding was extended to a pilot study to determine whether 1,25(OH)(2)D-3 treatment concurrently increases levels of intratumoral CD4(+) and CD8(+) T cells, increases intratumoral levels of immune cells expressing the early activation marker CD69, and prolongs time to HNSCC recurrence. The clinical trial comprised 16 patients with newly diagnosed HNSCC being untreated and 16 patients being treated with 1,25(OH)(2)D-3 during the 3-week interval between cancer diagnosis and surgical treatment. Immunologic effects of treatment were monitored by immunohistochemical analyses of surgically removed HNSCC. Clinical effectiveness of 1,25(OH)(2)D-3 treatment in this study was measured by the time to HNSCC recurrence. HNSCC tissues of patients who received treatment with 1,25(OH)(2)D-3 contained increased levels of CD4(+) cells and, more significantly, CD8(+) T cells. Also prominent was an increase in cells expressing the lymphoid activation marker CD69. Results of this pilot study suggest that patients treated with 1,25(OH)(2)D-3 had a lengthier time to tumor recurrence compared with patients who were not treated before surgery. Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics. C1 [Walsh, Jarrett E.; Clark, Anna-Maria; Young, M. Rita I.] Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC USA. [Walsh, Jarrett E.; Clark, Anna-Maria; Day, Terry A.; Gillespie, M. Boyd; Young, M. Rita I.] Dept Otolaryngol Head & Neck Surg, Charleston, SC USA. [Young, M. Rita I.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Young, MRI (reprint author), Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC USA. EM rita.young@va.gov FU Clinical Science and Biomedical Laboratory Research and Development Services of the Department of Veterans Affairs; National Institutes of Health [R01CA85266, R01CA128837] FX The authors thank Bridgette Ransom, Kiwana Gibbs, and Kim Sutton for their technical contributions to the described analyses. These studies were supported by the Clinical Science and Biomedical Laboratory Research and Development Services of the Department of Veterans Affairs and by grants R01CA85266 and R01CA128837 from the National Institutes of Health to MRIY. NR 37 TC 20 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD JUL PY 2010 VL 71 IS 7 BP 659 EP 665 DI 10.1016/j.humimm.2010.04.008 PG 7 WC Immunology SC Immunology GA 620IO UT WOS:000279493000003 PM 20438786 ER PT J AU Qi, L Cornelis, MC Kraft, P Stanya, KJ Kao, WHL Pankow, JS Dupuis, J Florez, JC Fox, CS Pare, G Sun, Q Girman, CJ Laurie, CC Mirel, DB Manolio, TA Chasman, DI Boerwinkle, E Ridker, PM Hunter, DJ Meigs, JB Lee, CH van Dam, RM Hu, FB AF Qi, Lu Cornelis, Marilyn C. Kraft, Peter Stanya, Kristopher J. Kao, W. H. Linda Pankow, James S. Dupuis, Josee Florez, Jose C. Fox, Caroline S. Pare, Guillaume Sun, Qi Girman, Cynthia J. Laurie, Cathy C. Mirel, Daniel B. Manolio, Teri A. Chasman, Daniel I. Boerwinkle, Eric Ridker, Paul M. Hunter, David J. Meigs, James B. Lee, Chih-Hao van Dam, Rob M. Hu, Frank B. CA Meta-Anal Glucose Insulin-related Diabet Genetics Replication TI Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes SO HUMAN MOLECULAR GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; PHYSICAL-ACTIVITY; LIFE-STYLE; RISK; MELLITUS; LOCI; WOMEN; MEN; CLASSIFICATION; METAANALYSIS AB To identify type 2 diabetes (T2D) susceptibility loci, we conducted genome-wide association (GWA) scans in nested case-control samples from two prospective cohort studies, including 2591 patients and 3052 controls of European ancestry. Validation was performed in 11 independent GWA studies of 10 870 cases and 73 735 controls. We identified significantly associated variants near RBMS1 and ITGB6 genes at 2q24, best-represented by SNP rs7593730 (combined OR = 0.90, 95% CI = 0.86-0.93; P = 3.7 x 10(-8)). The frequency of the risk-lowering allele T is 0.23. Variants in this region were nominally related to lower fasting glucose and HOMA-IR in the MAGIC consortium (P < 0.05). These data suggest that the 2q24 locus may influence the T2D risk by affecting glucose metabolism and insulin resistance. C1 [Qi, Lu; Cornelis, Marilyn C.; Sun, Qi; van Dam, Rob M.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Stanya, Kristopher J.; Lee, Chih-Hao] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Florez, Jose C.; Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Qi, Lu; Cornelis, Marilyn C.; Sun, Qi; Hunter, David J.; van Dam, Rob M.; Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Pare, Guillaume; Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA. [Kao, W. H. Linda] Johns Hopkins Univ, Dept Epidemiol & Med, Baltimore, MD USA. [Pankow, James S.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Pare, Guillaume] McMaster Univ, Genet & Mol Epidemiol Lab, Hamilton, ON, Canada. [Girman, Cynthia J.] Merck Res Labs, Dept Epidemiol, N Wales, PA USA. [Laurie, Cathy C.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Mirel, Daniel B.] MIT, Broad Inst, Ctr Genotyping & Anal, Cambridge, MA 02142 USA. [Mirel, Daniel B.] Harvard Univ, Cambridge, MA 02142 USA. [Manolio, Teri A.] NHGRI, NIH, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA. RP Qi, L (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM nhlqi@channing.harvard.edu; nhbfh@channing.harvard.edu RI van Dam, Rob/F-9674-2010; OI van Dam, Rob/0000-0002-7354-8734; Dupuis, Josee/0000-0003-2871-3603; Pankow, James/0000-0001-7076-483X FU Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI) [U01HG004738, U01HG004422, U01HG004402, U01HG0047 29, U01HG004726, U01HG004735, U01HG004415, U01HG0 04436, U01HG004423, U01HG004728, RFAHG006033]; NIH (NIDCR) [U01DE018 993, U01DE018903]; NIH, NIAAA [U10AA008401]; NIH, NIDA [P01CA 089392, R01DA013423]; NIH, NCI [CA63464, CA54281, CA1367 92, Z01CP010200]; NIH GEI [U01HG04424, U01HG004438]; NIH [HHSN268200782096C, HHSN268200625226C, UL1RR025005, RO1 HL71981, R01DK075046, R90DK071507]; National Cancer Institute (NCI) [P01CA087969, P01CA055075, CA047988]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK058845, R01DK078616, K24 DK080140, K23 DK65978]; National Heart, Lung, and Blood Institute (NHLBI) [HL043851, HL69757, N01-HC-55015, N01-HC-55016, N01-HC55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01HC- 55022, R01HL087641, R01HL59367, R01HL086694]; Donald W. Reynolds Foundation; Fondation Leducq; Amgen; NIH Roadmap for Medical Research; NHLBI's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Massachusetts General Hospital; Doris Duke Charitable Foundation; American Heart Association; Boston Obesity Nutrition Research Center [DK46200]; Canadian Institutes of Health Research; [K01DK067207] FX The NHS/HPFS T2DGWAS(U01HG004399) is a component of a collaborative project that includes 13 other GWAS funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI) (U01HG004738, U01HG004422, U01HG004402, U01HG0047 29, U01HG004726, U01HG004735, U01HG004415, U01HG0 04436, U01HG004423, U01HG004728, RFAHG006033) with additional support from individual NIH (NIDCR: U01DE018 993, U01DE018903; NIAAA: U10AA008401, NIDA: P01CA 089392, R01DA013423; NCI: CA63464, CA54281, CA1367 92, Z01CP010200). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract 'High throughput genotyping for studying the genetic contributions to human disease' (HHSN268200782096C). Additional funding for the current research was provided by the National Cancer Institute (NCI, P01CA087969, P01CA055075), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, R01DK058845). The WGHS is supported by HL043851 and HL69757 from the National Heart, Lung, and Blood Institute (NHLBI) and CA047988 from NCI, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. The ARIC Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01HC- 55022, R01HL087641, R01HL59367 and R01HL086694 and NIH contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. W. H. L. K. was supported by K01DK067207. The FHS was partially supported by the NHLBI's Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (contract no. N02-HL-6-4278), and the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. FHS was also supported by the NIDDK: R01DK078616 to J. B. M., J. D. and J. C. F.; NIDDK K24 DK080140 to J. B. M. and NIDDK Research Career Award K23 DK65978, a Massachusetts General Hospital Physician Scientist DevelopmentAward and a Doris Duke Charitable Foundation Clinical Scientist Development Award to J. C. F. L. Q. is supported by National Institutes of Health grants RO1 HL71981, American Heart Association Scientist Development Award and the Boston Obesity Nutrition Research Center (DK46200). M. C. C. is a recipient of a Canadian Institutes of Health Research Fellowship. C. H. L. is supported by the American Heart Association and NIH (R01DK075046). K. J. S. is supported by NIH Roadmap training grant R90DK071507. NR 33 TC 116 Z9 119 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 1 PY 2010 VL 19 IS 13 BP 2706 EP 2715 DI 10.1093/hmg/ddq156 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 622OX UT WOS:000279674200015 PM 20418489 ER PT J AU Ramanadhan, S Kebede, S Mantopoulos, J Bradley, EH AF Ramanadhan, Shoba Kebede, Sosena Mantopoulos, Jeannie Bradley, Elizabeth H. TI Network-based social capital and capacity-building programs: an example from Ethiopia SO HUMAN RESOURCES FOR HEALTH LA English DT Article ID HOSPITAL MANAGEMENT; HEALTH MANAGEMENT; WEAK TIES; MODEL; ORGANIZATIONS; PERFORMANCE; KNOWLEDGE; SECTOR AB Introduction: Capacity-building programs are vital for healthcare workforce development in low-and middle-income countries. In addition to increasing human capital, participation in such programs may lead to new professional networks and access to social capital. Although network development and social capital generation were not explicit program goals, we took advantage of a natural experiment and studied the social networks that developed in the first year of an executive-education Master of Hospital and Healthcare Administration (MHA) program in Jimma, Ethiopia. Case description: We conducted a sociometric network analysis, which included all program participants and supporters (formally affiliated educators and mentors). We studied two networks: the Trainee Network (all 25 trainees) and the Trainee-Supporter Network (25 trainees and 38 supporters). The independent variable of interest was out-degree, the number of program-related connections reported by each respondent. We assessed social capital exchange in terms of resource exchange, both informational and functional. Contingency table analysis for relational data was used to evaluate the relationship between out-degree and informational and functional exchange. Discussion and evaluation: Both networks demonstrated growth and inclusion of most or all network members. In the Trainee Network, those with the highest level of out-degree had the highest reports of informational exchange, X(2) (1, N = 23) = 123.61, p < 0.01. We did not find a statistically significant relationship between out-degree and functional exchange in this network, X(2)(1, N = 23) = 26.11, p > 0.05. In the Trainee-Supporter Network, trainees with the highest level of out-degree had the highest reports of informational exchange, X(2) (1, N = 23) = 74.93, p < 0.05. The same pattern held for functional exchange, X(2) (1, N = 23) = 81.31, p < 0.01. Conclusions: We found substantial and productive development of social networks in the first year of a healthcare management capacity-building program. Environmental constraints, such as limited access to information and communication technologies, or challenges with transportation and logistics, may limit the ability of some participants to engage in the networks fully. This work suggests that intentional social network development may be an important opportunity for capacity-building programs as healthcare systems improve their ability to manage resources and tackle emerging problems. C1 [Ramanadhan, Shoba] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Kebede, Sosena; Mantopoulos, Jeannie; Bradley, Elizabeth H.] Yale Univ, Sch Publ Hlth, Div Hlth Policy & Adm, New Haven, CT 06520 USA. RP Ramanadhan, S (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St,LW 703, Boston, MA 02115 USA. EM shoba_ramanadhan@dfci.harvard.edu NR 49 TC 0 Z9 0 U1 3 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-4491 J9 HUM RESOUR HEALTH JI Hum. Resour. Health PD JUL 1 PY 2010 VL 8 AR 17 DI 10.1186/1478-4491-8-17 PG 11 WC Health Policy & Services; Industrial Relations & Labor SC Health Care Sciences & Services; Business & Economics GA 628XX UT WOS:000280159400001 PM 20594321 ER PT J AU Turchin, A Goldberg, SI Shubina, M Einbinder, JS Conlin, PR AF Turchin, Alexander Goldberg, Saveli I. Shubina, Maria Einbinder, Jonathan S. Conlin, Paul R. TI Encounter Frequency and Blood Pressure in Hypertensive Patients With Diabetes Mellitus SO HYPERTENSION LA English DT Article DE hypertension; encounter frequency; visit frequency; outcomes ID RANDOMIZED-CONTROLLED-TRIAL; PRIMARY-CARE; VISIT FREQUENCY; RISK-FACTORS; MICROVASCULAR COMPLICATIONS; ANTIHYPERTENSIVE TREATMENT; TREATMENT INTENSIFICATION; COST-EFFECTIVENESS; PHYSICIAN NOTES; MANAGEMENT AB The relationship between encounter frequency (average number of provider-patient encounters over a period of time) and blood pressure for hypertensive patients is unknown. We tested the hypothesis that shorter encounter intervals are associated with faster blood pressure normalization. We performed a retrospective cohort study of 5042 hypertensive patients with diabetes mellitus treated at primary care practices affiliated with 2 academic hospitals between 2000 and 2005. Distinct periods of continuously elevated blood pressure (>= 130/85 mm Hg) were studied. We evaluated the association of the average encounter interval with time to blood pressure normalization and rate of blood pressure decrease. Blood pressure of the patients with the average interval between encounters <= 1 month normalized after a median of 1.5 months at the rate of 28.7 mm Hg/month compared with 12.2 months at 2.6 mm Hg/month for the encounter interval >1 month (P<0.0001 for all). Median time to blood pressure normalization was 0.7 versus 1.9 months for the average encounter interval <= 2 weeks versus between 2 weeks and 1 month, respectively (P<0.0001). In proportional hazards analysis adjusted for patient demographics, initial blood pressure, and treatment intensification rate, a 1 month increase in the average encounter interval was associated with a hazard ratio of 0.764 for blood pressure normalization (P<0.0001). Shorter encounter intervals are associated with faster decrease in blood pressure and earlier blood pressure normalization. Greatest benefits were observed at encounter intervals (<= 2 weeks) shorter than what is currently recommended. (Hypertension. 2010; 56: 68-74.) C1 [Turchin, Alexander; Conlin, Paul R.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. [Shubina, Maria] Brigham & Womens Hosp, Ctr Clin Invest, Boston, MA 02115 USA. [Einbinder, Jonathan S.] Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. [Turchin, Alexander; Einbinder, Jonathan S.; Conlin, Paul R.] Harvard Univ, Sch Med, Boston, MA USA. [Turchin, Alexander; Einbinder, Jonathan S.] Partners HealthCare Syst, Clin Informat Res & Dev, Boston, MA USA. [Goldberg, Saveli I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Conlin, Paul R.] Vet Adm Boston Healthcare Syst, Boston, MA USA. RP Turchin, A (reprint author), Brigham & Womens Hosp, Div Endocrinol, 221 Longwood Ave, Boston, MA 02115 USA. EM aturchin@partners.org FU Agency for Healthcare Research and Quality [5R18HS017030]; Diabetes Action Research and Education Foundation FX This study was supported in part by grants from the Agency for Healthcare Research and Quality (5R18HS017030) and the Diabetes Action Research and Education Foundation. NR 51 TC 28 Z9 30 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD JUL 1 PY 2010 VL 56 IS 1 BP 68 EP 74 DI 10.1161/HYPERTENSIONAHA.109.148791 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 611XX UT WOS:000278859300015 PM 20497991 ER PT J AU Chirinos, JA Segers, P De Buyzere, ML Kronmal, RA Raja, MW De Bacquer, D Claessens, T Gillebert, TC St John-Sutton, M Rietzschel, ER AF Chirinos, Julio A. Segers, Patrick De Buyzere, Marc L. Kronmal, Richard A. Raja, Muhammad W. De Bacquer, Dirk Claessens, Tom Gillebert, Thierry C. St John-Sutton, Martin Rietzschel, Ernst R. TI Left Ventricular Mass Allometric Scaling, Normative Values, Effect of Obesity, and Prognostic Performance SO HYPERTENSION LA English DT Article DE left ventricular mass; body size; allometric ID POPULATION-ATTRIBUTABLE RISK; BODY-SIZE; NORMOTENSIVE CHILDREN; HEART-RATE; HYPERTROPHY; ASSOCIATION; IMPACT; ATHEROSCLEROSIS; OVERWEIGHT; GEOMETRY AB The need for left ventricular mass (LVM) normalization to body size is well recognized. Currently used allometric exponents to normalize LVM may not account for the confounding effect of sex. Because sex is a strong determinant of body size and LVM, we hypothesized that these are subject to potential bias. We analyzed data from 7528 subjects enrolled in the Asklepios Study (n = 2524) and the Multiethnic Study of Atherosclerosis (limited access data set; n = 5,004) to assess metric relationships between LVM and body size, generate normative data for indexed LVM, and compare the ability of normalization methods to predict cardiovascular events. The allometric exponent that adequately described the LVM-body height relationship was 1.7 in both studies and significantly different from both the unity and 2.7, whereas the LVM-body surface area relationship was approximately linear. LVM/height(2.7) consistently demonstrated important residual relationships with body height and systematically misclassified subjects regarding the presence of LVH. LVH defined by LVM/height(1.7) was more sensitive than LVM/body surface area to identify obesity-related LVH and was most consistently associated with cardiovascular events and all-cause death. In contrast to current assumptions, LVM/height(2.7) is not an adequate method to normalize LVM for body size. We provide more appropriate normalization methods, normative data by 2D echocardiography and gradient-echo cardiac MRI, and cutoffs for defining LVH, along with prognostic validation data. (Hypertension. 2010; 56: 91-98.) C1 [Chirinos, Julio A.; Raja, Muhammad W.; St John-Sutton, Martin] Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Segers, Patrick; Claessens, Tom] Univ Ghent, Inst Biomed Technol, B-9000 Ghent, Belgium. [De Buyzere, Marc L.; Gillebert, Thierry C.; Rietzschel, Ernst R.] Univ Ghent, Dept Cardiovasc Dis, B-9000 Ghent, Belgium. [De Bacquer, Dirk; Rietzschel, Ernst R.] Univ Ghent, Dept Publ Hlth, B-9000 Ghent, Belgium. [Kronmal, Richard A.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. RP Chirinos, JA (reprint author), Univ & Woodland Ave,Room 8B111, Philadelphia, PA 19104 USA. EM Julio.chirinos@uphs.upenn.edu RI Claessens, Tom/B-2737-2009; OI Claessens, Tom/0000-0002-3182-6820; Gillebert, Thierry/0000-0002-3832-919X FU Fonds voor Wetenschappelijk Onderzoek Vlaanderen [G.0.838.10]; National Heart, Lung, and Blood Institute FX The Asklepios Study was funded by Fonds voor Wetenschappelijk Onderzoek Vlaanderen grant G.0.838.10. MESA is conducted/supported by the National Heart, Lung, and Blood Institute in collaboration with MESA investigators. NR 24 TC 94 Z9 94 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD JUL 1 PY 2010 VL 56 IS 1 BP 91 EP U137 DI 10.1161/HYPERTENSIONAHA.110.150250 PG 16 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 611XX UT WOS:000278859300018 PM 20458004 ER PT J AU Suter, MJ Tearney, GJ Oh, WY Bouma, BE AF Suter, Melissa Jane Tearney, Guillermo J. Oh, Wang-Yuhl Bouma, Brett E. TI Progress in Intracoronary Optical Coherence Tomography SO IEEE JOURNAL OF SELECTED TOPICS IN QUANTUM ELECTRONICS LA English DT Article DE Cardiovascular; coronary arteries; intravascular imaging; optical coherence tomography (OCT); optical frequency-domain imaging (OFDI); polarization sensitive optical coherence tomography (PS-OCT) ID SIROLIMUS-ELUTING STENT; CORONARY ATHEROSCLEROTIC PLAQUES; DOMAIN MODE-LOCKING; INTRAVASCULAR ULTRASOUND; IN-VIVO; REAL-TIME; VULNERABLE PLAQUE; MYOCARDIAL-INFARCTION; ARTERY-DISEASE; SWEPT-SOURCE AB Understanding the etiology and evolution of the vulnerable coronary plaque is important for the early detection, treatment, and prevention of coronary artery disease. Intravascular optical coherence tomography (OCT) enables imaging of the coronary arteries in vivo with sufficient resolution to accurately differentiate arterial pathology, however, the clinical utility of this technology has been limited due to slow image acquisition rates. The development of high-speed Fourier-domain OCT techniques, including optical frequency-domain imaging, enables comprehensive microstructural imaging of long coronary artery segments. Other OCT advancements, including polarization sensitive OCT provide complementary birefringence information that is related to tissue composition. Together with new image processing, acquisition, and display techniques, these advances have enhanced the usability and utility of intracoronary OCT, bringing it closer to becoming a mainstream imaging modality in interventional cardiology. C1 [Suter, Melissa Jane; Tearney, Guillermo J.; Oh, Wang-Yuhl; Bouma, Brett E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Suter, Melissa Jane; Tearney, Guillermo J.; Oh, Wang-Yuhl; Bouma, Brett E.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Suter, MJ (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM msuter@partners.org; gtearney@partners.org; woh1@partners.org; bbouma@partners.org RI Oh, Wang-Yuhl/C-2055-2011 FU National Institutes of Health [R01HL0763998]; [K99-CA134920] FX Manuscript received August 11, 2009; revised October 5, 2009; accepted October 5, 2009. Date of publication March 22, 2010; date of current version August 6, 2010. This work was supported in part by the National Institutes of Health under Contract R01HL0763998. The work of M. J. Suter was supported by K99-CA134920. NR 106 TC 10 Z9 11 U1 0 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1077-260X J9 IEEE J SEL TOP QUANT JI IEEE J. Sel. Top. Quantum Electron. PD JUL-AUG PY 2010 VL 16 IS 4 BP 706 EP 714 DI 10.1109/JSTQE.2009.2035333 PG 9 WC Engineering, Electrical & Electronic; Optics; Physics, Applied SC Engineering; Optics; Physics GA 671WB UT WOS:000283541100002 ER PT J AU Zhuang, J Truccolo, W Vargas-Irwin, C Donoghue, JP AF Zhuang, Jun Truccolo, Wilson Vargas-Irwin, Carlos Donoghue, John P. TI Decoding 3-D Reach and Grasp Kinematics From High-Frequency Local Field Potentials in Primate Primary Motor Cortex SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Brain-machine interface; Kalman filter; local field potential (LFP); motor cortex; multiunit activity (MUA) ID ELECTROCORTICOGRAPHIC SIGNALS; MOVEMENT TRAJECTORIES; CORTICAL-NEURONS; PARIETAL CORTEX; HUMANS; TETRAPLEGIA; DIRECTION; ARM; PREDICTION; STABILITY AB Intracortical microelectrode array recordings generate a variety of neural signals with potential application as control signals in neural interface systems. Previous studies have focused on single and multiunit activity (MUA), as well as low-frequency local field potentials (LFPs), but have not explored higher frequency (> 200 Hz) LFPs. In addition, the potential to decode 3-D reach and grasp kinematics based on LFPs has not been demonstrated. Here, we use mutual information and decoding analyses to probe the information content about 3-D reaching and grasping of seven different LFP frequency bands in the range of 0.3-400 Hz. LFPs were recorded via 96-microelectrode arrays in primary motor cortex (M1) of two monkeys performing free reaching to grasp moving objects. Mutual information analyses revealed that higher frequency bands (e. g., 100-200 and 200-400 Hz) carried the most information about the examined kinematics. Furthermore, Kalman filter decoding revealed that broad-band high frequency LFPs, likely reflecting MUA, provided the best decoding performance as well as substantial accuracy in reconstructing reach kinematics, grasp aperture, and aperture velocity. These results indicate that LFPs, especially high frequency bands, could be useful signals for neural interfaces controlling 3-D reach and grasp kinematics. C1 [Zhuang, Jun; Truccolo, Wilson; Vargas-Irwin, Carlos; Donoghue, John P.] Brown Univ, Dept Neurosci, Providence, RI 02912 USA. [Truccolo, Wilson] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Donoghue, John P.] Brown Univ, Dept Elect Engn, Providence, RI 02912 USA. [Truccolo, Wilson; Donoghue, John P.] Brown Univ, Brown Inst Brain Sci, Providence, RI 02912 USA. [Donoghue, John P.] US Dept Vet Affairs, Rehabil R&D Serv, Providence, RI 02908 USA. RP Truccolo, W (reprint author), Brown Univ, Dept Neurosci, Providence, RI 02912 USA. EM zhuang.sh.cn@hotmail.com; wilson_truccolo@brown.edu; carlos_vargas_irwin@brown.edu; john_donoghue@brown.edu FU Office of Research and Development, Rehabilitation R&D Service, Department of Veterans Affairs; National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS) [NS-25074, 5K01NS057389-03]; China Scholarship Council FX The work of J. P. Donoghue was supported in part by the Office of Research and Development, Rehabilitation R&D Service, Department of Veterans Affairs under a VA Career Award and by the National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS) under Grant NS-25074 (Javits Award). The work of W. Truccolo was supported by the NIH-NINDS under Grant 5K01NS057389-03. The work of J. Zhuang was supported by the China Scholarship Council. NR 36 TC 72 Z9 73 U1 0 U2 6 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD JUL PY 2010 VL 57 IS 7 BP 1774 EP 1784 DI 10.1109/TBME.2010.2047015 PG 11 WC Engineering, Biomedical SC Engineering GA 611JR UT WOS:000278811900026 PM 20403782 ER PT J AU Yeo, BTT Sabuncu, MR Vercauteren, T Holt, DJ Amunts, K Zilles, K Golland, P Fischl, B AF Yeo, B. T. Thomas Sabuncu, Mert R. Vercauteren, Tom Holt, Daphne J. Amunts, Katrin Zilles, Karl Golland, Polina Fischl, Bruce TI Learning Task-Optimal Registration Cost Functions for Localizing Cytoarchitecture and Function in the Cerebral Cortex SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Cross validation error; functional magnetic resonance imaging (fMRI); histology; ill-posed; leave one out error; local maxima; local minima; model selection; objective function; parameter tuning; registration parameters; regularization; space of local optima; tradeoff ID CORTICAL SURFACE; INTERSUBJECT VARIABILITY; IMAGE REGISTRATION; BRAIN; SEGMENTATION; FMRI; REGRESSION; FRAMEWORK; SELECTION; ALIGNMENT AB Image registration is typically formulated as an optimization problem with multiple tunable, manually set parameters. We present a principled framework for learning thousands of parameters of registration cost functions, such as a spatially-varying tradeoff between the image dissimilarity and regularization terms. Our approach belongs to the classic machine learning framework of model selection by optimization of cross-validation error. This second layer of optimization of cross-validation error over and above registration selects parameters in the registration cost function that result in good registration as measured by the performance of the specific application in a training data set. Much research effort has been devoted to developing generic registration algorithms, which are then specialized to particular imaging modalities, particular imaging targets and particular postregistration analyses. Our framework allows for a systematic adaptation of generic registration cost functions to specific applications by learning the "free" parameters in the cost functions. Here, we consider the application of localizing underlying cytoarchitecture and functional regions in the cerebral cortex by alignment of cortical folding. Most previous work assumes that perfectly registering the macro-anatomy also perfectly aligns the underlying cortical function even though macro-anatomy does not completely predict brain function. In contrast, we learn 1) optimal weights on different cortical folds or 2) optimal cortical folding template in the generic weighted sum of squared differences dissimilarity measure for the localization task. We demonstrate state-of-the-art localization results in both histological and functional magnetic resonance imaging data sets. C1 [Yeo, B. T. Thomas; Sabuncu, Mert R.; Golland, Polina; Fischl, Bruce] MIT, Dept Elect Engn & Comp Sci, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Sabuncu, Mert R.; Fischl, Bruce] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. [Vercauteren, Tom] Mauna Kea Technol, F-75010 Paris, France. [Holt, Daphne J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02139 USA. [Amunts, Katrin] Rhein Westfal TH Aachen, Dept Psychiat & Psychotherapy, D-52425 Julich, Germany. [Amunts, Katrin; Zilles, Karl] Forschungszentrum Julich, Inst Neurosci & Med, D-52425 Julich, Germany. [Zilles, Karl] Univ Dusseldorf, C&O Vogt Inst Brain Res, D-52425 Julich, Germany. [Fischl, Bruce] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02139 USA. [Fischl, Bruce] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Yeo, BTT (reprint author), MIT, Dept Elect Engn & Comp Sci, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. EM ythomas@csail.mit.edu; msabuncu@csail.mit.edu; tom.vercauteren@maunakeatech.com; dholt@partners.org; kamunts@ukaachen.de; k.zilles@fz-juelich.de; polina@csail.mit.edu; fischl@nmr.mgh.harvard.edu RI Amunts, Katrin/I-3470-2013; Zilles, Karl/J-9704-2013; Vercauteren, Tom/I-7290-2013; OI Zilles, Karl/0000-0002-4705-4175; Amunts, Katrin/0000-0001-5828-0867; Zilles, Karl/0000-0001-9296-9959; Vercauteren, Tom/0000-0003-1794-0456; Yeo, B.T. Thomas/0000-0002-0119-3276 FU NAMIC (NIH NIBIB) [U54-EB005149]; NAC (NIH NCRR) [P41-RR13218]; mBIRN (NIH NCRR) [U24-RR021382]; NIH NINDS [R01-NS051826]; NSF CAREER [0642971]; National Institute on Aging [AG02238]; NCRR [P41-RR14075, R01 RR16594-01A1]; NIBIB [R01 EB001550, R01EB006758]; NINDS [R01 NS052585-01]; MIND Institute; Ellison Medical Foundation; A*STAR, Singapore FX Manuscript received October 24, 2009; revised April 21, 2010; accepted April 22, 2010. Date of publication June 07, 2010; date of current version June 30, 2010. This work was supported in part by the NAMIC (NIH NIBIB NAMIC U54-EB005149), in part by the NAC (NIH NCRR NAC P41-RR13218), in part by the mBIRN (NIH NCRR mBIRN U24-RR021382), in part by the NIH NINDS R01-NS051826 Grant, in part by the NSF CAREER 0642971 Grant, in part by the National Institute on Aging (AG02238), in part by the NCRR (P41-RR14075, R01 RR16594-01A1), in part by the NIBIB (R01 EB001550, R01EB006758), in part by the NINDS (R01 NS052585-01), and in part by the MIND Institute. Additional support was provided by The Autism & Dyslexia Project funded by the Ellison Medical Foundation. The work of B. T. Thomas Yeo was supported by the A*STAR, Singapore. Asterisk indicates corresponding author. NR 84 TC 32 Z9 32 U1 0 U2 7 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD JUL PY 2010 VL 29 IS 7 BP 1424 EP 1441 DI 10.1109/TMI.2010.2049497 PG 18 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 651KD UT WOS:000281925700008 PM 20529736 ER PT J AU Heliot, R Orsborn, AL Ganguly, K Carmena, JM AF Heliot, Rodolphe Orsborn, Amy L. Ganguly, Karunesh Carmena, Jose M. TI System Architecture for Stiffness Control in Brain-Machine Interfaces SO IEEE TRANSACTIONS ON SYSTEMS MAN AND CYBERNETICS PART A-SYSTEMS AND HUMANS LA English DT Article DE Brain-machine interfaces (BMIs); impedance control; musculoskeletal model; optimal control ID MULTIJOINT ARM MOVEMENTS; MACACA-MULATTA FORELIMB; DIRECT CORTICAL CONTROL; END-POINT STIFFNESS; IMPEDANCE CONTROL; MOTOR CORTEX; MUSCULOSKELETAL MODEL; MUSCLE ACTIVATION; UNSTABLE DYNAMICS; ELBOW MUSCLES AB Brain-machine interfaces (BMIs) provide a versatile tool for rehabilitation of severely disabled people. Current BMI systems focus on the control of kinematic variables. However, this approach limits the application space of BMI technology to simulated environments. Real-world rehabilitation robots, on the other hand, must operate in a variety of complex physical situations. BMI systems that are aimed toward prostheses must, then, control interaction forces with their environments. In this paper, we design a BMI-driven architecture that provides a critical link between neuronal ensemble activity and real-world dynamics. In particular, our system allows simultaneous estimation of kinematic and stiffness variables of a prosthetic device. This approach is achieved by recording instantaneous activities from cortical neural ensembles that input to a musculoskeletal model of the arm, from which limb kinematics and dynamics are estimated and converted into control signals of a prosthetic device. Using real neural and behavioral data from nonhuman primates, we show that our architecture can accurately predict kinematic and stiffness variables in different dynamic situations. This architecture has strong implications in the development of the next generation of neural prosthetics that will restore motor function in neurologically impaired patients. Moreover, it demonstrates a novel framework for studying how the brain learns and adapts to new environments. C1 [Heliot, Rodolphe; Orsborn, Amy L.] Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Brain Machine Interface Syst Lab, Berkeley, CA 94720 USA. [Carmena, Jose M.] Univ Calif Berkeley, Program Cognit Sci, Berkeley, CA 94720 USA. [Ganguly, Karunesh; Carmena, Jose M.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Orsborn, Amy L.] Univ Calif Berkeley, Joint Grad Grp Bioengn, Berkeley, CA 94729 USA. [Ganguly, Karunesh] San Francisco VA Med Ctr, Neurol & Rehabil Serv, San Francisco, CA 94121 USA. [Ganguly, Karunesh] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. RP Heliot, R (reprint author), Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Brain Machine Interface Syst Lab, Berkeley, CA 94720 USA. EM heliot@berkeley.edu; amyorsborn@berkeley.edu; carmena@eecs.berkeley.edu FU French "Delegation generale pour l'armement" [PDE 07C0067]; National Science Foundation; American Heart Association; Christopher and Dana Reeve Foundation FX The work of R. Heliot was supported in part by the French "Delegation generale pour l'armement" under Grant PDE 07C0067. The work of A. L. Orsborn was supported in part by the National Science Foundation Graduate Fellowship. The work of K. Ganguly was supported in part by the American Heart Association. The work of J. M. Carmena was supported in part by the Christopher and Dana Reeve Foundation. NR 47 TC 4 Z9 4 U1 2 U2 9 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1083-4427 J9 IEEE T SYST MAN CY A JI IEEE Trans. Syst. Man Cybern. Paart A-Syst. Hum. PD JUL PY 2010 VL 40 IS 4 BP 732 EP 742 DI 10.1109/TSMCA.2010.2044410 PG 11 WC Computer Science, Cybernetics; Computer Science, Theory & Methods SC Computer Science GA 611KN UT WOS:000278814100008 ER PT J AU Garcia-Williams, AG Miller, LJ Burkitt, KH Cuerdon, T Jain, R Fine, MJ Jernigan, JA Sinkowitz-Cochran, RL AF Garcia-Williams, Amanda G. Miller, LaToya J. Burkitt, Kelly H. Cuerdon, Timothy Jain, Rajiv Fine, Michael J. Jernigan, John A. Sinkowitz-Cochran, Ronda L. TI Beyond beta: Lessons Learned from Implementation of the Department of Veterans Affairs Methicillin-Resistant Staphylococcus aureus Prevention Initiative SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article ID BLOOD-STREAM INFECTIONS; INTERVENTION; REDUCE; ICU AB To describe the key strategies and potential pitfalls involved with implementing the Department of Veterans Affairs (VA) Methicillin-Resistant Staphylococcus aureus (MRSA) Prevention Initiative in a qualitative evaluation, we conducted in-depth interviews with MRSA Prevention Coordinators at 17 VA beta sites at 2 time points during program implementation. Infect Control Hosp Epidemiol 2010; 31(7):763-765 C1 [Garcia-Williams, Amanda G.; Jernigan, John A.; Sinkowitz-Cochran, Ronda L.] Ctr Dis Control & Prevent, Div Healthcare Qual Promot, Atlanta, GA 30333 USA. [Burkitt, Kelly H.; Fine, Michael J.] Univ Pittsburgh, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Miller, LaToya J.; Jain, Rajiv] Univ Pittsburgh, Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Fine, Michael J.] Univ Pittsburgh, Dept Med, Div Gen Internal Med, Pittsburgh, PA USA. Vet Affairs Cent Off, Off Qual & Performance, Washington, DC USA. RP Sinkowitz-Cochran, RL (reprint author), Ctr Dis Control & Prevent, Div Healthcare Qual Promot, 1600 Clifton Rd,MS A-31, Atlanta, GA 30333 USA. EM RLS7@cdc.gov NR 9 TC 4 Z9 4 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUL PY 2010 VL 31 IS 7 BP 763 EP 765 DI 10.1086/653818 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 605VB UT WOS:000278374000016 PM 20509763 ER PT J AU Kelsen, JR Rosh, J Heyman, M Winter, HS Ferry, G Cohen, S Mamula, P Baldassano, RN AF Kelsen, Judith R. Rosh, Joel Heyman, Mel Winter, Harland S. Ferry, George Cohen, Stanley Mamula, Petar Baldassano, Robert N. TI Phase I Trial of Sargramostim in Pediatric Crohn's Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE Crohn's disease; sargramostim; open-label study ID COLONY-STIMULATING FACTOR; INTESTINAL INFLAMMATION; IMMUNODEFICIENCY; CHILDREN AB Background: Improving granulocyte function may represent an effective therapy for Crohn's disease (CD). We performed a Phase I-2 trial of sargramostim (SRG) in children with CD. Methods: This was multicenter, open-label study in 6-16-year-old patients with moderate to severely active CD. Patients received either 4 or 6 mu g/kg SRG subcutaneously daily for 8 weeks, with and without concomitant corticosteroids (CS). The primary endpoint was identification of a safe and tolerable dose in children. The secondary endpoint was establishment of the pharmacokinetics (PK). Efficacy, a tertiary endpoint, was measured by the Pediatric CD Activity Index (PCDAI). Response was defined as a decrease from baseline of >= 12.5 points and remission as absolute PCDAI of <= 10. Results: In all, 22 patients were enrolled: 12 and 10 received 4 and 6 mg/kg, respectively; 19 completed the course. Both doses were found to be safe and well tolerated. Mild injection-site reactions occurred in 90% of patients. Three patients required dose reductions due to elevated absolute neutrophil counts. Following 4 mu g/kg the mean area under the curve (AUC) was 2.64 and 2.80 ngh/mL for the 6-11- and 12-16-year-old groups, respectively. The mean half-life (t(1/2)) was 1.22 and 1.59 hours, respectively. Following 6 mu g/kg, the mean AUC was 5.01 ngh/mL for the 12-16-year-old group, a 1.8-fold increase. A total of 16/18 patients (88%) achieved remission or response. Conclusions: Sargramostim at both 4 and 6 mg/kg was well tolerated. PK analysis suggested dose proportionality unaffected by CS exposure. Remission and response data are encouraging, but further trials are needed to assess efficacy. C1 [Kelsen, Judith R.; Mamula, Petar; Baldassano, Robert N.] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Kelsen, Judith R.; Mamula, Petar; Baldassano, Robert N.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Rosh, Joel] Goryeb Childrens Hosp, Morristown, NJ USA. [Heyman, Mel] UCSF Childrens Hosp, San Francisco, CA USA. [Winter, Harland S.] Massachusetts Gen Hosp, Pediat GI Unit, Boston, MA 02114 USA. [Ferry, George] Texas Childrens Hosp, Baylor Med Ctr, Houston, TX 77030 USA. [Cohen, Stanley] Childrens Ctr Digest Healthcare, Atlanta, GA USA. RP Baldassano, RN (reprint author), MD3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM Baldassano@email.chop.edu FU Berlex FX This project was funded in part by Berlex. NR 20 TC 12 Z9 12 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD JUL PY 2010 VL 16 IS 7 BP 1203 EP 1208 DI 10.1002/ibd.21204 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 623DS UT WOS:000279718800018 PM 20052780 ER PT J AU Sands, BE Jacobson, EW Sylwestrowicz, T Younes, Z Dryden, G Fedorak, R Greenbloom, S AF Sands, Bruce E. Jacobson, Eric W. Sylwestrowicz, Thomas Younes, Ziad Dryden, Gerald Fedorak, Richard Greenbloom, Susan TI Randomized, Double-Blind, Placebo-Controlled Trial of the Oral Interleukin-12/23 Inhibitor Apilimod Mesylate for Treatment of Active Crohn's Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE Crohn's disease; interleukin-12; interleukin-23; apilimod mesylate; STA-5326 ID INFLAMMATORY-BOWEL-DISEASE; CLINICAL-TRIALS; MONOCLONAL-ANTIBODY; ULCERATIVE-COLITIS; IL-23; PATHOGENESIS; VALIDATION; EXPRESSION; EFFICACY; MODERATE AB Background: Interleukin-12 (IL-12) and interleukin-23 (IL-23) are inflammatory cytokines linked to the Th-1 and Th-17 phenotypes associated with Crohn's disease (CD). We investigated the activity and safety of apilimod mesylate (formerly STA-5326), an oral IL-12 and IL-23 inhibitor, in patients with active CD. Methods: We performed a multicenter, Phase 2, randomized, double-blinded, placebo-controlled study to evaluate the efficacy of apilimod mesylate in treating 220 adult patients with moderate-to-severe CD (Crohn's Disease Activity Index [CDAI] score 220- 450). Patients were stratified according to C-reactive protein (CRP) levels and corticosteroid use and were randomly assigned to receive placebo or apilimod mesylate 50 mg daily or 100 mg daily. The study was divided into an induction phase (43 days) and a maintenance phase (125 days). The primary analysis involved a comparison of the proportion of patients experiencing clinical response, defined as at least a 100-point decrease in CDAI score from baseline at day 29. Data on adverse events were also collected. Results: In all, 220 of the planned 282 patients were enrolled when the Data Monitoring Committee determined that the drug was not efficacious as a treatment and closed enrollment. A clinical response was experienced by 18 patients (24.7%) in the 50-mg daily (QD) group (n = 73) and 19 patients (25.7%) in the 100 mg QD group (n = 74), as compared with 21 patients (28.8%) in the placebo group (n = 73) on day 29 (P = 0.71 for each comparison). No significant adverse safety signal was observed. Conclusions: Apilimod was well-tolerated but did not demonstrate efficacy over placebo in patients with active CD. C1 [Sands, Bruce E.] Massachusetts Gen Hosp, Gastroenterol Unit, Boston, MA 02114 USA. [Sands, Bruce E.] Massachusetts Gen Hosp, MGH Crohns & Colitis Ctr, Boston, MA 02114 USA. [Sands, Bruce E.] Harvard Univ, Sch Med, Boston, MA USA. [Jacobson, Eric W.] Synta Pharmaceut, Lexington, MA USA. [Sylwestrowicz, Thomas] Univ Saskatchewan, St Pauls Hosp, Saskatoon, SK, Canada. [Younes, Ziad] Gastroenterol Ctr MidS, German Town, TN USA. [Dryden, Gerald] Univ Louisville, Div Gastroenterol, Louisville, KY 40292 USA. [Fedorak, Richard] Univ Alberta, Zeidler Ledcor Ctr, Edmonton, AB, Canada. [Greenbloom, Susan] Toronto Digest Dis Associates Inc, Toronto, ON, Canada. RP Sands, BE (reprint author), Massachusetts Gen Hosp, Gastroenterol Unit, 55 Fruit St,GRJ-719, Boston, MA 02114 USA. EM bsands@partners.org OI Dryden, Gerald/0000-0001-9787-4537; Fedorak, Richard/0000-0002-7382-0080 FU Synta Pharmaceuticals Corp FX Funded by Synta Pharmaceuticals Corp. NR 24 TC 31 Z9 34 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1078-0998 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD JUL PY 2010 VL 16 IS 7 BP 1209 EP 1218 DI 10.1002/ibd.21159 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 623DS UT WOS:000279718800019 PM 19918967 ER PT J AU Goo, YA Tsai, YSS Liu, AY Goodlett, DR Yang, CC AF Goo, Young Ah Tsai, Yihsuan S. Liu, Alvin Y. Goodlett, David R. Yang, Claire C. TI Urinary Proteomics Evaluation in Interstitial Cystitis/Painful Bladder Syndrome: A Pilot Study SO INTERNATIONAL BRAZ J UROL LA English DT Article DE interstitial cystitis; painful bladder syndrome; urine proteomics ID CHRONIC PELVIC PAIN; EPIDERMAL-GROWTH-FACTOR; ANTIPROLIFERATIVE FACTOR; HUMAN PROSTATE; PROTEIN; EXPRESSION; MARKERS AB Purpose: Interstitial cystitis/painful bladder syndrome (IC/PBS) is characterized by chronic pain, pressure and discomfort felt in the pelvis or bladder. An in-depth shotgun proteomics study was carried out to profile the urinary proteome of women with IC/PBS to identify possible specific proteins and networks associated with IC/PBS. Materials and Methods: Urine samples from ten female IC/PBS patients and ten female asymptomatic, healthy control subjects were analyzed in quadruplicate by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on a hybrid linear ion trap-orbitrap mass spectrometer. Gas-phase fractionation (GPF) was used to enhance protein identification. Differences in protein quantity were determined by peptide spectral counting. Results: alpha-1B-glycoprotein (A1BG) and orosomucoid-1 (ORM1) were detected in all IC/PBS patients, and 60% of these patients had elevated expression of these two proteins compared to control subjects. Transthyretin (TTR) and hemopexin (HPX) were detected in all control individuals, but >= 60% of the IC/PBS patients had decreased expression levels of these two proteins. Enrichment functional analysis showed cell adhesion and response to stimuli were down-regulated whereas response to inflammation, wounding, and tissue degradation were up-regulated in IC/PBS. Activation of neurophysiological processes in synaptic inhibition, and lack of DNA damage repair may also be key components of IC/PBS. Conclusion: There are qualitative and quantitative differences between the urinary proteomes of women with and without IC/PBS. We identified a number of proteins as well as pathways/networks that might contribute to the pathology of IC/PBS or result from perturbations induced by this condition. C1 [Liu, Alvin Y.; Yang, Claire C.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Goo, Young Ah; Tsai, Yihsuan S.; Goodlett, David R.] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. [Liu, Alvin Y.] Univ Washington, Inst Stem Cell & Regenerat Med, Seattle, WA 98195 USA. [Yang, Claire C.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Goodlett, David R.] Inst Syst Biol, Seattle, WA USA. RP Yang, CC (reprint author), Univ Washington, Dept Urol, Box 356510, Seattle, WA 98195 USA. EM cyang@uw.edu RI Tsai, Yihsuan/I-1924-2013 OI Tsai, Yihsuan/0000-0003-2107-4300 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 DK065202]; National Institute of Environmental Health Sciences [5P30ES007033-12]; National Center For Research Resources [1S10RR023044-01]; Robert Wood Johnson Foundation [64189] FX This work was supported by: National Institute of Diabetes and Digestive and Kidney Diseases U01 DK065202; National Institute of Environmental Health Sciences 5P30ES007033-12; National Center For Research Resources 1S10RR023044-01, and Robert Wood Johnson Foundation 64189. NR 31 TC 16 Z9 16 U1 0 U2 1 PU BRAZILIAN SOC UROL PI RIO DE JANEIRO PA RUA BAMBINA, 153, RIO DE JANEIRO, 2251-050, BRAZIL SN 1677-5538 J9 INT BRAZ J UROL JI Int. Braz J Urol PD JUL-AUG PY 2010 VL 36 IS 4 BP 464 EP 478 DI 10.1590/S1677-55382010000400010 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA 668RZ UT WOS:000283288700014 PM 20815953 ER PT J AU Thase, ME Nierenberg, AA Vrijland, P van Oers, HJJ Schutte, AJ Simmons, JH AF Thase, Michael E. Nierenberg, Andrew A. Vrijland, Peter van Oers, Helga J. J. Schutte, Albert-Jan Simmons, John H. TI Remission with mirtazapine and selective serotonin reuptake inhibitors: a meta-analysis of individual patient data from 15 controlled trials of acute phase treatment of major depression SO INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE controlled-trial; meta-analysis; remission; selective serotonin reuptake inhibitors; mirtazapine ID DOUBLE-BLIND; ANTIDEPRESSANT DRUGS; RATING-SCALE; EFFICACY; VENLAFAXINE; TOLERABILITY; DISORDER; FLUOXETINE; ONSET; PAROXETINE AB Antidepressants that enhance both serotonergic and noradrenergic neurotransmission may be more effective than selective serotonin reuptake inhibitors (SSRIs) for acute-phase therapy of major depressive disorder. Mirtazapine in particular has been suggested to have a faster onset of action than reuptake inhibitors. The aim of this study is to compare the remission rates and time to remission in patients with major depression taking either mirtazapine or an SSRI in an all-inclusive set of studies. Data were obtained from all eligible randomized controlled studies contrasting mirtazapine and SSRIs. Meta-analyses of remission rates and time to remission, together with a supportive analysis of mean change from baseline Hamilton Depression Rating Scales-17 were performed, using individual patient data from 15 randomized controlled trials of mirtazapine (N = 1484) versus various SSRIs (N = 1487) across 6 weeks of double-blind therapy. Analyses were repeated for the eight studies that lasted at least 8 weeks. Remission rates for patients treated with mirtazapine were significantly higher when compared with those treated with an SSRI after 1 (3.4 vs. 1.6%, P = 0.0017), 2 (13.0 vs. 7.8%, P<0.0001), 4 (33.1 vs. 25.1%, P<0.0001), and 6 weeks (43.4 vs. 37.5%, P = 0.0006) of treatment. Mirtazapine-treated patients had a 74% higher likelihood of achieving remission during the first 2 weeks of therapy compared with patients treated with SSRIs. In conclusion, the findings indicate that mirtazapine may be a more rapidly effective antidepressant than SSRIs. Int Clin Psychopharmacol 25: 189-198 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Thase, Michael E.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vrijland, Peter; van Oers, Helga J. J.] Organon Int Inc, Molenstraat, Netherlands. [Schutte, Albert-Jan; Simmons, John H.] Organon Int Inc, Roseland, NJ USA. RP Thase, ME (reprint author), Univ Penn, Sch Med, 3535 Market St,Suite 670, Philadelphia, PA 19104 USA. EM thase@mail.med.upenn.edu FU Organon NV FX The authors gratefully acknowledge Anja Heukels, and Bert van der Meulen, formerly employed by GCI Biometrics, NV Organon, Oss, The Netherlands, prior to the merger with Schering-Plough Corporation, for their substantial statistical work on previous versions of this manuscript. This study is based on a series of trials funded by Organon NV, which became part of Schering-Plough in November, 2007, which in turn merged with Merck and Company in late 2009. Dr Thase and Dr Nierenberg have been paid consultants to Organon, as well as to the manufacturers of the comparator medications used in these studies. NR 39 TC 27 Z9 37 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0268-1315 J9 INT CLIN PSYCHOPHARM JI Int. Clin. Psychopharmacol. PD JUL PY 2010 VL 25 IS 4 BP 189 EP 198 DI 10.1097/YIC.0b013e328330adb2 PG 10 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 612EN UT WOS:000278879700001 PM 20531012 ER PT J AU Farabaugh, AH Bitran, S Witte, J Alpert, J Chuzi, S Clain, AJ Baer, L Fava, M McGrath, PJ Dording, C Mischoulon, D Papakostas, GI AF Farabaugh, Amy H. Bitran, Stella Witte, Janet Alpert, Jonathan Chuzi, Sarah Clain, Alisabet J. Baer, Lee Fava, Maurizio McGrath, Patrick J. Dording, Christina Mischoulon, David Papakostas, George I. TI Anxious depression and early changes in the HAMD-17 anxiety-somatization factor items and antidepressant treatment outcome SO INTERNATIONAL CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE antidepressants; anxiety; anxious depression; depression; predictors; remission ID PREDICTORS; FLUOXETINE; OUTPATIENTS; PREVALENCE AB The objective of this study was to assess the relationship between early changes in anxiety/somatization symptoms and treatment outcome among major depressive disorder patients during a 12-week trial of fluoxetine. We also examined the relationship between anxious depression and treatment response. Five hundred and ten major depressive disorder patients received 12 weeks of fluoxetine with flexible dosing [target dosages: 10 mg/day (week 1), 20 mg/day (weeks 2-4), 40 mg/day (weeks 4-8), and 60 mg/day (weeks 5-12)]. We assessed the relationship between early changes in 17-item Hamilton Rating Scale for Depression (HAMD-17)-anxiety/somatization factor items and depressive remission, as well as whether anxious depression at baseline predicted remission at study endpoint. Baseline HAMD-17 scores were considered as covariates and the Bonferroni correction (P <= 0.008) was used for multiple comparisons. Adjusting for baseline HAMD-17 scores, patients who experienced greater early improvement in somatic symptoms (gastrointestinal) were significantly more likely to attain remission (HAMD-17<8) at endpoint than those without early improvement (P=0.006). Early changes in the remaining items did not predict remission, nor did anxious depression at baseline. In conclusion, among the anxiety/somatization factor items, only early changes in somatic symptoms (gastrointestinal) predicted remission. Future studies are warranted to further investigate this relationship as well as that between anxious depression and treatment outcome. Int Clin Psychopharmacol 25: 214-217 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Farabaugh, Amy H.; Bitran, Stella; Witte, Janet; Alpert, Jonathan; Chuzi, Sarah; Clain, Alisabet J.; Baer, Lee; Fava, Maurizio; Dording, Christina; Mischoulon, David; Papakostas, George I.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [McGrath, Patrick J.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [McGrath, Patrick J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Farabaugh, AH (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, 50 Staniford St,Suite 401, Boston, MA 02114 USA. EM afarabaugh@partners.org RI McGrath, Patrick/I-6410-2013; Papakostas, George/I-6905-2013; OI McGrath, Patrick/0000-0001-7217-7321; Papakostas, George/0000-0002-2465-5103; Alpert, Jonathan/0000-0002-4332-908X FU National Institute of Mental Health [R10 MG56058]; Eli Lily and Company; State of New York FX This study was supported by the National Institute of Mental Health Grant R10 MG56058 and the State of New York. Medication donated by Eli Lily and Company. NR 16 TC 12 Z9 12 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0268-1315 J9 INT CLIN PSYCHOPHARM JI Int. Clin. Psychopharmacol. PD JUL PY 2010 VL 25 IS 4 BP 214 EP 217 DI 10.1097/YIC.0b013e328339fbbd PG 4 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 612EN UT WOS:000278879700004 PM 20400905 ER PT J AU McCluggage, WG Young, RH AF McCluggage, W. Glenn Young, Robert H. TI Myxoid Change of the Myometrium and Cervical Stroma: Description of a Hitherto Unreported Non-neoplastic Phenomenon With Discussion of Myxoid Uterine Lesions SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Myometrium; Cervix; Myxoid change; Immunohistochemistry ID INFLAMMATORY MYOFIBROBLASTIC TUMOR; UTERUS; LEIOMYOMA; LEIOMYOSARCOMA; DISTINCTION AB We report 3 cases of a hitherto undescribed phenomenon in women aged 46 to 49 in which there was replacement of the myometrium or cervical stroma by an accumulation of hypocellular myxoid stromal material containing bland spindle-shaped cells and small blood vessels. In all cases, this change was conspicuous, and in 2 it was multifocal and widespread, resulting in consideration of an infiltrative myxoid mesenchymal neoplasm. Immunohistochemistry revealed a characteristic immunophenotype with diffuse strong positivity with CD34 and CD10 but no immunoreactivity with the smooth muscle markers desmin, alpha-smooth muscle actin, and h-caldesmon. In comparison, 3 cases of uterine myxoid leiomyoma were positive with smooth muscle markers and negative with CD34 and CD10. We believe the lesion we describe to be an unusual pseudoneoplastic, possibly degenerative, phenomenon. The patients past medical histories were unremarkable, with no history of connective tissue disease (myometrial myxoidosis has rarely been described in association with lupus erytematosus) or Carney's syndrome. Two patients had been prescribed local or systemic progestogens, raising the possibility of an association with these compounds. Pathologists should be aware of this unusual pseudoneoplastic phenomenon to avoid a misdiagnosis of a neoplastic lesion. C1 [McCluggage, W. Glenn] Royal Grp Hosp Trust, Dept Pathol, Belfast BT12 6BA, Antrim, North Ireland. [Young, Robert H.] Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. [Young, Robert H.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP McCluggage, WG (reprint author), Royal Grp Hosp Trust, Dept Pathol, Grosvenor Rd, Belfast BT12 6BA, Antrim, North Ireland. EM glenn.mccluggage@belfasttrust.hscni.net NR 24 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2010 VL 29 IS 4 BP 351 EP 357 DI 10.1097/PGP.0b013e3181c6a79a PG 7 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA 613IX UT WOS:000278973700010 PM 20567149 ER PT J AU Quaye, AA Raskin, KA Ecker, JL Leffert, LR AF Quaye, A. A. Raskin, K. A. Ecker, J. L. Leffert, L. R. TI Management of a parturient with high-grade osteosarcoma of the proximal femur: a multidisciplinary approach SO INTERNATIONAL JOURNAL OF OBSTETRIC ANESTHESIA LA English DT Article DE Osteosarcoma; Pregnancy; Neuraxial anesthesia; Spinal; Epidural ID OSTEOGENIC-SARCOMA; SOFT-TISSUE; CHEMOTHERAPY; PREGNANCY; GESTATION; TUMORS; BONE AB Osteosarcoma is the most common primary malignant bone tumor, yet it is exceedingly rare in pregnancy. We present a case of a 33-year-old multiparous woman diagnosed with high-grade osteosarcoma during the third trimester of pregnancy. A plan was formulated to perform cesarean delivery at 33 weeks of gestation under spinal anesthesia, and, in subsequent surgery, radical femoral neck resection with limb salvage and adjuvant chemotherapy. The outcome was a healthy newborn baby boy and a disease-free mother. This case highlights the benefits of multidisciplinary planning: balancing the needs of the developing fetus with those of the mother, mitigating the risk of pathologic fracture and ensuring timely oncologic therapy. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Quaye, A. A.; Leffert, L. R.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Raskin, K. A.] Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02114 USA. [Ecker, J. L.] Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Quaye, AA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. EM aquaye@partners.org NR 13 TC 2 Z9 3 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-289X J9 INT J OBSTET ANESTH JI Int. J. Obstet. Anesth. PD JUL PY 2010 VL 19 IS 3 BP 340 EP 342 DI 10.1016/j.ijoa.2010.03.013 PG 3 WC Anesthesiology; Obstetrics & Gynecology SC Anesthesiology; Obstetrics & Gynecology GA 631WJ UT WOS:000280381000019 PM 20627530 ER PT J AU Jin, CN Rajabi, H Kufe, D AF Jin, Caining Rajabi, Hasan Kufe, Donald TI miR-1226 targets expression of the mucin 1 oncoprotein and induces cell death SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE microRNA; MUC1; reactive oxygen species; mitochondria; apoptosis; necrosis ID CHRONIC LYMPHOCYTIC-LEUKEMIA; SURVIVAL RESPONSE; OXIDATIVE STRESS; TRANSCRIPTION FACTOR; MUC1-C ONCOPROTEIN; BETA-CATENIN; MICRORNA; APOPTOSIS; P53; GENE AB The MUC1 oncoprotein is aberrantly overexpressed in human carcinomas and hematologic malignancies. Micro-RNAs (miRNAs) have been implicated in the suppression and induction of oncogenesis. The present studies demonstrate that the MUC1 mRNA 3 untranslated region (3'UTR) contains a highly conserved motif for binding of a novel miRNA, miR-1226, that has no known targets. The results show that miR-1226 is expressed in human breast cancer cell lines and non-malignant mammary epithelial cells. We also show that miR-1226 interacts with the MUC1 mRNA 3'UTR and that miR-1226 downregulates endogenous MUC1 protein levels. Consistent with miR-1226-induced downregulation of MUC1 expression, the results demonstrate that miR-1226 induces i) an increase in reactive oxygen species, ii) loss of the mitochondrial transmembrane potential, and iii) a decrease in cell survival. These findings indicate that expression of the MUC1 oncoprotein is downregulated by miR-1226 and that miR-1226 thereby functions as a tumor suppressor by promoting the induction of cell death. C1 [Jin, Caining; Rajabi, Hasan; 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 RI Jin, Caining/A-1870-2010; Xie, Huangming/B-2260-2012 FU National Cancer Institute [CA97098, CA42802] FX This work was supported by Grant CA97098 and CA42802 awarded by the National Cancer Institute. The authors acknowledge Dr Isidore Rigoutsos, Thomas Jefferson University Medical College, for his critical reading of the manuscript and his insightful suggestions. NR 43 TC 24 Z9 24 U1 0 U2 1 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD JUL PY 2010 VL 37 IS 1 BP 61 EP 69 DI 10.3892/ijo_00000653 PG 9 WC Oncology SC Oncology GA 615KU UT WOS:000279135000008 PM 20514397 ER PT J AU Urdaneta, RA Rodriguez, S McNeil, DC Weed, M Chuang, SK AF Urdaneta, Rainier A. Rodriguez, Sujey McNeil, D. Cary Weed, Meghan Chuang, Sung-Kiang TI The Effect of Increased Crown-to-Implant Ratio on Single-Tooth Locking-Taper Implants SO INTERNATIONAL JOURNAL OF ORAL & MAXILLOFACIAL IMPLANTS LA English DT Article; Proceedings Paper CT 5th International Workshop on Biology and Culture of the Tench CY SEP 29-OCT 03, 2008 CL Ceresole d Alba, ITALY DE cementless restorations; crown-to-implant ratio; plateau design dental implants; resin crowns; stress ID FINITE-ELEMENT-ANALYSIS; PARTIALLY EDENTULOUS PATIENTS; RISK-FACTORS; BONE LOSS; PROSTHESES; BRANEMARK; DIAMETER; SURVIVAL; FAILURE; SYSTEM AB Purpose: It has been proposed that increased crown heights lead to greater crestal stresses on dental implants, crestal bone loss, and other complications. The purpose of this study was to evaluate the effect of increased crown-to-implant ratio (C/IR) on single-tooth implants. Materials and Methods: A retrospective cohort study was conducted between July 2001 and August 2003. The cohort was composed of patients who had at least one single-tooth Bicon implant restored with a cementless restoration and attended recall examinations in 2004, 2005, and 2007, during which several clinical and radiographic variables were documented. Descriptive statistics and univariate and multivariate mixed-effects regression models, adjusted for multiple implants in the same patient, were used. Results: The cohort was composed of 81 subjects who received 326 Bicon implants. The mean duration of follow-up was 70.7 months. Mean change in the mesiodistal crestal bone levels was -0.33 mm. The mean C/IR was 1.6 (range, 0.79 to 4.95). Forty implant restorations (16%) had a C/IR >= 2. Implant restorations with increased C/IR were significantly more likely to have increased mesiodistal crown width, larger implant diameter, larger distance to mesial and distal adjacent structures, and deeper sulcular probings. Increased C/IR had a statistically significant effect in the loosening of maxillary anterior Integrated Abutment Crowns (Bicon) as well as a significant effect in the fracture of 2-mm-wide titanium abutment posts used to restore posterior areas. A C/IR up to 4.95 did not lead to an increased risk of crestal bone loss or to an increase in implant failures, crown failures, or crown fractures. Conclusion: Larger C/IR was associated with a significant increase in prosthetic complications but had no significant effect on crestal bone levels on single-tooth locking-taper implants. INT J ORAL MAXILLOFAC IMPLANTS 2010;25:729-743 C1 [Urdaneta, Rainier A.; Weed, Meghan] Implant Dent Ctr, Boston, MA USA. [Rodriguez, Sujey] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA. [McNeil, D. Cary] Univ Minnesota, Sch Dent, Grad Program Prosthodont, Minneapolis, MN 55455 USA. [Chuang, Sung-Kiang] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Chuang, Sung-Kiang] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Chuang, Sung-Kiang] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Urdaneta, RA (reprint author), 25 Prairie Ave, Auburndale, MA 02466 USA. EM rainieru@yahoo.com NR 36 TC 37 Z9 42 U1 0 U2 2 PU QUINTESSENCE PUBLISHING CO INC PI HANOVER PARK PA 4350 CHANDLER DRIVE, HANOVER PARK, IL 60133 USA SN 0882-2786 J9 INT J ORAL MAX IMPL JI Int. J. Oral Maxillofac. Implants PD JUL-AUG PY 2010 VL 25 IS 4 BP 729 EP 743 PG 15 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 641GR UT WOS:000281113300009 PM 20657868 ER PT J AU Sperduto, PW Chao, ST Sneed, PK Luo, XH Suh, J Roberge, D Bhatt, A Jensen, AW Brown, PD Shih, H Kirkpatrick, J Schwer, A Gaspar, LE Fiveash, JB Chiang, V Knisely, J Sperduto, CM Mehta, M AF Sperduto, Paul W. Chao, Samuel T. Sneed, Penny K. Luo, Xianghua Suh, John Roberge, David Bhatt, Amit Jensen, Ashley W. Brown, Paul D. Shih, Helen Kirkpatrick, John Schwer, Amanda Gaspar, Laurie E. Fiveash, John B. Chiang, Veronica Knisely, Jonathan Sperduto, Christina Maria Mehta, Minesh TI DIAGNOSIS-SPECIFIC PROGNOSTIC FACTORS, INDEXES, AND TREATMENT OUTCOMES FOR PATIENTS WITH NEWLY DIAGNOSED BRAIN METASTASES: A MULTI-INSTITUTIONAL ANALYSIS OF 4,259 PATIENTS SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Brain metastases; prognosis; radiotherapy; stereotactic radiosurgery ID RANDOMIZED PHASE-III; PARTITIONING ANALYSIS RPA; RADIATION-THERAPY; STEREOTACTIC RADIOSURGERY; NEUROCOGNITIVE FUNCTION; COST-EFFECTIVENESS; ACCELERATED-FRACTIONATION; SINGLE METASTASES; TRIAL; RADIOTHERAPY AB Purpose: Controversy endures regarding the optimal treatment of patients with brain metastases (BMs). Debate persists, despite many randomized trials, perhaps because BM patients are a heterogeneous population. The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis-Specific Graded Prognostic Assessment [DS-GPA]). Methods and Materials: A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. After exclusion of the patients with recurrent BMs or incomplete data, 4,259 patients with newly diagnosed BMs remained eligible for analysis. Univariate and multivariate analyses of the prognostic factors and outcomes by primary site and treatment were performed. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment. Results: The significant prognostic factors varied by diagnosis. For non small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. For melanoma and renal cell cancer, the significant prognostic factors were Karnofsky performance status and the number of BMs. For breast and gastrointestinal cancer, the only significant prognostic factor was the Karnofsky performance status. Two new DS-GPA indexes were thus designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma. The median survival by GPA score, diagnosis, and treatment were determined. Conclusion: The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making. (C) 2010 Elsevier Inc. C1 [Sperduto, Paul W.] Univ Minnesota, Gamma Knife Ctr, Waconia, MN 55387 USA. [Chao, Samuel T.; Suh, John] Cleveland Clin, Dept Radiat Oncol, Cleveland, OH 44106 USA. [Sneed, Penny K.] Univ Calif San Francisco, Dept Radiat Oncol, Sch Med, San Francisco, CA 94143 USA. [Luo, Xianghua] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Roberge, David] McGill Univ, Ctr Hlth, Dept Radiat Oncol, Montreal, ON, Canada. [Bhatt, Amit; Mehta, Minesh] Univ Wisconsin, Dept Human Oncol, Madison, WI USA. [Jensen, Ashley W.; Brown, Paul D.] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. [Shih, Helen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Kirkpatrick, John] Duke Univ, Med Ctr, Div Radiat Oncol, Durham, NC 27710 USA. [Schwer, Amanda; Gaspar, Laurie E.] Univ Colorado, Hlth Sci Ctr, Dept Radiat Oncol, Denver, CO USA. [Fiveash, John B.] Univ Alabama, Med Ctr, Dept Radiat Oncol, Birmingham, AL 35294 USA. [Chiang, Veronica] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT USA. [Knisely, Jonathan] Yale Univ, Sch Med, Dept Radiat Oncol, New Haven, CT USA. [Sperduto, Christina Maria] Minneapolis Radiat Oncol, Minneapolis, MN USA. RP Sperduto, PW (reprint author), Univ Minnesota, Gamma Knife Ctr, 560 S Maple St, Waconia, MN 55387 USA. EM psperduto@mropa.com RI Luo, Xianghua/D-6934-2011; OI Kirkpatrick, John/0000-0002-4019-0350; mehta, minesh/0000-0002-4812-5713 NR 31 TC 290 Z9 300 U1 0 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2010 VL 77 IS 3 BP 655 EP 661 DI 10.1016/j.ijrobp.2009.08.025 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 610OE UT WOS:000278741800004 PM 19942357 ER PT J AU Kim, B Chen, YLE Kirsch, DG Goldberg, SI Kobayashi, W Kung, JH Wolfgang, JA Doppke, K Rosenberg, AE Nielsen, GP Raskin, KA Springfield, DS Schwab, JH Gebhardt, MC Yoon, SS Hornicek, FJ DeLaney, TF AF Kim, BoKyong Chen, Yen-Lin E. Kirsch, David G. Goldberg, Saveli I. Kobayashi, Wendy Kung, John Hyun Wolfgang, John A. Doppke, Karen Rosenberg, Andrew E. Nielsen, G. Petur Raskin, Kevin A. Springfield, Dempsey S. Schwab, Joseph H. Gebhardt, Mark C. Yoon, Sam S. Hornicek, Francis J. DeLaney, Thomas F. TI AN EFFECTIVE PREOPERATIVE THREE-DIMENSIONAL RADIOTHERAPY TARGET VOLUME FOR EXTREMITY SOFT TISSUE SARCOMA AND THE EFFECT OF MARGIN WIDTH ON LOCAL CONTROL SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE Soft tissue sarcomas; Extremity; Preoperative radiotherapy; Radiation volume; Local failure ID RADIATION-THERAPY; POSTOPERATIVE RADIOTHERAPY; NEOADJUVANT CHEMOTHERAPY; SURGICAL RESECTION; PROGNOSTIC-FACTORS; RANDOMIZED TRIAL; HIGH-GRADE; BODY-WALL; SURGERY; RECURRENCE AB Purpose: There is little information on the appropriate three-dimensional (3D) preoperative radiotherapy (XRT) volume for extremity soft-tissue sarcomas (STS). We retrospectively analyzed the pattern of local failure (LF) to help elucidate optimal field design. Methods and Materials: We analyzed the 56 patients who underwent computed tomography planned XRT for Stage I to III extremity STS between June 2000 and December 2006. Clinical target volume (CTV) included the T1 post gadolinium-defined gross tumor volume with 1- to 1.5-cm radial and 3.5-cm longitudinal margins. Planning target volume expansion was 5 to 7 mm, and >= 95% of dose was delivered to the planning target volume. Preoperative XRT was 44 to 59.4 Gy (median, 50). Postoperative boost of 10 to 20 Gy was given to 12 patients (6 with positive and 6 with close margins). Results: Follow-up ranged from 15 to 76 months (median, 41 months). The 5-year local control, freedom from distant metastasis, disease-free survival, and overall survival were 88.5%, 80.0%, 77.5% and 82.8%, respectively. Three patients (all with positive margin) experienced local failure (LE) as first relapse (2 isolated, 1 with distant failure), and 2 additional patients (all with margin<1 mm) had late LF after distant metastasis. The LFs were within the CTV in 3 patients and within and also extending beyond the CTV in 2 patients. Conclusions: These target volume definitions appear to he appropriate for most patients. No local recurrences were observed with surgical margins >= 1 mm, and it appears that these may be adequate for patients with extremity STS treated with preoperative radiotherapy. (C) 2910 Elsevier Inc. C1 [DeLaney, Thomas F.] Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Dept Radiat Oncol, Boston, MA 02114 USA. [Raskin, Kevin A.; Springfield, Dempsey S.; Schwab, Joseph H.; Hornicek, Francis J.] Massachusetts Gen Hosp, Dept Orthopaed Oncol, Boston, MA 02114 USA. [Yoon, Sam S.] Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. [Rosenberg, Andrew E.; Nielsen, G. Petur] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kim, BoKyong] Dankook Univ Hosp, Dept Radiat Oncol, Chenoan, South Korea. [Gebhardt, Mark C.] Beth Israel Deaconess Med Ctr, Dept Orthopaed Surg, Boston, MA 02215 USA. RP DeLaney, TF (reprint author), Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Dept Radiat Oncol, 30 Fruit St, Boston, MA 02114 USA. EM tdelaney@partners.org NR 25 TC 20 Z9 22 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2010 VL 77 IS 3 BP 843 EP 850 DI 10.1016/j.ijrobp.2009.06.086 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 610OE UT WOS:000278741800030 PM 20005638 ER PT J AU El Annan, J Goyal, S Zhang, Q Freeman, GJ Sharpe, AH Dana, R AF El Annan, Jaafar Goyal, Sunali Zhang, Qiang Freeman, Gordon J. Sharpe, Arlene H. Dana, Reza TI Regulation of T-Cell Chemotaxis by Programmed Death-Ligand 1 (PD-L1) in Dry Eye-Associated Corneal Inflammation SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CHEMOKINE GENE-EXPRESSION; KERATOCONJUNCTIVITIS SICCA; ALLOGRAFT SURVIVAL; ENDOTHELIAL-CELLS; TEAR FLUID; RECEPTOR; MICE; TOLERANCE; SJOGRENS; DISEASE AB PURPOSE. Given that dry eye disease (DED) is associated with T cell-mediated inflammation of the ocular surface and that PD-L1 is an important negative or inhibitory regulator of immune responses constitutively expressed at high levels by corneal epithelial cells, the authors studied the expression and function of PD-L1 in DED. METHODS. Dry eye was induced in untreated wild-type mice, PD-L1(-/-) mice, and wild-type mice treated with anti-PD-L1 antibody by exposing these mice to a desiccating environment in the controlled environment chamber modified with subcutaneous administration of scopolamine. Real-time PCR was used to quantify the expression of chemokine gene transcript levels of multiple CC and CXC chemokine ligands and receptors. Epifluorescence microscopy was used to evaluate corneal infiltration of CD3(+) T cells after immunohistochemical staining. RESULTS. The increased expression of specific chemokine ligands and receptors in PD-L1(-/-) corneas of normal mice is associated with significant increases in T-cell homing into these corneas. Similar, and more enhanced, increases in T-cell infiltration were observed in PD-L1(-/-) DED mice or DED mice treated with anti-PD-L1 antibody compared with controls. In addition, the authors found significantly decreased expression of PD-L1 by corneal epithelial cells in DED and significantly increased corneal fluorescein staining score with PD-L1 functional blockade using anti-PD-L1 antibody. CONCLUSIONS. Downregulation of corneal epithelial PD-L1 amplifies dry eye-associated corneal inflammation and epitheliopathy by increasing the expression of chemokine ligands and receptors that promote T-cell homing to the ocular surface. (Invest Ophthalmol Vis Sci. 2010; 51:3418-3423) DOI:10.1167/iovs.09-3684 C1 [El Annan, Jaafar; Goyal, Sunali; Zhang, Qiang; Dana, Reza] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [El Annan, Jaafar; Goyal, Sunali; Zhang, Qiang; Dana, Reza] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol, Boston, MA 02114 USA. [Freeman, Gordon J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02114 USA. [Sharpe, Arlene H.] Harvard Univ, Sch Med, Dept Pathol, 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 Allergan Inc. FX Supported in part by a research grant from Allergan Inc. NR 45 TC 11 Z9 11 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUL PY 2010 VL 51 IS 7 BP 3418 EP 3423 DI 10.1167/iovs.09-3684 PG 6 WC Ophthalmology SC Ophthalmology GA 614HX UT WOS:000279047500014 PM 20019373 ER PT J AU Goetti, R Leschka, S Desbiolles, L Klotz, E Samaras, P von Boehmer, L Stenner, F Reiner, C Stolzmann, P Scheffel, H Knuth, A Marincek, B Alkadhi, H AF Goetti, Robert Leschka, Sebastian Desbiolles, Lotus Klotz, Ernst Samaras, Panagiotis von Boehmer, Lotta Stenner, Frank Reiner, Caecilia Stolzmann, Paul Scheffel, Hans Knuth, Alexander Marincek, Borut Alkadhi, Hatem TI Quantitative Computed Tomography Liver Perfusion Imaging Using Dynamic Spiral Scanning With Variable Pitch Feasibility and Initial Results in Patients With Cancer Metastases SO INVESTIGATIVE RADIOLOGY LA English DT Article DE liver; perfusion; computed tomography; metastasis ID COLORECTAL-CANCER; MEASUREMENT REPRODUCIBILITY; HEPATIC PERFUSION; TUMOR VASCULARITY; CT; ANGIOGENESIS; MDCT; IMAGES AB Purpose: To assess the feasibility and image quality of computed tomography (CT) liver perfusion imaging using an adaptive 4D spiral-mode, developed to extend the z-axis coverage, and to report initial qualitative and quantitative results in patients with cancer metastases. Materials and Methods: A total of 21 patients with liver metastases of various origins underwent CT perfusion imaging (100 kV and 150 mAs/rot) using a 4D spiral-mode with single-source 64-slice CT (n = 7) with a scan range of 6.7cm (protocol A: 16 cycles, 46.5 seconds examination time), or dual-source 128-slice CT with a scan range of 14.8 cm (protocol B: 16 cycles, 46.5 seconds examination time, n = 7; protocol C: 12 cycles, 51.0 seconds examination time, n = 7). Ability to suspend respiration during perfusion imaging was monitored. Two independent readers assessed image quality on a 4-point scale, both before and after motion correction, and performed a qualitative (ie, arterial enhancement pattern and enhancement change over time) and quantitative perfusion (ie, arterial liver perfusion [ALP]; portal-venous perfusion [PVP]; hepatic perfusion index [HPI]) analysis. Results: Of 21 patients, 7 (33%) could suspend respiration throughout the perfusion study and 14 (67%) resumed shallow breathing during the perfusion scan. The 21 patients had a total of 88 metastases. The scan range of protocol A covered at least 1 metastasis in all patients (total 20/34 [58.8%] metastases). The scan range of protocol B and C covered 53 of 54 (98.1%) metastases, whereas one metastasis in segment VIII was only partially imaged. Image quality was diagnostic both before and after motion correction, whereas being significantly better after motion correction (P < 0.001). Qualitative perfusion analysis of 67 metastases revealed diffuse arterial enhancement in 3 (4.5%), sparse enhancement in 11 (16.4%), peripheral-nodular enhancement in 9 (13.4%), rim-like enhancement in 15 (22.4%), and none in 29 (43.3%) metastases. Enhancement over time of 67 metastases showed a centripetal progression in 6 (8.9%), sustained portal phase in 16 (23.9%), wash-out in 16 (23.9%), and none in 29 (43.3%) metastases. Quantitative perfusion analysis revealed significantly higher arterial liver perfusion and HPI in metastases and metastasis borders than in adjacent normal liver tissue (P < 0.001 each). Portal-venous perfusion was significantly lower in metastases and metastasis borders than in normal liver tissue (P < 0.001). There were no significant differences in image quality and qualitative perfusion analysis between the 3 protocols (P = n.s.). Calculated effective radiation doses were 13.4 mSv for protocol A, 30.7 mSv for protocol B, and 23.0 mSv for protocol C. Conclusion: CT perfusion imaging of the liver using the 4D spiral-mode is feasible with diagnostic image quality, and enables the reliable qualitative and quantitative analysis of the normal and metastatic liver parenchyma. Radiation dose issues must be considered when determining the scan range, number of cycles, and scan duration of the perfusion CT protocol. C1 [Alkadhi, Hatem] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Goetti, Robert; Leschka, Sebastian; Desbiolles, Lotus; Reiner, Caecilia; Stolzmann, Paul; Scheffel, Hans; Marincek, Borut; Alkadhi, Hatem] Univ Zurich Hosp, Inst Diagnost Radiol, CH-8091 Zurich, Switzerland. [Klotz, Ernst] Siemens Healthcare, Forchheim, Germany. [Samaras, Panagiotis; von Boehmer, Lotta; Stenner, Frank; Knuth, Alexander] Univ Zurich Hosp, Div Oncol, CH-8091 Zurich, Switzerland. RP Alkadhi, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM halkadhi@partners.org RI Goetti, Robert/I-8961-2012 NR 28 TC 54 Z9 59 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-9996 J9 INVEST RADIOL JI Invest. Radiol. PD JUL PY 2010 VL 45 IS 7 BP 419 EP 426 DI 10.1097/RLI.0b013e3181e1937b PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 618YZ UT WOS:000279394300009 PM 20498611 ER PT J AU Hakeem, A Bhatti, S Karmali, KN Dillie, KS Cook, JR Xu, JQ Samad, Z Chang, SM AF Hakeem, Abdul Bhatti, Sabha Karmali, Kunal N. Dillie, Kathryn S. Cook, Jeffrey R. Xu, Jiaqiong Samad, Zainab Chang, Su Min TI Renal Function and Risk Stratification of Diabetic and Nondiabetic Patients Undergoing Evaluation for Coronary Artery Disease SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE diabetic; renal function; risk stratification ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; EMISSION COMPUTED-TOMOGRAPHY; INCREMENTAL PROGNOSTIC VALUE; SILENT-MYOCARDIAL-ISCHEMIA; HIGH BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; ALL-CAUSE; GENERAL-POPULATION; PERFUSION SPECT AB OBJECTIVES The aim of this study was to evaluate the impact of renal function by estimated glomerular filtration rate (eGFR) on risk stratification of diabetic and nondiabetic patients undergoing myocardial perfusion imaging (MPI) by single-photon emission computed tomography for suspected ischemia. BACKGROUND Coronary artery disease is the leading cause of death among diabetic persons; however, diabetic persons are a very heterogeneous group in terms of cardiovascular risk, necessitating further risk stratification. METHODS Patients (n = 1,747, age 65 +/- 10 years, 37% diabetic) undergoing MPI were followed for cardiac death (CD) for a mean of 2.15 +/- 0.8 years. Chronic kidney disease (CKD) was defined by an eGFR <60 ml/min. RESULTS In the presence of a normal scan, annual CD rate was 0.9% for those with no diabetes mellitus (DM) and no CKD, 0.5% in the DM alone group, 2.35% in CKD alone, and 2.9% in those with both DM and CKD (p < 0.001). Patients with DM+CKD had a 2.7-fold risk of CD compared with no DM no CKD (p = 0.001) after controlling for age, ejection fraction, history of coronary artery disease, and other risk factors. The risk of CD increased as a function of the presence and severity of perfusion defects, regardless of CKD or DM status. Presence of CKD conferred a several-fold higher risk of CD for the various strata of perfusion defects. Log-rank test for difference in probability of CD was nonsignificant for comparison between patients with no DM no CKD and those with DM alone (p = 0.73) but was significant for comparison between patients with no DM no CKD and patients with CKD alone (p < 0.001) or DM+CKD (p < 0.001). CONCLUSIONS MPI and eGFR provide valuable risk stratification for diabetic and nondiabetic patients. Diabetic patients without CKD seem to have similar short-term cardiac outcomes compared with nondiabetic patients. Underlying CKD seems to identify a high-risk subgroup of diabetic patients. (J Am Coll Cardiol Img 2010;3:734-45) (c) 2010 by the American College of Cardiology Foundation C1 [Hakeem, Abdul; Bhatti, Sabha] Univ Cincinnati, Coll Med, Div Cardiovasc Dis, Cincinnati, OH USA. [Karmali, Kunal N.; Cook, Jeffrey R.] Univ Wisconsin Hosp & Clin, Dept Internal Med, Madison, WI 53792 USA. [Karmali, Kunal N.; Cook, Jeffrey R.] Univ Wisconsin Hosp & Clin, William S Middleton Mem Vet Adm Hosp, Madison, WI 53792 USA. [Dillie, Kathryn S.] Wisconsin Affiliated Hosp, Coll Med, Milwaukee, WI USA. [Xu, Jiaqiong] Methodist Hosp, Res Inst, Ctr Biostat, Houston, TX 77030 USA. [Samad, Zainab] Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. [Chang, Su Min] Methodist Hosp, DeBakey Heart & Vasc Ctr, Houston, TX 77030 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 42 TC 17 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JUL PY 2010 VL 3 IS 7 BP 734 EP 745 DI 10.1016/j.jcmg.2010.06.001 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 647OB UT WOS:000281626700009 PM 20633852 ER PT J AU Kimmel, AD Weinstein, MC Anglaret, X Goldie, SJ Losina, E Yazdanpanah, Y Messou, E Cotich, KL Walensky, RP Freedberg, KA AF Kimmel, April D. Weinstein, Milton C. Anglaret, Xavier Goldie, Sue J. Losina, Elena Yazdanpanah, Yazdan Messou, Eugene Cotich, Kara L. Walensky, Rochelle P. Freedberg, Kenneth A. CA CEPAC-Int Investigators TI Laboratory Monitoring to Guide Switching Antiretroviral Therapy in Resource-Limited Settings: Clinical Benefits and Cost-Effectiveness SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE laboratory monitoring; diagnostic tests; HIV RNA; viral load; HIV/AIDS; antiretroviral therapy ID HIV-INFECTED ADULTS; COTE-DIVOIRE; VIROLOGICAL FAILURE; VIRAL LOAD; DRUG-RESISTANCE; POOR SETTINGS; SOUTH-AFRICA; SCALING-UP; CELL COUNT; REGIMEN AB Background: As second-line antiretroviral therapy (ART) availability increases in resource-limited settings, questions about the value of laboratory monitoring remain. We assessed the outcomes and cost-effectiveness (CE) of laboratory monitoring to guide switching ART. Methods: We used a computer model to project life expectancy and costs of different strategies to guide ART switching in patients in Cote d'Ivoire. Strategies included clinical assessment, CD4 count, and HIV RNA testing. Data were from clinical trials and cohort studies from Cote d'Ivoire and the literature. Outcomes were compared using the incremental CE ratio. We conducted multiple sensitivity analyses to assess uncertainty in model parameters. Results: Compared with first-line ART only, second-line ART increased life expectancy by 24% with clinical monitoring only, 46% with CD4 monitoring, and 61% with HIV RNA monitoring. The incremental CE ratio of switching based on clinical monitoring was $1670 per year of life gained (YLS) compared with first-line ART only; biannual CD4 monitoring was $2120 per YLS. The CE ratio of biannual HIV RNA testing ranged from $2920 ($87/test) to $1990 per YLS ($25/test). If second-line ART costs were reduced, the CE of HIV RNA monitoring improved. Conclusions: In resource-limited settings, CD4 count and HIV RNA monitoring to guide switching to second-line ART improve survival and, under most conditions, are cost-effective. C1 [Kimmel, April D.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY 10065 USA. [Kimmel, April D.; Weinstein, Milton C.; Goldie, Sue J.; Cotich, Kara L.; Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Weinstein, Milton C.; Losina, Elena; Walensky, Rochelle P.; Freedberg, Kenneth A.] Harvard Univ, Sch Med, Boston, MA USA. [Anglaret, Xavier] INSERM, U897, Bordeaux, France. [Anglaret, Xavier; Messou, Eugene] Programme PAC CI, Abidjan, Cote Ivoire. [Losina, Elena; Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Losina, Elena; Walensky, Rochelle P.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Yazdanpanah, Yazdan] Ctr Hosp Tourcoing, Serv Univ Malad Infect & Voyageur, Lille, France. [Yazdanpanah, Yazdan] Fac Med Lille, EA 2694, F-59045 Lille, France. [Walensky, Rochelle P.; Freedberg, Kenneth A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kimmel, AD (reprint author), Weill Cornell Med Coll, Dept Publ Hlth, 402 E 67th St, New York, NY 10065 USA. EM adk2010@med.cornell.edu RI Anglaret, Xavier/F-7333-2013; OI Walensky, Rochelle P./0000-0002-8795-379X FU National Institute of Allergy and Infectious Diseases [T32 AI007433, R01 AI058736, K24 AI062476, K25 AI50436, CFAR P30 AI42851]; French Agence National de Recherches sur le SIDA [ANRS 1286]; Agency for Healthcare Research and Quality [T32 HS000055]; Doris Duke Charitable Foundation [CSDA 2005075]; Project on Justice, Welfare and Economics; Weatherhead Center for International Affairs, Harvard University; Graduate Society; Graduate School of Arts and Sciences, Harvard University FX Supported in part by the National Institute of Allergy and Infectious Diseases (T32 AI007433, R01 AI058736, K24 AI062476, K25 AI50436, and CFAR P30 AI42851), the French Agence National de Recherches sur le SIDA (ANRS 1286), the Agency for Healthcare Research and Quality (T32 HS000055), the Doris Duke Charitable Foundation (CSDA 2005075), the Project on Justice, Welfare and Economics, Weatherhead Center for International Affairs, Harvard University, and the Graduate Society Summer Fellowship, Graduate School of Arts and Sciences, Harvard University. NR 71 TC 34 Z9 35 U1 0 U2 5 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 JUL 1 PY 2010 VL 54 IS 3 BP 258 EP 268 DI 10.1097/QAI.0b013e3181d0db97 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 613YV UT WOS:000279022300005 PM 20404739 ER PT J AU Cheng, CE Irwin, B Mauriello, D Hemminger, L Pappert, A Kimball, AB AF Cheng, Carol E. Irwin, Blair Mauriello, Dana Hemminger, Laura Pappert, Amy Kimball, Alexandra B. TI Health Disparities Among Different Ethnic and Racial Middle and High School Students in Sun Exposure Beliefs and Knowledge SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Skin cancer; Sun safety; Tanning; Sun protection; Healthcare disparities; Perception; Beliefs; Minorities; Adolescents; Ability to learn ID PROTECTION; CANCER AB Racial and ethnic differences may influence sun protection behavior. Adolescent students were administered a sun protection questionnaire and educational program. White people had the greatest pretest knowledge which resulted in the highest score, and blacks and Hispanics scored lower. White people who found tanned individuals attractive had greater score improvements. All groups improved after intervention. (C) 2010 Society for Adolescent Health and Medicine. All rights reserved. C1 [Kimball, Alexandra B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, CURTIS,Dept Dermatol, Boston, MA 02114 USA. [Irwin, Blair; Pappert, Amy] UMDNJ Robert Wood Johnson Med Sch, Dept Dermatol, New Brunswick, NJ USA. [Hemminger, Laura] UMDNJ Sch Publ Hlth, New Brunswick, NJ USA. RP Kimball, AB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, CURTIS,Dept Dermatol, 50 Staniford St,Suite 240, Boston, MA 02114 USA. EM akimball@partners.org FU Women's Dermatological Society FX Blair Irwin was funded through a grant from the Women's Dermatological Society. NR 10 TC 9 Z9 10 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUL PY 2010 VL 47 IS 1 BP 106 EP 109 DI 10.1016/j.jadohealth.2009.12.028 PG 4 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 609IE UT WOS:000278648800016 PM 20547300 ER PT J AU Jarvinen, KM Amalanayagam, S Bock, SA Shreffler, WG Noone, S Sicherer, SH Sampson, HA Nowak-Wegrzyn, A AF Jarvinen, Kirsi M. Amalanayagam, Sujitha Bock, S. Allan Shreffler, Wayne G. Noone, Sally Sicherer, Scott H. Sampson, Hugh A. Nowak-Wegrzyn, Anna TI Differences in treatment of food challenge-induced reactions reflect physicians' protocols more than reaction severity Reply SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID ANAPHYLACTIC REACTIONS; CHILDREN C1 [Jarvinen, Kirsi M.; Amalanayagam, Sujitha; Shreffler, Wayne G.; Noone, Sally; Sicherer, Scott H.; Sampson, Hugh A.; Nowak-Wegrzyn, Anna] Mt Sinai Sch Med, Div Pediat Allergy & Immunol, New York, NY 10029 USA. [Jarvinen, Kirsi M.; Amalanayagam, Sujitha; Shreffler, Wayne G.; Noone, Sally; Sicherer, Scott H.; Sampson, Hugh A.; Nowak-Wegrzyn, Anna] Mt Sinai Sch Med, Jaffe Food Allergy Inst, New York, NY USA. [Bock, S. Allan] Boulder Valley Asthma & Allergy Clin, Boulder, CO USA. [Shreffler, Wayne G.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. RP Jarvinen, KM (reprint author), Mt Sinai Sch Med, Div Pediat Allergy & Immunol, New York, NY 10029 USA. EM kirsi.jarvinen-seppo@mssm.edu NR 10 TC 1 Z9 1 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2010 VL 126 IS 1 BP 182 EP 183 DI 10.1016/j.jaci.2010.03.039 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 627SE UT WOS:000280061800040 ER PT J AU Moskowitz, SM Garber, E Chen, Y Clock, SA Tabibi, S Miller, AK Doctor, M Saiman, L AF Moskowitz, Samuel M. Garber, Elizabeth Chen, Yunhua Clock, Sarah A. Tabibi, Setareh Miller, Amanda K. Doctor, Michael Saiman, Lisa TI Colistin susceptibility testing: evaluation of reliability for cystic fibrosis isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE peptide antibiotics; polymyxins; antibiotic resistance; disc diffusion; MICs ID CATIONIC ANTIMICROBIAL PEPTIDES; 2-COMPONENT REGULATORY SYSTEM; IN-VITRO ACTIVITY; POLYMYXIN-B; AGAR DILUTION; RESISTANCE; DIFFUSION; AGENTS; ETEST; METHANESULFONATE AB Objectives: Antibiotic susceptibility methods that are commonly used to test bacterial isolates from patients with cystic fibrosis are of uncertain reliability for the polymyxins. To assess the reliability of four standard testing methods, this pilot study used a challenge set that included polymyxin-resistant isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia. Methods: Twenty-five P. aeruginosa and 12 S. maltophilia isolates were tested for susceptibility to colistin (polymyxin E). Repeatability (concordance of replicates performed concurrently), reproducibility (concordance of replicates performed over time) and comparability (concordance of different methods) of agar dilution, broth microdilution, Etest and disc diffusion were assessed through the use of descriptive statistics and scatterplot analyses. Results: All four methods displayed excellent repeatability (overall concordance rate of 99%). However, analysis of reproducibility revealed substantially lower rates of concordance (74% for agar dilution, 84% for broth microdilution and Etest, and 91% for disc diffusion). In addition, comparability to agar dilution of the three other methods was generally poor, with overall rates of very major error ranging from 12% for broth microdilution to 18% for Etest and disc diffusion. Conclusions: Compared with agar dilution, other susceptibility testing methods give high rates of apparent false polymyxin susceptibility for cystic fibrosis isolates of P. aeruginosa and S. maltophilia. Prospective study of the correlation between in vitro susceptibility and clinical response is needed to clarify whether these discrepancies reflect oversensitivity of the agar dilution method or insensitivity of the other methods. C1 [Moskowitz, Samuel M.; Miller, Amanda K.] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Garber, Elizabeth; Chen, Yunhua; Clock, Sarah A.; Tabibi, Setareh; Doctor, Michael; Saiman, Lisa] Columbia Univ, Dept Pediat, New York, NY 10027 USA. RP Moskowitz, SM (reprint author), Massachusetts Gen Hosp, Div Pediat Pulm Med, 175 Cambridge St, Boston, MA 02114 USA. EM smoskowitz@partners.org FU NIH [R01 AI067653]; France Foundation; Chiesi Pharmaceuticals; Bayer FX This work was supported by a grant from the NIH to S. M. M. (R01 AI067653).; S. M. M. and L. S. have received lecture fees from the France Foundation, a third-party sponsor of continuing medical education activities. L. S. has received grant support from Chiesi Pharmaceuticals and Bayer, and has served on advisory boards to Chiesi, Novartis, Gilead, Axio and Transave. All other authors: none to declare. NR 36 TC 16 Z9 16 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD JUL PY 2010 VL 65 IS 7 BP 1416 EP 1423 DI 10.1093/jac/dkq131 PG 8 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 625WC UT WOS:000279926500017 PM 20430789 ER PT J AU Matsuo, M Kato, F Oogai, Y Kawai, T Sugai, M Komatsuzawa, H AF Matsuo, Miki Kato, Fuminori Oogai, Yuichi Kawai, Toshihisa Sugai, Motoyuki Komatsuzawa, Hitoshi TI Distinct two-component systems in methicillin-resistant Staphylococcus aureus can change the susceptibility to antimicrobial agents SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Letter DE antimicrobial peptides; cell wall inhibitors; gene regulation C1 [Matsuo, Miki; Oogai, Yuichi; Komatsuzawa, Hitoshi] Kagoshima Univ, Dept Oral Microbiol, Sch Med & Dent Sci, Kagoshima 8908544, Japan. [Kato, Fuminori; Sugai, Motoyuki] Hiroshima Univ, Dept Bacteriol, Grad Sch Biomed Sci, Hiroshima 7348553, Japan. [Kawai, Toshihisa] Forsyth Inst, Dept Immunol, Boston, MA USA. RP Komatsuzawa, H (reprint author), Kagoshima Univ, Dept Oral Microbiol, Sch Med & Dent Sci, Sakuragaoka 8-35-1, Kagoshima 8908544, Japan. EM hkomatsu@dent.kagoshima-u.ac.jp FU NIDCR NIH HHS [DE-18310] NR 5 TC 15 Z9 15 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD JUL PY 2010 VL 65 IS 7 BP 1536 EP 1537 DI 10.1093/jac/dkq141 PG 2 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 625WC UT WOS:000279926500037 PM 20430791 ER PT J AU Kellogg, DL Zhao, JL Wu, YB Johnson, JM AF Kellogg, Dean L., Jr. Zhao, Joan L. Wu, Yubo Johnson, John M. TI VIP/PACAP receptor mediation of cutaneous active vasodilation during heat stress in humans SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE laser-Doppler flowmetry; VPAC2; PAC1; thermoregulation; microdialysis ID VASOACTIVE-INTESTINAL-PEPTIDE; CYCLASE-ACTIVATING POLYPEPTIDE; HUMAN-SKIN; CYSTIC-FIBROSIS; CARDIOVASCULAR ADJUSTMENTS; VASCULAR-RESPONSES; VPAC RECEPTORS; MESSENGER-RNA; SWEAT GLANDS; BLOOD-FLOW AB Kellogg DL Jr, Zhao JL, Wu Y, Johnson JM. VIP/PACAP receptor mediation of cutaneous active vasodilation during heat stress in humans. J Appl Physiol 109: 95-100, 2010. First published April 15, 2010; doi:10.1152/japplphysiol.01187.2009.-Vasoactive intestinal peptide (VIP) is implicated in cutaneous active vasodilation in humans. VIP and the closely related pituitary adenylate cyclase activating peptide (PACAP) act through several receptor types: VIP through VPAC1 and VPAC2 receptors and PACAP through VPAC1, VPAC2, and PAC1 receptors. We examined participation of VPAC2 and/or PAC1 receptors in cutaneous vasodilation during heat stress by testing the effects of their specific blockade with PACAP6-38. PACAP6-38 dissolved in Ringer's was administered by intradermal microdialysis at one forearm site while a control site received Ringer's solution. Skin blood flow was monitored by laser-Doppler flowmetry (LDF). Blood pressure was monitored noninvasively and cutaneous vascular conductance (CVC) calculated. A 5- to 10-min baseline period was followed by similar to 70 min of PACAP6-38 (100 mu M) perfusion at one site in normothermia and a 3-min period of body cooling. Whole body heating was then performed to engage cutaneous active vasodilation and was maintained until CVC had plateaued at an elevated level at all sites for 5-10 min. Finally, 58 mM sodium nitroprusside was perfused through both microdialysis sites to effect maximal vasodilation. No CVC differences were found between control and PACAP6-38-treated sites during normothermia (19 +/- 3%max untreated vs. 20 +/- 3%max, PACAP6-38 treated; P > 0.05 between sites) or cold stress (11 +/- 2%max untreated vs. 10 +/- 2%max, PACAP6-38 treated, P > 0.05 between sites). PACAP6-38 attenuated the increase in CVC during whole body heating when compared with untreated sites (59 +/- 3%max untreated vs. 46 +/- 3%max, PACAP6-38 treated, P < 0.05). We conclude that VPAC2 and/or PAC1 receptor activation is involved in cutaneous active vasodilation in humans. C1 [Kellogg, Dean L., Jr.; Zhao, Joan L.; Wu, Yubo] Univ Texas Hlth Sci Ctr San Antonio, Div Geriatr & Gerontol, Dept Med, San Antonio, TX 78229 USA. [Kellogg, Dean L., Jr.; Johnson, John M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Physiol, San Antonio, TX 78229 USA. [Kellogg, Dean L., Jr.; Zhao, Joan L.; Wu, Yubo] Univ Texas Hlth Sci Ctr San Antonio, Ctr Geriatr Res Educ & Clin, Dept Vet Affairs, Audie L Murphy Mem Vet Hosp Div, San Antonio, TX 78229 USA. RP Kellogg, DL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Geriatr & Gerontol, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM kelloggd@uthscsa.edu FU National Heart, Lung, and Blood Institute [HL-065599] FX This work was supported in part by National Heart, Lung, and Blood Institute Grant HL-065599. NR 54 TC 18 Z9 19 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD JUL PY 2010 VL 109 IS 1 BP 95 EP 100 DI 10.1152/japplphysiol.01187.2009 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 617OY UT WOS:000279291500013 PM 20395540 ER PT J AU Spencer, TJ Adler, LA Qiao, MH Saylor, KE Brown, TE Holdnack, JA Schuh, KJ Trzepacz, PT Kelsey, DK AF Spencer, Thomas J. Adler, Lenard A. Qiao, Meihua Saylor, Keith E. Brown, Thomas E. Holdnack, James A. Schuh, Kory J. Trzepacz, Paula T. Kelsey, Douglas K. TI Validation of the Adult ADHD Investigator Symptom Rating Scale (AISRS) SO JOURNAL OF ATTENTION DISORDERS LA English DT Article DE atomoxetine; clinical improvement; hyperactivity; attention deficit ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; VALIDITY; COEFFICIENT; RELIABILITY; ATOMOXETINE; CHILDREN; PLACEBO; VERSION; TRIAL AB Objective: Validation of the Adult ADHD Investigator Symptom Rating Scale (AISRS) that measures aspects of ADHD in adults. Method: Psychometric properties of the AISRS total and AISRS subscales are analyzed and compared to the Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) and the Clinical Global Impression-ADHD-Severity Scale using data from a placebo-controlled 6-month clinical trial of once-daily atomoxetine. Results: The AISRS has high internal consistency, good convergent, and discriminant validities; modest divergent validity; and small ceiling and floor effects (<= 1%). It correlates highly with the CAARS-Inv:SV. Factor analysis confirms 2 AISRS subscales, hyperactivity-impulsive scale and inattention. The AISRS total and AISRS subscales perform stably. All scales demonstrate responsiveness to change with medication. Conclusion: The AISRS and its subscales are robust, valid efficacy measures of ADHD symptoms in adult patients. Its anchored items and semistructured interview are advancements over existing scales. (J. of Att. Dis. 2010; 14(1) 57-68). C1 [Spencer, Thomas J.] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Adler, Lenard A.] NYU, Sch Med, New York, NY USA. [Qiao, Meihua; Schuh, Kory J.; Kelsey, Douglas K.] Lilly USA LLC, Indianapolis, IN USA. [Saylor, Keith E.] NeuroScience Inc, Herndon, VA USA. [Brown, Thomas E.] Yale Univ, Sch Med, Hamden, CT USA. [Holdnack, James A.] Harcourt Assessment Inc, Bear, DE USA. [Trzepacz, Paula T.] Lilly Res Labs, Indianapolis, IN USA. RP Spencer, TJ (reprint author), Harvard Univ, Sch Med, 55 Fruit St,Warren 705, Boston, MA 02114 USA. EM SPENCER@HELIX.MGH.HARVARD.EDU OI Adler, Len/0000-0002-9812-8234 NR 31 TC 31 Z9 31 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0547 J9 J ATTEN DISORD JI J. Atten. Disord. PD JUL PY 2010 VL 14 IS 1 BP 57 EP 68 DI 10.1177/1087054709347435 PG 12 WC Psychology, Developmental; Psychiatry SC Psychology; Psychiatry GA 615DX UT WOS:000279114700008 PM 19794135 ER PT J AU Pai, S Ledoux, WR AF Pai, Shruti Ledoux, William R. TI The Effect of Target Strain Error on Plantar Tissue Stress SO JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME LA English DT Article DE overshoot; diabetes; subcutaneous; soft tissue; viscoelastic ID VISCOELASTIC PROPERTIES; RELAXATION; LIGAMENTS; PAD AB Accurate quantification of soft tissue properties, specifically the stress relaxation behavior of viscoelastic tissues such as plantar tissue, requires precise testing under physiologically relevant loading. However limitations of testing equipment often result in target strain errors that can contribute to large stress errors and confound comparative results to an unknown extent. Previous investigations have modeled this artifact, but they have been unable to obtain empirical data to validate their models. Moreover, there are no studies that address this issue for plantar tissue. The purpose of this research was to directly measure the difference in peak force for a series of small target strain errors within the range of our typical stress relaxation experiments for the subcutaneous plantar soft tissue. Five plantar tissue specimens were tested to seven incremental target strain error levels of 0.9%, 0.6%, 0.3%, 0.0%, 0.3%, 0.6%, and 0.9%, so as to undershoot and overshoot the target displacement in 0.3% increments. The imposed straits errors were accurately attained using a special compensation feature of our materials testing software that can drive the actuator to within 0% (1-2 mu m) of the target level for cyclic tests. Since stress relaxation tests are not cyclic, we emulated the ramp portion of our stress relaxation tests with 5 Hz triangle waves. The average total stress variation for all specimens was 25 +/- 5%, with the highest and lowest stresses corresponding to the largest and smallest strain errors 40.9% and 0.9%, respectively. A strain overshoot of 0.3%, the target strain error observed in our typical stress relaxation experiments, corresponded to an average stress overshoot of 3 +/- 1%. Plantar tissue in compression is sensitive to small target strain errors that can result its stress errors that are several fold larger The extent to which the overshoot may affect the peak stress will likely differ in magnitude for other soft tissues and loading modes. [DOI: 10.1115/1.4001398] C1 [Pai, Shruti; Ledoux, William R.] VA RR&D Ctr Excellence Limb Loss Prevent & Prosth, Seattle, WA 98108 USA. [Pai, Shruti; Ledoux, William R.] Univ Washington, Dept Mech Engn, Seattle, WA 98195 USA. [Pai, Shruti; Ledoux, William R.] VA Puget Sound, Seattle, WA 98108 USA. [Ledoux, William R.] Univ Washington, Dept Orthopaed & Sports Med, Seattle, WA 98195 USA. RP Ledoux, WR (reprint author), VA RR&D Ctr Excellence Limb Loss Prevent & Prosth, Seattle, WA 98108 USA. EM shruti.pai@gmail.com; wrledoux@u.washington.edu RI Ledoux, William/K-6815-2015 OI Ledoux, William/0000-0003-4982-7714 FU NIH [1R01 DK75633-03]; Department of Veterans Affairs, RRD Service FX This study was supported by NIH under Grant No. 1R01 DK75633-03 and the Department of Veterans Affairs, RR&D Service. NR 14 TC 4 Z9 4 U1 0 U2 1 PU ASME-AMER SOC MECHANICAL ENG PI NEW YORK PA THREE PARK AVE, NEW YORK, NY 10016-5990 USA SN 0148-0731 J9 J BIOMECH ENG-T ASME JI J. Biomech. Eng.-Trans. ASME PD JUL PY 2010 VL 132 IS 7 AR 071001 DI 10.1115/1.4001398 PG 4 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 622AW UT WOS:000279631400001 PM 20590279 ER PT J AU Raymond, SB Boas, DA Bacskai, BJ Kumar, ATN AF Raymond, Scott B. Boas, David A. Bacskai, Brian J. Kumar, Anand T. N. TI Lifetime-based tomographic multiplexing SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE near-infrared fluorescence; tomography; lifetime; small animal imaging ID DIFFUSE OPTICAL TOMOGRAPHY; FLUORESCENCE MOLECULAR TOMOGRAPHY; IN-VIVO; TURBID MEDIA; CONTRAST; SYSTEM; RESOLUTION AB Near-infrared (NIR) fluorescence tomography of multiple fluorophores has previously been limited by the bandwidth of the NIR spectral regime and the broad emission spectra of most NIR fluorophores. We describe in vivo tomography of three spectrally overlapping fluorophores using fluorescence lifetime-based separation. Time-domain images are acquired using a voltage-gated, intensified charge-coupled device (CCD) in free-space transmission geometry with 750 nm Ti:sapphire laser excitation. Lifetime components are fit from the asymptotic portion of fluorescence decay curve and reconstructed separately with a lifetime-adjusted forward model. We use this system to test the in vivo lifetime multiplexing suitability of commercially available fluorophores, and demonstrate lifetime multiplexing in solution mixtures and in nude mice. All of the fluorophores tested exhibit nearly monoexponential decays, with narrow in vivo lifetime distributions suitable for lifetime multiplexing. Quantitative separation of two fluorophores with lifetimes of 1.1 and 1.37 ns is demonstrated for relative concentrations of 1:5. Finally, we demonstrate tomographic imaging of two and three fluorophores in nude mice with fluorophores that localize to distinct organ systems. This technique should be widely applicable to imaging multiple NIR fluorophores in 3-D. (C) 2010 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3469797] C1 [Boas, David A.; Kumar, Anand T. N.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Raymond, Scott B.] Harvard Mit Div Hlth Sci & Technol, Charlestown, MA 02129 USA. [Bacskai, Brian J.] Massachusetts Gen Hosp, Dept Neurol, Alzheimers Res Unit, Charlestown, MA 02129 USA. RP Kumar, ATN (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, 149 13th St, Charlestown, MA 02129 USA. EM ankumar@nmr.mgh.harvard.edu OI Raymond, Scott/0000-0001-7008-8974 FU NIH [EB000768, AG026240, T32 EB001680] FX This research was supported by NIH EB000768 and AG026240. Raymond was supported by NIH T32 EB001680. NR 30 TC 19 Z9 19 U1 0 U2 9 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD JUL-AUG PY 2010 VL 15 IS 4 AR 046011 DI 10.1117/1.3469797 PG 9 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 643XZ UT WOS:000281335400046 PM 20799813 ER PT J AU Cheung, CL Livshits, G Zhou, YH Meigs, JB McAteer, JB Florez, JC Cupples, LA Demissie, S Kiel, DP Karasik, D AF Cheung, Ching-Lung Livshits, Gregory Zhou, Yanhua Meigs, James B. McAteer, Jarred B. Florez, Jose C. Cupples, L. Adrienne Demissie, Serkalem Kiel, Douglas P. Karasik, David TI Hip Geometry Variation Is Associated With Bone Mineralization Pathway Gene Variants: The Framingham Study SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE MINERALIZATION; ENPP1; ALPL; ANKH; BONE GEOMETRY; BONE MINERAL DENSITY; ASSOCIATION ID QUANTITATIVE TRAIT LOCI; ARTERIAL CALCIFICATION; GENOME SCREEN; ENPP1 GENE; ANKH GENE; LOW BMD; DENSITY; POLYMORPHISMS; RISK; OSTEOPOROSIS AB Mineralization of bone matrix is an important process in bone formation; thus defects in mineralization have been implicated in bone mineral density (BMD) and bone structure alterations. Three central regulators of phosphate balance, ALPL, ANKH, and ENPP1, are central in the matrix mineralization process; therefore, the genes encoding them are considered important candidates genes for BMD and bone geometry. To test for an association between these three candidate genes and BMD and bone geometry traits, 124 informative single-nucleotide polymorphisms (SNPs) were selected and genotyped in 1513 unrelated subjects from the Framingham offspring cohort. Initial results showed that SNP rs1974201 in the gene ENPP1 was a susceptibility variant associated with several hip geometric indices, with the strongest p value of 3.8 x 10(-7) being observed for femoral neck width. A few modest associations were observed between SNPs in or near ALPL and several bone traits, but no association was observed with ANKH. The association signals observed for SNPs around rs1974201 were attenuated after conditional analysis on rs1974201. Transcription factor binding-site prediction revealed that the HOXA7 binding site was present in the reference sequence with the major allele, whereas this potential binding site is lost in the sequence with the minor allele of rs1974201. In conclusion, we found evidence for association of bone geometry variation with an SNP in ENPP1, a gene in the mineralization pathway. The alteration of a binding site of the deregulator of extracellular matrix HOXA7 warrants further investigation. (C) 2010 American Society for Bone and Mineral Research. C1 [Cheung, Ching-Lung; Kiel, Douglas P.; Karasik, David] Harvard Univ, Sch Med, Hebrew SeniorLife Inst Aging Res, Boston, MA 02131 USA. [Livshits, Gregory] Tel Aviv Univ, Sackler Fac Med, Dept Anat & Anthropol, Human Populat Biol Res Unit, IL-69978 Tel Aviv, Israel. [Zhou, Yanhua; Cupples, L. Adrienne; Demissie, Serkalem] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Meigs, James B.; McAteer, Jarred B.; Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet, Boston, MA 02114 USA. [Meigs, James B.; McAteer, Jarred B.; Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Meigs, James B.; Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02131 USA. [McAteer, Jarred B.; Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Cupples, L. Adrienne] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. RP Karasik, D (reprint author), Harvard Univ, Sch Med, Hebrew SeniorLife Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. EM karasik@hrca.harvard.edu RI CHEUNG, Ching-Lung/C-2529-2012; OI Kiel, Douglas/0000-0001-8474-0310; Karasik, David/0000-0002-8826-0530; Cheung, Ching Lung/0000-0002-6233-9144 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Diabetes Association; NIDDK [K24 DK080140]; NHLBI [1U01 HL066582]; National Institute on Arthritis Musculoskeletal and Skin Diseases; National Institute on Aging [R01 AR/AG 41398, R01 AR 050066, AR 057118]; Men's Associates of Hebrew SeniorLife; Massachusetts General Hospital; Doris Duke Charitable Foundation FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), an American Diabetes Association Career Development Award, and NIDDK K24 DK080140 (JBM), NHLBI 1U01 HL066582, and grants from the National Institute on Arthritis Musculoskeletal and Skin Diseases, and the National Institute on Aging Grants R01 AR/AG 41398 (DPK) and R01 AR 050066 and AR 057118 (DK). The postdoctoral fellowship of CLC is generously supported by the Men's Associates of Hebrew SeniorLife. JCF is supported by a Massachusetts General Hospital Physician Scientist Development Award and a Doris Duke Charitable Foundation Clinical Scientist Development Award. NR 52 TC 11 Z9 11 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 2010 VL 25 IS 7 BP 1564 EP 1571 DI 10.1359/jbmr.091102 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 632BU UT WOS:000280395900012 PM 19888898 ER PT J AU Rogers, IS Cury, RC Blankstein, R Shapiro, MD Nieman, K Hoffmann, U Brady, TJ Abbara, S AF Rogers, Ian S. Cury, Ricardo C. Blankstein, Ron Shapiro, Michael D. Nieman, Koen Hoffmann, Udo Brady, Thomas J. Abbara, Suhny TI Comparison of postprocessing techniques for the detection of perfusion defects by cardiac computed tomography in patients presenting with acute ST-segment elevation myocardial infarction SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article DE Cardiac computed tomography; Minimum intensity projection; Postprocessing techniques; ST-segment myocardial infarction AB BACKGROUND: Despite rapid advances in cardiac computed tomography (CT), a strategy for optimal visualization of perfusion abnormalities on CT has yet to be validated. OBJECTIVE: We evaluated the performance of several postprocessing techniques of source data sets to detect and characterize perfusion defects in acute myocardial infarctions with cardiac CT. METHODS: Twenty-one subjects (18 men; 60 +/- 13 years) that were successfully treated with percutaneous coronary intervention for ST-segment myocardial infarction underwent 64-slice cardiac CT and 1.5 Tesla cardiac magnetic resonance imaging (MRI) scans after revascularization. Delayed enhancement MR images were analyzed to identify the location of infarcted myocardium. Contiguous short-axis images of the left ventricular myocardium were created from the CT source images with 0.75-mm multiplanar reconstruction (MPR), 5-mm MPR, 5-mm maximal intensity projection (MIP), and 5-mm minimum intensity projection (MinIP) techniques. Segments already confirmed to contain infarction by MRI were then evaluated qualitatively and quantitatively with CT. RESULTS: Overall, 143 myocardial segments were analyzed. On qualitative analysis, the MinIP and thick MPR techniques had greater visibility and definition than the thin MPR and MIP techniques (P < 0.001). On quantitative analysis, the absolute difference in Hounsfield unit attenuation between normal and infarcted segments was significantly greater for the MinIP (65.4 Hounsfield unit [HU]) and thin MPR (61.2 HU) techniques. However, the relative difference in Hounsfield unit attenuation was significantly greatest for the MinIP technique alone (95%; P < 0.001). Contrast to noise was greatest for the MinIP (4.2) and thick MPR (4.1) techniques (P < 0.001). CONCLUSION: The results of our current investigation found that MinIP and thick MPR detected infarcted myocardium with greater visibility and definition than MIP and thin MPR. (c) 2010 Society of Cardiovascular Computed Tomography. All rights reserved. C1 [Rogers, Ian S.; Cury, Ricardo C.; Blankstein, Ron; Shapiro, Michael D.; Nieman, Koen; Hoffmann, Udo; Abbara, Suhny] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Rogers, Ian S.; Cury, Ricardo C.; Blankstein, Ron; Shapiro, Michael D.; Nieman, Koen; Hoffmann, Udo; Abbara, Suhny] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Rogers, Ian S.; Cury, Ricardo C.; Blankstein, Ron; Shapiro, Michael D.; Nieman, Koen; Hoffmann, Udo; Brady, Thomas J.; Abbara, Suhny] Harvard Univ, Sch Med, Boston, MA USA. [Rogers, Ian S.] Stanford Univ, Div Cardiovasc Med, Stanford, CA 94305 USA. RP Abbara, S (reprint author), Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM sabbara@partners.org FU Bracco; National Institutes of Health [T32HL076136] FX Dr Abbara has consulted with Partners Imaging, Magellan Healthcare, Perceptive Informatics and has received research funding from Bracco. The remaining authors report no conflicts of interest.; Drs. Rogers, Blankstein, and Shapiro received support for this study from National Institutes of Health grant T32HL076136. NR 18 TC 15 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD JUL-AUG PY 2010 VL 4 IS 4 BP 258 EP 266 DI 10.1016/j.jcct.2010.04.003 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA V26BQ UT WOS:000208521500005 PM 20579617 ER PT J AU Shapiro, MD Sarwar, A Nieman, K Nasir, K Brady, TJ Cury, RC AF Shapiro, Michael D. Sarwar, Ammar Nieman, Koen Nasir, Khurram Brady, Thomas J. Cury, Ricardo C. TI Cardiac computed tomography for prediction of myocardial viability after reperfused acute myocardial infarction SO JOURNAL OF CARDIOVASCULAR COMPUTED TOMOGRAPHY LA English DT Article DE Magnetic resonance imaging; Multidetector computed tomography; Myocardial infarction; Revascularization; Viability AB BACKGROUND: Perfusion defects (PDs) detected with cardiac magnetic resonance (CMR) imaging predict the functional recovery of myocardial function after acute myocardial infarction. OBJECTIVE: We evaluated the ability of cardiac computed tomography (CCT) to predict the recovery of regional left ventricular (LV) systolic function after ST elevation myocardial infarction (STEMI). METHODS: Seventeen patients (mean age, 60 +/- 10 years) presenting with STEMI were prospectively studied. Each patient underwent CCT and CMR at baseline and after an average of 6 months. Areas of PD were quantified. Segmental LV systolic function was semiquantitatively assessed by CMR. An improvement at 6 months by >= 1 category in the regional wall motion score was considered LV recovery. RESULTS: Coronary artery revascularization was successfully performed with postprocedural TIMI 3 flow in 16 cases. On CCT assessment, 107 of 289 segments (37%) had some degree of PD. On follow-up, segments with <25% PD at baseline had no worsening of wall motion. In segments with >75% PD, 89% (9 of 11) showed akinesis or worsening of wall motion. The odds ratio for improvement in segmental wall motion with increasing PD category was 0.63 (95% CI, 0.42-0.97; P = 0.035). The degree of PD on CT predicted LV recovery at follow-up (P < 0.0001). CONCLUSIONS: The transmural extent of myocardial infarction as detected and quantified with CCT predicts the recovery of regional systolic LV function after revascularization for acute STEMI. (C) 2010 Society of Cardiovascular Computed Tomography. All rights reserved. C1 [Shapiro, Michael D.; Sarwar, Ammar; Nieman, Koen; Nasir, Khurram; Brady, Thomas J.; Cury, Ricardo C.] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Sarwar, Ammar] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Shapiro, Michael D.] Oregon Hlth & Sci Univ, Div Cardiovasc Med, Portland, OR 97201 USA. [Cury, Ricardo C.] Baptist Cardiac & Vasc Inst, Cardiovasc MR & CT Program, Miami, FL 33176 USA. RP Cury, RC (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. EM rcury@baptisthealth.net FU NIH [1T32 HL076136-02] FX Dr. Shapiro and Dr. Nasir have received support from NIH grant 1T32 HL076136-02. NR 22 TC 9 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-5925 J9 J CARDIOVASC COMPUT JI J. Cardiovasc. Comput. Tomogr. PD JUL-AUG PY 2010 VL 4 IS 4 BP 267 EP 273 DI 10.1016/j.jcct.2010.04.004 PG 7 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA V26BQ UT WOS:000208521500006 PM 20580906 ER PT J AU Ahmed, H Neuzil, P Skoda, J D'Avila, A Donaldson, DM Laragy, MC Reddy, VY AF Ahmed, Humera Neuzil, Petr Skoda, Jan D'Avila, Andre Donaldson, David M. Laragy, Margaret C. Reddy, Vivek Y. TI The Permanency of Pulmonary Vein Isolation Using a Balloon Cryoablation Catheter SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE atrial fibrillation; catheter ablation; cryoablation; pulmonary veins ID CIRCUMFERENTIAL ULTRASOUND ABLATION; ATRIAL-FIBRILLATION; LONG-TERM; RADIOFREQUENCY ABLATION; ANTRUM ISOLATION; CONDUCTION; RESUMPTION; ANATOMY; OSTIUM AB Methods and Results: Twelve atrial fibrillation patients underwent PV isolation using either a 23-mm or 28-mm cryoballoon. For each vein, after electrical isolation was verified with the use of a circular mapping cathether, 2 bonus balloon ablation lesions were placed. Gaps in balloon occlusion were overcome using either a spot cryocatheter or a "pull-down" technique. A prespecified second procedure was performed at 8-12 weeks to assess for long-term PV isolation. Acute PV isolation was achieved in all PVs in the patient cohort (n = 48 PVs), using the cryoballoon alone in 47/48 PVs (98%); a "pull-down" technique was employed for 5 PVs (1 right superior pulmonary vein, 2 right inferior pulmonary veins, and 2 left inferior pulmonary veins). The gap in the remaining vein was ablated with a spot cryocatheter. During the second mapping procedure, 42 of 48 PVs (88%) remained isolated. One vein had reconnected in 2 patients, while 2 veins had reconnected in another 2 patients. All PVs initially isolated with the "pull-down" technique remained isolated at the second procedure. Conclusions: Cryoballoon ablation allows for durable PV isolation with the use of a single balloon. With maintained chronic isolation in most PVs, it may represent a significant step toward consistent and lasting ablation procedures. (J Cardiovasc Electrophysiol, Vol. pp. 731-737, July 2010). C1 [Reddy, Vivek Y.] Mt Sinai Hosp, Mt Sinai Sch Med, Cardiac Arrhythmia Serv, Zena & Michael A Weiner Cardiovasc Inst, New York, NY 10029 USA. [Neuzil, Petr; Skoda, Jan; Reddy, Vivek Y.] Homolka Hosp, Cardiac Arrhythmia Serv, Prague, Czech Republic. [Donaldson, David M.; Laragy, Margaret C.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. RP Reddy, VY (reprint author), Mt Sinai Hosp, Mt Sinai Sch Med, Cardiac Arrhythmia Serv, Zena & Michael A Weiner Cardiovasc Inst, 1 Gustave L Levy Pl,Box 1030, New York, NY 10029 USA. EM vivek.reddy@mountsinai.org RI d'Avila, Andre Luiz/F-8009-2010; d'Avila, Andre/A-7693-2009 OI d'Avila, Andre Luiz/0000-0001-8769-1411; FU Cryocath Technologies, Inc FX V. Reddy and P. Neuzil have received research grant support from Cryocath Technologies, Inc. NR 26 TC 37 Z9 39 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-3873 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD JUL PY 2010 VL 21 IS 7 BP 731 EP 737 DI 10.1111/j.1540-8167.2009.01703.x PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 615VU UT WOS:000279166900001 PM 20132391 ER PT J AU Thiagalingam, A D'Avila, A Foley, L Guerrero, JL Lambert, H Leo, G Ruskin, JN Reddy, VY AF Thiagalingam, Aravinda D'Avila, Andre Foley, Lori Guerrero, J. Luis Lambert, Hendrik Leo, Giovanni Ruskin, Jeremy N. Reddy, Vivek Y. TI Importance of Catheter Contact Force During Irrigated Radiofrequency Ablation: Evaluation in a Porcine Ex Vivo Model Using a Force-Sensing Catheter SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE ablation; arrhythmia; atrial fibrillation; irrigated-tip catheter; ventricular tachycardia ID ELECTRODE-TISSUE CONTACT; LESION SIZE; ENDOCARDIAL CONTACT; IN-VITRO; IMPEDANCE; TIP; DIMENSIONS; SYSTEM; SAFETY AB Methods and Results: Freshly excised hearts from 11 male pigs were perfused and superfused using fresh, heparinized, oxygenated swine blood in an ex vivo model. One-minute ablations were placed using one of 3 different power control strategies (impedance control-15 target impedance drop, and 20 W or 30 W fixed power) and 3 different contact forces (2 g, 20 g, and 60 g) to give a grid of 9 ablation groups. The force sensing catheter (Tacticath (TM), Endosense SA) was irrigated at 17 mL/min for all of the ablations. Of a total 101 ablations, no thrombus formation was noted but popping was seen in 17 lesions. The lesion depth and incidence of pops was 5.0 +/- 1.3 mm /0%, 5.0 +/- 1.6 mm /10% and 6.7 +/- 2.5 mm /45% for the 15 , 20 W, and 30 W groups (P < 0.01), respectively, and 4.4 +/- 1.8 mm /3%, 5.8 +/- 1.6 mm /17% and 6.6 +/- 2.0 mm /37% for the 2 g, 20 g, and 60 g groups, respectively (P < 0.01). The impedance drop in the first 5 seconds was significantly correlated to catheter contact force: 9.7 +/- 9.9 , 22.3 +/- 11.0 , and 41.7 +/- 22.1 , respectively, for the 2 g, 20 g, and 60 g groups (Pearson's r = 0.65, P < 0.01). Conclusion: Catheter contact force has an important impact on both ablation lesion size and the incidence of pops. (J Cardiovasc Electrophysiol, Vol. pp. 806-811, July 2010). C1 [Thiagalingam, Aravinda; D'Avila, Andre; Ruskin, Jeremy N.; Reddy, Vivek Y.] Massachusetts Gen Hosp, Cardiac Electrophysiol Dept, Boston, MA 02114 USA. Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Cardiovasc Surg Unit, Boston, MA 02114 USA. [Lambert, Hendrik; Leo, Giovanni] Endosense SA Endosense SA 42, Geneva, Switzerland. RP Reddy, VY (reprint author), Mt Sinai Sch Med, Cardiac Arrhythmia Serv, 1 Gustave L Levy Pl,Box 1030, New York, NY 10029 USA. EM Vivek.reddy@mountsinai.org RI d'Avila, Andre Luiz/F-8009-2010; d'Avila, Andre/A-7693-2009 OI d'Avila, Andre Luiz/0000-0001-8769-1411; FU NHLBI NIH HHS [HL68064] NR 18 TC 105 Z9 107 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-3873 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD JUL PY 2010 VL 21 IS 7 BP 806 EP 811 DI 10.1111/j.1540-8167.2009.01693.x PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 615VU UT WOS:000279166900014 PM 20132400 ER PT J AU Wang, Y Lin, HH Lin, SQ Qu, J Xiao, JA Huang, YD Xiao, YC Fu, XB Yang, YG Li, XK AF Wang, Yi Lin, Haihuan Lin, Shaoqiang Qu, Jia Xiao, Jian Huang, Yadong Xiao, Yechen Fu, Xiaobing Yang, Yongguang Li, Xiaokun TI Cell-penetrating peptide TAT-mediated delivery of acidic FGF to retina and protection against ischemia-reperfusion injury in rats SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE cell-penetrating peptide; fibroblast growth factor; ischemia and reperfusion injury; retina; transactivator of transcription peptide ID FIBROBLAST-GROWTH-FACTOR; VIVO PROTEIN TRANSDUCTION; BLOOD-BRAIN-BARRIER; MYOCARDIAL-ISCHEMIA; EXPRESSION; AFGF; APOPTOSIS; CORNEA; MOUSE; MODEL AB The development of non-invasive ocular drug delivery systems is of practical importance in the treatment of retinal disease. In this study, we evaluated the efficacy of transactivator of transcription protein transduction domain (TAT-PTD, TAT(49-57)) as a vehicle to deliver acidic FGF (aFGF) to retina in rats. TAT-conjugated aFGF-His (TAT-aFGF-His) exhibited efficient penetration into the retina following topical administration to the ocular surface. Immunochemical staining with anti-His revealed that TAT-aFGF-His proteins were readily found in the retina (mainly in the ganglion cell layer) at 30 min. and remained detectable for at least 8 hrs after administration. In contrast, His+ proteins were undetectable in the retina after topical administration of aFGF-His, indicating that aFGF-His cannot penetrate the ocular barrier. Furthermore, TAT-aFGF-His, but not aFGF-His, mediated significant protection against retinal ischemia-reperfusion (IR) injury. After IR injury, retina from TAT-aFGF-His-treated rats showed better-maintained inner retinal layer structure, reduced apoptosis of retinal ganglion cells and improved retinal function compared to those treated with aFGF-His or PBS. These results indicate that conjugation of TAT to aFGF-His can markedly improve the ability of aFGF-His to penetrate the ocular barrier without impairing its biological function. Thus, TAT(49-57) provides a potential vehicle for efficient drug delivery in the treatment of retinal disease. C1 [Wang, Yi; Lin, Haihuan; Lin, Shaoqiang; Xiao, Jian; Li, Xiaokun] Wenzhou Med Coll, Sch Pharmaceut Sci, Key Lab Biotechnol Pharmaceut Engn Zhejiang Prov, Wenzhou, Zhejiang, Peoples R China. [Qu, Jia] Hosp Eye, Wenzhou Med Coll, Wenzhou, Zhejiang, Peoples R China. [Wang, Yi; Yang, Yongguang] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Huang, Yadong] Jinan Univ, Natl Engn Res Ctr Gene Med, Guangzhou, Guangdong, Peoples R China. [Xiao, Yechen] Jilin Agr Univ, Engn Res Ctr Bioreactor & Pharmaceut Dev, Minist Educ, Changchun, Peoples R China. [Fu, Xiaobing] Peoples Liberat Army Gen Hosp, Wound Healing & Cell Biol Lab, Inst Basic Med Sci, Postgrad Med Coll, Beijing, Peoples R China. RP Li, XK (reprint author), Wenzhou Med Coll, Sch Pharmaceut Sci, Key Lab Biotechnol Pharmaceut Engn Zhejiang Prov, Wenzhou, Zhejiang, Peoples R China. EM xiaokunli@163.net FU Zhejiang Province Extremely Key Subject Building; Zhejiang province key Natural Science Foundation [Z205755]; National Natural Scientific Foundation of China [30670541]; New Century Excellent Talents in University; Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents; National Basic Research Program of China [2005CB522603] FX The study was supported by grants from Zhejiang Province Extremely Key Subject Building Funding 'Pharmacology and Biochemical Pharmaceutics 2008' and Zhejiang province key Natural Science Foundation (Z205755 to X. L.), and National Natural Scientific Foundation of China (30670541 to Y.H.), The Program of New Century Excellent Talents in University, and Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents (X. L.), The National Basic Research Program of China (973 grant no. 2005CB522603) and by the 5010 Project of Wenzhou Medical College. NR 37 TC 18 Z9 20 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD JUL PY 2010 VL 14 IS 7 BP 1998 EP 2005 DI 10.1111/j.1582-4934.2009.00786.x PG 8 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 641PT UT WOS:000281141900012 PM 19432810 ER EF