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 uniq