FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Talkowski, ME Maussion, G Crapper, L Rosenfeld, JA Blumenthal, I Hanscom, C Chiang, C Lindgren, A Pereira, S Ruderfer, D Diallo, AB Lopez, JP Turecki, G Chen, ES Gigek, C Harris, DJ Lip, V An, Y Biagioli, M MacDonald, ME Lin, M Haggarty, SJ Sklar, P Purcell, S Kellis, M Schwartz, S Shaffer, LG Natowicz, MR Shen, YP Morton, CC Gusella, JF Ernst, C AF Talkowski, Michael E. Maussion, Gilles Crapper, Liam Rosenfeld, Jill A. Blumenthal, Ian Hanscom, Carrie Chiang, Colby Lindgren, Amelia Pereira, Shahrin Ruderfer, Douglas Diallo, Alpha B. Lopez, Juan Pablo Turecki, Gustavo Chen, Elizabeth S. Gigek, Carolina Harris, David J. Lip, Va An, Yu Biagioli, Marta MacDonald, Marcy E. Lin, Michael Haggarty, Stephen J. Sklar, Pamela Purcell, Shaun Kellis, Manolis Schwartz, Stuart Shaffer, Lisa G. Natowicz, Marvin R. Shen, Yiping Morton, Cynthia C. Gusella, James F. Ernst, Carl TI Disruption of a Large Intergenic Noncoding RNA in Subjects with Neurodevelopmental Disabilities SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENE-EXPRESSION; CHROMATIN; REARRANGEMENTS; REVEALS; GENOME AB Large intergenic noncoding (linc) RNAs represent a newly described class of ribonucleic acid whose importance in human disease remains undefined. We identified a severely developmentally delayed 16-year-old female with karyotype 46,XX,t(2;11)(p25.1;p15.1)dn in the absence of clinically significant copy number variants (CNVs). DNA capture followed by next-generation sequencing of the translocation breakpoints revealed disruption of a single noncoding gene on chromosome 2, LINC00299, whose RNA product is expressed in all tissues measured, but most abundantly in brain. Among a series of additional, unrelated subjects referred for clinical diagnostic testing who showed CNV affecting this locus, we identified four with exon-crossing deletions in association with neurodevelopmental abnormalities. No disruption of the LINC00299 coding sequence was seen in almost 14,000 control subjects. Together, these subjects with disruption of LINC00299 implicate this particular noncoding RNA in brain development and raise the possibility that, as a class, abnormalities of lincRNAs may play a significant role in human developmental disorders. C1 [Maussion, Gilles; Crapper, Liam; Diallo, Alpha B.; Lopez, Juan Pablo; Turecki, Gustavo; Chen, Elizabeth S.; Gigek, Carolina; Ernst, Carl] McGill Univ, Douglas Hosp, Res Inst, Dept Psychiat, Quebec City, ON H4H 1R3, Canada. [Talkowski, Michael E.; Blumenthal, Ian; Hanscom, Carrie; Chiang, Colby; Biagioli, Marta; MacDonald, Marcy E.; Haggarty, Stephen J.; Purcell, Shaun; Shen, Yiping; Ernst, Carl] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Talkowski, Michael E.; Biagioli, Marta; MacDonald, Marcy E.; Haggarty, Stephen J.; Gusella, James F.] Harvard Univ, Dept Neurol & Genet, Boston, MA 02114 USA. [Talkowski, Michael E.; MacDonald, Marcy E.; Lin, Michael; Purcell, Shaun; Kellis, Manolis; Morton, Cynthia C.; Gusella, James F.] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02114 USA. [Rosenfeld, Jill A.; Shaffer, Lisa G.] Signature Genom Inc, PerkinElmer, Spokane, WA 99207 USA. [Lindgren, Amelia; Pereira, Shahrin; Morton, Cynthia C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Lindgren, Amelia; Pereira, Shahrin; Morton, Cynthia C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ruderfer, Douglas; Sklar, Pamela; Purcell, Shaun] Mt Sinai Sch Med, Dept Psychiat & Genet, New York, NY 10029 USA. [Ruderfer, Douglas; Sklar, Pamela; Purcell, Shaun] Mt Sinai Sch Med, Dept Genom Sci, New York, NY 10029 USA. [Harris, David J.; Lip, Va; An, Yu; Shen, Yiping] Harvard Univ, Sch Med, Dept Lab Med, Boston Childrens Hosp, Boston, MA 02115 USA. [Harris, David J.; Lip, Va; Shen, Yiping] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [An, Yu] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China. [An, Yu] Fudan Univ, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Lin, Michael; Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02114 USA. [Schwartz, Stuart] Genzyme Genet Inc, Labcorp, Res Triangle Pk, NC 27709 USA. [Natowicz, Marvin R.] Cleveland Clin, Inst Pathol & Lab Med, Cleveland, OH 44195 USA. [Natowicz, Marvin R.] Cleveland Clin, Inst Genom Med, Cleveland, OH 44195 USA. [Shen, Yiping] Shanghai Jiao Tong Univ, Sch Med, Shanghai Childrens Med Ctr, Shanghai 200127, Peoples R China. [Natowicz, Marvin R.] Cleveland Clin, Inst Neurol & Pediat, Cleveland, OH 44195 USA. RP Ernst, C (reprint author), McGill Univ, Douglas Hosp, Res Inst, Dept Psychiat, Quebec City, ON H4H 1R3, Canada. EM carl.ernst@mcgill.ca RI Ruderfer, Douglas/M-5795-2016; OI Ruderfer, Douglas/0000-0002-2365-386X; Chiang, Colby/0000-0002-4113-6065; Chen, Elizabeth/0000-0002-3573-0164; Haggarty, Stephen J./0000-0002-7872-168X FU NIH [GM061354, HD065286, K99MH095867, R33MH087896]; Simons Foundation for Autism Research; Nancy Lurie Marks Family Foundation; Canada Institute of Health Research Canada Research Chair in Psychiatric Genetics FX We thank the subjects and their families for participating in this study. This work was funded by NIH GM061354 (J.F.G. and C.C.M.), HD065286 (J.F.G.), K99MH095867 (M.E.T.), and R33MH087896 (S.J.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. M.E.T. and J.F.G. are supported by the Simons Foundation for Autism Research and the Nancy Lurie Marks Family Foundation. C.E. is funded by a Canada Institute of Health Research Canada Research Chair in Psychiatric Genetics. NR 15 TC 24 Z9 24 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC 7 PY 2012 VL 91 IS 6 BP 1128 EP 1134 DI 10.1016/j.ajhg.2012.10.016 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 055LI UT WOS:000312417400018 PM 23217328 ER PT J AU Elbers, CC Guo, YR Tragante, V van Iperen, EPA Lanktree, MB Castillo, BA Chen, F Yanek, LR Wojczynski, MK Li, YR Ferwerda, B Ballantyne, CM Buxbaum, SG Chen, YDI Chen, WM Cupples, LA Cushman, M Duan, YA Duggan, D Evans, MK Fernandes, JK Fornage, M Garcia, M Garvey, WT Glazer, N Gomez, F Harris, TB Halder, I Howard, VJ Keller, MF Kamboh, MI Kooperberg, C Kritchevsky, SB LaCroix, A Liu, K Liu, YM Musunuru, K Newman, AB Onland-Moret, NC Ordovas, J Peter, I Post, W Redline, S Reis, SE Saxena, R Schreiner, PJ Volcik, KA Wang, XB Yusuf, S Zonderland, AB Anand, SS Becker, DM Psaty, B Rader, DJ Reiner, AP Rich, SS Rotter, JI Sale, MM Tsai, MY Borecki, IB Hegele, RA Kathiresan, S Nalls, MA Taylor, HA Hakonarson, H Sivapalaratnam, S Asselbergs, FW Drenos, F Wilson, JG Keating, BJ AF Elbers, Clara C. Guo, Yiran Tragante, Vinicius van Iperen, Erik P. A. Lanktree, Matthew B. Castillo, Berta Almoguera Chen, Fang Yanek, Lisa R. Wojczynski, Mary K. Li, Yun R. Ferwerda, Bart Ballantyne, Christie M. Buxbaum, Sarah G. Chen, Yii-Der Ida Chen, Wei-Min Cupples, L. Adrienne Cushman, Mary Duan, Yanan Duggan, David Evans, Michele K. Fernandes, Jyotika K. Fornage, Myriam Garcia, Melissa Garvey, W. Timothy Glazer, Nicole Gomez, Felicia Harris, Tamara B. Halder, Indrani Howard, Virginia J. Keller, Margaux F. Kamboh, M. Ilyas Kooperberg, Charles Kritchevsky, Stephen B. LaCroix, Andrea Liu, Kiang Liu, Yongmei Musunuru, Kiran Newman, Anne B. Onland-Moret, N. Charlotte Ordovas, Jose Peter, Inga Post, Wendy Redline, Susan Reis, Steven E. Saxena, Richa Schreiner, Pamela J. Volcik, Kelly A. Wang, Xingbin Yusuf, Salim Zonderland, Alan B. Anand, Sonia S. Becker, Diane M. Psaty, Bruce Rader, Daniel J. Reiner, Alex P. Rich, Stephen S. Rotter, Jerome I. Sale, Michele M. Tsai, Michael Y. Borecki, Ingrid B. Hegele, Robert A. Kathiresan, Sekar Nalls, Michael A. Taylor, Herman A., Jr. Hakonarson, Hakon Sivapalaratnam, Suthesh Asselbergs, Folkert W. Drenos, Fotios Wilson, James G. Keating, Brendan J. TI Gene-Centric Meta-Analysis of Lipid Traits in African, East Asian and Hispanic Populations SO PLOS ONE LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; DENSITY-LIPOPROTEIN-CHOLESTEROL; SINGLE-NUCLEOTIDE POLYMORPHISM; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; CHAIN FATTY-ACIDS; METABOLIC SYNDROME; ASSOCIATION RESOURCE; NATURAL-SELECTION; YOUNG-ADULTS AB Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of similar to 2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom similar to 50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8x10(-7) and p = 1.5x10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5x10(-1)2). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report. C1 [Elbers, Clara C.; Ferwerda, Bart; Gomez, Felicia] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Elbers, Clara C.; Tragante, Vinicius; Onland-Moret, N. Charlotte; Asselbergs, Folkert W.] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands. [Elbers, Clara C.; Onland-Moret, N. Charlotte; Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Guo, Yiran; Castillo, Berta Almoguera; Li, Yun R.; Hakonarson, Hakon; Keating, Brendan J.] Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Gen, Philadelphia, PA 19104 USA. [Guo, Yiran] BGI Shenzhen, Shenzhen, Peoples R China. [Tragante, Vinicius; Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands. [van Iperen, Erik P. A.] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, NL-1105 AZ Amsterdam, Netherlands. [Lanktree, Matthew B.] Univ Western Ontario, Dept Med, Schulich Sch Med & Dent, London, ON, Canada. [Lanktree, Matthew B.] Univ Western Ontario, Dept Biochem, Schulich Sch Med & Dent, London, ON, Canada. [Chen, Fang; Chen, Wei-Min; Rich, Stephen S.; Sale, Michele M.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Sch Med, GeneSTAR Res Program, Div Gen Internal Med, Baltimore, MD USA. [Wojczynski, Mary K.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Ballantyne, Christie M.] Baylor Coll Med, Houston, TX 77030 USA. [Buxbaum, Sarah G.] Jackson State Univ, Jackson Heart Study, Jackson, MS USA. [Chen, Yii-Der Ida; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Chen, Wei-Min] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Cupples, L. Adrienne; Glazer, Nicole] Boston Univ, Boston, MA 02215 USA. [Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA USA. [Wojczynski, Mary K.; Duan, Yanan; Borecki, Ingrid B.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA. [Wojczynski, Mary K.; Duan, Yanan; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Garcia, Melissa; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Reis, Steven E.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kooperberg, Charles; LaCroix, Andrea; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Kritchevsky, Stephen B.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Liu, Yongmei] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Kamboh, M. Ilyas; Wang, Xingbin] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ordovas, Jose] Tufts Univ, JM USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Peter, Inga] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Post, Wendy] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Redline, Susan] Brigham & Womens Hosp, Boston, MA 02115 USA. [Redline, Susan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Saxena, Richa] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Saxena, Richa] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Schreiner, Pamela J.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Volcik, Kelly A.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Yusuf, Salim; Anand, Sonia S.] McMaster Univ, Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada. [Psaty, Bruce] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA USA. [Sale, Michele M.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. [Sale, Michele M.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Tsai, Michael Y.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Hegele, Robert A.] Univ Western Ontario, Robarts Res Inst, London, ON, Canada. [Keller, Margaux F.; Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Taylor, Herman A., Jr.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Taylor, Herman A., Jr.] Jackson State Univ, Tougaloo Coll, Jackson, MS USA. [Sivapalaratnam, Suthesh] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Drenos, Fotios] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Cushman, Mary] Univ Vermont, Dept Med, Thrombosis & Hemostasis Program, Burlington, VT USA. [Fernandes, Jyotika K.] Med Univ S Carolina, Coll Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Howard, Virginia J.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Zonderland, Alan B.] NIA, Lab Personal & Cognit, NIH, Bethesda, MD 20892 USA. [Evans, Michele K.] NIA, Hlth Dispar Unit, NIH, Baltimore, MD 21224 USA. [Halder, Indrani] Univ Pittsburgh, Inst Heart & Vasc, Sch Med, Pittsburgh, PA USA. [Buxbaum, Sarah G.] Jackson State Univ, Sch Hlth Sci, Dept Epidemiol & Biostat, Jackson, MS USA. RP Elbers, CC (reprint author), Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. EM bkeating@mail.med.upenn.edu RI Newman, Anne/C-6408-2013; Reis, Steven/J-3957-2014; Guo, Yiran/H-4120-2011; Onland-Moret, N. Charlotte/G-9185-2011; Hegele, Robert/G-3301-2011; Buxbaum, Sarah/E-1970-2013 OI Newman, Anne/0000-0002-0106-1150; Lanktree, Matthew/0000-0002-5750-6286; Kritchevsky, Stephen/0000-0003-3336-6781; van Iperen, Erik/0000-0001-7107-3168; Guo, Yiran/0000-0002-6549-8589; Cupples, L. Adrienne/0000-0003-0273-7965; Kamboh, M. Ilyas/0000-0002-3453-1438; Buxbaum, Sarah/0000-0002-4886-3564 FU National Heart, Lung, and Blood Institute; Massachusetts Institute of Technology - Broad Institute [N01-HC-65226]; Netherlands Organization for Scientific Research (NWO); Netherlands Organisation for Health Research and Development (ZonMw) [90700342] FX The CARe Consortium wishes to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. The following nine parent studies have contributed parent study data, ancillary study data, and DNA samples through the Massachusetts Institute of Technology - Broad Institute (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Cleveland Family Study (CFS), the Cooperative Study of Sickle Cell Disease (CSSCD), the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). C. C. E is supported by a Rubicon grant from the Netherlands Organization for Scientific Research (NWO). F. W. A. is supported by a clinical fellowship from the Netherlands Organisation for Health Research and Development (ZonMw grant 90700342). Additional funding information can be found in the Supporting Information S1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 16 Z9 16 U1 2 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 7 PY 2012 VL 7 IS 12 AR e50198 DI 10.1371/journal.pone.0050198 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 050OT UT WOS:000312064100013 PM 23236364 ER PT J AU Daley, GQ AF Daley, George Q. TI Cellular Alchemy and the Golden Age of Reprogramming SO CELL LA English DT Editorial Material ID EMBRYONIC STEM-CELLS; NUCLEAR TRANSPLANTATION; PARKINSONIAN MICE; DEFINED FACTORS; SOMATIC-CELLS; FIBROBLASTS AB The 2012 Nobel Prize in Medicine or Physiology recognizes the architects of two of the great paradigm-shifting discoveries of the last half-century of biology. In experiments performed nearly 50 years apart, Gurdon and Yamanaka made feasible the reawakening of pluripotency inherent in all cells and challenged forever our notions of cellular identity. C1 [Daley, George Q.] Childrens Hosp, Howard Hughes Med Inst, Manton Ctr Orphan Dis Res, Div Pediat Hematol Oncol,Stem Cell Transplantat P, Boston, MA 02115 USA. [Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Daley, George Q.] Broad Inst, Boston, MA 02115 USA. [Daley, George Q.] Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Childrens Hosp, Howard Hughes Med Inst, Manton Ctr Orphan Dis Res, Div Pediat Hematol Oncol,Stem Cell Transplantat P, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu FU Howard Hughes Medical Institute NR 20 TC 8 Z9 9 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 7 PY 2012 VL 151 IS 6 BP 1151 EP 1154 DI 10.1016/j.cell.2012.11.016 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 049RA UT WOS:000311999900002 PM 23217698 ER PT J AU Sebastian, C Zwaans, BMM Silberman, DM Gymrek, M Goren, A Zhong, L Ram, O Truelove, J Guimaraes, AR Toiber, D Cosentino, C Greenson, JK MacDonald, AI McGlynn, L Maxwell, F Edwards, J Giacosa, S Guccione, E Weissleder, R Bernstein, BE Regev, A Shiels, PG Lombard, DB Mostoslavsky, R AF Sebastian, Carlos Zwaans, Bernadette M. M. Silberman, Dafne M. Gymrek, Melissa Goren, Alon Zhong, Lei Ram, Oren Truelove, Jessica Guimaraes, Alexander R. Toiber, Debra Cosentino, Claudia Greenson, Joel K. MacDonald, Alasdair I. McGlynn, Liane Maxwell, Fraser Edwards, Joanne Giacosa, Sofia Guccione, Ernesto Weissleder, Ralph Bernstein, Bradley E. Regev, Aviv Shiels, Paul G. Lombard, David B. Mostoslavsky, Raul TI The Histone Deacetylase SIRT6 Is a Tumor Suppressor that Controls Cancer Metabolism SO CELL LA English DT Article ID MULTIPLE INTESTINAL NEOPLASIA; RNA-POLYMERASE-I; C-MYC; GENE-EXPRESSION; RIBOSOMAL DNA; LIFE-SPAN; GROWTH; TRANSCRIPTION; STRESS; PROLIFERATION AB Reprogramming of cellular metabolism is a key event during tumorigenesis. Despite being known for decades (Warburg effect), the molecular mechanisms regulating this switch remained unexplored. Here, we identify SIRT6 as a tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. By using a conditional SIRT6 allele, we show that SIRT6 deletion in vivo increases the number, size, and aggressiveness of tumors. SIRT6 also functions as a regulator of ribosome metabolism by corepressing MYC transcriptional activity. Lastly, Sirt6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism. C1 [Zwaans, Bernadette M. M.; Greenson, Joel K.; Lombard, David B.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Lombard, David B.] Univ Michigan, Inst Gerontol, Ann Arbor, MI 48109 USA. [Sebastian, Carlos; Silberman, Dafne M.; Goren, Alon; Zhong, Lei; Ram, Oren; Toiber, Debra; Cosentino, Claudia; Giacosa, Sofia; Bernstein, Bradley E.; Mostoslavsky, Raul] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Goren, Alon; Ram, Oren; Bernstein, Bradley E.; Regev, Aviv] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Gymrek, Melissa; Bernstein, Bradley E.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Gymrek, Melissa] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Goren, Alon; Ram, Oren; Regev, Aviv] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Goren, Alon; Ram, Oren; Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Goren, Alon; Ram, Oren; Bernstein, Bradley E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Goren, Alon; Ram, Oren; Truelove, Jessica; Guimaraes, Alexander R.; Weissleder, Ralph; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Regev, Aviv] MIT, Dept Biol, Cambridge, MA 02140 USA. [MacDonald, Alasdair I.; McGlynn, Liane; Maxwell, Fraser; Edwards, Joanne; Shiels, Paul G.] Univ Glasgow, MVLS, Inst Canc Sci, Glasgow G12 8QQ, Lanark, Scotland. [Guccione, Ernesto] Inst Mol & Cell Biol, Proteos 138673, Singapore. [Silberman, Dafne M.] CEFyBO UBA CONICET, Sch Med, Dept Human Biochem, Buenos Aires, DF, Argentina. RP Lombard, DB (reprint author), Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. EM davidlom@umich.edu; rmostoslavsky@mgh.harvard.edu RI ASTAR, IMCB/E-2320-2012; Edwards, Joanne/J-1903-2015; OI Edwards, Joanne/0000-0002-7192-6906; /0000-0002-6086-3903 FU NIH [GM093072-01, DK088190-01A1, GM101171]; Sidney Kimmel Cancer Research Foundation; Richard D. and Katherine M. O'Connor Research Fund of the University of Michigan Comprehensive Cancer Center; Nathan Shock Center [AG013283]; Pardee Foundation; Beatriu de Pinos Postdoctoral Fellowship (Generalitat de Catalunya); National Defense Science and Engineering Graduate Fellowship; Brain Power for Israel Foundation; Fondazione Umberto Veronesi; NHGRI Center of Excellence in Genome Science [P50HG006193] FX This work was supported by NIH awards GM093072-01 and DK088190-01A1 (R.M.) and GM101171 (D.B.L.), the Sidney Kimmel Cancer Research Foundation (R.M.), the Richard D. and Katherine M. O'Connor Research Fund of the University of Michigan Comprehensive Cancer Center (D.B.L.), the Nathan Shock Center (AG013283; D.B.L.), and the Pardee Foundation (D.B.L.). R.M. is a Howard Goodman Scholar and an MGH Research Scholar. D.B.L. is a New Scholar in Aging of the Ellison Medical Foundation. C.S. is the recipient of a Beatriu de Pinos Postdoctoral Fellowship (Generalitat de Catalunya). M.G. is supported by a National Defense Science and Engineering Graduate Fellowship. D.T. is the recipient of the Brain Power for Israel Foundation. C.C. is supported by a Fellowship from the Fondazione Umberto Veronesi. A.R. is supported by a P50HG006193 from the NHGRI Center of Excellence in Genome Science. D.B.L. would like to thank Dr. Chuxia Deng (NIDDK/NIH) for the floxed SIRT6 mouse strain. We thank Nabeel Bardeesy, Eric Fearon, Alexandros Tzatsos, Polina Paskaleva, Kevin Haigis, Agustina D'Urso, Marco Bezzi, and the Mostoslavsky and Lombard labs for technical advice, reagents, and helpful discussions. We thank the ENCODE Chromatin Project at the Broad Institute for data sharing. R.M. is a member of Sirtris scientific advisory board. NR 44 TC 216 Z9 226 U1 3 U2 125 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 7 PY 2012 VL 151 IS 6 BP 1185 EP 1199 DI 10.1016/j.cell.2012.10.047 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 049RA UT WOS:000311999900010 PM 23217706 ER PT J AU Xu, YF Xu, C Kato, A Tempel, W Abreu, JG Bian, CB Hu, YG Hu, D Zhao, B Cerovina, T Diao, JB Wu, FZ He, HH Cui, QY Clark, E Ma, C Barbara, A Veenstra, GJC Xu, GL Kaiser, UB Liu, XS Sugrue, SP He, X Min, JR Kato, Y Shi, YG AF Xu, Yufei Xu, Chao Kato, Akiko Tempel, Wolfram Abreu, Jose Garcia Bian, Chuanbing Hu, Yeguang Hu, Di Zhao, Bin Cerovina, Tanja Diao, Jianbo Wu, Feizhen He, Housheng Hansen Cui, Qingyan Clark, Erin Ma, Chun Barbara, Andrew Veenstra, Gert Jan C. Xu, Guoliang Kaiser, Ursula B. Liu, X. Shirley Sugrue, Stephen P. He, Xi Min, Jinrong Kato, Yoichi Shi, Yujiang Geno TI Tet3 CXXC Domain and Dioxygenase Activity Cooperatively Regulate Key Genes for Xenopus Eye and Neural Development SO CELL LA English DT Article ID EMBRYONIC STEM-CELLS; DNA METHYLATION; MAMMALIAN DNA; SELF-RENEWAL; 5-HYDROXYMETHYLCYTOSINE; MOUSE; 5-METHYLCYTOSINE; PROTEINS; GENOME; 5-CARBOXYLCYTOSINE AB Ten-Eleven Translocation (Tet) family of dioxygenases dynamically regulates DNA methylation and has been implicated in cell lineage differentiation and oncogenesis. Yet their functions and mechanisms of action in gene regulation and embryonic development are largely unknown. Here, we report that Xenopus Tet3 plays an essential role in early eye and neural development by directly regulating a set of key developmental genes. Tet3 is an active 5mC hydroxylase regulating the 5mC/5hmC status at target gene promoters. Biochemical and structural studies further demonstrate that the Tet3 CXXC domain is critical for specific Tet3 targeting. Finally, we show that the enzymatic activity and CXXC domain are both crucial for Tet3's biological function. Together, these findings define Tet3 as a transcription regulator and reveal a molecular mechanism by which the 5mC hydroxylase and DNA binding activities of Tet3 cooperate to control target gene expression and embryonic development. C1 [Xu, Chao; Tempel, Wolfram; Bian, Chuanbing; Cerovina, Tanja; Min, Jinrong] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada. [Xu, Yufei; Hu, Yeguang; Hu, Di; Clark, Erin; Ma, Chun; Barbara, Andrew; Kaiser, Ursula B.; Shi, Yujiang Geno] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens,Dept Med, Boston, MA 02115 USA. [Xu, Chao; Tempel, Wolfram; Bian, Chuanbing; Cerovina, Tanja; Min, Jinrong] Univ Toronto, Dept Physiol, Toronto, ON M5G 1L7, Canada. [Kato, Akiko; Kato, Yoichi] Florida State Univ, Coll Med, Dept Biomed Sci, Tallahassee, FL 32306 USA. [Abreu, Jose Garcia; He, Xi] Harvard Univ, Sch Med, Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Hu, Di; Zhao, Bin; Diao, Jianbo; Wu, Feizhen; Ma, Chun] Fudan Univ, Inst Biomed Sci, Lab Epigenet, Shanghai 200032, Peoples R China. [He, Housheng Hansen; Liu, X. Shirley] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [He, Housheng Hansen; Liu, X. Shirley] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Cui, Qingyan; Xu, Guoliang] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China. [Veenstra, Gert Jan C.] Radboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci, NL-6500 HB Nijmegen, Netherlands. [Liu, X. Shirley] Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA. [Sugrue, Stephen P.] Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. RP Min, JR (reprint author), Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada. EM jr.min@utoronto.ca; yoichi.kato@med.fsu.edu; yujiang_shi@hms.harvard.edu RI PCM, PG/D-1034-2013; Neurociencia, Inct/I-1011-2013; Min, Jinrong/G-3449-2011; Abreu, Jose/G-6159-2010; Veenstra, Gert Jan C./D-4963-2012; Xu, Chao/G-3885-2010 OI Abreu, Jose/0000-0002-9875-7786; Veenstra, Gert Jan C./0000-0002-7787-4940; Xu, Chao/0000-0003-0444-7080 FU NIH [GM078458, GM087641, GM074241]; Brigham and Women's Hospital Biomedical Research Institute; Chinese Ministry of Education Project 985; CNPq (Brazil); Boston Children's Hospital Intellectual and Developmental Disabilities Research Center [P30 HD-18655]; Canadian Institutes for Health Research; Canadian Foundation for Innovation; Genome Canada through Ontario Genomics Institute; GlaxoSmithKline; Eli Lilly; Pfizer; Novartis Research Foundation; Life Technologies; Ontario Innovation Trust; Ontario Ministry for Research and Innovation; Wellcome Trust; U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357] FX We thank R. Harland for helpful discussions, A Khorasani for critical reading of the manuscript and Q. Xu and L. Jiang for statistical analyses. We also thank R. Moon, W. Harris, J. Yang, X. Wang, M. Vetter and J.-P. Saint-Jeannet for valuable discussions and technical help. This work was supported by NIH grants GM078458 to Y.G.S., GM087641 to Y.K., and GM074241 to X.H., Brigham and Women's Hospital Biomedical Research Institute fund to sustain research excellence to Y.G.S., and Chinese Ministry of Education Project 985 to Biomedical Core Facility, Fudan University. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. J. G. A. was funded partially by CNPq (Brazil). Y.G.S. is a Pew Scholar. X. H. acknowledges support by Boston Children's Hospital Intellectual and Developmental Disabilities Research Center (P30 HD-18655). The Structural Genomics Consortium is a registered charity (No. 1097737) that receives funds from Canadian Institutes for Health Research, Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Eli Lilly, Pfizer, Novartis Research Foundation, Life Technologies, Ontario Innovation Trust, Ontario Ministry for Research and Innovation and Wellcome Trust (JM). Argonne National Laboratory is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. NR 30 TC 97 Z9 102 U1 2 U2 58 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 7 PY 2012 VL 151 IS 6 BP 1200 EP 1213 DI 10.1016/j.cell.2012.11.014 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 049RA UT WOS:000311999900011 PM 23217707 ER PT J AU Ruas, JL White, JP Rao, RR Kleiner, S Brannan, KT Harrison, BC Greene, NP Wu, J Estall, JL Irving, BA Lanza, IR Rasbach, KA Okutsu, M Nair, KS Yan, Z Leinwand, LA Spiegelman, BM AF Ruas, Jorge L. White, James P. Rao, Rajesh R. Kleiner, Sandra Brannan, Kevin T. Harrison, Brooke C. Greene, Nicholas P. Wu, Jun Estall, Jennifer L. Irving, Brian A. Lanza, Ian R. Rasbach, Kyle A. Okutsu, Mitsuharu Nair, K. Sreekumaran Yan, Zhen Leinwand, Leslie A. Spiegelman, Bruce M. TI A PGC-1 alpha Isoform Induced by Resistance Training Regulates Skeletal Muscle Hypertrophy SO CELL LA English DT Article ID TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; MICE; ATROPHY; GROWTH; FIBERS; MASS; HOMEOSTASIS; METABOLISM; EXPRESSION; MYOSTATIN AB PGC-1 alpha is a transcriptional coactivator induced by exercise that gives muscle many of the best known adaptations to endurance-type exercise but has no effects on muscle strength or hypertrophy. We have identified a form of PGC-1 alpha (PGC-1 alpha 4) that results from alternative promoter usage and splicing of the primary transcript. PGC-1 alpha 4 is highly expressed in exercised muscle but does not regulate most known PGC-1 alpha targets such as the mitochondrial OXPHOS genes. Rather, it specifically induces IGF1 and represses myostatin, and expression of PGC-1 alpha 4 in vitro and in vivo induces robust skeletal muscle hypertrophy. Importantly, mice with skeletal muscle-specific transgenic expression of PGC-1 alpha 4 show increased muscle mass and strength and dramatic resistance to the muscle wasting of cancer cachexia. Expression of PGC-1 alpha 4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1 alpha protein that regulates and coordinates factors involved in skeletal muscle hypertrophy. C1 [Ruas, Jorge L.; White, James P.; Rao, Rajesh R.; Kleiner, Sandra; Brannan, Kevin T.; Wu, Jun; Estall, Jennifer L.; Rasbach, Kyle A.; Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Cell Biol, Boston, MA 02115 USA. [Harrison, Brooke C.; Leinwand, Leslie A.] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. [Greene, Nicholas P.; Okutsu, Mitsuharu; Yan, Zhen] Univ Virginia, Dept Med, Charlottesville, VA 22908 USA. [Irving, Brian A.; Lanza, Ian R.; Nair, K. Sreekumaran] Mayo Clin, Div Endocrinol, Endocrine Res Unit, Rochester, MN 55905 USA. RP Ruas, JL (reprint author), Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden. EM jorge.ruas@ki.se; bruce_spiegelman@dfci.harvard.edu RI Greene, Nicholas/A-6076-2013; Greene, Nicholas/G-7399-2015; Irving, Brian/B-9683-2016; OI Greene, Nicholas/0000-0002-9504-9362; Irving, Brian/0000-0002-4131-9523; LEINWAND, LESLIE/0000-0003-1470-4810; Ruas, Jorge/0000-0002-1110-2606 FU NIH [DK061562, 5K01AR55676-2, T32HL07284, AR050429, GM29090]; Novartis; Wenner-Gren Foundations, Sweden; AHA [09POST2010078, 12SDG8070003]; Novartis, Inc.; [RR024151]; [AG09531] FX We thank Drs. Srikripa Devarakonda and Sibylle Jager for valuable discussions. ERR alpha and ERR gamma KO myoblasts were a kind gift from Dr. Zhidan Wu (Novartis Institutes for Biomedical Research). The MEF2C/Myogenin promoter cassette was kindly provided by Dr. Eric Olson (University of Texas Southwestern Medical Center). LLC cells were kindly donated by Dr. Jose M. Garcia (Baylor College of Medicine). This project was supported by grants (DK061562) from the NIH and from Novartis to B.M.S. J.L.R. was supported in part by a grant from the Wenner-Gren Foundations, Sweden. This research was supported in part by grants to B. C. H. (NIH, 5K01AR55676-2), N.P.G. (NIH, T32HL07284), J.W. (AHA, 09POST2010078 and 12SDG8070003), B.A.I. (RR024151 and AG09531), Z.Y. (NIH, AR050429), and L. A. L. (NIH, GM29090). B. M. S. is a shareholder and consultant to Ember Therapeutics and has received funding in the form of sponsored research from Novartis, Inc. NR 40 TC 172 Z9 176 U1 3 U2 48 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 7 PY 2012 VL 151 IS 6 BP 1319 EP 1331 DI 10.1016/j.cell.2012.10.050 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 049RA UT WOS:000311999900020 PM 23217713 ER PT J AU Han, D Ybanez, MD Johnson, HS McDonald, JN Mesropyan, L Sancheti, H Martin, G Martin, A Lim, AM Dara, L Cadenas, E Tsukamoto, H Kaplowitz, N AF Han, Derick Ybanez, Maria D. Johnson, Heather S. McDonald, Jeniece N. Mesropyan, Lusine Sancheti, Harsh Martin, Gary Martin, Alanna Lim, Atalie M. Dara, Lily Cadenas, Enrique Tsukamoto, Hidekazu Kaplowitz, Neil TI Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice BIOGENESIS, REMODELING, AND FUNCTIONAL ALTERATIONS SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SKELETAL-MUSCLE MITOCHONDRIA; CHRONIC ETHANOL-CONSUMPTION; RAT-LIVER; ENERGY-METABOLISM; DEPENDENT HEPATOTOXICITY; SUPEROXIDE ANION; SWIFT INCREASE; FAT DIET; NECROSIS; EXERCISE AB Liver mitochondria undergo dynamic alterations following chronic alcohol feeding to mice. Intragastric alcohol feeding to mice resulted in 1) increased state III respiration (109% compared with control) in isolated liver mitochondria, probably due to increased levels of complexes I, IV, and V being incorporated into the respiratory chain; 2) increased mitochondrial NAD(+) and NADH levels (similar to 2-fold), with no change in the redox status; 3) alteration in mitochondrial morphology, with increased numbers of elongated mitochondria; and 4) enhanced mitochondrial biogenesis in the liver, which corresponded with an up-regulation of PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator-1 alpha). Oral alcohol feeding to mice, which is associated with less liver injury and steatosis, slightly enhanced respiration in isolated liver mitochondria (30.8% compared with control), lower than the striking increase caused by intragastric alcohol feeding. Mitochondrial respiration increased with both oral and intragastric alcohol feeding despite extensive N-acetylation of mitochondrial proteins. The alcohol-induced mitochondrial alterations are probably an adaptive response to enhance alcohol metabolism in the liver. Isolated liver mitochondria from alcohol-treated mice had a greater rate of acetaldehyde metabolism and respiration when treated with acetaldehyde than control. Aldehyde dehydrogenase-2 levels were unaltered in response to alcohol, suggesting that the greater acetaldehyde metabolism by isolated mitochondria from alcohol-treated mice was due to increased mitochondrial respiration that regenerated NAD(+), the rate-limiting substrate in alcohol/acetaldehyde metabolism. Overall, our work suggests that mitochondrial plasticity in the liver may be an important adaptive response to the metabolic stress caused by alcohol intake and could potentially play a role in many other vital functions performed by the liver. C1 [Han, Derick; Lim, Atalie M.; Dara, Lily; Kaplowitz, Neil] Univ So Calif, Keck Sch Med, Res Ctr Liver Dis, Los Angeles, CA 90089 USA. [Lim, Atalie M.; Dara, Lily; Kaplowitz, Neil] Univ So Calif, Keck Sch Med, So Calif Res Ctr Alcohol Liver & Pancreat Dis, Los Angeles, CA 90089 USA. [Sancheti, Harsh; Cadenas, Enrique] Univ So Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90089 USA. [Martin, Gary; Martin, Alanna] Occidental Coll, Dept Biol, Los Angeles, CA 90041 USA. [Tsukamoto, Hidekazu] Univ So Calif, Keck Sch Med, So Calif Res Ctr Alcohol Liver & Pancreat Dis & C, Los Angeles, CA 90089 USA. [Tsukamoto, Hidekazu] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90089 USA. [Tsukamoto, Hidekazu] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90089 USA. RP Han, D (reprint author), Univ So Calif, Keck Sch Med, Res Ctr Liver Dis, 2011 Zonal Ave,HMR 101, Los Angeles, CA 90089 USA. EM derickh@usc.edu OI Sancheti, Harsh/0000-0001-8084-4550 FU National Institutes of Health Grant [AA016911, AA14428, P50AA11999] FX This work was supported, in whole or in part, by National Institutes of Health Grant AA016911 (to D. H.), AA14428 (to N. K.), and P50AA11999 (to H. T.). NR 57 TC 23 Z9 23 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 7 PY 2012 VL 287 IS 50 BP 42165 EP 42179 DI 10.1074/jbc.M112.377374 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 051CT UT WOS:000312103000054 PM 23086958 ER PT J AU Kimani, S Ghosh, G Ghogare, A Rudshteyn, B Bartusik, D Hasan, T Greer, A AF Kimani, Stanley Ghosh, Goutam Ghogare, Ashwini Rudshteyn, Benjamin Bartusik, Dorota Hasan, Tayyaba Greer, Alexander TI Synthesis and Characterization of Mono-, Di-, and Tri-Poly(ethylene glycol) Chlorin e(6) Conjugates for the Photokilling of Human Ovarian Cancer Cells SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID SINGLET OXYGEN; PHOTODYNAMIC THERAPY; SUBCELLULAR-LOCALIZATION; CELLULAR UPTAKE; DERIVATIVES; LIFETIME; DYES; PH; E6; PHOTOSENSITIZER AB PEGylated chlorin e(6) photosensitizers were synthesized with tri(ethylene glycol) attached at the ester bond(s) for a 1:1 conjugate at the 173-position, a 2:1 conjugate at the 15(2)- and 17(3)-positions, and a 3:1 conjugate at the 13(1)-, 15(2)-, and 17(3)-positions. These chlorin sensitizers were studied for hydrolytic stability and solubility, as well as ovarian OVCAR-5 cancer cell uptake, localization, and phototoxicity. Increasing numbers of the PEG groups in the mono-, di-, and tri-PEG chlorin conjugates increased the water solubility and sensitivity to hydrolysis and uptake into the ovarian cancer cells. The PEG chlorin conjugates accumulated in the cytoplasm and mitrochondria, but not in lysosomes. Higher phototoxicity was roughly correlated with higher numbers of PEG groups, with the tri-PEG chlorin conjugate showing the best overall ovarian cancer cell photokilling of the series. Singlet oxygen lifetimes, solvent deuteration, and the effects of additives azide ion and D-mannitol were examined to help clarify the photokilling mechanisms. A Type-II (singlet oxygen) photosensitized mechanism is suggested for the di- and tri-PEG chlorin conjugates; however, a more complicated process based in part on a Type-I (radicals or radical ions) mechanism is suggested for the parent chlorin e6 and the mono-PEG chlorin conjugate. C1 [Kimani, Stanley; Hasan, Tayyaba] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Kimani, Stanley; Hasan, Tayyaba] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kimani, Stanley; Ghosh, Goutam; Ghogare, Ashwini; Rudshteyn, Benjamin; Bartusik, Dorota; Greer, Alexander] CUNY Brooklyn Coll, Dept Chem, Brooklyn, NY 11210 USA. [Kimani, Stanley; Ghosh, Goutam; Ghogare, Ashwini; Rudshteyn, Benjamin; Bartusik, Dorota; Greer, Alexander] CUNY Brooklyn Coll, Grad Ctr, Brooklyn, NY 11210 USA. RP Hasan, T (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM thasan@partners.org; agreer@brooklyn.cuny.edu FU NIH-National Institute of General Medical Sciences [SC1GM093830]; NIH-National Cancer Institute [5R01CA160998]; Barry M. Goldwater Scholarship; Arnold and Ruth T. Kaufman Undergraduate Chemistry Research Award at Brooklyn College FX S.K., G.G., A.G., B.R., D.B., and A.G. acknowledge support from the NIH-National Institute of General Medical Sciences (SC1GM093830). Grant support to T.H. was provided by the NIH-National Cancer Institute (5R01CA160998). B.R. is the recipient of a Barry M. Goldwater Scholarship and the Arnold and Ruth T. Kaufman Undergraduate Chemistry Research Award at Brooklyn College. Computational support was provided by the College of Staten Island CUNY High Performance Computing Facility. We also thank Leda Lee for the graphic arts work. NR 44 TC 9 Z9 9 U1 2 U2 35 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD DEC 7 PY 2012 VL 77 IS 23 BP 10638 EP 10647 DI 10.1021/jo301889s PG 10 WC Chemistry, Organic SC Chemistry GA 048PX UT WOS:000311926100018 PM 23126407 ER PT J AU Moseley, CK Carlin, SM Neelamegam, R Hooker, JM AF Moseley, Christian K. Carlin, Stephen M. Neelamegam, Ramesh Hooker, Jacob M. TI An Efficient and Practical Radiosynthesis of [C-11]Temozolomide SO ORGANIC LETTERS LA English DT Article ID ANTITUMOR DRUG TEMOZOLOMIDE; POSITRON-EMISSION-TOMOGRAPHY; IMIDAZOTETRAZINES; ACTIVATION; ROUTES AB Temozolomide (TMZ) is a prodrug for an alkylating agent used for the treatment of malignant brain tumors. A positron emitting version, [C-11]TMZ, has been utilized to help elucidate the mechanism and biodistribution of TMZ. Challenges in [C-11]TMZ synthesis and reformulation make it difficult for routine production. A highly reproducible one-pot radiosynthesis of [C-11]TMZ with a radiochemical yield of 17 +/- 5% and >= 97% radiochemical purity is reported. C1 [Moseley, Christian K.; Carlin, Stephen M.; Neelamegam, Ramesh; Hooker, Jacob M.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Hooker, JM (reprint author), Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA 02129 USA. EM hooker@nmr.mgh.harvard.edu OI Hooker, Jacob/0000-0002-9394-7708 FU NCRR NIH HHS [S10 RR026666, S10 RR017208] NR 15 TC 5 Z9 5 U1 0 U2 12 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 DEC 7 PY 2012 VL 14 IS 23 BP 5872 EP 5875 DI 10.1021/ol302791x PG 4 WC Chemistry, Organic SC Chemistry GA 048PW UT WOS:000311926000016 PM 23151019 ER PT J AU Jia, X Schumann, J Paganetti, H Jiang, SB AF Jia, Xun Schuemann, Jan Paganetti, Harald Jiang, Steve B. TI GPU-based fast Monte Carlo dose calculation for proton therapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID DEFORMABLE IMAGE REGISTRATION; TRACK-REPEATING ALGORITHM; CLINICAL IMPLEMENTATION; GRAPHICS HARDWARE; PLAN OPTIMIZATION; RADIATION-THERAPY; BEAM THERAPY; RECONSTRUCTION; RADIOTHERAPY; SIMULATION AB Accurate radiation dose calculation is essential for successful proton radiotherapy. Monte Carlo (MC) simulation is considered to be the most accurate method. However, the long computation time limits it from routine clinical applications. Recently, graphics processing units (GPUs) have been widely used to accelerate computationally intensive tasks in radiotherapy. We have developed a fast MC dose calculation package, gPMC, for proton dose calculation on a GPU. In gPMC, proton transport is modeled by the class II condensed history simulation scheme with a continuous slowing down approximation. Ionization, elastic and inelastic proton nucleus interactions are considered. Energy straggling and multiple scattering are modeled. Secondary electrons are not transported and their energies are locally deposited. After an inelastic nuclear interaction event, a variety of products are generated using an empirical model. Among them, charged nuclear fragments are terminated with energy locally deposited. Secondary protons are stored in a stack and transported after finishing transport of the primary protons, while secondary neutral particles are neglected. gPMC is implemented on the GPU under the CUDA platform. We have validated gPMC using the TOPAS/Geant4 MC code as the gold standard. For various cases including homogeneous and inhomogeneous phantoms as well as a patient case, good agreements between gPMC and TOPAS/Geant4 are observed. The gamma passing rate for the 2%/2 mm criterion is over 98.7% in the region with dose greater than 10% maximum dose in all cases, excluding low-density air regions. With gPMC it takes only 6-22 s to simulate 10 million source protons to achieve similar to 1% relative statistical uncertainty, depending on the phantoms and energy. This is an extremely high efficiency compared to the computational time of tens of CPU hours for TOPAS/Geant4. Our fast GPU-based code can thus facilitate the routine use of MC dose calculation in proton therapy. C1 [Jia, Xun; Jiang, Steve B.] Univ Calif San Diego, Ctr Adv Radiotherapy Technol, Dept Radiat Med & Appl Sci, La Jolla, CA 92037 USA. [Schuemann, Jan; Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Schuemann, Jan; Paganetti, Harald] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Jia, X (reprint author), Univ Calif San Diego, Ctr Adv Radiotherapy Technol, Dept Radiat Med & Appl Sci, La Jolla, CA 92037 USA. EM xunjia@ucsd.edu; jschuemann@partners.org; hpaganetti@partners.org; sbjiang@ucsd.edu FU University of California; [R01 CA140735] FX This work is supported in part by the University of California Lab Fees Research Program and in part by R01 CA140735 ('PBeam: Fast and Easy Monte Carlo System for Proton Therapy'). NR 41 TC 49 Z9 50 U1 2 U2 26 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD DEC 7 PY 2012 VL 57 IS 23 BP 7783 EP 7797 DI 10.1088/0031-9155/57/23/7783 PG 15 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 040UX UT WOS:000311351400009 PM 23128424 ER PT J AU Norton, WE McCannon, CJ Schall, MW Mittman, BS AF Norton, Wynne E. McCannon, C. Joseph Schall, Marie W. Mittman, Brian S. TI A stakeholder-driven agenda for advancing the science and practice of scale-up and spread in health SO IMPLEMENTATION SCIENCE LA English DT Article DE Scale-up; Spread; Healthcare; Public health; Improvement; Implementation; Dissemination; Health systems research; Healthcare delivery ID INTERNATIONAL HEALTH; IMPROVEMENT; CARE; RECOMMENDATIONS; ORGANIZATIONS; INNOVATIONS; SERVICES AB Background: Although significant advances have been made in implementation science, comparatively less attention has been paid to broader scale-up and spread of effective health programs at the regional, national, or international level. To address this gap in research, practice and policy attention, representatives from key stakeholder groups launched an initiative to identify gaps and stimulate additional interest and activity in scale-up and spread of effective health programs. We describe the background and motivation for this initiative and the content, process, and outcomes of two main phases comprising the core of the initiative: a state-of-the-art conference to develop recommendations for advancing scale-up and spread and a follow-up activity to operationalize and prioritize the recommendations. The conference was held in Washington, D. C. during July 2010 and attended by 100 representatives from research, practice, policy, public health, healthcare, and international health communities; the follow-up activity was conducted remotely the following year. Discussion: Conference attendees identified and prioritized five recommendations (and corresponding sub-recommendations) for advancing scale-up and spread in health: increase awareness, facilitate information exchange, develop new methods, apply new approaches for evaluation, and expand capacity. In the follow-up activity, 'develop new methods' was rated as most important recommendation; expanding capacity was rated as least important, although differences were relatively minor. Summary: Based on the results of these efforts, we discuss priority activities that are needed to advance research, practice and policy to accelerate the scale-up and spread of effective health programs. C1 [Norton, Wynne E.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Hlth Behav, Birmingham, AL 35294 USA. [McCannon, C. Joseph; Schall, Marie W.] Inst Healthcare Improvement, Cambridge, MA 02138 USA. [Mittman, Brian S.] VA Greater Los Angeles Healthcare Syst, VA Ctr Implementat Practice & Res Support, North Hills, CA 91343 USA. RP Norton, WE (reprint author), Univ Alabama Birmingham, Sch Publ Hlth, Dept Hlth Behav, 1665 Univ Blvd, Birmingham, AL 35294 USA. EM wenorton@uab.edu OI Mittman, Brian/0000-0003-3589-9178 FU Agency for Healthcare Research and Quality [1R13HS019422-01]; Commonwealth Fund [20100353]; Veterans Health Administration; Quality Enhancement Research Initiative; John A. Hartford Foundation; Patrick and Catherine Weldon Donaghue Medical Research Foundation FX The state-of-the-art conference on scale-up/spread was supported by grant 1R13HS019422-01 from the Agency for Healthcare Research and Quality (PI: McCannon); grant #20100353 from the Commonwealth Fund (PI: McCannon); funding from The Veterans Health Administration, Quality Enhancement Research Initiative, The John A. Hartford Foundation, and The Patrick and Catherine Weldon Donaghue Medical Research Foundation. Views expressed in this paper do not necessarily reflect the official policies of the Department of Health and Human Services or Department of Veterans Affairs; nor does mention of trade names, commercial practices, or organizations imply endorsement by the US Government. NR 33 TC 6 Z9 6 U1 1 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD DEC 6 PY 2012 VL 7 AR 118 DI 10.1186/1748-5908-7-118 PG 6 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 104AY UT WOS:000315962700001 PM 23216748 ER PT J AU Huang, J Sabater-Lleal, M Asselbergs, FW Tregouet, D Shin, SY Ding, JZ Baumert, J Oudot-Mellakh, T Folkersen, L Johnson, AD Smith, NL Williams, SM Ikram, MA Kleber, ME Becker, DM Truong, V Mychaleckyj, JC Tang, WH Yang, Q Sennblad, B Moore, JH Williams, FMK Dehghan, A Silbernagel, G Schrijvers, EMC Smith, S Karakas, M Tofler, GH Silveira, A Navis, GJ Lohman, K Chen, MH Peters, A Goel, A Hopewell, JC Chambers, JC Saleheen, D Lundmark, P Psaty, BM Strawbridge, RJ Boehm, BO Carter, AM Meisinger, C Peden, JF Bis, JC McKnight, B Ohrvik, J Taylor, K Franzosi, MG Seedorf, U Collins, R Franco-Cereceda, A Syvanen, AC Goodall, AH Yanek, LR Cushman, M Muller-Nurasyid, M Folsom, AR Basu, S Matijevic, N van Gilst, WH Kooner, JS Hofman, A Danesh, J Clarke, R Meigs, JB Kathiresan, S Reilly, MP Klopp, N Harris, TB Winkelmann, BR Grant, PJ Hillege, HL Watkins, H Spector, TD Becker, LC Tracy, RP Marz, W Uitterlinden, AG Eriksson, P Cambien, F Morange, PE Koenig, W Soranzo, N van der Harst, P Liu, YM O'Donnell, CJ Hamsten, A AF Huang, Jie Sabater-Lleal, Maria Asselbergs, Folkert W. Tregouet, David Shin, So-Youn Ding, Jingzhong Baumert, Jens Oudot-Mellakh, Tiphaine Folkersen, Lasse Johnson, Andrew D. Smith, Nicholas L. Williams, Scott M. Ikram, Mohammad A. Kleber, Marcus E. Becker, Diane M. Vinh Truong Mychaleckyj, Josyf C. Tang, Weihong Yang, Qiong Sennblad, Bengt Moore, Jason H. Williams, Frances M. K. Dehghan, Abbas Silbernagel, Guenther Schrijvers, Elisabeth M. C. Smith, Shelly Karakas, Mahir Tofler, Geoffrey H. Silveira, Angela Navis, Gerjan J. Lohman, Kurt Chen, Ming-Huei Peters, Annette Goel, Anuj Hopewell, Jemma C. Chambers, John C. Saleheen, Danish Lundmark, Per Psaty, Bruce M. Strawbridge, Rona J. Boehm, Bernhard O. Carter, Angela M. Meisinger, Christa Peden, John F. Bis, Joshua C. McKnight, Barbara Ohrvik, John Taylor, Kent Franzosi, Maria Grazia Seedorf, Udo Collins, Rory Franco-Cereceda, Anders Syvaenen, Ann-Christine Goodall, Alison H. Yanek, Lisa R. Cushman, Mary Mueller-Nurasyid, Martina Folsom, Aaron R. Basu, Saonli Matijevic, Nena van Gilst, Wiek H. Kooner, Jaspal S. Hofman, Albert Danesh, John Clarke, Robert Meigs, James B. Kathiresan, Sekar Reilly, Muredach P. Klopp, Norman Harris, Tamara B. Winkelmann, Bernhard R. Grant, Peter J. Hillege, Hans L. Watkins, Hugh Spector, Timothy D. Becker, Lewis C. Tracy, Russell P. Maerz, Winfried Uitterlinden, Andre G. Eriksson, Per Cambien, Francois Morange, Pierre-Emmanuel Koenig, Wolfgang Soranzo, Nicole van der Harst, Pim Liu, Yongmei O'Donnell, Christopher J. Hamsten, Anders CA DIAGRAM Consortium CARDIoGRAM Consortium C4D Consortium CARDIOGENICS Consortium TI Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation SO BLOOD LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; GENETIC-VARIATION; SUSCEPTIBILITY LOCI; TYPE-1 EXPRESSION; CIRCADIAN CLOCK; PLASMA-LEVELS; TISSUE; RISK AB We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 x 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 x 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 x 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, dis-covery P = 2.9 x 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1. (Blood. 2012;120(24):4873-4881) C1 [Huang, Jie; Johnson, Andrew D.; Yang, Qiong; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Hamsten, Anders] Karolinska Inst, Atherosclerosis Res Unit, Ctr Mol Med, Karolinska Univ Hosp Solna,Dept Med, S-17176 Stockholm, Sweden. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Asselbergs, Folkert W.] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands. [Tregouet, David; Oudot-Mellakh, Tiphaine; Vinh Truong; Cambien, Francois] Univ Paris 06, INSERM, UMR S 937, ICAN Inst, Paris, France. [Shin, So-Youn; Soranzo, Nicole] Wellcome Trust Sanger Inst, Hinxton, England. [Ding, Jingzhong] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Baumert, Jens; Peters, Annette; Meisinger, Christa] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.; Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, VA Off Res & Dev, Seattle, WA USA. [Williams, Scott M.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Ikram, Mohammad A.; Dehghan, Abbas; Schrijvers, Elisabeth M. C.; Hofman, Albert] Erasmus Med Ctr MC Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, Mohammad A.; Uitterlinden, Andre G.] Erasmus MC Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Kleber, Marcus E.] Ludwigshafen Risk & Cardiovasc Hlth LURIC Study N, Freiburg, Germany. [Kleber, Marcus E.; Maerz, Winfried] Heidelberg Univ, Fac Med, Mannheim Inst Publ Hlth, Mannheim, Germany. [Becker, Diane M.; Yanek, Lisa R.] Johns Hopkins Sch Med, Div Internal Med, Baltimore, MD USA. [Mychaleckyj, Josyf C.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Tang, Weihong; Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Yang, Qiong; Chen, Ming-Huei] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Moore, Jason H.] Dartmouth Med Sch, Dept Genet, Lebanon, NH USA. [Moore, Jason H.] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Williams, Frances M. K.; Spector, Timothy D.; Soranzo, Nicole] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Dehghan, Abbas; Schrijvers, Elisabeth M. C.; Hofman, Albert; Uitterlinden, Andre G.] Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Silbernagel, Guenther] Univ Tubingen, Dept Internal Med, Div Endocrinol Diabetol Nephrol Vasc Dis & Clin C, Tubingen, Germany. [Smith, Shelly; Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Karakas, Mahir; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany. [Tofler, Geoffrey H.] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Navis, Gerjan J.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. [Lohman, Kurt] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Goel, Anuj; Peden, John F.; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford, England. [Goel, Anuj; Peden, John F.; Watkins, Hugh] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Hopewell, Jemma C.; Collins, Rory; Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, London, England. [Saleheen, Danish] Ctr Noncommunicable Dis Pakistan, Karachi, Pakistan. [Saleheen, Danish; Danesh, John] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge, England. [Lundmark, Per; Syvaenen, Ann-Christine] Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden. [Psaty, Bruce M.; Bis, Joshua C.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Boehm, Bernhard O.] Univ Ulm, Grad Sch Mol Diabetol & Endocrinol, Div Endocrinol Diabet & Metab, D-89069 Ulm, Germany. [Carter, Angela M.; Grant, Peter J.] Univ Leeds, Div Cardiovasc & Diabet Res, Leeds, W Yorkshire, England. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Taylor, Kent] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Franzosi, Maria Grazia] Ist Mario Negri, Dept Cardiovasc Res, Milan, Italy. [Seedorf, Udo] Univ Munster, LIFA, Gesell Arterioskleroseforsch 5, D-48149 Munster, Germany. [Franco-Cereceda, Anders] Karolinska Inst, Dept Mol Med & Surg, Cardiothorac Surg Unit, S-17176 Stockholm, Sweden. [Goodall, Alison H.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT USA. [Cushman, Mary] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Mueller-Nurasyid, Martina] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Chair Genet Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Basu, Saonli] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Matijevic, Nena] Univ Texas Hlth Sci Ctr Houston, Hemostasis Lab, Houston, TX USA. [van Gilst, Wiek H.; Hillege, Hans L.; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Broad Inst Harvard & Massachusetts Inst Technol M, Program Med & Populat Genet, Cambridge, MA USA. [Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Klopp, Norman] German Resrarch Ctr Environm Hlth, Helmholtz Zentrum Munchen, Div Mol Epidemiol, Neuherberg, Germany. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Winkelmann, Bernhard R.] Cardiol Team Sachsenhausen, Frankfurt, Germany. [Becker, Lewis C.] Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol & Biochem, Burlington, VT USA. [Maerz, Winfried] Synlab Acad, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Morange, Pierre-Emmanuel] Univ Aix Marseille 2, UMR S 626, INSERM, Marseille, France. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Hamsten, A (reprint author), Karolinska Inst, Atherosclerosis Res Unit, Ctr Mol Med, Karolinska Univ Hosp Solna,Dept Med, Bldg L8-03, S-17176 Stockholm, Sweden. EM odonnellc@nhlbi.nih.gov; anders.hamsten@ki.se RI Meisinger, Christine/B-5358-2014; Yang, Qiong/G-5438-2014; Strawbridge, Rona/H-5422-2012; Boehm, Bernhard/F-8750-2015; Peters, Annette/A-6117-2011; Tregouet, David-Alexandre/E-3961-2016; Williams, Scott/B-9491-2012; Johnson, Andrew/G-6520-2013; Sabater-Lleal, Maria/I-5832-2013; OI Strawbridge, Rona/0000-0001-8506-3585; Williams, Frances/0000-0002-2998-2744; Ikram, Mohammad Arfan/0000-0003-0372-8585; Seedorf, Udo/0000-0003-4652-5358; Folkersen, Lasse/0000-0003-0708-9530; Soranzo, Nicole/0000-0003-1095-3852; Meisinger, Christa/0000-0002-9026-6544; Watkins, Hugh/0000-0002-5287-9016; Ouwehand, Willem/0000-0002-7744-1790; Kleber, Marcus/0000-0003-0663-7275; Dehghan, Abbas/0000-0001-6403-016X; Sabater Lleal, Maria/0000-0002-0128-379X FU Biotechnology and Biological Sciences Research Council; British Heart Foundation [, RG/08/014/24067]; Department of Health; Intramural NIH HHS; Medical Research Council [, G0700931, MC_U137686857]; NCATS NIH HHS [UL1 TR000124]; NCRR NIH HHS [M01 RR00052, RR-024156, RR018787, UL1-RR-025005]; NHGRI NIH HHS [U01-HG-004402]; NHLBI NIH HHS [N01-HC-85084, 1U01 HL072518, HL080295, HL087652, HL105756, HL65234, HL67466, N01 HC-15103, N01 HC-55222, N01 HC085086, N01 HC095166, N01-HC-25195, N01-HC-35129, N01-HC-45133, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-75150, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85085, N01-HC-85086, N01-HC-85239, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, N02-HL-6-4278, P01 HL074940, R01 HL095603, R01 HL095796, R01 HL59684, R01-HL-086694, R01-HL-087641, R01-HL-59367, R01-HL59367, R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, R01HL071259, U01 HL072518]; NIA NIH HHS [1R01AG032098-01A1, AG-023629, AG-027058, AG-15928, AG-20098, N01AG62101, N01AG62103, N01AG62106]; NIDDK NIH HHS [DK063491, K24 DK080140]; NIGMS NIH HHS [P20 GM103534, T32 GM080178]; NLM NIH HHS [LM010098, R01 LM010098]; PHS HHS [HHSN268200625226C, HHSN268200782096C, HHSN268201200036C]; Wellcome Trust [, 090532] NR 37 TC 26 Z9 27 U1 0 U2 17 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 6 PY 2012 VL 120 IS 24 BP 4873 EP 4881 DI 10.1182/blood-2012-06-436188 PG 9 WC Hematology SC Hematology GA 064ZO UT WOS:000313115300031 PM 22990020 ER PT J AU Castellanos-Rizaldos, E Milbury, CA Makrigiorgos, GM AF Castellanos-Rizaldos, Elena Milbury, Coren Audrey Makrigiorgos, G. Mike TI Enrichment of Mutations in Multiple DNA Sequences Using COLD-PCR in Emulsion SO PLOS ONE LA English DT Article ID RESOLUTION MELTING ANALYSIS; COLORECTAL-CANCER; AMPLIFICATION; KRAS; IDENTIFICATION; SENSITIVITY; PROTOCOL; SAMPLES AB Background: Multiplex detection of low-level mutant alleles in the presence of wild-type DNA would be useful for several fields of medicine including cancer, pre-natal diagnosis and infectious diseases. COLD-PCR is a recently developed method that enriches low-level mutations during PCR cycling, thus enhancing downstream detection without the need for special reagents or equipment. The approach relies on the differential denaturation of DNA strands which contain Tm-lowering mutations or mismatches, versus 'homo-duplex' wild-type DNA. Enabling multiplex-COLD-PCR that can enrich mutations in several amplicons simultaneously is desirable but technically difficult to accomplish. Here we describe the proof of principle of an emulsion-PCR based approach that demonstrates the feasibility of multiplexed-COLD-PCR within a single tube, using commercially available mutated cell lines. This method works best with short amplicons; therefore, it could potentially be used on highly fragmented samples obtained from biological material or FFPE specimens. Methods: Following a multiplex pre-amplification of TP53 exons from genomic DNA, emulsions which incorporate the multiplex product, PCR reagents and primers specific for a given TP53 exon are prepared. Emulsions with different TP53 targets are then combined in a single tube and a fast-COLD-PCR program that gradually ramps up the denaturation temperature over several PCR cycles is applied (temperature-tolerant, TT-fast-eCOLD-PCR). The range of denaturation temperatures applied encompasses the critical denaturation temperature (T-c) corresponding to all the amplicons included in the reaction, resulting to a gradual enrichment of mutations within all amplicons encompassed by emulsion. Results: Validation for TT-fast-eCOLD-PCR is provided for TP53 exons 6-9. Using dilutions of mutated cell-line into wild-type DNA, we demonstrate simultaneous mutation enrichment between 7 to 15-fold in all amplicons examined. Conclusions: TT-fast-eCOLD-PCR expands the versatility of COLD-PCR and enables high-throughput enrichment of low-level mutant alleles over multiple sequences in a single tube. Citation: Castellanos-Rizaldos E, Milbury CA, Makrigiorgos GM (2012) Enrichment of Mutations in Multiple DNA Sequences Using COLD-PCR in Emulsion. PLoS ONE 7(12): e51362. doi:10.1371/journal.pone.0051362 C1 [Castellanos-Rizaldos, Elena; Milbury, Coren Audrey; Makrigiorgos, G. Mike] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div DNA Repair & Genome Stabil,Dept Radiat Oncol, Boston, MA 02115 USA. [Makrigiorgos, G. Mike] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Makrigiorgos, G. Mike] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol,Div Med Phys & Biophys, Boston, MA 02115 USA. RP Makrigiorgos, GM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Div DNA Repair & Genome Stabil,Dept Radiat Oncol, 44 Binney St, Boston, MA 02115 USA. EM mmakrigiorgos@lroc.harvard.edu FU Innovative Molecular Analysis Technologies Program of the National Cancer Institute (NCI) [CA-111994, CA-151164] FX This work was supported by the Innovative Molecular Analysis Technologies Program of the National Cancer Institute (NCI), grants CA-111994 and CA-151164 (GMM). The contents of this manuscript do not necessarily represent the official views of the National Cancer Institute 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 33 TC 1 Z9 2 U1 1 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 6 PY 2012 VL 7 IS 12 AR e51362 DI 10.1371/journal.pone.0051362 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 057UO UT WOS:000312589700039 PM 23236486 ER PT J AU Kim, J Keay, SK You, S Loda, M Freeman, MR AF Kim, Jayoung Keay, Susan K. You, Sungyong Loda, Massimo Freeman, Michael R. TI A Synthetic Form of Frizzled 8-Associated Antiproliferative Factor Enhances p53 Stability through USP2a and MDM2 SO PLOS ONE LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; BLADDER EPITHELIAL-CELLS; INTERSTITIAL CYSTITIS PATIENTS; DEUBIQUITINATING ENZYME USP2A; TUMOR-SUPPRESSOR; CARCINOMA CELLS; PROSTATE-CANCER; URINE MARKERS; CYCLIN D1; PROTEIN AB Frizzled 8-associated Antiproliferative Factor (APF) is a sialoglycopeptide urinary biomarker of interstitial cystitis/painful bladder syndrome (IC/PBS), a chronic condition of unknown etiology with variable symptoms that generally include pelvic and/or perineal pain, urinary frequency, and urgency. We previously reported that native human APF suppresses the proliferation of normal bladder epithelial cells through a mechanism that involves increased levels of p53. The goal of this study was to delineate the regulatory mechanism whereby p53 expression is regulated by APF. Two APF-responsive cell lines (T24 bladder carcinoma cells and the immortalized human bladder epithelial cell line, TRT-HU1) were treated with asialo-APF (as-APF), a chemically synthesized form of APF. Biochemical analysis revealed that as-APF increased p53 levels in two ways: by decreasing ubiquitin specific protease 2a (USP2a) expression leading to enhanced ubiquitination of murine double minute 2 E3 ubiquitin ligase (MDM2), and by suppressing association of p53 with MDM2, thus impairing p53 ubiquitination. Biological responses to as-APF were suppressed by increased expression of wild type, but not mutant USP2a, which enhanced cell growth via upregulation of a cell cycle mediator, cyclin D1, at both transcription and protein levels. Consistent with this, gene silencing of USP2a with siRNA arrested cell proliferation. Our findings suggest that APF upregulates cellular p53 levels via functional attenuation of the USP2a-MDM2 pathway, resulting in p53 accumulation and growth arrest. These data also imply that targeting USP2a, MDM2, p53 and/or complex formation by these molecules may be relevant in the development of novel therapeutic approaches to IC/PBS. Citation: Kim J, Keay SK, You S, Loda M, Freeman MR (2012) A Synthetic Form of Frizzled 8-Associated Antiproliferative Factor Enhances p53 Stability through USP2a and MDM2. PLoS ONE 7(12): e50392. doi:10.1371/journal.pone.0050392 C1 [Kim, Jayoung; You, Sungyong; Freeman, Michael R.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Surg, Div Canc Biol & Therapeut, Los Angeles, CA 90048 USA. [Kim, Jayoung; You, Sungyong; Freeman, Michael R.] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Biomed Sci, Los Angeles, CA 90048 USA. [Kim, Jayoung; Freeman, Michael R.] Childrens Hosp, Urol Dis Res Ctr, Boston, MA 02115 USA. [Kim, Jayoung; Freeman, Michael R.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Kim, Jayoung; Freeman, Michael R.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Keay, Susan K.] Univ Maryland, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21201 USA. [Keay, Susan K.] VA Maryland Hlth Care Ctr, Baltimore, MD USA. [Loda, Massimo] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA USA. [Loda, Massimo] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Loda, Massimo] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Kim, J (reprint author), Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Surg, Div Canc Biol & Therapeut, Los Angeles, CA 90048 USA. EM Jayoung.Kim@cshs.org FU NIH [R37 DK47556, R01 DK57691, P50 DK65298, R01 CA131945, R01 DK52596]; Fishbein Family IC Research Foundation/Interstitial Cystitis Association; New York Academy of Medicine; Children's Hospital Boston Faculty Development FX This research was supported by: NIH grants R37 DK47556, R01 DK57691, P50 DK65298 (to MRF); R01 CA131945 (to ML); R01 DK52596 (to SKK); and the Fishbein Family IC Research Foundation/Interstitial Cystitis Association; New York Academy of Medicine; and Children's Hospital Boston Faculty Development (to JK); JK is an American Urological Association Foundation Research Scholar and an Eleanor and Miles Shore Scholar of Harvard Medical School. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 3 Z9 3 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 6 PY 2012 VL 7 IS 12 AR e50392 DI 10.1371/journal.pone.0050392 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 057UO UT WOS:000312589700014 PM 23236372 ER PT J AU Talkowski, ME Ordulu, Z Pillalamarri, V Benson, CB Blumenthal, I Connolly, S Hanscom, C Hussain, N Pereira, S Picker, J Rosenfeld, JA Shaffer, LG Wilkins-Haug, LE Gusella, JF Morton, CC AF Talkowski, Michael E. Ordulu, Zehra Pillalamarri, Vamsee Benson, Carol B. Blumenthal, Ian Connolly, Susan Hanscom, Carrie Hussain, Naveed Pereira, Shahrin Picker, Jonathan Rosenfeld, Jill A. Shaffer, Lisa G. Wilkins-Haug, Louise E. Gusella, James F. Morton, Cynthia C. TI Clinical Diagnosis by Whole-Genome Sequencing of a Prenatal Sample SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BALANCED CHROMOSOME REARRANGEMENTS; CHARGE ASSOCIATION; ROUTINE; UPDATE; CHD7 AB Conventional cytogenetic testing offers low-resolution detection of balanced karyotypic abnormalities but cannot provide the precise, gene-level knowledge required to predict outcomes. The use of high-resolution whole-genome deep sequencing is currently impractical for the purpose of routine clinical care. We show here that whole-genome "jumping libraries" can offer an immediately applicable, nucleotide-level complement to conventional genetic diagnostics within a time frame that allows for clinical action. We performed large-insert sequencing of DNA extracted from amniotic-fluid cells with a balanced de novo translocation. The amniotic-fluid sample was from a patient in the third trimester of pregnancy who underwent amniocentesis because of severe polyhydramnios after multiple fetal anomalies had been detected on ultrasonography. Using a 13-day sequence and analysis pipeline, we discovered direct disruption of CHD7, a causal locus in the CHARGE syndrome (coloboma of the eye, heart anomaly, atresia of the choanae, retardation, and genital and ear anomalies). Clinical findings at birth were consistent with the CHARGE syndrome, a diagnosis that could not have been reliably inferred from the cytogenetic breakpoint. This case study illustrates the potential power of customized whole-genome jumping libraries when used to augment prenatal karyotyping. C1 [Talkowski, Michael E.; Gusella, James F.; Morton, Cynthia C.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Talkowski, Michael E.; Pillalamarri, Vamsee; Blumenthal, Ian; Hanscom, Carrie; Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Talkowski, Michael E.; Gusella, James F.; Morton, Cynthia C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Ordulu, Zehra; Pereira, Shahrin; Wilkins-Haug, Louise E.; Morton, Cynthia C.] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Benson, Carol B.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Morton, Cynthia C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Connolly, Susan] Childrens Hosp, Dept Radiol, Boston, MA 02115 USA. [Picker, Jonathan] Childrens Hosp, Dept Psychiat, Div Genet, Boston, MA 02115 USA. [Hussain, Naveed] Univ Connecticut, Dept Pediat, Farmington, CT USA. [Rosenfeld, Jill A.; Shaffer, Lisa G.] PerkinElmer, Signature Genom Labs, Spokane, WA USA. RP Morton, CC (reprint author), Harvard Univ, Sch Med, Dept Neurol, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM cmorton@partners.org OI Hussain, Naveed/0000-0002-1809-5760 FU National Institutes of Health [GM061354, HD065286, MH087123, MH095867]; Simons Foundation for Autism Research; Nancy Lurie Marks Family Foundation FX Supported by grants from the National Institutes of Health (GM061354, to Drs. Morton and Gusella; HD065286, to Dr. Gusella; and MH087123 and MH095867, to Dr. Talkowski). Drs. Talkowski and Gusella are supported by the Simons Foundation for Autism Research and the Nancy Lurie Marks Family Foundation. NR 19 TC 60 Z9 65 U1 1 U2 17 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 6 PY 2012 VL 367 IS 23 BP 2226 EP 2232 DI 10.1056/NEJMoa1208594 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 048DO UT WOS:000311890600009 PM 23215558 ER PT J AU Treon, SP Xu, L Hunter, ZR AF Treon, Steven P. Xu, Lian Hunter, Zachary R. TI MYD88 L265P Somatic Mutation in IgM MGUS Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Treon, Steven P.; Xu, Lian; Hunter, Zachary R.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM steven_treon@dfci.harvard.edu RI Hunter, Zachary/H-3018-2013 OI Hunter, Zachary/0000-0002-1689-1691 NR 3 TC 2 Z9 2 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 6 PY 2012 VL 367 IS 23 BP 2256 EP 2257 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 048DO UT WOS:000311890600021 ER PT J AU Winters-Stone, KM Li, FZ Horak, F Luoh, SW Bennett, JA Nail, L Dieckmann, N AF Winters-Stone, Kerri M. Li, Fuzhong Horak, Fay Luoh, Shiuh-Wen Bennett, Jill A. Nail, Lillian Dieckmann, Nathan TI Comparison of tai chi vs. strength training for fall prevention among female cancer survivors: study protocol for the GET FIT trial SO BMC CANCER LA English DT Article DE Resistance training; Exercise; Physical function; Postural stability; Muscle strength; Chemotherapy; Neoplasm; Fracture ID RANDOMIZED CONTROLLED-TRIAL; LOWER-EXTREMITY FUNCTION; RECEIVING ADJUVANT CHEMOTHERAPY; PHYSICAL PERFORMANCE BATTERY; BREAST-CANCER; OLDER-ADULTS; EXERCISE PROGRAM; BODY-COMPOSITION; ENERGY-BALANCE; WOMENS HEALTH AB Background: Women with cancer are significantly more likely to fall than women without cancer placing them at higher risk of fall-related fractures, other injuries and disability. Currently, no evidence-based fall prevention strategies exist that specifically target female cancer survivors. The purpose of the GET FIT (Group Exercise Training for Functional Improvement after Treatment) trial is to compare the efficacy of two distinct types of exercise, tai chi versus strength training, to prevent falls in women who have completed treatment for cancer. The specific aims of this study are to: 1) Determine and compare the efficacy of both tai chi training and strength training to reduce falls in older female cancer survivors, 2) Determine the mechanism(s) by which tai chi and strength training each reduces falls and, 3) Determine whether or not the benefits of each intervention last after structured training stops. Methods/Design: We will conduct a three-group, single-blind, parallel design, randomized controlled trial in women, aged 50-75 years old, who have completed chemotherapy for cancer comparing 1) tai chi 2) strength training and 3) a placebo control group of seated stretching exercise. Women will participate in supervised study programs twice per week for six months and will be followed for an additional six months after formal training stops. The primary outcome in this study is falls, which will be prospectively tracked by monthly self-report. Secondary outcomes are maximal leg strength measured by isokinetic dynamometry, postural stability measured by computerized dynamic posturography and physical function measured by the Physical Performance Battery, all measured at baseline, 3, 6 and 12 months. The sample for this trial (N=429, assuming 25% attrition) will provide adequate statistical power to detect at least a 47% reduction in the fall rate over 1 year by being in either of the 2 exercise groups versus the control group. Discussion: The GET FIT trial will provide important new knowledge about preventing falls using accessible and implementable exercise interventions for women following chemotherapy for cancer. ClinicalTrials.gov NCT01635413 C1 [Winters-Stone, Kerri M.; Bennett, Jill A.; Nail, Lillian; Dieckmann, Nathan] Oregon Hlth & Sci Univ, Sch Nursing, Portland, OR 97239 USA. [Winters-Stone, Kerri M.; Luoh, Shiuh-Wen; Bennett, Jill A.; Nail, Lillian] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA. [Li, Fuzhong] Oregon Res Inst, Eugene, OR 97403 USA. [Horak, Fay] Oregon Hlth & Sci Univ, Sch Med, Portland, OR 97239 USA. [Luoh, Shiuh-Wen] Portland VA Med Ctr, Portland, OR 97239 USA. RP Winters-Stone, KM (reprint author), Oregon Hlth & Sci Univ, Sch Nursing, Portland, OR 97239 USA. EM wintersk@ohsu.edu OI Li, Fuzhong/0000-0001-6644-4702 FU NCI NIH HHS [R01 CA163474]; NIA NIH HHS [R37 AG006457] NR 78 TC 8 Z9 9 U1 7 U2 41 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD DEC 5 PY 2012 VL 12 AR 577 DI 10.1186/1471-2407-12-577 PG 10 WC Oncology SC Oncology GA 067CJ UT WOS:000313270100001 PM 23217054 ER PT J AU Boros, E Polasek, M Zhang, ZD Caravan, P AF Boros, Eszter Polasek, Miloslav Zhang, Zhaoda Caravan, Peter TI Gd(DOTAla): A Single Amino Acid Gd-complex as a Modular Tool for High Relaxivity MR Contrast Agent Development SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SOLID-PHASE SYNTHESIS; HIGH MAGNETIC-FIELD; WATER EXCHANGE; SERUM-ALBUMIN; GADOLINIUM COMPLEXES; STRUCTURAL ENTRY; LANTHANIDE; BINDING; MS-325; OPTIMIZATION AB MR imaging at high magnetic fields benefits from an increased signal-to-noise ratio; however T-1-based MR contrast agents show decreasing relaxivity (r(1)) at higher fields. High field, high relaxivity contrast agents can be designed by carefully controlling the rotational dynamics of the molecule. To this end, we investigated applications of the alanine analogue of Gd(DOTA), Gd(DOTAla). Fmoc-protected DOTAla suitable for solid phase peptide synthesis was synthesized and integrated into polypeptide structures. Gd(III) coordination results in very rigid attachment of the metal chelate to the peptide backbone through both the amino acid side chain and coordination of the amide carbonyl. Linear and cyclic monomers (GdL1, GdC1), dimers (Gd(2)L2, Gd(2)C2), and trimers (Gd(3)L3, Gd(3)C3) were prepared and relaxivities were determined at different field strengths ranging from 0.47 to 11.7 T. Amide carbonyl coordination was indirectly confirmed by determination of the hydration number q for the EuL1 integrated into a peptide backbone, q = 0.96 +/- 0.09. The water residency time of GdL1 at 37 degrees C was optimal for relaxivity, tau(M) = 17 +/- 2 ns. Increased molecular size leads to increased per Gd relaxivity (from r(1) = 7.5 for GdLl to 12.9 mM(-1) s(-1) for Gd(3)L3 at 1.4 T, 37 degrees C). The cyclic, multimeric derivatives exhibited slightly higher relaxivities than the corresponding linearized multimers (Gd(2)C2: r(1) = 10.5 mM(-1) s(-1) versus Gd(2)C2-red r(1) = 9 mM(-1) s(-1) at 1.4 T, 37 degrees C). Overall, all six synthesized Gd complexes had higher relaxivities at low, intermediate, and high fields than the clinically used small molecule contrast agent [Gd(HP-DO3A)(H2O)]. C1 [Boros, Eszter; Polasek, Miloslav; Zhang, Zhaoda; Caravan, Peter] Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Med Sch, Charlestown, MA 02129 USA. RP Caravan, P (reprint author), Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Med Sch, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM caravan@nmr.mgh.harvard.edu RI Polasek, Miloslav/G-5949-2014 FU National Institute of Biomedical Imaging and Bioengineering [R01EB009062]; National Center for Research Resources [P41RR14075]; Swiss National Science Foundation FX Dr. Mohammad A. Yaseen is warmly acknowledged for measurement of the luminescence lifetimes of Eu(LI). Dr. Daniel Schuhle is acknowledged for helpful discussions. This work was supported in part by awards R01EB009062 from the National Institute of Biomedical Imaging and Bioengineering and P41RR14075 from the National Center for Research Resources. E.B. acknowledges the Swiss National Science Foundation for a fellowship for prospective researchers. NR 52 TC 38 Z9 38 U1 0 U2 84 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD DEC 5 PY 2012 VL 134 IS 48 BP 19858 EP 19868 DI 10.1021/ja309187m PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 047VM UT WOS:000311869600055 PM 23157602 ER PT J AU Vernochet, C Mourier, A Bezy, O Macotela, Y Boucher, J Rardin, MJ An, D Lee, KY Ilkayeva, OR Zingaretti, CM Emanuelli, B Smyth, G Cinti, S Newgard, CB Gibson, BW Larsson, NG Kahn, R AF Vernochet, Cecile Mourier, Arnaud Bezy, Olivier Macotela, Yazmin Boucher, Jeremie Rardin, Matthew J. An, Ding Lee, Kevin Y. Ilkayeva, Olga R. Zingaretti, Cristina M. Emanuelli, Brice Smyth, Graham Cinti, Saverio Newgard, Christopher B. Gibson, Bradford W. Larsson, Nils-Goeran Kahn, Ronald TI Adipose-Specific Deletion of TFAM Increases Mitochondrial Oxidation and Protects Mice against Obesity and Insulin Resistance SO CELL METABOLISM LA English DT Article ID ELECTRON-TRANSPORT CHAIN; SKELETAL-MUSCLE; KNOCKOUT MICE; COMPLEX-I; GENE-EXPRESSION; TISSUE; WHITE; FAT; DYSFUNCTION; PGC-1-ALPHA AB Obesity and type 2 diabetes are associated with mitochondrial dysfunction in adipose tissue, but the role for adipose tissue mitochondria in the development of these disorders is currently unknown. To understand the impact of adipose tissue mitochondria on whole-body metabolism, we have generated a mouse model with disruption of the mitochondrial transcription factor A (TFAM) specifically in fat. F-TFKO adipose tissue exhibit decreased mtDNA copy number, altered levels of proteins of the electron transport chain, and perturbed mitochondrial function with decreased complex I activity and greater oxygen consumption and uncoupling. As a result, F-TFKO mice exhibit higher energy expenditure and are protected from age- and diet-induced obesity, insulin resistance, and hepatosteatosis, despite a greater food intake. Thus, TFAM deletion in the adipose tissue increases mitochondrial oxidation that has positive metabolic effects, suggesting that regulation of adipose tissue mitochondria may be a potential therapeutic target for the treatment of obesity. C1 [Vernochet, Cecile; Bezy, Olivier; Macotela, Yazmin; Boucher, Jeremie; An, Ding; Lee, Kevin Y.; Emanuelli, Brice; Smyth, Graham; Kahn, Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. [Mourier, Arnaud; Larsson, Nils-Goeran] Max Planck Inst Biol Ageing, D-50931 Cologne, Germany. [Rardin, Matthew J.; Gibson, Bradford W.] Buck Inst Res Aging, Novato, CA 94945 USA. [Ilkayeva, Olga R.; Newgard, Christopher B.] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27704 USA. [Zingaretti, Cristina M.; Cinti, Saverio] United Hosp Ancona, Department Expt & Clin Med, I-60020 Ancona, Italy. [Zingaretti, Cristina M.; Cinti, Saverio] United Hosp Ancona, Diagnost Electron Microscopy Unit, I-60020 Ancona, Italy. [Cinti, Saverio] IRCCS San Raffaele Pisana, Adipose Organ Lab, I-00163 Rome, Italy. [Bezy, Olivier] Pfizer, Cardiovasc Metab & Endocrine Dis, Cambridge, MA 02139 USA. [Macotela, Yazmin] UNAM, Inst Neurobiol, Queretaro 76230, Mexico. RP Kahn, R (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. EM c.ronald.kahn@joslin.harvard.edu RI MOURIER, Arnaud/I-8117-2012; Emanuelli, Brice/M-2097-2016; Smyth, Gordon/B-5276-2008; OI MOURIER, Arnaud/0000-0002-5413-611X; Smyth, Gordon/0000-0001-9221-2892; Emanuelli, Brice/0000-0001-5795-5666 FU Joslin Diabetes Microscopy Core [P30 DK36836]; NIH [S10-RR025545, DK-082659]; Eli Lilly Foundation; European Community [Health-F2-2011-278373]; Mary K. Iacocca Professorship FX The authors are grateful to Alison Burkart for helpful discussion and manuscript editing; Siegfried Ussar for help with mitochondria isolation; Michael Rourk for animal care; Chris Cahill for confocal microscopy assistance (Joslin Diabetes Microscopy Core, P30 DK36836 and NIH S10-RR025545); Girijesh Buruzula and Joyce LaVecchio for flow cytometry assistance; Alan Clermont (DERC Physiology Core); and H. Li (DERC Specialized Assay Core). This work was supported by NIH grant DK-082659, a grant from the Eli Lilly Foundation, the European Community's FP7, Grant Health-F2-2011-278373 to S.C., and the Mary K. Iacocca Professorship to C.R.K. C.R.K. is a founder and SAB member of Ember Therapeutics. NR 48 TC 53 Z9 57 U1 3 U2 25 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 DEC 5 PY 2012 VL 16 IS 6 BP 765 EP 776 DI 10.1016/j.cmet.2012.10.016 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 055ML UT WOS:000312420600009 PM 23168219 ER PT J AU Derecka, M Gornicka, A Koralov, SB Szczepanek, K Morgan, M Raje, V Sisler, J Zhang, QF Otero, D Cichy, J Rajewsky, K Shimoda, K Poli, V Strobl, B Pellegrini, S Harris, TE Seale, P Russell, AP McAinch, AJ O'Brien, PE Keller, SR Croniger, CM Kordula, T Larner, AC AF Derecka, Marta Gornicka, Agnieszka Koralov, Sergei B. Szczepanek, Karol Morgan, Magdalena Raje, Vidisha Sisler, Jennifer Zhang, Qifang Otero, Dennis Cichy, Joanna Rajewsky, Klaus Shimoda, Kazuya Poli, Valeria Strobl, Birgit Pellegrini, Sandra Harris, Thurl E. Seale, Patrick Russell, Aaron P. McAinch, Andrew J. O'Brien, Paul E. Keller, Susanna R. Croniger, Colleen M. Kordula, Tomasz Larner, Andrew C. TI Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity SO CELL METABOLISM LA English DT Article ID ADULT HUMANS; SKELETAL-MUSCLE; WHITE 3T3-L1; PPAR-GAMMA; RECEPTOR; GENE; ADIPOCYTES; INTERFERON; EXPRESSION; FAT AB Mice lacking the Jak tyrosine kinase member Tyk2 become progressively obese due to aberrant development of Myf5+ brown adipose tissue (BAT). Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, are dramatically decreased in mice placed on a high-fat diet and in obese humans. Expression of Tyk2 or the constitutively active form of the transcription factor Stat3 (CAStat3) restores differentiation in Tyk2(-/-) brown preadipocytes. Furthermore, Tyk2(-/-) mice expressing CAStat3 transgene in BAT also show improved BAT development, normal levels of insulin, and significantly lower body weights. Stat3 binds to PRDM16, a master regulator of BAT differentiation, and enhances the stability of PRDM16 protein. These results define Tyk2 and Stat3 as critical determinants of brown fat lineage and suggest that altered levels of Tyk2 are associated with obesity in both rodents and humans. C1 [Derecka, Marta; Szczepanek, Karol; Morgan, Magdalena; Raje, Vidisha; Sisler, Jennifer; Zhang, Qifang; Kordula, Tomasz; Larner, Andrew C.] Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Richmond, VA 23298 USA. [Derecka, Marta; Szczepanek, Karol; Morgan, Magdalena; Raje, Vidisha; Sisler, Jennifer; Zhang, Qifang; Kordula, Tomasz; Larner, Andrew C.] Virginia Commonwealth Univ, Mol Biol & Massey Canc Ctr, Richmond, VA 23298 USA. [Gornicka, Agnieszka] Cleveland Clin Fdn, Dept Immunol, Cleveland, OH 44195 USA. [Koralov, Sergei B.] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Otero, Dennis] Univ Calif San Diego, Dept Biol Sci, La Jolla, CA 92093 USA. [Cichy, Joanna] Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Immunol, PL-30387 Krakow, Poland. [Rajewsky, Klaus] Harvard Univ, Sch Med, Children Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Shimoda, Kazuya] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Shimoda, Kazuya] Miyazaki Univ, Fac Med, Dept Gastroenterol & Hematol, Kiyotake, Miyazaki 8891692, Japan. [Poli, Valeria] Univ Turin, Ctr Mol Biotechnol, Dept Genet Biol & Biochem, I-10126 Turin, Italy. [Strobl, Birgit] Univ Vet Med Vienna, Dept Biomed Sci, Inst Anim Breeding & Genet, A-1210 Vienna, Austria. [Pellegrini, Sandra] Inst Pasteur, Dept Immunol, F-75724 Paris, France. [Harris, Thurl E.] Univ Virginia, Sch Med, Dept Pharmacol, Charlottesville, VA 22903 USA. [Seale, Patrick] Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. [Russell, Aaron P.] Deakin Univ, Sch Exercise & Nutr Sci, Ctr Phys Activ & Nutr CPAN Res, Burwood 3125, Australia. [McAinch, Andrew J.] Victoria Univ, Sch Biomed & Hlth Sci, Biomed & Lifestyle Dis BioLED Unit, St Albans 3021, Australia. [O'Brien, Paul E.] Monash Univ, CORE, Alfred Hosp, Melbourne, Vic 3004, Australia. [Keller, Susanna R.] Univ Virginia, Sch Med, Dept Med, Charlottesville, VA 22908 USA. [Croniger, Colleen M.] Case Western Reserve Univ, Sch Med, Dept Nutr, Cleveland, OH 44106 USA. RP Larner, AC (reprint author), Virginia Commonwealth Univ, Dept Biochem & Mol Biol, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM alarner@vcu.edu RI zhang, qifang/F-9857-2013; zhang, qifang/H-5691-2013; Pellegrini, Sandra/G-5546-2015; Poli, Valeria/A-9215-2012; OI Pellegrini, Sandra/0000-0001-5837-7589; Poli, Valeria/0000-0002-3739-3966; Strobl, Birgit/0000-0001-5716-3212; McAinch, Andrew/0000-0002-8762-4865; Raje, Vidisha/0000-0003-1808-6511 FU Austrian Science Fund [FWF SFB-F28]; [R01 AI059710-01]; [R21 AI088487] FX This work was supported in part by R01 AI059710-01 and R21 AI088487 to A.C.L. B.S. was supported by the Austrian Science Fund (FWF SFB-F28). We would like to thank Dr. Bruce Spiegelman for his advice. NR 41 TC 21 Z9 22 U1 1 U2 27 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 DEC 5 PY 2012 VL 16 IS 6 BP 814 EP 824 DI 10.1016/j.cmet.2012.11.005 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 055ML UT WOS:000312420600013 PM 23217260 ER PT J AU Shanmugasundararaj, S Das, J Sandberg, WS Zhou, XJ Wang, D Messing, RO Bruzik, KS Stehle, T Miller, KW AF Shanmugasundararaj, Sivananthaperumal Das, Joydip Sandberg, Warren S. Zhou, Xiaojuan Wang, Dan Messing, Robert O. Bruzik, Karol S. Stehle, Thilo Miller, Keith W. TI Structural and Functional Characterization of an Anesthetic Binding Site in the Second Cysteine-Rich Domain of Protein Kinase C delta SO BIOPHYSICAL JOURNAL LA English DT Article ID GATED ION-CHANNEL; X-RAY-STRUCTURE; HYDROGEN-BONDS; INHALED ANESTHETICS; FIREFLY LUCIFERASE; CRYSTAL-STRUCTURES; PHORBOL ESTERS; ACTIVATION; ALPHA; DIACYLGLYCEROL AB Elucidating the principles governing anesthetic-protein interactions requires structural determinations at high resolutions not yet achieved with ion channels. Protein kinase C (PKC) activity is modulated by general anesthetics. We solved the structure of the phorbol-binding domain (C1B) of PKC delta complexed with an ether (methoxymethylcycloprane) and with an alcohol (cyclopropylmethanol) at 1.36-angstrom resolution. The cyclopropane rings of both agents displace a single water molecule in a surface pocket adjacent to the phorbol-binding site, making van der Waals contacts with the backbone and/or side chains of residues Asn-237 to Ser-240. Surprisingly, two water molecules anchored in a hydrogen-bonded chain between Thr-242 and Lys-260 impart elasticity to one side of the binding pocket. The cyclopropane ring takes part in pi-acceptor hydrogen bonds with the amide of Met-239. There is a crucial hydrogen bond between the oxygen atoms of the anesthetics and the hydroxyl of Tyr-236. A Tyr-236-Phe mutation results in loss of binding. Thus, both van der Waals interactions and hydrogen-bonding are essential for binding to occur. Ethanol failed to bind because it is too short to benefit from both interactions. Cyclopropylmethanol inhibited phorbol-ester-induced PKC delta activity, but failed to do so in PKC delta containing the Tyr-236-Phe mutation. C1 [Shanmugasundararaj, Sivananthaperumal; Das, Joydip; Sandberg, Warren S.; Zhou, Xiaojuan; Miller, Keith W.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Stehle, Thilo] Massachusetts Gen Hosp, Lab Dev Immunol, Boston, MA 02114 USA. [Sandberg, Warren S.; Miller, Keith W.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Wang, Dan; Messing, Robert O.] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Emeryville, CA USA. [Bruzik, Karol S.] Univ Illinois, Coll Pharm, Chicago, IL USA. RP Miller, KW (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. EM k_miller@helix.mgh.harvard.edu RI Messing, Robert/D-3642-2015 OI Messing, Robert/0000-0002-5345-4431 FU U.S. Public Health Service [GM 069726, AA018316]; Foundation for Anesthesia Education and Research award; Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital; State of California for medical research on alcohol and substance abuse through University of California, San Francisco; National Center for Research Resources at the National Institutes of Health [RR-15301]; National Institute of General Medical Sciences, National Institutes of Health [GM-0080]; U.S. Department of Energy [DE-AC02-98CH10886] FX We thank Elizabeth Kelly for assistance with the anesthetic potency measurements, Dr. Peter M. Blumberg for providing the PKCd C1B construct and Dr. David Jones for providing us with the structure factor file for his LUSH structure. Molecular graphics images were produced using the University of California, San Francisco, Chimera package (59) from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR01081) or using Pymol (60). S. S. thanks V. Stojanoff, M. Allaire, J. Jakoncic, and F. Yokaichiya of beam line X6A, and N. Sukumar of BM8, for their support during data collection.; This research was supported by grants from the U.S. Public Health Service to K. W. M. (GM 069726) and R.O.M. (AA018316), by a Foundation for Anesthesia Education and Research award to W. S. S., by the Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital, and by funds provided by the State of California for medical research on alcohol and substance abuse through University of California, San Francisco, to R.O.M. This work is based upon research conducted at the Northeastern Collaborative Access Team beam lines (BM8) of the Advanced Photon Source, which is supported by award RR-15301 from the National Center for Research Resources at the National Institutes of Health. Research carried out (in whole or in part) at X6A beam line was funded by the National Institute of General Medical Sciences, National Institutes of Health, under agreement GM-0080. The National Synchrotron Light Source, Brookhaven National Laboratory is supported by the U.S. Department of Energy under contract no. DE-AC02-98CH10886. NR 61 TC 10 Z9 10 U1 0 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD DEC 5 PY 2012 VL 103 IS 11 BP 2331 EP 2340 DI 10.1016/j.bpj.2012.10.034 PG 10 WC Biophysics SC Biophysics GA 049DX UT WOS:000311963300012 PM 23283232 ER PT J AU Egawa, K Kitagawa, K Inoue, K Takayama, M Takayama, C Saitoh, S Kishino, T Kitagawa, M Fukuda, A AF Egawa, Kiyoshi Kitagawa, Kyoko Inoue, Koichi Takayama, Masakazu Takayama, Chitoshi Saitoh, Shinji Kishino, Tatsuya Kitagawa, Masatoshi Fukuda, Atsuo TI Decreased Tonic Inhibition in Cerebellar Granule Cells Causes Motor Dysfunction in a Mouse Model of Angelman Syndrome SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID UBIQUITIN-DEPENDENT DEGRADATION; AMINOBUTYRIC-ACID TRANSPORTER-1; GABA(A) RECEPTORS; PURKINJE NEURONS; RAT CEREBELLUM; A RECEPTORS; UBE3A; EXPRESSION; BINDING; LIGASE AB Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the UBE3A gene encoding a ubiquitin E3 ligase. Motor dysfunction is a characteristic feature of Angelman syndrome, but neither the mechanisms of action nor effective therapeutic strategies have yet been elucidated. We report that tonic inhibition is specifically decreased in cerebellar granule cells of Ube3a-deficient mice, a model of Angelman syndrome. As a mechanism underlying this decrease in tonic inhibition, we show that Ube3a controls degradation of gamma-aminobutyric acid (GABA) transporter 1 (GAT1) and that deficiency of Ube3a induces a surplus of GAT1 that results in a decrease in GABA concentrations in the extrasynaptic space. Administering low doses of 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (THIP), a selective extrasynaptic GABA(A) receptor agonist, improves the abnormal firing properties of a population of Purkinje cells in cerebellar brain slices and reduces cerebellar ataxia in Ube3a-deficient mice in vivo. These results suggest that pharmacologically increasing tonic inhibition may be a useful strategy for alleviating motor dysfunction in Angelman syndrome. C1 [Egawa, Kiyoshi; Inoue, Koichi; Takayama, Masakazu; Fukuda, Atsuo] Hamamatsu Univ Sch Med, Dept Neurophysiol, Hamamatsu, Shizuoka 4313192, Japan. [Kitagawa, Kyoko; Kitagawa, Masatoshi] Hamamatsu Univ Sch Med, Dept Mol Biol, Hamamatsu, Shizuoka 4313192, Japan. [Takayama, Chitoshi] Univ Ryukyus, Sch Med, Dept Mol Anat, Nishihara, Okinawa 9030215, Japan. [Saitoh, Shinji] Nagoya City Univ, Grad Sch Med Sci, Dept Pediat & Neonatol, Nagoya, Aichi 4678601, Japan. [Kishino, Tatsuya] Nagasaki Univ, Ctr Frontier Life Sci, Nagasaki 8528523, Japan. RP Egawa, K (reprint author), Massachusetts Gen Hosp, Dept Neurol, 16th St,CNY B-114, Boston, MA 02114 USA. EM cdh67560@par.odn.ne.jp; axfukuda@hama-med.ac.jp OI Fukuda, Atsuo/0000-0001-7112-4834; Saitoh, Shinji/0000-0001-6911-3351 FU Japan Society for the Promotion of Science [23791166, 22390041]; Ministry of Education, Culture, Sports, Science, and Technology, Japan [21026013, 23115506] FX This work was supported by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science #23791166 (K.E.); Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, #21026013 and 23115506 (to A.F.); and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science #22390041 (to A.F.). NR 63 TC 24 Z9 24 U1 3 U2 24 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD DEC 5 PY 2012 VL 4 IS 163 AR 163ra157 DI 10.1126/scitranslmed.3004655 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 049PU UT WOS:000311996700004 PM 23220633 ER PT J AU Traverso, G McMahon, GT AF Traverso, Giovanni McMahon, Graham T. TI Residency Training and International Medical Graduates Coming to America No More SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID EDUCATION C1 [McMahon, Graham T.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Traverso, Giovanni] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Traverso, Giovanni; McMahon, Graham T.] Harvard Univ, Sch Med, Boston, MA USA. [Traverso, Giovanni] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Traverso, Giovanni] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. RP McMahon, GT (reprint author), Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, 221 Longwood Ave, Boston, MA 02115 USA. EM gmcmahon@partners.org RI McMahon, Graham/D-3740-2009 OI McMahon, Graham/0000-0003-4288-6535 FU NIDDK NIH HHS [T32 DK007191] NR 10 TC 9 Z9 9 U1 3 U2 16 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 DEC 5 PY 2012 VL 308 IS 21 BP 2193 EP 2194 DI 10.1001/jama.2012.14681 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 047HI UT WOS:000311829500008 PM 23212494 ER PT J AU Volpp, KG Shea, JA Small, DS Basner, M Zhu, JS Norton, L Ecker, A Novak, C Bellini, LM Dine, CJ Mollicone, DJ Dinges, DF AF Volpp, Kevin G. Shea, Judy A. Small, Dylan S. Basner, Mathias Zhu, Jingsan Norton, Laurie Ecker, Adrian Novak, Cristina Bellini, Lisa M. Dine, C. Jessica Mollicone, Daniel J. Dinges, David F. TI Effect of a Protected Sleep Period on Hours Slept During Extended Overnight In-hospital Duty Hours Among Medical Interns A Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID VIGILANCE TEST PVT; PSYCHOMOTOR VIGILANCE; DOSE-RESPONSE; WORK; RESTRICTION; ALERTNESS; MORTALITY; RECOVERY; DURATION; REFORM AB Context A 2009 Institute of Medicine report recommended protected sleep periods for medicine trainees on extended overnight shifts, a position reinforced by new Accreditation Council for Graduate Medical Education requirements. Objective To evaluate the feasibility and consequences of protected sleep periods during extended duty. Design, Setting, and Participants Randomized controlled trial conducted at the Philadelphia VA Medical Center medical service and Oncology Unit of the Hospital of the University of Pennsylvania (2009-2010). Of the 106 interns and senior medical students who consented, 3 were not scheduled on any study rotations. Among the others, 44 worked at the VA center, 16 at the university hospital, and 43 at both. Intervention Twelve 4-week blocks were randomly assigned to either a standard intern schedule (extended duty overnight shifts of up to 30 hours; equivalent to 1200 overnight intern shifts at each site), or a protected sleep period (protected time from 12: 30 AM to 5: 30 AM with handover of work cell phone; equivalent to 1200 overnight intern shifts at each site). Participants were asked to wear wrist actigraphs and complete sleep diaries. Main Outcome Measures Primary outcome was hours slept during the protected period on extended duty overnight shifts. Secondary outcome measures included hours slept during a 24-hour period (noon to noon) by day of call cycle and Karolinska sleepiness scale. Results For 98.3% of on-call nights, cell phones were signed out as designed. At the VA center, participants with protected sleep had a mean 2.86 hours (95% CI, 2.57-3.10 hours) of sleep vs 1.98 hours (95% CI, 1.68-2.28 hours) among those who did not have protected hours of sleep (P<.001). At the university hospital, participants with protected sleep had a mean 3.04 hours (95% CI, 2.77-3.45 hours) of sleep vs 2.04 hours (95% CI, 1.79-2.24) among those who did not have protected sleep (P<.001). Participants with protected sleep were significantly less likely to have call nights with no sleep: 5.8% (95% CI, 3.0%-8.5%) vs 18.6% (95% CI, 13.9%-23.2%) at the VA center (P<.001) and 5.9% (95% CI, 3.1%-8.7%) vs 14.2% (95% CI, 9.9%-18.4%) at the university hospital (P=.001). Participants felt less sleepy after on-call nights in the intervention group, with Karolinska sleepiness scale scores of 6.65 (95% CI, 6.35-6.97) vs 7.10 (95% CI, 6.85-7.33; P=.01) at the VA center and 5.91 (95% CI, 5.64-6.16) vs 6.79 (95% CI, 6.57-7.04; P<.001) at the university hospital. Conclusions For internal medicine services at 2 hospitals, implementation of a protected sleep period while on call resulted in an increase in overnight sleep duration and improved alertness the next morning. C1 [Volpp, Kevin G.; Shea, Judy A.; Norton, Laurie; Novak, Cristina] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Shea, Judy A.; Zhu, Jingsan; Norton, Laurie; Novak, Cristina; Bellini, Lisa M.; Dine, C. Jessica] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Basner, Mathias; Ecker, Adrian; Dinges, David F.] Univ Penn, Perelman Sch Med, Dept Psychiat, Div Sleep & Chronobiol, Philadelphia, PA 19104 USA. [Volpp, Kevin G.] Univ Penn, Wharton Sch, Dept Hlth Care Management, Philadelphia, PA 19104 USA. [Small, Dylan S.] Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA. [Volpp, Kevin G.; Shea, Judy A.; Small, Dylan S.; Zhu, Jingsan; Norton, Laurie; Novak, Cristina] Univ Penn, Leonard Davis Inst, Ctr Hlth Incent & Behav Econ, Philadelphia, PA 19104 USA. [Mollicone, Daniel J.] Pulsar Informat Inc, Philadelphia, PA USA. RP Volpp, KG (reprint author), Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, 1120 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM volpp70@wharton.upenn.edu RI Emchi, Karma/Q-1952-2016 FU Veterans Affairs Health Services Research and Development Service [08-429]; National Institutes of Health [NR004281] FX This work was funded by educational grant 08-429 from the Veterans Affairs Health Services Research and Development Service. Dr Dinges was also supported in part by grant NR004281 from the National Institutes of Health. NR 34 TC 12 Z9 12 U1 1 U2 20 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 DEC 5 PY 2012 VL 308 IS 21 BP 2208 EP 2217 DI 10.1001/jama.2012.34490 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 047HI UT WOS:000311829500012 PM 23212498 ER PT J AU Lubitz, SA Ellinor, PT AF Lubitz, Steven A. Ellinor, Patrick T. TI Personalized medicine and atrial fibrillation: will it ever happen? SO BMC MEDICINE LA English DT Review DE Atrial fibrillation; genetics; personalized medicine; risk prediction; pharmacogenetics ID OF-FUNCTION MUTATION; EXPERT CONSENSUS STATEMENT; SUDDEN CARDIAC DEATH; SHORT QT SYNDROME; DILATED CARDIOMYOPATHY; FAMILIAL AGGREGATION; CHROMOSOME 4Q25; KCNQ1 MUTATION; RISK-FACTOR; ANTICOAGULATION CONTROL AB Atrial fibrillation (AF) is a common arrhythmia of substantial public health importance. Recent evidence demonstrates a heritable component underlying AF, and genetic discoveries have identified common variants associated with the arrhythmia. Ultimately one hopes that the consideration of genetic variation in clinical practice may enhance care and improve health outcomes. In this review we explore areas of potential clinical utility in AF management including those relating to pharmacogenetics and risk prediction. C1 [Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Charlestown, MA 02129 USA. RP Lubitz, SA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St,4th Floor, Charlestown, MA 02129 USA. EM slubitz@partners.org FU NIH [1RO1HL092577, 1RO1HL104156, 5R21DA027021, 1K24HL105780]; AHA grant [12FTF11350014]; Corrigan Minehan Innovation in Cardiovascular Research Spark Award FX PTE is supported by NIH grants 1RO1HL092577, 1RO1HL104156, 5R21DA027021 and 1K24HL105780. SAL is supported by an AHA grant 12FTF11350014 and a Corrigan Minehan Innovation in Cardiovascular Research Spark Award. NR 103 TC 6 Z9 6 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD DEC 4 PY 2012 VL 10 AR 155 DI 10.1186/1741-7015-10-155 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 103YK UT WOS:000315955300001 PM 23210687 ER PT J AU Szymanski, C Bel, A Cohen, I Touchot, B Handschumacher, MD Desnos, M Carpentier, A Menasche, P Hagege, AA Levine, RA Messas, E AF Szymanski, Catherine Bel, Alain Cohen, Iris Touchot, Bernard Handschumacher, Mark D. Desnos, Michel Carpentier, Alain Menasche, Philippe Hagege, Albert A. Levine, Robert A. Messas, Emmanuel CA Leducq Fdn MITRAL Transatlantic TI Comprehensive Annular and Subvalvular Repair of Chronic Ischemic Mitral Regurgitation Improves Long-Term Results With the Least Ventricular Remodeling SO CIRCULATION LA English DT Article DE echocardiography; mitral valve chordae; mitral valve regurgitation; myocardial infarction; regurgitation; remodeling ID 3-DIMENSIONAL ECHOCARDIOGRAPHIC RECONSTRUCTION; ACUTE MYOCARDIAL-INFARCTION; LEAFLET 2ND-ORDER CHORDAE; DOPPLER-ECHOCARDIOGRAPHY; VALVE ANNULOPLASTY; MECHANISM; SEVERITY; REVASCULARIZATION; RECOMMENDATIONS; MORTALITY AB Background-Undersized ring annuloplasty for ischemic mitral regurgitation (MR) is associated with variable results and > 30% MR recurrence. We tested whether subvalvular repair by severing second-order mitral chordae can improve annuloplasty by reducing papillary muscle tethering. Methods and Results-Posterolateral myocardial infarction known to produce chronic remodeling and MR was created in 28 sheep. At 3 months, sheep were randomized to sham surgery versus isolated undersized annuloplasty versus isolated bileaflet chordal cutting versus the combined therapy (n = 7 each). At baseline, chronic myocardial infarction (3 months), and euthanasia (6.6 months), we measured left ventricular (LV) volumes and ejection fraction, wall motion score index, MR regurgitation fraction and vena contracta, mitral annulus area, and posterior leaflet restriction angle (posterior leaflet to mitral annulus area) by 2-dimensional and 3-dimensional echocardiography. All groups were comparable at baseline and chronic myocardial infarction, with mild to moderate MR (MR vena contracta, 4.6 +/- 0.1 mm; MR regurgitation fraction, 24.2 +/- 2.9%) and mitral annulus dilatation (P < 0.01). At euthanasia, MR progressed to moderate to severe in controls but decreased to trace with ring plus chordal cutting versus trace to mild with chordal cutting alone versus mild to moderate with ring alone (MR vena contracta, 5.9 +/- 1.1 mm in controls, 0.5 +/- 0.08 with both, 1.0 +/- 0.3 with chordal cutting alone, 2.0 +/- 0.4 with ring alone; P < 0.01). In addition, LV end-systolic volume increased by 108% in controls versus 28% with ring plus chordal cutting, less than with each intervention alone (P < 0.01). In multivariate analysis, LV end-systolic volume and mitral annulus area most strongly predicted MR (r(2) = 0.82, P < 0.01). Conclusions-Comprehensive annular and subvalvular repair improves long- term reduction of both chronic ischemic MR and LV remodeling without decreasing global or segmental LV function at follow-up. (Circulation. 2012;126:2720-2727.) C1 [Messas, Emmanuel] Hop Europeen Georges Pompidou, INSERM, U633, PARCC,Dept Cardiovasc Med, F-75015 Paris, France. [Szymanski, Catherine; Bel, Alain; Cohen, Iris; Touchot, Bernard; Desnos, Michel; Carpentier, Alain; Menasche, Philippe; Hagege, Albert A.; Messas, Emmanuel] Univ Paris 05, Fac Med, Paris, France. [Szymanski, Catherine; Bel, Alain; Cohen, Iris; Touchot, Bernard; Desnos, Michel; Carpentier, Alain; Menasche, Philippe; Hagege, Albert A.; Messas, Emmanuel] Hop Europeen Georges Pompidou, AP HP, Dept Cardiol & Cardiovasc Surg, F-75015 Paris, France. [Handschumacher, Mark D.; Levine, Robert A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA USA. RP Messas, E (reprint author), Hop Europeen Georges Pompidou, INSERM, U633, PARCC,Dept Cardiovasc Med, 20 Rue Leblanc, F-75015 Paris, France. EM emmanuel.messas@egp.aphp.fr FU National Institutes of Health, Bethesda, MD [R01 HL38176, HL72265]; Fondation Leducq, Mitral Network of Excellence, Paris, France [07CVD04]; Federation Francaise de Cardiologie FX This study was supported in part by grants R01 HL38176 and HL72265 from the National Institutes of Health, Bethesda, MD, and by the Fondation Leducq, Mitral Network of Excellence, grant 07CVD04, Paris, France. Dr Catherine Szymanski was supported by a grant from the Federation Francaise de Cardiologie. NR 47 TC 18 Z9 18 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 4 PY 2012 VL 126 IS 23 BP 2720 EP 2727 DI 10.1161/CIRCULATIONAHA.111.033472 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200013 PM 23139296 ER PT J AU Khouri, MG Douglas, PS Mackey, JR Martin, M Scott, JM Scherrer-Crosbie, M Jones, LW AF Khouri, Michel G. Douglas, Pamela S. Mackey, John R. Martin, Miguel Scott, Jessica M. Scherrer-Crosbie, Marielle Jones, Lee W. TI Cancer Therapy-Induced Cardiac Toxicity in Early Breast Cancer Addressing the Unresolved Issues SO CIRCULATION LA English DT Review DE cardiomyopathies; chemotherapy; heart failure; women ID LEFT-VENTRICULAR DYSFUNCTION; HIGH-DOSE CHEMOTHERAPY; ANTHRACYCLINE-INDUCED CARDIOTOXICITY; TRASTUZUMAB-RELATED CARDIOTOXICITY; CONGESTIVE-HEART-FAILURE; DOXORUBICIN-INDUCED CARDIOMYOPATHY; DRUG-INDUCED CARDIOTOXICITY; ADJUVANT ENDOCRINE THERAPY; PROGENITOR-CELL FUNCTION; ASSOCIATION TASK-FORCE C1 [Khouri, Michel G.; Douglas, Pamela S.; Jones, Lee W.] Duke Univ, Med Ctr, Durham, NC USA. [Mackey, John R.] Cross Canc Inst, Edmonton, AB T6G 1Z2, Canada. [Martin, Miguel] Univ Complutense, Hosp Gen Univ Gregorio Maranon, E-28040 Madrid, Spain. [Scott, Jessica M.] NASA, Johnson Space Ctr, Houston, TX USA. [Scherrer-Crosbie, Marielle] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Jones, LW (reprint author), Duke Canc Inst, Box 3085, Durham, NC 27710 USA. EM lee.w.jones@duke.edu OI MARTIN, MIGUEL/0000-0001-9237-3231 FU National Institutes of Health [CA143254, CA142566, CA138634, CA133895]; Susan G. Komen Investigator Initiated Grant FX Dr Jones is supported by National Institutes of Health grants CA143254, CA142566, CA138634, and CA133895 and funds from George and Susan Beischer. Dr Scherrer-Crosbie is supported by a Susan G. Komen Investigator Initiated Grant. NR 146 TC 58 Z9 59 U1 0 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 4 PY 2012 VL 126 IS 23 BP 2749 EP 2763 DI 10.1161/CIRCULATIONAHA.112.100560 PG 15 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200016 PM 23212997 ER PT J AU Bart, BA Goldsmith, SR Lee, KL Stevenson, LW O'Connor, CM Bull, DA Redfield, MM Deswal, A Rouleau, JL LeWinter, MM Ofili, EO Givertz, MM Semigran, MJ Felker, GM Chen, HH Hernandez, AF Anstrom, KJ McNulty, SE Velazquez, EJ Mascette, AM Braunwald, E AF Bart, Bradley A. Goldsmith, Steven R. Lee, Kerry L. Stevenson, Lynne W. O'Connor, Christopher M. Bull, David A. Redfield, Margaret M. Deswal, Anita Rouleau, Jean L. LeWinter, Martin M. Ofili, Elizabeth O. Givertz, Micheal M. Semigran, Marc J. Felker, G. M. Chen, Horng H. Hernandez, Adrian F. Anstrom, Kevin J. McNulty, Steven E. Velazquez, Eric J. Mascette, Alice M. Braunwald, Eugene TI Cardiorenal Rescue Study in Acute Decompensated Heart Failure: Results of CARRESS-HF, for the Heart Failure Clinical Research Network SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association CY NOV 03-07, 2012 CL Los Angeles, CA SP Amer Heart Assoc DE Acute heart failure; Diuretics; Renal function; Device C1 [Bart, Bradley A.; Goldsmith, Steven R.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Lee, Kerry L.; O'Connor, Christopher M.; Felker, G. M.; Hernandez, Adrian F.; Anstrom, Kevin J.; McNulty, Steven E.; Velazquez, Eric J.] Duke Univ, Durham, NC USA. [Stevenson, Lynne W.; Givertz, Micheal M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bull, David A.] Univ Utah, Salt Lake City, UT USA. [Redfield, Margaret M.; Chen, Horng H.] Mayo Clin, Rochester, MN USA. [Deswal, Anita] Baylor Coll Med, Houston, TX 77030 USA. [Deswal, Anita] VA Med Cntr, Houston, TX USA. [Rouleau, Jean L.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [LeWinter, Martin M.] Univ Vermont, Berlington, VT USA. [Ofili, Elizabeth O.] Morehouse Sch Med, Atlanta, GA 30310 USA. [Semigran, Marc J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mascette, Alice M.] NHLBI, Bethesda, MD 20892 USA. [Braunwald, Eugene] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 4 PY 2012 VL 126 IS 23 BP 2786 EP 2786 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200046 ER PT J AU Semigran, M Bonderman, D Ghio, S Felix, SB Ghofrani, HA Michelakis, ED Mitrovic, V Oudiz, RJ Roessig, L Scalise, AV AF Semigran, Marc Bonderman, Diana Ghio, Stefano Felix, Stephan B. Ghofrani, Hossein A. Michelakis, Evangelos D. Mitrovic, Veselin Oudiz, Ronald J. Roessig, Lothar Scalise, Andrea V. TI Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial (LEPHT) SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association CY NOV 03-07, 2012 CL Los Angeles, CA SP Amer Heart Assoc DE Heart failure; Pulmonary hypertension; Vasodilator agents C1 [Semigran, Marc] Massachusetts Gen Hosp, Heart Cntr, Boston, MA 02114 USA. [Bonderman, Diana] Med Univ Vienna, Vienna, Austria. [Ghio, Stefano] Fdn Policlin S Matteo, Pavia, Italy. [Felix, Stephan B.] Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany. [Ghofrani, Hossein A.] Univ Hosp Giessen & Marburg, Giessen, Germany. [Michelakis, Evangelos D.] Univ Alberta, Edmonton, AB, Canada. [Mitrovic, Veselin] Kerckhoff Heart Cntr, Bad Nauheim, Germany. [Oudiz, Ronald J.] Harbor UCLA Med Cntr, Los Angeles Biomed Rsch Inst, Torrance, CA USA. [Roessig, Lothar] Bayer Pharma AG, Berlin, Germany. [Scalise, Andrea V.] Bayer Hispania SL, Barcelona, Spain. NR 0 TC 2 Z9 2 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 DEC 4 PY 2012 VL 126 IS 23 BP 2789 EP 2790 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200053 ER PT J AU Desai, NR Kohli, P Giugliano, RP Kim, JB Mohanavelu, S Hoffman, E Liu, T Scott, R Wasserman, S Sabatine, MS AF Desai, Nihar R. Kohli, Payal Giugliano, Robert P. Kim, Jae B. Mohanavelu, Satishkumar Hoffman, Elaine Liu, Thomas Scott, Robert Wasserman, Scott Sabatine, Marc S. TI AMG 145, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9), Facilitates Achievement of NCEP LDL-Cholesterol Goals in High-Risk Patients SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association CY NOV 03-07, 2012 CL Los Angeles, CA SP Amer Heart Assoc DE Lipids; Cholesterol-lowering drugs; Quality improvement C1 [Desai, Nihar R.; Kohli, Payal; Giugliano, Robert P.; Hoffman, Elaine; Sabatine, Marc S.] Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp, Boston, MA 02115 USA. [Kim, Jae B.; Mohanavelu, Satishkumar; Liu, Thomas; Scott, Robert; Wasserman, Scott] Amgen Inc, Thousand Oaks, CA 91320 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 4 PY 2012 VL 126 IS 23 BP 2791 EP 2791 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200058 ER PT J AU Saxena, V Ramdas, S Ochoa, CR Wallace, D Bhide, P Kohane, I AF Saxena, Vishal Ramdas, Shweta Ochoa, Courtney Rothrock Wallace, David Bhide, Pradeep Kohane, Isaac TI Structural, Genetic, and Functional Signatures of Disordered Neuro-Immunological Development in Autism Spectrum Disorder SO PLOS ONE LA English DT Article ID SET ENRICHMENT ANALYSIS; EXPRESSION; ASSOCIATION; SUSCEPTIBILITY; CYTOKINE; PROTEINS; CHILDREN; BRAIN; IDENTIFICATION; SCHIZOPHRENIA AB Background: Numerous linkage studies have been performed in pedigrees of Autism Spectrum Disorders, and these studies point to diverse loci and etiologies of autism in different pedigrees. The underlying pattern may be identified by an integrative approach, especially since ASD is a complex disorder manifested through many loci. Method: Autism spectrum disorder (ASD) was studied through two different and independent genome-scale measurement modalities. We analyzed the results of copy number variation in autism and triangulated these with linkage studies. Results: Consistently across both genome-scale measurements, the same two molecular themes emerged: immune/chemokine pathways and developmental pathways. Conclusion: Linkage studies in aggregate do indeed share a thematic consistency, one which structural analyses recapitulate with high significance. These results also show for the first time that genomic profiling of pathways using a recombination distance metric can capture pathways that are consistent with those obtained from copy number variations (CNV). C1 [Saxena, Vishal; Bhide, Pradeep] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Saxena, Vishal] Massachusetts Gen Hosp, Dept Med, Charlestown, MA USA. [Saxena, Vishal; Kohane, Isaac] Harvard Univ, Sch Med, Boston, MA USA. [Saxena, Vishal; Wallace, David] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Ochoa, Courtney Rothrock] Univ S Alabama Coll, Ctr Lung Biol, Mobile, AL USA. [Saxena, Vishal; Kohane, Isaac] Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Ramdas, Shweta] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA. RP Saxena, V (reprint author), Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. EM vishal@mit.edu OI Bhide, Pradeep/0000-0003-4236-9415 FU Conte Center for Computational System Genomics of Neuropsychiatric Phenotypes(National Institutes of Health) [P50MH94267]; Nancy Lurie Marks Foundation FX The research was funded in part by Conte Center for Computational System Genomics of Neuropsychiatric Phenotypes(National Institutes of Health P50MH94267). ISK was supported in part by the Nancy Lurie Marks Foundation. No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 8 Z9 8 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 4 PY 2012 VL 7 IS 12 AR e48835 DI 10.1371/journal.pone.0048835 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 051EQ UT WOS:000312108500002 PM 23239965 ER PT J AU Kim, DH Ghaffari, R Lu, NS Wang, SD Lee, SP Keum, H D'Angelo, R Klinker, L Su, YW Lu, CF Kim, YS Ameen, A Li, YH Zhang, YH de Graff, B Hsu, YY Liu, ZJ Ruskin, J Xu, LZ Lu, C Omenetto, FG Huang, YG Mansour, M Slepian, MJ Rogers, JA AF Kim, Dae-Hyeong Ghaffari, Roozbeh Lu, Nanshu Wang, Shuodao Lee, Stephen P. Keum, Hohyun D'Angelo, Robert Klinker, Lauren Su, Yewang Lu, Chaofeng Kim, Yun-Soung Ameen, Abid Li, Yuhang Zhang, Yihui de Graff, Bassel Hsu, Yung-Yu Liu, ZhuangJian Ruskin, Jeremy Xu, Lizhi Lu, Chi Omenetto, Fiorenzo G. Huang, Yonggang Mansour, Moussa Slepian, Marvin J. Rogers, John A. TI Electronic sensor and actuator webs for large-area complex geometry cardiac mapping and therapy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE flexible electronics; semiconductor nanomaterials; stretchable electronics; implantable biomedical devices; cardiac electrophysiology ID PERSISTENT ATRIAL-FIBRILLATION; CATHETER ABLATION; EPICARDIAL ACTIVATION; PULMONARY VEINS; SOCK ELECTRODE; IN-VIVO; ARRHYTHMIAS; HEART; ELECTROPHYSIOLOGY; ELECTROGONIOMETER AB Curved surfaces, complex geometries, and time-dynamic deformations of the heart create challenges in establishing intimate, non-constraining interfaces between cardiac structures and medical devices or surgical tools, particularly over large areas. We constructed large area designs for diagnostic and therapeutic stretchable sensor and actuator webs that conformally wrap the epicardium, establishing robust contact without sutures, mechanical fixtures, tapes, or surgical adhesives. These multifunctional web devices exploit open, mesh layouts and mount on thin, bio-resorbable sheets of silk to facilitate handling in a way that yields, after dissolution, exceptionally low mechanical moduli and thicknesses. In vivo studies in rabbit and pig animal models demonstrate the effectiveness of these device webs for measuring and spatially mapping temperature, electrophysiological signals, strain, and physical contact in sheet and balloon-based systems that also have the potential to deliver energy to perform localized tissue ablation. C1 [Keum, Hohyun; Kim, Yun-Soung; Ameen, Abid; Xu, Lizhi; Lu, Chi; Rogers, John A.] Univ Illinois, Dept Mat Sci & Engn, Urbana, IL 61801 USA. [Kim, Dae-Hyeong] Seoul Natl Univ, Sch Chem & Biol Engn, World Class Univ Program Chem Convergence Energy, Inst Basic Sci,Ctr Nanoparticle Res, Seoul 151742, South Korea. [Lu, Nanshu] Univ Texas Austin, Dept Aerosp Engn & Engn Mech, Austin, TX 78712 USA. [Ghaffari, Roozbeh; Lee, Stephen P.; D'Angelo, Robert; Klinker, Lauren; de Graff, Bassel; Hsu, Yung-Yu] MC10 Inc, Cambridge, MA 02140 USA. [Wang, Shuodao; Su, Yewang; Lu, Chaofeng; Li, Yuhang; Zhang, Yihui; Huang, Yonggang] Northwestern Univ, Dept Mech Engn, Evanston, IL 60208 USA. [Wang, Shuodao; Su, Yewang; Lu, Chaofeng; Li, Yuhang; Zhang, Yihui; Huang, Yonggang] Northwestern Univ, Dept Civil & Environm Engn, Evanston, IL 60208 USA. [Su, Yewang; Zhang, Yihui] Tsinghua Univ, Ctr Mech & Mat, Beijing 100084, Peoples R China. [Lu, Chaofeng] Zhejiang Univ, Soft Matter Res Ctr, Hangzhou 310058, Zhejiang, Peoples R China. [Lu, Chaofeng] Zhejiang Univ, Dept Civil Engn, Hangzhou 310058, Zhejiang, Peoples R China. [Li, Yuhang] Harbin Inst Technol, Sch Astronaut, Harbin 150001, Peoples R China. [Liu, ZhuangJian] ASTAR, Inst High Performance Comp, Singapore 138632, Singapore. [Ruskin, Jeremy; Mansour, Moussa] Massachusetts Gen Hosp, Cardiac Arrhythmia Unit, Boston, MA 02140 USA. [Omenetto, Fiorenzo G.] Tufts Univ, Dept Biomed Engn, Medford, MA 02155 USA. [Slepian, Marvin J.] Univ Arizona, Sarver Heart Ctr, Dept Med, Tucson, AZ 85724 USA. [Slepian, Marvin J.] Univ Arizona, Sarver Heart Ctr, Dept Biomed Engn, Tucson, AZ 85724 USA. RP Rogers, JA (reprint author), Univ Illinois, Dept Mat Sci & Engn, Urbana, IL 61801 USA. EM jrogers@illinois.edu RI Lu, Chaofeng/C-2162-2009; Huang, Yonggang/B-6998-2009; Xu, Lizhi/D-8143-2016; Wang, Shuodao/H-6014-2011; Rogers, John /L-2798-2016; OI Xu, Lizhi/0000-0001-6888-0524; Lee, Stephen/0000-0002-8521-8652 FU World Class University (WCU) program through the National Research Foundation of Korea; Ministry of Education, Science and Technology [R31-10013, 2012R1A1A1004925]; Basic Science Research Program through the Korea National Research Foundation; National Security Science and Engineering Faculty Fellowship; Cockrell School of Engineering at the University of Texas at Austin FX We thank Roja Nunna and Nishan Subedi for implementation and testing of the data acquisition system, and Behrooz Dehdashti and members of the Sarver Heart Center for help with in vivo animal studies. This material is based on work conducted at the Materials Research Laboratory and Center for Microanalysis of Materials (DE-FG02-07ER46453) at the University of Illinois at Urbana-Champaign. This work was supported by the World Class University (WCU) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R31-10013) and the Basic Science Research Program through the Korea National Research Foundation funded by Ministry of Education, Science and Technology Grant 2012R1A1A1004925. J.A.R. has received a National Security Science and Engineering Faculty Fellowship. N.L. receives support from the startup fund from the Cockrell School of Engineering at the University of Texas at Austin. NR 55 TC 72 Z9 74 U1 15 U2 116 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 4 PY 2012 VL 109 IS 49 BP 19910 EP 19915 DI 10.1073/pnas.1205923109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054MF UT WOS:000312347200019 PM 23150574 ER PT J AU Lewis, LD Weiner, VS Mukamel, EA Donoghue, JA Eskandar, EN Madsen, JR Anderson, WS Hochberg, LR Cash, SS Brown, EN Purdon, PL AF Lewis, Laura D. Weiner, Veronica S. Mukamel, Eran A. Donoghue, Jacob A. Eskandar, Emad N. Madsen, Joseph R. Anderson, William S. Hochberg, Leigh R. Cash, Sydney S. Brown, Emery N. Purdon, Patrick L. TI Rapid fragmentation of neuronal networks at the onset of propofol-induced unconsciousness SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE electrophysiology; single units; GABA; cortical networks ID LESS-THAN-1 HZ OSCILLATION; INDUCED ALPHA-RHYTHM; GENERAL-ANESTHESIA; SLEEP ELECTROENCEPHALOGRAM; BURST-SUPPRESSION; POINT PROCESS; SLOW; CONSCIOUSNESS; BRAIN; EEG AB The neurophysiological mechanisms by which anesthetic drugs cause loss of consciousness are poorly understood. Anesthetic actions at the molecular, cellular, and systems levels have been studied in detail at steady states of deep general anesthesia. However, little is known about how anesthetics alter neural activity during the transition into unconsciousness. We recorded simultaneous multiscale neural activity from human cortex, including ensembles of single neurons, local field potentials, and intracranial electrocorticograms, during induction of general anesthesia. We analyzed local and global neuronal network changes that occurred simultaneously with loss of consciousness. We show that propofol-induced unconsciousness occurs within seconds of the abrupt onset of a slow (<1 Hz) oscillation in the local field potential. This oscillation marks a state in which cortical neurons maintain local patterns of network activity, but this activity is fragmented across both time and space. Local (<4 mm) neuronal populations maintain the millisecond-scale connectivity patterns observed in the awake state, and spike rates fluctuate and can reach baseline levels. However, neuronal spiking occurs only within a limited slow oscillation-phase window and is silent otherwise, fragmenting the time course of neural activity. Unexpectedly, we found that these slow oscillations occur asynchronously across cortex, disrupting functional connectivity between cortical areas. We conclude that the onset of slow oscillations is a neural correlate of propofol-induced loss of consciousness, marking a shift to cortical dynamics in which local neuronal networks remain intact but become functionally isolated in time and space. C1 [Brown, Emery N.; Purdon, Patrick L.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Hochberg, Leigh R.; Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Eskandar, Emad N.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Lewis, Laura D.; Weiner, Veronica S.; Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Donoghue, Jacob A.; Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA. [Brown, Emery N.; Purdon, Patrick L.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Donoghue, Jacob A.; Cash, Sydney S.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Eskandar, Emad N.; Madsen, Joseph R.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Mukamel, Eran A.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Mukamel, Eran A.] Univ Calif San Diego, Ctr Theoret Biol Phys, La Jolla, CA 92093 USA. [Madsen, Joseph R.] Boston Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Anderson, William S.] Johns Hopkins Univ Hosp, Sch Med, Dept Neurosurg, Baltimore, MD 21287 USA. [Hochberg, Leigh R.] Dept Vet Affairs, Rehabil Res & Dev Serv, Providence, RI 02908 USA. [Hochberg, Leigh R.] Brown Univ, Sch Engn, Inst Brain Sci, Providence, RI 02912 USA. RP Purdon, PL (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM patrickp@nmr.mgh.harvard.edu FU Center for Integration of Medicine and Innovative Technology; National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) [NS062092, K08NS066099-01A1]; National Eye Institute [EY017658]; National Institute on Drug Abuse [NS063249]; National Science Foundation [IOB 0645886]; Howard Hughes Medical Institute; Klingenstein Foundation; NIH [DP1OD003646, R01-MH071847, DP2-OD006454, K25-NS057580]; Department of Veterans Affairs Career Development Transition Award; Doris Duke Charitable Foundation-Clinical Scientist Development Award; Massachusetts General Hospital-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke; NIH/National Institute on Deafness and Other Communications Disorders [R01DC009899]; Canadian Institute of Health Research Fellowship FX We thank A. Dykstra and A. Chan for help with electrode localization methods, A. Smith for sharing spike rate Bayesian estimation code, and D. Ba for assistance with GLM fitting code. This work was funded by a grant from the Center for Integration of Medicine and Innovative Technology and by National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) Grants NS062092 (to S. S. C.) and K08NS066099-01A1 (to W. S. A.); by National Eye Institute Grant EY017658, National Institute on Drug Abuse Grant NS063249, National Science Foundation Grant IOB 0645886, the Howard Hughes Medical Institute, and the Klingenstein Foundation (to E.N.E.); by NIH Director's Pioneer Award DP1OD003646 and Grant R01-MH071847 (to E.N.B.); by a Department of Veterans Affairs Career Development Transition Award, a Doris Duke Charitable Foundation-Clinical Scientist Development Award, Massachusetts General Hospital-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke, and NIH/National Institute on Deafness and Other Communications Disorders Grant R01DC009899 (to L. R. H.); by a Canadian Institute of Health Research Fellowship (to L. D. L.); and by NIH New Innovator Award DP2-OD006454 and K-Award K25-NS057580 (to P.L.P.). NR 51 TC 95 Z9 96 U1 0 U2 20 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 4 PY 2012 VL 109 IS 49 BP E3377 EP E3386 DI 10.1073/pnas.1210907109 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054MF UT WOS:000312347200011 PM 23129622 ER PT J AU Peisley, A Jo, MH Lin, C Wu, B Orme-Johnson, M Walz, T Hohng, S Hur, S AF Peisley, Alys Jo, Myung Hyun Lin, Cecilie Wu, Bin Orme-Johnson, McGhee Walz, Thomas Hohng, Sungchul Hur, Sun TI Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antiviral; innate immunity; filament dynamics; helicase; viral RNA ID DOUBLE-STRANDED-RNA; RECEPTOR RIG-I; INNATE IMMUNE-RESPONSE; SINGLE-MOLECULE; PATTERN-RECOGNITION; STRUCTURAL BASIS; ACTIVATION; DNA; HELICASE; FORMS AB The viral sensor MDA5 distinguishes between cellular and viral dsRNAs by length-dependent recognition in the range of similar to 0.5-7 kb. The ability to discriminate dsRNA length at this scale sets MDA5 apart from other dsRNA receptors of the immune system. We have shown previously that MDA5 forms filaments along dsRNA that disassemble upon ATP hydrolysis. Here, we demonstrate that filament formation alone is insufficient to explain its length specificity, because the intrinsic affinity of MDA5 for dsRNA depends only moderately on dsRNA length. Instead, MDA5 uses a combination of end disassembly and slow nucleation kinetics to "discard" short dsRNA rapidly and to suppress rebinding. In contrast, filaments on long dsRNA cycle between partial end disassembly and elongation, bypassing nucleation steps. MDA5 further uses this repetitive cycle of assembly and disassembly processes to repair filament discontinuities, which often are present because of multiple, internal nucleation events, and to generate longer, continuous filaments that more accurately reflect the length of the underlying dsRNA scaffold. Because the length of the continuous filament determines the stability of the MDA5-dsRNA interaction, the mechanism proposed here provides an explanation for how MDA5 uses filament assembly and disassembly dynamics to discriminate between self vs. nonself dsRNA. C1 [Peisley, Alys; Wu, Bin; Hur, Sun] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Lin, Cecilie; Walz, Thomas] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Walz, Thomas] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Peisley, Alys; Wu, Bin; Orme-Johnson, McGhee; Hur, Sun] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Jo, Myung Hyun; Hohng, Sungchul] Seoul Natl Univ, Dept Phys & Astron, Seoul 151747, South Korea. RP Hur, S (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM hur@idi.harvard.edu RI Wu, Bin/C-4715-2015 FU GlaxoSmithKline; Creative Research Initiatives (Physical Genetics Laboratory) [2009-0081562]; World Class University program of the National Research Foundation of Korea [R31-10032]; Massachusetts Life Sciences Center; Pew Scholarship FX We thank S. Harrison for rotavirus particles. A. P. and B. W. are recipients of postdoctoral fellowships from GlaxoSmithKline. T. W. is an Investigator in the Howard Hughes Medical Institute. S. Hohng is the recipient of Grants 2009-0081562 from the Creative Research Initiatives (Physical Genetics Laboratory) and R31-10032 from the World Class University program of the National Research Foundation of Korea. S. Hur is the recipient of a New Investigator Award from Massachusetts Life Sciences Center and a Pew Scholarship. NR 37 TC 42 Z9 42 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 4 PY 2012 VL 109 IS 49 BP E3340 EP E3349 DI 10.1073/pnas.1208618109 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054MF UT WOS:000312347200007 PM 23129641 ER PT J AU Leonardi, S Thomas, L Neely, ML Tricoci, P Lopes, RD White, HD Armstrong, PW Giugliano, RP Antman, EM Califf, RM Newby, LK Mahaffey, KW AF Leonardi, Sergio Thomas, Laine Neely, Megan L. Tricoci, Pierluigi Lopes, Renato D. White, Harvey D. Armstrong, Paul W. Giugliano, Robert P. Antman, Elliott M. Califf, Robert M. Newby, L. Kristin Mahaffey, Kenneth W. TI Comparison of the Prognosis of Spontaneous and Percutaneous Coronary Intervention-Related Myocardial Infarction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE angioplasty; cardiovascular; clinical trial; creatine kinase; diagnostic techniques; endpoint determination; myocardial infarction; surrogate endpoint ID ST-SEGMENT ELEVATION; COMPOSITE END-POINTS; UNIVERSAL DEFINITION; INVASIVE MANAGEMENT; MEDICAL-MANAGEMENT; ADVERSE OUTCOMES; CLINICAL-TRIALS; MORTALITY; RISK; EPTIFIBATIDE AB Objectives This study compared prognoses of myocardial infarction related to percutaneous coronary intervention (PCI, procedural MI) using increasing creatine kinase-myocardial band (CK-MB) thresholds with spontaneous MI. Background Procedural MI usually is defined by a CK-MB elevation of more than 3 times the upper limit of normal (ULN), but higher thresholds have been proposed. Methods Patients from the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) study and the SYNERGY (Superior Yield of the New strategy of Enoxaparin, Revascularization and GIYcoprotein IIb/IIIa inhibitors) study treated with PCI were included. The primary end point was 1-year all-cause mortality from 24 h after PCI. To determine an enzymatic threshold for procedural MI with a prognosis similar to that of spontaneous MI, we redefined procedural MI using increasing CK-MB thresholds and compared corresponding hazard ratios with those of spontaneous MI (CK-MB more than twice the ULN). Hazard ratios for mortality for procedural and spontaneous MI were calculated using Cox proportional hazards regression and Global Registry of Acute Cardiac Events covariates for risk adjustment. Results Nine thousand eighty-seven patients who underwent PCI (46.8%) were included; 773 procedural MI and 239 spontaneous MI occurred within 30 days. Adjusted hazard ratios for 1-year death were 1.39 (95% confidence interval [CI]: 1.01 to 1.89) for procedural MI and 5.37 (95% CI: 3.90 to 7.38) for spontaneous MI. The CK-MB threshold for procedural MI that achieved the same prognosis as spontaneous MI was 27.7 times the ULN (95% CI: 13.9 to 58.4), but this differed between the SYNERGY study (57.9 times the ULN, 95% CI: 17.9 to 63.6) and the EARLY-ACS study (20.4 times the ULN, 95% CI: 5.16 to 24.2). Of all procedural MI, 49 (6%) had CK-MB elevations of 27.7 or more times the ULN. Conclusions The current enzymatic definition of procedural MI (CK-MB more than 3 times the ULN) used in clinical trials is less strongly associated with death than that of spontaneous MI. Procedural MI achieves similar prognosis for 1-year mortality when much higher CK-MB thresholds are applied. (J Am Coll Cardiol 2012;60:2296-304) (C) 2012 by the American College of Cardiology Foundation C1 [Leonardi, Sergio; Thomas, Laine; Neely, Megan L.; Tricoci, Pierluigi; Lopes, Renato D.; Newby, L. Kristin; Mahaffey, Kenneth W.] Duke Clin Res Inst, Durham, NC 27705 USA. [Leonardi, Sergio] Fdn IRCCS Policlin S Matteo, Pavia, Italy. [White, Harvey D.] Green Lane Cardiovasc Serv, Auckland, New Zealand. [Armstrong, Paul W.] Canadian VIGOUR Ctr, Edmonton, AB, Canada. [Giugliano, Robert P.; Antman, Elliott M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp, Boston, MA 02115 USA. [Califf, Robert M.] Duke Translat Med Inst, Durham, NC USA. RP Leonardi, S (reprint author), Duke Clin Res Inst, 2400 Pratt St,Room 0311, Durham, NC 27705 USA. EM sergio.leonardi@duke.edu OI Leonardi, Sergio/0000-0002-4800-6132 FU Schering-Plough; Sanofi-Aventis; Merck, Inc.; Bristol-Myers Squibb; Schering-Plough Research Institute; Eli Lilly Company; Daiichi Sankyo; Amylin; JJ-Scios; Merck/Schering Plough; Novartis; Bristol-Myers Squibb Foundation; AstraZeneca; diaDexus; Eli Lilly Co.; GlaxoSmithKline; Murdock Study; NHLBI; Regado Biosciences, Inc.; Roche; Abbott Vascular; Amgen Inc.; Amylin Inc.; Baxter; Edwards Lifesciences; Guidant Corp.; Ikaria; Johnson Johnson; KAI; Luitpold Pharmaceuticals; Medtronic; Portola Pharmaceuticals; POZEN Pharmaceuticals; Regado Biosciences; Roche Diagnostic; The Medicines Co. FX EARLY-ACS was funded by Schering-Plough, and SYNERGY was funded by Sanofi-Aventis. The current analyses were funded by Merck, Inc. Dr. Tricoci has served on an advisory board and has received research grants from Merck, Inc. Dr. Lopes received a research grant from Bristol-Myers Squibb. Dr. White has received research grants from Schering-Plough and Merck, Inc. Dr. Armstrong has received research grants from Schering-Plough Research Institute and Merck, Inc. Dr. Giugliano is a consultant to Beckman-Coulter; and received research grant support from Merck. Dr. Antman has received research grants from Eli Lilly & Company and Daiichi Sankyo. Dr. Califf has received research grants from Amylin, J&J-Scios, Merck/Schering Plough, Novartis, and the Bristol-Myers Squibb Foundation; is a consultant for J&J-Scios, Novartis, Bayer, Roche, Pfizer, and the Bristol-Myers Squibb Foundation; and has equity in NITROX LLC. Dr. Newby has received research grants from Amylin, AstraZeneca, Bristol-Myers Squibb, diaDexus, Eli Lilly & Co., GlaxoSmithKline, Merck, Inc., Murdock Study, NHLBI, Regado Biosciences, Inc., Roche, and Schering-Plough; and is a consultant for AstraZeneca, Daiichi-Sankyo, Eli Lilly & Co., Genentech, Johnson & Johnson, and Novartis. Dr. Mahaffey has received research grants from Abbott Vascular, Amgen Inc., Amylin Inc., AstraZeneca, Baxter, Bayer HealthCare, Boehringer Ingelheim, Brisol-Myers Squibb, Cordis, Daiichi Sankyo, Edwards Lifesciences, Eli Lilly & Co., GlaxoSmithKline, Guidant Corp., Ikaria, Johnson & Johnson, KAI, Luitpold Pharmaceuticals, Medtronic, Merck, Inc., Novartis, Portola Pharmaceuticals, POZEN Pharmaceuticals, Regado Biosciences, Roche Diagnostic, Schering-Plough, and The Medicines Co.; and is a consultant for Adolor, Amgen, AstraZeneca, Bayer HealthCare, Biotronik, Boehringer Ingelheim, Briston-Myers Squibb, Daiichi Sankyo, Eli Lilly & Co., Elsevier (AHJ), Exeter Group, Forest, Genentech, GlaxoSmithKline, Gilead Science, Haemonetics, Johnson & Johnson, Medtronic Inc., Merck & Co., Novartis, Orexigen, Orth/McNeill, Pfizer, Polymedix, Sanofi-Aventis, Schering-Plough, South East Area Health Education Center (SEAHEC), Springer Publishing, St. Jude Medical, Sun Pharma, and WebMD. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 28 TC 15 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD DEC 4 PY 2012 VL 60 IS 22 BP 2296 EP 2304 DI 10.1016/j.jacc.2012.09.005 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 045FN UT WOS:000311680500007 PM 23122801 ER PT J AU Robbins, GK Lester, W Johnson, KL Chang, YC Estey, G Surrao, D Zachary, K Lammert, SM Chueh, HC Meigs, JB Freedberg, KA AF Robbins, Gregory K. Lester, William Johnson, Kristin L. Chang, Yuchiao Estey, Gregory Surrao, Dominic Zachary, Kimon Lammert, Sara M. Chueh, Henry C. Meigs, James B. Freedberg, Kenneth A. TI Efficacy of a Clinical Decision-Support System in an HIV Practice A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ELECTRONIC HEALTH RECORD; PHYSICIAN ORDER ENTRY; AMBULATORY-CARE; ANTIRETROVIRAL THERAPY; FOLLOW-UP; INFECTED PATIENTS; DELIVERY-SYSTEM; PATIENT SAFETY; ALERTS; INFORMATICS AB Background: Data to support improved patient outcomes from clinical decision-support systems (CDSSs) are lacking in HIV care. Objective: To test the efficacy of a CDSS in improving HIV outcomes in an outpatient clinic. Design: Randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00678600) Setting: Massachusetts General Hospital HIV Clinic. Participants: HIV care providers and their patients. Intervention: Computer alerts were generated for virologic failure (HIV RNA level >400 copies/mL after a previous HIV RNA level <= 400 copies/mL), evidence of suboptimal follow-up, and 11 abnormal laboratory test results. Providers received interactive computer alerts, facilitating appointment rescheduling and repeated laboratory testing, for half of their patients and static alerts for the other half. Measurements: The primary end point was change in CD4 cell count. Other end points included time to clinical event, 6-month suboptimal follow-up, and severe laboratory toxicity. Results: Thirty-three HIV care providers followed 1011 patients with HIV. In the intervention group, the mean increase in CD4 cell count was greater (0.0053 vs. 0.0032 x 10(9) cells/L per month; difference, 0.0021 x 10(9) cells/L per month [95% CI, 0.0001 to 0.004]; P = 0.040) and the rate of 6-month suboptimal follow-up was lower (20.6 vs. 30.1 events per 100 patient-years; P = 0.022) than those in the control group. Median time to next scheduled appointment was shorter in the intervention group than in the control group after a suboptimal follow-up alert (1.71 vs. 3.48 months; P < 0.001) and after a toxicity alert (2.79 vs. >6 months; P = 0.072). More than 90% of providers supported adopting the CDSS as part of standard care. Limitation: This was a 1-year informatics study conducted at a single hospital subspecialty clinic. Conclusion: A CDSS using interactive provider alerts improved CD4 cell counts and clinic follow-up for patients with HIV. Wider implementation of such systems can provide important clinical benefits. C1 [Robbins, Gregory K.] Harvard Univ, Massachusetts Gen Hosp, Div Infect Dis, Ctr AIDS Res, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Robbins, GK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Infect Dis, Ctr AIDS Res, 55 Fruit St,Cox 5, Boston, MA 02114 USA. EM grobbins@partners.org OI Lester, William/0000-0003-4086-9280 FU National Institute of Allergy and Infectious Diseases [K01AI062435, K24AI062476, P30AI42851, K24DK080140, R37AI42006]; Massachusetts General Hospital; National Institute of Allergy and Infectious Diseases FX By the National Institute of Allergy and Infectious Diseases (K01AI062435, K24AI062476, P30AI42851, K24DK080140, and R37AI42006) and the Massachusetts General Hospital Clinical Research Program.; National Institute of Allergy and Infectious Diseases. NR 56 TC 6 Z9 6 U1 8 U2 9 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 4 PY 2012 VL 157 IS 11 BP 757 EP + DI 10.7326/0003-4819-157-11-201212040-00003 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 049RC UT WOS:000312000100001 PM 23208165 ER PT J AU Shaheen, NJ Weinberg, DS Denberg, TD Chou, R Qaseem, A Shekelle, P AF Shaheen, Nicholas J. Weinberg, David S. Denberg, Thomas D. Chou, Roger Qaseem, Amir Shekelle, Paul CA Amer Coll Phys TI Upper Endoscopy for Gastroesophageal Reflux Disease: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ESOMEPRAZOLE 40 MG; SEVERE EROSIVE ESOPHAGITIS; OPEN-ACCESS ENDOSCOPY; QUALITY-OF-LIFE; BARRETTS-ESOPHAGUS; UNITED-STATES; GASTROINTESTINAL ENDOSCOPY; GASTRIC CARDIA; TIME TRENDS; SURVEILLANCE AB Background: Upper endoscopy is commonly used in the diagnosis and management of gastroesophageal reflux disease (GERD). Evidence demonstrates that it is indicated only in certain situations, and inappropriate use generates unnecessary costs and exposes patients to harms without improving outcomes. Methods: The Clinical Guidelines Committee of the American College of Physicians reviewed evidence regarding the indications for, and yield of, upper endoscopy in the setting of GERD, and to highlight how clinicians can increase the delivery of high-value health care. Best Practice Advice 1: Upper endoscopy is indicated in men and women with heartburn and alarm symptoms (dysphagia, bleeding, anemia, weight loss, and recurrent vomiting). Best Practice Advice 2: Upper endoscopy is indicated in men and women with: Typical GERD symptoms that persist despite a therapeutic trial of 4 to 8 weeks of twice-daily proton-pump inhibitor therapy. Severe erosive esophagitis after a 2-month course of proton-pump inhibitor therapy to assess healing and rule out Barrett esophagus. Recurrent endoscopy after this follow-up examination is not indicated in the absence of Barrett esophagus. History of esophageal stricture who have recurrent symptoms of dysphagia. Best Practice Advice 3: Upper endoscopy may be indicated: In men older than 50 years with chronic GERD symptoms (symptoms for more than 5 years) and additional risk factors (nocturnal reflux symptoms, hiatal hernia, elevated body mass index, tobacco use, and intra-abdominal distribution of fat) to detect esophageal adenocarcinoma and Barrett esophagus. For surveillance evaluation in men and women with a history of Barrett esophagus. In men and women with Barrett esophagus and no dysplasia, surveillance examinations should occur at intervals no more frequently than 3 to 5 years. More frequent intervals are indicated in patients with Barrett esophagus and dysplasia. Ann Intern Med. 2012; 157: 808-816. www.annals.org For author affiliations, see end of text. C1 [Qaseem, Amir] Amer Coll Physicians, Philadelphia, PA 19106 USA. Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Harvard Vanguard Med Associates, Auburndale, MA 02466 USA. Oregon Hlth & Sci Univ, Portland, OR 97239 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Qaseem, A (reprint author), Amer Coll Physicians, 190 N Independence Mall W, Philadelphia, PA 19106 USA. RI Shaheen, Nicholas/A-1898-2013 FU National Cancer Institute [U54CA163060, U54CA156733] FX Financial support for the development of this best practice advice paper comes exclusively from the ACP's operating budget. Dr. Shaheen is supported by the National Cancer Institute (grant U54CA163060 and U54CA156733). NR 73 TC 49 Z9 51 U1 0 U2 8 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 4 PY 2012 VL 157 IS 11 BP 808 EP + DI 10.7326/0003-4819-157-11-201212040-00008 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 049RC UT WOS:000312000100006 PM 23208168 ER PT J AU D'Alcante, CC Diniz, JB Fossaluza, V Batistuzzo, MC Lopes, AC Shavitt, RG Deckersbach, T Malloy-Diniz, L Miguel, EC Hoexter, MQ AF D'Alcante, Carina C. Diniz, Juliana B. Fossaluza, Victor Batistuzzo, Marcelo C. Lopes, Antonio C. Shavitt, Roseli G. Deckersbach, Thilo Malloy-Diniz, Leandro Miguel, Euripedes C. Hoexter, Marcelo Q. TI Neuropsychological predictors of response to randomized treatment in obsessive-compulsive disorder SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE Cognitive-behavioral therapy; Neuropsychology; Obsessive-compulsive disorder; Serotonin reuptake inhibitors; Treatment-naive ID SEROTONIN REUPTAKE INHIBITORS; COGNITIVE-BEHAVIORAL THERAPY; CLINICAL-TRIAL; PREFRONTAL CORTEX; NAIVE PATIENTS; IMPAIRMENT; PHARMACOTHERAPY; PERFORMANCE; DIMENSIONS; INVENTORY AB Objective: To identify neuropsychological predictors of treatment response to cognitive-behavioral therapy (CBT) and fluoxetine in treatment-naive adults with obsessive-compulsive disorder (OCD). Method: Thirty-eight adult outpatients with OCD underwent neuropsychological assessment, including tasks of intellectual function, executive functioning and visual and verbal memory, before randomization to a 12-week clinical trial of either CBT or fluoxetine. Neuropsychological measures were used to identify predictors of treatment response in OCD. Results: Neuropsychological measures that predicted a better treatment response to either CBT or fluoxetine were higher verbal IQ (Wechsler Abbreviated Scale of Intelligence) (p = 0.008); higher verbal memory on the California Verbal Learning Test (p = 0.710); shorter time to complete part D (Dots) (p<0.001), longer time to complete part W (Words) (p = 0.025) and less errors on part C (Colors) (p<0.001) in the Victoria Stroop Test (VST). Fewer perseverations on the California Verbal Learning Test, a measure of mental flexibility, predicted better response to CBT, but worse response to fluoxetine (p = 0.002). Conclusion: In general, OCD patients with better cognitive and executive abilities at baseline were more prone to respond to either CBT or fluoxetine. Our finding that neuropsychological measures of mental flexibility predicted response to treatment in opposite directions for CBT and fluoxetine suggests that OCD patients with different neuropsychological profiles may respond preferentially to one type of treatment versus the other. Further studies with larger samples of OCD patients are necessary to investigate the heuristic value of such findings in a clinical context. (C) 2012 Elsevier Inc. All rights reserved. C1 [D'Alcante, Carina C.; Diniz, Juliana B.; Fossaluza, Victor; Batistuzzo, Marcelo C.; Lopes, Antonio C.; Shavitt, Roseli G.; Miguel, Euripedes C.; Hoexter, Marcelo Q.] Univ Sao Paulo, Sch Med, Dept Psychiat, Obsess Compuls Disorder Spectrum Project Clin, BR-78505453 Sao Paulo, Brazil. [Fossaluza, Victor] Univ Sao Paulo, Inst Math & Stat, BR-78505453 Sao Paulo, Brazil. [Deckersbach, Thilo] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Malloy-Diniz, Leandro] Univ Fed Minas Gerais, Inst Biol Sci, Grad Program Neurosci, Belo Horizonte, MG, Brazil. [Hoexter, Marcelo Q.] Fed Univ Sao Paulo UNIFESP, Dept Psychiat, Interdisciplinary Lab Clin Neurosci LiNC, Sao Paulo, Brazil. RP D'Alcante, CC (reprint author), Univ Sao Paulo, Med Sch Sao Paulo, Rua Dr Ovidio Pires de Campos, BR-78505453 Sao Paulo, Brazil. EM chaubetca@hcnet.usp.br RI Malloy-Diniz, Leandro/D-7829-2013; Miguel, Euripedes/B-2871-2008; Fossaluza, Victor/B-3377-2014; Hoexter, Marcelo/D-7620-2013; Batistuzzo, Marcelo/H-7790-2015 OI Malloy-Diniz, Leandro/0000-0002-6606-1354; Fossaluza, Victor/0000-0002-9328-0210; Hoexter, Marcelo/0000-0002-9302-4380; FU National Council for Scientific and Technological Development (CNPq: Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) [521369/96-7, 475919/2006-8, 481791/2004-3]; Foundation for the Support of Research in the State of Sao Paulo (FAPESP: Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) [05/55628-08, 05/04206-6, 06/61459-7, 06/50273-0]; FAPESP [06/58286-3] FX This study received financial support in the form of grants provided by the following Brazilian governmental agencies: the National Council for Scientific and Technological Development (CNPq: Conselho Nacional de Desenvolvimento Cientifico e Tecnologico), grant numbers: 521369/96-7, 475919/2006-8 and 481791/2004-3; and the Foundation for the Support of Research in the State of Sao Paulo (FAPESP: Fundacao de Amparo a Pesquisa do Estado de Sao Paulo), grant numbers: 05/55628-08, 05/04206-6,06/61459-7 and 06/50273-0). Dr. Carina received research support from FAPESP (06/58286-3). All other authors report no competing interests. NR 63 TC 20 Z9 21 U1 5 U2 41 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD DEC 3 PY 2012 VL 39 IS 2 BP 310 EP 317 DI 10.1016/j.pnpbp2012.07.002 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 035JU UT WOS:000310943500014 PM 22789662 ER PT J AU Britton, KA Pedley, A Massaro, JM Corsini, EM Murabito, JM Hoffmann, U Fox, CS AF Britton, Kathryn A. Pedley, Alison Massaro, Joseph M. Corsini, Erin M. Murabito, Joanne M. Hoffmann, Udo Fox, Caroline S. TI Prevalence, Distribution, and Risk Factor Correlates of High Thoracic Periaortic Fat in the Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE body fat distribution; obesity; perivascular adipose tissue; risk factors; visceral adipose tissue ID PERIVASCULAR ADIPOSE-TISSUE; METABOLICALLY-OBESE; PHYSICAL-ACTIVITY; DISEASE; ASSOCIATION; NUTRITION; COHORT AB Background-Thoracic periaortic adipose tissue (TAT) is associated with atherosclerosis and cardiovascular disease (CVD) risk factors and may play a role in obesity-mediated vascular disease. We sought to determine the prevalence, distribution, and risk factor correlates of high TAT. Methods and Results-Participants from the Framingham Heart Study (n=3246, 48% women, mean age 51.1 years) underwent multidetector computed tomography; high TAT and visceral adipose tissue (VAT) were defined on the basis of sex-specific 90th percentiles in a healthy referent sample. The prevalence of high TAT was 38.1% in women and 35.7% in men. Among individuals without high VAT, 10.1% had high TAT. After adjustment for age and VAT, both women and men with high TAT in the absence of high VAT were older and had a higher prevalence of CVD (P<0.0001) compared with those without high TAT. In addition, men in this group were more likely to be smokers (P=0.02), whereas women were more likely to have low high-density lipoprotein cholesterol (P=0.005). Conclusions-Individuals in our community-based sample with high TAT in the absence of high VAT were characterized by an adverse cardiometabolic profile. This adipose tissue phenotype may identify a subset of individuals with distinct metabolic characteristics. C1 [Britton, Kathryn A.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Britton, Kathryn A.; Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Britton, Kathryn A.; Pedley, Alison; Murabito, Joanne M.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Corsini, Erin M.; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Metab & Hypertens, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBIs Framingham Heart Study, 75 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Murabito, Joanne/0000-0002-0192-7516; Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; National Heart, Lung, and Blood Institute [K12 HL083786] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract N01-HC-25195). Dr. Britton was supported by a Research Career Development Award (K12 HL083786) from the National Heart, Lung, and Blood Institute. NR 26 TC 18 Z9 18 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD DEC PY 2012 VL 1 IS 6 AR UNSP e004200 DI 10.1161/JAHA.112.004200 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 243RY UT WOS:000326335900007 PM 23316328 ER PT J AU Thanassoulis, G Massaro, JM Corsini, E Rogers, I Schlett, CL Meigs, JB Hoffmann, U O'Donnell, CJ Fox, CS AF Thanassoulis, George Massaro, Joseph M. Corsini, Erin Rogers, Ian Schlett, Christopher L. Meigs, James B. Hoffmann, Udo O'Donnell, Christopher J. Fox, Caroline S. TI Periaortic Adipose Tissue and Aortic Dimensions in the Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE adipose tissue; aneurysm; aorta; peripheral vascular disease ID PERICARDIAL FAT; RISK-FACTORS; ANEURYSMS; DISEASE; HEALTH; COMMUNITY; DIAMETER; OBESITY; COHORT AB Background-Periaortic fat, because of its contiguity with the aorta, may promote vascular remodeling and aortic dilatation. However, the relations between perioartic fat depots and aortic dimensions have not been previously described. Methods and Results-A total of 3001 individuals (mean age 50 +/- 10 years, 49% women) from the Framingham Offspring and Third Generation cohorts underwent computed tomography for quantification of periaortic fat and aortic dimensions. We estimated the association between quantitative periaortic and visceral adipose tissue volumes (per standard deviation [SD] increment of volume) with aortic dimensions in both the thorax and abdomen. Thoracic periaortic fat was associated with higher thoracic aortic dimensions (beta coefficient per SD of fat volume 0.67 mm, 95% confidence interval 0.58 to 0.76 mm; P<0.001). The association persisted after adjustment for age, sex, and cardiovascular risk factors including body mass index and visceral adipose tissue volume. Results for the association of periaortic fat and abdominal aortic dimensions were similar. Further adjustment for adipokines (resistin and adiponectin) had no significant impact on these associations. Conclusions-Periaortic fat volume was associated with aortic dimensions in both the thorax and abdomen, supporting the notion that local fat depots may contribute to aortic remodeling. Further work to understand the mechanisms underlying this association is warranted. C1 [Thanassoulis, George; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, NIH, Framingham Heart Study, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Corsini, Erin; Rogers, Ian; Schlett, Christopher L.; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, NIH, Intramural Res, Bethesda, MD 20892 USA. RP Fox, CS (reprint author), NHLBI, NIH, Framingham Heart Study, Framingham, MA USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Canadian Institute of Health Research; Fonds de Recherche en Sante du Quebec FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195). Dr Thanassoulis was supported by a Research Fellowship from the Canadian Institute of Health Research and the Fonds de Recherche en Sante du Quebec. NR 25 TC 18 Z9 18 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD DEC PY 2012 VL 1 IS 6 AR UNSP e000885 DI 10.1161/JAHA.112.000885 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 243RY UT WOS:000326335900021 PM 23316310 ER PT J AU Dietrich, EA Gebhard, KH Fasching, CE Giacaman, RA Kappes, JC Ross, KF Herzberg, MC AF Dietrich, Elizabeth A. Gebhard, Kristin H. Fasching, Claudine E. Giacaman, Rodrigo A. Kappes, John C. Ross, Karen F. Herzberg, Mark C. TI Short Communication HIV Type 1 Escapes Inactivation by Saliva via Rapid Escape into Oral Epithelial Cells SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID PERMISSIVE CELLS; KERATINOCYTES; TRANSMISSION; INFECTION AB Saliva contains anti-HIV-1 factors, which show unclear efficacy in thwarting mucosal infection. When incubated in fresh, unfractionated whole saliva, infectious HIV-1 IIIb and BaL (X4- and R5-tropic, respectively) persisted from 4 to at least 30 min in a saliva concentration-dependent manner. In salivary supernatant for up to 6 h, both infectious HIV-1 strains "escaped" into immortalized oral epithelial cells; infectious BaL showed selectively enhanced escape in the presence of saliva. Fluorescently labeled HIV-1 virus-like particles entered oral epithelial cells within minutes of exposure. Using a previously unrecognized mechanism, therefore, strains of HIV-1 escape inactivation by saliva via rapid uptake into oral epithelial cells. C1 [Herzberg, Mark C.] Univ Minnesota, Sch Dent, Dept Diagnost & Biol Sci, Minneapolis, MN 55455 USA. [Dietrich, Elizabeth A.; Gebhard, Kristin H.; Fasching, Claudine E.; Giacaman, Rodrigo A.; Ross, Karen F.; Herzberg, Mark C.] Minneapolis VA Med Ctr, Mucosal & Vaccine Res Ctr, Minneapolis, MN USA. [Kappes, John C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Kappes, John C.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Kappes, John C.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Kappes, John C.] Birmingham Vet Affairs Med Ctr, Res Serv, Birmingham, AL USA. RP Herzberg, MC (reprint author), Univ Minnesota, Sch Dent, Dept Diagnost & Biol Sci, 17-164 Moos Tower,515 Delaware St SE, Minneapolis, MN 55455 USA. EM mcherzb@umn.edu RI Giacaman, Rodrigo/A-9811-2010 OI Giacaman, Rodrigo/0000-0003-3362-5173 FU NIH/ NIDCR [R01DE015503, R21DE015506]; Minneapolis VA Medical Center; UAB Center for AIDS Research Virology and Sequencing Cores [P30-AI-27767]; Genetically Defined Microbe and Expression Core of the UAB Mucosal HIV and Immunobiology Center [R24 DK-64400]; Veterans Affairs, Research Service FX The support of NIH/ NIDCR R01DE015503 (M. C. H.), R21DE015506 (K. F. R.), and funds from the Minneapolis VA Medical Center by J.C.K. and M. C. H. is greatly appreciated. Research in J.C.K.'s laboratory was supported by the UAB Center for AIDS Research Virology and Sequencing Cores (P30-AI-27767), the Genetically Defined Microbe and Expression Core of the UAB Mucosal HIV and Immunobiology Center (R24 DK-64400), and a Merit Review Award from the Veterans Affairs, Research Service. NR 16 TC 5 Z9 5 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD DEC PY 2012 VL 28 IS 12 BP 1574 EP 1578 DI 10.1089/aid.2011.0069 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 047FW UT WOS:000311825000007 PM 22077822 ER PT J AU Cayabyab, MJ Macovei, L Campos-Neto, A AF Cayabyab, Mark J. Macovei, Lilia Campos-Neto, Antonio TI Current and novel approaches to vaccine development against tuberculosis SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Review DE tuberculosis; Mycobacterium tuberculosis; vaccine; antigen; adjuvant; recombinant protein; delivery system ID T-CELL RESPONSES; BACILLUS-CALMETTE-GUERIN; RECOMBINANT MYCOBACTERIUM-SMEGMATIS; MULTIDRUG-RESISTANT TUBERCULOSIS; MICROBIAL ENUMERATION TECHNIQUE; ACTIVE PULMONARY TUBERCULOSIS; HIV-ASSOCIATED TUBERCULOSIS; GUINEA-PIG MODEL; PROTECTIVE IMMUNITY; TUBERCLE-BACILLI AB Antibiotics and vaccines are the two most successful medical countermeasures that humans have created against a number of pathogens. However a select few e.g., Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) have evaded eradication by vaccines and therapeutic approaches. TB is a global public health problem that kills 1.4 million people per year. The past decade has seen significant progress in developing new vaccine candidates, but the most fundamental questions in understanding disease progression and protective host responses that are responsible for controlling Mtb infection still remain poorly resolved. Current TB treatment requires intense chemotherapy with several antimicrobials, while the only approved vaccine is the classical viable whole-cell based Bacille-Calmette-Guerin (BCG) that protects children from severe forms of TB, but fails to protect adults. Taken together, there is a growing need to conduct basic and applied research to develop novel vaccine strategies against TB. This review is focused on the discussion surrounding current strategies and innovations being explored to discover new protective antigens, adjuvants, and delivery systems in the hopes of creating an efficacious TB vaccine. C1 [Cayabyab, Mark J.; Macovei, Lilia; Campos-Neto, Antonio] Forsyth Inst, Cambridge, MA 02142 USA. [Cayabyab, Mark J.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Campos-Neto, A (reprint author), Forsyth Inst, Infect Dis Res Ctr, 245 1st St, Cambridge, MA 02142 USA. EM acampos@forsyth.org FU National Institutes of Health [R01 AI076425] FX Financial support: This work was supported by the following grants from the National Institutes of Health: R01 AI076425 to A. Campos-Neto. NR 168 TC 11 Z9 12 U1 1 U2 9 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD DEC PY 2012 VL 2 AR UNSP 154 DI 10.3389/fcimb.2012.00154 PG 16 WC Immunology; Microbiology SC Immunology; Microbiology GA 221EC UT WOS:000324639400003 PM 23230563 ER PT J AU Utech, AE Tadros, EM Hayes, TG Garcia, JM AF Utech, Anne E. Tadros, Eiriny M. Hayes, Teresa G. Garcia, Jose M. TI Predicting survival in cancer patients: the role of cachexia and hormonal, nutritional and inflammatory markers SO JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE LA English DT Article DE Inflammation; Anorexia; Interleukin-6; TNF-alpha; Testosterone ID RESTING ENERGY-EXPENDITURE; TUMOR-BEARING RATS; CELL LUNG-CANCER; PROINFLAMMATORY CYTOKINES; SYMPTOM ASSESSMENT; TERMINAL CANCER; SERUM-LEVELS; WEIGHT-LOSS; FOOD-INTAKE; HYPOGONADISM AB Background Cancer can lead to weight loss, anorexia, and poor nutritional status, which are associated with decreased survival in cancer patients. Methods Male cancer patients (n=136) were followed for a mean time of 4.5 years. Variables were obtained at baseline: cancer stage, albumin, hemoglobin, tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, bioavailable testosterone, appetite questionnaire, and weight change from baseline to 18 months. Primary statistical tests included Kaplan-Meier survival analysis and Cox proportional hazard regression (PHREG). Results Univariate PHREG showed that cancer stage, albumin, hemoglobin, TNF-alpha, IL-6, and weight change were each significantly associated with mortality risk (P<0.05), but bioavailable testosterone was not. Multivariate PHREG analysis established that weight change and albumin were jointly statistically significant even after adjusting for stage. Conclusion In this sample of male oncology patients, cancer stage, serum albumin, and weight loss predicted survival. High levels of inflammatory markers and hemoglobin are associated with increased mortality, but do not significantly improve the ability to predict survival above and beyond cancer stage, albumin, and weight loss. C1 [Utech, Anne E.; Tadros, Eiriny M.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Houston, TX 77030 USA. [Hayes, Teresa G.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Div Hematol & Oncol, Houston, TX 77030 USA. [Garcia, Jose M.] Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Houston, TX 77030 USA. RP Garcia, JM (reprint author), Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Houston, TX 77030 USA. EM jgarcia1@bcm.edu FU Dept. of Veterans Affairs [BX000507, CX000174]; Abbott; Aeterna Zentaris; Helsinn Therapeutics FX This material is based upon work supported by the Dept. of Veterans Affairs (MREP, SCVAHNCDA, MERIT awards BX000507 and CX000174). Dr. Garcia receives research support from Abbott, Aeterna Zentaris, and Helsinn Therapeutics. The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia, and Muscle [35]. NR 35 TC 25 Z9 25 U1 0 U2 2 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 2190-5991 J9 J CACHEXIA SARCOPENI JI J. Caxhexia Sarcopenia Muscle PD DEC PY 2012 VL 3 IS 4 BP 245 EP 251 DI 10.1007/s13539-012-0075-5 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 218WV UT WOS:000324464200005 PM 22648739 ER PT J AU Ghobrial, IM AF Ghobrial, Irene M. TI Are you sure this is Waldenstrom macroglobulinemia? SO HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM LA English DT Article ID CONSENSUS PANEL RECOMMENDATIONS; 2ND INTERNATIONAL WORKSHOP; LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA; IGM MONOCLONAL GAMMOPATHY; FREE LIGHT-CHAIN; PHASE-II TRIAL; UNDETERMINED SIGNIFICANCE; PROGNOSTIC-FACTORS; MULTIPLE-MYELOMA; FOLLOW-UP AB Waldenstrom macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by the presence of lymphoplasmacytic cells in the BM and IgM monoclonal protein in the serum. The origin of the malignant clone is thought to be a B cell arrested after somatic hypermutation in the germinal center and before terminal differentiation to plasma cells. In this review, recent advances in the genetic and epigenetic regulators of tumor progression are discussed. Risk factors include IgM-monoclonal gammopathy of undermined significance, familial disease, and immunological factors. The clinical manifestations of the disease include those related to clonal infiltration of the BM, lymph nodes, and, rarely, other sites such as pulmonary or CNS infiltration (Bing-Neel syndrome). Other manifestations are related to the IgM monoclonal protein, including hyperviscosity, cryoglobulinemia, protein-protein interactions, Ab-mediated disorders such as neuropathy, hemolytic anemia, and Schnitzler syndrome. IgM deposition in organs can lead to amyloidogenic manifestations in WM. The diagnostic workup for a patient with WM and rare presentations of WM are described herein. Prognosis of WM depends on 5 major factors in the International Staging System, including age, anemia, thrombocytopenia, beta-2 microglobulin, and IgM level. The differential diagnosis of WM includes IgM-multiple myeloma, marginal zone lymphoma, mantle cell lymphoma, and follicular lymphoma. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ghobrial, IM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St,D1B30, Boston, MA 02115 USA. EM Irene_ghobrial@dfci.harvard.edu FU International Waldenstrom Macroglobulinemia Foundation [1R01F0003743]; Heje fellowship; Kirsch Laboratory for Waldenstrom at Dana-Farber Cancer Institute, Boston, MA FX This study was supported in part by the International Waldenstrom Macroglobulinemia Foundation (1R01F0003743), Heje fellowship, and Kirsch Laboratory for Waldenstrom at Dana-Farber Cancer Institute, Boston, MA. NR 58 TC 14 Z9 15 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 1520-4391 EI 1520-4383 J9 HEMATOL-AM SOC HEMAT JI Hematol.-Am. Soc. Hematol. Educ. Program PD DEC PY 2012 BP 586 EP 594 DI 10.1182/asheducation-2012.1.586 PG 9 WC Education, Scientific Disciplines; Hematology SC Education & Educational Research; Hematology GA 209KT UT WOS:000323755900087 ER PT J AU Corro, G Rocco, CA De Candia, C Catano, G Turk, G Mangano, A Aulicino, PC Bologna, R Sen, L AF Corro, Guillermo Rocco, Carlos A. De Candia, Cristian Catano, Gabriel Turk, Gabriela Mangano, Andrea Aulicino, Paula C. Bologna, Rosa Sen, Luisa TI Genetic and Functional Analysis of HIV Type 1 nef Gene Derived from Long-Term Nonprogressor Children: Association of Attenuated Variants with Slow Progression to Pediatric AIDS SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DISEASE PROGRESSION; PERINATAL INFECTION; STRUCTURAL DEFECTS; REPEAT SEQUENCES; NATURAL-HISTORY; TRANSGENIC MICE; T-CELLS; TRANSMISSION; REPLICATION AB Among persons infected by HIV-1, the rate of progression to AIDS is multifactorial being affected by host and viral factors, including the HIV-encoded negative factor (Nef). Our aim was to define whether variations in the nef gene as well as its functions may be associated with slower HIV disease course in infected children. The proviral HIV-1 nef gene was cloned, sequenced, and compared in children with contrasting disease course: 10 long-term nonprogressors (LTNP) and six rapid progressor (RP). The CD4 and MHC-I down-modulation ability of nef alleles derived from LTNP and RP children was analyzed. We observed that only one of our 10 LTNP had a protective genetic background, and out of them, 40% had defective nef genes, carrying substitutions at the (AWLEAQ(56-61)) and the (Rxx(22-24)) domains, and that those alleles were unable of down-regulate CD4 and MHC-I. The emergence or presence of Nef L58V substitution was associated with viral attenuation, indicated by a reduction in HIV viral loads, a persistent preservation of CD4(+) T cell counts, and lack of AIDS-related symptoms. Our results demonstrate that HIV-1 perinatally infected children carrying functionally defective nef HIV-1 strains have prolonged asymptomatic phases without therapy, suggesting a relevant role of CD4 and MHC-I down-modulation Nef domains on in vivo HIV-1 pathogenesis and pediatric immunodeficiency outcome. C1 [Corro, Guillermo; Rocco, Carlos A.; Mangano, Andrea; Aulicino, Paula C.; Sen, Luisa] Hosp Pediat Prof Dr Juan P Garran, Lab Biol Celular & Retrovirus, Buenos Aires, DF, Argentina. [Corro, Guillermo; Mangano, Andrea; Aulicino, Paula C.; Sen, Luisa] Consejo Nacl Invest Cient & Tecn, Buenos Aires, DF, Argentina. [De Candia, Cristian; Turk, Gabriela] Univ Buenos Aires, Natl Reference Ctr AIDS, Buenos Aires, DF, Argentina. [Catano, Gabriel] S Texas Vet Hlth Care Syst, Vet Adm Res Ctr AIDS & HIV Infect 1, San Antonio, TX USA. [Catano, Gabriel] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Bologna, Rosa] Hosp Pediat Prof Dr Juan P Garrahan, Serv Infectol, Buenos Aires, DF, Argentina. RP Corro, G (reprint author), 1881 Combate Pozos St,C1245AAM, Buenos Aires, DF, Argentina. EM gcorro2@gmail.com NR 54 TC 6 Z9 6 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD DEC PY 2012 VL 28 IS 12 BP 1617 EP 1626 DI 10.1089/aid.2012.0020 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 047FW UT WOS:000311825000013 PM 22583022 ER PT J AU Mifflin, J AF Mifflin, Jeffrey TI CLEAVING AN UNKNOWN WORLD: The Powell Expeditions and the Scientific Exploration of the Colorado Plateau SO JOURNAL OF THE WEST LA English DT Book Review C1 [Mifflin, Jeffrey] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Mifflin, J (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ABC-CLIO PI SANTA BARBARA PA 130 CREMONA DR, SANTA BARBARA, CA 93117 USA SN 0022-5169 J9 J WEST JI J. West PD WIN PY 2012 VL 51 IS 1 BP 86 EP 87 PG 2 WC History SC History GA 134FA UT WOS:000318194400014 ER PT J AU Sun, JZ Wang, GI Goyal, VK Varshney, LR AF Sun, John Z. Wang, Grace I. Goyal, Vivek K. Varshney, Lav R. TI A framework for Bayesian optimality of psychophysical laws SO JOURNAL OF MATHEMATICAL PSYCHOLOGY LA English DT Article DE Relative Error; Bayesian Quantization; Weber-Fechner; Psychophysical Scale ID WEBER-FECHNER LAW; INFORMATION; INTENSITY; DISCRIMINATION; COMPRESSION; MAGNITUDE; EQUATION; SYSTEM; CORTEX; BRAIN AB The Weber-Fechner law states that perceived intensity is proportional to physical stimuli on a logarithmic scale. In this work, we formulate a Bayesian framework for the scaling of perception and find logarithmic and related scalings are optimal under expected relative error fidelity. Therefore, the Weber-Fechner law arises as being information theoretically efficient under the constraint of limited representability. An even stronger connection is drawn between the Weber-Fechner law and a Bayesian framework when neural storage or communication is the dominant concern, such as for numerosity. Theoretical results and experimental verification for perception of sound intensity are both presented. (C) 2012 Elsevier Inc. All rights reserved. C1 [Sun, John Z.; Wang, Grace I.; Goyal, Vivek K.; Varshney, Lav R.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Wang, Grace I.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Varshney, Lav R.] IBM Thomas J Watson Res Ctr, Hawthorne, NY 10532 USA. RP Varshney, LR (reprint author), IBM Thomas J Watson Res Ctr, Hawthorne, NY 10532 USA. EM varshney@alum.mit.edu FU National Science Foundation [0643836, 1115159] FX This material is based upon work supported by the National Science Foundation under Grants 0643836 and 1115159. The authors thank the reviewers, the associate editor, Bo Wen, Dmitri B. Chklovskii, Barbara Shinn-Cunningham, Katherine Heller, and Jeff Beck for their insightful comments. NR 49 TC 14 Z9 15 U1 2 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-2496 J9 J MATH PSYCHOL JI J. Math. Psychol. PD DEC PY 2012 VL 56 IS 6 BP 495 EP 501 DI 10.1016/j.jmp.2012.08.002 PG 7 WC Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods; Psychology, Mathematical SC Mathematics; Mathematical Methods In Social Sciences; Psychology GA 119IP UT WOS:000317091300009 ER PT J AU Vernochet, C Kahn, CR AF Vernochet, Cecile Kahn, C. Ronald TI Mitochondria, obesity and aging SO AGING-US LA English DT Editorial Material C1 [Vernochet, Cecile] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Vernochet, C (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu FU NIDDK NIH HHS [R01 DK031036, R01 DK082659, R37 DK031036] NR 7 TC 9 Z9 10 U1 0 U2 4 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD DEC PY 2012 VL 4 IS 12 BP 859 EP 860 PG 2 WC Cell Biology SC Cell Biology GA 104HD UT WOS:000315981800003 PM 23363767 ER PT J AU Thesen, T McDonald, CR Carlson, C Doyle, W Cash, S Sherfey, J Felsovalyi, O Girard, H Barr, W Devinsky, O Kuzniecky, R Halgren, E AF Thesen, Thomas McDonald, Carrie R. Carlson, Chad Doyle, Werner Cash, Syd Sherfey, Jason Felsovalyi, Olga Girard, Holly Barr, William Devinsky, Orrin Kuzniecky, Ruben Halgren, Eric TI Sequential then interactive processing of letters and words in the left fusiform gyrus SO NATURE COMMUNICATIONS LA English DT Article ID ANTEROVENTRAL TEMPORAL-LOBE; DEPTH-RECORDED POTENTIALS; FORM AREA; SPATIOTEMPORAL DYNAMICS; OCCIPITOTEMPORAL CORTEX; BRAIN IMAGES; TIME-COURSE; FMRI; RECOGNITION; PERCEPTION AB Despite decades of cognitive, neuropsychological and neuroimaging studies, it is unclear if letters are identified before word-form encoding during reading, or if letters and their combinations are encoded simultaneously and interactively. Here using functional magnetic resonance imaging, we show that a 'letter-form' area (responding more to consonant strings than false fonts) can be distinguished from an immediately anterior 'visual word-form area' in ventral occipito-temporal cortex (responding more to words than consonant strings). Letter-selective magnetoencephalographic responses begin in the letter-form area similar to 60 ms earlier than word-selective responses in the word-form area. Local field potentials confirm the latency and location of letter-selective responses. This area shows increased high-gamma power for similar to 400 ms, and strong phase-locking with more anterior areas supporting lexico-semantic processing. These findings suggest that during reading, visual stimuli are first encoded as letters before their combinations are encoded as words. Activity then rapidly spreads anteriorly, and the entire network is engaged in sustained integrative processing. C1 [Thesen, Thomas; Carlson, Chad; Doyle, Werner; Barr, William; Devinsky, Orrin; Kuzniecky, Ruben] NYU, Dept Neurol, Comprehens Epilepsy Ctr, New York, NY 10016 USA. [Thesen, Thomas; McDonald, Carrie R.; Sherfey, Jason; Felsovalyi, Olga; Girard, Holly; Halgren, Eric] Univ Calif San Diego, Dept Radiol, Multimodal Imaging Lab, La Jolla, CA 92037 USA. [Thesen, Thomas; McDonald, Carrie R.; Sherfey, Jason; Felsovalyi, Olga; Girard, Holly; Halgren, Eric] Univ Calif San Diego, Dept Neurosci, Multimodal Imaging Lab, La Jolla, CA 92037 USA. [Cash, Syd] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Cambridge, MA 02114 USA. [Halgren, Eric] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92037 USA. [Halgren, Eric] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92037 USA. [Halgren, Eric] Univ Calif San Diego, Kavli Inst Mind & Brain, La Jolla, CA 92037 USA. RP Thesen, T (reprint author), NYU, Dept Neurol, Comprehens Epilepsy Ctr, New York, NY 10016 USA. EM thomas.thesen@med.nyu.edu OI Barr, William/0000-0001-7711-7758; Devinsky, Orrin/0000-0003-0044-4632 FU NIH [NS18741]; FACES FX We thank Anders Dale and Donald Hagler for analysis tools, and Mark Blumberg and Amy Trongnetrpunya for help with data collection. This research was supported by grants from NIH (NS18741) and FACES. NR 51 TC 33 Z9 33 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC PY 2012 VL 3 AR 1284 DI 10.1038/ncomms2220 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109HH UT WOS:000316356700051 PM 23250414 ER PT J AU Yu, WY Chory, EJ Wernimont, AK Tempel, W Scopton, A Federation, A Marineau, JJ Qi, J Barsyte-Lovejoy, D Yi, JN Marcellus, R Iacob, RE Engen, JR Griffin, C Aman, A Wienholds, E Li, FL Pineda, J Estiu, G Shatseva, T Hajian, T Al-awar, R Dick, JE Vedadi, M Brown, PJ Arrowsmith, CH Bradner, JE Schapira, M AF Yu, Wenyu Chory, Emma J. Wernimont, Amy K. Tempel, Wolfram Scopton, Alex Federation, Alexander Marineau, Jason J. Qi, Jun Barsyte-Lovejoy, Dalia Yi, Joanna Marcellus, Richard Iacob, Roxana E. Engen, John R. Griffin, Carly Aman, Ahmed Wienholds, Erno Li, Fengling Pineda, Javier Estiu, Guillermina Shatseva, Tatiana Hajian, Taraneh Al-awar, Rima Dick, John E. Vedadi, Masoud Brown, Peter J. Arrowsmith, Cheryl H. Bradner, James E. Schapira, Matthieu TI Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors SO NATURE COMMUNICATIONS LA English DT Article ID EXCHANGE MASS-SPECTROMETRY; MIXED-LINEAGE LEUKEMIA; H3K79 METHYLATION; PROTEIN METHYLTRANSFERASES; HISTONE METHYLTRANSFERASE; DRUG DISCOVERY; SET DOMAIN; CELLS AB Selective inhibition of protein methyltransferases is a promising new approach to drug discovery. An attractive strategy towards this goal is the development of compounds that selectively inhibit binding of the cofactor, S-adenosylmethionine, within specific protein methyltransferases. Here we report the three-dimensional structure of the protein methyltransferase DOT1L bound to EPZ004777, the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy. This structure and those of four new analogues reveal remodelling of the catalytic site. EPZ004777 and a brominated analogue, SGC0946, inhibit DOT1L in vitro and selectively kill mixed lineage leukaemia cells, in which DOT1L is aberrantly localized via interaction with an oncogenic MLL fusion protein. These data provide important new insight into mechanisms of cell-active S-adenosylmethionine-competitive protein methyltransferase inhibitors, and establish a foundation for the further development of drug-like inhibitors of DOT1L for cancer therapy. C1 [Yu, Wenyu; Wernimont, Amy K.; Tempel, Wolfram; Scopton, Alex; Barsyte-Lovejoy, Dalia; Li, Fengling; Shatseva, Tatiana; Hajian, Taraneh; Vedadi, Masoud; Brown, Peter J.; Arrowsmith, Cheryl H.; Schapira, Matthieu] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada. [Chory, Emma J.; Federation, Alexander; Marineau, Jason J.; Qi, Jun; Yi, Joanna; Pineda, Javier; Bradner, James E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chory, Emma J.; Iacob, Roxana E.; Engen, John R.] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Yi, Joanna] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Marcellus, Richard; Griffin, Carly; Aman, Ahmed; Al-awar, Rima] Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada. [Wienholds, Erno; Dick, John E.] Univ Toronto, Campbell Family Inst, Ontario Canc Inst, Princess Margaret Canc Ctr,Univ Hlth Network, Toronto, ON M5G 1L7, Canada. [Wienholds, Erno; Dick, John E.] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1L7, Canada. [Pineda, Javier; Estiu, Guillermina] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. [Bradner, James E.] Harvard Univ, Dept Med, Sch Med, Boston, MA USA. [Schapira, Matthieu] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada. RP Arrowsmith, CH (reprint author), Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada. EM carrow@uhnresearch.ca; james_bradner@dfci.harvard.edu; matthieu.schapira@utoronto.ca FU National Science Foundation [OCI-1053575]; National Cancer Institute [Y1-CO-1020]; National Institute of General Medical Sciences [Y1-GM-1104]; US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]; Leukaemia and Lymphoma Society (SCOR); National Institutes of Health [R01 CA152314, K08CA128972]; American Society of Hematology; William Lawrence and Blanche Hughes Foundation; Steamboat Foundation Award; Northeastern University; Barnett Institute of Chemical and Biological Analysis; NIH [R01-GM086507]; Canadian Institutes of Health Research, Eli Lilly Canada; Genome Canada; GlaxoSmithKline; Ontario Ministry of Economic Development and Innovation; Novartis Research Foundation; Pfizer; AbbVie; Takeda; Wellcome Trust FX We wish to thank Dr Abdellah Allali-Hassani and Guillermo Senisterra for their expert advice on biochemical assays, and Dr Aled Edwards for critical comments on the manuscript. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number OCI-1053575. The computations were performed on Kraken at the National Institute for Computational Sciences (http://www.nics.tennessee.edu/). X-ray diffraction data were collected at the LRL Collaborative Access Team (LRL-CAT) beam line facilities at Sector 31 of the Advanced Photon Source operated by Eli Lilly and Company, GM/CA CAT that is funded in whole or in part with Federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Sciences (Y1-GM-1104); the Advanced Photon Source supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. J.E.B., J.Q. and J.J.M. are supported by the Leukaemia and Lymphoma Society (SCOR), the National Institutes of Health (R01 CA152314 and K08CA128972), the American Society of Hematology and the William Lawrence and Blanche Hughes Foundation. E.J.C. is supported by a Steamboat Foundation Award. We would like to acknowledge Northeastern University and the Barnett Institute of Chemical and Biological Analysis for financial support, partial funding from NIH R01-GM086507 and a research agreement with the Waters Corporation (J.R.E.). The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from Canadian Institutes of Health Research, Eli Lilly Canada, Genome Canada, GlaxoSmithKline, the Ontario Ministry of Economic Development and Innovation, the Novartis Research Foundation, Pfizer, AbbVie, Takeda and the Wellcome Trust. C.H.A. holds a Canada Research Chair in Structural Genomics. Funding for OICR is provided by the Ontario Ministry of Economic Development and Innovation. NR 28 TC 78 Z9 78 U1 7 U2 53 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC PY 2012 VL 3 AR 1288 DI 10.1038/ncomms2304 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109HH UT WOS:000316356700055 PM 23250418 ER PT J AU Srivastava, MK Dubinett, S Sharma, S AF Srivastava, Minu K. Dubinett, Steven Sharma, Sherven TI Targeting MDSCs enhance therapeutic vaccination responses against lung cancer SO ONCOIMMUNOLOGY LA English DT Editorial Material DE immune suppression; immunotherapy; lung cancer; myeloid-derived suppressor cells ID SUPPRESSOR-CELLS; BONE-MARROW AB Myeloid-derived suppressor cells (MDSCs) are important regulators of immune responses. These cells suppress the cytotoxic activities of natural killer (NK)-cell and T-cell effectors and promote tumor growth. We demonstrated that depleting MDSCs improve therapeutic responses to vaccination in a murine model of lung cancer. This approach may prove beneficial against tumors in which MDSC exert prominent immunosuppressive effects. C1 [Srivastava, Minu K.; Dubinett, Steven; Sharma, Sherven] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Lung Canc Res Program, Los Angeles, CA 90095 USA. [Dubinett, Steven; Sharma, Sherven] Univ Calif Los Angeles, David Geffen Sch Med, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. [Srivastava, Minu K.; Dubinett, Steven; Sharma, Sherven] Vet Affairs Greater Los Angeles Healthcare Syst, Mol Gene Med Lab, Los Angeles, CA USA. RP Sharma, S (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Lung Canc Res Program, Los Angeles, CA 90095 USA. EM ssharma@mednet.ucla.edu FU NCATS NIH HHS [UL1 TR000124] NR 8 TC 10 Z9 10 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 2162-4011 J9 ONCOIMMUNOLOGY JI OncoImmunology PD DEC PY 2012 VL 1 IS 9 BP 1650 EP 1651 DI 10.4161/onci.21970 PG 2 WC Oncology; Immunology SC Oncology; Immunology GA 108GY UT WOS:000316281700035 PM 23264925 ER PT J AU Uebel, M AF Uebel, Michael TI Psychoanalysis and the Question of Violence: From Masochism to Shame SO AMERICAN IMAGO LA English DT Article ID WORLD-WAR-II; TRAINING PSYCHOTHERAPISTS; MENTAL-HEALTH; GUILT; MIND; ZEN; EMBARRASSMENT; PERSPECTIVES; ATTRIBUTES; COMPASSION C1 US Dept Vet Affairs, Cent Texas Vet Hlth Care Syst, Washington, DC 20420 USA. RP Uebel, M (reprint author), US Dept Vet Affairs, Cent Texas Vet Hlth Care Syst, Washington, DC 20420 USA. NR 133 TC 0 Z9 0 U1 1 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0065-860X J9 AM IMAGO JI Am. Imago PD WIN PY 2012 VL 69 IS 4 BP 473 EP 505 PG 33 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA 099YP UT WOS:000315662200003 ER PT J AU Cassuto, O Dufies, M Jacquel, A Robert, G Ginet, C Dubois, A Hamouda, A Puissant, A Luciano, F Karsenti, JM Legros, L Cassuto, JP Lenain, P Auberger, P AF Cassuto, Ophelie Dufies, Maeva Jacquel, Arnaud Robert, Guillaume Ginet, Clemence Dubois, Alix Hamouda, Amine Puissant, Alexandre Luciano, Frederic Karsenti, Jean-Michel Legros, Laurence Cassuto, Jill Patrice Lenain, Pascal Auberger, Patrick TI All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to Ponatinib SO ONCOTARGET LA English DT Article DE CML; BCR ABL; TKI; Resistance; Ponatinib ID CHRONIC MYELOID-LEUKEMIA; BCR-ABL INHIBITORS; CML CELLS; IMATINIB; APOPTOSIS; AP24534; MUTANT; LYN; DIFFERENTIATION; OVEREXPRESSION AB The advent of tyrosine kinase inhibitor (TKI) therapy has considerably improved the survival of patients suffering chronic myelogenous leukemia (CML). Indeed, inhibition of BCR-ABL by imatinib, dasatinib or nilotinib triggers durable responses in most patients suffering from this disease. Moreover, resistance to imatinib due to kinase domain mutations can be generally circumvented using dasatinib or nilotinib, but the multi-resistant T315I mutation that is insensitive to these TKIs, remains to date a major clinical problem. In this line, ponatinib (AP24534) has emerged as a promising therapeutic option in patients with all kinds of BCR-ABL mutations, especially the T315I one. However and surprisingly, the effect of ponatinib has not been extensively studied on imatinib-resistant CML cell lines. Therefore, in the present study, we used several CML cell lines with different mechanisms of resistance to TKI to evaluate the effect of ponatinib on cell viability, apoptosis and signaling. Our results show that ponatinib is highly effective on both sensitive and resistant CML cell lines, whatever the mode of resistance and also on BaF3 murine B cells carrying native BCR-ABL or T315I mutation. We conclude that ponatinib could be effectively used for all types of TKI-resistant patients. C1 [Cassuto, Ophelie; Dufies, Maeva; Jacquel, Arnaud; Robert, Guillaume; Ginet, Clemence; Dubois, Alix; Hamouda, Amine; Puissant, Alexandre; Luciano, Frederic; Auberger, Patrick] Fac Med Nice, INSERM, Team Cell Death Differentiat Inflammat & Canc U10, C3M, F-06034 Nice, France. [Cassuto, Ophelie; Dufies, Maeva; Jacquel, Arnaud; Robert, Guillaume; Ginet, Clemence; Dubois, Alix; Hamouda, Amine; Puissant, Alexandre; Luciano, Frederic; Auberger, Patrick] Equipe Labellisee Ligue Natl Canc 2011 2013, Paris, France. [Cassuto, Ophelie; Karsenti, Jean-Michel; Legros, Laurence; Cassuto, Jill Patrice; Auberger, Patrick] CHU Nice, Serv Hematol Clin & Transplantat, Nice, France. [Cassuto, Ophelie; Lenain, Pascal] CLCC, Ctr Henri Becquerel, Rouen, France. [Puissant, Alexandre] Dana Farber Canc Inst, Pediat Oncol Dept, Boston, MA 02115 USA. RP Auberger, P (reprint author), Fac Med Nice, INSERM, Team Cell Death Differentiat Inflammat & Canc U10, C3M, U210, F-06034 Nice, France. EM auberger@unice.fr RI PUISSANT, ALEXANDRE/O-9575-2016; AUBERGER, Patrick/G-1491-2013 OI PUISSANT, ALEXANDRE/0000-0002-3997-9282; AUBERGER, Patrick/0000-0002-2481-8275 FU Ligue Nationale Contre le Cancer (LNCC, Equipe Labellisee); Association pour la Recherche contre le Cancer (ARC); Institut National de Canceropoles [INCA-PL-2010-219]; Fondation de France; Fondation pour la Recherche Medicale; Ligue Nationale Contre le Cancer FX This work was supported by The Ligue Nationale Contre le Cancer (LNCC, Equipe Labellisee 2011-2013), The Association pour la Recherche contre le Cancer (ARC), The Institut National de Canceropoles (INCA-PL-2010-219) and The Fondation de France. OC, GR and AJ A are fellowships from the Fondation pour la Recherche Medicale, the Fondation de France and the Ligue Nationale Contre le Cancer, respectively. NR 23 TC 16 Z9 19 U1 0 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC PY 2012 VL 3 IS 12 BP 1557 EP 1565 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 101UZ UT WOS:000315801200016 PM 23238683 ER PT J AU Herrmann, H Blatt, K Shi, JW Gleixner, KV Cerny-Reiterer, S Mullauer, L Vakoc, CR Sperr, WR Horny, HP Bradner, JE Zuber, J Valent, P AF Herrmann, Harald Blatt, Katharina Shi, Junwei Gleixner, Karoline V. Cerny-Reiterer, Sabine Muellauer, Leonhard Vakoc, Christopher R. Sperr, Wolfgang R. Horny, Hans-Peter Bradner, James E. Zuber, Johannes Valent, Peter TI Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem-and progenitor cells in acute myeloid leukemia (AML) SO ONCOTARGET LA English DT Article DE AML; leukemic stem cells; BRD4; JQ1; targeted therapy ID ACUTE MYELOGENOUS LEUKEMIA; INITIATING CELLS; PROGNOSTIC MARKERS; THERAPEUTIC TARGET; TRANSPLANTATION; CLASSIFICATION; CANCER; MICE; HETEROGENEITY; EXPRESSION AB Acute myeloid leukemia (AML) is a life-threatening stem cell disease characterized by uncontrolled proliferation and accumulation of myeloblasts. Using an advanced RNAi screen-approach in an AML mouse model we have recently identified the epigenetic 'reader' BRD4 as a promising target in AML. In the current study, we asked whether inhibition of BRD4 by a small-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosis in primary human AML stem-and progenitor cells. Primary cell samples were obtained from 37 patients with freshly diagnosed AML (n=23) or refractory AML (n=14). BRD4 was found to be expressed at the mRNA and protein level in unfractionated AML cells as well as in highly enriched CD34(+)/CD38(-) and CD34(+)/CD38(+) stem-and progenitor cells in all patients examined. In unfractionated leukemic cells, submicromolar concentrations of JQ1 induced major growth-inhibitory effects (IC50 0.05-0.5 mu M) in most samples, including cells derived from relapsed or refractory patients. In addition, JQ1 was found to induce apoptosis in CD34(+)/CD38(-) and CD34(+)/CD38(+) stem- and progenitor cells in all donors examined as evidenced by combined surface/Annexin-V staining. Moreover, we were able to show that JQ1 synergizes with ARA-C in inducing growth inhibition in AML cells. Together, the BRD4-targeting drug JQ1 exerts major anti-leukemic effects in a broad range of human AML subtypes, including relapsed and refractory patients and all relevant stem-and progenitor cell compartments, including CD34(+)/CD38(-) and CD34(+)/CD38(+) AML cells. These results characterize BRD4-inhibition as a promising new therapeutic approach in AML which should be further investigated in clinical trials. C1 [Herrmann, Harald; Cerny-Reiterer, Sabine; Sperr, Wolfgang R.; Valent, Peter] Ludwig Boltzmann Cluster Oncol, Vienna, Austria. [Blatt, Katharina; Gleixner, Karoline V.; Sperr, Wolfgang R.] Med Univ Vienna, Div Hematol & Hemostaseol, Dept Internal Med 1, Vienna, Austria. [Shi, Junwei; Vakoc, Christopher R.; Zuber, Johannes] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Muellauer, Leonhard] Med Univ Vienna, Dept Pathol, Vienna, Austria. [Bradner, James E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Horny, Hans-Peter] Univ Munich, Inst Pathol, D-80539 Munich, Germany. [Zuber, Johannes] Res Inst Mol Pathol IMP, Vienna, Austria. RP Valent, P (reprint author), Ludwig Boltzmann Cluster Oncol, Vienna, Austria. EM peter.valent@meduniwien.ac.at OI Vakoc, Christopher/0000-0002-1158-7180 FU Cancer Stem Cell Research Grant from the Medical University of Vienna; Burroughs-Wellcome Fund Career Award for Medical Scientists FX This study was supported by a Cancer Stem Cell Research Grant from the Medical University of Vienna. C.R.V. is supported by a Burroughs-Wellcome Fund Career Award for Medical Scientists. NR 51 TC 64 Z9 66 U1 1 U2 20 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD DEC PY 2012 VL 3 IS 12 BP 1588 EP 1599 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 101UZ UT WOS:000315801200019 PM 23249862 ER PT J AU Saunders, GH Chisolm, TH Wallhagen, MI AF Saunders, Gabrielle H. Chisolm, Theresa H. Wallhagen, Margaret I. TI Older Adults and Hearing Help-Seeking Behaviors SO AMERICAN JOURNAL OF AUDIOLOGY LA English DT Article DE adults; aging; amplification or hearing aids; auditory rehabilitation; hearing loss; outcomes ID QUALITY-OF-LIFE; NEGATIVE CONSEQUENCES; URINARY-INCONTINENCE; IMPAIRMENT; AID; POPULATION; PEOPLE; CARE; AGE; DETERMINANTS AB Purpose: To review the current literature on help seeking for hearing health care among older adults. Method: The authors conducted a literature review regarding help seeking for hearing-related communication difficulties as well as for other chronic medical conditions. Results: Untreated hearing loss can lead to numerous negative secondary consequences; uptake and use of hearing aids remain low, despite the fact that hearing aids provide an effective treatment option for older adults with hearing loss. The authors describe models relevant to understanding the help-seeking and decision-making behaviors of older adults with hearing loss and discuss recommendations for future research. Conclusion: Because of the considerable overlap in factors associated with help-seeking behaviors across chronic medical conditions and because help-seeking behaviors are complex, help seeking should be examined within the framework of a multifactorial model, such as the health belief model or the transtheoretical stages of change model. C1 [Saunders, Gabrielle H.] Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR USA. [Chisolm, Theresa H.] Univ S Florida, Tampa, FL USA. [Wallhagen, Margaret I.] Univ Calif San Francisco, Sch Nursing, San Francisco, CA 94143 USA. RP Saunders, GH (reprint author), Portland VA Med Ctr, Natl Ctr Rehabilitat Auditory Res, Portland, OR USA. EM Gabrielle.saunders@va.gov NR 48 TC 21 Z9 23 U1 3 U2 16 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1059-0889 J9 AM J AUDIOL JI Am. J. Audiol. PD DEC PY 2012 VL 21 IS 2 BP 331 EP 337 DI 10.1044/1059-0889(2012/12-0028) PG 7 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 083HY UT WOS:000314455400020 PM 23233518 ER PT J AU Eisner, BH Sheth, S Herrick, B Pais, VM Sawyer, M Miller, N Hurd, KJ Humphreys, MR AF Eisner, Brian H. Sheth, Sonali Herrick, Benjamin Pais, Vernon M., Jr. Sawyer, Mark Miller, Nicole Hurd, Kimberly J. Humphreys, Mitchell R. TI The effects of ambient temperature, humidity and season of year on urine composition in patients with nephrolithiasis SO BJU INTERNATIONAL LA English DT Article DE kidney stone; risk; urine; weather; temperature; humidity ID KIDNEY-STONES; RISK-FACTORS; CALCIUM; UROLITHIASIS; TIME AB OBJECTIVE To understand the effects of temperature, humidity and season of year on 24-h urine composition in patients with nephrolithiasis. PATIENTS AND METHOD A retrospective review was performed of patients evaluated at four metabolic stone clinics. Multivariate linear regression models examined the relationship between mean temperature, average humidity, season of year and 24-h urine composition. Multivariate models adjusted for known risk factors for stone disease. Mean temperature and average humidity data were obtained from http://www.weatherunderground.com based on patient-provided addresses. RESULTS A total of 599 patients were included in the study, comprising 239 women and 360 men with a mean age of 53.6 years (SD 15.0). Mean temperature was 16.9 degrees C (SD 4.8, range -21.1 to 38.3 degrees C) and average humidity was 58.1% (SD 23.5, range 11 -100%). On multivariate linear regression, increasing temperature was associated with increasing urine calcium (beta = 11.3, 95% CI 2.2-20.0), super-saturation of calcium oxalate (beta = 0.6, 95% CI 0.2-0.9), super-saturation of calcium phosphate (beta = 0.14, 95% CI 0.03-0.2), and decreasing urine sodium (beta = -5.2, 95% CI -10.3 to -0.1). As seasons become warmer (i.e. from winter to autumn to spring to summer), changes were increased urine volume (beta = 0.09, 95% CI 0.01-0.2) and decreased super-saturation of calcium phosphate (beta = -0.2, 95% CI -0.3 to -0.03). There were no associations between quintile of humidity and any 24-h urine constituents. CONCLUSIONS Increasing temperature may increase stone risk by increasing urine excretion of calcium, and the super-saturation of calcium oxalate and calcium phosphate. These findings were independent of humidity and of season of year. This appears to be related to a physiological impact of temperature itself, rather than to geographic location. C1 [Eisner, Brian H.; Sheth, Sonali] Massachusetts Gen Hosp Urol, Boston, MA USA. [Herrick, Benjamin; Pais, Vernon M., Jr.] Dartmouth Hitchcock Med Ctr Urol, Lebanon, NH USA. [Sawyer, Mark; Miller, Nicole] Vanderbilt Univ, Med Ctr Urol, Nashville, TN USA. [Hurd, Kimberly J.; Humphreys, Mitchell R.] Mayo Clin, Dept Urol, Phoenix, AZ USA. RP Eisner, BH (reprint author), Dept Urol, GRB 1102,55 Fruit St, Boston, MA 02114 USA. EM beisner@partners.org NR 11 TC 10 Z9 10 U1 0 U2 38 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 J9 BJU INT JI BJU Int. PD DEC PY 2012 VL 110 IS 11C BP E1014 EP E1017 DI 10.1111/j.1464-410X.2012.11186.x PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 091DQ UT WOS:000315029700041 PM 22578009 ER PT J AU Sullivan, MP Cristofaro, V Radisavljevic, ZM Yalla, SV AF Sullivan, Maryrose P. Cristofaro, Vivian Radisavljevic, Ziv M. Yalla, Subbarao V. TI Regional distribution and molecular interaction of caveolins in bladder smooth muscle SO BJU INTERNATIONAL LA English DT Article DE bladder; smooth muscle; caveolin; caveolae ID URINARY-BLADDER; SIGNAL-TRANSDUCTION; CELLS; COLOCALIZATION; EXPRESSION; DETRUSOR; MOUSE; RAT AB OBJECTIVE To determine the regional expression profile of caveolin isoforms (integral membrane proteins abundant in caveolae), the spatial relationships among caveolin proteins within specific smooth muscle (SM) regions and the extent of their molecular interactions in bladder SM (BSM). MATERIALS AND METHODS Regional differences in the expression of caveolin family members were determined by quantitative reverse transcriptase-polymerase chain reaction and Western blot of RNA and protein extracted from the base, body and dome of rat bladders. To evaluate the distribution of caveolin-1 (Cav-1), Cav-2 and Cav-3 within the bladder, longitudinal tissue sections from the base to dome were processed for confocal microscopy and quantified for intensity of immunoreactivity (IR) and extent of co-localisation. Interactions among Cav-1, Cav-2 and Cav-3 were determined by co-immunoprecipitation. RESULTS Differential expression of Cav-1 and Cav-3 was detected among bladder regions, with lowest expression in the bladder base relative to the dome. Cav-1 was highly expressed in all regions, although an increase in IR from submucosa to serosa was detected in each region. The distribution of Cav-2 IR generally paralleled Cav-1, but progressively decreased from submucosa to serosa in each region. Cav-3 expression predominated in the medial region of BSM increasing progressively from base to dome, but was poorly expressed in the outer SM layer particularly in the dome. Cav-1 co-precipitated extensively with both Cav-2 and Cav-3. Co-precipitation between Cav-3 and Cav-2 was also detected. CONCLUSIONS The isoform-specific spatial distribution and distinct molecular interactions among caveolins in BSM may contribute to the contractile heterogeneity of BSM cells and facilitate differential modulation of responses to local stimuli. As BSM caveolae regulate key signalling processes involved in contraction, altered expression of caveolin proteins may generate a regional imbalance in contraction/relaxation responses, thus leading to bladder dysfunction. C1 [Sullivan, Maryrose P.; Cristofaro, Vivian; Radisavljevic, Ziv M.; Yalla, Subbarao V.] Harvard Univ, Brigham & Womens Hosp, Vet Affairs Boston Healthcare Syst, Div Urol,Dept Surg,Med Sch, Boston, MA 02115 USA. RP Sullivan, MP (reprint author), VA Boston Healthcare Syst, Div Urol, 1400 VFW Pkwy, Boston, MA 02132 USA. EM msullivan@rics.bwh.harvard.edu FU Medical Research service, Department of Veteran's Affairs, Washington, DC FX Supported by Medical Research service, Department of Veteran's Affairs, Washington, DC. NR 28 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 J9 BJU INT JI BJU Int. PD DEC PY 2012 VL 110 IS 11C BP E1163 EP E1172 DI 10.1111/j.1464-410X.2012.11410.x PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 091DQ UT WOS:000315029700066 PM 22897417 ER PT J AU Chopra, V Quinti, L Kim, J Vollor, L Narayanan, KL Edgerly, C Cipicchio, PM Lauver, MA Choi, SH Silverman, RB Ferrante, RJ Hersch, S Kazantsev, AG AF Chopra, Vanita Quinti, Luisa Kim, Jinho Vollor, Lorraine Narayanan, K. Lakshmi Edgerly, Christina Cipicchio, Patricia M. Lauver, Molly A. Choi, Soo Hyuk Silverman, Richard B. Ferrante, Robert J. Hersch, Steven Kazantsev, Aleksey G. TI The Sirtuin 2 Inhibitor AK-7 Is Neuroprotective in Huntington's Disease Mouse Models SO CELL REPORTS LA English DT Article ID DEACETYLASE; PROTEIN; MICE AB Inhibition of sirtuin 2 (SIRT2) deacetylase mediates protective effects in cell and invertebrate models of Parkinson's disease and Huntington's disease (HD). Here we report the in vivo efficacy of a brain-permeable SIRT2 inhibitor in two genetic mouse models of HD. Compound treatment resulted in improved motor function, extended survival, and reduced brain atrophy and is associated with marked reduction of aggregated mutant huntingtin, a hallmark of HD pathology. Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans. C1 [Chopra, Vanita; Quinti, Luisa; Vollor, Lorraine; Narayanan, K. Lakshmi; Hersch, Steven; Kazantsev, Aleksey G.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. [Kim, Jinho; Edgerly, Christina; Cipicchio, Patricia M.; Lauver, Molly A.; Ferrante, Robert J.] Univ Pittsburgh, Dept Neurol Surg, Pittsburgh, PA 15213 USA. [Kim, Jinho; Edgerly, Christina; Cipicchio, Patricia M.; Lauver, Molly A.; Ferrante, Robert J.] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. [Kim, Jinho; Edgerly, Christina; Cipicchio, Patricia M.; Lauver, Molly A.; Ferrante, Robert J.] Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15213 USA. [Kim, Jinho; Edgerly, Christina; Cipicchio, Patricia M.; Lauver, Molly A.; Ferrante, Robert J.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr GR H 00, Pittsburgh, PA 15206 USA. [Choi, Soo Hyuk; Silverman, Richard B.] Northwestern Univ, Ctr Mol Innovat & Drug Discovery, Chem Life Proc Inst, Dept Mol Biosci,Dept Chem, Evanston, IL 60208 USA. RP Kazantsev, AG (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. EM akazantsev@partners.org FU NIH [1U01NS066912-01A1] FX This study was supported by NIH grant 1U01NS066912-01A1 to A.G.K., S.H., R.J.F., and R.B.S. A.G.K., S.H., V.C., R.J.F., and R.B.S. designed the research; V.C., L.Q., L.V., L.K., J.K., C.E., P.M.C., and S.H.C. performed research; V.C., L.Q., and R.J.F. analyzed data; and A.G.K., V.C., S.H., R.J.F., and R.B.S. wrote the paper. NR 25 TC 48 Z9 48 U1 1 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD DEC PY 2012 VL 2 IS 6 BP 1492 EP 1497 DI 10.1016/j.celrep.2012.11.001 PG 6 WC Cell Biology SC Cell Biology GA 083JJ UT WOS:000314459200004 PM 23200855 ER PT J AU Hansson, J Rafiee, MR Reiland, S Polo, JM Gehring, J Okawa, S Huber, W Hochedlinger, K Krijgsveld, J AF Hansson, Jenny Rafiee, Mahmoud Reza Reiland, Sonja Polo, Jose M. Gehring, Julian Okawa, Satoshi Huber, Wolfgang Hochedlinger, Konrad Krijgsveld, Jeroen TI Highly Coordinated Proteome Dynamics during Reprogramming of Somatic Cells to Pluripotency SO CELL REPORTS LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; EMBRYONIC STEM-CELLS; INTERACTION NETWORK; DEFINED FACTORS; SELF-RENEWAL; IPS CELLS; COMPLEX; MOUSE; FIBROBLASTS; EXPRESSION AB Generation of induced pluripotent stem cells (iPSCs) is a process whose mechanistic underpinnings are only beginning to emerge. Here, we applied in-depth quantitative proteomics to monitor proteome changes during the course of reprogramming of fibroblasts to iPSCs. We uncover a two-step resetting of the proteome during the first and last 3 days of reprogramming, with multiple functionally related proteins changing in expression in a highly coordinated fashion. This comprised several biological processes, including changes in the stoichiometry of electron transport-chain complexes, repressed vesicle-mediated transport during the intermediate stage, and an EMT-like process in the late phase. In addition, we demonstrate that the nucleoporin Nup210 is essential for reprogramming by its permitting of rapid cellular proliferation and subsequent progression through MET. Along with the identification of proteins expressed in a stage-specific manner, this study provides a rich resource toward an enhanced mechanistic understanding of cellular reprogramming. C1 [Hansson, Jenny; Rafiee, Mahmoud Reza; Reiland, Sonja; Gehring, Julian; Okawa, Satoshi; Huber, Wolfgang; Krijgsveld, Jeroen] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany. [Polo, Jose M.; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Polo, Jose M.; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Polo, Jose M.; Hochedlinger, Konrad] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Polo, Jose M.; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Hochedlinger, Konrad] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Hochedlinger, Konrad] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Krijgsveld, J (reprint author), European Mol Biol Lab, Genome Biol Unit, Meyerhofstr 1, D-69117 Heidelberg, Germany. EM jeroen.krijgsveld@embl.de RI Hansson, Jenny/J-5062-2014; Reiland, Sonja/O-9810-2014; OI Hansson, Jenny/0000-0001-9174-8089; Reiland, Sonja/0000-0003-1791-7504; Huber, Wolfgang/0000-0002-0474-2218; Gehring, Julian/0000-0003-0070-4975 FU Netherlands Organisation for Scientific Research (NWO) FX We gratefully acknowledge the EMBL Proteomics Core Facility for excellent technical support. We thank Bernd Fischer for advice in statistics, Ryan Walsh for secondary MEF cells, and Martin W. Hetzer for Nup210 shRNA. This work was supported by a Vidi grant from the Netherlands Organisation for Scientific Research (NWO). NR 72 TC 90 Z9 92 U1 5 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD DEC PY 2012 VL 2 IS 6 BP 1579 EP 1592 DI 10.1016/j.celrep.2012.10.014 PG 14 WC Cell Biology SC Cell Biology GA 083JJ UT WOS:000314459200015 PM 23260666 ER PT J AU Manor, I Ben-Hayun, R Aharon-Peretz, J Salomy, D Weizman, A Daniely, Y Megiddo, D Newcorn, JH Biederman, J Adler, LA AF Manor, Iris Ben-Hayun, Rachel Aharon-Peretz, Judith Salomy, Dana Weizman, Abraham Daniely, Yaron Megiddo, Dalia Newcorn, Jeffrey H. Biederman, Joseph Adler, Lenard A. TI A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Evaluating the Efficacy, Safety, and Tolerability of Extended-Release Metadoxine in Adults With Attention-Deficit/Hyperactivity Disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID COMORBIDITY SURVEY REPLICATION; ADHD; PREVALENCE; PREDICTORS; PERSISTENT; SYMPTOMS; VALIDITY; TRIAL AB Objective: To evaluate the efficacy, safety, and tolerability of an oral extended-release (ER) formulation of the nonstimulant metadoxine in the treatment of adult attention-deficit/hyperactivity disorder (ADHD). Method:This was a 1:1 randomized, double-blind, placebo-controlled, parallel-design, phase 2 study of metadoxine ER 1,400 mg/d treatment for 6 weeks, following a 2-week baseline/screening period, involving 120 adults with DSM-IV defined ADHD. A follow-up assessment occurred 2 weeks after the trial was completed. Efficacy measures included changes in Conners'Adult ADHD Rating Scale-Investigator Rated (CAARS-INV) total ADHD symptoms score with adult ADHD prompts (primary measure), response rates (>= 25% or 40% improvement in CAARS-INV total ADHD symptom score),Test of Variables of Attention (TOVA) performance, and Adult ADHD Quality of Life (AAQoL) total score. The study was conducted from March 15, 2011, to August 21, 2011. Results: Intent-to-treat analysis revealed that subjects receiving metadoxine ER showed statistically significant improvement in CAARS-INV total ADHD symptoms score (P = .02), higher rate of response (>= 25% [P = .03] or >= 40% [P = .04] improvement) on the CAARS-INV total ADHD symptoms score, and improvement in TOVA score (P = .02) and AAQoL score (P = .01) compared with the placebo group. Improvements in ADHD symptoms (scored by CAARS-INV) were significantly different in subjects treated with metadoxine ER versus placebo as early as 2 weeks following treatment initiation. Metadoxine ER was generally well tolerated, with nausea (17% [10/58] vs 0% [0/59]), fatigue (31% [18/58] vs 27% [16/59]), and headaches (29% [17/58] vs 39% [23/59]) being the most frequently reported adverse effects for the metadoxine ER and placebo groups, respectively. Conclusions: Findings suggest that metadoxine ER is a well-tolerated and effective treatment for adults with ADHD. C1 [Manor, Iris; Salomy, Dana; Weizman, Abraham] Geha Mental Hlth Ctr, Petah Tiqwa, Israel. [Manor, Iris; Weizman, Abraham] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Ben-Hayun, Rachel; Aharon-Peretz, Judith] Rambam Hlth Care Campus, Haifa, Israel. [Daniely, Yaron; Megiddo, Dalia] Alcobra Ltd, Tel Aviv, Israel. [Newcorn, Jeffrey H.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Adler, Lenard A.] NYU, Med Ctr, Dept Psychiat, New York, NY 10016 USA. [Adler, Lenard A.] NYU, Med Ctr, Dept Child & Adolescent Psychiat, New York, NY 10016 USA. [Adler, Lenard A.] New York VA Harbor Healthcare Syst, Psychiat Serv, New York, NY USA. [Biederman, Joseph] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Biederman, Joseph] Harvard Univ, Sch Med, Boston, MA USA. RP Adler, LA (reprint author), NYU Sch Med, 650 1st Ave,7th Floor, New York, NY 10016 USA. EM lenard.adler@nyumc.org OI Newcorn, Jeffrey /0000-0001-8993-9337; Adler, Len/0000-0002-9812-8234 FU Alcobra; ElMindA; Janssen; McNeil; Shire; Massachusetts General Hospital (MGH) Psychiatry Academy; Children's Hospital of Southwest Florida/Lee Memorial Health System; MGH Psychiatry Academy; National Institute on Drug Abuse; Chelsea Therapeutics; Theravance; Eli Lilly; Bristol-Myers Squibb; Alcobra Ltd, Tel Aviv, Israel FX Dr Manor has been a consultant to Enzymotec, Janssen-Cilag, Teva, and Novartis; has received research support from Alcobra; and has been on a speakers/advisory board for Janssen-Cilag. Dr Weizman has been a consultant to Eli Lilly, Sanofi-Aventis, Pfizer, Lundbeck, and Teva and has been on a speakers/advisory board for AstraZeneca, Eli Lilly, Pfizer, Teva, Lundbeck, and Sanofi-Aventis. Dr Daniely is an employee of Alcobra. Dr Megiddo is an employee of, consultant to, and stock shareholder in Alcobra. Dr Newcorn has been a consultant to Alcobra, Eli Lilly, Biobehavioral Diagnostics, Shire, Neos, and Otsuica and has received honoraria from and been on the advisory boards of Eli Lilly, Ortho-McNeil-Janssen, and Shire. Dr Biederman is currently receiving research support from ElMindA, Janssen, McNeil, and Shire; in 2012, he received an honorarium from the Massachusetts General Hospital (MGH) Psychiatry Academy and the Children's Hospital of Southwest Florida/Lee Memorial Health System for tuition-funded CME courses; in 2011, he gave a single unpaid talk for Juste Pharmaceutical Spain, received honoraria from the MGH Psychiatry Academy for a tuition-funded CME course, received an honorarium for presenting at an international scientific conference on ADHD, received an honorarium from Cambridge University Press for a chapter publication, and received departmental royalties from a copyrighted rating scale used for ADHD diagnoses, paid by Eli Lilly, Shire, and AstraZeneca; these royalties were paid to the Department of Psychiatry at MGH. Dr Adler has been a consultant to Alcobra, Otsuka, Shire, Theravance, National Football League, and Major League Baseball; has received grant/research support from National Institute on Drug Abuse, Shire, Chelsea Therapeutics, Theravance, Eli Lilly, and Bristol-Myers Squibb; has received an options grant from Alcobra; has received honoraria from Alcobra, Otsuka, Shire, Theravance, National Football League, and Major League Baseball; and has received royalty payments (as inventor) from New York University for license of adult ADHD scales and training materials since 2004. Drs Ben-Haynn, Aharon-Peretz, and Salomy report no potential conflict of interest.; This study was funded by Alcobra Ltd, Tel Aviv, Israel. NR 35 TC 7 Z9 7 U1 1 U2 15 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD DEC PY 2012 VL 73 IS 12 BP 1517 EP 1523 DI 10.4088/JCP.12m07767 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 090SR UT WOS:000315000800003 PM 23290324 ER PT J AU Papakostas, GI Vitolo, OV IsHak, WW Rapaport, MH Zajecka, JM Kinrys, G Mischoulon, D Lipkin, SH Hails, KA Abrams, J Ward, SG Meisner, A Schoenfeld, DA Shelton, RC Winokur, A Okasha, MS Bari, MA Fava, M AF Papakostas, George I. Vitolo, Ottavio V. IsHak, Waguih W. Rapaport, Mark H. Zajecka, John M. Kinrys, Gustavo Mischoulon, David Lipkin, Samuel H. Hails, Katherine A. Abrams, Jonah Ward, Sean G. Meisner, Allison Schoenfeld, David A. Shelton, Richard C. Winokur, Andrew Okasha, Mahmoud S. Bari, Mohammed A. Fava, Maurizio TI A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Sequential Parallel Comparison Trial of Ziprasidone as Monotherapy for Major Depressive Disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID INTERNATIONAL NEUROPSYCHIATRIC INTERVIEW; MEDIAL PREFRONTAL CORTEX; ANTIPSYCHOTIC-DRUGS; CLINICAL-TRIALS; ACETYLCHOLINE-RELEASE; NUCLEUS-ACCUMBENS; DOPAMINE RELEASE; EXTENDED-RELEASE; POOLED ANALYSIS; RAT-BRAIN AB Objective: To study ziprasidone monotherapy for major depressive disorder, defined according to the DSM-IV. Method: One hundred twenty outpatients were enrolled between June 2008 and September 2010 in a 12-week study that was divided into two 6-week periods according to the sequential parallel comparison design. Patients were randomized in a 2:3:3 fashion to receive ziprasidone for 12 weeks, placebo for 6 weeks followed by ziprasidone for 6 weeks, or placebo for 12 weeks. The main outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS-17), with the Quick Inventory of Depressive Symptomatology, Self-Rated (QIDS-SR), and Clinical Global Impressions-Severity of Illness scale (CGI-S) serving as the study secondary measures. Results: One hundred twenty patients (53 women [44.1%]) were randomized to treatment. The mean (SD) age of these patients was 43.7 (11.0) years. Mean (SD) baseline HDRS-17, CGI-S, and QIDS-SR scores were 19.9 (5.0), 4.3 (0.6), and 15.6 (3.0), respectively. There was no statistically significant difference in reduction of depressive symptoms, response rates, or remission rates between ziprasidone- or placebo-treated patients. This was true for both the study primary as well as secondary outcome scales. Conclusions: In conclusion, treatment with ziprasidone monotherapy was not associated with any statistically significant advantage in efficacy over placebo. Although studies involving larger sample size would be required to have adequate statistical power to detect treatment differences smaller than 2.5 points on the HDRS-17, such differences would be of questionable clinical relevance. C1 [Papakostas, George I.; Vitolo, Ottavio V.; Mischoulon, David; Lipkin, Samuel H.; Hails, Katherine A.; Fava, Maurizio] Harvard Univ, Massachusetts Gen Hosp, Ctr Treatment Resistant Depress, Depress Clin & Res Program,Med Sch, Boston, MA 02114 USA. [Kinrys, Gustavo] Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Sch Med, Boston, MA 02114 USA. [Schoenfeld, David A.] Harvard Univ, Massachusetts Gen Hosp, Ctr Biostat, Sch Med, Boston, MA 02114 USA. [Kinrys, Gustavo; Mischoulon, David; Abrams, Jonah; Ward, Sean G.; Fava, Maurizio] Massachusetts Gen Hosp, CTNI, Boston, MA 02114 USA. [Meisner, Allison] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02114 USA. [IsHak, Waguih W.] Cedars Sinai Med Ctr, Dept Psychiat & Behav Neurosci, Los Angeles, CA 90048 USA. [IsHak, Waguih W.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Bari, Mohammed A.] Synergy Res Ctr, San Diego, CA USA. [Rapaport, Mark H.] Emory Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Zajecka, John M.] Rush Univ, Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. [Shelton, Richard C.] Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA. [Winokur, Andrew] Univ Connecticut, Ctr Hlth, Dept Psychiat, Farmington, CT 06032 USA. [Okasha, Mahmoud S.] Comprehens Psychiat Care, Norwich, CT USA. RP Papakostas, GI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Treatment Resistant Depress, Depress Clin & Res Program,Med Sch, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM gpapakostas@partners.org RI Papakostas, George/I-6905-2013; IsHak, Waguih/C-1336-2011 OI Papakostas, George/0000-0002-2465-5103; IsHak, Waguih/0000-0003-1970-4756 FU Forest; National Institute of Mental Health (NIMH); Pamlab; Pfizer; Ridge Diagnostics; Sunovion; AstraZeneca; Cyberonics; Hoffman-LaRoche; NIMH; Novartis; Otsuka; Shire; Takeda; Bristol-Myers Squibb; Eli Lilly; Bowman Family Foundation; Cederroth; FisherWallace; Ganeden; Lichtwer Pharma; Nordic Naturals; Roche; CytRx; ISIS; Elan; Euthymics Bioscience; Janssen; Otsuka, Pamlab; Repligen; St. Jude Medical; Forest Research Institute; Takeda Global Research; Abbot Laboratories; Alkermes; Aspect Medical Systems; AstraZeneca,; BioResearch; BrainCells; CeNeRx BioPharma; Cephalon; Clinical Trials Solutions; Clintara; Covance; Covidien; ElMindA; EnVivo Pharmaceuticals; Forest Pharmaceuticals; Ganeden Biotech; GlaxoSmithKline; Icon Clinical Research; i3 Innovus/Ingenix; Johnson & Johnson Pharmaceutical Research Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; National Alliance for Research on Schizophrenia Depression; National Center for Complementary and Alternative Medicine; NIDA; Novartis AG; Organon; Pharmavite; Photothera; RCT Logic; Sanofi-Aventis; Solvay; Synthelabo; Wyeth-Ayerst; Adamed; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; Belvoir Media Group; Boehringer Ingelheim GmbH; CME Institute/Physicians Postgraduate Press; Eli Lilly and Company; Imedex; Massachusetts General Hospital (MGH) Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; PharmaStar; United BioSource; Pfizer, Inc. FX Over the past 12 months, Dr Papakostas has served as an advisor/consultant for Brainsway Ltd, Eli Lilly, Pamlab, Takeda, Theracos, and Ridge Diagnostics; has received honoraria from AstraZeneca PLC, Hoffman-LaRoche AG, Lundbeck A/S, Otsuka, and Pfizer; and has received research support from Forest, National Institute of Mental Health (NIMH), Pamlab, Pfizer, Ridge Diagnostics, and Sunovion. Over the past 12 months, Dr IsHak has received research support from Pfizer. Over the past 12 months, Dr Rapaport has served as an advisor/consultant to the NIMH, the National Institute on Drug Abuse (NIDA), the National Center for Complimentary and Alternative Medicine, and PAX (unpaid). Over the past 12 months, Dr Zajecka has served as a consultant/advisor for Abbott, Pamlab, Shire, and Takeda and has received research support from AstraZeneca, Cyberonics, Hoffman-LaRoche, NIMH, Novartis, Otsuka, Pfizer, Shire, and Takeda. Although Dr Zajecka has served on the speaker's bureau for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Otsuka, and Pamlab during the past 12 months, he has divested himself of these relationships effective September 1, 2011. Over the past 12 months, Dr Kinrys has received research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, and Pfizer and has also served as an advisor/consultant for AstraZeneca, Forest, and Pfizer. Over the past 12 months, Dr Mischoulon has received research support from the Bowman Family Foundation, Bristol-Myers Squibb, Cederroth, FisherWallace, Ganeden, Lichtwer Pharma, and Nordic Naturals; has received honoraria for consulting, speaking, and writing from Pamlab, Bristol-Myers Squibb, and Nordic Naturals; and has received royalties from Back Bay Scientific for PMS Escape, and from Lippincott Williams & Wilkins for his book, entitled Natural Medications for Psychiatric Disorders: Considering the Alternatives. Over the past 12 months, Dr Schoenfeld has served as a consultant/advisor for Averion, Gerson Lehrman Group, Guidepoint Global, Neuronova, Cytokinetics, GlaxoSmithKline, Merck, Aggennix, Pfizer, and Baker Botts and has received research support from AstraZeneca, Roche, CytRx, and ISIS. Over the past 12 months, Dr Shelton has served as a consultant for Eli Lilly, Cyberonics, Janssen, Medtronic, Pamlab, Pfizer, Ridge Diagnostics, and Takeda Pharmaceuticals and has received grant/research support from Bristol-Myers Squibb, Eli Lilly, Elan, Euthymics Bioscience, Forest, Janssen, Novartis, Otsuka, Pamlab, Pfizer, Repligen, Ridge Diagnostics, St. Jude Medical, and Takeda. Over the past 12 months, Dr Okasha has received research support from Bristol-Myers Squibb, Euthymics Bioscience, Forest Research Institute, Pfizer, and Takeda Global Research and has served as a guest speaker for Forest.; In his lifetime, Dr Fava has received research support from Abbot Laboratories, Alkermes, Aspect Medical Systems, AstraZeneca, BioResearch, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clinical Trials Solutions, Clintara, Covance, Covidien, Eli Lilly, ElMindA, EnVivo Pharmaceuticals, Euthymics Bioscience, Forest Pharmaceuticals, Ganeden Biotech, GlaxoSmithKline, Icon Clinical Research, i3 Innovus/Ingenix, Johnson & Johnson Pharmaceutical Research & Development, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, National Alliance for Research on Schizophrenia & Depression, National Center for Complementary and Alternative Medicine, NIDA, NIMH, Novartis AG, Organon, Pamlab, Pfizer, Pharmavite, Photothera, Roche, RCT Logic, Sanofi-Aventis, Shire, Solvay, Synthelabo, and Wyeth-Ayerst; has been a consultant or advisor to Abbott, Affectis AG, Alkermes, Amarin Pharma, Aspect Medical Systems, AstraZeneca, Auspex, Bayer AG, Best Practice Project Management, BioMarin Pharmaceuticals, Biovall, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clinical Trials Solutions, CNS Response, Compellis, Cypress, DiagnoSearch Life Sciences (P), Dainippon Sumitomo Pharma, Dov, Edgemont, Eisai, Eli Lilly, EnVivo, ePharmaSolutions, EPIX, Euthymics Bioscience, Fabre-Kramer, Forest, GenOmind, GlaxoSmithKline, Grunenthal GmbH, i3 Innovus/Ingenis, Janssen, Jazz, Johnson & Johnson Pharmaceutical Research & Development, Knoll, Labopharm, Lorex, Lundbeck, MedAvante, Merck, MSI Methylation Sciences, Naurex, Neuronetics, Next Wave Pharmaceuticals, Novartis AG, Nutrition 21, Orexigen Therapeutics, Organon, Otsuka, Pamlab, Pfizer, PharmaStar, Pharmavite, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals, Puretech Ventures, PsychoGenics, Psylin Neurosciences, Rexahn, Ridge Diagnostics, Roche, RCT Logic, Sanofi-Aventis, Sepracor, Servier, Schering-Plough, Solvay, Somaxon, Somerset, Sunovion, Supernus, Synthelabo, Takeda, Tal Medical, Tetragenex, Trans Form, Transcept, and Vanda; has received speaking/publishing fees from Adamed, Advanced Meeting Partners, American Psychiatric Association, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Cephalon, CME Institute/Physicians Postgraduate Press, Eli Lilly and Company, Forest Pharmaceuticals, GlaxoSmithKline, Imedex, Massachusetts General Hospital (MGH) Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier, Novartis AG, Organon, Pfizer, PharmaStar, United BioSource, and Wyeth-Ayerst; has equity holdings in Compel lis; receives copyright royalties for the MGH Cognitive & Physical Functioning Questionnaire, Sexual Functioning Inventory, Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs & Symptoms, and SAFER; and has a patent application for a combination of azapirones and bupropion in major depressive disorder. Dr Fava also has a patent for Sequential Parallel Comparison Design (SPCD) and a patent for research and licensing of SPCD with RCT Logic; Lippincott, Williams & Wilkins; Wolkers Kluwer; and World Scientific Publishing. Drs Vitolo, Winokur, and Bari; Mss Hails and Meisner; and Messrs Lipkin, Abrams, and Ward report no potential or other conflicts of interest.; This trial was funded by Pfizer, Inc. Massachusetts General Hospital assisted with the coordination of this study. NR 31 TC 14 Z9 14 U1 2 U2 6 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD DEC PY 2012 VL 73 IS 12 BP 1541 EP 1547 DI 10.4088/JCP.12m07670 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 090SR UT WOS:000315000800006 PM 23290327 ER PT J AU Mallery, RM Klein, JP Pless, ML AF Mallery, Robert M. Klein, Joshua P. Pless, Misha L. TI Isolated Sixth Nerve Palsy From Hemorrhage of a Pontine Cavernous Malformation SO JOURNAL OF NEURO-OPHTHALMOLOGY LA English DT Editorial Material ID NATURAL-HISTORY AB A 32-year-old woman who developed binocular horizontal diplopia was found to have an isolated fascicular sixth nerve palsy secondary to hemorrhage of a cavernous malformation within the left pontine tegmentum. There was sparing of the paramedian pontine reticular formation and absence of a horizontal gaze palsy. The natural history of cavernous malformations and a mechanism by which hemorrhage of these vascular lesions may produce minimal neurologic signs, including isolated ocular motor cranial nerve palsies, is discussed. Magnetic resonance imaging (MRI) that includes susceptibility-weighted sequences leads to their accurate diagnosis. Journal of Neuro-Ophthalmology 2012;32:335-337 doi: 10.1097/WNO.0b013e31825e42ca (c) 2012 by North American Neuro-Ophthalmology Society C1 [Mallery, Robert M.; Pless, Misha L.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Mallery, Robert M.; Klein, Joshua P.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Pless, ML (reprint author), 15 Parkman St,WACC Suite 835, Boston, MA 02114 USA. EM pless.misha@mgh.harvard.edu NR 5 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1070-8022 J9 J NEURO-OPHTHALMOL JI J. Neuro-Ophthal. PD DEC PY 2012 VL 32 IS 4 BP 335 EP 337 DI 10.1097/WNO.0b013e31825e42ca PG 3 WC Clinical Neurology; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 048FI UT WOS:000311895300009 PM 22743823 ER PT J AU Verhulst, S Dau, T Shera, CA AF Verhulst, Sarah Dau, Torsten Shera, Christopher A. TI Nonlinear time-domain cochlear model for transient stimulation and human otoacoustic emission SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID BASILAR-MEMBRANE; COHERENT REFLECTION; CHINCHILLA; MECHANICS; RESPONSES; LEVEL; EARS AB This paper describes the implementation and performance of a nonlinear time-domain model of the cochlea for transient stimulation and human otoacoustic emission generation. The nonlinearity simulates compressive growth of measured basilar-membrane impulse responses. The model accounts for reflection and distortion-source otoacoustic emissions (OAEs) and simulates spontaneous OAEs through manipulation of the middle-ear reflectance. The model was calibrated using human psychoacoustical and otoacoustic tuning parameters. It can be used to investigate time-dependent properties of cochlear mechanics and the generator mechanisms of otoacoustic emissions. Furthermore, the model provides a suitable preprocessor for human auditory perception models where realistic cochlear excitation patterns are desired. (C) 2012 Acoustical Society of America. [http://dx.doi.org/10.1121/1.4763989] C1 [Verhulst, Sarah; Dau, Torsten] Tech Univ Denmark, Dept Elect Engn, Ctr Appl Hearing Res, DK-2800 Lyngby, Denmark. [Shera, Christopher A.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. RP Verhulst, S (reprint author), Tech Univ Denmark, Dept Elect Engn, Ctr Appl Hearing Res, Orsteds Plads Bldg 352, DK-2800 Lyngby, Denmark. EM save@bu.edu FU DTU; Oticon Foundation; NIDCD, National Institutes of Health [R01 DC003687] FX The authors would like to thank Diek Duifhuis and Peter Van Hengel for providing the original source code of the FORTRAN models presented in van Netten and Duifhuis (1983), Duifhuis et al. (1985), van Hengel (1996), and Duifhuis (2012). The code of these models is available at http://extras.springer.com/2012/978-1-4419-6117-4. Bastian Epp is acknowledged for help in compiling the different FORTRAN files into an executable, and Peter L. Soendergaard is thanked for help in adjusting the model to read in.wav files and for future integration of the model into the Auditory Model Toolbox. Work supported by DTU, the Oticon Foundation, and Grant No. R01 DC003687 from the NIDCD, National Institutes of Health. NR 40 TC 23 Z9 23 U1 0 U2 12 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD DEC PY 2012 VL 132 IS 6 BP 3842 EP 3848 DI 10.1121/1.4763989 PG 7 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 090RB UT WOS:000314995600028 PM 23231114 ER PT J AU Ford, EC de Los Santos, LF Pawlicki, T Sutlief, S Dunscombe, P AF Ford, E. C. de Los Santos, L. Fong Pawlicki, T. Sutlief, S. Dunscombe, P. TI Consensus recommendations for incident learning database structures in radiation oncology SO MEDICAL PHYSICS LA English DT Article DE patient safety; radiation therapy; brachytherapy; incident learning ID IMPROVING PATIENT SAFETY; RADIOTHERAPY; THERAPY; ERRORS; SYSTEM; RISK AB Purpose: Incident learning plays a key role in improving quality and safety in a wide range of industries and medical disciplines. However, implementing an effective incident learning system is complex, especially in radiation oncology. One current barrier is the lack of technical standards to guide users or developers. This report, the product of an initiative by the Work Group on Prevention of Errors in Radiation Oncology of the American Association of Physicists in Medicine, provides technical recommendations for the content and structure of incident learning databases in radiation oncology. Methods: A panel of experts was assembled and tasked with developing consensus recommendations in five key areas: definitions, process maps, severity scales, causality taxonomy, and data elements. Experts included representatives from all major North American radiation oncology organizations as well as users and developers of public and in-house reporting systems with over two decades of collective experience. Recommendations were developed that take into account existing incident learning systems as well as the requirements of outside agencies. Results: Consensus recommendations are provided for the five major topic areas. In the process mapping task, 91 common steps were identified for external beam radiation therapy and 88 in brachytherapy. A novel feature of the process maps is the identification of "safety barriers," also known as critical control points, which are any process steps whose primary function is to prevent errors or mistakes from occurring or propagating through the radiotherapy workflow. Other recommendations include a ten-level medical severity scale designed to reflect the observed or estimated harm to a patient, a radiation oncology-specific root causes table to facilitate and regularize root-cause analyses, and recommendations for data elements and structures to aid in development of electronic databases. Also presented is a list of key functional requirements of any reporting system. Conclusions: Incident learning is recognized as an invaluable tool for improving the quality and safety of treatments. The consensus recommendations in this report are intended to facilitate the implementation of such systems within individual clinics as well as on broader national and international scales. (C) 2012 American Association of Physicists in Medicine. [http://dx.doi.org/10.1118/1.4764914] C1 [Ford, E. C.] Univ Washington, Med Ctr, Dept Radiat Oncol, Seattle, WA 98195 USA. [de Los Santos, L. Fong] Mayo Clin, Dept Radiat Oncol, Rochester, MN 55905 USA. [Pawlicki, T.] Univ Calif San Diego, Dept Radiat Med & Appl Sci, La Jolla, CA 92093 USA. [Sutlief, S.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Dunscombe, P.] Univ Calgary, Dept Oncol, Calgary, AB T2N 1N4, Canada. RP Ford, EC (reprint author), Univ Washington, Med Ctr, Dept Radiat Oncol, Box 356043,1959 NE Pacific St, Seattle, WA 98195 USA. EM eford@uw.edu FU American Association of Physicists in Medicine FX The American Association of Physicists in Medicine is acknowledged for funding the members and guests of the WGPE who attended the Workshop. The partnering organizations, mentioned above, are also acknowledged for their support of this endeavor by sponsoring their representatives. Corbi Foster and Noel Crisman-Fillhart, from AAPM Headquarters provided much of the logistical support of the Workshop. Finally all the participants are recognized for their active involvement and contributions to this effort. WGPE members and guests, fully sponsored by the AAPM, were: Peter Dunscombe, Luis Fong de Los Santos, Eric Ford, Anne Greener, Jennifer Johnson, Ajay Kapur, Janaki Krishnamoorthy, Sasa Mutic, Todd Pawlicki, Steven Sutlief, Stephanie Terezakis M.D., Bruce Thomadsen. Representatives of partnering organizations were: Jean-Pierre Bissonnette (COMP), Jim Deye (NIH), Rachel Hackett (AAMD), Sandra Hayden (ASRT), James Hevezi (ACR), Ola Holmberg (IAEA), Jatinder Palta (ASTRO/NROR), Emily Wilson (ASTRO). Dr. Barrett Caldwell served as a consultant to the Causal Taxonomies group. The authors also acknowledge valuable discussions with Peter Gabriel, M.D. and Edna Volz, MS of the University of Pennsylvania, and Howard Bergendahl, M.S., J.D. (Bergendahl Institute, LLC). This report has been reviewed and approved by the AAPM. References to AAPM Task Group-100 have been reviewed and approved by the TG-100 writing group and parent committees within AAPM. NR 30 TC 34 Z9 34 U1 0 U2 4 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD DEC PY 2012 VL 39 IS 12 BP 7272 EP 7290 DI 10.1118/1.4764914 PG 19 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 049FJ UT WOS:000311967400011 PM 23231278 ER PT J AU Cloud, LJ Rosenblatt, A Margolis, RL Ross, CA Pillai, JA Corey-Bloom, J Tully, HM Bird, T Panegyres, PK Nichter, CA Higgins, DS Helmers, SL Factor, SA Jones, R Testa, CM AF Cloud, Leslie J. Rosenblatt, Adam Margolis, Russel L. Ross, Christopher A. Pillai, Jagan A. Corey-Bloom, Jody Tully, Hannah M. Bird, Thomas Panegyres, Peter K. Nichter, Charles A. Higgins, Donald S., Jr. Helmers, Sandra L. Factor, Stewart A. Jones, Randi Testa, Claudia M. TI Seizures in Juvenile Huntington's Disease: Frequency and Characterization in a Multicenter Cohort SO MOVEMENT DISORDERS LA English DT Article DE Huntington's disease; juvenile Huntington's disease; seizures ID EARLY-ONSET; AGE AB Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult-onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic-clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required. (C) 2012 Movement Disorder Society C1 [Cloud, Leslie J.; Rosenblatt, Adam; Testa, Claudia M.] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA 23298 USA. [Rosenblatt, Adam] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23298 USA. [Margolis, Russel L.; Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Neurobiol,Dept Neurol, Baltimore, MD 21205 USA. [Margolis, Russel L.; Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD USA. [Pillai, Jagan A.; Corey-Bloom, Jody] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Tully, Hannah M.; Bird, Thomas] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Tully, Hannah M.] Seattle Childrens Hosp, Seattle, WA USA. [Bird, Thomas] Univ Washington, Geriatr Res Ctr, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Panegyres, Peter K.] Neurodegenerat Disorders Res Pty Ltd, Subiaco, WA, Australia. [Nichter, Charles A.; Higgins, Donald S., Jr.] Albany Med Coll, Dept Neurol, Albany, NY 12208 USA. [Higgins, Donald S., Jr.] Samuel Stratton VA Med Ctr, Neurol Serv, Albany, NY USA. [Helmers, Sandra L.; Factor, Stewart A.; Jones, Randi] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. RP Cloud, LJ (reprint author), Virginia Commonwealth Univ, Dept Neurol, 1001 E Broad St,Suite 222,POB 980539, Richmond, VA 23298 USA. EM lcloud@vcu.edu RI Ross, Christopher/H-8395-2013 NR 10 TC 13 Z9 13 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD DEC PY 2012 VL 27 IS 14 BP 1797 EP 1800 DI 10.1002/mds.25237 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 089GN UT WOS:000314899000018 PM 23124580 ER PT J AU Mata, IF Checkoway, H Hutter, CM Samii, A Roberts, JW Kim, HM Agarwal, P Alvarez, V Ribacoba, R Pastor, P Lorenzo-Betancor, O Infante, J Sierra, M Gomez-Garre, P Mir, P Ritz, B Rhodes, SL Colcher, A Van Deerlin, V Chung, KA Quinn, JF Yearout, D Martinez, E Farin, FM Wan, JY Edwards, KL Zabetian, CP AF Mata, Ignacio F. Checkoway, Harvey Hutter, Carolyn M. Samii, Ali Roberts, John W. Kim, Hojoong M. Agarwal, Pinky Alvarez, Victoria Ribacoba, Renee Pastor, Pau Lorenzo-Betancor, Oswaldo Infante, Jon Sierra, Maria Gomez-Garre, Pilar Mir, Pablo Ritz, Beate Rhodes, Shannon L. Colcher, Amy Van Deerlin, Vivianna Chung, Kathryn A. Quinn, Joseph F. Yearout, Dora Martinez, Erica Farin, Federico M. Wan, Jia Y. Edwards, Karen L. Zabetian, Cyrus P. TI Common Variation in the LRRK2 Gene is a Risk Factor for Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; LRRK2; SNP ID GENOME-WIDE ASSOCIATION; EXONIC VARIANTS; METAANALYSIS; MUTATIONS; REGION; SNCA AB Background: Common variants in the LRRK2 gene influence the risk of Parkinson's disease (PD) in Asians, but whether the same is true in European-derived populations is less clear. Methods: We genotyped 66 LRRK2 tagging single-nucleotide polymorphisms (SNPs) in 575 PD patients and 689 controls from the northwestern United States (tier 1). PD-associated SNPs (P < .05) were then genotyped in an independent sample of 3617 cases and 2512 controls from the United States and Spain (tier 2). Logistic regression was used to model additive SNP genotype effects adjusted for age and sex among white individuals. Results: Two regions showed independent association with PD in tier 1, and SNPs in both regions were successfully replicated in tier 2 (rs10878226, combined odds ratio [OR], 1.20; 95% confidence interval [CI], 1.08-1.33; P = 6.3 x 10(-4); rs11176013, OR, 0.89; CI, 0.83-0.95; P = 4.6 x 10(-4)). Conclusions: Our data suggest that common variation within LRRK2 conveys susceptibility for PD in individuals of European ancestry. (C) 2012 Movement Disorder Society C1 [Mata, Ignacio F.; Samii, Ali; Kim, Hojoong M.; Yearout, Dora; Martinez, Erica; Zabetian, Cyrus P.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Mata, Ignacio F.; Samii, Ali; Kim, Hojoong M.; Yearout, Dora; Martinez, Erica; Zabetian, Cyrus P.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Checkoway, Harvey; Farin, Federico M.] Univ Washington, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. [Hutter, Carolyn M.; Wan, Jia Y.; Edwards, Karen L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Hutter, Carolyn M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Canc Prevent Program, Seattle, WA 98104 USA. [Roberts, John W.] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Agarwal, Pinky] Evergreen Hosp, Med Ctr, Booth Gardner Parkinsons Care Ctr, Kirkland, WA USA. [Alvarez, Victoria] Hosp Univ Cent Asturias, Inst Invest Nefrol IRSINFRIAT, Genet Mol Lab, Oviedo, Spain. [Ribacoba, Renee] Hosp Univ Cent Asturias, Dept Neurol, Oviedo, Spain. [Pastor, Pau; Lorenzo-Betancor, Oswaldo] Univ Navarra, Ctr Appl Med Res, Div Neurosci, Neurogenet Lab, E-31080 Pamplona, Spain. [Pastor, Pau; Lorenzo-Betancor, Oswaldo] Univ Navarra, Dept Neurol, Clin Univ Navarra, Sch Med, E-31080 Pamplona, Spain. [Pastor, Pau; Lorenzo-Betancor, Oswaldo; Infante, Jon; Gomez-Garre, Pilar; Mir, Pablo] Inst Salud Carlos III, CIBERNED, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain. [Infante, Jon; Sierra, Maria] Marques de Valdecilla Univ Hosp, Dept Neurol, Santander, Spain. [Gomez-Garre, Pilar; Mir, Pablo] Univ Seville, CSIC, Hosp Univ Virgen del Rocio,Inst Biomed Sevilla IB, Unidad Trastornos Movimiento,Serv Neurol & Neurof, Seville, Spain. [Ritz, Beate; Rhodes, Shannon L.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Ritz, Beate] Univ Calif Los Angeles, Sch Publ Hlth, Dept Environm Hlth Sci, Los Angeles, CA 90024 USA. [Ritz, Beate] Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90024 USA. [Colcher, Amy] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Van Deerlin, Vivianna] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. [Chung, Kathryn A.; Quinn, Joseph F.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Chung, Kathryn A.; Quinn, Joseph F.] Portland VA Med Ctr, Portland, OR USA. RP Mata, IF (reprint author), VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr S 182, 1660 S Columbian Way, Seattle, WA 98108 USA. EM nachofm@u.washington.edu; zabetian@u.washington.edu RI Pastor, Pau/C-9834-2009; Ritz, Beate/E-3043-2015; IBIS, MOVIMIENTO/P-3309-2015; Mir, Pablo/C-8662-2013 OI Pastor, Pau/0000-0002-7493-8777; Mir, Pablo/0000-0003-1656-302X FU BLRD VA [I01 BX000531]; NIEHS NIH HHS [P01 ES016732, P30 ES007033, P42 ES004696, R01 ES010544, U54 ES012078]; NINDS NIH HHS [P50 NS038367, P50 NS053488, P50 NS062684, R01 NS065070] NR 20 TC 0 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD DEC PY 2012 VL 27 IS 14 BP 1822 EP 1825 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 089GN UT WOS:000314899000024 PM 23115130 ER PT J AU Lipshultz, SE Miller, TL Lipsitz, SR Neuberg, DS Dahlberg, SE Colan, SD Silverman, LB Henkel, JM Franco, VI Cushman, LL Asselin, BL Clavell, LA Athale, U Michon, B Laverdiere, C Schorin, MA Larsen, E Usmani, N Sallan, SE AF Lipshultz, Steven E. Miller, Tracie L. Lipsitz, Stuart R. Neuberg, Donna S. Dahlberg, Suzanne E. Colan, Steven D. Silverman, Lewis B. Henkel, Jacqueline M. Franco, Vivian I. Cushman, Laura L. Asselin, Barbara L. Clavell, Luis A. Athale, Uma Michon, Bruno Laverdiere, Caroline Schorin, Marshall A. Larsen, Eric Usmani, Naheed Sallan, Stephen E. CA Dana-Farber Canc Inst Acute TI Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes SO PEDIATRICS LA English DT Article DE anthracycline; cardiotoxicity; doxorubicin; leukemia; pediatrics ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CONTINUOUS INTRAVENOUS-INFUSION; CHILDHOOD-CANCER SURVIVOR; LATE CARDIOTOXICITY; PROSPECTIVE (PCHIV)-C-2-H-2; REDUCED CARDIOTOXICITY; 5-YEAR SURVIVORS; ADULT SURVIVORS; WEEKLY SCHEDULE; LATE MORTALITY AB BACKGROUND AND OBJECTIVES: Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL). METHODS: The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m(2) of doxorubicin in 30 mg/m2 doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function. RESULTS: A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with >= 1 echocardiogram >= 3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event-free survival rates did not differ between the 2 groups (continuous-infusion, 83% versus bolus-infusion, 78%; P = .24). CONCLUSIONS: In survivors of childhood high-risk ALL, continuous-infusion doxorubicin, compared with bolus-infusion, provided no long-term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion. Pediatrics 2012;130:1003-1011 C1 [Lipshultz, Steven E.; Miller, Tracie L.; Henkel, Jacqueline M.; Franco, Vivian I.; Cushman, Laura L.] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33101 USA. [Lipshultz, Steven E.; Miller, Tracie L.] Univ Miami, Sylvester Comprehens Canc Ctr, Jackson Mem Med Ctr, Holtz Childrens Hosp, Miami, FL 33101 USA. [Lipsitz, Stuart R.] Brigham & Womens Hosp, Dept Gen Internal Med, Boston, MA 02115 USA. [Neuberg, Donna S.; Dahlberg, Suzanne E.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Silverman, Lewis B.; Sallan, Stephen E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Colan, Steven D.] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Silverman, Lewis B.; Sallan, Stephen E.] Childrens Hosp, Dept Med, Boston, MA 02115 USA. [Asselin, Barbara L.] Univ Rochester, Sch Med & Dent, Rochester, NY USA. [Clavell, Luis A.] San Jorge Childrens Hosp, Santurce, PR USA. [Athale, Uma] McMaster Univ, Hamilton, ON, Canada. [Michon, Bruno] Ctr Hosp Univ Quebec, Quebec City, PQ, Canada. [Laverdiere, Caroline] Ctr Hosp St Justine, Montreal, PQ, Canada. [Schorin, Marshall A.] Inova Fairfax Hosp Children, Falls Church, VA USA. [Larsen, Eric] Maine Childrens Canc Program, Portland, ME USA. [Usmani, Naheed] Univ Massachusetts, Med Ctr, Worcester, MA USA. RP Lipshultz, SE (reprint author), Univ Miami, Miller Sch Med, Dept Pediat D820, POB 016820, Miami, FL 33101 USA. EM slipshultz@med.miami.edu FU National Institutes of Health [HL072705, HL078522, HL053392, CA127642, CA068484, HD052104, AI50274, HD052102, HL087708, HL079233, HL004537, HL087000, HL007188, HL094100, HL095127, HD80002]; Children's Cardiomyopathy Foundation; Women's Cancer Association; Lance Armstrong Foundation; STOP Children's Cancer Foundation; Scott Howard Fund; Michael Garil Fund; National Institutes of Health (NIH) FX This work was supported in part by grants from the National Institutes of Health (HL072705, HL078522, HL053392, CA127642, CA068484, HD052104, AI50274, CA068484, HD052102, HL087708, HL079233, HL004537, HL087000, HL007188, HL094100, HL095127, and HD80002); Children's Cardiomyopathy Foundation; Women's Cancer Association; Lance Armstrong Foundation; STOP Children's Cancer Foundation; Scott Howard Fund; and the Michael Garil Fund. Funded by the National Institutes of Health (NIH). NR 48 TC 27 Z9 28 U1 0 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD DEC PY 2012 VL 130 IS 6 BP 1003 EP 1011 DI 10.1542/peds.2012-0727 PG 9 WC Pediatrics SC Pediatrics GA 087YZ UT WOS:000314802000048 PM 23166343 ER PT J AU Brown, SD Donelan, K Martins, Y Burmeister, K Buchmiller, TL Sayeed, SA Mitchell, C Ecker, JL AF Brown, Stephen D. Donelan, Karen Martins, Yolanda Burmeister, Kelly Buchmiller, Terry L. Sayeed, Sadath A. Mitchell, Christine Ecker, Jeffrey L. TI Differing Attitudes Toward Fetal Care by Pediatric and Maternal-Fetal Medicine Specialists SO PEDIATRICS LA English DT Article DE prenatal care; pediatrics; pregnancy complications; treatment refusal; attitudes ID OUTCOMES; PREGNANCY; DIAGNOSIS; CHILDRENS; EXPOSURE; IMPROVES; ALCOHOL; INFANTS; BRAIN AB OBJECTIVES: The expansion of pediatric-based fetal care raises questions regarding pediatric specialists' involvement in pregnancies when maternal conditions may affect pediatric outcomes. For several such conditions, we compared pediatric and obstetric specialists' attitudes regarding whether and when pediatrics consultation should be offered and their views about seeking court authorization to override maternal refusal of physician recommendations. METHODS: We used a mail survey of 434 maternal-fetal medicine specialists (MFMs) and fetal care pediatric specialists (FCPs) (response rate: MFM, 60.9%; FCP, 54.2%). RESULTS: FCPs were more likely than MFMs to indicate that pediatric counseling should occur before decisions regarding continuing or interrupting pregnancies complicated by maternal alcohol abuse (FCP versus MFM: 63% vs 36%), cocaine abuse (FCP versus MFM: 60% vs 32%), use of seizure medications (FCP versus MFM: 62% vs 33%), and diabetes (FCP versus MFM: 56% vs 27%) (all P < .001). For all conditions, MFMs were more than twice as likely as FCPs to think that no pediatric specialist consultation was ever necessary. FCPs were more likely to agree that seeking court interventions was appropriate for maternal refusal to enter a program to discontinue cocaine use (FCP versus MFM: 72% vs 33%), refusal of azidothymidine to prevent perinatal HIV transmission (80% vs 41%), and refusal of percutaneous transfusion for fetal anemia (62% vs 28%) (all P < .001). CONCLUSIONS: Pediatric and obstetric specialists differ considerably regarding pediatric specialists' role in prenatal care for maternal conditions, and regarding whether to seek judicial intervention for maternal refusal of recommended treatment. Pediatrics 2012;130:e1534-e1540 C1 [Brown, Stephen D.] Boston Childrens Hosp, Dept Radiol, Boston, MA 02115 USA. [Buchmiller, Terry L.] Boston Childrens Hosp, Dept Surg, Boston, MA 02115 USA. [Martins, Yolanda; Burmeister, Kelly] Boston Childrens Hosp, Clin Res Ctr, Boston, MA 02115 USA. [Buchmiller, Terry L.] Boston Childrens Hosp, Adv Fetal Care Ctr, Boston, MA 02115 USA. [Sayeed, Sadath A.] Boston Childrens Hosp, Div Newborn Med, Boston, MA 02115 USA. [Mitchell, Christine] Boston Childrens Hosp, Off Eth, Boston, MA 02115 USA. [Donelan, Karen] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Ecker, Jeffrey L.] Massachusetts Gen Hosp, Maternal Fetal Med Div, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Martins, Yolanda] Dana Farber Canc Inst, Ctr Populat Sci, Boston, MA 02115 USA. [Sayeed, Sadath A.; Mitchell, Christine] Harvard Univ, Sch Med, Div Med Eth, Boston, MA USA. RP Brown, SD (reprint author), Boston Childrens Hosp, Dept Radiol, 300 Longwood Ave, Boston, MA 02115 USA. EM stephen.brown@childrens.harvard.edu OI Martins, Yolanda/0000-0002-3983-3531 FU Greenwall Foundation; Kornfeld Program in Bioethics and Patient Care; Harvard University Milton Fund; American Roentgen Ray Society Leonard Berlin Scholarship in Medical Professionalism; Faculty Career Development Award, Office of Faculty Development, Boston Children's Hospital FX Funding was provided by grants from the Greenwall Foundation, the Kornfeld Program in Bioethics and Patient Care, and the Harvard University Milton Fund. Dr Brown received salary support from the American Roentgen Ray Society Leonard Berlin Scholarship in Medical Professionalism, and a Faculty Career Development Award, Office of Faculty Development, Boston Children's Hospital. NR 41 TC 5 Z9 5 U1 2 U2 9 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD DEC PY 2012 VL 130 IS 6 BP E1534 EP E1540 DI 10.1542/peds.2012-1352 PG 7 WC Pediatrics SC Pediatrics GA 087YZ UT WOS:000314802000015 PM 23129074 ER PT J AU Nabi-Burza, E Regan, S Drehmer, J Ossip, D Rigotti, N Hipple, B Dempsey, J Hall, N Friebely, J Weiley, V Winickoff, JP AF Nabi-Burza, Emara Regan, Susan Drehmer, Jeremy Ossip, Deborah Rigotti, Nancy Hipple, Bethany Dempsey, Janelle Hall, Nicole Friebely, Joan Weiley, Victoria Winickoff, Jonathan P. TI Parents Smoking in Their Cars With Children Present SO PEDIATRICS LA English DT Article DE parents; pediatrics; secondhand smoke; smoking in car; tobacco control; tobacco smoke ID ENVIRONMENTAL TOBACCO-SMOKE; INFANT-DEATH-SYNDROME; SECONDHAND SMOKE; PASSIVE SMOKING; EXPOSURE; CHILDHOOD; HEALTH; POLLUTION; DISEASE; ASTHMA AB OBJECTIVE: To determine prevalence and factors associated with strictly enforced smoke-free car policies among smoking parents. METHODS: As part of a cluster, randomized controlled trial addressing parental smoking, exit interviews were conducted with parents whose children were seen in 10 control pediatric practices. Parents who smoked were asked about smoking behaviors in their car and receipt of smoke-free car advice at the visit. Parents were considered to have a "strictly enforced smoke-free car policy" if they reported having a smoke-free car policy and nobody had smoked in their car within the past 3 months. RESULTS: Of 981 smoking parents, 817 (83%) had a car; of these, 795 parents answered questions about their car smoking policy. Of these 795 parents, 29% reported having a smoke-free car policy, and 24% had a strictly enforced smoke-free car policy. Of the 562 parents without a smoke-free car policy, 48% reported that smoking occurred with children present. Few parents who smoke (12%) were advised to have a smoke-free car. Multivariable logistic regression controlling for parent age, gender, education, and race showed that having a younger child and smoking <= 10 cigarettes per day were associated with having a strictly enforced smoke-free car policy. CONCLUSIONS: The majority of smoking parents exposed their children to tobacco smoke in cars. Coupled with the finding of low rates of pediatricians addressing smoking in cars, this study highlights the need for improved pediatric interventions, public health campaigns, and policies regarding smoke-free car laws to protect children from tobacco smoke. Pediatrics 2012;130:e1471-e1478 C1 [Nabi-Burza, Emara; Hipple, Bethany; Dempsey, Janelle; Hall, Nicole; Friebely, Joan; Winickoff, Jonathan P.] Massachusetts Gen Hosp Children, Ctr Child & Adolescent Hlth Res & Policy, Boston, MA 02114 USA. [Nabi-Burza, Emara; Rigotti, Nancy; Hipple, Bethany; Dempsey, Janelle; Hall, Nicole; Friebely, Joan; Winickoff, Jonathan P.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Regan, Susan; Rigotti, Nancy] Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA. [Drehmer, Jeremy; Weiley, Victoria] Amer Acad Pediat, Pediat Res Off Settings, Elk Grove Village, IL USA. [Winickoff, Jonathan P.] Amer Acad Pediat, AAP Richmond Ctr Excellence, Elk Grove Village, IL USA. [Ossip, Deborah] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. RP Winickoff, JP (reprint author), Massachusetts Gen Hosp Children, Ctr Child & Adolescent Hlth Res & Policy, 15 Floor,Suite 1542A,100 Cambridge St, Boston, MA 02114 USA. EM jwinickoff@partners.org OI Drehmer, Jeremy/0000-0002-5022-5836 FU National Institutes of Health National Cancer Institute [R01-CA127127]; National Institute on Drug Abuse; Agency for Healthcare Research and Quality; Flight Attendant Medical Research Institute; Health Resources and Services Administration's Maternal and Child Health Bureau [HRSA 5-UA6-10-001]; American Academy of Pediatrics; National Institutes of Health (NIH) FX Supported by the National Institutes of Health National Cancer Institute grant R01-CA127127 (to Dr Winickoff), the National Institute on Drug Abuse, and the Agency for Healthcare Research and Quality. This study was also partially supported by a grant from the Flight Attendant Medical Research Institute to the AAP Julius B. Richmond Center, and the Pediatric Research in Office Settings Network receives core funding from theHealth Resources and Services Administration's Maternal and Child Health Bureau (HRSA 5-UA6-10-001) and the American Academy of Pediatrics. The funders had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript. Funded by the National Institutes of Health (NIH). NR 43 TC 14 Z9 14 U1 0 U2 11 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD DEC PY 2012 VL 130 IS 6 BP E1471 EP E1478 DI 10.1542/peds.2012-0334 PG 8 WC Pediatrics SC Pediatrics GA 087YZ UT WOS:000314802000007 PM 23147972 ER PT J AU Healy, BC Degano, IR Schreck, A Rintell, D Weiner, H Chitnis, T Glanz, BI AF Healy, Brian C. Degano, Irene R. Schreck, Ana Rintell, David Weiner, Howard Chitnis, Tanuja Glanz, Bonnie I. TI The impact of a recent relapse on patient-reported outcomes in subjects with multiple sclerosis SO QUALITY OF LIFE RESEARCH LA English DT Article DE Clinical relapse; Depression; Fatigue; Health related quality of life; Multiple sclerosis ID QUALITY-OF-LIFE; DISEASE; PEOPLE AB Purpose In this study, we estimate the impact of a recent relapse on physical and mental health in subjects with relapsing-remitting multiple sclerosis (RRMS) using validated patient-reported outcome (PRO) measures. Methods Subjects enrolled in the Comprehensive Longitudinal Investigation of MS at the Brigham and Women's Hospital with RRMS were eligible for enrollment. Subjects with a clinical visit within 45 days of a relapse were identified and divided into groups based on whether the relapse occurred before (recent relapse) (n = 59) or after the visit (pre-relapse) (n = 31). A group of subjects with no relapses was also identified (remission) (n = 336). PRO measures in these three groups were compared. All outcomes were compared using a t test and linear regression controlling for age, disease duration, sex, and EDSS. Results Subjects with a recent relapse had significantly worse functioning on several physical and mental health scales compared to subjects in remission even after adjusting for potential confounders. Subjects with a recent relapse also showed significant deterioration on PRO measures over 1 year compared to subjects in remission (P < 0.05 for each comparison). Subjects in the pre-relapse group were not significantly different than subjects in remission. Conclusions Clinical relapses have a measurable effect on PRO in subjects with RRMS. C1 [Healy, Brian C.; Degano, Irene R.; Schreck, Ana; Rintell, David; Weiner, Howard; Chitnis, Tanuja; Glanz, Bonnie I.] Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, Brookline, MA 02445 USA. [Healy, Brian C.; Rintell, David; Weiner, Howard; Chitnis, Tanuja; Glanz, Bonnie I.] Harvard Univ, Sch Med, Dept Neurol, Brookline, MA USA. [Healy, Brian C.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. RP Healy, BC (reprint author), Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, 6th Floor,1 Brookline Pl, Brookline, MA 02445 USA. EM bchealy@partners.org RI Roman Degano, Irene/C-1826-2012 FU Nancy Davis Foundation; Merck Serono FX The CLIMB study is funded in part by the Nancy Davis Foundation and Merck Serono. NR 24 TC 9 Z9 9 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD DEC PY 2012 VL 21 IS 10 BP 1677 EP 1684 DI 10.1007/s11136-011-0108-0 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 089MT UT WOS:000314915400001 PM 22237991 ER PT J AU Stillman, MJ Chinnery, PF Kleindorfer, D Pittock, SJ Sahin, M Selcen, D Traynor, B Cash, SS Titulaer, M AF Stillman, Michael J. Chinnery, Patrick F. Kleindorfer, Dawn Pittock, Sean J. Sahin, Mustafa Selcen, Duygu Traynor, Brian Cash, Sydney S. Titulaer, Maarten TI What Do New ANA Members Think of the Future of Academic Neurology? SO ANNALS OF NEUROLOGY LA English DT Editorial Material C1 [Chinnery, Patrick F.] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Kleindorfer, Dawn] Univ Cincinnati, Cincinnati, OH 45221 USA. [Pittock, Sean J.; Selcen, Duygu] Mayo Clin, Rochester, MN USA. [Sahin, Mustafa] Childrens Hosp Boston, Boston, MA USA. [Traynor, Brian] NIA, NIH, Bethesda, MD 20892 USA. [Cash, Sydney S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Titulaer, Maarten] IDIBAPS Univ Barcelona, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2012 VL 72 IS 6 BP A8 EP A9 DI 10.1002/ana.23826 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 086CH UT WOS:000314660100003 PM 23280853 ER PT J AU Galarce, EM Viswanath, K AF Galarce, Ezequiel M. Viswanath, K. TI Crisis Communication: An Inequalities Perspective on the 2010 Boston Water Crisis SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Article DE crisis communication; communication inequalities; behavioral compliance; social determinants ID RISK COMMUNICATION; DRINKING-WATER; OUTBREAK; INFORMATION; MODEL AB Objective: Although the field of crisis risk communication has generated substantial research, the interaction between social determinants, communication processes, and behavioral compliance has been less well studied. With the goal of better understanding these interactions, this report examines how social determinants influenced communications and behavioral compliance during the 2010 Boston, Massachusetts, water crisis. Methods: An online survey was conducted to assess Boston residents' knowledge, beliefs, attitudes, mass and interpersonal communication, and preventive behaviors on emergency preparedness topics dealing with the water crisis. Of a total sample of 726 respondents, approximately one-third (n=267) reported having been affected by the water crisis. Only data from affected participants were analyzed. Results: Following an order to boil water, 87.5% of respondents refrained from drinking unboiled tap water. These behaviors and other cognitive and attitudinal factors, however, were not uniform across population subgroups. All communication and behavioral compliance variables varied across sociodemographic factors. Conclusions: Crisis communication, in conjunction with other public health preparedness fields, is central to reducing the negative impact of sudden hazards. Emergency scenarios such as the Boston water crisis serve as unique opportunities to understand how effectively crisis messages are conveyed to and received by different segments of the population. (Disaster Med Public Health Preparedness. 2012; 6:349-356) C1 [Galarce, Ezequiel M.; Viswanath, K.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Viswanath, K.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Galarce, EM (reprint author), Univ Calif San Francisco, Robert Wood Johnson Fdn, Hlth & Soc Scholars Program, Ctr Community Hlth, 3333 Calif St,St 465, San Francisco, CA 94118 USA. EM galarcee@chc.ucsf.edu FU Centers for Disease Control and Prevention [1P01TP000307] FX This research was supported by Centers for Disease Control and Prevention grant 1P01TP000307 (Dr Viswanath). NR 33 TC 7 Z9 7 U1 3 U2 24 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 1935-7893 J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD DEC PY 2012 VL 6 IS 4 BP 349 EP 356 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 083WY UT WOS:000314497800007 PM 23241465 ER PT J AU Coleman, CN Hrdina, C Casagrande, R Cliffer, KD Mansoura, MK Nystrom, S Hatchett, R Caro, JJ Knebel, AR Wallace, KS Adams, SA AF Coleman, C. Norman Hrdina, Chad Casagrande, Rocco Cliffer, Kenneth D. Mansoura, Monique K. Nystrom, Scott Hatchett, Richard Caro, J. Jaime Knebel, Ann R. Wallace, Katherine S. Adams, Steven A. TI User-Managed Inventory: An Approach to Forward-Deployment of Urgently Needed Medical Countermeasures for Mass-Casualty and Terrorism Incidents SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Article DE medical countermeasures; user-managed inventory; nuclear ID NUCLEAR DETONATION; SCARCE RESOURCES; SURGE CAPACITY; HEALTH; ALLOCATION AB The user-managed inventory (UMI) is an emerging idea for enhancing the current distribution and maintenance system for emergency medical countermeasures (MCMs). It increases current capabilities for the dispensing and distribution of MCMs and enhances local/regional preparedness and resilience. In the UMI, critical MCMs, especially those in routine medical use ("dual utility") and those that must be administered soon after an incident before outside supplies can arrive, are stored at multiple medical facilities (including medical supply or distribution networks) across the United States. The medical facilities store a sufficient cache to meet part of the surge needs but not so much that the resources expire before they would be used in the normal course of business. In an emergency, these extra supplies can be used locally to treat casualties, including evacuees from incidents in other localities. This system, which is at the interface of local/regional and federal response, provides response capacity before the arrival of supplies from the Strategic National Stockpile (SNS) and thus enhances the local/regional medical responders' ability to provide life-saving MCMs that otherwise would be delayed. The UMI can be more cost-effective than stockpiling by avoiding costs due to drug expiration, disposal of expired stockpiled supplies, and repurchase for replacement. (Disaster Med Public Health Preparedness. 2012; 6:408-414) C1 [Coleman, C. Norman; Hrdina, Chad; Cliffer, Kenneth D.; Mansoura, Monique K.; Nystrom, Scott; Hatchett, Richard; Knebel, Ann R.] US Dept HHS, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. [Coleman, C. Norman] NCI, Radiat Res Program, NIH, Bethesda, MD 20892 USA. [Casagrande, Rocco] Gryphon Sci, Takoma Pk, MD USA. [Caro, J. Jaime] UnitedBiosource Corp, Lexington, MA USA. [Caro, J. Jaime] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Caro, J. Jaime] McGill Univ, Div Gen Internal Med, Montreal, PQ, Canada. [Wallace, Katherine S.] US Dept Vet Affairs, Off Operat Secur & Preparedness, Washington, DC USA. [Adams, Steven A.] Ctr Dis Control & Prevent, Div Strateg Natl Stockpile, Off Publ Hlth Preparedness & Response, Atlanta, GA USA. RP Coleman, CN (reprint author), 6130 Execut Blvd, Rockville, MD 20852 USA. EM Norman.Coleman@nih.gov NR 16 TC 4 Z9 4 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 1935-7893 J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD DEC PY 2012 VL 6 IS 4 BP 408 EP 414 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 083WY UT WOS:000314497800015 PM 23241473 ER PT J AU Easler, JJ Zureikat, A Papachristou, GI AF Easler, Jeffrey J. Zureikat, Amer Papachristou, Georgios I. TI An update on minimally invasive therapies for pancreatic necrosis SO EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY LA English DT Review DE acute pancreatitis; endoscopic necrosectomy; infected pancreatic necrosis; minimally invasive techniques; necrosectomy; necrosis; pancreas; pancreatic fluid collections; pancreatic necrosis; walled-off pancreatic necrosis ID INFECTED NECROTIZING PANCREATITIS; STANDARD PERCUTANEOUS DRAINAGE; ACUTE BILIARY PANCREATITIS; DUAL MODALITY DRAINAGE; ENDOSCOPIC NECROSECTOMY; RETROPERITONEAL APPROACH; RADIOLOGICAL PROCEDURES; SURGICAL-MANAGEMENT; CATHETER DRAINAGE; REDUCES LENGTH AB Pancreatic necrosis is a local complication of severe acute pancreatitis associated with multiple organ dysfunction, infection and increased mortality. While surgery is the mainstay for invasive management, studies have demonstrated that delaying necrosectomy translates to improved patient outcomes. Minimally invasive therapies have been described both for early and late management of necrotic pancreatic collections and fall into three broad categories: endoscopic, radiology assisted percutaneous drainage and laparoscopic or retroperitoneal surgical techniques. Such interventions may serve as temporizing measures delaying necrosectomy, but more importantly, as best demonstrated in recent randomized controlled trials, can serve as alternative approaches resulting in improved patient outcomes. Access to these techniques is based on their availability at expert centers. Minimally invasive therapies have increased in popularity, with a general consensus among experts being that reduced complications and mortality rates are realized by approaches other than open necrosectomy. However, additional well-designed, randomized trials are needed. C1 [Easler, Jeffrey J.; Papachristou, Georgios I.] Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. [Zureikat, Amer] Univ Pittsburgh Med, Div Gastrointestinal Surg, Pittsburgh, PA USA. [Papachristou, Georgios I.] Vet Affairs Pittsburgh Hlth Syst, Div Gastroenterol, Pittsburgh, PA USA. RP Papachristou, GI (reprint author), Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA USA. EM papachri@pitt.edu NR 44 TC 4 Z9 4 U1 0 U2 12 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1747-4124 J9 EXPERT REV GASTROENT JI Expert Rev. Gastroenterol. Hepatol. PD DEC PY 2012 VL 6 IS 6 BP 745 EP 753 DI 10.1586/EGH.12.48 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 083JZ UT WOS:000314460900016 PM 23237259 ER PT J AU Unglert, CI Warger, WC Hostens, J Namati, E Birngruber, R Bouma, BE Tearney, GJ AF Unglert, Carolin I. Warger, William C., II Hostens, Jeroen Namati, Eman Birngruber, Reginald Bouma, Brett E. Tearney, Guillermo J. TI Validation of two-dimensional and three-dimensional measurements of subpleural alveolar size parameters by optical coherence tomography SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE alveolar structure; alveolar volume; ray-tracing; optical coherence tomography ID REFRACTIVE-INDEX; TISSUE AB Optical coherence tomography (OCT) has been increasingly used for imaging pulmonary alveoli. Only a few studies, however, have quantified individual alveolar areas, and the validity of alveolar volumes represented within OCT images has not been shown. To validate quantitative measurements of alveoli from OCT images, we compared the cross-sectional area, perimeter, volume, and surface area of matched subpleural alveoli from microcomputed tomography (micro-CT) and OCT images of fixed air-filled swine samples. The relative change in size between different alveoli was extremely well correlated (r > 0.9, P < 0.0001), but OCT images underestimated absolute sizes compared to micro-CT by 27% (area), 7% (perimeter), 46% (volume), and 25% (surface area) on average. We hypothesized that the differences resulted from refraction at the tissue-air interfaces and developed a ray-tracing model that approximates the reconstructed alveolar size within OCT images. Using this model and OCT measurements of the refractive index for lung tissue (1.41 for fresh, 1.53 for fixed), we derived equations to obtain absolute size measurements of superellipse and circular alveoli with the use of predictive correction factors. These methods and results should enable the quantification of alveolar sizes from OCT images in vivo. (c) 2012 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.JBO.17.12.126015] C1 [Unglert, Carolin I.; Warger, William C., II; Namati, Eman; Bouma, Brett E.; Tearney, Guillermo J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Unglert, Carolin I.; Warger, William C., II; Namati, Eman; Bouma, Brett E.; Tearney, Guillermo J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Unglert, Carolin I.] Air Liquide Ctr Rech Claude Delorme, Med Gases Grp, Les Loges En Josas, France. [Hostens, Jeroen] Bruker MicroCT, B-2550 Kontich, Belgium. [Birngruber, Reginald] Med Univ Lubeck, Inst Biomed Opt, D-23562 Lubeck, Germany. [Bouma, Brett E.; Tearney, Guillermo J.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Tearney, Guillermo J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Unglert, CI (reprint author), Wellman Ctr Photomed, 40 Parkman St,RSL 160, Boston, MA 02114 USA. EM cunglert@mgh.harvard.edu RI Birngruber, Reginald/Q-2342-2016 FU Air Liquide R&D, Medical Gases, Les-Loges-en-Josas, France; Center for Biomedical OCT Research and Translation [P41EB015903]; National Center for Research Resources; National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health FX The authors thank Elkan Halpern from the MGH Institute for Technology Assessment and Benoit Piednoir from Air Liquide for expert statistical advice, as well as Hao Wang and Veronica Delaney for help with the tissue paste preparation and with the index measurement. This work has been supported by Air Liquide R&D, Medical Gases, Les-Loges-en-Josas, France. Additional funds were provided by the Center for Biomedical OCT Research and Translation through grant number P41EB015903, awarded by the National Center for Research Resources and the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. NR 23 TC 6 Z9 6 U1 0 U2 8 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD DEC PY 2012 VL 17 IS 12 AR 126015 DI 10.1117/1.JBO.17.12.126015 PG 11 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 083ZB UT WOS:000314504400023 PM 23235834 ER PT J AU Chang, BH Stein, NR Trevino, K Stewart, M Hendricks, A Skarf, LM AF Chang, Bei-Hung Stein, Nathan R. Trevino, Kelly Stewart, Max Hendricks, Ann Skarf, Lara M. TI End-of-life spiritual care at a VA medical center: Chaplains' perspectives SO PALLIATIVE & SUPPORTIVE CARE LA English DT Article DE End of life; Spiritual care; Chaplains; Veterans ID QUALITY AB Objective: Spiritual care is an essential component of quality palliative care. Recognizing the importance, the Department of Veterans Affairs (VA) mandates the inclusion of chaplains in a palliative care consult team (PCCT). The purpose of this study is to explain the process and content of spiritual care provided in a VA Medical Center from chaplains' perspectives. Method: Five Christian chaplains who provide care to patients at end of life were interviewed. Each interview was recorded and transcribed. Analysis based on the grounded theory was used to identify themes from each interview question. Results: The PCCT in this study appeared to have a strong referral and communication system in which every palliative care patient was seen by a chaplain and the care plan was discussed with an interdisciplinary team. Chaplains reported providing a range of services, which addressed religious, spiritual, emotional, family, and illness concerns. Chaplains were aware of the unique spiritual needs of veterans, including working through guilt for killing in war and requiring forgiveness. Chaplains' ideas for improvement of spiritual care services included increasing time to provide care, providing bereavement care and support to families, and adding chaplains with different religious backgrounds. Chaplains reported how their own spirituality influenced the care they provided. Significance of results: Spiritual care in the VA can include a range of services and should consider the unique needs of the veteran population. Future studies can build upon our findings from chaplains to learn about the perspectives of patients, family, and other healthcare providers of spiritual care. This information would allow identification of strengths of current spiritual care practices and areas for care improvement, and ultimately could improve the wellbeing of patients at the end of life. C1 [Chang, Bei-Hung; Stein, Nathan R.; Stewart, Max; Hendricks, Ann; Skarf, Lara M.] VA Boston Healthcare Syst, Boston, MA USA. [Chang, Bei-Hung] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Trevino, Kelly] Dana Farber Canc Inst, Boston, MA 02115 USA. [Trevino, Kelly] Harvard Univ, Sch Med, Boston, MA USA. RP Chang, BH (reprint author), 150 S Huntington Ave,152H, Boston, MA 02130 USA. EM bhchang@bu.edu NR 12 TC 5 Z9 5 U1 0 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1478-9515 J9 PALLIAT SUPPORT CARE JI Palliat. Support Care PD DEC PY 2012 VL 10 IS 4 BP 273 EP 278 DI 10.1017/S1478951511001003 PG 6 WC Health Policy & Services SC Health Care Sciences & Services GA 083KF UT WOS:000314461700006 PM 22612863 ER PT J AU Sanders, MA Shirk, SD Burgin, CJ Martin, LL AF Sanders, Matthew A. Shirk, Steve D. Burgin, Chris J. Martin, Leonard L. TI The Gargle Effect: Rinsing the Mouth With Glucose Enhances Self-Control SO PSYCHOLOGICAL SCIENCE LA English DT Article ID ANTERIOR CINGULATE CORTEX; EGO DEPLETION; PERFORMANCE C1 [Sanders, Matthew A.; Martin, Leonard L.] Univ Georgia, Dept Psychol, Athens, GA 30602 USA. [Shirk, Steve D.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Burgin, Chris J.] Tennessee Technol Univ, Dept Counseling & Psychol, Cookeville, TN USA. RP Sanders, MA (reprint author), Univ Georgia, Dept Psychol, Athens, GA 30602 USA. EM sandersm@uga.edu NR 15 TC 33 Z9 33 U1 1 U2 22 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD DEC PY 2012 VL 23 IS 12 BP 1470 EP 1472 DI 10.1177/0956797612450034 PG 3 WC Psychology, Multidisciplinary SC Psychology GA 083YL UT WOS:000314502600006 PM 23090756 ER PT J AU Stanford, RH Buikema, AR Riedel, AA Camargo, CA Rey, GG Chapman, KR AF Stanford, Richard H. Buikema, Ami R. Riedel, Aylin A. Camargo, Carlos A., Jr. Rey, Gabriel Gomez Chapman, Kenneth R. TI Asthma controller delay and recurrence risk after an emergency department visit or hospitalization SO RESPIRATORY MEDICINE LA English DT Article DE Managed care; Emergency hospital service; Emergency care; Hospitalization; Anti-asthmatic agents ID EXACERBATIONS; ADULTS; MEDICATIONS; DISCHARGE; TRIAL AB Background: Patients who have asthma-related emergency department (ED) visits or hospitalizations are at risk for recurrent exacerbation events. Our objectives were to assess whether receiving a controller medication at discharge affects risk of recurrence and whether delaying controller initiation alters this risk. Methods: Asthma patients with an ED visit or inpatient (IP) stay who received a controller dispensing within 6 months were identified from healthcare claims. Cox proportional hazards of the time to first recurrence of an asthma-related ED or IP visit in the 6-month period following the initial event were constructed, with time following discharge without controller medication as the primary predictor. Results: A total of 6139 patients met inclusion criteria, 78% with an ED visit and 22% with an IP visit; 15% had a recurrence within 6 months. The adjusted hazard ratio (HR) associated with not having controller medication at discharge was 1.79 (95% confidence interval [CI], 1.42 -2.25). The controller-by-time interaction was significant (P<0.001), with hazard rising as time-to-controller initiation increased. Delaying initiation by 1 day approximately tripled the risk (HR 2.95; 95%Cl 1.48-5.88). Sensitivity analyses, including accounting for controller fills prior to the index event, did not substantially alter these results. Conclusions: This observational study shows that the risk of a recurrent asthma-related ED visit or IP stay increased as the time to initiate a controller increased. Our findings support the importance of early controller initiation following an asthma-related ED or IP visit in reducing risk of recurrence. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Stanford, Richard H.] GlaxoSmithKline, US Hlth Outcomes, Res Triangle Pk, NC 27709 USA. [Buikema, Ami R.; Riedel, Aylin A.; Rey, Gabriel Gomez] Optumlnsight, Eden Prairie, MN 55344 USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chapman, Kenneth R.] Univ Hlth Network, Asthma & Airway Ctr, Toronto, ON M5T 2S8, Canada. RP Stanford, RH (reprint author), GlaxoSmithKline, US Hlth Outcomes, 5 Moore Dr, Res Triangle Pk, NC 27709 USA. EM richard.h.stanford@gsk.com OI Buikema, Ami/0000-0002-2481-4872; Chapman, Kenneth/0000-0002-2498-9859 FU Boehringer-Ingelheim; GlaxoSmithKline; Grifols; Nyconned (Takeda); Family Physicians Airways Group of Canada; Canadian Network for Respiratory Care; Talecris; Research Triangle Park; North Carolina FX RHS is employed by GlaxoSnnithKline. ARB, AAR, and GGR are employed by OptumInsight, which was contracted by GlaxoSmithKline to conduct the study. CAC has served as a consultant to AstraZeneca, Dey, Genentech, GlaxSmithKline, Merck, Novartis, Pfizer, and sanofi-aventis. KRC holds the GSK-CIHR Research Chair in Respiratory Healthcare Delivery at the University Health Network, has served as a consultant to CSL Behring, GlaxoSmithKline, Novartis, Nycomed (Takeda), and Talecris (Grifols), and has received payment for lectures or service on speakers bureaus from Boehringer-Ingelheim, GlaxoSmithKline, Grifols, Nyconned (Takeda), Family Physicians Airways Group of Canada, Canadian Network for Respiratory Care, and Talecris.; This study was funded by GlaxoSmithKline, Research Triangle Park, North Carolina. The study sponsor was not involved in the study design, collection, analysis, or interpretation of data, the writing of the manuscript, or the decision to submit the manuscript for publication beyond the role of RHS as a study author. NR 18 TC 5 Z9 5 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD DEC PY 2012 VL 106 IS 12 BP 1631 EP 1638 DI 10.1016/j.rmed.2012.08.017 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 088TM UT WOS:000314860000002 PM 22990041 ER PT J AU Hunter, RC Klepac-Ceraj, V Lorenzi, MM Grotzinger, H Martin, TR Newman, DK AF Hunter, Ryan C. Klepac-Ceraj, Vanja Lorenzi, Magen M. Grotzinger, Hannah Martin, Thomas R. Newman, Dianne K. TI Phenazine Content in the Cystic Fibrosis Respiratory Tract Negatively Correlates with Lung Function and Microbial Complexity SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE phenazine; cystic fibrosis; Pseudomonas aeruginosa; biofilm; microbiome ID PSEUDOMONAS-AERUGINOSA PYOCYANIN; AIRWAY EPITHELIAL-CELLS; BACTERIAL DIVERSITY; ANTIBIOTICS; INFECTIONS; SPUTUM; GENE; PATHOGENESIS; ACQUISITION; MECHANISMS AB Although much is known about how virulence factors affect pathogens and host tissues in vitro, far less is understood about their dynamics in vivo. As a step toward characterizing the chemistry of infected environments, we measured phenazine abundance in the lungs of patients with cystic fibrosis (CF). Phenazines are redox-active small molecules produced by Pseudomonas aeruginosa that damage host epithelia, curb the growth of competing organisms, and play physiologically important roles in the cells that produce them. Here, we quantify phenazines within expectorated sputum, characterize the P. aeruginosa populations responsible for phenazine production, and assess their relationship to CF lung microflora. Chemical analyses of expectorated sputum showed that the concentrations of two phenazines, namely, pyocyanin (PYO) and phenazine-1-carboxylic acid (PCA), were negatively correlated (rho = -0.68 and -0.57, respectively) with lung function. Furthermore, the highest phenazine concentrations were found in patients whose pulmonary function showed the greatest rates of decline. The constituent P. aeruginosa populations within each patient showed diverse capacities for phenazine production. Early during infection, individual isolates produced more PYO than later during infection. However, total PYO concentrations in sputum at any given stage correlated well with the average production by the total P. aeruginosa population. Finally, bacterial community complexity was negatively correlated with phenazine concentrations and declines in lung function, suggesting a link to the refinement of the overall microbial population. Together, these data demonstrate that phenazines negatively correlate with CF disease states in ways that were previously unknown, and underscore the importance of defining in vivo environmental parameters to better predict clinical outcomes of infections. C1 [Hunter, Ryan C.; Grotzinger, Hannah; Newman, Dianne K.] CALTECH, Div Biol Sci, Pasadena, CA 91125 USA. [Newman, Dianne K.] CALTECH, Div Geol & Planetary Sci, Pasadena, CA 91125 USA. [Hunter, Ryan C.; Newman, Dianne K.] CALTECH, Howard Hughes Med Inst, Pasadena, CA 91125 USA. [Klepac-Ceraj, Vanja] Forsyth Inst, Dept Mol Genet, Cambridge, MA USA. [Lorenzi, Magen M.; Martin, Thomas R.] Childrens Hosp Boston, Dept Pediat, Boston, MA USA. RP Newman, DK (reprint author), CALTECH, Div Biol, 147-75,1200 E Calif Blvd, Pasadena, CA 91125 USA. EM dkn@caltech.edu OI Klepac-Ceraj, Vanja/0000-0001-5387-5706; Hunter, Ryan/0000-0003-3841-1676 FU Howard Hughes Medical Institute; Canadian Cystic Fibrosis Foundation; Cystic Fibrosis Foundation Center FX This work was supported by the Howard Hughes Medical Institute (D.K.N.); by the Canadian Cystic Fibrosis Foundation (R.C.H); and by a grant from the Cystic Fibrosis Foundation Center to Children's Hospital Boston for the sequencing of samples. NR 71 TC 70 Z9 73 U1 7 U2 46 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD DEC PY 2012 VL 47 IS 6 BP 738 EP 745 DI 10.1165/rcmb.2012-0088OC PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 082QH UT WOS:000314406800003 PM 22865623 ER PT J AU Stolley, JM Gong, DP Farley, K Zhao, PC Cooley, J Crouch, EC Benarafa, C Remold-O'Donnell, E AF Stolley, J. Michael Gong, Dapeng Farley, Kalamo Zhao, Picheng Cooley, Jessica Crouch, Erika C. Benarafa, Charaf Remold-O'Donnell, Eileen TI Increased Surfactant Protein D Fails to Improve Bacterial Clearance and Inflammation in serpinB1(-/-) Mice SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE surfactant protein D; lung infection; inflammation; serpinB1; proteolysis ID PULMONARY SURFACTANT; CYSTIC-FIBROSIS; LUNG INJURY; NEUTROPHIL ELASTASE; IN-VITRO; INFECTION; COLLECTINS; GENE; EXPRESSION; BINDING AB Previously, we described the protective role of the neutrophil serine protease inhibitor serpinB1 in preventing early mortality of Pseudomonas aeruginosa lung infection by fostering bacterial clearance and limiting inflammatory cytokines and proteolytic damage. Surfactant protein D(SP-D), which maintains the antiinflammatory pulmonary environment and mediates bacterial removal, was degraded in infected serpinB1-deficient mice. Based on the hypothesis that increased SP-D would rescue or mitigate the pathological effects of serpinB1 deletion, we generated two serpinB1(-/-) lines overexpressing lung-specific rat SP-D and inoculated the mice with P. aeruginosa. Contrary to predictions, bacterial counts in the lungs of SP-D-low serpinB1(-/-) and SP-D-high serpinB1(-/-) mice were 4 logs higher than wild-type and not different from serpinB1(-/-) mice. SP-D overexpression also failed to mitigate inflammation (TNF-alpha), lung injury (free protein, albumin), or excess neutrophil death (free myeloperoxidase, elastase). These pathological markers were higher for infected SP-D-high serpinB1(-/-) mice than for serpinB1(-/-) mice, although the differences were not significant after controlling for multiple comparisons. The failure of transgenic SP-D to rescue antibacterial defense of serpin-B1-deficient mice occurred despite 5-fold or 20-fold increased expression levels, largely normal structure, and dose-dependent bacteria-aggregating activity. SP-D of infected wild-type mice was intact in 43-kD monomers by reducing SDS-PAGE. By contrast, proteolytic fragments of 35, 17, and 8 kD were found in infected SP-D-low serpinB1(-/-), SP-D-high serpinB1(-/-) mice, and serpinB1(-/-) mice. Thus, although therapies to increase lung concentration of SP-D may have beneficial applications, the findings suggest that therapy with SP-D may not be beneficial for lung inflammation or infection if the underlying clinical condition includes excess proteolysis. C1 [Stolley, J. Michael; Gong, Dapeng; Farley, Kalamo; Zhao, Picheng; Cooley, Jessica; Remold-O'Donnell, Eileen] Boston Childrens Hosp, Immune Dis Inst, Boston, MA USA. [Stolley, J. Michael; Gong, Dapeng; Farley, Kalamo; Zhao, Picheng; Cooley, Jessica; Remold-O'Donnell, Eileen] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA. [Remold-O'Donnell, Eileen] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA. [Gong, Dapeng; Farley, Kalamo; Zhao, Picheng; Remold-O'Donnell, Eileen] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Crouch, Erika C.] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. [Crouch, Erika C.] Washington Univ, Sch Med, Dept Immunol, St Louis, MO USA. [Benarafa, Charaf] Univ Bern, Theodor Kocher Inst, CH-3012 Bern, Switzerland. RP Remold-O'Donnell, E (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, 3 Blackfan Circle, Boston, MA 02115 USA. EM remold@idi.harvard.edu RI ZHAO, PICHENG/G-3737-2014; OI Benarafa, Charaf/0000-0002-2049-7769 FU National Institutes of Health [HL-066548]; Parker B. Francis Fellowship in Pulmonary Research FX This work was supported by National Institutes of Health grant HL-066548 (E.R-O'D.) and by a Parker B. Francis Fellowship in Pulmonary Research (C.B.). NR 46 TC 3 Z9 3 U1 2 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD DEC PY 2012 VL 47 IS 6 BP 792 EP 799 DI 10.1165/rcmb.2012-0145OC PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 082QH UT WOS:000314406800009 PM 23024061 ER PT J AU Kim, JK Vinarsky, V Wain, J Zhao, R Jung, K Choi, J Lam, A Pardo-Saganta, A Breton, S Rajagopal, J Yun, SH AF Kim, Jun Ki Vinarsky, Vladimir Wain, John Zhao, Rui Jung, Keehoon Choi, Jinwoo Lam, Adam Pardo-Saganta, Ana Breton, Sylvie Rajagopal, Jayaraj Yun, Seok Hyun TI In Vivo Imaging of Tracheal Epithelial Cells in Mice during Airway Regeneration SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE in vivo fluorescence microscopy; mouse imaging; epithelial regeneration ID STEM-CELLS; LUNG; EXPRESSION; PROMOTER AB Many human lung diseases, such as asthma, chronic obstructive pulmonary disease, bronchiolitis obliterans, and cystic fibrosis, are characterized by changes in the cellular composition and architecture of the airway epithelium. Intravital fluorescence microscopy has emerged as a powerful approach in mechanistic studies of diseases, but it has been difficult to apply this tool for in vivo respiratory cell biology in animals in a minimally invasive manner. Here, we describe a novel miniature side-view confocal probe capable of visualizing the epithelium in the mouse trachea in vivo at a single-cell resolution. We performed serial real-time endotracheal fluorescence microscopy in live transgenic reporter mice to view the three major cell types of the large airways, namely, basal cells, Clara cells, and ciliated cells. As a proof-of-concept demonstration, we monitored the regeneration of Clara cells over 18 days after a sulfur dioxide injury. Our results show that in vivo tracheal microscopy offers a new approach in the study of altered, regenerating, or metaplastic airways in animal models of lung diseases. C1 [Kim, Jun Ki; Jung, Keehoon; Choi, Jinwoo; Yun, Seok Hyun] Harvard Univ, Sch Med, Boston, MA USA. [Kim, Jun Ki; Jung, Keehoon; Choi, Jinwoo; Yun, Seok Hyun] Wellman Ctr Photomed, Boston, MA USA. [Vinarsky, Vladimir; Wain, John; Zhao, Rui; Lam, Adam; Pardo-Saganta, Ana; Rajagopal, Jayaraj] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Kim, Jun Ki; Yun, Seok Hyun] Korea Adv Inst Sci & Technol, WCU Grad Sch Nanosci & Technol, Taejon 305701, South Korea. [Breton, Sylvie] Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Div Nephrol, Boston, MA 02114 USA. [Rajagopal, Jayaraj] Harvard Stem Cell Inst, Holyoke Ctr, Cambridge, MA USA. [Yun, Seok Hyun] Harvard Massachusetts Inst Technol Hlth Sci & Tec, Cambridge, MA USA. RP Yun, SH (reprint author), 65 Lansdowne St,UP-5, Cambridge, MA 02139 USA. EM syun@hms.harvard.edu RI Zhao, Rui/J-7110-2014 FU National Institutes of Health [RC2DK088661, U54CA143837, R01AI081734, P41EB015903, P30HL101287, HD040793, DK085715, T32HL007874]; National Research Foundation of Korea [R31-2008-000-10071-0, 2009-352-C00042]; Harvard Stem Cell Institute FX This work was supported by National Institutes of Health grants RC2DK088661, U54CA143837, R01AI081734, P41EB015903, P30HL101287, HD040793, DK085715, and T32HL007874, National Research Foundation of Korea grants R31-2008-000-10071-0 and 2009-352-C00042, and by the Harvard Stem Cell Institute. NR 17 TC 10 Z9 10 U1 0 U2 12 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD DEC PY 2012 VL 47 IS 6 BP 864 EP 868 DI 10.1165/rcmb.2012-0164OC PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 082QH UT WOS:000314406800017 PM 22984086 ER PT J AU Fried-Oken, M Rowland, C Daniels, D Dixon, M Fuller, B Mills, C Noethe, G Small, J Still, K Oken, B AF Fried-Oken, Melanie Rowland, Charity Daniels, Darlene Dixon, Mayling Fuller, Bret Mills, Carolyn Noethe, Glory Small, Jeon Still, Kevin Oken, Barry TI AAC to Support Conversation in Persons with Moderate Alzheimer's Disease SO AUGMENTATIVE AND ALTERNATIVE COMMUNICATION LA English DT Article DE AAC; Alzheimer's disease; Dementia; Aided conversation ID MEMORY AIDS; DEMENTIA; ADULTS; PREVALENCE; DIAGNOSIS; STATE AB Even though we know that external memory aids support communication in Alzheimer's disease, the components of the communication aids for individuals with Alzheimer's disease have not been studied systematically. The goal of these two pilot experiments was to examine differences in conversational performance of adults with Alzheimer's disease related to the presence and absence of an aid, the type of symbol embedded in the aid, and the presence or absence of voice output. In Experiment 1, 30 adults with moderate-to-severe Alzheimer's disease participated in 10-min conversations with and without personalized AAC boards. There was no effect of AAC, regardless of symbol type, and a deleterious effect of voice output. In Experiment 2, modified spaced-retrieval training preceded conversations, standardized prompts were presented, and semantically-based dependent variables were examined. For the 11 participants in the second experiment, there was a significant effect of AAC, showing that the presence of AAC was associated with greater use of targeted words during personal conversations. We discuss new information about the contribution of AAC for persons with Alzheimer's disease, and demonstrate how the applied research process evolves over the course of a long-term commitment to a scientific investigation. C1 [Fried-Oken, Melanie; Rowland, Charity; Daniels, Darlene; Dixon, Mayling; Mills, Carolyn; Noethe, Glory; Still, Kevin; Oken, Barry] Oregon Hlth & Sci Univ, Portland, OR 97207 USA. [Fuller, Bret] Portland VA Med Ctr, Portland, OR USA. [Small, Jeon] Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Fried-Oken, M (reprint author), Oregon Hlth & Sci Univ, POB 574, Portland, OR 97207 USA. EM friedm@ohsu.edu FU U.S. Department of Health and Human Services, National Institutes of Health [R21 HD47754, P30 AG008017]; U.S. Department of Education, National Institute on Disability and Rehabilitation Research [H133G040176]; Oregon Tax Check-Off Alzheimer's Research Grant FX We acknowledge support from the U.S. Department of Health and Human Services, National Institutes of Health grant R21 HD47754 and P30 AG008017; the U.S. Department of Education, National Institute on Disability and Rehabilitation Research grant H133G040176; and the 2004 Oregon Tax Check-Off Alzheimer's Research Grant. We thank the participants and their caregivers for inviting us into their homes and permitting us to document their conversations. NR 47 TC 5 Z9 5 U1 3 U2 26 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0743-4618 EI 1477-3848 J9 AUGMENT ALTERN COMM JI Augment. Altern. Commun. PD DEC PY 2012 VL 28 IS 4 BP 219 EP 231 DI 10.3109/07434618.2012.732610 PG 13 WC Audiology & Speech-Language Pathology; Rehabilitation SC Audiology & Speech-Language Pathology; Rehabilitation GA 077DO UT WOS:000314008300003 PM 23256854 ER PT J AU Chen, H Manning, AK Dupuis, J AF Chen, Han Manning, Alisa K. Dupuis, Josee TI A Method of Moments Estimator for Random Effect Multivariate Meta-Analysis SO BIOMETRICS LA English DT Article DE Between-study covariance matrix; Heterogeneity; Method of moments estimator; Multivariate meta-analysis; Random effect model ID REGRESSION; OUTCOMES AB Meta-analysis is a powerful approach to combine evidence from multiple studies to make inference about one or more parameters of interest, such as regression coefficients. The validity of the fixed effect model meta-analysis depends on the underlying assumption that all studies in the meta-analysis share the same effect size. In the presence of heterogeneity, the fixed effect model incorrectly ignores the between-study variance and may yield false positive results. The random effect model takes into account both within-study and between-study variances. It is more conservative than the fixed effect model and should be favored in the presence of heterogeneity. In this paper, we develop a noniterative method of moments estimator for the between-study covariance matrix in the random effect model multivariate meta-analysis. To our knowledge, it is the first such method of moments estimator in the matrix form. We show that our estimator is a multivariate extension of DerSimonian and Laird's univariate method of moments estimator, and it is invariant to linear transformations. In the simulation study, our method performs well when compared to existing random effect model multivariate meta-analysis approaches. We also apply our method in the analysis of a real data example. C1 [Chen, Han; Manning, Alisa K.; Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Manning, Alisa K.] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA. [Manning, Alisa K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Manning, Alisa K.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Chen, H (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, 801 Massachusetts Ave, Boston, MA 02118 USA. EM hanchen@bu.edu OI Dupuis, Josee/0000-0003-2871-3603; Chen, Han/0000-0002-9510-4923 FU NIH [R01 DK078616, U01 DK85526]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center FX This research was partially supported by NIH awards R01 DK078616 and U01 DK85526. A portion of this research was conducted using the Linux Clusters for Genetic Analysis (LinGA) computing resource funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center and contributions from individual investigators. NR 15 TC 73 Z9 73 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2012 VL 68 IS 4 BP 1278 EP 1284 DI 10.1111/j.1541-0420.2012.01761.x PG 7 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 080IX UT WOS:000314236200029 PM 22551393 ER PT J AU Kieran, MW Kalluri, R Cho, YJ AF Kieran, Mark W. Kalluri, Raghu Cho, Yoon-Jae TI The VEGF Pathway in Cancer and Disease: Responses, Resistance, and the Path Forward SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID ENDOTHELIAL-GROWTH-FACTOR; RENAL-CELL CARCINOMA; PHASE-II TRIAL; TYROSINE KINASE INHIBITOR; ACUTE MYELOID-LEUKEMIA; ADVANCED SOLID TUMORS; METASTATIC BREAST-CANCER; ANTI-ANGIOGENIC THERAPY; BEVACIZUMAB PLUS IRINOTECAN; ANTIANGIOGENIC AGENT SU5416 AB Antiangiogenesis was proposed as a novel target for the treatment of cancer 40 years ago. Since the original hypothesis put forward by Judah Folkman in 1971, factors that mediate angiogenesis, their cellular targets, many of the pathways they signal, and inhibitors of the cytokines and receptors have been identified. Vascular endothelial growth factor (VEGF) is the most prominent among the angiogenic cytokines and is believed to play a central role in the process of neovascularization, both in cancer as well as other inflammatory diseases. This article reviews the biology of VEGF and its receptors, the use of anti-VEGF approaches in clinical disease, the toxicity of these therapies, and the resistance mechanisms that have limited the activity of these agents when used as monotherapy. C1 [Kieran, Mark W.] Dana Farber Canc Inst, Dept Pediat Med Neurooncol, Boston, MA 02115 USA. [Kieran, Mark W.] Childrens Hosp, Div Pediat Oncol, Boston, MA 02115 USA. [Kalluri, Raghu] Beth Israel Deaconess Med Ctr, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Cho, Yoon-Jae] Stanford Univ, Dept Neurol & Neurosurg, Stanford, CA 94305 USA. [Cho, Yoon-Jae] Lucile Packard Childrens Hosp, Stanford, CA 94305 USA. RP Kieran, MW (reprint author), Dana Farber Canc Inst, Dept Pediat Med Neurooncol, Boston, MA 02115 USA. EM mark_kieran@dfci.harvard.edu RI Kalluri, Raghu/E-2677-2015; OI Kalluri, Raghu/0000-0002-2190-547X; Kieran, Mark/0000-0003-2184-7692 NR 195 TC 55 Z9 56 U1 1 U2 13 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD DEC PY 2012 VL 2 IS 12 AR a006593 DI 10.1101/cshperspect.a006593 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 080ZD UT WOS:000314282700007 PM 23209176 ER PT J AU Nienhuis, AW Nathan, DG AF Nienhuis, Arthur W. Nathan, David G. TI Pathophysiology and Clinical Manifestations of the beta-Thalassemias SO COLD SPRING HARBOR PERSPECTIVES IN MEDICINE LA English DT Article ID HEMOGLOBIN-STABILIZING PROTEIN; TRANSFERRIN-BOUND IRON; LABILE PLASMA IRON; SICKLE-CELL-ANEMIA; FETAL-HEMOGLOBIN; MAGNETIC-RESONANCE; CHELATION-THERAPY; CARDIAC IRON; GLOBIN GENE; INEFFECTIVE ERYTHROPOIESIS AB The beta-thalassemia syndromes reflect deficient or absent beta-globin synthesis usually owing to a mutation in the beta-globin locus. The relative excess of alpha-globin results in the formation of insoluble aggregates leading to ineffective erythropoiesis and shortened red cell survival. A relatively high capacity for fetal hemoglobin synthesis is a major genetic modifier of disease severity, with polymorphisms in other genes also having a significant role. Iron overload secondary to enhanced absorption and red cell transfusions causes an increase in liver iron and in various other tissues, leading to endocrine and cardiac dysfunction. Modern chelation regimens are effective in removing iron and preserving or restoring organ function. C1 [Nienhuis, Arthur W.] St Jude Childrens Res Hosp, Dept Hematol, Memphis, TN 38105 USA. [Nathan, David G.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Nathan, David G.] Childrens Hosp, Div Hematol & Oncol, Boston, MA 02215 USA. RP Nienhuis, AW (reprint author), St Jude Childrens Res Hosp, Dept Hematol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM arthur.nienhuis@stjude.org NR 105 TC 25 Z9 26 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 2157-1422 J9 CSH PERSPECT MED JI Cold Spring Harb. Perspect. Med. PD DEC PY 2012 VL 2 IS 12 AR a011726 DI 10.1101/cshperspect.a011726 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 080ZD UT WOS:000314282700004 PM 23209183 ER PT J AU Pace, CA Lioznov, D Cheng, DM Wakeman, SE Raj, A Walley, AY Coleman, SM Bridden, C Krupitsky, E Samet, JH AF Pace, C. A. Lioznov, D. Cheng, D. M. Wakeman, S. E. Raj, A. Walley, A. Y. Coleman, S. M. Bridden, C. Krupitsky, E. Samet, J. H. TI Sexually transmitted infections among HIV-infected heavy drinkers in St Petersburg, Russia SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE sexually transmitted infection; HIV; AIDS; STIs; risk behaviour; alcohol drinking; Russia ID TRANSMISSION RISKS; UNITED-STATES; SEX WORK; SYPHILIS; PREVALENCE; MEN; FEDERATION; CHLAMYDIA; GONORRHEA; DIAGNOSIS AB The objective of this study was to estimate the prevalence and identify correlates of four sexually transmitted infections (STIs) among HIV-infected Russians reporting heavy alcohol use and recent unprotected sex, we conducted a cross-sectional analysis of baseline data from the HERMITAGE study. The primary outcome was any current STI, based on urine tests for Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis and serological testing for infection with Treponema pallidum. Data on potential demographic and behavioural predictors of STI were obtained from surveys administered at study entry. Of 682 participants, 12.8% (95% confidence interval [CI] 10.3, 15.3) tested positive for at least one STI. In a multivariable model adjusted for gender, age and marital status, only sex trade involvement over the last three months was significantly associated with an increased odds of STI (adjusted odds ratio [AOR] 2.00, 95% CI 1.13, 3.55). Given that STIs were common in this HIV-infected cohort, and that few patient characteristics predicted STI, the current practice of screening HIV-infected Russians for syphilis alone merits re-evaluation. C1 [Pace, C. A.; Cheng, D. M.; Walley, A. Y.; Bridden, C.; Samet, J. H.] Boston Univ, Sch Med, Clin Addict Res & Educ CARE Unit, Dept Med,Sect Gen Internal Med,Boston Med Ctr, Boston, MA 02118 USA. [Lioznov, D.] Pavlov State Med Univ, Dept Infect Dis & Epidemiol, St Petersburg, Russia. [Cheng, D. M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Wakeman, S. E.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Raj, A.] Univ Calif San Diego, Dept Med, Div Global Publ Hlth, San Diego, CA 92103 USA. [Coleman, S. M.] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02118 USA. [Krupitsky, E.] Pavlov State Med Univ, St Petersburg Sci Res Ctr Addict & Psychopharmaco, St Petersburg, Russia. [Samet, J. H.] Boston Univ, Sch Publ Hlth, Dept Community Hlth Sci, Boston, MA 02118 USA. RP Pace, CA (reprint author), Boston Univ, Sch Med, Clin Addict Res & Educ CARE Unit, Dept Med,Sect Gen Internal Med,Boston Med Ctr, 801 Massachusetts Ave,2nd Floor, Boston, MA 02118 USA. EM Christine.pace@bmc.org RI Lioznov, Dmitry/J-2539-2013; OI Lioznov, Dmitry/0000-0003-3643-7354; Samet, Jeffrey/0000-0002-0897-3400; Bridden, Carly/0000-0002-7208-7235; Walley, Alexander/0000-0002-8158-4882 FU National Institute of Alcohol Abuse and Alcoholism (NIAAA) [R01AA016059, K24-AA015674]; National Institute of Drug Abuse (NIDA) [R25DA13582]; National Institute of Allergy and Infectious Diseases (NIAID) [T32 AI052074-06A2] FX CAP, DL, SEW, AYW, AR, EK and JHS conceived the research question and designed the analysis. JHS obtained funding for the parent HERMITAGE study. DMC and SMC conducted the statistical analysis. All authors participated in interpretation of data. All authors participated in preparation of the manuscript and have approved the final draft for submission. The authors wish to acknowledge the participants in the HERMITAGE study, as well as the clinical and administrative study staff, particularly Elena Blokhina, Victoria Churchill and the Data Coordinating Center at Boston University. In addition, we are grateful to Aseem Mehta for assistance with the literature review, and Guillermo Madico for advice on STI laboratory testing. Support for this work came from the National Institute of Alcohol Abuse and Alcoholism (NIAAA; R01AA016059 and K24-AA015674), the National Institute of Drug Abuse (NIDA; R25DA13582) and the National Institute of Allergy and Infectious Diseases (NIAID; T32 AI052074-06A2). NR 31 TC 7 Z9 8 U1 0 U2 10 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0956-4624 J9 INT J STD AIDS JI Int. J. STD AIDS PD DEC PY 2012 VL 23 IS 12 BP 853 EP 858 DI 10.1258/ijsa.2012.012004 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 069WJ UT WOS:000313467500004 PM 23258823 ER PT J AU von Lutzau, P Otto, M Hechler, T Metzing, S Wolfe, J Zernikow, B AF von Luetzau, Pia Otto, Michael Hechler, Tanja Metzing, Sabine Wolfe, Joanne Zernikow, Boris TI Children Dying from Cancer: Parents' perspectives on symptoms, quality of life, characteristics of death, and end-of-life decisions SO JOURNAL OF PALLIATIVE CARE LA English DT Article DE end-of-life care period; children; cancer; end-of-life decision ID RESEARCH PARTICIPATION; PEDIATRIC ONCOLOGY; PALLIATIVE CARE; EXPERIENCES; PERCEPTIONS; FATIGUE; PEOPLE; HOME; PAIN AB In this study, we investigated the experience of children who died of cancer, as perceived by their parents. All the pediatric oncology departments in one German federal state were contacted and asked to invite parents who had lost a child to cancer in the period 2005-2006 to participate. Those parents who accepted were interviewed by means of a semi-structured questionnaire. In the participating 16 departments, 158 children died in 2005-2006. Parents of 48 children (38.3 percent) agreed to participate and were interviewed. Nearly all of the children had suffered from at least one distressing symptom. Pain and fatigue occurred most frequently. Symptoms were successfully treated over 65 percent of the time. In all, 64 percent of the children received home care services; 50 percent died at home, and only 10 percent in the ICU. Results suggest that some progress has been made in pediatric palliative care. To further improve end-of-life care for children with cancer, it is also necessary to evaluate parents' perspectives on structures for pediatric palliative care delivery. C1 [von Luetzau, Pia; Otto, Michael; Hechler, Tanja; Zernikow, Boris] Childrens & Adolescents Hosp, Pediat Palliat Care Ctr, Datteln, Germany. [von Luetzau, Pia; Otto, Michael; Hechler, Tanja; Zernikow, Boris] Childrens & Adolescents Hosp, German Pediat Pain Ctr, Datteln, Germany. [von Luetzau, Pia; Otto, Michael; Hechler, Tanja; Zernikow, Boris] Univ Witten Herdecke, Fac Hlth, Sch Med, Dept Childrens Pain Therapy & Paediat Palliat Car, D-45711 Datteln, Germany. [Metzing, Sabine] Univ Witten Herdecke, Fac Hlth, Sch Nursing Sci, Witten, Germany. [Wolfe, Joanne] Harvard Univ, Sch Med, Boston, MA USA. [Wolfe, Joanne] Boston Childrens Hosp, Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA USA. RP von Lutzau, P (reprint author), Childrens & Adolescents Hosp, Pediat Palliat Care Ctr, Datteln, Germany. EM p.vonluetzau@kinderklinik-datteln.de FU German Children's Cancer Fund FX We would like to thank the study participants, the interviewers (E. Baum, D. Behnen, R. Bruggemann, M. Czech, M. Fortkord, C. Hansen, A. Menke, and D. Wunnenberg), and the German Children's Cancer Fund, which supported the survey. In addition, we thank all of the departments that participated in the research and that helped us to contact the parents who shared their perspectives with us: the Department of Pediatric and Adolescent Medicine, University Hospital Aachen (clinical director, Prof. Dr. N. Wagner); the Department of Pediatric Oncology, Gilead Hospital, Bielefeld (clinical director, Dr. N. Jorch); the Department of Hematology and Oncology, University Clinic for Children, Bonn (clinical director, Prof. Dr. D. Dilloo); the Department of Hematology and Oncology, Children's and Adolescents' Hospital, Datteln, Witten/Herdecke University (clinical director, Prof. Dr. M. Paulussen); the Department of Pediatric Medicine, Klinikunn Lippe (clinical director, Dr. T. Brune); the Department of Pediatric Oncology, Dortmund Children's Hospital (clinical director, Prof. Dr. D. Schneider); the Clinic for Pediatrics III, University Clinic of Essen (clinical director, Prof. Dr. A. Eggert); the Department of Pediatric Medicine, Children's Hospital, Herdecke (clinical director, PD Dr. A. Langler); the Department of Pediatric Oncology, Children's Clinic, University Hospital of Koln (clinical director, Prof. Dr. F. Berthold); the Department of Pediatric Oncology, Children's Hospital Amsterdamer Strasse, Koln (clinical director, Dr. A. Prokop); the Department of Pediatric Oncology, HELIOS Klinikum Krefeld (clinical director, Prof. Dr. T. Niehues); the Department of Pediatric Medicine, Klinikum Minden (clinical director, Prof. Dr. B. Erdlenbruch); the Department of Hematology and Oncology, University Clinic for Children, Munster (clinical director, Prof. Dr. H. Jurgens); the Department of Pediatric Oncology, Children's Red Cross Hospital, Siegen (clinical director, Prof. Dr. R. Burghard); the Department of Pediatric Medicine, Asklepiop Klinik St. Augustin (clinical director, Prof. Dr. G. Horneff); and the Department of Pediatric Medicine, HELIOS Klinikum Wuppertal (clinical director, Prof. Dr. S. Wirth). NR 44 TC 16 Z9 17 U1 4 U2 29 PU CENTRE RECHERCHE INSTITUT UNIV GERIATRIE MONTREAL PI MONTREAL PA 4565 CHEMIN QUEEN MARY, MONTREAL, QUEBEC H3W 1W5, CANADA SN 0825-8597 J9 J PALLIAT CARE JI J. Palliative Care PD WIN PY 2012 VL 28 IS 4 BP 274 EP 281 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 082IQ UT WOS:000314385900006 PM 23413763 ER PT J AU Neveu, G Cassonnet, P Vidalain, PO Rolloy, C Mendoza, J Jones, L Tangy, F Muller, M Demeret, C Tafforeau, L Lotteau, V Rabourdin-Combe, C Trave, G Dricot, A Hill, DE Vidal, M Favre, M Jacob, Y AF Neveu, Gregory Cassonnet, Patricia Vidalain, Pierre-Olivier Rolloy, Caroline Mendoza, Jose Jones, Louis Tangy, Frederic Muller, Mandy Demeret, Caroline Tafforeau, Lionel Lotteau, Vincent Rabourdin-Combe, Chantal Trave, Gilles Dricot, Amelie Hill, David E. Vidal, Marc Favre, Michel Jacob, Yves TI Comparative analysis of virus-host interactomes with a mammalian high-throughput protein complementation assay based on Gaussia princeps luciferase SO METHODS LA English DT Article DE Comparative interactomics; HPV; E6; E7; Interactome; Complementation assay ID HUMAN-PAPILLOMAVIRUS E6; RETINOBLASTOMA TUMOR-SUPPRESSOR; E7 ONCOPROTEIN; E6-AP; P53; UBIQUITINATION; ASSOCIATION; COMPLEXES; MECHANISM; DATABASE AB Comparative interactomics is a strategy for inferring potential interactions among orthologous proteins or "interologs". Herein we focus, in contrast to standard homology-based inference, on the divergence of protein interaction profiles among closely related organisms, showing that the approach can correlate specific traits to phenotypic differences. As a model, this new comparative interactomic approach was applied at a large scale to human papillomaviruses (HPVs) proteins. The oncogenic potential of HPVs is mainly determined by the E6 and E7 early proteins. We have mapped and overlapped the virus-host protein interaction networks of E6 and E7 proteins from 11 distinct HPV genotypes, selected for their different tropisms and pathologies. We generated robust and comprehensive datasets by combining two orthogonal protein interaction assays: yeast two-hybrid (Y2H), and our recently described "high-throughput Gaussia princeps protein complementation assay" (HT-GPCA). HT-GPCA detects protein interaction by measuring the interaction-mediated reconstitution of activity of a split G. princeps luciferase. Hierarchical clustering of interaction profiles recapitulated HPV phylogeny and was used to correlate specific virus-host interaction profiles with pathological traits, reflecting the distinct carcinogenic potentials of different HPVs. This comparative interactomics constitutes a reliable and powerful strategy to decipher molecular relationships in virtually any combination of microorganism-host interactions. (c) 2012 Elsevier Inc. All rights reserved. C1 [Neveu, Gregory; Cassonnet, Patricia; Rolloy, Caroline; Mendoza, Jose; Muller, Mandy; Demeret, Caroline; Favre, Michel; Jacob, Yves] Inst Pasteur, Unite Genet Papillomavirus & Canc Humain GPCH, F-75015 Paris, France. [Vidalain, Pierre-Olivier; Tangy, Frederic] Inst Pasteur, Unite Genom Virale & Vaccinat G2V, F-75015 Paris, France. [Jones, Louis] Inst Pasteur, Grp Logiciels & Banques Donnees, F-75015 Paris, France. [Tafforeau, Lionel; Lotteau, Vincent; Rabourdin-Combe, Chantal] IFR 128 BioSci, IMAP Team, F-69007 Lyon, France. [Trave, Gilles] ESBS, CNRS, UMR 7175, Equipe Oncoprot, F-67412 Illkirch Graffenstaden, France. [Dricot, Amelie; Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA. [Dricot, Amelie; Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Dricot, Amelie; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Jacob, Y (reprint author), Inst Pasteur, Unite Genet Papillomavirus & Canc Humain GPCH, 25 Rue Docteur Roux, F-75015 Paris, France. EM yves.jacob@pasteur.fr RI Hill, David/B-6617-2011; lotteau, vincent/M-8143-2014; TRAVE, Gilles/P-8577-2016; OI Tafforeau, Lionel/0000-0002-8468-7422; Neveu, Gregory/0000-0002-2363-6031 FU Institut Pasteur; Ligue nationale contre le Cancer [R05/75-129, RS07/75-75]; Association pour la Recherche sur le Cancer [3731XA0531F, 4867]; Agence Nationale de la Recherche (EPI-HPV-3D program); Center of Excellence in Genomic Science (CEGS) [P50-HG004233, R01-H6001715]; National Human Genome Research Institute (NHGRI); Conseil General de la Vienne; Pasteur Weizmann foundation; Ministere de l'education nationale, de la recherche et de la technologie (MENRT) fellowship FX We thank Richard Paul, Katherine Kean and Michael Cusick for critical reading of the manuscript. This work was supported in part by funding from the Institut Pasteur, and by grants from the Ligue nationale contre le Cancer (grants R05/75-129 and RS07/75-75), the Association pour la Recherche sur le Cancer (grants 3731XA0531F and 4867), and the Agence Nationale de la Recherche (EPI-HPV-3D program) and by Center of Excellence in Genomic Science (CEGS) grants P50-HG004233 and R01-H6001715 from the National Human Genome Research Institute (NHGRI) (M. V, DE.H). G.N. was a recipient of the Conseil General de la Vienne and Pasteur Weizmann foundation. C.R. was a recipient of a Ministere de l'education nationale, de la recherche et de la technologie (MENRT) fellowship. NR 35 TC 20 Z9 20 U1 0 U2 14 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD DEC PY 2012 VL 58 IS 4 BP 349 EP 359 DI 10.1016/j.ymeth.2012.07.029 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 082FS UT WOS:000314378300006 PM 22898364 ER PT J AU Tusset, C Noel, SD Trarbach, EB Silveira, LFG Jorge, AAL Brito, VN Cukier, P Seminara, SB de Mendonca, BB Kaiser, UB Latronico, AC AF Tusset, Cintia Noel, Sekoni D. Trarbach, Ericka B. Silveira, Leticia F. G. Jorge, Alexander A. L. Brito, Vinicius N. Cukier, Priscila Seminara, Stephanie B. de Mendonca, Berenice B. Kaiser, Ursula B. Latronico, Ana Claudia TI Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders SO ARQUIVOS BRASILEIROS DE ENDOCRINOLOGIA E METABOLOGIA LA English DT Article DE Neurokinin B; neurokinin B receptor; central precocious puberty; normosmic isolated hypogonadotropic hypogonadism; constitutional delay of growth and puberty ID GONADOTROPIN-RELEASING-HORMONE; HYPOGONADOTROPIC HYPOGONADISM; NEUROKININ-B; TACHYKININ RECEPTORS; CONSTITUTIONAL DELAY; PROPEPTIDE MUTATION; ARCUATE NUCLEUS; REPRODUCTION; INHERITANCE; PATTERNS AB Objective: To investigate the presence of variants in the TAC3 and TACR3 genes, which encode NKB and its receptor (NK3R), respectively, in a large cohort of patients with idiopathic central pubertal disorders. Subjects and methods: Two hundred and thirty seven patients were studied: 114 with central precocious puberty (CPP), 73 with normosmic isolated hypogonadotropic hypogonadism (IHH), and 50 with constitutional delay of growth and puberty (CDGP). The control group consisted of 150 Brazilian individuals with normal pubertal development. Genomic DNA was extracted from peripheral blood and the entire coding region of both TAC3 and TACR3 genes were amplified and automatically sequenced. Results: We identified one variant (p.A63P) in NKB and four variants, p.G18D, p.L58L (c.172C > T), p.W275* and p.A449S in NK3R, which were absent in the control group. The p.A63P variant was identified in a girl with CPP, and p.A449S in a girl with CDGP. The known p.G18D, p.L58L, and p.W275* variants were identified in three unrelated males with normosmic IHH. Conclusion: Rare variants in the TAC3 and TACR3 genes were identified in patients with central pubertal disorders. Loss-of-function variants of TACR3 were associated with the normosmic IHH phenotype. Arq Bras Endocrinol Metab. 2012; 56(9):646-52 C1 [Tusset, Cintia; Trarbach, Ericka B.; Silveira, Leticia F. G.; Jorge, Alexander A. L.; Brito, Vinicius N.; Cukier, Priscila; de Mendonca, Berenice B.; Latronico, Ana Claudia] Univ Sao Paulo, Fac Med, Lab Hormonios & Genet Mol LIM42, Unidade Endocrinol Desenvolvimento,Hosp Clin, Sao Paulo, Brazil. [Noel, Sekoni D.; Kaiser, Ursula B.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. [Noel, Sekoni D.; Kaiser, Ursula B.] Brigham & Womens Hosp, Harvard Ctr Reprod Sci, Boston, MA 02115 USA. [Seminara, Stephanie B.] Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Unit, Boston, MA 02114 USA. [Seminara, Stephanie B.] Massachusetts Gen Hosp, Harvard Ctr Reprod Sci, Boston, MA 02114 USA. RP Latronico, AC (reprint author), Av Dr Eneas de Carvalho Aguiar 155,2 Andar,Bloco, BR-05403900 Sao Paulo, Brazil. EM cintiatusset@yahoo.com.br; anacl@usp.br RI BRITO, VINICIUS/B-3776-2013; Silveira, Leticia/D-3975-2014; Jorge, Alexander/C-7697-2012; Trarbach, Ericka/I-5395-2012 OI BRITO, VINICIUS/0000-0003-4140-6296; Jorge, Alexander/0000-0003-2567-7360; FU Fapesp [05/04726]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [302825/2011-8, 305743/2011-8]; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) [U54 HD28138] FX this study was supported by Fapesp grants 05/04726 and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) grants 302825/2011-8 (to A.C.L.), by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) grants 305743/2011-8 (to B.B.M.), and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), by means of the cooperative agreement U54 HD28138 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research (to U.B.K.). NR 34 TC 13 Z9 15 U1 0 U2 3 PU SBEM-SOC BRASIL ENDOCRINOLOGIA & METABOLOGIA PI RIO DE JANEIRO, RJ PA RUA HUMAITA, 85 CJ 501, RIO DE JANEIRO, RJ, 22261-000, BRAZIL SN 0004-2730 J9 ARQ BRAS ENDOCRINOL JI Arq. Bras. Endocrinol. Metabol. PD DEC PY 2012 VL 56 IS 9 BP 646 EP 652 PG 7 GA 072XL UT WOS:000313706900008 PM 23329188 ER PT J AU Babu, K Hu, ZT Chien, SC Garriga, G Kaplan, JM AF Babu, Kavita Hu, Zhitao Chien, Shih-Chieh Garriga, Gian Kaplan, Joshua M. TI Using C. elegans to understand the function and regulation of cell adhesion molecules SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Meeting Abstract CT 19th Biennial Meeting of the International-Society-for-Developmental-Neuroscience (ISDN) CY JAN 11-14, 2012 CL Mumbai, INDIA SP Int Soc Dev Neurosci (ISDN) C1 [Babu, Kavita; Hu, Zhitao; Kaplan, Joshua M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Chien, Shih-Chieh; Garriga, Gian] Univ Calif Berkeley, Dept Mol Cell Biol, Berkeley, CA 94720 USA. [Babu, Kavita] Indian Inst Sci Educ & Res, Mohali 140306, Punjab, India. EM kavitababu@iisermohali.ac.in NR 1 TC 0 Z9 0 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD DEC PY 2012 VL 30 IS 8 BP 665 EP 665 DI 10.1016/j.ijdevneu.2012.03.314 PG 1 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 077EE UT WOS:000314009900129 ER PT J AU Schroy, PC Emmons, KM Peters, E Glick, JT Robinson, PA Lydotes, MA Mylvaganam, SR Coe, AM Chen, CA Chaisson, CE Pignone, MP Prout, MN Davidson, PK Heeren, TC AF Schroy, Paul C., III Emmons, Karen M. Peters, Ellen Glick, Julie T. Robinson, Patricia A. Lydotes, Maria A. Mylvaganam, Shamini R. Coe, Alison M. Chen, Clara A. Chaisson, Christine E. Pignone, Michael P. Prout, Marianne N. Davidson, Peter K. Heeren, Timothy C. TI Aid-Assisted Decision Making and Colorectal Cancer Screening A Randomized Controlled Trial SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SERVICES TASK-FORCE; PATIENT PREFERENCES; UPDATE; IMPACT; RECOMMENDATION; INTERVENTIONS; SURVEILLANCE; PERCEPTIONS; GUIDELINES; RATIONALE AB Background: Shared decision making (SDM) is a widely recommended yet unproven strategy for increasing colorectal cancer (CRC) screening uptake. Previous trials of decision aids to increase SDM and CRC screening uptake have yielded mixed results. Purpose: To assess the impact of decision aid-assisted SDM on CRC screening uptake. Design: RCT. Setting/participants: The study was conducted at an urban, academic safety-net hospital and community health center between 2005 and 2010. Participants were asymptomatic, average-risk patients aged 50-75 years due for CRC screening. Intervention: Study participants (n = 825) were randomized to one of two intervention arms (decision aid plus personalized risk assessment or decision aid alone) or control arm. The interventions took place just prior to a routine office visit with their primary care providers. Main outcome measures: The primary outcome was completion of a CRC screening test within 12 months of the study visit. Logistic regression was used to identify predictors of test completion and mediators of the intervention effect. Analysis was completed in 2011. Results: Patients in the decision-aid group were more likely to complete a screening test than control patients (43.1% vs 34.8%, p = 0.046) within 12 months of the study visit; conversely, test uptake for the decision aid and decision aid plus personalized risk assessment arms was similar (43.1% vs 37.1%, p = 0.15). Assignment to the decision-aid arm (AOR = 1.48, 95% CI = 1.04, 2.10), black race (AOR = 1.52, 95% CI = 1.12, 2.06) and a preference for a patient-dominant decision-making approach (AOR = 1.55, 95% CI = 1.02, 2.35) were independent determinants of test completion. Activation of the screening discussion and enhanced screening intentions mediated the intervention effect. Conclusions: Decision aid-assisted SDM has a modest impact on CRC screening uptake. A decision aid plus personalized risk assessment tool is no more effective than a decision aid alone. C1 [Schroy, Paul C., III; Glick, Julie T.; Robinson, Patricia A.; Lydotes, Maria A.; Mylvaganam, Shamini R.; Coe, Alison M.; Davidson, Peter K.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Chen, Clara A.; Chaisson, Christine E.] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA. [Prout, Marianne N.] Boston Univ, Dept Epidemiol, Boston, MA 02215 USA. [Heeren, Timothy C.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Emmons, Karen M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Peters, Ellen] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Pignone, Michael P.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. RP Schroy, PC (reprint author), Boston Med Ctr, 85 E Concord St,Suite 7715, Boston, MA 02118 USA. EM paul.schroy@bmc.org OI Prout, Marianne/0000-0001-8747-6199; Pignone, Michael/0000-0002-6657-7342; Heeren, Timothy/0000-0001-5643-3559; Chaisson, Christine/0000-0002-3207-9257 FU Agency for Healthcare Research and Quality [RO1HS013912]; National Cancer Institute [K05CA 129166]; National Science Foundation [SES-1047757, SES-0517770] FX The study was supported by grant RO1HS013912 from the Agency for Healthcare Research and Quality (PI, Paul C. Schroy III). Dr. Pignone's effort was supported by a National Cancer Institute Established Investigator Award K05CA 129166. Dr. Peters's effort was supported in part by the National Science Foundation (SES-1047757 and SES-0517770). NR 48 TC 23 Z9 23 U1 8 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2012 VL 43 IS 6 BP 573 EP 583 DI 10.1016/j.amepre.2012.08.018 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 071FR UT WOS:000313574800002 PM 23159252 ER PT J AU Kuznetsov, HS Marsh, T Markens, BA Castano, Z Greene-Colozzi, A Hay, SA Brown, VE Richardson, AL Signoretti, S Battinelli, EM McAllister, SS AF Kuznetsov, Hanna S. Marsh, Timothy Markens, Beth A. Castano, Zafira Greene-Colozzi, April Hay, Samantha A. Brown, Victoria E. Richardson, Andrea L. Signoretti, Sabina Battinelli, Elisabeth M. McAllister, Sandra S. TI Identification of Luminal Breast Cancers That Establish a Tumor-Supportive Macroenvironment Defined by Proangiogenic Platelets and Bone Marrow-Derived Cells SO CANCER DISCOVERY LA English DT Article ID ANTI-ANGIOGENESIS THERAPY; ALPHA-GRANULES; ASPIRIN; METASTASIS; EXPRESSION; GROWTH; CD24; TRANSFORMATION; NEPHRECTOMY; CARCINOMA AB Breast cancer recurrence rates vary following treatment, suggesting that tumor cells disseminate early from primary sites but remain indolent indefinitely before progressing to symptomatic disease. The reasons why some indolent disseminated tumors erupt into overt disease are unknown. We discovered a novel process by which certain luminal breast cancer (LBC) cells and patient tumor specimens (LBC "instigators") establish a systemic macroenvironment that supports outgrowth of otherwise-indolent disseminated tumors ("responders"). Instigating LBCs secrete cytokines that are absorbed by platelets, which are recruited to responding tumor sites where they aid vessel formation. Instigator-activated bone marrow cells enrich responding tumor cell expression of CD24, an adhesion molecule for platelets, and provide a source of VEGF receptor 2(+) tumor vessel cells. This cascade results in growth of responder adenocarcinomas and is abolished when platelet activation is inhibited by aspirin. These findings highlight the macroenvironment as an important component of disease progression that can be exploited therapeutically. SIGNIFICANCE: Currently, processes that mediate progression of otherwise indolent tumors are not well understood, making it difficult to accurately predict which cancer patients are likely to relapse. Our findings highlight the macroenvironment as an important component of disease progression that can be exploited to more accurately identify patients who would benefit from adjuvant therapy. Cancer Discov; 2(12); 1150-65. (C) 2012 AACR. C1 [McAllister, Sandra S.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Brown, Victoria E.; Richardson, Andrea L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Castano, Zafira; Signoretti, Sabina; Battinelli, Elisabeth M.; McAllister, Sandra S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Greene-Colozzi, April; Richardson, Andrea L.; Signoretti, Sabina] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [McAllister, Sandra S.] Harvard Stem Cell Inst, Boston, MA USA. [McAllister, Sandra S.] Broad Inst Harvard & MIT, Cambridge, MA USA. RP McAllister, SS (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Hematol, 1 Blackfan Circle,Karp 5-214, Boston, MA 02115 USA. EM smcallister1@partners.org RI McAllister, Sandra/J-7373-2012; Silva, Mariana/B-9530-2012 FU Dana-Farber/Harvard Breast Cancer SPORE NCI [2 P50 CA89393-06]; Dana Farber/Harvard Cancer Center Kidney Cancer SPORE [P50 CA101942]; NIH NHLBI [K08HL097070]; Malcolm Hecht Jr. Hematology Research Endowment; Dana Farber/Harvard Cancer Center Breast Cancer SPORE NCI [5 P30 CA006516-46-2010-01-NN-02]; Harvard Stem Cell Institute; BWH Biomedical Research Institute FX This work was supported in part by funds from the Dana-Farber/Harvard Breast Cancer SPORE NCI, 2 P50 CA89393-06 (A.L. Richardson); the Dana Farber/Harvard Cancer Center Kidney Cancer SPORE P50 CA101942 (S. Signoretti); NIH NHLBI K08HL097070 and the Malcolm Hecht Jr. Hematology Research Endowment (EMB); the Dana Farber/Harvard Cancer Center Breast Cancer SPORE NCI 5 P30 CA006516-46-2010-01-NN-02, Harvard Stem Cell Institute, and BWH Biomedical Research Institute (S.S. McAllister). S.A. Hay is an American Cancer Society Fuller Research Fellow. NR 47 TC 34 Z9 34 U1 1 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD DEC PY 2012 VL 2 IS 12 BP 1150 EP 1165 DI 10.1158/2159-8290.CD-12-0216 PG 16 WC Oncology SC Oncology GA 072AZ UT WOS:000313641700026 PM 22896036 ER PT J AU Losordo, DW Kibbe, MR Mendelsohn, F Marston, W Driver, VR Sharafuddin, M Teodorescu, V Wiechmann, BN Thompson, C Kraiss, L Carman, T Dohad, S Huang, P Junge, CE Story, K Weistroffer, T Thorne, TM Millay, M Runyon, JP Schainfeld, R AF Losordo, Douglas W. Kibbe, Melina R. Mendelsohn, Farrell Marston, William Driver, Vickie R. Sharafuddin, Melhem Teodorescu, Victoria Wiechmann, Bret N. Thompson, Charles Kraiss, Larry Carman, Teresa Dohad, Suhail Huang, Paul Junge, Candice E. Story, Kenneth Weistroffer, Tara Thorne, Tina M. Millay, Meredith Runyon, John Paul Schainfeld, Robert CA Autologous CD34 Cell Therapy Criti TI A Randomized, Controlled Pilot Study of Autologous CD34+ Cell Therapy for Critical Limb Ischemia SO CIRCULATION-CARDIOVASCULAR INTERVENTIONS LA English DT Article DE peripheral vascular disease; revascularization; reperfusion; randomized trial; stem cells ID PERIPHERAL ARTERIAL-DISEASE; GROWTH-FACTOR PLASMID; DOUBLE-BLIND; CONTROLLED-TRIAL; INTRAMUSCULAR INJECTION; PARENTERAL THERAPY; 6-MONTH OUTCOMES; LIPO-ECRAPROST; GENE-THERAPY; ANGIOGENESIS AB Background-Critical limb ischemia portends a risk of major amputation of 25% to 35% within 1 year of diagnosis. Preclinical studies provide evidence that intramuscular injection of autologous CD34+ cells improves limb perfusion and reduces amputation risk. In this randomized, double-blind, placebo-controlled pilot study, we evaluated the safety and efficacy of intramuscular injections of autologous CD34+ cells in subjects with moderate or high-risk critical limb ischemia, who were poor or noncandidates for surgical or percutaneous revascularization (ACT34-CLI). Methods and Results-Twenty-eight critical limb ischemia subjects were randomized and treated: 7 to 1x10(5) (low-dose) and 9 to 1x10(6) (high-dose) autologous CD34+ cells/kg; and 12 to placebo (control). Intramuscular injections were distributed into 8 sites within the ischemic lower extremity. At 6 months postinjection, 67% of control subjects experienced a major or minor amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.137). This trend continued at 12 months, with 75% of control subjects experiencing any amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.058). Amputation incidence was lower in the combined cell-treated groups compared with control group (6 months: P=0.125; 12 months: P=0.054), with the low-dose and high-dose groups individually showing trends toward improved amputation-free survival at 6 months and 12 months. No adverse safety signal was associated with cell administration. Conclusions-This study provides evidence that intramuscular administration of autologous CD34+ cells was safe in this patient population. Favorable trends toward reduced amputation rates in cell-treated versus control subjects were observed. These findings warrant further exploration in later-phase clinical trials. C1 [Losordo, Douglas W.; Weistroffer, Tara; Thorne, Tina M.; Millay, Meredith] Northwestern Univ, NW Mem Hosp, Div Cardiovasc Med, Chicago, IL 60611 USA. [Losordo, Douglas W.; Weistroffer, Tara; Thorne, Tina M.; Millay, Meredith] Northwestern Univ, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA. [Kibbe, Melina R.] Northwestern Univ, NW Mem Hosp, Div Cardiol, Chicago, IL 60611 USA. [Kibbe, Melina R.] Northwestern Univ, NW Mem Hosp, Div Vasc Surg, Chicago, IL 60611 USA. [Mendelsohn, Farrell] Ctr Therapeut Angiogenesis, Birmingham, AL USA. [Marston, William] Univ N Carolina, Div Vasc Surg, Chapel Hill, NC USA. [Driver, Vickie R.] Boston Med Ctr, Dept Surg, Boston, MA USA. [Driver, Vickie R.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Sharafuddin, Melhem] Univ Iowa, Dept Surg, Iowa City, IA 52242 USA. [Teodorescu, Victoria] Mt Sinai Sch Med, Div Vasc Surg, New York, NY USA. [Wiechmann, Bret N.] Vasc & Intervent Phys, Gainesville, FL USA. [Thompson, Charles] Orlando Reg Med Ctr Vasc Specialist Cent FL, Orlando, FL USA. [Kraiss, Larry] Univ Utah, Div Vasc Surg, Salt Lake City, UT USA. [Carman, Teresa] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Dohad, Suhail] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Huang, Paul] Swedish Med Ctr, Seattle, WA USA. [Losordo, Douglas W.; Junge, Candice E.; Story, Kenneth] Baxter Healthcare Corp, Deerfield, IL 60015 USA. [Runyon, John Paul] Christ Hosp, Cincinnati, OH 45219 USA. [Schainfeld, Robert] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Losordo, DW (reprint author), Baxter Healthcare Corp, 1 Baxter Pkwy, Deerfield, IL 60015 USA. EM douglas_losordo@baxter.com OI Huang, Paul/0000-0003-0563-921X FU NIH [HL-53354, HL-77428, HL-63414, HL-80137, HL95874, HLPO1-108795, HL-57516] FX Baxter Healthcare Corporation. This study was supported in part by grants from the NIH (HL-53354, HL-77428, HL-63414, HL-80137, HL95874, HLPO1-108795, HL-57516). NR 24 TC 50 Z9 55 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-7640 J9 CIRC-CARDIOVASC INTE JI Circ.-Cardiovasc. Interv. PD DEC PY 2012 VL 5 IS 6 BP 821 EP 830 DI 10.1161/CIRCINTERVENTIONS.112.968321 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 071GA UT WOS:000313576500021 PM 23192920 ER PT J AU Pham, PCT Pham, PMT Pham, PTT AF Pham, Phuong-Chi T. Pham, Phuong-Mai T. Pham, Phuong-Thu T. TI Patients with diabetes mellitus Type 2 and hypomagnesemia may have enhanced glomerular filtration via hypocalcemia SO CLINICAL NEPHROLOGY LA English DT Article DE hypomagnesemia; diabetes mellitus; glomerular hyperfiltration; hypocalcemia ID HUMAN MAGNESIUM-DEFICIENCY; LOWER SERUM MAGNESIUM; PARATHYROID-HORMONE; CALCIUM; VASOCONSTRICTION; HYPERFILTRATION; RESISTANCE; INSULIN; KIDNEY AB Introduction: Hypomagnesemia and glomerular hyperfiltration are commonly observed in patients with diabetes mellitus Type 2 (DM2). In the current study, we examined the relationship between hypomagnesemia and glomerular filtration rates in DM2 patients. Materials and methods: Data were obtained for DM2 patients without documented kidney disease seen at UCLA-Olive View Medical Center during January through March 2001. Data for hemoglobin, hemoglobin A1C (HbA1C), routine electrolytes, lipid profiles, urinalyses, history of hypertension, and pharmacy profiles were retrieved. Estimation of glomerular filtration rate (eGFR) was based on the CKD-epi formula. Multivariate analyses were performed to determine the correlations between eGFR and clinical factors including age, gender, history of hypertension, the use of diuretics, renin angiotensin system (RAS) inhibitors, acetylsalicylic acid, and statins, serum calcium, magnesium, hemoglobin, HbA1C, lipid profile, and degree of proteinuria. Results: 550 patients (54% females) with mean age 57.5 +/- 11.0 years and eGFR 95.7 +/- 14.8 ml/min/1.73 m(2) were included. Multivariate analysis revealed negative correlations with eGFR for age (Pearson-correlation-coefficient: -0.7, p < 0.0001), hypertension (-0.32, p < 0.0001), magnesium (-0.21, p < 0.0001), calcium (-0.13, p = 0.009), proteinuria (-0.17, p < 0.0001), and the use of RAS inhibitors (-0.21, p < 0.0001), and diuretics (-0.24, p < 0.0001) and a positive correlation for HbA1C (0.28, p < 0.0001). Further analysis of the interaction between serum magnesium and calcium, defined as magnesium x calcium (Mg x Ca), revealed a more significant correlation with eGFR than either cation alone (-0.24, p < 0.0001). Conclusions: Serum magnesium, calcium, and (Mg x Ca) all had significant negative correlations with eGFR. In particular, (Mg x Ca) had the strongest correlation with eGFR. C1 [Pham, Phuong-Chi T.] Olive View UCLA Med Ctr, Div Nephrol & Hypertens, Sylmar, CA 91342 USA. [Pham, Phuong-Mai T.] VA Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr, Dept Internal Med, North Hills, CA USA. [Pham, Phuong-Thu T.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Pham, PCT (reprint author), Olive View UCLA Med Ctr, Div Nephrol & Hypertens, 14445 Olive View Dr,2B-182, Sylmar, CA 91342 USA. EM pham.pchi@ucla.edu NR 28 TC 3 Z9 3 U1 0 U2 3 PU DUSTRI-VERLAG DR KARL FEISTLE PI DEISENHOFEN-MUENCHEN PA BAHNHOFSTRASSE 9 POSTFACH 49, D-82032 DEISENHOFEN-MUENCHEN, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD DEC PY 2012 VL 78 IS 6 BP 442 EP 448 DI 10.5414/CN107525 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 068YF UT WOS:000313401400003 PM 23073059 ER PT J AU Sabuncu, MR Van Leemput, K AF Sabuncu, Mert R. Van Leemput, Koen CA Alzheimers Dis Neuroimaging TI The Relevance Voxel Machine (RVoxM): A Self-Tuning Bayesian Model for Informative Image-Based Prediction SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Image classification; pattern recognition ID DEFORMATION-BASED MORPHOMETRY; FEATURE-SELECTION TECHNIQUES; SUPPORT VECTOR MACHINE; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; ALZHEIMERS-DISEASE; CORTICAL SURFACE; PATTERN-CLASSIFICATION; VARIABLE SELECTION; COORDINATE SYSTEM AB This paper presents the relevance voxel machine (RVoxM), a dedicated Bayesian model for making predictions based on medical imaging data. In contrast to the generic machine learning algorithms that have often been used for this purpose, the method is designed to utilize a small number of spatially clustered sets of voxels that are particularly suited for clinical interpretation. RVoxM automatically tunes all its free parameters during the training phase, and offers the additional advantage of producing probabilistic prediction outcomes. We demonstrate RVoxM as a regression model by predicting age from volumetric gray matter segmentations, and as a classification model by distinguishing patients with Alzheimer's disease from healthy controls using surface-based cortical thickness data. Our results indicate that RVoxM yields biologically meaningful models, while providing state-of-the-art predictive accuracy. C1 [Sabuncu, Mert R.; Van Leemput, Koen] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Sabuncu, Mert R.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Van Leemput, Koen] Tech Univ Denmark, Dept Informat & Math Modeling, DK-2800 Lyngby, Denmark. [Van Leemput, Koen] Aalto Univ, Dept Informat & Comp Sci, FI-00076 Aalto, Finland. [Van Leemput, Koen] Aalto Univ, Dept Biomed Engn & Computat Sci, FI-00076 Aalto, Finland. RP Sabuncu, MR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RI Van Leemput, Koen/A-9197-2009 OI Van Leemput, Koen/0000-0001-6466-5309 FU NIH NCRR [P41-RR14075]; NIBIB [R01EB006758, R01EB013565, 1K25EB013649-01]; NINDS [R01NS052585]; Academy of Finland [133611]; Finnish Funding Agency for Technology and Innovation (ComBrain); Harvard Catalyst, Harvard Clinical and Translational Science Center (NIH) [1KL2RR025757-01]; NIH K25 grant [1K25EB013649-01]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; National Institutes of Health [P30 AG010129, K01 AG030514] FX This work was supported by the NIH NCRR (P41-RR14075), the NIBIB (R01EB006758, R01EB013565, 1K25EB013649-01), the NINDS (R01NS052585), the Academy of Finland (133611), the Finnish Funding Agency for Technology and Innovation (ComBrain), and the Harvard Catalyst, Harvard Clinical and Translational Science Center (NIH grant 1KL2RR025757-01 and financial contributions from Harvard and its affiliations) and an NIH K25 grant (1K25EB013649-01, NIH NIBIB). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health Rev March 26, 2012. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This work was also supported by the National Institutes of Health under Grant P30 AG010129 and Grant K01 AG030514. NR 88 TC 17 Z9 17 U1 0 U2 7 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD DEC PY 2012 VL 31 IS 12 BP 2290 EP 2306 DI 10.1109/TMI.2012.2216543 PG 17 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 072RT UT WOS:000313690600011 PM 23008245 ER PT J AU Parast, L Cheng, SC Cai, TX AF Parast, Layla Cheng, Su-Chun Cai, Tianxi TI Landmark Prediction of Long-Term Survival Incorporating Short-Term Event Time Information SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Risk prediction; Survival time; Varying-coefficient model ID VARYING-COEFFICIENT MODELS; STAGE RENAL-DISEASE; SUDDEN CARDIAC DEATH; RISK-PREDICTION; BREAST-CANCER; DIALYSIS PATIENTS; MULTISTATE MODEL; COMPETING RISKS; REGRESSION; PERFORMANCE AB In recent years, a wide range of markers have become available as potential tools to predict risk or progression of disease. In addition to such biological and genetic markers, short-term outcome information may be useful in predicting long-term disease outcomes. When such information is available, it would be desirable to combine this along with predictive markers to improve the prediction of long-term survival. Most existing methods for incorporating censored short-term event information in predicting long-term survival focus on modeling the disease process and are derived under restrictive parametric models in a multistate survival setting. When such model assumptions fail to hold, the resulting prediction of long-term outcomes may be invalid or inaccurate. When there is only a single discrete baseline covariate, a fully nonparametric estimation procedure to incorporate short-term event time information has been previously proposed. However, such an approach is not feasible for settings with one or more continuous covariates due to the curse of dimensionality. In this article, we propose to incorporate short-term event time information along with multiple covariates collected up to a landmark point via a flexible varying-coefficient model. To evaluate and compare the prediction performance of the resulting landmark prediction rule, we use robust nonparametric procedures that do not require the correct specification of the proposed varying-coefficient model. Simulation studies suggest that the proposed procedures perform well in finite samples. We illustrate them here using a dataset of postdialysis patients with end-stage renal disease. C1 [Parast, Layla] RAND Corp, Santa Monica, CA 90401 USA. [Cheng, Su-Chun] Dana Farber Canc Inst, Boston, MA 02115 USA. [Cai, Tianxi] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Parast, L (reprint author), RAND Corp, Santa Monica, CA 90401 USA. EM Layla_Parast@rand.org; scheng@jimmy.harvard.edu; tcai@hsph.harvard.edu FU National Institutes of Health [T32GM074897, R01AI052817, R01-GM079330, U54LM008748] FX Layla Parast is Associate Statistician, RAND Corporation, Santa Monica, CA 90401 (E-mail: Layla_Parast@rand.org). This work was completed while Parast was a Ph.D. candidate in biostatistics at Harvard University. Su-Chun Cheng is Senior Research Scientist, Dana-Farber Cancer Institute, Boston, MA 02115 (E-mail: scheng@jimmy.harvard.edu). Tianxi Cai is Professor, Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115 (E-mail: tcai@hsph.harvard.edu). The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government. The authors are grateful to the editor, an associate editor, and the reviewers for their insightful comments on the article. Support for this research was provided by National Institutes of Health grants T32GM074897 (Parast), R01AI052817 (Parast), R01-GM079330 (Cai), and U54LM008748 (Cai). NR 60 TC 5 Z9 5 U1 1 U2 8 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD DEC PY 2012 VL 107 IS 500 BP 1492 EP 1501 DI 10.1080/01621459.2012.721281 PG 10 WC Statistics & Probability SC Mathematics GA 068VP UT WOS:000313394600018 PM 23293405 ER PT J AU Hsieh, DT Pfeifer, HH Thiele, EA AF Hsieh, David T. Pfeifer, Heidi H. Thiele, Elizabeth A. TI Dietary Management of Epilepsy SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material ID GLYCEMIC-INDEX TREATMENT; MODIFIED ATKINS DIET; KETOGENIC DIET; CHILDHOOD EPILEPSY; EFFICACY C1 [Hsieh, David T.; Pfeifer, Heidi H.; Thiele, Elizabeth A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Hsieh, DT (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM david.hsieh@us.af.mil NR 11 TC 2 Z9 2 U1 0 U2 4 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD DEC 1 PY 2012 VL 86 IS 11 BP 1000 EP + PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 047YL UT WOS:000311877300006 PM 23198664 ER PT J AU Atlas, SJ Ashburner, JM Chang, YC Lester, WT Barry, MJ Grant, RW AF Atlas, Steven J. Ashburner, Jeffrey M. Chang, Yuchiao Lester, William T. Barry, Michael J. Grant, Richard W. TI Population-Based Breast Cancer Screening in a Primary Care Network SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID INCREASE RECOMMENDATION; COLORECTAL CANCERS; PATIENT REMINDERS; MAMMOGRAPHY; INTERVENTIONS; PROVIDERS; QUALITY; MODEL; COMMUNICATION; METAANALYSIS AB Objectives:To assess the ability of a health information technology system to facilitate population-based breast cancer screening. Study Design: Cohort study with 2-year follow-up after a 1-year cluster randomized trial. Methods: Study population was women 42 to 69 years old receiving care within a 12-practice primary care network. The management informatics system (1) identified women overdue for mammograms, (2) connected them to primary care providers using a web-based tool, (3) created automatically generated outreach letters for patients specified by providers, (4) monitored for subsequent mammography scheduling and completion, and (5) provided practice delegates with a list of women remaining unscreened for reminder phone calls. Eligible women overdue for a mammogram during a 1-year study period included those overdue at study start (prevalent cohort) and those who became overdue during follow-up (incident cohort).The main outcome measure was mammography completion rates over 3 years. Results: Among 32,688 eligible women, 9795 (30%) were overdue for screening (4487 intervention, 5308 control). Intervention patients were somewhat younger, more likely to be non-Hispanic white, and more likely to have health insurance compared with control patients. Adjusted completion rates in the prevalent cohort In = 6697) were significantly higher among intervention patients after 3 years (51.7% vs 45.8%; P = .0021. For patients in the incident cohort (n = 3098), adjusted completion rates after 2 years were 53.8% versus 48.7%, respectively (P = .052). Conclusions: Population-based informatics systems can enable sustained increases in mammography screening rates beyond rates seen with office-based visit reminders. (Am J Manag Care. 2012;18(12):821-829) C1 [Atlas, Steven J.; Ashburner, Jeffrey M.; Chang, Yuchiao; Barry, Michael J.; Grant, Richard W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gen Med Div,Med Serv, Boston, MA 02114 USA. [Lester, William T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Comp Sci Lab, Boston, MA 02114 USA. RP Atlas, SJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gen Med Div,Med Serv, 50 Staniford St, Boston, MA 02114 USA. EM satlas@partners.org OI Lester, William/0000-0003-4086-9280; Grant, Richard/0000-0002-6164-8025 FU National Cancer Institute [NCI 1 R21 CA121908]; Agency for Healthcare Research and Quality [AHRQ R18 HS018161] FX Grant funding was provided by the National Cancer Institute (NCI 1 R21 CA121908) and by institutional support through the Massachusetts General Hospital Primary Care Operations Improvement program.; Drs Atlas and Grant are supported by a grant from the Agency for Healthcare Research and Quality (AHRQ R18 HS018161). The other authors. (JMA, YC, WTL, MJB) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. NR 26 TC 6 Z9 6 U1 0 U2 4 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 DEC PY 2012 VL 18 IS 12 BP 821 EP 829 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 062JO UT WOS:000312916300005 PM 23286611 ER PT J AU Unni, US Raj, T Sambashivaiah, S Kuriyan, R Uthappa, S Vaz, M Regan, MM Kurpad, AV AF Unni, Uma S. Raj, Tony Sambashivaiah, Sucharita Kuriyan, Rebecca Uthappa, Sheila Vaz, Mario Regan, Meredith M. Kurpad, Anura V. TI The effect of a controlled 8-week metabolic ward based lysine supplementation on muscle function, insulin sensitivity and leucine kinetics in young men SO CLINICAL NUTRITION LA English DT Article DE Indian adults; Lysine requirement; Skeletal muscle; Muscle strength; Insulin sensitivity ID AMINO-ACID OXIDATION; ASIAN INDIAN MEN; BODY-COMPOSITION; PROTEIN-SYNTHESIS; BALANCE TECHNIQUE; ELDERLY-MEN; MASS; RESISTANCE; GLUCOSE; REQUIREMENTS AB Background & aims: The 2007 FAO/WHO/UNU lysine requirement is 30 mg kg(-1) d(-1). Developing country populations may be at risk of lysine deficiency, with effects on muscle and its function. The effect of an 8 wk lysine supplementation diet on muscle mass and function was assessed. Methods: Healthy, under and well-nourished men were studied before and after 8 wk, during which low (n = 20) and high (n = 20) lysine diets were consumed. The low lysine diets (similar to 25 and similar to 40 mg kg(-1) d(-1) for under and well-nourished respectively) were based on the subjects' habitual lysine intake, while the high lysine diet supplied 80 mg kg(-1) d(-1) Anthropometry, muscle function, insulin sensitivity (IS) and leucine kinetics were measured before and after the experimental period. Results: The high lysine diet had a small positive effect (about +7.5%) on muscle strength, but no effect on other parameters. Over the 8 wk period in the whole group, the change in muscle strength correlated with the change in muscle mass (r = 0.5, P = 0.001), while the change in muscle mass correlated with the change in IS (r = 0.3, P = 0.04), but there were no intake specific differences. Conclusion: Over an 8 wk controlled feeding period, an intake of 80 mg lysine kg(-1) d(-1) had a small positive effect on muscle strength, but no other effects. (C) 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. C1 [Unni, Uma S.; Raj, Tony; Sambashivaiah, Sucharita; Kuriyan, Rebecca; Vaz, Mario; Kurpad, Anura V.] St Johns Natl Acad Hlth Sci, St Johns Res Inst, Div Nutr, Bangalore 560034, Karnataka, India. [Unni, Uma S.; Uthappa, Sheila] St Johns Med Coll, Dept Biochem, Bangalore 560034, Karnataka, India. [Regan, Meredith M.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Kurpad, AV (reprint author), St Johns Natl Acad Hlth Sci, St Johns Res Inst, Div Nutr, Bangalore 560034, Karnataka, India. EM uma@sjri.res.in; tonyraj@sjri.res.in; sucharita.dr@gmail.com; rebecca@sjri.res.in; sheilauthappa@hotmail.com; mariovaz@sjri.res.in; mregan@jimmy.harvard.edu; a.kurpad@sjri.res.in FU Ajinomoto Amino Acid Research Program FX Authors acknowledge the financial support provided by Ajinomoto Amino Acid Research Program, which had no role in study design, in the collection, analysis and interpretation of data. The authors acknowledge the assistance of Dr. G. Ramakrishnan, Dr. S. Shastry and Mr. Vincent in the conduct of these studies. NR 30 TC 0 Z9 0 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0261-5614 J9 CLIN NUTR JI Clin. Nutr. PD DEC PY 2012 VL 31 IS 6 BP 903 EP 910 DI 10.1016/j.clnu.2012.03.008 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 067NH UT WOS:000313301100013 PM 22524975 ER PT J AU Anderson, E Siegel, E White, D Barrett, LF AF Anderson, Eric Siegel, Erika White, Dominique Barrett, Lisa Feldman TI Out of Sight but Not Out of Mind: Unseen Affective Faces Influence Evaluations and Social Impressions SO EMOTION LA English DT Article DE affect; continuous flash suppression; consciousness; person perception ID MEDIAL PREFRONTAL CORTEX; TOP-DOWN FACILITATION; RHESUS-MONKEY; ORBITOFRONTAL CORTEX; BINOCULAR-RIVALRY; VISUAL AWARENESS; FEARFUL FACES; CONNECTIONS; PERCEPTION; EMOTION AB Using Continuous Flash Suppression (CFS), we demonstrated in four experiments that affective information extracted from unseen faces influences both affective and personality judgments of neutral faces. In four experiments, participants judged neutral faces as more pleasant or unpleasant (Studies 1 and 2) or as more or less trustworthy, likable, and attractive (Study 3) or as more or less competent or interpersonally warm (Study 4) when paired with unseen smiling or scowling faces compared to when paired with unseen neutral faces. These findings suggest that affective influences are a normal part of everyday experience and provide evidence for the affective foundations consciousness. Affective misattribution arises even when affective changes occur after a neutral stimulus is presented, demonstrating that these affective influences cannot be explained as a simple semantic priming effect. These findings have implications for understanding the constructive nature of experience, as well as the role of affect in social impressions. C1 [Anderson, Eric; Siegel, Erika; Barrett, Lisa Feldman] Northeastern Univ, Dept Psychol, Boston, MA 02115 USA. [White, Dominique] Boston Coll, Dept Psychol, Chestnut Hill, MA 02167 USA. [Barrett, Lisa Feldman] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Barrett, Lisa Feldman] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. RP Barrett, LF (reprint author), Northeastern Univ, Dept Psychol, 125 Nightingale Hall,360 Huntington Ave, Boston, MA 02115 USA. EM l.barrett@neu.edu OI Anderson, Eric/0000-0002-4215-6308 FU NIH HHS [DP1 OD003312, DP1OD003312] NR 64 TC 16 Z9 16 U1 6 U2 33 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1528-3542 J9 EMOTION JI Emotion PD DEC PY 2012 VL 12 IS 6 BP 1210 EP 1221 DI 10.1037/a0027514 PG 12 WC Psychology, Experimental SC Psychology GA 047YZ UT WOS:000311878700007 PM 22506501 ER PT J AU Maurovich-Horvat, P Schlett, CL Alkadhi, H Nakano, M Otsuka, F Stolzmann, P Scheffel, H Ferencik, M Kriegel, MF Seifarth, H Virmani, R Hoffmann, U AF Maurovich-Horvat, Pal Schlett, Christopher L. Alkadhi, Hatem Nakano, Masataka Otsuka, Fumiyuki Stolzmann, Paul Scheffel, Hans Ferencik, Maros Kriegel, Matthias F. Seifarth, Harald Virmani, Renu Hoffmann, Udo TI The Napkin-Ring Sign Indicates Advanced Atherosclerotic Lesions in Coronary CT Angiography SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE computed tomography; coronary artery disease; histopathology; napkin-ring sign; plaque attenuation pattern; vulnerable coronary plaque ID MULTISLICE COMPUTED-TOMOGRAPHY; INCREMENTAL PROGNOSTIC VALUE; RISK-ASSESSMENT STRATEGIES; MULTIDETECTOR-ROW CT; INTRAVASCULAR ULTRASOUND; NONINVASIVE ASSESSMENT; VULNERABLE PLAQUE; ARTERY-DISEASE; STABLE ANGINA; CULPRIT AB OBJECTIVES This study sought to determine the accuracy of plaque pattern assessment by coronary computed tomography angiography (CCTA) to differentiate between early and advanced atherosclerotic lesions as defined by histology. BACKGROUND A ringlike attenuation pattern of coronary atherosclerotic plaques termed as napkin-ring sign (NRS) was described in CCTA of patients who had acute coronary syndrome. METHODS All procedures were performed in accordance with local and federal regulations and the Declaration of Helsinki. Approval of the local ethics committees was obtained. We investigated 21 coronary arteries of 7 donor hearts. Overall, 611 histological sections were obtained and coregistered with CCTA images. The CCTA cross sections were read in random order for conventional plaque categories (noncalcified [NCP], mixed [MP], calcified [CP]) and plaque patterns (homogenous, heterogeneous with no napkin-ring sign [non-NRS], and heterogeneous with NRS). RESULTS No plaque was detected in 134 (21.9%), NCP in 254 (41.6%), MP in 191 (31.3%), and CP in 32 (5.2%) CCTA cross sections. The NCP and MP were further classified into homogenous plaques (n = 207, 46.5%), non-NRS plaques (n = 200, 44.9%), and NRS plaques (n = 38, 8.6%). The specificities of NCP and MP to identify advanced lesions were moderate (57.9%, 95% confidence interval [CI]: 50.1% to 65.6%, and 72.1%, 95% CI: 64.7% to 79.4%, respectively), which were similar to the homogenous and heterogeneous plaques (62.6%, 95% CI: 54.8% to 70.3%, and 67.3%, 95% CI: 58.6% to 76.1%, respectively). In contrast, the specificity of the NRS to identify advanced lesions was excellent (98.9%, 95% CI: 97.6% to 100%). The diagnostic performance of the pattern-based scheme to identify advanced lesions was significantly better than that of the conventional plaque scheme (area under the curve: 0.761 vs. 0.678, respectively; p = 0.001). CONCLUSIONS The assessment of the plaque pattern improves diagnostic accuracy of CCTA to identify advanced atherosclerotic lesions. The CCTA finding of NRS has a high specificity and high positive predictive value for the presence of advanced lesions. (J Am Coll Cardiol Img 2012; 5: 1243-52) (C) 2012 by the American College of Cardiology Foundation C1 [Maurovich-Horvat, Pal; Schlett, Christopher L.; Alkadhi, Hatem; Stolzmann, Paul; Scheffel, Hans; Ferencik, Maros; Kriegel, Matthias F.; Seifarth, Harald; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, Boston, MA 02114 USA. [Maurovich-Horvat, Pal; Schlett, Christopher L.; Alkadhi, Hatem; Stolzmann, Paul; Scheffel, Hans; Ferencik, Maros; Kriegel, Matthias F.; Seifarth, Harald; Hoffmann, Udo] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Maurovich-Horvat, Pal] Semmelweis Univ, Ctr Heart, Budapest, Hungary. [Nakano, Masataka; Otsuka, Fumiyuki; Virmani, Renu] CV Path Inst Inc, Gaithersburg, MD USA. RP Hoffmann, U (reprint author), Massachusetts Gen Hosp, Cardiac MR PET CT Program, Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org OI Maurovich-Horvat, Pal/0000-0003-0885-736X FU GE Healthcare; Deutsche Forschungsgemeinschaft [DFG Se 2029/1-1]; Terumo Corporation; [TAMOP-4.2.1/B-09/1/KMR-2010-0001] FX From the *Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; dagger Heart Center, Semmelweis University, Budapest, Hungary; and the double dagger CV Path Institute Inc., Gaithersburg, Maryland. This work was supported by an unrestricted grant from GE Healthcare. Dr. Maurovich-Horvat received support from grant no. TAMOP-4.2.1/B-09/1/KMR-2010-0001. Dr. Seifarth was supported by a grant from Deutsche Forschungsgemeinschaft (grant no. DFG Se 2029/1-1). Dr. Virmani has been a consultant to Terumo Corporation, from whom he has received research grant support. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. NR 45 TC 37 Z9 39 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD DEC PY 2012 VL 5 IS 12 BP 1243 EP 1252 DI 10.1016/j.jcmg.2012.03.019 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 066WF UT WOS:000313251400009 PM 23236975 ER PT J AU Simmons-Stern, NR Deason, RG Brandler, BJ Frustace, BS O'Connor, MK Ally, BA Budson, AE AF Simmons-Stern, Nicholas R. Deason, Rebecca G. Brandler, Brian J. Frustace, Bruno S. O'Connor, Maureen K. Ally, Brandon A. Budson, Andrew E. TI Music-based memory enhancement in Alzheimer's Disease: Promise and limitations SO NEUROPSYCHOLOGIA LA English DT Article DE Alzheimer's disease; Recognition memory; Music; Mnemonics; Familiarity; Recollection ID MILD COGNITIVE IMPAIRMENT; FALSE RECOGNITION; OLDER-ADULTS; NEURAL BASIS; DEMENTIA; FAMILIARITY; RECOLLECTION; DIAGNOSIS; PICTURES; FLUENCY AB In a previous study (Simmons-Stern, Budson & Ally, 2010), we found that patients with Alzheimer's disease (AD) better recognized visually presented lyrics when the lyrics were also sung rather than spoken at encoding. The present study sought to further investigate the effects of music on memory in patients with AD by making the content of the song lyrics relevant for the daily life of an older adult and by examining how musical encoding alters several different aspects of episodic memory. Patients with AD and healthy older adults studied visually presented novel song lyrics related to instrumental activities of daily living (IADL) that were accompanied by either a sung or a spoken recording. Overall, participants performed better on a memory test of general lyric content for lyrics that were studied sung as compared to spoken. However, on a memory test of specific lyric content, participants performed equally well for sung and spoken lyrics. We interpret these results in terms of a dual-process model of recognition memory such that the general content questions represent a familiarity-based representation that is preferentially sensitive to enhancement via music, while the specific content questions represent a recollection-based representation unaided by musical encoding. Additionally, in a test of basic recognition memory for the audio stimuli, patients with AD demonstrated equal discrimination for sung and spoken stimuli. We propose that the perceptual distinctiveness of musical stimuli enhanced metamemorial awareness in AD patients via a non-selective distinctiveness heuristic, thereby reducing false recognition while at the same time reducing true recognition and eliminating the mnemonic benefit of music. These results are discussed in the context of potential music-based memory enhancement interventions for the care of patients with AD. Published by Elsevier Ltd. C1 [Simmons-Stern, Nicholas R.; Deason, Rebecca G.; Brandler, Brian J.; Frustace, Bruno S.; O'Connor, Maureen K.; Budson, Andrew E.] VA Boston Healthcare Syst, Ctr Translat Cognit Neurosci, Boston, MA 02130 USA. [Simmons-Stern, Nicholas R.; Deason, Rebecca G.; Brandler, Brian J.; Frustace, Bruno S.; O'Connor, Maureen K.; Budson, Andrew E.] Boston Univ, Sch Med, Dept Neurol, Alzheimers Dis Ctr, Boston, MA 02118 USA. [O'Connor, Maureen K.] Bedford Vet Adm Hosp, Dept Psychol, Bedford, MA USA. [Ally, Brandon A.] Vanderbilt Univ, Dept Neurol, Nashville, TN USA. [Ally, Brandon A.] Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. [Ally, Brandon A.] Vanderbilt Univ, Dept Psychiat, Nashville, TN USA. RP Deason, RG (reprint author), VA Boston Healthcare Syst, Ctr Translat Cognit Neurosci, 150 S Huntington Ave,Mailstop 151-C, Boston, MA 02130 USA. EM rdeason@bu.edu OI Ally, Brandon/0000-0002-6034-7968 FU National Institute on Aging [R01 AG025815, K23 AG031925, P30 AG13846]; Department of Veterans Affairs, Veterans Health Administration FX This research was supported by National Institute on Aging grants R01 AG025815 (AEB), K23 AG031925 (BAA), P30 AG13846 (AEB), and a Department of Veterans Affairs, Veterans Health Administration, VISN 1 Early Career Development Award to RGD. This material is also the result of work supported with resources and the use of facilities at the VA Boston Healthcare System, Boston, MA We would additionally like to thank our vocalist Anna Miller, and Levi Miller for his help with data processing. NR 50 TC 14 Z9 15 U1 2 U2 83 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 EI 1873-3514 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD DEC PY 2012 VL 50 IS 14 BP 3295 EP 3303 DI 10.1016/j.neuropsychologia.2012.09.019 PG 9 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 065IT UT WOS:000313142700015 PM 23000133 ER PT J AU Wang, H Jurado, KA Wu, XL Shun, MC Li, X Ferris, AL Smith, SJ Patel, PA Fuchs, JR Cherepanov, P Kvaratskhelia, M Hughes, SH Engelman, A AF Wang, Hao Jurado, Kellie A. Wu, Xiaolin Shun, Ming-Chieh Li, Xiang Ferris, Andrea L. Smith, Steven J. Patel, Pratiq A. Fuchs, James R. Cherepanov, Peter Kvaratskhelia, Mamuka Hughes, Stephen H. Engelman, Alan TI HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75 knockout cells but does not contribute to the antiviral activity of a potent LEDGF/p75-binding site integrase inhibitor SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PREINTEGRATION COMPLEX-FORMATION; RETROVIRAL DNA INTEGRATION; SMALL-MOLECULE INHIBITORS; TYPE-1 REPLICATION; CHROMATIN-BINDING; COACTIVATOR P75; HUMAN GENOME; IN-VITRO; DOMAIN AB The binding of integrase (IN) to lens epithelium-derived growth factor (LEDGF)/p75 in large part determines the efficiency and specificity of HIV-1 integration. However, a significant residual preference for integration into active genes persists in Psip1 (the gene that encodes for LEDGF/p75) knockout (KO) cells. One other cellular protein, HRP2, harbors both the PWWP and IN-binding domains that are important for LEDGF/p75 co-factor function. To assess the role of HRP2 in HIV-1 integration, cells generated from Hdgfrp2 (the gene that encodes for HRP2) and Psip1/Hdgfrp2 KO mice were infected alongside matched control cells. HRP2 depleted cells supported normal infection, while disruption of Hdgfrp2 in Psip1 KO cells yielded additional defects in the efficiency and specificity of integration. These deficits were largely restored by ectopic expression of either LEDGF/p75 or HRP2. The double-KO cells nevertheless supported residual integration into genes, indicating that IN and/or other host factors contribute to integration specificity in the absence of LEDGF/p75 and HRP2. Psip1 KO significantly increased the potency of an allosteric inhibitor that binds the LEDGF/p75 binding site on IN, a result that was not significantly altered by Hdgfrp2 disruption. These findings help to rule out the host factor-IN interactions as the primary antiviral targets of LEDGF/p75-binding site IN inhibitors. C1 [Wang, Hao; Jurado, Kellie A.; Shun, Ming-Chieh; Li, Xiang; Engelman, Alan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Wang, Hao; Jurado, Kellie A.; Shun, Ming-Chieh; Li, Xiang; Engelman, Alan] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Wu, Xiaolin] SAIC Frederick Inc, Lab Mol Technol, Frederick, MD 21702 USA. [Ferris, Andrea L.; Smith, Steven J.; Hughes, Stephen H.] Frederick Natl Lab Canc Res, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Patel, Pratiq A.; Fuchs, James R.] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. [Cherepanov, Peter] Canc Res UK, London Res Inst, Clare Hall Labs, S Mimms EN6 3LD, Herts, England. [Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Engelman, A (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. EM alan_engelman@dfci.harvard.edu RI wang, hao/O-6217-2014; Cherepanov, Peter/F-6859-2010 OI Cherepanov, Peter/0000-0002-0634-538X FU US National Institutes of Health (NIH) [AI039394, AI081581, AI097044]; National Cancer Institute's Intramural Center for Cancer Research; UK Medical Research Council [G1000917] FX US National Institutes of Health (NIH) [AI039394 to A. E., AI081581 to M. K., AI097044 to J.R.F.]; National Cancer Institute's Intramural Center for Cancer Research, which supports the HIV Drug Resistance Program [to S. H. H.]; UK Medical Research Council [G1000917 to P. C.]. Funding for open access charge: US NIH [AI039394]. NR 70 TC 34 Z9 34 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD DEC PY 2012 VL 40 IS 22 BP 11518 EP 11530 DI 10.1093/nar/gks913 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 069DG UT WOS:000313414800036 PM 23042676 ER PT J AU Canolty, RT Ganguly, K Carmena, JM AF Canolty, Ryan T. Ganguly, Karunesh Carmena, Jose M. TI Task-Dependent Changes in Cross-Level Coupling between Single Neurons and Oscillatory Activity in Multiscale Networks SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID FIELD POTENTIAL OSCILLATIONS; PRIMATE MOTOR CORTEX; SENSORIMOTOR CORTEX; PARIETAL CORTEX; CELL ASSEMBLIES; ORIENTATION SELECTIVITY; GAMMA OSCILLATIONS; PREFRONTAL CORTEX; BETA-OSCILLATIONS; WORKING-MEMORY AB Understanding the principles governing the dynamic coordination of functional brain networks remains an important unmet goal within neuroscience. How do distributed ensembles of neurons transiently coordinate their activity across a variety of spatial and temporal scales? While a complete mechanistic account of this process remains elusive, evidence suggests that neuronal oscillations may play a key role in this process, with different rhythms influencing both local computation and long-range communication. To investigate this question, we recorded multiple single unit and local field potential (LFP) activity from microelectrode arrays implanted bilaterally in macaque motor areas. Monkeys performed a delayed center-out reach task either manually using their natural arm (Manual Control, MC) or under direct neural control through a brain-machine interface (Brain Control, BC). In accord with prior work, we found that the spiking activity of individual neurons is coupled to multiple aspects of the ongoing motor beta rhythm (10-45 Hz) during both MC and BC, with neurons exhibiting a diversity of coupling preferences. However, here we show that for identified single neurons, this beta-to-rate mapping can change in a reversible and task-dependent way. For example, as beta power increases, a given neuron may increase spiking during MC but decrease spiking during BC, or exhibit a reversible shift in the preferred phase of firing. The within-task stability of coupling, combined with the reversible cross-task changes in coupling, suggest that task-dependent changes in the beta-to-rate mapping play a role in the transient functional reorganization of neural ensembles. We characterize the range of task-dependent changes in the mapping from beta amplitude, phase, and inter-hemispheric phase differences to the spike rates of an ensemble of simultaneously-recorded neurons, and discuss the potential implications that dynamic remapping from oscillatory activity to spike rate and timing may hold for models of computation and communication in distributed functional brain networks. C1 [Canolty, Ryan T.; Carmena, Jose M.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Ganguly, Karunesh] San Francisco VA Med Ctr, San Francisco, CA USA. [Ganguly, Karunesh] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Carmena, Jose M.] Univ Calif Berkeley, UCB UCSF Joint Grad Grp Bioengn, Berkeley, CA 94720 USA. RP Canolty, RT (reprint author), Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. EM carmena@eecs.berkeley.edu FU NIH NINDS [1K99NS070627-01A1]; NSF [CBET-0954243]; DARPA [N66001-10-C-2008] FX This work was supported by grants from the NIH NINDS (1K99NS070627-01A1 to RTC), NSF (CBET-0954243 to JMC), and a DARPA Contract N66001-10-C-2008 to JMC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 80 TC 15 Z9 15 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2012 VL 8 IS 12 AR e1002809 DI 10.1371/journal.pcbi.1002809 PG 23 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 062EI UT WOS:000312901500016 PM 23284276 ER PT J AU Sze, JA Goodkind, MS Gyurak, A Levenson, RW AF Sze, Jocelyn A. Goodkind, Madeleine S. Gyurak, Anett Levenson, Robert W. TI Aging and Emotion Recognition: Not Just a Losing Matter SO PSYCHOLOGY AND AGING LA English DT Article DE aging; emotion recognition; empathic accuracy; social interaction ID AGE-RELATED DIFFERENCES; ADULT LIFE-SPAN; EMPATHIC ACCURACY; FACIAL EXPRESSIONS; SOCIOEMOTIONAL SELECTIVITY; PHYSIOLOGICAL LINKAGE; MARITAL INTERACTION; GENDER-DIFFERENCES; SOCIAL COGNITION; SEX-DIFFERENCES AB Past studies on emotion recognition and aging have found evidence of age-related decline when emotion recognition was assessed by having participants detect single emotions depicted in static images of full or partial (e.g., eye region) faces. These tests afford good experimental control but do not capture the dynamic nature of real-world emotion recognition, which is often characterized by continuous emotional judgments and dynamic multimodal stimuli. Research suggests that older adults often perform better under conditions that better mimic real-world social contexts. We assessed emotion recognition in young, middle-aged, and older adults using two traditional methods (single emotion judgments of static images of faces and eyes) and an additional method in which participants made continuous emotion judgments of dynamic, multimodal stimuli (videotaped interactions between young, middle-aged, and older couples). Results revealed an Age x Test interaction. Largely consistent with prior research, we found some evidence that older adults performed worse than young adults when judging single emotions from images of faces (for sad and disgust faces only) and eyes (for older eyes only), with middle-aged adults falling in between. In contrast, older adults did better than young adults on the test involving continuous emotion judgments of dyadic interactions, with middle-aged adults falling in between. In tests in which target stimuli differed in age, emotion recognition was not facilitated by an age match between participant and target. These findings are discussed in terms of theoretical and methodological implications for the study of aging and emotional processing. C1 [Sze, Jocelyn A.] San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA. [Goodkind, Madeleine S.] VA Palo Alto Hlth Care Syst, Sierra Pacific Mental Illness Res Educ & Clin Ctr, Palo Alto, CA USA. [Goodkind, Madeleine S.; Gyurak, Anett] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Gyurak, Anett] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. [Levenson, Robert W.] Univ Calif Berkeley, Inst Personal & Social Res, Dept Psychol, Berkeley, CA 94720 USA. RP Levenson, RW (reprint author), Univ Calif Berkeley, Inst Personal & Social Res, Dept Psychol, 4143 Tolman Hall MC 5050, Berkeley, CA 94720 USA. EM boblev@socrates.berkeley.edu FU NIA NIH HHS [R01 AG041762, R37 AG017766, R37-AG017766] NR 82 TC 14 Z9 14 U1 2 U2 39 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD DEC PY 2012 VL 27 IS 4 BP 940 EP 950 DI 10.1037/a0029367 PG 11 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 067PB UT WOS:000313306500020 PM 22823183 ER PT J AU Gilman, SE AF Gilman, Stephen E. TI The successes and challenges of life course epidemiology: A commentary on Gibb, Fergusson and Horwood (2012) SO SOCIAL SCIENCE & MEDICINE LA English DT Editorial Material DE Life course epidemiology; Mental health; Social inequality; Income ID SOCIOECONOMIC-STATUS; ADULT HEALTH; UNNECESSARY ADJUSTMENT; DEVELOPMENTAL ORIGINS; SENSITIVITY-ANALYSIS; FAMILY DISRUPTION; MAJOR DEPRESSION; COHORT PROFILE; HEART-DISEASE; RISK C1 [Gilman, Stephen E.] Harvard Univ, Dept Soc Human Dev & Hlth, Sch Publ Hlth, Boston, MA 02115 USA. [Gilman, Stephen E.] Harvard Univ, Dept Epidemiol, Sch Publ Hlth, Boston, MA 02115 USA. [Gilman, Stephen E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Gilman, SE (reprint author), Harvard Univ, Dept Soc Human Dev & Hlth, Sch Publ Hlth, 677 Huntington Ave, Boston, MA 02115 USA. EM sgilman@hsph.harvard.edu RI Gilman, Stephen/E-7632-2010 OI Gilman, Stephen/0000-0002-8331-6419 FU NIMH NIH HHS [MH087544] NR 56 TC 4 Z9 4 U1 0 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD DEC PY 2012 VL 75 IS 12 BP 2124 EP 2128 DI 10.1016/j.socscimed.2012.08.007 PG 5 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 060DX UT WOS:000312757800009 PM 22959838 ER PT J AU Caspi, CE Kawachi, I Subramanian, SV Adamkiewicz, G Sorensen, G AF Caspi, Caitlin E. Kawachi, Ichiro Subramanian, S. V. Adamkiewicz, Gary Sorensen, Glorian TI The relationship between diet and perceived and objective access to supermarkets among low-income housing residents (vol 75, pg 1254, 2012) SO SOCIAL SCIENCE & MEDICINE LA English DT Correction C1 [Caspi, Caitlin E.; Kawachi, Ichiro; Subramanian, S. V.; Adamkiewicz, Gary; Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02114 USA. [Adamkiewicz, Gary; Sorensen, Glorian] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. RP Caspi, CE (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Kresge 7th Floor,677 Huntingon Ave, Boston, MA 02114 USA. EM caitlincaspi@gmail.com NR 1 TC 0 Z9 0 U1 3 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD DEC PY 2012 VL 75 IS 12 BP 2540 EP 2540 DI 10.1016/j.socscimed.2012.09.002 PG 1 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 060DX UT WOS:000312757800061 ER PT J AU Gordon, JA AF Gordon, James A. TI Reflections on the Consensus Process: A Leadership Role for Emergency Medicine in Educational Scholarship and Practice Across Health Care SO ACADEMIC EMERGENCY MEDICINE LA English DT Editorial Material ID SIMULATION AB In just a few decades, emergency medicine (EM) has assumed a leadership role in medical education across many academic medical centers. This rapid evolution suggests medical education as a natural priority area for EM scholarship. This year's Academic Emergency Medicine consensus conference provides an ideal forum to focus on educational research as a core element of the specialty's academic portfolio. C1 [Gordon, James A.] Massachusetts Gen Hosp, MGH Learning Lab, Boston, MA 02114 USA. [Gordon, James A.] Massachusetts Gen Hosp, Div Med Simulat, Dept Emergency Med, Boston, MA 02114 USA. [Gordon, James A.] Harvard Univ, Sch Med, Gilbert Program Med Simulat, Boston, MA USA. RP Gordon, JA (reprint author), Massachusetts Gen Hosp, MGH Learning Lab, Boston, MA 02114 USA. EM jgordon3@partners.org NR 11 TC 2 Z9 2 U1 1 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 EI 1553-2712 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2012 VL 19 IS 12 SI SI BP 1333 EP 1335 DI 10.1111/acem.12020 PG 3 WC Emergency Medicine SC Emergency Medicine GA 059XX UT WOS:000312740100004 PM 23216790 ER PT J AU Choo, EK Fernandez, R Hayden, EM Schneider, JI Clyne, B Ginsburg, S Gruppen, LD AF Choo, Esther K. Fernandez, Rosemarie Hayden, Emily M. Schneider, Jeffrey I. Clyne, Brian Ginsburg, Shiphra Gruppen, Larry D. TI An Agenda for Increasing Grant Funding of Emergency Medicine Education Research SO ACADEMIC EMERGENCY MEDICINE LA English DT Article ID SCHOOL-OF-MEDICINE; RESEARCH PRODUCTIVITY; FACULTY-DEVELOPMENT; CRITICAL-APPRAISAL; PROGRAM; PUBLICATIONS; OPPORTUNITY; OUTCOMES; QUALITY; GUIDE AB Funding is a perennial challenge for medical education researchers. Through a consensus process, the authors developed a multifaceted agenda for increasing funding of education research in emergency medicine (EM). Priority agenda items include developing resources to increase the competitiveness of medical education research faculty in grant applications, identifying means by which departments may bolster their faculty's grant writing success, taking long-term steps to increase the number of grants available to education researchers in the field, and encouraging a shift in cultural attitudes toward education research. C1 [Choo, Esther K.; Clyne, Brian] Brown Univ, Dept Emergency Med, Warren Alpert Med Sch, Providence, RI 02912 USA. [Fernandez, Rosemarie] Univ Washington, Div Emergency Med, Seattle, WA 98195 USA. [Hayden, Emily M.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Schneider, Jeffrey I.] Boston Univ, Sch Med, Dept Emergency Med, Boston Med Ctr, Boston, MA 02118 USA. [Ginsburg, Shiphra] Univ Toronto, Dept Med, Wilson Ctr Res Educ, Fac Med, Toronto, ON, Canada. [Gruppen, Larry D.] Univ Michigan, Sch Med, Dept Med Educ, Ann Arbor, MI USA. RP Choo, EK (reprint author), Brown Univ, Dept Emergency Med, Warren Alpert Med Sch, Providence, RI 02912 USA. EM esther_choo@brown.edu RI Ginsburg, Shiphra/C-1695-2008; OI Ginsburg, Shiphra/0000-0002-4595-6650; Schneider, Jeffrey/0000-0002-7861-2854; Choo, Esther/0000-0001-8847-5745; Gruppen, Larry/0000-0002-2107-0126 NR 39 TC 1 Z9 1 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD DEC PY 2012 VL 19 IS 12 SI SI BP 1434 EP 1441 DI 10.1111/acem.12041 PG 8 WC Emergency Medicine SC Emergency Medicine GA 059XX UT WOS:000312740100018 PM 23252424 ER PT J AU Shiwaku, Y Anada, T Yamazaki, H Honda, Y Morimoto, S Sasaki, K Suzuki, O AF Shiwaku, Y. Anada, T. Yamazaki, H. Honda, Y. Morimoto, S. Sasaki, K. Suzuki, O. TI Structural, morphological and surface characteristics of two types of octacalcium phosphate-derived fluoride-containing apatitic calcium phosphates SO ACTA BIOMATERIALIA LA English DT Article DE Octacalcium phosphate; Fluoride; Hydrolysis; Fluoride-containing hydroxyapatite; Scaffold materials ID IN-VITRO; HYDROXYAPATITE COATINGS; THERMODYNAMIC ANALYSIS; BIOLOGICAL RESPONSES; SPRAYED COATINGS; BONE-FORMATION; ENAMEL; HYDROLYSIS; CELLS; SOLUBILITY AB Octacalcium phosphate (OCP) has been reported to stimulate bone regeneration during hydrolysis into hydroxyapatite (HA). The present study was designed to characterize structural, morphological and surface properties of fluoride-containing apatitic calcium phosphates (CaP) obtained through OCP hydrolysis or direct precipitation of OCP in the presence of 12-230 ppm of fluoride (F). The products were characterized by chemical analysis, X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), selected area electron diffraction (SAED) and Fourier transform infrared spectroscopy (FTIR) as well as measurements of surface area, solubility, osteoblastic activities and bovine serum albumin (BSA) adsorption. XRD analysis re-confirmed that both preparations yielded more apatitic CaP with a higher concentration of F. However, the co-precipitated products (CF-CaP) maintained the properties of OCP, in particular the solubility, whereas the hydrolysis products (HF-CaP) had the characteristics of fluoridated apatite. The crystals of plate-like OCP were changed to the crystals of rod-like CF-CaP and small irregular HF-CaP with the advance of the hydrolysis. The SAED analysis detected both OCP and apatite crystals even in the most hydrolyzed CF-CaP. Mouse bone marrow stromal ST-2 cells grew better on CF-CaP compared with HF-CaP. BSA adsorption was inhibited on HF-CaP more than on CF-CaP. These results show that OCP produces physicochemically distinct apatitic fluoridated CaP during hydrolysis, regarding the structure, the crystal morphology and the protein adsorption, depending on the fluoride introduction route, which provides biologically interesting material. (c) 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. C1 [Shiwaku, Y.; Anada, T.; Honda, Y.; Morimoto, S.; Suzuki, O.] Tohoku Univ, Grad Sch Dent, Div Craniofacial Funct Engn, Aoba Ku, Sendai, Miyagi 9808575, Japan. [Shiwaku, Y.; Sasaki, K.] Tohoku Univ, Grad Sch Dent, Div Adv Prosthet Dent, Aoba Ku, Sendai, Miyagi 9808575, Japan. [Yamazaki, H.] Forsyth Inst, Dept Biomineralizat, Cambridge, MA 02142 USA. RP Suzuki, O (reprint author), Tohoku Univ, Grad Sch Dent, Div Craniofacial Funct Engn, Aoba Ku, 4-1 Sehyo Machi, Sendai, Miyagi 9808575, Japan. EM suzuki-o@m.tohoku.ac.jp FU Ministry of Education, Science, Sports and Culture of Japan [23390450, 23659909, 23106010]; Iketani Science and Technology Foundation FX This study was supported in part by Grants-in-aid (23390450, 23659909 and 23106010) from the Ministry of Education, Science, Sports and Culture of Japan and Iketani Science and Technology Foundation. The authors thank Professor Hiroshi Masumoto at The Center for Interdisciplinary Research (CIR), Tohoku University, for his direction in observing the present materials by FE-SEM. NR 56 TC 17 Z9 17 U1 2 U2 46 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 J9 ACTA BIOMATER JI Acta Biomater. PD DEC PY 2012 VL 8 IS 12 BP 4417 EP 4425 DI 10.1016/j.actbio.2012.07.041 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 060GR UT WOS:000312765000027 PM 22868193 ER PT J AU Jain, RK AF Jain, Rakesh K. TI Delivery of molecular and cellular medicine to solid tumors SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Tumor microcirculation; Angiogenesis; Blood flow; Vascular permeability; Diffusion and convection; Receptor-ligand binding; Interstitial pressure; Lymphatics; Cell adhesion and deformation; Cancer detection and treatment ID INTERSTITIAL FLUID PRESSURE; ENDOTHELIAL GROWTH-FACTOR; NATURAL-KILLER-CELLS; VASCULAR-PERMEABILITY FACTOR; COLON ADENOCARCINOMA XENOGRAFT; POSITRON-EMISSION-TOMOGRAPHY; ENZYME-CONJUGATED ANTIBODIES; INDUCED LEUKOCYTE ADHESION; HUMAN-MELANOMA XENOGRAFTS; NECROSIS-FACTOR-ALPHA AB To reach cancer cells in a tumor, a blood-borne therapeutic molecule or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium, and finally migrate through the interstitium. Unfortunately, tumors often develop in ways that hinder each of these steps. Our research goals are to analyze each of these steps experimentally and theoretically, and then integrate the resulting information in a unified theoretical framework. This paradigm of analysis and synthesis has allowed us to obtain a better understanding of physiological barriers in solid tumors, and to develop novel strategies to exploit and/or to overcome these barriers for improved cancer detection and treatment. (C) 2012 Elsevier B.V. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. RP Jain, RK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu FU National Cancer Institute; National Science Foundation; American Cancer Society FX I thank Carol Lyons, Larry Baxter and Stuart Friedrich for their help with the references, Lance Munn for his help with Figures 1-3, Fan Yuan with Figures 4 and 7, Gabriel Helmlinger with Figure 6, David Berk with Figure 8, Marc Dellian with Figure 9, Larry Baxter with Figure 10, Paolo Netti with Figure 11, and Yves Boucher with Table 2. Research described here was primarily supported by grants from the National Cancer Institute, the National Science Foundation and the American Cancer Society. NR 150 TC 40 Z9 41 U1 2 U2 65 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X EI 1872-8294 J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD DEC PY 2012 VL 64 SU S BP 353 EP 365 DI 10.1016/j.addr.2012.09.011 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 058EK UT WOS:000312616700031 PM 24511174 ER PT J AU Thomas, B Mimiaga, MJ Mayer, KH Closson, EE Johnson, CV Menon, S Mani, J Vijaylakshmi, R Dilip, M Betancourt, T Safren, SA AF Thomas, Beena Mimiaga, Matthew J. Mayer, Kenneth H. Closson, Elizabeth E. Johnson, Carey V. Menon, Sunil Mani, Jamuna Vijaylakshmi, R. Dilip, Meenalochini Betancourt, Theresa Safren, Steven A. TI ENSURING IT WORKS: A COMMUNITY-BASED APPROACH TO HIV PREVENTION INTERVENTION DEVELOPMENT FOR MEN WHO HAVE SEX WITH MEN IN CHENNAL INDIA SO AIDS EDUCATION AND PREVENTION LA English DT Article ID IDENTIFIED MEN; RISK; PREVALENCE; BEHAVIOR; MUMBAI; MSM; INFECTION; VIOLENCE; STIGMA; SAMPLE AB Men who have sex with men (MSM) in India have an HIV seroprevalence 22 times greater than the country's general population and face unique challenges that may hinder the effectiveness of current HIV prevention efforts. To obtain an understanding of the logistical and sociocultural barriers MSM experience while accessing HIV prevention services, focus groups and key informant interviews were conducted with 55 MSM in Chennai, India. Qualitative data were analyzed using descriptive qualitative content analysis. Sixty-five percent of participants identified as kothi (receptive partners), 9% as panthi (insertive partners), 22% as double decker (receptive and insertive), and 4% did not disclose. Themes included: (a) fatigue with current HIV risk reduction messages; (b) increased need for non-judgmental and confidential services; and (c) inclusion of content that acknowledges individual and structural-level determinants of risk such as low self-esteem, depression, and social discrimination. MSM interventions may benefit from approaches that address multilevel psychosocial factors, including skills building and strategies to foster self-acceptance and increased social support. C1 [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Behav Med Serv,Dept Psychiat, Boston, MA 02114 USA. [Thomas, Beena; Mani, Jamuna; Vijaylakshmi, R.; Dilip, Meenalochini] Indian Council Med Res, TB Res Ctr, Madras, Tamil Nadu, India. [Mimiaga, Matthew J.; Mayer, Kenneth H.; Closson, Elizabeth E.; Johnson, Carey V.; Safren, Steven A.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Mimiaga, Matthew J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02114 USA. [Mayer, Kenneth H.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Infect Dis, Boston, MA 02114 USA. [Menon, Sunil] Sahodaran, Madras, Tamil Nadu, India. [Betancourt, Theresa] Harvard Univ, Sch Publ Hlth, Francois Xavier Bagnoud Ctr Hlth & Human Rights, Boston, MA 02114 USA. RP Mimiaga, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Behav Med Serv,Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM mmimiaga@partners.org FU NIMH NIH HHS [R21 MH085314, R21 MH085314-01] NR 43 TC 10 Z9 10 U1 3 U2 10 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0899-9546 J9 AIDS EDUC PREV JI Aids Educ. Prev. PD DEC PY 2012 VL 24 IS 6 BP 483 EP 499 PG 17 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 058IV UT WOS:000312628200001 PM 23206199 ER PT J AU Psaros, C Barinas, J Robbins, GK Bedoya, CA Safren, SA Park, ER AF Psaros, Christina Barinas, Jennifer Robbins, Gregory K. Bedoya, C. Andres Safren, Steven A. Park, Elyse R. TI Intimacy and Sexual Decision Making: Exploring the Perspective of HIV Positive Women Over 50 SO AIDS PATIENT CARE AND STDS LA English DT Article ID OLDER WOMEN; CLINICAL-TRIAL; BODY-IMAGE; HIV/AIDS; AGE; LIPODYSTROPHY; KNOWLEDGE; ATTITUDES; BEHAVIOR; ADULTS AB Due to advances made in HIV treatment, the population of individuals with HIV over the age of 50 is growing. Aging women face many developmental challenges and some of these challenges, including having or maintaining intimate partner relationships, may be particularly pronounced for aging women living with HIV. However, research exploring the psychosocial needs of aging women with HIV is limited. Thus, the aim of this study was to explore factors that impact intimate partner relationships for older women with HIV. Nineteen women (mean age = 56.79, SD = 4.63 years) referred from Boston-area community organizations and hospitals completed in-depth individual interviews. Forty-seven percent of participants identified themselves as Black/African American, and 37% as White/Caucasian. Average time since diagnosis was 16.32 years (SD = 5.70). Interviews continued until saturation of content was reached. Inclusion criteria included: biologically born female; aged 50 years or older; diagnosis of HIV/AIDS; and English speaking. Qualitative interviews were coded by two raters and content analyses were conducted using NVivo 9 software. The findings are described across the following three main themes: (1) stigma; (2) body image concerns; and (3) the disclosure dilemma. The themes and issues identified by this study may help guide sexual health-related interventions for older HIV-infected women. C1 [Psaros, Christina] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Behav Med Serv,Dept Psychiat, Boston, MA 02114 USA. [Robbins, Gregory K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Infect Dis, Boston, MA 02114 USA. RP Psaros, C (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Behav Med Serv,Dept Psychiat, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM cpsaros@partners.org FU Harvard University Center for AIDS Research (CFAR); NIH [P30 AI060354]; NIAID; NCI; NICHD; NHLBI; NIDA; NIMH; NIA; NCCAM; FIC; OAR FX Dr. Psaros' time was supported by the Harvard University Center for AIDS Research (CFAR), an NIH funded program (P30 AI060354) which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, NCCAM, FIC, and OAR. Additional author time was supported by K01 AI062435 (Robbins), and K24 MH094214 (Safren). NR 38 TC 7 Z9 7 U1 0 U2 17 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 DEC PY 2012 VL 26 IS 12 BP 755 EP 760 DI 10.1089/apc.2012.0256 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 048CB UT WOS:000311886700007 PM 23199193 ER PT J AU O'Neil, CK Hanlon, JT Marcum, ZA AF O'Neil, Christine K. Hanlon, Joseph T. Marcum, Zachary A. TI Adverse Effects of Analgesics Commonly Used by Older Adults With Osteoarthritis: Focus on Non-Opioid and Opioid Analgesics SO AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY LA English DT Review DE adverse drug events; aged; analgesics; osteoarthritis ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; EMERGENCY-DEPARTMENT VISITS; ELDERLY-PATIENTS; KNEE OSTEOARTHRITIS; UNITED-STATES; CYCLO-OXYGENASE-2 INHIBITORS; PHARMACOLOGICAL MANAGEMENT; ACETAMINOPHEN ABSORPTION; MYOCARDIAL-INFARCTION; OARSI RECOMMENDATIONS AB Background: Osteoarthritis (OA) is the most common cause of disability in older adults, and although analgesic use can be helpful, it can also result in adverse drug events. Objective: To review the recent literature to describe potential adverse drug events associated with analgesics commonly used by older adults with OA. Methods: To identify articles for this review, a systematic search of the English-language literature from January 2001 to June 2012 was conducted using PubMed, MEDLINE, EBSCO, and the Cochrane Database of Systematic Reviews for publications related to the medical management of OA. Search terms used were "analgesics," "acetaminophen," "nonsteroidal anti-inflammatory drugs" (NSAIDs), "opioids," "pharmacokinetics," "pharmacodynamics," and "adverse drug events." The search was restricted to those articles that concerned humans aged >= 65 years. A manual search of the reference lists from identified articles and the authors' article files, book chapters, and recent reviews was conducted to identify additional articles. From these, the authors identified those studies that examined analgesic use in older adults. Results: There are limited data to suggest that non-frail elders are more likely than their younger counterparts to develop acetaminophen-induced hepatotoxicity. However, decreased hepatic phase II metabolism in frail elders may result in increased risk of hepatotoxicity. It is now well established that older adults are at higher risk of NSAID-induced gastrointestinal toxicity and renal insufficiency. Insofar as opioids, the data that suggest an increased risk of falls, fractures, or delirium need to be tempered by the potential risk of inadequately treating severe chronic OA-related pain. Conclusions: Acetaminophen is the mainstay frontline analgesic for treating OA-related pain in older adults. NSAIDs should be limited to short-term use only, and for moderate to severe OA-related pain, opioids may be preferable in individuals without substance abuse or dependence issues. (Am J Geriatr Pharmacother. 2012;10: 331-342)(C) 2012 Elsevier HS Journals, Inc. All rights reserved. C1 [O'Neil, Christine K.] Duquesne Univ, Dept Pharm Practice, Sch Pharm, Pittsburgh, PA 15219 USA. [Hanlon, Joseph T.; Marcum, Zachary A.] Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.; Marcum, Zachary A.] Univ Pittsburgh, Geriatr Pharmaceut Outcomes & Geroinformat Res &, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Dept Biomed Informat, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. [Hanlon, Joseph T.; Marcum, Zachary A.] Vet Affairs Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. RP Marcum, ZA (reprint author), Univ Pittsburgh, Sch Med Geriatr, 3471 5th Ave,Ste 500, Pittsburgh, PA 15213 USA. EM zam12@pitt.edu FU National Institute on Aging [R56AG 027017, P30AG024827, T32 AG021885, K07AG033174, R01AG034056, R01AG028050]; National Institute of Nursing Research grant [R01 NR010135]; Agency for Healthcare Research and Quality grants [R01 HS017695, K12 HS019461, R01HS018721]; VA Health Services Research grant [IIR-06-062] FX Supported in part by National Institute on Aging grants and contracts (R56AG 027017, P30AG024827, T32 AG021885, K07AG033174, R01AG034056, and R01AG028050), a National Institute of Nursing Research grant (R01 NR010135), Agency for Healthcare Research and Quality grants (R01 HS017695, K12 HS019461, and R01HS018721), and a VA Health Services Research grant (IIR-06-062). Dr. O'Neil helped with the literature search, study design, data collection, data interpretation, and writing of the manuscript. Dr. Marcum helped with the literature search, table creation, study design, data collection, data interpretation, and writing of the manuscript. Dr. Hanlon helped with the study design, data collection, data interpretation, and writing of the manuscript. NR 67 TC 49 Z9 53 U1 3 U2 27 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 1543-5946 J9 AM J GERIATR PHARMAC JI Am. J. Geriatr. Pharmacother. PD DEC PY 2012 VL 10 IS 6 BP 331 EP 342 DI 10.1016/j.amjopharm.2012.09.004 PG 12 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 064NT UT WOS:000313083000001 PM 23036838 ER PT J AU Egan, CA Marakovitz, SE O'Rourke, JA Osiecki, L Illmann, C Barton, L McLaughlin, E Proujansky, R Royal, J Cowley, H Rangel-Lugo, M Pauls, DL Scharf, JM Mathews, CA AF Egan, Crystelle A. Marakovitz, Susan E. O'Rourke, Julia A. Osiecki, Lisa Illmann, Cornelia Barton, Lauren McLaughlin, Elizabeth Proujansky, Rachel Royal, Justin Cowley, Heather Rangel-Lugo, Martha Pauls, David L. Scharf, Jeremiah M. Mathews, Carol A. CA Tourette Syndrome Assoc Int TI Effectiveness of a Web-Based Protocol for the Screening and Phenotyping of Individuals With Tourette Syndrome for Genetic Studies SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE rapid phenotyping; genome wide association study (GWAS); Internet; recruitment; neuropsychiatric disorder ID GENOME-WIDE ASSOCIATION; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; OBSESSIVE-COMPULSIVE SYMPTOMS; MAJOR DEPRESSIVE DISORDER; PSYCHOMETRIC PROPERTIES; SELF-REPORT; INTERNET; POPULATION; RELIABILITY; FEASIBILITY AB Genome-wide association studies (GWAS) and other emerging technologies offer great promise for the identification of genetic risk factors for complex psychiatric disorders, yet such studies are constrained by the need for large sample sizes. Web-based collection offers a relatively untapped resource for increasing participant recruitment. Therefore, we developed and implemented a novel web-based screening and phenotyping protocol for genetic studies of Tourette syndrome (TS), a childhood-onset neuropsychiatric disorder characterized by motor and vocal tics. Participants were recruited over a 13-month period through the membership of the Tourette Syndrome Association (TSA; n = 28,878). Of the TSA members contacted, 4.3% (1,242) initiated the questionnaire, and 79.5% (987) of these were enrollment eligible. 63.9% (631) of enrolled participants completed the study by submitting phenotypic data and blood specimens. Age was the only variable that predicted study completion; children and young adults were significantly less likely to be study completers than adults 26 and older. Compared to a clinic-based study conducted over the same time period, the web-based method yielded a 60% larger sample. Web-based participants were older and more often female; otherwise, the sample characteristics did not differ significantly. TS diagnoses based on the web-screen demonstrated 100% accuracy compared to those derived from in-depth clinical interviews. Our results suggest that a web-based approach is effective for increasing the sample size for genetic studies of a relatively rare disorder and that our web-based screen is valid for diagnosing TS. Findings from this study should aid in the development of web-based protocols for other disorders. (C) 2012 Wiley Periodicals, Inc. C1 [Egan, Crystelle A.; Rangel-Lugo, Martha; Mathews, Carol A.] Univ Calif San Francisco, Dept Psychiat, Langley Porter Psychiat Inst, San Francisco, CA 94143 USA. [Marakovitz, Susan E.] Integrated Ctr Child Dev, Newton, MA USA. [O'Rourke, Julia A.] Massachusetts Gen Hosp, Dept Pediat, Lurie Ctr Autism, Boston, MA 02114 USA. [O'Rourke, Julia A.] Massachusetts Gen Hosp, Dept Med, Comp Sci Lab, Boston, MA 02114 USA. [Osiecki, Lisa; Illmann, Cornelia; Barton, Lauren; McLaughlin, Elizabeth; Proujansky, Rachel; Royal, Justin; Pauls, David L.; Scharf, Jeremiah M.] Massachusetts Gen Hosp, Psychiat Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. [Illmann, Cornelia; Barton, Lauren; McLaughlin, Elizabeth; Proujansky, Rachel; Royal, Justin; Pauls, David L.; Scharf, Jeremiah M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Cowley, Heather] Tourette Syndrome Assoc, Bayside, NY USA. [Scharf, Jeremiah M.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Scharf, Jeremiah M.] Brigham & Womens Hosp, Div Cognit & Behav Neurol, Boston, MA 02115 USA. RP Egan, CA (reprint author), Univ Calif San Francisco, Dept Psychiat, Langley Porter Psychiat Inst, 401 Parnassus Ave,Box F-0984, San Francisco, CA 94143 USA. EM caegan@my.uri.edu FU National Institute for Neurological Disorders and Stroke (NINDS) [U01 NS40024-S1, U01 NS40024, MH085057]; Tourette Syndrome Association (TSA) FX Grant sponsor: National Institute for Neurological Disorders and Stroke (NINDS); Grant numbers: U01 NS40024-S1, U01 NS40024, MH085057; Grant sponsor: Tourette Syndrome Association (TSA). NR 51 TC 3 Z9 3 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC PY 2012 VL 159B IS 8 BP 987 EP 996 DI 10.1002/ajmg.b.32107 PG 10 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 059SI UT WOS:000312725200011 PM 23090870 ER PT J AU Brown, A Hirsch, R Laor, T Hannon, MJ Levesque, MC Starz, T Francis, K Kwoh, CK AF Brown, Amanda Hirsch, Raphael Laor, Tal Hannon, Michael J. Levesque, Marc C. Starz, Terence Francis, Kimberly Kwoh, C. Kent TI Do patients with juvenile idiopathic arthritis in clinical remission have evidence of persistent inflammation on 3T magnetic resonance imaging? SO ARTHRITIS CARE & RESEARCH LA English DT Article ID EARLY RHEUMATOID-ARTHRITIS; AMERICAN-COLLEGE; SELECT CATEGORIES; FOLLOW-UP; RHEUMATOLOGY/EUROPEAN LEAGUE; DISEASE; CHILDREN; CRITERIA; THERAPY; CLASSIFICATION AB Objective Up to 90% of adults with rheumatoid arthritis (RA) in clinical remission have persistent synovitis and/or bone marrow lesions (BMLs) on magnetic resonance imaging (MRI). MRI findings in patients with juvenile idiopathic arthritis (JIA) in clinical remission have not been described. We utilized 3T MRI with contrast enhancement to examine JIA patients with hand and/or wrist involvement who were in clinical remission and compared them with a cohort of adult RA patients. Methods In total, 11 JIA patients and 10 RA patients with arthritis involving the hands and/or wrists were identified by their primary rheumatologist as being in physician-defined clinical remission, having no signs or symptoms of active arthritis and no medication changes for at least 6 months. A study rheumatologist performed a joint evaluation for tenderness, swelling, and limitation of motion, and study participants self-reported tender joint counts. The participants underwent MRI with intravenous contrast enhancement of 1 hand and wrist with a history of prior symptoms. A pediatric musculoskeletal radiologist blinded to the clinical data scored the MRIs for synovitis, tenosynovitis, and/or BMLs. Results Sixty-three percent of the JIA cohort and 70% of the RA cohort had MRI findings of synovitis, BMLs, and/or tenosynovitis. All pediatric patients with MRI abnormalities had normal physician tender and swollen joint counts. The patients' self-report of painful joint counts did not predict MRI abnormalities. Conclusion Over one-half of the patients in clinical remission had MRI evidence of persistent inflammation, defined as the presence of synovitis, tenosynovitis, or BMLs. A substantial portion of patients with JIA may have subclinical disease despite clinical remission. C1 [Brown, Amanda] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Hirsch, Raphael; Francis, Kimberly] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Hirsch, Raphael; Hannon, Michael J.; Levesque, Marc C.; Starz, Terence; Francis, Kimberly; Kwoh, C. Kent] Univ Pittsburgh, Pittsburgh, PA USA. [Laor, Tal] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Laor, Tal] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Kwoh, C. Kent] VA Pittsburgh Healthcare, Pittsburgh, PA USA. RP Kwoh, CK (reprint author), S702 BSTWR,200 Lothrop St, Pittsburgh, PA 15206 USA. EM kwoh@pitt.edu FU Children's Hospital of Pittsburgh; NIH [R21-AR-056690, T32-AR-052282, P60-AR-054731] FX Supported in part by the Children's Hospital of Pittsburgh. Dr. Hirsch's work was supported by the NIH (grants R21-AR-056690 and T32-AR-052282). Dr. Kwoh's work was supported by the NIH (grant P60-AR-054731). NR 45 TC 12 Z9 12 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD DEC PY 2012 VL 64 IS 12 BP 1846 EP 1854 DI 10.1002/acr.21774 PG 9 WC Rheumatology SC Rheumatology GA 045NZ UT WOS:000311704800008 PM 22740386 ER PT J AU Richards, JS Cannon, GW Hayden, CL Amdur, RL Lazaro, D Mikuls, TR Reimold, AM Caplan, L Johnson, DS Schwab, P Cherascu, BN Kerr, GS AF Richards, J. Steuart Cannon, Grant W. Hayden, Candace L. Amdur, Richard L. Lazaro, Deana Mikuls, Ted R. Reimold, Andreas M. Caplan, Liron Johnson, Dannette S. Schwab, Pascale Cherascu, Bogdan N. Kerr, Gail S. TI Adherence with bisphosphonate therapy in US veterans with rheumatoid arthritis SO ARTHRITIS CARE & RESEARCH LA English DT Article ID HEALTH-ASSESSMENT QUESTIONNAIRE; HIP FRACTURE; DISEASE-ACTIVITY; MEDICATION ADHERENCE; OSTEOPOROTIC WOMEN; RISK; PERSISTENCE; ALENDRONATE; DATABASES; RATES AB Objective Pharmacy Benefits Management program data for patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were linked with clinical data to determine bisphosphonate adherence and persistence among US veterans with rheumatoid arthritis (RA) and to determine factors associated with adherence. Methods The primary outcome measures were the duration of bisphosphonate therapy and the medication possession ratio (MPR). Patients with an MPR <0.80 were classified as nonadherent. Potential covariates considered in the analysis included patient demographics, RA disease activity and severity parameters, and factors associated with osteoporosis risk. Associations of patient factors with duration of therapy and adherence were examined using multivariable regression modeling. Results Bisphosphonates were prescribed to 573 (41.5%) of 1,382 VARA subjects. The mean +/- SD duration of therapy for bisphosphonates was 39.2 +/- 31.4 months. A longer duration of therapy correlated with older age, more years of education, and dual x-ray absorptiometry testing. The mean +/- SD MPR of VARA subjects for bisphosphonate therapy was 0.69 +/- 0.28; 302 (52.7%) were nonadherent. In multivariate analyses, nonadherence with bisphosphonate therapy was associated with a longer duration of RA disease (odds ratio [OR] 1.02, 95% confidence interval [95% CI] 1.001.04) and duration of bisphosphonate therapy >32 months (OR 1.63, 95% CI 1.042.57). Whites were less likely to have a low MPR compared with nonwhites (OR 0.52, 95% CI 0.300.88). Conclusion Nonadherence with bisphosphonates was common in this cohort of RA patients and was associated with nonwhite ethnicity, a longer duration of RA disease, and a greater duration of bisphosphonate therapy. C1 [Richards, J. Steuart; Amdur, Richard L.] VA Med Ctr, Washington, DC USA. [Richards, J. Steuart; Amdur, Richard L.] Georgetown Univ, Washington, DC USA. [Cannon, Grant W.; Hayden, Candace L.] George E Whalen VA Med Ctr, Salt Lake City, UT USA. [Cannon, Grant W.; Hayden, Candace L.] Univ Utah, Salt Lake City, UT USA. [Lazaro, Deana] Brooklyn VA, New York, NY USA. [Mikuls, Ted R.] Omaha VA Med Ctr, Omaha, NE USA. [Mikuls, Ted R.] Univ Nebraska Med Ctr, Omaha, NE USA. [Reimold, Andreas M.] VA Med Ctr, Dallas, TX USA. [Reimold, Andreas M.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Caplan, Liron] Denver VA Med Ctr, Denver, CO USA. [Caplan, Liron] Univ Colorado, Aurora, CO USA. [Johnson, Dannette S.] DO GV Sonny Montgomery VA Med Ctr, Jackson, MS USA. [Johnson, Dannette S.] Univ Mississippi, Jackson, MS USA. [Schwab, Pascale] Portland VA, Portland, OR USA. [Cherascu, Bogdan N.] Iowa City VA, Iowa City, IA USA. [Kerr, Gail S.] Howard Univ, Washington, DC 20059 USA. [Kerr, Gail S.] Georgetown Univ, VA Med Ctr, Washington, DC USA. RP Richards, JS (reprint author), DC VA Med Ctr, 50 Irving St NW, Washington, DC 20422 USA. EM john.richards1@va.gov FU VA Health Services Research and Development grant [SHP 08-172] FX Supported by a VA Health Services Research and Development grant (SHP 08-172). NR 31 TC 7 Z9 7 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD DEC PY 2012 VL 64 IS 12 BP 1864 EP 1870 DI 10.1002/acr.21777 PG 7 WC Rheumatology SC Rheumatology GA 045NZ UT WOS:000311704800010 PM 22740421 ER PT J AU Wright, EA Katz, JN Baron, JA Wright, RJ Malchau, H Mahomed, N Prokopetz, JJZ Losina, E AF Wright, Elizabeth A. Katz, Jeffrey N. Baron, John A. Wright, R. John Malchau, Henrik Mahomed, Nizar Prokopetz, Julian J. Z. Losina, Elena TI Risk factors for revision of primary total hip replacement: Results from a national case-control study SO ARTHRITIS CARE & RESEARCH LA English DT Article ID ARTHROPLASTY REGISTER; JOINT REPLACEMENT; IMPLANT FAILURE; SURVIVAL; INFECTION; OUTCOMES; INDEX AB Objective To study the risk factors for revision of primary total hip replacement (THR) in a US population-based sample. Methods Using Medicare claims, we identified beneficiaries from 29 US states who underwent primary THR between July 1, 1995 and June 30, 1996, with followup through December 31, 2008. Potential cases had International Classification of Diseases, Ninth Revision, Clinical Modification codes indicating a revision THR. Each case was matched by state with 1 control THR recipient who was alive and unrevised when the case had a revision THR. We abstracted hospital records to document potential risk factors. We examined the associations between preoperative factors and revision risk using multivariate conditional logistic regression. Results The analysis data set contained 719 of 836 casecontrol pairs with complete data for analysis variables. The factors associated with higher revision odds in multivariate models were age =75 years at primary surgery (odds ratio [OR] 1.52 [95% confidence interval (95% CI) 1.201.92]), height in the highest tertile (OR 1.40 [95% CI 1.061.85]), weight in the highest tertile (OR 1.66 [95% CI 1.242.22]), cemented femoral component (OR 1.44 [95% CI 1.101.87]), prior contralateral primary THR (OR 1.36 [95% CI 1.051.76]), other prior orthopedic surgery (OR 1.45 [95% CI 1.131.84]), and living with others (versus alone; OR 1.26 [95% CI 0.991.61]). Conclusion This first US population-based casecontrol study of risk factors for revision of primary THR showed that younger, taller, and heavier patients and those receiving a cemented femoral component had a greater likelihood of undergoing a revision THR over a 12-year followup period. Effects of age and body size on revision risk should be addressed by clinicians with patients considering primary THR. C1 [Wright, Elizabeth A.] Brigham & Womens Hosp, Orthoped & Arthrit Ctr Outcomes Res, Boston, MA 02115 USA. [Katz, Jeffrey N.; Losina, Elena] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Katz, Jeffrey N.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Baron, John A.] Univ N Carolina, Chapel Hill, NC USA. [Malchau, Henrik] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wright, Elizabeth A.; Wright, R. John; Malchau, Henrik] Harvard Univ, Sch Med, Boston, MA USA. [Mahomed, Nizar] Toronto Western Hosp, Univ Hlth Network, Toronto, ON M5T 2S8, Canada. [Losina, Elena] Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Wright, EA (reprint author), Brigham & Womens Hosp, Orthoped & Arthrit Ctr Outcomes Res, 75 Francis St,OBC-4, Boston, MA 02115 USA. EM wright@hsph.harvard.edu OI Malchau, Henrik/0000-0002-4291-2441 FU NIH [P60-AR-47782, K24-AR-057827] FX Supported by the NIH (grants P60-AR-47782 and K24-AR-057827). NR 29 TC 6 Z9 7 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD DEC PY 2012 VL 64 IS 12 BP 1879 EP 1885 DI 10.1002/acr.21760 PG 7 WC Rheumatology SC Rheumatology GA 045NZ UT WOS:000311704800012 PM 23193090 ER PT J AU Guo, J Song, LG Liu, ML Mahon, MJ AF Guo, Jun Song, Lige Liu, Minlin Mahon, Matthew J. TI Fluorescent ligand-directed co-localization of the parathyroid hormone 1 receptor with the brush-border scaffold complex of the proximal tubule reveals hormone-dependent changes in ezrin immunoreactivity consistent with inactivation SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE Parathyroid hormone; Parathyroid hormone receptor; Ezrin; NHERF1; NHERF2; Megalin ID OPOSSUM KIDNEY-CELLS; REGULATORY FACTOR-I; EZRIN/RADIXIN/MOESIN ERM PROTEINS; KINASE ANCHORING PROTEIN; COTRANSPORTER NAPI-IIA; PHOSPHATE-TRANSPORT; MEMBRANE MICRODOMAINS; LLC-PK1 CELLS; RAT-KIDNEY; CYCLIC-AMP AB Through binding to parathyroid hormone (PTH), PTH1R interacts with kidney-specific scaffold proteins, including the sodium hydrogen exchanger regulatory factors 1 and 2 (NHERFs), and ezrin. To facilitate in vivo localization, tetramethylrhodamine-labeled PTH (PTH-TMR) was used as a fluorescent probe. In mice, PTH-TMR localizes to luminal surfaces of tubular Si segments that overlap PTH1R immunostaining, but does not directly overlap with megalin-specific antibodies. FTH-TMR staining directly overlaps with Npt2a in nascent, endocytic vesicles, marking the location of transporter regulation. PICA substrate antibodies display marked staining increases in segments labeled with PTH-TMR, demonstrating a functional effect. In the presence of secondary hyperparathyroidism, PTH-TMR staining is markedly reduced and shifts to co-localizing with megalin. At 15 min post-injection, PTH-TMR-labeled vesicles do not co-localize with either NHERF or ezrin, suggesting PTH1R dissociation from the scaffold complex. At the 5 min time point, FTH-TMR stains the base of microvilli where it localizes with both NHERF2 and ezrin, and only partially with NHERF1. Strikingly, the bulk of ezrin protein becomes undetectable with the polyclonal, CS3145 antibody, revealing a PTH-induced conformational change in the scaffold. A second ezrin antibody (3C12) is capable of detecting the altered ezrin protein. The CS3145 antibody only binds to the active form of ezrin and fails to recognize the inactive form, while the 3C12 reagent can detect either active or inactive ezrin. Here we show that the PTH1R is part of the ezrin scaffold complex and that acute actions of PTH suggest a rapid inactivation of ezrin in a spatially defined manner. (C) 2012 Elsevier B.V. All rights reserved. C1 [Mahon, Matthew J.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Mahon, MJ (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St Their 10, Boston, MA 02114 USA. EM mahon@helix.mgh.harvard.edu FU NIH [P01 DK073911] FX This study was funded by a program project grant from the NIH (P01 DK073911) to Dr. John Potts. Thanks to Drs. Tom Gardella, Dennis Brown, Daniel C. Biemesderfer, Chris Yun and Jurg Biber for providing invaluable reagents. NR 50 TC 6 Z9 6 U1 0 U2 36 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD DEC PY 2012 VL 1823 IS 12 BP 2243 EP 2253 DI 10.1016/j.bbamcr.2012.09.010 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 058JF UT WOS:000312629200016 PM 23036889 ER PT J AU Crane, PK Carle, A Gibbons, LE Insel, P Mackin, RS Gross, A Jones, RN Mukherjee, S Curtis, SM Harvey, D Weiner, M Mungas, D AF Crane, Paul K. Carle, Adam Gibbons, Laura E. Insel, Philip Mackin, R. Scott Gross, Alden Jones, Richard N. Mukherjee, Shubhabrata Curtis, S. McKay Harvey, Danielle Weiner, Michael Mungas, Dan CA Alzheimer's Dis Neuroimaging TI Development and assessment of a composite score for memory in the Alzheimer's Disease Neuroimaging Initiative (ADNI) SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Memory; psychometrics; longitudinal analysis; cognition; hippocampus ID ITEM RESPONSE THEORY; MILD COGNITIVE IMPAIRMENT; DIAGNOSIS; DEMENTIA; NETWORK; DECLINE; MODEL AB We sought to develop and evaluate a composite memory score from the neuropsychological battery used in the Alzheimer's Disease (AD) Neuroimaging Initiative (ADNI). We used modern psychometric approaches to analyze longitudinal Rey Auditory Verbal Learning Test (RAVLT, 2 versions), AD Assessment Schedule - Cognition (ADAS-Cog, 3 versions), Mini-Mental State Examination (MMSE), and Logical Memory data to develop ADNI-Mem, a composite memory score. We compared RAVLT and ADAS-Cog versions, and compared ADNI-Mem to RAVLT recall sum scores, four ADAS-Cog-derived scores, the MMSE, and the Clinical Dementia Rating Sum of Boxes. We evaluated rates of decline in normal cognition, mild cognitive impairment (MCI), and AD, ability to predict conversion from MCI to AD, strength of association with selected imaging parameters, and ability to differentiate rates of decline between participants with and without AD cerebrospinal fluid (CSF) signatures. The second version of the RAVLT was harder than the first. The ADAS-Cog versions were of similar difficulty. ADNI-Mem was slightly better at detecting change than total RAVLT recall scores. It was as good as or better than all of the other scores at predicting conversion from MCI to AD. It was associated with all our selected imaging parameters for people with MCI and AD. Participants with MCI with an AD CSF signature had somewhat more rapid decline than did those without. This paper illustrates appropriate methods for addressing the different versions of word lists, and demonstrates the additional power to be gleaned with a psychometrically sound composite memory score. C1 [Crane, Paul K.; Gibbons, Laura E.; Mukherjee, Shubhabrata; Curtis, S. McKay] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. [Carle, Adam] Univ Cincinnati, Sch Med, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Carle, Adam] Univ Cincinnati, Coll Arts & Sci, Cincinnati, OH 45229 USA. [Insel, Philip; Mackin, R. Scott; Weiner, Michael] San Francisco VA Med Ctr, CIND, San Francisco, CA 94121 USA. [Gross, Alden; Jones, Richard N.] Hebrew Senior Life, Inst Aging Res, Dept Psychiat, Boston, MA 02131 USA. [Harvey, Danielle] Univ Calif Davis, Dept Publ Hlth Sci, Div Biostat, Davis, CA 95616 USA. [Mungas, Dan] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. RP Crane, PK (reprint author), Univ Washington, Harborview Med Ctr, Box 359780,325 9th Ave, Seattle, WA 98104 USA. EM pcrane@u.washington.edu; gibbonsl@u.washington.edu RI Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007; Crane, Paul/C-8623-2014; Jones, Richard/J-3488-2013; OI Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532; Jones, Richard/0000-0002-1049-218X; Crane, Paul/0000-0003-4278-7465; Mukherjee, Shubhabrata/0000-0003-2522-2884 FU Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; NIH [P30 AG010129, K01 AG030514, R01 AG029672, P50 AG05136, R13 AG030995]; Dana Foundation. Data management FX Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. Data management and the specific analyses reported here wer\e supported by NIH grant R01 AG029672 (Paul Crane, PI), P50 AG05136 (Murray Raskind, PI), and R13 AG030995 (Dan Mungas, PI). NR 25 TC 63 Z9 64 U1 1 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2012 VL 6 IS 4 BP 502 EP 516 DI 10.1007/s11682-012-9186-z PG 15 WC Neuroimaging SC Neurosciences & Neurology GA 061VL UT WOS:000312878200003 PM 22782295 ER PT J AU Gibbons, LE Carle, AC Mackin, RS Harvey, D Mukherjee, S Insel, P Curtis, SM Mungas, D Crane, PK AF Gibbons, Laura E. Carle, Adam C. Mackin, R. Scott Harvey, Danielle Mukherjee, Shubhabrata Insel, Philip Curtis, S. McKay Mungas, Dan Crane, Paul K. CA Alzheimer's Dis Neuroimaging TI A composite score for executive functioning, validated in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with baseline mild cognitive impairment SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Executive function; Mild cognitive impairment; Item response theory; Composite scores ID EPISODIC MEMORY; BIOMARKER SIGNATURE; CONVERSION; DEMENTIA; MCI; HETEROGENEITY; DECLINE AB The Alzheimer's Disease Neuroimaging Initiative (ADNI) measures abilities broadly related to executive function (EF), including WAIS-R Digit Symbol Substitution, Digit Span Backwards, Trails A and B, Category Fluency, and Clock Drawing. This study investigates whether a composite executive function measure based on these multiple indicators has better psychometric characteristics than the widely used individual components. We applied item response theory methods to 800 ADNI participants to derive an EF composite score (ADNI-EF) from the above measures. We then compared ADNI-EF with component measures in 390 longitudinally-followed participants with mild cognitive impairment (MCI) with respect to: (1) Ability to detect change over time; (2) Ability to predict conversion to dementia; (3) Strength of cross-sectional association with MRI-derived measures of structures involved in frontal systems, and (4) Strength of baseline association with cerebrospinal fluid (CSF) levels of amyloid beta(1-42), total tau, and phosphorylated tau(181P). ADNI-EF showed the greatest change over time, followed closely by Category Fluency. ADNI-EF needed a 40 % smaller sample size to detect change. ADNI-EF was the strongest predictor of AD conversion. ADNI-EF was the only measure significantly associated with all the MRI regions, though other measures were more strongly associated in a few of the regions. ADNI-EF was associated with all the CSF measures. ADNI-EF appears to be a useful composite measure of EF in MCI, as good as or better than any of its composite parts. This study demonstrates an approach to developing a psychometrically sophisticated composite score from commonly-used tests. C1 [Gibbons, Laura E.; Mukherjee, Shubhabrata; Curtis, S. McKay; Crane, Paul K.] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. [Carle, Adam C.] Univ Cincinnati, Sch Med, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Carle, Adam C.] Univ Cincinnati, Coll Arts & Sci, Cincinnati, OH 45229 USA. [Mackin, R. Scott; Insel, Philip] San Francisco VA Med Ctr, CIND, San Francisco, CA 94121 USA. [Harvey, Danielle] Univ Calif Davis, Dept Publ Hlth Sci, Div Biostat, Davis, CA 95616 USA. [Mungas, Dan] UC Davis Med Ctr, Dept Neurol3, Sacramento, CA 95817 USA. RP Gibbons, LE (reprint author), Univ Washington, Harborview Med Ctr, Box 359780,325 9th Ave, Seattle, WA 98104 USA. EM gibbonsl@washington.edu RI Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007; Crane, Paul/C-8623-2014; OI Mukherjee, Shubhabrata/0000-0003-2522-2884; Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532; Crane, Paul/0000-0003-4278-7465 FU National Institute on Aging [R01 AG 029672, P50 AG05136, R13 AG030995]; National Institute of Mental Health [K08MH081065]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; NIH [P30 AG010129, K01 AG030514]; Dana Foundation FX Supported by grants R01 AG 029672 (P Crane), P50 AG05136 (Raskind), and R13 AG030995 (Mungas) from the National Institute on Aging, and K08MH081065 (Mackin) from the National Institute of Mental Health.; Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. NR 45 TC 56 Z9 56 U1 4 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2012 VL 6 IS 4 BP 517 EP 527 DI 10.1007/s11682-012-9176-1 PG 11 WC Neuroimaging SC Neurosciences & Neurology GA 061VL UT WOS:000312878200004 PM 22644789 ER PT J AU Park, LQ Gross, AL McLaren, DG Pa, J Johnson, JK Mitchell, M Manly, JJ AF Park, Lovingly Quitania Gross, Alden L. McLaren, Donald G. Pa, Judy Johnson, Julene K. Mitchell, Meghan Manly, Jennifer J. CA Alzheimer's Dis Neuroimaging TI Confirmatory factor analysis of the ADNI neuropsychological battery SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE ADNI; Neuropsychology; Cognition; Cognitive change; Confirmatory factor analysis ID MILD COGNITIVE IMPAIRMENT; ITEM RESPONSE THEORY; ALZHEIMERS-DISEASE; MEASUREMENT INVARIANCE; MEMORY DECLINE; DEMENTIA; VALIDITY; MODEL; RELIABILITY; BIOMARKERS AB The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a large multi-center study designed to develop optimized methods for acquiring longitudinal neuroimaging, cognitive, and biomarker measures of AD progression in a large cohort of patients with Alzheimer's disease (AD), patients with Mild Cognitive Impairment, and healthy controls. Detailed neuropsychological testing was conducted on all participants. We examined the factor structure of the ADNI Neuropsychological Battery across older adults with differing levels of clinical AD severity based on the Clinical Dementia Rating Scale (CDR). Confirmatory factor analysis (CFA) of 23 variables from 10 neuropsychological tests resulted in five factors (memory, language, visuospatial functioning, attention, and executive function/processing speed) that were invariant across levels of cognitive impairment. Thus, these five factors can be used as indicators of cognitive function in older adults who are participants in ADNI. C1 [Park, Lovingly Quitania] Univ Calif Davis, UCDMC Dept Neurol, Alzheimers Dis Ctr, Sacramento, CA 95817 USA. [Gross, Alden L.] Harvard Univ, Sch Med, Inst Aging Res, Boston, MA USA. [Gross, Alden L.] Beth Israel Deaconess Med Ctr, Div Gerontol, Boston, MA 02215 USA. [Pa, Judy; Johnson, Julene K.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [McLaren, Donald G.; Mitchell, Meghan] ENRM Vet Hosp, Geriatr Res Educ & Clin Ctr, Bedford, MA USA. [McLaren, Donald G.; Mitchell, Meghan] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McLaren, Donald G.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Johnson, Julene K.] Univ Calif San Francisco, Dept Social & Behav Sci, Inst Hlth & Aging, San Francisco, CA USA. [Manly, Jennifer J.] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, Dept Neurol, New York, NY USA. RP Park, LQ (reprint author), Univ Calif Davis, UCDMC Dept Neurol, Alzheimers Dis Ctr, 4860 Y St,Suite 3900, Sacramento, CA 95817 USA. EM lovingly.quitania@ucdmc.ucdavis.edu RI Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007; OI Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532; McLaren, Donald/0000-0002-0566-4610 FU National Institute on Aging [R13AG030995, P01 AG031720, AG036694, AG027171, K01 AG034175, R01 AG031252, AG022538, AG028786, AG037212]; National Institutes of Health [T32 AG023480]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; NIH [P30 AG010129, K01 AG030514]; Dana Foundation FX We gratefully acknowledge a conference grant from the National Institute on Aging (R13AG030995, PI: Dan Mungas) that facilitated data analysis for this project.; Dr. Park was supported by a grant from the National Institute of Aging (R01 AG031252 PI: Sarah Farias). Dr. Gross was supported by a National Institutes of Health Translational Research in Aging fellowship (T32 AG023480, PI: Lewis Lipsitz) and a grant from the National Institute on Aging (P01 AG031720 PI: Sharon Inouye). Dr. McLaren was supported by National Institute on Aging grants AG036694 (PI: Reisa Sperling) and AG027171 (PI: Alireza Atri). Dr. Pa was supported by the National Institute on Aging (K01 AG034175, PI: Dr. Pa). Dr. Johnson was supported by a grant from the National Institute of Aging grant AG022538 (PI: Johnson). Dr. Manly was supported by National Institute on Aging grants AG028786 (PI: Manly) and AG037212 (PI: Mayeux).; Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. NR 57 TC 8 Z9 9 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2012 VL 6 IS 4 BP 528 EP 539 DI 10.1007/s11682-012-9190-3 PG 12 WC Neuroimaging SC Neurosciences & Neurology GA 061VL UT WOS:000312878200005 PM 22777078 ER PT J AU Johnson, JK Gross, AL Pa, J McLaren, DG Park, LQ Manly, JJ AF Johnson, Julene K. Gross, Alden L. Pa, Judy McLaren, Donald G. Park, Lovingly Quitania Manly, Jennifer J. TI Longitudinal change in neuropsychological performance using latent growth models: a study of mild cognitive impairment SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE ADNI; Neuropsychology; Cognition; Mild cognitive impairment; Cognitive change; Executive function ID ALZHEIMERS-DISEASE; OLDER PERSONS; INDIVIDUAL-DIFFERENCES; DEFICITS; DECLINE; HETEROGENEITY; CONVERSION; ATTENTION; DEMENTIA; MEMORY AB The goal of the current study was to examine cognitive change in both healthy controls (n = 229) and individuals with mild cognitive impairment (MCI) (n = 397) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We applied latent growth modeling to examine baseline and longitudinal change over 36 months in five cognitive factors derived from the ADNI neuropsychological test battery (memory, executive function/processing speed, language, attention and visuospatial). At baseline, MCI patients demonstrated lower performance on all of the five cognitive factors when compared to controls. Both controls and MCI patients declined on memory over 36 months; however, the MCI patients declined at a significantly faster rate than controls. The MCI patients also declined over 36 months on the remaining four cognitive factors. In contrast, the controls did not exhibit significant change over 36 months on the non-memory cognitive factors. Within the MCI group, executive function declined faster than memory, while the other factor scores changed slower than memory over time. These findings suggest different patterns of cognitive change in healthy older adults and MCI patients. The findings also suggest that, when compared with memory, executive function declines faster than other cognitive factors in patients with MCI. Thus, decline in non-memory domains may be an important feature for distinguishing healthy older adults and persons with MCI. C1 [Johnson, Julene K.] Univ Calif San Francisco, Inst Hlth & Aging, Dept Social & Behav Sci, San Francisco, CA 94118 USA. [Johnson, Julene K.; Pa, Judy] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94118 USA. [Gross, Alden L.] Beth Israel Deaconess Med Ctr, Div Gerontol, Boston, MA 02215 USA. [Gross, Alden L.] Harvard Univ, Sch Med, Inst Aging Res, Boston, MA USA. [McLaren, Donald G.] ENRM Vet Hosp, Geriatr Res Educ & Clin Ctr, Boston, MA USA. [McLaren, Donald G.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McLaren, Donald G.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Park, Lovingly Quitania] Univ Calif Davis, Dept Neurol, Alzheimers Dis Ctr, Davis, CA 95616 USA. [Manly, Jennifer J.] Columbia Univ, Med Ctr, Dept Neurol, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. RP Johnson, JK (reprint author), Univ Calif San Francisco, Inst Hlth & Aging, Dept Social & Behav Sci, 3333 Calif St,Suite 340, San Francisco, CA 94118 USA. EM julene.johnson@ucsf.edu RI Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007 OI McLaren, Donald/0000-0002-0566-4610; Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532 FU National Institute on Aging (NIA) [R13 AG030995, R01 AG022538, P01 AG031720, P01 AG036694, K23 AG027171, K01 AG034175, R01 AG031252, R01 AG028786, R01 AG037212]; National Institutes of Health [T32AG023480-07, P30 AG010129, K01 AG030514]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; Dana Foundation FX We gratefully acknowledge a conference grant from the National Institute on Aging (NIA) (R13 AG030995, PI: Mungas) that facilitated data analysis for this project.; Dr. Johnson was supported by NIA grant R01 AG022538 (PI: Johnson). Dr. Gross was supported by a National Institutes of Health Translational Research in Aging fellowship (T32AG023480-07) and NIA grant P01 AG031720 (PI: Inouye). Dr. McLaren was supported by NIA grants P01 AG036694 (PI: Sperling) and K23 AG027171 (PI: Atri). Dr. Pa was supported by NIA grant K01 AG034175 (PI: Pa). Dr. Park was supported by NIA grant R01 AG031252 (PI: Farias). Dr. Manly was supported by NIA grants R01 AG028786 (PI: Manly) and R01 AG037212 (PI: Mayeux).; Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. NR 56 TC 17 Z9 17 U1 1 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2012 VL 6 IS 4 BP 540 EP 550 DI 10.1007/s11682-012-9161-8 PG 11 WC Neuroimaging SC Neurosciences & Neurology GA 061VL UT WOS:000312878200006 PM 22562439 ER PT J AU Gross, AL Manly, JJ Pa, J Johnson, JK Park, LQ Mitchell, MB Melrose, RJ Inouye, SK McLaren, DG AF Gross, Alden L. Manly, Jennifer J. Pa, Judy Johnson, Julene K. Park, Lovingly Quitania Mitchell, Meghan B. Melrose, Rebecca J. Inouye, Sharon K. McLaren, Donald G. CA Alzheimer's Dis Neuroimaging TI Cortical signatures of cognition and their relationship to Alzheimer's disease SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE MRI; Freesurfer; Cortical thickness; ADNI; Cognition; Brain mapping ID MAGNETIC-RESONANCE IMAGES; SURFACE-BASED ANALYSIS; MINI-MENTAL-STATE; MILD AD DEMENTIA; COORDINATE SYSTEM; EPISODIC MEMORY; BRAIN ATROPHY; IMPAIRMENT; MRI; PREDICTION AB Recent changes in diagnostic criteria for Alzheimer's disease (AD) state that biomarkers can enhance certainty in a diagnosis of AD. In the present study, we combined cognitive function and brain morphology, a potential imaging biomarker, to predict conversion from mild cognitive impairment to AD. We identified four biomarkers, or cortical signatures of cognition (CSC), from regressions of cortical thickness on neuropsychological factors representing memory, executive function/processing speed, language, and visuospatial function among participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Neuropsychological factor scores were created from a previously validated multidimensional factor structure of the neuropsychological battery in ADNI. Mean thickness of each CSC at the baseline study visit was used to evaluate risk of conversion to clinical AD among participants with mild cognitive impairment (MCI) and rate of decline on the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. Of 307 MCI participants, 119 converted to AD. For all domain-specific CSC, a one standard deviation thinner cortical thickness was associated with an approximately 50 % higher hazard of conversion and an increase of approximately 0.30 points annually on the CDR-SB. In combined models with a domain-specific CSC and neuropsychological factor score, both CSC and factor scores predicted conversion to AD and increasing clinical severity. The present study indicated that factor scores and CSCs for memory and language both significantly predicted risk of conversion to AD and accelerated deterioration in dementia severity. We conclude that predictive models are best when they utilize both neuropsychological measures and imaging biomarkers. C1 [Gross, Alden L.; Inouye, Sharon K.] Harvard Univ, Sch Med, Inst Aging Res, Hebrew SeniorLife, Boston, MA 02115 USA. [Gross, Alden L.; Inouye, Sharon K.] Beth Israel Deaconess Med Ctr, Div Gerontol, Boston, MA 02215 USA. [Manly, Jennifer J.] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA. [Pa, Judy; Johnson, Julene K.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Johnson, Julene K.] Univ Calif San Francisco, Dept Social & Behav Sci, Inst Hlth & Aging, San Francisco, CA USA. [Park, Lovingly Quitania] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. [Mitchell, Meghan B.; McLaren, Donald G.] Edith Nourse Rogers Mem Vet Adm Hosp, Geriatr Res Educ & Clin Ctr, Bedford, MA 01730 USA. [Mitchell, Meghan B.; McLaren, Donald G.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Melrose, Rebecca J.] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Melrose, Rebecca J.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [McLaren, Donald G.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Gross, AL (reprint author), Harvard Univ, Sch Med, Inst Aging Res, Hebrew SeniorLife, 1200 Ctr St,Rm 634, Boston, MA 02115 USA. EM aldengross@hsl.harvard.edu; jjm71@columbia.edu; judy.pa@ucsf.edu; Julene.Johnson@ucsf.edu; lovingly.quitania@ucdmc.ucdavis.edu; Meghan.Mitchell@va.gov; rjmelrose@ucla.edu; sharoninouye@hsl.harvard.edu; mclaren@nmr.mgh.harvard.edu RI Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007; OI Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532; McLaren, Donald/0000-0002-0566-4610 FU National Institute on Aging [R13AG030995]; NIH [T32AG023480-07, P30 AG010129, K01 AG030514]; NIA [P01AG031720, RO1 AG036694, K23 AG027171, R01 AG022538, K01 AG034175, R01 AG031252]; VA Career Development Award & UCLA Semel Scholar Award; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; Dana Foundation FX We gratefully acknowledge a conference grant from the National Institute on Aging (R13AG030995, PI: Mungas) that facilitated data analysis for this project. Dr. Gross was supported by an NIH Translational Research in Aging fellowship (T32AG023480-07, PI: Lipsitz) and the NIA (P01AG031720, PI: Inouye). Dr. McLaren was supported by NIA grant RO1 AG036694 (PI: Sperling) and K23 AG027171 (PI: Atri). Dr. Bruce Rosen (MGH-Harvard-MIT Martinos Center for Biomedical Imaging) provided guidance, space, and resources for this research. Dr. Johnson was supported by the NIA (R01 AG022538, PI: Johnson). Dr. Melrose was supported by a VA Career Development Award & UCLA Semel Scholar Award. Dr. Pa was supported by the NIA Career Development Award (K01 AG034175, PI: Pa). Dr. Park was supported by a grant from the National Institute of Aging (R01 AG031252 PI: Farias). Dr. Inouye holds the Milton and Shirley F. Levy Family Chair in Alzheimer's Disease.; Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. NR 75 TC 6 Z9 6 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2012 VL 6 IS 4 BP 584 EP 598 DI 10.1007/s11682-012-9180-5 PG 15 WC Neuroimaging SC Neurosciences & Neurology GA 061VL UT WOS:000312878200009 PM 22718430 ER PT J AU Stricker, NH Dodge, HH Dowling, NM Han, SD Erosheva, EA Jagust, WJ AF Stricker, Nikki H. Dodge, Hiroko H. Dowling, N. Maritza Han, S. Duke Erosheva, Elena A. Jagust, William J. CA Alzheimer's Dis Neuroimaging TI CSF biomarker associations with change in hippocampal volume and precuneus thickness: implications for the Alzheimer's pathological cascade SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Biomarkers; Beta amyloid; Phosphorylated tau; MRI; Alzheimer's disease; Hippocampus; Precuneus ID MILD COGNITIVE IMPAIRMENT; NEUROIMAGING INITIATIVE SUBJECTS; PHOSPHORYLATED TAU-PROTEIN; CEREBROSPINAL-FLUID TAU; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; BETA-AMYLOID BURDEN; DEFAULT NETWORK; MRI BIOMARKERS; DISEASE AB Neurofibrillary tangles (NFT) and amyloid plaques are hallmark neuropathological features of Alzheimer's disease (AD). There is some debate as to which neuropathological feature comes first in the disease process, with early autopsy studies suggesting that NFT develop first, and more recent neuroimaging studies supporting the early role of amyloid beta (A beta) deposition. Cerebrospinal fluid (CSF) biomarkers of A beta(42) and hyperphosphorylated tau (p-tau) have been shown to serve as in vivo proxy measures of amyloid plaques and NFT, respectively. The aim of this study was to examine the association between CSF biomarkers and rate of atrophy in the precuneus and hippocampus. These regions were selected because the precuneus appears to be affected early and severely by A beta deposition, and the hippocampus similarly by NFT pathology. We predicted (1) baseline A beta(42) would be related to accelerated rate of cortical thinning in the precuneus and volume loss in the hippocampus, with the latter relationship expected to be weaker, (2) baseline p-tau(181p) would be related to accelerated rate of hippocampal atrophy and cortical thinning in the precuneus, with the latter relationship expected to be weaker. Using all ADNI cohorts, we fitted separate linear mixed-effects models for changes in hippocampus and precuneus longitudinal outcome measures with baseline CSF biomarkers modeled as predictors. Results partially supported our hypotheses: Both baseline p-tau(181p) and A beta(42) were associated with hippocampal atrophy over time. Neither p-tau(181p) nor A beta(42) were significantly related to cortical thinning in the precuneus over time. However, follow-up analyses demonstrated that having abnormal levels of both A beta(42) and p-tau(181p) was associated with an accelerated rate of atrophy in both the hippocampus and precuneus. Results support early effects of A beta in the Alzheimer's disease process, which are less apparent than and perhaps dependent on p-tau effects as the disease progresses. However, amyloid deposition alone may be insufficient for emergence of significant morphometric changes and clinical symptoms. C1 [Stricker, Nikki H.] VA Boston Med Ctr 116B, Boston, MA 02130 USA. [Stricker, Nikki H.] VA Boston Healthcare Syst, Psychol Serv, Boston, MA USA. [Stricker, Nikki H.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Dodge, Hiroko H.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Dowling, N. Maritza] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA. [Han, S. Duke] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA. [Erosheva, Elena A.] Univ Washington, Dept Stat, Seattle, WA 98195 USA. [Erosheva, Elena A.] Univ Washington, Sch Social Work, Seattle, WA 98195 USA. [Jagust, William J.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Jagust, William J.] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. RP Stricker, NH (reprint author), VA Boston Med Ctr 116B, 150 S Huntington Ave, Boston, MA 02130 USA. EM stricker@bu.edu RI Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007 OI Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532 FU National Institute on Aging [R13 AG030995]; Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health); National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; NIH [P30 AG010129, K01 AG030514, P30 AG008017, R01 AG029672-01A1]; Dana Foundation FX This manuscript was a collaborative effort from the 2011 Friday Harbor Advanced Psychometrics Workshop, funded by the National Institute on Aging R13 AG030995. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-LaRoche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, P30 AG008017, R01 AG029672-01A1 and the Dana Foundation. NR 60 TC 17 Z9 17 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2012 VL 6 IS 4 BP 599 EP 609 DI 10.1007/s11682-012-9171-6 PG 11 WC Neuroimaging SC Neurosciences & Neurology GA 061VL UT WOS:000312878200010 PM 22614327 ER PT J AU Han, SD Gruhl, J Beckett, L Dodge, HH Stricker, NH Farias, S Mungas, D AF Han, S. Duke Gruhl, Jonathan Beckett, Laurel Dodge, Hiroko H. Stricker, Nikki H. Farias, Sarah Mungas, Dan CA Alzheimer's Dis Neuroimaging TI Beta amyloid, tau, neuroimaging, and cognition: sequence modeling of biomarkers for Alzheimer's Disease SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Beta amyloid; Tau; Memory; Executive Functions; Neuroimaging ID SURFACE-BASED ANALYSIS; CSF BIOMARKERS; OLDER PERSONS; A-BETA; DECLINE; BRAIN; NEUROPATHOLOGY; SEGMENTATION; DEMENTIA; POPULATION AB Alzheimer's disease (AD) is associated with a cascade of pathological events involving formation of amyloid-based neuritic plaques and tau-based neurofibrillary tangles, changes in brain structure and function, and eventually, cognitive impairment and functional disability. The precise sequence of when each of these disease markers becomes abnormal is not yet clearly understood. The present study systematically tested the relationship between classes of biomarkers according to a proposed model of temporal sequence by Jack et al. (Lancet Neurology 9:119-128, 2010). We examined temporal relations among four classes of biomarkers: CSF A beta, CSF tau, neuroimaging variables (hippocampal volume, ventricular volume, FDG PET), and cognitive variables (memory and executive function). Random effects modeling of longitudinal data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) was used to test hypotheses that putative earlier markers of AD predicted change in later markers, and that intervening markers reduced effects of earlier on later markers. Specifically, we hypothesized that CSF tau would explain CSF A beta's relation to neuroimaging and cognitive variables, and neuroimaging variables would explain tau's relation to cognitive variables. Consistent with hypotheses, results indicated that CSF A beta effects on cognition change were substantially attenuated by CSF tau and measures of brain structure and function, and CSF tau effects on cognitive change were attenuated by neuroimaging variables. Contrary to hypotheses, CSF A beta and CSF tau were observed to have independent effects on neuroimaging and CSF tau had a direct effect on baseline cognition independent of brain structure and function. These results have implications for clarifying the temporal sequence of AD changes and corresponding biomarkers. C1 [Han, S. Duke] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Han, S. Duke] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA. [Gruhl, Jonathan] Univ Washington, Dept Stat, Seattle, WA 98195 USA. [Beckett, Laurel] Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Dodge, Hiroko H.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Stricker, Nikki H.] VA Boston Healthcare Syst, Psychol Serv, Boston, MA USA. [Stricker, Nikki H.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Farias, Sarah; Mungas, Dan] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA. RP Han, SD (reprint author), Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, 600 S Paulina St,1022, Chicago, IL 60612 USA. EM Duke_Han@rush.edu RI Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007; Finger, Elizabeth/B-6453-2015; OI Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532; Beckett, Laurel/0000-0002-2418-9843 FU ADNI (National Institutes of Health) [U01 AG024904]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; NIH [P30 AG010129, K01 AG030514]; Dana Foundation FX This manuscript was a collaborative effort from the 2011 Friday Harbor Advanced Psychometrics Workshop (R13 AG030995), and used with gracious permission data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) downloaded on 6/1/11. Data collection and sharing for this project was funded by ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. NR 39 TC 16 Z9 16 U1 2 U2 24 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2012 VL 6 IS 4 BP 610 EP 620 DI 10.1007/s11682-012-9177-0 PG 11 WC Neuroimaging SC Neurosciences & Neurology GA 061VL UT WOS:000312878200011 PM 22648764 ER PT J AU Ramanan, VK Kim, S Holohan, K Shen, L Nho, K Risacher, SL Foroud, TM Mukherjee, S Crane, PK Aisen, PS Petersen, RC Weiner, MW Saykin, AJ AF Ramanan, Vijay K. Kim, Sungeun Holohan, Kelly Shen, Li Nho, Kwangsik Risacher, Shannon L. Foroud, Tatiana M. Mukherjee, Shubhabrata Crane, Paul K. Aisen, Paul S. Petersen, Ronald C. Weiner, Michael W. Saykin, Andrew J. CA ADNI TI Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Memory; Psychometrics; Alzheimer's disease; Mild cognitive impairment; Pathway analysis; Genome-wide association study ID MILD COGNITIVE IMPAIRMENT; MINI-MENTAL STATE; STATISTICAL-METHODS; MULTIPLE-SCLEROSIS; QUANTITATIVE TRAIT; APOLIPOPROTEIN-E; SET ENRICHMENT; TYPE-4 ALLELE; AXON GUIDANCE; OLDER-ADULTS AB Memory deficits are prominent features of mild cognitive impairment (MCI) and Alzheimer's disease (AD). The genetic architecture underlying these memory deficits likely involves the combined effects of multiple genetic variants operative within numerous biological pathways. In order to identify functional pathways associated with memory impairment, we performed a pathway enrichment analysis on genome-wide association data from 742 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. A composite measure of memory was generated as the phenotype for this analysis by applying modern psychometric theory to item-level data from the ADNI neuropsychological test battery. Using the GSA-SNP software tool, we identified 27 canonical, expertly-curated pathways with enrichment (FDR-corrected p-value < 0.05) against this composite memory score. Processes classically understood to be involved in memory consolidation, such as neurotransmitter receptor-mediated calcium signaling and long-term potentiation, were highly represented among the enriched pathways. In addition, pathways related to cell adhesion, neuronal differentiation and guided outgrowth, and glucose- and inflammation-related signaling were also enriched. Among genes that were highly-represented in these enriched pathways, we found indications of coordinated relationships, including one large gene set that is subject to regulation by the SP1 transcription factor, and another set that displays co-localized expression in normal brain tissue along with known AD risk genes. These results 1) demonstrate that psychometrically-derived composite memory scores are an effective phenotype for genetic investigations of memory impairment and 2) highlight the promise of pathway analysis in elucidating key mechanistic targets for future studies and for therapeutic interventions. C1 [Ramanan, Vijay K.; Kim, Sungeun; Holohan, Kelly; Shen, Li; Nho, Kwangsik; Risacher, Shannon L.; Saykin, Andrew J.] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Ctr Neuroimaging, Indianapolis, IN USA. [Ramanan, Vijay K.; Holohan, Kelly; Foroud, Tatiana M.; Saykin, Andrew J.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN USA. [Ramanan, Vijay K.] Indiana Univ Sch Med, Med Scientist Training Program, Indianapolis, IN USA. [Kim, Sungeun; Shen, Li; Nho, Kwangsik; Foroud, Tatiana M.; Saykin, Andrew J.] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN USA. [Mukherjee, Shubhabrata; Crane, Paul K.] Univ Washington, Dept Med, Seattle, WA USA. [Aisen, Paul S.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. [Petersen, Ronald C.] Mayo Clin Minnesota, Dept Neurol, Rochester, MN USA. [Weiner, Michael W.] San Francisco VA Med Ctr, Ctr Imaging Neurodegenerat Dis, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Weiner, Michael W.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. RP Saykin, AJ (reprint author), Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Ctr Neuroimaging, Indianapolis, IN USA. EM asaykin@iupui.edu RI Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007; Crane, Paul/C-8623-2014; OI Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532; Mukherjee, Shubhabrata/0000-0003-2522-2884; Shen, Li/0000-0002-5443-0503; Crane, Paul/0000-0003-4278-7465 FU Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; NIH [P30 AG010129, K01 AG030514]; Dana Foundation; NSF [IIS-1117335]; NIA [R13 AG030995, R01 AG19771, P30 AG10133, R01 AG029672] FX Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. Data management and the specific analyses reported here were supported by NSF IIS-1117335 (Shen), NIA R13 AG030995 (Mungas), NIA R01 AG19771 (Saykin), P30 AG10133 (Saykin/Ghetti), and R01 AG029672 (Crane). The authors declare that they have no conflict of interest. NR 79 TC 25 Z9 25 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2012 VL 6 IS 4 BP 634 EP 648 DI 10.1007/s11682-012-9196-x PG 15 WC Neuroimaging SC Neurosciences & Neurology GA 061VL UT WOS:000312878200013 PM 22865056 ER PT J AU Mukherjee, S Trittschuh, E Gibbons, LE Mackin, RS Saykin, A Crane, PK AF Mukherjee, Shubhabrata Trittschuh, Emily Gibbons, Laura E. Mackin, R. Scott Saykin, Andrew Crane, Paul K. CA Alzheimer's Dis Neuroimaging TI Dysexecutive and amnesic AD subtypes defined by single indicator and modern psychometric approaches: relationships with SNPs in ADNI SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Memory; Executive functioning; Alzheimer's disease; Phenotype; Genetic analyses; Psychometrics ID GENOME-WIDE ASSOCIATION; ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; DYSFUNCTION; CONSORTIUM; BIOMARKERS; PHENOTYPES; DIAGNOSIS; PATTERNS; PROGRESS AB Previous investigators have suggested the existence of distinct cognitive phenotypes of Alzheimer's disease (AD): a dysexecutive subgroup with executive functioning worse than memory and an amnesic subgroup with memory worse than executive functioning. We evaluated data from the AD Neuroimaging Initiative. We assigned people with AD to dysexecutive and amnesic subgroups using single indicators, and analogously using the ADNI-Mem and ADNI-EF composite scores developed using modern psychometric approaches. We evaluated associations between subgroup membership, APOE genotype, and single nucleotide polymorphisms (SNPs) are associated with AD, and brain vascular disease defined as white matter hyperintensities (WMH) and MRI-identified infarcts. We hypothesized that APOE epsilon 4 and alleles associated with higher risk for AD would predict amnesic subgroup membership; alleles associated with higher WMH or infarct burden would predict dysexecutive subgroup membership. Classification agreement between the two approaches was only fair (kappa = 0.23). There was no relationship between APOE alleles and the dysexecutive or amnesic phenotypes defined by either categorization approach. There were 58 AD-related and 25 WMH- or infarct-related SNPs for which odds ratios were > 1.5 or < 0.67 for dysexecutive vs. amnesic subgroup defined by either categorization approach. Higher proportions of SNPs had odds ratios in the hypothesized direction for the subgroups defined by the modern psychometric approach for AD-related (58 % vs. 38 %, p-value < 0.001) and brain vascular disease-related SNPs (48 vs. 32 %, p-value = 0.01). Genetic variation may underlie differential performance in memory and executive functioning among people with AD. Modern psychometric composite scores produced group assignments with more SNP associations in the hypothesized direction. C1 [Mukherjee, Shubhabrata; Gibbons, Laura E.; Crane, Paul K.] Univ Washington, Dept Med, Seattle, WA USA. [Trittschuh, Emily] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Trittschuh, Emily] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Mackin, R. Scott] San Francisco VA Med Ctr, CIND, San Francisco, CA USA. [Saykin, Andrew] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Ctr Neuroimaging, Indianapolis, IN USA. RP Mukherjee, S (reprint author), Box 359780,325 9th Ave, Seattle, WA 98104 USA. EM smukherj@u.washington.edu RI Kowall, Neil/G-6364-2012; Preda, Adrian /K-8889-2013; Saykin, Andrew/A-1318-2007; Crane, Paul/C-8623-2014; OI Kowall, Neil/0000-0002-6624-0213; Preda, Adrian /0000-0003-3373-2438; Saykin, Andrew/0000-0002-1376-8532; Crane, Paul/0000-0003-4278-7465; Mukherjee, Shubhabrata/0000-0003-2522-2884 FU Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]; National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering; Canadian Institutes of Health Research; NIH [P30 AG010129, K01 AG030514, R01 AG029672, R13 AG030995]; NIA [P50 AG05136] FX Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. Data management and the specific analyses reported here were supported by NIH grant R01 AG029672 (Paul Crane, PI), R13 AG030995 (Mungas), and P50 AG05136 (Raskind), from the NIA. NR 37 TC 5 Z9 5 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD DEC PY 2012 VL 6 IS 4 BP 649 EP 660 DI 10.1007/s11682-012-9207-y PG 12 WC Neuroimaging SC Neurosciences & Neurology GA 061VL UT WOS:000312878200014 PM 23161456 ER PT J AU Gertow, K Sennblad, B Strawbridge, RJ Ohrvik, J Zabaneh, D Shah, S Veglia, F Fava, C Kavousi, M McLachlan, S Kivimaki, M Bolton, JL Folkersen, L Gigante, B Leander, K Vikstrom, M Larsson, M Silveira, A Deanfield, J Voight, BF Fontanillas, P Sabater-Lleal, M Colombo, GI Kumari, M Langenberg, C Wareham, NJ Uitterlinden, AG Gabrielsen, A Hedin, U Franco-Cereceda, A Nyyssonen, K Rauramaa, R Tuomainen, TP Savonen, K Smit, AJ Giral, P Mannarino, E Robertson, CM Talmud, PJ Hedblad, B Hofman, A Erdmann, J Reilly, MP O'Donnell, CJ Farrall, M Clarke, R Franzosi, MG Seedorf, U Syvanen, AC Hansson, GK Eriksson, P Samani, NJ Watkins, H Price, JF Hingorani, AD Melander, O Witteman, JCM Baldassarre, D Tremoli, E de Faire, U Humphries, SE Hamsten, A AF Gertow, Karl Sennblad, Bengt Strawbridge, Rona J. Oehrvik, John Zabaneh, Delilah Shah, Sonia Veglia, Fabrizio Fava, Cristiano Kavousi, Maryam McLachlan, Stela Kivimaeki, Mika Bolton, Jennifer L. Folkersen, Lasse Gigante, Bruna Leander, Karin Vikstrom, Max Larsson, Malin Silveira, Angela Deanfield, John Voight, Benjamin F. Fontanillas, Pierre Sabater-Lleal, Maria Colombo, Gualtiero I. Kumari, Meena Langenberg, Claudia Wareham, Nick J. Uitterlinden, Andre G. Gabrielsen, Anders Hedin, Ulf Franco-Cereceda, Anders Nyyssonen, Kristiina Rauramaa, Rainer Tuomainen, Tomi-Pekka Savonen, Kai Smit, Andries J. Giral, Philippe Mannarino, Elmo Robertson, Christine M. Talmud, Philippa J. Hedblad, Bo Hofman, Albert Erdmann, Jeanette Reilly, Muredach P. O'Donnell, Christopher J. Farrall, Martin Clarke, Robert Franzosi, Maria Grazia Seedorf, Udo Syvanen, Ann-Christine Hansson, Goran K. Eriksson, Per Samani, Nilesh J. Watkins, Hugh Price, Jacqueline F. Hingorani, Aroon D. Melander, Olle Witteman, Jacqueline C. M. Baldassarre, Damiano Tremoli, Elena de Faire, Ulf Humphries, Steve E. Hamsten, Anders TI Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE atherosclerosis; carotid intima-media thickness; coronary artery disease; genetics ID GENOME-WIDE ASSOCIATION; VASCULAR SMOOTH-MUSCLE; CARDIOVASCULAR RISK; MYOCARDIAL-INFARCTION; WHITEHALL-II; ATHEROSCLEROSIS; SUSCEPTIBILITY; METAANALYSIS; ROTTERDAM; CALCIFICATION AB Background-Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results-To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMTmean, IMTmax, and IMTmean-max), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75x10(-7) for IMTmax; replication P=7.24x10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53x10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83x10(-4), n= 82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). Conclusions-This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent. (Circ Cardiovasc Genet. 2012;5:656-665.) C1 [Gertow, Karl; Sennblad, Bengt; Strawbridge, Rona J.; Oehrvik, John; Folkersen, Lasse; Larsson, Malin; Silveira, Angela; Sabater-Lleal, Maria; Eriksson, Per; Hamsten, Anders] Karolinska Univ Hosp Solna, Ctr Mol Med, Atherosclerosis Res Unit, Dept Med,Karolinska Inst, S-17176 Stockholm, Sweden. [Folkersen, Lasse; Uitterlinden, Andre G.; Hansson, Goran K.] Karolinska Univ Hosp Solna, Ctr Mol Med, Expt Cardiovasc Res Unit, Dept Med,Karolinska Inst, S-17176 Stockholm, Sweden. [Zabaneh, Delilah; Shah, Sonia] UCL, Genet Inst, London, England. [Kivimaeki, Mika; Kumari, Meena; Langenberg, Claudia; Hingorani, Aroon D.] UCL, Genet Epidemiol Grp, Dept Epidemiol & Publ Hlth, London, England. [Talmud, Philippa J.; Humphries, Steve E.] UCL, BHF Labs, Dept Med, Ctr Clin Pharmacol, London, England. [Veglia, Fabrizio; Colombo, Gualtiero I.; Baldassarre, Damiano; Tremoli, Elena] IRCCS, Ctr Cardiol Monzino, Milan, Italy. [Fava, Cristiano; Hedblad, Bo; Melander, Olle] Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin Res Ctr, Lund, Sweden. [Fava, Cristiano] Univ Verona, Hosp Policlin GB Rossi, Dept Med, Div Internal Med C, Verona, Italy. [Kavousi, Maryam; Uitterlinden, Andre G.; Hofman, Albert; Witteman, Jacqueline C. M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Kavousi, Maryam; Uitterlinden, Andre G.; Hofman, Albert; Witteman, Jacqueline C. M.] Sponsored Netherlands Consortium Healthy Ageing, Netherlands Genom Initiat, Rotterdam, Netherlands. [McLachlan, Stela; Bolton, Jennifer L.; Robertson, Christine M.; Price, Jacqueline F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Gigante, Bruna; Leander, Karin; Vikstrom, Max; de Faire, Ulf] Karolinska Inst, Div Cardiovasc Epidemiol, Inst Environm Med, Stockholm, Sweden. [Hedin, Ulf; Franco-Cereceda, Anders] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Deanfield, John] Great Ormond St Hosp Sick Children, Cardiothorac Unit, London, England. [Voight, Benjamin F.; Fontanillas, Pierre] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Voight, Benjamin F.; Fontanillas, Pierre] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Voight, Benjamin F.; Fontanillas, Pierre] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Langenberg, Claudia; Wareham, Nick J.] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 2QQ, England. [Nyyssonen, Kristiina; Tuomainen, Tomi-Pekka] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Rauramaa, Rainer; Savonen, Kai] Fdn Res Hlth Exercise & Nutr, Kuopio Res Inst Exercise Med, Kuopio, Finland. [Rauramaa, Rainer; Savonen, Kai] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland. [Smit, Andries J.] Univ Groningen, Univ Med Ctr Groningen, Dept Med, NL-9713 AV Groningen, Netherlands. [Giral, Philippe] Grp Hop Pitie Salpetriere, AP HP, Serv Endocrinol Metab, Unites Prevent Cardiovasc, Paris, France. [Mannarino, Elmo] Univ Perugia, Dept Clin & Expt Med, I-06100 Perugia, Italy. [Erdmann, Jeanette] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Reilly, Muredach P.] Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA 19104 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. [Farrall, Martin; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford, England. [Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Farrall, Martin; Watkins, Hugh] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Franzosi, Maria Grazia] Inst Mario Negri, Dept Cardiovasc Res, Milan, Italy. [Seedorf, Udo] Univ Munster, LIFA, Gesell Arterioskleroseforsch eV, Munster, Germany. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden. [Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Samani, Nilesh J.] Glenfield Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester, Leics, England. [Baldassarre, Damiano; Tremoli, Elena] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy. RP Gertow, K (reprint author), Karolinska Univ Hosp Solna, Ctr Mol Med, Atherosclerosis Res Unit, Dept Med,Karolinska Inst, Bldg L8 03, S-17176 Stockholm, Sweden. EM karl.gertow@ki.se RI Sabater-Lleal, Maria/I-5832-2013; Shah, Sonia/N-7547-2013; Colombo, Gualtiero/B-4737-2010; Strawbridge, Rona/H-5422-2012; Veglia, Fabrizio/K-1958-2016; Leander, Karin/C-7261-2017; Baldassarre, Damiano/J-3295-2016; Erdmann, Jeanette/P-7513-2014; OI Shah, Sonia/0000-0001-5860-4526; Colombo, Gualtiero/0000-0002-7348-1939; Strawbridge, Rona/0000-0001-8506-3585; Veglia, Fabrizio/0000-0002-9378-8874; Leander, Karin/0000-0002-1404-9222; TREMOLI, ELENA/0000-0002-0929-6106; Baldassarre, Damiano/0000-0002-2766-8882; mannarino, elmo/0000-0002-9771-8056; Kivimaki, Mika/0000-0002-4699-5627; Talmud, Philippa/0000-0002-5560-1933; Seedorf, Udo/0000-0003-4652-5358; Erdmann, Jeanette/0000-0002-4486-6231; Gigante, Bruna/0000-0003-4508-7990; Folkersen, Lasse/0000-0003-0708-9530; Humphries, Stephen E/0000-0002-8221-6547; Kumari, Meena/0000-0001-9716-1035; Watkins, Hugh/0000-0002-5287-9016; Hedin, Ulf/0000-0001-9212-3945; Sabater Lleal, Maria/0000-0002-0128-379X FU Medical Research Council-GlaxoSmithKline pilot program grant [ID 85374]; European Commission [QLG1-CT-2002-00896, Health F2 2008 200647, FP7-HEALTH- 2007-A-201668]; Swedish Heart-Lung Foundation [20090541]; Swedish Research Council [8691, 0593, 12660]; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Sderberg Foundation; Swedish Foundation for Strategic Research; Stockholm County Council [562183]; Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet; Stockholm County Council, Academy of Finland [110413]; Ministry of Education and Culture of Finland; City of Kuopio; British Heart Foundation (BHF) [RG2008/014, RG2008/08, RG005/014, PG1041133124260, RG1081008]; Italian Ministry of Health (Ricerca Corrente); University College London Genetics Institute; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly [014-93-015; RIDE2]; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Netherlands Organization of Scientific Research (De Nederlandse Organisatie voor Wetenschappelijk Onderzoek) [175.010.2005.011, 911-03-012]; Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging [050-060-810]; Netherlands Organization of Scientific Research [918-76-619]; Medical Research Council; National Institutes of Health [R01HL36310, AG13196]; European Research Council [ERC-StG-282255]; Chief Scientist Office of the Scottish Executive Health Department; AFA Insurance Foundation; European Community Sixth Framework Program [LSHM-CT-2007-037273]; AstraZeneca; Wellcome Trust [090532/Z/09/Z]; Strategic Cardiovascular Program of Karolinska Institutet; Foundation for Strategic Research; BHF Center of Research Excellence; Marie Curie Intra European Fellowship within the seventh Framework Program of the European Union [PIEF-GA-2009-252361]; National Heart, Lung and Blood Institute [R01HL36310]; Medical Research Foundation; National Heart, Blood and Lung Institute [HL36310]; Academy of Finland [110413]; French Health Ministry; European Commission 6th Framework Program; European Commission Seventh Framework Program on Diabetes FX The authors fully acknowledge the thousands of study participants who volunteered their time to help advance science and the scores of research staff and scientists who have made this research possible. The Edinburgh Artery Study would particularly like to acknowledge all staff and participants. The authors representing the Rotterdam Study are grateful to the participants and staff, the participating general practitioners, and the pharmacists. Whitehall-II genotyping was, in part, supported by a Medical Research Council-GlaxoSmithKline pilot program grant (ID 85374). David Altshuler, Sekar Kathiresan, and " The Pfizer Broad-Massachusetts General Hospital-Broad Genetics Collaboration" are acknowledged for supporting the genotyping in the MDC study. Members, sources of funding, and disclosures of the CARDIOGRAM consortium are listed in onlineonly Data Supplement Section S7. Members of the PROCARDIS consortium are listed in online-only Data Supplement Section S8. Members of the writing group and affiliations by participating study are listed in online-only Data Supplement Section S9.; The IMPROVE study was supported by the European Commission (Contract No. QLG1-CT-2002-00896), the Swedish Heart-Lung Foundation, the Swedish Research Council (projects 8691 and 0593), the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Sderberg Foundation, the Swedish Foundation for Strategic Research, the Stockholm County Council (project 562183), the Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and Stockholm County Council, Academy of Finland (Grant 110413), the Ministry of Education and Culture of Finland, the City of Kuopio, the British Heart Foundation (BHF) (RG2008/014), and the Italian Ministry of Health (Ricerca Corrente). The University College London Genetics Institute supported Dr Zabaneh and S. Shah, and Dr Humphries was supported by the BHF (RG2008/08). The Rotterdam Study was funded by the Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), 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. The Rotterdam Genome-Wide Association study was funded by the Netherlands Organization of Scientific Research (De Nederlandse Organisatie voor Wetenschappelijk Onderzoek) Investments (number 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2) and the Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (project 050-060-810). The present work was further supported by a Netherlands Organization of Scientific Research grant (vici, 918-76-619). The Whitehall-II study was supported by the Medical Research Council, the BHF, and the National Institutes of Health (R01HL36310). Drs Humphries and Talmud were supported by BHF RG005/014. The Malm Diet and Cancer Study was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, and the European Research Council (ERC-StG-282255). The Edinburgh Artery Study was financed by the BHF and the Chief Scientist Office of the Scottish Executive Health Department. The Advanced Study of Aortic Pathology Study was supported by the Swedish Research Council (12660), the Swedish Heart-Lung Foundation (20090541), the European Commission (FAD, Health F2 2008 200647), and a donation from Fredrik Lundberg. The Biobank of Karolinska Endarterectomies Study was funded by the Swedish Heart-Lung Foundation, the Swedish Research Council, the European Commission (AtheroRemo; FP7-HEALTH- 2007-A-201668), the AFA Insurance Foundation, and the Torsten and Ragnar Sderberg Foundation. PROCARDIS was supported by the European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the BHF, the Wellcome Trust (Contract No. 090532/Z/09/Z), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Sderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council. M. Farall and H. Watkins are supported by the BHF Center of Research Excellence. Dr SabaterLleal is a recipient of a Marie Curie Intra European Fellowship within the seventh Framework Program of the European Union (PIEF-GA-2009-252361).; Dr McLachlan reports stock ownership interest in Pfizer. Dr Kivim ki reports receiving research grant support from the National Heart, Lung and Blood Institute (R01HL36310; principal investigator). Dr Deanfield reports receiving research grant support from the BHF and Medical Research Foundation and honoraria payment and payment for speakers' bureau appointments (Novartis, Roche, Merck, Danone, Pfizer). Dr Voight reports receiving research grant support from the National Institutes of Health (A Genome-Wide Association Study for Early Onset MI; postdoc) and an industry grant (Toward Therapeutical Markers for MI in a T2D Background; postdoc). Dr Kumari reports receiving research grant support from the BHF (PG1041133124260, RG1081008), the National Institutes of Health (AG13196), the Medical Research Council, and the National Heart, Blood and Lung Institute (HL36310). Dr Gabrielsen was employed by Bayer after completion of the study. Dr Hedin reports consultant relationship with Cardoz AB. Dr Nyyssnen reports receiving research grant support from the Academy of Finland for the IMPROVE study (Grant 110413). Dr Giral reports receiving Hospital Clinical Research Program research grant support, awarded by the French Health Ministry. Dr Clarke reports receiving research grant support from the BHF. Dr Franzosi reports receiving research grant support from the European Commission 6th Framework Program as collaborator in the PROCARDIS project. Dr Hingorani reports receiving research grant support from the BHF. Dr Baldassarre reports receiving research grant support from the European Commission (Contract No. QLG1-CT-2002-00896) for the IMPROVE study. Dr Tremoli reports receiving research grant support from the European Commission (Contract No. QLG1-CT-2002-00896) for the IMPROVE study. Dr Humphries reports receiving research grant support from the BHF (RG2008/08, program and project grants on cardiovascular genetics) and the European Commission Seventh Framework Program on Diabetes, and discloses speakers' bureau appointment payment (Genzyme meeting on FH, Amsterdam, November 2011) and 1 consultant/advisory board relationship (Store Gene, a Coronary Heart Disease risk genetic testing University College London spin-off company). NR 33 TC 13 Z9 13 U1 0 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2012 VL 5 IS 6 BP 656 EP 665 DI 10.1161/CIRCGENETICS.112.963660 PG 10 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 060JY UT WOS:000312774800014 PM 23152477 ER PT J AU Matar, AJ Crepeau, RL Pathiraja, V Robson, S Fishman, JA Spitzer, TR Sachs, DH Huang, CA Duran-Struuck, R AF Matar, Abraham J. Crepeau, Rebecca L. Pathiraja, Vimukthi Robson, Simon Fishman, Jay A. Spitzer, Thomas R. Sachs, David H. Huang, Christene A. Duran-Struuck, Raimon TI Effects of Mobilization Regimens in Donors on Outcomes of Hematopoietic Cell Transplantation in Miniature Swine SO COMPARATIVE MEDICINE LA English DT Article ID BONE-MARROW-TRANSPLANTATION; NECROSIS-FACTOR-ALPHA; VERSUS-HOST-DISEASE; HEALTHY-INDIVIDUALS; CHIMERISM; PIGS; COMPLICATIONS; COAGULATION; IMMUNOTOXIN; ENGRAFTMENT AB Toxicities and complications associated with hematopoietic cell transplantation currently limit this potentially curative therapy for malignant and nonmalignant blood disorders. Miniature swine provide a clinically relevant model for studies to improve posttransplantation outcomes. Miniature swine recipients of high-dose haploidentical hepatopoietic cell transplantation after reduced-intensity conditioning consisting of low-dose (100 cGy) total-body irradiation, partial T-cell depletion by using a CD3 immunotoxin, and a 45-d course of cyclosporine A typically successfully engraft without graft-versus-host disease. We recently observed broad variability in engraftment outcomes that correlates with the occurrence of adverse reactions in donors after cytokine treatment to mobilize hematopoietic progenitor cells from the bone marrow to the peripheral blood for collection. Haploidentical recipients (n = 16) of cells from donors remaining healthy during cytokine treatment engrafted with multilineage chimerism, did not develop graft-versus-host disease, and did not require any blood products. In comparison, identically conditioned recipients of cells from donors that had severe reactions during cytokine treatment had adverse outcomes, including the development of clinically significant thrombocytopenia requiring blood product support in 8 of 11 swine. Furthermore, all 11 recipients lost peripheral blood myeloid chimerism (indicating lack of engraftment of donor stem cells). These data suggest that posttransplantation complications in swine are influenced by the health status of the donor before and during the collection of hematopoietic cells by leukapheresis. C1 [Matar, Abraham J.; Crepeau, Rebecca L.; Pathiraja, Vimukthi; Sachs, David H.; Huang, Christene A.; Duran-Struuck, Raimon] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. [Spitzer, Thomas R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Fishman, Jay A.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Robson, Simon] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Duran-Struuck, R (reprint author), Columbia Univ, Columbia Ctr Translat Immunol, New York, NY 10027 USA. EM Rd2605@columbia.edu FU NIAID NIH HHS [P01 AI045897, R01 AI084657] NR 24 TC 1 Z9 1 U1 0 U2 1 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD DEC PY 2012 VL 62 IS 6 BP 487 EP 494 PG 8 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 059DJ UT WOS:000312684300005 PM 23561882 ER PT J AU Nield, M Hoo, GWS AF Nield, Margaret Hoo, Guy W. Soo TI Real-Time Telehealth for COPD Self-Management Using Skype (TM) SO COPD-JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE LA English DT Article DE Social support; Dyspnea; Breathing strategy; Telecommunication ID OBSTRUCTIVE PULMONARY-DISEASE; SOCIAL SUPPORT; HOME TELEHEALTH; DYSPNEA; HEALTH; STATEMENT; OUTCOMES AB The utility of real-time interactive voice and video telehealth for teaching pursed-lips breathing (PLB) in chronic obstructive pulmonary disease (COPD) is unknown. This was a pilot study to determine its feasibility and efficacy on the key variables of social support and dyspnea. A randomized control study design with repeated measures (baseline, 4 and 12 weeks) was used. All participants in the control and intervention groups received PLB instruction at baseline, but only the intervention group received one weekly PLB reinforcement session for 4 weeks via home computer and Skype (TM) software. Outcome measures were Medical Outcomes Study Social Support Survey and dyspnea assessment (visual analogue scales for intensity and distress, modified Borg after six-minute walk distance, and Shortness of Breath Questionnaire for activity-associated dyspnea). A total of 22 participants with COPD (mean FEV1 % predicted = 56) were randomized; 16 (9 telehealth, 7 control) completed the protocol. Intent-to-treat analysis at week 4, but not week 12, demonstrated significantly improved total social support (P = 0.02) and emotional/informational subscale (P = 0.03) scores. Dyspnea intensity decreased (P = 0.08) for the intervention group with a minimal clinical important difference of 10.4 units. Analysis of only participants who completed the protocol demonstrated a significant decrease in dyspnea intensity (P = <0.01) for the intervention group at both week 4 and 12. Real-time telehealth is a feasible, innovative approach for PLB instruction in the home with outcomes of improved social support and decreased dyspnea. C1 [Nield, Margaret] VA Greater Los Angeles Healthcare Syst, W Los Angeles VA Healthcare Ctr, Los Angeles, CA 90073 USA. [Hoo, Guy W. Soo] Univ Calif Los Angeles, W Los Angeles VA Healthcare Ctr, Pulm & Crit Care Sect, Los Angeles, CA USA. [Hoo, Guy W. Soo] Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. RP Nield, M (reprint author), VA Greater Los Angeles Healthcare Syst, W Los Angeles VA Healthcare Ctr, 11301 Wilshire Blvd,111Q, Los Angeles, CA 90073 USA. EM pegnield@gmail.com FU Breathe California of Los Angeles County; National Institutes of Health [P20 NR010671-01] FX Margaret Nield has no conflict of interest to disclose. Guy W. Soo Hoo is a member of the board of Breathe California of Los Angeles County. The funding sources (Breathe California of Los Angeles County and in part by National Institutes of Health [Grant P20 NR010671-01]) had no role in the design or conduct of the study, collection, management, analysis or interpretation of the data or preparation, review or approval of the manuscript. The authors are responsible for the content and the writing of this paper. NR 37 TC 13 Z9 13 U1 2 U2 25 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1541-2555 J9 COPD JI COPD-J. Chronic Obstr. Pulm. Dis. PD DEC PY 2012 VL 9 IS 6 BP 611 EP 619 DI 10.3109/15412555.2012.708067 PG 9 WC Respiratory System SC Respiratory System GA 056PO UT WOS:000312503400006 PM 22946768 ER PT J AU Li, N Zhang, ST Hou, JB Jang, IKK Yu, B AF Li, Ning Zhang, Shaotao Hou, Jingbo Jang, I. K. -Kyung Yu, Bo TI Assessment of Pulmonary Artery Morphology by Optical Coherence Tomography SO HEART LUNG AND CIRCULATION LA English DT Article DE Pulmonary artery; Optical coherence tomography; Histology; Imaging ID HYPERTENSION AB Since its invention, optical coherence tomography (OCT) has been primarily used for the diagnosis of coronary artery disease. A few feasibility studies of OCT to visualise the pulmonary arteries were reported. However, OCT findings in the pulmonary arteries have not been validated using histology as the gold standard. To validate OCT findings for pulmonary arterial imaging, we selected 27 pulmonary arteries from 11 cadavers (6 males, 5 females, mean age 39.6 +/- 21.3 years). Comparison of OCT images and histology was performed. Each histological sample was examined using three types of stains, and the quantified results were analysed by statistics. In conclusion, there was a strong correlation between histology and OCT measurements of the pulmonary arterial wall thickness, the pulmonary arterial wall has a single-layered structure with an average thickness of 0.162 mm. We propose that OCT is probably a useful tool of diagnosing pulmonary artery hypertension and may provide a means to study the pulmonary remodelling process. (Heart, Lung and Circulation 2012;21:778-781) (C) 2012 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). C1 [Li, Ning; Zhang, Shaotao; Hou, Jingbo; Yu, Bo] Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Harbin 150086, Heilongjiang, Peoples R China. [Li, Ning; Zhang, Shaotao; Hou, Jingbo; Yu, Bo] Chinese Minist Educ, Key Lab Myocardial Ischemia, Harbin, Heilongjiang, Peoples R China. [Jang, I. K. -Kyung] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. RP Yu, B (reprint author), Harbin Med Univ, Affiliated Hosp 2, Dept Cardiol, Harbin 150086, Heilongjiang, Peoples R China. EM yubodr@163.com NR 10 TC 7 Z9 7 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1443-9506 J9 HEART LUNG CIRC JI Heart Lung Circ. PD DEC PY 2012 VL 21 IS 12 BP 778 EP 781 DI 10.1016/j.hlc.2012.07.014 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 059FB UT WOS:000312688700002 PM 22884790 ER PT J AU Yonekawa, Y AF Yonekawa, Yoshihiro TI Epidemiology and Management of Uveal Melanoma SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Uveal melanoma; Choroidal melanoma; Proton beam irradiation; Brachytherapy; Enucleation ID COMS RANDOMIZED-TRIAL; COLLABORATIVE OCULAR MELANOMA; PROTON-BEAM IRRADIATION; INTRAARTERIAL HEPATIC FOTEMUSTINE; CHOROIDAL MELANOMA; MALIGNANT-MELANOMA; PLAQUE RADIOTHERAPY; RISK-FACTORS; IODINE-125 BRACHYTHERAPY; RADIATION RETINOPATHY AB Uveal melanoma is the most common primary intraocular malignancy in adults. The annual incidence is approximately 5 per million in the United States. Risk factors include white race, fair skin, light iris color, ancestry from northern latitudes, and ocular/oculodermal melanocytosis. Historically, enucleation was the definitive treatment for uveal melanoma, but brachytherapy and proton beam irradiation are now the most commonly employed treatments. However, there are no effective therapies against metastatic uveal melanoma. Recent studies suggest that the pathogenesis of uveal melanoma includes activation of the MAPK pathway via GNAQ/11, and that metastatic potential may be modulated by mechanisms involving BAP1. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Retina Serv, Boston, MA 02114 USA. RP Yonekawa, Y (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM ivana_kim@meei.harvard.edu NR 103 TC 16 Z9 16 U1 0 U2 9 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD DEC PY 2012 VL 26 IS 6 BP 1169 EP + DI 10.1016/j.hoc.2012.08.004 PG 17 WC Oncology; Hematology SC Oncology; Hematology GA 058IJ UT WOS:000312627000004 PM 23116575 ER PT J AU Cascio, EW Riley, KJ McCormack, J Flanagan, R AF Cascio, Ethan W. Riley, Kent J. McCormack, Joe Flanagan, Rob TI Single Event Effects in Power MOSFETs Due to the Secondary Neutron Environment in a Proton Therapy Center SO IEEE TRANSACTIONS ON NUCLEAR SCIENCE LA English DT Article; Proceedings Paper CT IEEE Radiation Effects Data Workshop (REDW) is Part of the Nuclear and Space Radiation Effects Conference (NSREC) CY JUL 16-20, 2012 CL Miami, FL SP IEEE Nucl & Plasma Sci Soc, Inst Elect & Elect Engineers Inc (IEEE) DE Neutron radiation effects; power MOSFETs; protons; single event burnout ID BURNOUT AB Secondary neutron induced single event burnouts (SEB) in power MOSFETs to be installed in an X-ray generator located in a proton therapy treatment vault are characterized. This is done using both accelerated and in situ testing. Experimental techniques and schematics are presented that allow non-destructive testing of multiple MOSFETs in parallel for in situ real time measurements. C1 [Cascio, Ethan W.; Riley, Kent J.; McCormack, Joe] Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. [Flanagan, Rob] MPI Software Inc, Wayland, MA 01778 USA. RP Cascio, EW (reprint author), Massachusetts Gen Hosp, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. FU U.S. National Institutes of Health National Cancer Institute [6-PO1 CA21239] FX This work was supported by the U.S. National Institutes of Health National Cancer Institute under Grant 6-PO1 CA21239. NR 14 TC 1 Z9 1 U1 0 U2 2 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0018-9499 EI 1558-1578 J9 IEEE T NUCL SCI JI IEEE Trans. Nucl. Sci. PD DEC PY 2012 VL 59 IS 6 BP 3154 EP 3159 DI 10.1109/TNS.2012.2221741 PN 1 PG 6 WC Engineering, Electrical & Electronic; Nuclear Science & Technology SC Engineering; Nuclear Science & Technology GA 056JX UT WOS:000312486000073 ER PT J AU Springelkamp, H Lee, K Ramdas, WD Vingerling, JR Hofman, A Klaver, CCW Sonka, M Abramoff, MD Jansonius, NM AF Springelkamp, Henriet Lee, Kyungmoo Ramdas, Wishal D. Vingerling, Johannes R. Hofman, Albert Klaver, Caroline C. W. Sonka, Milan Abramoff, Michael D. Jansonius, Nomdo M. TI Optimizing the Information Yield of 3-D OCT in Glaucoma SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OPTICAL COHERENCE TOMOGRAPHY; FIBER LAYER THICKNESS; SPECTRAL-DOMAIN OCT; OPEN-ANGLE GLAUCOMA; CIRRUS HD-OCT; NERVE HEAD; STRATUS OCT; REPRODUCIBILITY; EYES; REPEATABILITY AB PURPOSE. To determine, first, which regions of 3-D optical coherence tomography (OCT) volumes can be segmented completely in the majority of subjects and, second, the relationship between analyzed area and thickness measurement test-retest variability. METHODS. Three-dimensional OCT volumes (6X6 mm) centered around the fovea and optic nerve head (ONH) of 925 Rotterdam Study participants were analyzed; 44 participants were scanned twice. Volumes were segmented into 10 layers, and we determined the area where all layers could be identified in at least 95% (macula) or 90% (ONH) of subjects. Macular volumes were divided in 2 x 2, 4 x 4, 6 x 6, 8 x 8, or 68 blocks. We placed two circles around the ONH; the ONH had to fit into the smaller circle, and the larger circle had to fit into the segmentable part of the volume. The area between the circles was divided in 3 to 12 segments. We determined the test-retest variability (coefficient of repeatability) of the retinal nerve fiber layer (RNFL) and ganglion cell layer (RGCL) thickness measurements as a function of size of blocks/segments. RESULTS. Eighty-two percent of the macular volume could be segmented in at least 95% of subjects; for the ONH, this was 65% in at least 90%. The radii of the circles were 1.03 and 1.84 mm. Depending on the analyzed area, median test-retest variability ranged from 8% to 15% for macular RNFL, 11% to 22% for macular RGCL, 5% to 11% for the two together, and 18% to 22% for ONH RNFL. CONCLUSIONS. Test-retest variability hampers a detailed analysis of 3-D OCT data. Combined macular RNFL and RGCL thickness averaged over larger areas had the best test-retest variability. (Invest Ophthalmol Vis Sci. 2012; 53: 8162-8171) DOI:10.1167/iovs.12-10551 C1 [Springelkamp, Henriet; Ramdas, Wishal D.; Vingerling, Johannes R.; Klaver, Caroline C. W.] Erasmus MC, Dept Ophthalmol, Rotterdam, Netherlands. [Springelkamp, Henriet; Ramdas, Wishal D.; Vingerling, Johannes R.; Hofman, Albert; Klaver, Caroline C. W.; Jansonius, Nomdo M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Lee, Kyungmoo; Sonka, Milan; Abramoff, Michael D.] Univ Iowa, Dept Elect & Comp Engn, Iowa City, IA 52242 USA. [Abramoff, Michael D.] Univ Iowa, Dept Ophthalmol & Visual Sci, Iowa City, IA USA. [Abramoff, Michael D.] Univ Iowa, Dept Biomed Engn, Iowa City, IA 52242 USA. [Abramoff, Michael D.] US Dept Vet Affairs, Iowa City, IA USA. [Jansonius, Nomdo M.] Univ Groningen, Univ Med Ctr Groningen, Dept Ophthalmol, Groningen, Netherlands. RP Abramoff, MD (reprint author), Univ Iowa Hosp & Clin, Dept Ophthalmol & Visual Sci PFP 11205, Iowa City, IA 52242 USA. EM michael-abramoff@uiowa.edu RI Klaver, Caroline/A-2013-2016 FU Rotterdam: Stichting Lijf en Leven, Krimpen aan de Lek, The Netherlands; MD Fonds, Utrecht, The Netherlands; Rotterdamse Vereniging Blindenbelangen, Rotterdam, The Netherlands; Stichting Oogfonds Nederland, Utrecht, The Netherlands; Blindenpenning, Amsterdam, The Netherlands; Blindenhulp, The Hague, The Netherlands; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Doorn, The Netherlands; Landelijke Stichting voor Blinden en Slechtzienden, Utrecht, The Netherlands; Swart van Essen, Rotterdam, The Netherlands; Stichting Winckel-Sweep, Utrecht, The Netherlands; Henkes Stichting, Rotterdam, The Netherlands; Lameris Ootech BV, Nieuwegein, The Netherlands; Medical Workshop, de Meern, The Netherlands; Topcon Europe BV, Capelle aan de IJssel, The Netherlands; Heidelberg Engineering, Dossenheim, Germany; Iowa: National Institute of Health [EY019112] FX Supported by Rotterdam: Stichting Lijf en Leven, Krimpen aan de Lek; MD Fonds, Utrecht; Rotterdamse Vereniging Blindenbelangen, Rotterdam; Stichting Oogfonds Nederland, Utrecht; Blindenpenning, Amsterdam; Blindenhulp, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Doorn; Landelijke Stichting voor Blinden en Slechtzienden, Utrecht; Swart van Essen, Rotterdam; Stichting Winckel-Sweep, Utrecht; Henkes Stichting, Rotterdam; Lameris Ootech BV, Nieuwegein; Medical Workshop, de Meern; Topcon Europe BV, Capelle aan de IJssel; all in The Netherlands; and Heidelberg Engineering, Dossenheim, Germany; Iowa: National Institute of Health Grant EY019112. The authors alone are responsible for the content and writing of the paper. NR 40 TC 3 Z9 3 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2012 VL 53 IS 13 BP 8162 EP 8171 DI 10.1167/iovs.12-10551 PG 10 WC Ophthalmology SC Ophthalmology GA 064EX UT WOS:000313056000034 PM 23154462 ER PT J AU Mima, A Qi, W Hiraoka-Yamomoto, J Park, K Matsumoto, M Kitada, M Li, Q Mizutani, K Yu, E Shimada, T Lee, J Shoelson, SE Jobin, C Rask-Madsen, C King, GL AF Mima, Akira Qi, Weier Hiraoka-Yamomoto, Junko Park, Kyoungmin Matsumoto, Motonobu Kitada, Munehiro Li, Qian Mizutani, Koji Yu, Edward Shimada, Takeshi Lee, Jongsoon Shoelson, Steven E. Jobin, Christian Rask-Madsen, Christian King, George L. TI Retinal Not Systemic Oxidative and Inflammatory Stress Correlated with VEGF Expression in Rodent Models of Insulin Resistance and Diabetes SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; IMPAIRED GLUCOSE-TOLERANCE; NF-KAPPA-B; MACULAR EDEMA; IN-VIVO; RETINOPATHY; ACTIVATION; PERICYTES; NEOVASCULARIZATION; PERMEABILITY AB PURPOSE. To correlate changes between VEGF expression with systemic and retinal oxidative stress and inflammation in rodent models of obesity induced insulin resistance and diabetes. METHODS. Retinal VEGF mRNA and protein levels were assessed by RT-PCR and VEGF ELISA, respectively. Urinary 8-hydroxydeoxyguanosine (8-OHdG), blood levels of C-reactive protein (CRP), malondialdehyde (MDA), and CD11b/c positive cell ratio were used as systemic inflammatory markers. Retinal expression of Nox2, Nox4, and p47phox mRNA levels were measured as oxidative stress markers. TNF-alpha, inter-cellular adhesion molecule-1 (ICAM-1), IL1 beta, and activation of nuclear factor kappa B (NF-kappa B) were used as retinal inflammatory markers. RESULTS. Retinal VEGF mRNA and protein expression increased in Zucker diabetic fatty (ZDF(fa/fa)) rats and streptozotosin (STZ) induced diabetic Sprague-Dawley rats, after two months of disease, but not in Zucker fatty (ZF) rats. Systemic markers of oxidative stress and inflammation were elevated in insulin resistant and diabetic rats. Some oxidative stress and inflammatory markers (TNF-alpha, IL-6, ICAM-1, and IL1-beta) were upregulated in the retina of ZDF(fa/fa) and STZ diabetic rats after 4 months of disease. In contrast, activation of NF-kappa B in the retina was observed in high fat fed nondiabetic and diabetic cis-NF-kappa B-EGFP mice, ZF, ZDF(fa/fa), and STZ-induced diabetic rats. CONCLUSIONS. Only persistent hyperglycemia and diabetes increased retinal VEGF expression. Some markers of inflammation and oxidative stress were elevated in the retina and systemic circulation of obese and insulin resistant rodents with and without diabetes. Induction of VEGF and its associated retinal pathologies by diabetes requires chronic hyperglycemia and factors in addition to inflammation and oxidative stress. (Invest Ophthalmol Vis Sci. 2012; 53: 8424-8432) DOI: 10.1167/iovs.12-10207 C1 [King, George L.] Harvard Univ, Dianne Nunnally Hoppes Lab Diabet Complicat, Div Res, Joslin Diabet Ctr,Med Sch, Boston, MA 02215 USA. [Jobin, Christian] Univ N Carolina, Dept Med, Chapel Hill, NC USA. RP King, GL (reprint author), Harvard Univ, Dianne Nunnally Hoppes Lab Diabet Complicat, Div Res, Joslin Diabet Ctr,Med Sch, 1 Joslin Pl, Boston, MA 02215 USA. EM George.king@joslin.harvard.edu FU National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [DK053105, R01EY016150]; National Institutes of Health [EY018677]; Manpei Suzuki Diabetes Foundation; Kanzawa Medical Research Foundation; NOVARTIS Foundation, Japan; Diabetes Endocrinology Research Center [P30DK036836]; Juvenile Diabetes Research Foundation FX Supported by Grants DK053105 and R01EY016150 from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (GLK) and EY018677 from the National Institutes of Health (CRM), a Research Fellowship (Manpei Suzuki Diabetes Foundation, Kanzawa Medical Research Foundation, NOVARTIS Foundation, Japan [AM]), Diabetes Endocrinology Research Center (P30DK036836), and a Juvenile Diabetes Research Foundation Postdoctoral Fellowship (WQ). NR 40 TC 12 Z9 14 U1 1 U2 11 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2012 VL 53 IS 13 BP 8424 EP 8432 DI 10.1167/iovs.12-10207 PG 9 WC Ophthalmology SC Ophthalmology GA 064EX UT WOS:000313056000066 PM 23197686 ER PT J AU Perry, LP Jakobiec, FA Zakka, FR Walton, DS AF Perry, Lynn P. Jakobiec, Frederick A. Zakka, Fouad R. Walton, David S. TI Newborn primary congenital glaucoma: Histopathologic features of the anterior chamber filtration angle SO JOURNAL OF AAPOS LA English DT Article ID UPDATE AB We present histopathologic findings that have not been previously reported as associated with abnormalities of the anterior chamber angle underlying newborn primary congenital glaucoma as a distinct entity. The major histopathologic findings were partial absence and retrodisplacement of Schlemm's canal, hypoplasia of the trabecular meshwork, broad attachment of ciliary muscle to the meshwork, and anterior insertion of hypoplastic iris with the formation of a pseudomembrane. These profound anatomic derangements explain why goniosurgery is frequently unsuccessful in cases of newborn glaucoma. C1 [Jakobiec, Frederick A.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. [Perry, Lynn P.; Jakobiec, Frederick A.; Zakka, Fouad R.; Walton, David S.] Harvard Univ, Dept Ophthalmol, Sch Med, Boston, MA 02114 USA. RP Jakobiec, FA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, David G Cogan Lab Ophthalm Pathol, Boston, MA 02114 USA. EM Fred_Jakobiec@meei.harvard.edu FU Heed Foundation FX Supported in part by the Heed Foundation (LPP). NR 6 TC 6 Z9 6 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 1091-8531 J9 J AAPOS JI J. AAPOS PD DEC PY 2012 VL 16 IS 6 BP 565 EP 568 DI 10.1016/j.jaapos.2012.06.012 PG 4 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 059AM UT WOS:000312676800015 PM 23158552 ER PT J AU Lin, F Vance, DE Gleason, CE Heidrich, SM AF Lin, Feng Vance, David E. Gleason, Carey E. Heidrich, Susan M. TI Caring for Older Adults with Mild Cognitive Impairment An Update for Nurses SO JOURNAL OF GERONTOLOGICAL NURSING LA English DT Article ID MINI-MENTAL-STATE; OF-THE-LITERATURE; ALZHEIMERS-DISEASE; INSTRUMENTAL ACTIVITIES; NEUROPSYCHIATRIC SYMPTOMS; SIGNIFICANT OTHERS; PHYSICAL-ACTIVITY; GROUP-THERAPY; RATING-SCALE; DEMENTIA AB Mild cognitive impairment (MCI) is a mild decline in single or multiple cognitive domains, while global cognition and basic activities of daily living remain intact. Nurses play an important role in early detection of MCI and providing care to maintain maximum independence for individuals with MCI. This article seeks to provide nurses with a review of the most recent research regarding the etiology and diagnosis of MCI, related risk and protective factors, patient and family experiences, and current interventions. This update provides research evidence to inform nursing practice of MCI care. C1 [Lin, Feng] Univ Rochester, Med Ctr, Sch Nursing, Rochester, NY 14642 USA. [Vance, David E.] Univ Alabama Birmingham, Sch Nursing, Birmingham, AL USA. [Gleason, Carey E.] Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. [Heidrich, Susan M.] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP Lin, F (reprint author), Univ Rochester, Med Ctr, Sch Nursing, HWH 2W128,601 Elmwood Ave, Rochester, NY 14642 USA. EM vankee_lin@urmc.rochester.edu OI Vance, David/0000-0002-0498-6263 FU NIA NIH HHS [P50 AG033514] NR 107 TC 1 Z9 1 U1 3 U2 13 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0098-9134 J9 J GERONTOL NURS JI J. Gerontol. Nurs. PD DEC PY 2012 VL 38 IS 12 BP 22 EP 37 DI 10.3928/00989134-20121112-99 PG 19 WC Geriatrics & Gerontology; Gerontology; Nursing SC Geriatrics & Gerontology; Nursing GA 064AQ UT WOS:000313043700006 PM 23189995 ER PT J AU Turiano, NA Hill, PL Roberts, BW Spiro, A Mroczek, DK AF Turiano, Nicholas A. Hill, Patrick L. Roberts, Brent W. Spiro, Avron, III Mroczek, Daniel K. TI Smoking mediates the effect of conscientiousness on mortality: The Veterans Affairs Normative Aging Study SO JOURNAL OF RESEARCH IN PERSONALITY LA English DT Article DE Personality; Conscientiousness; Mortality; Longevity; Smoking; Mediation ID ALL-CAUSE MORTALITY; PERSONALITY-TRAITS; SOCIOECONOMIC-STATUS; PROSPECTIVE COHORT; OLDER MEN; LIFE-SPAN; HEALTH; LONGEVITY; PREDICTORS; MECHANISMS AB This study examined the relationship between conscientiousness and mortality over 18 years and whether smoking behavior mediated this relationship. We utilized data from the Veterans Affairs Normative Aging Study on 1349 men who completed the Goldberg (1992) adjectival markers of the Big Five. Over the 18-year follow-up, 547 (41%) participants died. Through proportional hazards modeling in a structural equation modeling framework, we found that higher levels of conscientiousness significantly predicted longer life, and that this effect was mediated by current smoking status at baseline. Methodologically, we also demonstrate the effectiveness of using a structural equation modeling framework to evaluate mediation when using a censored outcome such as mortality. (C) 2012 Elsevier Inc. All rights reserved. C1 [Turiano, Nicholas A.] Univ Rochester, Sch Med & Dent, Dept Psychiat, Rochester, NY 14642 USA. [Turiano, Nicholas A.; Mroczek, Daniel K.] Ctr Aging & Life Course, W Lafayette, IN USA. [Hill, Patrick L.; Roberts, Brent W.] Univ Illinois, Dept Psychol, Champaign, IL USA. [Spiro, Avron, III] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr MA, Boston, MA USA. [Spiro, Avron, III] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Spiro, Avron, III] Boston Univ, Sch Med, Boston, MA 02118 USA. [Spiro, Avron, III] Boston Univ, Sch Dent Med, Boston, MA 02118 USA. [Mroczek, Daniel K.] Purdue Univ, Dept Human Dev & Family Studies, W Lafayette, IN 47907 USA. RP Turiano, NA (reprint author), 300 Crittenden Blvd,Box Psych, Rochester, NY 14642 USA. EM nicholas_turiano@urmc.rochester.edu; phill1@illinois.edu; broberts@cyrus.psych.illinois.edu; aspiro3@bu.edu; dmroczek@purdue.edu FU NIA NIH HHS [T32 AG025671, R01 AG018436, R01 AG021178]; NIMH NIH HHS [T32 MH018911] NR 48 TC 8 Z9 8 U1 3 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0092-6566 J9 J RES PERS JI J. Res. Pers. PD DEC PY 2012 VL 46 IS 6 BP 719 EP 724 DI 10.1016/j.jrp.2012.08.009 PG 6 WC Psychology, Social SC Psychology GA 058IA UT WOS:000312626100010 PM 23504043 ER PT J AU Van der Wilden, G Albers, C Haefeli, P Zimmerman, H Exadaktylos, A Levy, P Birkham, O Michailidou, M Sideris, A Velmahos, G Alam, H King, D Fagenholz, P Yeh, D de Moya, MA Inaba, K AF Van der Wilden, Gwen Albers, Christof Haefeli, Peter Zimmerman, Heinz Exadaktylos, Aris Levy, Phillip Birkham, Oscar Michailidou, Maria Sideris, Antonios Velmahos, George Alam, Hasan King, David Fagenholz, Peter Yeh, Dante de Moya, Marc A. Inaba, Kenji TI Using micropower impulse radar technology to screen for pneumothorax: An international bi-institutional study SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the Western-Trauma-Association CY FEB 26-MAR 03, 2012 CL Vail, CO SP Western Trauma Assoc DE Pneumothorax; micropower impulse radar; trauma ID BLUNT CHEST TRAUMA; COMPUTED-TOMOGRAPHY; THORACIC ULTRASOUND; BEDSIDE ULTRASOUND; RADIOGRAPHY; ULTRASONOGRAPHY; SENSITIVITY; DIAGNOSIS AB BACKGROUND: Pneumothoraces (PTXs) are a common entity in thoracic trauma. Micropower impulse radar (MIR) has been able to detect PTXs in surgical patients. However, this technology has not been tested previously on trauma patients. The purpose of this study was to determine the sensitivity and specificity of MIR to detect clinically significant PTXs. We hypothesized that MIR technology can effectively screen trauma patients for clinically significant PTXs. METHODS: This was a prospective observational study in Level I trauma centers in Boston, Massachusetts, and Bern, Switzerland. All trauma patients undergoing a chest computed tomographic (CT) scan were eligible for the study. Consent was obtained, and readings were performed within 30 minutes before or after the CT scan. The patients had eight lung fields tested (four on each side). The qualitative and quantitative MIR results were blinded and stored on the device. We then compared the results of the MIR to the CT scan and the need for chest tube drainage. We defined PTXs as clinically significant if they required a chest tube. RESULTS: Seventy-five patients were enrolled, with a mean age of 46 +/- 16 years. Eighty-four percent were male. The screening test took approximately 1 minute. All but two patients had blunt chest trauma. Six true-positives, 6 false-positives, 63 true-negatives, and 0 false-negatives resulted in an overall sensitivity of 100%. CONCLUSION: MIR is an easy to use handheld technology that effectively screened patients for clinically significant PTXs, with a sensitivity and negative predictive value of 100%. MIR may be used for rapid, repeatable, and ongoing surveillance of trauma patients. (J Trauma Acute Care Surg. 2012;73: 1418-1422. Copyright (C) 2012 by Lippincott Williams & Wilkins) C1 [Van der Wilden, Gwen; Birkham, Oscar; Michailidou, Maria; Sideris, Antonios; Velmahos, George; Alam, Hasan; King, David; Fagenholz, Peter; Yeh, Dante; de Moya, Marc A.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Van der Wilden, Gwen; Birkham, Oscar; Michailidou, Maria; Sideris, Antonios; Velmahos, George; Alam, Hasan; King, David; Fagenholz, Peter; Yeh, Dante; de Moya, Marc A.] Harvard Univ, Sch Med, Boston, MA USA. [Albers, Christof; Haefeli, Peter; Zimmerman, Heinz; Exadaktylos, Aris] Univ Hosp Bern, Dept Emergency Med, CH-3010 Bern, Switzerland. [Albers, Christof; Haefeli, Peter; Zimmerman, Heinz; Exadaktylos, Aris] Univ Bern, Bern, Switzerland. [Inaba, Kenji] Univ So Calif, Div Trauma & Crit Care, Los Angeles, CA USA. RP de Moya, MA (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM mdemoya@partners.org RI Albers, Christoph/B-3529-2013; OI King, David/0000-0003-1028-1478 NR 22 TC 1 Z9 1 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 2163-0755 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD DEC PY 2012 VL 73 IS 6 BP 1418 EP 1422 DI 10.1097/TA.0b013e318270bbe4 PG 5 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 058FV UT WOS:000312620400010 PM 23188233 ER PT J AU Jin, G Duggan, M Imam, A deMoya, MA Sillesen, M Hwabejire, J Jepsen, CH Liu, BL Mejaddam, AY Lu, J Smith, WM Velmahos, GC Socrate, S Alam, HB AF Jin, Guang Duggan, Michael Imam, Ayesha deMoya, Marc A. Sillesen, Martin Hwabejire, John Jepsen, Cecilie H. Liu, Baoling Mejaddam, Ali Y. Lu, Jennifer Smith, William Michael Velmahos, George C. Socrate, Simona Alam, Hasan B. TI Pharmacologic resuscitation for hemorrhagic shock combined with traumatic brain injury SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the Western-Trauma-Association CY FEB 26-MAR 03, 2012 CL Vail, CO SP Western Trauma Assoc DE Brain; trauma; resuscitation; valproic acid; swine ID FOCAL CEREBRAL-ISCHEMIA; HISTONE DEACETYLASE INHIBITION; INDUCED NEURONAL APOPTOSIS; VALPROIC ACID; HEAD-INJURY; FLUID RESUSCITATION; INTRACRANIAL-PRESSURE; ADHESION MOLECULES; MODEL; ACTIVATION AB BACKGROUND: We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, can improve survival after hemorrhagic shock (HS), protect neurons from hypoxia-induced apoptosis, and attenuate the inflammatory response. We have also shown that administration of 6% hetastarch (Hextend [Hex]) after traumatic brain injury (TBI) decreases brain swelling, without affecting size of the lesion. This study was performed to determine whether addition of VPA to flex would decrease the lesion size in a clinically relevant large animal model of TBI + HS. METHODS: Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters, intracranial pressure, and brain tissue oxygenation. A custom-designed, computer-controlled cortical impact device was used to create a TBI through a 20-mm craniotomy: 15-mm cylindrical tip impactor at 4-m/s velocity, 100-millisecond dwell time, and 12-mm penetration depth. Volume-controlled hemorrhage was started (40% blood volume) concurrent with the TBI. After 2 hours of shock, animals were randomized to one of three resuscitation groups (n = 7 per group) as follows: (1) isotonic sodium chloride solution; (2) 6% hetastarch, Hex; and (3) Hex and VPA 300 mg/kg (Hex + VPA). Volumes of Hex matched the shed blood, whereas that of the isotonic sodium chloride solution was three times the volume. VPA treatment was started after an hour of shock. After 6 hours of postresuscitation monitoring, brains were sectioned into 5-mm slices and stained with 2, 3, 5-Triphenyltetrazolium chloride to quantify the lesion size (mm(3)) and brain swelling (percent change compared with uninjured side). Levels of acetylated histone H3 were determined to quantify acetylation, and myeloperoxidase and interleuldne-1 beta (IL-1 beta) levels were measured as markers of brain inflammation. RESULTS:. Combination of 40% blood loss with cortical impact and a period of shock (2 hours) and resuscitation resulted in a highly reproducible brain injury. Lesion size and brain swelling in the Hex + VPA group (1,989 [156.8] mm(3), and 19% [1.6%], respectively) were significantly smaller than the isotonic sodium chloride solution group (3,335 [287.9] mm(3) and 36% [2.2%], respectively). Hex alone treatment significantly decreased the swelling (27% [1.6%]) without reducing the lesion size. The number of CD11b-positive cells as well as myeloperoxidase and IL-1 levels in the brains were significantly reduced by the VPA treatment. CONCLUSION: In a combined HS and TBI model, treatment with artificial colloid (Hex) improves hemodynamic parameters and reduces swelling, without affecting the actual size of the brain lesion. Addition of VPA effectively reduces both the size of brain lesion and associated swelling by attenuating the inflammatory response. (J Trauma Acute Care Surg. 2012;73: 1461-1470. Copyright (C) 2012 by Lippincott Williams & Wilkins) C1 [Alam, Hasan B.] Univ Michigan Hosp, Taubman Ctr 2920, Dept Surg, Ann Arbor, MI 48109 USA. [Jin, Guang; Duggan, Michael; Imam, Ayesha; deMoya, Marc A.; Hwabejire, John; Jepsen, Cecilie H.; Liu, Baoling; Mejaddam, Ali Y.; Lu, Jennifer; Smith, William Michael; Velmahos, George C.; Alam, Hasan B.] Harvard Univ, Sch Med, Dept Surg,Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02115 USA. [Socrate, Simona] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Alam, HB (reprint author), Univ Michigan Hosp, Taubman Ctr 2920, Dept Surg, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM alamh@med.umich.edu NR 53 TC 24 Z9 24 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 2163-0755 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD DEC PY 2012 VL 73 IS 6 BP 1461 EP 1470 DI 10.1097/TA.0b013e3182782641 PG 10 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 058FV UT WOS:000312620400017 PM 23188239 ER PT J AU Schneider, JC Gerrard, P Goldstein, R DiVita, MA Niewczyk, P Ryan, CM Tan, WH Kowalske, K Zafonte, R AF Schneider, Jeffrey C. Gerrard, Paul Goldstein, Richard DiVita, Margaret A. Niewczyk, Paulette Ryan, Colleen M. Tan, Wei-Han Kowalske, Karen Zafonte, Ross TI Predictors of transfer from rehabilitation to acute care in burn injuries SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article DE Burn injury; rehabilitation; risk factors; complications; outcomes ID RISK-FACTORS; HOSPITAL READMISSION; INPATIENT REHABILITATION; STROKE REHABILITATION; 30-DAY READMISSION; ADULT PATIENTS; HEART-FAILURE; DEATH; MORTALITY; OUTCOMES AB BACKGROUND: Transfer to acute care from rehabilitation represents an interruption in a patient's recovery and a potential deficiency in quality of care. The objective of this study was to examine predictors of transfer to acute care in the inpatient burn rehabilitation population. METHODS: Data are obtained from Uniform Data System for Medical Rehabilitation from 2002 to 2010 for patients with a primary diagnosis of burn injury. Predictor variables include demographic, medical, and facility data. Descriptive statistics are calculated for acute and nonacute transfer patients. Logistic regression analysis is used to determine significant predictors of acute transfer within the first 3 days. A scoring system is developed to determine the risk of acute transfer. RESULTS: There were 78 acute transfers in the first 3 days of a total of 4,572 burn admissions. Functional level at admission, age, and admission classification are significant predictors of transfer to acute care (p < 0.05). Total body surface area burned and medical comorbidities were not significantly associated with acute transfer risk. A 12-point acute transfer risk scoring system was developed, which demonstrates validity. CONCLUSION: Efforts to reduce readmissions to acute care should include greater scrutiny of older, lower-functioning patients with burn injury who are evaluated for admission to inpatient rehabilitation. This acute transfer scoring system may be useful to clinicians, health care institutions, and policymakers to help predict those patients at highest risk for early transfer to the acute hospital from rehabilitation. (J Trauma Acute Care Surg. 2012;73: 1596-1601. Copyright (c) 2012 by Lippincott Williams & Wilkins) C1 [Schneider, Jeffrey C.; Gerrard, Paul; Goldstein, Richard; Tan, Wei-Han; Zafonte, Ross] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA 02114 USA. [Ryan, Colleen M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Surg Serv,Sumner Redstone Burn Ctr, Boston, MA USA. [Ryan, Colleen M.] Shriners Hosp Children, Boston, MA USA. [DiVita, Margaret A.; Niewczyk, Paulette] Daemen Coll, Uniform Data Syst Med Rehabil, Amherst, NY USA. [Niewczyk, Paulette] Daemen Coll, Dept Hlth Care Studies, Amherst, NY USA. [Kowalske, Karen] Univ Texas SW Med Ctr Dallas, Dept Phys Med & Rehabil, Dallas, TX 75390 USA. RP Schneider, JC (reprint author), Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, 125 Nashua St, Boston, MA 02114 USA. EM jcschneider@partners.org OI Gerrard, Paul/0000-0003-0654-5354; DiVita, Margaret/0000-0002-4878-2959 NR 30 TC 17 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 2163-0755 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD DEC PY 2012 VL 73 IS 6 BP 1596 EP 1601 DI 10.1097/TA.0b013e318270d73d PG 6 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 058FV UT WOS:000312620400037 PM 23188249 ER PT J AU Orman, JA Geyer, D Jones, J Schneider, EB Grafman, J Pugh, MJ DuBose, J AF Orman, Jean A. Geyer, Dennis Jones, John Schneider, Eric B. Grafman, Jordan Pugh, Mary Jo DuBose, Joseph TI Epidemiology of moderate-to-severe penetrating versus closed traumatic brain injury in the Iraq and Afghanistan wars SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article DE Traumatic and penetrating brain injury; military; epidemiology; Operation Enduring Freedom/Iraqi Freedom; Operation New Dawn ID COMBAT WOUNDS; FREEDOM; HOSPITALIZATIONS; BATTLEFIELD AB BACKGROUND: US combat operations in Iraq and Afghanistan have resulted in a greater proportion of service members with head and neck wounds caused by explosions compared with that of previous wars. Although penetrating traumatic brain injury (TBI) is frequently associated with these wounds, the epidemiology of penetrating TBI from these conflicts has not been well described. METHODS: The Joint Theater Trauma Registry was queried for January 2003 through December 2010 to identify all patients with moderate-to-severe brain injury with a maximum Abbreviated Injury Scale (AIS) score of the head of 3 or greater and a diagnosis of penetrating or closed TBI in accordance with the Department of Defense Traumatic Brain Injury Surveillance definition. The epidemiology of these injuries was examined, including demographics, TBI severity, overall injury severity, and surgical interventions provided. RESULTS: A total of 1,255 TBI patients (774 penetrating, 481 closed) meeting criteria were identified. Penetrating brain injuries were more severe, more likely to be battle related, and less likely to be isolated injuries than a group of moderate-to-severe closed TBIs within the same range of anatomic injury severity. During the 5-year period of the Iraq war with the largest numbers of TBIs (2004-2008), the numbers of penetrating TBIs exceeded closed TBIs by a ratio of 2:1. During the 3-year period of the Afghanistan war with the greatest numbers of TBIs (2008-2010), the ratio of penetrating to closed TBIs was substantially lower, approximately 1.3:1. CONCLUSION: This study represents the first comprehensive report on the epidemiology of moderate-to-severe penetrating and closed TBIs resulting from the wars in Iraq and Afghanistan using Joint Theater Trauma Registry data. With the maturing theater of conflicts, penetrating TBIs were substantially less predominant compared with closed TBIs. While this finding may reflect changes in the use of protective measures and tactics or improvements in diagnosis of closed TBIs, additional research is needed to identify the reason for this shift and the subsequent effect on outcome after combat-related TBIs. (J Trauma Acute Care Surg. 2012;73: S496-S502. Copyright (C) 2012 by Lippincott Williams & Wilkins) C1 [Orman, Jean A.] USA, Inst Surg Res, ATTN MCMR SRR, Ft Sam Houston, TX 78234 USA. [Orman, Jean A.; Pugh, Mary Jo] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Geyer, Dennis] San Antonio Mil Med Ctr, Dept Surg, Neurosurg Serv, San Antonio, TX USA. [Pugh, Mary Jo] S Texas Vet Hlth Care Syst, San Antonio, TX USA. [Schneider, Eric B.] Johns Hopkins Sch Med, Ctr Surg Trials & Outcomes Res, Baltimore, MD USA. [DuBose, Joseph] Univ Maryland Med Syst, R Adams Cowley Shock Trauma Ctr, Baltimore, MD USA. [Jones, John] Northwestern Univ, Rehabil Inst Chicago, Chicago, IL 60611 USA. [Grafman, Jordan] Northwestern Univ, Dept Phys Med & Rehabil, Chicago, IL 60611 USA. RP Orman, JA (reprint author), USA, Inst Surg Res, ATTN MCMR SRR, 3698 Chambers Pass, Ft Sam Houston, TX 78234 USA. EM Jean.A.Orman@amedd.army.mil OI Grafman, Jordan H./0000-0001-8645-4457; Pugh, Mary Jo/0000-0003-4196-7763 FU South Texas Veterans Healthcare System FX We acknowledge JTTR for providing data for this study and Ms. Susan West and Ms. Celina Garcia of the JTTR staff for their invaluable assistance in preparing the data set. Some work for this study was supported by resources of the South Texas Veterans Healthcare System. NR 38 TC 8 Z9 9 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD DEC PY 2012 VL 73 SU 5 BP S496 EP S502 DI 10.1097/TA.0b013e318275473c PG 7 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 056QT UT WOS:000312506900020 PM 23192076 ER PT J AU Tsai, J Rosenheck, RA Decker, SE Desai, RA Harpaz-Rotem, I AF Tsai, Jack Rosenheck, Robert A. Decker, Suzanne E. Desai, Rani A. Harpaz-Rotem, Ilan TI Trauma Experience Among Homeless Female Veterans: Correlates and Impact on Housing, Clinical, and Psychosocial Outcomes SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; MILITARY SEXUAL TRAUMA; WOMEN VETERANS; COOCCURRING DISORDERS; SUBSTANCE-ABUSE; MENTAL-HEALTH; RISK-FACTORS; VICTIMIZATION; ASSOCIATION; THERAPY AB This study examined lifetime exposure to traumatic events as reported by 581 homeless female veterans enrolled in a Homeless Women Veterans Program across 11 sites to characterize the types of trauma they experienced; their correlation with baseline characteristics; and their association with housing, clinical outcomes, and psychosocial functioning over a 1-year treatment period. Almost all participants endorsed multiple types and episodes of traumatic events. Among the most common were having someone close experience a serious or life-threatening illness (82%) and rape (67%). Exploratory factor analysis revealed 6 potential trauma categories: being robbed, experiencing accident or disasters, illness or death of others, combat, sexual assault, and physical assault. At baseline, trauma from sexual assault was associated with more days homeless (beta = .18, p < .001), trauma from accidents or disasters was associated with poorer physical health (beta = -.23, p < .001), and trauma from being robbed was related to greater use of drugs (beta = .22, p < .001). Trauma reported at baseline, however, was not predictive of 1-year outcomes, suggesting type and frequency of trauma does not negatively affect the housing gains homeless women veterans can achieve through homeless services. C1 [Tsai, Jack; Rosenheck, Robert A.; Decker, Suzanne E.; Harpaz-Rotem, Ilan] Vet Affairs New England Mental Illness, Res Educ & Clin Ctr, West Haven, CT USA. [Tsai, Jack; Rosenheck, Robert A.; Decker, Suzanne E.; Desai, Rani A.; Harpaz-Rotem, Ilan] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Rosenheck, Robert A.; Desai, Rani A.] Yale Univ, Sch Epidemiol & Publ Hlth, New Haven, CT USA. [Desai, Rani A.] US Dept Vet Affairs, NE Program Evaluat Ctr, West Haven, CT USA. [Harpaz-Rotem, Ilan] VA Connecticut Healthcare Syst, Clin Neurosci Div, Natl Ctr Posttraumat Stress Disorder, West Haven, CT USA. RP Tsai, J (reprint author), VACT, 950 Campbell Ave,151D, West Haven, CT 06516 USA. EM Jack.Tsai@yale.edu RI Tsai, Jack/D-3889-2013; OI Tsai, Jack/0000-0002-0329-648X NR 37 TC 4 Z9 4 U1 3 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD DEC PY 2012 VL 25 IS 6 BP 624 EP 632 DI 10.1002/jts.21750 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 051TW UT WOS:000312151400003 PM 23225030 ER PT J AU Haak, CS Farinelli, WA Tam, J Doukas, AG Anderson, RR Haedersdal, M AF Haak, Christina S. Farinelli, William A. Tam, Joshua Doukas, Apostolos G. Anderson, R. Rox Haedersdal, Merete TI Fractional laser-assisted delivery of methyl aminolevulinate: Impact of laser channel depth and incubation time SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE drug delivery; fractional CO2 laser; photosensitizer ID BASAL-CELL CARCINOMA; NONMELANOMA SKIN-CANCER; PHOTODYNAMIC THERAPY; ENDOGENOUS PROTOPORPHYRIN; PROSPECTIVE TRIAL; GUIDELINES; PHOTOTHERMOLYSIS; MULTICENTER; SURGERY; UPDATE AB Background and Objectives Pretreatment of skin with ablative fractional lasers (AFXL) enhances the uptake of topical photosensitizers used in photodynamic therapy (PDT). Distribution of photosensitizer into skin layers may depend on depth of laser channels and incubation time. This study evaluates whether depth of intradermal laser channels and incubation time may affect AFXL-assisted delivery of methyl aminolevulinate (MAL). Materials and Methods Yorkshire swine were treated with CO2 AFXL at energy levels of 37, 190, and 380?mJ/laser channel and subsequent application of MAL cream (Metvix (R)) for 30, 60, 120, and 180?minutes incubation time. Fluorescence photography and fluorescence microscopy quantified MAL-induced porphyrin fluorescence (PpIX) at the skin surface and at five specific skin depths (120, 500, 1,000, 1,500, and 1,800?mu m). Results Laser channels penetrated into superficial (similar to 300?mu m), mid (similar to 1,400?mu m), and deep dermis/upper subcutaneous fat layer (similar to 2,100?mu m). Similar fluorescence intensities were induced at the skin surface and throughout skin layers independent of laser channel depth (180?minutes; P?-/- mice, George Washington and the COBRE Animal Pathobiology Core, as well as Margaret H. Romano and the Core Histology Laboratory at MUSC for their technical assistance. NR 43 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD DEC PY 2012 VL 99 IS 3-4 BP 124 EP 130 DI 10.1016/j.prostaglandins.2012.08.003 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 056SN UT WOS:000312511800008 PM 22940715 ER PT J AU Schouten, R AF Schouten, Ronald TI Psychiatric Consultation in Problem Employee Situations SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article DE Occupational psychiatry; Americans with Disabilities Act; Violence risk assessment; Fitness for duty evaluations; Workplace violence; Disability discrimination ID EXPERT WITNESS; CLINICIAN; VIOLENCE AB This article focuses on psychiatric consultation in "problem employee situations," a broad term that refers to any situation in which there is conflict between an employee and the employer or coworkers. It summarizes key principles and observations that are common to psychiatric consultations in the workplace and then offers case examples that are representative of such consultations and highlights those principles. Although the focus is on psychiatric consultation to employers, an employee may seek consultation himself or herself, especially when prospects for adversarial proceedings arise. The principles described here apply in both sets of circumstances. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Law & Psychiat Serv, Boston, MA 02114 USA. RP Schouten, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Law & Psychiat Serv, 15 Parkman St,WAC 812, Boston, MA 02114 USA. EM rschouten@partners.org NR 13 TC 0 Z9 0 U1 1 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD DEC PY 2012 VL 35 IS 4 BP 901 EP + DI 10.1016/j.psc.2012.08.010 PG 15 WC Psychiatry SC Psychiatry GA 058FE UT WOS:000312618700009 PM 23107569 ER PT J AU Simpson, TL Stappenbeck, CA Varra, AA Moore, SA Kaysen, D AF Simpson, Tracy L. Stappenbeck, Cynthia A. Varra, Alethea A. Moore, Sally A. Kaysen, Debra TI Symptoms of Posttraumatic Stress Predict Craving Among Alcohol Treatment Seekers: Results of a Daily Monitoring Study SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article DE alcohol craving; PTSD; daily monitoring; self-medication hypothesis ID ECOLOGICAL MOMENTARY ASSESSMENT; SUBSTANCE USE DISORDERS; TIMELINE FOLLOW BACK; PTSD CHECKLIST; CUE REACTIVITY; PSYCHOMETRIC PROPERTIES; DRINKING PATTERNS; FEMALE VETERANS; NEGATIVE AFFECT; SEXUAL ASSAULT AB Alcohol use disorders (AUDs) and Posttraumatic Stress Disorder (PTSD) commonly co-occur. Craving for alcohol is a common aspect of AUD, with and without PTSD, and is one of the key predictors of continued problematic alcohol use among treatment seekers. The present study sought to investigate the self-medication hypothesis using daily Interactive Voice Response (IVR) reports to examine the relationships between PTSD symptomatology and both same-day and next-day alcohol craving. Twenty-nine individuals with an AUD (26 of whom screened positive for PTSD) entering AUD treatment provided daily IVR data for up to 28 days regarding their alcohol use, craving, and 7 symptoms of PTSD. Given the nested nature of daily data, generalized estimating equations using a negative binomial distribution and a log link function were used to test hypotheses. Results suggest that days with greater overall PTSD severity are associated with greater alcohol craving, and greater reports of startle and anger/irritability were particularly associated with same-day craving. The next-day results suggest that the combination of the 7 PTSD symptoms did not predict next-day craving. However, greater distress from nightmares the previous night, emotional numbing, and hypervigilance predicted greater next-day craving, while greater anger/irritability predicted lower next-day craving. These findings highlight the importance of assessing the relationship between specific symptoms of PTSD and alcohol cravings in order to increase our understanding of the functional interplay among them for theory building. Additionally, clinicians may be better able to refine treatment decisions to more efficiently break the cycle between PTSD-related distress and AUD symptoms. C1 [Simpson, Tracy L.; Stappenbeck, Cynthia A.; Varra, Alethea A.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. [Simpson, Tracy L.; Varra, Alethea A.; Moore, Sally A.; Kaysen, Debra] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Moore, Sally A.] Evidence Based Treatment Ctr Seattle PLLC, Seattle, WA USA. RP Simpson, TL (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. EM Tracy.Simpson@va.gov NR 70 TC 22 Z9 22 U1 4 U2 16 PU EDUCATIONAL PUBLISHING FOUNDATION-AMERICAN PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X EI 1939-1501 J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD DEC PY 2012 VL 26 IS 4 BP 724 EP 733 DI 10.1037/a0027169 PG 10 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA 059CM UT WOS:000312682000005 PM 22369221 ER PT J AU Berbeco, RI Korideck, H Ngwa, W Kumar, R Patel, J Sridhar, S Johnson, S Price, BD Kimmelman, A Makrigiorgos, GM AF Berbeco, Ross I. Korideck, Houari Ngwa, Wilfred Kumar, Rajiv Patel, Janki Sridhar, Srinivas Johnson, Sarah Price, Brendan D. Kimmelman, Alec Makrigiorgos, G. Mike TI DNA Damage Enhancement from Gold Nanoparticles for Clinical MV Photon Beams SO RADIATION RESEARCH LA English DT Article ID TARGETED DRUG-DELIVERY; DOSE ENHANCEMENT; RADIATION-THERAPY; PLATFORM AB Berbeco, R. I., Korideck, H., Ngwa, W., Kumar, R., Patel, J., Sridhar, S., Johnson, S., Price, B. D., Kimmelman, A. and Makrigiorgos, G. M. DNA Damage Enhancement from Gold Nanoparticles for Clinical MV Photon Beams. Radiat. Res. 178, 604-608 (2012). In this study, we quantify the relative damage enhancement due to the presence of gold nanoparticles (GNP) in vitro in a clinical 6 MV beam for various delivery parameters and depths. It is expected that depths and delivery modes that produce a larger proportions of low-energy photons will have a larger effect on the cell samples containing GNP. HeLa cells with and without 50 nm GNP were irradiated at depths of 1.5, 5, 10, 15 and 20 cm. Conventional beams with square aperture sizes 5, 10 and 15 cm at isocenter, and flattening filter free (FFF) beams were used. Relative DNA damage enhancement with GNP was evaluated by gamma-H2AX staining. Statistically significant increases in DNA damage with GNP, compared to the absence of GNP, were observed for all depths and delivery modes. Relative to the shallowest depth, damage enhancement was observed to increase as a function of increasing depth for all deliveries. For the conventional (open field) delivery, DNA damage enhancement with GNP was seen to increase as a function of field size. For FFF delivery, a substantial increase in enhancement was found relative to the conventional field delivery. The measured relative DNA damage enhancement validates the theoretically predicted trends as a function of depth and delivery mode for clinical MV photon beams. The results of this study open new possibilities for the clinical development of gold nanoparticle-aided radiation therapy. (c) 2012 by Radiation Research Society C1 [Berbeco, Ross I.; Korideck, Houari; Ngwa, Wilfred; Kimmelman, Alec; Makrigiorgos, G. Mike] Brigham & Womens Hosp, Dept Radiat Oncol, Div Med Phys & Biophys, Dana Farber Canc Inst, Boston, MA 02115 USA. [Berbeco, Ross I.; Korideck, Houari; Ngwa, Wilfred; Johnson, Sarah; Price, Brendan D.; Kimmelman, Alec; Makrigiorgos, G. Mike] Harvard Univ, Sch Med, Boston, MA USA. [Kumar, Rajiv; Patel, Janki; Sridhar, Srinivas] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Johnson, Sarah; Price, Brendan D.] Dana Farber Canc Inst, Dept Radiat Oncol, Div Genom Instabil & DNA Repair, Boston, MA 02115 USA. RP Berbeco, RI (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, Div Med Phys & Biophys, Dana Farber Canc Inst, 75 Francis St,ASBI-L2, Boston, MA 02115 USA. EM rberbeco@lroc.harvard.edu FU BWH Biomedical Research Institute; NTH grant [CA93602] FX The authors would like to thank Buford J. Maddox and Cliff Miner for assistance with the flattening filter free delivery on the clinical linear accelerator. This project was supported, in part, by a grant from the BWH Biomedical Research Institute and by NTH grant CA93602 to BDP. NR 26 TC 26 Z9 28 U1 0 U2 20 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD DEC PY 2012 VL 178 IS 6 BP 604 EP 608 DI 10.1667/RR3001.1 PG 5 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 060AV UT WOS:000312748900011 PM 23148509 ER PT J AU Shuja, F Kwolek, CJ AF Shuja, Fahad Kwolek, Christopher J. TI Treating the Paravisceral Aorta with Parallel Endografts (Chimneys and Snorkels) SO SEMINARS IN VASCULAR SURGERY LA English DT Article ID ENDOVASCULAR ANEURYSM REPAIR; BRANCH VESSELS; GRAFT; PATHOLOGIES; EXPERIENCE; OUTCOMES; PATENCY; COMPLEX; STENTS; TRIAL AB While excellent results can be achieved with the open repair of juxtarenal and suprarenal aortic aneurysms in good-risk patients, the outcomes in high-risk patients are less favorable. The use of standard infrarenal endografts to treat these patients has been limited due to the absence of a suitable proximal landing zone. Using infrarenal endografts outside the instructions for use has been shown to lead to poorer outcomes with a higher incidence of type I endoleaks and graft migration. Fenestrated and branched endografts are viable options, but until recently have not been commercially available within the United States. In addition, they require meticulous preoperative planning and 4 to 6 weeks to manufacture. This makes them unsuitable for use in the urgent setting. Others have looked at the use of parallel covered stents placed alongside the main endograft body, the "chimney" or "snorkel" graft technique, to allow for continued perfusion to visceral/renal vessels. This technique allows for proximal placement of the landing zone of the main body, while maintaining blood flow to critical branches. The purpose of this article is to review the current literature on chimney grafts, their efficacy, and associated morbidity and mortality. Semin Vase Surg 25:200-202 (C) 2012 Published by Elsevier Inc. C1 [Shuja, Fahad; Kwolek, Christopher J.] Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. RP Kwolek, CJ (reprint author), Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, 15 Parkman St,WAC 442, Boston, MA 02114 USA. EM ckwolek@partners.org RI caicedo valdes, diego/I-1145-2012 NR 24 TC 3 Z9 3 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0895-7967 J9 SEMIN VASC SURG JI Semin. Vasc. Surg. PD DEC PY 2012 VL 25 IS 4 BP 200 EP 202 DI 10.1053/j.semvascsurg.2012.09.005 PG 3 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 056RX UT WOS:000312510200005 PM 23206566 ER PT J AU Kushida, CA Nichols, DA Holmes, TH Quan, SF Walsh, JK Gottlieb, DJ Simon, RD Guilleminault, C White, DP Goodwin, JL Schweitzer, PK Leary, EB Hyde, PR Hirshkowitz, M Green, S McEvoy, LK Chan, C Gevins, A Kay, GG Bloch, DA Crabtree, T Dement, WC AF Kushida, Clete A. Nichols, Deborah A. Holmes, Tyson H. Quan, Stuart F. Walsh, James K. Gottlieb, Daniel J. Simon, Richard D., Jr. Guilleminault, Christian White, David P. Goodwin, James L. Schweitzer, Paula K. Leary, Eileen B. Hyde, Pamela R. Hirshkowitz, Max Green, Sylvan McEvoy, Linda K. Chan, Cynthia Gevins, Alan Kay, Gary G. Bloch, Daniel A. Crabtree, Tami Dement, William C. TI Effects of Continuous Positive Airway Pressure on Neurocognitive Function in Obstructive Sleep Apnea Patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) SO SLEEP LA English DT Article DE Obstructive sleep apnea; continuous positive airway pressure; neurocognitive function; randomized controlled trial; sleepiness ID PRINCIPAL COMPONENT ANALYSIS; NEUROPSYCHOLOGICAL DEFICITS; CLINICAL-TRIALS; APNEA/HYPOPNEA SYNDROME; BREATHING DISORDERS; COGNITIVE FUNCTION; PROPENSITY SCORE; CPAP THERAPY; PERFORMANCE; SELECTION AB Study Objective: To determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA). Design, Setting, and Participants: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures. Intervention: Active or sham CPAP Measurements: Three neurocognitive variables, each representing a neurocognitive domain: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F]) Results: The primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test. Conclusions: CPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship. C1 [Kushida, Clete A.; Nichols, Deborah A.; Holmes, Tyson H.; Guilleminault, Christian; Leary, Eileen B.; Hyde, Pamela R.; Bloch, Daniel A.; Dement, William C.] Stanford Univ, Stanford, CA 94305 USA. [Quan, Stuart F.; Goodwin, James L.; Green, Sylvan] Univ Arizona, Tucson, AZ USA. [Walsh, James K.; Schweitzer, Paula K.] St Lukes Hosp, Chesterfield, MO USA. [Gottlieb, Daniel J.] VA Boston Healthcare Syst, Boston, MA USA. [Quan, Stuart F.; Gottlieb, Daniel J.; White, David P.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Simon, Richard D., Jr.] Providence St Mary Med Ctr, Walla Walla, WA USA. [Hirshkowitz, Max] VAMC Sleep Ctr, Houston, TX USA. [McEvoy, Linda K.] Univ Calif San Diego, San Diego, CA 92103 USA. [Chan, Cynthia; Gevins, Alan] SAM Technol Inc, San Francisco, CA USA. [Chan, Cynthia; Gevins, Alan] San Francisco Brain Res Inst, San Francisco, CA USA. [Kay, Gary G.] Georgetown Univ, Sch Med, Washington, DC USA. RP Kushida, CA (reprint author), Stanford Sleep Med Ctr, 450 Broadway St,MC 5704,Pavill C,2nd Floor, Redwood City, CA 94063 USA. EM clete@stanford.edu FU Respironics, Inc.; ResMed; Pacific Medico Co., Ltd.; Merck Co.; Cephalon; Ventus Medical; Jazz Pharmaceuticals; Respironics; Pfizer; Somnus; Vanda Pharmaceuticals; Neurogen; Sanofi-Aventis; Apnex; World Class CME; Apnex Medical; Merck Sharpe Dohme FX This study was funded by Respironics, Inc. Dr. Kushida received research support through Stanford University from ResMed, Pacific Medico Co., Ltd., Merck & Co., Cephalon, Ventus Medical, Jazz Pharmaceuticals, and Respironics. Dr. Walsh receives research support from Pfizer, Merck & Co., Somnus, Vanda Pharmaceuticals, Neurogen, Sanofi-Aventis, Ventus Medical, Respironics, Apnex, and Jazz Pharmaceuticals. He has consulted for Sanofi-Aventis, Respironics, Transcept, Neurogen, Glaxo-SmithKline, Eli Lilly, Merck & Co., Kingsdown, Vanda Pharmaceuticals, Ventus Medical, Vivus Inc., and Somnus Therapeutics, Inc. Dr. Simon has consulted for Asante Communications and has received sponsorship fees from World Class CME. Dr. White is the chief medical officer for Philips Respironics. Dr. Schweitzer has received research support from Apnex Medical, Merck Sharpe & Dohme, Vanda Pharmaceuticals, and Ventus Medical. She also serves on the speaker bureau for Somaxon Pharmaceuticals. Dr. Hirshkowitz serves on the speaker bureau for Cephalon and Somaxon Pharmaceuticals. Dr. Gevins is employed by Technology, Inc. Dr. Kay is the president of a contract research organization; clients in the last 12 months: Allergan, Arena, Factor Nutrition, Helicon, Merck & Co., Pfizer, Shire, Vivus Inc., and Watson. The other authors have indicated no financial conflicts of interest. NR 71 TC 80 Z9 81 U1 3 U2 16 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD DEC 1 PY 2012 VL 35 IS 12 BP 1593 EP U40 DI 10.5665/sleep.2226 PG 30 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 063LO UT WOS:000313000600005 PM 23204602 ER PT J AU Jonker, MA Sauerhammer, TM Faucher, LD Schurr, MJ Kudsk, KA AF Jonker, Mark A. Sauerhammer, Tina M. Faucher, Lee D. Schurr, Michael J. Kudsk, Kenneth A. TI Bilateral versus Unilateral Bronchoalveolar Lavage for the Diagnosis of Ventilator-Associated Pneumonia SO SURGICAL INFECTIONS LA English DT Article ID NOSOCOMIAL PNEUMONIA; QUANTITATIVE CULTURES; RANDOMIZED-TRIAL; TRAUMA PATIENTS; RISK-FACTORS; BLIND; EFFICACY; BRONCHOSCOPY; MANAGEMENT; ACCURACY AB Background: Ventilator-associated pneumonia (VAP) complicates the clinical course of critically injured intubated patients. Bronchoscopic bronchoalveolar lavage (BAL) represents an invasive and accurate means of VAP diagnosis. Unilateral and blinded techniques offer less invasive alternatives to bronchoscopic BAL. This study evaluated clinical criteria as well as unilateral directed versus bilateral BAL for VAP diagnosis. Methods: A retrospective chart review of 113 consecutive intubated trauma patients with clinically suspected VAP undergoing unilateral versus bilateral BAL was performed with comparison of positive culture results (>10(4) colony-forming units [CFU]/mL). Culture results were compared with chest radiograph (CXR) infiltrates and white blood cell (WBC) count elevation. Results: Bilateral BAL was more likely to be positive than unilateral BAL (50.4% vs. 25.5%). In 37.1% of bilateral BALs, there was discordance between the sides of positivity or the bacteria isolated. A CXR infiltrate and WBC count elevation did not predict positive BAL. Conclusions: Clinical indicators of VAP are inaccurate, and bilateral bronchoscopic BAL is more likely than unilateral BAL to provide a positive sample in intubated trauma patients. Techniques that do not sample both lungs reliably should be avoided for diagnosis in this patient population. C1 [Jonker, Mark A.; Sauerhammer, Tina M.; Faucher, Lee D.; Schurr, Michael J.; Kudsk, Kenneth A.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Madison, WI USA. [Kudsk, Kenneth A.] William S Middleton Mem Vet Adm Med Ctr, Vet Adm Surg Serv, Madison, WI USA. RP Kudsk, KA (reprint author), 600 Highland Ave,H4-736 CSC, Madison, WI 53792 USA. EM kudsk@surgery.wisc.edu FU National Institute of Health (NIH) [R01 GM53439]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Service FX This research is supported by National Institute of Health (NIH) Grant R01 GM53439.; This material is also based on work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Service. The contents of this article do not represent the views of the Dept. of Veterans Affairs or the United States Government. NR 32 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-2964 J9 SURG INFECT JI Surg. Infect. PD DEC PY 2012 VL 13 IS 6 BP 391 EP 395 DI 10.1089/sur.2011.081 PG 5 WC Infectious Diseases; Surgery SC Infectious Diseases; Surgery GA 061GF UT WOS:000312835800008 PM 23240724 ER PT J AU Rodrigues, FSLM Yang, XY Nikaido, M Liu, QS Kelsh, RN AF Rodrigues, Frederico S. L. M. Yang, Xueyan Nikaido, Masataka Liu, Qingsong Kelsh, Robert N. TI A Simple, Highly Visual in Vivo Screen for Anaplastic Lymphoma Kinase Inhibitors SO ACS CHEMICAL BIOLOGY LA English DT Article ID PROTEIN-TYROSINE KINASE; NON-HODGKINS-LYMPHOMA; CELL LUNG-CANCER; ALK KINASE; ACTIVATING MUTATIONS; C-MET; NEUROBLASTOMA; ZEBRAFISH; GENE; IDENTIFICATION AB Anaplastic lymphoma kinase (ALK) is an important drug target in many cancers, including lymphoma, neuroblastoma, and lung cancer. Here, we demonstrate proof-of-principle for a novel and inexpensive assay for ALK inhibitor activity and identification in zebrafish. We demonstrate that the human oncogenic ALK fusion, NPM-ALK, drives overproduction of iridophores, a highly visible, shiny pigment cell-type in zebrafish. Treatment with the potent ALK inhibitor, TAE684, fully inhibits production of ALK-dependent iridophores. Using our assay, we test multiple properties of TAE684 in vivo, including efficacy, specificity, and toxicity. We note that TAE684 also inhibits the closely related leukocyte tyrosine kinase (Ltk) that is required for endogenous iridophore development. Similar effects are observed with an independent inhibitor, Crizotinib. Our assay can thus be utilized to identify ALK or LTK inhibitors. Importantly, the natural reflectivity of iridophores lends itself to automation for high throughput assessment of ALK and LTK inhibitor compounds in vivo. C1 [Rodrigues, Frederico S. L. M.; Yang, Xueyan; Nikaido, Masataka; Kelsh, Robert N.] Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath BA2 7AY, Avon, England. [Liu, Qingsong] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Liu, Qingsong] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kelsh, RN (reprint author), Univ Bath, Dept Biol & Biochem, Ctr Regenerat Med, Bath BA2 7AY, Avon, England. EM bssrnk@bath.ac.uk RI Kelsh, Robert/B-6445-2008; OI Kelsh, Robert/0000-0002-9381-0066; liu, qing song/0000-0002-7829-2547 FU MRC [G0400806]; Wellcome Trust [066326, 077454]; Fundacao para a Ciencia e Tecnologia (FCT) FX We wish to thank S. Elworthy for the original suggestion to use the NPM-ALK assay as a kinase inhibitor screen, R. Jager for the NPM-ALK clone, C. Chien for IRES-eGFP fragment, and N. Gray, P. Janne, and C. Miduturu for providing kinase profiling data. We thank C. de Paiva for technical assistance with some Vatalanib experiments. We are grateful to C. Anastasaki for the schematic figures and to M. Morais for the chemical structure figures. We thank E. Patton for comments on versions of this manuscript. We gratefully acknowledge the support of the MRC (grant G0400806 to R.N.K.), the Wellcome Trust (grants 066326 and 077454), and Fundacao para a Ciencia e Tecnologia (FCT; to F.S.L.M.R.) for funding this work. NR 34 TC 5 Z9 6 U1 0 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD DEC PY 2012 VL 7 IS 12 BP 1968 EP 1974 DI 10.1021/cb300361a PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 057LE UT WOS:000312564000005 PM 22985331 ER PT J AU Mader, BJ Pivtoraiko, VN Flippo, HM Klocke, BJ Roth, KA Mangieri, LR Shacka, JJ AF Mader, Burton J. Pivtoraiko, Violetta N. Flippo, Hilary M. Klocke, Barbara J. Roth, Kevin A. Mangieri, Leandra R. Shacka, John J. TI Rotenone Inhibits Autophagic Flux Prior to Inducing Cell Death SO ACS CHEMICAL NEUROSCIENCE LA English DT Article DE Rotenone; autophagy; lysosome; cell death; Parkinson's disease; SH-SY5Y ID LYSOSOMAL DEGRADATION PATHWAY; PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; MEMBRANE PERMEABILIZATION; DOPAMINERGIC-NEURONS; SH-SY5Y CELLS; DYSFUNCTION; APOPTOSIS; MODELS; CLEARANCE AB Rotenone, which selectively inhibits mitochondrial complex I, induces oxidative stress, alpha-synuclein accumulation, and dopaminergic neuron death, principal pathological features of Parkinson's disease. The autophagy-lysosome pathway degrades damaged proteins and organelles for the intracellular maintenance of nutrient and energy balance. While it is known that rotenone causes autophagic vacuole accumulation, the mechanism by which this effect occurs has not been thoroughly investigated. Treatment of differentiated SH-SY5Y cells with rotenone (10 mu M) induced the accumulation of autophagic vacuoles at 6 h and 24 h as indicated by Western blot analysis for microtubule associated protein-light chain 3-II (MAP-LC3-II). Assessment of autophagic flux at these time points indicated that autophagic vacuole accumulation resulted from a decrease in their effective lysosomal degradation, which was substantiated by increased levels of autophagy substrates p62 and alpha-synuclein. Inhibition of lysosomal degradation may be explained by the observed decrease in cellular ATP levels, which in turn may have caused the observed concomitant increase in acidic vesicle pH. The early (6 h) effects of rotenone on cellular energetics and autophagy-lysosome pathway function preceded the induction of cell death and apoptosis. These findings indicate that the classical mitochondrial toxin rotenone has a pronounced effect on macroautophagy completion that may contribute to its neurotoxic potential. C1 [Shacka, John J.] Univ Alabama Birmingham, Dept Pathol, Div Neuropathol, Birmingham, AL 35294 USA. Birmingham VA Med Ctr, Birmingham, AL USA. RP Shacka, JJ (reprint author), Univ Alabama Birmingham, Dept Pathol, Div Neuropathol, SC 930G4,1530 3rd Ave S, Birmingham, AL 35294 USA. EM shacka@uab.edu RI di Ronza, Alberto/H-7674-2016; OI di Ronza, Alberto/0000-0002-9813-5143; Mangieri, Leandra/0000-0001-8981-0103; Roth, Kevin/0000-0002-0643-995X FU VA Merit Award [1 101 BX000957-01]; NIH R01s (National) [NS35107, NS41962, CA134773] FX J.J.S. is supported by a VA Merit Award 1 101 BX000957-01. K.A.R. is supported by NIH R01s (National NS35107, NS41962, and CA134773. We also thank the UAB Neuroscience Core facilities (NS047466 and NS057098) for technical assistance. NR 41 TC 25 Z9 25 U1 2 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1948-7193 J9 ACS CHEM NEUROSCI JI ACS Chem. Neurosci. PD DEC PY 2012 VL 3 IS 12 BP 1063 EP 1072 DI 10.1021/cn300145z PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Neurosciences SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Neurosciences & Neurology GA 057LH UT WOS:000312564400010 PM 23259041 ER PT J AU Blevins, JE Moralejo, DH Wolden-Hanson, TH Thatcher, BS Ho, JM Kaiyala, KJ Matsumoto, K AF Blevins, James E. Moralejo, Daniel H. Wolden-Hanson, Tami H. Thatcher, Brendan S. Ho, Jacqueline M. Kaiyala, Karl J. Matsumoto, Kozo TI Alterations in activity and energy expenditure contribute to lean phenotype in Fischer 344 rats lacking the cholecystokinin-1 receptor gene SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE satiety; meal size; cholecystokinin; CCK1 receptors ID DEPENDENT DIABETES-MELLITUS; C-FOS EXPRESSION; TOKUSHIMA FATTY RAT; QUANTITATIVE-TRAIT LOCUS; INDUCED OBESE RATS; BRAIN-STEM NUCLEI; FOOD-INTAKE; BODY-WEIGHT; MICE LACKING; A RECEPTORS AB Blevins JE, Moralejo DH, Wolden-Hanson TH, Thatcher BS, Ho JM, Kaiyala KJ, Matsumoto K. Alterations in activity and energy expenditure contribute to lean phenotype in Fischer 344 rats lacking the cholecystokinin-1 receptor gene. Am J Physiol Regul Integr Comp Physiol 303: R1231-R1240, 2012. First published October 31, 2012; doi:10.1152/ajpregu.00393.2012.-CCK is hypothesized to inhibit meal size by acting at CCK1 receptors (CCK1R) on vagal afferent neurons that innervate the gastrointestinal tract and project to the hindbrain. Earlier studies have shown that obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which carry a spontaneous null mutation of the CCK1R, are hyperphagic and obese. Recent findings show that rats with CCK1R-null gene on a Fischer 344 background (Cck1r(-/-)) are lean and normophagic. In this study, the metabolic phenotype of this rat strain was further characterized. As expected, the CCK1R antagonist, devazepide, failed to stimulate food intake in the Cck1r(-/-) rats. Both Cck1r(+/+) and Cck1r(-/-) rats became diet-induced obese (DIO) when maintained on a high-fat diet relative to chow-fed controls. Cck1r(-/-) rats consumed larger meals than controls during the dark cycle and smaller meals during the light cycle. These effects were accompanied by increased food intake, total spontaneous activity, and energy expenditure during the dark cycle and an apparent reduction in respiratory quotient during the light cycle. To assess whether enhanced responsiveness to anorexigenic factors may contribute to the lean phenotype, we examined the effects of melanotan II (MTII) on food intake and body weight. We found an enhanced effect of MTII in Cck1r(-/-) rats to suppress food intake and body weight following both central and peripheral administration. These results suggest that the lean phenotype is potentially driven by increases in total spontaneous activity and energy expenditure. C1 [Moralejo, Daniel H.] Univ Texas MD Anderson Canc Ctr, Dept Vet Sci, Bastrop, TX USA. [Blevins, James E.; Wolden-Hanson, Tami H.; Thatcher, Brendan S.; Ho, Jacqueline M.] VA Puget Sound Hlth Care Syst, Off Res & Dev, Med Res Serv, Dept Vet Affairs Med Ctr, Seattle, WA USA. [Blevins, James E.; Ho, Jacqueline M.] Univ Washington, Sch Med, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. [Kaiyala, Karl J.] Univ Washington, Dept Dent Publ Hlth Sci, Seattle, WA 98195 USA. [Matsumoto, Kozo] Kyoto Sangyo Univ, Fac Life Sci, Dept Anim Med Sci, Kyoto 603, Japan. RP Moralejo, DH (reprint author), UT MD Anderson Canc Ctr, Dept Vet Sci, Michale E Keeling Ctr Comparat Med & Res, 650 Cool Water Dr, Bastrop, TX 78602 USA. EM moralejo@uw.edu FU Office of Research and Development, Medical Research Service, Department of Veterans Affairs (VA); VA Puget Sound Health Care System Rodent Metabolic and Behavioral Phenotyping Core; biomedical research core program of the National Institutes of Health (NIH) Diabetes Research Center at the University of Washington; American Diabetes Association [1-05-JF-32]; Department of VA Merit Review Research Program, NIH [DK-17047, RO1DK-61516, P30DK017047-31, P30KD017047-31689] FX This material is based upon work supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs (VA), the VA Puget Sound Health Care System Rodent Metabolic and Behavioral Phenotyping Core, the biomedical research core program of the National Institutes of Health (NIH) Diabetes Research Center at the University of Washington, and the American Diabetes Association. The research in our laboratory has been supported by the Department of VA Merit Review Research Program, NIH Grants DK-17047, RO1DK-61516, P30DK017047-31, and P30KD017047-31689, and by the Junior Faculty Award 1-05-JF-32 by the American Diabetes Association. NR 56 TC 4 Z9 4 U1 1 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD DEC PY 2012 VL 303 IS 12 BP R1231 EP R1240 DI 10.1152/ajpregu.00393.2012 PG 10 WC Physiology SC Physiology GA 057SQ UT WOS:000312584700003 PM 23115121 ER PT J AU Kim, KS Kim, MJ Kononen, E Lounatmaa, K Summanen, P Finegold, SM AF Kim, Keun-Sung Kim, Min-Ju Kononen, Eija Lounatmaa, Kari Summanen, Paula Finegold, Sydney M. TI Single nucleotide polymorphisms are randomly dispersed and mostly synonymous in partial rpoB and cpn60 genes of Campylobacter showae human isolates SO ANAEROBE LA English DT Article DE Campylobacter showae; 16S rRNA gene; rpoB gene; cpn60 gene; SNPs AB The partial 16S rRNA, rpoB, and cpn60 genes congruently allow this study to identify all the eight isolates as the species Campylobacter showae. To our knowledge, this is the first report to reveal the interspecies and intraspecies sequence variations present in the three genes of the C. showae isolates. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Kim, Keun-Sung; Kim, Min-Ju] Chung Ang Univ, Dept Food Sci & Technol, Ansung 456756, Kyungki Do, South Korea. [Kononen, Eija] Natl Inst Hlth & Welf, Bacteriol Unit, Helsinki, Finland. [Kononen, Eija] Univ Turku, Inst Dent, Turku, Finland. [Lounatmaa, Kari] Oy Lounatmaa Ltd, Helsinki, Finland. [Summanen, Paula] W Los Angeles Vet Affairs Med Ctr, Res Serv, Los Angeles, CA 90073 USA. [Finegold, Sydney M.] W Los Angeles Vet Affairs Med Ctr, Infect Dis Sect, Los Angeles, CA 90073 USA. [Finegold, Sydney M.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Finegold, Sydney M.] Univ Calif Los Angeles, Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA. RP Kim, KS (reprint author), Chung Ang Univ, Dept Food Sci & Technol, Ansung 456756, Kyungki Do, South Korea. EM keunsung@cau.ac.kr FU DOD [W81XWH-0510134]; VA Merit Review funds FX This work has been supported, in part, by DOD Grant # W81XWH-0510134 and by VA Merit Review funds. NR 5 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1075-9964 J9 ANAEROBE JI Anaerobe PD DEC PY 2012 VL 18 IS 6 BP 626 EP 629 DI 10.1016/j.anaerobe.2012.09.006 PG 4 WC Microbiology SC Microbiology GA 056FK UT WOS:000312473600012 PM 23022203 ER PT J AU Jung, D Bhattacharyya, N AF Jung, David Bhattacharyya, Neil TI Association of Hearing Loss With Decreased Employment and Income Among Adults in the United States SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE employment; hearing loss; income; wage ID EXPENDITURE; PREVALENCE AB Objectives: We evaluated the association of hearing loss with employment and income in adults. Methods: Patients with a coded diagnosis of hearing loss were identified from the 2006 and 2008 Medical Expenditure Panel Survey linked household and medical conditions files and compared to patients without hearing loss. Differences in employment, wage income, and Supplemental Security Income were evaluated with multivariate regression models after adjustment for several demographic and Charlson comorbidity variables. Results: An estimated 933,921 88,474 adults were identified with hearing loss (54.7% of whom were male; mean age for all, 51.0 years). Patients with hearing loss were more likely to be unemployed or partly unemployed than those without hearing loss (adjusted odds ratio, 2.2; p < 0.001). Similarly, adults with hearing loss were less likely to have any wage income than those without hearing loss (adjusted odds ratio, 2.5; p < 0.001). The population with hearing loss earned a mean wage of $23,481 +/- $3,366, versus $31,272 +/- $517 for the population without hearing loss (difference in wages, $7,791; p < 0.001). The association between hearing loss and receiving Supplemental Security Income was not significant (p = 0.109). Conclusions: Adults with hearing loss are more likely to be unemployed and on average earn significantly less wage income than adults without hearing loss. Further work is needed to determine the potential impact of treatment on these differences. C1 [Jung, David] Massachusetts Eye & Ear Infirm, Harvard Otolaryngol Training Program, Boston, MA 02114 USA. [Jung, David; Bhattacharyya, Neil] Harvard Univ, Sch Med, Dept Otol & Laryngol, Cambridge, MA 02138 USA. [Bhattacharyya, Neil] Brigham & Womens Hosp, Div Otolaryngol, Boston, MA 02115 USA. RP Jung, D (reprint author), Massachusetts Eye & Ear Infirm, Harvard Otolaryngol Training Program, 243 Charles St, Boston, MA 02114 USA. NR 14 TC 12 Z9 13 U1 2 U2 6 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD DEC PY 2012 VL 121 IS 12 BP 771 EP 775 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA 056CX UT WOS:000312467100001 PM 23342548 ER PT J AU Nierenberg, AA Bentley, KH Farabaugh, AH Fava, M Deckersbach, T AF Nierenberg, Andrew A. Bentley, Kate H. Farabaugh, Amy H. Fava, Maurizio Deckersbach, Thilo TI The absence of depressive symptoms is not the presence of wellness: Validation of the Clinical Positive Affect Scale SO AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY LA English DT Article DE Clinical positive affect scale; self-report questionnaire; validation ID NEGATIVE AFFECT SCHEDULE; ABUSE SCREENING-TEST; DSM-IV ANXIETY; PSYCHOMETRIC PROPERTIES; RESIDUAL SYMPTOMS; BECK DEPRESSION; POPULATION; DISORDERS; INVENTORY; MOOD AB Objective: Many patients with depression respond or remit with current treatments, but often experience persistent distress, in part because they perceive that they have not returned to their normal or premorbid state. Some continue to have a lack of subjective psychological well-being and positive affect following treatment. It would be useful to measure these deficits and explore whether interventions can improve them. Currently, no clinically useful scale has been developed to measure positive affect. To fill this gap, we developed the Clinical Positive Affect Scale (CPAS). Method: The purpose of this study is to describe the development and validation of the CPAS, a 16-item self-report measurement of self-perceived affective and cognitive correlates of positive affect, in a sample of 300 college students. Results: A principal component analysis with varimax rotation showed one major factor of positive affect, with all items revealing high loadings (>= 0.65) on the single factor. The CPAS also demonstrated good internal consistency (alpha=0.97) and strong part-whole correlations. Finally, the CPAS revealed some degree of divergent validity through moderately strong negative correlations with validated measures of depression, anxiety and drug abuse. Conclusions: This study supports the validity of the CPAS, which may help clinicians and researchers to assess patients' current self-perceived levels of hedonic capacity and enthusiasm for life. C1 [Nierenberg, Andrew A.] Massachusetts Gen Hosp, Dept Psychiat, Bipolar Clin, Boston, MA 02114 USA. [Bentley, Kate H.] Boston Univ, Boston, MA 02215 USA. [Farabaugh, Amy H.; Fava, Maurizio] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Nierenberg, Andrew A.; Deckersbach, Thilo] Massachusetts Gen Hosp, Res Program, Boston, MA 02114 USA. RP Nierenberg, AA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Bipolar Clin, 50 Staniford St,5th Floor, Boston, MA 02114 USA. EM anierenberg@partners.org FU MGH from Cephalon; MGH from NIMH; MGH from PamLabs; MGH from Pfizer Pharmaceuticals; MGH from Shire; Astra Zeneca; Eli Lilly; Janssen Pharmaceuticals; Bristol-Myers Squibb; NARSAD; HMS; NIMH; Abbott Laboratories; Alkermes, Inc.; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells, Inc.; Cephalon, Inc.; Clinical Trials Solutions LLC; Clintara LLC; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Icon Clinical Research; Johnson & Johnson Pharmaceutical Research Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; NCCAM; NIDA; Novartis AG; Organon Pharmaceuticals; PamLab LLC; Pfizer, Inc.; Pharmavite(R) LLC; Roche; RCT Logic LLC; Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Synthelabo; Wyeth-Ayerst Laboratories; TSA; OCF; MGH Psychiatry Academy; Systems Research and Applications Corporation; Boston University; Catalan Agency for Health Technology Assessment and Research; National Association of Social Workers Massachusetts; Massachusetts Medical Society; Oxford University Press; NIH; NIA; Forest Research Institute; Shire Development, Inc.; Medtronic; Cyberonics; Northstar FX AAN has received grant/research support through MGH from: Cephalon, NIMH, PamLabs, Pfizer Pharmaceuticals, and Shire. He has received honoraria from: American Society for Clinical Psychopharmacology, APSARD, Belvoir Publishing, Hillside Hospital, IMEDEX, ISBD, MBL Publishing, and Physicians Postgraduate Press.; AAN is a presenter for the Massachusetts General Hospital Psychiatry Academy (MGHPA). The education programs conducted by the MGHPA were supported through Independent Medical Education (IME) grants from the following pharmaceutical companies in 2008: Astra Zeneca, Eli Lilly, and Janssen Pharmaceuticals; in 2009: Astra Zeneca, Bristol-Myers Squibb, and Eli Lilly.; AHF's research has been funded by NARSAD, HMS, and NIMH. She has received honoraria from the MGH Psychiatry Academy. She has equity holdings in Pfizer, GlaxoSmithKlein, and Wyeth.; MF has received research support from the following: Abbott Laboratories, Alkermes, Inc., Aspect Medical Systems, AstraZeneca, BioResearch, BrainCells, Inc., Bristol-Myers Squibb, Cephalon, Inc., Clinical Trials Solutions LLC, Clintara LLC, Covidien, Eli Lilly and Company, EnVivo Pharmaceuticals, Inc., Forest Pharmaceuticals, Inc., Ganeden Biotech, Inc., GlaxoSmithKline, Icon Clinical Research, Johnson & Johnson Pharmaceutical Research & Development, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, NARSAD, NCCAM, NIDA, NIMH, Novartis AG, Organon Pharmaceuticals, PamLab LLC, Pfizer, Inc., Pharmavite (R) LLC, Roche, RCT Logic LLC, Sanofi-Aventis US LLC, Shire, Solvay Pharmaceuticals, Inc., Synthelabo, and Wyeth-Ayerst Laboratories.; TD's research has been funded by NIMH, NARSAD, TSA, and OCF. He has received honoraria, consultation fees and/or royalties from the MGH Psychiatry Academy, BrainCells, Inc., Systems Research and Applications Corporation, Boston University, the Catalan Agency for Health Technology Assessment and Research, the National Association of Social Workers Massachusetts, Massachusetts Medical Society and Oxford University Press. He has also participated in research funded by NIH, NIA, Janssen Pharmaceuticals, The Forest Research Institute, Shire Development, Inc., Medtronic, Cyberonics, and Northstar. NR 37 TC 8 Z9 8 U1 1 U2 7 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0004-8674 J9 AUST NZ J PSYCHIAT JI Aust. N. Z. J. Psych. PD DEC PY 2012 VL 46 IS 12 BP 1165 EP 1172 DI 10.1177/0004867412459810 PG 8 WC Psychiatry SC Psychiatry GA 048BI UT WOS:000311884800008 PM 22990434 ER PT J AU Stone, RM AF Stone, Richard M. TI Is it time to revisit standard post-remission therapy? SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE acute myeloid leukemia (AML); maintenance; post-remission; risk-adapted; standard therapy; transplant ID ACUTE MYELOID-LEUKEMIA; HIGH-DOSE CYTARABINE; STEM-CELL TRANSPLANTATION; TRANS-RETINOIC ACID; AGE 60 YEARS; GROUP-B; ELDERLY-PATIENTS; CANCER; INTENSIFICATION; CHEMOTHERAPY AB There are several strategies for improving post-remission therapy in acute myeloid leukemia (AML). One is a risk-adapted strategy for younger adults in which patients with non-favorable characteristics based on cytogenetics and genetics are allocated to allogeneic stem cell transplantation and others receive intensive high-dose ara-C-based therapies. Additional genetic data and/or minimal residual disease level may prove useful in post-remission therapeutic choice. Future approaches, badly needed in older AML patients, may include the addition of new agents to currently used therapies or maintenance with DNA methyltransferase inhibitors. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Stone, Richard M.] Dana Farber Canc Inst, Adult Leukemia Program, Boston, MA 02115 USA. [Stone, Richard M.] Harvard Univ, Sch Med, Boston, MA USA. RP Stone, RM (reprint author), Dana Farber Canc Inst, Adult Leukemia Program, 450 Brookline Ave,MIB 17, Boston, MA 02115 USA. EM rstone@partners.org FU Genzyme Corporation; Infinity; Ariad; Agios FX Consulting fees: Genzyme Corporation; Infinity; Ariad; Agios. NR 22 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD DEC PY 2012 VL 25 IS 4 BP 437 EP 441 DI 10.1016/j.beha.2012.10.006 PG 5 WC Hematology SC Hematology GA 057PD UT WOS:000312574600006 PM 23200540 ER PT J AU Steensma, DR AF Steensma, David R. TI Can hypomethylating agents provide a platform for curative therapy in myelodysplastic syndromes? SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE azacitidine; decitabine; hypomethylating agent; myelodysplastic syndrome (MDS) ID ACUTE MYELOID-LEUKEMIA; STEM-CELL TRANSPLANTATION; RANDOMIZED PHASE-III; LOW-DOSE AZACITIDINE; REGULATORY T-CELLS; DNA METHYLATION; GROUP-B; MAINTENANCE THERAPY; EPIGENETIC CHANGES; ELDERLY-PATIENTS AB The hypomethylating agents (HMAs) azacitidine and decitabine have changed the treatment landscape of myelodysplastic syndromes (MDS) since their approval by the United States Food and Drug Administration (US FDA) in 2004 and 2006, respectively. However, neither agent is able to cure patients with MDS, and when patients fail to respond to treatment with these agents, their prognosis is poor. For this reason, investigators are currently testing combination regimens with an HMA as a backbone and altering the dose, schedule, and method of delivery of HMAs. Additionally, more than 30 new molecules are currently being tested in interventional studies for which patients with MDS are eligible to enroll. These efforts may further improve outcomes for patients with MDS. For the time being, allogeneic stem cell transplantation (ASCT) remains patients' only real opportunity for cure and should be performed whenever possible in patients with higher-risk disease. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Steensma, David R.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Steensma, David R.] Harvard Univ, Sch Med, Boston, MA USA. RP Steensma, DR (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Suite D1B30 Mayer 1B21, Boston, MA 02215 USA. EM david_steensma@dfci.harvard.edu OI Steensma, David/0000-0001-5130-9284 NR 65 TC 9 Z9 10 U1 2 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD DEC PY 2012 VL 25 IS 4 BP 443 EP 451 DI 10.1016/j.beha.2012.10.007 PG 9 WC Hematology SC Hematology GA 057PD UT WOS:000312574600007 PM 23200541 ER PT J AU Walovitch, RC Chokron, P Agarwal, S AF Walovitch, Richard C. Chokron, Patrick Agarwal, Sheela TI US FDA draft Guidance Standard for Clinical Trial Imaging Endpoints: more than just imaging? SO BIOMARKERS IN MEDICINE LA English DT Review DE adjudication; BICR; blinded review; DMIHP; DMIP; FDA guidance document; imaging; imaging contract research organization; independent review committee; subjective assessment ID GASTROINTESTINAL STROMAL TUMORS; POSITRON-EMISSION-TOMOGRAPHY; PROGRESSION-FREE SURVIVAL; IMATINIB MESYLATE; THERMAL ABLATION; EARLY PREDICTION; THERAPY; CRITERIA; ONCOLOGY; EFFICACY AB The current cost of developing a successful drug is typically over a billion dollars, with the registration trial(s) determining the success or failure of the entire development program. Often the primary endpoint of these trials is a subjective assessment. For registration trials with subjective endpoints, a regulatory agency may require a blinded independent central review (BICR) of the trial data. The BICR is a mechanism to reduce bias in open-labeled trials and to potentially increase accuracy and precision. A decision tree algorithm has been developed that can be used to determine when and what type of a BICR is needed. The US FDA draft Guidance Standard for Clinical Trial Imaging Endpoints can be used as an effective process map in exploring the value and use of BICRs in imaging, and in any hard to interpret variable subjective assessment in general. C1 [Walovitch, Richard C.; Chokron, Patrick] Worldcare Clin LLC, Boston, MA 02114 USA. [Agarwal, Sheela] Massachusetts Gen Hosp, Div Abdominal & Intervent Radiol, Boston, MA 02114 USA. RP Walovitch, RC (reprint author), Worldcare Clin LLC, 7 Bulfinch Pl, Boston, MA 02114 USA. EM rwalovitch@wcclinical.com NR 39 TC 0 Z9 0 U1 1 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1752-0363 J9 BIOMARK MED JI Biomark. Med. PD DEC PY 2012 VL 6 IS 6 BP 839 EP 847 DI 10.2217/BMM.12.74 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 055LA UT WOS:000312416600024 PM 23227850 ER PT J AU Fang, QQ Kaeli, DR AF Fang, Qianqian Kaeli, David R. TI Accelerating mesh-based Monte Carlo method on modern CPU architectures SO BIOMEDICAL OPTICS EXPRESS LA English DT Article ID COMPLEX HETEROGENEOUS TISSUES; OPTICAL-SIMULATION; PHOTON MIGRATION; LIGHT TRANSPORT; MOUSE; BODY; CODE AB In this report, we discuss the use of contemporary ray-tracing techniques to accelerate 3D mesh-based Monte Carlo photon transport simulations. Single Instruction Multiple Data (SIMD) based computation and branch-less design are exploited to accelerate ray-tetrahedron intersection tests and yield a 2-fold speed-up for ray-tracing calculations on a multi-core CPU. As part of this work, we have also studied SIMD-accelerated random number generators and math functions. The combination of these techniques achieved an overall improvement of 22% in simulation speed as compared to using a non-SIMD implementation. We applied this new method to analyze a complex numerical phantom and both the phantom data and the improved code are available as open-source software at http://mcx.sourceforge.net/mmc/. (C) 2012 Optical Society of America C1 [Fang, Qianqian] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Kaeli, David R.] Northeastern Univ, Dept Elect & Comp Engn, Boston, MA 02115 USA. RP Fang, QQ (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM fangq@nmr.mgh.harvard.edu FU Bill & Melinda Gates Foundation [OPP1035992] FX QF wishes to thank the funding support from the Bill & Melinda Gates Foundation (#OPP1035992). NR 23 TC 0 Z9 0 U1 0 U2 3 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 2156-7085 J9 BIOMED OPT EXPRESS JI Biomed. Opt. Express PD DEC 1 PY 2012 VL 3 IS 12 PG 8 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 059ML UT WOS:000312709500016 ER PT J AU Mai, CT Riehle-Colarusso, T O'Halloran, A Cragan, JD Olney, RS Lin, A Feldkamp, M Botto, LD Rickard, R Anderka, M Ethen, M Stanton, C Ehrhardt, J Canfield, M AF Mai, Cara T. Riehle-Colarusso, Tiffany O'Halloran, Alissa Cragan, Janet D. Olney, Richard S. Lin, Angela Feldkamp, Marcia Botto, Lorenzo D. Rickard, Russel Anderka, Marlene Ethen, Mary Stanton, Carol Ehrhardt, Joan Canfield, Mark CA Natl Birth Defects Prevention Netw TI Selected birth defects data from population-based birth defects surveillance programs in the United States, 2005-2009: Featuring critical congenital heart defects targeted for pulse oximetry screening SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article ID PREVALENCE; DISEASE C1 [Mai, Cara T.; Riehle-Colarusso, Tiffany; Cragan, Janet D.; Olney, Richard S.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [O'Halloran, Alissa] Carter Consulting, Atlanta, GA USA. [Lin, Angela] MassGen Hosp Children, Genet Unit, Boston, MA USA. [Lin, Angela; Anderka, Marlene] Massachusetts Dept Publ Hlth, Massachusetts Ctr Birth Defects Res & Prevent, Boston, MA USA. [Feldkamp, Marcia; Botto, Lorenzo D.] Univ Utah, Dept Pediat, Div Med Genet, Hlth Sci Ctr, Salt Lake City, UT USA. [Feldkamp, Marcia; Botto, Lorenzo D.] Utah Dept Hlth, Utah Birth Defect Network, Salt Lake City, UT 84116 USA. [Rickard, Russel; Stanton, Carol] Colorado Dept Publ Hlth & Environm, Denver, CO USA. [Ethen, Mary; Canfield, Mark] Texas Dept State Hlth Serv, Birth Defects Epidemiol & Surveillance Branch, Austin, TX USA. [Ehrhardt, Joan] Michigan Dept Community Hlth, Lansing, MI USA. RP Mai, CT (reprint author), Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, 1600 Clifton Rd, Atlanta, GA 30333 USA. EM cmai@cdc.gov FU Intramural CDC HHS [CC999999] NR 9 TC 9 Z9 9 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD DEC PY 2012 VL 94 IS 12 SI SI BP 970 EP 983 DI 10.1002/bdra.23098 PG 14 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 056YH UT WOS:000312527100003 PM 24083317 ER PT J AU Luquetti, DV Saltzman, BS Vivaldi, D Pimenta, LA Hing, AV Cassell, CH Starr, JR Heike, CL AF Luquetti, Daniela V. Saltzman, Babette S. Vivaldi, Daniela Pimenta, Luiz A. Hing, Anne V. Cassell, Cynthia H. Starr, Jacqueline R. Heike, Carrie L. TI Evaluation of ICD-9-CM codes for craniofacial microsomia SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE craniofacial microsomia; hemifacial microsomia; oculo-auriculo-vertebral spectrum; microtia; Goldenhar; birth defects surveillance; ICD-9-CM ID HEMIFACIAL MICROSOMIA; MICROTIA; SPECTRUM AB BACKGROUND Craniofacial microsomia (CFM) is a congenital condition characterized by microtia and mandibular underdevelopment. Healthcare databases and birth defects surveillance programs could be used to improve knowledge of CFM. However, no specific International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code exists for this condition, which makes standardized data collection challenging. Our aim was to evaluate the validity of existing ICD-9-CM codes to identify individuals with CFM. METHODS Study sample eligibility criteria were developed by an expert panel and matched to 11 ICD-9-CM codes. We queried hospital discharge data from two craniofacial centers and identified a total of 12,254 individuals who had =1 potentially CFM-related code(s). We reviewed all (n = 799) medical records identified at the University of North Carolina (UNC) and 500 randomly selected records at Seattle Children's Hospital (SCH). Individuals were classified as a CFM case or non-case. RESULTS Thirty-two individuals (6%) at SCH and 93 (12%) at UNC met the CFM eligibility criteria. At both centers, 59% of cases and 95% of non-cases had only one code assigned. At both centers, the most frequent codes were 744.23 (microtia), 754.0 and 756.0 (nonspecific codes), and the code 744.23 had a positive predictive value (PPV) >80% and sensitivity >70%. The code 754.0 had a sensitivity of 3% (PPV <1%) at SCH and 36% (PPV = 5%) at UNC, whereas 756.0 had a sensitivity of 38% (PPV = 5%) at SCH and 18% (PPV = 26%) at UNC. CONCLUSIONS These findings suggest the need for a specific CFM code to facilitate CFM surveillance and research. Birth Defects Research (Part A), 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Luquetti, Daniela V.; Saltzman, Babette S.; Hing, Anne V.; Heike, Carrie L.] Seattle Childrens Hosp, Craniofacial Ctr, Seattle, WA USA. [Luquetti, Daniela V.; Hing, Anne V.; Heike, Carrie L.] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Vivaldi, Daniela; Pimenta, Luiz A.] Univ N Carolina, Sch Dent, Craniofacial Ctr, Chapel Hill, NC USA. [Vivaldi, Daniela; Pimenta, Luiz A.] Univ N Carolina, Sch Dent, Dept Dent Ecol, Chapel Hill, NC 27599 USA. [Cassell, Cynthia H.] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA USA. [Starr, Jacqueline R.] Forsyth Inst, Cambridge, MA USA. [Starr, Jacqueline R.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Luquetti, Daniela V.; Saltzman, Babette S.; Vivaldi, Daniela; Pimenta, Luiz A.; Hing, Anne V.; Starr, Jacqueline R.; Heike, Carrie L.] FACIAL, Seattle, WA USA. RP Luquetti, DV (reprint author), 1900 9th Ave,Room 520,C9S-5, Seattle, WA 98101 USA. EM daniela.luquetti@seattlechildrens.org OI Starr, Jacqueline/0000-0002-3039-2311 FU National Institute of Dental and Craniofacial Research in the National Institutes of Health [RC1 DE 020270] FX Supported by a grant from the National Institute of Dental and Craniofacial Research in the National Institutes of Health (grant number RC1 DE 020270). NR 15 TC 1 Z9 1 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD DEC PY 2012 VL 94 IS 12 SI SI BP 990 EP 995 DI 10.1002/bdra.23059 PG 6 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 056YH UT WOS:000312527100005 PM 22903955 ER PT J AU Ten Berg, P Ring, D AF Ten Berg, Paul Ring, David TI Quantitative 3D-CT Anatomy of Hamate Osteoarticular Autograft for Reconstruction of the Middle Phalanx Base SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID PROXIMAL INTERPHALANGEAL JOINT; FRACTURE-DISLOCATIONS; ARTHROPLASTY AB Background Hamate osteoarticular autografts are difficult to obtain and it is unclear to what degree the graft matches the joint surface to be replaced and whether a direct ulnar approach might provide a more reliable graft than the standard proximal to distal approach. Purpose We modeled hemihamate osteotomies using quantitative three-dimensional CT (3D-CT) to measure the amount of hamate articular surface used and the match with the native volar base of the middle phalanx. Methods In virtual hemihamate osteotomies (standard and direct ulnar) on CTs of 20 patients (11 men and nine women), we measured the percentage of hamate articular surface used for each finger, the match of the articular contour, and the percentage of hamate articular surface removed. Results The autograft in the standard approach used an average of 26% of the hamate articular surface and had an average 75% match of the articular contour with the volar half of the middle phalanx base. A direct ulnar approach removed an additional small margin of dorsal ulnar hamate with an average maximum width of 2.5 mm and volume of 27 mm 3. Conclusions An osteoarticular allograft from the hamate to replace the volar half of the middle phalanx base uses less than 1/3 of the hamate articular surface even if the dorsal ulnar margin of the hamate is taken with the graft. Clinical Relevance These data suggest that it might be feasible to make the deep cut from a direct ulnar approach. C1 [Ten Berg, Paul; Ring, David] Harvard Univ, Orthopaed Hand & Upper Extrem Serv, Sch Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ten Berg, Paul] Acad Med Ctr, Amsterdam, Netherlands. RP Ring, D (reprint author), Harvard Univ, Orthopaed Hand & Upper Extrem Serv, Sch Med, Massachusetts Gen Hosp, Yawkey 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org NR 11 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD DEC PY 2012 VL 470 IS 12 BP 3492 EP 3498 DI 10.1007/s11999-012-2372-x PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 054UO UT WOS:000312370200031 PM 22538961 ER PT J AU Kramer, JR Bayless, ML Lorenzi, GM Ziegler, GK Larkin, ME Lackaye, ME Harth, J Diminick, LJ Anderson, KL Braffett, BH Cleary, PA AF Kramer, John R. Bayless, Margaret L. Lorenzi, Gayle M. Ziegler, Georgia K. Larkin, Mary E. Lackaye, Mary E. Harth, Judith Diminick, Lisa J. Anderson, Karen L. Braffett, Barbara H. Cleary, Patricia A. CA DCCT-EDIC Study Grp TI Participant characteristics and study features associated with high retention rates in a longitudinal investigation of type 1 diabetes mellitus SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania Annual Conference on Statistical Issues in Clinical Trials CY APR 13-13, 2011 CL Philadelphia, PA ID CLINICAL-TRIAL; ACCORD AB Background The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study has sustained an extraordinarily high level of participant involvement for over two decades. Purpose In order to identify specific characteristics of EDIC that contributed most strongly to retention, study-designed questionnaires were distributed to 1334 participants. Methods Confidential questionnaires were completed during EDIC Years 15-17. Participants were classified as Completely Adherent (completed all visits), Partly Adherent (missed >1 visit or major portion of a visit), or Inactive (did not participate for >5 years). Questionnaire items addressed specific aspects of clinic visits, evaluation procedures, staff-participant relationships, and medical/health-care support provided by EDIC. Results The most commonly cited reasons for continuing participation were Cutting Edge Tests to assess diabetes complications (79.3%), Annual Evaluations (67.7%), a desire to Help Others (65.2%), and Better Care for Diabetes (61.6%). Women chose Cutting Edge Tests as their first or second most important reason significantly more often than men, whereas men chose Better Care for Diabetes more frequently. Individuals with at least three diabetes-related complications were more likely than those with fewer complications to choose Annual Evaluations as their first or second reason for continued involvement. Limitations The small proportion of individuals who discontinued participation restricted our ability to identify factors associated with suspended involvement. In addition, our analysis is limited to a cohort with type 1 diabetes followed in an observational study after an average participation time of 6.5 years in a randomized trial. Conclusions The primary reasons identified by respondents for their long-term commitment are consistent with shorter-term studies and underscore the importance of expert medical care, supportive staff-participant relationships, and involvement with clinically and scientifically meaningful research. Clinical Trials 2012; 9: 798-805. http://ctj.sagepub.com C1 [Kramer, John R.] Univ Iowa, Carver Coll Med, Dept Psychiat, MEB, Iowa City, IA 52242 USA. [Bayless, Margaret L.] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Lorenzi, Gayle M.] Univ Calif San Diego, Sch Med, Dept Med, San Diego, CA 92103 USA. [Ziegler, Georgia K.] Mayo Clin, Rochester, MN USA. [Larkin, Mary E.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Lackaye, Mary E.] Weill Cornell Med Coll, Dept Endocrinol, New York, NY USA. [Harth, Judith] Univ Western Ontario, Schulich Sch Med & Dent, Dept Med, London, ON, Canada. [Diminick, Lisa J.; Anderson, Karen L.; Braffett, Barbara H.; Cleary, Patricia A.] George Washington Univ, Off Vice President Res, Res Facil A, Ctr Biostat, Rockville, MD USA. RP Kramer, JR (reprint author), Univ Iowa, Carver Coll Med, Dept Psychiat, MEB, Iowa City, IA 52242 USA. EM john-kramer@uiowa.edu FU Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease; National Eye Institute; National Institute of Neurologic Disorders and Stroke; Genetic Clinical Research Centers Program; Clinical Translational Science Center Program, Bethesda, Maryland, USA FX The DCCT/EDIC has been supported by U01 Cooperative Agreement grants (1983-93) and contracts (1994-present) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease, and through support by the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the Genetic Clinical Research Centers Program (1993-2007), and Clinical Translational Science Center Program (2006-present), Bethesda, Maryland, USA. NR 16 TC 5 Z9 5 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2012 VL 9 IS 6 BP 798 EP 805 DI 10.1177/1740774512458986 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 055XZ UT WOS:000312452600019 PM 23027646 ER PT J AU IsHak, WW Bolton, MA Bensoussan, JC Dous, G Nguyen, TT Powell-Hicks, AL Gardner, JE Ponton, KM AF IsHak, Waguih William Bolton, Michael A. Bensoussan, Jean-Charles Dous, GeorgeV. Nguyen, Trang T. Powell-Hicks, Allycin L. Gardner, Jennifer E. Ponton, Kimberly M. TI Quality of life in body dysmorphic disorder SO CNS SPECTRUMS LA English DT Review DE Body dysmorphic disorder; body image; dysmorphophobia; quality of life ID COMPULSIVE DISORDER; SOCIAL PHOBIA; INDIVIDUALS; COMORBIDITY; POPULATION; PREVALENCE AB Body dysmorphic disorder (BDD) has a significant impact on the patients' quality of life (QOL). This is an initial literature review of QOL in patients with BDD, examining the extent of QOL impairments, the impact of psychiatric comorbidity on QOL, and the effect of treatment on QOL in BDD. Studies were identified through PubMed, MEDLINE, and PsycINFO searches from 1960-2011 using the keywords: "quality of life," "body dysmorphic disorder," "dysmorphophobia," and "body image." Studies included in this review were selected using specific criteria by two authors reaching consensus. Most BDD research studies have used symptom severity measures mainly to study BDD and its treatments. BBD with or without comorbidities is significantly associated with poor QOL and functioning. Studies show that treatment of BDD, either by psychopharmacological treatments such as selective serotonin reuptake inhibitors (SSRIs) or cognitive behavior therapy, might have positive effects on QOL, although these results need to be replicated in larger studies. In conclusion, QOL could add significant value to the assessment of BDD if used as one of the primary measures in research and clinical work in BDD, by providing more information and clearer understanding on the impact of the illness on satisfaction with activities of daily life and overall sense of wellbeing before and after treatment. Received 10 March 2012; Accepted 16 July 2012 C1 [IsHak, Waguih William] Univ Calif Los Angeles, David Geffen Sch Med, Psychiat Residency Training Program, Los Angeles, CA 90048 USA. [IsHak, Waguih William; Bensoussan, Jean-Charles; Dous, GeorgeV.; Powell-Hicks, Allycin L.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Bolton, Michael A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gardner, Jennifer E.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. RP IsHak, WW (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Psychiat Residency Training Program, 8730 Alden Dr,Thalians W-157, Los Angeles, CA 90048 USA. EM Waguih.Ishak@cshs.org RI IsHak, Waguih/C-1336-2011 OI IsHak, Waguih/0000-0003-1970-4756 FU NARSAD; Pfizer FX Waguih William IsHak, MD, has received research support from NARSAD (quality of life in major depression) and Pfizer (ziprasidone monotherapy for major depression). The remaining authors have nothing to disclose. NR 28 TC 5 Z9 5 U1 3 U2 25 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1092-8529 J9 CNS SPECTRUMS JI CNS Spectr. PD DEC PY 2012 VL 17 IS 4 BP 167 EP 175 DI 10.1017/S1092852912000624 PG 9 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 056XZ UT WOS:000312526000002 PM 22939280 ER PT J AU Barbash, I Kabraji, S Han, M Kohn, R Thompson, R AF Barbash, Ian Kabraji, Sheheryar Han, Maria Kohn, Rachel Thompson, Ryan TI A CROSS-SECTIONAL STUDY OF DISCREPANCIES IN CODE STATUS DOCUMENTATION FOR HOSPITALIZED PATIENTS SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Barbash, Ian] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 718 BP U196 EP U196 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700678 ER PT J AU Cummings, B Cowl, A El Saleeby, C Yager, P Shank, E Noviski, N AF Cummings, Brian Cowl, Allison El Saleeby, Chadi Yager, Phoebe Shank, Eric Noviski, Natan TI CARDIOVASCULAR EFFECTS OF DEXMEDETOMIDINE INFUSION WITHOUT A LOADING DOSE IN CRITICALLY ILL CHILDREN SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Cummings, Brian; El Saleeby, Chadi; Yager, Phoebe; Shank, Eric; Noviski, Natan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cowl, Allison] Univ Connecticut, Storrs, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 959 BP U261 EP U261 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045701228 ER PT J AU Cummings, B Ahmed, F Noviski, N AF Cummings, Brian Ahmed, Faheem Noviski, Natan TI REDUCTION OF REPETITIVE IMAGING ON PEDIATRIC PATIENTS REFERRED TO A PICU: A QUALITY INITIATIVE SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Ahmed, Faheem] Kings Coll London, Sch Med, London, England. [Cummings, Brian; Noviski, Natan] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 139 BP U45 EP U45 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700104 ER PT J AU Elmer, J Hou, P Schreiber, H Duran-Mendicuti, MA Pallin, DJ Wilcox, SR Chang, Y Okechukwu, I Pontes-Neto, O Bajwa, E Hess, DR Avery, L Camargo, CA Greenberg, SM Rosand, J Goldstein, J AF Elmer, Jonathan Hou, Peter Schreiber, Hannah Duran-Mendicuti, Maria Alejandra Pallin, Daniel J. Wilcox, Susan R. Chang, Yuchiao Okechukwu, Ikenna Pontes-Neto, Octavio Bajwa, Ednan Hess, Dean R. Avery, Laura Camargo, Carlos A., Jr. Greenberg, Steven M. Rosand, Jonathan Goldstein, Joshua TI ACUTE RESPIRATORY DISTRESS SYNDROME AFTER SPONTANEOUS INTRACEREBRAL HEMORRHAGE SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Elmer, Jonathan] Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15260 USA. [Hou, Peter; Schreiber, Hannah; Duran-Mendicuti, Maria Alejandra; Pallin, Daniel J.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Wilcox, Susan R.; Chang, Yuchiao; Okechukwu, Ikenna; Pontes-Neto, Octavio; Bajwa, Ednan; Hess, Dean R.; Avery, Laura; Camargo, Carlos A., Jr.; Greenberg, Steven M.; Rosand, Jonathan; Goldstein, Joshua] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Pallin, Daniel/H-6382-2013; Pontes-Neto, Octavio/G-4294-2012 OI Pallin, Daniel/0000-0002-8517-9702; Pontes-Neto, Octavio/0000-0003-0317-843X NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 388 BP U111 EP U111 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700351 ER PT J AU Glisic, E Riker, R Kelner, A Perrey, H Fraser, G AF Glisic, Elizabeth Riker, Richard Kelner, Andrew Perrey, Hilary Fraser, Gilles TI TRANSITIONING PATIENTS TREATED WITH DEXMEDETOMIDINE TO ENTERAL CLONIDINE: A RETROSPECTIVE STUDY SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Glisic, Elizabeth; Riker, Richard; Kelner, Andrew; Fraser, Gilles] Maine Med Ctr, Portland, ME USA. [Perrey, Hilary] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 1110 BP U300 EP U300 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045701376 ER PT J AU Hobai, I Morse, J Abbasi, W Chen, E Siwik, D Colucci, W AF Hobai, Ion Morse, Justin Abbasi, Wafaa Chen, Estela Siwik, Deborah Colucci, Wilson TI PROLONGED EXPOSURE TO BACTERIAL LIPOPOLYSACCHARIDE AND INFLAMMATORY CYTOKINES INHIBITS EXCITATION CONTRACTION COUPLING IN ADULT RAT CARDIOMYOCYTES. SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Hobai, Ion] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hobai, Ion; Siwik, Deborah; Colucci, Wilson] Boston Univ, Med Ctr, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 168 BP U53 EP U53 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700133 ER PT J AU Hwang, D Yagoda, D Perrey, H Tehan, T Guanci, M Ananian, L Currier, P Cobb, JP Rosand, J AF Hwang, David Yagoda, Daniel Perrey, Hilary Tehan, Tara Guanci, Mary Ananian, Lillian Currier, Paul Cobb, J. Perren Rosand, Jonathan TI CONSISTENCY OF COMMUNICATION AMONG INTENSIVE CARE UNIT STAFF AS PERCEIVED BY FAMILY MEMBERS OF PATIENTS SURVIVING TO DISCHARGE SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Hwang, David] Yale New Haven Med Ctr, New Haven, CT USA. [Yagoda, Daniel; Perrey, Hilary; Tehan, Tara; Guanci, Mary; Ananian, Lillian; Currier, Paul; Cobb, J. Perren; Rosand, Jonathan] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 890 BP U243 EP U243 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045701159 ER PT J AU Mehta, N Pichoff, D McAdam, A Paster, B Priebe, G AF Mehta, Nilesh Pichoff, Darla McAdam, Alexander Paster, Bruce Priebe, Gregory TI MICROBIOME IDENTIFICATION USING CULTURE-INDEPENDENT MOLECULAR TECHNIQUE IN MECHANICALLY VENTILATED CHILDREN - NEW INSIGHTS SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Mehta, Nilesh; Pichoff, Darla; McAdam, Alexander; Priebe, Gregory] Boston Childrens Hosp, Boston, MA USA. [Paster, Bruce] Forsyth Inst, Cambridge, MA 02142 USA. RI Mehta, Nilesh/G-7073-2016 NR 0 TC 0 Z9 0 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 177 BP U55 EP U55 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700142 ER PT J AU Moromizato, T Mendu, M McKane, C Gibbons, F Christopher, K AF Moromizato, Takuhiro Mendu, Mallika McKane, Caitlin Gibbons, Fiona Christopher, Kenneth TI ERYTHROCYTE TRANSFUSION AND ACUTE KIDNEY INJURY IN THE CRITICALLY ILL SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Moromizato, Takuhiro; Mendu, Mallika; McKane, Caitlin; Christopher, Kenneth] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gibbons, Fiona] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 636 BP U175 EP U175 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700597 ER PT J AU Moromizato, T Marmarelis, M Mendu, M McKane, C Gibbons, F Christopher, K AF Moromizato, Takuhiro Marmarelis, Melina Mendu, Mallika McKane, Caitlin Gibbons, Fiona Christopher, Kenneth TI DIABETES MELLITUS AND COMMUNITY BLOODSTREAM INFECTION IN THE CRITICALLY ILL SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Moromizato, Takuhiro; Mendu, Mallika; McKane, Caitlin; Christopher, Kenneth] Brigham & Womens Hosp, Boston, MA 02115 USA. [Marmarelis, Melina] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Gibbons, Fiona] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 361 BP U103 EP U104 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700324 ER PT J AU Moromizato, T Litonjua, A Braun, A Gibbons, F Giovannucci, E Christopher, K AF Moromizato, Takuhiro Litonjua, Augusto Braun, Andrea Gibbons, Fiona Giovannucci, Edward Christopher, Kenneth TI PRE-HOSPITAL SERUM VITAMIN D LEVELS AND MORTALITY FOLLOWING CORONARY ARTERY BYPASS GRAFTING SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Moromizato, Takuhiro; Litonjua, Augusto; Christopher, Kenneth] Brigham & Womens Hosp, Boston, MA 02115 USA. [Braun, Andrea; Gibbons, Fiona] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 38 BP U28 EP U28 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700039 ER PT J AU Moromizato, T Litonjua, A Braun, A Gibbons, F Giovannucci, E Christopher, K AF Moromizato, Takuhiro Litonjua, Augusto Braun, Andrea Gibbons, Fiona Giovannucci, Edward Christopher, Kenneth TI PRE-HOSPITAL VITAMIN D DEFICIENCY AND SEPSIS IN THE CRITICALLY ILL SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Moromizato, Takuhiro; Litonjua, Augusto; Christopher, Kenneth] Brigham & Womens Hosp, Boston, MA 02115 USA. [Braun, Andrea; Gibbons, Fiona] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 24 BP U24 EP U24 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700025 ER PT J AU Sheridan, R Stoddard, F Kazis, L Lee, A Meyer, W Kagan, R Palmieri, T Herndon, D Tompkins, R AF Sheridan, Robert Stoddard, Fredrick Kazis, Lewis Lee, Austin Meyer, Walter Kagan, Richard Palmieri, Tina Herndon, David Tompkins, Ronald TI LONG-TERM POST-TRAUMATIC STRESS SYMPTOMS VARY INVERSELY WITH EARLY OPIATE DOSING IN CHILDREN RECOVERING FROM SERIOUS BURNS-EFFECTS DURABLE AT FOUR YEARS SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Sheridan, Robert; Stoddard, Fredrick; Kazis, Lewis; Lee, Austin; Meyer, Walter; Kagan, Richard; Palmieri, Tina; Herndon, David] Massachusetts Gen Hosp, Shriners Hosp Children, Boston, MA 02114 USA. [Sheridan, Robert] Boston VA Healthcare Syst, Boston, MA USA. [Kazis, Lewis; Lee, Austin] Boston Univ, Boston, MA 02215 USA. [Meyer, Walter; Herndon, David] Univ Texas Med Branch, Galveston, TX USA. [Kagan, Richard] Univ Cincinnati, Cincinnati, OH 45221 USA. [Palmieri, Tina] Univ Calif Davis, Davis, CA USA. [Tompkins, Ronald] Harvard Univ, Sch Med, Shriners Hosp Children, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 129 BP U42 EP U43 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700094 ER PT J AU Thoma, B Pizzi, L McDaniel, C Li, J Mearns, E Wordell, C Cavarocchi, N AF Thoma, Brandi Pizzi, Laura McDaniel, Cara Li, Julius Mearns, Elizabeth Wordell, Cindy Cavarocchi, Nicholas TI DEXMEDETOMIDINE VERSUS PROPOFOL AND MIDAZOLAM IN PATIENTS UNDERGOING CORONARY ARTERY BYPASS GRAFTING SURGERY SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Thoma, Brandi; McDaniel, Cara; Wordell, Cindy] Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. [Pizzi, Laura; Mearns, Elizabeth] Thomas Jefferson Univ, Sch Pharm, Philadelphia, PA USA. [Li, Julius] S Texas Vet Hlth Care Syst, San Antonio, TX 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 1120 BP U302 EP U302 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045701386 ER PT J AU Voscopoulos, C Freeman, J Brayanov, J Ladd, D Lalli, M MacNabb, CM Eikermann, M AF Voscopoulos, Christopher Freeman, Jenny Brayanov, Jordan Ladd, Diane Lalli, Michael MacNabb, C. Marshall Eikermann, Matthias TI EVALUATION OF A NON-INVASIVE RESPIRATORY VOLUME MONITOR DURING OBSTRUCTED BREATHING SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Voscopoulos, Christopher] Brigham & Womens Hosp, Boston, MA 02115 USA. [Freeman, Jenny; Lalli, Michael; MacNabb, C. Marshall] Resp Mot Inc, Waltham, MA USA. [Brayanov, Jordan] Harvard Univ, Cambridge, MA 02138 USA. [Ladd, Diane] W Virginia Univ, Morgantown, WV 26506 USA. [Eikermann, Matthias] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 103 BP U35 EP U36 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700068 ER PT J AU Yager, P Dapul, H Murphy, S Clark, M Zheng, H Noviski, N AF Yager, Phoebe Dapul, Heda Murphy, Sarah Clark, Maureen Zheng, Hui Noviski, Natan TI COMPARISON OF FACE-TO-FACE VERSUS TELEMEDICINE PATIENT ASSESSMENT IN A PEDIATRIC INTENSIVE CARE UNIT SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Yager, Phoebe; Dapul, Heda; Murphy, Sarah; Clark, Maureen; Zheng, Hui; Noviski, Natan] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 253 BP U75 EP U75 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700216 ER PT J AU Tanner, JM Friedlander, AH Chang, TI AF Tanner, J. M. Friedlander, A. H. Chang, T. I. TI Bilateral bifid mandibular condyles diagnosed with three-dimensional reconstruction SO DENTOMAXILLOFACIAL RADIOLOGY LA English DT Article DE bifid mandibular condyle ID BEAM COMPUTED-TOMOGRAPHY; TEMPOROMANDIBULAR-JOINT; POPULATION AB Bifid mandibular condyles (BMCs) are rare anomalies. The overwhelming majority of prior reports described their predominantly unilateral occurrence diagnosed by panoramic radiography. We present an even rarer case of bilateral BMC initially identified by panoramic radiography and confirmed with colour-enhanced three-dimensional CT. These images substantiate the theory that the secondary condyles arise from the neck of the mandible (Lopez-Lopez et al. Bifid condyle: review of the literature of the last 10 years and report of two cases. Cianio 2010; 28: 136-140). Dentomaxillofacial Radiology (2012) 41, 691-695. doi: 10.1259/dmfr/15030240 C1 [Tanner, J. M.; Chang, T. I.] VA Greater Los Angeles Healthcare Syst, Oral & Maxillofacial Surg Sect, Los Angeles, CA 90073 USA. RP Chang, TI (reprint author), VA Greater Los Angeles Healthcare Syst, Oral & Maxillofacial Surg Sect, 11301 Wilshire Blvd W160, Los Angeles, CA 90073 USA. EM Tina.Chang2@va.gov NR 16 TC 0 Z9 0 U1 0 U2 1 PU BRITISH INST RADIOLOGY PI LONDON PA 36 PORTLAND PLACE, LONDON W1N 4AT, ENGLAND SN 0250-832X J9 DENTOMAXILLOFAC RAD JI Dentomaxillofac. Radiol. PD DEC PY 2012 VL 41 IS 8 BP 691 EP 695 DI 10.1259/dmfr/15030240 PG 5 WC Dentistry, Oral Surgery & Medicine; Radiology, Nuclear Medicine & Medical Imaging SC Dentistry, Oral Surgery & Medicine; Radiology, Nuclear Medicine & Medical Imaging GA 056TM UT WOS:000312514300012 PM 22241877 ER PT J AU Ning, MM Lopez, M Cao, J Buonanno, FS Lo, EH AF Ning, MingMing Lopez, Mary Cao, Jing Buonanno, Ferdinando S. Lo, Eng H. TI Application of proteomics to cerebrovascular disease SO ELECTROPHORESIS LA English DT Review DE Biomarker; Cerebrovascular disease; Cerebrospinal fluid (CSF); Mass spectrometry; Pharmaco-proteomics; Stroke ID FOCAL CEREBRAL-ISCHEMIA; BLOOD-BRAIN-BARRIER; MATRIX-METALLOPROTEINASE EXPRESSION; TISSUE-PLASMINOGEN ACTIVATOR; STROKE-PRONE RATS; SELDI-TOF-MS; SUBARACHNOID HEMORRHAGE; CEREBROSPINAL-FLUID; SYSTEMS BIOLOGY; INTRACEREBRAL HEMORRHAGE AB While neurovascular diseases such as ischemic and hemorrhagic stroke are the leading causes of disability in the world, the repertoire of therapeutic interventions has remained remarkably limited. There is a dire need to develop new diagnostic, prognostic, and therapeutic options. The study of proteomics is particularly enticing for cerebrovascular diseases such as stroke, which most likely involve multiple gene interactions resulting in a wide range of clinical phenotypes. Currently, rapidly progressing neuroproteomic techniques have been employed in clinical and translational research to help identify biologically relevant pathways, to understand cerebrovascular pathophysiology, and to develop novel therapeutics and diagnostics. Future integration of proteomic with genomic, transcriptomic, and metabolomic studies will add new perspectives to better understand the complexities of neurovascular injury. Here, we review cerebrovascular proteomics research in both preclinical (animal, cell culture) and clinical (blood, urine, cerebrospinal fluid, microdialyates, tissue) studies. We will also discuss the rewards, challenges, and future directions for the application of proteomics technology to the study of various disease phenotypes. To capture the dynamic range of cerebrovascular injury and repair with a translational targeted and discovery approach, we emphasize the importance of complementing innovative proteomic technology with existing molecular biology models in preclinical studies, and the need to advance pharmacoproteomics to directly probe clinical physiology and gauge therapeutic efficacy at the bedside. C1 [Ning, MingMing; Cao, Jing; Buonanno, Ferdinando S.; Lo, Eng H.] Massachusetts Gen Hosp, Dept Neurol, Clin Prote Res Ctr, Boston, MA 02114 USA. [Ning, MingMing; Cao, Jing; Buonanno, Ferdinando S.; Lo, Eng H.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ning, MingMing; Lo, Eng H.] Massachusetts Gen Hosp, Dept Neurol & Radiol, Neuroprotect Res Lab, Boston, MA 02114 USA. [Lopez, Mary] Thermo Fisher BRIMS, Cambridge, MA USA. RP Ning, MM (reprint author), Massachusetts Gen Hosp, Dept Neurol, Clin Prote Res Ctr, 15 Parkman St,ACC-739C, Boston, MA 02114 USA. EM ning@hms.harvard.edu FU NIH/NINDS [R01 NS067139, P01-NS55104] FX This work was supported by the NIH/NINDS: R01 NS067139 (Ning) and P01-NS55104 (Lo). NR 145 TC 3 Z9 3 U1 3 U2 31 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD DEC PY 2012 VL 33 IS 24 SI SI BP 3582 EP 3597 DI 10.1002/elps.201200481 PG 16 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 057FT UT WOS:000312548900002 PM 23161401 ER PT J AU Kamnaksh, A Kwon, SK Kovesdi, E Ahmed, F Barry, ES Grunberg, NE Long, J Agoston, D AF Kamnaksh, Alaa Kwon, Sook-Kyung Kovesdi, Erzsebet Ahmed, Farid Barry, Erin S. Grunberg, Neil E. Long, Joseph Agoston, Denes TI Neurobehavioral, cellular, and molecular consequences of single and multiple mild blast exposure SO ELECTROPHORESIS LA English DT Article DE Blast; Cumulative effect; Neurobehavior; Protein biomarkers; Traumatic brain injury ID TRAUMATIC BRAIN-INJURY; POSTTRAUMATIC-STRESS-DISORDER; HIPPOCAMPAL SLICE CULTURES; ENDOTHELIAL GROWTH-FACTOR; ISCHEMIA/REPERFUSION INJURY; ADULT HIPPOCAMPUS; COMBAT VETERANS; IRAQI FREEDOM; NEUROGENESIS; PTSD AB Mild traumatic brain injury, caused by the exposure to single or repeated blast overpressure, is a principal concern due to its pathological complexity and neurobehavioral similarities with posttraumatic stress disorder. In this study, we exposed rats to a single or multiple (five total; administered on consecutive days) mild blasts, assessed their behavior at 1 and 16 days postinjury) and performed histological and protein analyses of brains and plasma at an early (2 h) and a late (22 days) termination time point. One day postinjury, multiple-injured (MI) rats showed the least general locomotion and the most depression- and anxiety-related behaviors among the experimental groups; there were no such differences at 16 days. However, at the later time point, both injured groups displayed elevated levels of select protein biomarkers. Histology showed significantly increased numbers of TUNEL+ (terminal-deoxy-transferase-mediated dUTP nick-end labeling)-positive cells in the dorsal and ventral hippocampus (DHC and VHC) of both injured groups as early as 2 h after injury. At 22 days, the increase was limited to the VHC of MI animals. Our findings suggest that the exposure to mild blast overpressure triggers early hippocampal cell death as well as neuronal, glial, and vascular damage that likely contribute to significant, albeit transient increases in depression- and anxiety-related behaviors. However, the severity of the observed pathological changes in MI rats failed to support the hypothesized cumulative effect of repeated injury. We infer that at this blast frequency, a potential conditioning phenomenon counteracts with and reduces the extent of subsequent damage in MI rats. C1 [Agoston, Denes] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Sch Med, Bethesda, MD 20814 USA. [Kamnaksh, Alaa; Kwon, Sook-Kyung; Ahmed, Farid; Barry, Erin S.; Grunberg, Neil E.; Agoston, Denes] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Kovesdi, Erzsebet] US Dept Vet Affairs, Vet Affairs Cent Off, Washington, DC USA. [Barry, Erin S.; Grunberg, Neil E.] Walter Reed Army Inst Res, Dept Med & Clin Psychol, Silver Spring, MD USA. [Long, Joseph] Walter Reed Army Inst Res, Blast Induced Neurotrauma Branch, Ctr Mil Psychiat & Neurosci, Silver Spring, MD USA. RP Agoston, D (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Sch Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM vagoston@usuhs.edu FU Center for Neuroscience and Regenerative Medicine [G1703F] FX We thank the Neurotrauma Team at the Walter Reed Army Institute of Research for their technical help during the exposures. This work was supported by the Center for Neuroscience and Regenerative Medicine grant number G1703F. The views, opinions, and/or findings contained herein are those of the authors and should not be construed as an official position, policy, or decision of the Department of the Army or the Department of Defense. Animal handling and treatments were conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations related to animals and experiments involving animals, and adhered to principles stated in the Guide to the Care and Use of Laboratory Animals, National Research Council. The facilities are fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. NR 68 TC 18 Z9 19 U1 1 U2 17 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD DEC PY 2012 VL 33 IS 24 SI SI BP 3680 EP 3692 DI 10.1002/elps.201200319 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 057FT UT WOS:000312548900011 PM 23161523 ER PT J AU De Calisto, J Villablanca, EJ Mora, JR AF De Calisto, Jaime Villablanca, Eduardo J. Mora, J. Rodrigo TI Fc gamma RI (CD64): An identity card for intestinal macrophages SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Editorial Material DE Gut mucosal interface; Immune tolerance; Inflammation; Intestinal immune homeostasis; Macrophages ID CD103(+) DENDRITIC CELLS; HIGH-AFFINITY RECEPTOR; HUMAN NEUTROPHILS; RESPONSES; EXPRESSION; INFLAMMATION; HOMEOSTASIS; MONOCYTES; IMMUNITY; SUBSET AB Macrophages are becoming increasingly recognized as key cellular players in intestinal immune homeostasis. However, differentiating between macrophages and dendritic cells (DCs) is often difficult, and finding a specific phenotypic signature for intestinal macrophage identification has remained elusive. In this issue of the European Journal of Immunology, Tamoutounour et al. [Eur. J. Immunol. 2012. 42: 3150-3166] identify CD64 as a specific macrophage marker that can be used to discriminate DCs from macrophages in the murine small and large intestine, under both steady-state and inflammatory conditions. The authors also propose a sequential monocyte-waterfall model for intestinal macrophage differentiation, with implications for immune tolerance and inflammation at the gut mucosal interface. This Commentary will discuss the advantages and potential limitations of CD64 as a marker for intestinal macrophages. C1 [De Calisto, Jaime; Villablanca, Eduardo J.; Mora, J. Rodrigo] Harvard Univ, Gastrointestinal Unit, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Mora, JR (reprint author), Harvard Univ, Gastrointestinal Unit, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,GRJ 815, Boston, MA 02114 USA. EM j_rodrigo_mora@hms.harvard.edu RI Villablanca, Eduardo/E-1380-2016 OI Villablanca, Eduardo/0000-0001-9522-9729 FU NCCDPHP CDC HHS [DP2 2009A054301]; NIAID NIH HHS [P30 AI060354]; NIH HHS [DP2 OD006512] NR 31 TC 4 Z9 4 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2012 VL 42 IS 12 BP 3136 EP 3140 DI 10.1002/eji.201243061 PG 5 WC Immunology SC Immunology GA 057FJ UT WOS:000312547800009 PM 23255010 ER PT J AU Aleksic, M Liddy, N Molloy, PE Pumphrey, N Vuidepot, A Chang, KM Jakobsen, BK AF Aleksic, Milos Liddy, Nathaniel Molloy, Peter E. Pumphrey, Nick Vuidepot, Annelise Chang, Kyong-Mi Jakobsen, Bent K. TI Different affinity windows for virus and cancer-specific T-cell receptors: Implications for therapeutic strategies SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Immunotherapy; T-cell; Thymic selection; Tumor immunology ID MEDULLARY EPITHELIAL-CELLS; GENE-EXPRESSION; HUMAN THYMUS; ANTIGEN; PEPTIDES; SINGLE; CRYSTALLIZATION; RECOGNITION; LYMPHOCYTES; VACCINATION AB T-cell destiny during thymic selection depends on the affinity of the TCR for autologous peptide ligands presented in the context of MHC molecules. This is a delicately balanced process; robust binding leads to negative selection, yet some affinity for the antigen complex is required for positive selection. All TCRs of the resulting repertoire thus have some intrinsic affinity for an MHC type presenting an assortment of peptides. Generally, TCR affinities of peripheral T cells will be low toward self-derived peptides, as these would have been presented during thymic selection, whereas, by serendipity, binding to pathogen-derived peptides that are encountered de novo could be stronger. A crucial question in assessing immunotherapeutic strategies for cancer is whether natural TCR repertoires have the capacity for efficiently recognizing tumor-associated peptide antigens. Here, we report a comprehensive comparison of TCR affinities to a range of HLA-A2 presented antigens. TCRs that bind viral antigens fall within a strikingly higher affinity range than those that bind cancer-related antigens. This difference may be one of the key explanations for tumor immune escape and for the deficiencies of T-cell vaccines against cancer. C1 [Aleksic, Milos; Liddy, Nathaniel; Molloy, Peter E.; Pumphrey, Nick; Vuidepot, Annelise; Jakobsen, Bent K.] Immunocore Ltd, Abingdon OX14 4RX, Oxon, England. [Chang, Kyong-Mi] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Chang, Kyong-Mi] Univ Penn, Philadelphia, PA 19104 USA. RP Jakobsen, BK (reprint author), Immunocore Ltd, 57C Milton Pk, Abingdon OX14 4RX, Oxon, England. EM bent.jakobsen@immunocore.com FU Immunocore Ltd., Abingdon, United Kingdom; NIH [AI047519]; Abramson Cancer Center FACS facility; Philadelphia VA Medical Research FX We would like to thank Peter Bader, Debbie Baker, Giovanna Bossi, Scott Burrows, Enzo Cerundolo, Sophie Conchon, Linda Hibbert, Erik Hooijberg John Miles, Yasuharu Nishimura, Samantha Paston, Jim Riley, Andrew Sewell, Robert Thimme, and Cassian Yee for providing T-cell clones; Hyosun Cho for work on the HCV-specific T cell lines; Conor Hayes, Qin Su, and Arsen Volkov for isolating TCR chains by RACE-PCR; Brian Cameron, Emma Gostick, Nikolai Lissin, Tara Mahon, and Alex Powlesland for protein production and SPR measurements; and Joanne Oates and Karen Pulford for assistance in manuscript preparation. This work was funded by Immunocore Ltd., Abingdon, United Kingdom. K.C. is also supported in part by: NIH AI047519, Abramson Cancer Center FACS facility and Philadelphia VA Medical Research. The contents of the publications/presentations do not represent the views of the VA or the US government. NR 36 TC 55 Z9 55 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2012 VL 42 IS 12 BP 3174 EP 3179 DI 10.1002/eji.201242606 PG 6 WC Immunology SC Immunology GA 057FJ UT WOS:000312547800014 PM 22949370 ER PT J AU Baker, ML Seeley, ES Pai, R Suriawinata, AA Mino-Kenudson, M Zamboni, G Kloppel, G Longnecker, DS AF Baker, Michael L. Seeley, E. Scott Pai, Reetesh Suriawinata, Arief A. Mino-Kenudson, Mari Zamboni, Giuseppe Kloeppel, Gunter Longnecker, Daniel S. TI Invasive mucinous cystic neoplasms of the pancreas SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE Mucinous cystic neoplasm; Intraductal papillary mucinous neoplasm; Mucinous cystadenoma; Mucinous cystadenocarcinoma; Colloid carcinoma; MUC2; CDX2; Pancreas ID CYSTADENOCARCINOMA; FEATURES; CARCINOMA; STROMA; TUMORS; PROGNOSIS; BEHAVIOR AB Mucinous cystic neoplasms (MCN) and intraductal papillary mucinous neoplasms (IPMN) of the pancreas both appear to have been included and intermixed in some early reports of pancreatic cystic neoplasms. Recognition of their distinguishing features evolved during the last decade of the twentieth century. One legacy of the early period is the statement that mucinous cystic neoplasms sometimes progress to invasive colloid carcinoma. It is now recognized that colloid carcinomas characteristically arise from IPMN. We set out to see if we could find MCN that invaded as colloid carcinomas and found no examples in MCN collected in two academic medical centers. We then sought to expand the number of MCN by evaluating series from additional centers. This yielded no examples of colloid carcinomas associated with 291 MCN, however one MCN exhibited a minor component with colloid (non-cystic mucinous) growth pattern within the fibrous wall of the neoplasm. The expression of CDX2, a marker of intestinal differentiation that is found in colloid carcinomas was examined by immunostaining in the original MCN series and in the MCN with the intratumoral colloid growth pattern. Focal expression of CDX2 was found in 22 of 43 MCN including the MCN that exhibited the intratumoral colloid growth pattern. Overall, the data suggest that MCN rarely, if ever, invade as colloid carcinoma but the expression of CDX2 by some MCN and the observation of intratumoral colloid growth pattern in one MCN seems to leave open the possibility that MCN might rarely invade as colloid carcinoma. The majority of malignant MCN invade with a tubular (ductal) pattern, and rarely the invasive component was anaplastic. (C) 2012 Elsevier Inc. All rights reserved. C1 [Baker, Michael L.; Suriawinata, Arief A.; Longnecker, Daniel S.] Dartmouth Hitchcock Med Ctr, Dept Pathol, Lebanon, NH 03756 USA. [Baker, Michael L.; Suriawinata, Arief A.; Longnecker, Daniel S.] Dartmouth Med Sch, Lebanon, NH 03756 USA. [Seeley, E. Scott; Pai, Reetesh] Stanford Hosp & Clin, Dept Pathol, Stanford, CA USA. [Seeley, E. Scott; Pai, Reetesh] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Harvard Univ, Sch Med, Boston, MA USA. [Zamboni, Giuseppe] Osped S Cuore Don Calabria, Dept Pathol, Calabria, Italy. [Zamboni, Giuseppe] Univ Verona, I-37100 Verona, Italy. [Kloeppel, Gunter] Tech Univ Munich, Dept Pathol, D-8000 Munich, Germany. [Kloeppel, Gunter] Univ Kiel, Dept Pathol, D-24098 Kiel, Germany. RP Baker, ML (reprint author), Texas Childrens Hosp, Dept Pathol, 6621 Fannin St,Suite AB1195, Houston, TX 77030 USA. EM bakerm10@lsus.edu RI Giuseppe, Zamboni/A-5991-2016 OI Giuseppe, Zamboni/0000-0001-7428-4673 NR 28 TC 12 Z9 13 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD DEC PY 2012 VL 93 IS 3 SI SI BP 345 EP 349 DI 10.1016/j.yexmp.2012.07.005 PG 5 WC Pathology SC Pathology GA 056CN UT WOS:000312466100012 PM 22902940 ER PT J AU Ji, JY Miles, WO Korenjak, M Zheng, YN Dyson, NJ AF Ji, Jun-Yuan Miles, Wayne O. Korenjak, Michael Zheng, Yani Dyson, Nicholas J. TI In Vivo Regulation of E2F1 by Polycomb Group Genes in Drosophila SO G3-GENES GENOMES GENETICS LA English DT Article DE cell proliferation; E2F1; Su(z)2; PcG; Drosophila ID GROUP PROTEIN COMPLEXES; POSTERIOR SEX COMBS; CELL-CYCLE; HISTONE H3; TRANSCRIPTION FACTOR; ECTOPIC EXPRESSION; TUMOR SUPPRESSION; RNA INTERFERENCE; S-PHASE; MELANOGASTER AB The E2F transcription factors are important regulators of the cell cycle whose function is commonly misregulated in cancer. To identify novel regulators of E2F1 activity in vivo, we used Drosophila to conduct genetic screens. For this, we generated transgenic lines that allow the tissue-specific depletion of dE2F1 by RNAi. Expression of these transgenes using Gal4 drivers in the eyes and wings generated reliable and modifiable phenotypes. We then conducted genetic screens testing the capacity of Exelixis deficiencies to modify these E2F1-RNAi phenotypes. From these screens, we identified mutant alleles of Suppressor of zeste 2 [Su(z)2] and multiple Polycomb group genes as strong suppressors of the E2F1-RNA interference phenotypes. In validation of our genetic data, we find that depleting Su(z)2 in cultured Drosophila cells restores the cell-proliferation defects caused by reduction of dE2F1 by elevating the level of dE2f1. Furthermore, analyses of methylation status of histone H3 lysine 27 (H3K27me) from the published modENCODE data sets suggest that the genomic regions harboring dE2f1 gene and certain dE2f1 target genes display H3K27me during development and in several Drosophila cell lines. These in vivo observations suggest that the Polycomb group may regulate cell proliferation by repressing the transcription of dE2f1 and certain dE2F1 target genes. This mechanism may play an important role in coordinating cellular differentiation and proliferation during Drosophila development. C1 [Ji, Jun-Yuan; Zheng, Yani] Texas A&M Hlth Sci Ctr, Dept Mol & Cellular Med, Coll Med, College Stn, TX 77843 USA. [Ji, Jun-Yuan; Miles, Wayne O.; Korenjak, Michael; Dyson, Nicholas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Canc Ctr,Lab Mol Oncol, Charlestown, MA 02129 USA. [Ji, Jun-Yuan; Miles, Wayne O.; Korenjak, Michael; Dyson, Nicholas J.] Harvard Univ, Dept Pathol, Sch Med, Charlestown, MA 02129 USA. RP Ji, JY (reprint author), Texas A&M Hlth Sci Ctr, Dept Mol & Cellular Med, Coll Med, College Stn, TX 77843 USA. EM ji@medicine.tamhsc.edu FU Fund for Medical Discovery Postdoctoral Fellowship from Massachusetts General Hospital; Texas A&M Health Science Center; American Heart Association; National Institutes of Health [R01GM053203] FX We thank Richard Carthew and Andre Bernard for sharing the pWIZ vector, Fajun Yang for his advice in generating pWIZ-dE2f1 constructs, Doug Renee at the MGH Drosophila transgene core facility for his help in making transgenic flies, Bill Fowle at the Northeastern University for his expertise with scanning electron microscopy, and Rebecca Wang for technical assistant. We appreciate Keith Maggert as well as the anonymous reviewers for critical reading of the manuscript and constructive comments. We are grateful to Richard Carthew, Robert Duronio, Richard Emmons, Antonio Garcia-Bellido, Vincenzo Pirrotta, Chao-Ting Wu, and the Bloomington Drosophila Stock Center for mutant stocks and reagents used in this work. This work is supported in part by a Fund for Medical Discovery Postdoctoral Fellowship from Massachusetts General Hospital, a startup fund from Texas A&M Health Science Center and a grant from the American Heart Association to J.-Y.J., and National Institutes of Health grant (R01GM053203) to N.J.D., the James and Shirley Curvey MGH Research Scholar. The first author would like to dedicate this paper to the memory of Professor Gerold Schubiger for his many years of inspiration and support. NR 63 TC 7 Z9 7 U1 1 U2 4 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 2160-1836 J9 G3-GENES GENOM GENET JI G3-Genes Genomes Genet. PD DEC 1 PY 2012 VL 2 IS 12 BP 1651 EP 1660 DI 10.1534/g3.112.004333 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 055ZZ UT WOS:000312458000016 PM 23275887 ER PT J AU Newhouse, JP Price, M Huang, J McWilliams, JM Hsu, J AF Newhouse, Joseph P. Price, Mary Huang, Jie McWilliams, J. Michael Hsu, John TI Steps To Reduce Favorable Risk Selection In Medicare Advantage Largely Succeeded, Boding Well For Health Insurance Exchanges SO HEALTH AFFAIRS LA English DT Article ID ADVERSE SELECTION; ADJUSTMENT; MODEL AB Within Medicare, the Medicare Advantage program has historically attracted better risks-healthier, lower-cost patients-than has traditional Medicare. The disproportionate enrollment of lower-cost patients and avoidance of higher-cost ones during the 1990s-known as favorable selection-resulted in Medicare's spending more per beneficiary who enrolled in Medicare Advantage than if the enrollee had remained in traditional Medicare. We looked at two measures that can indicate whether favorable selection is taking place-predicted spending on beneficiaries and mortality-and studied whether policies that Medicare implemented in the past decade succeeded in reducing favorable selection in Medicare Advantage. We found that these policies-an improved risk adjustment formula and a prohibition on monthly disenrollment by beneficiaries-largely succeeded. Differences in predicted spending between those switching from traditional Medicare to Medicare Advantage relative to those who remained in traditional Medicare markedly narrowed, as did adjusted mortality rates. Because insurance exchanges set up under the Affordable Care Act will employ similar policies to combat risk selection, our results give reason for optimism about managing competition among health plans. C1 [Newhouse, Joseph P.] Harvard Univ, Div Hlth Policy Res & Educ, Boston, MA 02115 USA. [Newhouse, Joseph P.] Harvard Univ, Interfac Initiat Hlth Policy, Boston, MA 02115 USA. [Price, Mary; Huang, Jie] Kaiser Permanente No Calif Div Res, Oakland, CA USA. [McWilliams, J. Michael] Brigham & Womens Hosp, Boston, MA 02115 USA. [Hsu, John] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Program Clin Econ & Policy Anal, Boston, MA 02114 USA. [Newhouse, Joseph P.] Harvard Univ, Comm Higher Degrees Hlth Policy, Boston, MA 02115 USA. RP Newhouse, JP (reprint author), Harvard Univ, Div Hlth Policy Res & Educ, Boston, MA 02115 USA. EM newhouse@hcp.med.harvard.edu FU National Institute on Aging [P01-032952] FX Earlier versions of this article were presented at the International Health Economics Association meeting, in Toronto, Ontario, July 2011, and the American Society of Health Economists meeting, in Minneapolis, Minnesota, July 2012. The authors acknowledge support from the National Institute on Aging, Grant No. P01-032952. Joseph Newhouse is a director of, and holds equity in, Aetna, which sells Medicare Advantage products. The authors thank Thomas G. McGuire and three reviewers for comments. NR 25 TC 26 Z9 26 U1 0 U2 14 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD DEC PY 2012 VL 31 IS 12 BP 2618 EP 2628 DI 10.1377/hlthaff.2012.0345 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 057ZA UT WOS:000312602100004 PM 23213145 ER PT J AU McWilliams, JM Hsu, J Newhouse, JP AF McWilliams, J. Michael Hsu, John Newhouse, Joseph P. TI New Risk-Adjustment System Was Associated With Reduced Favorable Selection In Medicare Advantage SO HEALTH AFFAIRS LA English DT Article ID BIASED SELECTION; HMOS AB Health plans participating in the Medicare managed care program, called Medicare Advantage since 2003, have historically attracted healthier enrollees than has the traditional fee-for-service program. Medicare Advantage plans have gained financially from this favorable risk selection since their payments have traditionally been adjusted only minimally for clinical characteristics of enrollees, causing overpayment for healthier enrollees and underpayment for sicker ones. As a result, a new risk-adjustment system was phased in from 2004 to 2007, and a lock-in provision instituted to limit midyear disenrollment by enrollees experiencing health declines whose exodus could benefit plans financially. To determine whether these reforms were associated with intended reductions in risk selection, we compared differences in self-reported health care use and health between Medicare Advantage and traditional Medicare beneficiaries before versus after these reforms were implemented. We similarly compared differences between those who switched into or out of Medicare Advantage and nonswitchers. Most differences in 2001-03 were substantially narrowed by 2006-07, suggesting reduced selection. Similar risk-adjustment methods may help reduce incentives for plans competing in health insurance exchanges and accountable care organizations to select patients with favorable clinical risks. C1 [McWilliams, J. Michael; Hsu, John] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [McWilliams, J. Michael] Brigham & Womens Hosp, Boston, MA 02115 USA. [Hsu, John] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Program Clin Econ & Policy Anal, Boston, MA 02114 USA. [Newhouse, Joseph P.] Harvard Univ, Div Hlth Policy Res & Educ, Boston, MA 02115 USA. [Newhouse, Joseph P.] Harvard Univ, Comm Higher Degrees Hlth Policy, Boston, MA 02115 USA. [Newhouse, Joseph P.] Harvard Univ, Interfac Initiat Hlth Policy, Boston, MA 02115 USA. RP McWilliams, JM (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. EM mcwilliams@hcp.med.harvard.edu FU National Institute on Aging [K08 AG038354, P01 AG032952]; American Federation for Aging Research FX Findings were previously reported at the Society of General Internal Medicine Annual Meeting, Orlando, Florida, May 2012; and at the AcademyHealth Annual Research Meeting, Orlando, Florida, June 2012. This study was supported by grants from the Beeson Career Development Award Program (National Institute on Aging Grant No. K08 AG038354 and American Federation for Aging Research) and from the National Institute on Aging (Grant No. P01 AG032952). Joseph Newhouse is a director of and holds equity in Aetna, which sells Medicare Advantage plans. Michael McWilliams and John Hsu have no conflicts of interest to disclose. The authors are grateful to Pasha Hamed and Mary Price for statistical programming, to Austin Frakt and Jeff Souza for sharing statistical code, and to Thomas G. McGuire and John Z. Ayanian for helpful comments on an earlier draft. NR 20 TC 19 Z9 19 U1 0 U2 8 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD DEC PY 2012 VL 31 IS 12 BP 2630 EP 2640 DI 10.1377/hlthaff.2011.1344 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 057ZA UT WOS:000312602100006 PM 23213147 ER PT J AU Reed, ME Graetz, I Fung, V Newhouse, JP Hsu, J AF Reed, Mary E. Graetz, Ilana Fung, Vicki Newhouse, Joseph P. Hsu, John TI In Consumer-Directed Health Plans, A Majority Of Patients Were Unaware Of Free Or Low-Cost Preventive Care SO HEALTH AFFAIRS LA English DT Article ID EXPENDITURES; EMPLOYER; SERVICES; COVERAGE AB Consumer-directed health plans are plans with high deductibles that typically require patients to bear no out-of-pocket costs for preventive care, such as annual physicals or screening tests, in order to ease financial barriers and encourage patients to seek such care. We surveyed people in California who had a consumer-directed health plan and found that fewer than one in five understood that their plan exempted preventive office visits, medical tests, and screenings from their deductible, meaning that this care was free or had a modest copayment. Roughly one in five said that they had delayed or avoided a preventive office visit, test, or screening because of cost. Those who were confused about the exemption were significantly more likely to report avoiding preventive visits because of cost concerns. Special efforts to educate consumers about preventive care cost-sharing exemptions may be necessary as more health plans, including Medicare, adopt this model. C1 [Reed, Mary E.; Graetz, Ilana] Kaiser Permanente, No Calif Div Res, Oakland, CA 94612 USA. [Graetz, Ilana] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Fung, Vicki] MidAtlantic Permanente Med Grp, Midatlantic Permanente Res Inst, Rockville, MD USA. [Newhouse, Joseph P.] Harvard Univ, Div Hlth Policy Res & Educ, Boston, MA 02115 USA. [Newhouse, Joseph P.] Harvard Univ, Comm Higher Degrees Hlth Policy, Boston, MA 02115 USA. [Hsu, John] Massachusetts Gen Hosp, Program Clin Econ & Policy Anal, Mongan Inst Hlth Policy, Boston, MA 02114 USA. [Hsu, John] Harvard Univ, Sch Med, Boston, MA USA. RP Reed, ME (reprint author), Kaiser Permanente, No Calif Div Res, Oakland, CA 94612 USA. EM mary.e.reed@kp.org RI Graetz, Ilana/N-1189-2016 OI Graetz, Ilana/0000-0003-3664-5815 FU Kaiser Foundation Research Institute FX Findings included in this article were presented at the AcademyHealth Annual Research Meeting, June 2010, in Boston, Massachusetts. This study was funded by the Kaiser Foundation Research Institute. Joseph Newhouse is a director of and holds equity in Aetna, which sells consumer-directed health plans. NR 20 TC 15 Z9 15 U1 1 U2 5 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD DEC PY 2012 VL 31 IS 12 BP 2641 EP 2648 DI 10.1377/hlthaff.2012.0059 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 057ZA UT WOS:000312602100007 PM 23213148 ER PT J AU Kind, AJH Jensen, L Barczi, S Bridges, A Kordahl, R Smith, MA Asthana, S AF Kind, Amy J. H. Jensen, Laury Barczi, Steve Bridges, Alan Kordahl, Rebecca Smith, Maureen A. Asthana, Sanjay TI Low-Cost Transitional Care With Nurse Managers Making Mostly Phone Contact With Patients Cut Rehospitalization At A VA Hospital SO HEALTH AFFAIRS LA English DT Article ID CONTROLLED-TRIAL; HEART-FAILURE; VETERANS; DEMENTIA; INTERVENTION; VALIDATION; MEDICARE; PROGRAM; QUALITY AB The Coordinated-Transitional Care (C-TraC) Program was designed to improve care coordination and outcomes among veterans with high-risk conditions discharged to community settings from the William S. Middleton Memorial Veterans Hospital, in Madison, Wisconsin. Under the program, patients work with nurse case managers on care and health issues, including medication reconciliation, before and after hospital discharge, with all contacts made by phone once the patient is at home. Patients who received the C-TraC protocol experienced one-third fewer rehospitalizations than those in a baseline comparison group, producing an estimated savings of $1,225 per patient net of programmatic costs. This model requires a relatively small amount of resources to operate and may represent a viable alternative for hospitals seeking to offer improved transitional care as encouraged by the Affordable Care Act. In particular, the model may be attractive for providers in rural areas or other care settings challenged by wide geographic dispersion of patients or by constrained resources. C1 [Kind, Amy J. H.] William S Middleton Mem Vet Adm Med Ctr, Coordinated Transit Care Program C TraC, GRECC, Madison, WI USA. [Kind, Amy J. H.; Barczi, Steve; Asthana, Sanjay] Univ Wisconsin, Sch Med & Publ Hlth, Div Geriatr & Gerontol, Madison, WI 53706 USA. [Asthana, Sanjay] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53706 USA. [Kordahl, Rebecca] William S Middleton Mem Vet Adm Med Ctr, Patient Care Serv, Madison, WI USA. [Smith, Maureen A.] Univ Wisconsin, Hlth Innovat Program, Madison, WI 53706 USA. RP Kind, AJH (reprint author), William S Middleton Mem Vet Adm Med Ctr, Coordinated Transit Care Program C TraC, GRECC, Madison, WI USA. EM ajk@medicine.wisc.edu FU VA Transformation-21 Grant, "Patient-Centric Alternatives to Institutional Extended Care"; Madison VA Geriatrics Research, Education, and Clinical Center (GRECC) [2012-08]; National Institute on Aging [K23AG034551]; National Institute on Aging, in partnership with the American Federation for Aging Research; John A. Hartford Foundation; Atlantic Philanthropies; Starr Foundation; University of Wisconsin School of Medicine and Public Health's Health Innovation Program; Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research; Clinical and Translational Science Award program of the National Center for Research Resources, National Institutes of Health [1UL1RR025011]; VA Office of Geriatrics and Extended Care in the VA Central Office; Veterans Integrated Service Network 12; William S. Middleton Memorial Veterans Hospital FX Some of the information in this article was presented as a poster at the annual meeting of the American Geriatrics Society, Seattle, Washington, May 3, 2012. The design, implementation, and assessment of the C-TraC Program and the writing of this article were supported by a VA Transformation-21 Grant, "Patient-Centric Alternatives to Institutional Extended Care," and the Madison VA Geriatrics Research, Education, and Clinical Center (GRECC-Manuscript No. 2012-08); and were funded through the National Institute on Aging Paul B. Beeson Patient-Oriented Research Career Development Award (K23AG034551 [PI Kind], National Institute on Aging, in partnership with the American Federation for Aging Research, the John A. Hartford Foundation, the Atlantic Philanthropies, and the Starr Foundation). Additional support was provided by the University of Wisconsin School of Medicine and Public Health's Health Innovation Program; the Community-Academic Partnerships core of the University of Wisconsin Institute for Clinical and Translational Research; and the Clinical and Translational Science Award program of the National Center for Research Resources, National Institutes of Health (Grant No. 1UL1RR025011). No funding source had a role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. The authors acknowledge Ken Shay, Barbara Hyduke, and Karen Massey in the VA Office of Geriatrics and Extended Care in the VA Central Office and the leadership of both the Veterans Integrated Service Network 12 and the William S. Middleton Memorial Veterans Hospital for their support of the C-TraC Program; Peggy Munson for Institutional Review Board assistance; Sheila Kelly and Megan Carey for data abstraction; and Colleen Brown, Andrea Gilmore, Melissa Hovanes, Brock Polnaszek, and Joanna Wong for manuscript formatting and graphics. NR 27 TC 23 Z9 24 U1 1 U2 18 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD DEC PY 2012 VL 31 IS 12 BP 2659 EP 2668 DI 10.1377/hlthaff.2012.0366 PG 10 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 057ZA UT WOS:000312602100009 PM 23213150 ER PT J AU Das, J Holla, A Das, V Mohanan, M Tabak, D Chan, B AF Das, Jishnu Holla, Alaka Das, Veena Mohanan, Manoj Tabak, Diana Chan, Brian TI In Urban And Rural India, A Standardized Patient Study Showed Low Levels Of Provider Training And Huge Quality Gaps SO HEALTH AFFAIRS LA English DT Article ID LOW-INCOME COUNTRIES; MEDICAL-EDUCATION; CARE; PERFORMANCE; SERVICES; DOCTORS; IMPACT; DELHI AB This article reports on the quality of care delivered by private and public providers of primary health care services in rural and urban India. To measure quality, the study used standardized patients recruited from the local community and trained to present consistent cases of illness to providers. We found low overall levels of medical training among health care providers; in rural Madhya Pradesh, for example, 67 percent of health care providers who were sampled reported no medical qualifications at all. What's more, we found only small differences between trained and untrained doctors in such areas as adherence to clinical checklists. Correct diagnoses were rare, incorrect treatments were widely prescribed, and adherence to clinical checklists was higher in private than in public clinics. Our results suggest an urgent need to measure the quality of health care services systematically and to improve the quality of medical education and continuing education programs, among other policy changes. C1 [Holla, Alaka] World Bank, Human Dev Network, Chief Economists Off, Washington, DC 20433 USA. [Das, Veena] Johns Hopkins Univ, Baltimore, MD USA. [Mohanan, Manoj] Duke Univ, Sanford Sch Publ Policy, Durham, NC USA. [Tabak, Diana] Univ Toronto, Dept Family & Community Med, Toronto, ON M5S 1A1, Canada. [Tabak, Diana] Univ Toronto, Standardized Patient Program, Toronto, ON M5S 1A1, Canada. [Chan, Brian] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Chan, Brian] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Das, J (reprint author), Ctr Policy Res, New Delhi, India. EM jdas1@worldbank.org FU Global Health Program of the Bill & Melinda Gates Foundation [50728] FX This study was funded by the Global Health Program of the Bill & Melinda Gates Foundation through Grant No. 50728, which was made to Innovations for Poverty Action, in New Haven, Connecticut. The authors thank Purshottam, Rajan Singh, Devender, Charu Nanda, Simi Bajaj, Geeta, the standardized patients, and all of the other members of the Institute for Socioeconomic Research on Democracy and Development in Delhi for conducting the fieldwork. Monisha Ashok, Anvesha Khandelwal, Carl Liebersohn, Suzanne Plant, and especially Aakash Mohpal provided invaluable research assistance. The authors thank Michael Kremer, Karthik Muralidharan, Sreela Dasgupta, and the staff of the Center for Policy Research, New Delhi, for many helpful discussions and comments. The findings, interpretations, and conclusions expressed in this article are those of the authors and do not necessarily represent the views of the World Bank, its executive directors, or the governments they represent. NR 33 TC 66 Z9 66 U1 0 U2 9 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD DEC PY 2012 VL 31 IS 12 BP 2774 EP 2784 DI 10.1377/hlthaff.2011.1356 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 057ZA UT WOS:000312602100021 PM 23213162 ER PT J AU Park, JD Metlay, J Asch, JM Asch, DA AF Park, James D. Metlay, Jessica Asch, Jeremy M. Asch, David A. TI The New York Times Readers' Opinions About Paying People to Take Their Medicine SO HEALTH EDUCATION & BEHAVIOR LA English DT Article DE chronic disease management; health policy; health promotion; media; qualitative methods ID FINANCIAL INCENTIVES; HEALTH; ACCEPTABILITY; SMOKING AB Background. There has been considerable interest in using financial incentives to help people improve their health. However, paying people to improve their health touches on strongly held views about personal responsibility. Method. The New York Times printed two articles in June 2010 about patient financial incentives, which resulted in 394 comments from their online audience. The authors systematically analyzed those online responses to news media in order to understand the range of themes that were expressed regarding the use of financial incentives to improve health. Results. The New York Times online readers revealed a broad range of attitudes about paying individuals to be healthy. Many comments reflected disdain for financial incentives, describing them as "absurd" or "silly." Other comments reflected the notion that financial incentives reward individuals for being irresponsible toward their health. Many individuals communicated concerns that paying individuals for healthy behaviors may weaken their internal drive to be healthy. A smaller set of comments conveyed support for financial incentives, recognizing it as a small sum to pay to prevent or offset higher costs related to chronic diseases. Conclusions. Although a measurable group of individuals supported financial incentives, most readers revealed negative perceptions of these approaches and an appeal for greater personal responsibility for individual health. Despite experimental success of financial incentives, negative perceptions may limit their public acceptability and uptake. C1 [Park, James D.] Univ Penn, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Metlay, Jessica] Vassar Coll, Poughkeepsie, NY 12601 USA. [Asch, Jeremy M.] Brandeis Univ, Waltham, MA USA. [Asch, David A.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Park, JD (reprint author), Univ Penn, Div Gen Internal Med, 1005 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM jdpark@mail.med.upenn.edu OI Asch, David/0000-0002-7970-286X FU PHS HHS [T32-HP-10026] NR 26 TC 3 Z9 3 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD DEC PY 2012 VL 39 IS 6 BP 725 EP 731 DI 10.1177/1090198111428645 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 057JM UT WOS:000312559300010 PM 22467634 ER PT J AU Akiyoshi, T Hirohashi, T Alessandrini, A Chase, CM Farkash, EA Smith, RN Madsen, JC Russell, PS Colvin, RB AF Akiyoshi, Takurin Hirohashi, Tsutomu Alessandrini, Alessandro Chase, Catherine M. Farkash, Evan A. Smith, R. Neal Madsen, Joren C. Russell, Paul S. Colvin, Robert B. TI Role of complement and NK cells in antibody mediated rejection SO HUMAN IMMUNOLOGY LA English DT Article ID RENAL-ALLOGRAFT REJECTION; TRANSPLANTED MOUSE HEARTS; IFN-GAMMA PRODUCTION; INTERFERON-GAMMA; KIDNEY-TRANSPLANTATION; C4D DEPOSITION; HYPERACUTE REJECTION; HUMORAL ANTIBODIES; ENDOTHELIAL-CELLS; CORONARY ARTERIOSCLEROSIS AB Despite extensive research on T cells and potent immunosuppressive regimens that target cellular mediated rejection, few regimens have been proved to be effective on antibody-mediated rejection (AMR), particularly in the chronic setting. C4d deposition in the graft has been proved to be a useful marker for AMR; however, there is an imperfect association between C4d and AMR. While complement has been considered as the main player in acute AMR, the effector mechanisms in chronic AMR are still debated. Recent studies support the role of NK cells and direct effects of antibody on endothelium cells in a mechanism suggesting the presence of a complement-independent pathway. Here, we review the history, currently available systems and progress in experimental animal research. Although there are consistent findings from human and animal research, transposing the experimental results from rodent to human has been hampered by the differences in endothelial functions between species. We briefly describe the findings from patients and compare them with results from animals, to propose a combined perspective. (C) 2012 Published by Elsevier Inc. on behalf of American Society for Histocompatibility and Immunogenetics. C1 [Akiyoshi, Takurin; Farkash, Evan A.; Smith, R. Neal; Colvin, Robert B.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hirohashi, Tsutomu; Alessandrini, Alessandro; Chase, Catherine M.; Madsen, Joren C.; Russell, Paul S.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Colvin, RB (reprint author), Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Thier 831, Boston, MA 02114 USA. EM colvin@helix.mgh.harvard.edu FU National Institutes of Health; Roche Organ Transplantation Research Foundation; American Society of Transplantation FX The authors acknowledge grant support from the National Institutes of Health, the Roche Organ Transplantation Research Foundation, and the American Society of Transplantation. NR 85 TC 25 Z9 25 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD DEC PY 2012 VL 73 IS 12 SI SI BP 1226 EP 1232 DI 10.1016/j.humimm.2012.07.330 PG 7 WC Immunology SC Immunology GA 047WN UT WOS:000311872300004 PM 22850181 ER PT J AU Mahida, S Ellinor, PT AF Mahida, Saagar Ellinor, Patrick T. TI New Advances in the Genetic Basis of Atrial Fibrillation SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE atrial fibrillation; genetics; inherited arrhythmias; molecular biology; heart rate ID GENOME-WIDE ASSOCIATION; CA2+-ACTIVATED K+ CHANNELS; OF-FUNCTION MUTATION; CHROMOSOME 4Q25; SMALL-CONDUCTANCE; EUROPEAN ANCESTRY; PACEMAKER CHANNEL; ISCHEMIC-STROKE; HEART-FAILURE; HOMEOBOX GENE AB New Genetic Loci for Atrial Fibrillation. Over the past decade, compelling evidence has emerged from population-based studies to suggest that AF is a heritable disease. More recently, we have begun to elucidate the genetic substrate underlying AF. Genome-wide association studies (GWAS) have led to the identification of multiple risk loci that confer increased susceptibility to the arrhythmia. These loci harbor intriguing candidate genes including those encoding ion channels, transcription factors, and signaling molecules. Current efforts are ongoing to functionally validate the role of these genes in disease pathogenesis. In the future, novel genotyping technologies such as exome sequencing and whole-genome sequencing promise to uncover a greater proportion of the heritability underlying AF. In this article we review recent advances in AF genetics research and discuss future developments in the field. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1400-1407, December 2012) C1 [Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Mahida, Saagar; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. EM pellinor@partners.org FU NIH [1RO1HL092577, 5R21DA027021, 1RO1HL104156, 1K24HL105780] FX Dr. Ellinor is supported by NIH grants 1RO1HL092577, 5R21DA027021, 1RO1HL104156, and 1K24HL105780. NR 72 TC 16 Z9 17 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-3873 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD DEC PY 2012 VL 23 IS 12 BP 1400 EP 1406 DI 10.1111/j.1540-8167.2012.02445.x PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 057CC UT WOS:000312538500025 PM 23066792 ER PT J AU Huynh, TN Weigt, SS Sugar, CA Shapiro, S Kleerup, EC AF Huynh, Thanh N. Weigt, S. Sam Sugar, Catherine A. Shapiro, Shelley Kleerup, Eric C. TI Prognostic factors and outcomes of patients with pulmonary hypertension admitted to the intensive care unit SO JOURNAL OF CRITICAL CARE LA English DT Article DE Pulmonary hypertension; Intensive care unit; Pulmonary artery catheterization ID CRITICALLY-ILL PATIENTS; RIGHT HEART-FAILURE; ARTERIAL-HYPERTENSION; PROSTACYCLIN; MANAGEMENT; DISEASE; CATHETER; INFUSION; THERAPY AB Purpose: Patients with pulmonary hypertension (PH) can decompensate to the point where they require care in the intensive care unit (ICU). Our objective is to examine the outcomes and characteristics of patients with PH admitted to the ICU. Methods: This is a retrospective study of 99 patients with PH who were admitted to the medical ICU of a single tertiary care center. Baseline characteristics, interventions during ICU admission, and ICU and 6-month outcome were documented. Univariate and multivariate logistic regressions were used to evaluate association of patient characteristics with mortality. Results: Intensive care unit mortality was 30%, and 6-month mortality was 40%. Acute Physiology and Chronic Health Evaluation II score, World Health Organization Group 3 PH, and preexisting treatment with a prostacyclin at time of ICU admission were associated with worse outcome. Patients who received cardiopulmonary resuscitation had 100% mortality. The requirement for mechanical ventilation and dialysis was also associated with increased mortality. Pulmonary artery catheter placement was associated with reduced mortality, specifically if it was placed early during ICU admission and if associated with a change in the present management. Conclusions: Mortality is high in critically ill patients with PH. The identification of prognostic baseline characteristics and interventions in the ICU is important and warrants further investigation. (C) 2012 Elsevier Inc. All rights reserved. C1 [Huynh, Thanh N.; Weigt, S. Sam; Kleerup, Eric C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Pulm & Crit Care Med, Los Angeles, CA 90095 USA. [Sugar, Catherine A.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA. [Sugar, Catherine A.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Shapiro, Shelley] Univ Calif Los Angeles, Dept Cardiol, VA Greater Healthcare Syst, Los Angeles, CA 90095 USA. RP Huynh, TN (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Pulm & Crit Care Med, BOX 951690,37-131 CHS, Los Angeles, CA 90095 USA. EM thuynh@mednet.ucla.edu FU NCRR NIH HHS [L30 RR033215] NR 23 TC 5 Z9 5 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 0883-9441 J9 J CRIT CARE JI J. Crit. Care PD DEC PY 2012 VL 27 IS 6 AR 739.e7 DI 10.1016/j.jcrc.2012.08.006 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA 057YF UT WOS:000312599800034 PM 23089677 ER PT J AU Carter, SC Konijeti, R Hu, J AF Carter, Stacey C. Konijeti, Ramdev Hu, Jim TI Selective Suture Ligation of the Dorsal Vein Complex During Robot-Assisted Laparoscopic Radical Prostatectomy SO JOURNAL OF ENDOUROLOGY LA English DT Article AB Technique for apical dissection and control of the dorsal vein complex (DVC) during robot-assisted laparoscopic radical prostatectomy (RALP) affects blood loss, apical positive margins, and recovery of urinary control. Over the past 7 years, our technique for apical dissection has been spurred by the overarching goal of minimizing injury to the rhabdosphincter to improve urinary continence, evolving from stapling to suture ligation of the DVC before bladder neck dissection to an athermal DVC division followed by selective suture ligation (DVC-SSL) before RALP anastomosis. Assessment of patient-reported quality of life outcomes demonstrates earlier recovery of continence with DVC-SSL. C1 [Carter, Stacey C.; Hu, Jim] Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, Los Angeles, CA 90024 USA. [Konijeti, Ramdev] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Hu, J (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Urol, 924 Westwood Blvd,Ste 1000, Los Angeles, CA 90024 USA. EM JCHu@mednet.ucla.edu NR 1 TC 4 Z9 5 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 J9 J ENDOUROL JI J. Endourol. PD DEC PY 2012 VL 26 IS 12 BP 1576 EP 1577 DI 10.1089/end.2012.0415 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 054XQ UT WOS:000312379200009 PM 23146080 ER PT J AU Velmurugan, K Bouchard, R Mahaffey, G Pugazhenthi, S AF Velmurugan, Kalpana Bouchard, Ron Mahaffey, Gregory Pugazhenthi, Subbiah TI Neuroprotective actions of Glucagon-like peptide-1 in differentiated human neuroprogenitor cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Alzheimer's disease; apoptosis; CREB; glucagon-like peptide-1; human neuroprogenitor cells; signal transduction ID ELEMENT-BINDING PROTEIN; NEURAL STEM-CELLS; TRANSGENIC MOUSE MODEL; ALZHEIMERS-DISEASE; HIPPOCAMPAL-NEURONS; PROMOTES NEUROGENESIS; DIABETES-MELLITUS; DOWN-REGULATION; BCL-2 PROMOTER; CREB AB Glucagon-like peptide-1 (GLP-1)-based therapies are currently available for the treatment of type 2 diabetes, based on their actions on pancreatic beta cells. GLP-1 is also known to exert neuroprotective actions. To determine its mechanism of action, we developed a neuron-rich cell culture system by differentiating human neuroprogenitor cells in the presence of a combination of neurotrophins and retinoic acid. The neuronal nature of these cells was characterized by neurogenesis pathway-specific array. GLP-1 receptor expression was seen mainly in the neuronal population. Culture of neurons in the presence of A beta oligomers resulted in the induction of apoptosis as shown by the activation of caspase-3 and caspase-6. Exendin-4, a long-acting analog of GLP-1, protected the neurons from apoptosis induced by A beta oligomers. Exendin-4 stimulated cyclic AMP response element binding protein phosphorylation, a regulatory step in its activation. A transient transfection assay showed induction of a reporter linked to CRE site-containing human brain-derived neurotrophic factor promoter IV, by the growth factor through multiple signaling pathways. The anti-apoptotic action of exendin-4 was lost following down-regulation of cAMP response element binding protein. Withdrawal of neurotrophins resulted in the loss of neuronal phenotype of differentiated neuroprogenitor cells, which was prevented by incubation in the presence of exendin-4. Diabetes is a risk factor in the pathogenesis of Alzheimer's disease. Our findings suggest that GLP-1-based therapies can decrease the incidence of Alzheimer's disease among aging diabetic population. C1 [Velmurugan, Kalpana; Bouchard, Ron; Pugazhenthi, Subbiah] Vet Affairs Med Ctr, Endocrinol Sect, Denver, CO USA. [Velmurugan, Kalpana; Bouchard, Ron; Mahaffey, Gregory; Pugazhenthi, Subbiah] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. RP Pugazhenthi, S (reprint author), Univ Colorado Denver, Denver VA Med Ctr, Mail Stop 8106,12801 E 17th Ave, Aurora, CO 80045 USA. EM subbiah.pugazhenthi@ucdenver.edu FU Veterans Administration [NEUD-004-07F] FX This work was carried out with the use of resources and facilities at Denver VA Medical Center. This study was supported by Merit Review grant NEUD-004-07F from the Veterans Administration (to S. P.). RT-PCR analysis was performed at the University of Colorado Cancer Center Core Facility. Digital deconvolution microscopy was carried out at the VA Microscopy Core Facility. Authors declare that there is no conflict of interest associated with this manuscript. NR 48 TC 18 Z9 18 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2012 VL 123 IS 6 BP 919 EP 931 DI 10.1111/jnc.12036 PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 051WK UT WOS:000312158500004 PM 23020846 ER PT J AU Wang, GI Delgutte, B AF Wang, Grace I. Delgutte, Bertrand TI Sensitivity of cochlear nucleus neurons to spatio-temporal changes in auditory nerve activity SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article DE coincidence detection; spatio-temporal pattern; cochlear nucleus; auditory nerve; anesthetized cat ID LATERAL SUPERIOR OLIVE; MASKING PERIOD PATTERNS; SPHERICAL BUSHY CELLS; LOW-FREQUENCY NEURONS; SOUND PRESSURE LEVEL; INFERIOR COLLICULUS; DISCHARGE PATTERNS; OCTOPUS CELLS; ONSET NEURONS; GLYCINERGIC INHIBITION AB Wang GI, Delgutte B. Sensitivity of cochlear nucleus neurons to spatio-temporal changes in auditory nerve activity. J Neurophysiol 108: 3172-3195, 2012. First published September 12, 2012; doi:10.1152/jn.00160.2012.-The spatio-temporal pattern of auditory nerve (AN) activity, representing the relative timing of spikes across the tonotopic axis, contains cues to perceptual features of sounds such as pitch, loudness, timbre, and spatial location. These spatio-temporal cues may be extracted by neurons in the cochlear nucleus (CN) that are sensitive to relative timing of inputs from AN fibers innervating different cochlear regions. One possible mechanism for this extraction is "cross-frequency" coincidence detection (CD), in which a central neuron converts the degree of coincidence across the tonotopic axis into a rate code by preferentially firing when its AN inputs discharge in synchrony. We used Huffman stimuli (Carney LH. J Neurophysiol 64: 437-456, 1990), which have a flat power spectrum but differ in their phase spectra, to systematically manipulate relative timing of spikes across tonotopically neighboring AN fibers without changing overall firing rates. We compared responses of CN units to Huffman stimuli with responses of model CD cells operating on spatio-temporal patterns of AN activity derived from measured responses of AN fibers with the principle of cochlear scaling invariance. We used the maximum likelihood method to determine the CD model cell parameters most likely to produce the measured CN unit responses, and thereby could distinguish units behaving like cross-frequency CD cells from those consistent with same-frequency CD (in which all inputs would originate from the same tonotopic location). We find that certain CN unit types, especially those associated with globular bushy cells, have responses consistent with cross-frequency CD cells. A possible functional role of a cross-frequency CD mechanism in these CN units is to increase the dynamic range of binaural neurons that process cues for sound localization. C1 [Wang, Grace I.; Delgutte, Bertrand] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Wang, Grace I.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Wang, Grace I.; Delgutte, Bertrand] MIT, Elect Res Lab, Cambridge, MA 02139 USA. [Delgutte, Bertrand] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Delgutte, B (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM bertrand_delgutte@meei.harvard.edu OI , /0000-0003-1349-9608 FU National Institute on Deafness and Other Communication Disorders [R01 DC-002258, P30 DC-005209] FX This work was supported by National Institute on Deafness and Other Communication Disorders Grants R01 DC-002258 and P30 DC-005209. NR 89 TC 4 Z9 4 U1 0 U2 9 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD DEC PY 2012 VL 108 IS 12 BP 3172 EP 3195 DI 10.1152/jn.00160.2012 PG 24 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 057UI UT WOS:000312589100002 PM 22972956 ER PT J AU Cao, KX Rosenberg, AE Hakim, J Masiakos, PT AF Cao, Kevin Xi Rosenberg, Andrew E. Hakim, Joseph Masiakos, Peter T. TI Axillary calcifying fibrous tumor (CFT) in an 8 year old girl SO JOURNAL OF PEDIATRIC SURGERY LA English DT Article DE Calcifying fibrous tumor; Calcifying fibrous pseudotumor; Inflammatory myofibroblastic tumor; Childhood fibrous tumors with psammoma bodies ID INFLAMMATORY MYOFIBROBLASTIC TUMOR; ADRENAL-GLAND; PSEUDOTUMOR; PLEURA; FEATURES; LESION; NECK AB Calcifying fibrous tumors (CFTs) are benign soft tissue masses that can occur at many sites. This case report outlines the diagnostic workup for this rare, fast-growing, solitary mass in an otherwise healthy 8year old patient. We also describe the radiographic and pathological characteristics unique to this lesion. (C) 2012 Elsevier Inc. All rights reserved. C1 [Cao, Kevin Xi; Masiakos, Peter T.] Massachusetts Gen Hosp, Div Pediat Surg, Boston, MA 02114 USA. [Rosenberg, Andrew E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hakim, Joseph] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Masiakos, PT (reprint author), Massachusetts Gen Hosp, Div Pediat Surg, Boston, MA 02114 USA. EM pmasiakos@partners.org NR 37 TC 1 Z9 1 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0022-3468 J9 J PEDIATR SURG JI J. Pediatr. Surg. PD DEC PY 2012 VL 47 IS 12 BP 2341 EP 2344 DI 10.1016/j.jpedsurg.2012.10.008 PG 4 WC Pediatrics; Surgery SC Pediatrics; Surgery GA 050SD UT WOS:000312073400048 PM 23217902 ER PT J AU Keung, EZ Liu, XX Nuzhad, A Rabinowits, G Patel, V AF Keung, Emily Z. Liu, Xiaoxia Nuzhad, Afrin Rabinowits, Guilherme Patel, Vihas TI In-Hospital and Long-Term Outcomes after Percutaneous Endoscopic Gastrostomy in Patients with Malignancy SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID CLINICAL PALLIATIVE CARE; PEG-TUBE PLACEMENT; NECK-CANCER; ADVANCED HEAD; COMPLICATIONS; SURGEONS; THERAPY; CHEMORADIOTHERAPY; MORTALITY; DEMENTIA AB BACKGROUND: Although percutaneous endoscopic gastrostomy (PEG) is widely performed for nutrition or palliation, PEG-associated outcomes in cancer patients remain poorly described. We examined the safety and benefits of PEG placement in this population at our institution. STUDY DESIGN: A 5-year retrospective review of patients with malignancy (excluding head/neck and thoracic malignancy) who underwent PEG at our institution was performed. RESULTS: One hundred and eighty-nine patients with malignancy underwent PEG; 33.9% had hematologic malignancy, 66.1% had nonhematologic malignancy, and 44.4% had metastatic disease. Indications for PEG were enteral access (73%) and gastric decompression/ management of obstructive symptoms (27%). Few patients achieved independence from total parenteral nutrition (22%) or diet advancement (24.6%). Overall rates of major complications (eg, aspiration, tube dislodgement/leakage, bleeding, visceral injury, respiratory failure after procedure, and cardiac arrest) and minor complications (eg, superficial infection and ileus) were 10.2% and 11.3%, respectively. All-cause in-hospital mortality was high (19.6%) and was associated with ICU admission (p = 0.018), earlier bone marrow transplantation (p = 0.022), steroid treatment (p = 0.024), and lower preoperative albumin (p = 0.003). Code status was changed after PEG in 44 patients from full code to DNR/do no intubate or comfort measures only. CONCLUSIONS: Percutaneous endoscopic gastrostomy placement in this study population was associated with major procedure-related complications. The majority of patients failed to achieve total parenteral nutrition independence or advancement of diet. Nearly 25% of patients declined aggressive resuscitation strategies after undergoing surgery for PEG. This study cautions to carefully weigh the risks and benefits of PEG placement in this patient population. Prospective studies are needed to uncover factors affecting the decision process and patient selection. (J Am Coll Surg 2012; 215: 777-786. (c) 2012 by the American College of Surgeons) C1 [Keung, Emily Z.; Nuzhad, Afrin; Patel, Vihas] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Liu, Xiaoxia] Brigham & Womens Hosp, Dept Anesthesiol, Boston, MA 02115 USA. [Rabinowits, Guilherme] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Patel, V (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM vpatel3@partners.org NR 45 TC 16 Z9 16 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD DEC PY 2012 VL 215 IS 6 BP 777 EP 786 DI 10.1016/j.jamcollsurg.2012.08.013 PG 10 WC Surgery SC Surgery GA 057WU UT WOS:000312595800004 PM 22999329 ER PT J AU Kousoulis, AA Economopoulos, KP Hatzinger, M Eshraghian, A Tsiodras, S AF Kousoulis, Antonis A. Economopoulos, Konstantinos P. Hatzinger, Martin Eshraghian, Ahad Tsiodras, Sotirios TI The Fatal Disease of Emperor Galerius SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Editorial Material ID FOURNIERS-GANGRENE; INFECTIONS; MANAGEMENT; SECONDARY; DIAGNOSIS C1 [Kousoulis, Antonis A.] Univ Athens, Hist Med Dept, Athens 18344, Greece. [Kousoulis, Antonis A.; Economopoulos, Konstantinos P.] Soc Jr Doctors, Athens, Greece. [Tsiodras, Sotirios] Univ Athens, Sch Med, Attikon Univ Hosp, Acad Dept Internal Med & Infect Dis 4, Athens 18344, Greece. [Economopoulos, Konstantinos P.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Hatzinger, Martin] Markushospital, Dept Urol, Frankfurt, Germany. [Eshraghian, Ahad] Shiraz Univ Med Sci, Dept Internal Med, Gastroenterohepatol Res Ctr, Shiraz, Iran. RP Kousoulis, AA (reprint author), Univ Athens, Hist Med Dept, 131 Lambrou Katsoni St, Athens 18344, Greece. EM antonis.kousoulis@sni.gr RI Kousoulis, Antonis/D-5540-2011; OI Kousoulis, Antonis/0000-0002-8763-3358; Tsiodras, Sotirios/0000-0002-0463-4321; Economopoulos, Konstantinos/0000-0003-4856-0405 NR 28 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 EI 1879-1190 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD DEC PY 2012 VL 215 IS 6 BP 890 EP 893 DI 10.1016/j.jamcollsurg.2012.05.039 PG 4 WC Surgery SC Surgery GA 057WU UT WOS:000312595800015 PM 22863796 ER PT J AU O'Hare, AM Walker, R Haneuse, S Crane, PK McCormick, WC Bowen, JD Larson, EB AF O'Hare, Ann M. Walker, Rod Haneuse, Sebastian Crane, Paul K. McCormick, Wayne C. Bowen, James D. Larson, Eric B. TI Relationship Between Longitudinal Measures of Renal Function and Onset of Dementia in a Community Cohort of Older Adults SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE dementia; renal function; eGFR; variability; trajectory ID CHRONIC KIDNEY-DISEASE; COGNITIVE FUNCTION; IMPAIRMENT; ALBUMINURIA; HEALTH; DECLINE; RISK; MICROALBUMINURIA; ASSOCIATION; POPULATION AB Objectives To evaluate the association between dynamic measures of renal function ascertained over time and onset of dementia. Design Prospective community cohort study. Setting Group Health, Seattle, Washington. Participants Two thousand nine hundred sixty-eight adults aged 65 and older followed for the development of dementia over a median of 6.0 years (interquartile range 3.110.1 years). Measurements Time-varying measures of renal function were constructed based on 49,340 serum creatinine measurements and included average estimated glomerular filtration rate (eGFR), eGFR trajectory, and variability in eGFR around this trajectory over 5-year exposure windows. The association between these three eGFR exposure measures and risk of dementia was estimated using a Cox regression model adjusted for other participant characteristics. Time-varying measures of urine protein by dipstick were also adjusted for in sensitivity analyses. Results Participants with a lower eGFR had a higher incidence of dementia, but this did not reach statistical significance in adjusted analyses (omnibus P = .14). There were trends toward a higher adjusted incidence of dementia in participants with positive eGFR trajectories (omnibus P = .07) and greater variability in eGFR (omnibus P = .04) over time. The results of sensitivity analyses, including those in which time-varying measures of proteinuria were included, were consistent with those of the primary analysis. Conclusion In a community cohort of older adults followed for a median of 6 years, strong associations were not found between measures of kidney disease severity and progression and incident dementia. J Am Geriatr Soc 60:2215-2222, 2012. C1 [O'Hare, Ann M.] VA Puget Sound Healthcare Syst, Dept Med, Seattle, WA 98119 USA. [O'Hare, Ann M.; Crane, Paul K.; McCormick, Wayne C.; Larson, Eric B.] Univ Washington, Dept Med, Seattle, WA USA. [Haneuse, Sebastian] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bowen, James D.] Swedish Med Ctr, Swedish Neurosci Inst, Seattle, WA USA. RP O'Hare, AM (reprint author), VA Puget Sound Healthcare Syst, Dept Med, 1160 S Columbian Way, Seattle, WA 98119 USA. EM Ann.OHare@va.gov RI Crane, Paul/C-8623-2014; OI Crane, Paul/0000-0003-4278-7465 FU National Institutes of Health [U01 AG006781, 1K23AG28980] FX This work was supported by National Institutes of Health Grants U01 AG006781 (PI: Larson) and 1K23AG28980 (PI: O'Hare). NR 32 TC 7 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2012 VL 60 IS 12 BP 2215 EP 2222 DI 10.1111/j.1532-5415.2012.04238.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 056AY UT WOS:000312460500003 PM 23231548 ER PT J AU Pierluissi, E Mehta, KM Kirby, KA Boscardin, WJ Fortinsky, RH Palmer, RM Landefeld, CS AF Pierluissi, Edgar Mehta, Kala M. Kirby, Katharine A. Boscardin, W. John Fortinsky, Richard H. Palmer, Robert M. Landefeld, C. Seth TI Depressive Symptoms After Hospitalization in Older Adults: Function and Mortality Outcomes SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE depression symptoms; hospitalized older adults; elderly; function; mortality ID CONGESTIVE-HEART-FAILURE; RANDOMIZED-CONTROLLED-TRIAL; ELDERLY MEDICAL INPATIENTS; ACUTE CORONARY SYNDROME; MYOCARDIAL-INFARCTION; MAJOR DEPRESSION; HEALTH; CARE; DISEASE; ILLNESS AB Objectives To determine the relationship between depressive symptoms after hospitalization and survival and functional outcomes. Design Secondary analysis of a prospective cohort study. Setting General medical service of two urban, teaching hospitals in Ohio. Participants Hospitalized individuals aged 70 and older. Measurements Ten depressive symptoms, instrumental activities of daily living (IADLs), and basic activities of daily living (ADLs) were measured at hospital discharge and 1, 3, 6, and 12 months later. Participant-specific changes in depressive symptoms (slopes) were determined using all data points. Four groups were also defined according to number of depressive symptoms (=3 symptoms, low; 410 symptoms, high) at discharge and follow-up: lowlow, lowhigh, highlow, and highhigh. Mortality was measured 3, 6, and 12 months after hospital discharge. Results Participant-specific discharge depressive symptoms and change in depressive symptoms over time (slopes) were associated (P < .05) with functional and mortality outcomes. At 1 year, more participants in the lowlow depressive symptom group (49%) were alive and independent in IADLs and ADLs than in the lowhigh group (37%, P = .02), and more participants in the highlow group (39%) were alive and independent in IADLs and ADLs than in the highhigh group (19%, P < .001). Conclusion Number of depressive symptoms and change in number of depressive symptoms during the year after discharge were associated with functional and mortality outcomes in hospitalized older adults. Fewer participants with persistently high or increasing depressive symptoms after hospitalization were alive and functionally independent 1 year later than participants with decreasing or persistently low symptoms, respectively. J Am Geriatr Soc 60:2254-2262, 2012. C1 [Pierluissi, Edgar; Mehta, Kala M.; Kirby, Katharine A.; Boscardin, W. John] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94110 USA. [Mehta, Kala M.; Boscardin, W. John] San Francisco VA Med Ctr, Hlth Serv Res Enhancement Award Program, San Francisco, CA USA. [Boscardin, W. John] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94110 USA. [Fortinsky, Richard H.] Univ Connecticut, Ctr Aging, Farmington, CT USA. [Palmer, Robert M.] Univ Pittsburgh, Div Geriatr Med & Gerontol, Pittsburgh, PA USA. [Landefeld, C. Seth] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. RP Pierluissi, E (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, 1001 Potrero Ave,Room 5H17, San Francisco, CA 94110 USA. EM epierluissi@medsfgh.ucsf.edu FU National Institute on Aging (NIA) [RO1 AG029233]; S.D. Bechtel, Jr. Foundation; NIA [RO1 AG029233, K-01AG025444, AG-10418-03]; NIA, National Institute of Nursing Research, and the National Center for Minority Health and Health Disparities [P30 AG 15272 350]; John A. Hartford Foundation [88277-3G, 2006-0108]; Summa Health System Foundation FX This work was supported by National Institute on Aging (NIA) Grant RO1 AG029233 and a grant from the S.D. Bechtel, Jr. Foundation (Principal Investigator, Dr. Landefeld). Dr. Mehta was supported by a Research Career Scientist Award from the NIA (K-01AG025444). She was an affiliate of the Center for Aging in Diverse Communities at the University of California at San Francisco, a part of the P30 AG 15272 350 Resource Centers for Minority Aging Research Program (NIA, National Institute of Nursing Research, and the National Center for Minority Health and Health Disparities). Dr. Pierluissi was supported by an administrative supplement to NIA Grant RO1 AG029233. The Acute Care for Elders studies were supported by grants from the John A. Hartford Foundation (88277-3G and 2006-0108), the NIA (AG-10418-03), and the Summa Health System Foundation. NR 46 TC 9 Z9 9 U1 5 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2012 VL 60 IS 12 BP 2254 EP 2262 DI 10.1111/jgs.12008 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 056AY UT WOS:000312460500008 PM 23176725 ER PT J AU Adams, K Bayliss, E Blumenthal, D Boyd, C Guralnik, J Krist, AH LaCroix, A Naylor, MD Patrick, DL Reuben, D Tinetti, M Wallace, RB Ware, JE Wolff, JL Hadley, E Salive, ME AF Adams, Karen Bayliss, Elizabeth Blumenthal, David Boyd, Cynthia Guralnik, Jack Krist, Alexander H. LaCroix, Andrea Naylor, Mary D. Patrick, Donald L. Reuben, David Tinetti, Mary Wallace, Robert B. Ware, John E., Jr. Wolff, Jennifer L. Hadley, Evan Salive, Marcel E. CA Working Grp Hlth Outcomes Older Pe TI Universal Health Outcome Measures for Older Persons with Multiple Chronic Conditions SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE geriatrics; chronic disease; comorbidity; outcome assessment; quality measurement ID QUALITY-OF-LIFE; GENERALIZED ANXIETY DISORDER; INFORMATION-SYSTEM PROMIS; PHYSICAL FUNCTION; FAMILY CAREGIVERS; INSTRUMENTS; PERFORMANCE; ADULTS; ACCURACY; VALIDITY AB Older adults with multiple chronic conditions (MCCs) require considerable health services and complex care. Because the persistence and progression of diseases and courses of treatments affect health status in multiple dimensions, well-validated universal outcome measures across diseases are needed for research, clinical care, and administrative purposes. An expert panel meeting held by the National Institute on Aging in September 2011 recommends that older persons with MCCs complete a brief initial composite measure that includes general health; pain; fatigue; and physical health, mental health, and social role function, along with gait speed measurement. Suitable composite measures include the Medical Outcomes Study 8 (SF-8) and 36 (SF-36) -item Short-Form Survey and the Patient Reported Outcomes Measurement Information System 29-item Health Profile. Based on responses to items in the initial measure, short follow-on measures should be selectively targeted to symptom burden, depression, anxiety, and daily activities. Persons unable to walk a short distance to assess gait speed should be assessed using a physical function scale. Remaining gaps to be considered for measure development include disease burden, cognitive function, and caregiver burden. Routine outcome assessment of individuals with MCCs could facilitate system-based care improvement and clinical effectiveness research. J Am Geriatr Soc 60: 2333-2341, 2012. C1 [Salive, Marcel E.] NIA, Geriatr Branch, Div Geriatr & Clin Gerontol, NIH, Bethesda, MD 20892 USA. [Bayliss, Elizabeth] Kaiser Permanente, Inst Hlth Res, Oakland, CA USA. [Blumenthal, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wolff, Jennifer L.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Guralnik, Jack] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Krist, Alexander H.] Virginia Commonwealth Univ, Med Ctr, Richmond, VA 23284 USA. [LaCroix, Andrea] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Naylor, Mary D.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Patrick, Donald L.] Univ Washington, Seattle, WA 98195 USA. [Reuben, David] UCLA Sch Med, Los Angeles, CA USA. [Tinetti, Mary] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Wallace, Robert B.] Univ Iowa, Coll Publ Hlth, Iowa City, IA 52242 USA. [Ware, John E., Jr.] Univ Massachusetts, Sch Med, Amherst, MA 01003 USA. RP Salive, ME (reprint author), NIA, Geriatr Branch, Div Geriatr & Clin Gerontol, NIH, 7201 Wisconsin Ave,Suite 3C307, Bethesda, MD 20892 USA. EM saliveme@nia.nih.gov FU National Institute of Mental Health [K01MH082885]; NIH; NIA; Agency for Healthcare Research and Quality FX Jennifer Wolff was supported by National Institute of Mental Health Grant K01MH082885.; John E. Ware, Jr., PhD, is Chief Science Officer and Founder, John Ware Research Group (JWRG), Inc., a for-profit business funded by NIH SBIR grants and unrestricted gifts or industry grants to develop and integrate generic and disease-specific patient-reported outcome measures for use in research and improving healthcare outcomes. He has received grants from NIH, NIA, and the Agency for Healthcare Research and Quality and various honoraria from academic institutions (<$5,000 annually). He is a consultant to the medical products industry on measurement issues and clinical trial results and interpretations (< 10,000 annually), is the principal shareholder of JWRG, Inc., and has provided expert testimony in Food and Drug Administration review panel hearings (3 in past 5 years). He is the primary or co-inventor for numerous patents, all sold with the sale of Quality Metric, Inc. in March 2010. NR 46 TC 28 Z9 28 U1 8 U2 36 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2012 VL 60 IS 12 BP 2333 EP 2341 DI 10.1111/j.1532-5415.2012.04240.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 056AY UT WOS:000312460500020 ER PT J AU Kirkman, MS Briscoe, VJ Clark, N Florez, H Haas, LB Halter, JB Huang, ES Korytkowski, MT Munshi, MN Odegard, PS Pratley, RE Swift, CS AF Kirkman, M. Sue Briscoe, Vanessa Jones Clark, Nathaniel Florez, Hermes Haas, Linda B. Halter, Jeffrey B. Huang, Elbert S. Korytkowski, Mary T. Munshi, Medha N. Odegard, Peggy Soule Pratley, Richard E. Swift, Carrie S. TI Diabetes in Older Adults: A Consensus Report SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; NUTRITION EXAMINATION SURVEY; INTENSIVE GLUCOSE CONTROL; LIFE-STYLE INTERVENTION; QUALITY-OF-LIFE; HOC EPIDEMIOLOGIC ANALYSIS; BASE-LINE CHARACTERISTICS; NURSING-HOME RESIDENTS; BLOOD-PRESSURE CONTROL; 10-YEAR FOLLOW-UP C1 [Halter, Jeffrey B.] Univ Michigan, Div Geriatr Med, Ann Arbor, MI 48109 USA. [Kirkman, M. Sue] Amer Diabet Assoc, Alexandria, VA USA. [Briscoe, Vanessa Jones] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Clark, Nathaniel] Diabet Ctr Cape Cod, Hyannis, MA USA. [Florez, Hermes] Univ Miami, Ctr Geriatr Res Educ & Clin, Miami Vet Affairs Healthcare Syst, Miami, FL USA. [Haas, Linda B.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Huang, Elbert S.] Univ Chicago, Gen Internal Med Sect, Chicago, IL 60637 USA. [Korytkowski, Mary T.] Univ Pittsburgh, Div Endocrinol, Pittsburgh, PA USA. [Munshi, Medha N.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Munshi, Medha N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Odegard, Peggy Soule] Univ Washington, Dept Pharm, Seattle, WA 98195 USA. [Pratley, Richard E.] Florida Hosp Diabet Inst, Orlando, FL USA. [Swift, Carrie S.] Kadlec Med Ctr, Richland, WA USA. RP Halter, JB (reprint author), Univ Michigan, Div Geriatr Med, Ann Arbor, MI 48109 USA. EM jhalter@med.umich.edu FU Association of Subspecialty Professors through the John A. Hartford Foundation; Lilly USA, LLC; Novo Nordisk; Medco Foundation; sanofi-aventis; Department of Veterans Affairs Geriatric Research, Education and Clinical Centers program; National Institutes of Health/U.S. Department of Health Human Services [1R18AE000049-01]; National Institute on Aging Claude D. Pepper Older Americans Independence Center [P30 AG024824]; National Institute of Diabetes and Digestive and Kidney Diseases, Diabetes Research and Training Center [P60 DK20595]; National Institute of Diabetes and Digestive and Kidney Diseases, Chicago Center for Diabetes Translational Research [P30 DK092949]; National Institute of Diabetes and Digestive and Kidney Diseases [RO1 DK081796] FX The authors thank Bobbie Alexander, Monique Lindsy, and Earnestine Walker for their assistance with the consensus development conference. The consensus development conference was supported by a planning grant from the Association of Subspecialty Professors (through a grant from the John A. Hartford Foundation), by educational grants from Lilly USA, LLC and Novo Nordisk, and sponsorships from the Medco Foundation and sanofi-aventis. Sponsors had no influence on the selection of speakers or writing group members, topics and content presented at the conference, or the content of this report. M.S.K.'s opinions in this work are her own and do not represent official position of the ADA.; H.F.'s work is partially supported by the Department of Veterans Affairs Geriatric Research, Education and Clinical Centers program and the National Institutes of Health/U.S. Department of Health & Human Services grant 1R18AE000049-01. J.B.H.'s work is supported in part by the National Institute on Aging Claude D. Pepper Older Americans Independence Center (P30 AG024824). E.S.H.'s work is supported in part through the following National Institute of Diabetes and Digestive and Kidney Diseases support: Diabetes Research and Training Center (P60 DK20595), Chicago Center for Diabetes Translational Research (P30 DK092949), and a project grant (RO1 DK081796). NR 131 TC 85 Z9 88 U1 2 U2 21 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2012 VL 60 IS 12 BP 2342 EP 2356 DI 10.1111/jgs.12035 PG 15 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 056AY UT WOS:000312460500021 PM 23106132 ER PT J AU Friedlander, AH AF Friedlander, Arthur H. TI Poor Dental Health and Dementia SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Letter ID ALZHEIMERS-DISEASE; COGNITIVE FUNCTION; MANAGEMENT; LIFE; NUN C1 [Friedlander, Arthur H.] VA Greater Los Angeles, Grad Medicat Educ, Los Angeles, CA 90095 USA. [Friedlander, Arthur H.] Ronald Reagan UCLA Med Ctr, Hosp Dent Serv, Los Angeles, CA USA. [Friedlander, Arthur H.] Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. RP Friedlander, AH (reprint author), VA Greater Los Angeles, Grad Medicat Educ, Los Angeles, CA 90095 USA. NR 7 TC 0 Z9 0 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2012 VL 60 IS 12 BP 2382 EP 2383 DI 10.1111/jgs.12017 PG 2 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 056AY UT WOS:000312460500039 PM 23231568 ER PT J AU Chang, H Yanachkov, IB Dix, EJ Li, YF Barnard, MR Wright, GE Michelson, AD Frelinger, AL AF Chang, H. Yanachkov, I. B. Dix, E. J. Li, Y. F. Barnard, M. R. Wright, G. E. Michelson, A. D. Frelinger, A. L., III TI Modified diadenosine tetraphosphates with dual specificity for P2Y1 and P2Y12 are potent antagonists of ADP-induced platelet activation SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE diadenosine; platelet; receptor ID P2Y(1) RECEPTOR ANTAGONISTS; DINUCLEOSIDE POLYPHOSPHATES; BIOLOGICAL-ACTIVITY; P2X(1) RECEPTORS; AGGREGATION; ANALOGS; INHIBITION; IDENTIFICATION; NUCLEOTIDES; DERIVATIVES AB Chang H, Yanachkov IB, Dix EJ, Li YF, Barnard MR, Wright GE, Michelson AD, Frelinger AL 3rd. Modified diadenosine tetraphosphates with dual specificity for P2Y1 and P2Y12 are potent antagonists of ADP-induced platelet activation. J Thromb Haemost 2012; 10: 257380. Summary. Background: Diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A), a natural compound stored in platelet dense granules, inhibits ADP-induced platelet aggregation. Ap4A inhibits the platelet ADP receptors P2Y1 and P2Y12, is a partial agonist of P2Y12, and is a full agonist of the platelet ATP-gated ion channel P2X1. Modification of the Ap4A tetraphosphate backbone enhances inhibition of ADP-induced platelet aggregation. However, the effects of these Ap4A analogs on human platelet P2Y1, P2Y12 and P2X1 are unclear. Objective: To determine the agonist and antagonist activities of diadenosine tetraphosphate analogs towards P2Y1, P2Y12, and P2X1. Methods: We synthesized the following Ap4A analogs: P1,P4-dithiotetraphosphate; P2,P3-chloromethylenetetraphosphate; P1-thio-P2,P3-chloromethylenetetraphosphate; and P1,P4-dithio-P2,P3-chloromethylenetetraphosphate. We then measured the effects of these analogs on: (i) ADP-induced platelet aggregation; (ii) P2Y1-mediated changes in cytosolic Ca2+; (iii) P2Y12-mediated changes in vasodilator-stimulated phosphoprotein phosphorylation; and (iv) P2X1-mediated entry of extracellular Ca2+.Results: Ap4A analogs with modifications in the phosphate backbone inhibited both P2Y1 and P2Y12, and showed no agonist activity towards these receptors. The dithio modification increased inhibition of P2Y1, P2Y12, and platelet aggregation, whereas the chloromethylene modification increased inhibition of P2Y12 and platelet aggregation, but decreased P2Y1 inhibition. Combining the dithio and chloromethylene modifications increased P2Y1 and P2Y12 inhibition. As compared with Ap4A, each modification decreased agonist activity towards P2X1, and the dual modification completely eliminated P2X1 agonist activity. Conclusions: As compared with Ap4A, tetraphosphate backbone analogs of Ap4A have diminished activity towards P2X1 but inhibit both P2Y1 and P2Y12 and, with greater potency, inhibit ADP-induced platelet aggregation. Thus, diadenosine tetraphosphate analogs with dual receptor selectivity may have potential as antiplatelet drugs. C1 [Barnard, M. R.; Michelson, A. D.; Frelinger, A. L., III] Harvard Univ, Boston Childrens Hosp, Sch Med,Div Hematol Oncol, Ctr Platelet Res Studies,Dana Farber Canc Inst, Boston, MA 02115 USA. [Chang, H.; Li, Y. F.; Barnard, M. R.; Michelson, A. D.; Frelinger, A. L., III] Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA USA. [Chang, H.] Chang Gung Univ, Chang Gung Mem Hosp, Div Hematol, Taipei, Taiwan. [Yanachkov, I. B.; Dix, E. J.; Wright, G. E.] GLSynthesis Inc, Worcester, MA USA. RP Frelinger, AL (reprint author), Harvard Univ, Boston Childrens Hosp, Sch Med,Div Hematol Oncol, Ctr Platelet Res Studies,Dana Farber Canc Inst, 300 Longwood Ave,Karp 07212, Boston, MA 02115 USA. EM andrew.frelinger@childrens.harvard.edu FU SBIR from the National Heart, Lung and Blood Institute [HL081992, HL088828]; GLSynthesis; Eli Lilly; Lilly FX This work was supported in part by SBIR grants HL081992 and HL088828 (to I. B. Yanachkov) from the National Heart, Lung and Blood Institute. A. L. Frelinger and A. D. Michelson have been investigators on research grants to Boston Children's Hospital from GLSynthesis and Eli Lilly. A. D. Michelson has been a member of the Data Monitoring Committee of a clinical trial sponsored by Lilly. I. B. Yanachkov and G. E. Wright are employees of GLSynthesis, Inc. E. J. Dix has been a consultant to GLSynthesis, Inc. The other authors state that they have no conflict of interest. NR 38 TC 8 Z9 8 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD DEC PY 2012 VL 10 IS 12 BP 2573 EP 2580 DI 10.1111/jth.12035 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 057CN UT WOS:000312539600019 PM 23083103 ER PT J AU Hartnick, CJ AF Hartnick, Christopher J. TI Management of complex pediatric voice disorders SO LARYNGOSCOPE LA English DT Article DE Pediatric; voice; dysphonia C1 Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Hartnick, CJ (reprint author), Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. EM christopher_hartnick@meei.harvard.edu NR 2 TC 1 Z9 1 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD DEC PY 2012 VL 122 SU 4 BP S87 EP S88 DI 10.1002/lary.23813 PG 2 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 056ZY UT WOS:000312532500017 PM 23254616 ER PT J AU Zhang, X Inukai, T Hirose, K Akahane, K Kuroda, I Honna-Oshiro, H Kagami, K Goi, K Nakamura, K Kobayashi, M Endo, M Yagita, H Kurosawa, H Look, AT Honda, H Inaba, T Nakazawa, S Sugita, K AF Zhang, X. Inukai, T. Hirose, K. Akahane, K. Kuroda, I. Honna-Oshiro, H. Kagami, K. Goi, K. Nakamura, K. Kobayashi, M. Endo, M. Yagita, H. Kurosawa, H. Look, A. Thomas Honda, H. Inaba, T. Nakazawa, S. Sugita, K. TI Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors SO LEUKEMIA LA English DT Article DE graft-versus-leukemia effect; acute lymphoblastic leukemia; TNF-related apoptosis-inducing ligand; E2A-HLF ID NF-KAPPA-B; CHIMERIC TRANSCRIPTION FACTOR; LIGAND TRAIL; DNA-BINDING; MYELOID-LEUKEMIA; TUMOR-METASTASIS; E2A GENE; CELLS; CASPASE-8; PATHWAYS AB t(17;19)-acute lymphoblastic leukemia (ALL) shows extremely poor prognosis. E2A-HLF derived from t(17;19) blocks apoptosis induced by the intrinsic mitochondrial pathway and has a central role in leukemogenesis and chemoresistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed on cytotoxic T cells and natural killer cells and binds with death receptors (DR4/DR5), inducing apoptosis by dual activation of intrinsic and extrinsic pathways, and TRAIL mediates the graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT). We found that cell lines and patients' samples of t(17;19)ALL expressed death receptors for TRAIL, and recombinant soluble TRAIL immediately induced apoptosis into t(17;19)-ALL cell lines. E2A-HLF induced gene expression of DR4/DR5, which was dependent on the DNA-binding and transactivation activities of E2A-HLF through the 50 upstream region of the start site at least in the DR4 gene. Introduction of E2A-HLF into non-t(17;19)-ALL cell line upregulated DR4 and DR5 expression, and sensitized to proapoptotic activity of recombinant soluble TRAIL. Finally, a newly diagnosed t(17;19)-ALL patient underwent allo-SCT immediately after induction of first complete remission, and the patient has survived without relapse for over 3-1/2 years after allo-SCT. These findings suggest that E2A-HLF sensitizes t(17;19)-ALL to the GVL effect by upregulating death receptors for TRAIL. Leukemia (2012) 26, 2483-2493; doi:10.1038/leu.2012.139 C1 [Zhang, X.; Inukai, T.; Hirose, K.; Akahane, K.; Kuroda, I.; Honna-Oshiro, H.; Kagami, K.; Goi, K.; Nakazawa, S.; Sugita, K.] Univ Yamanashi, Sch Med, Dept Pediat, Yamanashi 4093898, Japan. [Nakamura, K.; Kobayashi, M.] Hiroshima Univ, Grad Sch Biomed Sci, Dept Pediat, Hiroshima, Japan. [Endo, M.] Iwate Med Univ, Sch Med, Dept Pediat, Morioka, Iwate 020, Japan. [Yagita, H.] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan. [Kurosawa, H.] Dokkyo Med Univ, Sch Med, Dept Pediat, Mibu, Tochigi, Japan. [Look, A. Thomas] Dana Farber Canc Inst, Boston, MA 02115 USA. [Honda, H.] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Dis Model, Hiroshima, Japan. [Inaba, T.] Hiroshima Univ, Res Inst Radiat Biol & Med, Dept Mol Oncol, Hiroshima, Japan. RP Inukai, T (reprint author), Univ Yamanashi, Sch Med, Dept Pediat, 1110 Shimokatou, Yamanashi 4093898, Japan. EM tinukai@yamanashi.ac.jp FU Ministry of Education, Science and Culture in Japan FX We thank H Goto (Department of Pediatrics, Yokohama City University, Japan) for YCUB-2 cell line, F Rauscher III (Wister Institute, PA) for the pMT-CB6+ expression vector and T Sakai (Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Japan) for the vectors for DR5 reporter assay. This work was supported in part by research grants from the Ministry of Education, Science and Culture in Japan. NR 50 TC 3 Z9 3 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD DEC PY 2012 VL 26 IS 12 BP 2483 EP 2493 DI 10.1038/leu.2012.139 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 052GP UT WOS:000312186000006 PM 22743623 ER PT J AU Vesole, DH Oken, MM Heckler, C Greipp, PR Katz, MS Jacobus, S Morrow, GR AF Vesole, D. H. Oken, M. M. Heckler, C. Greipp, P. R. Katz, M. S. Jacobus, S. Morrow, G. R. CA Univ Rochester Canc Ctr Eastern Cooperative Oncology Grp TI Oral antibiotic prophylaxis of early infection in multiple myeloma: a URCC/ECOG randomized phase III study SO LEUKEMIA LA English DT Article DE antibiotics; multiple myeloma; infections ID RISK AB Multiple myeloma (MM) is a malignancy of clonal plasma cells, resulting in an increased production of ineffective immunoglobulins with suppression of non-involved immunoglobulins. Patients with MM are at increased risk of infectious complications, particularly streptococcal and staphylococcal infections. This study evaluated the impact of prophylactic antibiotics on the incidence of serious bacterial infections (SBIs) during the first 2 months of treatment in patients with newly diagnosed MM. Patients with MM receiving initial chemotherapy were randomized on a 1: 1: 1 basis to daily ciprofloxacin (C; 500mg twice daily), trimethoprim-sulfamethoxazole (T; DS twice daily) or observation (O) and evaluated for SBI (Eastern Cooperative Oncology Group >= grade 3) for the first 2 months of treatment. From July 1998 to January 2008, 212 MM patients were randomized to C (n = 69), T (n = 76) or O (n 67). The incidence of SBI was comparable among groups: C = 12.5%, T = 6.8% and O = 15.9%; P = 0.218. Further, any infection during the first 2 months was also comparable (20% vs 23% vs 22%, respectively, P = 0.954). We demonstrate that prophylactic antibiotics did not decrease the incidence of SBI (>= grade 3) within the first 2 months of treatment. We conclude that routine use of prophylactic antibiotics should not be mandated for patients receiving induction chemotherapy. Leukemia (2012) 26, 2517-2520; doi:10.1038/leu.2012.124 C1 [Vesole, D. H.] Hackensack Univ, Med Ctr, John Theurer Canc Ctr, Hackensack, NJ 07601 USA. [Oken, M. M.] Northwestern Hosp, Minneapolis, MN USA. [Heckler, C.; Morrow, G. R.] Univ Rochester, Rochester, NY USA. [Greipp, P. R.] Mayo Clin, Div Hematol, Rochester, MN USA. [Katz, M. S.] Eastern Cooperat Oncol Grp, Boston, MA USA. [Jacobus, S.] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. RP Vesole, DH (reprint author), Hackensack Univ, Med Ctr, John Theurer Canc Ctr, 92 2nd St, Hackensack, NJ 07601 USA. EM dvesole@humed.com FU ECOG [CA13650, CA21115, CA23318] FX We thank the members and staff of URCC and ECOG and the patients and their families. This work was supported in part by ECOG Grant numbers CA13650, CA21115 and CA23318. NR 15 TC 16 Z9 16 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD DEC PY 2012 VL 26 IS 12 BP 2517 EP 2520 DI 10.1038/leu.2012.124 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 052GP UT WOS:000312186000010 PM 22678167 ER PT J AU Mangos, S Amaral, AP Faul, C Juppner, H Reiser, J Wolf, M AF Mangos, Steve Amaral, Ansel P. Faul, Christian Jueppner, Harald Reiser, Jochen Wolf, Myles TI Expression of fgf23 and aklotho in developing embryonic tissues and adult kidney of the zebrafish, Danio rerio SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE corpuscles of Stannius; FGF23; kidney; klotho; pronephros; zebrafish ID VITAMIN-D METABOLISM; KLOTHO; STANNIOCALCIN; HOMEOSTASIS; REGULATOR; PHOSPHATE; PROTEIN; CHANNEL; FAMILY; TUBULE AB Fibroblast growth factor 23 (FGF23) is an endocrine hormone that is secreted by bone and acts on the kidney and parathyroid glands to regulate phosphate homeostasis. The effects of FGF23 on phosphate homeostasis are mediated by binding to FGF receptors and their coreceptor, klotho, which are abundantly expressed in the kidney and parathyroid glands. However, the mechanisms of how FGF23 regulates phosphate handling in the proximal tubule are unclear because klotho is primarily expressed in the distal nephron in humans and rodents. The purpose of this study was to gain additional insight into the FGF23-klotho system by investigating the spatial and temporal aspects of the expression of fgf23 and klotho in the zebrafish, Danio rerio. Here, we report that zebrafish fgf23 begins to be expressed after organogenesis and is continually expressed into adulthood in the corpuscles of Stannius, which are endocrine glands that lie in close proximity to the nephron and are thought to contribute to calcium and phosphate homeostasis in fish. Zebrafish klotho expression can be detected by 24-h postfertilization in the brain, pancreas and the distal pronephros, and by 56-h postfertilization in liver. Expression in the distal pronephros persists throughout development, and by Day 5, there is also strong expression in the proximal pronephros. klotho continues to be expressed in the tubules of the metanephros of the adult kidney. These data indicate conservation of the FGF23-klotho system across species and suggest a likely role for klotho in the proximal and distal tubules. C1 [Mangos, Steve; Amaral, Ansel P.; Faul, Christian; Reiser, Jochen; Wolf, Myles] Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. [Jueppner, Harald] Harvard Univ, Sch Med, Dept Med, Endocrine Unit,Massachusetts Gen Hosp, Boston, MA USA. RP Wolf, M (reprint author), Univ Miami, Miller Sch Med, Dept Med, Div Nephrol & Hypertens, Miami, FL 33136 USA. EM mwolf2@med.miami.edu FU National Institutes of Health [R01DK076116, R01DK081374] FX M.W. was supported by grants R01DK076116 and R01DK081374 from the National Institutes of Health. NR 32 TC 5 Z9 5 U1 0 U2 33 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD DEC PY 2012 VL 27 IS 12 BP 4314 EP 4322 DI 10.1093/ndt/gfs335 PG 9 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 058PK UT WOS:000312645800013 PM 22885518 ER PT J AU De Cosmo, S Prudente, S Lamacchia, O Lucchesi, D Shah, H Mendonca, C Pucci, L Mercuri, L Gervino, EV Hauser, TH Bailetti, D Penno, G Cignarelli, M Doria, A Trischitta, V AF De Cosmo, Salvatore Prudente, Sabrina Lamacchia, Olga Lucchesi, Daniela Shah, Hetal Mendonca, Christine Pucci, Laura Mercuri, Luana Gervino, Ernest V. Hauser, Thomas H. Bailetti, Diego Penno, Giuseppe Cignarelli, Mauro Doria, Alessandro Trischitta, Vincenzo TI The 9p21 coronary artery disease locus and kidney dysfunction in patients with Type 2 diabetes mellitus SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE albuminuria; coronary artery disease; gene polymorphism; glomerular filtration rate ID HEART-DISEASE; MYOCARDIAL-INFARCTION; ASSOCIATION; RISK; HERITABILITY; NEPHROPATHY; FAMILIES AB We investigated whether the coronary artery disease (CAD) locus on chromosome 9p21 (as represented by single nucleotide polymorphism rs2383206) is associated with low estimated glomerular filtration rate (eGFR) or increased urinary albumin excretion in patients with Type 2 diabetes mellitus (T2DM). Four samples, including a total of 3167 patients, were studied. The presence of low eGFR (60 mL/min/1.73m(2)) was estimated from serum creatinine by means of the Modification of Diet in Renal Disease Study equation. Increased urinary albumin excretion was defined as an albumincreatinine ratio (ACR) epsilon 2.5 mg/mmol in men and epsilon 3.5 mg/mmol in women. No association was found between rs2383206 and low eGFR or increased ACR in each sample as well as in a pooled analysis (overall odds ratio 1.07, 95 confidence interval 0.941.22, P 0.31 and overall odds ratio 1.00, 95 confidence interval 0.901.12, P 0.95, respectively). No interaction was observed between rs2383206 and poor glycemic control [HbA1c was above the median in the pooled sample (7.7) in modulating eGFR or ACR (P for interaction 0.42 and 0.90, respectively)]. Variability at the 9p21 CAD locus is unlikely to play a role in modulating susceptibility to kidney dysfunction in patients with T2DM. C1 [De Cosmo, Salvatore] IRCSS Casa Sollievo Sofferenza, Clin Unit Endocrinol, Dept Med Sci, San Giovanni Rotondo, Italy. [Prudente, Sabrina; Mercuri, Luana; Bailetti, Diego; Trischitta, Vincenzo] IRCSS Casa Sollievo Sofferenza, Mendel Lab, San Giovanni Rotondo, Italy. [Lamacchia, Olga; Cignarelli, Mauro] Univ Foggia, Dept Med Sci, Foggia, Italy. [Lucchesi, Daniela; Pucci, Laura; Penno, Giuseppe] Univ Pisa, Dept Endocrinol & Metab, Pisa, Italy. [Shah, Hetal; Mendonca, Christine; Doria, Alessandro] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Shah, Hetal; Gervino, Ernest V.; Hauser, Thomas H.; Doria, Alessandro] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Gervino, Ernest V.; Hauser, Thomas H.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Trischitta, Vincenzo] IRCSS Casa Sollievo Sofferenza, Res Unit Diabet & Endocrine Dis, San Giovanni Rotondo, Italy. [Trischitta, Vincenzo] Univ Roma La Sapienza, Dept Expt Med, Rome, Italy. RP De Cosmo, S (reprint author), IRCSS Casa Sollievo Sofferenza, Clin Unit Endocrinol, Dept Med Sci, San Giovanni Rotondo, Italy. EM sdecosm@tin.it RI Prudente, Sabrina/H-2886-2016; De Cosmo, Salvatore/J-7420-2016; Trischitta, Vincenzo/K-1487-2016; OI Prudente, Sabrina/0000-0001-9220-8981; De Cosmo, Salvatore/0000-0001-8787-8286; Trischitta, Vincenzo/0000-0003-1174-127X; PUCCI, LAURA/0000-0002-8162-4039 FU Italian Ministry of Health [RF2009, RC2011, RC2012, RC2010]; Fondazione Roma "Sostegno alla ricerca scientifica biomedica"; Accordo Programma Quadro in Materia di Ricerca Scientifica nella Regione Puglia-PST FX This work was supported by Italian Ministry of Health Grants: RF2009 (S.D.C.), RC2011 and RC2012 (S.P.), RC2010 (V.T.); Fondazione Roma "Sostegno alla ricerca scientifica biomedica 2008" (V.T.); Accordo Programma Quadro in Materia di Ricerca Scientifica nella Regione Puglia-PST 2006. NR 13 TC 3 Z9 3 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD DEC PY 2012 VL 27 IS 12 BP 4411 EP 4413 DI 10.1093/ndt/gfs148 PG 3 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 058PK UT WOS:000312645800028 PM 22622453 ER PT J AU Canellos, GP AF Canellos, George P. TI Treatment for Favorable Localized Hodgkin Lymphoma: the Final Answer Is Awaited SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID LONG-TERM; RADIATION-THERAPY; DISEASE; CHEMOTHERAPY; RADIOTHERAPY; DOXORUBICIN; MORTALITY; SURVIVORS; TRIAL C1 [Canellos, George P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Canellos, George P.] Harvard Univ, Sch Med, Boston, MA USA. RP Canellos, GP (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 22 TC 0 Z9 0 U1 1 U2 3 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD DEC PY 2012 VL 26 IS 12 BP 1199 EP + PG 3 WC Oncology SC Oncology GA 058AA UT WOS:000312605000012 PM 23413601 ER PT J AU McKay, RR Kantof, P AF McKay, Rana R. Kantof, Philip TI Prostate Cancer 2012: Where Do We Stand and Where Are We Heading? SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID ABIRATERONE C1 [McKay, Rana R.; Kantof, Philip] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP McKay, RR (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [T32 CA009172] NR 9 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD DEC PY 2012 VL 26 IS 12 BP 1222 EP 1224 PG 2 WC Oncology SC Oncology GA 058AA UT WOS:000312605000018 PM 23413607 ER PT J AU Wang, SX Song, L Tan, YH Ma, YX Tian, YH Jin, X Lim, G Zhang, SZ Chen, L Mao, JR AF Wang, Shuxing Song, Li Tan, Yonghui Ma, Yuxin Tian, Yinghong Jin, Xu Lim, Grewo Zhang, Shuzhuo Chen, Lucy Mao, Jianren TI A Functional Relationship Between Trigeminal Astroglial Activation and NR1 Expression in a Rat Model of Temporomandibular Joint Inflammation SO PAIN MEDICINE LA English DT Article DE Trigeminal Pain; NMDA Receptor; NR1; Astroglia; GFAP; Sp5C ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; PERIPHERAL-NERVE INJURY; NEUROPATHIC PAIN; INTRACEREBROVENTRICULAR INJECTION; THERMAL HYPERALGESIA; PERSISTENT PAIN; NITRIC-OXIDE; NEUROIMMUNE ACTIVATION; CUTANEOUS HYPERALGESIA; SUBNUCLEUS CAUDALIS AB Objective To examine the hypothesis that glial activation would regulate the expression of the N-methyl-D-aspartate receptor subunit 1 (NR1) in the trigeminal subnucleus caudalis (Sp5C) after temporomandibular joint (TMJ) inflammation. Methods Inflammation of TMJ was produced in rats by injecting 50?mu L complete Freund's adjuvant (CFA) into unilateral TMJ space. Sham control rats received incomplete Freund's adjuvant injection. Mechanical nociception in the affected and non-affected TMJ site was tested by using a digital algometer. Fractalkine, fluorocitrate, and/or MK801 were intracisternally administrated to examine the relationship between astroglial activation and NR1 upregulation. Results CFA TMJ injection resulted in persistent ipsilateral mechanical hyperalgesia 1, 3, and 5 days after CFA injection. The inflammation also induced significant upregulation of CX3C chemokine receptor 1 and glial fibrillary acidic protein (GFAP) beginning on day 1 and of NR1 beginning on day 3 within the ipsilateral Sp5C. Intracisternal administration of fluorocitrate for 5 days blocked the development of mechanical hyperalgesia as well as the upregulation of GFAP and NR1 in the Sp5C. Conversely, intracisternal injection of fractalkine for 5 days exacerbated the expression of NR1 in Sp5C and mechanical hyperalgesia induced by TMJ inflammation. Moreover, once daily intracisternal fractalkine administration for 5 days in naive rats induced the upregulation of NR1 and mechanical hyperalgesia. Conclusions These results suggest that astroglial activation contributes to the mechanism of TMJ pain through the regulation of NR1 expression in Sp5C. C1 [Wang, Shuxing; Song, Li; Tan, Yonghui; Ma, Yuxin; Tian, Yinghong; Jin, Xu; Lim, Grewo; Zhang, Shuzhuo; Chen, Lucy; Mao, Jianren] Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, MGH Ctr Translat Pain Res,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Song, Li] Sichuan Univ, W China Hosp, Dept Anesthesia, Chengdu 610064, Sichuan, Peoples R China. [Tan, Yonghui] Peking Univ, Sch & Hosp Stomatol, Ctr TMD & Orofacial Pain, Beijing 100871, Peoples R China. [Zhang, Shuzhuo] Beijing Inst Pharmacol & Toxicol, Beijing, Peoples R China. RP Mao, JR (reprint author), Harvard Univ, Sch Med, Dept Anesthesia Crit Care & Pain Med, MGH Ctr Translat Pain Res,Massachusetts Gen Hosp, Boston, MA 02114 USA. EM jmao@partners.org FU NIH [R01DE18214, R01DE18538, P20DA26002] FX This study is supported by NIH RO1 grants NIH grants R01DE18214, R01DE18538, and P20DA26002. There is no conflict of interest in this project. NR 41 TC 4 Z9 4 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1526-2375 J9 PAIN MED JI Pain Med. PD DEC PY 2012 VL 13 IS 12 BP 1590 EP 1600 DI 10.1111/j.1526-4637.2012.01511.x PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 058QW UT WOS:000312649700009 PM 23110394 ER PT J AU Varraso, R Camargo, CA AF Varraso, Raphaelle Camargo, Carlos A., Jr. TI Can dietary interventions improve asthma control? SO PRIMARY CARE RESPIRATORY JOURNAL LA English DT Editorial Material ID SOY; ASSOCIATION; ISOFLAVONES; PREVALENCE; NUTRITION; ADULTS; HEALTH; WOMEN; FOOD C1 [Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Varraso, Raphaelle] INSERM, CESP Ctr Res Epidemiol & Populat Hlth, U1018, Resp & Environm Epidemiol Team, Villejuif, France. [Varraso, Raphaelle] Univ Paris 11, UMRS 1018, Villejuif, France. RP Camargo, CA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, 326 Cambridge St,Suite 410, Boston, MA 02114 USA. EM ccamargo@partners.org RI Varraso, Raphaelle/R-8740-2016 OI Varraso, Raphaelle/0000-0002-3338-7825 NR 15 TC 1 Z9 1 U1 0 U2 1 PU PRIMARY CARE RESPIRATORY SOC-PCRS UK PI WATERBECK PA EDITORIAL OFFICE, SMITHY HOUSE, WATERBECK, LOCKERBIE DG11 3EY, SCOTLAND SN 1471-4418 J9 PRIM CARE RESP J JI Prim. Care Respir. J. PD DEC PY 2012 VL 21 IS 4 BP 367 EP 368 DI 10.4104/pcrj.2012.00095 PG 2 WC Primary Health Care; Respiratory System SC General & Internal Medicine; Respiratory System GA 056WW UT WOS:000312523100005 PM 23138842 ER PT J AU Han, H Ahn, DH Song, J Hwang, TY Roh, S AF Han, Hyeree Ahn, Dong Hyun Song, Jinhee Hwang, Tae Yeon Roh, Sungwon TI Development of Mental Health Indicators in Korea SO PSYCHIATRY INVESTIGATION LA English DT Article DE Mental health; Mental health indicator; Development AB Objective Promoting mental health and preventing mental health problems are important tasks for international organizations and nations. Such goals entail the establishment of active information networks and effective systems and indicators to assess the mental health of populations. This being said, there is a need in Korea develop ways to measure the state of mental health in Korea. Methods This paper reviews the mental health indicator development policies and practices of seven organizations, countries, and regions: WHO, OECD, EU, United States, Australia, UK, and Scotland. Using Delphi method, we conducted two surveys of mental health indicators for experts in the field of mental health. The survey questionnaire included 5 domains: mental health status, mental health factor, mental health system, mental health service, and quality of mental health services. We considered 124 potential mental health indicators out of more than 600 from indicators of international organizations and foreign countries. Results We obtained the top 30 mental health indicators from the surveys. Among them, 10 indicators belong to the mental health system. The most important five mental health indicators are suicide rate, rate of increase in mental disorder treatment, burden caused by mental disorders, adequacy of identifying problems of mental health projects and deriving solutions, and annual prevalence of mental disorders. Conclusion Our study provides information about the process for indicator development and the use of survey results to measure the mental health status of the Korean population. The aim of mental health indicator development is to improve the mental health system by better grasping the current situation. We suggest these mental health indicators can monitor progress in efforts to implement reform policies, provide community services, and involve users, families and other stakeholders in mental health promotion, prevention, care and rehabilitation. Psychiatry Investig 2012;9:311-318 C1 [Han, Hyeree; Song, Jinhee; Roh, Sungwon] Seoul Natl Hosp, Minist Hlth & Welf, Dept Mental Hlth Res, Seoul 143711, South Korea. [Ahn, Dong Hyun] Hanyang Univ, Coll Med, Dept Psychiat, Seoul 133791, South Korea. [Song, Jinhee] Catholic Univ Korea, Dept Social Welf, Puchon, South Korea. [Hwang, Tae Yeon] Yongin Mental Hosp, WHO Collaborating Ctr PSR & CMH, Yongin, South Korea. [Roh, Sungwon] Harvard Univ, Sch Med, Dept Psychiat, Ctr Addict Med,Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Roh, S (reprint author), Seoul Natl Hosp, Minist Hlth & Welf, Dept Mental Hlth Res, 398 Neungdong Ro, Seoul 143711, South Korea. EM swroh@korea.kr FU Lee Si-Hyung Social Psychiatry Research Fund of the Korean Foundation of Neuropsychiatric Research; National Center for Mental Health Research and Education of Seoul National Hospital FX This study was conducted with the support of Lee Si-Hyung Social Psychiatry Research Fund of the Korean Foundation of Neuropsychiatric Research (DHA and SR) and the National Center for Mental Health Research and Education of Seoul National Hospital (HH). The authors would also like to acknowledge the contributions of the participating experts: Jeongyee Bae, RN, PhD, Inje University; Yong-Mae Baek, PhD, Catholic University of Daegu; An Kee Chang, MD, Seoul National Hospital; Duk Hee Chun, PhD, Tongwon College; Duck-Gyu Kang, PhD, Haein Mental Health Center; Donghyeon Kim, MD, Choongmoosarang Hospital; Sun Ah Kim, RN, PhD, Yonsei University; Yoon Kim, MD, PhD, Seoul National University; Jong-Eun Lee, RN, PhD, Inha University; Jonggook Lee, MD, Yong-In Mental Hospital; Woo Kyeong Lee, PhD, Yong-In Mental Hospital; Yu Jin Lee, MD, PhD, Gachon University; Kyoung A Nam, RN, PhD, Ajou University; Jong-Woo Paik, MD, PhD, Kyung Hee University; Yongjin Seo, MD, Yong-In Mental Hospital; Jun Mo Sung, PhD, Korea Nazarene University; Hae-Joo Yoon, MA, Seoul National Hospital. NR 14 TC 1 Z9 1 U1 14 U2 22 PU KOREAN NEUROPSYCHIATRIC ASSOC PI SEOUL PA RN 522, G-FIVE CENTRAL PLAZA 1685-8 SEOCHO 4-DONG, SEOCHO-GU, SEOUL, 137-882, SOUTH KOREA SN 1738-3684 J9 PSYCHIAT INVEST JI Psychiatry Investig. PD DEC PY 2012 VL 9 IS 4 BP 311 EP 318 DI 10.4306/pi.2012.9.4.311 PG 8 WC Psychiatry SC Psychiatry GA 056VI UT WOS:000312519100001 PM 23251193 ER PT J AU Najafzadeh, M Marra, CA Lynd, LD Wiseman, SM AF Najafzadeh, Mehdi Marra, Carlo A. Lynd, Larry D. Wiseman, Sam M. TI Cost-Effectiveness of Using a Molecular Diagnostic Test to Improve Preoperative Diagnosis of Thyroid Cancer SO VALUE IN HEALTH LA English DT Article DE cost-effectiveness; gene expression; molecular diagnostic test; thyroid cancer; fine needle aspiration biopsy; The Bethesta System for Reporting Thyroid Cytopathology (TBSRTC) ID FINE-NEEDLE-ASPIRATION; RECOMBINANT HUMAN THYROTROPIN; RADIOIODINE ABLATION; UNITED-STATES; NODULES; CARCINOMA; CYTOLOGY; BIOPSY; SIMULATION; MANAGEMENT AB Objective: Fine-needle aspiration biopsy (FNAB) is a safe and inexpensive diagnostic procedure for evaluating thyroid nodules. Up to 25% of the results from an FNAB, however, may not be diagnostic or may be indeterminate, leading to a subsequent diagnostic thyroid surgery. A new molecularly based diagnostic test could potentially reduce indeterminate cytological results and, with high accuracy, provide a definitive diagnosis for cancer in thyroid nodules. The aim of the study was to estimate the cost-effectiveness of utilizing a molecular diagnostic (DX) test as an adjunct to FNAB, compared with NoDX, to improve the preoperative diagnosis of thyroid nodules. Methods: We constructed a patient-level simulation model to estimate the clinical and economic outcomes of using a DX test compared with current practice (NoDX) for the diagnosis of thyroid nodules. By using a cost-effectiveness framework, we measured incremental clinical benefits in terms of quality-adjusted life-years and incremental costs over a 10-year time horizon. Results: Assuming 95% sensitivity and specificity of the Dx test when used as an adjunct to FNAB, the utilization of the DX test resulted in a gain of 0.046 quality-adjusted life-years (95% confidence interval 0.019-0.078) and a saving of $1087 (95% confidence interval $691-$1533) in direct costs per patient. If the cost of the Dx test is less than $1087 per test, we expect to save quality-adjusted life-years and reduce costs when it is utilized. Sensitivity of the DX test, compared with specificity, had a larger influence on the overall outcomes. C1 [Wiseman, Sam M.] Univ British Columbia, Dept Surg, Vancouver, BC V6Z 1Y63, Canada. [Wiseman, Sam M.] Univ British Columbia, Dept Surg, St Pauls Hosp, Vancouver, BC V6Z 1Y63, Canada. [Najafzadeh, Mehdi] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Harvard MGH Ctr Genom Vulnerable Populat & Hlth D, Boston, MA 02114 USA. [Marra, Carlo A.; Lynd, Larry D.] Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC V6Z 1Y63, Canada. [Marra, Carlo A.; Lynd, Larry D.] St Pauls Hosp, Ctr Hlth Evaluat & Outcome Sci, Vancouver, BC V6Z 1Y6, Canada. RP Wiseman, SM (reprint author), Univ British Columbia, Dept Surg, St Pauls Hosp, C303-1081 Burrard St, Vancouver, BC V6Z 1Y63, Canada. EM smwiseman@providencehealth.bc.ca FU National Research Council; Canadian Institute for Health Research Canada (CIHR) FX Source of financial support: This study was supported by the National Research Council Industrial Assistance Program (to Dr. Lesley Esford). Dr. Mehdi Najafzadeh was supported by a Canadian Institute for Health Research Canada (CIHR) Graduate Scholarship during the course of this study. NR 30 TC 10 Z9 10 U1 2 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD DEC PY 2012 VL 15 IS 8 BP 1005 EP 1013 DI 10.1016/j.jval.2012.06.017 PG 9 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 055RT UT WOS:000312435300003 PM 23244801 ER PT J AU Anaya, HD Chan, K Karmarkar, U Asch, SM Goetz, MB AF Anaya, Henry D. Chan, Kee Karmarkar, Uday Asch, Steven M. Goetz, Matthew Bidwell TI Budget Impact Analysis of HIV Testing in the VA Healthcare System SO VALUE IN HEALTH LA English DT Article; Proceedings Paper CT International-Association-of-Physicians in AIDS Care (IAPAC) CY 2009 CL New Orleans, LA SP Int Assoc Phys AIDS Care (IAPAC) DE budget impact analysis; cost-effectiveness; facility costs; HIV testing ID REVISED RECOMMENDATIONS; COST-EFFECTIVENESS; UNITED-STATES; SETTINGS; VETERANS; ERA AB Objectives: The long-term cost effectiveness of routine HIV testing is favorable relative to other medical interventions. Facility-specific costs of expanded HIV testing and care for newly identified patients, however, are less well defined. To aid in resource allocation decisions, we developed a spreadsheet-based budget-impact tool populated with estimates of facility-specific HIV testing and care costs incurred with an expanded testing program. Methods: We modeled intervention effects on quarterly costs of antiretroviral therapy (ART), outpatient resource utilization, and staff expenditures in the Department of Veterans Affairs over a 2-year period of increasing HIV testing rates. We used HIV prevalence estimates, screening rates, counseling, positive tests, Veterans Affairs treatment, and published sources as inputs. We evaluated a single-facility cohort of 20,000 patients and at baseline assumed a serodiagnostic rate of 0.45%. Results: Expanding testing from 2% to 15% annually identified 21 additional HIV-positive patients over 2 years at a cost of approximately $290,000, more than 60% of which was due to providing ART to newly diagnosed patients. While quarterly testing costs decreased longitudinally as fewer persons required testing, quarterly ART costs increased from $10,000 to more than $60,000 over 2 years as more infected patients were identified and started on ART. In sensitivity analyses, serodiagnostic and annual HIV testing rates had the greatest cost impact. Conclusions: Expanded HIV testing costs are greatest during initial implementation and predominantly due to ART for new patients. Cost determinations of expanded HIV testing provide an important tool for managers charged with allocating resources within integrated systems providing both HIV testing and care. C1 [Anaya, Henry D.; Asch, Steven M.; Goetz, Matthew Bidwell] VA Greater Los Angeles Healthcare Syst, Ctr Study Healthcare Provider Behav, VA Greater Los Angeles Hlth Serv, Res & Dev Ctr Excellence, Los Angeles, CA 90073 USA. [Anaya, Henry D.; Asch, Steven M.; Goetz, Matthew Bidwell] Vet Affairs Qual Enhancement Res Initiat HIV Hepa, Los Angeles, CA 90073 USA. [Anaya, Henry D.; Asch, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med & Hlth Serv Res GIM & HSR, Los Angeles, CA 90095 USA. [Chan, Kee] Boston Univ, Dept Hlth Sci, Sargent Coll Hlth & Rehabil Sci, Boston, MA 02215 USA. [Chan, Kee] Edith Nourse Rogers Mem Vet Hosp, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Karmarkar, Uday] UCLA Anderson Sch Business, Los Angeles, CA USA. [Asch, Steven M.] RAND Hlth, Santa Monica, CA USA. [Goetz, Matthew Bidwell] VA Greater Los Angeles Healthcare Syst, Dept Med, Sect Infect Dis, Los Angeles, CA 90073 USA. RP Anaya, HD (reprint author), VA Greater Los Angeles Healthcare Syst, Ctr Study Healthcare Provider Behav, VA Greater Los Angeles Hlth Serv, Res & Dev Ctr Excellence, 11301 Wilshire Blvd,111G, Los Angeles, CA 90073 USA. EM hemy.anaya@va.gov OI Goetz, Matthew/0000-0003-4542-992X NR 17 TC 5 Z9 5 U1 0 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 J9 VALUE HEALTH JI Value Health PD DEC PY 2012 VL 15 IS 8 BP 1022 EP 1028 DI 10.1016/j.jval.2012.08.2205 PG 7 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 055RT UT WOS:000312435300005 PM 23244803 ER PT J AU Glanz, BI Degano, IR Rintell, DJ Chitnis, T Weiner, HL Healy, BC AF Glanz, Bonnie I. Degano, Irene R. Rintell, David J. Chitnis, Tanuja Weiner, Howard L. Healy, Brian C. TI Work Productivity in Relapsing Multiple Sclerosis: Associations with Disability, Depression, Fatigue, Anxiety, Cognition, and Health-Related Quality of Life SO VALUE IN HEALTH LA English DT Article DE depression; fatigue; multiple sclerosis; quality of life; work productivity ID ACTIVITY IMPAIRMENT QUESTIONNAIRE; EMPLOYMENT STATUS; VALIDITY; IMPACT; UNEMPLOYMENT; ARTHRITIS; DISEASE; PRESENTEEISM; INDIVIDUALS; INSTRUMENTS AB Objectives: To characterize work productivity in relapsing multiple sclerosis (MS) by using a work productivity scale and to identify associations between work productivity and disability, depression, fatigue, anxiety, cognition, and health-related quality of life. Methods: Three hundred seventy-seven subjects with a clinically isolated syndrome or relapsing remitting MS participated in the study. Subjects underwent neurological examinations and completed patient-reported outcome and cognitive measures. Subjects also completed the Work Productivity and Activity Impairment Questionnaire: General Health to quantify absenteeism (missing work because of health problems), presenteeism (impairment while working), overall work impairment, and daily activity impairment attributable to health problems. Univariate correlations and multivariate models were used to determine the associations between each work productivity variable and clinical, patient-reported outcome, and cognitive measures. Results: Seventy-six percent of subjects were employed. Fourteen percent of working subjects reported absenteeism, and 47% reported presenteeism. The mean work time lost because of absenteeism was 4%, and the mean work time lost because of presenteeism was 12%. Absenteeism was not significantly associated with disease or patient-reported outcome measures. Statistically significant correlations (0.32-0.53) were found between presenteeism and increasing disability, fatigue, depression, anxiety, and reduced quality of life. No associations were observed between presenteeism and disease duration or cognitive function. Conclusions: Subjects with clinically isolated syndrome/relapsing remitting MS reported substantial work productivity losses due to presenteesim. Presenteeism was associated with increasing fatigue, depression, anxiety, and reduced quality of life. It is possible that the early identification and treatment of fatigue and mental health symptoms may improve productivity while working and extend employment for individuals with MS. C1 [Glanz, Bonnie I.; Degano, Irene R.; Rintell, David J.; Chitnis, Tanuja; Weiner, Howard L.; Healy, Brian C.] Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, Brookline, MA 02445 USA. [Glanz, Bonnie I.; Degano, Irene R.; Rintell, David J.; Chitnis, Tanuja; Weiner, Howard L.; Healy, Brian C.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Healy, Brian C.] Massachusetts Gen Hosp, Biostat Ctr, Boston, MA 02114 USA. RP Glanz, BI (reprint author), Brigham & Womens Hosp, Partners Multiple Sclerosis Ctr, 1 Brookline Pl,Suite 227, Brookline, MA 02445 USA. EM bglanz@partners.org RI Roman Degano, Irene/C-1826-2012 FU Nancy Davis Foundation; Merck Serono S.A. FX Source of financial support: This research was funded in part by the Nancy Davis Foundation and Merck Serono S.A. NR 50 TC 18 Z9 19 U1 2 U2 42 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD DEC PY 2012 VL 15 IS 8 BP 1029 EP 1035 DI 10.1016/j.jval.2012.07.010 PG 7 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 055RT UT WOS:000312435300006 PM 23244804 ER PT J AU Faraone, SV Biederman, J Wozniak, J AF Faraone, Stephen V. Biederman, Joseph Wozniak, Janet TI Examining the Comorbidity Between Attention Deficit Hyperactivity Disorder and Bipolar I Disorder: A Meta-Analysis of Family Genetic Studies SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID EMOTIONAL SELF-REGULATION; DEFICIT/HYPERACTIVITY DISORDER; CO-MORBIDITY; HIGH-RISK; PSYCHIATRIC-DISORDERS; CLINICAL-TRIALS; ONSET MANIA; CHILDREN; PARENTS; ADHD AB Objective: The existence of comorbidity between attention deficit hyperactivity disorder (ADHD) and bipolar I disorder has been documented in clinical and epidemiological studies, in studies of children and adults, and in diagnosed ADHD and bipolar I patient samples. Yet questions remain about the validity of diagnosing bipolar I disorder in ADHD youth. The authors aim to clarify these issues by reviewing family genetic studies of ADHD and bipolar I disorder. Method: The authors applied random-effects meta-analysis to family genetic studies of ADHD and bipolar I disorder. Twenty bipolar proband studies provided 37 estimates of the prevalence of ADHD in 4,301 relatives of bipolar probands and 1,937 relatives of comparison probands. Seven ADHD proband studies provided 12 estimates of the prevalence of bipolar I disorder in 1,877 relatives of ADHD probands and 1,601 relatives of comparison probands. Results: These studies found a significantly higher prevalence of ADHD among relatives of bipolar probands and a significantly higher prevalence of bipolar I disorder among relatives of ADHD probands. These results could not be accounted for by publication biases, unusual results from any one observation, sample characteristics, or study design features. The authors found no evidence of heterogeneity in the ADHD or bipolar family studies. Conclusions: The results suggest that ADHD plus bipolar comorbidity cannot be accounted for by misdiagnoses, but additional research is needed to rule out artifactual sources of comorbidity. More research is also needed to determine whether comorbidity of ADHD and bipolar I disorder constitutes a familial subtype distinct from its constituent disorders, which if confirmed would have implications for diagnostic nosology and genetic studies. (Am J Psychiatry 2012; 169:1256-1266) C1 [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat & Neurosci, New York, NY USA. SUNY Upstate Med Univ, Dept Physiol, New York, NY USA. Massachusetts Gen Hosp, Psychiat Serv, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Faraone, SV (reprint author), SUNY Upstate Med Univ, Dept Psychiat & Neurosci, New York, NY USA. EM sfaraone@childpsychresearch.org OI Faraone, Stephen/0000-0002-9217-3982 FU Alcobra; Shire; NIH; Eli Lilly; Janssen; McNeil; Novartis; Pfizer; Elminda; Fundacion Areces; Medice Pharmaceuticals; Spanish Child Psychiatry Association; Abbott; Alza; AstraZeneca; Bristol-Myers Squibb; Celltech; Cephalon; Esai; Forest; GlaxoSmithKline; Gliatech; Merck; NARSAD; National Institute on Drug Abuse; New River; National Institute of Child Health and Human Development; NIMH; Noven; Neurosearch; Organon; Otsuka; Pharmacia; Prechter Foundation; Stanley Foundation; UCB Pharma; Wyeth; Primedia/Massachusetts General Hospital Psychiatry Academy; Boehringer-Ingelheim; Sepracor; UCB (Schwarz) Pharma FX Dr. Faraone has received consulting fees and support from Alcobra and Shire and support from NIH; has received consulting or advisory board fees or participated in continuing medical education programs sponsored by Eli Lilly, Janssen, McNeil, Novartis, Pfizer, and Shire; and has received royalties from Guilford Press and Oxford University Press. Dr. Biederman has received support from Elminda, Janssen, McNeil, and Shire; has received speakers fees from Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association; has received research support, consultation fees, or speakers fees from Abbott, Alza, AstraZeneca, Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Esai, Forest, GlaxoSmithKline, Gliatech, Janssen, McNeil, Merck, NARSAD, National Institute on Drug Abuse, New River, National Institute of Child Health and Human Development, NIMH, Novartis, Noven, Neurosearch, Organon, Otsuka, Pfizer, Pharmacia, the Prechter Foundation, Shire, the Stanley Foundation, UCB Pharma, and Wyeth. Dr. Wozniak has received speaking fees from McNeil, Primedia/Massachusetts General Hospital Psychiatry Academy; has served on advisory boards for Pfizer and Shire; and has received research support from Eli Lilly, McNeil, NIMH, and Shire. Dr. Wozniak's spouse has served on speakers bureaus for Boehringer-Ingelheim, Cephalon, GlaxoSmithKline, King, Sanofi-Aventis, Sepracor, Takeda; has served on advisory boards for Axon Labs, Boehringer-Ingelheim, GlaxoSmithKline, Jazz Pharmaceuticals, Neurogen, Novartis, Novadel Pharma, Pfizer, Sepracor, Takeda, and UCB (Schwarz) Pharma; and has received research support from Boehringer-Ingelheim, GlaxoSmithKline, Sepracor, and UCB (Schwarz) Pharma. NR 78 TC 29 Z9 29 U1 5 U2 17 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 2012 VL 169 IS 12 BP 1256 EP 1266 DI 10.1176/appi.ajp.2012.12010087 PG 11 WC Psychiatry SC Psychiatry GA 052EC UT WOS:000312179500008 PM 23212057 ER PT J AU Papakostas, GI Shelton, RC Zajecka, JM Etemad, B Rickels, K Clain, A Baer, L Dalton, ED Sacco, GR Schoenfeld, D Pencina, M Meisner, A Bottiglieri, T Nelson, E Mischoulon, D Alpert, JE Barbee, JG Zisook, S Fava, M AF Papakostas, George I. Shelton, Richard C. Zajecka, John M. Etemad, Bijan Rickels, Karl Clain, Alisabet Baer, Lee Dalton, Elizabeth D. Sacco, Garret R. Schoenfeld, David Pencina, Michael Meisner, Allison Bottiglieri, Teodoro Nelson, Erik Mischoulon, David Alpert, Jonathan E. Barbee, James G. Zisook, Sidney Fava, Maurizio TI L-Methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID SEROTONIN REUPTAKE INHIBITORS; PSYCHIATRIC CLINICAL-TRIALS; SERUM FOLATE; FOLIC-ACID; PLACEBO-RESPONSE; DISORDER; ANTIDEPRESSANT; HOMOCYSTEINE; DEFICIENCY; AUGMENTATION AB Objective: The authors conducted two multicenter sequential parallel comparison design trials to investigate the effect of L-methylfolate augmentation in the treatment of major depressive disorder in patients who had a partial response or no response to selective serotonin reuptake inhibitors (SSRIs). Method: In the first trial, 148 outpatients with SSRI-resistant major depressive disorder were enrolled in a 60-day study divided into two 30-day periods. Patients were randomly assigned, in a 2:3:3 ratio, to receive L-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by L-methylfolate (7.5 mg/day) for 30 days, or placebo for 60 days. SSRI dosages were kept constant throughout the study. In the second trial, with 75 patients, the design was identical to the first, except that the L-methylfolate dosage was 15 mg/day during both 30-day periods. Results: In the first trial, no significant difference was observed in outcomes between the treatment groups. In the second trial, adjunctive L-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive L-methylfolate at 15 mg/day. L-Methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo. Conclusions: Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRls. (Am J Psychiatry 2012; 169:1267-1274) C1 [Papakostas, George I.] Massachusetts Gen Hosp, Ctr Treatment Resistant Depress, Depress Clin & Res Program, Ctr Biostat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Clin Trials Network & Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Clin Res Inst, Boston, MA USA. Boston Univ, Dept Biostat, Boston, MA 02215 USA. Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA. Rush Univ, Med Ctr, Chicago, IL 60612 USA. Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Baylor Res Inst, Inst Metab Dis, Dallas, TX USA. Univ Cincinnati, Acad Hlth Ctr, Dept Psychiat, Cincinnati, OH USA. Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. San Diego VA Healthcare Serv, San Diego, CA USA. RP Papakostas, GI (reprint author), Massachusetts Gen Hosp, Ctr Treatment Resistant Depress, Depress Clin & Res Program, Ctr Biostat, Boston, MA 02114 USA. EM gpapakostas@partners.org RI Papakostas, George/I-6905-2013; OI Papakostas, George/0000-0002-2465-5103; Alpert, Jonathan/0000-0002-4332-908X FU Abbott; AstraZeneca; Brainsway; Bristol-Myers Squibb; Cephalon; Dey Pharma; Eli Lilly; Forest; GlaxoSmithKline; Lundbeck; NIMH; Otsuka; Pamlab; Ridge Diagnostics; Roche; Takeda; Theracos; Sunovion; Cyberonics; Elan; Euthymics Bioscience; Janssen Pharmaceutica; Medtronic; Novartis; Pfizer; Repligen; Takeda Pharmaceuticals; St. Jude Medical; Boehringer-Ingelheim; Hoffman-LaRoche; McNeil; Shire; National Heart, Lung and Blood Institute; Harvard School of Public Health; Bowman Family Foundation; Cederroth; FisherWallace; Ganeden; Lichtwer Pharma; Nordic Naturals; Alkermes; APA; Lorex; Aspect Medical Systems; J & J Pharmaceuticals; MGH Psychiatry Academy/Reed Medical Education; MGH Psychiatry Academy/Primedia; Organon; Pharmavite; Sanofi/Synthelabo; Solvay; Wyeth-Ayerst; Xian-Janssen; Belvoir Publishing; Dey Pharmaceuticals; Sheppard Pratt Health System; BioResearch; BrainCells; Bio-Pharma; Clinical Trials Solutions; Clintara; Covidien; EnVivo Pharmaceuticals; Ganeden Biotech; Icon Clinical Research; i3 Innovus; Johnson & Johnson Pharmaceutical Research and Development; Lorex Pharmaceuticals; NARSAD; National Center for Complementary and Alternative Medicine; National Institute on Drug Abuse; Photothera; RCT Logic; Sanofi-Aventis; Synthelabo FX Dr. Papakostas has received research support from, served as a consultant or speaker for, or received honoraria for CME activities for Abbott, AstraZeneca, Brainsway, Bristol-Myers Squibb, Cephalon, Dey Pharma, Eli Lilly, Forest, GlaxoSmithKline, Lundbeck, NIMH, Otsuka, Pamlab, Ridge Diagnostics, Roche, Takeda, Theracos, and Sunovion. Dr. Shelton has received research support or served as a consultant for Bristol-Myers Squibb, Eli Lilly, Cyberonics, Elan, Euthymics Bioscience, Forest, Janssen Pharmaceutica, Medtronic, Novartis, Otsuka, Pamlab, Pfizer, Repligen, Ridge Diagnostics, Takeda Pharmaceuticals, and St. Jude Medical. Dr. Zajecka has received research support from or served as a consultant, adviser, or speaker for Abbott, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Hoffman-LaRoche, McNeil, Novartis, Otsuka, Pamlab, Pfizer, Shire, and Takeda. Dr. Schoenfeld is a patent holder for the sequential parallel design used in this study; the patent is owned by his employer, Massachusetts General Hospital. Dr. Pencina has served as a consultant for Pamlab and RCT Logic. Ms. Meisner has served as a consultant for Massachusetts General Hospital and Pamlab, has received a grant from the National Heart, Lung and Blood Institute, and has received funds from grants at the Harvard School of Public Health. Dr. Bottiglieri has received research support from and has served as a consultant for Pamlab, has served as the chairman of the advisory board for Methylation Sciences, and holds stock options in Methylation Sciences. Dr. Nelson has received research support from AstraZeneca, Eli Lilly, GlaxoSmithKline, and Pamlab. Dr. Mischoulon has received research support or honoraria for, consulting, speaking, and writing from the Bowman Family Foundation, Bristol-Myers Squibb, Cederroth, FisherWallace, Ganeden, Lichtwer Pharma, Nordic Naturals, and Pamlab and has received royalties from Back Bay Scientific and Lippincott Williams & Wilkins. Dr. Alpert has received research support from or served as an adviser, consultant, or speaker for Abbott, Alkermes, APA, Lichtwer Pharma, Lorex, Aspect Medical Systems, AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, Forest, GlaxoSmithkline, J & J Pharmaceuticals, MGH Psychiatry Academy/Reed Medical Education, MGH Psychiatry Academy/Primedia, Novartis, Organon, Pamlab, Pfizer, Pharmavite, Roche, Sanofi/Synthelabo, Solvay, Wyeth-Ayerst, and Xian-Janssen and has received editorial fees from Belvoir Publishing. Dr. Barbee has received research support from or served as a speaker for AstraZeneca, Bristol-Myers Squibb, Dey Pharmaceuticals, Eli Lilly, Forest, Merck, Pfizer, and Sheppard Pratt Health System and has done forensic consulting work for various attorneys. Dr. Zisook has received research support from Pamlab. Dr.; Fava has received research support from Abbott, Alkermes, Aspect Medical Systems, AstraZeneca, BioResearch, BrainCells, Bristol-Myers Squibb, Cephalon, Bio-Pharma, Clinical Trials Solutions, Clintara, Covidien, Eli Lilly, EnVivo Pharmaceuticals, Euthymics Bioscience, Forest, Ganeden Biotech, GlaxoSmithKline, Icon Clinical Research, i3 Innovus, Johnson & Johnson Pharmaceutical Research and Development, Lichtwer Pharma, Lorex Pharmaceuticals, NARSAD, National Center for Complementary and Alternative Medicine, National Institute on Drug Abuse, NIMH, Novartis, Organon, Pamlab, Pfizer, Pharmavite, Photothera, Roche, RCT Logic, Sanofi-Aventis, Shire, Solvay, Synthelabo, and Wyeth-Ayerst; he has served as an adviser or consultant (unpaid except as otherwise noted) for Abbott Laboratories, Affectis Pharmaceuticals, Alkermes, Amarin Pharma, Aspect Medical Systems, AstraZeneca, Auspex Pharmaceuticals, Bayer, Best Practice Project Management, BioMarin Pharmaceuticals, Biovail, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Clinical Trials Solutions, CNS Response, Compellis Pharmaceuticals, Cypress Pharmaceutical, DiagnoSearch Life Sciences, Dinippon Sumitomo Pharma, Dov Pharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly, ePharmaSolutions, EPIX Pharmaceuticals, Euthymics Bioscience, Fabre-Kramer, Forest, GenOmind, GlaxoSmithKline, Grunenthal, i3 Innovus, Janssen Pharmaceutica, Jazz Pharmaceuticals, Johnson SE Johnson Pharmaceutical Research and Development (remunerated), Knoll Pharmaceuticals, Labopharm, Lorex Pharmaceuticals, Lundbeck, MedAvante, Merck, MSI Methylation Sciences, Naurex, Neuronetics, Novartis, Nutrition 21, Orexigen Therapeutics, Organon, Otsuka, Pamlab, Pfizer, PharmaStar, Pharmavite, PharmoRx Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceuticals, Puretech Ventures, PsychoGenics, Psylin Neurosciences, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche, RCT Logic, Sanofi-Aventis, Sepracor, Servier Laboratories, Schering-Plough, Solvay, Somaxon, Somerset Pharmaceuticals, Sunovion, Synthelabo, Takeda, Tetragenex, Trans-Form Pharmaceuticals, Transcept Pharmaceuticals, and Vanda Pharmaceuticals; he has provided speaking/publishing (unpaid except as otherwise noted) for Adamed, Advanced Meeting Partners, APA, American Society of Clinical Psychopharmacology, AstraZeneca, Belvoir Media Group (remunerated), Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, CME Institute/Physicians Postgraduate Press (remunerated), Eli Lilly, Forest, GlaxoSmithKline, Imedex, MGH Psychiatry Academy/Primedia, MGH Psychiatry Academy/Reed Elsevier (remunerated), Novartis, Organon, Pfizer, PharrnaStar, United BioSource, and Wyeth-Ayerst; he has equity holdings in Compellis; he is a patent holder for the sequential parallel design used in this study (the patent is owned by Massachusetts General Hospital) and has a patent application for a combination of ketamine and scopolamine in major depression; and he receives royalties from Lippincott Williams & Wilkins. The other authors report no financial relationships with commercial interests. NR 35 TC 77 Z9 79 U1 4 U2 31 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 2012 VL 169 IS 12 BP 1267 EP 1274 DI 10.1176/appi.ajp.2012.11071114 PG 8 WC Psychiatry SC Psychiatry GA 052EC UT WOS:000312179500009 PM 23212058 ER PT J AU Fanous, AH Zhou, BY Aggen, SH Bergen, SE Amdur, RL Duan, JB Sanders, AR Shi, JX Mowry, BJ Olincy, A Amin, F Cloninger, CR Silverman, JM Buccola, NG Byerley, WF Black, DW Freedman, R Dudbridge, F Holmans, PA Ripke, S Gejman, PV Kendler, KS Levinson, DF AF Fanous, Ayman H. Zhou, Baiyu Aggen, Steven H. Bergen, Sarah E. Amdur, Richard L. Duan, Jubao Sanders, Alan R. Shi, Jianxin Mowry, Bryan J. Olincy, Ann Amin, Farooq Cloninger, C. Robert Silverman, Jeremy M. Buccola, Nancy G. Byerley, William F. Black, Donald W. Freedman, Robert Dudbridge, Frank Holmans, Peter A. Ripke, Stephan Gejman, Pablo V. Kendler, Kenneth S. Levinson, Douglas F. CA Schizophrenia Psychiat Genome-Wide TI Genome-Wide Association Study of Clinical Dimensions of Schizophrenia: Polygenic Effect on Disorganized Symptoms SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID MENTAL-RETARDATION; COMMON VARIANTS; DELTA-CATENIN; PSYCHOSIS; GENES; RISK; CLASSIFICATION; PHENOTYPES; MUTATIONS; HAPLOTYPE AB Objective: Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia. Method: Based on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, and mood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor. Results: No genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples. Conclusions: The polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia). (Am J Psychiatry 2012; 169:1309-1317) C1 [Fanous, Ayman H.] Mental Hlth Serv Line, Washington, DC USA. Vet Affairs Med Ctr, Washington, DC 20422 USA. Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Res, Boston, MA 02114 USA. NorthShore Univ HealthSyst Res Inst, Ctr Psychiat Genet, Evanston, IL USA. Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. Queensland Ctr Mental Hlth Res, Brisbane, Qld, Australia. Univ Colorado Denver, Dept Psychiat, Aurora, CO USA. Atlanta Vet Affairs Med Ctr, Dept Psychiat & Behav Sci, Atlanta, GA USA. Emory Univ, Atlanta, GA 30322 USA. Washington Univ, Dept Psychiat, St Louis, MO USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Louisiana State Univ, Hlth Sci Ctr, Sch Nursing, New Orleans, LA USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Univ Iowa, Carver Coll Med, Mental Hlth Clin Res Ctr, Iowa City, IA USA. Univ Iowa, Dept Psychiat, Carver Coll Med, Iowa City, IA 52242 USA. Inst Publ Hlth, Med Res Council Biostat Unit, Cambridge, England. MRC Ctr Neuropsychiat Genet & Genom, Dept Psychol Med & Neurol, Sch Med, Cardiff, S Glam, Wales. Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. Broad Inst Harvard, Cambridge, MA USA. MIT, Cambridge, MA 02139 USA. RP Fanous, AH (reprint author), Mental Hlth Serv Line, Washington, DC USA. RI Hansen, Thomas/O-5965-2014; Holmans, Peter/F-4518-2015; OI Hansen, Thomas/0000-0001-6703-7762; Holmans, Peter/0000-0003-0870-9412; Bergen, Sarah/0000-0002-5888-0034; Buccola, Nancy/0000-0003-1378-4636 FU AstraZeneca; NIH R01 [MH-67257, MH-59588, MH-59571, MH-59565, MH-59587, MH-60870, MH-59566, MH-59586, MH-61675, MH-60879, MH-81800]; NIH U01 [MH-46276, MH-46289, MH-46318, MH-79469, MH-79470]; VA grant [1101CX000278]; NARSAD Young Investigator Awards; Genetic Association Information Network (GAIN); Paul Michael Donovan Charitable Foundation; National Center for Research Resources [U54 RR020278] FX Dr. Black has received research support from AstraZeneca. All other authors report no financial relationships with commercial interests.; Data collection, genotyping, and analysis were supported by NIH R01 grants (MH-67257 to Dr. Buccola, MH-59588 to Dr. Mowry, MH-59571 to Dr. Gejman, MH-59565 to Dr. Freedman, MH-59587 to Dr. Amin, MH-60870 to Dr. Byerley, MH-59566 to Dr. Black, MH-59586 to Dr. Silverman, MH-61675 to Dr. Levinson, MH-60879 to Dr. Cloninger, and MH-81800 to Dr. Gejman), NIH U01 grants (MH-46276 to Dr. Cloninger, MH-46289 to Dr. Charles Kaufmann, MH-46318 to Dr. Ming T. Tsuang, MH-79469 to Dr. Gejman, and MH-79470 to Dr. Levinson), VA grant 1101CX000278 (to Dr. Fanous), NARSAD Young Investigator Awards (to Drs. Duan and Saunders), the Genetic Association Information Network (GAIN), and the Paul Michael Donovan Charitable Foundation. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis at MIT and Harvard (by S. Gabriel and D.B. Mirel), with support from grant U54 RR020278 from the National Center for Research Resources. Genotyping of half of the European ancestry sample and almost all the African American sample was carried out with support from GAIN. NR 38 TC 38 Z9 38 U1 2 U2 23 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 2012 VL 169 IS 12 BP 1309 EP 1317 DI 10.1176/appi.ajp.2012.12020218 PG 9 WC Psychiatry SC Psychiatry GA 052EC UT WOS:000312179500014 PM 23212062 ER PT J AU Lawson, EH Louie, R Zingmond, DS Brook, RH Hall, BL Han, L Rapp, M Ko, CY AF Lawson, Elise H. Louie, Rachel Zingmond, David S. Brook, Robert H. Hall, Bruce L. Han, Lein Rapp, Michael Ko, Clifford Y. TI A Comparison of Clinical Registry Versus Administrative Claims Data for Reporting of 30-Day Surgical Complications SO ANNALS OF SURGERY LA English DT Article DE Administrative claims; clinical registry; complications; postoperative; quality measurement; surgery ID QUALITY IMPROVEMENT PROGRAM; POSTOPERATIVE ADVERSE EVENTS; NSQIP AB Objectives: To compare the recording of 30-day postoperative complications between a national clinical registry and Medicare inpatient claims data and to determine whether the addition of outpatient claims data improves concordance with the clinical registry. Background: Policymakers are increasingly discussing use of postoperative complication rates for value-based purchasing. There is debate regarding the optimal data source for such measures. Methods: Patient records (2005-2008) from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) were linked to Medicare inpatient and outpatient claims data sets. We assessed the ability of (1) Medicare inpatient claims and (2) Medicare inpatient and outpatient claims to detect a core set of ACS-NSQIP 30-day postoperative complications: superficial surgical site infection (SSI), deep/organ-space SSI, any SSI (superficial and/or deep/organ-space), urinary tract infection, pneumonia, sepsis, deep venous thrombosis (DVT), pulmonary embolism, venous thromboembolism (DVT and/or pulmonary embolism), and myocardial infarction. Agreement of patient-level complications by ACS-NSQIP versus Medicare was assessed by. statistics. Results: A total of 117,752 patients from more than 200 hospitals were studied. The sensitivity of inpatient claims data for detecting ACS-NSQIP complications ranged from 0.27 to 0.78; the percentage of false-positives ranged from 48% to 84%. Addition of outpatient claims data improved sensitivity slightly but also greatly increased the percentage of false-positives. Agreement was routinely poor between clinical and claims data for patient-level complications. Conclusions: This analysis demonstrates important differences between ACS-NSQIP and Medicare claims data sets for measuring surgical complications. Poor accuracy potentially makes claims data suboptimal for evaluating surgical complications. These findings have meaningful implications for performance measures currently being considered. C1 [Lawson, Elise H.; Louie, Rachel; Zingmond, David S.; Brook, Robert H.; Ko, Clifford Y.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Brook, Robert H.] RAND Corp, Santa Monica, CA USA. [Brook, Robert H.] Univ Calif Los Angeles, Jonathan & Karin Fielding Sch Publ Hlth, Los Angeles, CA 90095 USA. [Hall, Bruce L.; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL USA. [Hall, Bruce L.] Washington Univ, Sch Med, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Barnes Jewish Hosp, St Louis Vet Affairs Med Ctr, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Ctr Hlth Policy, St Louis, MO USA. [Hall, Bruce L.] Washington Univ, Olin Business Sch, St Louis, MO USA. [Han, Lein; Rapp, Michael] Ctr Medicare Serv, Baltimore, MD USA. [Han, Lein; Rapp, Michael] Ctr Medicaid Serv, Baltimore, MD USA. [Rapp, Michael] George Washington Univ, Sch Med & Hlth Sci, Dept Emergency Med, Washington, DC 20052 USA. [Ko, Clifford Y.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Lawson, EH (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, 10833 Le Conte Ave,72-215 CHS, Los Angeles, CA 90095 USA. EM elawson@mednet.ucla.edu FU VA Health Services Research and Development program [RWJ 65-020]; American College of Surgeons through the Robert Wood Johnson Foundation Clinical Scholars Program; Centers for Medicare & Medicaid Services (CMS) FX E.H.L.'s time was supported by the VA Health Services Research and Development program (RWJ 65-020) and the American College of Surgeons through the Robert Wood Johnson Foundation Clinical Scholars Program. This study was funded by a contract from the Centers for Medicare & Medicaid Services (CMS). None of the remaining authors had any conflicts of interests to declare. The views expressed in this article represent the authors' views and do not necessarily represent official policy or opinions of the Department of Health and Human Services, the Centers for Medicare & Medicaid Services. NR 15 TC 106 Z9 106 U1 0 U2 9 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 DEC PY 2012 VL 256 IS 6 BP 973 EP 981 DI 10.1097/SLA.0b013e31826b4c4f PG 9 WC Surgery SC Surgery GA 053HC UT WOS:000312261000022 PM 23095667 ER PT J AU Fitzgibbons, SC Chen, J Jagsi, R Weinstein, D AF Fitzgibbons, Shimae C. Chen, Jie Jagsi, Reshma Weinstein, Debra TI Long-Term Follow-Up on the Educational Impact of ACGME Duty Hour Limits A Pre-Post Survey Study SO ANNALS OF SURGERY LA English DT Article DE acreditation council for graduate medical education; duty hour limits; graduate medical education; resident fatigue; resident well-being; work hours ID ORTHOPEDIC-SURGERY RESIDENTS; ACCREDITATION-COUNCIL; ATTENDING SURGEONS; 80-HOUR WORKWEEK; PATIENT SAFETY; RESTRICTIONS; REFORM; ATTITUDES; PERSPECTIVES; PREPAREDNESS AB Objective: To evaluate the long-term impact of the 2003 Accreditation Council for Graduate Medical Education (ACGME) duty hour limits on residents' perception of education. Background: Eight years after the introduction of the ACGME duty hour limits, graduate medical education programs implemented a revised set of standards. Currently, limited data exist related to the long-term impact of the 2003 standards on resident education. Methods: A yearly survey from 2003 to 2009 was administered to orthopedic residents in a multi-institutional program, inquiring about several aspects of the resident's educational experience, work hours, amount of sleep, fatigue and its impact, and preparedness for practice. Results: A total of 216 responses (69%) were obtained from surveyed orthopedic residents between 2003 and 2009. There was no significant change in the average reported hours of sleep (34.6 hours per week in 2003 vs 33.7 hours per week between 2004 and 2009) despite a decrease in the mean reported number of work hours (74.5 hours in 2003 vs 66.2 hours in 2009; P = 0.046). However, a decrease in perceived fatigue and its negative impact on patient safety and quality of care was noted. The perceived sufficiency of direct clinical experience, the number of hours spent performing major procedures, and the overall satisfaction with education also decreased. Finally, the residents' sense of clinical preparedness diminished after the work hour limits were in place. Conclusions: After the implementation of the 2003 duty hour limits, residents' perceptions of fatigue improved without any increase in the reported amount of sleep. In addition, decreased resident satisfaction with their education and a diminished sense of clinical preparedness were noted. Additional studies are needed to better understand the influence of work hours and fatigue on the outcomes of education, resident well-being, and patient care to guide the optimal design and delivery of graduate medical education. C1 [Weinstein, Debra] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Fitzgibbons, Shimae C.] Lahey Clin Med Ctr, Dept Gen Surg, Burlington, MA 01803 USA. [Chen, Jie] Univ Massachusetts, Off Grad Studies, Boston, MA 02125 USA. [Jagsi, Reshma] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. RP Weinstein, D (reprint author), Massachusetts Gen Hosp, Dept Internal Med, Bulfinch 230, Boston, MA 02114 USA. EM dweinstein@partners.org OI Jagsi, Reshma/0000-0001-6562-1228 NR 34 TC 29 Z9 30 U1 0 U2 2 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 DEC PY 2012 VL 256 IS 6 BP 1108 EP 1112 DI 10.1097/SLA.0b013e31825ffb33 PG 5 WC Surgery SC Surgery GA 053HC UT WOS:000312261000044 PM 23069864 ER PT J AU Garone, C Rubio, JC Calvo, SE Naini, A Tanji, K DiMauro, S Mootha, VK Hirano, M AF Garone, Caterina Carlos Rubio, Juan Calvo, Sarah E. Naini, Ali Tanji, Kurenai DiMauro, Salvatore Mootha, Vamsi K. Hirano, Michio TI MPV17 Mutations Causing Adult-Onset Multisystemic Disorder With Multiple Mitochondrial DNA Deletions SO ARCHIVES OF NEUROLOGY LA English DT Article ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; DEPLETION SYNDROME; POLG MUTATIONS; NAVAJO NEUROHEPATOPATHY; GENE; PROTEIN; PARKINSONISM; DISEASE AB Objective: To identify the cause of an adult-onset multisystemic disease with multiple deletions of mitochondrial DNA (mtDNA). Design: Case report. Setting: University hospitals. Patient: A 65-year-old man with axonal sensorimotor peripheral neuropathy, ptosis, ophthalmoparesis, diabetes mellitus, exercise intolerance, steatohepatopathy, depression, parkinsonism, and gastrointestinal dysmotility. Results: Skeletal muscle biopsy revealed ragged-red and cytochrome-c oxidase-deficient fibers, and Southern blot analysis showed multiple mtDNA deletions. No deletions were detected in fibroblasts, and the results of quantitative polymerase chain reaction showed that the amount of mtDNA was normal in both muscle and fibroblasts. Exome sequencing using a mitochondrial library revealed compound heterozygous MPV17 mutations (p.LysMet88-89MetLeu and p.Leu143*), a novel cause of mtDNA multiple deletions. Conclusions: In addition to causing juvenile-onset disorders with mtDNA depletion, MPV17 mutations can cause adult-onset multisystemic disease with multiple mtDNA deletions. Arch Neurol. 2012; 69(12): 1648-1651. Published online September 10, 2012. doi:10.1001/archneurol.2012.405 C1 [Garone, Caterina; Carlos Rubio, Juan; Naini, Ali; DiMauro, Salvatore; Hirano, Michio] Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USA. [Tanji, Kurenai] Columbia Univ, Med Ctr, Dept Pathol, New York, NY 10032 USA. [Calvo, Sarah E.; Mootha, Vamsi K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA USA. [Calvo, Sarah E.; Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. [Calvo, Sarah E.; Mootha, Vamsi K.] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Calvo, Sarah E.; Mootha, Vamsi K.] MIT, Cambridge, MA 02139 USA. [Garone, Caterina] Univ Turin, Joint PhD Program, I-10124 Turin, Italy. [Garone, Caterina] Univ Bologna, Joint PhD Program, I-40126 Bologna, Italy. [Carlos Rubio, Juan] Hosp 12 Octubre, Unidad Genom, Ctr Invest, E-28041 Madrid, Spain. RP Hirano, M (reprint author), Columbia Univ, Med Ctr, Dept Neurol, 630 W 168th St,P&S 4-423, New York, NY 10032 USA. EM mh29@columbia.edu OI Garone, Caterina/0000-0003-4928-1037 FU Associazione Malattie Metaboliche Congenite ereditarie; National Institutes of Health [R01HD056103, 1R01HD057543, U54NS078059]; Muscular Dystrophy Association; Marriott Mitochondrial Disorder Clinical Research Fund FX Dr Garone is supported by the Associazione Malattie Metaboliche Congenite ereditarie. Dr Hirano is supported by National Institutes of Health grants R01HD056103, 1R01HD057543, and U54NS078059, by a Muscular Dystrophy Association grant, and by the Marriott Mitochondrial Disorder Clinical Research Fund. NR 21 TC 22 Z9 22 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 2012 VL 69 IS 12 BP 1648 EP 1651 DI 10.1001/archneurol.2012.405 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 052KI UT WOS:000312196100018 PM 22964873 ER PT J AU Mukkamala, SK Costa, RA Fung, A Sarraf, D Gallego-Pinazo, R Freund, KB AF Mukkamala, Sri Krishna Costa, Rogerio A. Fung, Adrian Sarraf, David Gallego-Pinazo, Roberto Freund, K. Bailey TI Optical Coherence Tomographic Imaging of Sub-Retinal Pigment Epithelium Lipid SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID OCCULT CHOROIDAL NEOVASCULARIZATION; AGE-RELATED MACULOPATHY; DIABETIC-MACULAR-EDEMA; HYPERREFLECTIVE FOCI; APOLIPOPROTEIN-B; BASAL DEPOSITS; DEGENERATION; DRUSEN; CHOLESTEROL; DETACHMENT AB Objective: To describe an optical coherence tomographic finding of layered hyperreflective bands beneath the retinal pigment epithelium (RPE), the so-called onion sign believed to represent lipid within a vascularized pigment epithelial detachment. Methods: This retrospective observational case series involved reviewing clinical histories of patients with the onion sign. Imaging studies analyzed included spectral-domain optical coherence tomography, color and red-free photographs, near infrared reflectance, fundus autofluorescence, and blue-light fundus autofluorescence. Results: A total of 22 eyes of 20 patients with sub-RPE hyperreflective bands were identified. There were 15 women and 5 men with a mean patient age of 76 years (range, 60-92 years). Snellen best-corrected visual acuities ranged from 20/25 to counting fingers, with a median of 20/80. Two patients had bilateral involvement, and 3 of 17 eyes had multifocal onion signs in the same eye. All eyes had neovascular age-related macular degeneration, with type 1 (sub-RPE) neovascularization. In all patients, the onion sign correlated with areas of yellow-gray exudates seen clinically that appeared bright on red-free and near infrared reflectance imaging. No specific fundus autofluorescence or blue-light fundus autofluorescence pattern was identified. Conclusions: The onion sign refers to layered hyperreflective bands in the sub-RPE space usually associated with chronic exudation from type 1 neovascularization in patients with age-related macular degeneration. With an associated bright near infrared reflectance, these bands may correspond to lipid, collagen, or fibrin. Because the onion sign colocalizes to areas of exudation that are known to consist of lipoprotein, we propose that this finding may represent layers of precipitated lipid in the sub-RPE space. To our knowledge, this is the first report of lipid detected in the sub-RPE space on clinical examination. Arch Ophthalmol. 2012;130(12):1547-1553. Published online August 13, 2012. doi:10.1001/archophthalmol.2012.2491 C1 [Mukkamala, Sri Krishna; Fung, Adrian; Freund, K. Bailey] Vitreous Retina Macula Consultants New York, New York, NY 10022 USA. [Mukkamala, Sri Krishna; Fung, Adrian; Freund, K. Bailey] LuEsther T Mertz Retinal Res Ctr, New York, NY USA. [Mukkamala, Sri Krishna; Freund, K. Bailey] NYU, Dept Ophthalmol, New York, NY 10016 USA. [Mukkamala, Sri Krishna; Freund, K. Bailey] Columbia Univ, Edward S Harkness Eye Inst, New York, NY USA. [Costa, Rogerio A.] Ctr Brasileiro Ciencias Visuais, Belo Horizonte, MG, Brazil. [Sarraf, David] Univ Calif Los Angeles, Jules Stein Eye Inst, Retinal Disorders & Ophthalm Genet Div, Los Angeles, CA 90024 USA. [Sarraf, David] Greater Los Angeles VA Healthcare Ctr, Los Angeles, CA USA. [Gallego-Pinazo, Roberto] Univ & Polytech Hosp, Dept Ophthalmol, Valencia, Spain. RP Freund, KB (reprint author), Vitreous Retina Macula Consultants New York, 460 Pk Ave,5th Fl, New York, NY 10022 USA. EM kbfnyf@aol.com RI Costa, Rogerio/E-6930-2013; OI Costa, Rogerio/0000-0002-0800-2233; Freund, K. Bailey/0000-0002-7888-9773 FU LuEsther T. Mertz Retinal Research Center; Manhattan Eye, Ear, and Throat Institute; Macula Foundation Inc; Karl Kirchgessner Foundation FX This study was supported by funding from the LuEsther T. Mertz Retinal Research Center; the Manhattan Eye, Ear, and Throat Institute; the Macula Foundation Inc; and the Karl Kirchgessner Foundation Ophthalmology Endowment Fund to Dr Sarraf. NR 37 TC 7 Z9 7 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2012 VL 130 IS 12 BP 1547 EP 1553 DI 10.1001/archophthalmol.2012.2491 PG 7 WC Ophthalmology SC Ophthalmology GA 052KA UT WOS:000312195300007 PM 22892986 ER PT J AU Menda, SA Chen, M Naseri, A AF Menda, Shivali A. Chen, Michael Naseri, Ayman TI Technique for Shortening a Long Clear Corneal Incision SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID CATARACT-SURGERY AB An optimal clear corneal incision creates a self-sealing intrastomal tunnel. Variability in incision length may pose surgical difficulties for subsequent phacoemulsification. An incision that is too long may lead to challenges including decreased instrument mobility, decreased visibility due to corneal striae, stromal hydration, and a difficult angle of approach to the cataract. These sequelae may lead to surgical complications or abandonment of the original incision. We describe a technique for shortening a long clear corneal incision with the intentional creation of a flap of corneal tissue at the posterior internal wound edge. This technique is a simple and quick modification that may avoid the pitfalls of an incision that is too long. Arch Ophthalmol. 2012;130(12):1589-1590 C1 [Naseri, Ayman] San Francisco VA Med Ctr, Dept Ophthalmol, San Francisco, CA 94121 USA. [Menda, Shivali A.; Chen, Michael; Naseri, Ayman] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA USA. RP Naseri, A (reprint author), San Francisco VA Med Ctr, Dept Ophthalmol, 4150 Clement St, San Francisco, CA 94121 USA. EM ayman.naseri@va.gov NR 5 TC 1 Z9 1 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2012 VL 130 IS 12 BP 1589 EP 1590 PG 2 WC Ophthalmology SC Ophthalmology GA 052KA UT WOS:000312195300015 PM 23229702 ER PT J AU Skondra, D Chang, GC Farber, HW Eliott, D AF Skondra, Dimitra Chang, Grace C. Farber, Harrison W. Eliott, Dean TI Ophthalmologic Diagnosis of Exacerbation of Idiopathic Pulmonary Arterial Hypertension SO ARCHIVES OF OPHTHALMOLOGY LA English DT Letter ID OPEN-ANGLE GLAUCOMA C1 [Skondra, Dimitra; Chang, Grace C.; Eliott, Dean] Harvard Univ, Sch Med, Retina Serv, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Farber, Harrison W.] Boston Univ, Sch Med, Pulm Hypertens Ctr, Boston Med Ctr, Boston, MA 02118 USA. RP Eliott, D (reprint author), Harvard Univ, Sch Med, Retina Serv, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM dean_eliott@meei.harvard.edu NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2012 VL 130 IS 12 BP 1619 EP 1621 PG 4 WC Ophthalmology SC Ophthalmology GA 052KA UT WOS:000312195300029 PM 23229713 ER PT J AU Hariri, LP Mino-Kenudson, M Mark, EJ Suter, MJ AF Hariri, Lida P. Mino-Kenudson, Mari Mark, Eugene J. Suter, Melissa J. TI In Vivo Optical Coherence Tomography The Role of the Pathologist SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT Houston Lung Symposium / Spring Seminar of the Houston-Society-of-Clinical-Pathologists / Advances in Lung Cancer Seminar of the Department-of-Pathology-and-Genomic-Medicine-of-the-Methodist-Hospital CY APR 28-29, 2012 CL Houston, TX SP Methodist Hosp, Dept Pathol & Genom Medi, Houston Soc Clin Pathologists (HSCP) ID CORONARY-ARTERY-DISEASE; HIGH-GRADE DYSPLASIA; CELL LUNG-CANCER; BARRETTS-ESOPHAGUS; INTRAVASCULAR ULTRASOUND; ATHEROSCLEROTIC PLAQUES; INTESTINAL METAPLASIA; COMPUTED-TOMOGRAPHY; VULNERABLE PLAQUE; BRONCHIAL LESIONS AB Optical coherence tomography (OCT) is a nondestructive, high-resolution imaging modality, providing cross-sectional, architectural images at near histologic resolutions, with penetration depths up to a few millimeters. Optical frequency domain imaging is a second-generation OCT technology that has equally high resolution with significantly increased image acquisition speeds and allows for large area, high-resolution tissue assessments. These features make OCT and optical frequency domain imaging ideal imaging techniques for surface and endoscopic imaging, specifically when tissue is unsafe to obtain and/or suffers from biopsy sampling error. This review focuses on the clinical impact of OCT in coronary, esophageal, and pulmonary imaging and the role of the pathologist in interpreting high-resolution OCT images as a complement to standard tissue pathology. (Arch Pathol Lab Med. 2012; 136: 1492-1501; doi: 10.5858/arpa.2012-0252-SA) C1 [Hariri, Lida P.; Mino-Kenudson, Mari; Mark, Eugene J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Suter, Melissa J.] Massachusetts Gen Hosp, Dept Pulm, Boston, MA 02114 USA. [Suter, Melissa J.] Massachusetts Gen Hosp, Crit Care Unit, Boston, MA 02114 USA. [Hariri, Lida P.; Suter, Melissa J.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hariri, Lida P.; Mino-Kenudson, Mari; Mark, Eugene J.; Suter, Melissa J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Hariri, LP (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren Bldg 219, Boston, MA 02114 USA. EM lhariri@partners.org NR 81 TC 9 Z9 9 U1 0 U2 4 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD DEC PY 2012 VL 136 IS 12 BP 1492 EP 1501 DI 10.5858/arpa.2012-0252-SA PG 10 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 053HO UT WOS:000312262300006 PM 23194041 ER PT J AU Kradin, RL AF Kradin, Richard L. TI Guiding the Pulmonologist's Hand: What They Need to Know About Lung Pathology and What is Lost in Translation SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID USUAL INTERSTITIAL PNEUMONIA; IDIOPATHIC PULMONARY-FIBROSIS; RESPIRATORY-DISTRESS-SYNDROME; TRANSBRONCHIAL BIOPSY; ORGANIZING PNEUMONIA; DISEASE; HYPERSENSITIVITY; PATHOGENESIS; DIAGNOSIS; FEATURES AB Increasing subspecialization in the practice of medicine has led to certain discrepancies in how pathologists and pulmonologists imagine lung disease. This article, written by a pathologist who also practices pulmonology at a large, academic hospital, highlights his perspective on the important role of the pathologist in guiding the hand of the pulmonary clinician. (Arch Pathol Lab Med. 2012; 136: 1528-1532; doi: 10.5858/arpa.2012-0273-SA) C1 [Kradin, Richard L.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Kradin, Richard L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Kradin, RL (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, 55 Fruit St,Warren 253, Boston, MA 02114 USA. EM rkradin@partners.org NR 28 TC 1 Z9 1 U1 1 U2 2 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD DEC PY 2012 VL 136 IS 12 BP 1528 EP 1532 DI 10.5858/arpa.2012-0273-SA PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 053HO UT WOS:000312262300011 PM 23194046 ER PT J AU Chen, RC Zhang, YY Chen, MH McMahon, E Loffredo, M McPherson, CP Nguyen, AU Nguyen, PL D'Amico, AV AF Chen, Ronald C. Zhang, Yuanye Chen, Ming-Hui McMahon, Elizabeth Loffredo, Marian McPherson, Carol P. Nguyen, Angela U. Nguyen, Paul L. D'Amico, Anthony V. TI Patient-reported quality of life during radiation treatment for localized prostate cancer: results from a prospective phase II trial SO BJU INTERNATIONAL LA English DT Article DE prostate cancer; radiation therapy; quality of life; clinical trial ID INTENSITY-MODULATED RADIOTHERAPY; RADICAL PROSTATECTOMY; INTRARECTAL BALLOON; ENDORECTAL BALLOON; GLAND LOCALIZATION; CLINICAL-TRIALS; THERAPY; OUTCOMES; IMMOBILIZATION; GENITOURINARY AB OBJECTIVE To evaluate data collected from a phase II trial to describe the time course and trajectory of patient-reported acute urinary and bowel symptom development during radiation therapy (RT) for prostate cancer. PATIENTS AND METHODS In all, 100 patients with intermediate- or high-risk prostate cancer received 72 Gy of RT to the prostate and seminal vesicles, with 6 months of concurrent androgen deprivation therapy; a rectal balloon was used for prostate immobilization. Patients completed the validated Prostate Cancer Symptom Indices questionnaire every 12 weeks, reporting urinary and bowel symptoms on a four- or five-point Likert scale. A score of =3 in a symptom is associated with clinically meaningful distress. Cumulative incidence of each symptom is reported. Bonferroni corrections of P values were used to adjust for multiple comparisons. RESULTS Urinary symptoms were frequent at baseline and worsened during treatment. By the end of RT, 2850% of patients developed clinically meaningful obstructive and irritative urinary symptoms. Acute bowel symptoms were less frequent. Each bowel symptom increased in frequency by 926% from baseline to end of RT. Urinary incontinence was rare. Overall, symptom burden at the end of treatment was modest. CONCLUSIONS Urinary symptoms were common during RT, and bowel symptoms were less frequent. These results inform patients and physicians during the decision-making process about potential patient quality of life experiences during RT, and also provide a benchmark for comparative effectiveness studies against newer treatments and technologies. C1 [Chen, Ronald C.; McPherson, Carol P.] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27599 USA. [Chen, Ronald C.] Univ N Carolina, Sheps Ctr Hlth Serv Res, Chapel Hill, NC 27599 USA. [Zhang, Yuanye; Chen, Ming-Hui] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. [McMahon, Elizabeth; Loffredo, Marian; Nguyen, Angela U.; Nguyen, Paul L.; D'Amico, Anthony V.] Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. [McMahon, Elizabeth; Loffredo, Marian; Nguyen, Angela U.; Nguyen, Paul L.; D'Amico, Anthony V.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Chen, RC (reprint author), Univ N Carolina, Dept Radiat Oncol, CB 7512,101 Manning Dr, Chapel Hill, NC 27599 USA. EM ronald_chen@med.unc.edu RI zhang, yuanye/H-6315-2013 FU Varian Medical Systems FX Paul Nguyen received a research grant from Varian Medical Systems. NR 26 TC 7 Z9 7 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 J9 BJU INT JI BJU Int. PD DEC PY 2012 VL 110 IS 11 BP 1690 EP 1695 DI 10.1111/j.1464-410X.2012.11117.x PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 053BY UT WOS:000312245900027 PM 22502770 ER PT J AU Nakabayashi, M Werner, L Courtney, KD Buckle, G Oh, WK Bubley, GJ Hayes, JH Weckstein, D Elfiky, A Sims, DM Kantoff, PW Taplin, ME AF Nakabayashi, Mari Werner, Lilian Courtney, Kevin D. Buckle, Geoffrey Oh, William K. Bubley, Glen J. Hayes, Julia H. Weckstein, Douglas Elfiky, Aymen Sims, Danny M. Kantoff, Philip W. Taplin, Mary-Ellen TI Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer SO BJU INTERNATIONAL LA English DT Article DE bicalutamide; castration-resistant prostate cancer; everolimus; mTOR; RAD001 ID RENAL-CELL CARCINOMA; ANDROGEN RECEPTOR MUTATIONS; MAMMALIAN TARGET; HORMONAL-THERAPY; SOLID TUMORS; MTOR; PATHWAY; INHIBITION; PTEN; RAPAMYCIN AB OBJECTIVES To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration-resistant prostate cancer (CRPC). To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC. PATIENTS AND METHODS A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC. The primary endpoint was a composite of prostate-specific antigen (PSA) level and measurable disease response by standard criteria. This single-stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of =40% from a response rate of =20%, as expected for bicalutamide alone (a= 0.10, power = 0.90). RESULTS In total, 36 men were enrolled, with a median (range) age of 68 (6072) years and median (range) baseline PSA level of 22.2 (8.4121.3) ng/mL, and 89% had metastatic disease. There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months. There were two patients with a confirmed PSA level decline =50%. The median (interquartile range) time to progression was 8.7 (7.915.9) weeks. The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients. CONCLUSION The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population. C1 [Nakabayashi, Mari; Courtney, Kevin D.; Buckle, Geoffrey; Hayes, Julia H.; Elfiky, Aymen; Kantoff, Philip W.; Taplin, Mary-Ellen] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02215 USA. [Werner, Lilian] Dana Farber Canc Inst, Dept Med, Div Med Oncol, Boston, MA 02215 USA. [Werner, Lilian] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA USA. [Bubley, Glen J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Oh, William K.] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Weckstein, Douglas; Sims, Danny M.] New Hampshire Oncol Hematol, Hooksett, NH USA. RP Taplin, ME (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM mary_taplin@dfci.harvard.edu RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 52 TC 42 Z9 42 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 J9 BJU INT JI BJU Int. PD DEC PY 2012 VL 110 IS 11 BP 1729 EP 1735 DI 10.1111/j.1464-410X.2012.11456.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 053BY UT WOS:000312245900034 PM 22928480 ER PT J AU Fung, C Chen, X Grandis, JR Duvvuri, U AF Fung, Christopher Chen, Xing Grandis, Jennifer R. Duvvuri, Umamaheswar TI EGFR tyrosine kinase inhibition induces autophagy in cancer cells SO CANCER BIOLOGY & THERAPY LA English DT Article DE EGFR; erlotinib; gefitinib; epidermal; autophagy; TKI; rapamycin ID LUNG-CANCER; CARCINOMA; INDUCTION; HEAD; NECK; RESISTANCE; ERLOTINIB; LINES; APOPTOSIS; SURVIVAL AB The epidermal growth factor receptor (EGFR) signaling pathway is frequently dysregulated in a variety of human malignancies. As a result, agents have been developed to selectively inhibit the tyrosine kinase function of EGFR (EGFR-TKI) for cancer therapy. However, the clinical efficacy of these drugs to date has been limited by both acquired and intrinsic resistance. Macroautophagy, a process of intracellular proteolysis, has been shown to be activated in response to EGFR targeted therapy. However, the specific role of the induction of autophagy remains controversial. Here we show that autophagy is induced in a dose-dependent manner by in vitro treatment of multiple cancer cell lines with EGFR-TKI. Additionally, we find that in cells highly resistant to EGFR-TKI, autophagy is not robustly activated and that co-treatment of these cells with rapamycin, a known inducer of autophagy, can partially restore sensitivity to EGFR-TKI. Finally, we demonstrate that, in resistant cell lines, EGFR-TKI sensitivity can be further inhibited by siRNA-mediated depletion of the critical autophagy protein ATG7. Thus, our data suggests that defective autophagy may be an EGFR-TKI resistance mechanism and that activation of autophagy may be a viable strategy to augment the cytotoxic effect of EGFR-TKIs. C1 [Fung, Christopher; Chen, Xing; Grandis, Jennifer R.; Duvvuri, Umamaheswar] Univ Pittsburgh, Sch Med, Dept Otolaryngol, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Grandis, Jennifer R.] Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. [Fung, Christopher] Howard Hughes Med Inst, Med Fellows Program, Chevy Chase, MD USA. RP Duvvuri, U (reprint author), Univ Pittsburgh, Sch Med, Dept Otolaryngol, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. EM duvvuriu@upmc.edu FU Howard Hughes Medical Institute [57006715]; National Institutes of Health [5P50CA097190, 2R01CA098372]; American Cancer Society [CRP-08-229-01]; United States Department of Veteran's Affairs [CDA-2-057-10S] FX These studies were supported by grants 57006715 (C.F.) from the Howard Hughes Medical Institute, 5P50CA097190 and 2R01CA098372 (J.G.) from the National Institutes of Health, CRP-08-229-01 (J.G.) from the American Cancer Society, and CDA-2-057-10S (U.D.) from the United States Department of Veteran's Affairs. The ideas in this article do not represent the views of the Department of Veteran's Affairs. NR 29 TC 25 Z9 27 U1 2 U2 16 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD DEC PY 2012 VL 13 IS 14 BP 1417 EP 1424 DI 10.4161/cbt.22002 PG 8 WC Oncology SC Oncology GA 052QD UT WOS:000312212200009 PM 22954701 ER PT J AU Joh, HK Cho, E Choueiri, TK AF Joh, Hee-Kyung Cho, Eunyoung Choueiri, Toni K. TI ABO blood group and risk of renal cell cancer SO CANCER EPIDEMIOLOGY LA English DT Article DE ABO blood-group system; Blood group antigens; Carcinoma; Renal cell; Kidney neoplasms ID PANCREATIC-CANCER; GROUP ANTIGENS; GROUP ALLELES; CARCINOMA; DISEASE; TRIALS; COHORT AB Background: The genetic determinants of sporadic renal cell cancer (RCC) are largely unknown. Previous studies have suggested associations between ABO blood group and risk of various cancers. However, its relationship to RCC remains unclear and no prospective data are available. Methods: We prospectively followed up 77,242 women in the Nurses' Health Study and 30,071 men in the Health Professionals Follow-Up Study from 1996 to 2008. The information on the ABO blood group was collected from participants' self-reports in 1996. Incidence of pathology-confirmed RCC was compared using hazard ratios (HRs) and 95% confidence intervals (CIs) derived from Cox proportional hazards models. Results: During 12 years of follow-up, 163 cases of incident RCC were documented in women and 88 cases in men. The multivariate HRs between non-O blood group (combined group of A, AB, and B) vs. blood group O were 1.51 (95% CI 1.09-2.09) in women, 1.08 (95% CI 0.70-1.66) in men, and 1.32 (95% CI 0.95-1.82) in the pooled cohorts. The associations between ABO blood group and RCC were consistent across strata of known risk factors for RCC including age, obesity, smoking, and history of hypertension (Pinteraction >= 0.32). Conclusions: We found a suggestive non-significant association between non-O blood group and increased risk of RCC in the pooled cohorts of men and women, and this association was significant in women. Our findings need to be replicated by other prospective studies. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Choueiri, Toni K.] Brigham & Womens Hosp, Dana Farber Canc Inst, Kidney Canc Ctr, Boston, MA 02215 USA. [Choueiri, Toni K.] Harvard Univ, Sch Med, Boston, MA 02215 USA. [Joh, Hee-Kyung] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02215 USA. [Joh, Hee-Kyung; Cho, Eunyoung] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02215 USA. [Joh, Hee-Kyung] Seoul Natl Univ, Coll Med, Dept Med, Seoul, South Korea. [Cho, Eunyoung] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA. RP Choueiri, TK (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Kidney Canc Ctr, 450 Brookline Ave, Boston, MA 02215 USA. EM hjoh@hsph.harvard.edu; eunyoung.cho@channing.harvard.edu; Toni_Choueiri@dfci.harvard.edu RI Joh, Hee Kyung/J-5674-2012 FU National Institutes of Health, Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Programs of Research Excellence (SPORE) [CA137764, CA87969, CA55075]; Trust Family Fund for Kidney Cancer Research FX This study was supported by research grant CA137764, CA87969, and CA55075 from the National Institutes of Health, Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Programs of Research Excellence (SPORE), and the Trust Family Fund for Kidney Cancer Research. NR 29 TC 13 Z9 15 U1 0 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1877-7821 J9 CANCER EPIDEMIOL JI Cancer Epidemiol. PD DEC PY 2012 VL 36 IS 6 BP 528 EP 532 DI 10.1016/j.canep.2012.07.001 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 053HB UT WOS:000312260900016 PM 22841339 ER PT J AU Hawkins, BM Drachman, DE AF Hawkins, Beau M. Drachman, Douglas E. TI Transradial access for carotid stenting: Exceptional outcomes in experienced hands... will the results be generalizable? SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material ID LEARNING-CURVE C1 [Drachman, Douglas E.] Massachusetts Gen Hosp, Cardiovasc Fellowship Program, Div Cardiol, Vasc Med Sect, Boston, MA 02114 USA. RP Drachman, DE (reprint author), Massachusetts Gen Hosp, Cardiovasc Fellowship Program, Div Cardiol, Vasc Med Sect, 55 Fruit St,Gray Bigelow 800, Boston, MA 02114 USA. EM ddrachman@partners.org NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD DEC 1 PY 2012 VL 80 IS 7 BP 1088 EP 1089 DI 10.1002/ccd.24730 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 051RO UT WOS:000312144900007 PM 23225649 ER PT J AU Grosu, HB Lee, YI Lee, J Eden, E Eikermann, M Rose, KM AF Grosu, Horiana B. Lee, Young Im Lee, Jarone Eden, Edward Eikermann, Matthias Rose, Keith M. TI Diaphragm Muscle Thinning in Patients Who Are Mechanically Ventilated SO CHEST LA English DT Article ID DYSFUNCTION; THICKNESS; VARIABILITY; AREA AB Background: Approximately 40% of patients in medical ICUs require mechanical ventilation (MV). Approximately 20% to 25% of these patients will encounter difficulties in discontinuing MV. Multiple studies have suggested that MV has an unloading effect on the respiratory muscles that leads to diaphragmatic atrophy and dysfunction, a process called ventilator-induced diaphragmatic dysfunction (VIDD). VIDD may be an important factor affecting when and if MV can be discontinued. A sensitive and specific diagnostic test for VIDD could provide the physician with valuable information that might influence decisions regarding extubation or tracheostomy. The purpose of this study was to quantify, using daily sonographic assessments, the rate and degree of diaphragm thinning during MV. Methods: Seven intubated patients receiving MV during acute care were included. Using sonography, diaphragm muscle thickness was measured daily from the day of intubation until the patient underwent extubation or tracheostomy or died. We analyzed our data using standard descriptive statistics, linear regression, and mixed-model effects. Results: The overall rate of decrease in the diaphragm thickness of all seven patients over time averaged 6% per day of MV, which differed significantly from zero. Similarly, the diaphragm thickness decreased for each patient over time. Conclusion: Sonographic assessment of the diaphragm provides noninvasive measurement of diaphragmatic thickness and the degree of diaphragm thinning in patients receiving MV. Our data show that diaphragm muscle thinning starts within 48 h after initiation of MV. However, it is unclear if diaphragmatic thinning correlates with diaphragmatic atrophy or pulmonary function. The relationship between diaphragm thinning and diaphragm strength remains to be elucidated. CHEST 2012; 142(6):1455-1460 C1 [Grosu, Horiana B.; Lee, Young Im; Eden, Edward; Rose, Keith M.] Columbia Univ, Coll Phys & Surg, St Lukes & Roosevelt Hosp, Div Pulm Crit Care & Sleep Med, New York, NY USA. [Lee, Jarone; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Rose, KM (reprint author), St Lukes Roosevelt Hosp, Div Pulm & Crit Care, 1000 10th Ave, New York, NY 10019 USA. EM KRose@chpnet.org NR 16 TC 45 Z9 47 U1 1 U2 5 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2012 VL 142 IS 6 BP 1455 EP 1460 DI 10.1378/chest.11-1638 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 053PA UT WOS:000312283800019 PM 23364680 ER PT J AU Donington, J Ferguson, M Mazzone, P Handy, J Schuchert, M Fernando, H Loo, B Lanuti, M de Hoyos, A Detterbeck, F Pennathur, A Howington, J Landreneau, R Silvestri, G AF Donington, Jessica Ferguson, Mark Mazzone, Peter Handy, John, Jr. Schuchert, Matthew Fernando, Hiran Loo, Billy, Jr. Lanuti, Michael de Hoyos, Alberto Detterbeck, Frank Pennathur, Arjun Howington, John Landreneau, Rodney Silvestri, Gerard CA Soc Thoracic Surg TI American College of Chest Physicians and Society of Thoracic Surgeons Consensus Statement for Evaluation and Management for High-Risk Patients With Stage I Non-small Cell Lung Cancer SO CHEST LA English DT Article ID BODY RADIATION-THERAPY; PERCUTANEOUS RADIOFREQUENCY ABLATION; QUALITY-OF-LIFE; IDIOPATHIC PULMONARY-FIBROSIS; PROSPECTIVE PHASE-II; AIR-FLOW LIMITATION; SUBLOBAR RESECTION; STEREOTACTIC RADIOTHERAPY; SEGMENTAL RESECTION; EXERCISE CAPACITY AB Background: The standard treatment of stage I non-small cell lung cancer (NSCLC) is lobectomy with systematic mediastinal lymph node evaluation. Unfortunately, up to 25% of patients with stage I NSCLC are not candidates for lobectomy because of severe medical comorbidity. Methods: A panel of experts was convened through the Thoracic Oncology Network of the American College of Chest Physicians and the Workforce on Evidence-Based Surgery of the Society of Thoracic Surgeons. Following a literature review, the panel developed 13 suggestions for evaluation and treatment through iterative discussion and debate until unanimous agreement was achieved. Results: Pretreatment evaluation should focus primarily on measures of cardiopulmonary physiology, as respiratory failure represents the greatest interventional risk. Alternative treatment options to lobectomy for high-risk patients include sublobar resection with or without brachytherapy, stereotactic body radiation therapy, and radiofrequency ablation. Each is associated with decreased procedural morbidity and mortality but increased risk for involved lobe and regional recurrence compared with lobectomy, but direct comparisons between modalities are lacking. Conclusions: Therapeutic options for the treatment of high-risk patients are evolving quickly. Improved radiographic staging and the diagnosis of smaller and more indolent tumors push the risk-benefit decision toward parenchymal-sparing or nonoperative therapies in high-risk patients. Unbiased assessment of treatment options requires uniform reporting of treatment populations and outcomes in clinical series, which has been lacking to date. CHEST 2012; 142(6):1620-1635 C1 [Donington, Jessica] NYU, Sch Med, Dept Cardiothorac Surg, New York, NY 10016 USA. [Ferguson, Mark] Univ Chicago, Dept Surg, Chicago, IL 60637 USA. [Mazzone, Peter] Cleveland Clin Fdn, Dept Pulm Allergy & Crit Care Med, Cleveland, OH 44195 USA. [Handy, John, Jr.] Providence Canc Ctr, Portland, OR USA. [Schuchert, Matthew; Pennathur, Arjun; Landreneau, Rodney] Univ Pittsburgh, Med Ctr, Dept Cardiothorac Surg, Pittsburgh, PA USA. [Fernando, Hiran] Boston Med Ctr, Dept Cardiothorac Surg, Boston, MA USA. [Loo, Billy, Jr.] Stanford Univ, Sch Med, Dept Radiat Oncol, Stanford, CA 94305 USA. [Lanuti, Michael] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. [de Hoyos, Alberto] NW Mem Hosp, Dept Cardiothorac Surg, Chicago, IL 60611 USA. [Detterbeck, Frank] Yale Univ, Sch Med, Dept Thorac Surg, New Haven, CT USA. [Howington, John] Northshore Univ Hlth Syst, Dept Surg, Evanston, IL USA. [Silvestri, Gerard] Med Univ S Carolina, Div Pulm Med & Crit Care, Charleston, SC USA. RP Donington, J (reprint author), NYU, Sch Med, Dept Cardiothorac Surg, 530 1st Ave,Ste 9V, New York, NY 10016 USA. EM Jessica.donington@nyumc.org OI Fernando, Hiran/0000-0002-5330-7036 FU Department of Defense; National Institutes of Health; University of Texas South-western; Varian Medical Systems, Inc.; Intuitive Surgical, Inc. FX The authors have reported to CHEST the following conflicts of interest: Dr Loo receives lung cancer research funding from the Department of Defense, the National Institutes of Health, and Varian Medical Systems, Inc. He also receives funding from the University of Texas South-western for clinical trials patient enrollment. He has received speaking honoraria from General Electric Company; Gerson Lehrman Group, Inc; Varian Medical Systems, Inc; and Siemens AG. Dr Ferguson receives educational research support from Intuitive Surgical, Inc. Drs Donington, Mtizzone, Handy, Schuchert, Fernando, Lanuti, de Hoyos, Detterbeck, Pennathur, Howington, Landreneau, and Silvestri have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. NR 116 TC 52 Z9 53 U1 0 U2 8 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD DEC PY 2012 VL 142 IS 6 BP 1620 EP 1635 DI 10.1378/chest.12-0790 PG 16 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 053PA UT WOS:000312283800041 PM 23208335 ER PT J AU Hall, AL Bowden, MG Kautz, SA Neptune, RR AF Hall, A. L. Bowden, M. G. Kautz, S. A. Neptune, R. R. TI Biomechanical variables related to walking performance 6-months following post-stroke rehabilitation SO CLINICAL BIOMECHANICS LA English DT Article DE Hemiparesis; Body-weight supported treadmill training; Gait; Follow-up; Walking speed ID BODY-WEIGHT SUPPORT; CHRONIC STROKE; GAIT SPEED; TREADMILL; RECOVERY; CLASSIFICATION; LOCOMOTOR; SURVIVORS; STEPS AB Background: Body-weight supported treadmill training has been shown to be effective in improving walking speed in post-stroke hemiparetic subjects, and those that have shown improvements generally maintain them after the completion of rehabilitation. However, currently no biomechanical variables are known to be related to those who will either continue to improve or regress in their self-selected walking speed during the 6-month period following rehabilitation. The objective of this study was to identify those biomechanical variables that are associated with subjects who continue (or did not continue) to improve their self-selected walking speed following the completion of rehabilitation. Methods: Experimental kinematic and kinetic data were recorded from 18 hemiparetic subjects who participated in a 6-month follow-up study after completing a 12-week locomotor training program that included stepping on a treadmill with partial body weight support and manual assistance. Pearson correlation coefficients were used to determine which biomechanical variables evaluated during the post-training session were related to changes in self-selected walking speed from post-training to a 6-month follow-up session. Findings: Following the completion of rehabilitation, the majority of subjects increased or retained (i.e., did not change) their self-selected walking speed from post-training to the follow-up session. Post-training step length symmetry and daily step activity were positively related to walking speed improvements. Interpretation: Motor control deficits that lead to persistent step length asymmetry and low daily step activity at the end of rehabilitation are associated with poorer outcomes six months after completion of the program. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Hall, A. L.; Neptune, R. R.] Univ Texas Austin, Dept Mech Engn, Austin, TX 78712 USA. [Bowden, M. G.; Kautz, S. A.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Bowden, M. G.; Kautz, S. A.] Med Univ S Carolina, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Bowden, M. G.; Kautz, S. A.] Med Univ S Carolina, Div Phys Therapy, Charleston, SC 29425 USA. RP Neptune, RR (reprint author), Univ Texas Austin, Dept Mech Engn, 1 Univ Stn C2200, Austin, TX 78712 USA. EM rneptune@mail.utexas.edu RI Kinney, Allison/J-5814-2013; OI Kinney, Allison/0000-0003-3553-0733; Kautz, Steven/0000-0003-3151-8235 FU NIH [RO1 NS055380]; Rehabilitation Research & Development Service of the VA FX The authors would like to thank Helen Emery, Erin Carr, Dr. Bhavana Raja, Dr. Cameron Nott, Dr. Chitra Balasubramanian, Kelly Rooney and Ryan Knight for help with the data collection and processing and the members of the Neuromuscular Biomechanics Lab at The University of Texas at Austin for their insightful comments on the manuscript. This work was funded by NIH grant RO1 NS055380 and the Rehabilitation Research & Development Service of the VA. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NINDS or VA. NR 32 TC 13 Z9 13 U1 1 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 J9 CLIN BIOMECH JI Clin. Biomech. PD DEC PY 2012 VL 27 IS 10 BP 1017 EP 1022 DI 10.1016/j.clinbiomech.2012.07.006 PG 6 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA 055MO UT WOS:000312420900007 PM 22917626 ER PT J AU Raja, B Neptune, RR Kautz, SA AF Raja, Bhavana Neptune, Richard R. Kautz, Steven A. TI Coordination of the non-paretic leg during hemiparetic gait: Expected and novel compensatory patterns SO CLINICAL BIOMECHANICS LA English DT Article DE Electromyography; Stroke; Walking; Muscle ID RECTUS FEMORIS TRANSFER; GROUND REACTION FORCES; STIFF-KNEE GAIT; POSTSTROKE HEMIPARESIS; STROKE PATIENTS; WALKING; FLEXION; SPEED; SUPPORT; POWER AB Background: Post-stroke hemiparesis is usually considered a unilateral motor control deficit of the paretic leg, while the non-paretic leg is assumed to compensate for paretic leg impairments and have minimal to no deficits. While the non-paretic leg electromyography (EMG) patterns are clearly altered, how the non-paretic leg acts to compensate remains to be established. Methods: Kinesiological data were recorded from sixty individuals with chronic hemiparesis (age: 60.9, SD=12.6 years, 21 females, 28 right hemiparetic, time since stroke: 4.5 years, SD 3.9 years), divided into three speed-based groups, and twenty similarly aged healthy individuals (age: 65.1, SD=10.4 years, 15 females). All walked on an instrumented split-belt treadmill at their self-selected speed and control subjects also walked at slower speeds matching those of the persons with hemiparesis. We determined the differences in magnitude and timing of non-paretic EMG activity relative to healthy control subjects in four pre-defined regions of stance phase of the gait cycle. Findings: Integrated EMG activity and EMG timing in the non-paretic leg were different in many muscles. Multiple compensatory patterns identified included: increased EMG output when the muscle was typically active in controls and novel compensatory EMG patterns that appeared to provide greater propulsion or support with little evidence of impaired motor performance. Interpretation: Most novel compensations were made possible by altered kinematics of the paretic and non-paretic leg (i.e., early stance plantarflexor activity provided propulsion due to the decreased advancement of the non-paretic foot) while others (late single limb stance knee extensor and late stance hamstring activity) appeared to be available mechanisms for increasing propulsion. Published by Elsevier Ltd. C1 [Kautz, Steven A.] Ralph H Johnson VA Med Ctr, Charleston, SC USA. [Neptune, Richard R.] Univ Texas Austin, Austin, TX 78712 USA. [Raja, Bhavana] Univ Florida, Rehabil Sci Doctoral Program, Gainesville, FL USA. [Kautz, Steven A.] Malcom Randall VA Med Ctr, Brain Rehabil Res Ctr, Gainesville, FL USA. [Kautz, Steven A.] Med Univ S Carolina, Coll Hlth Profess, Dept Hlth Sci & Res, Charleston, SC 29425 USA. [Kautz, Steven A.] Med Univ S Carolina, Coll Hlth Profess, Div Phys Therapy, Charleston, SC 29425 USA. RP Kautz, SA (reprint author), 77 President St,MSC 700, Charleston, SC 29425 USA. EM kautz@musc.edu OI Kautz, Steven/0000-0003-3151-8235 FU NIH [RO1 HD46820]; Rehabilitation Research & Development Service of the VA FX The authors would like to thank Helen Emery, Dr. Mark Bowden, Kelly Rooney, Francis Bergschneider, Dr. Cameron Nott and Ryan Knight for help with the data collection and processing. This work was funded by NIH grant RO1 HD46820 and the Rehabilitation Research & Development Service of the VA The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, NICHD, VA or the United States Government. NR 25 TC 12 Z9 13 U1 2 U2 16 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 J9 CLIN BIOMECH JI Clin. Biomech. PD DEC PY 2012 VL 27 IS 10 BP 1023 EP 1030 DI 10.1016/j.clinbiomech.2012.08.005 PG 8 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA 055MO UT WOS:000312420900008 PM 22981679 ER PT J AU Kohli, P Cannon, CP AF Kohli, Payal Cannon, Christopher P. TI The Importance of Matching Language to Type of Evidence: Avoiding the Pitfalls of Reporting Outcomes Data SO CLINICAL CARDIOLOGY LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; DRUG-ELUTING STENTS; BARE-METAL STENTS; FOLLOW-UP; POSTMENOPAUSAL ESTROGEN; MYOCARDIAL-INFARCTION; UPDATED GUIDELINES; 11-YEAR MORTALITY; LDL CHOLESTEROL; RISK AB Results from different types of clinical research studies provide different types of evidence for evaluating the effects of a new drug or intervention. For this reason, it is important to recognize this phenomenon during reporting and to choose appropriate language to match the type of study that was done, because this can become critical to the interpretation and application of the results in clinical practice. In this article, we aim to highlight this issue through a series of examples and provide some guidance on what the appropriate language for different types of studies should be. This editorial review was cowritten and developed as an expanded background piece to accompany the statement by the HEART Group journal editors, which is being published simultaneously with this article. The authors have no funding, financial relationships, or conflicts of interest to disclose. C1 [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, Boston, MA 02115 USA. [Kohli, Payal] Univ Calif San Francisco, Div Cardiol, San Francisco, CA USA. RP Cannon, CP (reprint author), Brigham & Womens Hosp, TIMI Study Grp, Div Cardiovasc, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM cpcannon@partners.org NR 18 TC 26 Z9 27 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-9289 J9 CLIN CARDIOL JI Clin. Cardiol. PD DEC PY 2012 VL 35 IS 12 BP 714 EP 717 DI 10.1002/clc.22066 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 053CW UT WOS:000312248700005 PM 23192955 ER PT J AU Udell, JA Scirica, BM Braunwald, E Raz, I Steg, PG Davidson, J Hirshberg, B Bhatt, DL AF Udell, Jacob A. Scirica, Benjamin M. Braunwald, Eugene Raz, Itamar Steg, Ph. Gabriel Davidson, Jaime Hirshberg, Boaz Bhatt, Deepak L. TI Statin and Aspirin Therapy for the Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus SO CLINICAL CARDIOLOGY LA English DT Review ID AMERICAN-HEART-ASSOCIATION; PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; OF-CARDIOLOGY FOUNDATION; SECONDARY PREVENTION; COLLABORATIVE METAANALYSIS; MYOCARDIAL-INFARCTION; SCIENTIFIC STATEMENT; DISEASE PREVENTION; VASCULAR OUTCOMES AB Patients with type 2 diabetes mellitus are at 2 to 4 times increased risk of cardiovascular events compared with those without diabetes, both among patients with multiple risk factors only and those with established atherothrombosis. In this review, we provide recommendations for the use of statins and aspirin for the prevention of cardiovascular events in high-risk patients with diabetes mellitus. C1 [Bhatt, Deepak L.] VA Boston Healthcare Syst, Dept Med, Boston, MA 02132 USA. [Udell, Jacob A.; Scirica, Benjamin M.; Braunwald, Eugene; Bhatt, Deepak L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. [Raz, Itamar] Hadassah Hebrew Univ, Sch Med, Dept Med, Diabet Unit, Jerusalem, Israel. [Steg, Ph. Gabriel] INSERM, U698, Paris, France. [Steg, Ph. Gabriel] Univ Paris Diderot, Paris, France. [Steg, Ph. Gabriel] Hop Bichat Claude Bernard, AP HP, Dept Cardiol, F-75877 Paris, France. [Davidson, Jaime] Univ Texas SW Med Sch, Dept Med, Div Endocrinol, Dallas, TX USA. [Hirshberg, Boaz] AstraZeneca, Res & Dev, Wilmington, DE USA. RP Bhatt, DL (reprint author), VA Boston Healthcare Syst, Dept Med, 1400 VFW Pkwy, Boston, MA 02132 USA. EM dlbhattmd@post.harvard.edu FU AstraZeneca; Bristol-Myers Squibb; Canadian Institutes for Health Research (CIHR); Canadian Foundation for Women's Health; Merck; Johnson Johnson; Bayer Healthcare; Gilead Sciences; Lexicon; Arena Pharmaceuticals; Servier; Amarin; Eisai; Ethicon; Medtronic; Sanofi Aventis; The Medicines Company FX The SAVOR-TIMI 53 trial is sponsored by AstraZeneca and Bristol-Myers Squibb. Dr. Udell is a recipient of a Postdoctoral Research Fellowship from the Canadian Institutes for Health Research (CIHR) and Canadian Foundation for Women's Health. Dr. Scirica receives research grants from AstraZeneca, Bristol-Myers Squibb, Merck, Johnson & Johnson, Bayer Healthcare, and Gilead Sciences and consultancy fees from Gilead Sciences, Lexicon, and Arena Pharmaceuticals. Dr. Braunwald receives research grants from AstraZeneca and Bristol-Myers Squibb. Dr. Raz has received honoraria/expenses for advisory board participation from AstraZeneca, Bristol-Myers Squibb, Novo Nordisk, Merck, Sharp & Dohme, and Eli Lilly; has served as a consultant for Andromea, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, HealOr, Insuline, Teva, and TransPharma; and has participated in speakers bureaus for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novo Nordisk, Johnson & Johnson, and Roche. Dr. Steg receives research grants from Servier. Dr. Davidson participated on advisory panels for AstraZeneca, Bristol-Myers Squibb, Merck, Johnson & Johnson, Boehringer Ingelheim, Eli Lilly, Generex Biotechnology, Novo Nordisk A/S, Roche Diagnostics, and Takeda Pharmaceutical Company and participated in speaker's bureaus for Eli Lilly and Takeda Pharmaceutical Company. Dr. Hirshberg is an employee of and holds stock in AstraZeneca. Dr. Bhatt discloses the following relationships-Advisory Board: Medscape Cardiology; Board of Directors: Boston VA Research Institute, Society of Chest Pain Centers; Chair: American Heart Association Get With The Guidelines Science Subcommittee; Honoraria: American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), WebMD (CME steering committees); Research Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company; Unfunded Research: FlowCo, PLx Pharma, Takeda. The design and conduct of the SAVOR-TIMI 53 study are being done by the academic executive committee in collaboration with the sponsors. NR 46 TC 8 Z9 8 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-9289 J9 CLIN CARDIOL JI Clin. Cardiol. PD DEC PY 2012 VL 35 IS 12 BP 722 EP 729 DI 10.1002/clc.22032 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 053CW UT WOS:000312248700006 PM 22760763 ER PT J AU Acharya, D Robertson, P Kay, GN Jackson, L Warnock, DG Plumb, VJ Tallaj, JA AF Acharya, Deepak Robertson, Peter Kay, G. Neal Jackson, Leslie Warnock, David G. Plumb, Vance J. Tallaj, Jose A. TI Arrhythmias in Fabry Cardiomyopathy SO CLINICAL CARDIOLOGY LA English DT Article ID ENZYME REPLACEMENT THERAPY; LEFT-VENTRICULAR HYPERTROPHY; HUMAN ALPHA-GALACTOSIDASE; CARDIAC MANIFESTATIONS; DISEASE; INVOLVEMENT; IMPROVEMENT; PREVALENCE; TRIAL AB Background: Prior studies suggest that the incidence of ventricular arrhythmias is high in patients with Fabry cardiomyopathy. This study evaluated the incidence of significant arrhythmias in a series of patients with Fabry cardiomyopathy. Hypothesis: Arrhythmias are important causes of morbidity and mortality in Fabry Cardiomyopathy. Methods: This study was a retrospective chart review of 19 patients with known Fabry cardiomyopathy. Device interrogation reports were reviewed for those who had implantable devices. Electrocardiogram, Holter monitor, and event monitors were reviewed in those who did not have implantable devices. Results: Eighteen of nineteen patients were on enzyme replacement therapy (ERT). Nine (47%) out of 19 patients had implantable devices. Implant indications included symptomatic bradycardia, nonsustained ventricular tachycardia, conduction abnormalities, palpitations, and syncope. Mean follow-up in the patients with devices was 50 +/- 23 months. Two patients received implantable cardioverter-defibrillator (ICD) shocks, 1 of which was inappropriate for atrial fibrillation. Patients were paced in the atrium 71% +/- 37% of the time and paced in the ventricle 49% +/- 52% of the time. Four patients with devices were paced more than 95% of the time. Patients with an ICD had lower heart rates prior to ICD implant than the group that did not have devices (60 +/- 10 vs 78 +/- 16, P = 0.03). Of the patients without devices, only 1 had sudden cardiac death. Patients with implanted devices had higher left ventricular (LV) mass indices compared to patients without implanted devices (136 +/- 40 g/m2 vs 93 +/- 19 g/m2, P = 0.008). Conclusions: Significant ventricular arrhythmias are uncommon in patients with Fabry cardiomyopathy on ERT, but utilization of pacing is high. Sudden cardiac death in Fabry cardiomyopathy may be related to bradycardia. The authors have no funding, financial relationships, or conflicts of interest to disclose. C1 [Acharya, Deepak; Robertson, Peter; Kay, G. Neal; Plumb, Vance J.; Tallaj, Jose A.] Univ Alabama Birmingham, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Jackson, Leslie; Warnock, David G.] Univ Alabama Birmingham, Div Nephrol, Birmingham, AL USA. [Tallaj, Jose A.] Birmingham VA Med Ctr, Dept Med, Birmingham, AL USA. RP Acharya, D (reprint author), THT 321,1900 Univ Blvd, Birmingham, AL 35226 USA. EM dacharya@cardiology.uab.edu NR 26 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-9289 J9 CLIN CARDIOL JI Clin. Cardiol. PD DEC PY 2012 VL 35 IS 12 BP 738 EP 740 DI 10.1002/clc.22047 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 053CW UT WOS:000312248700008 PM 22886820 ER PT J AU Park, MY Altman, RK Orencole, M Kumar, P Parks, KA Heist, KE Singh, JP Picard, MH AF Park, Mi Young Altman, Robert K. Orencole, Mary Kumar, Prabhat Parks, Kimberly A. Heist, Kevin E. Singh, Jagmeet P. Picard, Michael H. TI Characteristics of Responders to Cardiac Resynchronization Therapy: The Impact of Echocardiographic Left Ventricular Volume SO CLINICAL CARDIOLOGY LA English DT Article ID DEFIBRILLATOR IMPLANTATION TRIAL; SPECKLE TRACKING; MADIT-CRT; PREDICTORS; DYSSYNCHRONY; GENDER; STRAIN; SIZE AB Background: One-third of patients who receive cardiac resynchronization therapy (CRT) are classified as nonresponders. Characteristics of responders to CRT have been studied in multiple clinical trials. Hypothesis: Independent predictors of CRT response may be identified by studying a series of patients in routine clinical practice. Method: One hundred twenty-five patients were examined retrospectively from a multidisciplinary CRT clinic program. Echocardiographic CRT response was defined as a decrease in left ventricular (LV) end-systolic volume of =15% and/or absolute increase of 5% in LV ejection fraction at the 6-month visit. Results: There were 81 responders and 44 nonresponders. By univariate analyses, female sex, nonischemic cardiomyopathy etiology, baseline QRS duration, the presence of left bundle branch block (LBBB), and left ventricular end-diastolic volume (LVEDV) index predicted CRT response. However, multivariate analysis demonstrated that only QRS duration, LBBB, and LVEDV index were independent predictors (QRS width, odds ratio [OR]: 1.027, 95% confidence interval [CI]: 1.0041.050, P = 0.023; LBBB, OR: 3.568, 95% CI: 1.2849.910, P = 0.015; LVEDV index, OR: 0.970, 95% CI: 0.9530.987, P = 0.001). Although female sex and nonischemic etiology were associated with an improved CRT response on univariate analyses, after adjusting for LV volumes they were not independent predictors. Conclusions: QRS width, LBBB, and LVEDV index are independent predictors for echocardiographic CRT response. Previously reported differences in CRT response for sex and cardiomyopathy etiology are associated with differences in baseline LV volumes in our clinical practice. Dr. Heist has received research grants (modest) from Biotronik, Boston Scientific, and St. Jude Medical; honoraria (modest) from Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical; and consultant/advisory board positions (modest) from Boston Scientific, Sorin and St. Jude Medical. Dr. Singh has received research grants (significant) from Biotronik, Boston Scientific, Medtronic, and St. Jude Medical; and consultant/advisory board positions (modest) from Biosense Webster, Biotronik, Boston Scientific, CardioInsight, Medtronic, Sorin, St. Jude Medical, and Thoratec Inc. The statistical analysis was conducted with support from Harvard Catalyst. The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 RR 025758, and financial contributions from Harvard University and its affiliated academic healthcare centers). The authors have no other funding, financial relationships, or conflicts of interest to disclose. C1 [Park, Mi Young; Altman, Robert K.; Orencole, Mary; Kumar, Prabhat; Parks, Kimberly A.; Heist, Kevin E.; Singh, Jagmeet P.; Picard, Michael H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Heart, Boston, MA 02114 USA. RP Picard, MH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Heart, Yawkey 5E,55 Fruit St, Boston, MA 02114 USA. EM mhpicard@partners.org OI Altman, Robert/0000-0002-1612-3561; Picard, Michael/0000-0002-9264-3243 FU Biotronik; Boston Scientific; St. Jude Medical; Medtronic; Harvard University; National Center for Advancing Translational Sciences, National Institutes of Health [UL1 RR 025758] FX Dr. Heist has received research grants (modest) from Biotronik, Boston Scientific, and St. Jude Medical; honoraria (modest) from Biotronik, Boston Scientific, Medtronic, Sorin, and St. Jude Medical; and consultant/advisory board positions (modest) from Boston Scientific, Sorin and St. Jude Medical. Dr. Singh has received research grants (significant) from Biotronik, Boston Scientific, Medtronic, and St. Jude Medical; and consultant/advisory board positions (modest) from Biosense Webster, Biotronik, Boston Scientific, CardioInsight, Medtronic, Sorin, St. Jude Medical, and Thoratec Inc.; The statistical analysis was conducted with support from Harvard Catalyst. The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 RR 025758, and financial contributions from Harvard University and its affiliated academic healthcare centers). NR 15 TC 0 Z9 0 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0160-9289 EI 1932-8737 J9 CLIN CARDIOL JI Clin. Cardiol. PD DEC PY 2012 VL 35 IS 12 DI 10.1002/clc.22043 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 053CW UT WOS:000312248700014 ER PT J AU Sonnenberg, A AF Sonnenberg, Amnon TI Effects of Birth Cohort on Long-Term Trends in Mortality From Colorectal Cancer SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article DE Colonoscopy Screening; Cohort Study; Epidemiology; Helicobacter pylori ID HELICOBACTER-PYLORI INFECTION; PEPTIC-ULCER; RISK; RATES; METAANALYSIS; POLYPECTOMY; PREVENTION; ENDOSCOPY; VETERANS; AUTOPSY AB BACKGROUND & AIMS: The decrease in mortality from colorectal cancer might have begun before widespread use of screening colonoscopy and sigmoidoscopy examinations. We examined long-term time trends in colorectal cancer mortality in 6 European countries to determine when the reduction began. METHODS: We analyzed mortality data from the national statistical offices of the United Kingdom (England and Wales), France, Italy, The Netherlands, Sweden, and Switzerland during the past 66 to 107 years. The data were made available by the national statistical offices of the 6 countries. Age-specific rates of death were plotted against the period of death, as period-age contours, and against the period of birth, as cohort-age contours. RESULTS: Long-term time trends in mortality from cancers of the rectum and colon each increased among generations born from 1800 to 1880, and then decreased among all subsequent generations, in all 6 countries analyzed. Similar temporal patterns also were observed when data from men and women were analyzed separately. The birth cohort patterns of colorectal cancer mortality resemble those of gastric cancer and peptic ulcer. CONCLUSIONS: Time trends of mortality from colorectal cancer, in 6 European countries, are associated with birth cohort patterns: colorectal cancer mortality decreased among all generations since 1880. These patterns indicate that in addition to the use of screening colonoscopy, other factors, such as changes in Helicobacter pylori infection, may have affected mortality. C1 Oregon Hlth & Sci Univ, Portland VA Med Ctr, Div Gastroenterol, Portland, OR 97239 USA. RP Sonnenberg, A (reprint author), Oregon Hlth & Sci Univ, Portland VA Med Ctr, Div Gastroenterol, P3-GI,3710 SW US,Vet Hosp Rd, Portland, OR 97239 USA. EM sonnenbe@ohsu.edu NR 27 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD DEC PY 2012 VL 10 IS 12 BP 1389 EP 1394 DI 10.1016/j.cgh.2012.09.008 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 053IW UT WOS:000312265900017 PM 22982097 ER PT J AU Khan, AM Chirinos, JA Litt, H Yang, W Rosas, SE AF Khan, Abigail May Chirinos, Julio A. Litt, Harold Yang, Wei Rosas, Sylvia E. TI FGF-23 and the Progression of Coronary Arterial Calcification in Patients New to Dialysis SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID CHRONIC KIDNEY-DISEASE; GROWTH-FACTOR 23; LEFT-VENTRICULAR HYPERTROPHY; RENAL-TRANSPLANT RECIPIENTS; CARDIOVASCULAR-DISEASE; HEMODIALYSIS-PATIENTS; COMPUTED-TOMOGRAPHY; SERUM PHOSPHORUS; CALCIUM; MORTALITY AB Background and objective Fibroblast growth factor 23 (FGF-23), a regulator of phosphorus metabolism, is a risk marker in CKD. FGF-23 has been associated with coronary arterial calcification (CAC), but it is not known whether FGF-23 predicts CAC progression in CKD. The aim of this study was to evaluate the association of FGF-23 with CAC progression in advanced CKD. Design, setting, participants, & measurements FGF-23 levels and CAC were measured by electrocardiography-triggered multislice computed tomography in 99 individuals initiating dialysis. Patients were enrolled in the study from April 2008 to July 2010. CAC was calculated using Agatston and calcium volume score. Sixty-seven study participants had repeat CAC measures at 1 year. Linear regression was used to assess the association of FGF-23 with CAC. Results The mean age of study participants was 50 years; 33% were women, and 64% were black. The median FGF-23 level was 1238 relative units (RU)/ml (interquartile range, 515-2218 RU/ml). According to Agatston score, FGF-23 was not associated with baseline CAC (P=0.14) but was significantly associated with CAC progression. There was a 192.3-Agatston unit change in CAC score per 1-SD change in FGF-23 (P=0.008) in models adjusting for known risk factors for CAC and serum phosphate. This association persisted after adjustment for high-sensitivity C-reactive protein, 25-OH vitamin D levels, and the use of phosphorus binders. Results were similar when change in calcium volume score was used. Conclusions In individuals with advanced CKD, serum FGF-23 is strongly associated with CAC progression. FGF-23 may be a marker of cardiovascular risk in CKD. Clin J Am Soc Nephrol 7: 2017-2022, 2012. doi:10.2215/CJN.02160212 C1 [Khan, Abigail May; Chirinos, Julio A.] Hosp Univ Penn, Div Cardiovasc, Philadelphia, PA 19104 USA. [Chirinos, Julio A.; Rosas, Sylvia E.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Litt, Harold] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Yang, Wei] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Rosas, Sylvia E.] Univ Penn, Renal Electrolyte & Hypertens Div, Perelman Sch Med, Philadelphia, PA 19104 USA. RP Rosas, SE (reprint author), 3400 Spruce St,1 Founders Bldg, Philadelphia, PA 19010 USA. EM Sylvia.rosas@uphs.upenn.edu FU National Institutes of Health grant [R21 HL 086971]; American Recovery and Reinvestment Act supplement; National Center for Research Resources [UL1RR024134] FX This work was supported by National Institutes of Health grant R21 HL 086971 and an American Recovery and Reinvestment Act supplement. Salary support was also provided by the Veterans Health Administration and R01 DK 080033 (S.E.R). The project described was supported by grant UL1RR024134 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Funding sources had no involvement in study design, data collection, analysis, and interpretation, writing of the report, or decision to submit the paper for publication. NR 32 TC 24 Z9 26 U1 0 U2 32 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD DEC PY 2012 VL 7 IS 12 BP 2017 EP 2022 DI 10.2215/CJN.02160212 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 051FK UT WOS:000312111400016 PM 22997345 ER PT J AU Young, BA Chan, C Blagg, C Lockridge, R Golper, T Finkelstein, F Shaffer, R Mehrotra, R AF Young, Bessie A. Chan, Christopher Blagg, Christopher Lockridge, Robert Golper, Thomas Finkelstein, Fred Shaffer, Rachel Mehrotra, Rajnish CA ASN Dialysis Advisory Grp TI How to Overcome Barriers and Establish a Successful Home HD Program SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID STAGE RENAL-DISEASE; QUALITY-OF-LIFE; IN-CENTER HEMODIALYSIS; PERITONEAL-DIALYSIS PATIENTS; SELF-CARE DIALYSIS; RANDOMIZED CONTROLLED-TRIAL; CHRONIC KIDNEY-DISEASE; NOCTURNAL HEMODIALYSIS; CONVENTIONAL HEMODIALYSIS; UNITED-STATES AB Home hemodialysis (HD) is an underused dialysis modality in the United States, even though it provides an efficient and probably cost-effective way to provide more frequent or longer dialysis. With the advent of newer home HD systems that are easier for patients to learn, use, and maintain, patient and provider interest in home HD is increasing. Although barriers for providers are similar to those for peritoneal dialysis, home HD requires more extensive patient training, nursing education, and infrastructure support in order to maintain a successful program. In addition, because many physicians and patients do not have experience with home HD, reluctance to start home HD programs is widespread. This in-depth review describes barriers to home HD, focusing on patients, individual physicians and practices, and dialysis facilities, and offers suggestions for how to overcome these barriers and establish a successful home HD program. Clin J Am Soc Nephrol 7: 2023-2032, 2012. doi:10.2215/CJN.07080712 C1 [Young, Bessie A.] Univ Washington, Div Nephrol, Kidney Res Inst, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Chan, Christopher] Univ Toronto, Toronto, ON, Canada. [Blagg, Christopher] NW Kidney Ctr, Seattle, WA USA. [Lockridge, Robert] Univ Virginia, Dept Med, Div Nephrol, Lynchburg, VA USA. [Golper, Thomas] Vanderbilt Univ, Nashville, TN USA. [Finkelstein, Fred] St Raphaels Med Ctr, New Haven, CT USA. [Shaffer, Rachel] Amer Soc Nephrol, Washington, DC USA. [Mehrotra, Rajnish] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. RP Young, BA (reprint author), Vet Affairs Puget Sound Hlth Care Syst 152 E, 1660 S Columbian Way, Seattle, WA 98108 USA. EM youngb@u.washington.edu OI Saggi, Subodh/0000-0001-9126-7226 FU Veterans Affairs Puget Sound Health Care System; Baxter Healthcare; DaVita; Mitsubishi; Shire; Takeda; Vifor FX This material is the result of work supported by resources from the Veterans Affairs Puget Sound Health Care System.; C.C. serves as a member of the scientific advisory board for Baxter Healthcare. C.B. is a consultant to DEKA Research and Development Corporation. R.L. serves as a member of the scientific advisory board for Fresenius Medical Care. T.G. conducts consultant activity for Baxter, Fresenius, DaVita, Takeda-Affymax, and Q Source. F.F. serves as a member of the scientific advisory board for NxStage and conducts consultant activity for Baxter Healthcare. R.S. is an employee of the American Society of Nephrology. R.M. has received grant support and/or honoraria from Baxter Healthcare, DaVita, Mitsubishi, Shire, Takeda, and Vifor. NR 97 TC 24 Z9 24 U1 2 U2 15 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD DEC PY 2012 VL 7 IS 12 BP 2023 EP 2032 DI 10.2215/CJN.07080712 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 051FK UT WOS:000312111400017 PM 23037981 ER PT J AU Riegel, B Glaser, D Richards, K Sayers, SL Marzolf, A Weintraub, WS Goldberg, LR AF Riegel, Barbara Glaser, Dale Richards, Kathy Sayers, Steven L. Marzolf, Amy Weintraub, William S. Goldberg, Lee R. TI Modifiable factors associated with sleep dysfunction in adults with heart failure SO EUROPEAN JOURNAL OF CARDIOVASCULAR NURSING LA English DT Article DE Heart failure; sleep; sleep dysfunction; self-rated health; medications; sleep hygiene; depression ID QUALITY-OF-LIFE; GLOBAL PERCEIVED HEALTH; PRIMARY-CARE PATIENTS; SELF-RATED HEALTH; OLDER-ADULTS; DAYTIME SLEEPINESS; BLOOD-PRESSURE; POOR HEALTH; INSOMNIA; POPULATION AB Background: Sleep dysfunction contributes to poor quality of life in adults with heart failure (HF). The purpose of this study was to identify factors associated with sleep dysfunction that may be modifiable. Methods: Data were collected from 266 subjects enrolled from three sites in the U. S. Sleep dysfunction was measured over the past month with the Pittsburgh Sleep Quality Index, using a score > 10 to indicate sleep dysfunction. Potentially modifiable clinical, behavioral, and psychological factors thought to be associated with sleep dysfunction were analyzed with hierarchical logistic regression analysis. Results: When covariates of age, gender, race, data collection site, and New York Heart Association (NYHA) functional class were entered on the first step, only NYHA was a significant correlate of sleep dysfunction. When the clinical, behavioral, and psychological factors were entered, correlates of sleep dysfunction were the number of drugs known to cause daytime somnolence (OR = 2.08), depression (OR = 1.83), worse overall perceived health (OR = 1.64), and better sleep hygiene (OR = 1.40). Although most (54%) subjects had sleep disordered breathing (SDB), SDB was not a significant predictor of sleep dysfunction. Discussion: Factors associated with sleep dysfunction in HF include medications with sleepiness as a side-effect, depression, poorer health perceptions, and better sleep hygiene. Sleep dysfunction may motivate HF patients to address sleep hygiene. Eliminating medications with sleepiness as a side-effect, treating depression and perceptions of poor health may improve sleep quality in HF patients. C1 [Riegel, Barbara] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Glaser, Dale] Glaser Consulting, San Diego, CA USA. [Glaser, Dale] Univ San Diego, Sch Nursing, San Diego, CA 92110 USA. [Richards, Kathy] George Mason Univ, Fairfax, VA 22030 USA. [Sayers, Steven L.; Goldberg, Lee R.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Sayers, Steven L.] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. [Marzolf, Amy] Univ Penn, Heart Failure & Transplant Ctr, Philadelphia, PA 19104 USA. [Weintraub, William S.] Christiana Care Hlth Syst, Newark, DE USA. RP Riegel, B (reprint author), Univ Penn, Sch Nursing, 418 Curie Blvd, Philadelphia, PA 19104 USA. EM briegel@nursing.upenn.edu OI Goldberg, Lee/0000-0002-7906-9638 FU National Heart, Lung & Blood Institute [RO1 HL084394-01A1]; Philadelphia Veterans Affairs Medical Center; VISN 4 Mental Illness Research, Education, and Clinical Center (MIREC) FX This work was funded by a grant from the National Heart, Lung & Blood Institute (RO1 HL084394-01A1) and by the Philadelphia Veterans Affairs Medical Center, VISN 4 Mental Illness Research, Education, and Clinical Center (MIREC). NR 60 TC 7 Z9 7 U1 1 U2 13 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1474-5151 J9 EUR J CARDIOVASC NUR JI Eur. J. Cardiovasc. Nurs. PD DEC PY 2012 VL 11 IS 4 BP 402 EP 409 DI 10.1016/j.ejcnurse.2011.02.001 PG 8 WC Cardiac & Cardiovascular Systems; Nursing SC Cardiovascular System & Cardiology; Nursing GA 054MS UT WOS:000312348500006 PM 21353642 ER PT J AU Jensen, RJ AF Jensen, Ralph J. TI Blocking GABA(C) receptors increases light responsiveness of retinal ganglion cells in a rat model of retinitis pigmentosa SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE retinal degeneration; retinal ganglion cell; light responsiveness; GABA(C) receptor antagonist; retinitis pigmentosa ID TIGER SALAMANDER RETINA; ROD BIPOLAR CELLS; SYNAPTIC-TRANSMISSION; TRANSGENIC RAT; RHO-SUBUNITS; MOUSE RETINA; INHIBITION; TERMINALS; DEGENERATION; SYSTEM AB Previous studies in a mouse model of retinitis pigmentosa indicate that the GABAergic system in the retina may be overactive. GABA is known to act on GABA(C) receptors present on the axon terminals of bipolar cells to inhibit the release of excitatory neurotransmitter from these cells. The present study examined the effects of a GABA(C) receptor antagonist on the light-evoked responses of retinal ganglion cells (RGCs) in a rat model of retinitis pigmentosa. Extracellular recordings were made from RGCs in retinas isolated from P23H transgenic rats and non-dystrophic Sprague-Dawley (SD) rats. Spike activity of RGCs was measured in response to brief flashes of light over a range of light intensities. Intensity response curves were evaluated prior to and during bath application of the GABA(C) receptor antagonist TPMPA. I found that TPMPA consistently increased the sensitivity of P23H rat RGCs to light flashes. For ON-center RGCs (n = 21), the average increase in light sensitivity was 0.63 log unit. For OFF-center RGCs (n = 6), the average increase was 0.38 log unit. TPMPA increased the maximum peak response of ON-center RGCs by 22% and OFF-center RGCs by 11%. However, the increase in maximum peak response of OFF-center RGCs was not statistically significant. TPMPA had no significant effect on the dynamic operating range of either ON-center or OFF-center RGCs. Nine ON-center SD rat RGCs were also tested. In contrast to what was observed for P23H rat RGCs, TPMPA decreased the sensitivity of these RGCs to light flashes, on average by 0.20 log unit. In conclusion, GABA(C) receptors may be novel targets for therapeutic interventions aimed at increasing light responsiveness in patients with retinitis pigmentosa or other diseases involving degeneration of photoreceptors. Published by Elsevier Ltd. C1 VA Boston Healthcare Syst, Boston, MA 02130 USA. RP Jensen, RJ (reprint author), VA Boston Healthcare Syst, Mail Stop 151E,150 S Huntington Ave, Boston, MA 02130 USA. EM Ralph.jensen@va.gov FU Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service. NR 27 TC 7 Z9 8 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD DEC PY 2012 VL 105 BP 21 EP 26 DI 10.1016/j.exer.2012.10.005 PG 6 WC Ophthalmology SC Ophthalmology GA 052CZ UT WOS:000312176600004 PM 23085337 ER PT J AU Foley, D Murphy, M Ghobrial, I O'Gorman, P Weinstock, M Anderson, K AF Foley, D. Murphy, M. Ghobrial, I O'Gorman, P. Weinstock, M. Anderson, K. TI OCCURRENCE OF EXTRA-MEDULLARY DISEASE IN MULTIPLE MYELOMA SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 [Foley, D.; Murphy, M.; Ghobrial, I; Weinstock, M.; Anderson, K.] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Foley, D.; O'Gorman, P.] Mater Misericordiae Univ Hosp, Dept Haematol, Dublin, Ireland. NR 1 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0021-1265 J9 IRISH J MED SCI JI Irish J. Med. Sci. PD DEC PY 2012 VL 181 SU 11 MA 19 BP S448 EP S448 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 053HA UT WOS:000312260800020 ER PT J AU Murphy, M Foley, D Aljawai, Y Ghobrial, I Anderson, K AF Murphy, M. Foley, D. Aljawai, Y. Ghobrial, I. Anderson, K. TI ANALYSIS OF TUMOR MARKER EXPRESSION, KARYOTYPE AND CYTOGENETIC MUTATIONS IN PATIENTS WITH MULTIPLE MYELOMA AT DFCI SO IRISH JOURNAL OF MEDICAL SCIENCE LA English DT Meeting Abstract C1 [Murphy, M.; Foley, D.; Aljawai, Y.; Ghobrial, I.; Anderson, K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0021-1265 J9 IRISH J MED SCI JI Irish J. Med. Sci. PD DEC PY 2012 VL 181 SU 11 MA 28 BP S451 EP S451 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 053HA UT WOS:000312260800029 ER PT J AU Tanpowpong, P Broder-Fingert, S Katz, AJ Camargo, CA AF Tanpowpong, Pornthep Broder-Fingert, Sarabeth Katz, Aubrey J. Camargo, Carlos A., Jr. TI Clinical and histopathological features of children with type I diabetes and positive celiac disease serology SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Meeting Abstract C1 [Tanpowpong, Pornthep; Broder-Fingert, Sarabeth; Katz, Aubrey J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp Children, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0815-9319 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD DEC PY 2012 VL 27 SU 5 SI SI BP 140 EP 140 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 053AV UT WOS:000312242700431 ER PT J AU Tanpowpong, P Broder-Fingert, S Katz, AJ Camargo, CA AF Tanpowpong, Pornthep Broder-Fingert, Sarabeth Katz, Aubrey J. Camargo, Carlos A., Jr. TI Predictors of gluten avoidance in adults without previously diagnosed celiac disease SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Meeting Abstract C1 [Tanpowpong, Pornthep; Broder-Fingert, Sarabeth; Katz, Aubrey J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp Children, Boston, MA USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0815-9319 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD DEC PY 2012 VL 27 SU 5 SI SI BP 141 EP 142 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 053AV UT WOS:000312242700435 ER PT J AU Fagin, AP Susarla, SM Donoff, RB Kaban, LB Dodson, TB AF Fagin, Adam P. Susarla, Srinivas M. Donoff, Robert B. Kaban, Leonard B. Dodson, Thomas B. TI What Factors Are Associated With Functional Sensory Recovery Following Lingual Nerve Repair? SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID INFERIOR ALVEOLAR NERVE; MANDIBULAR 3RD MOLARS; MANAGEMENT; REMOVAL; MICROSURGERY; INJURIES; DAMAGE AB Purpose: To identify factors associated with functional sensory recovery (FSR) after lingual nerve repair. Materials and Methods: This retrospective cohort study was composed of subjects who underwent lingual nerve repair from 2004 through 2010. The predictor variables were demographic, anatomic, and operative measurements. The primary outcome measurement was FSR (ie, FSR achieved, yes or no). The secondary outcome measurements were time to FSR and an improvement of at least 2 levels on the British Medical Research Council scale of neurosensory function. Descriptive, bivariate, and multiple logistic regression statistics were computed to identify associations between the predictor variables and FSR. A Cox proportional hazards model was used to identify associations between the predictors and time to FSR. P <= .05 was considered statistically significant. Results: The sample was composed of 55 subjects with a mean age of 30.7 +/- 11.2 years. The mean duration from injury to repair was 151.6 days (range, 41 to 384 days). Most patients (74.5%) achieved FSR postoperatively, with a mean time to FSR of 262.8 days (median, 208 days). Eighty-six percent of subjects showed an improvement of at least 2 levels on the British Medical Research Council scale. In multiple regression models, younger subjects were more likely to achieve FSR (odds ratio, 1.10; 95% confidence interval, 1.01 to 1.18; P = .02); subjects with better preoperative neurosensory function achieved FSR faster (hazard ratio, 1.9; 95% confidence interval, 1.2 to 3.1; P = .01). Conclusion: Most patients undergoing lingual nerve repair achieved FSR. Younger subjects were more likely to achieve FSR. Subjects with better preoperative neurosensory function achieved FSR faster. (c) 2012 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 70:2907-2915, 2012 C1 [Fagin, Adam P.; Donoff, Robert B.; Kaban, Leonard B.; Dodson, Thomas B.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Dodson, Thomas B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Dodson, TB (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, WRN 1201, Boston, MA 02114 USA. EM tbdodson@partners.org OI Susarla, Srinivas/0000-0003-0155-8260 FU Massachusetts General Hospital Physicians Organization; Department of Oral and Maxillofacial Surgery Education and Research Fund; Center for Applied Clinical Investigation; Oral and Maxillofacial Surgery Foundation Fellowship in Clinical Investigation FX This work was supported by the Massachusetts General Hospital Physicians Organization (T.B.D., L.B.K.), the Department of Oral and Maxillofacial Surgery Education and Research Fund (A.F., S.M.S.), the Center for Applied Clinical Investigation (S.M.S., T.B.D.), and the Oral and Maxillofacial Surgery Foundation Fellowship in Clinical Investigation (S.M.S.). NR 23 TC 7 Z9 7 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD DEC PY 2012 VL 70 IS 12 BP 2907 EP 2915 DI 10.1016/j.joms.2012.03.019 PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 053IC UT WOS:000312263700033 PM 22695009 ER PT J AU Lovejoy, TI Turk, DC Morasco, BJ AF Lovejoy, Travis I. Turk, Dennis C. Morasco, Benjamin J. TI Evaluation of the Psychometric Properties of the Revised Short-Form McGill Pain Questionnaire SO JOURNAL OF PAIN LA English DT Article DE Chronic pain; McGill Pain Questionnaire; psychometric reliability; validity ID NEUROPATHIC PAIN; VALIDATION; INVENTORY; SCALE AB The recently revised version of the Short-Form McGill Pain Questionnaire (SF-MPQ-2) was created to assess both neuropathic and non-neuropathic pain. The current study extends prior research by testing the reliability and validity of the SF-MPQ-2 in a sample of U.S. veteran patients with a range of chronic pain diagnoses. Participants (N = 186) completed the SF-MPQ-2, a sociodemographic questionnaire, the Structured Clinical Interview for the DSM-IV, and self-report pain and psychiatric measures. Pain diagnoses were extracted from the electronic medical record. The SF-MPQ-2 total and scale scores demonstrated good-to-excellent internal consistency. Convergent and discriminant validity were supported, and SF-MPQ-2 total and scale scores increased with number of pain diagnoses and pain severity. Confirmatory factor analyses indicated that a 4-factor model fit the data better than a single-factor model. However, high intercorrelations among the 4 latent constructs were observed, and a second-order global pain construct also emerged. Overall, the SF-MPQ-2 demonstrated excellent reliability and validity in a sample of U.S. veteran patients with chronic neuropathic and non-neuropathic pain. Future psychometric studies of the SF-MPQ-2 should employ longitudinal data to evaluate the ability of scale scores to uniquely predict clinical and health service outcomes. Perspective: This article presents the psychometric properties of a revised version of the SF-MPQ-2. This measure may have great utility as a screening tool in clinical practice and as an outcome measure in clinical trials. Published by Elsevier Inc. on behalf of the American Pain Society C1 [Lovejoy, Travis I.; Morasco, Benjamin J.] Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, Portland, OR 97239 USA. [Turk, Dennis C.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. [Morasco, Benjamin J.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. RP Lovejoy, TI (reprint author), Portland VA Med Ctr, Mental Hlth & Clin Neurosci Div, P3MHDC,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM travis.lovejoy@va.gov FU United States National Institute on Drug Abuse [K23DA023467]; Endo; Johnson Johnson; Philips Respironics; National Institutes of Health; Eli Lilly; OrthoMcNeill- Janssen; Pfizer; SK LifeScience FX This material is the result of work supported with resources and the use of facilities at the Portland VA Medical Center. This study was supported in part by award K23DA023467 from the United States National Institute on Drug Abuse to Dr. Morasco. Dr. Turk has received research support from Endo, Johnson & Johnson, Philips Respironics, and the National Institutes of Health, and consulting fees from Eli Lilly, OrthoMcNeill- Janssen, Pfizer, Philips Respironics, and SK LifeScience. He is also a Special Government Employee of the U.S. Food and Drug Administration. No other author reports having any potential conflict of interest. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs or the National Institute on Drug Abuse. NR 28 TC 20 Z9 22 U1 3 U2 25 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD DEC PY 2012 VL 13 IS 12 BP 1250 EP 1257 DI 10.1016/j.jpain.2012.09.011 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 053NR UT WOS:000312280200012 PM 23182230 ER PT J AU Mercier, PP Lysaght, AC Bandyopadhyay, S Chandrakasan, AP Stankovic, KM AF Mercier, Patrick P. Lysaght, Andrew C. Bandyopadhyay, Saurav Chandrakasan, Anantha P. Stankovic, Konstantina M. TI Energy extraction from the biologic battery in the inner ear SO NATURE BIOTECHNOLOGY LA English DT Article ID BIOFUEL CELL; ELECTRICITY; CIRCUIT; HEARING AB Endocochlear potential (EP) is a battery-like electrochemical gradient found in and actively maintained by the inner ear(1,2). Here we demonstrate that the mammalian EP can be used as a power source for electronic devices. We achieved this by designing an anatomically sized, ultra-low quiescent-power energy harvester chip integrated with a wireless sensor capable of monitoring the EP itself. Although other forms of in vivo energy harvesting have been described in lower organisms(3-5), and thermoelectric(6), piezoelectric(7) and biofuel(8,9) devices are promising for mammalian applications, there have been few, if any, in vivo demonstrations in the vicinity of the ear, eye and brain. In this work, the chip extracted a minimum of 1.12 nW from the EP of a guinea pig for up to 5 h, enabling a 2.4 GHz radio to transmit measurement of the EP every 40-360 s. With future optimization of electrode design, we envision using the biologic battery in the inner ear to power chemical and molecular sensors, or drug-delivery actuators for diagnosis and therapy of hearing loss and other disorders. C1 [Mercier, Patrick P.; Bandyopadhyay, Saurav; Chandrakasan, Anantha P.] MIT, Microsyst Technol Labs, Cambridge, MA 02139 USA. [Lysaght, Andrew C.; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Lysaght, Andrew C.; Stankovic, Konstantina M.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Lysaght, Andrew C.; Stankovic, Konstantina M.] Harvard Massachusetts Inst Technol, Program Speech & Hearing Biosci & Technol, Joint Div Hlth Sci & Technol, Cambridge, MA USA. [Stankovic, Konstantina M.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Chandrakasan, AP (reprint author), MIT, Microsyst Technol Labs, Cambridge, MA 02139 USA. EM anantha@mtl.mit.edu; konstantina_stankovich@meei.harvard.edu FU C2S2 Focus Center; Interconnect Focus Center; Focus Center Research Program (FCRP); Semiconductor Research Corporation entity; US National Institutes of Health [K08 DC010419, T32 DC00038]; Bertarelli Foundation FX We acknowledge support from the C2S2 Focus Center and the Interconnect Focus Center, two of six research centers funded under the Focus Center Research Program (FCRP), a Semiconductor Research Corporation entity (A. P. C., P. P. M., S. B.), and from US National Institutes of Health grants K08 DC010419 (K. M. S.) and T32 DC00038 (A. C. L.) and the Bertarelli Foundation (K. M. S.). We thank J.J. Guinan Jr. for experimental assistance and advice, and B. Zhu for preliminary studies. NR 31 TC 53 Z9 54 U1 8 U2 79 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD DEC PY 2012 VL 30 IS 12 BP 1240 EP + DI 10.1038/nbt.2394 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 050ZA UT WOS:000312092400028 PM 23138225 ER PT J AU Milber, JM Noorigian, JV Morley, JF Petrovitch, H White, L Ross, GW Duda, JE AF Milber, Joshua M. Noorigian, Joseph V. Morley, James F. Petrovitch, Helen White, Lon Ross, G. Webster Duda, John E. TI Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease SO NEUROLOGY LA English DT Article ID ALPHA-SYNUCLEIN PATHOLOGY; SUBSTANTIA-NIGRA; BODY DISEASE; DEMENTIA; BRAIN; BODIES; RELEVANCE; DEATH; MEN AB Objective: To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD). Methods: We examined the extent of nigral dysfunction and degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed. Results: Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained relatively constant across Braak PD stages in ILBD. Conclusions: These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD. Neurology (R) 2012; 79: 2307-2314 C1 [Milber, Joshua M.; Noorigian, Joseph V.; Morley, James F.; Duda, John E.] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA USA. [Morley, James F.; Duda, John E.] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Petrovitch, Helen; Ross, G. Webster] Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. [Petrovitch, Helen; White, Lon; Ross, G. Webster] Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. [Petrovitch, Helen; White, Lon; Ross, G. Webster] Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. [Petrovitch, Helen; White, Lon; Ross, G. Webster] Kuakini Med Ctr, Honolulu Asian Aging Study, Honolulu, HI USA. RP Duda, JE (reprint author), Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA USA. EM john.duda@va.gov FU Biomedical Laboratory Research and Development Service of the Department of Veterans Affairs; United States Department of the Army [DAMD17-98-1-8621]; National Institutes of Health: National Institute of Neurological Disorders and Stroke [5 R01 NS041265]; National Institute on Aging [1 U01 AG19349, 5 R01 AG017155]; Office of Research and Development, Medical Research Service Department of Veterans Affairs; Department of Defense; NINDS, NIH; NIA, NIH; Northwestern Foundation; Michael J. Fox Foundation; Department of Veterans Affairs; NIH; Michael J. Fox Foundation for Parkinson Research; Samueli Institute FX Supported by a Merit Award from the Biomedical Laboratory Research and Development Service of the Department of Veterans Affairs (J.E. Duda, PI) and by the United States Department of the Army, grant DAMD17-98-1-8621; National Institutes of Health: National Institute of Neurological Disorders and Stroke grant 5 R01 NS041265; National Institute on Aging grants 1 U01 AG19349 and 5 R01 AG017155; and the Office of Research and Development, Medical Research Service Department of Veterans Affairs.; J. Milber and J. Noorigian have no disclosures. J. Morley has received compensation for articles written in the PD Monitor and Commentary, a publication supported by an educational grant from Teva Neuroscience. H. Petrovitch and L. White have no disclosures. G. Webster Ross receives salary support from the Department of Veterans Affairs and research support from the Department of Defense; NINDS, NIH; NIA, NIH; Northwestern Foundation; and the Michael J. Fox Foundation. J. Duda has received research support from the Department of Veterans Affairs, the NIH, the Michael J. Fox Foundation for Parkinson Research, and the Samueli Institute. He holds common stock in C. R. Bard, Inc., Celgene Corp., Clarient, Inc., and Johnson & Johnson. Go to Neurology.org for full disclosures. NR 34 TC 34 Z9 34 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC PY 2012 VL 79 IS 24 BP 2307 EP 2314 DI 10.1212/WNL.0b013e318278fe32 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 053MA UT WOS:000312274500007 PM 23152586 ER PT J AU Auriel, E Gurol, ME Ayres, A Dumas, AP Schwab, KM Vashkevich, A Martinez-Ramirez, S Rosand, J Viswanathan, A Greenberg, SM AF Auriel, Eitan Gurol, Mahmut Edip Ayres, Alison Dumas, Andrew P. Schwab, Kristin M. Vashkevich, Anastasia Martinez-Ramirez, Sergi Rosand, Jonathan Viswanathan, Anand Greenberg, Steven M. TI Characteristic distributions of intracerebral hemorrhage-associated diffusion-weighted lesions SO NEUROLOGY LA English DT Article ID CEREBRAL AMYLOID ANGIOPATHY; BLOOD-PRESSURE REDUCTION; CORTICAL MICROINFARCTS; VASCULAR DEMENTIA; BRAIN; INFARCTS; DISEASE; BURDEN; IMAGES; IMPACT AB Objectives: To determine whether small diffusion-weighted imaging (DWI) lesions occur beyond the acute posthemorrhage time window in patients with intracerebral hemorrhage (ICH) and to characterize their spatial distribution in patients with lobar and deep cerebral hemorrhages. Methods: In this cross-sectional study, we retrospectively analyzed 458 MRI scans obtained in the acute (<7 days after ICH) or nonacute (>14 days after ICH) phases from 392 subjects with strictly lobar (n = 276) and deep (n = 116) ICH (48.7% women; mean age 72.8 +/- 11.7 years). DWI, apparent diffusion coefficient maps, fluid-attenuated inversion recovery, and T2* MRIs were reviewed for the presence and location of DWI lesions. Results: We identified 103 DWI hyperintense lesions on scans from 62 subjects, located mostly in lobar brain regions (90 of 103, 87.4%). The lesions were not uniformly distributed throughout the brain lobes; patients with strictly lobar ICH had relative overrepresentation of lesions in frontal lobe, and patients with deep ICH in parietal lobe (p = 0.002). Although the frequency of DWI lesions tended to be greater on scans performed within 7 days after ICH (39 of 214, 18.2%), they continued at high frequency in the nonacute period as well (23 of 178, 12.9%, odds ratio 1.5, 95% confidence interval 0.86-2.6 for acute vs nonacute). There was also no difference in frequency of lesions on acute and nonacute scans among 66 subjects with MRIs in both time periods (8 of 66 acute, 10 of 66 nonacute, odds ratio 0.77, 95% confidence interval 0.25-2.4). Conclusions: The high frequency of DWI lesions beyond the acute post-ICH period and their characteristic distributions suggest that they are products of the small vessel diseases that underlie ICH. Neurology (R) 2012;79:2335-2341 C1 [Greenberg, Steven M.] Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, Dept Neurol, J Philip Kistler Stroke Res Ctr, Boston, MA 02114 USA. EM sgreenberg@partners.org RI Gurol, Edip/J-2279-2014; OI Gurol, Edip/0000-0002-2169-4457; Ayres, Alison/0000-0002-5492-1695 FU National Institutes of Health [R01AG026484]; American Heart Association FX All funding entities had no involvement in study design, data collection, analysis, and interpretation, writing of the manuscript, or in the decision to submit for publication. The project described was supported by grant R01AG026484 from the National Institutes of Health.; E. Auriel, M.E. Gurol, A. Ayres, A.P. Dumas, K.M. Schwab, A. Vashkevich, and S. Martinez-Ramirez report no disclosures. J. Rosand receives research support from the NIH and American Heart Association. A. Viswanathan reports no disclosures. S.M. Greenberg receives research support from the NIH and serves as consultant and on the advisory board of Hoffman-La Roche. NR 38 TC 18 Z9 18 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC PY 2012 VL 79 IS 24 BP 2335 EP 2341 DI 10.1212/WNL.0b013e318278b66f PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 053MA UT WOS:000312274500011 PM 23197745 ER PT J AU Frisbie, JH Sharma, GVRK AF Frisbie, J. H. Sharma, G. V. R. K. TI Response: Pulmonary embolism in chronic spinal cord injury SO SPINAL CORD LA English DT Letter ID PROPHYLACTIC ANTICOAGULANT-THERAPY C1 [Frisbie, J. H.; Sharma, G. V. R. K.] Harvard Univ, Sch Med, Boston VA Healthcare Syst, Boston, MA 02114 USA. RP Frisbie, JH (reprint author), Harvard Univ, Sch Med, Boston VA Healthcare Syst, Boston, MA 02114 USA. EM jfrisbie@comcast.net NR 7 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 J9 SPINAL CORD JI Spinal Cord PD DEC PY 2012 VL 50 IS 12 BP 932 EP 932 DI 10.1038/sc.2012.115 PG 1 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 052MA UT WOS:000312200700019 ER PT J AU Bonatti, H Barroso, LF Sawyer, RG Kotton, CN Sifri, CD AF Bonatti, H. Barroso, L. F., II Sawyer, R. G. Kotton, C. N. Sifri, C. D. TI Cryptosporidium enteritis in solid organ transplant recipients: multicenter retrospective evaluation of 10 cases reveals an association with elevated tacrolimus concentrations SO TRANSPLANT INFECTIOUS DISEASE LA English DT Article DE tacrolimus toxicity; Cryptosporidium; cryptosporidiosis; enteritis; parasitic infection; infection; transplantation; diarrhea ID DIFFICILE-ASSOCIATED DIARRHEA; HUMAN-IMMUNODEFICIENCY-VIRUS; SINGLE-CENTER EXPERIENCE; ALLOGENEIC BONE-MARROW; RENAL-TRANSPLANT; CLOSTRIDIUM-DIFFICILE; LIVER-TRANSPLANTATION; SCLEROSING CHOLANGITIS; PARASITIC INFECTIONS; WATERBORNE OUTBREAK AB Background Cryptosporidial enteritis, a diarrheal infection of the small intestine caused by the apicomplexan protozoa Cryptosporidium, is infrequently recognized in transplant recipients from developed countries. Methods A retrospective review of all cases of cryptosporidiosis in solid organ transplant (SOT) recipients at 2 centers from January 2001 to October 2010 was performed and compared with transplant recipients with community-onset Clostridium difficile infection (CDI). A literature search was performed with regard to reported cases of cryptosporidiosis in SOT recipients. Results Eight renal, 1 liver, and 1 lung transplant recipient were diagnosed with cryptosporidiosis at median 46.0 months (interquartile range [IQR] 25.262.8) following SOT. Symptoms existed for a median 14 days (IQR 10.514.8) before diagnosis. For the 9 patients receiving tacrolimus (TAC), mean TAC levels increased from 6.3 +/- 1.1 to 21.3 +/- 9.2 ng/mL (P = 0.0007) and median serum creatinine increased temporarily from 1.3 (IQR 1.11.7) to 2.4 (IQR 2.04.6) mg/dL (P = 0.008). By comparison, 8 SOT recipients (6 kidney, 2 liver) hospitalized with community-onset CDI had a mean TAC level of 10.8 +/- 2.8 ng/dL during disease compared with 9.2 +/- 2.3 ng/mL at baseline (P = 0.07) and had no change in median creatinine. All patients recovered from Cryptosporidium enteritis after receiving various chemotherapeutic regimens. Conclusions Cryptosporidiosis should be recognized as an important cause of diarrhea after SOT and is associated with elevated TAC levels and acute kidney injury. Increased TAC levels may reflect altered drug metabolism in the small intestine. C1 [Barroso, L. F., II; Sifri, C. D.] Univ Virginia Hlth Syst, Div Infect Dis & Int Hlth, Dept Med, Charlottesville, VA 22908 USA. [Bonatti, H.; Sawyer, R. G.] Univ Virginia Hlth Syst, Dept Surg, Charlottesville, VA 22908 USA. [Kotton, C. N.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Sifri, CD (reprint author), Univ Virginia Hlth Syst, Div Infect Dis & Int Hlth, Dept Med, POB 800473, Charlottesville, VA 22908 USA. EM csifri@virginia.edu NR 90 TC 14 Z9 14 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-2273 J9 TRANSPL INFECT DIS JI Transpl. Infect. Dis. PD DEC PY 2012 VL 14 IS 6 BP 635 EP 648 DI 10.1111/j.1399-3062.2012.00719.x PG 14 WC Immunology; Infectious Diseases; Transplantation SC Immunology; Infectious Diseases; Transplantation GA 051TA UT WOS:000312149100021 PM 22340660 ER PT J AU Williams, EC Bradley, KA Gupta, S Harris, AHS AF Williams, Emily C. Bradley, Katharine A. Gupta, Shalini Harris, Alex H. S. TI Association Between Alcohol Screening Scores and Mortality in Black, Hispanic, and White Male Veterans SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Alcohol; Race; Ethnicity; Mortality; AUDIT-C ID ALL-CAUSE MORTALITY; BEHAVIORAL-COUNSELING INTERVENTIONS; DEATH REPORTING SYSTEM; PRIMARY-CARE PATIENTS; UNITED-STATES; HEALTH-STATUS; RACIAL-DIFFERENCES; PROBLEM DRINKING; VIOLENT DEATHS; PUBLIC-HEALTH AB Background Scores on the Alcohol Use Disorders Identification Test Consumption (AUDIT-C) questionnaire are associated with mortality, but whether or how associations vary across race/ethnicity is unknown. Methods Self-reported black (n = 13,068), Hispanic (n = 9,466), and white (n = 182,688) male Veterans Affairs (VA) outpatients completed the AUDIT-C via mailed survey. Logistic regression models evaluated whether race/ethnicity modified the association between AUDIT-C scores (0, 1 to 4, 5 to 8, and 9 to 12) and mortality after 24 months, adjusting for demographics, smoking, and comorbidity. Results Adjusted mortality rates were 0.036, 0.033, and 0.054, for black, Hispanic, and white patients with AUDIT-C scores of 1 to 4, respectively. Race/ethnicity modified the association between AUDIT-C scores and mortality (p = 0.0022). Hispanic and white patients with scores of 0, 5 to 8, and 9 to 12 had significantly increased risk of death compared to those with scores of 1 to 4; Hispanic ORs: 1.93, 95% CI 1.50 to 2.49; 1.57, 1.07 to 2.30; 1.82, 1.04 to 3.17, respectively; white ORs: 1.34, 95% CI 1.29 to 1.40; 1.12, 1.03 to 1.21; 1.81, 1.59 to 2.07, respectively. Black patients with scores of 0 and 5 to 8 had increased risk relative to scores of 1 to 4 (ORs 1.28, 1.06 to 1.56 and 1.50, 1.13 to 1.99), but there was no significant increased risk for scores of 9 to 12 (ORs 1.27, 0.77 to 2.09). Post hoc exploratory analyses suggested an interaction between smoking and AUDIT-C scores might account for some of the observed differences across race/ethnicity. Conclusions Among male VA outpatients, associations between alcohol screening scores and mortality varied significantly depending on race/ethnicity. Findings could be integrated into systems with automated risk calculators to provide demographically tailored feedback regarding medical consequences of drinking. C1 [Williams, Emily C.] Vet Affairs VA Puget Sound Hlth Care Syst, NW Ctr Excellence Hlth Serv Res & Dev HSR&D, Seattle, WA USA. [Williams, Emily C.; Bradley, Katharine A.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Bradley, Katharine A.] Grp Hlth Res Inst, Seattle, WA USA. [Williams, Emily C.; Bradley, Katharine A.] VA Puget Sound Hlth Care Syst, NW Ctr Excellence HSR&D, Seattle, WA 98101 USA. [Bradley, Katharine A.] Univ Washington, Dept Med, Seattle, WA USA. [Gupta, Shalini; Harris, Alex H. S.] VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk, CA USA. RP Williams, EC (reprint author), VA Puget Sound Hlth Care Syst, NW Ctr Excellence HSR&D, 1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM emily.williams3@va.gov FU VA Office of Quality and Performance; VA Health Services Research and Development (HSRD); VA Substance Use Disorders Quality Enhancement Research Initiative (SUD-QuERI); National Institute of Alcohol Abuse and Alcoholism [R03 AA016793-01]; NIAAA [1R03AA016793-01A1]; VA Health Services Research and Development; VA Palo Alto Healthcare System Center for Healthcare Evaluation; Substance Use Disorders QUERI FX The authors gratefully acknowledge Rachel M. Thomas, MPH, for assistance with manuscript preparation. This study was supported by the VA Office of Quality and Performance, VA Health Services Research and Development (HSR&D), VA Substance Use Disorders Quality Enhancement Research Initiative (SUD-QuERI), and a grant from the National Institute of Alcohol Abuse and Alcoholism (R03 AA016793-01; Harris, PI). This study was funded by NIAAA 1R03AA016793-01A1 and conducted with support from the VA Health Services Research and Development, VA Palo Alto Healthcare System Center for Healthcare Evaluation, and the Substance Use Disorders QUERI and the VA Office of Quality and Performance. NR 61 TC 4 Z9 4 U1 2 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD DEC PY 2012 VL 36 IS 12 BP 2132 EP 2140 DI 10.1111/j.1530-0277.2012.01842.x PG 9 WC Substance Abuse SC Substance Abuse GA 051MN UT WOS:000312131400014 PM 22676340 ER PT J AU Greene, SJ Harinstein, ME Vaduganathan, M Subacius, H Konstam, MA Zannad, F Maggioni, AP Swedberg, K Butler, J Gheorghiade, M AF Greene, Stephen J. Harinstein, Matthew E. Vaduganathan, Muthiah Subacius, Haris Konstam, Marvin A. Zannad, Faiez Maggioni, Aldo P. Swedberg, Karl Butler, Javed Gheorghiade, Mihai CA EVEREST Trial Investigators TI Prognostic Value of Monocyte Count in Patients Hospitalized for Heart Failure With Reduced Ejection Fraction (from the EVEREST Trial) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CELL-ADHESION MOLECULES; PERIPHERAL MONOCYTOSIS; DOUBLE-BLIND; INFLAMMATION; TOLVAPTAN; LYMPHOCYTES; ACTIVATION; THERAPY AB Monocytes play a critical role in the pathophysiology of heart failure (HF), but few studies have evaluated the prognostic implications of an increased monocyte count in patients with HF and reduced ejection fraction (EF). The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) examined the effects of tolvaptan in patients with worsening HF and EF <= 40%. This post hoc analysis evaluated the primary end points of all-cause mortality and cardiovascular mortality or HF hospitalization in 3,717 patients. At baseline, 265 (7.1%) had an increased monocyte count defined by >= 800/mu l. Patients with increased monocyte count tended to have an increased EF and were less likely to have a history of diabetes mellitus, hypercholesterolemia, or coronary revascularization but were more likely to have higher HF functional class and to be taking HF therapies such as diuretics, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and digoxin (p <0.05 for all comparisons). At median follow-up of 9.9 months, increased monocyte count was predictive of all-cause mortality (hazard ratio 1.27, 95% confidence interval 1.003 to 1.60, p = 0.047) but was not associated with cardiovascular mortality or HF hospitalization (hazard ratio 1.06, 95% confidence interval 0.87 to 1.30, p = 0.55). Similar results were seen when monocyte count was analyzed as a continuous variable. However, after adjustment for baseline clinical risk factors, monocyte count was not predictive of either primary end point. In conclusion, increased monocyte count occurs in a minority of patients hospitalized with HF and is associated with poor postdischarge prognosis. However, it does not contribute prognostic value above other more traditional risk factors. (c) 2012 Published by Elsevier Inc. (Am J Cardiol 2012;110:1657-1662) C1 [Greene, Stephen J.; Gheorghiade, Mihai] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Harinstein, Matthew E.] Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Pittsburgh, PA USA. [Vaduganathan, Muthiah] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Subacius, Haris] Northwestern Univ, Feinberg Sch Med, Div Cardiol, Dept Med, Chicago, IL 60611 USA. [Konstam, Marvin A.] Tufts Med Ctr, Div Cardiol, Dept Med, Boston, MA USA. [Zannad, Faiez] Univ Lorraine, CHU Cardiol, Inserm CIC 9501, Nancy, France. [Zannad, Faiez] Univ Lorraine, CHU Cardiol, U961, Nancy, France. [Maggioni, Aldo P.] ANMCO Res Ctr, Florence, Italy. [Swedberg, Karl] Univ Gothenburg, Dept Mol & Clin Med, Sahlgrenska Acad, Gothenburg, Sweden. [Butler, Javed] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. RP Gheorghiade, M (reprint author), Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. EM m-gheorghiade@northwestern.edu OI Subacius, Haris/0000-0003-4061-1220; Maggioni, Aldo Pietro/0000-0003-2764-6779 FU Otsuka, Inc., Rockville, Maryland; Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois FX Financial and material support for the EVEREST trial was provided by Otsuka, Inc., Rockville, Maryland. Database management was performed by the sponsor. Mr. Subacius conducted all final analyses for this report with funding from the Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois. NR 20 TC 3 Z9 3 U1 0 U2 5 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 1 PY 2012 VL 110 IS 11 BP 1657 EP 1662 DI 10.1016/j.amjcard.2012.07.035 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 047UW UT WOS:000311868000018 PM 22917555 ER PT J AU Neilan, TG Coelho-Filho, OR Pena-Herrera, D Shah, RV Jerosch-Herold, M Francis, SA Moslehi, J Kwong, RY AF Neilan, Tomas G. Coelho-Filho, Otavio R. Pena-Herrera, Diego Shah, Ravi V. Jerosch-Herold, Michael Francis, Sanjeev A. Moslehi, Javid Kwong, Raymond Y. TI Left Ventricular Mass in Patients With a Cardiomyopathy After Treatment With Anthracyclines SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CARDIOVASCULAR MAGNETIC-RESONANCE; ACUTE LYMPHOBLASTIC-LEUKEMIA; DIFFUSE MYOCARDIAL FIBROSIS; DOXORUBICIN THERAPY; HEART-FAILURE; DYSFUNCTION; CHILDHOOD; CANCER; ECHOCARDIOGRAPHY; QUANTIFICATION AB We aimed to describe the cardiac magnetic resonance (CMR) findings and determine the prognostic variables in patients with a cardiomyopathy after treatment with anthracyclines. CMR imaging was performed in 91 patients (58% men, mean age 43 +/- 18 years, and mean anthracycline dose of 276 +/- 82 mg/m(2)) with a reduced ejection fraction after anthracycline-based chemotherapy. Major adverse cardiovascular events were defined as cardiovascular death, appropriate implantable cardioverter-defibrillator therapy, and admission for decompensated heart failure. Patients presented a median of 88 months (interquartile range 37 to 138) after chemotherapy and were followed for 27 months (interquartile range 22 to 38). Late gadolinium enhancement was an uncommon finding (5 patients, 6%) despite a reduced ejection fraction (36 +/- 8%). An inverse association was found between the anthracycline dose and the indexed left ventricular (LV) mass by CMR (r = -0.67, p < 0.001). A total of 52 adverse cardiac events occurred (event rate of 22%/year). When the patients were grouped according to the presence or absence of a major adverse cardiovascular event, the indexed LV mass and glomerular filtration rate were lower and the anthracycline dose was greater among the patients who experienced an adverse event. In a multivariate model, the indexed LV mass demonstrated the strongest association with major adverse cardiovascular events (hazard ratio 0.89, chi-square 26, p < 0.001). In conclusion, myocardial scar by late gadolinium enhancement-CMR is infrequent in patients with anthracycline-cardiomyopathy despite a reduced ejection fraction, the event rate in patients with established anthracycline-cardiotoxicity is high, and indexed LV mass by CMR imaging is a predictor of adverse cardiovascular events. (c) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1679-1686) C1 [Neilan, Tomas G.; Coelho-Filho, Otavio R.; Pena-Herrera, Diego; Shah, Ravi V.; Moslehi, Javid; Kwong, Raymond Y.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Jerosch-Herold, Michael] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Neilan, Tomas G.; Shah, Ravi V.; Francis, Sanjeev A.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Moslehi, Javid] Harvard Univ, Sch Med, Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA. RP Neilan, TG (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. EM tneilan@partners.org FU American Heart Association Dallas, Texas [12FTF12060588]; National Institutes of Health (T32 Training) [T32HL09430101A1]; Career Development grant [K08HL097031-02]; [R01HL090634-01A1]; [R01HL091157] FX This work was supported in part by the American Heart Association (Fellow to Faculty grant 12FTF12060588, to T. G. N.; Dallas, Texas), the National Institutes of Health (T32 Training Grant T32HL09430101A1, to T. G. N.; and Career Development grant K08HL097031-02, to J. M.; and project grants R01HL090634-01A1 [to M. J. H.] and R01HL091157 [to R. Y. K.]; Bethesda, Maryland). NR 28 TC 27 Z9 28 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 1 PY 2012 VL 110 IS 11 BP 1679 EP 1686 DI 10.1016/j.amjcard.2012.07.040 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 047UW UT WOS:000311868000021 PM 22917553 ER PT J AU Hughes, KR Gandara, RMC Javkar, T Sablitzky, F Hock, H Potten, CS Mahida, YR AF Hughes, Kevin R. Gandara, Ricardo M. C. Javkar, Tanvi Sablitzky, Fred Hock, Hanno Potten, Christopher S. Mahida, Yashwant R. TI Heterogeneity in histone 2B-green fluorescent protein-retaining putative small intestinal stem cells at cell position 4 and their absence in the colon SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE epithelial stem cells; apoptosis; regeneration; Paneth cells ID TEMPLATE DNA STRANDS; PANETH CELLS; EPITHELIAL-CELLS; MURINE SMALL; MOUSE; POPULATIONS; RENEWAL; CYCLE; CRYPTS; GENE AB Hughes KR, G ndara RM, Javkar T, Sablitzky F, Hock H, Potten CS, Mahida YR. Heterogeneity in histone 2B-green fluorescent protein-retaining putative small intestinal stem cells at cell position 4 and their absence in the colon. Am J Physiol Gastrointest Liver Physiol 303: G1188-G1201, 2012. First published September 20, 2012; doi: 10.1152/ajpgi.00080.2012.-Stem cells have been identified in two locations in small intestinal crypts; those intercalated between Paneth cells and another population (which retains DNA label) are located above the Paneth cell zone, at cell position 4. Because of disadvantages associated with the use of DNA label, doxycycline-induced transient transgenic expression of histone 2B (H2B)-green fluorescent protein (GFP) was investigated. H2B-GFP-retaining putative stem cells were consistently seen, with a peak at cell position 4, over chase periods of up to 112 days. After a 28-day chase, a subpopulation of the H2B-GFP-retaining cells was cycling, but the slow cycling status of the majority was illustrated by lack of expression of pHistone H3 and Ki67. Although some H2B-GFP-retaining cells were sensitive to low-dose radiation, the majority was resistant to low-and high-dose radiation-induced cell death, and a proportion of the surviving cells proliferated during subsequent epithelial regeneration. Long-term retention of H2B-GFP in a subpopulation of small intestinal Paneth cells was also seen, implying that they are long lived. In contrast to the small intestine, H2B-GFP-retaining epithelial cells were not seen in the colon from 28-day chase onward. This implies important differences in stem cell function between these two regions of the gastrointestinal tract, which may have implications for region-specific susceptibility to diseases (such as cancer and ulcerative colitis), in which epithelial stem cells and their progeny are involved. C1 [Hughes, Kevin R.; Gandara, Ricardo M. C.; Javkar, Tanvi; Potten, Christopher S.; Mahida, Yashwant R.] Univ Nottingham, Inst Infect Immun & Inflammat, Queens Med Ctr, Nottingham NG7 2UH, England. [Sablitzky, Fred] Univ Nottingham, Sch Biol, Nottingham NG7 2RD, England. [Hock, Hanno] Harvard Univ, Sch Med, Boston, MA USA. [Hock, Hanno] Massachusetts Gen Hosp, Ctr Canc, Harvard Stem Cell Inst, Boston, MA USA. [Hock, Hanno] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Potten, Christopher S.] Epistem, Manchester, Lancs, England. RP Mahida, YR (reprint author), Univ Nottingham, Inst Infect Immun & Inflammat, Queens Med Ctr, C Floor,West Block, Nottingham NG7 2UH, England. EM yash.mahida@nottingham.ac.uk RI Sablitzky, Fred/A-2276-2011 OI Sablitzky, Fred/0000-0001-9718-1546 FU Medical Research Council; FCT-Portuguese Foundation for Science and Technology [SFRH/BD/22873/2005] FX These studies were supported by the Medical Research Council and FCT-Portuguese Foundation for Science and Technology (Fellowship SFRH/BD/22873/2005, to R. Gandara). NR 39 TC 11 Z9 11 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD DEC PY 2012 VL 303 IS 11 BP G1188 EP G1201 DI 10.1152/ajpgi.00080.2012 PG 14 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 048YC UT WOS:000311948100002 PM 22997199 ER PT J AU Abrahamson, MJ Peters, A AF Abrahamson, Martin J. Peters, Anne TI Intens